WO1999045938B1 - Thrombin preparation and products and fibrin sealant methods employing same - Google Patents

Thrombin preparation and products and fibrin sealant methods employing same

Info

Publication number
WO1999045938B1
WO1999045938B1 PCT/US1999/005034 US9905034W WO9945938B1 WO 1999045938 B1 WO1999045938 B1 WO 1999045938B1 US 9905034 W US9905034 W US 9905034W WO 9945938 B1 WO9945938 B1 WO 9945938B1
Authority
WO
WIPO (PCT)
Prior art keywords
prothrombin
thrombin
fibrinogen
precipitate
blood plasma
Prior art date
Application number
PCT/US1999/005034
Other languages
French (fr)
Other versions
WO1999045938A1 (en
Inventor
David H Sierra
Original Assignee
Biosurgical Corp
David H Sierra
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biosurgical Corp, David H Sierra filed Critical Biosurgical Corp
Priority to CA002322741A priority Critical patent/CA2322741A1/en
Priority to JP2000535352A priority patent/JP2002506038A/en
Priority to EP99909912A priority patent/EP1061931A2/en
Priority to AU29005/99A priority patent/AU2900599A/en
Publication of WO1999045938A1 publication Critical patent/WO1999045938A1/en
Publication of WO1999045938B1 publication Critical patent/WO1999045938B1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • 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
    • A61L24/10—Polypeptides; Proteins
    • A61L24/106—Fibrin; Fibrinogen
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Diabetes (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Surgery (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention employs liposomes having an outer surface presenting both acidic and basic polar groups, for example phosphatidyl for rapid, high yield generation of thrombin from prothrombin-containing material. The source material for the prothrombin can be the subject to be treated with the product thrombin, providing an autologous thrombin product. Also, a fibrinogen component can be generated from the same blood sample, yielding a fully autologous fibrin sealant when activated with thrombin product from the same blood sample.

Claims

AMENDED CLAIMS[received by the International Bureau on 12 October 1999 (12.10.99); original claims 1-17 replaced by amended claims 1-19 (3 pages)]
1. A method of preparing a thrombin material suitable for use as a fibrin sealant component, wherein prothrombin-containing material is treated with a synthetic activator agent to convert prothrombin to thrombin and yield a thrombin material containing available thrombin, the method being characterized by the prothrombin-containing material being a platelet- and fϊbrinogen-depleted blood sample and by the activator agent comprising an extended surface area material capable of activating conversion of prothrombin to thrombin.
2. A method according to claim 1 characterized in that the extended surface area material is covered with polar groups of a nature found on the exterior surfaces of activated platelets or endothelial cells.
3. A method according to claim 1 characterized in that the polar groups comprise phosphatidyl groups and basic nitrogen groups.
4. A method according to claim 1, 2 or 3 characterized in that the extended surface area material comprises phospholipid liposomes.
5. A method according to claim 1 characterized in that the aqueous medium comprises factor V, factor X and and calcium ions.
6. A method according to claim 1 characterized in that the blood plasma sample is a human blood plasma sample.
7. A method according to claim 1 characterized in that the blood plasma sample is an autologous human blood plasma sample.
8. A method according to claim 6 characterized in that the aqueous medium comprises a reduced proportion of antithrombin III relative to prothrombin as compared with the proportions in blood plasma.
18
9. A method according to claim 6 characterized in that the prothrombin material comprises a precipitate obtained from fibrinogen- and factor XHI-depleted plasma.
10. A method of preparing a thrombin material suitable for use as an autologous sealant component, the method comprising: a) treating a blood plasma sample obtained by removal of cellular and platelet components from a whole blood sample to yield a fibrinogen precipitate containing fibrinogen and factor XIII and to provide fibrinogen- and factor XIII- depleted plasma; and being characterized by: b) treating the fibrinogen- and factor XHI-depleted plasma to yield a prothrombin- containing precipitate; and c) treating the prothrombin-containing precipitate to yield thrombin.
11. A method according to claim 10 characterized in that the treatment of the prothrombin-containing precipitate in step c) comprises dissolving the prothrombin- containing precipitate in an aqueous reagent and exposing the dissolved prothrombin- containing material to an extended surface area substrate capable of converting prothrombin to thrombin.
12. A method according to claim 11 characterized in that the extended surface area material comprises a suspension of phosphatidyl liposomes.
13. A method according to claim 12 characterized in that the phosphatidyl liposomes comprise a major proportion of phosphatidyl choline and a minor proportion of phosphatidyl serine.
14. A method of preparing an optionally autologous fibrin composition comprising separate fibrinogen and thrombin components mixable to provide a sealant, the method comprising the steps of: a) removal of cellular and platelet components from a sample of patient autologous blood to yield a plasma supernatant; and b) generating a precipitate containing fibrinogen and Factor XIII from the plasma
19 supernatant for reconstitution as the fibrinogen component of the fibrin sealant; characterized by c) treating the plasma supernatant from step b) to yield a prothrombin-containing precipitate; and d) separating the prothrombin-containing precipitate from step c) and dissolving the prothrombin-containing precipitate in a sufficent quantity for solution of a tissue- compatible aqueous activation reagent comprising: i) a sufficient quantity of calcium chloride, or an equivalent thereof, to be effective in the tissue sealant; and ii) an effective quantity of a dispersed, tissue-compatible prothrombin- converting particulate substrate; to provide a thrombin-containing component.
15. A method according to claim 14 characterized in that the particulate substrate comprises phosphatidyl liposomes having a major proportion of phosphatidyl choline and a minor proportion of phosphatidyl serine.
16. A method according to claim 15 characterized in that the treatment of step c) comprises reducing the ionic strength and the pH of the solution to the isoelectric point of prothrombin.
17. Thrombin material characterized by being produced by the method of claim 1.
18. Thrombin material characterized by being produced by the method of claim 10.
19. An autologous fibrin sealant composition characterized by being produced by the method of claim 14.
20 STATEMENT UNDER ARTICLE 19(1)
Claim 1 has been amended to acknowledge Holly et al. US Patent No. 5,502,034. Holly et al. do not employ blood plasma samples as a source of prothrombin, as required by the characterizing clause of amended claim 1, but use genetically modified host cells raised in a culture medium, see column 10, lines 51-55. Nor do Holly et al. appear to employ an extended surface area material to activate conversion of prothrombin to thrombin. The phosphatidylcholine and phosphatidylserine materials mentioned at column 5, lines 33-35 are used in solution.
None of Jones et al., Smeets et al. or Kung et al. teaches a commercially deployable method for the production of a thrombin material suitable for use as a fibrinogen polymerization activator component of a fibrin sealant. Rather, each reference teaches a laboratory investigational method for studying prothrombin activation. Jones et al. 's end product is a deep blue p-nitroaniline solution the thrombin in which has been taken up in hydrolyzing S-2238 and therefore does not contain available thrombin, see page 713, lines 6-10 from the bottom. Moreover, Jones et al. does not employ fibrinogen-depleted blood plasma, as required by amended claim 1.
Smeets et al. employ purified prothrombin (a "coagulation factor" as described in the second paragraph on page 421) as a prothrombin source, not blood plasma. Further, the prothrombin is bovine, not human, as specified in claim 6, yet alone autologous, as set forth in claim 7. Kung et al. also employ isolated bovine prothrombin, not blood plasma, see page 25839, righthand column, lines 2-4.
The remaining references appear to be of interest only as background regarding production of thrombin and its use in fibrin sealants.
21 Furthermore, the references neither teach nor suggest use of prothrombin material comprised by a plasma precipitate, as defined in claims 9, 10 and 14 nor do they teach preparation of both a fibrinogen-containing component and a thrombin containing component from an autologous patient blood sample, by the method defined in claim 14.
22
PCT/US1999/005034 1998-03-10 1999-03-10 Thrombin preparation and products and fibrin sealant methods employing same WO1999045938A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002322741A CA2322741A1 (en) 1998-03-10 1999-03-10 Thrombin preparation and products and fibrin sealant methods employing same
JP2000535352A JP2002506038A (en) 1998-03-10 1999-03-10 Thrombin preparation and thrombin product and fibrin sealant method using the same
EP99909912A EP1061931A2 (en) 1998-03-10 1999-03-10 Thrombin preparation and products and fibrin sealant methods employing same
AU29005/99A AU2900599A (en) 1998-03-10 1999-03-10 Thrombin preparation and products and fibrin sealant methods employing same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7761998P 1998-03-10 1998-03-10
US60/077,619 1998-03-10

Publications (2)

Publication Number Publication Date
WO1999045938A1 WO1999045938A1 (en) 1999-09-16
WO1999045938B1 true WO1999045938B1 (en) 1999-12-02

Family

ID=22139138

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/005034 WO1999045938A1 (en) 1998-03-10 1999-03-10 Thrombin preparation and products and fibrin sealant methods employing same

Country Status (5)

Country Link
EP (1) EP1061931A2 (en)
JP (1) JP2002506038A (en)
AU (1) AU2900599A (en)
CA (1) CA2322741A1 (en)
WO (1) WO1999045938A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9265858B2 (en) 2012-06-12 2016-02-23 Ferrosan Medical Devices A/S Dry haemostatic composition
US9533069B2 (en) 2008-02-29 2017-01-03 Ferrosan Medical Devices A/S Device for promotion of hemostasis and/or wound healing

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062828A1 (en) 1996-04-30 2000-10-26 Medtronic, Inc. Autologous fibrin sealant and method for making the same
US6274090B1 (en) 1998-08-05 2001-08-14 Thermogenesis Corp. Apparatus and method of preparation of stable, long term thrombin from plasma and thrombin formed thereby
US6472162B1 (en) 1999-06-04 2002-10-29 Thermogenesis Corp. Method for preparing thrombin for use in a biological glue
JP2003517888A (en) * 1999-12-22 2003-06-03 ヘノゲン・ソシエテ・アノニム Bone producing products
DE102011112955A1 (en) 2011-09-13 2013-03-14 Medizinische Hochschule Hannover Method for producing a biological tissue construct and use of specific autologous cells
RU2657955C2 (en) 2012-03-06 2018-06-18 Ферросан Медикал Дивайсиз А/С Pressurised container containing haemostatic paste
RU2589648C2 (en) * 2012-09-25 2016-07-10 Стем Селл Партнерс Ллк Method and apparatus for producing serum with thrombin from one donor
US9724078B2 (en) 2013-06-21 2017-08-08 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
CA2928963C (en) 2013-12-11 2020-10-27 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
CA2960309A1 (en) 2014-10-13 2016-04-21 Ferrosan Medical Devices A/S Dry composition for use in haemostasis and wound healing
JP6747650B2 (en) 2014-12-24 2020-08-26 フェロサン メディカル デバイシーズ エイ／エス Syringe for holding and mixing the first substance and the second substance
BR112017027695A2 (en) 2015-07-03 2018-09-04 Ferrosan Medical Devices As first and second substance retention and mixing syringe
CN112368028A (en) 2018-05-09 2021-02-12 弗罗桑医疗设备公司 Method for preparing a hemostatic composition
CN112997967A (en) * 2021-03-09 2021-06-22 复旦大学附属华山医院 Thrombin magnetic bead and preparation method thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5226877A (en) * 1989-06-23 1993-07-13 Epstein Gordon H Method and apparatus for preparing fibrinogen adhesive from whole blood
EP0624199B1 (en) * 1991-12-31 1999-05-06 Zymogenetics, Inc. Methods for producing thrombin
US5266462A (en) * 1992-06-03 1993-11-30 Baxter Diagnostics Inc. Measurement of platelet activities
US5219995A (en) * 1992-07-14 1993-06-15 Alpha Therapeutic Corporation Plasma fraction purification
US5330974A (en) * 1993-03-01 1994-07-19 Fibratek, Inc. Therapeutic fibrinogen compositions

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9533069B2 (en) 2008-02-29 2017-01-03 Ferrosan Medical Devices A/S Device for promotion of hemostasis and/or wound healing
US9265858B2 (en) 2012-06-12 2016-02-23 Ferrosan Medical Devices A/S Dry haemostatic composition

Also Published As

Publication number Publication date
AU2900599A (en) 1999-09-27
JP2002506038A (en) 2002-02-26
CA2322741A1 (en) 1999-09-16
WO1999045938A1 (en) 1999-09-16
EP1061931A2 (en) 2000-12-27

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