Formulation of human antibodies for treating TNF-α associated disorders

• US 8,802,102 B2
• Filed: 01/03/2014
• Issued: 08/12/2014
• Est. Priority Date: 08/16/2002
• Status: Expired due to Term

• Current Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Original Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Inventors: Krause, Hans-Juergen, Baust, Lisa, Dickes, Michael
• Primary Examiner(s): Bunner, Bridget E
• Application Number:
  US14/147,287
• Publication Number:
  US 20140127222A1
• Time in Patent Office: 221 Days
• Field of Search: None
• US Class Current: 424/158.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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: A61K 9/19 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 Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A liquid aqueous pharmaceutical formulation is described which has a high protein concentration, a pH of between about 4 and about 8, and enhanced stability.

Claims

1. A stable liquid aqueous pharmaceutical formulation comprising

(a) a human IgG1 anti-human Tumor Necrosis Factor alpha (TNFα

) antibody, or an antigen-binding portion thereof, at a concentration of 45 to 105 mg/ml,

(b) a polyol,

(c) a polysorbate at a concentration of 0.1 to 10 mg/ml, and

(d) a buffer system comprising succinate and having a pH of 4.5 to 7.0,

wherein the antibody comprises the light chain variable region and the heavy chain variable region of D2E7.

2. The formulation of claim 1, wherein the concentration of the antibody or antigen-binding portion is 50 to 100 mg/ml.

3. The formulation of claim 2, wherein the concentration of the antibody or antigen-binding portion is 50 mg/ml.

4. The formulation of claim 1, wherein the formulation has a shelf life of at least 18 months.

5. The formulation of claim 1, wherein the antibody is D2E7.

6. The formulation of claim 5, comprising:

(a) 50-100 mg/ml of the antibody or antigen-binding portion,

(b) trehalose, and

(c) 0.5-5 mg/ml of polysorbate 80,

wherein said buffer has a pH of 5.0 to 6.5.

7. The formulation of claim 5, comprising

(a) 50 mg/ml of D2E7,

(b) 7.5-15 mg/ml mannitol, and

(c) 0.5-5 mg/ml of polysorbate 80,

wherein said buffer has a pH of 4.5 to 6.0.

8. The formulation of claim 1, wherein the polyol is a sugar alcohol.

9. The formulation of claim 8, wherein the sugar alcohol is mannitol.

10. The formulation of claim 1, wherein the polyol is a sugar.

11. The formulation of claim 10 wherein the sugar is a nonreducing sugar.

12. The formulation of claim 11, wherein the nonreducing sugar is trehalose.

13. The formulation of claim 1, wherein the polysorbate is polysorbate 20.

14. The formulation of claim 1, wherein the polysorbate is polysorbate 80.

15. The formulation of claim 14, wherein the polysorbate 80 concentration is from 0.5 to 5 mg/ml.

16. The formulation of claim 14, wherein the polysorbate 80 concentration is 1 mg/ml.

17. The formulation of claim 1, wherein the pH is from 4.5 to 6.0.

18. The formulation of claim 17, wherein the pH is from 4.8 to 5.5.

19. The formulation of claim 1, which is suitable for single use subcutaneous injection.

20. The formulation of claim 1, comprising:

(a) 50-100 mg/ml of the antibody or antigen-binding portion,

(b) trehalose, and

(c) 0.5-5 mg/ml of polysorbate 80,

wherein said buffer has a pH of 5.0 to 6.5.

21. A stable liquid aqueous pharmaceutical formulation comprising

(a) 45 to 105 mg/ml of a human IgG1 anti-human Tumor Necrosis Factor alpha (hTNFα

) antibody,

(b) trehalose,

(c) 0.1-10 mg/ml of polysorbate 80, and

(d) a buffer system comprising succinate and having a pH of 4.5 to 7.0,

wherein the antibody comprises the light chain variable region and the heavy chain variable region of D2E7.

22. The formulation of claim 21, wherein the concentration of the antibody is from 50-100 mg/ml.

23. The formulation of claim 21, wherein the concentration of the antibody is 50 mg/ml.

24. The formulation of claim 21, wherein the formulation has a shelf life of at least 18 months.

25. The formulation of claim 21, wherein the antibody is D2E7.

26. The formulation of claim 21, comprising

(a) 50-100 mg/ml of the antibody,

(b) trehalose, and

(c) 0.5-5 mg/ml of polysorbate 80.

27. The formulation of claim 21, wherein the pH is from 4.5 to 6.0.

28. The formulation of claim 21, wherein the pH is from 4.8 to 5.5.

29. The formulation of claim 21, which is suitable for single use subcutaneous injection.