Hydrogel interferon formulations

• US 7,879,320 B2
• Filed: 05/13/2005
• Issued: 02/01/2011
• Est. Priority Date: 05/17/2004
• Status: Expired due to Fees

• Current Assignee: Ares Trading SA (Merck & Co., Inc.)
• Original Assignee: Ares Trading SA (Merck & Co., Inc.)
• Inventors: Zambaldi, Ilaria, Pompili, Silvia, Del Curto, Maria Dorly, Esposito, Pierandrea
• Primary Examiner(s): Saoud; Christine J
• Assistant Examiner(s): Seharaseyon; Jegatheesan
• Application Number:
  US11/596,599
• Publication Number:
  US 20070248674A1
• Time in Patent Office: 2,090 Days
• Field of Search: None
• US Class Current: 424/85.6
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is related to pharmaceutical Poloxamer hydrogel formulations containing an interferon. In particular, the invention relates to sustained release hydrogel formulations of interferon-beta, method of preparation and use thereof.

Claims

1. A pharmaceutical composition comprising:

a) an interferon (IFN);

b) a poloxamer hydrogel selected from Poloxamer 407 or Poloxamer 338;

c) an antioxidant;

d) a surfactant;

e) a solution-to-gel temperature transition modifier at a concentration of about 1% to about 3%; and

f) a buffer.

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

3. The composition according to claim 2, wherein the interferon is recombinant IFN-beta.

4. The composition according to claim 3, wherein the interferon is recombinant IFN-beta 1a.

5. The composition according to claim 1, wherein the solution-to-gel temperature transition modifier is trehalose or cyclodextrin.

6. The composition according to claim 1, wherein the poloxamer hydrogel is Poloxamer 407.

7. The composition according to claim 6, wherein the composition comprises 20 to 25% w/w of Poloxamer 407.

8. The composition according to claim 1, wherein said composition comprises:

a) 10-800 μ

g/mL interferon;

b) 20%-30% (w/w) poloxamer hydrogel;

c) antioxidant at 100 to 800 fold molar excess (with respect to said interferon);

d) about 0.01 mg/mL to about 10 mg/mL surfactant;

e) about 1% to about 3% (w/w) solution-to-gel modifier; and

f) a buffer.

9. The composition according to claim 8, wherein the surfactant comprises about 0.01 mg/mL to about 10 mg/mL Poloxamer 188.

10. The composition according to claim 9, wherein the composition further comprises trehalose as a solution-to-gel modifier.

11. The composition according to claim 8, wherein the composition comprises hydroxypropyl beta cyclodextrin as a solution-to-gel modifier.

12. A method of treating multiple sclerosis comprising a step of administering a composition according to claim 1 to an individual in need of treatment.

13. The composition according to claim 1, wherein the solution-to-gel temperature transition modifier is trehalose.

14. The composition according to claim 1, wherein the solution-to-gel temperature transition modifier is cyclodextrin.

15. The composition according to claim 1, wherein the solution-to-gel temperature transition modifier is present at a concentration of about 2.6% (w/w).

16. A composition comprising:

a) Poloxamer 407—

25% w/w

Acetate buffer 50 mM/pH 3.8—

74.7% w/w

r-hIFNbeta 1a—

0.012% w/w

L-Methionine—

0.03% w/w

Poloxamer 188—

0.24% w/w;

b) Poloxamer 407—

25% w/w

Acetate buffer 50 mM/pH 3.8—

72.04% w/w

r-hIFNbeta 1a—

0.012% w/w

L-Methionine—

0.03% w/w

Poloxamer 188—

0.24% w/w

Glycerol—

2.6% w/w;

c) Poloxamer 407—

25% w/w

Acetate buffer 50 mM/pH 3.8—

72.04% w/w

r-hIFNbeta 1a—

0.012% w/w

L-Methionine—

0.03% w/w

Poloxamer 188—

0.24% w/w

PEG—

2.6% w/w;

Poloxamer 407—

25% w/w

Acetate buffer 50 mM/pH 3.8—

72.04% w/w

r-h-IFNbeta 1a—

0.012% w/w,

L-Methionine—

0.03% w/w

Poloxamer 188—

0.24% w/w

Trehalose—

2.6% w/w;

or

e) Poloxamer 407—

20% w/w

Acetate buffer 50 mM/pH 3.8—

77.34% w/w

r-h-IFNbeta 1a—

0.015% w/w

L-Methionine—

0.04% w/w

Hydroxypropyl-β

-Cyclodextrin—

2.6% w/w.

17. A method for preparing an IFN hydrogel composition comprising adding a calculated amount of poloxamer hydrogel selected from Poloxamer 407 or Poloxamer 338 to a buffered solution at a temperature wherein a homogeneous polymer solution is formed and then adding an interferon.

18. The method according to claim 17, wherein the buffer solution contains about 1% to about 3% (w/w) solution-to-gel temperature transition modifier.

19. The method according to claim 17, wherein the buffer solution contains a solution-to-gel temperature transition modifier selected from trehalose and cyclodextrin.

20. The method according to claim 17, wherein the interferon is added from an interferon solution comprising interferon and stabilizers selected from L-methionine, Poloxamer 188 or a combination thereof.