Hemophilia treatment by inhalation of coagulation factors

• US 20050008580A1
• Filed: 04/08/2004
• Published: 01/13/2005
• Est. Priority Date: 04/09/2003
• Status: Abandoned Application

• Current Assignee: Novartis Pharma AG (Novartis Ag), Wyeth (Pfizer Inc.)
• Original Assignee: Nektar Therapeutics Incorporated, Wyeth (Pfizer Inc.)
• Inventors: Keith, James C., Gong, David K., Warne, Nicholas W., Schaub, Robert G., Webb, Chandra A., Dorner, Andrew J., Hastedt, Jayne E.
• Application Number:
  US10/820,656
• Publication Number:
  US 20050008580A1
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 38/4846 Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61M 11/02 operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised sprayers for horticulture A01G, A01H; killing insects A01M; air humidifying by nozzles F24F6/14, F24F6/18; cooling by spraying F28B, F28C
• CPC Class Codes: A61M 15/0028 using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
• CPC Class Codes: A61M 2202/064 Powder
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

Hemophilia treatment by the inhalation of coagulation factors. Dry powder Factor IX is aerosolized to a mass median aerodynamic diameter of 4 μm or less, with at least 90% monomer content, at least 80% activity level, and 10% water or less. The aerosol is slowly, and deeply inhaled into the lung, and followed by a maximal exhale.

Claims

1. ) A method of treating hemophilia, said method comprising

a) aerosolizing a Factor IX (F.IX), wherein the aerosolized F.IX:

i) has a mass median aerodynamic diameter (MMAD) of between 2 and 4 μ

m, has a fine particle fraction percent less than 3.3 μ

m (FPF<sub>%<

3.3 μ

m</sub>) of at least 50%,

ii) is at least 90% monomeric,

iii) wherein the after-aerosolization activity/pre-aerosolization activity is at least 80%; and

iv) is a dry powder having less than 10% water (wt/wt);

b) inhaling the aerosolized F.IX and allowing the aerosolized F.IX to deposit in the lung;

c) followed by exhalation.

2. ) The method of claim 1, wherein the MMAD is 2.8 to 3.6 μ

m, the FPF<sub>%<

3.3 μ

m</sub> is at least 60%, the monomer content is at least 95% and the after-aerosolization activity/pre-aerosolization activity is at least 90%.

3. ) The method of claim 1, wherein the MMAD is about 3-3.5 μ

m, the FPF<sub>%<

3.3 μ

m</sub> is at least 64%, the monomer content is at least 97%, and the after-aerosolization activity/pre-aerosolization activity is at least 95%.

4. ) The method of claim 1, wherein the F.IX is aerosolized without alcohol.

5. ) The method of claim 1, wherein the F.IX is recombinant.

6. ) The method of any of claims 1 through 5, wherein the F.IX comprises a tri-leucine excipient.

7. ) The method of claim 6, wherein the tri-leucine/F.IX ratio is 0.5-1.5 wt/wt.

13. ) The method of claim 6, wherein the tri-leucine/F.IX ratio is 0.5-1.5 wt/wt.

8. ) A method of treating hemophilia, said method comprising the inhalation of aerosolized, dry Factor IX (F.IX), wherein the aerosolized dry F.IX:

a) comprises a surface active di- or tri-peptide, b) has a MMAD of between 2.8-3.5 μ

m, c) an FPF<sub>%<

3.3 μ

m</sub> of greater than 60%, d) a monomer content of at least 95%, e) the after-aerosolization activity/pre-aerosolization activity is at least 80%, and f) less than 10% water.

9. ) The method of claim 8, wherein the MMAD is about 3-3.5 μ

m, the FPF<sub>%<

3.3 μ

m</sub> is at least 64%, the after-aerosolization activity/pre-aerosolization activity is at least 90%;

the monomer content is at least 97% and the water content is less than 5%.

10. ) The method of claim 8, wherein the F.IX does not contain alcohol.

11. ) The method of claim 8, wherein the F.IX is recombinant.

12. ) The method of any of claims 8 through 11, wherein the F.IX comprises a tri-leucine excipient.

14. ) A method of preventing hemophilic bleeding in advance of a hemophilic assault, said method comprising

a) aerosolizing a Factor IX (F.IX), wherein the aerosolized F.IX:

i) has a mass median aerodynamic diameter (MMAD) of between 2 and 4 μ

m,

ii) has a fine particle fraction percent less than 3.3 μ

m (FPF<sub>%<

3.3 μ

m</sub>) of at least 50%,

iii) is at least 90% monomeric,

iv) wherein the after-aerosolization activity/pre-aerosolization activity is at least 80%; and

v) is a dry powder having less than 10% water (wt/wt);

b) inhaling the aerosolized F.IX at least once per week and allowing the aerosolized F.IX to deposit in the lung;

c) followed by exhalation.

15. ) The method of claim 14, wherein the inhalation is bi-weekly.

16. ) The method of claim 14, wherein the inhalation is every 2 to 3 days.

17. ) A composition comprising aerosolizable dry F.IX having, when aerosolized an MMAD between 2 and 4 μ

m, an FPF<sub>%<

3.3 μ

m</sub> of at least 50%, an emitted dose (ED) of at least 50%, a monomer content of at least 95%, wherein the after-aerosolization activity/pre-aerosolization activity is at least 80%, less than 10% water, and a surface active di- or tri-peptide excipient, but does not have ethanol.

18. ) The composition of claim 17, wherein the MMAD is between 2.8 and 3.6 μ

m, the ED is at least 60%, the after-aerosolization activity/pre-aerosolization activity is at least 95%, the FPF<sub>%<

3.3 μ

m</sub> is at least 65% and less than 5% water.

19. ) The composition of claim 17, wherein the MMAD is between 3 and 3.5 μ

m, the FPF<sub>%<

3.3 μ

m</sub> is at least 64%, the ED is at least 80%, wherein the after-aerosolization activity/pre-aerosolization activity is at least 95%, the monomer content is at least 97% and the water content is less than 5%.

20. ) A blister pack containing F.IX, wherein the blister pack is waterproof and contains F.IX that is at least 90% monomeric and has less than 10% (wt/wt) water and a surface active di- or tri-peptide excipient, but does not have ethanol.

21. ) The blister pack of claim 20, wherein the F.IX is at least 95% monomeric and has less than 5% (wt/wt) water and the excipient is a dileucyl or a tri-leucine.

22. ) The blister pack of claim 20, wherein the F.IX is at least 97% monomeric and has less than 5% (wt/wt) water and the excipient is tri-leucine.

23. ) The blister pack of any of claims 20 to 22, wherein the F.IX is recombinant F.IX.

24. ) A dry powdered F.IX comprising a biologically active recombinant Factor IX that is at least 90% monomeric and has less than 10% water, and a surface active di- or tri-peptide excipient, but does not have ethanol.

25. ) The dry powdered F.IX of claim 24, wherein the excipient is tri-leucine.

26. ) The dry powdered F.IX of claim 25, wherein there ratio of F.IX to excipient is 0.2-5.0/1.

27. ) A composition comprising dry, dispersible powder and a solid content of about 50 wt % glycosylated F.IX, about 40 wt % trileucine and about 10 wt % buffer.

28. ) A composition comprising dry, dispersible powder and a solid content of 40-60 wt % glycosylated F.IX, 40-60 wt % trileucine and 0-10 wt % buffer.