# US 10,307,483 B2 · Pharmaceutical formulations and methods of making the same

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- Number: US 10,307,483 B2
- Document ID: US10307483B2
- Status: Granted
- Kind: B2
- Application number: 15/958,261
- Filed: 2018-04-20
- Published: 2018-09-13
- Granted: 2019-06-04
- Earliest claimed: 2016-10-21
- Assignees: Amgen Inc.
- Applicants: Amgen Inc.
- Inventors: Monica Goss; Nicole Ball
- Web page: https://patentgrep.com/patent/US10307483B2

## CPC

- A61K 38/1793: {for cytokines; for lymphokines; for 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 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 39/39591: {Stabilisation, fragmentation}
- 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
- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07K 14/7151: {for tumor necrosis factor [TNF], for lymphotoxin [LT]}
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/32: fusions with soluble part of a cell surface receptor, "decoy receptors"
- 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 invention relates to the formulation of pharmaceutical compositions of etanercept. The invention also relates to methods of removing buffer and of formulating pharmaceutical compositions of etanercept.

## Claims

### Claim 1

A pharmaceutical composition comprising between 75 mM and 150 mM NaCl, between 5 mM and 100 mM arginine, between 0.5% and 2% (w/v) sucrose, and between 40 mg/mL and 100 mg/mL etanercept, wherein the pharmaceutical composition comprises less than 2.0 mM total additional buffering agent, and the pH of the composition is between 6.1 and 6.5.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises less than 1.5 mM total additional buffering agent.

### Claim 3 (depends on 2)

The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises less than 1.0 mM total additional buffering agent.

### Claim 4 (depends on 2)

The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises less than 0.5 mM total additional buffering agent.

### Claim 5 (depends on 2)

The pharmaceutical composition of claim 2, wherein the pharmaceutical formulation comprises less than 0.25 mM total additional buffering agent.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5, wherein the arginine is L-arginine.

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6 comprising about 50 mg/mL etanercept, about 120 mM NaCl, about 25 mM L-arginine hydrochloride, and about 1% (w/v) sucrose.

### Claim 8 (depends on 7)

The pharmaceutical composition of claim 7, wherein less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography after two weeks' storage at approximately 25° C.

### Claim 9 (depends on 7)

The pharmaceutical composition claim 7, wherein etanercept consists of a dimer of the amino acid sequence of SEQ ID NO: 1.

### Claim 10 (depends on 2)

The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises 0.1 mM or less total additional buffering agent.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10, wherein the arginine is L-arginine.

### Claim 12 (depends on 11)

The pharmaceutical composition claim 11, wherein etanercept consists of a dimer of the amino acid sequence of SEQ ID NO: 1.

### Claim 13 (depends on 11)

The pharmaceutical composition of claim 11 comprising about 50 mg/mL etanercept, about 120 mM NaCl, about 25 mM L-arginine hydrochloride, and about 1% (w/v) sucrose.

### Claim 14 (depends on 13)

The pharmaceutical composition claim 13, wherein etanercept consists of a dimer of the amino acid sequence of SEQ ID NO: 1.

### Claim 15 (depends on 13)

The pharmaceutical composition of claim 13, wherein said pharmaceutical composition maintains a pH of between about 6.1 and about 6.5 for at least two weeks during said storage at approximately 25° C.

### Claim 16 (depends on 15)

The pharmaceutical composition claim 15, wherein etanercept consists of a dimer of the amino acid sequence of SEQ ID NO: 1.

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1, wherein the arginine is L-arginine.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein the L-arginine is L-arginine hydrochloride.

### Claim 19 (depends on 17)

The pharmaceutical composition of claim 17, wherein the L-arginine is L-arginine base.

### Claim 20 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition maintains a pH between 6.1 and 6.5 when stored at controlled room temperature (CRT) for 2 weeks.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, wherein the pharmaceutical composition maintains a pH between about 6.2 and about 6.3 when stored at controlled room temperature (CRT) for 2 weeks.

### Claim 22 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition maintains a pH of between 5.8 and 6.7 for at least two weeks when stored at approximately 25° C. and wherein less than 6% of the total etanercept is aggregated in a high molecular weight form as assessed using size exclusion chromatography.

### Claim 23 (depends on 1)

The pharmaceutical composition of claim 1, wherein said pharmaceutical composition maintains a pH of between about 6.1 and about 6.5 for at least two weeks during said-storage at approximately 25° C.

### Claim 24 (depends on 1)

The pharmaceutical composition of claim 1, wherein said pharmaceutical composition maintains a pH of between about 6.2 and about 6.4 for at least two weeks during said-storage at approximately 25° C.

### Claim 25 (depends on 1)

The pharmaceutical composition of claim 1, wherein less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography after two weeks' storage at approximately 25° C.

### Claim 26 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has an osmolality of about 180 to about 420 milliosmolals.

### Claim 27 (depends on 26)

The pharmaceutical composition of claim 26, wherein the pharmaceutical composition has an osmolality of about 250 to about 350 milliosmolals.

### Claim 28 (depends on 27)

The pharmaceutical composition of claim 27, wherein the pharmaceutical composition has an osmolality of about 290 to about 310 milliosmolals.

### Claim 29 (depends on 28)

The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has an osmolality of about 300 to about 310 milliosmolals.

### Claim 30 (depends on 1)

The pharmaceutical composition of claim 1 consisting essentially of about 50 mg/mL etanercept, about 120 mM NaCl, about 25 mM L-arginine hydrochloride, about 1% (w/v) sucrose and water.

### Claim 31 (depends on 30)

The pharmaceutical composition of claim 30, wherein said pharmaceutical composition maintains a pH of between about 6.1 and about 6.5 for at least two weeks during said storage at approximately 25° C.

### Claim 32 (depends on 30)

The pharmaceutical composition of claim 30, wherein less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography after two weeks' storage at approximately 25° C.

### Claim 33 (depends on 30)

The pharmaceutical composition claim 30, wherein etanercept consists of a dimer of the amino acid sequence of SEQ ID NO: 1.

### Claim 34 (depends on 1)

The pharmaceutical composition of claim 1 consisting of about 50 mg/mL etanercept, about 120 mM NaCl, about 25 mM L-arginine hydrochloride, about 1% (w/v) sucrose, and water.

### Claim 35 (depends on 34)

The pharmaceutical composition of claim 34, wherein said pharmaceutical composition maintains a pH of between about 6.1 and about 6.5 for at least two weeks during said storage at approximately 25° C.

### Claim 36 (depends on 34)

The pharmaceutical composition of claim 34, wherein less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography after two weeks' storage at approximately 25° C.

### Claim 37 (depends on 34)

The pharmaceutical composition claim 34, wherein etanercept consists of a dimer of the amino acid sequence of SEQ ID NO: 1.

### Claim 38 (depends on 1)

The pharmaceutical composition of claim 1, further comprising polysorbate 20.

### Claim 39 (depends on 38)

The pharmaceutical composition of claim 38, wherein the polysorbate 20 concentration (w/v) is between about 0.001% and about 0.1%.

### Claim 40 (depends on 39)

The pharmaceutical composition of claim 39, wherein the polysorbate 20 concentration (w/v) is about 0.005%, about 0.01%, or about 0.015%.

### Claim 41 (depends on 1)

The pharmaceutical composition claim 1, wherein etanercept consists of a dimer of the amino acid sequence of SEQ ID NO: 1.

### Claim 42 (depends on 1)

The pharmaceutical composition of claim 1, wherein said solution maintains a pH of between about 6.1 and about 6.5 for at least two weeks during said storage at approximately 25° C., and wherein less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography after two weeks' storage at approximately 25° C.

### Claim 43 (depends on 1)

A kit comprising the pharmaceutical composition of claim 1 in a drug product form and instructions for storage and use.

### Claim 44 (depends on 1)

A single-dose container containing the pharmaceutical composition of claim 1.

### Claim 45 (depends on 44)

The single-dose container of claim 44, wherein said single dose container is a vial, a syringe, or an autoinjector.

### Claim 46 (depends on 44)

The single-dose container of claim 44, containing an aqueous formulation consisting of etanercept at 50.0 mg/mL, sodium chloride at 120 mM, L-arginine hydrochloride at 25 mM, and sucrose at 1.0% (w/v).