Ferring B.v.

Polypeptide Laboratories A/s

Jon Holbech Rasmussen

Jens Fomsgaard

Anders Nilsson

Ulf Annby

Birgitta Mörnstam

Anders Tsirk

Grégoire Schwach

Tine Elisabeth Gottschalk Bøving

Stefan Hansen

Palle H Rasmussen

Palle Hedengran Rasmussen

Wolfgang Oliver Wachs

Wolfgang O Wachs

Tine Elisabeth Gottschalk Boeving

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, a and processes for providing this lyophilized degarelix drug substance.

Manufacture of degarelix

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.

Manufacture of Degarelix

The present invention relates to a liquid (or solution)-phase manufacturing process for preparing the decapeptide Degarelix, its protected precursor, and other useful intermediates. The invention further relates to polypeptides useful in the solution-phase manufacturing process and to the purification of Degarelix itself. Degarelix can be obtained by subjecting a Degarelix precursor according to formula (II): (P)AA-AA-AA-AA(P)-AA-AA(P)-AA-AA(P)-AA-AA-NH(II) or a salt or solvate thereof, to a treatment with a cleaving agent in an organic solvent, wherein Pis an amino protecting groups; preferably acetyl; Pis hydrogen or a hydroxy! protecting group, preferably a hydroxyl protecting group; Pis hydrogen or an amino protecting groups; preferably an amino protecting groups; and Pis an amino protecting group.

Process for the manufacture of Degarelix and its intermediates

The peptides Ac-D-2Nal-D-4ClPhe-D-3Pal-OH and Boc-D-2Nal-D-4ClPhe-D-3Pal-OH are intermediates useful in the synthesis of LHRH analogs by coupling with suitable heptapeptides, in particular with the heptapeptides P-Ser(P)-MMeTry(P)-D-Lys(Nic)-Leu-Lys(iPr,P)-Pro-D-AlaNHand P-Ser(P)-NMeTry(P)-D-Asn-Leu-Lys(iPr,P)-Pro-D-AlaNH.

Intermediates for LHRH antagonist synthesis, process for the production, and process for LHRH antagonist production

A nona- or decapeptide is purified from residual organic solvent by dissolving in a solvent comprising water and at least one C&#x2013;Calcohol followed by precipitation into a vigorously stirred solvent consisting of an alkyl ester of a carboxylic acid, the ester comprising from 3 to 6 carbon atoms, and one or several non-polar compounds selected from hexane, heptane, octane, cyclohexane, methylcyclohexane, and, optionally, of up to 5% of acetic or propionic acid, isolating the precipitated nona- or decapeptide, followed by washing with a mixture of C&#x2013;Cesters and drying, with the provisio that the water content of the solvent comprising water and the at least one alcohol is below 8% (v/v), and that the volume ratio of the dissolution solvent mixture and the precipitation solvent mixture is 1:10 or higher. Also described is the monoacetate of Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH.

Peptide purification

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Jon Holbech Rasmussen