# US 10,765,721 B2 · Manufacture of Degarelix

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- Number: US 10,765,721 B2
- Document ID: US10765721B2
- Status: Granted
- Kind: B2
- Application number: 16/224,843
- Filed: 2018-12-19
- Published: 2019-07-25
- Granted: 2020-09-08
- Earliest claimed: 2012-06-01
- Assignees: Ferring B.V.
- Applicants: Ferring B.V.
- Inventors: Grégoire Schwach; Anders Nilsson; Tine Elisabeth Gottschalk Bøving; Jon Holbech Rasmussen; Birgitta Mörnstam; Anders Tsirk; Ulf Annby; Jens Fomsgaard
- Web page: https://patentgrep.com/patent/US10765721B2

## CPC

- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- 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 38/09: Luteinising hormone-releasing hormone [LHRH] {, i.e. Gonadotropin-releasing hormone [GnRH]}; Related peptides
- A61K 38/25: Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- 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
- A61P 35/00: Antineoplastic agents
- C07K 7/06: having 5 to 11 amino acids
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention provides methods for producing a lyophilized degarelix product which, upon reconstitution with water for injection in an amount of 20 mg/ml, shows a viscosity of up to 15 mPas. The present invention also provides a lyophilized degarelix drug substance which shows, upon dissolution in water in an amount of 20 mg/ml, a viscosity of up to 3.2 mPas, and processes for providing this lyophilized degarelix drug substance.

## Claims

### Claim 1

A lyophilized degarelix drug substance having a viscosity of up to 3.2 mPas, as determined upon dissolution in an amount of 20 mg degarelix free base in 1 ml of water containing 2.5% (w/V) mannitol, and the lyophilized degarelix drug substance has an acetic acid concentration ranging from 4.5% to 10.00% (w/w) and a water content of 10% (w/w) or less, wherein the lyophilized degarelix drug substance is prepared by a method, comprising:
a. purifying degarelix obtained by a liquid or solid phase peptide synthesis to obtain a degarelix solution with a purity of at least 95%, as determined by high-performance liquid chromatography (HPLC);
b. evaporating a solvent to concentrate the degarelix solution to obtain aggregated degarelix;
c. deaggregating the aggregated degarelix with acetic acid to obtain deaggregated degarelix; and
d. lyophilizing the deaggregated degarelix to provide the lyophilized degarelix drug substance.

### Claim 2 (depends on 1)

The substance according to claim 1, wherein the purity of the degarelix solution obtained in step (a) is at least 97.5%, as determined by HPLC.

### Claim 3 (depends on 1)

The substance according to claim 1, wherein step (a) further comprises a pre-concentration step comprising pre-equilibrating a pre-concentration column with a pre-equilibrating buffer; diluting the degarelix with water; loading the degarelix onto the pre-concentration column; washing the pre-concentration column with a first washing buffer comprising ethanol and aqueous ammonium acetate, and then a second washing solution comprising ethanol, acetic acid, and water; and eluting degarelix from the pre-concentration column.

### Claim 4 (depends on 1)

The substance according to claim 1, wherein the evaporating of step (b) is carried out at or below 40° C.

### Claim 5 (depends on 1)

The substance according to claim 1, wherein the deaggreagated degarelix obtained in step (c) has an acetic acid concentration ranging from 6% to 40% (v/v).

### Claim 6 (depends on 1)

The substance according to claim 1, wherein step (c) is carried out over 1 to 15 hours.

### Claim 7 (depends on 1)

The substance according to claim 1, wherein step (d) comprises a primary drying procedure and a secondary drying procedure, both of which are conducted at a pressure less than or equal to 0.5 mbar.

### Claim 8 (depends on 7)

The substance according to claim 7, wherein the primary drying procedure is carried out at a primary drying temperature of about 20° C.

### Claim 9 (depends on 7)

The substance according to claim 7, wherein the secondary drying procedure is carried out at a secondary drying temperature ranging from 15° C. to 25° C.

### Claim 10 (depends on 1)

The substance according to claim 1, wherein step (d) is carried out over a period of about 5 days.

### Claim 11

A method of preparing a lyophilized degarelix drug substance, comprising:
a. purifying degarelix as obtained by liquid or solid phase peptide synthesis to obtain a degarelix solution with a purity of at least 95%, as determined by high-performance liquid chromatography (HPLC);
b. isolating the degarelix solution via lyophilization to obtain isolated degarelix;
c. dissolving the isolated degarelix to obtain a reconstituted degarelix solution, wherein the reconstituted degarelix solution of step (c) has a degarelix concentration ranging from 10 to 20 g degarelix/L of aqueous 2% acetic acid; and
d. lyophilizing the reconstituted degarelix solution to provide the lyophilized degarelix drug substance,
wherein the lyophilized degarelix drug substance has a viscosity of less than 3.2 mPas, as determined upon dissolution in 1 mL of aqueous 2.5% (w/V) mannitol solution of an amount of the lyophilized degarelix drug substance necessary to achieve a degarelix concentration of 20 mg/mL; and wherein the lyophilized degarelix drug substance has an acetic acid concentration ranging from 4.5% to 10.00% (w/w) and a water content of 10% (w/w) or less.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the purity of the degarelix solution obtained in step (a) is at least 97.5%, as determined by HPLC.

### Claim 13

A method of preparing a degarelix drug substance, comprising the following steps a, b, and d; or a, c, and d:
a. purifying degarelix as obtained by liquid or solid phase peptide synthesis to obtain a degarelix solution with a purity of at least 95%, as determined by high-performance liquid chromatography (HPLC); and
b. evaporating a solvent to concentrate the degarelix solution to obtain aggregated degarelix and deaggregating the aggregated degarelix with acetic acid;
c. loading the degarelix solution onto a chromatographic column and eluting degarelix from the column with acetic acid;
d. isolating the degarelix via spray drying to provide the degarelix drug substance, and
wherein the degarelix drug substance has a viscosity of less than 3.2 mPas, as determined upon dissolution in 1 mL of aqueous 2.5% (w/V) mannitol solution of an amount of the degarelix drug substance necessary to achieve a degarelix concentration of 20 mg/mL; and wherein the degarelix drug substance has an acetic acid concentration ranging from 4.5% to 10.00% (w/w) and a water content of 10% (w/w) or less.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the purity of the degarelix solution obtained in step (a) is at least 97.5%, as determined by HPLC.

### Claim 15 (depends on 13)

The method according to claim 13, wherein the spray drying of step (d) comprises an inlet temperature of about 120° C., an outlet temperature of about 85° C., an atomizing air flow rate of about 600 L/h, a liquid feed rate of about 3 mL/min, and an aspirator rate of about 30 m3/h.

### Claim 16

A method of preparing a degarelix drug substance, comprising:
a. purifying degarelix as obtained by liquid or solid phase peptide synthesis to obtain a degarelix solution with a purity of at least 95%, as determined by high-performance liquid chromatography (HPLC); and
b. isolating the degarelix via spray drying to provide the degarelix drug substance, wherein the degarelix drug substance provided has a viscosity of less than 3.2 mPas, as determined upon dissolution in 1 mL of aqueous 2.5% (w/V) mannitol solution of an amount of the degarelix drug substance necessary to achieve a degarelix concentration of 20 mg/mL; and wherein said degarelix drug substance has an acetic acid concentration ranging from 4.5% to 10.00% (w/w) and a water content of 10% (w/w) or less.

### Claim 17 (depends on 11)

A lyophilized degarelix drug substance prepared by the method according to claim 11.

### Claim 18 (depends on 13)

A lyophilized degarelix drug substance prepared by the method according to claim 13.

### Claim 19 (depends on 16)

A lyophilized degarelix drug substance prepared by the method according to claim 16.