# US 12,109,267 B2 · Liquid pharmaceutical composition

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- Number: US 12,109,267 B2
- Document ID: US12109267B2
- Status: Granted
- Kind: B2
- Application number: 17/979,309
- Filed: 2022-11-02
- Published: 2023-10-26
- Granted: 2024-10-08
- Earliest claimed: 2014-05-23
- Assignees: Fresenius Kabi Deutschland GmbH
- Applicants: Fresenius Kabi Deutschland GmbH
- Inventors: Gianluca Rinaldi; Silvia Fratarcangeli; Alessandra Del Rio
- Web page: https://patentgrep.com/patent/US12109267B2

## CPC

- A61K 39/39591: {Stabilisation, fragmentation}
- 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 47/02: Inorganic compounds
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- 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
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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
- 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)

## Abstract

The present invention relates to novel liquid pharmaceutical compositions of adalimumab, which include adalimumab or a biosimilar thereof, an histidine buffering agent such as histidine (or histidine buffer system such as histidine/imidazolium-histidine), and a sugar stabiliser such as trehalose. Such a combination of components furnishes formulations having a stability (e.g. on storage and when exposed to stress) which is comparable to or an improvement upon those known in the art, and with fewer ingredients. Such advances will help adalimumab treatments to become more widely available at lower cost, and prolong the viability of pre-loaded delivery devices (e.g. pre-filled syringes) to reduce unnecessary waste of the drug.

## Claims

### Claim 1

A liquid pharmaceutical composition comprising:
a) adalimumab;
b) 0.77-1.55 mg/mL free histidine;
c) 15-35 mg/mL mannitol;
d) 0.05-1.5 mg/mL polysorbate 20;
e) 5-12 mg/mL salt tonicifier;
f) water for injection;
wherein the composition:
has a pH between 5.0 and 6.7; and
is free of amino acids other than histidine.

### Claim 2 (depends on 1)

The liquid pharmaceutical composition of claim 1, wherein at least 99 wt % of the composition consists of:
a) adalimumab;
a) 0.77-1.55 mg/mL free histidine;
b) 15-35 mg/mL mannitol;
c) 0.05-1.5 mg/mL polysorbate 20;
d) 5-12 mg/mL salt tonicifier;
e) water for injection;
wherein the composition:
has a pH between 5.0 and 6.7; and
is free of amino acids other than histidine.

### Claim 3 (depends on 1)

The liquid pharmaceutical composition of claim 1, wherein the salt tonicifier is a protonated histidine salt.

### Claim 4 (depends on 3)

The liquid pharmaceutical composition of claim 3, wherein the protonated histidine salt is an imidazolium histidine salt.

### Claim 5 (depends on 4)

The liquid pharmaceutical composition of claim 4, wherein the imidazolium histidine salt is histidine hydrochloride.

### Claim 6 (depends on 4)

The liquid pharmaceutical composition of claim 4, comprising free histidine in equilibrium with its imidazolium form.

### Claim 7 (depends on 1)

The liquid pharmaceutical composition of claim 1, wherein the composition has an ionic strength of 25-100 mM.

### Claim 8 (depends on 1)

The liquid pharmaceutical composition of claim 1, wherein the salt tonicifier is present at a concentration of 40-60 mM.

### Claim 9 (depends on 1)

The liquid pharmaceutical composition of claim 1, wherein the composition comprises a phosphate buffer system, wherein disodium hydrogen phosphate salts are present at a concentration of at most 0.1 mM.

### Claim 10 (depends on 1)

The liquid pharmaceutical composition of claim 1, wherein at least 99 wt % of the composition consists of:
a) adalimumab;
b) 0.77-1.55 mg/mL free histidine;
c) 15-35 mg/mL mannitol;
d) 0.05-1.5 mg/mL polysorbate 20;
e) 5-12 mg/mL histidine hydrochloride;
f) water for injection;
wherein the composition:
has a pH between 5.0 and 6.7; and
is free of amino acids other than histidine.

### Claim 11 (depends on 1)

The liquid pharmaceutical composition of claim 1, wherein at least 99 wt % of the composition consists of:
a) adalimumab;
b) 0.77-1.55 mg/mL free histidine;
c) 15-35 mg/mL mannitol;
d) 0.05-1.5 mg/mL polysorbate 20;
e) 5-12 mg/mL histidine hydrochloride;
f) a phosphate buffer system, wherein disodium hydrogen phosphate salts are present at a concentration of at most 0.1 mM;
g) water for injection;
wherein the composition:
has a pH between 5.0 and 6.7; and
is free of amino acids other than histidine.