Stable liquid formulations of antibodies

• US 7,740,842 B2
• Filed: 01/24/2006
• Issued: 06/22/2010
• Est. Priority Date: 05/31/2001
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Fauquex, Pierre F, Arvinte, Tudor
• Primary Examiner(s): Szperka; Michael
• Assistant Examiner(s): Kim; Yunsoo
• Application Number:
  US11/338,138
• Publication Number:
  US 20060127395A1
• Time in Patent Office: 1,610 Days
• Field of Search: None
• US Class Current: 424/130.1
• 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 E25 anti-IgE antibody at a concentration of at least 80 mg/ml, and further comprising acetic acid at a concentration of at least 0.001%.

3. The stable aqueous solution of claim 1, wherein the acetic acid is present in a final concentration of at least about 0.01%.

4. The stable aqueous solution of claim 1 wherein the pH of said aqueous solution is above pH 3.

5. The stable aqueous solution of claim 1 wherein the pH of said aqueous solution is between pH 3 and about pH 6.

6. The stable aqueous solution of claim 1 wherein less than 5% of the E25 is present as aggregates after storage for at least 1 month at 30°

C. and/or at least 1 year at about 4°

C.

7. The stable aqueous solution of claim 1, further including CaCl₂.

8. The stable aqueous solution of claim 1, further including MgCl₂.

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

10. The stable aqueous solution of claim 9, wherein the additive is polysorbate.

11. The stable aqueous solution of claim 9, wherein the additive is a sugar.

12. The stable aqueous solution of claim 11, wherein the sugar is selected from the group consisting of trehalose, sucrose, mannitol, sorbitol, fructose, maltose, lactose and dextran.

13. The stable aqueous solution of claim 9, wherein the additive is a buffering agent.

14. The stable aqueous solution of claim 1 wherein said aqueous solution is isotonic.

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

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

17. The slow release formulation of claim 16 selected from the group consisting of polymeric nanoparticles, polymeric microparticles, and gels.

18. The slow release formulation of claim 17, wherein the gel is a hyaluronic acid gel.

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

20. A process for the preparation of an aqueous solution according to claim 1, which process comprises admixing an E25 anti-IgE antibody with an acetic acid acidic component.

25. The process of claim 20, wherein the acidic component is present in a final concentration of at least 0.001%.

26. The process of claim 20, wherein the pH of said aqueous solution is above pH 3.

27. The process of claim 20, wherein the pH of said aqueous solution is between pH 3 and about pH 6.

2. A stable aqueous solution comprising an E25 anti-IgE antibody at a concentration of at least 80 mg/ml and acetic acid, wherein the stable aqueous solution does not contain sodium acetate.

21. A process for the preparation of a therapeutic liquid formulation comprising an E25 anti-IgE antibody, wherein in a first step an aqueous solution including an E25 anti-IgE antibody at a concentration of at least 80 mg/ml and acetic acid at a concentration of at least 0.01% is prepared, and, in a second step, at least one pharmaceutically acceptable additive is added to said aqueous solution.

22. A process for the preparation of a therapeutic liquid formulation comprising an E25 anti-IgE antibody at a concentration of more than 80 mg/ml, wherein

in a first step an E25 anti-IgE antibody solution in a suitable buffer is concentrated to a concentration of between about 10 mg/ml and 80 mg/ml;

in a second step, the concentrated solution obtained in the first step is diafiltered with an aqueous solution of acetic acid, 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 80 mg/ml.

23. A process for the preparation of a therapeutic liquid formulation comprising an E25 anti-IgE antibody at a concentration of more than 80 mg/ml, wherein

in a first step an E25 anti-IgE antibody solution in a suitable buffer is concentrated to a concentration of between about 10 mg/ml and 80 mg/ml;

in a second step, the concentrated solution obtained in the first step is diafiltered with an aqueous solution of acetic acid;

in a third step, the solution obtained in the second step is further concentrated to an intermediate concentration of between about 100 and 150 mg/ml E25 anti-IgE antibody;

in a fourth step, the intermediate concentrated solution obtained in the third step is diafiltered with an aqueous solution of acetic acid 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 E25 anti-IgE antibody.

24. The process of claim 23, 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.

28. A therapeutic liquid formulation obtained by preparing an aqueous solution including an E25 anti-IgE antibody at a concentration of at least 80 mg/ml and acetic acid at a concentration of at least 0.01%;

and adding at least one pharmaceutically acceptable additive to said aqueous solution.

29. The therapeutic liquid formulation of claim 28 wherein less than 5% of the E25 is present as aggregates after storage for at least 1 month at 30°

C. and/or at least 1 year at about 4°

C.

30. The therapeutic liquid formulation of claim 28, further including CaCl₂ at a concentration of between about 50 mM and 200 mM.

31. The therapeutic liquid formulation of claim 28, further including MgCl₂ at a concentration of between about 50 mM and 200 mM.

32. The therapeutic liquid formulation of claim 28, further including at least one additive.

33. The therapeutic liquid formulation of claim 32, wherein the additive is polysorbate.

34. The therapeutic liquid formulation of claim 32, wherein the additive is a sugar.

35. The therapeutic liquid formulation of claim 34, wherein the sugar is selected from the group consisting of trehalose, sucrose, mannitol, sorbitol, fructose, maltose, lactose and dextran.

36. The therapeutic liquid formulation of claim 32, wherein the additive is a buffering agent.

37. The therapeutic liquid formulation of claim 28, wherein said liquid formulation is isotonic.

38. A process for the preparation of a therapeutic liquid formulation comprising an anti-IgE E25 antibody, which process comprises adding acetic acid on the last purification step of the preparation of said antibody.

39. A stable aqueous solution, comprising:

(i) an E25 anti-IgE antibody at a concentration of at least 80 mg/ml, (ii) acetic acid and (iii) CaCl₂ and/or MgCl₂.

40. The stable aqueous solution of claim 39, wherein the concentration of CaCl₂ is between about 50 mM and 200 mM.

41. The stable aqueous solution of claim 39, wherein the concentration of MgCl₂ is between about 50 mM and 200 mM.

42. The stable aqueous solution of claim 39, wherein the acetic acid is present in a final concentration of at least 0.001%.

43. The stable aqueous solution of claim 39, wherein the acetic acid is present in a final concentration of at least 0.01%.

44. A method of treating an allergic disease in a patient, comprising administering to the patient an effective amount of the stable aqueous solution according to claim 39.