Formulations including a topical decongestant and a topical corticosteroid suitable for nasal administration and method for treating obstructive sleep apnea

• US 20040235807A1
• Filed: 05/21/2003
• Published: 11/25/2004
• Est. Priority Date: 05/21/2003
• Status: Abandoned Application

• Current Assignee: Tedor Pharma, Inc.
• Original Assignee: Tedor Pharma, Inc.
• Inventors: Weinrich, Karl P., Kaplan, Leonard W.
• Application Number:
  US10/443,672
• Publication Number:
  US 20040235807A1
• Time in Patent Office: Days
• US Class Current: 514/171
• 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 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants

Abstract

A pharmaceutical formulation is provided for nasal drug administration of a topically administrable decongestant, a topically administrable corticosteroid and a pharmaceutically acceptable carrier, and may optionally include further carriers, therapeutic extenders, and the like. Such formulations may also optionally further include a therapeutically active member selected from the group consisting of a topical antibiotic, a topical antihistamine (preferably a non-sedating antihistamine), a leukotriene D₄ antagonist, a 5-lipoxygenase inhibitor, and a FLAP antagonist, or a pharmaceutically acceptable salt thereof. In addition, methods for using the formulation to treat decongestant/corticosteroids-responsive conditions, diseases or disorders such as chronic obstructive nasal congestion and/or obstructive sleep apnea conditions, are provided, as are drug delivery devices and dosage forms for housing and/or dispensing the formulations.

Claims

1. A method for treating a patient suffering from a condition, disease or disorder that is responsive to treatment with a decongestant/corticosteroid combination, comprising nasally administering to the patient a pharmaceutical formulation for intranasal drug administration, wherein the formulation comprises:

a therapeutically effective amount of a topically administrable decongestant;

a therapeutically effective amount of a topically administrable corticosteroid; and

a pharmaceutically acceptable carrier that is suitable for nasal drug administration.

2. The method of claim 1, wherein the topically administrable decongestant is a sympathomimetic amine.

3. The method of claim 2 wherein the sympathomimetic amine is selected from the group consisting of:

oxymetazoline, xylometazoline, naphazoline, tetrahydrozoline, phenylephrine, pharmaceutically acceptable salts thereof, and combinations of any of the foregoing.

4. The method of claim 1, wherein the topically administrable corticosteroid is selected from the group consisting of:

beclomethasone, budesonide, flunisolide, fluticasone, flunidolone, mometasone, triamcinolone, dexamethasone, pharmaceutically acceptable salts and esters thereof.

5. The method of claim 3, wherein the topically administrable corticosteroid is selected from the group consisting of:

beclomethasone, budesonide, flunisolide, fluticasone, flunidolone, mometasone, triamcinolone, dexamethasone, and pharmaceutically acceptable salts and esters thereof.

6. The method of claim 5, wherein the formulation further comprises a therapeutically effective amount of an additional topically administrable pharmaceutically active agent.

7. The method of claim 6, wherein the additional active agent is selected from an antibiotic, an anticholinergic, an antihistamine, a leukotriene D₄ antagonist, a 5-lipoxygenase inhibitor, a FLAP antagonist and combinations thereof.

8. The method of claim 7, wherein the additional active agent is an antihistamine.

9. The method of claim 8, wherein the antihistamine is a non-sedating type antihistamine.

10. The method of claim 1, wherein the patient is suffering from obstructive sleep apnea.

11. The method of claim 5, wherein the patient is suffering from obstructive sleep apnea.

12. The method of claim 10, wherein the formulation is administered at least once daily for a period greater than 14 days.

13. The method of claim 11, wherein the formulation is administered at least once daily for a period greater than 30 days.

14. The method of claim 1, wherein the patient is suffering from chronic nasal congestion.

15. The method of claim 5, wherein the patient is suffering from chronic nasal congestion.

16. The method of claim 14, wherein the formulation is administered at least once daily for a period greater than 14 days.

17. The method of claim 15, wherein the formulation is administered at least once daily for a period greater than 30 days.

18. The method of claim 1, wherein the formulation is administered in the form of a dry powder.

19. The method of claim 18, wherein the corticosteroid is mometasone or an ester thereof.

20. The method of claim 19, wherein the corticosteroid is a mometasone ester.

21. The method of claim 20, wherein the mometasone ester is anhydrous mometasone furoate.

22. The method of claim 20, wherein the mometasone ester is anhydrous mometasone furoate monohydrate.

23. The method of claim 18, wherein the carrier is fructose, galactose, glucose, lactitol, lactose, maltitol, maltose, mannitol, melezitose, myoinositol, palatinite, raffinose, stachyose, sucrose, trehalose, xylitol, hydrates thereof, or a combination of any of the foregoing.

24. The method of claim 23, wherein the carrier is lactose.

25. The method of claim 1, wherein the formulation is administered in the form of an aqueous solution.

26. The method of claim 25, wherein the carrier comprises a biocompatible hydrophilic polymer.

27. The method of claim 26, wherein the biocompatible hydrophilic polymer comprises polyvinylpyrrolidone or a derivative thereof.

28. The method of claim 27, wherein the polyvinylpyrrolidone polymer or a derivative thereof has an average molecular weight of about 10,000 to 360,000.

29. The method of claim 28, wherein the polyvinylpyrrolidone or polyvinylpyrrolidone derivative is present in the formulation in an amount from 0.50 to 15.00% by weight/volume of the aqueous carrier.

30. The method of claim 26, wherein the formulation further comprises a crosslinking agent capable of crosslinking chains of the biocompatible hydrophilic polymer.

31. The method of claim 30, wherein the crosslinking forms a polymeric structure having bioadhesive properties.

32. The method of claim 31, wherein the bioadhesive properties provide an extended therapeutic effect for an active agent present in the formulation.

33. The method of claim 31, wherein the biocompatible hydrophilic polymer is polyvinylpyrrolidone or a derivative thereof.

34. The method of claim 33, wherein the cross-linking agent comprises short to mid-length chains of polyethylene glycol.

35. The method of claim 1, wherein the corticosteroid represents approximately 0.01% to 1% by weight of the pharmaceutical formulation.

36. The method of claim 35, wherein the corticosteroid represents approximately 0.05% to 0.5% by weight.

37. The method of claim 36, wherein the corticosteroid represents approximately 0.05% to 0.1% by weight.

38. The method of claim 1, wherein the formulation is administered in a unit dosage form containing corticosteroid in an amount of approximately 10 to 100 micrograms.

39. The method of claim 1, wherein the decongestant represents approximately 0.001% to 0.2% by weight of the administered pharmnaceutical formulation.

40. The method of claim 39, wherein the decongestant represents approximately 0.01% to 0.1% by weight.

41. The method of claim 40, wherein the decongestant represents approximately 0.025 to 0.05% by weight.

42. The method claim 8, wherein the antihistamine represents approximately 0.001 to 2.0% by weight of the pharmaceutical formulation.

43. The method of claim 42, wherein the formulation is administered in the form of a liquid nasal spray or aerosol composition.

44. A pharmaceutical formulation for nasal drug administration, comprising:

a therapeutically effective amount of a topically administrable decongestant;

a therapeutically effective amount of a topically administrable corticosteroid; and

a pharmaceutically acceptable carrier that is suitable for nasal drug administration.

45. The formulation of claim 44, wherein the topically administrable decongestant is a sympathomimetic amine.

46. The formulation of claim 45, wherein the sympathomimetic amine is selected from the group consisting of:

oxymetazoline, xylometazoline, naphazoline, phenylephrine, pharmaceutically acceptable salts thereof, and combinations of any of the foregoing.

47. The formulation of claim 44, wherein the topically administrable corticosteroid is selected from the group consisting of:

beclomethasone, budesonide, flunisolide, fluticasone, flunidolone, mometasone, triamcinolone, dexamethasone, pharmaceutically acceptable salts and esters thereof.

48. The formulation of claim 45, wherein the topically administrable corticosteroid is selected from the group consisting of:

beclomethasone, budesonide, flunisolide, fluticasone, flunidolone, mometasone, triamcinolone, dexamethasone, and pharmaceutically acceptable salts and esters thereof.

49. The formulation of claim 48, wherein the formulation further comprises a therapeutically effective amount of an additional topically administrable pharmaceutically active agent.

50. The formulation of claim 49, wherein the additional active agent is selected from the group consisting of:

an antibiotic, an anticholinergic, an antihistamine, a leukotriene D₄ antagonist, a 5-lipoxygenase inhibitor, a FLAP antagonist and combinations thereof.

51. The formulation of claim 50, wherein the additional active agent is an antihistamine.

52. The formulation of claim 51, wherein the antihistamine is a non-sedating type antihistamine.

53. The formulation of claim 44, in a dry powder form.

54. The formulation of claim 53, wherein the corticosteroid is mometasone or an ester thereof.

55. The formulation of claim 54, wherein the corticosteroid is a mometasone ester.

56. The formulation of claim 55, wherein the mometasone ester is anhydrous mometasone furoate.

57. The formulation of claim 55, wherein the mometasone ester is anhydrous mometasone furoate monohydrate.

58. The formulation of claim 53, wherein the carrier is fructose, galactose, glucose, lactitol, lactose, maltitol, maltose, mannitol, melezitose, myoinositol, palatinite, raffinose, stachyose, sucrose, trehalose, xylitol, hydrates thereof, or a combination of any of the foregoing.

59. The formulation of claim 58, wherein the carrier is lactose.

60. The formulation of claim 44 in the form of an aqueous solution.

61. The formulation of claim 60, comprising a hydrophilic polymer.

62. The formulation of claim 61, wherein the hydrophilic polymer comprises polyvinylpyrrolidone or a derivative thereof.

63. The formulation of claim 62, wherein the polyvinylpyrrolidone polymer or a derivative flunisolide, fluticasone, flunidolone, mometasone, triamcinolone, dexamethasone, and thereof has an average molecular weight of about 10,000 to 360,000.

64. The formulation of claim 63, wherein the polyvinylpyrrolidone or polyvinylpyrrolidone derivative is present in the formulation in an amount from 0.50 to 15.00% by weight/volume of the aqueous carrier.

65. The formulation of claim 61, further comprising a cross-linking agent capable of crosslinking polymer chains.

66. The formulation of claim 65, wherein the crosslinking forms a polymeric structure having bioadhesive properties.

67. The formulation of claim 66, wherein the bioadhesive properties provide an extended therapeutic effect for an active agent present in the formulation.

68. The formulation of claim 60, wherein the corticosteroid represents approximately 0.01% to 1% by weight.

69. The formulation of claim 68, wherein the corticosteroid represents approximately 0.05% to 0.5% by weight.

70. The formulation of claim 69, wherein the corticosteroid represents approximately 0.05% to 0.1% by weight.

71. The formulation of claim 69, in a unit dosage form wherein corticosteroid is present in an amount of approximately 10 to 100 micrograms.

72. The formulation of claim 69, wherein the decongestant represents approximately 0.001% to 0.2% by weight.

73. The formulation of claim 69, wherein the decongestant represents approximately 0.01% to 0. 1% by weight.

74. The formulation of claim 73, wherein the corticosteroid represents approximately 0.025 to 0.05% by weight.

75. The formulation of claim 51, wherein the antihistamine represents approximately 0.001 to 2.0% by weight.

76. The formulation of claim 51, in the form of liquid nasal spray or aerosol composition.

77. An nasal administrable drug delivery device, comprising:

a pharmaceutical formulation as described in claim 44, and a means for housing and dispensing unit dosages of the formulation into or through a nasal passage of a patient.

78. The drug delivery device of claim 77, comprising a dry powder inhaler, metered-dose inhaler, nebulizer or pump spray bottle.

79. The drug delivery device of claim 78, in the form of a dry powder inhaler.

80. A dry powder inhaler for orienting and positioning a capsule containing a pharmaceutical formulation to be administered via inhalation through a nasal opening, comprising:

a dispensing chamber containing a capsule of a dry powder pharmaceutical formulation as described in claim 44;

a tube for receiving the capsule to be oriented and dispensed;

a ramp surface extending substantially across the tube from one wall to an opposite wall thereof, and

an elongate dispensing passage having a diameter less than that of the tube and sized to receive the capsule only when the elongate axis of the capsule is generally parallel to the axis of the passage, the passage extending from an inlet end formed by an aperture in the ramp'"'"'s surface to a dispensing outlet, the passage being adjacent to one wall of the tube such that the axis of the passage is parallel to, but radially offset from, an axis of the tube,

whereby when the inhaler is positioned with the passage below the tube and the axis of the passage is substantially vertical, a capsule located in the tube is guided by the ramp surface towards the inlet end of the passage.

81. A unit dosage form containing a pharmaceutical composition as described in claim 44.

82. The unit dosage form of claim 81, in the form of a capsule.

83. The dosage form of claim 82, wherein the capsule is a hydroxypropyl methylcellulose capsule.

84. A nasal drug delivery device, comprising:

a pharmaceutical formulation as described in claim 60, and a means for housing and dispensing metered unit dosages of the formulation via a patient'"'"'s nasal opening.

85. A nasal drug delivery device, comprising:

a pharmaceutical formulation as described in claim 67, and a means for housing and dispensing metered unit dosages of the formulation into a patients nasal passages and/or sinuses.