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WO2009097429A1 - Agent hémostatique primaire agissant rapidement - Google Patents

Agent hémostatique primaire agissant rapidement Download PDF

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Publication number
WO2009097429A1
WO2009097429A1 PCT/US2009/032439 US2009032439W WO2009097429A1 WO 2009097429 A1 WO2009097429 A1 WO 2009097429A1 US 2009032439 W US2009032439 W US 2009032439W WO 2009097429 A1 WO2009097429 A1 WO 2009097429A1
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WO
WIPO (PCT)
Prior art keywords
hemostatic agent
primary hemostatic
factor
primary
agent
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2009/032439
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English (en)
Inventor
Leon Wortham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2009097429A1 publication Critical patent/WO2009097429A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)

Definitions

  • the present invention describes various hemostatic agents.
  • One is a hemostatic agent unique and is a novel primary hemostatic agent.
  • Methods of use and manufacture of the fast acting agent are also provided.
  • the fast acting composition and methods of the present invention are suitable for accelerating the arresting blood flow, maintaining hemostasis and for accelerating and ameliorating the healing process after various types of surgical and nonsurgical procedures or wound healing in mammals, including humans.
  • fibrin glue is an effective bioadhesive.
  • fibrin glue used in animals and humans suggests that an advantage of using fibrin glue rather than synthetic plastics (e.g., cyanoacrylic) or sutures is that fibrin glue promotes local coagulation. Fibrin glues also appear to support regrowth of new tissue and the extracellular matrix.
  • fibrin glue has been formed by mixing two components, exogenous human fibrinogen (obtained from a source other than the patient being treated, such as a freeze- dried plasma protein concentration of fibrinogen/Factor Xlll/fibronectin, and an activating enzyme, such as thrombin).
  • exogenous human fibrinogen obtained from a source other than the patient being treated, such as a freeze- dried plasma protein concentration of fibrinogen/Factor Xlll/fibronectin
  • an activating enzyme such as thrombin
  • Thrombin is a common physiological instigator of clotting. Thrombin from a number of mammalian sources, most commonly bovine, is routinely used in commercial available fibrin glues. Human thrombin can be employed in the formulation of fibrin glue as can other appropriately catalyzing enzymes, such as reptiles or selected venoms (Fenton II, J.W. et al, J. Biol. Chem., 252:3587-3598 (1977); Gaffney, P.J., et al, Thrombos.
  • Fibrinogen may be in an intimate admixture with other proteins that are typically found in uncoagulated whole blood, in platelet-rich plasma, in plasma, in cryoprecipitate, or in precipitates of plasma obtained by a method such as Cohn precipitations of plasma.
  • additional protein components may include for example, fibronectin, immunoglobulin, particularly, IqG, and plasminogen.
  • Thrombin is derived from blood plasma by the fractionation of plasma.
  • Marx on Mar. 4, 1997 disclosed a fibrin glue composition in which exogenous fibrinogen and thrombin are mixed together prior to the fibrin glue mixture for the delivery of agents to the tissue being treated.
  • U.S. Pat. No. 5,290,522 issued to Sierra et al, on Mar. 1, 1994 discloses a surgical adhesive material comprising of a composition of fibrinogen, collagen, thrombin and calcium, in which the thrombin is mixed with exogenous fibrinogen prior to the application of the fibrin glue to the tissue.
  • That fibrin glue like all the current hemostatic agents used to control bleeding, are applied as an adjunct to a bleeding wound. Therefore, there exists a need for a one component primary hemostatic agent that can be applied as a first defense to arrest all forms of bleeding, even in the presence of anticoagulant therapy and coagulopathy without any pre- mixing or preparation.
  • the invention is a novel primary hemostatic agent that has Factors Ha, Vila, IXa, and Xa, together in a pharmaceutically acceptable carrier such as water.
  • the primary fast acting hemostatic agent of the invention may comprise of
  • the fast acting primary hemostatic agent of the invention may contain other clotting factors, growth factors, antibiotics, trace metals, etc., as long as it contains no significant amounts of fibrinogen, which would cause the premature formation of a clot.
  • the agent contains Factor Ha, Factor Vila, Factor IXa, and
  • Factor Xa There can be about 0.0001 - 10,000,000 IU/ml of each of these factors.
  • the fast acting agent is formulated in a form selected from the group consisting of a liquid, aerosol, foam, paste, ointment, gel, emulsion, powder, moldable form, surgical dressing, wound packing, bandage, swab, catheter, fiber optic, syringe, and the like.
  • one method is: isolating each protein, Factor II, Factor VII, Factor IX, and Factor
  • the method involves blending the activated Factors in a pharmaceutically acceptable carrier to produce a primary hemostatic agent.
  • the Factor II, Factor VII, Factor IX and Factor X may be produced through recombinant DNA techniques, or may be purified from blood, or other suitable tissue sources.
  • the invention also teaches methods of using the primary hemostatic agent.
  • the novel primary hemostatic agent does not pre-clot and does not require mixing of components prior to or simultaneously with use, it is particularly suitable for use in surgical procedures or emergency applications where the primary hemostatic agent can be applied to an internal portion of a patient via a tube, such as an endoscope, or via a syringe, and the like.
  • the primary hemostatic agent can be administered with devices such as a bandage, surgical dressing, wound packing, swab, syringe, tubing, endoscope, spray bottle, and aerosol canister, and the like.
  • the primary fast acting hemostatic agent of the present invention utilizes the clotting factors of the organism being treated (the "host"), including the hosts' fibrinogen naturally present at a wound, to form a clot on contact with the tissue being treated to arrest blood flow.
  • the present invention may contain Factor Ha, Factor Vila, Factor IXa and Factor Xa, and is not mixed with fibrinogen prior to application to the tissue being treated.
  • the primary hemostatic agent of the present invention Factor Ha, Factor Vila,
  • Factor IXa and Factor Xa interacts with the hosts' intrinsic and extrinsic clotting cascade system, accelerating the process to achieve hemostasis within seconds.
  • the addition of the primary hemostatic agent's Factor Vila and Factor Xa to the host's anticoagulated blood overcomes the inhibiting effect of the presence of the anticoagulant drugs, Coumadin and heparin, respectively.
  • the combination of the active Factors in the primary hemostatic agent will overcome every type of coagulopathy in the hosts' blood, to achieve hemostasis within seconds.
  • the primary hemostatic agent of the invention provides several additional advantages.
  • the agent may be utilized in endoscopic or any other scopic surgical procedures, in which the primary hemostatic agent is applied through an endoscope to access the tissue being treated, such as an internal organ.
  • Another advantage of the primary hemostatic agent when it is applied to the tissue being treated there is no loss of tissue, allowing the tissue to heal faster.
  • Still another advantage of the primary hemostatic agent is a substantial reduction of blood loss, resulting in fewer or the elimination of blood transfusions.
  • the one component characteristic property of a fast acting agent allows a wider range of delivery systems for the primary hemostatic agent to be delivered to the tissue being treated.
  • the agent may be incorporated in hydrous or anhydrous forms into bandages, dressings, and packing materials for large wounds, or part of first aid kits for domestic, industrial or military applications, or wherever it is desired to arrest the flow of blood.
  • the primary hemostatic agent may also be formulated with a pharmaceutical acceptable carrier in a dry delivery form such as bandages, surgical dressings, wound packing, swabs such as Q-Tips, etc.
  • a pharmaceutical acceptable carrier such as bandages, surgical dressings, wound packing, swabs such as Q-Tips, etc.
  • the agent may alternatively be formulated to be presented in liquid, aerosol, gel, emulsions, paste, ointments, foam and moldable forms.
  • Liquids may be delivered internally, for example, through syringes or tubing such as catheters or fiber optic tubing or endoscopes. Of course liquids may be applied to any surface location as well. Aerosols may be delivered from spray bottles, tubing and aerosol canisters.
  • Foams may be comprised of the hemostatic agent formulated with maltodextran, dextran or other starches, albumin and a surfactant. Moldable forms may be comprised of the primary hemostatic agent formulated in maltodextran, dextran or other starches and gelatins. Gels and pastes can be formed with suitable thickness and emulsions are well known in the art. Powders may comprise almost pure ingredients or contain suitable fillers, excipients, and the like. Aerosols can be formed from liquid forms and suitable dispersants. All of these formulations and/or delivery systems are well known in the art and need not be detailed herein.
  • the present invention affords a new generation of hemostatic agents whose advantages and uses will become apparent from the following disclosure of the present invention.
  • the present invention establishes a unique, safe and effecting primary hemostatic agent, formulated for widespread use and numerous surgical and nonsurgical applications.
  • a primary hemostatic agent is a tool used as a first line of defense to control bleeding, and can be applied to both minor and major forms of hemorrhages.
  • An adjunct hemostatic agent is of a biological or nonbiological material applied to only minor or oozing forms of bleeding from a wound.
  • Any carrier including water, that can be used to formulate a composition for medical uses. This term is well known in the art and need not be described further herein.
  • the primary hemostatic agent of the present invention comprises a composition of
  • the following components are admixed with Factor Ha 0.00001 - 10,000,000 IU/ml, preferred range, (1-100,000 IU/ml); Factor Vila 0.00001 - 10,000,000 IU/ml, preferred range, (1-100,000 IU/ml); Factor IXa 0.00001 - 10,000,000 IU/ml, preferred range (1-100,000 IU/ml); Factor Xa 0.00001 - 10,000,000 IU/ml, preferred range (1-100,000 IU/ml).
  • Blend with a pharmaceutically acceptable carrier if desired.
  • Such carriers and blending techniques are well known in the art and need not be described herein.
  • Factor II, Factor VII, Factor IX, and Factor X for use in the composition of the primary hemostatic agent of the present invention can be obtained from other than a human source, such as from animals, or may be synthetically produced, such as the recombinant DNA techniques known by those skilled in the art.
  • the human blood plasma used as a source for the individual Factors should be tested for contaminants such as lipid-enveloped viruses such as HIV and HCV (also known as non-A-non B hepatitis virus), as well as cytomegalovirus (CMV), Epstein-Barr virus, and the herpes simplex viruses.
  • HIV and HCV also known as non-A-non B hepatitis virus
  • CMV cytomegalovirus
  • Epstein-Barr virus Epstein-Barr virus

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un agent hémostatique doté du facteur IIa et d'autres facteurs activés dans un transporteur pharmaceutiquement acceptable sans fibrinogène afin de fournir une coagulation rapide dans un véhicule qui peut être administré sous forme liquide, par bandage, coiffe, remplissage, tampon, liquide, aérosol, pâte, onguent, forme, gel, émulsion, poudre ou forme que l'on peut mouler.
PCT/US2009/032439 2008-01-29 2009-01-29 Agent hémostatique primaire agissant rapidement Ceased WO2009097429A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2436708P 2008-01-29 2008-01-29
US61/024,367 2008-01-29

Publications (1)

Publication Number Publication Date
WO2009097429A1 true WO2009097429A1 (fr) 2009-08-06

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Family Applications (1)

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PCT/US2009/032439 Ceased WO2009097429A1 (fr) 2008-01-29 2009-01-29 Agent hémostatique primaire agissant rapidement

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WO (1) WO2009097429A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170020995A1 (en) * 2015-07-24 2017-01-26 Leon Wortham Serine Protease Primary Hemostatic Agent

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504064A (en) * 1991-04-10 1996-04-02 Oklahoma Medical Research Foundation Treatment of bleeding with modified tissue factor in combination with an activator of FVII
US6410260B2 (en) * 1997-09-26 2002-06-25 Leon Wortham Fibrin glue without fibrinogen and biosealant compositions and methods
US20040005350A1 (en) * 2002-06-28 2004-01-08 Looney Dwayne Lee Hemostatic wound dressings and methods of making same
US20070160653A1 (en) * 2006-01-11 2007-07-12 Fischer Thomas H Hemostatic textile

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504064A (en) * 1991-04-10 1996-04-02 Oklahoma Medical Research Foundation Treatment of bleeding with modified tissue factor in combination with an activator of FVII
US6410260B2 (en) * 1997-09-26 2002-06-25 Leon Wortham Fibrin glue without fibrinogen and biosealant compositions and methods
US20040005350A1 (en) * 2002-06-28 2004-01-08 Looney Dwayne Lee Hemostatic wound dressings and methods of making same
US20070160653A1 (en) * 2006-01-11 2007-07-12 Fischer Thomas H Hemostatic textile

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170020995A1 (en) * 2015-07-24 2017-01-26 Leon Wortham Serine Protease Primary Hemostatic Agent

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