CA2041989C - Aqueous pharmaceutical formulations of erythropoietin and the use thereof - Google Patents
Aqueous pharmaceutical formulations of erythropoietin and the use thereof Download PDFInfo
- Publication number
- CA2041989C CA2041989C CA002041989A CA2041989A CA2041989C CA 2041989 C CA2041989 C CA 2041989C CA 002041989 A CA002041989 A CA 002041989A CA 2041989 A CA2041989 A CA 2041989A CA 2041989 C CA2041989 C CA 2041989C
- Authority
- CA
- Canada
- Prior art keywords
- erythropoietin
- epo
- aqueous
- physiologically tolerated
- alkali metal
- 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
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
- A61K38/22—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]
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Inorganic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Aqueous pharmaceutical formulations of proteins with erythropoietin activity, especially of human native and of recombinant human erythropoietin (EPO) are described.
Highly purified EPO without foreign proteins or other customary stabilizers retains at least about 78% of its original activity for at least 1 year at room temperature in a physiologically tolerated aqueous phosphate buffer which contains a physiologically tolerated alkali metal halide but otherwise no stabilizing additives and has a pH of 6 to 8. The products in this aqueous pharmaceutical formulation are particularly suitable for subcutaneous or intramuscular administration.
Highly purified EPO without foreign proteins or other customary stabilizers retains at least about 78% of its original activity for at least 1 year at room temperature in a physiologically tolerated aqueous phosphate buffer which contains a physiologically tolerated alkali metal halide but otherwise no stabilizing additives and has a pH of 6 to 8. The products in this aqueous pharmaceutical formulation are particularly suitable for subcutaneous or intramuscular administration.
Description
2~419~9 . ,..
BEHRINGWERRE ARTIENGESELLSCHAFT HOE 90/B 021 - Ma 787 Dr. LP/VO
Description Aqueous pharmaceutical formulations of erythropoietin and the use thereof The invention relates to aqueous pharmaceutical formula-tions of purified erythropoietin, in particular of hwnan native and of recombinant human erythropoietin (rh EPO).
The formulations of the invention - without foreign proteins, sugars, amino acids or other customary stabili-zers - retain at least about 78~ of their original activity for at least one year at a temperature of 4-8°C.
Erythropoietin (EPO) is a glycoprotein with 166 amino acids, 3 glycosylation sites at amino-acid positions 24, 38 and 83 and a molecular weight of about 34,000. EPO can either be isolated from natural sources such as human urine (cf., for example, Miyake et al., J. Biol. Chem., vol. 252 (1977), 5558-5564) or be prepared by genetic engineering processes (cf., for example, EP-A 0,148,605 and 0,267,678). Aqueous solutions of erythropoietin are unstable at temperatures from about 3°C to room tempera-ture.
Patients with kidney failure are unable to form EPO and thus suffer from anemia. Attempts to compensate for this undersupply of EPO by administering EPO and to reduce the symptoms of anemia have already been successful. Further clinical uses comprise administration of hEPO for iatro-genic anemia after chemotherapy or radiotherapy of malignant diseases.
A single dose of EPO amounts to only a few microgrammes.
Because of the short half-life after i.v. administration, physiological plasma levels can best be achieved by subcutaneous injection.
The pharmaceutical formulations of erythropoietin 20~Z989 hitherto proposed or available contain added detergents and/or proteins, sugars or polyalcohols, which are intended, on the one hand, to stabilize EPO and, on the other hand, to prevent adsorption of EPO onto the inner wall of the storage container (i.e. the ampoule) (EP-B-0,178,576; EP-A-0,178,665; G. Krystal et al., Blood vol. 67 (1986), l, 71 - 79). Subcutaneous or i.m.
administration of EPO stabilized in this way results in local inflammation with the formation of granulomas.
Highly pure EPO prepared by known processes (EP-A-0,236,059; US-A 4,667,159; PCT/US 86/01342 {= WO 86/07594)) lost more than 25% of its activity within one week on storage at 24°C. EP-B-0,178,576 also discloses a solution of human erythropoietin, which has been reductively methylated with l4C-formaldehyde, in PBS;
cf. Experiment 1 and 2.
The object on which the invention is based is to provide aqueous pharmaceutical formulations of purified erythro-poietin which are free of the customary stabilizing additives and nevertheless have adequate stability at temperatures from about 3°C to room temperature and are suitable in particular for subcutaneous or intramuscular administration.
It has been found, surprisingly, that purified erythro-poietin (about 99% pure), especially purified native or recombinant human erythropoietin, is stable for a lengthy period at temperatures from 4 to 8°C in a physiologically tolerated aqueous phosphate buffer of pH 6 to 8 which contains a physiologically tolerated alkali metal halide, but otherwise no stabilizing additives, in sealed test tubes or glass ampoules.
Hence the invention relates to aqueous pharmaceutical formulations of purified erythropoietin in a physiologi-cally tolerated aqueous phosphate buffer of pH 6 to 8 which contains a physiologically tolerated alkali metal halide, but otherwise no stabilizing additives. A buffer . ,... 2U4~.98~
BEHRINGWERRE ARTIENGESELLSCHAFT HOE 90/B 021 - Ma 787 Dr. LP/VO
Description Aqueous pharmaceutical formulations of erythropoietin and the use thereof The invention relates to aqueous pharmaceutical formula-tions of purified erythropoietin, in particular of hwnan native and of recombinant human erythropoietin (rh EPO).
The formulations of the invention - without foreign proteins, sugars, amino acids or other customary stabili-zers - retain at least about 78~ of their original activity for at least one year at a temperature of 4-8°C.
Erythropoietin (EPO) is a glycoprotein with 166 amino acids, 3 glycosylation sites at amino-acid positions 24, 38 and 83 and a molecular weight of about 34,000. EPO can either be isolated from natural sources such as human urine (cf., for example, Miyake et al., J. Biol. Chem., vol. 252 (1977), 5558-5564) or be prepared by genetic engineering processes (cf., for example, EP-A 0,148,605 and 0,267,678). Aqueous solutions of erythropoietin are unstable at temperatures from about 3°C to room tempera-ture.
Patients with kidney failure are unable to form EPO and thus suffer from anemia. Attempts to compensate for this undersupply of EPO by administering EPO and to reduce the symptoms of anemia have already been successful. Further clinical uses comprise administration of hEPO for iatro-genic anemia after chemotherapy or radiotherapy of malignant diseases.
A single dose of EPO amounts to only a few microgrammes.
Because of the short half-life after i.v. administration, physiological plasma levels can best be achieved by subcutaneous injection.
The pharmaceutical formulations of erythropoietin 20~Z989 hitherto proposed or available contain added detergents and/or proteins, sugars or polyalcohols, which are intended, on the one hand, to stabilize EPO and, on the other hand, to prevent adsorption of EPO onto the inner wall of the storage container (i.e. the ampoule) (EP-B-0,178,576; EP-A-0,178,665; G. Krystal et al., Blood vol. 67 (1986), l, 71 - 79). Subcutaneous or i.m.
administration of EPO stabilized in this way results in local inflammation with the formation of granulomas.
Highly pure EPO prepared by known processes (EP-A-0,236,059; US-A 4,667,159; PCT/US 86/01342 {= WO 86/07594)) lost more than 25% of its activity within one week on storage at 24°C. EP-B-0,178,576 also discloses a solution of human erythropoietin, which has been reductively methylated with l4C-formaldehyde, in PBS;
cf. Experiment 1 and 2.
The object on which the invention is based is to provide aqueous pharmaceutical formulations of purified erythro-poietin which are free of the customary stabilizing additives and nevertheless have adequate stability at temperatures from about 3°C to room temperature and are suitable in particular for subcutaneous or intramuscular administration.
It has been found, surprisingly, that purified erythro-poietin (about 99% pure), especially purified native or recombinant human erythropoietin, is stable for a lengthy period at temperatures from 4 to 8°C in a physiologically tolerated aqueous phosphate buffer of pH 6 to 8 which contains a physiologically tolerated alkali metal halide, but otherwise no stabilizing additives, in sealed test tubes or glass ampoules.
Hence the invention relates to aqueous pharmaceutical formulations of purified erythropoietin in a physiologi-cally tolerated aqueous phosphate buffer of pH 6 to 8 which contains a physiologically tolerated alkali metal halide, but otherwise no stabilizing additives. A buffer . ,... 2U4~.98~
composed of 50 mM sodium phosphate, 100 mM NaCl, pH 7.8, is particularly preferred. The concentration of erythro-poietin in the aqueous buffer solution is 50 - 1000 ~g per ml of buffer solution.
Examples of physiologically tolerated aqueous phosphate buffers are sodium phosphate buffer and potassium phos-phate buffer, preferably sodium phosphate buffer.
Examples of physiologically tolerated alkali metal halides are sodium chloride and potassium chloride, preferably sodium chloride. A preferred phosphate buffer is a buffer containing 50 mM sodium phosphate, 100 mM
NaCl, pH 7.8. This buffer is also called PBS for brevity.
The aqueous solutions of erythropoietin in PBS are very well suited for subcutaneous or intramuscular administra tion.
The invention additionally relates to the use of the aqueous pharmaceutical formulations for preparing in~ec-tion products for subcutaneous or intramuscular adminis-tration. Subcutaneous administration is particularly preferred because, by contrast with the known formula-tions stabilized With proteins, it causes no irritation or inflammatory pain. This has emerged from clinical trials.
The examples illustrate the invention.
xample 1 Purification of rh EPO
The purification of rh EPO started from serum-containing or serum-free medium which was conditioned by rh EPO-producing animal cells by the process described in EP-A 0,267,678, page 6, line 45, to page 9, line 5. The process comprises (1) clarification, concentration and dialysis of the culture medium, .~ 2~4~.~89 (2) ion exchange chromatography, {3) preparative reverse phase HPLC and {4) gel filtration chromatography.
For the gel filtration chromatography, the column was equilibrated with PBS, i.e. 50 mM sodium phosphate buffer, 100 mM NaCl, pH 7.8. With this buffer solution, rh EPO was eluted in a single symmetrical peak {measure-ment of the eluate at 280 nm). The resulting rh EPO was at least 99% pure according to SDS-PAGE.
Examples of physiologically tolerated aqueous phosphate buffers are sodium phosphate buffer and potassium phos-phate buffer, preferably sodium phosphate buffer.
Examples of physiologically tolerated alkali metal halides are sodium chloride and potassium chloride, preferably sodium chloride. A preferred phosphate buffer is a buffer containing 50 mM sodium phosphate, 100 mM
NaCl, pH 7.8. This buffer is also called PBS for brevity.
The aqueous solutions of erythropoietin in PBS are very well suited for subcutaneous or intramuscular administra tion.
The invention additionally relates to the use of the aqueous pharmaceutical formulations for preparing in~ec-tion products for subcutaneous or intramuscular adminis-tration. Subcutaneous administration is particularly preferred because, by contrast with the known formula-tions stabilized With proteins, it causes no irritation or inflammatory pain. This has emerged from clinical trials.
The examples illustrate the invention.
xample 1 Purification of rh EPO
The purification of rh EPO started from serum-containing or serum-free medium which was conditioned by rh EPO-producing animal cells by the process described in EP-A 0,267,678, page 6, line 45, to page 9, line 5. The process comprises (1) clarification, concentration and dialysis of the culture medium, .~ 2~4~.~89 (2) ion exchange chromatography, {3) preparative reverse phase HPLC and {4) gel filtration chromatography.
For the gel filtration chromatography, the column was equilibrated with PBS, i.e. 50 mM sodium phosphate buffer, 100 mM NaCl, pH 7.8. With this buffer solution, rh EPO was eluted in a single symmetrical peak {measure-ment of the eluate at 280 nm). The resulting rh EPO was at least 99% pure according to SDS-PAGE.
(5) Dilution The combined rh EPO fractions from the gel filtration step ( 4 ) contained 0 .1 - 0 . 8 mg of EPO per ml and were dispensed in single doses of 100 ~g/ml using the sodium phosphate/sodium chloride buffer (PBS) pH 7.8.
Example 2 Stability testing The stability of the PBS solution of rh EPO obtained as in Example 1 was tested after storage of the single doses in sterile glass tubes, comparing with various stabili-zers. The activity of rh EPO was measured by the incor-poration of 3T into mouse spleen cells treated with phenylhydrazine in a conventional manner. The data shown in the Table which follows are related to the initial activity of the employed rh EPO = 100%.
i w v . ~ ,~.. ~~4989 _ - 5 -(a) Storage at 4 - 8°C
Stabilizer Amount of stabilizer % activity (wt./wt. relative to after 12 EPO) based on 100 ~g months EPO/ml PBS
PBS alone - 7g,5 PBS + sorbitol 5000 51 PBS + glycerol 6150 0 PBS + HaemaccelR 100 68 (b) Storage at 37C (accelerated test) Stabilizer Amount of % Activ ity after months stabilizer 1 2 3 6 PBS alone - 86.3 39 11.2 9.9 PBS + sorbitol 5000 33.5 10.75.1 0 PBS + HaemaccelR 100 42 14.86.0 5.1 Note: HaemaccelR is a degraded gelatin The surprisingly better stabilization of rh EPO in PBS
(pH 7.8) without further addition of a stabilizer is evident Tables.
from the
Example 2 Stability testing The stability of the PBS solution of rh EPO obtained as in Example 1 was tested after storage of the single doses in sterile glass tubes, comparing with various stabili-zers. The activity of rh EPO was measured by the incor-poration of 3T into mouse spleen cells treated with phenylhydrazine in a conventional manner. The data shown in the Table which follows are related to the initial activity of the employed rh EPO = 100%.
i w v . ~ ,~.. ~~4989 _ - 5 -(a) Storage at 4 - 8°C
Stabilizer Amount of stabilizer % activity (wt./wt. relative to after 12 EPO) based on 100 ~g months EPO/ml PBS
PBS alone - 7g,5 PBS + sorbitol 5000 51 PBS + glycerol 6150 0 PBS + HaemaccelR 100 68 (b) Storage at 37C (accelerated test) Stabilizer Amount of % Activ ity after months stabilizer 1 2 3 6 PBS alone - 86.3 39 11.2 9.9 PBS + sorbitol 5000 33.5 10.75.1 0 PBS + HaemaccelR 100 42 14.86.0 5.1 Note: HaemaccelR is a degraded gelatin The surprisingly better stabilization of rh EPO in PBS
(pH 7.8) without further addition of a stabilizer is evident Tables.
from the
Claims (7)
1. An aqueous pharmaceutical formulation of purified erythropoietin in a physiologically tolerated aqueous buffer solution of pH 6 to 8 which contains a physiologically tolerated alkali metal phosphate and alkali metal halide, but otherwise no stabili-zing additives.
2. A formulation as claimed in claim 1, wherein the aqueous buffer solution is composed of 50 mM sodium phosphate, 100 mM NaCl, pH 7.8.
3. A formulation as claimed in claim 1 or 2, wherein the erythropoietin is human native or recombinant erythropoietin.
4. A formulation as claimed in any of claims 1 to 3, wherein the concentration of erythropoietin is 50 - 1000 µg per ml of buffer solution.
5. The use of an aqueous formulation of purified erythropoietin as claimed in any of claims 1 to 4 for preparing injection products.
6. A process for preparing a stable pharmaceutical formulation of erythropoietin as claimed in claim 1, which comprises dissolving erythropoietin with a purity of ~ 99% in a physiologically tolerated aqueous buffer solution of pH 6 to 8, said buffer solution containing a physiologically tolerated alkali metal phosphate and alkali metal halide, but otherwise no stabilizing additives.
7. An aqueous pharmaceutical formulation as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4014654A DE4014654A1 (en) | 1990-05-08 | 1990-05-08 | GALENIC AQUEOUS FORMULATIONS OF ERYTHROPOIETIN AND THEIR USE |
| DEP4014654.5 | 1990-05-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2041989A1 CA2041989A1 (en) | 1991-11-09 |
| CA2041989C true CA2041989C (en) | 2001-07-31 |
Family
ID=6405907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002041989A Expired - Lifetime CA2041989C (en) | 1990-05-08 | 1991-05-07 | Aqueous pharmaceutical formulations of erythropoietin and the use thereof |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0456153B1 (en) |
| JP (1) | JP2922331B2 (en) |
| KR (1) | KR100203546B1 (en) |
| AT (1) | ATE120646T1 (en) |
| AU (1) | AU652361B2 (en) |
| CA (1) | CA2041989C (en) |
| DE (2) | DE4014654A1 (en) |
| DK (1) | DK0456153T3 (en) |
| ES (1) | ES2073063T3 (en) |
| IE (1) | IE65925B1 (en) |
| NO (1) | NO301805B1 (en) |
| PT (1) | PT97584B (en) |
| ZA (1) | ZA913435B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9917606A (en) | 1998-11-06 | 2002-12-31 | Bio Sidus S A | Procedure for the purification of recombinant human erythropoietin from cell culture supernatants and recombinant human erythropoietin obtained with such procedure |
| ATE291436T2 (en) | 2000-05-15 | 2005-04-15 | Hoffmann La Roche | LIQUID MEDICINAL PREPARATION CONTAINING AN ERYTHROPOIETIN DERIVATIVE |
| DE10234192B4 (en) | 2002-07-26 | 2009-11-26 | Epoplus Gmbh Co.Kg | Use of erythropoietin |
| EP1537876A1 (en) * | 2003-12-01 | 2005-06-08 | BioGeneriX AG | Erythropoietin solution formulation |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57149228A (en) * | 1981-03-11 | 1982-09-14 | Ajinomoto Co Inc | Novel erythropoietin and its preparation |
| JPH0686480B2 (en) * | 1983-02-21 | 1994-11-02 | 雪印乳業株式会社 | Monoclonal antibody for erythropoietin production |
| JPS6191131A (en) * | 1984-10-09 | 1986-05-09 | Chugai Pharmaceut Co Ltd | Method and composition for preventing adsorption of pharmaceutical |
| JPS6197229A (en) * | 1984-10-18 | 1986-05-15 | Chugai Pharmaceut Co Ltd | Stable erythropoietin preparation |
| DE3729863A1 (en) * | 1987-09-05 | 1989-03-16 | Boehringer Mannheim Gmbh | STABILIZED ERYTHROPOIETIN LYOPHILISATES |
-
1990
- 1990-05-08 DE DE4014654A patent/DE4014654A1/en not_active Withdrawn
-
1991
- 1991-04-29 AU AU76183/91A patent/AU652361B2/en not_active Expired
- 1991-05-06 DK DK91107308.8T patent/DK0456153T3/en active
- 1991-05-06 KR KR1019910007286A patent/KR100203546B1/en not_active IP Right Cessation
- 1991-05-06 EP EP91107308A patent/EP0456153B1/en not_active Expired - Lifetime
- 1991-05-06 AT AT91107308T patent/ATE120646T1/en not_active IP Right Cessation
- 1991-05-06 ES ES91107308T patent/ES2073063T3/en not_active Expired - Lifetime
- 1991-05-06 DE DE59105075T patent/DE59105075D1/en not_active Expired - Lifetime
- 1991-05-07 PT PT97584A patent/PT97584B/en not_active IP Right Cessation
- 1991-05-07 NO NO911788A patent/NO301805B1/en not_active IP Right Cessation
- 1991-05-07 IE IE154991A patent/IE65925B1/en not_active IP Right Cessation
- 1991-05-07 CA CA002041989A patent/CA2041989C/en not_active Expired - Lifetime
- 1991-05-07 ZA ZA913435A patent/ZA913435B/en unknown
- 1991-05-08 JP JP3131953A patent/JP2922331B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| AU7618391A (en) | 1991-11-14 |
| CA2041989A1 (en) | 1991-11-09 |
| NO911788L (en) | 1991-11-11 |
| IE65925B1 (en) | 1995-11-29 |
| NO911788D0 (en) | 1991-05-07 |
| EP0456153A1 (en) | 1991-11-13 |
| ZA913435B (en) | 1992-02-26 |
| DE4014654A1 (en) | 1991-11-14 |
| JP2922331B2 (en) | 1999-07-19 |
| DK0456153T3 (en) | 1995-08-07 |
| KR100203546B1 (en) | 1999-06-15 |
| PT97584A (en) | 1992-01-31 |
| KR910019636A (en) | 1991-12-19 |
| IE911549A1 (en) | 1991-11-20 |
| PT97584B (en) | 1998-08-31 |
| JPH04225923A (en) | 1992-08-14 |
| ATE120646T1 (en) | 1995-04-15 |
| ES2073063T3 (en) | 1995-08-01 |
| NO301805B1 (en) | 1997-12-15 |
| EP0456153B1 (en) | 1995-04-05 |
| AU652361B2 (en) | 1994-08-25 |
| DE59105075D1 (en) | 1995-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5661125A (en) | Stable and preserved erythropoietin compositions | |
| EP1417972B1 (en) | Stabilized teriparatide solutions | |
| JP4493334B2 (en) | L-methionine as a stabilizer for NESP / EPO in HSA-free compositions | |
| EP0909564B1 (en) | Erythropoietin solution preparation stabilized with amino acids | |
| EP1336410A1 (en) | Protein injection preparations | |
| PT1988913E (en) | G-csf liquid formulation | |
| IE58161B1 (en) | Stable composition of interleukin-2 | |
| EP0178665A2 (en) | Stable erythropoietin preparation and process for formulating the same | |
| AU749815B2 (en) | Protein-free preparations | |
| US4980165A (en) | Pharmaceutical formulations of plasminogen activator proteins | |
| EP0503583A1 (en) | Composition for sustained release of erythropoietin | |
| CA2041989C (en) | Aqueous pharmaceutical formulations of erythropoietin and the use thereof | |
| EP0355348B1 (en) | Superoxide dismutase composition | |
| CA2046876A1 (en) | Stabilisation of glycosated t-pa | |
| JPH0378847B2 (en) | ||
| EP0815869A1 (en) | Method of preventing tpo adsorption and stable tpo-containing composition | |
| JPH1112194A (en) | Pharmaceutical composition of tissue plasminogen activation factor | |
| MXPA97006987A (en) | Methods to prevent trombopoyetine (tpo) adsorption and stable compositions containing | |
| MXPA97006985A (en) | Methods to prevent trombopoyetine (tpo) adsorption and stable compositions containing | |
| KR19980702973A (en) | Adsorption prevention method of thrombopoietin (TF) and stable composition containing TPO | |
| JPH06340548A (en) | Aqueous solution composition of peptides relating to calcitonin gene | |
| JP2001081040A (en) | Tissue plasminogen activator-containing composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |