High concentration anti-TNFα antibody liquid formulations

• US 8,821,865 B2
• Filed: 11/11/2011
• Issued: 09/02/2014
• Est. Priority Date: 11/11/2010
• Status: Active Grant

• Current Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Original Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Inventors: Neu, Michael, Tschoepe, Markus, Weber, Carsten, Fraunhofer, Wolfgang, Redden, Laura, Gastens, Martin, Feick, Alexander
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US13/294,692
• Publication Number:
  US 20120263731A1
• Time in Patent Office: 1,026 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 47/26 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/90 : characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• 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

The invention provides a liquid aqueous pharmaceutical formulation comprising a human anti-TNFa antibody, or antigen-binding portion thereof, which reduces pain associated with injection in a subject by at least about 50% when compared to injecting an otherwise identical formulation comprising at least one salt and/or at least one buffer. The invention also provides a liquid aqueous pharmaceutical formulation comprising a human anti-TNFa antibody, or antigen-binding portion thereof, having increased bioavailability upon subcutaneous administration into a subject. The formulation may comprise a therapeutic protein, such as a human anti-TNF-alpha antibody, or an antigen-binding portion thereof, or a biosimilar thereof.

Claims

1. A liquid aqueous formulation comprising:

(1) 100 mg/ml of adalimumab;

(2) 1.0 mg/ml of polysorbate-80; and

,

(3) 42 mg/ml of mannitol;

wherein the formulation has a pH of 4.7 to 5.7 and does not contain a buffer or a salt, and wherein injection of the formulation into a human subject results in a Pain Visual Analog Scale (VAS) score of less than 1.0.

11. A pre-filled syringe or autoinjector device, comprising the formulation of any one of claims 1-7, 8, 9 and 10.

2. A liquid aqueous formulation comprising:

(1) 100 mg/ml of adalimumab;

(2) 1.0 mg/ml of polysorbate-80; and

,

(3) 42 mg/ml of mannitol;

wherein the formulation has a pH of 4.7 to 5.7 and does not contain a buffer or a salt, and

wherein injection of the formulation reduces pain associated with the injection in a human subject by at least about 50% when compared to injection of an otherwise identical formulation that comprises a salt and/or a buffer.

4. The formulation of claim 2, wherein the pain associated with the injection is assessed using a Pain Visual Analog Scale (VAS).

5. The formulation of claim 2, wherein the otherwise identical formulation comprises a citrate phosphate buffer and sodium chloride.

3. A liquid aqueous formulation consisting essentially of:

(1) 100 mg/ml of adalimumab;

(2) 1.0 mg/ml of polysorbate-80; and

(3) 42 mg/ml of mannitol,

wherein the formulation has a pH of 4.7 to 5.7, and wherein injection of the formulation into a human subject results in a Pain Visual Analog Scale (VAS) score of less than 1.0.

6. A liquid aqueous formulation comprising:

(1) 100 mg/ml of adalimumab;

(2) 1.0 mg/ml of polysorbate-80; and

,

(3) 42 mg/ml of mannitol;

wherein the formulation has a pH of 4.7 to 5.7, and wherein the formulation is stable up to about 30°

C. for at least 6 days.

7. The formulation of claim 6, wherein the formulation is stable up to about 30°

C. for 10 days.

8. A liquid aqueous formulation comprising:

(1) 100 mg/ml of adalimumab;

(2) 1.0 mg/ml of polysorbate-80; and

,

(3) 42 mg/ml of mannitol;

wherein the formulation has a pH of 4.7 to 5.7, and wherein the formulation has a characteristic selected from the group consisting of;

a) a conductivity of less than about 2 mS/cm;

b) a hydrodynamic diameter (D_h) which is at least about 50% less than the D_h of the protein in a buffered solution at a given concentration; and

c) a hydrodynamic diameter (D_h) of less than about 4 nm.

9. A liquid aqueous formulation consisting essentially of 1.0 mg/ml of polysorbate-80 and 40 mg of adalimumab,

wherein the concentration of adalimumab is 100 mg/ml, and

wherein the formulation has a pH of 4.7 to 5.7, and

wherein the formulation provides increased bioavailability of the adalimumab to a human subject upon subcutaneous injection of the formulation relative to a formulation comprising a citrate phosphate buffer, sodium chloride, and mannitol.

10. A liquid aqueous formulation consisting essentially of 1.0 mg/ml of polysorbate-80 and 40 mg of adalimumab, wherein the formulation has an adalimumab concentration of 100 mg/ml a pH of 4.7-5.7, and

wherein the formulation provides increased bioavailability of adalimumab in a human subject upon subcutaneous injection of the formulation, such that adalimumab has an area under the curve, 0-360 minutes (AUC_0-360) greater than 1300 μ

g/hr/ml.