Stable pharmaceutical liquid formulations of the fusion protein TNFR:Fc

Patent metadata

Field	Value
Publication number	US-9453067-B2
Application number	US-201214112587-A
Country	US
Kind code	B2
Filing date	Apr 19, 2012
Priority date	Apr 20, 2011
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The present invention relates to stable pharmaceutical liquid formulations of the fusion protein TNFR:Fc comprising different buffer systems and stabilizers. In particular, it could be demonstrated that the physical stability of TNFR:Fc is significantly improved by using a citrate buffer system and lysine as stabilizer.

First claim

The invention claimed is:

1. A pharmaceutical composition, comprising TNFR:Fc, a citrate buffer and an amino acid or a pharmaceutically acceptable salt thereof, the amino acid being lysine or proline; wherein the citrate buffer is at a concentration from 25 mM to 120 mM and the amino acid is at a concentration from 15 mM to 100 mM.

2. The pharmaceutical composition of claim 1 , wherein the amino acid is lysine or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1 , further comprising a tonicity modifier, wherein the tonicity modifier is selected from the group consisting of sodium chloride, cysteine, histidine, glycine, potassium chloride, sucrose, glucose and mannitol.

4. The pharmaceutical composition of claim 3 , comprising at least one tonicity modifier at a total concentration from 5 mM to 200 mM.

5. The pharmaceutical composition of claim 1 , further comprising at least one excipient, wherein the at least one excipient is selected from the group consisting of lactose, glycerol, xylitol, sorbitol, mannitol, maltose, inositol, trehalose, glucose, bovine serum albumin (BSA), dextran, polyvinyl acetate (PVA), hydroxypropyl methylcellulose (HPMC), polyethyleneimine (PEI), gelatine, polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC), polyethylene glycol (PEG), ethylene glycol, glycerol, dimethysulfoxide (DMSO), dimethylformamide (DMF), L-serine, sodium glutamate, alanine, glycine, sarcosine, gamma-aminobutyric acid (GABA); polyoxyethylene sorbitan monolaurate, preferably Tween-20; polyoxyethylene sorbitan monooleate, preferably Tween-80; sodium dodecyl sulphate (SDS), polysorbate, polyoxyethylene copolymer, potassium phosphate, sodium acetate, ammonium sulfate, magnesium sulfate, sodium sulfate, trimethylamine N-oxide, betaine, zinc ions, copper ions, calcium ions, manganese ions, magnesium ions, CHAPS, sucrose monolaurate, and 2-O-beta-mannoglycerate.

6. The pharmaceutical composition of claim 5 , comprising the at least one excipient at a total concentration from 0.1 mM to 0.7 mM.

7. The pharmaceutical composition of claim 1 , comprising TNFR:Fc at a concentration from 0.1 mM to 0.7 mM.

8. The pharmaceutical composition of claim 1 , wherein said composition further comprises a pharmaceutically acceptable solvent.

9. The pharmaceutical composition of claim 1 , wherein the composition is lyophilized.

10. The pharmaceutical composition of claim 1 ,
consisting essentially of 0.1 mM to 0.7 mM TNFR:Fc, 25 mM to 120 mM citrate buffer, 15 mM to 100 mM lysine, 10 to 100 mM sucrose and 5 mM to 200 mM sodium chloride at a pH value of about 6.3; or
consisting essentially of 0.3 mM TNFR:Fc, 50 mM citrate buffer, 25 mM lysine, 29 mM sucrose and 75 mM sodium chloride at a pH value of about 6.3; or
consisting essentially of 0.3 mM TNFR:Fc, 25 mM citrate buffer, 25 mM lysine, 29 mM sucrose and 88 mM sodium chloride at a pH value of about 6.3; or
consisting essentially of 0.1 mM to 0.7 mM TNFR:Fc, 25 mM to 120 mM citrate buffer, 15 mM to 100 mM proline, 10 mM to 100 mM sucrose and 5 mM to 200 mM sodium chloride at a pH value of about 6.3; or
consisting essentially of 0.3 mM TNFR:Fc, 25 mM citrate buffer, 25 mM proline, 29 mM sucrose and 75 mM sodium chloride at a pH value of about 6.3.

11. The pharmaceutical composition of claim 1 , wherein TNFR:Fc is etanercept.

12. A kit comprising a composition of claim 1 and instructions for use of said composition, wherein the composition is contained in a pre-filled syringe or wherein the composition is contained in a pre-filled vial.

13. The pharmaceutical composition of claim 3 , wherein the tonicity modifier is sodium chloride, sucrose, or a combination thereof.

14. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is free of a phosphate buffer and arginine.

15. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises:
(i) 50 mM citrate and 25 mM lysine;
(ii) 25 mM citrate and 25 mM lysine; or
(iii) 25 mM citrate and 25 mM proline;

and wherein the pharmaceutical composition is free of a phosphate buffer.

16. The kit of claim 12 , wherein the composition is lyophilized and contained in a vial.

Assignees

• Deutel Britta
• Lauber Thomas
• Fuertinger Sabine
• Sandoz Ag

Inventors

• Deutel Britta
• Lauber Thomas
• Fuertinger Sabine

Classifications

• A61P37/00

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  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/00

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• A61P25/28

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