IL112088A - Stable stem cell factor formulations with improved stability and methods for their production - Google Patents

Stable stem cell factor formulations with improved stability and methods for their production

Info

Publication number: IL112088A
Authority: IL; Israel
Prior art keywords: scf; formulations; formulation; lyophilized; sucrose
Prior art date: 1993-12-22

Application number

IL11208894A

Other languages

English (en)

Other versions

IL112088A0 (en

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.)

1993-12-22

Filing date

1994-12-20

Publication date

2001-04-30

1994-12-20 Application filed by Amgen Inc filed Critical Amgen Inc

1995-03-15 Publication of IL112088A0 publication Critical patent/IL112088A0/xx

2001-04-30 Publication of IL112088A publication Critical patent/IL112088A/en

Links

239000000203 mixture Substances 0.000 title claims abstract description 119
238000009472 formulation Methods 0.000 title claims abstract description 108
210000000130 stem cell Anatomy 0.000 title claims abstract description 16
238000000034 method Methods 0.000 title claims description 26
238000004519 manufacturing process Methods 0.000 title description 7
HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 32
229930006000 Sucrose Natural products 0.000 claims abstract description 30
239000005720 sucrose Substances 0.000 claims abstract description 30
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 29
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 29
235000013922 glutamic acid Nutrition 0.000 claims abstract description 29
239000004220 glutamic acid Substances 0.000 claims abstract description 29
239000000872 buffer Substances 0.000 claims description 25
239000003795 chemical substances by application Substances 0.000 claims description 12
239000004067 bulking agent Substances 0.000 claims description 9
230000001105 regulatory effect Effects 0.000 claims description 6
238000002156 mixing Methods 0.000 claims description 2
SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 2
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 abstract description 26
229930195725 Mannitol Natural products 0.000 abstract description 26
239000000594 mannitol Substances 0.000 abstract description 26
235000010355 mannitol Nutrition 0.000 abstract description 26
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract description 14
HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 abstract description 14
150000001413 amino acids Chemical class 0.000 description 38
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FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 14
229910019142 PO4 Inorganic materials 0.000 description 12
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 12
239000010452 phosphate Substances 0.000 description 12
238000001035 drying Methods 0.000 description 11
238000004108 freeze drying Methods 0.000 description 9
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235000011009 potassium phosphates Nutrition 0.000 description 7
239000000047 product Substances 0.000 description 7
239000011780 sodium chloride Substances 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
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235000019446 polyethylene glycol 8000 Nutrition 0.000 description 6
BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 5
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
239000000539 dimer Substances 0.000 description 5
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238000004007 reversed phase HPLC Methods 0.000 description 5
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239000004332 silver Substances 0.000 description 5
239000001632 sodium acetate Substances 0.000 description 5
235000017281 sodium acetate Nutrition 0.000 description 5
241000894007 species Species 0.000 description 5
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
239000002202 Polyethylene glycol Substances 0.000 description 4
239000007853 buffer solution Substances 0.000 description 4
238000004132 cross linking Methods 0.000 description 4
238000012258 culturing Methods 0.000 description 4
238000007710 freezing Methods 0.000 description 4
230000008014 freezing Effects 0.000 description 4
239000007788 liquid Substances 0.000 description 4
239000000463 material Substances 0.000 description 4
210000005259 peripheral blood Anatomy 0.000 description 4
239000011886 peripheral blood Substances 0.000 description 4
229920001223 polyethylene glycol Polymers 0.000 description 4
238000002360 preparation method Methods 0.000 description 4
239000003381 stabilizer Substances 0.000 description 4
108091029865 Exogenous DNA Proteins 0.000 description 3
108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 3
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HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
210000002798 bone marrow cell Anatomy 0.000 description 3
238000000502 dialysis Methods 0.000 description 3
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238000004255 ion exchange chromatography Methods 0.000 description 3
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238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 3
238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
229940074404 sodium succinate Drugs 0.000 description 3
ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 3
239000000243 solution Substances 0.000 description 3
239000003643 water by type Substances 0.000 description 3
108020004414 DNA Proteins 0.000 description 2
239000004471 Glycine Substances 0.000 description 2
108010002386 Interleukin-3 Proteins 0.000 description 2
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108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
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IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
230000009471 action Effects 0.000 description 2
239000004480 active ingredient Substances 0.000 description 2
239000011149 active material Substances 0.000 description 2
229960003237 betaine Drugs 0.000 description 2
238000004166 bioassay Methods 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
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230000006240 deamidation Effects 0.000 description 2
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239000003814 drug Substances 0.000 description 2
230000002708 enhancing effect Effects 0.000 description 2
239000012634 fragment Substances 0.000 description 2
KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
239000001963 growth medium Substances 0.000 description 2
230000003394 haemopoietic effect Effects 0.000 description 2
235000014304 histidine Nutrition 0.000 description 2
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239000012931 lyophilized formulation Substances 0.000 description 2
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239000002609 medium Substances 0.000 description 2
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238000012986 modification Methods 0.000 description 2
150000007523 nucleic acids Chemical group 0.000 description 2
239000008194 pharmaceutical composition Substances 0.000 description 2
229920005862 polyol Polymers 0.000 description 2
150000003077 polyols Chemical class 0.000 description 2
230000008569 process Effects 0.000 description 2
239000003223 protective agent Substances 0.000 description 2
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239000007858 starting material Substances 0.000 description 2
239000011550 stock solution Substances 0.000 description 2
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
238000012360 testing method Methods 0.000 description 2
PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 1
208000030507 AIDS Diseases 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
206010002961 Aplasia Diseases 0.000 description 1
239000004475 Arginine Substances 0.000 description 1
206010065553 Bone marrow failure Diseases 0.000 description 1
102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
229920002307 Dextran Polymers 0.000 description 1
108010092408 Eosinophil Peroxidase Proteins 0.000 description 1
241000588724 Escherichia coli Species 0.000 description 1
108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
102000014150 Interferons Human genes 0.000 description 1
108010050904 Interferons Proteins 0.000 description 1
108010002352 Interleukin-1 Proteins 0.000 description 1
108090000174 Interleukin-10 Proteins 0.000 description 1
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108010065805 Interleukin-12 Proteins 0.000 description 1
108010002350 Interleukin-2 Proteins 0.000 description 1
108090000978 Interleukin-4 Proteins 0.000 description 1
108010002616 Interleukin-5 Proteins 0.000 description 1
108010002586 Interleukin-7 Proteins 0.000 description 1
108090001007 Interleukin-8 Proteins 0.000 description 1
108010002335 Interleukin-9 Proteins 0.000 description 1
ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
229930064664 L-arginine Natural products 0.000 description 1
235000014852 L-arginine Nutrition 0.000 description 1
102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
241000124008 Mammalia Species 0.000 description 1
108010025020 Nerve Growth Factor Proteins 0.000 description 1
102000007072 Nerve Growth Factors Human genes 0.000 description 1
208000028389 Nerve injury Diseases 0.000 description 1
108091028043 Nucleic acid sequence Proteins 0.000 description 1
241000219492 Quercus Species 0.000 description 1
230000018199 S phase Effects 0.000 description 1
JXXCENBLGFBQJM-FYZOBXCZSA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)C[C@H](O)CC(O)=O JXXCENBLGFBQJM-FYZOBXCZSA-N 0.000 description 1
239000004469 amino acid formulation Substances 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
208000007502 anemia Diseases 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
235000009697 arginine Nutrition 0.000 description 1
238000003556 assay Methods 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
210000000988 bone and bone Anatomy 0.000 description 1
239000001768 carboxy methyl cellulose Substances 0.000 description 1
235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
239000008112 carboxymethyl-cellulose Substances 0.000 description 1
229960004203 carnitine Drugs 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
230000022131 cell cycle Effects 0.000 description 1
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230000008859 change Effects 0.000 description 1
238000002512 chemotherapy Methods 0.000 description 1
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238000004925 denaturation Methods 0.000 description 1
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230000001419 dependent effect Effects 0.000 description 1
238000011033 desalting Methods 0.000 description 1
238000011161 development Methods 0.000 description 1
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238000011026 diafiltration Methods 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000012149 elution buffer Substances 0.000 description 1
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238000000855 fermentation Methods 0.000 description 1
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239000012530 fluid Substances 0.000 description 1
239000012537 formulation buffer Substances 0.000 description 1
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238000001415 gene therapy Methods 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000003365 glass fiber Substances 0.000 description 1
238000003306 harvesting Methods 0.000 description 1
208000000509 infertility Diseases 0.000 description 1
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238000005342 ion exchange Methods 0.000 description 1
201000002364 leukopenia Diseases 0.000 description 1
239000006193 liquid solution Substances 0.000 description 1
238000011068 loading method Methods 0.000 description 1
229960003646 lysine Drugs 0.000 description 1
238000005259 measurement Methods 0.000 description 1
210000003593 megakaryocyte Anatomy 0.000 description 1
239000012528 membrane Substances 0.000 description 1
238000000329 molecular dynamics simulation Methods 0.000 description 1
235000013923 monosodium glutamate Nutrition 0.000 description 1
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239000003900 neurotrophic factor Substances 0.000 description 1
102000045246 noggin Human genes 0.000 description 1
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239000011148 porous material Substances 0.000 description 1
238000004321 preservation Methods 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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239000011734 sodium Substances 0.000 description 1
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238000010561 standard procedure Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
208000011580 syndromic disease Diseases 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
206010043554 thrombocytopenia Diseases 0.000 description 1
210000003014 totipotent stem cell Anatomy 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
238000005406 washing Methods 0.000 description 1

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
- A61K38/18—Growth factors; Growth regulators

Landscapes

Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Epidemiology (AREA)
Chemical & Material Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Immunology (AREA)
Zoology (AREA)
Pharmacology & Pharmacy (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Gastroenterology & Hepatology (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Medicinal Preparation (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Medicines Containing Material From Animals Or Micro-Organisms (AREA)

IL11208894A 1993-12-22 1994-12-20 Stable stem cell factor formulations with improved stability and methods for their production IL112088A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US08/172,507 US6288030B1 (en)	1993-12-22	1993-12-22	Stem cell factor formulations and methods

Publications (2)

Publication Number	Publication Date
IL112088A0 IL112088A0 (en)	1995-03-15
IL112088A true IL112088A (en)	2001-04-30

Family

ID=22627993

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL11208894A IL112088A (en)	1993-12-22	1994-12-20	Stable stem cell factor formulations with improved stability and methods for their production

Country Status (13)

Country	Link
US (4)	US6288030B1 (fr)
EP (1)	EP0732935B1 (fr)
CN (1)	CN1105575C (fr)
AT (1)	ATE173402T1 (fr)
AU (1)	AU696860B2 (fr)
CA (1)	CA2182970C (fr)
DE (1)	DE69414723T2 (fr)
DK (1)	DK0732935T3 (fr)
ES (1)	ES2123951T3 (fr)
IL (1)	IL112088A (fr)
NZ (1)	NZ278252A (fr)
WO (1)	WO1995017206A1 (fr)
ZA (1)	ZA9410189B (fr)

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US6267958B1 (en)	1995-07-27	2001-07-31	Genentech, Inc.	Protein formulation
GB9515839D0 (en) *	1995-08-02	1995-10-04	Q One Biotech Ltd	Feline stem cell factor
TW518219B (en) *	1996-04-26	2003-01-21	Chugai Pharmaceutical Co Ltd	Erythropoietin solution preparation
US6017876A (en)	1997-08-15	2000-01-25	Amgen Inc.	Chemical modification of granulocyte-colony stimulating factor (G-CSF) bioactivity
US6541033B1 (en)	1998-06-30	2003-04-01	Amgen Inc.	Thermosensitive biodegradable hydrogels for sustained delivery of leptin
US6420339B1 (en)	1998-10-14	2002-07-16	Amgen Inc.	Site-directed dual pegylation of proteins for improved bioactivity and biocompatibility
US6245740B1 (en)	1998-12-23	2001-06-12	Amgen Inc.	Polyol:oil suspensions for the sustained release of proteins
US6500418B1 (en)	1999-02-12	2002-12-31	The Washington University	Stimulating neutrophil function to treat inflammatory bowel disease
US8106098B2 (en)	1999-08-09	2012-01-31	The General Hospital Corporation	Protein conjugates with a water-soluble biocompatible, biodegradable polymer
US6472208B1 (en) *	1999-12-13	2002-10-29	Héma-Québec	Method of producing human IFN-α using sendai virus-infected hematopoietic stem cells
US7311905B2 (en)	2002-02-13	2007-12-25	Anthrogenesis Corporation	Embryonic-like stem cells derived from post-partum mammalian placenta, and uses and methods of treatment using said cells
EP2206772A3 (fr) *	2000-12-06	2010-08-04	Robert J. Hariri	Procédé de collecte de cellules souches placentaires
US20080152629A1 (en) *	2000-12-06	2008-06-26	James Edinger	Placental stem cell populations
EP2336299A1 (fr) *	2001-02-14	2011-06-22	Anthrogenesis Corporation	Placenta post-gravidique de mammifere, son utilisation et cellules souches placentaires correspondantes
US7700090B2 (en)	2002-02-13	2010-04-20	Anthrogenesis Corporation	Co-culture of placental stem cells and stem cells from a second source
US20030191056A1 (en)	2002-04-04	2003-10-09	Kenneth Walker	Use of transthyretin peptide/protein fusions to increase the serum half-life of pharmacologically active peptides/proteins
JP3963786B2 (ja) *	2002-06-11	2007-08-22	富士通株式会社	情報処理装置
KR101042448B1 (ko)	2002-11-26	2011-06-16	안트로제네시스 코포레이션	세포요법제, 세포요법제 단위 및 이를 이용한 치료방법
CN1770976A (zh) *	2003-02-13	2006-05-10	人类起源公司	利用脐带血治疗患有疾病、紊乱或状况的个体的用途
GB0321337D0 (en) *	2003-09-11	2003-10-15	Massone Mobile Advertising Sys	Method and system for distributing advertisements
NZ548049A (en) *	2003-12-02	2009-01-31	Celgene Corp	Methods and compositions for the treatment and management of hemoglobinopathy and anemia
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- 1994-12-21 ZA ZA9410189A patent/ZA9410189B/xx unknown
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1998
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1999
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Also Published As

Publication number	Publication date
EP0732935A1 (fr)	1996-09-25
US20020013258A1 (en)	2002-01-31
EP0732935B1 (fr)	1998-11-18
US6020469A (en)	2000-02-01
CA2182970A1 (fr)	1995-06-29
DE69414723T2 (de)	1999-07-22
NZ278252A (en)	1998-04-27
ES2123951T3 (es)	1999-01-16
IL112088A0 (en)	1995-03-15
US6288030B1 (en)	2001-09-11
WO1995017206A1 (fr)	1995-06-29
US5965522A (en)	1999-10-12
AU1442295A (en)	1995-07-10
CN1105575C (zh)	2003-04-16
DE69414723D1 (de)	1998-12-24
HK1008815A1 (en)	1999-05-21
ATE173402T1 (de)	1998-12-15
CN1142771A (zh)	1997-02-12
AU696860B2 (en)	1998-09-17
DK0732935T3 (da)	1999-08-02
CA2182970C (fr)	2000-11-28
ZA9410189B (en)	1995-08-25

Legal Events

Date	Code	Title
2001-10-31	FF	Patent granted
2002-02-10	KB	Patent renewed
2005-02-20	KB	Patent renewed
2009-07-20	KB	Patent renewed
2013-08-29	MM9K	Patent not in force due to non-payment of renewal fees

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