# US 2014/0154773 A1 · Thrombin solution and methods of use thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2014/0154773 A1
- Document ID: US20140154773A1
- Status: Published application
- Kind: A1
- Application number: 13/783,592
- Filed: 2013-03-04
- Published: 2014-06-05
- Earliest claimed: 2012-12-03
- Assignees: Omrix Biopharmaceuticals Ltd.
- Applicants: Omrix Biopharmaceuticals Ltd.
- Inventors: Roberto Meidler; Oleg Belyaev; Liliana Bar; Israel Nur
- Web page: https://patentgrep.com/patent/US20140154773A1

## CPC

- C12N 9/96: Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
- 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 38/4833: {Thrombin (3.4.21.5)}
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- C12N 9/6429: {Thrombin (3.4.21.5)}
- C12Y 304/21005: Thrombin (3.4.21.5)
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)
- C12Y: ENZYMES
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are methods for lyophilization of an aqueous thrombin solution, thrombin solutions for use in such lyophilization methods, and solid thrombin compositions produced by such methods.

## Claims

### Claim 1

A method for lyophilization of an aqueous thrombin solution, the method comprising:
providing the aqueous thrombin solution comprising about 1 to less than about 4.6% (w/v) of a saccharide or sugar alcohol; at least about 0.7 to lower than about 1.75% (w/v) sodium chloride; about 0.2 to about 3% (w/v) albumin; calcium chloride; and sodium acetate; and
lyophilizing the aqueous thrombin solution.

### Claim 2 (depends on 1)

The method of claim 1, wherein the aqueous thrombin solution comprises about 200 to about 2000 IU/ml thrombin; about 0.3 to about 1.5% (w/v) calcium chloride; and about 0.14 to about 1% (w/v) sodium acetate.

### Claim 3 (depends on 2)

The method of claim 2, wherein the aqueous thrombin solution comprises: about 1.6 to less than about 4.6% (w/v) saccharide or sugar alcohol; about 0.7 to about 1.7% (w/v) sodium chloride; higher than about 0.2 to lower than about 3% albumin (w/v); about 0.3 to about 1.2% (w/v) calcium chloride; and about 0.14 to about 0.7% (w/v) sodium acetate.

### Claim 4 (depends on 3)

The method of claim 3, wherein the saccharide or sugar alcohol is present at a concentration of 2% (w/v); the albumin is present at a concentration of about 0.6% (w/v); the sodium chloride is present at a concentration of about 0.76% (w/v); the calcium chloride is present at a concentration of about 0.6% (w/v) and the sodium acetate is present at a concentration of about 0.27% (w/v).

### Claim 5 (depends on 1)

The method of claim 1, the aqueous thrombin solution consisting essentially of thrombin; saccharide or sugar alcohol; sodium chloride; albumin; calcium chloride; and sodium acetate.

### Claim 6 (depends on 1)

The method of claim 1, wherein the sugar alcohol is mannitol.

### Claim 7 (depends on 6)

The method of claim 6, wherein the mannitol is present at a concentration of about 2% (w/v).

### Claim 8 (depends on 1)

The method of claim 1, wherein the aqueous thrombin solution comprises a single saccharide or sugar alcohol.

### Claim 9 (depends on 1)

The method of claim 1, wherein the aqueous thrombin solution is devoided of at least one of polyethylene glycol and histidine.

### Claim 10 (depends on 1)

The method of claim 1, wherein the height of the aqueous thrombin solution in a lyophilization vessel is no greater than about 10 mm or is about 8 mm.

### Claim 11 (depends on 10)

The method of claim 10, wherein a total lyophilization time is no greater than about 35 hours or no greater than about 30 hours.

### Claim 12 (depends on 1)

The method of claim 1, wherein the height of the aqueous thrombin solution in a lyophilization vessel is no greater than about 20 mm, in the range of about 15 to about 19 mm, or about 17 mm.

### Claim 13 (depends on 12)

The method of claim 12, wherein a total lyophilization time is no greater than about 68 hours.

### Claim 14

An aqueous thrombin solution comprising:
about 1 to less than about 4.6% (w/v) saccharide or sugar alcohol;
at least about 0.7 to lower than about 1.75% (w/v) sodium chloride;
about 0.2 to about 3% (w/v) albumin;
calcium chloride; and
sodium acetate.

### Claim 15 (depends on 14)

The aqueous thrombin solution of claim 14, comprising:
about 200 to about 2000 IU/ml thrombin;
about 0.3 to about 1.5% (w/v) calcium chloride; and
about 0.14 to about 1% (w/v) sodium acetate.

### Claim 16 (depends on 15)

The aqueous thrombin solution of claim 15, comprising:
about 1.6 to less than about 4.6% (w/v) saccharide or sugar alcohol;
about 0.7 to about 1.7% (w/v) sodium chloride;
higher than about 0.2 to lower than about 3% albumin;
about 0.3 to about 1.2% (w/v) calcium chloride; and
about 0.14 to about 0.7% (w/v) sodium acetate.

### Claim 17 (depends on 16)

The aqueous thrombin solution of claim 16, wherein the saccharide or sugar alcohol is present at a concentration of about 2% (w/v); the albumin is present at a concentration of about 0.6% (w/v), the sodium chloride is present at a concentration of about 0.76% (w/v), the calcium chloride is present at a concentration of about 0.6% (w/v) and the sodium acetate is present at a concentration of about 0.27% (w/v).

### Claim 18 (depends on 14)

The aqueous thrombin solution of claim 14, wherein the aqueous thrombin solution comprises a single saccharide or sugar alcohol and/or is devoided of at least one of polyethylene glycol and histidine.

### Claim 19 (depends on 1)

A solid thrombin composition obtainable according to the method of claim 1.

### Claim 20 (depends on 19)

The solid composition of claim 19, comprising about 19.5% to about 78% (w/w of the total composition) mannitol, about 1% to about 20% (w/w of the total composition) sodium acetate; about 2% to about 53% (w/w of the total composition) albumin; about 2.5% to about 31% (w/w of the total composition) calcium chloride; and about 6% to about 45% (w/w of the total composition) sodium chloride.