Stable liquid formulations of antibodies

• US 20060127395A1
• Filed: 01/23/2006
• Published: 06/15/2006
• Est. Priority Date: 05/31/2001
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Fauquex, Pierre Francois, Arvinte, Tudor
• Granted Patent: US 7,740,842 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: 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
• CPC Class Codes: 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
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07K 16/4291 against IgE

Abstract

The present invention provides stable liquid formulations of antibodies suitable for parenteral administration. Also, provided are aqueous solutions which have high concentrations of therapeutical antibodies which may be used to produce therapeutical liquid formulations. The present invention also relates to uses, such as medical uses, of the stable liquid formulations and processes for the production of the stable liquid formulations.

Claims

1. A stable aqueous solution comprising an antibody at a concentration of at least 50 mg/ml, and further comprising at least one acidic component.

2. The aqueous solution of claim 1 comprising an antibody at a concentration of at least 50 mg/ml and an acidic component.

3. The aqueous solution of claim 1, wherein the acidic component is present in a final concentration of at least 0.001%.

4. The aqueous solution of claim 1 wherein the acidic component is acetic acid.

5. The aqueous solution of claim 1 wherein the pH of said aqueous solution is above pH3.

6. The aqueous solution of claim 1 wherein the antibody has an isoelectric point between pH 6 and pH 8.

7. The aqueous solution of claim 1 wherein the antibody is selected from anti-IgE antibodies E25, E26, E27 or their biologically active fragments or derivatives.

8. The aqueous solution of claim 1 having a stability of at least 1 year at about 4°

C.

9. The aqueous solution of claim 1, further including CaCl2.

10. The aqueous solution of claim 1, further including MgCl2.

11. The aqueous solution of claim 1, further including at least one additive.

12. The aqueous solution of claim 11, wherein the additive is Tween 20.

13. The aqueous solution of claim 11, wherein the additive is a sugar.

14. The aqueous solution of claim 13, wherein the sugar is selected from the group of trehalose, sucrose, mannitol, sorbitol, fructose, maltose, lactose or a dextran.

15. The aqueous solution of claim 11, wherein the additive is a buffering agent.

16. The aqueous solution of claim 1 wherein said aqueous solution is isotonic.

17. A nasal spray comprising the aqueous solution as claimed in claim 1.

18. A slow release formulation comprising the aqueous solution as claimed in claim 1.

19. The slow release formulation of claim 18 selected from the group of polymeric nano- or microparticles, or from gels.

20. The slow release formulation of claim 19, wherein the gel is a hylauronic acid gel.

21. A delivery system which contains the aqueous solution as claimed in claim 1, selected from the group of single use injection syringes or inhalation devices.

22. Use of the aqueous solution according to claim 1 for the production of a delivery system for the treatment of a disease.

24. Use of the aqueous solution according to claim 1 in a drying or freeze-drying process.

25. A process for the preparation of a aqueous solution according to claim 1, which process comprises admixing an antibody with an acidic component.

30. The process of claim 25, wherein the acidic component is present in a final concentration of at least 0.001%.

31. The process of claim 25, wherein the acidic component is acetic acid.

32. The process of claim 25, wherein the pH of said aqueous solution is above pH3.

33. The process of claim 25, wherein the antibody has an isoelectric point between pH 6 and pH 8.

34. The process of claim 25, wherein the antibody is selected from anti-IgE antibodies E25, E26, E27 or their biologically active fragments or derivatives.

47. The aqueous solution according to claim 1 for L use in medicine.

48. Use of an aqueous solution according to claim 1 for the manufacture of a medicament for the treatment of disease.

49. Use of an aqueous solution according to claim 1 for the manufacture of a medicament for the treatment of an allergic disease.

23. Use of an acidic component for the preparation of an aqueous solution comprising an antibody having a concentration of at least 50 mg/ml.

26. A process for the preparation of a therapeutical liquid formulation comprising an antibody, wherein in a first step an aqueous solution including an antibody at a concentration of at least 50 mg/ml and at least one acidic component is prepared, and, in a second step, at least one pharmaceutically acceptable additive is added to said aqueous solution.

35. A therapeutical liquid formulation obtained by a process of claim 26.

36. A therapeutical liquid formulation obtainable by a process of claim 26.

37. The therapeutical liquid formulation of claim 35 having a stability of at least 1 year at about 4°

C.

38. The therapeutical liquid formulation of claim 35, further including CaCl2 at a concentration of between 50 mM and 200 mM.

39. The therapeutical liquid formulation of claim 35, further including MgCl2 at a concentration of between 50 mM and 200 mM.

40. The therapeutical liquid formulation of claim 35, further including at least one additive.

41. The therapeutical liquid formulation of claim 40, wherein the additive is Tween 20.

42. The therapeutical liquid formulation of claim 40, wherein the additive is a sugar.

43. The therapeutical liquid formulation of claim 42, wherein the sugar is selected from the group of trehalose, sucrose, mannitol, sorbitol, fructose, maltose, lactose or a dextran.

44. The therapeutical liquid formulation of claim 40, wherein the additive is a buffering agent.

45. The therapeutical liquid formulation of claim 35, wherein said liquid formulation is isotonic.

27. A process for the preparation of a therapeutical liquid formulation comprising an antibody at a concentration of more than 50 mg/ml, wherein

in a first step an antibody solution in a suitable buffer is concentrated to a concentration of between about 10 mg/ml and about 50 mg/ml;

in a second step, the concentrated solution obtained in the first step is diafiltered with an aqueous solution of at least one acidic component, optionally containing MgCl2 and/or CaCl2 and/or further suitable additives; and

,

in a third step, the solution obtained in the second step is further concentrated to a concentration of more than 50 mg/ml.

28. A process for the preparation of a therapeutical liquid formulation comprising an antibody at a concentration of more than 50 mg/ml, wherein

in a first step an antibody solution in a suitable buffer is concentrated to a concentration of between about 10 mg/ml and about 50 mg/ml;

in a second step, the concentrated solution obtained in the first step is diafiltered with an aqueous solution of at least one acidic component;

in a third step, the solution obtained in the second step is further concentrated to an intermediate concentration of between about 100 and about 200 mg/ml;

in a fourth step, the intermediate concentrated solution obtained in the third step is diafiltered with an aqueous solution of at least one acidic component and further containing MgCl2 and/or CaCl2 and/or further suitable additives; and

,

in a fifth step, the solution obtained in the fourth step is further concentrated to a concentration of more than 150 mg/ml.

29. The process of claim 28, wherein between the third and fourth step a solution of MgCl2 and/or CaCl2 and/or further suitable additives is directly added to the intermediate concentrated solution obtained in the third step.

46. A process for the preparation of a therapeutical liquid formulation comprising an antibody, which process comprises adding an acidic component on the last purification step of the preparation of said antibody.