Formulations and methods for treating rhinosinusitis

• US 20050180925A1
• Filed: 03/12/2005
• Published: 08/18/2005
• Est. Priority Date: 04/16/2003
• Status: Active Grant

• Current Assignee: Mylan Specialty L.P. (Pfizer Inc.)
• Original Assignee: Dey LP (Pfizer Inc.)
• Inventors: Chaudry, Imtiaz
• Granted Patent: US 8,309,061 B2
• Time in Patent Office: Days
• US Class Current: 424/46
• 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 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61L 2/0035 Gamma radiation
• CPC Class Codes: A61L 2/07 Steam
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals

Abstract

The invention involves methods and formulations for treating or preventing rhinosinusitis, including but not limited to, bacterial-induced, viral-induced and/or fungus-induced rhinosinusitis in mammals, and/or rhinosinusitis not induced by an infective agent, such as bacteria, fungus or virus. In one embodiment, the formulation of the present invention comprises an anti-inflammatory agent (e.g. fluticasone propionate) having a specific particle size distribution profile. The formulation may also comprise an antifungal agent, antibiotic or antiviral agent.

Claims

1. A formulation for the treatment of symptoms associated with rhinosinusitis in a mammal suffering from rhinosinusitis, the formulation comprising:

(a) about 10 mcg to about 2000 mcg of an anti-inflammatory agent, the anti-inflammatory agent having the following particle size distribution profile;

i. about 10% of the anti-inflammatory particles has an average particle size of less than about 0.40 microns;

ii. about 25% of the anti-inflammatory particles have an average particle size of less than about 1.4 microns;

iii. about 50% of the anti-inflammatory particles have an average particle size of less than about 2.5 microns; and

iv. about 75% of the anti-inflammatory particles have an average particle size of less than about 6.0 microns;

wherein the formulation is suitable for administration by the intranasal route of the mammal.

3. The formulation of claims 1 or 2, comprising about 25 mcg to about 400 mcg of an anti-inflammatory agent.

4. The formulation of claims 1 or 2, comprising about 75 to about 300 mcg of an anti-inflammatory.

5. The formulation of claims 1 or 2, comprising about 200 mcg of an anti-inflammatory agent.

6. The formulation of claims 1 or 2, wherein the anti-inflammatory agent is fluticasone propionate.

7. The formulation of claims 1 or 2, wherein the anti-inflammatory agent is beclonethasone or mometasone.

8. The formulation of claims 1 or 2, wherein the anti-inflammatory agent is Betamethasone, Dexamethasone, Flunisolide, Mometasone a Ciclesomide.

23. The formulation of claims 1, 2, 9 or 10, further comprising about 0.01% to about 90% by weight on a dried weight basis of one or more of the following compounds:

(a) polysorbate 80;

(b) disodium edetate dihydrate, USP;

(c) sodium citrate dihydrate, USP;

(d) sodium chloride, USP; and

(e) purified water, USP.

24. The formulation of claim 23, wherein the:

(a) polysorbate 80 is present in an amount of about 0.4 mg/ml;

(b) disodium edetate dihydrate, USP is present in an amount of about 1 mg/ml;

(c) sodium citrate dihydrate, USP is present in an amount of about 0.065 mg/ml; and

(d) sodium chloride, USP is present in an amount of about 8.8 mg/ml.

25. The formulation of claim 23, wherein said formulation is a sterile aqueous solution or aqueous suspension suitable for administration to the nasal-paranasal mucosa.

2. A formulation for the treatment of symptoms associated with non-bacterial, non-viral or non-fungus induced rhinosinusitis in a mammal suffering from said rhinosinusitis, the formulation comprising:

(a) about 10 mcg to about 2000 mcg of an anti-inflammatory agent, the 1 anti-inflammatory agent having the following particle size distribution profile;

i. about 10% of the steroidal anti-inflammatory particles has an average particle size of less than about 0.40 microns;

ii. about 25% of the steroidal anti-inflammatory particles have an average particle size of less than about 1.4 microns;

iii. about 50% of the steroidal anti-inflammatory particles have an average particle size of less than about 2.5 microns; and

iv. about 75% of the steroidal anti-inflammatory particles have an average particle size of less than about 6.0 microns;

wherein the formulation is suitable for administration by the intranasal route of the mammal.

9. A formulation for the treatment of symptoms associated with rhinosinusitis in a mammal suffering thereof, the formulation comprises an anti-inflammatory agent, the anti-inflammatory agent having particle size distribution profile:

i. about 10% of the steroidal anti-inflammatory particles have an average particle size of less that about 0.1 microns to about 1.5 microns;

ii. about 25% of the steroidal anti-inflammatory particles have an average particle size of less than about 0.1 microns to about 2.0 microns microns;

iii. about 50% of the steroidal anti-inflammatory particles have an average particle size of less than about 0.1 microns to about 3.0 microns;

iv. about 75% of the steroidal anti-inflammatory particles have a particle size of less than about 0.1 microns to about 8.0 microns;

v. about 90% of the steroid particles have a particle size of less than about 0.1 microns to about 8.0 microns;

wherein the formulation is suitable for the administration by the intranasal route of the mammal.

10. A formulation for the treatment of symptoms associated with non-bacterial, non-viral or non-fungus induced rhinosinusitis in a mammal suffering thereof, the formulation comprises an anti-inflammatory agent, the anti-inflammatory agent having particle size distribution profile:

i. about 10% of the steroidal anti-inflammatory particles have an average particle size of less that about 0.1 microns to about 1.5 microns;

ii. about 25% of the steroidal anti-inflammatory particles have an average particle size of less than about 0.10 microns to about 2.0 microns microns;

iii. about 50% of the steroidal anti-inflammatory particles have an average particle size of less than about 0.1 microns to about 3.0 microns;

iv. about 75% of the steroidal anti-inflammatory particles have a particle size of less than about 0.1 microns to about 8.0 microns;

v. about 90% of the steroid particles have a particle size of less than about 2.0 microns to about 10 microns;

wherein the formulation is suitable for the administration by the intranasal route of the mammal.

11. The formulations of claims 9 or 10, comprising about 25 mcg to about 400 mcg of the anti-inflammatory agent.

12. The formulation of claims 9 or 10, comprising about 75 mcg to about 300 mcg of the anti-inflammatory agent.

13. The formulations of claims 9 or 10, comprising about 200 mcg of said steroidal anti-inflammatory agent.

14. The formulations of claims 9 or 10, wherein the formulation is sterile.

15. The formulations of claims 9 or 10, wherein the formulation further comprises a preservative.

16. The formulations of claims 9 or 10, wherein the preservative is benzalkonium chloride.

17. The formulations of claims 9 or 10, wherein the formulation is stable.

18. The formulations of claims 9 or 10, wherein the formulation is an aqueous suspension or aqueous solution.

19. The formulations of claims 9 or 10, wherein the formulation is suitable for intranasal administration by a spray pump, by nebulization or metered dose spray pump.

20. The formulations of claims 9 or 10, wherein the anti-inflammatory agent is Fluticasone Propionate.

21. The formulations of claims 9 or 10, wherein the anti-inflammatory agent is Beclomethasone.

22. The formulation of claims 9 or 10, wherein the anti-inflammatory agent is Bethasone, Dexamethasonee, Funisolide, Mometasone, or Ciclesomide.

26. A method of treating symptoms associated with rhinosinusitis in a mammal in need thereof, said method comprising the step of applying to the mammal'"'"'s nasal-paranasal mucosa a formulation comprising:

(a) about 10 mcg to about 2000 mcg of an anti-inflammatory, wherein the anti-inflammatory has the following particle size distribution profile;

i. about 10% of the anti-inflammatory particles has a particle size of less than 0.40 microns;

ii. about 25% of the anti-inflammatory particles have a particle size of less than 1.4 microns;

iii. about 50% of the anti-inflammatory particles have a particle size of less than 2.5 microns;

iv. about 75% of the anti-inflammatory particles have a particle size of less than 6.0 microns;

wherein said formulation is suitable for the administration by the nasal-paranasal mucosa route of the mammal.

37. The method of claims 26, 27, 28 or 29, wherein the formulation is suitable for intranasal administration by a spray pump, nebulization or metered dose spray pump.

38. The method of claims 26, 27, 28 or 29, wherein the formulation is administered to said mammal as one spray in each nostril from 1 to about 10 times per day.

39. The method of claims 26, 27, 28 or 29 wherein said formulation is administered topically to the nasal-paranasal mucosa of said mammal from 1 to about 10 times per day.

42. The method of claims 26, 27, 28 or 29, wherein the formulation is a sterile aqueous suspension or aqueous solution in a metered-dose spray pump bottle, and wherein the formulation is administered to said mammal as one spray in each nostril from 1 to about 10 times per day.

43. The method of claims 26, 27, 28 or 29, comprising about 25 mcg to about 400 mcg of an anti-inflammatory agent.

44. The method of claims 26, 27, 28 or 29, comprising about 75 mcg to about 300 mcg of an anti-inflammatory.

45. The method of claims 26, 27, 28 or 29, comprising about 200 mcg of an anti-inflammatory agent.

46. The method of claims 26, 27, 28 or 29, wherein the anti-inflammatory agent is fluticasone propionate.

47. The method of claims 26, 27, 28 or 29, wherein the anti-inflammatory agent is beclonethasone or mometasone.

48. The method of claims 26, 27, 28 or 29, wherein the anti-inflammatory agent is Betamethasone, Dexamethasone, Flunisolide, Mometasone or Ciclesomide.

49. The method of claims 26, 27, 28 or 29, wherein the formulation is sterile.

50. The method of claims 26, 27, 28 or 29, wherein the formulation further comprises a preservative.

51. The method of claims 26, 27, 28 or 29, wherein the preservative is benzalkonium chloride.

52. The method of claims 26, 27, 28 or 29, wherein the formulation is stable.

53. The method of claims 26, 27, 28 or 29, wherein the formulation is an aqueous suspension or aqueous solution.

54. The method of claims 26, 27, 28 or 29, wherein the formulation is suitable for intranasal administration by a spray pump, by nebulization, or a metered dose spray pump.

55. The method of claims 26, 27, 28 or 29, further comprising about 0.01% to about 90% by weight on a dried weight basis of one or more of the following compounds:

(a) polysorbate 80;

(b) disodium edetate dihydrate, USP;

(c) sodium citrate dihydrate, USP;

(d) sodium chloride, USP; and

(e) purified water, USP.

56. The method of claims 26, 27, 28 or 29, wherein the:

(a) polysorbate 80 is present in an amount of about 0.4 mg/ml;

(b) disodium edetate dihydrate, USP is present in an amount of about 1 mg/ml;

(c) sodium citrate dihydrate, USP is present in an amount of about 0.065 mg/ml; and

(d) sodium chloride, USP is present in an amount of about 8.8 mg/ml.

27. A method of treating symptoms associated with non-fungus, non-bacterial or non-viral induced rhinosinusitis in a mammal, said method comprising the steps of applying to the mammal'"'"'s nasal-paranasal mucosa a formulation comprising:

(a) about 10 to about 2000 mcg an anti-inflammatory, wherein the steroidal anti-inflammatory agent has the following particle size distribution profile;

i. about 10% of the steroidal anti-inflammatory particles has a particle size of less than 0.40 microns;

ii. about 25% of the steroidal anti-inflammatory particles have a particle size of less than 1.4 microns;

iii. about 50% of the steroidal anti-inflammatory particles have a particle size of less than 2.5 microns; and

iv. about 75% of the steroidal anti-inflammatory particles have a particle size of less than 6.0 microns; and

wherein said formulation is suitable for administration to the nasal-paranasal mucosa.

28. A method of treating symptoms associated with rhinosinusitis in a mammal in need thereof, said method comprising the steps of applying to the mammal'"'"'s nasal-praranasal mucosa or formulation comprising:

(a) about 10 mcg to about 200 mcg of an anti-inflammatory, agent wherein the anti-inflammatory agent has the following particle size distribution profile;

i. about 10% or less of the anti-inflammatory particles have a particle size of less than about 0.1 microns to about 1.5 microns;

ii. about 25% or less of the anti-inflammatory particles have a particle size of less than about 0.10 microns to a bout 2.0 microns;

iii. about 50% or less of the anti-inflammatory particles have a particle size of less than about 0.1 microns to about 3.0 microns; and

iv. about 75% or less of the anti-inflammatory particles has a particle size of less than 0.1 microns to about 8.0 microns.

29. A method of treating symptoms associated with non-bacterial, non-fungal, non-viral induced rhinosinusitis in a mamma in need thereof, said method comprising the steps of applying to the mammals nasal-praranasal mucosa or formulation comprising:

(a) about 10 mcg to about 200 mcg of an anti-inflammatory, wherein the anti-inflammatory has the following particle size distribution profile;

i. about 10% or less of the anti-inflammatory particles have a particle size of less than about 0.10 microns to about 1.5 microns;

ii. about 25% or less of the anti-inflammatory particles have a particle size of less than about 0.10 microns to a bout 2.0 microns;

iii. about 50% or less of the anti-inflammatory particles have a particle size of less than about 0.7 microns to about 3.0 microns; and

iv. about 75% or less of the anti-inflammatory particles has a particle size of less than 2.0 microns to about 8.0 microns.