WO1993005799A1 - Compositions pharmaceutiques stables et lyophilisees contenant un facteur de stimulation de colonies de granulocytes et de macrophages - Google Patents
Compositions pharmaceutiques stables et lyophilisees contenant un facteur de stimulation de colonies de granulocytes et de macrophages Download PDFInfo
- Publication number
- WO1993005799A1 WO1993005799A1 PCT/EP1992/002084 EP9202084W WO9305799A1 WO 1993005799 A1 WO1993005799 A1 WO 1993005799A1 EP 9202084 W EP9202084 W EP 9202084W WO 9305799 A1 WO9305799 A1 WO 9305799A1
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- WO
- WIPO (PCT)
- Prior art keywords
- csf
- composition according
- anyone
- freeze
- composition
- Prior art date
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Classifications
-
- 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
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- Lyophilized stable pharmaceutical compositions containing a granulocyte macrophage colony stimulating factor containing a granulocyte macrophage colony stimulating factor.
- the present invention relates to freeze-dried (lyophilized) 5 compositions containing granulocyte-macrophage colony stimulating factor (GM-CSF).
- GM-CSF granulocyte-macrophage colony stimulating factor
- GM-CSF is a glycoprotein able to control the proliferation, maturation and differentiation of myeloid progenitor cells to form differentiated granulocytes, acrophages and certain 0 related hemopoietic cells.
- GM-CSF also enhances the function of mature blood cells and stimulates the production of other cytokines such as, for example, interleukin 1 and M-CSF. It is known that it is very difficult to prepare stable 5pharmaceutical compositions containing proteins since these substances easily undergo processes of degradation with consequent decrease or loss of their pharmacological activity. Degradation pathways for proteins can be separated into two • distinct classes, involving both chemical and physical ⁇ instability.
- chemical instability can include proteolysis, deamidation, oxidation, racemization and ⁇ -elimination.
- Physical instability refers to processes such as aggregation, precipitation, denaturation and adsorption to surface. 5Temperature, light, and humidity are the most important factors responsible for the above mentioned drop in the activity of the proteins.
- Freeze-drying also known as lyophilization
- lyophilization is a process commonly used in the manufacture of protein products that are insufficiently stable for distribution and use in aqueous solution, even if frozen.
- pharmaceutical protein products are not pure proteins, but are formulated products in which general chemical components have been added for specific purposes, e.g. to improve stability during the freeze-drying process and/or during subsequent storage. It would therefore be desirable to prepare a lyophilized composition containing GM-CSF with a long shelf life, able to endure physico- chemical and microbial degradations.
- a lyophilized composition which comprises a granulocyte macrophage colony stimulating factor (GM-CSF) , a pharmaceutically acceptable bulking agent, a polyoxyethylene sorbitan fatty acid ester and a basic amino acid.
- GM-CSF granulocyte macrophage colony stimulating factor
- said lyophilized compositions may also contain a suitable buffering agent such as, e.g. a monobasic alkali metal phosphate, preferably monobasic sodium phosphate.
- a suitable buffering agent such as, e.g. a monobasic alkali metal phosphate, preferably monobasic sodium phosphate.
- the GM-CSF contained in the pharmaceutical preparations of the present invention may be any GM-CSF molecule though it is, preferably, a recombinantly prepared GM-CSF, as obtained, for example, by expressing a recombinant DNA in an appropriate microbial host cell such as, e.g., a bacterial host, e.g. E. coli. a yeast or a mammalian cell.
- the GM-CSF is preferably human GM-GSF.
- GM-CSF a preferred one for use in the invention is the human GM-CSF whose amino acid sequence is shown in SEQ ID NO:l.
- This CM-CSF is a preferred reconibinant GM-CSF.
- a deletion, insertion, substitution or extension may be N-terminal, C-terminal or internal to the basic sequence and may comprise one or more amino acids.
- GM-CSF may be present in a very small amount.
- a pharmaceutical composition containing from 0. 1 to 5 mg of GM-CSF, preferably from 250 ⁇ g to 750 ⁇ g of GM-CSF may be administered.
- the amount of GM-CSF in the composition of the present invention is preferably from 0. 1 to 5% , most preferably from 0. 1 to 1% , by weight of the bulking agent .
- a pharmaceutically acceptable bulking agent may be • any bulking agent suitable for ' use in freeze-drying such as , for example , mannitol , lactose , polyvinylpyrrolidone (PVP) , dextran or glycine ; of these , mannitol is preferred.
- any bulking agent suitable for ' use in freeze-drying such as , for example , mannitol , lactose , polyvinylpyrrolidone (PVP) , dextran or glycine ; of these , mannitol is preferred.
- PVP polyvinylpyrrolidone
- polyoxyethylene sorbitan fatty acid esters examples include partial C 12 -2 0 saturated or unsaturated fatty acid esters of sorbitol and its mono- and di-anhydrides copolymerised with ethylene oxide . Typically, from 10 to 40 , for example about 20 moles of ethylene oxide for each mole of sorbitol and its anhydrides will be present .
- Polyoxyethlene sorbitan fatty acid esters are known generally as polysorbates . Examples of polysorbates include polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate, Chemical Abstracts C AS Reference No.
- 9005-64-5 which is a mixture of partial lauric esters or sorbitol and its mono- and di-anhydrides copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and its anhydrides, polysorbate 40 ( polyoxyethylene 20 sorbitan monopal itate, CAS No. 9005-66-
- polysorbate 60 polyoxyethylene 20 sorbitan monostearate CAS No. 9005-67-8
- polysorbate 65 polyoxyethylene 20 sorbitan tristearate, CAS No. 9005-71-4
- polysorbate 80 polyoxyethylene 20 sorbitan monoleate, CAS No. 9004-65-6)
- polysorbate 85 polyoxyethylene 20 sorbitan trioleate, CAS No. 9005-70-3
- polysorbate 80 also known as Tween 80.
- the amount of polysorbate is generally from 0.01% to 25%, preferably from 0.1%-to 1%, by weight of the bulking agent.
- Typical examples of basic amino acids for use in making the stable GM-CSF-containing pharmaceutical preparations of the present invention include lysine and arginine. These may be used either singly or in admixture.
- the amino acids are preferably used in an amount ranging from 0.001% to 5%, most preferably from 0.1% to 2%, by weight of the bulking agent. .
- the solution may also be buffered, e.g. to a pH of about 6.5, with a pharmaceutically acceptable buffering agent, such as monobasic sodium phosphate.
- Compositions of the present invention will normally . be formulated in solution prior to freeze-drying. The solution may be freeze-dried in any quantity although preferably, the solution will be divided into aliquots containing 5 from 10 to 1000, for example from 100 to 500, most preferably 250, / ⁇ g of GM-CSF.
- aliquots will be freeze-dried separately, e.g. in individual glass vials. Before the solution is freeze-dried, it may be sterilized by filtration. For example, a 0.22 ⁇ m polyvinylidenedifluoride membrane filter may be used for this purpose, to prevent adsorption of the molecules on the surface.
- a typical freeze-drying cycle used for GM-CSF containing pharmaceutical preparation may be, e.g., as follows: (a) freeze at -45°C, and maintain this temperature for' four hours; (b) primary drying at -45°C to +10°C for approximately, twenty hours, with vacuum level less than 13.3 Pa (0.1 torr) and a condenser temperature of -60°C; and (c) secondary drying at 10°C to +25°C for approximately twenty-four hours, with the ' same vacuum and condenser temperature as described in (b) above. Variations of this protocol which do not substantially alter the stability of the GM-CSF may be made.
- Aliquots of the composition of the present invention may be dispensed into sterile vials.
- Sterile glass vials can be suitable.
- the glass vials can be sealed with conventional rubber stoppers (chloro butyl rubber) because no losses of protein, due to adsorption of GM-CSF to the rubber surface, was observed.
- the lyophilized composition of the present invention may be srored for example under an inert gas, e.g. nitrogen.
- the freeze-dried product composition of the invention may be reconstituted using any aqueous physiologically acceptable sterile solvent.
- the solvent used will provide a reconstituted solution with a pH between about 5 and about 7.0, most preferably about 6.5
- a 0.9% aqueous solution of sodium chloride i.e. physiological saline
- the solution may contain an effective amount of an anti-microbial preservative agent such as, for example, benzalkonium chloride, in order to inhibit the microbial activity in reconstituted solutions of the present invention.
- an anti-microbial preservative agent such as, for example, benzalkonium chloride
- the invention thus provides both a method for preparing a lyophilized GM-CSF composition according to the invention, which process comprises mixing, in aqueous solution, GM-CSF, a pharmaceutically acceptable bulking agent, a polyoxyethylene sorbitan fatty acid ester and a basic amino acid, and freeze-drying the resulting solution; '. and a method of preparing an aqueous injectable GM-CSF solution which comprises reconstituting the freeze-dried composition of the present invention with a physiologically acceptable sterile aqueous solvent.
- the present invention also provides a kit containing the lyophilized compositions described above in a sterile vial and a physiologically acceptable sterile . aqueous solvent for reconstitution of the lyophilized composition.
- compositions or kits according to the present invention are useful in a method of treatment of the human or animal body, e.g. in the treatment of neutropenic disorders of cancer patients after chemotherapy.
- the GM-CSF is a reco binantly prepared human GM-CSF having the sequence shown in SEQ ID NO:l, which is prepared following the conventional recombinant techni ⁇ ues well known in the art
- rh GM-CSF. 25 It is, e.g., obtained as a solid bulk at a concentration of active substance of approximately 880 ⁇ g/mg expressed as protein content measured by the biuret reaction. This solid bulk is stored at about -20'C. It was observed that thawing and diluting this bulk to a concentration of about 125 ⁇ g/ml using a 2.5% mannitol solution does not affect protein stability. HP C analysis of this solution shows that the active drug substance (rh GM-CSF) is quantitatively recovered.
- a lyoprotectant is defined as a compound that stabilizes and prevents the degradation of the proteins both during freeze-drying and afterwards, during storage, whereas a cryoprotectant only infers protection from freezing damage.
- lyoprotectants such as Arginine significantly improved protein stability.
- Polysorbate 80 proved to be ineffective if used alone, but surprisingly this stabilizer worked well in combination, with arginine.
- the low stabilizing activity of polysorbate 80 might be expected, due to the low coordination ' power of this additive towards the water molecules.
- the synergistic effect of polysorbate 80 with arginine was quite unexpected.
- composition of rh GM-CSF formulation stabilized with polysorbate 80 and Arginine.
- Freeze-dried vials containing compositions according to the present invention comprising about 250 g of GM-CSF were examined for long term stability over various periods of time at different temperatures. The following parameters were examined and the acceptable standards are also given:
- GM-CSF working standard Acetonitrile, HPLC grade Water, HPLC grade
- Trifluoroacetic acid, analytical grade Phosphate buffer at pH 7.5 Transfer 7.3 g of sodium chloride and 3.2 g of Sodium dihydrogen phosphate in a 1000 ml volumetric flask.
- Membrane filter 0.22 ⁇ m porosity, Millipore Durapore GVWP, or equivalent
- Mobile phase (B) consisting of 95% acetonitrile-5% water containing 0.1% of trifluoroacetic acid (w/v) , filtered through the membrane filter and deaerated.
- the standard solution must be freshly prepared and used within a working day.
- the standard and sample solution are alternatively injected at least 2 times into the liquid chromatograph under the following experimental conditions:
- Detector sensitivity the detector "computer” output is connected to integrator for maximum sensitivity Injection volume : 100 ⁇ l
Abstract
Composition lyophilisée comportant un facteur de stimulation de colonies de granulocytes et de macrophages (GM-CSF), un diluant pharmaceutiquement acceptable, un ester d'acide gras de sorbitan de polyoxyéthylène, et un acide aminé basique. Ces compositions sont utilisées dans un procédé de traitement de l'organisme humain ou animal, par exemple dans le traitement des troubles neutropéniques chez les malades du cancer après la chimiothérapie.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9120304.2 | 1991-09-24 | ||
GB919120304A GB9120304D0 (en) | 1991-09-24 | 1991-09-24 | Stable pharmaceutical compositions containing a granulocyte macrophage colony stimulating factor |
Publications (1)
Publication Number | Publication Date |
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WO1993005799A1 true WO1993005799A1 (fr) | 1993-04-01 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1992/002084 WO1993005799A1 (fr) | 1991-09-24 | 1992-09-10 | Compositions pharmaceutiques stables et lyophilisees contenant un facteur de stimulation de colonies de granulocytes et de macrophages |
Country Status (2)
Country | Link |
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GB (1) | GB9120304D0 (fr) |
WO (1) | WO1993005799A1 (fr) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0852951A1 (fr) * | 1996-11-19 | 1998-07-15 | Roche Diagnostics GmbH | Compositions pharmaceutiques stables, lyophilisées d'anticorps monoclonaux ou polyclonaux |
KR19990009888A (ko) * | 1997-07-12 | 1999-02-05 | 성재갑 | 콜로니 자극 인자의 안정한 용액 제형 |
EP0920314A1 (fr) * | 1996-05-22 | 1999-06-09 | Smithkline Beecham Corporation | Minetique du g-csf non peptidique |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
EP1197221A1 (fr) * | 1999-03-01 | 2002-04-17 | Chugai Seiyaku Kabushiki Kaisha | Preparations stabilisees a longue conservation |
EP1908482A1 (fr) * | 2005-06-10 | 2008-04-09 | Chugai Seiyaku Kabushiki Kaisha | Stabilisant pour une préparation de protéine contenant de la méglumine et son utilisation |
US7666413B2 (en) | 2000-10-12 | 2010-02-23 | Genetech, Inc. | Method of reducing viscosity of high concentration protein formulations |
US8318161B2 (en) | 2009-03-06 | 2012-11-27 | Genentech, Inc. | Anti-oxidized LDL antibody formulation |
US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US8961964B2 (en) | 2003-04-04 | 2015-02-24 | Genentech, Inc. | High concentration antibody and protein formulations |
US9241994B2 (en) | 2005-06-10 | 2016-01-26 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical compositions containing sc(Fv)2 |
US9493569B2 (en) | 2005-03-31 | 2016-11-15 | Chugai Seiyaku Kabushiki Kaisha | Structural isomers of sc(Fv)2 |
WO2020002650A1 (fr) * | 2018-06-29 | 2020-01-02 | Targovax Asa | Formulation |
Citations (6)
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WO1989000582A2 (fr) * | 1987-07-17 | 1989-01-26 | Schering Biotech Corporation | Facteur stimulant la croissance des colonies de granulocytes-macrophages humains et ses muteines |
JPH01132514A (ja) * | 1987-11-17 | 1989-05-25 | Nippon Kayaku Co Ltd | 安定な総合ビタミン凍結乾燥製剤 |
WO1989010407A1 (fr) * | 1988-04-29 | 1989-11-02 | Genetics Institute, Inc. | M-csf dimerique homogene et formulations stables pendant le stockage |
EP0355811A2 (fr) * | 1988-08-24 | 1990-02-28 | Chugai Seiyaku Kabushiki Kaisha | Agent de contrôle des formations de thrombus |
WO1990008554A1 (fr) * | 1989-01-30 | 1990-08-09 | Schering Corporation | Traitement de dysfonctionnement leucocytaire a l'aide de gm-csf |
WO1992001442A1 (fr) * | 1990-07-18 | 1992-02-06 | Farmitalia Carlo Erba S.R.L. | Compositions pharmaceutiques stables comportant un facteur de croissance de fibroblaste |
-
1991
- 1991-09-24 GB GB919120304A patent/GB9120304D0/en active Pending
-
1992
- 1992-09-10 WO PCT/EP1992/002084 patent/WO1993005799A1/fr active Application Filing
Patent Citations (6)
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WO1989000582A2 (fr) * | 1987-07-17 | 1989-01-26 | Schering Biotech Corporation | Facteur stimulant la croissance des colonies de granulocytes-macrophages humains et ses muteines |
JPH01132514A (ja) * | 1987-11-17 | 1989-05-25 | Nippon Kayaku Co Ltd | 安定な総合ビタミン凍結乾燥製剤 |
WO1989010407A1 (fr) * | 1988-04-29 | 1989-11-02 | Genetics Institute, Inc. | M-csf dimerique homogene et formulations stables pendant le stockage |
EP0355811A2 (fr) * | 1988-08-24 | 1990-02-28 | Chugai Seiyaku Kabushiki Kaisha | Agent de contrôle des formations de thrombus |
WO1990008554A1 (fr) * | 1989-01-30 | 1990-08-09 | Schering Corporation | Traitement de dysfonctionnement leucocytaire a l'aide de gm-csf |
WO1992001442A1 (fr) * | 1990-07-18 | 1992-02-06 | Farmitalia Carlo Erba S.R.L. | Compositions pharmaceutiques stables comportant un facteur de croissance de fibroblaste |
Non-Patent Citations (1)
Title |
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Section Ch, Week 8927, 25 May 1989 Derwent Publications Ltd., London, GB; Class A96, AN 89-195616 & JP,A,1 132 514 (NIPPON KAYAKU KK) 25 May 1989 * |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US9180189B2 (en) | 1995-07-27 | 2015-11-10 | Genentech, Inc. | Treating a mammal with a formulation comprising an antibody which binds IgE |
US9283273B2 (en) | 1995-07-27 | 2016-03-15 | Genentech, Inc. | Protein formulation |
EP0920314A1 (fr) * | 1996-05-22 | 1999-06-09 | Smithkline Beecham Corporation | Minetique du g-csf non peptidique |
EP0920314A4 (fr) * | 1996-05-22 | 2001-08-16 | Smithkline Beecham Corp | Minetique du g-csf non peptidique |
EP0852951A1 (fr) * | 1996-11-19 | 1998-07-15 | Roche Diagnostics GmbH | Compositions pharmaceutiques stables, lyophilisées d'anticorps monoclonaux ou polyclonaux |
WO1998022136A3 (fr) * | 1996-11-19 | 1998-08-20 | Boehringer Mannheim Gmbh | Preparations pharmaceutiques lyophilisees stables d'anticorps monoclonaux ou polyclonaux |
US8758747B2 (en) | 1996-11-19 | 2014-06-24 | Roche Diagnostics Gmbh | Stable lyophilized pharmaceutical preparations of monoclonal or polyclonal antibodies |
KR100514207B1 (ko) * | 1996-11-19 | 2005-09-13 | 로셰 디아그노스틱스 게엠베하 | 단클론성 또는 다클론성 항체의 안정한 동결건조 제약학적 물질 |
KR19990009888A (ko) * | 1997-07-12 | 1999-02-05 | 성재갑 | 콜로니 자극 인자의 안정한 용액 제형 |
EP1700605A3 (fr) * | 1999-03-01 | 2007-06-13 | Chugai Seiyaku Kabushiki Kaisha | Préparations protéiques lyophilisées contenant de la méthionine durablement stables |
US6908610B1 (en) | 1999-03-01 | 2005-06-21 | Chugai Seiyaku Kabushiki Kaisha | Long-term stabilized formulations |
EP1197221A4 (fr) * | 1999-03-01 | 2003-01-29 | Chugai Pharmaceutical Co Ltd | Preparations stabilisees a longue conservation |
EP1197221A1 (fr) * | 1999-03-01 | 2002-04-17 | Chugai Seiyaku Kabushiki Kaisha | Preparations stabilisees a longue conservation |
US10166293B2 (en) | 2000-10-12 | 2019-01-01 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US7666413B2 (en) | 2000-10-12 | 2010-02-23 | Genetech, Inc. | Method of reducing viscosity of high concentration protein formulations |
US8142776B2 (en) | 2000-10-12 | 2012-03-27 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US10034940B2 (en) | 2003-04-04 | 2018-07-31 | Genentech, Inc. | High concentration antibody and protein formulations |
US8961964B2 (en) | 2003-04-04 | 2015-02-24 | Genentech, Inc. | High concentration antibody and protein formulations |
US9493569B2 (en) | 2005-03-31 | 2016-11-15 | Chugai Seiyaku Kabushiki Kaisha | Structural isomers of sc(Fv)2 |
US9241994B2 (en) | 2005-06-10 | 2016-01-26 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical compositions containing sc(Fv)2 |
US8945543B2 (en) | 2005-06-10 | 2015-02-03 | Chugai Seiyaku Kabushiki Kaisha | Stabilizer for protein preparation comprising meglumine and use thereof |
EP1908482A4 (fr) * | 2005-06-10 | 2012-12-19 | Chugai Pharmaceutical Co Ltd | Stabilisant pour une préparation de protéine contenant de la méglumine et son utilisation |
US9777066B2 (en) | 2005-06-10 | 2017-10-03 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical compositions containing sc(Fv)2 |
EP1908482A1 (fr) * | 2005-06-10 | 2008-04-09 | Chugai Seiyaku Kabushiki Kaisha | Stabilisant pour une préparation de protéine contenant de la méglumine et son utilisation |
US8318161B2 (en) | 2009-03-06 | 2012-11-27 | Genentech, Inc. | Anti-oxidized LDL antibody formulation |
WO2020002650A1 (fr) * | 2018-06-29 | 2020-01-02 | Targovax Asa | Formulation |
Also Published As
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