WO2008145323A1 - Pharmaceutical formulation for interferons - Google Patents
Pharmaceutical formulation for interferons Download PDFInfo
- Publication number
- WO2008145323A1 WO2008145323A1 PCT/EP2008/004165 EP2008004165W WO2008145323A1 WO 2008145323 A1 WO2008145323 A1 WO 2008145323A1 EP 2008004165 W EP2008004165 W EP 2008004165W WO 2008145323 A1 WO2008145323 A1 WO 2008145323A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical formulation
- interferon alpha
- present
- concentration
- methionine
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- 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]
- A61K38/212—IFN-alpha
-
- 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
- A61K47/20—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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—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
Definitions
- the present invention relates to a pharmaceutical formulation comprising interferon alpha (IFN ⁇ ) as active agent and an anti-oxidant.
- IFN ⁇ interferon alpha
- Interferons are naturally occurring proteins which have antiviral, antiproliferative and immunoregulatory activity.
- the interferon alpha family (INF ⁇ ) represents the predominant class of IFNs produced by stimulated peripheral blood lymphocytes.
- IFN ⁇ has therapeutic potential in a wide range of viral diseases, such as hepatitis B and hepatitis C, as well as proliferative disorders such as chronic myelogenous leukemia.
- IFN ⁇ is used in two forms in therapeutical applications: native (unmodified) IFN ⁇ and modified IFN ⁇ .
- One modification is the attachment of one or more polyethylenglycols (PEG) to IFN ⁇ .
- PEG polyethylenglycols
- Pegylated IFN ⁇ (PEG- IFN ⁇ ) shows improved pharmacokinetic properties compared to unmodified IFN ⁇ .
- EP 0 736 303 discloses an aqueous human serum free IFN ⁇ solution comprising
- IFN ⁇ a non-ionic detergent
- a buffer for adjusting pH to 4.5 - 5.5 a buffer for adjusting pH to 4.5 - 5.5 and benzyl alcohol.
- WO 04/096263 discloses a human serum free pharmaceutical composition for unmodified interferon beta (IFN ⁇ ) comprising methionine as antioxidant.
- IFN ⁇ interferon beta
- the antioxidant is present at a concentration of about 2mM to about 75 mM. In a more preferred embodiment, the antioxidant is methionine and is present at a concentration of about 2 mM to about 50 mM. In a further preferred
- the methionine is present in a concentration of about 2 mM to about 25 mM, even more preferably 2 mM to about 10 mM.
- the pharmaceutical formulation comprises a surfactant.
- the surfactant is preferably selected from the group of polyethylen-sorbitan esters, more preferably a polyethylen-sorbitan -polyethylen(20) -sorbitan ester.
- the surfactant is preferably present in an amount of about 0.001 - 0.05%.
- the pharmaceutical formulation comprises a buffer, preferably an acetate buffer of pH 4.0 to 6.5.
- the pharmaceutical formulation comprises an isotonic agent. More preferably, this may comprise excipients for the groups such as salts, for example sodium chloride, sugars or sugar alcohols, such as sucrose, trehalose or amino acids, such as glycine, arginine or other excipients used for parenteral purposes, for example EDTA.
- excipients for the groups such as salts, for example sodium chloride, sugars or sugar alcohols, such as sucrose, trehalose or amino acids, such as glycine, arginine or other excipients used for parenteral purposes, for example EDTA.
- the interferon alpha is present at a concentration of about 0.01 mg/ml to about 10 mg/ml.
- the interferon alpha is an interferon alpha conjugate, more preferably a PEG interferon alpha conjugate, even more preferably a monopegylated interferon alpha conjugate.
- Methods for protein pegylation are well known to a person skilled in the art and are for example disclosed in EP 0 809 996 and US 5,122,614 which are herein incorporated by reference.
- the interferon alpha is an interferon alpha 2a.
- the interferon is selected from the interferon molecules disclosed in WO 2005/113592 and WO 2004/046365 which are incorporated herein by reference.
- the interferon molecule has the amino acid sequence of Seq. Id. No. 1.
- the present invention is directed to the use of a pharmaceutical formulation of the present invention for the manufacture of a medicament for the treatment of hepatitis C infections.
- the medicament is for the treatment of a chronic hepatitis C infection, more preferably for the treatment of a chronic hepatitis C infection caused by hepatitic C virus having genotype 1.
- the formulation of the present invention is especially suitable for the storage of IFN ⁇ in vials, pref ⁇ lled syringes, ampoules, cartridges, etc.
- the formulation of the present invention can be used to stably store the protein IFN ⁇ at different temperatures, including frozen storage, storage under refrigerated conditions or at room temperature for given periods of time.
- Figure 1 shows the results of a 4 week stability test for IFN ⁇ formulations measuring oxidation
- Figure 2 shows the results of a 4 week stability test for IFN ⁇ formulations measuring aggregate formation.
- Stability tests for 4 formulations were performed to assess the effect of the pharmaceutical formulations of the present invention on oxidation and aggregation of IFN ⁇ .
- Stability tests a pegylated IFN ⁇ molecule having Seq. Id. No. 1 was used.
- the tested pharmaceutical formulations contained the following anti-oxidants and concentrations:
- F3 contains 1OmM methionine as anti-oxidant
- F4 contains 2mg/ml benzylalcohol as anti-oxidant and was used to assess the effect of benzylalcohol at a low concentration.
- the formulations Fl - F4 were stored for 4 weeks at 5°C, 25 0 C and 40 0 C. After 4 weeks storage at the given temperatures, the oxidation of the IFN ⁇ molecules in the formulations was measured. The results are graphically depicted in Figure 1. Significant oxidation occurs after 4 weeks storage at 40 0 C in absence of antioxidants. Addition of methionine (for example 2mM and 1OmM) or benzylalcohol (for example 2mg/ml) prevents oxidation.
- methionine for example 2mM and 1OmM
- benzylalcohol for example 2mg/ml
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a pharmaceutical formulation comprising interferon alpha (IFNα) as active agent and an antioxidant.
Description
Case 24273
PHARMACEUTICAL FORMULATION FOR INTERFERONS
The present invention relates to a pharmaceutical formulation comprising interferon alpha (IFNα) as active agent and an anti-oxidant.
Interferons (IFN) are naturally occurring proteins which have antiviral, antiproliferative and immunoregulatory activity. The interferon alpha family (INFα) represents the predominant class of IFNs produced by stimulated peripheral blood lymphocytes.
IFNα has therapeutic potential in a wide range of viral diseases, such as hepatitis B and hepatitis C, as well as proliferative disorders such as chronic myelogenous leukemia.
IFNα is used in two forms in therapeutical applications: native (unmodified) IFNα and modified IFNα. One modification is the attachment of one or more polyethylenglycols (PEG) to IFNα. Pegylated IFNα (PEG- IFNα ) shows improved pharmacokinetic properties compared to unmodified IFNα.
One problem recognized in connection with formulation of interferons into pharmaceutical products is aggregation of the interferon polypeptides.
EP 0 736 303 discloses an aqueous human serum free IFNα solution comprising
IFNα, a non-ionic detergent, a buffer for adjusting pH to 4.5 - 5.5 and benzyl alcohol.
WO 04/096263 discloses a human serum free pharmaceutical composition for unmodified interferon beta (IFNβ) comprising methionine as antioxidant.
Therefore, there is a need for a pharmaceutical formulation for IFNα or pegylated forms thereof, which leads to an increased molecule stability and reduced aggregation of IFNα.
It is an object of the present invention to provide a pharmaceutical formulation comprising IFNα as active agent and an antioxidant.
In a preferred embodiment, the antioxidant is present at a concentration of about 2mM to about 75 mM. In a more preferred embodiment, the antioxidant is methionine and is present at a concentration of about 2 mM to about 50 mM. In a further preferred
KP/ 17.03.2008
embodiment, the methionine is present in a concentration of about 2 mM to about 25 mM, even more preferably 2 mM to about 10 mM.
In a further preferred embodiment, the pharmaceutical formulation comprises a surfactant. The surfactant is preferably selected from the group of polyethylen-sorbitan esters, more preferably a polyethylen-sorbitan -polyethylen(20) -sorbitan ester. The surfactant is preferably present in an amount of about 0.001 - 0.05%.
In a further preferred embodiment, the pharmaceutical formulation comprises a buffer, preferably an acetate buffer of pH 4.0 to 6.5.
In a further preferred embodiment, the pharmaceutical formulation comprises an isotonic agent. More preferably, this may comprise excipients for the groups such as salts, for example sodium chloride, sugars or sugar alcohols, such as sucrose, trehalose or amino acids, such as glycine, arginine or other excipients used for parenteral purposes, for example EDTA.
In a further preferred embodiment, the interferon alpha is present at a concentration of about 0.01 mg/ml to about 10 mg/ml.
In a further preferred embodiment, the interferon alpha is an interferon alpha conjugate, more preferably a PEG interferon alpha conjugate, even more preferably a monopegylated interferon alpha conjugate. Methods for protein pegylation are well known to a person skilled in the art and are for example disclosed in EP 0 809 996 and US 5,122,614 which are herein incorporated by reference.
In a further preferred embodiment, the interferon alpha is an interferon alpha 2a.
In a further preferred embodiment, the interferon is selected from the interferon molecules disclosed in WO 2005/113592 and WO 2004/046365 which are incorporated herein by reference.
In a much preferred embodiment, the interferon molecule has the amino acid sequence of Seq. Id. No. 1.
In a second object, the present invention is directed to the use of a pharmaceutical formulation of the present invention for the manufacture of a medicament for the treatment of hepatitis C infections.
In a preferred embodiment the medicament is for the treatment of a chronic hepatitis C infection, more preferably for the treatment of a chronic hepatitis C infection caused by hepatitic C virus having genotype 1.
The formulation of the present invention is especially suitable for the storage of IFNα in vials, prefϊlled syringes, ampoules, cartridges, etc.
The formulation of the present invention can be used to stably store the protein IFNα at different temperatures, including frozen storage, storage under refrigerated conditions or at room temperature for given periods of time.
Short description of the drawings
Figure 1 shows the results of a 4 week stability test for IFNα formulations measuring oxidation and
Figure 2 shows the results of a 4 week stability test for IFNα formulations measuring aggregate formation.
Stability tests for 4 formulations were performed to assess the effect of the pharmaceutical formulations of the present invention on oxidation and aggregation of IFNα. In the stability tests a pegylated IFNα molecule having Seq. Id. No. 1 was used.
The tested pharmaceutical formulations contained the following anti-oxidants and concentrations:
• Fl contains no antioxidant and was used as control, • F2 contains 2mM methionine as anti-oxidant,
• F3 contains 1OmM methionine as anti-oxidant,
• F4 contains 2mg/ml benzylalcohol as anti-oxidant and was used to assess the effect of benzylalcohol at a low concentration.
The formulations Fl - F4 were stored for 4 weeks at 5°C, 25 0C and 40 0C. After 4 weeks storage at the given temperatures, the oxidation of the IFNα molecules in the formulations was measured. The results are graphically depicted in Figure 1. Significant oxidation occurs after 4 weeks storage at 400C in absence of antioxidants. Addition of methionine (for example 2mM and 1OmM) or benzylalcohol (for example 2mg/ml) prevents oxidation.
The results graphically depicted in Figure 2 stem from a stability test performed as described above but instead of measuring oxidation after 4 weeks storage, aggregate formation was determined. Under accelerated conditions (400C), formation of aggregates is observed in the absence of antioxidant (17%). Addition of methionine (both
concentrations) or benzylalcohol (2mg/ml) leads to a significant reduction in aggregation.
While there are shown and described presently preferred embodiments of the invention, it is to be distinctly understood that the invention is not limited thereto but may be otherwise variously embodied and practiced within the scope of the following claims.
Claims
1. A pharmaceutical formulation comprising an interferon alpha as active agent and an anti-oxidant.
2. The pharmaceutical formulation of claim 1, wherein the antioxidant is present at a concentration of about 2mM to about 75 mM.
3. The pharmaceutical formulation of claim 1 or 2, wherein the antioxidant is methionine.
4. The pharmaceutical formulation of claim 3, wherein the methionine is present at a concentration of about 2mM to about 75 mM.
5. The pharmaceutical formulation of claim 4, wherein the methionine is present at a concentration of about 2 mM to about 50 mM.
6. The pharmaceutical formulation of claim 5, wherein the methionine is present at a concentration of 2 mM to about 25 mM.
7. The pharmaceutical formulation of claim 6, wherein the methionine is present at a concentration of about 2 mM to about 10 mM.
8. The pharmaceutical formulation of one of the preceding claims, wherein it further comprises a surfactant.
9. The pharmaceutical formulation of claim 8, wherein the surfactant is selected from the group of polyethylen-sorbitan esters.
10. The pharmaceutical formulation of claim 9, wherein the surfactant is preferably a polyethylen-sorbitan -polyethylen(20) -sorbitan ester.
11. The pharmaceutical formulation of claims 8 to 10, wherein the surfactant is present in an amount of about 0.001 - 0.05 %.
12. The pharmaceutical formulation of one of the preceding claims, wherein it further comprises a buffer, preferably an acetate buffer of pH 4.0 to 6.5.
13. The pharmaceutical formulation of claim 12, wherein it comprises an acetate buffer of pH 5.5 to 6.5.
14. The pharmaceutical formulation of one of the preceding claims, wherein it further comprises an isotonic agent, preferably a salt, a sugar or a sugar alcohol.
15. The pharmaceutical formulation of claim 14, wherein the salt is preferably sodium chloride.
16. The pharmaceutical formulation of one of the preceding claims, wherein it further comprises an isotonic agent, preferably an amino acid.
17. The pharmaceutical formulation of any one of the preceding claims, wherein the interferon alpha is present at a concentration of about 0.01 mg/ml to about 5 mg/ml.
18. The pharmaceutical formulation of claim 17, wherein the interferon alpha is present at a concentration of about 0.05 mg/ml to about 0.1 mg/ml.
19. The pharmaceutical formulation of one of the preceding claims, wherein it further comprises EDTA.
20. The pharmaceutical formulation of any one the preceding claims, wherein the interferon alpha is an interferon alpha conjugate, preferably a PEG interferon alpha conjugate.
21. The pharmaceutical formulation of claim 20, wherein the pegylated interferon alpha conjugate is a monopegylated interferon alpha conjugate.
22. The pharmaceutical formulation of any one of the preceding claims, wherein the interferon alpha is an interferon alpha 2a.
23. The pharmaceutical formulation of any one of the preceding claims, wherein the interferon has the amino acid sequence of Seq. Id. No. 1.
24. Use of a pharmaceutical formulation of claims 1 to 23 for the manufacture of a medicament for the treatment of hepatitis C infections.
25. The use of claim 24, wherein the hepatitis C infection is a chronic hepatitis C infection.
26. The use of claim 24 or 25, wherein the hepatitis C infection is a hepatitis C genotype 1 infection.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07109262.1 | 2007-05-31 | ||
EP07109262 | 2007-05-31 |
Publications (1)
Publication Number | Publication Date |
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WO2008145323A1 true WO2008145323A1 (en) | 2008-12-04 |
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PCT/EP2008/004165 WO2008145323A1 (en) | 2007-05-31 | 2008-05-26 | Pharmaceutical formulation for interferons |
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Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011077402A2 (en) | 2009-12-23 | 2011-06-30 | Flamel Technologies | Amphiphilic polymer functionalised by methionine |
WO2016046101A1 (en) * | 2014-09-23 | 2016-03-31 | F. Hoffmann-La Roche Ag | Stable, benzyl alcohol-free aqueous solution formulations containing alpha-type interferon |
US9364519B2 (en) | 2011-09-01 | 2016-06-14 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
US9408893B2 (en) | 2011-08-29 | 2016-08-09 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for use in glycemic control in diabetes type 2 patients |
US9526764B2 (en) | 2008-10-17 | 2016-12-27 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1-agonist |
US9644017B2 (en) | 2008-01-09 | 2017-05-09 | Sanofi-Aventis Deutschland Gmbh | Insulin derivatives having an extremely delayed time-action profile |
US9707176B2 (en) | 2009-11-13 | 2017-07-18 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist and methionine |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
US9950039B2 (en) | 2014-12-12 | 2018-04-24 | Sanofi-Aventis Deutschland Gmbh | Insulin glargine/lixisenatide fixed ratio formulation |
US9981013B2 (en) | 2010-08-30 | 2018-05-29 | Sanofi-Aventis Deutschland Gmbh | Use of AVE0010 for the treatment of diabetes mellitus type 2 |
US10029011B2 (en) | 2009-11-13 | 2018-07-24 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine |
US10159713B2 (en) | 2015-03-18 | 2018-12-25 | Sanofi-Aventis Deutschland Gmbh | Treatment of type 2 diabetes mellitus patients |
US10434147B2 (en) | 2015-03-13 | 2019-10-08 | Sanofi-Aventis Deutschland Gmbh | Treatment type 2 diabetes mellitus patients |
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US5272135A (en) * | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
US5358708A (en) * | 1993-01-29 | 1994-10-25 | Schering Corporation | Stabilization of protein formulations |
EP0736303A2 (en) * | 1995-04-06 | 1996-10-09 | F. Hoffmann-La Roche Ag | Interferon solution |
WO2005069758A2 (en) * | 2004-01-09 | 2005-08-04 | Alza Corporation | Frequency assisted transdermal agent delivery method and system |
US20070059285A1 (en) * | 2003-05-01 | 2007-03-15 | Ares Trading S.A. | Human serum albumin-free stabilized interferon liquid formulations |
WO2007095288A2 (en) * | 2006-02-13 | 2007-08-23 | Nektar Therapeutics | Methionine-containing protein or peptide compositions and methods of making and using |
-
2008
- 2008-05-26 WO PCT/EP2008/004165 patent/WO2008145323A1/en active Application Filing
Patent Citations (6)
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US5272135A (en) * | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
US5358708A (en) * | 1993-01-29 | 1994-10-25 | Schering Corporation | Stabilization of protein formulations |
EP0736303A2 (en) * | 1995-04-06 | 1996-10-09 | F. Hoffmann-La Roche Ag | Interferon solution |
US20070059285A1 (en) * | 2003-05-01 | 2007-03-15 | Ares Trading S.A. | Human serum albumin-free stabilized interferon liquid formulations |
WO2005069758A2 (en) * | 2004-01-09 | 2005-08-04 | Alza Corporation | Frequency assisted transdermal agent delivery method and system |
WO2007095288A2 (en) * | 2006-02-13 | 2007-08-23 | Nektar Therapeutics | Methionine-containing protein or peptide compositions and methods of making and using |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9644017B2 (en) | 2008-01-09 | 2017-05-09 | Sanofi-Aventis Deutschland Gmbh | Insulin derivatives having an extremely delayed time-action profile |
US10117909B2 (en) | 2008-10-17 | 2018-11-06 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1 agonist |
US9526764B2 (en) | 2008-10-17 | 2016-12-27 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1-agonist |
US10029011B2 (en) | 2009-11-13 | 2018-07-24 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine |
US9707176B2 (en) | 2009-11-13 | 2017-07-18 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist and methionine |
US10028910B2 (en) | 2009-11-13 | 2018-07-24 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1-agonist and methionine |
WO2011077402A2 (en) | 2009-12-23 | 2011-06-30 | Flamel Technologies | Amphiphilic polymer functionalised by methionine |
US9981013B2 (en) | 2010-08-30 | 2018-05-29 | Sanofi-Aventis Deutschland Gmbh | Use of AVE0010 for the treatment of diabetes mellitus type 2 |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
US9408893B2 (en) | 2011-08-29 | 2016-08-09 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for use in glycemic control in diabetes type 2 patients |
US9987332B2 (en) | 2011-09-01 | 2018-06-05 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
US9364519B2 (en) | 2011-09-01 | 2016-06-14 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
JP2017528526A (en) * | 2014-09-23 | 2017-09-28 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Stable benzyl alcohol-free aqueous solution containing α-type interferon |
CN107073080A (en) * | 2014-09-23 | 2017-08-18 | 豪夫迈·罗氏有限公司 | The aqueous solution preparation without benzylalcohol of stabilization comprising alpha-interferon |
WO2016046101A1 (en) * | 2014-09-23 | 2016-03-31 | F. Hoffmann-La Roche Ag | Stable, benzyl alcohol-free aqueous solution formulations containing alpha-type interferon |
US9950039B2 (en) | 2014-12-12 | 2018-04-24 | Sanofi-Aventis Deutschland Gmbh | Insulin glargine/lixisenatide fixed ratio formulation |
US10434147B2 (en) | 2015-03-13 | 2019-10-08 | Sanofi-Aventis Deutschland Gmbh | Treatment type 2 diabetes mellitus patients |
US10159713B2 (en) | 2015-03-18 | 2018-12-25 | Sanofi-Aventis Deutschland Gmbh | Treatment of type 2 diabetes mellitus patients |
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