Stabilized interferon liquid formulations

• US 20070104682A1
• Filed: 12/10/2004
• Published: 05/10/2007
• Est. Priority Date: 12/11/2003
• Status: Active Grant

• Current Assignee: Ares Trading SA (Merck & Co., Inc.)
• Original Assignee: Ares Trading SA (Merck & Co., Inc.)
• Inventors: Del Curto, Maria
• Granted Patent: US 7,846,427 B2
• Time in Patent Office: Days
• US Class Current: 424/85.600
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 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
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators

Abstract

Stabilized liquid pharmaceutical composition comprising an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said formulation is a solution that comprises a buffer, a cyclodextrin, an isotonicity agent and an anti-oxidant are described here. Preferably the interferon is interferon beta-1a and the cyclodextrin is HPBCD. These formulations are stable at room temperature, thus bringing the advantage of lower costs for formulation storage and increased safety for the patient with respect to possible “errors” during handling. As a matter of fact, having such formulations stable at room temperature reduces the risk of formation of degradation products potentially responsible for adverse events (e.g. immunogenicity).

Claims

1. A stabilized liquid pharmaceutical composition comprising an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant.

2. The composition according to claim 1, wherein said interferon is IFN-beta.

3. The composition according to claim 2, wherein said IFN-beta is recombinant human IFN-beta.

4. The composition according to claim 1, wherein said buffer is present in an amount sufficient to maintain the pH of said composition within plus or minus 0.5 units of a specified pH, where the specified pH is about 3 to about 6.

5. The composition according to claim 4, wherein said pH is 3.8.

6. The composition according to claim claim 1, wherein said buffer is present at a concentration of about 5 mM to 500 mM.

7. The composition according to claim claim 6, wherein said buffer is present at a concentration of about 50 mM.

8. The composition according to claim claim 1, wherein the buffer is acetate buffer.

9. The composition according to claim 1, wherein said isotonicity agent is mannitol.

10. The composition according to claim 1, wherein said isotonicity agent is present at a concentration of about 0.5 mg/ml to about 500 mg/ml.

11. The composition according to claim 10, wherein said isotonicity agent is present at a concentration of about 50 mg/ml.

12. The composition according to claim 1, wherein said the antioxidant is methionine.

13. The composition according to claim 1, wherein said the antioxidant is present at a concentration of about 0.01 to about 5 mg/ml.

14. The composition according to claim 13, wherein said the antioxidant is present at a concentration of about 0.1 mg/ml.

15. The composition according to claim 1, wherein said interferon is present at a concentration of about 10 μ

g/ml to about 800 μ

g/ml.

16. The composition according to claim 1, wherein said cyclodextrin is present at a molar ratio vs. interferon of from 500-fold molar excess up to 700-fold molar excess.

17. The composition according to claim 1, wherein said interferon is present at a concentration of about 44, 88 or 276 μ

g/ml.

18. The composition according to claim 1, wherein said composition is an aqueous solution.

19. The composition according to claim 1, further comprising a bacteriostatic agent.

20. The composition according to claim 19, wherein said bacteriostatic agent is benzyl alcohol.

21. The composition according to claim 18, wherein said bacteriostatic agent is present at a concentration of about 0.1% to about 2%.

22. The composition according to claim 18, wherein said bacteriostatic agent is present at a concentration of about 0.2 or 0.3%.

23. The composition according to claim 1, wherein the isotonicity agent is mannitol, the anti-oxidant is methionine and the interferon is interferon beta.

24. The composition according to claim 1, wherein the composition is the following liquid formulation:

25. A method for preparing a stabilized liquid pharmaceutical composition comprising adding calculated amounts of 2-hydroxypropyl-beta-cyclodextrin, antioxidant and isotonicity agent to the buffered solution and then adding interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof.

26-31. -31. (canceled)

32. An article of manufacture comprising a container containing a stabilized liquid pharmaceutical composition comprising:

a) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant;

b) interferon-beta (IFN-beta) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant;

c) recombinant interferon-beta (IFN-beta) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant;

d) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent, an anti-oxidant and a buffer that is present in an amount sufficient to maintain the pH of said composition within plus or minus 0.5 units of a specified pH, wherein the specified pH is about 3 to about 6;

e) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent, an anti-oxidant and a buffer that is present in an amount sufficient to maintain the pH of said composition within plus or minus 0.5 units of a specified pH, wherein said pH is 3.8;

f) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said buffer is present at a concentration of about 5 mM to 500 mM;

g) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said buffer is present at a concentration of about 50 mM;

h) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises an acetate buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant;

i) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said isotonicity agent is mannitol;

j) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said isotonicity agent is present at a concentration of about 0.5 mg/ml to about 500 mg/ml;

k) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said isotonicity agent is present at a concentration of about 50 mg/ml;

l) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said the antioxidant is methionine;

m) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said the antioxidant is present at a concentration of about 0.01 to about 5 mg/ml;

n) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said the antioxidant is present at a concentration of about about 0.1 mg/ml;

o) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said interferon is present at a concentration of about 10 μ

g/ml to about 800 μ

g/ml;

p) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said cyclodextrin is present at a molar ratio vs. interferon of from 500-fold molar excess up to 700-fold molar excess;

q) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said interferon is present at a concentration of about 44, 88 or 276 μ

g/ml;

r) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein said composition is an aqueous solution;

s) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent, an anti-oxidant and a bacteriostatic agent;

t) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent, an anti-oxidant and a bacteriostatic agent, wherein said bacteriostatic agent is benzyl alcohol;

u) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent, an anti-oxidant and a bacteriostatic agent, wherein said bacteriostatic agent is present at a concentration of about 0. 1% to about 2%;

v) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent, an anti-oxidant and a bacteriostatic agent, wherein said bacteriostatic agent is present at a concentration of about 0.2 or 0.3%;

w) an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein the isotonicity agent is mannitol, the anti-oxidant is methionine and the interferon is interferon beta;

or

x) a composition comprising an interferon (IFN) or an isoform, mutein, fused protein, functional derivative, active fraction or salt thereof, wherein said composition is a solution that comprises a buffer, 2-hydroxypropyl-beta-cyclodextrin, an isotonicity agent and an anti-oxidant, wherein the composition is the following liquid formulation;

Interferon beta-1a44μ

g/mLHPBCD1.9mg/mLMethionine0.1mg/mLMannitol50mg/mLacetate buffer up to1mL

; and

wherein said container is hermetically sealed in conditions that are sterile and appropriate for storage prior to use.

33. The article of manufacture according to claim 32, wherein said container is for mono-dose or multi-dose administration.

34. The article of manufacture according to claim 33, wherein said container is a pre-filled syringe for mono-dose administration.

35. The article of manufacture according to claim 33, wherein said container is a vial.

36. The article of manufacture according to claim 33, wherein said container is a cartridge for an auto-injector.

37. The article of manufacture according to claim 32, wherein said article of manufacture is a kit for multi-dose administration of a pharmaceutical composition, said kit comprising a first container, said first container comprising a container containing said stabilized liquid pharmaceutical composition and a second container filled with a solution of a bacteriostatic agent.