Methods of manufacturing stable aqueous formulations of adalimumab

• US 10,286,072 B2
• Filed: 10/10/2017
• Issued: 05/14/2019
• Est. Priority Date: 09/07/2012
• Status: Active Grant

• Current Assignee: Coherus BioSciences Inc.
• Original Assignee: Coherus BioSciences Inc.
• Inventors: Manning, Mark, Payne, Robert W.
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US15/729,295
• Publication Number:
  US 20180028654A1
• Time in Patent Office: 581 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/542 oral/gastrointestinal
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• 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: A61K 9/08 Solutions composition of solutions A61K47/00
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• 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: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The invention provides aqueous pharmaceutical adalimumab compositions suitable for long-term storage of adalimumab, methods of manufacture of these compositions, methods of administration, and kits containing same.

Claims

1. A method of manufacturing an aqueous adalimumab formulation, wherein:

the aqueous adalimumab formulation comprises;

(i) adalimumab;

(ii) buffer; and

(iii) stabilizer; and

wherein the formulation is free of polyol, has a pH of about 5 to about 6, and is stable for one week at 40°

C. or two weeks at 25°

C., and

the method comprises (a) creating a formulation buffer comprising the buffer of the aqueous adalimumab formulation; and

(b) contacting a solution comprising adalimumab with the formulation buffer.

2. The method of claim 1, wherein the stabilizer is selected from the group consisting of an amino acid, a salt, EDTA, and a metal ion.

3. The method of claim 2, wherein the amino acid is selected from the group consisting of glycine, arginine and a combination thereof.

4. The method of claim 2, wherein the salt is selected from the group consisting of sodium chloride and sodium sulfate.

5. The method of claim 4, wherein the salt is, or includes, sodium sulfate.

6. The method of claim 5, wherein the buffer contains no citrate and consists of histidine, succinate, or a combination thereof;

and wherein the composition may further optionally include (i) phosphate acting as a stabilizer and not as a buffer, so that the composition has a pH of about 5 to about 6 without phosphate or (ii) PS80 surfactant;

or both.

7. The method of claim 6, wherein histidine is the sole buffer in the composition;

the composition has osmolality of about 180 to 420 mOsM;

the composition is suitable for administration to a subject as a single dosage;

the composition has a concentration of adalimumab in the range of 30 to about 50 mg/mL; and

the dosage contains about 10 to 80 mg of adalimumab.

8. The method of claim 7, wherein the dosage is about 40 mg and results in less pain upon administration to a subject in comparison to an adalimumab composition having a buffer that comprises citrate.

9. A method of manufacturing an aqueous adalimumab formulation, wherein:

the aqueous adalimumab formulation has a pH of about 5 to about 6 and comprises;

(i) adalimumab;

(ii) buffer, free of citrate, and consisting essentially of histidine, succinate, or both; and

(iii) stabilizer consisting essentially of;

(a) glycine, arginine, or both;

or

(a) and (b);

where (b) is sodium chloride, sodium sulfate, or both,

wherein the composition is free of polyol, and is stable for one week at 40°

C. or two weeks at 25°

C., and

the method comprises (a) creating a formulation buffer comprising the buffer of the aqueous adalimumab formulation; and

(b) contacting a solution comprising adalimumab with the formulation buffer.

10. The method of claim 9 comprising histidine as the sole buffer, and glycine.

11. The method of claim 9 comprising histidine as the sole buffer, and arginine.

12. The method of claim 9, wherein (b) is, or includes, sodium sulfate.

13. The method of claim 9 further comprising phosphate acting as a stabilizer and not as a buffer so that the composition has a pH of about 5 to about 6 without phosphate;

and, optionally, a surfactant.

14. The method of claim 9 having osmolality of about 180 to 420 mOsM;

wherein the composition is suitable for administration to a subject as a single dosage;

the composition has a concentration of adalimumab in the range of 30 to about 50 mg/mL;

and the dosage contains about 10 to 80 mg of adalimumab.

15. The method of claim 14, wherein the dosage is about 40 mg and results in less pain upon administration to a subject in comparison to an adalimumab composition having a buffer comprising citrate.

16. A method of manufacturing an aqueous adalimumab formulation, wherein:

the aqueous adalimumab composition comprises adalimumab and a citrate-free buffer, is free of a polyol, has a pH of about 5 to about 6, and is stable for one week at 40°

C. or two weeks at 25°

C., and

the method comprises (a) creating a formulation buffer comprising the buffer of the aqueous adalimumab formulation; and

(b) contacting a solution comprising adalimumab with the formulation buffer.

17. The method of claim 16 comprising:

(i) adalimumab;

(ii) buffer consisting solely of histidine, succinate, or a combination thereof; and

(iii) glycine, arginine, or both.

18. The method of claim 17 further comprising phosphate acting as a stabilizer and not as a buffer.

19. The method of claim 17 further comprising a salt selected from sodium chloride and sodium sulfate.

20. The method of claim 17 having osmolality of about 180 to 420 mOsM;

wherein the composition is suitable for administration to a subject as a single dosage;

the composition having a concentration of adalimumab in the range of 30 to about 50 mg/mL;

the dosage containing about 40 mg of adalimumab and resulting in less pain upon administration to a subject in comparison to an adalimumab composition having a buffer that comprises citrate.