Manufacture of Degarelix

Patent metadata

Field	Value
Publication number	US-11260102-B2
Application number	US-202016947382-A
Country	US
Kind code	B2
Filing date	Jul 30, 2020
Priority date	Jun 1, 2012
Publication date	Mar 1, 2022
Grant date	Mar 1, 2022

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.

First claim

The invention claimed is:

1. A method for modulating the viscosity of a degarelix drug substance, 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 a lyophilized degarelix drug substance,
wherein the lyophilized degarelix drug substance has a viscosity of up to 3.2 m Pas, as determined upon dissolution in an amount of 20 mg degarelix free base in 1 ml of water containing 2.5% (w/V) mannitol.

2. The method according to claim 1 , wherein the lyophilized degarelix drug substance is characterized by an acetic acid content ranging from 4.5% to 10% (w/w).

3. The method according to claim 1 , wherein the lyophilized degarelix drug substance is characterized by a water content ranging of 10% or less (w/w).

4. The method according to claim 1 , wherein the lyophilized degarelix drug substance shows an optical density of 0.10 AU or less at a concentration of 20 mg degarelix free base/ml in 2.5% (w/V) aqueous mannitol.

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

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

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

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

9. The method 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.

10. The method according to claim 9 , wherein the primary drying procedure is carried out at a primary drying temperature of about 20° C.

11. The method according to claim 9 , wherein the secondary drying procedure is carried out at a secondary drying temperature ranging from 15° C. to 25° C.

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

13. A method for modulating the viscosity of a degarelix drug substance, 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. loading the degarelix solution onto a chromatographic column;
c. eluting degarelix from the column with acetic acid at a concentration in the range of 20 to 50 wt. % to provide eluted degarelix; and
d. lyophilizing the eluted degarelix to provide the degarelix drug substance,
wherein the lyophilized degarelix drug substance has 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.

14. The method according to claim 13 , wherein the acetic acid concentration in step c is in the range of 27 to 37 wt. %.

15. The method according to claim 13 , wherein the eluted degarelix is filtered prior to lyophilization.

16. A method for modulating the viscosity of a degarelix drug substance, 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. adjusting the acetic acid concentration of the purified degarelix solution to 6 to 40% (w/w), if necessary; and
c. spray-drying the degarelix solution to provide the degarelix drug substance, wherein the degarelix drug substance has 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.

Assignees

• Ferring Bv

Inventors

• Schwach Grégoire
• Nilsson Anders
• Gottschalk Bøving Tine Elisabeth
• Rasmussen Jon Holbech
• Mörnstam Birgitta
• Tsirk Anders
• Annby Ulf
• Fomsgaard Jens

Classifications

• A61K38/09

  Luteinising hormone-releasing hormone [LHRH] {, i.e. Gonadotropin-releasing hormone [GnRH]}; Related peptides · CPC title

• C07K7/23

  Luteinising hormone-releasing hormone [LHRH]; Related peptides · CPC title

• A61K38/08 Primary

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K9/19

  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)} · CPC title

• A61K38/25

  Growth hormone-releasing factor [GH-RF], i.e. somatoliberin · CPC title