Inhalable formulation of a solution containing a tiotropium salt

• US 6,890,517 B2
• Filed: 03/24/2003
• Issued: 05/10/2005
• Est. Priority Date: 10/31/2000
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Drechsel, Karin, Barth, Petra, Schmelzer, Christel, Niklaus-Humke, Barbara
• Primary Examiner(s): Kunz, Gary
• Assistant Examiner(s): Haghighatian, Mina
• Application Number:
  US10/395,777
• Publication Number:
  US 20030181478A1
• Time in Patent Office: 778 Days
• Field of Search: 424/45, 424/46, 424/400, 514/826, 514/217.05, 514/291, 514/171, 239/333, 128/200.14
• US Class Current: 424/45
• 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 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• 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 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• 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 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Abstract

A liquid, propellant-free pharmaceutical preparation comprising:

• • (a) a first active substance comprising a tiotropium salt, in a concentration based on tiotropium of between 0.0005% and 5% by weight;
  • (b) a second active substance selected from the group consisting of: an antiallergic, antihistamine, steroid, and leukotriene antagonist;
  • (c) a solvent selected from water or a water/ethanol mixture; and
  • (d) a pharmacologically acceptable preservative,
  • wherein the pH of the preparation is adjusted to between 2.0 and 4.5 with an acid and the tiotropium salt is dissolved in the solvent,
  • optionally including a pharmacologically acceptable complexing agent, stabilizer, a pharmacologically acceptable cosolvent, or other pharmacologically acceptable adjuvants and additives; a method for administering a pharmaceutical preparation by nebulizing the pharmaceutical preparation in an inhaler, and a method of treating asthma or COPD in a patient using the pharmaceutical preparation.

Claims

1. A liquid, propellant-free pharmaceutical preparation comprising:

(a) a first active substance comprising a tiotropium salt, in a concentration based on tiotropium of between 0.0005% and 5% by weight;

(b) a second active substance selected from the group consisting of;

an antiallergic, antihistamine, steroid, and leukotriene antagonist;

(c) a solvent selected from water or a water/ethanol mixture; and

(d) a pharmacologically acceptable preservative,

wherein the pH of the preparation is adjusted to between 2.0 and 4.5 with an acid and the tiotropium salt is dissolved in the solvent,

optionally including a pharmacologically acceptable complexing agent, stabilizer, a pharmacologically acceptable cosolvent, or other pharmacologically acceptable adjuvants and additives.

2. The pharmaceutical preparation according to claim 1, wherein the tiotropium salt is a salt formed with HBr, HCl, HI, monomethylsulfuric acid ester, methanesulfonic acid, or-p-toluenesulfonic acid.

3. The pharmaceutical preparation according to claim 1, wherein the active substance is tiotropium bromide.

4. The pharmaceutical preparation according to claim 1, wherein the active substance is tiotropium bromide monohydrate.

5. The pharmaceutical preparation according to claim 1, wherein the solvent is water.

6. The pharmaceutical preparation according to claim 2, wherein the solvent is water.

7. The pharmaceutical preparation according to claim 3, wherein the solvent is water.

8. The pharmaceutical preparation according to claim 4, wherein the solvent is water.

9. The pharmaceutical preparation according to claim 1, wherein the solvent is a water-ethanol mixture with up to 90 vol. % of ethanol.

10. The pharmaceutical preparation according to claim 2, wherein the solvent is a water-ethanol mixture with up to 90 vol. % of ethanol.

11. The pharmaceutical preparation according to claim 3, wherein the solvent is a water-ethanol mixture with up to 90 vol. % of ethanol.

12. The pharmaceutical preparation according to claim 4, wherein the solvent is a water-ethanol mixture with up to 90 vol. % of ethanol.

13. The pharmaceutical preparation according to claim 9, wherein the solvent is a water-ethanol mixture with up to 70 vol. % of ethanol.

14. The pharmaceutical preparation according to claim 13, wherein the solvent is a water-ethanol mixture with up to 30 vol. % of ethanol.

15. The pharmaceutical preparation according to one of claims 1 to 4, wherein the pharmaceutical preparation does not contain a complexing agent.

16. The pharmaceutical preparation according to one of claims 1 to 4, wherein the pharmaceutical preparation does not contain a stabilizer.

17. The pharmaceutical preparation according to one of claims 1 to 4, wherein edetic acid salt is present in an amount of greater than 0 up to 25 mg/100 ml.

18. The pharmaceutical preparation according to claim 17, wherein edetic acid salt is present in an amount of from 5 to less than 10 mg/100 ml.

19. The pharmaceutical preparation according to claim 17, wherein the edetic acid salt is sodium edetate.

20. The pharmaceutical preparation according to one of claims 1 to 4, wherein the pH is between 2.5 and 3.5.

21. The pharmaceutical preparation according to claim 20, wherein the pH is between 2.7 and 3.3.

22. The pharmaceutical preparation according to claim 21, wherein the pH is between 2.7 and 3.0.

23. The pharmaceutical preparation according to one of claims 1 to 4, wherein the concentration based on tiotropium is between 0.0005% and 5% by weight.

24. The pharmaceutical preparation according to claim 23, wherein the concentration based on tiotropium is between 0.001% to 3% by weight.

25. The pharmaceutical preparation according to one of claims 1 to 4, wherein the pharmacologically acceptable preservative is benzalkonium chloride.

26. The pharmaceutical preparation according to one of claims 1 to 4, wherein the pharmaceutical preparation comprises a pharmacologically acceptable adjuvant or additive.

27. The pharmaceutical preparation according to claim 26, wherein pharmacologically acceptable adjuvant or additive is an antioxidant.

28. The pharmaceutical preparation according to one of claims 1 to 4, wherein the pharmaceutical preparation contains no cosolvents and/or pharmacologically acceptable adjuvants and additives apart from the preservative.

29. The pharmaceutical preparation according to one of claims 1 to 4, wherein the tiotropium salt is present in a concentration based on tiotropium of between 0.001% and 3% by weight.

30. The pharmaceutical preparation according to one of claims 1 to 4, wherein the tiotropium salt is present in a concentration based on tiotropium of between 0.001 % and 0.1 % by weight.

31. The pharmaceutical preparation according to one of claims 1 to 4, wherein the ingredients are dissolved in the solvent.

32. The pharmaceutical preparation according to one of claims 1 to 4, wherein the second active substance is in suspension in the solvent.

33. The pharmaceutical preparation according to one of claims 1 to 4, wherein the second active substance is a steroid.

34. The pharmaceutical preparation according to claim 33, wherein the concentration of the steroid is 0.05 wt. % to 5 wt. %.

35. The pharmaceutical preparation according to claim 33, wherein the steroid is selected from the group consisting of:

budesonide, beclomethasone dipropionate, fluticasone, and flunisolide.

36. The pharmaceutical preparation according to one of claims 1 to 4, wherein the second active substance is an antiallergic or an antihistamine.

37. The pharmaceutical preparation according to claim 36, wherein the concentration of the antiallergic or the antihistamine is 0.05 wt. % to 15 wt. %.

38. The pharmaceutical preparation according to claim 36, wherein the antiallergic or the antihistamine is selected from the group consisting of:

epinastine, nedocromil, disodium cromoglycate, astemizole, mequitazine, carbinoxamine, and clemastine, or a corresponding pharmaceutically acceptable salt thereof.

39. The pharmaceutical preparation according to one of claims 1 to 4, wherein the second active substance is a leukotriene antagonist.

40. The pharmaceutical preparation according to claim 39, wherein the concentration of the leukotriene antagonist is 0.05 wt. % to 10 wt. %.

41. The pharmaceutical preparation according to claim 39, wherein the leukotriene antagonist is selected from the group consisting of:

montelukast, pranlukast, zafirlukast, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, and 1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic acid, [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid.

42. A pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation comprises:

water as the solvent;

a surfactant;

0.1 wt. % of tiotropium bromide;

a second active substance selected from the group consisting of;

antiallergics, antihistamines, steroids, and leukotriene antagonists;

0.01 wt. % of benzalkonium chloride; and

0.05 wt. % of sodium edetate, wherein the pH of the preparation is adjusted to 3.0 with hydrochloric acid or citric acid.

43. A method for administering a pharmaceutical preparation according to one of claims 1 to 4, comprising nebulizing the pharmaceutical preparation in an inhaler selected from the group consisting of an inhaler according to FIGS. Ia or Ib.

44. A method for administering a pharmaceutical preparation according to one of claims 1 to 4, comprising nebulizing the pharmaceutical preparation in an inhaler which nebulizes defined amounts of the pharmaceutical preparation by the application of pressures from 100 to 600 bar through a nozzle having at least one nozzle opening with a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol.

45. The method according to claim 44, wherein at least one nozzle opening is at least two nozzle openings which are inclined relative to one another in the direction of the nozzle opening at an angle of from 20 degrees to 160 degrees.

46. The method according to claim 44, wherein the defined amounts of the pharmaceutical preparation are 10 to 50 microliters.

47. The method according to claim 43, wherein the inhaler is 9 cm to 15 cm long and 2 cm to 4 cm wide.

48. The method according to claim 44, wherein the inhaler is 9 cm to 15 cm long and 2 cm to 4 cm wide.

49. The method according to claim 43, wherein the mass of pharmaceutical formulation delivered in at least 97% of all actuations of the inhaler is between 5 mg and 30 mg within a range of tolerance of 25%.

50. The method according to claim 44, wherein the mass of pharmaceutical formulation delivered in at least 97% of all actuations of the inhaler is between 5 mg and 30 mg within a range of tolerance of 25%.

51. The method according to claim 43, wherein the mass of pharmaceutical formulation delivered in at least 97% of all actuations of the inhaler is between 5 mg and 30 mg within a range of tolerance of 20%.

52. The method according to claim 44, wherein the mass of pharmaceutical formulation delivered in at least 97% of all actuations of the inhaler is between 5 mg and 30 mg within a range of tolerance of 20%.

53. The method according to claim 43, wherein the mass of pharmaceutical formulation delivered in at least 98% of all actuations of the inhaler is between 5 mg and 30 mg within a range of tolerance of 20%.

54. The method according to claim 44, wherein the mass of pharmaceutical formulation delivered in at least 98% of all actuations of the inhaler is between 5 mg and 30 mg within a range of tolerance of 20%.

55. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation according to one of claims 1 to 4.

56. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 43.

57. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 44.

58. A method for administering a pharmaceutical preparation according to claim 26, comprising nebulizing the pharmaceutical preparation in an inhaler selected from the group consisting of an inhaler according to FIGS. Ia or Ib.

59. A method for administering a pharmaceutical preparation according to claim 26, comprising nebulizing the pharmaceutical preparation in an inhaler which nebulizes defined amounts of the pharmaceutical preparation by the application of pressures from 100 to 600 bar through a nozzle having at least one nozzle opening with a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol.

60. A method for administering a pharmaceutical preparation according to claim 28, comprising nebulizing the pharmaceutical preparation in an inhaler selected from the group consisting of an inhaler according to FIGS. Ia or Ib.

61. A method for administering a pharmaceutical preparation according to claim 28, comprising nebulizing the pharmaceutical preparation in an inhaler which nebulizes defined amounts of the pharmaceutical preparation by the application of pressures from 100 to 600 bar through a nozzle having at least one nozzle opening with a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol.

62. A method for administering a pharmaceutical preparation according to claim 33, comprising nebulizing the pharmaceutical preparation in an inhaler selected from the group consisting of an inhaler according to FIGS. Ia or Ib.

63. A method for administering a pharmaceutical preparation according to claim 33, comprising nebulizing the pharmaceutical preparation in an inhaler which nebulizes defined amounts of the pharmaceutical preparation by the application of pressures from 100 to 600 bar through a nozzle having at least one nozzle opening with a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol.

64. A method for administering a pharmaceutical preparation according to claim 36, comprising nebulizing the pharmaceutical preparation in an inhaler selected from the group consisting of an inhaler according to FIGS. Ia or Ib.

65. A method for administering a pharmaceutical preparation according to claim 36, comprising nebulizing the pharmaceutical preparation in an inhaler which nebulizes defined amounts of the pharmaceutical preparation by the application of pressures from 100 to 600 bar through a nozzle having at least one nozzle opening with a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol.

66. A method for administering a pharmaceutical preparation according to claim 39, comprising nebulizing the pharmaceutical preparation in an inhaler selected from the group consisting of an inhaler according to FIGS. Ia or Ib.

67. A method for administering a pharmaceutical preparation according to claim 39, comprising nebulizing the pharmaceutical preparation in an inhaler which nebulizes defined amounts of the pharmaceutical preparation by the application of pressures from 100 to 600 bar through a nozzle having at least one nozzle opening with a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol.

68. A method for administering a pharmaceutical preparation according to claim 41, comprising nebulizing the pharmaceutical preparation in an inhaler selected from the group consisting of an inhaler according to FIGS. Ia or Ib.

69. A method for administering a pharmaceutical preparation according to claim 41, comprising nebulizing the pharmaceutical preparation in an inhaler which nebulizes defined amounts of the pharmaceutical preparation by the application of pressures from 100 to 600 bar through a nozzle having at least one nozzle opening with a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol.

70. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 58.

71. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 59.

72. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 60.

73. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 61.

74. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 62.

75. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 63.

76. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 64.

77. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 65.

78. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 66.

79. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 67.

80. A method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 68.

81. method of treating asthma or COPD in a patient, the method comprising administering to the patient a pharmaceutical preparation using the method of claim 69.