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WO2005072772A1 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques Download PDF

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Publication number
WO2005072772A1
WO2005072772A1 PCT/FI2005/000065 FI2005000065W WO2005072772A1 WO 2005072772 A1 WO2005072772 A1 WO 2005072772A1 FI 2005000065 W FI2005000065 W FI 2005000065W WO 2005072772 A1 WO2005072772 A1 WO 2005072772A1
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WO
WIPO (PCT)
Prior art keywords
antibodies
immunoglobulin
trehalose
liquid composition
concentration
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.)
Ceased
Application number
PCT/FI2005/000065
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English (en)
Inventor
Jaakko Parkkinen
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.)
Suomen Punainen Risti Veripalvelu
Original Assignee
Suomen Punainen Risti Veripalvelu
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 Suomen Punainen Risti Veripalvelu filed Critical Suomen Punainen Risti Veripalvelu
Publication of WO2005072772A1 publication Critical patent/WO2005072772A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • 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

Definitions

  • the present invention relates to pharmaceutical compositions.
  • the present invention concerns parenterally-administrable formulations of antibodies.
  • the invention also concerns a method of producing such formulations and the uses thereof.
  • Immunoglobulins also called antibodies, are the main effector molecules of the humoral immune response. They have a basic four-peptide structure of two identical heavy and two identical light chains, which are joined by interchain disulfide bonds. The most common immunoglobulin class is IgG, which accounts for about 75 % of the total immunoglobulins in plasma of healthy individuals. IgG is further divided into subclasses with different heavy chain isotypes: IgGl, IgG2, IgG3 and IgG4. Other immunoglobulin classes comprise IgM, IgA, IgD and IgE.
  • Antibodies exert two major effector functions: activation of complement and opsonisation, i.e. the induction of phagocytosis.
  • Immunoglobulins have a "Y" shaped structure with two antigen binding Fab parts and an Fc part, which mediates the effector functions induced as a result of binding of the Fab part to the antigen.
  • a monoclonal antibody has a single type of antigen-binding Fab part, whereas polyclonal antibodies consist of a number of different immunoglobulin molecules with variable Fab parts.
  • antibodies are exploited therapeutically in prevention and treatment of various infectious diseases. Additionally, immunoglobulins exert different immunomodulatory activities, which form the basis for their therapeutic use in a number of clinical indications. Furthermore, monoclonal antibodies with a defined antigen-binding specificity have been developed for various targets ranging from infectious agents to body's own components and their therapeutic use covers a wide range of clinical disorders.
  • Antibodies can be extracted from blood of human blood donors and they can be produced by hybridoma technology and recombinant DNA technology. In view of their broad scope of biological activity, antibodies are valuable therapeutic agents.
  • antibodies are primarily formulated for parenteral, in particular intravenous, administration.
  • Immunoglobulin purified from normal human plasma is typically given intravenously ("Imrnune globulin intravenous human” or “Human normal immunoglobulin for intravenous administration”).
  • IVIG intravenous immunoglobulin
  • IVIG is formulated into liquid compositions having high purity with respect to the immunoglobulin component and low or practically no content of polymers and aggregates.
  • a liquid formulation of antibodies such as of IVIG
  • IVIG should be formulated by keeping the following goals in mind: 1.
  • the osmolarity should be close to physiological to make intravenous infusion of even large volumes possible; 2. Formation of polymeric IgG should be prevented during storage; and 3.
  • the substance added for stabilization and adjustment of osmolarity should be compatible with IgG: there must be no chemical reactions with the protein
  • compositions of antibodies formulated for intravenous administration are provided in the form of liquid formulations, in which the active component is mixed with suitable excipients and adjuvants, including stabilizers, osmolarity regulating agents and pharmaceutical carriers.
  • suitable excipients and adjuvants including stabilizers, osmolarity regulating agents and pharmaceutical carriers.
  • Stabilizers commonly used include sugars, such as maltose, glucose and sucrose.
  • amino acids needed for adjustment of physiological osmolarity may, however, cause side effects in intravenous immunoglobulin. Furthermore, amino acids are not compatible with reducing sugars, but may lead to the formation of Schiff bases.
  • a fourth object of the invention comprises a method of providing mammals with 1) passive immunization against infectious diseases, 2) immunomodulation to alleviate and cure various clinical disorders and 3) targeted therapy with monoclonal antibodies.
  • the invention is based on the idea of using a specific non-reducing disaccharide, viz. trehalose as a stabilizing agent at a concentration, which effectively prevents polymerization and aggregation of the antibodies in the liquid parenteral compositions.
  • trehalose Being a non-reducing sugar, trehalose does not react with amino acids or proteins as part of Maillard browning.
  • Trehalose is capable of stabilizing proteins during freeze-drying and spray-drying.
  • the present invention is based on the new finding that trehalose is capable of preventing polymer formation of proteins during storage in solution in a liquid formulation.
  • antibodies are admixed in an aqueous medium with trehalose and, optionally, other auxiliary agents known per se, at a concentration of about 0.001 M to 0.5 M to provide a parenterally-administrable liquid composition.
  • Such compositions can, e.g., be administered intravenously.
  • the present invention also provides for the use of trehalose in a liquid formulation of antibodies at a concentration, which effectively prevents polymerization of the antibodies.
  • the present invention also provides a new method of providing passive immunization of mammals against infectious diseases, which method comprises parenterally administering to the mammal a liquid immunoglobulin composition, which contains trehalose as a stabilizer in a concentration sufficient to effectively prevent polymerization of the immunoglobulin.
  • liquid compositions according to the present invention are mainly characterized by what is stated in the characterizing part of claim 1.
  • the method according to the invention for preparing the liquid compositions is characterized by what is stated in the characterizing part of claim 11 and the use comprises the features of claim 13.
  • trehalose effectively prevent polymerization and other undesired reactions of the antibodies, it also acts as an osmolarity regulating agent and partially or totally eliminates the need for additional osmolarity regulating agents in the compositions.
  • Figure 1 shows in graphical form the stabilizing effect of various sugars and glycine against polymer formation as a function of storage time in liquid formulations of antibodies ( ⁇ H 4.0);
  • Figure 2 gives a similar graphical representation of formation of chemical reactions products of various stabilizers as a function of storage time in liquid formulations of antibodies (pH 4.0); and Figure 3 gives a similar graphical representation of the stabilizing effect of trehalose and glycine against polymer formation as a function of storage time in liquid formulations of antibodies (pH 5.3).
  • the present invention provides novel liquid compositions of antibodies formulated for parenteral administration, wherein the antibodies are mixed in an aqueous medium with a stabilizing agent and optionally with other auxiliary agents known per se.
  • the stabilizing agent is, according to the present invention, at least partially comprised of trehalose, which is added in a concentration sufficient to provide for effectively preventing polymerization of the antibodies during storage.
  • the shelf life of immunoglobulin compositions typically is 1-3 years in refrigerator, i.e. at temperatures +2 - +8 °C.
  • the liquid compositions according to the present invention can be stored at room temperature (at about 25 °C) for extended periods of time (at least 6 months and up to 3 years), which makes the storage and handling easier and less risky particularly in outpatient use.
  • the novel liquid composition makes the immunoglobulin stable also at higher temperatures than room temperature, to which the immunoglobulin may be exposed during transportation and travelling of patients.
  • the novel composition makes it possible to manufacture intravenous immunoglobulin, in which no polymerization of antibodies takes place even during storage for 2-6 months at 37 °C.
  • no polymerization of immunoglobulin takes place it is meant that the level of polymerized immunoglobulin species is 0.1 mole-% or less and no increase in amount of polymerized species (during storage) can be found by size exclusion liquid chromatography.
  • the concentration of trehalose is typically 0.001 M to 0.5 M, in particular 0.01 - 0.4 M, in the present composition.
  • antibody or “antibodies” are used for designating any monoclonal and polyclonal antibodies of the IgG, IgA and IgM classes of animal or human origin. More specific explanations of the term “antibodies of human origin” can be found in US Patent No. 5,807,734, the contents, of which is herewith incorporated by reference.
  • the antibodies may also be chimeric antibodies, such as humanized mouse antibodies.
  • modified antibodies such as divalent and monovalent antibody fragments, single chain antibodies and single domain antibodies, are also included in the meaning of the terms "antibody” of "antibodies”.
  • the antibodies or modified antibodies may also be conjugated with other molecules, such as pharmaceutically actives effector units, including radionucleides, drugs and toxins, thereby forming therapeutically useful conjugates. Conjugated antibodies for parenteral administration may also be used for diagnostic purposes, such radionucleide-labelled antibodies for imaging.
  • immunoglobulin designates monoclonal and polyclonal immunoglobulins selected from the group of IgG, IgM and IgA.
  • Polyclonal immunoglobulin can be obtained by processing of plasma obtained from blood donors. Most methods are based on the cold ethanol precipitation process ("Cohn process"), but methods based on other precipitating agents, such as caprylic acid and PEG, and chromatographic methods have been developed. Polymers and aggregates can be removed from immunoglobulin by pepsin treatment, PEG precipitation and chromatography. Suitable methods of producing intravenous immunoglobulin are described in, e.g., US Patent No. 5,945,098, US Patent No 6,281,336, and in our copending patent application titled "Process for the Manufacture of Virus-Safe Immunoglobulin", the contents of which are herewith incorporated by reference.
  • the protein product is subjected to virus inactivation during the production process.
  • virus inactivation can be achieved by different methods, such as treatment with SD substances, caprylic acid or heat.
  • the process may contain effective virus removal steps such as precipitations, chromatography and virus filtration.
  • Monoclonal antibodies can be produced by hybridoma and recombinant technology. Similar purification methods can be applied as for polyclonal immunoglobulin preparations, including caprylic acid and PEG precipitation and chromatography. Suitable methods of producing monoclonal antibodies are described in, e.g., US Patent Nos. 5,807,734 and 6,600,022.
  • the immunoglobulin is recovered in the form of a liquid composition having a concentration of 1 to 250 g 1, although the suitable concentration of polyclonal immunoglobulin for its conventional therapeutic uses is in the range of some 10 to 250 g/1, e.g. 50 to 200 g/1.
  • the present invention makes it possible to produce such highly concentrated polyclonal Ig (e.g. IgG, IgA and IgM) compositions, which allows for facile administration of large amounts of immunoglobulins not only intraveneously but also subcutaneously and intramuscularly.
  • One particular advantage of subcutaneous administration is that it for home-treatment of patients with high doses of immunoglobulins.
  • the protein needs to be resuspended into an aqueous solution, which contains trehalose or to which trehalose is added once the protein has been dispersed in the solution.
  • parenteral formulations according to the present invention are readily produced from the obtained immunoglobulin-containing liquid compositions by adding trehalose as such or a mixture of trehalose and other conventional stabilizers to the IgG solution and pH is adjusted if necessary. The solution is then sterile filtered and filled aseptically to final containers, such as vials.
  • the stabilizing sugar used is a unique, naturally occurring disaccharide containing two glucose molecules bound in an , -1, 1 linkage. This structure results in a chemically stable, non-reducing sugar with many important functional characteristics.
  • Trehalose is found in nature in hundreds of plants and animals. It is an important source of energy, and has been shown to be a primary factor in stabilization of organisms during times of freezing and desication. Trehalose is consumed as part of a normal diet. Thus, the use thereof in the present invention is pharmacologically safe.
  • the osmolarity of the composition is in excess of about 150 mOsmol/kg, preferably > 240 mOsmol/kg.
  • This osmolarity range can be obtained by adding trehalose in a concentration sufficient to render the composition the desired osmolarity.
  • trehalose is added in a concentration sufficient as such to render the composition a physiological osmolarity (i.e. an osmolarity of about 200 mOsmol/kg or more).
  • the pH of the composition is 3.8-7.4.
  • compositions according to the present invention with conventional excipients and pharmaceutical carriers, such as a second stabilizer and/or a further osmolarity regulating component.
  • the conventional stabilizer can be selected from suitable sugars and amino acids, exemplified by maltose, glucose, sucrose and glycine; and it can be a polyol, such as a sugar alcohol.
  • Other conventional pharmaceutical excipients and adjuvants known in the art can be added to the composition.
  • Such carriers include, but are not limited to, albumin, liposomes, buffers, such as phosphate, acetate, succinate and maleate, electrolytes, glycerol, hydroxymethylcellulose, propylene glycol, polyethylene glycol, polyoxyethylenesorbitan, other surface active agents, vegetable oils, conventional anti-bacterial or anti-fungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Antioxidative agents may also be added, such metal chelators and oxygen radical scavengers.
  • a pharmaceutically-acceptable carrier within the scope of the present invention meets industry standards for sterility, stability, and non-pyrogenicity.
  • the molar ratio between the trehalose and any further stabilizer is greater than 0.05 (in other words, trehalose stands for at least 5 mole-% of the total amount of stabilizer component of the composition).
  • trehalose stands for at least 5 mole-% of the total amount of stabilizer component of the composition.
  • minor amounts e.g. 0.01 - 0.5 mg/ml
  • stabilizers of the polysorbate type can be employed, as compared to about 50 to 500 mmol trehalose/1 (corresponding to about n. 17 - 170 mg/ml).
  • the absolute concentration of the immunoglobulin varies depending on the actual immunoglobulin species and the intended use. Generally, the concentration is in the range of 1 to 250 g/1. For traditional pharmaceutical use, e.g. for passive immunization of mammals against infectious diseases, the concentration is typically about 50 to 160 g/L.
  • a suitable pharmaceutical composition comprises 50 to 160 g/1 immunoglobulin G and 0.1 to 0.4 M trehalose in a aqueous medium having an osmolarity > 240 mOsmol/kg. For monoclonal antibodies the concentration is typically less than 10 g/1.
  • the pharmaceutical compositions are administered to patients parenterally for passive immunization against infectious diseases, for immunomodulation in the treatment of different clinical disorders and for other antibody mediated activities, such as targeted use of monoclonal antibodies.
  • the administered dosage of antibodies is in the range of about 0.001 mg to 10 g/kg body weight, in particular about 0.1 to 1.0 g/kg body weight for intravenous immunoglobulin, and about 0.001 mg to 10 mg/kg body weight for monospecific polyclonal antibodies, such as anti-D immunoglobulin, and monoclonal antibodies.
  • parenteral administration routes include: intravenous, intramuscular, subcutaneous, rectal, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal.
  • present liquid compositions are formulated for intravenous, subcutaneous or intramuscular administration.
  • IgG was determined by immunoturbidimetry with a kit from ThermoClinical Labsystems.
  • the proportion of polymers was determined by size-exclusion liquid chromatography according to Ph. Eur. 3rd Ed. 1997:0338.
  • the formation of chemical reaction products was monitored by absorbance at 340 nm.
  • Polyclonal IgG was purified from Cohn fraction II of human plasma by DEAE-Sephadex chromatography, pepsin treatment, SD treatment, CM Sepharose chromatography and ultrafiltration.
  • the pure antibody solution contained about 12% F(ab') 2 fragments and 5% IgG dimers and no detectable IgG polymers. It was formulated to solutions containing 100 g/1 antibodies at pH 4.0 and one of the following stabilizers: 0.3 M trehalose, 0.3 M maltose, 0.3 M sucrose, 0.3 M glucose or 0.2 M glycine. The solutions were sterile filtered and filled aseptically into glass vials.
  • the vials were stored at 25 °C and 37 °C, and analyzed for polymers and chemical reaction products after 1, 2, 3 and 6 months. There was a clear increase in polymers after storage for one month at 37 °C in the presence of other stabilizers than trehalose, whereas no clear increase took place in the presence of trehalose during 6 months ( Figure 1). Similarly, the formation of chemical reaction products was clearly faster in the presence of other stabilizers than trehalose ( Figure 2). .
  • Polyclonal IgG was purified from Cohn fraction ⁇ +III of human plasma by caprylic acid precipitation, PEG precipitation, anion exchange chromatography and ultrafiltration as described in our copending patent application titled "Process for the Manufacture of Virus- Safe Immunoglobulin".
  • the pure IgG was formulated to solutions containing 100 g/1 of IgG at pH 5.3 and 0.2 M trehalose or 0.2 M glycine as a stabilizer.
  • the solutions were sterile filtered and filled aseptically into glass vials.
  • the vials were stored at 25 °C and 37 °C, and analyzed for polymers and chemical reaction products. There was a clear increase in polymers after storage for one month at 37 °C in the presence of glycine, whereas no increase took place in the presence of trehalose during 2 months ( Figure 3).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition liquide d'anticorps, par exemple l'immunoglobuline G, l'immunoglobuline M et l'immunoglobuline A, qui sont formulées pour l'administration parentérale. Les anticorps sont mélangés dans un milieu aqueux avec un agent stabilisant, et éventuellement, avec d'autres agents auxiliaires connus per se. Cette composition contient du tréhalose comme agent stabilisant à une concentration qui empêche efficacement la polymérisation des anticorps.
PCT/FI2005/000065 2004-01-30 2005-01-31 Compositions pharmaceutiques Ceased WO2005072772A1 (fr)

Applications Claiming Priority (2)

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US54000004P 2004-01-30 2004-01-30
US60/540,000 2004-01-30

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
WO2010100135A1 (fr) * 2009-03-05 2010-09-10 Ablynx N.V. Nouveaux complexes dimères de liaison antigénique, méthodes d'obtention/non obtention et leurs utilisations
US8110546B2 (en) * 2005-03-25 2012-02-07 Regeneron Pharmaceuticals, Inc. VEGF antagonist formulations
US8420081B2 (en) 2007-11-30 2013-04-16 Abbvie, Inc. Antibody formulations and methods of making same
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
US9265834B2 (en) 2009-03-05 2016-02-23 Ablynx N.V. Stable formulations of polypeptides and uses thereof
US9278131B2 (en) 2012-08-10 2016-03-08 Adocia Process for lowering the viscosity of highly concentrated protein solutions
US9309316B2 (en) 2005-12-20 2016-04-12 Bristol-Myers Squibb Company Stable subcutaneous protein formulations and uses thereof
WO2016085750A1 (fr) * 2014-11-25 2016-06-02 Regeneron Pharmaceuticals, Inc. Méthodes et formulations pour le traitement de pathologies oculaires vasculaires
US9402898B2 (en) 2012-01-23 2016-08-02 Regeneron Pharmaceuticals, Inc. Stabilized formulations containing anti-Ang2 antibodies
US9675692B2 (en) 2012-05-31 2017-06-13 Regeneron Pharmaceuticals, Inc. Stabilized formulations containing anti-DLL4 antibodies
US9884117B2 (en) 2009-09-03 2018-02-06 Ablynx N.V. Stable formulations of polypeptides and uses thereof
EP3145487B1 (fr) 2014-05-23 2018-08-22 Fresenius Kabi Deutschland GmbH Composition pharmaceutique liquide
US10426833B2 (en) 2014-05-23 2019-10-01 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US10493152B2 (en) 2014-05-23 2019-12-03 Fresenius Kabi Deutschland Gmbh Adalimumab formulations
US10501523B2 (en) 2014-07-18 2019-12-10 Sanofi IL-8 level based method of predicting the outcome of colon cancer treatment
US11033606B2 (en) 2011-04-26 2021-06-15 Sanofi Composition comprising aflibercept, folinic acid, 5-fluorouracil (5-FU) and irinotecan (FOLFIRI)
US11732024B2 (en) 2006-06-16 2023-08-22 Regeneron Pharmaceuticals, Inc. VEGF antagonist formulations suitable for intravitreal administration

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US8110546B2 (en) * 2005-03-25 2012-02-07 Regeneron Pharmaceuticals, Inc. VEGF antagonist formulations
US20120101035A1 (en) * 2005-03-25 2012-04-26 Regeneron Pharmaceuticals, Inc. VEGF Antagonist Formulations
US20120178683A1 (en) * 2005-03-25 2012-07-12 Regeneron Pharmaceuticals, Inc. Vegf antagonist formulations
US8404638B2 (en) * 2005-03-25 2013-03-26 Regeneron Pharmaceuticals, Inc. Dimer VEGF antagonist formulations
US11806398B2 (en) 2005-03-25 2023-11-07 Regeneron Pharmaceuticals, Inc. Citrate buffered VEGF antagonist formulations
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US9636400B2 (en) 2005-03-25 2017-05-02 Regeneron Pharmaceuticals, Inc. VEGF specific fusion protein antagonist formulations
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US10265401B2 (en) 2005-12-20 2019-04-23 Bristol-Myers Squibb Company Stable subcutaneous protein formulations and uses thereof
US9309316B2 (en) 2005-12-20 2016-04-12 Bristol-Myers Squibb Company Stable subcutaneous protein formulations and uses thereof
US12331099B2 (en) 2006-06-16 2025-06-17 Regeneron Pharmaceuticals, Inc. VEGF antagonist formulations suitable for intravitreal administration
US11732024B2 (en) 2006-06-16 2023-08-22 Regeneron Pharmaceuticals, Inc. VEGF antagonist formulations suitable for intravitreal administration
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US8420081B2 (en) 2007-11-30 2013-04-16 Abbvie, Inc. Antibody formulations and methods of making same
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
US9085619B2 (en) 2007-11-30 2015-07-21 Abbvie Biotechnology Ltd. Anti-TNF antibody formulations
US11191834B2 (en) 2007-11-30 2021-12-07 Abbvie Biotechnology Ltd Protein formulations and methods of making same
US9265834B2 (en) 2009-03-05 2016-02-23 Ablynx N.V. Stable formulations of polypeptides and uses thereof
US10919954B2 (en) 2009-03-05 2021-02-16 Ablynx N.V. Antigen binding dimer-complexes, methods of making/avoiding and uses thereof
US10005830B2 (en) 2009-03-05 2018-06-26 Ablynx N.V. Antigen binding dimer-complexes, methods of making/avoiding and uses thereof
WO2010100135A1 (fr) * 2009-03-05 2010-09-10 Ablynx N.V. Nouveaux complexes dimères de liaison antigénique, méthodes d'obtention/non obtention et leurs utilisations
US9884117B2 (en) 2009-09-03 2018-02-06 Ablynx N.V. Stable formulations of polypeptides and uses thereof
EP3438126A1 (fr) * 2009-09-03 2019-02-06 Ablynx N.V. Formulations stables de polypeptides et leurs utilisations
US11033606B2 (en) 2011-04-26 2021-06-15 Sanofi Composition comprising aflibercept, folinic acid, 5-fluorouracil (5-FU) and irinotecan (FOLFIRI)
US9402898B2 (en) 2012-01-23 2016-08-02 Regeneron Pharmaceuticals, Inc. Stabilized formulations containing anti-Ang2 antibodies
US9675692B2 (en) 2012-05-31 2017-06-13 Regeneron Pharmaceuticals, Inc. Stabilized formulations containing anti-DLL4 antibodies
US9278131B2 (en) 2012-08-10 2016-03-08 Adocia Process for lowering the viscosity of highly concentrated protein solutions
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US11752209B2 (en) 2014-05-23 2023-09-12 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US10772961B2 (en) 2014-05-23 2020-09-15 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
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