# US 10,307,496 B2 · Method for sterilization of aqueous polysaccharide solutions and sterile aqueous polysaccharide solutions

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- Number: US 10,307,496 B2
- Document ID: US10307496B2
- Status: Granted
- Kind: B2
- Application number: 15/375,666
- Filed: 2016-12-12
- Published: 2017-06-22
- Granted: 2019-06-04
- Earliest claimed: 2015-12-22
- Assignees: Heraeus Medical GmbH
- Applicants: Heraeus Medical GmbH
- Inventors: Sebastian Vogt; Thomas Kluge
- Web page: https://patentgrep.com/patent/US10307496B2

## CPC

- A61L 2/16: using chemical substances
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- C08L 1/284: {with hydroxylated hydrocarbon radicals}
- C08L 1/286: {substituted with acid radicals, e.g. carboxymethyl cellulose [CMC] (C08L1/282 takes precedence)}
- C08L 3/08: Ethers
- C08L 5/00: Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L 5/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- A61L 2103/05: Living organisms or biological materials
- C08B 11/02: Alkyl or cycloalkyl ethers
- C08B 11/12: substituted with carboxylic radicals {, e.g. carboxymethylcellulose [CMC]}
- C08B 37/0072: {Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates}
- 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
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21)

## Abstract

Sterilization method according to which an aqueous polysaccharide solution is stored in the presence of a lactone and a buffer system for a period of at least 24 hours, and a sterile polysaccharide solution produced in this way.

## Claims

### Claim 1

Method for sterilizing aqueous polysaccharide solutions, comprising:
adding a β-lactone to an aqueous solution of a polysaccharide in the presence of a buffer, thereby forming a mixture; and
storing the mixture at a temperature of 4° C. to 40° C. for a period of at least 24 hours, wherein the added β-lactone is present in the mixture in an amount greater than or equal to 0.5% by weight.

### Claim 2 (depends on 1)

Method according to claim 1, wherein the β-lactone is selected from compounds (a1) that are represented by general formula (I),
where R1, R2, R3, and R4, independently of each other, represent H, a substituted or non-substituted alkyl residue, halogen residue, nitro residue or cyano residue, and compounds (a2) that are selected from the group consisting of dimers of compounds (a1).

### Claim 3 (depends on 2)

Method according to claim 2, wherein the β-lactone is β-propiolactone (CAS number 57-57-8).

### Claim 4 (depends on 1)

Method according to claim 1, wherein the polysaccharide is selected from the group consisting of the sodium salt of hyaluronic acid, the sodium salt of carboxymethylcellulose, hydroxyethylcellulose, hydroxyethyl starch, methylcellulose, and oxidized cellulose.

### Claim 5 (depends on 1)

Method according to claim 1, wherein phosphate buffer with a pH value of 7.0-8.0 is used as buffer system.

### Claim 6 (depends on 5)

Method according to claim 5, wherein the phosphate buffer is selected from the group consisting of the combination of potassium hydrogenphosphate and disodium hydrogenphosphate, the combination of sodium hydrogenphosphate and disodium hydrogenphosphate, the combination of disodium phosphate and phosphoric acid, the combination of trisodium phosphate and sodium hydrogenphosphate, and the combination of trisodium phosphate and phosphoric acid.

### Claim 7 (depends on 4)

Method according to claim 4, wherein the 3-hydroxypropionic acid produced by the hydrolysis of the β-propiolactone is a component of the buffer system.

### Claim 8 (depends on 7)

Method according to claim 7, wherein the 3-hydroxypropanoic acid and the sodium salt of the hyaluronic acid or 3-hydroxypropanoic acid and the sodium salt of the carboxymethylcellulose form a buffer system.

### Claim 9 (depends on 1)

Method according to claim 1, wherein all of the components of the buffer together are dissolved in the aqueous polysaccharide solution at a concentration of greater than or equal to 0.5% by weight.

### Claim 10 (depends on 1)

Method according to claim 1, wherein the sterilization of the aqueous polysaccharide solution takes place inside a primary packaging means.

### Claim 11 (depends on 10)

Method according to claim 10, wherein the aqueous polysaccharide solution and the β-lactone are mixed immediately before the aqueous polysaccharide solution is filled into the primary packaging means.

### Claim 12 (depends on 1)

Method according to claim 1, wherein
the aqueous solution comprises a buffer system whose buffering capacity is sufficient to buffer the 3-hydroxypropanoic acid generated by hydrolysis of the β-lactone such that the pH value of the sterilized aqueous polysaccharide solution is equal to that of the unsterilized polysaccharide solution.

### Claim 13 (depends on 1)

Sterile polysaccharide solution produced according to the method of claim 1, wherein the aqueous polysaccharide solution comprises at least one polysaccharide that is at least partially soluble in water, in water and 3-hydroxypropionic acid, and in a buffer system.

### Claim 14 (depends on 13)

Sterile polysaccharide solution according to claim 13, wherein the buffer system comprises sodium ions, dihydrogenphosphate ions, hydrogenphosphate ions, phosphate ions, 3-hydroxypropionic acid, and 3-hydroxypropionate.

### Claim 15 (depends on 1)

A visco-supplementation or a pharmaceutical drug carrier in human and veterinary medicine, comprising a sterile polysaccharide solution produced with the method according to claim 1.