Etanercept formulations exhibiting marked reduction in sub-visible particles

• US 10,822,429 B2
• Filed: 01/08/2015
• Issued: 11/03/2020
• Est. Priority Date: 07/09/2012
• Status: Active Grant

• Current Assignee: Coherus BioSciences Inc.
• Original Assignee: Coherus BioSciences Inc.
• Inventors: Manning, Mark, Murphy, Brian, Farrar, Douglas, Herman, Alan
• Primary Examiner(s): Thakor, Devang K
• Application Number:
  US14/592,569
• Publication Number:
  US 20150125532A1
• Time in Patent Office: 2,126 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• 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 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 31/14 : for RNA viruses
• CPC Class Codes: C07K 14/70578 : NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 14/7151 : for tumor necrosis factor [TNF], for lymphotoxin [LT]
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 19/00 : Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The invention provides stabilized aqueous pharmaceutical etanercept compositions suitable for long-term storage of etanercept, with substantial reduction in sub-visible particles, and methods of manufacture of these compositions, methods of administration, and articles of manufacture.

Claims

1. An aqueous pharmaceutical composition stabilized for long term storage comprising:

etanercept at 25 to 75 mg/ml;

a surfactant at 0.01 to 0.05% w/v;

a metal ion selected from the group consisting of calcium, magnesium and zinc, wherein the metal ion is present at 2 mM to 20 mM;

a buffer selected from the group consisting of phosphate, histidine, citrate, maleate, tartrate, succinate, tris-(hydroxymethyl)-aminomethane, and bicarbonate;

wherein the composition has a pH of between 6 and 7, and the composition is free of arginine.

2. The stabilized composition of claim 1 wherein the surfactant is selected from the group consisting of polysorbate 80, polysorbate 60, polysorbate 40 and polysorbate 20.

3. The stabilized composition of claim 1 wherein the surfactant comprises polysorbate 80.

4. The stabilized composition of claim 1 wherein the composition has (i) less than 2500 particles/ml having a size of 5-10 μ

m;

(ii) less than 3500 particles having size of about 2-5 μ

m and (iii) less than 700 particles/ml having size of about 1-2 μ

m.

5. The stabilized composition of claim 1 wherein;

etanercept is present at 25 to 50 mg/ml;

the metal ion is magnesium; and

wherein the composition further comprises sucrose or trehalose at 0.5 to 6 wt %;

NaCl at 25 to 150 mM; and

the buffer is sodium phosphate at 1 to about 30 mM.

6. The stabilized composition of claim 1 wherein the metal ion is magnesium and wherein the composition further comprises NaCl at 0 to 100 mM;

and the buffer is sodium phosphate at 1 to 30 mM.

7. The stabilized composition of claim 1 wherein the composition is characterized by:

(a) an SEC analysis at T₄ of greater than 90 wt % monomer content; and

less than 3 wt % aggregate(s) content; and

(b) an HIC analysis at T₂ wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 4 wt %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and

the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %; and

(c) an HIC analysis at T4 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80, wt %; and

the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %.

8. A vial or injection device containing the etanercept formulation of claim 1 in final dosage form.

9. A vial or injection device containing the etanercept formulation of claim 5 in final dosage form.

10. A vial or injection device containing the etanercept formulation of claim 6 in final dosage form.

11. The stabilized composition of claim 5 wherein the composition has (i) less than 2500 particles/ml having a size of 5-10 μ

m;

(ii) less than 3500 particles having size of about 2-5 μ

m and (iii) less than 700 particles/ml having size of about 1-2 μ

m.

12. The stabilized composition of claim 6 wherein the composition has (i) less than 2500 particles/ml having a size of 5-10 μ

m;

(ii) less than 3500 particles having size of about 2-5 μ

m and (iii) less than 700 particles/ml having size of about 1-2 μ

m.

13. The stabilized composition of claim 5 wherein the composition is characterized by:

(a) an SEC analysis at T₄ of greater than 90 wt % monomer content; and

less than 3 wt % aggregate(s) content; and

(b) an HIC analysis at T₂ wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 4 wt %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and

the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %; and

(c) an HIC analysis at T4 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and

the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %.

14. The stabilized composition of claim 6 wherein the composition is characterized by:

(a) an SEC analysis at T₄ of greater than 90 wt % monomer content; and

less than 3 wt % aggregate(s) content; and

(b) an HIC analysis at T₂ wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 4 wt %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and

the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %; and

(c) an HIC analysis at T4 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt %;

the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and

the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %.

15. The stabilized composition of claim 1, wherein a number of sub-visible particles per ml of the formulation having size of 1-10 μ

m is at least about 50% lower than in the same composition having no surfactant.

16. The composition of claim 1, wherein said composition has less than about 1 wt % aggregate(s) content as determined by size exclusion chromatography after 4 weeks storage at 25°

C.

17. An aqueous pharmaceutical composition comprising:

etanercept at about 50 mg/ml;

up to 0.05% w/v surfactant;

2 mM to 20 mM metal ion;

about 25 mM to about 100 mM NaCl;

10 mM to 200 mM of a phosphate or citrate buffer;

wherein the composition has a pH of between 6 and 7,

wherein the composition is free of arginine,

wherein said composition has less than about 1 wt % aggregate(s) content as determined by size exclusion chromatography after 4 weeks storage at 25°

C., and

wherein the formulation has;

(i) less than about 2500 particles/ml having a size of about 5-10 μ

m;

(ii) less than about 3500 particles having size of about 2-5 μ

m, and

(iii) less than about 700 particles/ml having size of about 1-2 μ

m.