WO2009097429A1

WO2009097429A1 - A fast acting primary hemostatic agent

Info

Publication number: WO2009097429A1
Application number: PCT/US2009/032439
Authority: WO
Inventors: Leon Wortham
Original assignee: Leon Wortham
Priority date: 2008-01-29
Filing date: 2009-01-29
Publication date: 2009-08-06

Abstract

A hemostatic agent is provided with Factor IIa and other activated factors in a pharmaceutically acceptable carrier without fibrinogen to provide rapid coagulation in a vehicle that may be administered by liquid, bandage, dressing, packing, swab, liquid, aerosol, paste, ointment, form, gel, emulsion, powder or moldable form.

Description

A Fast Acting Primary Hemostatic Agent

The present application claims priority to the January 29, 2008 filing date of U.S. provisional patent application, Serial No. 61/024,367.

Field of the Invention

[0001] 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.

Background of the Invention

[0002] The use of hemostatic agents have been used in various surgical disciplines as reported by Spotnitz, W., Surg., VoI 142, Issue 4, S34-S38 (2007); Whong, H., Kirsch, W., etc., Polymer Reviews, VoI 45, Issue 4, 309-323 (2005); Erdogan, D., Busch, D., etc., Digestive Surgery, VoI 24, No. 4, 294-299 (2007); Voorlmolen, JH, Ringers, J., etc., Neurosurgery, 20(5): 702-9 (1987); Mormota, Y., Migamoto, Y., etc., J. of Biomedical Materials Research, VoI 63, Issue 5, 542-547 (2002); Wright, J., Kalns, J., etc., J. of Trauma - Injury Infection & Critical Care, 57(2): 224-230 (2004); Levy, J., Transfusion 44(s2), 585-625 (2004). [0003] A common hemostatic agent, fibrin glue, is an effective bioadhesive. For example, surgeons, dentists and veterinarians have reported that 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. [0004] In the past, 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). Prior to use, the plasma protein concentrates were conventionally solubilized in the presence of calcium chloride. Thrombin induced activation of fibrinogen resulting in the formation of fibrin. Factor XIII and calcium participated in the cross-linking and stabilization of the fibrin to produce a tight mesh of polymeric fibrin glue. Applied to tissue, the fibrin clot adhered to the site of application. The rate of coagulation and mechanical properties of the clot were dependant on the concentration of fibrinogen and thrombin. [0005] 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. Haemostas., 67:424- 427 (1992); European Patent Application No. EPO439156A1, Stacker K., et al., Toxicon 20:265- 273 (1982); and Pirkle, H. & Stacker, K., Thrombos Haemostas., 65:444-450 (1991). [0006] 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. Such additional protein components may include for example, fibronectin, immunoglobulin, particularly, IqG, and plasminogen.

[0007] Thrombin is derived from blood plasma by the fractionation of plasma.

Comprehensive reviews on the preparative technique of each have been published and are the basis for most commercial plasma fractionation procedures used by those skilled in the art

(Fenton II, J.W., supra; Gaffney, PJ., supra; EPO439156A1; and U.S. Pat.

No. 5,143,838).

[0008] However, the prior art fibrin glue compositions required the mixture of thrombin with exogenous fibrinogen to form an unwarranted, premature fibrin clot, prior to the application of the fibrin glue to the tissue being treated. For example, U.S. Pat. No. 5, 607, 694 issued to

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.

[0009] Similarly, 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.

[00010] 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.

Summary of the Present Invention

[00011] 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. [00012] The primary fast acting hemostatic agent of the invention may comprise of

0.00001 to 10,000,000 IU/ml Factor Ha, or 0.00001 to 10,000,000 IU/ml Factor Vila, or 0.00001 to 10,000,000 IU/ml Factor IXa, or 0.0001 to 10,000,000 IU/ml Factor Xa.

[00013] 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. In a preferred embodiment, 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.

[00014] In yet another embodiment, 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.

[00015] Methods of manufacturing the novel primary hemostatic agent are also provided.

For example, one method is: isolating each protein, Factor II, Factor VII, Factor IX, and Factor

X, from blood, and activating each Factor known by those skilled in the art. Next, the method involves blending the activated Factors in a pharmaceutically acceptable carrier to produce a primary hemostatic agent.

[00016] 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.

[00017] The invention also teaches methods of using the primary hemostatic agent.

Because 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. Alternatively, 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.

[00018] 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. Unlike other coagulation compositions of the past, 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.

[00019] 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. Furthermore, 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. [00020] The primary hemostatic agent of the invention provides several additional advantages. One important advantage is that it arrests blood flow immediately on contact with the tissue being treated and prevents unwanted, premature clot formation prior to the application to the tissue treated. As a result, 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. [00021] 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.

[00022] Still another advantage of the primary hemostatic agent is a substantial reduction of blood loss, resulting in fewer or the elimination of blood transfusions.

[00023] Furthermore, 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.

[00024] 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.

[00025] 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. The agent may alternatively be formulated to be presented in liquid, aerosol, gel, emulsions, paste, ointments, foam and moldable forms.

[00026] 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.

[00027] 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.

Description of the Present Invention

[00028] The invention can be understood by reference to the following definitions:

[00029] 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. [00030] An adjunct hemostatic agent is of a biological or nonbiological material applied to only minor or oozing forms of bleeding from a wound.

[00031] 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. [00032] Any human, mammalian or synthetically produced Factor II, Factor VII, Factor

IX, Factor X, and other clotting pathway components that are biologically active. [00033] The primary hemostatic agent of the present invention comprises a composition of

Factor Ha, Factor Vila, Factor IXa and Factor Xa. Set forth below is a description of steps for preparing one embodiment of the primary hemostatic agent of the present invention. Suitable ranges for elements are provided in parenthesis.

Example

1. Individual Factors II, VII, IX, X are isolated and purified from 3.8% citrated human plasma through column chromatography by methods well known skilled in the art. 2. Each of the isolated Factors are activated through methods well known skilled in the art.

3. In order to manufacture the primary hemostatic agent of the invention 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).

4. 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.

[00034] It is recognized that 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. Further, because of the general risks and problems of infections from pooled blood products, 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. [00035] While the present invention has been described in detail with respect to its preferred embodiment, it is appreciated that other variations of the present invention may be devised which do not depart from the inventive concept of the present invention. All art cited herein is expressly incorporated by reference and is re-listed here for convenience only.

Spotnitz, W., Surg., VoI 142, Issue 4, S34-S38 (2007); Whong, H., Kirsch, W., etc., Polymer Reviews, VoI 45, Issue 4, 309-323 (2005); Erdogan, D., Busch, D., etc., Digestive Surgery, VoI 24, No. 4, 294-299 (2007); Voorlmolen, JH, Ringers, J., etc., Neurosurgery, 20(5): 702-9 (1987); Mormota, Y., Migamoto, Y., etc., J. of Biomedical Materials Research, VoI 63, Issue 5, 542-547 (2002); Wright, J., Kalns, J., etc., J. of Trauma - Injury Infection & Critical Care, 57(2): 224-230 (2004); Levy, J., Transfusion 44(s2), 585-625 (2004), (Fenton II, J.W. et al, J. Biol. Chem., 252:3587-3598 (1977); Gaffney, PJ. , et al., Thrombos. Haemostas., 67:424-427 (1992); European Patent Application No. EPO439156A1, Stacker K., et al., Toxicon 20:265-273 (1982); and Pirkle, H. & Stacker, K., Thrombos Haemostas., 65:444-450 (1991), (Fenton II, J.W., supra; Gaffney, P.J., supra; EPO439156A1; and U.S. Pat. No. 5,143,838), U.S. Pat. No. 5, 607.694 issued to Marx on Mar. 4, 199, U.S. Pat. No. 5,290,522 issued to Sierra et al., on Mar. 1, 1994.

Claims

ClaimsWhat is claimed is:

1. A primary hemostatic agent comprising of Factor Ha together in a pharmaceutically acceptable carrier.

2. The primary hemostatic agent of claim 1, wherein there is from 0.0001 to 10,000,000 IU/ml of Factor Ha.

3. The primary hemostatic agent of claim 1, further comprising Factor Vila.

4. The primary hemostatic agent of claim 3, wherein there is from 0.00001 to 10,000,000 IU/ml of Factor Vila.

5. The primary hemostatic of claim 1, further comprising Factor IXa.

6. The primary hemostatic agent of claim 5, wherein there is from 0.0001 to 10,000,000 IU/ml of Factor IXa.

7. The primary hemostatic of claim 1, further comprising Factor Xa.

8. The primary hemostatic agent of claim 7, wherein there is from 0.0001 to 10,000,000 IU/ml of Factor Xa.

9. The primary hemostatic of claim 3, further comprising Factor IXa.

10. The primary hemostatic agent of claim 9, wherein there is from 0.0001 to 10,000,000 IU/ml of Factor IXa.

11. The primary hemostatic of claim 3, further comprising Factor Xa.

12. The primary hemostatic agent of claim 11, wherein there is from 0.0001 to 10,000,000 IU/ml of Factor Xa.

13. The primary hemostatic of claim 9, further comprising Factor Xa.

14. The primary hemostatic agent of claim 13, wherein there is from 0.0001 to 10,000,000 IU/ml of Factor Xa.

15. The primary hemostatic agent of claim 1, wherein the primary hemostatic agent is formulated in a form selected from the group consisting of a bandage, surgical dressing, wound packing, swab, liquid, aerosol, paste, ointment, foam, gel, emulsion, powder and moldable form.

16. The primary hemostatic agent of claim 3, wherein the primary hemostatic agent is formulated in a form selected from the group consisting of a bandage, surgical dressing, wound packing, swab, liquid, aerosol, paste, ointment, foam, gel, emulsion, powder and moldable form.

17. The primary hemostatic agent of claim 5, wherein the primary hemostatic agent is formulated in a form selected from the group consisting of a bandage, surgical dressing, wound packing, swab, liquid, aerosol, paste, ointment, foam, gel, emulsion, powder and moldable form.

18. The primary hemostatic agent of claim 7, wherein the primary hemostatic agent is formulated in a form selected from the group consisting of a bandage, surgical dressing, wound packing, swab, liquid, aerosol, paste, ointment, foam, gel, emulsion, powder and moldable form.

19. The primary hemostatic agent of claim 9, wherein the primary hemostatic agent is formulated in a form selected from the group consisting of a bandage, surgical dressing, wound packing, swab, liquid, aerosol, paste, ointment, foam, gel, emulsion, powder and moldable form.

20. The primary hemostatic agent of claim 11, wherein the primary hemostatic agent is formulated in a form selected from the group consisting of a bandage, surgical dressing, wound packing, swab, liquid, aerosol, paste, ointment, foam, gel, emulsion, powder and moldable form.

21. The primary hemostatic agent of claim 13, wherein the primary hemostatic agent is formulated in a form selected from the group consisting of a bandage, surgical dressing, wound packing, swab, liquid, aerosol, paste, ointment, foam, gel, emulsion, powder and moldable form.

22. A method of using a primary hemostatic agent, comprising administering novel primary hemostatic agent to an internal portion of a patient by a tube or syringe.