# US 2013/0156760 A1 · Protein Formulations and Methods of Making Same

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- Number: US 2013/0156760 A1
- Document ID: US20130156760A1
- Status: Published application
- Kind: A1
- Application number: 13/774,735
- Filed: 2013-02-22
- Published: 2013-06-20
- Earliest claimed: 2007-11-30
- Assignees: AbbVie Inc.
- Inventors: Wolfgang FRAUNHOFER; Annika BARTL; Hans-juergen KRAUSE; Markus TSCHOEPE; Katharina KALETA
- Web page: https://patentgrep.com/patent/US20130156760A1

## 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 9/08: Solutions {(composition of solutions A61K47/00)}
- 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)}
- A61K 38/21: Interferons {[IFN]}
- A61K 38/385: {Serum albumin}
- A61K 38/46: Hydrolases (3)
- A61K 38/4893: {Botulinum neurotoxin (3.4.24.69)}
- A61K 38/50: acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- C07K 1/34: by filtration, ultrafiltration or reverse osmosis
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 16/244: {Interleukins [IL]}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- 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)
- 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 provides an aqueous formulation comprising water and a protein, and methods of making the same. The aqueous formulation of the invention may be a high protein formulation and/or may have low levels of conductity resulting from the low levels of ionic excipients. Also included in the invention are formulations comprising water and proteins having low osmolality.

## Claims

### Claim 1

An aqueous formulation comprising a protein and water, wherein the formulation has a conductivity of less than about 2.5 mS/cm and the protein has a molecular weight (Mw) greater than about 47 kDa.

### Claim 2

An aqueous formulation comprising a protein at a concentration of at least about 10 ng/mL and water, wherein the formulation has a conductivity of less than about 2 mS/cm.

### Claim 3

An aqueous formulation comprising a protein at a concentration of at least about 50 mg/mL and water wherein the formulation has an osmolality of no more than about 30 mOsmol/kg.

### Claim 4

An aqueous formulation comprising water and a given concentration of a protein, wherein the protein has a hydrodynamic diameter (Dh) which is either at least about 50% less than the Dh of the protein in a buffered solution at the given concentration or the protein has a hydrodynamic diameter (Dh) of less than about 4 nm.

### Claim 5 (depends on 4)

The formulation of claim 4, wherein the Dh of the protein is at least about 50% less than the Dh of the protein in phosphate buffered saline (PBS) at the given concentration.

### Claim 6 (depends on 1, 2, 3, 4)

The formulation of any one of claims 1-4, wherein the protein is an antibody, or an antigen-binding fragment thereof.

### Claim 7 (depends on 6)

The formulation of claim 6, wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb).

### Claim 8 (depends on 6)

The formulation of claim 6, wherein the antibody, or antigen-binding fragment thereof, is an anti-TNFα or an anti-IL-12 antibody.

### Claim 9 (depends on 6)

The formulation of claim 6, wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of adalimumab, alemtuzumab, CEA-Scan Arcitumomab (fab fragment), cetuximab, trastuzumab, imciromab pentetate), capromab pendetide, infliximab), abciximab, rituximab, basiliximab, palivizumab, nofetumomab, omalizumab, daclizumab, ibritumomab tiuxetan, muromonab-CD3, edrecolomab, gemtuzumab ozogamicin), golimumab, certolizumab pegol, eculizumab, ustekinumab, panitumumab, tositumomab and I131 tositumomab, and bevacizumab.

### Claim 10 (depends on 1, 2, 3, 4)

The formulation of any one of claims 1-4, wherein the protein is a therapeutic protein.

### Claim 11 (depends on 10)

The formulation of claim 10, wherein the therapeutic protein is selected from the group consisting of dornase alfa, Rebif, becaplermin, alteplase, laronidase, alefacept, darbepoetin alfa, Becaplermin Concentrate, interferon beta-1b, Botulinum Toxin Type A, rasburicase, asparaginase, epoetin alfa), etanercept, agalsidase beta, interferon alfacon-1, interferon alfa-2a, anakinra), Botulinum Toxin Type B, pegfilgrastim, oprelvekin, filgrastim, denileukin diftitox, peginterferon alfa-2a, aldesleukin, dornase alfa, interferon beta-1a, becaplermin, reteplase, interferon alfa-2, tenecteplase, drotrecogin alfa, rilonacept, romiplostim, methoxypolyethylene glycol-epoetin beta, C1 esterase inhibitor, idursulfase, alglucosidase alfa, abatacept, galsulfase, palifermin and interferon gamma-1b.

### Claim 12 (depends on 1, 2, 3, 4)

The formulation of any one of claims 1-4, wherein the concentration of protein is 50 to 200 mg/ml.

### Claim 13 (depends on 1, 2, 3, 4)

The formulation of any one of claims 1-4, further comprising a non-ionizable excipient.

### Claim 14 (depends on 13)

The formulation of claim 13, wherein the non-ionizable excipient is a sugar or a polysorbate.

### Claim 15 (depends on 1, 2, 3, 4)

A method of treating a subject having a disorder, comprising administering to the subject the formulation of any one of claims 1-4.

### Claim 16 (depends on 1, 2, 3, 4)

A device comprising the formulation of any one claims 1-4.

### Claim 17 (depends on 16)

An article of manufacture comprising the device of claim 16.

### Claim 18

A method of preparing an aqueous formulation comprising a protein and water, the method comprising:
a) providing the protein in a first solution; and
b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved to thereby prepare the aqueous formulation.

### Claim 19

A method of preparing an aqueous formulation of a protein, the method comprising:
a) providing the protein in a first solution;
b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved to thereby prepare a diafiltered protein solution; and
c) concentrating the diafiltered protein solution to thereby prepare the aqueous formulation of the protein.

### Claim 20 (depends on 18, 19)

The method of claim 18 or 19, wherein the protein is an antibody, or an antigen-binding fragment thereof.

### Claim 21 (depends on 20)

The method of claim 20, wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb).

### Claim 22 (depends on 18, 19)

An aqueous formulation prepared according to the methods of claim 18 or 19.