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EP-4736950-A2 - PHARMACEUTICAL FORMULATIONS AND METHODS OF MAKING THE SAME

EP4736950A2EP 4736950 A2EP4736950 A2EP 4736950A2EP-4736950-A2

Abstract

The invention relates to the formulation of pharmaceutical compositions of etanercept. The invention relates to methos of removing buffer and of formulating pharmaceutical compositions of etanercept.

Inventors

  • BALL, Nicole
  • GOSS, Monica

Assignees

  • Amgen Inc.

Dates

Publication Date
20260506
Application Date
20171019

Claims (15)

  1. A method of preparing a pharmaceutical composition, the method comprising: purifying etanercept from a medium comprising cells expressing etanercept; and formulating etanercept to 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.
  2. The method of claim 1, wherein purifying comprises using one or more of fractionation on an ion-exchange column, ethanol precipitation, reverse phase HPLC, chromatography on silica, chromatography on an anion or cation exchange resin, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, optionally wherein purifying comprises using anion exchange chromatography (AEX).
  3. The method of claim 2, wherein purifying comprises: generating an intermediate pool from the medium via anion exchange chromatography (AEX); conditioning the intermediate pool, wherein the conditioned intermediate pool has a pH of between 6.2 and 6.4; and exchanging the conditioned intermediate pool against an unbuffered solution comprising between 120 mM NaCl, 25 mM arginine, and 1% (w/v) sucrose, wherein the unbuffered solution has a pH between 5.6 and 6.5, wherein the exchanging comprises ultrafiltration and/or diafiltration.
  4. The method of any one of claims 1-3, further comprising adding a surfactant to the composition, optionally wherein the surfactant is polysorbate 20.
  5. The method of any one of claims 1-4, further comprising filling a single-dose container with about a single dose of the pharmaceutical composition.
  6. A pharmaceutical composition comprising 120 mM NaCl, 25 mM L-arginine hydrochloride, 1% (w/v) sucrose, 50 mg/mL etanercept, and water, wherein the pharmaceutical composition comprises less than 2.0 mM total additional buffering agent, and the pH of the composition is 6.3 +/- 0.2.
  7. The pharmaceutical composition of claim 6, wherein (a) the pharmaceutical composition comprises less than 1.5 mM total additional buffering agent, (b) the pharmaceutical composition comprises less than 1.0 mM total additional buffering agent, (c) the pharmaceutical formulation comprises less than 0.5 mM total additional buffering agent, (d) the pharmaceutical composition comprises less than 0.25 mM total additional buffering agent, or (e) the pharmaceutical composition comprises less than 0.1 mM total additional buffering agent.
  8. The pharmaceutical composition of claim 6, wherein the osmolality of the pharmaceutical composition is from 250 to 350 mOsm/kg, or optionally from 290 to 310 mOsm/kg.
  9. The pharmaceutical composition of any one of claims 6-8, wherein a) the pharmaceutical composition maintains a pH from 6.1 to 6.5 when stored at controlled room temperature (CRT) for two weeks, or b) less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography.
  10. The pharmaceutical composition of any one of claims 6-9, wherein the additional buffering agent comprises at least one of: histidine, potassium phosphate, sodium citrate, potassium citrate, maleic acid, ammonium acetate, tris-(hydroxymethyl)-aminomethane (tris), and diethanolamine.
  11. The pharmaceutical composition of any one of claims 6-10, wherein the etanercept consists of a dimer with the amino acid sequence of SEQ ID NO: 1.
  12. The pharmaceutical composition of any one of claims 6-11 for use in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or psoriasis.
  13. The pharmaceutical composition of any one of claims 6-11 for subcutaneous, intramuscular, intravenous, intraperitoneal, intracerebrospinal, intra-articular, intrasynovial, and/or intrathecal administration.
  14. A single-dose container containing the pharmaceutical composition of any one of claims 6-11.
  15. The single-dose container of claim 14, wherein the single dose container is a vial, a syringe, or an autoinjector.

Description

Cross-Reference to Related Application This application claims the benefit of U.S. Provisional Application No. 62/411,458 filed October 21, 2016, which is incorporated in its entirety by reference herein. Field of the Invention 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. Background of the Invention Formulation of a protein drug can present many challenges for the pharmaceutical scientist. A formulation must be found that stabilizes the protein drug and makes it resistant to degradation by proteolysis, aggregation, misfolding, etc. Especially for engineered proteins that differ in substantial respects to known proteins, finding appropriate stability conditions can be challenging. It is also desirable to have the protein drug be in a format that is convenient for the patient. Desired properties include stability at ambient and refrigerated temperatures; suitability for long term storage, appropriate dosing times and volumes; and minimization of discomfort upon administration. Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. When expressed in mammalian cells, it forms a homodimeric complex with two domains of the TNF receptor. Thus, it is an artificial protein that is different from both antibodies and soluble TNF receptors, and therefore subject to different degradation pathways than either. Etanercept is commercially available as ENBREL® (Amgen Inc., Thousand Oaks, CA) and is approved to treat moderately to severely active rheumatoid arthritis, moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages two and older, chronic moderate to severe plaque psoriasis (PsO) in adults, psoriatic arthritis (PsA) in adults, and active ankylosing spondylitis (AS). Etanercept was first available in a lyophilized formulation to be reconstituted immediately before injection. Upon reconstitution of the lyophilized product with water for injection, the formulation is 10 mM Tris HCl, 4% mannitol, 1% sucrose, pH 7.4 at about 25 mg/mL However, this formulation is not stable for storage. It was discovered that a liquid formulation of etanercept could be achieved using arginine to stabilize the protein (see US Patent No. 7,648,702). An exemplary liquid formulation consists of 50 mg/mL etanercept, 25 mM phosphate buffer, 25 mM L-arginine hydrochloride, 100 mM NaCl, 1% Sucrose at pH 6.3 in water. Summary of the invention Provided herein are new and improved formulations of etanercept. In particular, the invention provides pharmaceutical compositions containing etanercept that are stable and can be conveniently stored as a liquid at controlled room temperature (CRT) for extended periods of time, even in the absence of an additional buffering agent. In addition, when the pharmaceutical compositions of the invention are injected into subjects, they also demonstrate significantly reduced injection pain as compared to the commercially available prior art formulation. Thus these pharmaceutical compositions are more convenient and advantageous for patients. Another aspect of the invention provides methods of formulating pharmaceutical preparations of etanercept at a desired pH but in the absence of additional buffering agent in the final formulation. In another aspect, the invention provides a pharmaceutical composition comprising etanercept, NaCl, arginine, and sucrose, wherein the pharmaceutical composition has essentially no additional buffering agent, and the pH of the composition is between 6.1 and 6.5. In one embodiment, the pharmaceutical composition is capable of maintaining the pH between 6.1 and 6.5 when stored at controlled room temperature (CRT) for 2 weeks. In another embodiment, the etanercept concentration is between 40 mg/mL and 100 mg/mL. In another embodiment, the pharmaceutical composition is isotonic. In another embodiment, the pharmaceutical composition contains: between 20 mM and 150 mM NaCl; between 5 mM and 100 mM arginine; and between 0.5% and 2% (w/v) sucrose. In another embodiment, the pharmaceutical composition comprises a surfactant. In another embodiment, the surfactant is polysorbate 20, polysorbate 80, or poloxamer 188. In another embodiment, the surfactant is polysorbate 20 at a concentration (w/v) of between 0.001% and 0.1%. In another embodiment, the surfactant is polysorbate 80 at a concentration (w/v) of between 0.001% and 0.1%. In another embodiment, the surfactant is poloxamer 188 at a concentration (w/v) of between 0.01% to 0.3%. In another embodiment, the pharmaceutical composition maintains a pH of between 5.8 and 6.7 for at leas