DE60031999D1 - Stabilisierte flüssige pharmazeutische zusammensetzung enthaltend polypeptide - Google Patents
Stabilisierte flüssige pharmazeutische zusammensetzung enthaltend polypeptideInfo
- Publication number
- DE60031999D1 DE60031999D1 DE60031999T DE60031999T DE60031999D1 DE 60031999 D1 DE60031999 D1 DE 60031999D1 DE 60031999 T DE60031999 T DE 60031999T DE 60031999 T DE60031999 T DE 60031999T DE 60031999 D1 DE60031999 D1 DE 60031999D1
- Authority
- DE
- Germany
- Prior art keywords
- pharmaceutical composition
- acid
- liquid pharmaceutical
- amino acid
- 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.)
- Expired - Lifetime
Links
- 239000007788 liquid Substances 0.000 title abstract 7
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 7
- 150000003839 salts Chemical group 0.000 abstract 8
- 235000001014 amino acid Nutrition 0.000 abstract 7
- 150000001413 amino acids Chemical class 0.000 abstract 7
- 239000004475 Arginine Substances 0.000 abstract 6
- 235000009697 arginine Nutrition 0.000 abstract 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 abstract 6
- 229920001184 polypeptide Polymers 0.000 abstract 6
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 6
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 6
- 239000002253 acid Substances 0.000 abstract 5
- 239000002585 base Substances 0.000 abstract 5
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 abstract 4
- 230000015572 biosynthetic process Effects 0.000 abstract 4
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 abstract 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 abstract 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 abstract 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 abstract 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 abstract 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 abstract 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 abstract 3
- 239000004472 Lysine Substances 0.000 abstract 3
- 150000007513 acids Chemical class 0.000 abstract 3
- 235000003704 aspartic acid Nutrition 0.000 abstract 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 abstract 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 abstract 3
- 239000012458 free base Substances 0.000 abstract 3
- 235000013922 glutamic acid Nutrition 0.000 abstract 3
- 239000004220 glutamic acid Substances 0.000 abstract 3
- 235000018977 lysine Nutrition 0.000 abstract 3
- 239000000203 mixture Substances 0.000 abstract 3
- 102000000588 Interleukin-2 Human genes 0.000 abstract 2
- 108010002350 Interleukin-2 Proteins 0.000 abstract 2
- 239000006172 buffering agent Substances 0.000 abstract 2
- 239000012669 liquid formulation Substances 0.000 abstract 2
- 239000001384 succinic acid Substances 0.000 abstract 2
- 239000013543 active substance Substances 0.000 abstract 1
- 239000000872 buffer Substances 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
Classifications
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
-
- 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
- A61K38/21—Interferons [IFN]
- A61K38/215—IFN-beta
-
- 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
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P31/18—Antivirals for RNA viruses for HIV
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Virology (AREA)
- Psychology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Communicable Diseases (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15769699P | 1999-10-04 | 1999-10-04 | |
| US157696P | 1999-10-04 | ||
| PCT/US2000/027156 WO2001024814A1 (en) | 1999-10-04 | 2000-10-03 | Stabilized liquid polypeptide-containing pharmaceutical compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE60031999D1 true DE60031999D1 (de) | 2007-01-04 |
| DE60031999T2 DE60031999T2 (de) | 2007-06-06 |
Family
ID=22564882
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60031999T Expired - Lifetime DE60031999T2 (de) | 1999-10-04 | 2000-10-03 | Stabilisierte flüssige polypeptid-haltige pharmazeutische zusammensetzungen |
| DE60044213T Expired - Lifetime DE60044213D1 (de) | 1999-10-04 | 2000-10-03 | Stabilisierte flüssige pharmazeutische Zusammensetzung enthaltend TFPI |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60044213T Expired - Lifetime DE60044213D1 (de) | 1999-10-04 | 2000-10-03 | Stabilisierte flüssige pharmazeutische Zusammensetzung enthaltend TFPI |
Country Status (18)
| Country | Link |
|---|---|
| US (4) | US6525102B1 (de) |
| EP (2) | EP1220682B1 (de) |
| JP (2) | JP2003510368A (de) |
| CN (2) | CN1245216C (de) |
| AT (2) | ATE464062T1 (de) |
| AU (2) | AU783306B2 (de) |
| BR (2) | BR0014486A (de) |
| CA (2) | CA2477857C (de) |
| CZ (2) | CZ305123B6 (de) |
| DE (2) | DE60031999T2 (de) |
| ES (1) | ES2276698T3 (de) |
| HU (3) | HU0800692D0 (de) |
| IL (3) | IL149008A0 (de) |
| NO (2) | NO20021567L (de) |
| NZ (2) | NZ529856A (de) |
| PL (2) | PL354987A1 (de) |
| PT (1) | PT1491208E (de) |
| WO (1) | WO2001024814A1 (de) |
Families Citing this family (139)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7006874B2 (en) * | 1996-01-05 | 2006-02-28 | Thermage, Inc. | Treatment apparatus with electromagnetic energy delivery device and non-volatile memory |
| JP2000247903A (ja) * | 1999-03-01 | 2000-09-12 | Chugai Pharmaceut Co Ltd | 長期安定化製剤 |
| NZ529856A (en) | 1999-10-04 | 2005-09-30 | Chiron Corp | Stabilized liquid polypeptide-containing pharmaceutical compositions |
| BR0016879A (pt) * | 1999-12-30 | 2002-12-03 | Chiron Corp | Métodos para transferência de interleucina-2 por via pulmonar |
| US6495534B2 (en) * | 2000-05-15 | 2002-12-17 | Pharmacia & Upjohn Spa | Stabilized aqueous suspensions for parenteral use |
| EP1935431A3 (de) | 2000-05-15 | 2008-08-13 | Health Research, Inc. | Krebsbehandlungen unter Verwendung einer Kombination aus einem HER2-Antikörper und Interleukin-2 |
| JP4147234B2 (ja) | 2004-09-27 | 2008-09-10 | キヤノン株式会社 | 吐出用液体、吐出方法、カートリッジ及び吐出装置 |
| US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
| ATE442862T2 (de) | 2000-10-12 | 2009-10-15 | Genentech Inc | Niederviskose konzentrierte proteinformulierungen |
| EP1378236B1 (de) * | 2001-03-23 | 2007-06-27 | Ajinomoto Co., Inc. | Mittel gegen stressinduzierte krankheiten |
| US6887462B2 (en) * | 2001-04-09 | 2005-05-03 | Chiron Corporation | HSA-free formulations of interferon-beta |
| DE10149030A1 (de) * | 2001-10-05 | 2003-04-10 | Viscum Ag | Stabile galenische gefriergetrocknete Arzneimittelzubereitung von rViscumin |
| HUP0501111A2 (en) | 2001-10-15 | 2007-12-28 | Chiron Corp | Treatment of severe pneumonia by administration of tissue factor pathway inhibitor |
| US7842668B1 (en) | 2001-11-13 | 2010-11-30 | Genentech, Inc. | Apo-2 ligand/trail formulations |
| EP2332531B1 (de) * | 2001-11-13 | 2019-07-10 | Genentech, Inc. | Reinigungsverfahren des Proteins Tumornekrosefaktor-verwandter Apoptose-induzierender Ligand/TRAIL |
| MXPA04008215A (es) | 2002-02-27 | 2004-11-26 | Immunex Corp | Formulacion polipeptidica. |
| EP1946776B1 (de) * | 2002-02-27 | 2017-01-18 | Immunex Corporation | Stabilisierte tnfr-fc-verbindung mit arginin |
| US6991805B1 (en) * | 2002-09-06 | 2006-01-31 | Health Research, Inc. | Temperature sensitive control of liposome-cell adhesion |
| US6964778B1 (en) * | 2002-09-06 | 2005-11-15 | Health Research, Inc. | Temperature controlled content release from liposomes |
| JP5057648B2 (ja) * | 2002-09-26 | 2012-10-24 | 塩野義製薬株式会社 | 安定化されたタンパク組成物 |
| DK1599222T3 (da) * | 2003-01-08 | 2009-04-27 | Novartis Vaccines & Diagnostic | Stabiliserede vandige pr parater omfattende v vsfaktorvej-inhibitor (TFPI) eller v vsfaktorvej-inhibitorvariant |
| WO2004062646A1 (en) * | 2003-01-08 | 2004-07-29 | Chiron Corporation | Stabilized lyophilized compositions comprising tissue factor pathway inhibitor or tissue factor pathway inhibitor variants |
| EP1803445A3 (de) * | 2003-01-08 | 2007-11-21 | Novartis Vaccines and Diagnostics, Inc. | Stabilisierte lyophilisierte Zubereitungen mit Gewebefaktor-Inhibitor (TFPI) oder Varianten des Gewebefaktor-Inhibitors |
| US20040208870A1 (en) * | 2003-01-30 | 2004-10-21 | Medimmune, Inc. | Stabilized high concentration anti-integrin alphanubeta3 antibody formulations |
| US20040208869A1 (en) * | 2003-01-30 | 2004-10-21 | Medimmune, Inc. | Uses of anti-integrin alphanubeta3 antibody formulations |
| CN1767815A (zh) * | 2003-03-31 | 2006-05-03 | 阿尔萨公司 | 非水单相载体和使用这类载体的制剂 |
| KR101208291B1 (ko) | 2003-04-04 | 2012-12-05 | 노파르티스 아게 | 고농도 항체 및 단백질 제형 |
| US7445933B2 (en) * | 2003-07-16 | 2008-11-04 | Abbott Laboratories, Inc. | Stable calibrators or controls for measuring human natriuretic peptides |
| US7291501B2 (en) * | 2003-07-16 | 2007-11-06 | Abbott Laboratories | Stable compositions for measuring human natriuretic peptides |
| EP1654283B1 (de) * | 2003-08-13 | 2011-07-13 | Novartis Vaccines and Diagnostics, Inc. | Verbessertes verfahren zur reinigung von tfpi und tfpi-analogen |
| US7141544B2 (en) | 2003-10-10 | 2006-11-28 | Baxter International, Inc. | Stabilization of pharmaceutical protein formulations with small peptides |
| DE10348550A1 (de) * | 2003-10-20 | 2005-06-16 | Hexal Biotech Forschungsgmbh | Stabile wässrige G-CSF-haltige Zusammensetzungen |
| CA2544853C (en) | 2003-11-04 | 2014-05-20 | Chiron Corporation | Use of antagonist anti-cd40 antibodies for treatment of autoimmune and inflammatory diseases, and organ transplant rejection |
| US20050136542A1 (en) * | 2003-12-19 | 2005-06-23 | Beckman Coulter, Inc. | Stabilized liquid reference solutions |
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- 2002-04-03 NO NO20021567A patent/NO20021567L/no not_active Application Discontinuation
- 2002-04-04 IL IL149008A patent/IL149008A/en active IP Right Grant
- 2002-11-18 US US10/299,039 patent/US7030086B2/en not_active Expired - Fee Related
-
2004
- 2004-10-15 NO NO20044406A patent/NO20044406L/no not_active Application Discontinuation
- 2004-10-29 JP JP2004317319A patent/JP2005068158A/ja active Pending
-
2005
- 2005-12-05 US US11/293,379 patent/US20060093598A1/en not_active Abandoned
- 2005-12-05 US US11/293,322 patent/US7807142B2/en not_active Expired - Fee Related
-
2006
- 2006-01-13 AU AU2006200141A patent/AU2006200141B2/en not_active Ceased
-
2007
- 2007-12-18 IL IL188230A patent/IL188230A0/en unknown
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