CA2408685A1 - Liquid pharmaceutical composition containing an erythropoietin derivate - Google Patents
Liquid pharmaceutical composition containing an erythropoietin derivate Download PDFInfo
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- CA2408685A1 CA2408685A1 CA002408685A CA2408685A CA2408685A1 CA 2408685 A1 CA2408685 A1 CA 2408685A1 CA 002408685 A CA002408685 A CA 002408685A CA 2408685 A CA2408685 A CA 2408685A CA 2408685 A1 CA2408685 A1 CA 2408685A1
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- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K38/22—Hormones
-
- 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
- A61K38/1816—Erythropoietin [EPO]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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
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- 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
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Abstract
The present invention relates to a liquid pharmaceutical composition comprising an erythropoietin protein, a multiple charged inorganic anion in a pharmaceutically acceptable buffer suitable to keep the solution pH in the range from about 5.5 to about 7.0, and optionally one or more pharmaceutical ly acceptable excipients. This composition is especially useful for the prophylaxis and treatment of diseases related to erythropoiesis.
Claims (60)
1. A liquid pharmaceutical composition comprising an erythropoietin protein, a multiple charged inorganic anion in a pharmaceutically acceptable buffer suitable to keep the solution pH in the range from about 5.5 to about 7.0, and optionally one or more pharmaceutically acceptable excipients.
2. The composition according to claim 1 which is an aqueous solution.
3. The composition according to claims 1 to 2 which is an isotonic solution.
4. The composition according to claims 1 to 3 wherein the anion is an anion of a multiple charged strong inorganic acid.
5. The composition according claims 1 to 4 wherein the anion is selected from the group consisting of sulfate, citrate or phosphate.
6. The composition according to claims 1 to 5 wherein the anion is a sulfate anion.
7. The composition according to claim 6 comprising 10 to 200 mmol/1 sulfate.
8. The composition according to claims 1 to 7 wherein the pH is 5.8 to 6.7
9. The composition according to claim 8 wherein the pH is 6.0 to 6.5
10. The composition according to claim 9 the pH is about 6.2.
11. The composition according to claims 1 to 10 wherein the buffer is selected form the group consisting of a phosphate or an arginine/H2SO4/Na2SO4 buffer.
12. The composition according to claim 11 wherein the buffer is a 10 to 50 mmol phosphate buffer.
13. The composition according claims 1 to 12 wherein the composition comprises one or more pharmaceutically acceptable excipients.
14. The composition according to claim 13 wherein one or more pharmaceutically acceptable excipients are selected form the group consisting of pharmaceutically acceptable salts, diluents, solvents and preservatives.
15. The composition according to claims 13 and 14 wherein the pharmaceutically acceptable excipients are selected from the group consisting of tonicity agents, polyols, anti-oxidants and non-ionic detergents.
16. The composition according to claims 13 to 15 wherein the pharmaceutically acceptable excipient a polyol.
17. The composition according to claim 16 wherein the polyol is selected from the group consisting of mannitol, sorbitol, glycerol, trehalose and saccharose.
18. The composition according to claim 17 wherein the polyol is mannitol.
19. The composition according to claims 13 to 18 comprising an anti-oxidant.
20. The composition according to claim 19 wherein the anti-oxidant is methionine.
21. The composition according to claims 13 to 20 comprising up to 1 mmol/1 CaCl2.
22. The composition according to claims 15 to 22 wherein the non-ionic detergent is polysorbate 80, polysorbate 20 or pluronic F68.
23. The composition according to claim 22 wherein the non-ionic detergent is pluronic F68.
24. The composition according to claims 22 or 23, wherein the composition comprises up to 1% (w/v) of the non-ionic detergent.
25. The composition according to any of claims 22 to 24, wherein the composition comprises up to 0.1% (w/v) of the non-ionic detergent.
26. The composition according to claims 1 to 25 wherein the erythropoietin protein is a human erythropoietin.
27. The composition according to claim 26 wherein the erythropoietin protein is expressed by endogenous gene activation.
28. The composition according to claims 26 to 27 wherein the erythropoietin protein has the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2.
29. The composition according to claims 26 to 28 wherein the protein has the sequence of human erythropoietin modified by the addition of from 1 to 6 glycosylation sites.
30. The composition according to claims 26 to 28 wherein the erythropoietin protein has the sequence of human erythropoietin modified by a modification selected from the group consisting of:
Asn30Thr32;
Asn51Thr53, Asn57Thr59;
Asn69;
Asn69Thr71;
Ser68Asn69Thr71;
Val87Asn88Thr90;
Ser87Asn88Thr90;
Ser87Asn88Gly89Thr90;
Ser87Asn88Thr90Thr92;
Ser87Asn88Thr90Ala162;
Asn69Thr71Ser87Asn88Thr90;
Asn30Thr32Val87Asn88Thr90;
Asn89Ile90Thr91;
Ser87Asn89Ile90Thr91;
Asn136Thr138;
Asn138Thr140;
Thr125; and Pro124Thr125.
Asn30Thr32;
Asn51Thr53, Asn57Thr59;
Asn69;
Asn69Thr71;
Ser68Asn69Thr71;
Val87Asn88Thr90;
Ser87Asn88Thr90;
Ser87Asn88Gly89Thr90;
Ser87Asn88Thr90Thr92;
Ser87Asn88Thr90Ala162;
Asn69Thr71Ser87Asn88Thr90;
Asn30Thr32Val87Asn88Thr90;
Asn89Ile90Thr91;
Ser87Asn89Ile90Thr91;
Asn136Thr138;
Asn138Thr140;
Thr125; and Pro124Thr125.
31. The composition of according to claims 26 to 30, wherein the sequence of human erythropoietin is modified by a rearrangement of at least one glycosylation site.
32. The composition of claim 31, wherein the rearrangement comprises deletion of any of the N-linked glycosylation sites in human erythropoietin and addition of an N-linked glycosylation site at position 88 of the sequence of human erythropoietin.
33. The composition of claim 31, wherein the glycoprotein has the sequence of human erythropoietin modified by a modification selected from the group consisting of Gln24 Ser87 Asn88 Thr90;
Gln38 Ser87 Asn88 Thr90; and G1n83 Ser87 Asn88 Thr90.
Gln38 Ser87 Asn88 Thr90; and G1n83 Ser87 Asn88 Thr90.
34. The composition according to claims 26 to 33, wherein the erythropoietin protein as defined in any of claims is pegylated.
35. The composition according to claim 34, wherein the erythropoietin protein is a conjugate, said conjugate comprising an erythropoietin glycoprotein having at least one free amino group and having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and selected from the group consisting of human erythropoietin and analogs thereof which have sequence of human erythropoietin modified by the addition of from 1 to 6 glycosylation sites or a rearrangement of at least one glycosylation site; said glycoprotein being covalently linked to "n" polyethylene glycol) groups of the formula -CO-(CH2)x-(OCH2CH2)m-OR with the -CO of each poly(ethylene glycol) group forming an amide bond with one of said amino groups; wherein R is lower alkyl; x is 2 or 3; m is from about 450 to about 900; n is from 1 to 3; and n and m are chosen so that the molecular weight of the conjugate minus the erythropoietin glycoprotein is from 20 kilodaltons to 100 kilodaltons.
36. The composition according to claim 35 with an erythropoietin protein of the formula:
P-(NHCO-(CH2)x-(OCH2CH2)m-OR]n (I) wherein m, n, x and R are as above, and P is the residue of the glycoprotein without the n amino group(s) which form amide linkages) with the polyethylene glycol) group(s).
P-(NHCO-(CH2)x-(OCH2CH2)m-OR]n (I) wherein m, n, x and R are as above, and P is the residue of the glycoprotein without the n amino group(s) which form amide linkages) with the polyethylene glycol) group(s).
37. The composition according to claim 36, wherein in formula (I) x is 2, m is to 750, n is 1 and R is methyl.
38. The composition according to claim 34, wherein the erythropoietin protein is a conjugate, said conjugate comprising an erythropoietin glycoprotein having at least one free amino group and having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and selected from the group consisting of human erythropoietin and analogs thereof which have the primary structure of human erythropoietin modified by the addition of from 1 to 6 glycosylation sites; said glycoprotein being covalently linked to from one to three lower-alkoxy poly(ethylene glycol) groups, each poly(ethylene glycol) group being covalently linked to the glycoprotein via a linker of the formula -C(O)-X-S-Y- with the C(O) of the linker forming an amide bond with one of said amino groups, X is -(CH2)k- or -CH2(O-CH2-CH2)k-, k is from 1 to 10, Y is the average molecular weight of each poly(ethylene glycol) moiety is from about 20 kilodaltons to about 40 kilodaltons, and the molecular weight of the conjugate is from about 51 kilodaltons to about 175 kilodaltons.
39. The conjugate of claim 38, of the formula:
wherein n is an integer from 1 to 3; m is an integer from 450 to 900; R is lower alkyl; X is -(CH2)k- or -CH2(O-CH2-CH2)k-, and P is the residue of the erythropoietin glycoprotein without the amino group or groups which form an amide linkage with X.
wherein n is an integer from 1 to 3; m is an integer from 450 to 900; R is lower alkyl; X is -(CH2)k- or -CH2(O-CH2-CH2)k-, and P is the residue of the erythropoietin glycoprotein without the amino group or groups which form an amide linkage with X.
40. The conjugate of claim 39, of the formula:
wherein n is an integer from 1 to 3; m is an integer from 450 to 900; R is lower alkyl; X is -(CH2)k- or -CH2(O-CH2-CH2)k-, and P is the residue of the erythropoietin glycoprotein without the amino group or groups which form an amide linkage with X.
wherein n is an integer from 1 to 3; m is an integer from 450 to 900; R is lower alkyl; X is -(CH2)k- or -CH2(O-CH2-CH2)k-, and P is the residue of the erythropoietin glycoprotein without the amino group or groups which form an amide linkage with X.
41. The composition of claims 1 to 40 comprising 10 µg to..10000 µg erythropoietin protein per ml.
42. The composition of claims 1 to 41 comprising 10 µg to 10000 µg erythropoietin protein per ml, 10 - 200 mmol/l sulfate, and 10 to 50 mmol/l phosphate pH 6.0 to 6.5.
43. The composition of claim 42 comprising up to 20 mM methionine, 1- 5 % of a polyol (w/v), up to 0.1% pluronic F68 (w/v) and optionally up to 1 mM CaCl2 .
44. The composition according to claim 42 or 43 comprising 10 µg to 10000 µg erythropoietin protein per ml, 40 mmol/l sulfate, 10 mmol/l phosphate, 3%
mannitol (w/v), 10 mM methionine, 0.01% pluronic F68 (w/v), pH 6.2.
mannitol (w/v), 10 mM methionine, 0.01% pluronic F68 (w/v), pH 6.2.
45. The composition claims 1 to 41 comprising 10 µg to 10000 µg erythropoietin protein per ml, 10 to 100 mmol/l NaCl, 10 to 50 mmol/l phosphate pH 6.0 to 7.0, optionally 1-5% of a polyol.
46. The composition of claim 45 up to 20 mM methionine, up to 0.1% pluronic and optionally 7.5 µmol/l CaCl2.
47. The composition of claim 45 or 46 comprising 10 µg to 10000 µg erythropoietin protein per ml, 100 mmol/l NaCl, 10 mM methionine, 0.01% pluronic F68, and 10 mmol/l phosphate, pH 7Ø
48. The composition of claims 1 to 41 comprising 10 µg to 10000 µg erythropoietin protein per ml, 10 to 50 mmol/l arginine, pH 6 to pH 6.5, 10 to 100 mmol/l sodium sulfate.
49. The composition of claim 48 comprising up to 20 mM methionine, up to 0.1%
pluronic F68, optionally up to 1 mmol/l CaCl2 and optionally 1- 5 % of a polyol.
pluronic F68, optionally up to 1 mmol/l CaCl2 and optionally 1- 5 % of a polyol.
50 50. The composition of claims 48 or 49, comprising 10 µg to 10000 µg erythropoietin protein per ml, 40 mmol/l arginine, pH 6.2, 30 mmol/l sodium sulfate, 3 % mannitol, 10 mM methionine, 0.01% pluronic F68 and optionally 1 mmol/l CaCl2.
51. The composition according to claims 1 to 41 comprising 25 to 2500 µg/ml erythropoietin and a) 10 mM sodium/potassium phosphate, 100 mM NaCl, pH 7.0 or b) 10 mM sodium phosphate, 120 mM sodium sulfate, pH 6.2 or c) 10 mM sodium phosphate, 40 mM sodium sulfate, 3% mannitol, pH 6.2 or d) 10 mM sodium phosphate, 40 mM sodium sulfate, 3% mannitol, 10 mM
methionine, 0.01% pluronic F68, pH 6.2 or e) 40 mM arginine, 30 mM sodium sulfate, 3% mannitol, pH 6.2 or f) 40 mM arginine, 30 mM sodium sulfate, 3% mannitol, 10 mM
methionine, 0.01% pluronic F68, pH 6.2.
methionine, 0.01% pluronic F68, pH 6.2 or e) 40 mM arginine, 30 mM sodium sulfate, 3% mannitol, pH 6.2 or f) 40 mM arginine, 30 mM sodium sulfate, 3% mannitol, 10 mM
methionine, 0.01% pluronic F68, pH 6.2.
52. The composition of claims 1 to 51 wherein the amount of erythropoietin is 50, 100, 400, 800 or 2500 µg/ml.
53. The composition of claim 52 comprising 10 mM sodium phosphate, 40 mM
sodium sulfate, 3% mannitol, 10 mM methionine, 0.01% pluronic F68, pH 6.2.
sodium sulfate, 3% mannitol, 10 mM methionine, 0.01% pluronic F68, pH 6.2.
54. The composition of claim 52 comprising 40 mM arginine, 30 mM sodium sulfate, 3% mannitol, 10 mM methionine, 0.01% pluronic F68, pH 6.2.
55. The composition of claims 1 to 54 which is a lyophilisate or a spray-dried powder.
56. A process for preparing a composition according to any of claims 1 - 54, comprising mixing a erythropoietin protein with a solution comprising a multiple, negatively charged anion and optionally one or more pharmaceutically acceptable excipients.
57. Use of a composition according to any of claims 1 - 54 for the preparation of medicaments useful for the treatment and prevention of diseases correlated with anemia in chronic renal failure patients (CRF), AIDS and/or for the treatment of cancer patients undergoing chemotherapy.
58. Method for the treatment and prevention of diseases involving anemia in chronic renal failure patients (CRF), AIDS and cancer patients undergoing chemotherapy comprising the step of administering to a patient a composition as claimed in any one of claims 1 to 54.
59. Device for local and systemic sustained release comprising a composition according to any of claims 1 - 54.
60. The invention as hereinbefore described.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00110355 | 2000-05-15 | ||
EP00110355.5 | 2000-05-15 | ||
PCT/EP2001/005187 WO2001087329A1 (en) | 2000-05-15 | 2001-05-08 | Liquid pharmaceutical composition containing an erythropoietin derivate |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2408685A1 true CA2408685A1 (en) | 2001-11-22 |
CA2408685C CA2408685C (en) | 2011-02-01 |
Family
ID=8168722
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2408685A Expired - Lifetime CA2408685C (en) | 2000-05-15 | 2001-05-08 | Liquid pharmaceutical composition containing an erythropoietin derivate |
Country Status (36)
Country | Link |
---|---|
US (2) | US7169754B2 (en) |
EP (2) | EP1525889A1 (en) |
JP (1) | JP3967594B2 (en) |
KR (3) | KR20070032815A (en) |
CN (1) | CN1309416C (en) |
AR (2) | AR035034A1 (en) |
AT (1) | ATE291436T2 (en) |
AU (1) | AU784091B2 (en) |
BR (1) | BRPI0110914B8 (en) |
CA (1) | CA2408685C (en) |
CZ (1) | CZ304855B6 (en) |
DE (1) | DE60109625T3 (en) |
DK (1) | DK1311285T4 (en) |
EC (2) | ECSP024352A (en) |
ES (1) | ES2237574T5 (en) |
HK (1) | HK1056683A1 (en) |
HR (1) | HRP20020880B1 (en) |
HU (1) | HU230874B1 (en) |
IL (2) | IL152659A0 (en) |
JO (1) | JO3404B1 (en) |
MA (1) | MA26901A1 (en) |
ME (1) | ME00673B (en) |
MX (1) | MXPA02011303A (en) |
MY (1) | MY128654A (en) |
NO (1) | NO330934B1 (en) |
NZ (1) | NZ522030A (en) |
PE (1) | PE20020050A1 (en) |
PL (1) | PL219131B1 (en) |
PT (1) | PT1311285E (en) |
RS (1) | RS51292B (en) |
RU (1) | RU2281116C2 (en) |
SI (1) | SI1311285T1 (en) |
TW (2) | TWI288644B (en) |
UY (1) | UY26704A1 (en) |
WO (1) | WO2001087329A1 (en) |
ZA (1) | ZA200208500B (en) |
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NZ522030A (en) * | 2000-05-15 | 2004-11-26 | F | Erythropoietin composition with a multiple charged inorganic anion i.e. a sulfate a citrate or a phosphate to stabilize the composition |
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KR100645843B1 (en) | 2000-12-20 | 2006-11-14 | 에프. 호프만-라 로슈 아게 | Erythropoietin conjugates |
FR2823220B1 (en) * | 2001-04-04 | 2003-12-12 | Genodyssee | NOVEL ERYTHROPOIETIN (EPO) POLYNUCLEOTIDES AND POLYPEPTIDES |
WO2002097038A2 (en) * | 2001-05-25 | 2002-12-05 | Human Genome Sciences, Inc. | Chemokine beta-1 fusion proteins |
US20030104996A1 (en) * | 2001-08-30 | 2003-06-05 | Tiansheng Li | L-methionine as a stabilizer for NESP/EPO in HSA-free formulations |
JP2003152145A (en) * | 2001-08-31 | 2003-05-23 | Sumitomo Electric Ind Ltd | Semiconductor heat dissipating substrate, method for its manufacture, and package |
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AU2004236174B2 (en) * | 2001-10-10 | 2011-06-02 | Novo Nordisk A/S | Glycopegylation methods and proteins/peptides produced by the methods |
US8008252B2 (en) | 2001-10-10 | 2011-08-30 | Novo Nordisk A/S | Factor VII: remodeling and glycoconjugation of Factor VII |
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- 2001-05-11 PE PE2001000421A patent/PE20020050A1/en active IP Right Grant
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- 2001-05-11 US US09/853,731 patent/US7169754B2/en not_active Expired - Lifetime
- 2001-05-14 UY UY26704A patent/UY26704A1/en not_active IP Right Cessation
- 2001-05-14 TW TW094134688A patent/TWI288644B/en not_active IP Right Cessation
- 2001-05-14 TW TW090111453A patent/TWI288643B/en not_active IP Right Cessation
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2002
- 2002-10-21 ZA ZA200208500A patent/ZA200208500B/en unknown
- 2002-11-05 IL IL152659A patent/IL152659A/en active IP Right Grant
- 2002-11-07 HR HR20020880A patent/HRP20020880B1/en not_active IP Right Cessation
- 2002-11-13 MA MA26907A patent/MA26901A1/en unknown
- 2002-11-14 NO NO20025450A patent/NO330934B1/en not_active IP Right Cessation
- 2002-11-20 EC EC2002004352A patent/ECSP024352A/en unknown
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2003
- 2003-12-11 HK HK03109033A patent/HK1056683A1/en unknown
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2004
- 2004-02-17 US US10/780,297 patent/US7202208B2/en not_active Expired - Lifetime
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2010
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2013
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