# US 8,465,739 B2 · Stable aqueous pharmaceutical formulations of daclizumab antibodies

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- Number: US 8,465,739 B2
- Document ID: US8465739B2
- Status: Granted
- Kind: B2
- Application number: 13/226,372
- Filed: 2011-09-06
- Published: 2011-12-29
- Granted: 2013-06-18
- Earliest claimed: 2001-11-08
- Assignees: AbbVie Biotherapeutics Inc.
- Applicants: Elizabet A. Kaisheva; Supriya Gupta; Shanti G. Duvur; Malathy Subramanian
- Inventors: Elizabet A. Kaisheva; Supriya Gupta; Shanti G. Duvur; Malathy Subramanian
- Web page: https://patentgrep.com/patent/US8465739B2

## CPC

- C07K 16/249: {Interferons}
- 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)}
- A61K 39/39591: {Stabilisation, fragmentation}
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 16/244: {Interleukins [IL]}
- C07K 16/246: {IL-2}
- C07K 16/2854: {against selectins, e.g. CD62}
- 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
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention is directed to a stable liquid pharmaceutical formulation comprising a high concentration, e.g. 50 mg/ml or more, of antibody in about 20-60 mM succinate buffer or 30-70 mM histidine buffer, having pH from about pH 5.5 to about pH 6.5, about 0.01-0.1% polysorbate, and a tonicity modifier that contributes to the isotonicity of the formulation. This liquid formulation is stable at refrigerated temperature (2-8° C.) for at least 1 year, and preferably 2 years. This liquid formulation is suitable for subcutaneous injection. The preferred antibodies include Daclizumab, a humanized anti-IL-2 receptor monoclonal antibody; HAIL-12, a humanized anti-IL-12 monoclonal antibody; HuEP5C7, a humanized anti-L selectin monoclonal antibody; and Flintozumab, a humanized anti-gamma interferon monoclonal antibody.

## Claims

### Claim 1

A stable aqueous pharmaceutical formulation, comprising:
about 20 mM to about 60 mM succinate buffer,
about 0.01% to about 0.1% polysorbate,
about 75 mM to about 150 mM sodium chloride, and
at least about 100 mg/ml of a daclizumab antibody,
wherein said aqueous pharmaceutical formulation has a pH in the range of about pH 5.5 to about pH 6.5; and
wherein the daclizumab in said aqueous pharmaceutical formulation shows no more than 10% aggregation after 3 months at room temperature as measured by size exclusion chromatography.

### Claim 2 (depends on 1)

The stable aqueous pharmaceutical formulation of claim 1 in which the polysorbate is polysorbate 80.

### Claim 3 (depends on 1)

The stable aqueous pharmaceutical formulation of claim 1 in which the succinate buffer is sodium succinate.

### Claim 4 (depends on 1)

The stable aqueous pharmaceutical formulation of claim 1 which has a pH of about pH 6.0.

### Claim 5 (depends on 1)

The stable aqueous pharmaceutical of claim 1, in which the amount of polysorbate is about 0.01% to about 0.05%.

### Claim 6 (depends on 1)

The stable aqueous pharmaceutical of claim 1, in which the amount of polysorbate is about 0.02% to about 0.04%.

### Claim 7 (depends on 1)

The stable aqueous pharmaceutical formulation of claim 1, wherein the daclizumab in said aqueous pharmaceutical formulation shows no more than 5% aggregation after 3 months at room temperature as measured by size exclusion chromatography.

### Claim 8 (depends on 1)

The stable aqueous pharmaceutical formulation of claim 1, wherein the daclizumab in said aqueous pharmaceutical formulation shows no more than 10% aggregation after 6 months at room temperature as measured by size exclusion chromatography.

### Claim 9 (depends on 1)

The stable aqueous pharmaceutical formulation of claim 1, wherein the daclizumab in said aqueous pharmaceutical formulation shows no more than 5% aggregation after 6 months at room temperature as measured by size exclusion chromatography.