US20180110856A1 - Pharmaceutical Formulations and Methods of Making the Same - Google Patents

Pharmaceutical Formulations and Methods of Making the Same Download PDF

Info

Publication number
US20180110856A1
US20180110856A1 US15/788,762 US201715788762A US2018110856A1 US 20180110856 A1 US20180110856 A1 US 20180110856A1 US 201715788762 A US201715788762 A US 201715788762A US 2018110856 A1 US2018110856 A1 US 2018110856A1
Authority
US
United States
Prior art keywords
pharmaceutical composition
etanercept
formulation
buffering agent
arginine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/788,762
Other languages
English (en)
Inventor
Monica GOSS
Nicole BALL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Priority to US15/788,762 priority Critical patent/US20180110856A1/en
Assigned to AMGEN INC. reassignment AMGEN INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BALL, Nicole, GOSS, Monica
Priority to US15/958,261 priority patent/US10307483B2/en
Publication of US20180110856A1 publication Critical patent/US20180110856A1/en
Priority to US16/144,120 priority patent/US11491223B2/en
Priority to US17/933,055 priority patent/US20230080571A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"

Definitions

  • 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.
  • 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.
  • finding appropriate stability conditions can be challenging.
  • 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.
  • TNFR tumor necrosis factor receptor
  • TNFR tumor necrosis factor receptor
  • Etanercept is commercially available as ENBREL® (Amgen Inc., Thousand Oaks, Calif.) and is approved to treat moderately to severely active rheumatoid arthritis, moderately to severely active polyarticularjuvenile 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.
  • ENBREL® Amgen Inc., Thousand Oaks, Calif.
  • the formulation 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 U.S. Pat. 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.
  • 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.
  • CRT controlled room temperature
  • the pharmaceutical compositions of the invention when 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.
  • 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.
  • 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.
  • the etanercept concentration is between 40 mg/mL and 100 mg/mL.
  • the pharmaceutical composition is isotonic.
  • 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.
  • the pharmaceutical composition comprises a surfactant.
  • the surfactant is polysorbate 20, polysorbate 80, or poloxamer 188.
  • the surfactant is polysorbate 20 at a concentration (w/v) of between 0.001% and 0.1%.
  • the surfactant is polysorbate 80 at a concentration (w/v) of between 0.001% and 0.1%.
  • the surfactant is poloxamer 188 at a concentration (w/v) of between 0.01% to 0.3%.
  • 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. In another embodiment, the pharmaceutical composition maintains a pH of between about 6.1 and about 6.5. In another embodiment, less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography. In another embodiment, the pharmaceutical composition consists essentially of about 40-100 mg/mL etanercept, about 120 mM NaCl, about 25 mM arginine, about 1% sucrose, and water. In another embodiment, the pharmaceutical composition consists essentially of about 40-100 mg/mL etanercept, about 120 mM NaCl, about 25 mM arginine, about 1% sucrose, about 0.01% polysorbate 20, and water.
  • the present invention provides a method of formulating a pharmaceutical composition of etanercept to remove an additional buffering agent and maintain pH from 6.1 to 6.5, comprising formulating the etanercept formulation in a formulation comprising an additional buffering agent at between pH 6.1 and 6.5, and exchanging the formulation comprising an additional buffering agent against a formulation that does not comprise an additional buffering agent and is between pH 5.6 and 6.5, and collecting the resulting pharmaceutical formulation.
  • the exchange step uses diafiltration.
  • the formulation that does not comprise an additional buffering agent is isotonic.
  • the formulation that does not comprise an additional buffering agent contains sucrose, arginine, and NaCl.
  • the formulation that does not comprise an additional buffering agent contains between 20 mM and 150 mM NaCl; between 5 mM and 100 mM arginine; and between 0.5% and 2% (w/v) sucrose.
  • the formulation that does not comprise an additional buffering agent consists essentially of about 120 mM NaCl, about 25 mM arginine, about 1% sucrose, and water.
  • the method of formulating a pharmaceutical composition of etanercept further comprises adding polysorbate.
  • the polysorbate is polysorbate 20 at a concentration (w/v) of between 0.001% and 0.1%.
  • the method of formulating a pharmaceutical composition of etanercept further comprises filtering the pharmaceutical composition. In another embodiment, the method of formulating a pharmaceutical composition of etanercept further comprises aliquoting the pharmaceutical composition into a drug product form.
  • the present invention provides a kit comprising a pharmaceutical composition of etanercept as described above in a drug product form and instructions for storage and use.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising etanercept, NaCl, arginine, sucrose, a phosphate buffer and benzyl alcohol, wherein the pH of the composition is between 6.1 and 6.5.
  • the benzyl alcohol is at a concentration (v/v) of between 0.1% and 5.0%.
  • the concentration of benzyl alcohol is about 0.9%.
  • the pharmaceutical composition comprising etanercept further comprises polysorbate 20 at a concentration (w/v) of between 0.001% and 0.1%.
  • the concentration of polysorbate 20 is about 0.004%.
  • the pharmaceutical composition comprising etanercept consists essentially of etanercept at about 40-100 mg/mL, arginine at about 25 mM, sodium chloride at about 100 mM, sucrose at a concentration (w/v) of about 1%, phosphate buffer at about 25 mM, and benzyl alcohol at a concentration (v/v) of about 0.9%.
  • the pharmaceutical composition comprising etanercept consists essentially of etanercept at about 40-100 mg/mL, arginine at about 25 mM, sodium chloride at about 100 mM, sucrose at a concentration (w/v) of about 1%, phosphate buffer at about 25 mM, benzyl alcohol at a concentration (v/v) of about 0.9%, and polysorbate 20 at a concentration (w/v) of about 0.004%.
  • the present invention provides a single-dose container containing a pharmaceutical composition comprising etanercept as described above.
  • the pharmaceutical composition consists essentially of etanercept at about 40-100 mg/mL, arginine at about 25 mM, sodium chloride at about 100 mM, sucrose at a concentration (w/v) of about 1%, phosphate buffer at about 25 mM, and benzyl alcohol at a concentration (v/v) of about 0.9%.
  • the pharmaceutical composition consists essentially of etanercept at about 40-100 mg/mL, arginine at about 25 mM, sodium chloride at about 100 mM, sucrose at a concentration (w/v) of about 1%, phosphate buffer at about 25 mM, benzyl alcohol at a concentration (v/v) of about 0.9%, and polysorbate 20 at a concentration (w/v) of about 0.004%.
  • the single dose container is a vial, a syringe, or an autoinjector.
  • the single-dose container contains an aqueous formulation consisting of etanercept at 50.0 mg/mL, sodium chloride at 120 mM, L-arginine at 25 mM, sucrose at 1.0% (w/v).
  • the present invention provides a method of preparing a single-dose container containing a pharmaceutical composition comprising etanercept as described above, comprising filling the single-dose container with about a single dose of the pharmaceutical composition under sterile conditions.
  • FIG. 1 shows the percent HMW (peak B) as detected by SEC for the etanercept stability assay of Example 3.
  • FIG. 2 shows the percent LMW as detected by dSEC for the etanercept stability assay of Example 3.
  • FIG. 3 shows the percent Peak 3 as detected by HIC for the etanercept stability assay of Example 3.
  • FIG. 4 shows the percent Peak 3 as detected by HIC for the stainless steel cryo-vessel storage etanercept stability assay of Example 4.
  • FIG. 5 shows the percent LMW as detected by dSEC for the stainless steel cryo-vessel storage etanercept stability assay of Example 4.
  • FIG. 6 shows the percent Peak B as detected by SEC for the stainless steel cryo-vessel storage etanercept stability assay of Example 4.
  • FIG. 7 shows the percent Peak B as detected by SEC for the freeze-thaw etanercept stability assay of Example 4.
  • FIG. 8 shows the pH stability of the conditioned AEX intermediate pool at controlled room temperature (CRT) in the assay of Example 6.
  • FIG. 9 shows the UF/DF pool pH (A) and conductivity (B) stability at CRT in the assay of Example 6.
  • FIG. 10 shows the pH (A) and conductivity (B) stability of etanercept formulated in SAS solution in the assay of Example 6.
  • the invention provides improved pharmaceutical compositions of etanercept.
  • pharmaceutical composition is understood to refer to a formulation of a polypeptide suitable for injection and/or administration into a patient in need thereof. More particularly, a pharmaceutical composition is substantially sterile and does not contain any agents that are unduly toxic or infectious to the recipient.
  • Etanercept is a soluble form of the p75 TNF receptor fused to an Fc domain of a human IgG1 (TNFR:Fc).
  • a commercially available etanercept is known as ENBREL® (Immunex Inc., Thousand Oaks, Calif.).
  • Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons (Physicians Desk Reference, 2002, Medical Economics Company Inc.). The full sequence expressed in CHO cells is shown below. However, it is to be understood that minor modifications and deletions of this sequence (up to 10%) may be possible and can be used within the scope of the invention.
  • CHO Chinese hamster ovary
  • the invention provides a pharmaceutical composition comprising etanercept but containing essentially no additional buffering agent.
  • additional buffering agent refers to a component of an etanercept composition or formulation, other than etanercept itself, that contributes significantly to the buffering capacity of the composition or formulation.
  • Etanercept itself has been shown herein to provide all the needed buffering to maintain the pH between 6.1 and 6.5, and in particular at about 6.2-6.3, under the conditions described below. As demonstrated below in Example 1, this pH range has been shown to be effective to maintain the desired stability characteristics of an etanercept formulation (less than 6% high molecule weight aggregates and less than 28% misfolded and clipped species).
  • total additional buffering agent refers collectively to all of the components of an etanercept composition or formulation, except for etanercept itself, that contribute significantly to the buffering capacity of the composition or formulation.
  • compositions according to the invention comprise less than 2.0 mM total additional buffering agent, less than 1.5 mM total additional buffering agent, less than 1.0 mM total additional buffering agent, less than 0.5 mM total additional buffering agent, less than 0.25 mM total additional buffering agent, less than 0.1 mM total additional buffering agent, or less than 0.05 mM of total additional buffering agent.
  • additional buffering agents are used to maintain the pH in a desired range, often at concentrations of 5.0 mM or higher.
  • additional buffering agents are histidine, potassium phosphate, sodium or potassium citrate, maleic acid, ammonium acetate, tris-(hydroxymethyl)-aminomethane (tris), various forms of acetate and diethanolamine.
  • One common buffering agent is sodium phosphate as its buffering capacity is at or near pH 6.2.
  • Sodium phosphate is the buffering agent used in the current commercial liquid formulation of etanercept since its desired pH is 6.3. In the invention described herein, essentially no sodium phosphate is present in the pharmaceutical formulation of etanercept.
  • the pH of the inventive pharmaceutical composition is maintained between 6.1 and 6.5, even after extended storage.
  • the pharmaceutical composition with essentially no additional buffering agent results in significantly less pain than the current buffered commercial formulation.
  • phosphate is often chosen as a buffer for pharmaceutical compositions because of the close to neutral pH buffering capacity and belief that it is one of the less painful buffer components (as compared to, for example, citrate buffer), the instant inventors have determined that phosphate buffer at around pH 6.3 does contribute to pain upon injection.
  • a “formulation solution” or “formulation buffer” is a solution or buffer that does not itself contain etanercept but is used to make a formulation comprising etanercept.
  • the etanercept concentration in the pharmaceutical compositions of the invention is between about 40 mg/mL and about 200 mg/mL in an aqueous formulation (e.g., water as the solvent). More preferably, the etanercept concentration is between about 40 mg/mL and about 100 mg/mL, yet more preferably between about 40 mg/mL and about 75 mg/mL, and optionally about 50 mg/mL.
  • the pharmaceutical compositions of the invention also contain arginine.
  • Arginine has been shown to make a substantial contribution to stabilizing etanercept in a liquid formulation (see U.S. Pat. No. 7,648,702, incorporated herein by reference).
  • Pharmaceutically appropriate forms of arginine are commercially available.
  • L-arginine e.g., L-arginine HCl or L-arginine base
  • L-arginine is the arginine used for pharmaceutical formulations. It is understood that within the pH range of 6.0 and 6.6, and in particular at a pH of about 6.2-6.3, arginine does not contribute meaningfully to the buffering capacity of a formulation.
  • the concentration of arginine in the compositions of the invention are preferably from about 1 mM to about 1 M, more preferably from about 10 mM to about 200 mM, or alternatively from about 5 mM to about 100 mM, more preferably from about 10 mM to about 100 mM, even more preferably from about 15 mM to about 75 mM, and yet more preferably at about 25 mM.
  • the pharmaceutical composition comprises about 50 mg/mL to 75 mg/mL etanercept and about 25 mM arginine, wherein the pharmaceutical composition has essentially no additional buffering agent, and the pH of the composition is between 6.0 and 6.6.
  • the term “about” is understood to mean that there can be variation in the concentration of a component of the described formulation that can be up to and including 10% of the given value. For example, if a formulation has about 10 mg/mL of a polypeptide, this is understood to mean that a formulation can have between 9 to 11 mg/mL of the stated polypeptide.
  • the pharmaceutical compositions may contain additional excipients, as long as those excipients are not additional buffering agents, and in particular are not phosphate buffering agents.
  • additional excipients include but are not limited to sugars/polyols such as: sucrose, lactose, glycerol, xylitol, sorbitol, mannitol, maltose, inositol, trehalose, glucose; polymers such as: serum albumin (bovine serum albumin (BSA), human SA or recombinant HA), dextran, PVA, hydroxypropyl methylcellulose (HPMC), polyethyleneimine, gelatin, polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC); non-aqueous solvents such as: polyhydric alcohols, (e.g., PEG, ethylene glycol and glycerol) dimethysulfoxide (DMSO) and dimethylformamide (DM).
  • the excipients include NaCl and/or sucrose.
  • NaCl may be present in the pharmaceutical composition at a concentration of from about 5 mM to about 200 mM, more preferably between about 20 mM to about 150 mM, even more preferably between about 80 mM to about 140 mM.
  • Sucrose may be added to a concentration of between about 0.5% to about 2% (w/v) sucrose, more preferably between about 0.8% to about 1.2% (w/v) sucrose, even more preferably at about 1% (w/v) sucrose.
  • the osmolality of a pharmaceutical composition is preferably regulated in order to maximize the active ingredient's stability and also to minimize discomfort to the patient upon administration. It is generally preferred that a pharmaceutical composition be isotonic with serum, i.e., having the same or similar osmolality, which is achieved by addition of a tonicity modifier. Serum is approximately 300+/ ⁇ 50 milliosmolals per kilogram, thus it is contemplated that the osmolality of an isotonic pharmaceutical composition will be from about 180 to about 420 milliosmolals. In some embodiments, the range will be from about 250 to about 350 milliosmolals.
  • a tonicity modifier is understood to be a molecule that contributes to the osmolality of a solution.
  • tonicity modifiers suitable for modifying osmolality include, but are not limited to amino acids (e.g., arginine, cysteine, histidine and glycine), salts (e.g., sodium chloride, potassium chloride and sodium citrate) and/or saccharides (e.g., sucrose, glucose and mannitol).
  • the concentration of the tonicity modifier in the formulation is preferably between about 1 mM to 1 M, more preferably about 10 mM to about 200 mM. In some embodiments, the concentrations of NaCl and sucrose are adjusted to generate a pharmaceutical composition that is isotonic.
  • the pharmaceutical composition contains about 40-100 mg/mL etanercept, about 120 mM NaCl, about 25 mM arginine, about 1% sucrose, and water.
  • the pharmaceutical composition can consist essentially of about 50-100 mg/mL etanercept, about 120 mM NaCl, about 25 mM arginine, about 1% sucrose, about 0.01% polysorbate 20, and water.
  • the pharmaceutical compositions of the invention may include a surfactant.
  • Surfactants are agents that reduce solution/surface induced stress.
  • examples of surfactants are polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80 (e.g., TWEEN-20® (Sigma-Aldrich, St. Louis, Mo.) or TWEEN-80® (Sigma-Aldrich, St. Louis, Mo.)), sodium dodecyl sulfate (SDS), polyoxyethylene copolymer, poloxamers, such as poloxomer 188 (e.g., PLURONIC® F-68 (Sigma-Aldrich, St.
  • polysorbate 20 can be included in the pharmaceutical compositions at a concentration (w/v) of between about 0.001% and about 0.03%. In particular embodiments illustrated below by example, polysorbate 20 can be included in the pharmaceutical formulations at a concentration (w/v) of 0.01% or at about 0.004%.
  • the examples below illustrate how one of skill in art can determine whether a formulation is capable of maintaining the pH in a desired range.
  • the pharmaceutical composition is formulated and stored in the test containers (which may be glass vials, glass syringes, plastic syringes, stainless steel vessels, or any manner of sterile device suitable for pharmaceutical compositions) and the pH is assessed at time 0, and then at indicated times as appropriate.
  • the testing conditions will anticipate needs for storage of the pharmaceutical composition, and will stress those conditions.
  • the formulations of the invention are able to maintain the desired pH under controlled room temperature (CRT) for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, and at least 24 weeks.
  • CRT controlled room temperature
  • CRT is defined by the USP, and has a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° C. to 25° C. (68° F. to 77° F.); that results in a mean kinetic temperature calculated to be not more than 25° C.; and that allows for excursions between 15° C. and 30° C. (59° F. and 86° F.) that are experienced in pharmacies, hospitals, and warehouses.
  • the pharmaceutical compositions of the invention exhibit particular quality attributes.
  • the testing of these quality attributes is also described below by way of example.
  • the pharmaceutical compositions of the invention contain less than 6% of the total etanercept aggregated in a high molecular weight form as assessed using size exclusion chromatography.
  • the pharmaceutical compositions of the invention contain less than 28% of the total amount of etanercept is in a misfolded form as assessed using hydrophobic interaction chromatography.
  • the pharmaceutical compositions of the invention are capable of remaining stable by maintaining pH and/or other noted quality attributes (minimum high molecular weight forms and minimum misfolded forms) for the following temperatures and extended time periods (1) at ⁇ 30° C. (frozen) for at least 4 weeks, at least 3 months, at least 6 months, at least 12 months, and at least 36 months; (2) for up to 1 freeze/thaw cycle, up to 2 freeze/thaw cycles, up to 3 freeze/thaw cycles, and up to 5 freeze/thaw cycles; (3) at 4° C. (refrigerated temperature) for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least at least 24 weeks, and at least 52 weeks; (4) at 25° C. (room temperature) for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 24 weeks; and (5) at 40° C. (accelerated stability testing) for at least 2 weeks.
  • pH and/or other noted quality attributes minimum high molecular weight forms and minimum mis
  • the pharmaceutical compositions of the invention also exhibit the surprising result of reduced pain upon injection into a subject.
  • This property can be assessed using the Visual Analog Scale (VAS) that has been validated by Gallagher et al, 2002, Am. J. Em. Med. v20; i4: 287-290. Trained health professionals administer the drug via injection, and within 30 seconds after each injection, subjects assessed their level of injection pain using a 100 mm Visual Analog Scale (VAS). A difference of 13 to 16 mm on the VAS is considered to be clinically meaningful. Using this technique, it was demonstrated that a placebo formulation without phosphate induced significantly less pain than a placebo formulation containing phosphate at pH 6.3 and the current commercial formulation containing both etanercept and phosphate at pH 6.3.
  • VAS Visual Analog Scale
  • etanercept is expressed recombinantly in CHO cells and secreted into the medium.
  • the medium is collected, filtered, and purified using, for example, various chromatography techniques.
  • protein A can be used to purify Fc domain containing polypeptides such as etanercept, and is advantageous as a first processing step.
  • the invention also provides a method of formulating a pharmaceutical composition of etanercept to remove buffer and maintain pH at a target range, comprising formulating the etanercept in a buffered formulation in the target range, and exchanging the buffered formulation against an unbuffered formulation that is within in or just below that target range, and collecting the resulting pharmaceutical formulation of the etanercept.
  • the method provides formulating a pharmaceutical composition of etanercept to remove buffer and maintain pH from 6.0 to 6.6, comprising formulating the etanercept formulation in a buffered formulation at between pH 6.0 to 6.6, and exchanging the buffered formulation against an unbuffered formulation that is between pH 5.6 and 6.5, and collecting the resulting pharmaceutical formulation.
  • a pharmaceutical composition of etanercept to remove buffer and maintain pH from 6.0 to 6.6
  • formulating the etanercept formulation in a buffered formulation at between pH 6.0 to 6.6 comprising formulating the etanercept formulation in a buffered formulation at between pH 6.0 to 6.6, and exchanging the buffered formulation against an unbuffered formulation that is between pH 5.6 and 6.5, and collecting the resulting pharmaceutical formulation.
  • the starting buffered etanercept formulation is at pH 7.2, it will be adjusted with a strong acid, such as HCl, to within the range 6.1 to 6.5.
  • the unbuffered formulation that is used for exchange should be titrated to between pH 5.6 and 6.5. Because the unbuffered formulation used for exchange has no buffering agent, care should be used during titration.
  • Dialysis makes use of selective diffusion through a semi-permeable membrane to remove unwanted smaller molecules from a larger protein formulation.
  • equilibrations are done serially until a desired fold reduction in the concentration of an unwanted molecule is achieved. For example, three serial equilibrations, each at or greater than 100-fold dilution, can be used to achieve a concentration reduction of 1,000,000-fold or greater.
  • Ultrafiltration and diafiltration are similar to dialysis in that they use a semi-permeable membrane. But unlike the passive diffusion of dialysis, ultrafiltration and diafiltration involves forcing solutions through the membrane using various techniques.
  • buffer exchange can be performed using gel filtration or size exclusion chromatography.
  • chromatographic techniques that also can be used to achieve buffer exchange that are well within the skill of those in the art such as ion exchange chromatography, hydrophobic interaction chromatography, and mixed mode chromatography.
  • the methods of the invention include collecting the resulting pharmaceutical formulation. At this point, essentially all buffer has been removed, but the pH is still maintained at the desired levels. For a pharmaceutical composition containing etanercept, the pH is maintained at between 6.0 and 6.6.
  • the pharmaceutical formulation may be further treated as necessary.
  • a surfactant can be added.
  • the pharmaceutical composition can be filtered.
  • the methods of the invention also include aliquoting the pharmaceutical compositions into a drug product form. Such drug product forms are distributed for final use by patients or health care providers.
  • the pharmaceutical compositions of this invention are particularly useful for parenteral administration, i.e., subcutaneously, intramuscularly, intravenously, intraperitoneal, intracerebrospinal, intra-articular, intrasynovial, and/or intrathecal. Parenteral administration can be by bolus injection or continuous infusion.
  • compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • the pharmaceutical compositions may, if desired, be presented in a vial, pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the dispenser device can comprise a syringe having a single dose of the liquid formulation ready for injection.
  • the pharmaceutical composition is aliquoted into a cassette component for use with a reusable autoinjector.
  • the pharmaceutical compositions can be provided packaged in or with an on-body injector device.
  • the pharmaceutical compositions can be aliquoted into a drug product form suitable for a needleless injection device.
  • the pharmaceutical composition can also be aliquoted into a format suitable as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the formulations may be modified with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the present invention is directed to a kit or container, which contains the pharmaceutical composition of the invention.
  • the kit can also be accompanied by instructions for the storage and use of the pharmaceutical compositions.
  • the container can be, for example, a single-use container, i.e., a container that holds one dose formulation of the present invention. It is understood that a single-use container might contain a single dose plus enough extra to ensure that a full single dose can be administered to a patient from the container, but not so much extra that the container could be used to administer a second dose.
  • Examples of containers suitable for use in certain aspects of the present invention include vials, syringes, and auto-injectors.
  • suitable auto-injectors include those found in U.S. Pat. Nos. 8,177,749, 8,052,645, and 8,920,374, in U.S. patent application Ser. Nos. 12/993,163, 13/269,750, 13/454,531, 14/112,479, 14/777,255, and 14/777,259, and in PCT Publications WO 2014/0089393, WO 2016/033496, and WO 2016/033507, each of which is incorporated herein by reference in its entirety.
  • etanercept-containing compositions and formulations of the present invention can be used in the treatment of patients with conditions that respond to treatment with etanercept.
  • conditions that respond to treatment with etanercept include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis.
  • Methods of treating patients with etanercept are described in, for example, U.S. Pat. Nos. 7,915,225, 8,119,605, 8,410,060, 8,722,631, and 8,119,604, each of which is incorporated herein by reference in its entirety.
  • This example demonstrates the effects of pH and buffer on etanercept at 50 mg/mL, and assesses the stability of a high concentration (100 mg/mL) solution without added phosphate buffer.
  • the following formulations were tested.
  • Enbrel drug substance in PASS 25 mM phosphate buffer, 25 mM L-arginine, 100 mM NaCl, 1% sucrose
  • PASS 25 mM phosphate buffer, 25 mM L-arginine, 100 mM NaCl, 1% sucrose
  • the material was dialyzed into the new formulations (without polysorbate) and concentrated to 50 mg/mL using 10,000 MWCO centripreps.
  • a sample of 50_SAS_100NaCl was also concentrated to 100 mg/mL (100_SAS_100NaCl).
  • Benzyl alcohol was spiked into the current formulation to a final concentration of 0.9%.
  • a 1% stock solution of polysorbate 20 was prepared fresh and spiked into all formulation to a final concentration of 0.004%. All formulations were manually filled into 1 mL long BD glass syringes to a volume of 0.5 mL and then stoppered using an ASPU vacuuming stoppering unit.
  • the pH was measured using a Mettler Toledo SevenEasy pH meter combined with a Mettler Inlab MicroProbe. Samples were warmed to room temperature prior to measurements. Osmolality was measured using The Advanced Osmometer Model 3900. Each measurement was performed using 250 ⁇ L of sample and 290 osmolality standards were tested to ensure the system was operating properly. Size exclusion HPLC was run on an Agilent 1100 HPLC with Chromeleon 7.2 software. Denatured size exclusion HPLC was run on an Agilent 1100 HPLC with Chromeleon 7.2 software.
  • the lower pH formulations During long term storage at 25° C. and 40° C., the lower pH formulations, A45SuT, A52SuT, and A58SuT, exhibited undesirable levels of low molecular weight degraded or clipped species when analyzed using denatured size exclusion chromatography.
  • the high concentration formulation 100_SAST_100NaCl stored at 25° C. and 40° C. began to show an increase in high molecular weight aggregates when analyzed using size exclusion chromatography, but performed similarly to the current commercial formulation at 4° C.
  • the PASST+BeOH (which is the current commercial formulation modified by the addition of 0.004% polysorbate 20 and 0.9% benzyl alcohol) performed similarly to the current commercial formulation at both 4° C. and 25° C.
  • This study was a single-center, randomized, single-blind, crossover design in which 48 healthy men and women received single SC injections of 6 solutions.
  • Test formulations (detailed below in Table 9) were administered by a trained healthcare professional in 6 unique sequences with 8 subjects randomized to each sequence. Injections were administered in each quadrant of the anterior abdominal wall and administered approximately 1 hour apart. Within 30 seconds after each injection, subjects assessed their level of injection pain using a 100 mm Visual Analog Scale (VAS). Adverse events were collected from the beginning of the first injection through 30 days after the first injection. Safety follow-up phone calls were conducted on day 2 (24 hours after the sixth injection) and day 31 (+2 days).
  • VAS Visual Analog Scale
  • Test formulation 1.0 100 mM sodium chloride, 25 mM without sodium L-arginine, 1.0% (w/v) sucrose, phosphate 0.01% (w/v) polysorbate 20 E.
  • Test formulation 0.51 100 mM sodium chloride, 25 mM without sodium L-arginine, 1.0% (w/v) sucrose, phosphate 0.01% (w/v) polysorbate 20 F.
  • VAS scores were calculated for VAS scores by solution. VAS scores were analyzed using an analysis of variance (ANOVA) model, which included sequence, solution, and period as independent variables, and subject within sequence as a random effect. No adjustment was made for multiple comparisons.
  • ANOVA analysis of variance
  • Solution C non-product specific placebo with benzyl alcohol
  • Solution D non-product specific placebo without sodium phosphate
  • No significant differences in mean VAS scores were found between Solutions C and D, between Solution B (etanercept placebo) and Solution F (active etanercept), or between different injection volumes (0.51 and 1.0 mL).
  • Solution A negative pain control
  • Enbrel drug substance in PASS 25 mM phosphate buffer, 25 mM L-arginine, 100 mM NaCl, 1% sucrose was used for this study.
  • the material was diafiltered into PASS and SAS_100NaCl (25 mM L-arginine, 100 mM NaCl, 1% sucrose) at 50 mg/mL and then ultrafiltered to ⁇ 75 mg/mL.
  • the 50 mg/mL formulations were prepared by diluting the post-UF/DF PASS and SAS material with the corresponding solution.
  • the SAST_120NaCl was prepared by diluting the 75 mg/mL SAS material using a concentrated NaCl stock solution to achieve a final concentration of 120 mM NaCl.
  • a 1% stock solution of polysorbate 20 was prepared fresh and spiked into all formulation to a final concentration of 0.010%. All formulations were manually filled into 1 mL long BD glass syringes to a volume of 1 mL and then stoppered using an ASPU vacuuming stoppering unit.
  • the pH was measured using a Mettler Toledo SevenEasy pH meter combined with a Mettler Inlab MicroProbe. Samples were warmed to room temperature prior to measurements. Protein concentration measurements using absorbance at 280 nM for all samples were performed at room temperature using the DropSense96 UV/Vis Lab Chip DS system. Each sample was measured neat with at least three replicates (3 ⁇ L each), including a formulation solution blank. Osmolality was measured using The Advanced Osmometer Model 3900. Each measurement was performed using 250 ⁇ L of sample and 290 mOsm osmolality standards were tested to ensure the system was operating properly. Size exclusion HPLC was run on an Agilent 1100 HPLC with Chromeleon 7.2 software.
  • Hydrophobic interaction HPLC was run on an Agilent 1100 HPLC with Chromeleon 7.2 software at an absorbance of 215 nm.
  • Denatured size exclusion HPLC was run on an Agilent 1100 HPLC with Chromeleon 7.2 software.
  • Sub-visible particle analysis was performed using a HACH HIAC/Royco particle counter system equipped with an HRLD-150 laser and Pharm Spec software. All samples were diluted with PASS formulation buffer to 25 mg/mL. Samples were thoroughly mixed, uncapped and degassed for 2 hours at 75 torr prior to analysis. Four (4) sips of 1.0 mL each (no tare volume) were performed, with the first sip discarded and the remaining three sips averaged. Data for particle sizes 2, 5, 10, and m was collected at all time points. The results account for the dilution and are reported as cumulative counts per milliliter.
  • the protein concentration of all formulations was tested at time zero.
  • the protein concentration results for all samples can be found in Table 13. All samples met the acceptance criteria.
  • Osmolality was tested at time zero only. The osmolality results for all samples can be found in Table 14. All formulations were at their target osmolality. Due to differences in buffer and excipient levels, the osmolality was not expected to be the same across the various formulations.
  • Peak B is the amount of high molecular weight species (aggregate) that forms. Results showed no differences in Peak B between the PASST control and the buffer-less formulations at 4° C. and 25° C., with minor differences being observed after twelve weeks at 40° C. ( FIG. 1 ). Peak B represents the total aggregate detected by SE-HPLC for these formulations. All samples remained acceptable (Peak B ⁇ 6%,) after 52 weeks of storage at 4° C., 24 weeks of storage at 25° C., and after twelve weeks of storage at 40° C.
  • Sub-visible particles were monitored by light obscuration particle counting (HIAC). Results were in line with historical PFS data and were similar between the formulations across all temperatures after twelve weeks. No trends could be established from this data set, as a single vial containing three pooled syringes was used at each time point and there is a high level of syringe-to-syringe variability in the contribution to silicone oil droplets.
  • HIAC light obscuration particle counting
  • Osmolality pH Sample (mg/mL) (mOsm) 0 F/T 3 F/T 5 F/T PASS 47.9 310 6.30 6.29 6.27 SAST_100NaCl 48.8 259 6.19 6.18 6.16 SAST_120NaCl 48.1 294 6.17 6.19 6.18 SAS_120NaCl 48.6 300 6.17 6.17 6.18
  • Etanercept 25 mg/mL, in TMS (10 mM Tris HCl, 4% mannitol, 1% sucrose, pH 7.4); SAS_100NaCl solution (100 mM NaCl, 25 mM L-arginine HCl, 1% sucrose, pH 6.3) for dialysis; PASS buffer (25 mM Phosphate, 100 mM NaCl, 25 mM L-arginine HCl, 1% sucrose, pH 6.3); 10,000 MWCO centripreps; 3-12 mL Slide-A-Lyzer dialysis cassettes, 10,000 MWCO; a Mettler Toledo MP220 pH meter and Mettler Toledo InLab MicroProbe.
  • TMS 10 mM Tris HCl, 4% mannitol, 1% sucrose, pH 7.4
  • SAS_100NaCl solution 100 mM NaCl, 25 mM L-arginine HCl, 1% sucrose, pH 6.3
  • the formulation solution that was chosen following this study was termed SAS (120 mM sodium chloride, 25 mM L-arginine, 1% sucrose, pH 6.3), without added phosphate buffer. Since the previous example demonstrated that it was difficult to attain the target pH of 6.3 when either dialyzing or using UF/DF when starting from etanercept in a sample at pH 7.56, a different method of exchange into the SAS formulation was needed. Two methods were evaluated that utilized separate final UF/DF starting material: 1) column 3 (AEX) intermediate pool as the starting material, and 2) Enbrel drug substance in PASS formulation buffer (PASS DS intermediate pool) as the starting material. Each method is described below and summarizes the development of a final UF/DF unit operation step to produce 50 g/L SAS formulated etanercept, including preparation of SAS formulation solution, final UF/DF load conditioning and processing.
  • SAS 120 mM sodium chloride, 25 mM L-arginine, 1% sucrose, pH 6.3
  • the SAS formulation solution is composed of 120 mM sodium chloride, 25 mM L-arginine, 1% sucrose, pH 6.3.
  • An SAS formulation solution was titrated to pH 6.3 using 10 N NaOH.
  • the volume of titrant required to reach the specific pH range was 4.4 L/L SAS formulation solution.
  • the pH of the permeate remained close to the pH of WFI rather than the pH of the SAS formulation solution. Without being bound to a particular theory, this is believed to be due to the low buffering capacity of the SAS formulation solution.
  • the expected range for conductivity of the permeate following membrane equilibration using the range of the SAS formulation solution preparation is 12-16 mS/cm.
  • a higher post equilibration pH than that of the SAS formulation solution is expected and should not raise concern or indicate that the membranes are not equilibrated.
  • AEX Intermediate Pool Starting Material Prior to transferring the AEX intermediate pool into the retentate tank of an UF/DF tank, the pool was conditioned using 2 M HCl to a target pH of 6.3 (acceptable range 6.2-6.4). The volume of titrant required to reach the specific pH range was approximately 2.8 mL/L AEX intermediate pool.
  • the conditioned AEX intermediate pool can be held for up to 52.6 hours at controlled room temperature (CRT).
  • CRT controlled room temperature
  • the pH of the pool during the hold is shown in FIG. 8 .
  • the final UF/DF SAS pool generated using AEX intermediate pool as the starting material, can be held for up to 96.3 hours at CRT.
  • the pH and conductivity during the hold are shown in FIGS. 9 A and B. Over the 96.3 hour hold, the pH and conductivity remain within acceptable limits.
  • PASS DS Intermediate Pool Starting Material No conditioning is required prior to transferring the PASS DS intermediate pool into the UF/DF retentate tank because the PASS DS intermediate pool is already within the acceptable pH range. In addition, since the starting material is 50 mg/mL PASS formulated Enbrel DS, the pool does not need to be concentrated to 50 g/L because it is already at the correct concentration to perform diafiltration.
  • the product quality results for the final SAS UF/DF pool, generated using PASS DS intermediate pool as the starting material, are shown in Table 21.
  • the step yield for Run 1 was outside of the acceptance criteria; however, it was most likely an artifact of bench-scale processing and considered not significant to the conclusions of the study.
  • the final SAS UF/DF pool also met acceptance criteria for product quality using SEC and HIC analysis, as described above.
  • the PASS pool does not require conditioning prior to UF/DF processing with SAS solution because this intermediate pool is already at the target pH (6.3).
  • a pool hold study was not performed for this intermediate pool because the conditions of the pool were unchanged from Enbrel PASS DS.
  • the pool can be held for up to 96 hours at 25° C.
  • the final UF/DF SAS pool generated using PASS DS intermediate pool as the starting material, can be held for up to 96.3 hours at CRT.
  • the pH and conductivity during the hold are shown in FIGS. 9 A and B. Over the 96.3 hour hold, the pH and conductivity remain within acceptable limits.
  • the SAS formulation solution can be held for up to 28 days at CRT.
  • the pH and conductivity are shown in FIGS. 10 A and B. Over the 42 day hold in small scale stainless steel stability chambers with very small headspace, the SAS formulation solution is demonstrated to maintain a pH within 5.6 to 6.5. There was precipitation observed at the 35 day and 42 day time points. The 21 day time point measurement of 5.09 appears to be an outlier due to the fact that the subsequent time points are within the proposed acceptance criteria.
  • the final UF/DF unit operation can produce 50 g/L SAS formulation product and achieve consistent product quality compared to the current commercial PASS formulation product under the following process recommendations: 1) utilizing either AEX intermediate pool, or PASS DS intermediate pool, as the starting material 2) the SAS solution can be held for at least 28 days at CRT and maintain a pH of 5.6 to 6.5, 3) the conditioned AEX intermediate pool can be held at CRT for at least 52.6 hours and maintain a pH of 6.3 ⁇ 0.1, and 4) the SAS formulated UF/DF pool can be held at CRT for at least 96.3 hours and maintain a pH of 6.1 to 6.5 and a conductivity of 10 to 14 mS/cm.
  • the goal of this example was to determine the effect on aggregation of increased levels of arginine, sucrose or sodium chloride on etanercept stability at 75 mg/mL at 40° C.
  • the levels of these excipients were each increased to maintain an isotonic formulation without added phosphate buffer. Additionally, histidine was evaluated as a buffer to replace phosphate.
  • Table 22 The formulations tested are summarized in Table 22.
  • Enbrel drug substance in PASS 25 mM phosphate buffer, 25 mM L-arginine, 100 mM NaCl, 1% sucrose
  • the material was dialyzed into the new formulations (without polysorbate) and concentrated to using 75 mg/mL using 30,000 MWCO centripreps.
  • a 1% stock solution of polysorbate 20 was prepared fresh and spiked into all formulation to a final concentration of 0.01%. All formulations were manually filled into 1 mL long BD glass syringes to a volume of 1.0 mL and then stoppered using an ASPU vacuuming stoppering unit.
  • the pH was measured using a Mettler Toledo pH meter combined with a Mettler MicroProbe. Samples were warmed to room temperature prior to measurements. Osmolality was measured using The Advanced Osmometer Model 3900. Each measurement was performed using 250 ⁇ L of sample and 290 osmolality standards were tested to ensure the system was operating properly. Size exclusion HPLC was run on an Agilent 1100 HPLC with Chromeleon 7.2 software.
  • Example 8 Stability of Formulations with Various Levels of Polysorbate 20
  • the results of the study showed that the 50 mg/mL formulations tested remained similar to the current commercial formulation after 24 weeks at recommended storage of 2-8° C., as well as at accelerated temperatures of 25° C. and 40° C.
  • the 100 mg/mL SAST formulation performed comparably to the 50 mg/mL formulations in terms of pH and subvisible particles; differences in aggregate levels by SEC were attributed to protein concentration.
  • Enbrel drug substance in TMS (10 mM tris buffer, 4% mannitol, 1% sucrose) at 25 mg/mL was used for this study.
  • the bulk used for the SAS formulation was titrated to pH 6.3.
  • the material was ultrafiltered to ⁇ 50 mg/mL etanercept, then diafiltered into PASS (25 mM phosphate, 25 mM L-arginine, 120 mM NaCl, 1% sucrose) or SAS (25 mM L-arginine, 120 mM NaCl, 1% sucrose) at 50 mg/mL etanercept.
  • the material for the high concentration arm was then ultrafiltered to 100 mg/mL etanercept.
  • a 1% stock solution of polysorbate 20 was prepared fresh and spiked into the formulations to the final concentrations as listed in Table 25. All formulations were manually filled into 1 mL long BD glass syringes to a volume of 1 mL and then stoppered using an ASPU vacuuming stoppering unit.
  • the pH of all formulations was measured at time zero and after twelve weeks at 40° C. and 24 weeks at 4° C. and 25° C. No trends were observed as a function of time or storage temperature.
  • the measured pH values for all samples can be found in Table 26. No drift in pH was observed after twelve weeks of storage at 40° C. or 24 weeks at 4° C. and 25° C. and all samples met the acceptance criteria of +/ ⁇ 0.2 pH units from the target pH of 6.3.
  • the protein concentration and osmolality of all formulations was tested at time zero. The protein concentration and osmolality results for all samples can be found in Table 26.
  • Peak B is the amount of high molecular weight species (aggregate) that forms. Results showed no differences in Peak B between the PASS control and the bufferless formulations at all temperatures at their respective protein concentrations (Table 27-29). Peak B represents the total aggregate detected by SE-HPLC for these formulations. All 50 mg/mL samples remained acceptable (Peak B ⁇ 6%,) after 24 weeks of storage at 4° C. and 25° C., and after 2 weeks of storage at 40° C.
  • Etanercept drug substance in TMS (10 mM tris buffer, 4% mannitol, 1% sucrose) at 25 mg/mL etanercept was used for this study.
  • the bulk used for the SAS formulation was titrated to pH 6.3. The material was ultrafiltered to ⁇ 50 mg/mL etanercept, then diafiltered into PASS (25 mM phosphate, 25 mM L-arginine, 120 mM NaCl, 1% sucrose) or SAS (25 mM L-arginine, 120 mM NaCl, 1% sucrose) at 50 mg/mL etanercept.
  • the pH was measured using a Mettler Toledo SevenEasy pH meter combined with a Mettler Inlab MicroProbe. Samples were warmed to room temperature prior to measurements. Protein concentration measurements using absorbance at 280 nM for all samples were performed at room temperature using the Nano Drop system. Size exclusion HPLC was run on an Agilent 1100 HPLC with Chromeleon 7.2 software. Sub-visible particle analysis was performed using a HACH HIAC/Royco particle counter system equipped with an HRLD-150 laser and Pharm Spec software. All samples were diluted with PASS formulation buffer to 25 mg/mL. Samples were thoroughly mixed, uncapped and degassed for 2 hours at 75 torr prior to analysis.
  • Stability in the plastic silicone oil free syringes is similar to stability in glass siliconized syringes.
  • the protein concentration of all formulations was tested at time zero.
  • the pH of all formulations was measured at time zero and after twelve weeks at 40° C. and 24 weeks at 4° C. and 25° C. No trends were observed as a function of time or storage temperature and all samples met the pH acceptance criteria of +/ ⁇ 0.2 pH units from the target pH of 6.3.
  • the protein concentration and measured pH values for all samples can be found in Table 31.
  • Peak B is the amount of high molecular weight species (aggregate) that forms. Results showed no differences in Peak B between the glass syringes and the COP plastic silicone oil free syringes (Table 32-34). Peak B represents the total aggregate detected by SE-HPLC for these formulations. All samples remained acceptable (Peak B ⁇ 6%,) after 24 weeks of storage at 4° C. and 25° C.
  • the long-term stability of the SAS formulation at 50 mg/mL etanercept and the current commercial etanercept formulation stored in glass siliconized syringes and COP silicone oil free syringes was assessed at 4° C., 25° C. and 40° C. No significant differences were observed between the formulations as a function of syringe type after 24 weeks by SE-HPLC. No drift in pH was observed and all formulations remained within acceptable ranges. Sub-visible particles were reduced in the COP silicone oil free plastic syringes and were consistent with historical PFS results when stored in the glass syringes. The results of the study showed that the SAS formulation at 50 mg/mL etanercept was stable and similar to the current commercial formulation after 24 weeks at the recommended storage temperature of 2° C. to 8° C. in various syringe types.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US15/788,762 2016-10-21 2017-10-19 Pharmaceutical Formulations and Methods of Making the Same Abandoned US20180110856A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/788,762 US20180110856A1 (en) 2016-10-21 2017-10-19 Pharmaceutical Formulations and Methods of Making the Same
US15/958,261 US10307483B2 (en) 2016-10-21 2018-04-20 Pharmaceutical formulations and methods of making the same
US16/144,120 US11491223B2 (en) 2016-10-21 2018-09-27 Pharmaceutical formulations and methods of making the same
US17/933,055 US20230080571A1 (en) 2016-10-21 2022-09-16 Pharmaceutical formulations and methods of making the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662411458P 2016-10-21 2016-10-21
US15/788,762 US20180110856A1 (en) 2016-10-21 2017-10-19 Pharmaceutical Formulations and Methods of Making the Same

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/958,261 Continuation US10307483B2 (en) 2016-10-21 2018-04-20 Pharmaceutical formulations and methods of making the same

Publications (1)

Publication Number Publication Date
US20180110856A1 true US20180110856A1 (en) 2018-04-26

Family

ID=61971152

Family Applications (4)

Application Number Title Priority Date Filing Date
US15/788,762 Abandoned US20180110856A1 (en) 2016-10-21 2017-10-19 Pharmaceutical Formulations and Methods of Making the Same
US15/958,261 Active US10307483B2 (en) 2016-10-21 2018-04-20 Pharmaceutical formulations and methods of making the same
US16/144,120 Active US11491223B2 (en) 2016-10-21 2018-09-27 Pharmaceutical formulations and methods of making the same
US17/933,055 Pending US20230080571A1 (en) 2016-10-21 2022-09-16 Pharmaceutical formulations and methods of making the same

Family Applications After (3)

Application Number Title Priority Date Filing Date
US15/958,261 Active US10307483B2 (en) 2016-10-21 2018-04-20 Pharmaceutical formulations and methods of making the same
US16/144,120 Active US11491223B2 (en) 2016-10-21 2018-09-27 Pharmaceutical formulations and methods of making the same
US17/933,055 Pending US20230080571A1 (en) 2016-10-21 2022-09-16 Pharmaceutical formulations and methods of making the same

Country Status (14)

Country Link
US (4) US20180110856A1 (ru)
EP (1) EP3528787A4 (ru)
JP (3) JP6884858B2 (ru)
KR (2) KR102413592B1 (ru)
CN (2) CN114917185B (ru)
AU (1) AU2017345490B2 (ru)
BR (1) BR112019007858A2 (ru)
CA (1) CA3040899A1 (ru)
CL (1) CL2019001053A1 (ru)
EA (1) EA201990998A1 (ru)
IL (1) IL266132B (ru)
MX (1) MX2019004580A (ru)
SG (1) SG11201903521XA (ru)
WO (1) WO2018075818A1 (ru)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10307483B2 (en) 2016-10-21 2019-06-04 Amgen Inc. Pharmaceutical formulations and methods of making the same
CN114206391A (zh) * 2019-08-09 2022-03-18 艾瑞克有限公司 包含抗体的新组合物
US11607451B2 (en) 2005-06-14 2023-03-21 Amgen Inc. Self-buffering antibody formulations

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4118113A1 (en) 2020-03-12 2023-01-18 Amgen Inc. Method for treatment and prophylaxis of crs in patients comprising a combination of bispecifc antibodies binding to cds x cancer cell and tnfalpha or il-6 inhibitor
WO2021229913A1 (ja) 2020-05-12 2021-11-18 日本電気株式会社 歪補償装置及び歪補償方法

Family Cites Families (156)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2837168A1 (de) 1978-08-25 1980-03-06 Blutspendedienst Dt Rote Kreuz Verfahren zur herstellung einer fuer die intravenoese anwendung geeigneten immunglobulinloesung
US4362661A (en) 1979-08-09 1982-12-07 Teijin Limited Immunoglobulin composition having a high monomer content, and process for production thereof
US4360457A (en) 1979-08-30 1982-11-23 Teijin Limited S-Sulfonated immunoglobulin composition having a high monomer content and a process for production thereof
US4374763A (en) 1979-09-17 1983-02-22 Morishita Pharmaceutical Co., Ltd. Method for producing gamma-globulin for use in intravenous administration and method for producing a pharmaceutical preparation thereof
US4396608A (en) 1981-08-24 1983-08-02 Cutter Laboratories Intravenously injectable immune serum globulin
US5702699A (en) 1982-09-23 1997-12-30 Cetus Corporation Process for the recovery of lipophilic proteins
US4681713A (en) 1984-03-15 1987-07-21 Toyo Boseki Kabushiki Kaisha Method of making a hollow fiber membrane for dialysis
US4597966A (en) 1985-01-09 1986-07-01 Ortho Diagnostic Systems, Inc. Histidine stabilized immunoglobulin and method of preparation
US6673347B1 (en) 1986-04-30 2004-01-06 Gryphon Therapeutics Polypeptide and protein derivatives and process for their preparation
GB8628104D0 (en) 1986-11-25 1986-12-31 Connaught Lab Pasteurization of immunoglobin solutions
DE3640513A1 (de) 1986-11-27 1988-06-09 Biotest Pharma Gmbh Verfahren zur herstellung eines virussicheren, lagerstabilen und intravenoes vertraeglichen immunglobulin-g-praeparates
JP2547556B2 (ja) 1987-02-06 1996-10-23 株式会社 ミドリ十字 ｒ−グロブリンの液状製剤
WO1990005183A1 (en) 1988-10-31 1990-05-17 Immunex Corporation Interleukin-4 receptors
US5395760A (en) 1989-09-05 1995-03-07 Immunex Corporation DNA encoding tumor necrosis factor-α and -β receptors
DK0417563T3 (da) 1989-09-12 2000-11-06 Hoffmann La Roche TNF-bindende proteiner
DE3939346A1 (de) 1989-11-29 1991-06-06 Behringwerke Ag Arzneimitel zur subkutanen oder intramuskulaeren applikation enthaltend polypeptide
US5945098A (en) 1990-02-01 1999-08-31 Baxter International Inc. Stable intravenously-administrable immune globulin preparation
US5177194A (en) 1990-02-01 1993-01-05 Baxter International, Inc. Process for purifying immune serum globulins
GB9017002D0 (en) 1990-08-02 1990-09-19 Health Lab Service Board Improved method for the purification of erwina l-asparaginase
JP3179538B2 (ja) 1990-12-11 2001-06-25 ノバルティス アクチエンゲゼルシャフト 安定なヒトカルシトニンの水性溶液
US5110910A (en) 1991-03-25 1992-05-05 Miles Inc. Virucidal euglobulin precipitation
US5256571A (en) 1991-05-01 1993-10-26 Cytyc Corporation Cell preservative solution
CA2126182C (en) 1991-12-20 2001-07-17 Man S. Co Humanized antibodies reactive with gpiib/iiia
US6004555A (en) 1992-03-05 1999-12-21 Board Of Regents, The University Of Texas System Methods for the specific coagulation of vasculature
US5298410A (en) 1993-02-25 1994-03-29 Sterling Winthrop Inc. Lyophilized formulation of polyethylene oxide modified proteins with increased shelf-life
US5484892A (en) 1993-05-21 1996-01-16 Dana-Farber Cancer Institute, Inc. Monoclonal antibodies that block ligand binding to the CD22 receptor in mature B cells
DE4344824C1 (de) 1993-12-28 1995-08-31 Immuno Ag Hochkonzentriertes Immunglobulin-Präparat und Verfahren zu seiner Herstellung
GB9401448D0 (en) 1994-01-26 1994-03-23 Ciba Geigy Ag Stable dry powders
US5580856A (en) 1994-07-15 1996-12-03 Prestrelski; Steven J. Formulation of a reconstituted protein, and method and kit for the production thereof
AU3272695A (en) 1994-08-12 1996-03-07 Immunomedics Inc. Immunoconjugates and humanized antibodies specific for b-cell lymphoma and leukemia cells
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
BRPI9715219B8 (pt) 1996-02-09 2015-07-07 Abbvie Biotechnology Ltd Vetor recombinante de expressão, e célula hospedeira procariótica.
TWI240627B (en) 1996-04-26 2005-10-01 Chugai Pharmaceutical Co Ltd Erythropoietin solution preparation
GB9610992D0 (en) 1996-05-24 1996-07-31 Glaxo Group Ltd Concentrated antibody preparation
TW555765B (en) 1996-07-09 2003-10-01 Amgen Inc Low molecular weight soluble tumor necrosis factor type-I and type-II proteins
KR20000067911A (ko) 1996-07-18 2000-11-25 씨에스엘 리미티드 면역글로불린 용액의 저온살균방법
TW491855B (en) 1996-08-07 2002-06-21 Csl Ltd Purification of immunoglobulins
EP0852951A1 (de) 1996-11-19 1998-07-15 Roche Diagnostics GmbH Stabile lyophilisierte pharmazeutische Zubereitungen von mono- oder polyklonalen Antikörpern
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US5886154A (en) 1997-06-20 1999-03-23 Lebing; Wytold R. Chromatographic method for high yield purification and viral inactivation of antibodies
JP3679406B2 (ja) 1998-05-20 2005-08-03 協和醗酵工業株式会社 遺伝子組換え抗体
US6436897B2 (en) 1998-06-01 2002-08-20 Celtrix Pharmaceuticals, Inc. Pharmaceutical formulations for IGF/IGFBP
DK2272870T3 (da) 1998-06-09 2013-08-05 Csl Behring Ag Fremgangsmåde til fremstilling af immunoglobuliner med henblik på intravenøs indgivelse og andre immunoglobulin-lignende produkter.
US6610206B1 (en) 1998-10-20 2003-08-26 Advanced Renal Technologies Buffered compositions for dialysis
IL127127A0 (en) 1998-11-18 1999-09-22 Peptor Ltd Small functional units of antibody heavy chain variable regions
US7294481B1 (en) 1999-01-05 2007-11-13 Immunex Corporation Method for producing recombinant proteins
KR20010101987A (ko) 1999-02-03 2001-11-15 스티븐 엠. 오드레 면역 반응과 관련된 신규한 폴리펩티드
DK1165119T3 (da) 1999-04-08 2003-12-15 Genentech Inc Sammensætning baseret på modsat ladede polypeptider
BR0010665A (pt) 1999-04-09 2004-03-09 Ortho Mcneil Pharm Inc ComposiçÈes farmacêuticas de eritropoietina
US20040220103A1 (en) 1999-04-19 2004-11-04 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
AU4363200A (en) 1999-04-19 2000-11-02 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical desorders
US20010021380A1 (en) 1999-04-19 2001-09-13 Pluenneke John D. Soluble tumor necrosis factor receptor treatment of medical disorders
PL211886B1 (pl) 1999-10-04 2012-07-31 Novartis Vaccines & Diagnostic Stabilizowana ciekła kompozycja farmaceutyczna, sposób zwiększania trwałości polipeptydu, sposób zwiększania trwałości podczas przechowywania kompozycji, sucha postać kompozycji oraz preparat zawierający kompozycję
AU768324B2 (en) 1999-12-14 2003-12-11 Genentech Inc. TNF-alpha antagonist and LFA-1 antagonist for treating LFA-1 or TNF-alpha mediated disorder
JP2004500063A (ja) 1999-12-16 2004-01-08 アムジェン　インコーポレイテッド Ｔｎｆｒ／ｏｐｇ様分子およびその使用
WO2001058473A1 (en) 2000-02-10 2001-08-16 Wyeth Method of treating or inhibiting cellular injury or cell death
DE60028830T2 (de) 2000-02-16 2007-01-18 Genentech, Inc., South San Francisco Anti-april antikörper und hybridomazellen
EP1304376A4 (en) 2000-07-25 2004-12-29 Takeda Chemical Industries Ltd PROCESS FOR PRODUCING RECOMBINANT PROTEIN
AU2001276737A1 (en) 2000-08-04 2002-02-18 Chugai Seiyaku Kabushiki Kaisha Protein injection preparations
ES2644275T3 (es) 2000-08-11 2017-11-28 Chugai Seiyaku Kabushiki Kaisha Preparaciones estabilizadas que contienen anticuerpos
DK1324776T4 (en) 2000-10-12 2018-05-28 Genentech Inc CONCENTRATED PROTEIN FORMULATIONS WITH REDUCED VISCOSITY
MXPA03005327A (es) 2000-12-14 2004-12-03 Fujisawa Pharmaceutical Co Anticuerpos anti-cd28 silenciados y el uso de estos.
US6693173B2 (en) 2000-12-26 2004-02-17 Alpha Therapeutic Corporation Method to remove citrate and aluminum from proteins
CN1854157B (zh) 2001-01-05 2013-01-02 辉瑞大药厂 胰岛素样生长因子i受体的抗体
ES2184594B1 (es) 2001-01-17 2004-01-01 Probitas Pharma Sa Procedimiento para la produccion de gammaglobulina g humana inactivada de virus.
HUP0303246A2 (hu) 2001-02-23 2003-12-29 Immunex Corporation Aktív fehérjék fokozott kinyerése
GB0113179D0 (en) 2001-05-31 2001-07-25 Novartis Ag Organic compounds
JP2004521474A (ja) 2001-06-25 2004-07-15 コーニンクレッカ　フィリップス　エレクトロニクス　エヌ　ヴィ 高圧ガス放電ランプおよび高圧ガス放電ランプの製造方法
JP4212470B2 (ja) 2001-06-26 2009-01-21 アムジェン フレモント インク． Ｏｐｇｌへの抗体
BR0212136A (pt) * 2001-08-23 2004-12-07 Genmab As Anticorpo monoclonal humano isolado, métodos para inibir a produção de tnfa em células t ou monócitos e a proliferação de célula t, hibridoma, transfectoma, animal não humano transgênico, método para produzir um anticorpo monoclonal humano, composição farmacêutica, métodos para tratar ou prevenir um distúrbio mediado pela il-15 humana, a psorìase e a artrite reumatóide, método para diagnosticar uma doença, ácido nucleico, e, vetor de expressão
US7247304B2 (en) 2001-08-23 2007-07-24 Genmab A/S Methods of treating using anti-IL-15 antibodies
IL159422A0 (en) 2001-09-20 2004-06-01 Cornell Res Foundation Inc Methods and compositions for treating or preventing skin disorders using binding agents specific for prostate-specific membrane antigen
ATE556591T1 (de) 2001-11-08 2012-05-15 Abbott Biotherapeutics Corp Stabile pharmazeutische flüssigformulierung von igg-antikörpern
US20030143603A1 (en) 2001-11-30 2003-07-31 Jill Giles-Komar Anti-TNF antibodies, compositions, methods and uses
MXPA04006053A (es) 2001-12-21 2005-03-31 Immunex Corp Metodos para purificacion de proteina.
EP3192528A1 (en) 2002-02-14 2017-07-19 Chugai Seiyaku Kabushiki Kaisha Formulation of anti-il6r antibody-containing solutions comprising a sugar as a stabilizer
CA2476776A1 (en) 2002-02-21 2003-09-04 Duke University Reagents and treatment methods for autoimmune diseases
PL215168B1 (pl) 2002-02-27 2013-10-31 Immunex Corp Formulacja polipeptydowa
AU2003220529B2 (en) 2002-03-27 2006-09-07 Immunex Corporation Methods for increasing polypeptide production
JP4761710B2 (ja) 2002-04-05 2011-08-31 アムジェン インコーポレイテッド 選択的ｏｐｇｌ経路インヒビターとしてのヒト抗ｏｐｇｌ中和抗体
US20030206898A1 (en) 2002-04-26 2003-11-06 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
JP4319979B2 (ja) 2002-04-26 2009-08-26 ジェネンテック・インコーポレーテッド タンパク質の非アフィニティ精製
GB0210121D0 (en) 2002-05-02 2002-06-12 Celltech R&D Ltd Biological products
CA2490423A1 (en) 2002-06-21 2003-12-31 Biogen Idec Inc. Buffered formulations for concentrating antibodies and methods of use thereof
PL218992B1 (pl) 2002-07-19 2015-02-27 Abbott Biotech Ltd Neutralizujące o wysokim powinowactwie izolowane ludzkie przeciwciało anty-TNFα, zastosowanie tego przeciwciała, kryształ zawierający ludzkie przeciwciało anty-TNFα i preparat zawierający ten kryształ
US20040033228A1 (en) 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
DE60326012D1 (de) 2002-11-01 2009-03-12 Bayer Healthcare Llc Verfahren zur Konzentration von Proteinen
US20040086532A1 (en) 2002-11-05 2004-05-06 Allergan, Inc., Botulinum toxin formulations for oral administration
US7511012B2 (en) 2002-12-20 2009-03-31 Amgen Inc. Myostatin binding agents
BRPI0408317A (pt) 2003-03-14 2006-03-07 Pharmacia Corp anticorpos do receptor de igf-i para o tratamento de cáncer
LT2335725T (lt) 2003-04-04 2017-01-25 Genentech, Inc. Didelės koncentracijos antikūno ir baltymo kompozicijos
WO2004104021A2 (en) 2003-05-14 2004-12-02 Dow Corning Corporation Controlled release of active agents utilizing repeat sequence protein polymers
US7354578B2 (en) 2003-06-06 2008-04-08 Regeneron Pharmaceuticals, Inc. Method of tumor regression with VEGF inhibitors
ES2315664T3 (es) 2003-06-30 2009-04-01 Domantis Limited Anticuerpos de dominio unico (dab) pegilados.
CA2543982C (en) 2003-11-07 2013-01-08 Immunex Corporation Antibodies that bind interleukin-4 receptor
EP1532983A1 (en) 2003-11-18 2005-05-25 ZLB Bioplasma AG Immunoglobulin preparations having increased stability
CN1953768B (zh) 2004-02-12 2010-10-13 默克专利有限公司 抗-egfr抗体的高浓缩液体制剂
US20070292346A1 (en) 2004-03-25 2007-12-20 Rong Fan Lng105 Antibody Composition and Methods of Use, and Use of Lng105 to Assess Lung Cancer Risk
MXPA06012992A (es) 2004-05-12 2007-02-12 Baxter Int Microesferas que comprenden proteina y que muestran inyectabilidad en altas concentraciones de este agente.
JPWO2006003999A1 (ja) 2004-07-05 2008-07-31 財団法人化学及血清療法研究所 ヒト抗ヒトｂ７ｒｐ−１抗体およびその抗体フラグメント
JP5015774B2 (ja) * 2004-07-29 2012-08-29 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ジフルオロ置換複素環化合物および液晶媒体における構成要素としてのその使用
TW200621282A (en) 2004-08-13 2006-07-01 Wyeth Corp Stabilizing formulations
US7300773B2 (en) 2004-08-27 2007-11-27 Wyeth Research Ireland Limited Production of TNFR-Ig
EP1685161A1 (en) 2004-08-30 2006-08-02 Lonza Biologics plc Affinity- plus ion exchange-chromatography for purifying antibodies
US20060051347A1 (en) 2004-09-09 2006-03-09 Winter Charles M Process for concentration of antibodies and therapeutic products thereof
WO2006064373A2 (en) 2004-12-16 2006-06-22 Genzyme Polyclonals S.A.S. Methods of purifying immunologlobulins
JP4498939B2 (ja) 2005-02-01 2010-07-07 東京応化工業株式会社 ポジ型レジスト組成物およびレジストパターン形成方法
US8597709B2 (en) 2005-04-12 2013-12-03 Inovobiologic Inc. Dietary supplement and methods of use
EP1909831A4 (en) 2005-06-14 2013-02-20 Amgen Inc PREPARATIONS OF SPONTANEOUS TAMPING PROTEINS
US7612181B2 (en) 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
US20070049732A1 (en) 2005-09-01 2007-03-01 Zurlo Eugene J Ultra-high yield intravenous immune globulin preparation
US8241692B2 (en) 2005-09-21 2012-08-14 Burcon Nutra Science (MB) Corp. Preparation of canola protein isolate involving isoelectric precipitation
US8067350B2 (en) 2005-12-15 2011-11-29 Kimberly-Clark Worldwide, Inc. Color changing cleansing composition
US20070202051A1 (en) 2006-02-10 2007-08-30 Pari Gmbh Aerosols for sinunasal drug delivery
NZ571757A (en) 2006-04-21 2012-01-12 Novartis Ag Antagonist anti-CD40 antibody pharmaceutical compositions comprising arginine-HCl and a citrate or citric acid buffer
AU2007240732B2 (en) 2006-04-21 2013-07-04 Amgen, Inc. Buffering agents for biopharmaceutical formulations
EP2059523A2 (en) 2006-09-15 2009-05-20 Barofold, Inc. High pressure treatment of proteins for reduced immunogenicity
KR20150002896A (ko) 2006-10-27 2015-01-07 애브비 바이오테크놀로지 리미티드 결정형 항-ｈＴＮＦ알파 항체
MX2009006594A (es) 2006-12-21 2009-08-12 Amgen Inc Formulaciones de ph regulado y estables que contienen polipeptidos.
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
SG10201604258YA (en) 2007-11-30 2016-07-28 Abbvie Biotechnology Ltd Anti-tnf antibody formulations
BRPI0908361A2 (pt) * 2008-02-07 2015-04-07 Amgen Inc Seringas previamente cheias contendo composição e métodos de preparação das mesmas e de estabilização de agente de ligação específico em composição.
CA3142745A1 (en) 2008-05-20 2009-11-26 Avant Medical Corp. Autoinjector system
US8052645B2 (en) 2008-07-23 2011-11-08 Avant Medical Corp. System and method for an injection using a syringe needle
US8177749B2 (en) 2008-05-20 2012-05-15 Avant Medical Corp. Cassette for a hidden injection needle
CN102159204B (zh) * 2008-09-19 2015-04-01 辉瑞公司 稳定的液体抗体制剂
EP3011953A1 (en) * 2008-10-29 2016-04-27 Ablynx N.V. Stabilised formulations of single domain antigen binding molecules
KR20110128333A (ko) 2009-03-06 2011-11-29 제넨테크, 인크. 항체 제제
US20110070227A1 (en) 2009-09-18 2011-03-24 Anna-Marie Novotney-Barry Treatment of Autoimmune and Inflammatory Diseases
PL2637690T3 (pl) 2010-11-11 2017-03-31 Abbvie Biotechnology Ltd Płynne formulacje zawierające przeciwciało anty-tnf alfa o wysokim stężeniu
US9173999B2 (en) 2011-01-26 2015-11-03 Kaleo, Inc. Devices and methods for delivering medicaments from a multi-chamber container
CA3021845C (en) 2011-04-20 2022-03-29 Amgen Inc. Autoinjector apparatus
US9453067B2 (en) * 2011-04-20 2016-09-27 Sandoz Ag Stable pharmaceutical liquid formulations of the fusion protein TNFR:Fc
UY34105A (es) * 2011-06-03 2012-07-31 Lg Life Sciences Ltd Formulación líquida estable de etanercept
MX358137B (es) 2011-07-01 2018-08-06 Biogen Idec Inc Composiciones del polipéptido de fusión tnfr: fc exentas de arginina y métodos de uso.
HUE045624T2 (hu) * 2011-10-18 2020-01-28 Coherus Biosciences Inc Magnézium ionokkal stabilizált etanercept készítmények
JP2015519382A (ja) * 2012-06-12 2015-07-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 治療用抗体のための医薬処方物
US8920374B2 (en) 2012-07-05 2014-12-30 Unitract Syringe Pty Ltd Drive control mechanisms and automatic injectors for injectable cartridges
PE20150762A1 (es) 2012-07-09 2015-06-20 Coherus Biosciences Inc Formulaciones de etanercept que muestran una marcada reduccion de la cantidad de particulas subvisibles
JP2015533797A (ja) * 2012-09-11 2015-11-26 コヒラス・バイオサイエンシズ・インコーポレイテッド 高純度および優れた収率の正確に折り畳まれたエタネルセプト
KR102132050B1 (ko) * 2012-10-26 2020-07-10 루핀 아틀란티스 홀딩스 에스에이 티엔에프알에프씨 융합 단백질의 안정한 약학 조성물
EP2919812A4 (en) * 2012-11-19 2016-05-18 Merck Sharp & Dohme Liquid formulations for TNFR: FC fusion proteins
JP6026002B2 (ja) * 2012-11-27 2016-11-16 アルテオジェン インコーポレイテッド タンパク質とＦｃドメインを融合した融合タンパク質の安定化用組成物
US9452138B2 (en) 2012-12-28 2016-09-27 Abbott Cardiovascular Systems Inc. Delivery of biologic therapeutics
TWI580452B (zh) 2013-03-15 2017-05-01 安美基公司 用於注射器之匣盒、注射器及使用包括自動注射器及匣盒之設備之方法
JP6336564B2 (ja) 2013-03-15 2018-06-06 アムゲン・インコーポレーテッド 薬物カセット、自動注入器、および自動注入器システム
AU2014261477A1 (en) 2013-05-02 2015-11-19 Mabxience, S.A. Alternative formulations for TNFR: Fc fusion polypeptides
CN105611938A (zh) * 2013-10-24 2016-05-25 免疫医疗有限责任公司 稳定的水性抗体配制品
US9700595B2 (en) 2013-11-29 2017-07-11 Ares Trading Sa Liquid formulation of a fusion protein comprising TNFR and Fc region
EP2975050B1 (en) 2014-07-18 2019-05-29 Sandoz Ag Quantification of misfolded TNFR2:Fc
EP3733228B1 (en) 2014-08-28 2024-03-06 UNL Holdings LLC Sensor systems for drug delivery devices
PT3185934T (pt) 2014-08-28 2018-10-19 Unl Holdings Llc Sensores de pele para dispositivos de administração de medicamento
US10959939B2 (en) 2014-12-22 2021-03-30 Ares Trading S.A. Liquid pharmaceutical composition of etanercept with lysine and proline
WO2016149139A1 (en) 2015-03-13 2016-09-22 Samsung Bioepis Co., Ltd. Anti-tnf-alpha polypeptide composition and use thereof
US9763976B1 (en) 2016-08-02 2017-09-19 Zo Skin Health, Inc. Composition and method for treating skin conditions
US20180110856A1 (en) 2016-10-21 2018-04-26 Amgen Inc. Pharmaceutical Formulations and Methods of Making the Same

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11607451B2 (en) 2005-06-14 2023-03-21 Amgen Inc. Self-buffering antibody formulations
US10307483B2 (en) 2016-10-21 2019-06-04 Amgen Inc. Pharmaceutical formulations and methods of making the same
US11491223B2 (en) 2016-10-21 2022-11-08 Amgen Inc. Pharmaceutical formulations and methods of making the same
CN114206391A (zh) * 2019-08-09 2022-03-18 艾瑞克有限公司 包含抗体的新组合物

Also Published As

Publication number Publication date
BR112019007858A2 (pt) 2019-07-02
JP6884858B2 (ja) 2021-06-09
CN114917185A (zh) 2022-08-19
US20230080571A1 (en) 2023-03-16
US11491223B2 (en) 2022-11-08
KR102446838B1 (ko) 2022-09-26
US10307483B2 (en) 2019-06-04
CN114917185B (zh) 2023-11-14
WO2018075818A1 (en) 2018-04-26
IL266132A (en) 2019-06-30
EP3528787A1 (en) 2019-08-28
MX2019004580A (es) 2019-08-12
EP3528787A4 (en) 2020-05-06
KR20190071760A (ko) 2019-06-24
CL2019001053A1 (es) 2019-08-02
CN109982685A (zh) 2019-07-05
CA3040899A1 (en) 2018-04-26
IL266132B (en) 2021-12-01
US20190022217A1 (en) 2019-01-24
KR20210158878A (ko) 2021-12-31
EA201990998A1 (ru) 2019-11-29
JP2021120393A (ja) 2021-08-19
JP7402195B2 (ja) 2023-12-20
SG11201903521XA (en) 2019-05-30
AU2017345490B2 (en) 2022-07-07
JP2024010026A (ja) 2024-01-23
KR102413592B1 (ko) 2022-06-27
CN109982685B (zh) 2022-03-11
US20180256718A1 (en) 2018-09-13
AU2017345490A1 (en) 2019-05-09
JP2019533679A (ja) 2019-11-21

Similar Documents

Publication Publication Date Title
US20230080571A1 (en) Pharmaceutical formulations and methods of making the same
US11129876B2 (en) Etanercept formulations stabilized with amino acids
EP2726090B1 (en) Arginine - free tnfr : fc- fusion polypeptide compositions
AU2020244614A1 (en) Stable protein solution formulation containing high concentration of an anti-VEGF antibody
US10258689B2 (en) Stable liquid formulation of etanercept
US9186401B2 (en) Concentrated human immunoglobulin composition
WO2017104778A1 (ja) 抗ヒトｔｓｌｐ受容体抗体含有医薬組成物
EP3897714A1 (en) Protein solution formulation containing high concentration of an anti-vegf antibody
EA041785B1 (ru) Фармацевтическая композиция и способ ее получения
KR20240053633A (ko) Vegf 수용체 융합 단백질을 위한 제제
JP2022546400A (ja) 高濃度の薬理学的に活性な抗体の新規製剤
NZ618054B2 (en) Stable liquid formulation of etanercept

Legal Events

Date Code Title Description
AS Assignment

Owner name: AMGEN INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GOSS, MONICA;BALL, NICOLE;REEL/FRAME:044918/0556

Effective date: 20180116

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION