# US 10,245,348 B2 · Process for making dry and stable hemostatic compositions

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- Number: US 10,245,348 B2
- Document ID: US10245348B2
- Status: Granted
- Kind: B2
- Application number: 14/804,084
- Filed: 2015-07-20
- Published: 2015-12-24
- Granted: 2019-04-02
- Earliest claimed: 2010-06-01
- Assignees: Baxter International Inc.; Baxter Healthcare S.A.
- Applicants: Baxter International Inc.; Baxter Healthcare S.A.
- Inventors: Andreas Goessl; Atsushi Edward Osawa; Cary J. Reich
- Web page: https://patentgrep.com/patent/US10245348B2

## CPC

- A61L 24/043: {Mixtures of macromolecular materials}
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/1658: {Proteins, e.g. albumin, gelatin}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 38/39: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
- A61K 38/4833: {Thrombin (3.4.21.5)}
- A61L 24/0015: {Medicaments; Biocides}
- A61L 24/10: Polypeptides; Proteins {(A61L24/043 takes precedence)}
- A61L 24/106: {Fibrin; Fibrinogen}
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- B65B 3/003: {Filling medical containers such as ampoules, vials, syringes or the like}
- B65B 5/12: Introducing successive articles, e.g. confectionery products, of different shape or size in predetermined positions
- B65B 55/02: Sterilising, e.g. of complete packages
- A61L 2300/418: Agents promoting blood coagulation, blood-clotting agents, embolising agents
- A61L 2300/802: Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
- A61L 2400/04: Materials for stopping bleeding
- A61L 2400/06: Flowable or injectable implant compositions
- C12Y 304/21005: Thrombin (3.4.21.5)
- Y10T 428/13: Hollow or container type article [e.g., tube, vase, etc.]
- 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 (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B65B: MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING (bundling and pressing devices for cigars A24C1/44; devices for tensioning and securing binders adapted to be supported by the article or articles to be bound B25B25/00; applying closure members to bottles, jars or similar containers B67B1/00-B67B6/00; concurrent cleaning, filling and closing of bottles B67C7/00; emptying bottles, jars, cans, casks, barrels or similar containers B67C9/00)
- C12Y: ENZYMES
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

Described is a process for making a dry and stable hemostatic composition, said process comprising a) providing a first component comprising a dry preparation of a coagulation inducing agent, b) providing a second component comprising a dry preparation of a biocompatible polymer suitable for use in hemostasis, c) providing said first component and said second component in a combined form in a final container, c1) either by filling said first component and said second component into said final container so as to obtain a dry mixture in said final container, c2) or by providing said first component or said second component in said final container and adding said second component or said first component so as to obtain a combination of said first component with said second component in said final container, d) finishing the final container to a storable pharmaceutical device containing said first component and said second component in a combined form as a dry and stable hemostatic composition.

## Claims

### Claim 1

A process for making a dry and stable hemostatic composition, the process comprising:
lyophilizing an aqueous preparation of thrombin in a container so as to provide a first component in the container, the first component comprising a dry preparation of thrombin;
compacting the first component in the container following the lyophilizing step;
adding a second component to the container following the lyophilizing step, the second component comprising a dry preparation of a biocompatible polymer suitable for use in hemostasis;
mixing the first component and the second component, so as to obtain a dry mixture of the first component with the second component in the container;
and finishing the container to a storable pharmaceutical device containing the first component and the second component in a combined form as a dry and stable hemostatic composition.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the container comprises a member selected from the group consisting of a syringe, a vial, and a tube.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the adding step is performed under aseptic conditions.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the finishing step comprises an ethylene oxide sterilization step or a treatment with ionizing irradiation.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the container is a container finished together with a diluent container with a pharmaceutically acceptable diluent for reconstituting the dry and stable hemostatic composition.

### Claim 6 (depends on 1)

The process according to claim 1, wherein the thrombin is human thrombin.

### Claim 7 (depends on 1)

The process according to claim 1, wherein the thrombin is recombinant human thrombin.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the thrombin is bovine thrombin.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the biocompatible polymer suitable for use in hemostasis contains a protein selected from the group consisting of gelatin, soluble collagen, albumin, hemoglobin, fibrinogen, fibrin, casein, fibronectin, elastin, keratin, laminin, and derivatives or combinations thereof.

### Claim 10 (depends on 1)

The process according to claim 1, wherein the biocompatible polymer suitable for use in hemostasis contains a polysaccharide selected from the group consisting of glycosaminoglycans, starch derivatives, cellulose derivatives, hemicellulose derivatives, xylan, agarose, alginate, chitosan, and derivatives or combinations thereof.

### Claim 11 (depends on 1)

The process according to claim 1, wherein the biocompatible polymer suitable for use in hemostasis contains a polymer selected from the group consisting of polyacrylates, polymethacrylates, polyacrylamides, polyvinyl resins, polylactide-glycolides, polcaprolactones, polyoxyethlenes, and derivatives and combinations thereof.

### Claim 12 (depends on 1)

The process according to claim 1, wherein the biocompatible polymer suitable for use in hemostasis contains a member selected from the group consisting of a crosslinked polysaccharide, a crosslinked protein, a crosslinked non-biologic polymer, and mixtures thereof.

### Claim 13 (depends on 1)

The process according to claim 1, wherein the biocompatible polymer suitable for use in hemostasis is a particulate material.

### Claim 14 (depends on 1)

The process according to claim 1, wherein the biocompatible polymer suitable for use in hemostasis is a cross-linked gelatin.

### Claim 15 (depends on 1)

The process according to claim 1, wherein the container further contains an amount of a stabilizer effective to inhibit modification of the polymer when exposed to the sterilizing radiation, and wherein the stabilizer is selected from the group consisting of ascorbic acid, sodium ascorbate, other salts of ascorbic acid, and an antioxidant.

### Claim 16 (depends on 1)

A method for delivering a hemostatic composition to a target site in a patient's body, the method comprising delivering a hemostatic composition produced by the process of claim 1 to the target site.

### Claim 17 (depends on 16)

A method according to claim 16 further comprising the step of contacting the hemostatic composition with a pharmaceutically acceptable diluent so as to obtain a hemostatic composition in a hydrogel form.

### Claim 18 (depends on 1)

The process according to claim 1, wherein the dry preparation of the biocompatible polymer is in granular form, and the step of adding the second component to the container comprises filling the dry preparation of the biocompatible polymer on top of the first component.

### Claim 19 (depends on 1)

The process according to claim 1, wherein compacting the first component in the container comprises compacting under vacuum.

### Claim 20 (depends on 1)

The process according to claim 1, wherein the step of adding the second component to the container comprises filling the dry preparation of the biocompatible polymer on top of the compacted first component.

### Claim 21 (depends on 1)

The process according to claim 1, further comprising compacting the second component in the container following the adding step.

### Claim 22 (depends on 1)

The process according to claim 1, wherein the container is one syringe.