Stable suspension formulations of erythropoietin receptor agonists

• US 20060030526A1
• Filed: 08/01/2005
• Published: 02/09/2006
• Est. Priority Date: 08/05/2004
• Status: Active Grant

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Liu, Kui, Desjardin, Michael A., Hill, Beth L., Li, Zengji
• Granted Patent: US 7,772,182 B2
• Time in Patent Office: Days
• US Class Current: 514/7.700
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61P 7/06 Antianaemics

Abstract

A suspension formulation for therapeutic use includes a non-aqueous, single-phase vehicle exhibiting viscous fluid characteristics and a particle formulation comprising an erythropoietin receptor agonist dispersed in the vehicle.

Claims

1. A suspension formulation for therapeutic use, comprising:

a non-aqueous, single-phase vehicle exhibiting viscous fluid characteristics; and

a particle formulation comprising an erythropoietin receptor agonist dispersed in the vehicle.

2. The suspension formulation of claim 1, which is stable at 40°

C. for at least 3 months.

3. The suspension formulation of claim 1, which is stable at 40°

C. for up to 12 months.

4. The suspension formulation of claim 1, wherein the particle formulation has a moisture content less than 5 wt % prior to being dispersed in the vehicle.

5. The suspension formulation of claim 1, wherein the particle formulation further comprises a buffer and a stabilizer selected from the group consisting of sugar, amino acid, polyol, polymer, and combinations thereof.

6. The suspension formulation of claim 5, wherein the buffer is selected from the group consisting of histidine and citrate buffers.

7. The suspension formulation of claim 5, wherein the sugar is sucrose.

8. The suspension formulation of claim 5, wherein the buffer is citrate buffer and the ratio of the stabilizer to erythropoietin receptor agonist is greater than 2.0.

9. The suspension formulation of claim 5, wherein the particle formulation further comprises at least one of a surfactant, a bulking agent, and a salt.

10. The suspension formulation of claim 1, wherein the vehicle comprises one or more components selected from the group consisting of solvents, polymers, non-polymers, and surfactants.

11. The suspension formulation of claim 1, wherein the erythropoietin receptor agonist is present in the suspension formulation in an amount ranging from approximately 0.1 to 40 wt %.

12. The suspension formulation of claim 1, wherein the erythropoietin receptor agonist is selected from the group consisting of epoetin alfa, epoetin beta, and darbepoetin alfa.

13. The suspension formulation of claim 1, which is deliverable using an implantable delivery device.

14. The suspension formulation of claim 1, which produces continuous release of the erythropoietin receptor agonist at target dosage for up to 12 months in an environment of use.

15. A method of stimulating erythropoiesis in a subject, comprising:

administering to the subject an effective amount of a suspension formulation comprising a non-aqueous, single-phase vehicle exhibiting viscous fluid characteristics and a particle formulation comprising an erythropoietin receptor agonist dispersed in the vehicle.

16. The method of claim 15, wherein administering to the subject is via an implantable delivery device.

17. The method of claim 15, wherein administering to the subject is long-term continuous administration.

18. An implantable delivery device, comprising:

a reservoir containing a suspension formulation in an amount sufficient to provide continuous delivery of an erythropoietin receptor agonist at a therapeutically effective rate in an environment of use, the suspension formulation comprising a non-aqueous, single-phase vehicle exhibiting viscous fluid characteristics and a particle formulation comprising an erythropoietin receptor agonist dispersed in the vehicle.

19. The implantable delivery device of claim 18, which provides continuous delivery of the erythropoietin receptor agonist for up to 3 months.

20. The implantable delivery device of claim 18, which provides continuous delivery of the erythropoietin receptor agonist for up to 12 months.