Dry powder aerosols of nanoparticulate drugs Number:7,521,068 from the United States Patent and Trademark Office (PTO) owispatent There invention discloses aqueous dispersions of nanoparticulate aerosol formulations, dry powder nanoparticulate aerosol formulation, propellant-based aerosol formulations, methods of using the formulations in aerosol delivery devices, and methods of making such formulations. The nanoparticles of the aqueous dispersions or dry powder formulations comprise insoluble drug particles having a surface modifier on the surface thereof.<H nanoparticulate, aerosols, Dry, powder, aero, 7521068.html, Patent, pto, 7521068

Title: Dry powder aerosols of nanoparticulate drugs

Abstract: There invention discloses aqueous dispersions of nanoparticulate aerosol formulations, dry powder nanoparticulate aerosol formulation, propellant-based aerosol formulations, methods of using the formulations in aerosol delivery devices, and methods of making such formulations. The nanoparticles of the aqueous dispersions or dry powder formulations comprise insoluble drug particles having a surface modifier on the surface thereof.

Patent Number: 7,521,068 Issued on 04/21/2009 to Bosch, et al.

Inventors: Bosch; H. William (Bryn Mawr, PA), Ostrander; Kevin D. (Reading, PA), Cooper; Eugene R. (Berwyn, PA)
Assignee: Elan Pharma International Ltd. (Dublin, IE)

Appl. No.: 09/190,138

Filed: November 12, 1998

Current U.S. Class: 424/489 ; 424/46; 424/490; 424/491; 514/169; 514/182; 514/2; 514/23; 514/826; 514/851; 514/872

Current International Class: A61K 8/00 (20060101); A61K 31/04 (20060101); A61K 31/12 (20060101); A61K 9/16 (20060101); A61K 9/14 (20060101); A61K 31/28 (20060101); A61K 31/33 (20060101); A61K 31/56 (20060101); A61K 31/70 (20060101); A61K 38/00 (20060101); A61K 38/02 (20060101)

Field of Search: 424/65,400,489

References Cited [Referenced By]

U.S. Patent Documents


4807814	February 1989	Douche et al.
4826821	May 1989	Clements
5118528	June 1992	Fessi et al.
5145684	September 1992	Liversidge et al.
5202110	April 1993	Dalby et al.
5225183	July 1993	Purewal et al.
5260478	November 1993	Bacon et al.
5264610	November 1993	Bacon
5300739	April 1994	Bittar
5322679	June 1994	Bacon et al.
5518738	May 1996	Eickhoff et al.
5747001	May 1998	Wiedmann et al.
5785049	July 1998	Smith et al.
5985309	November 1999	Edwards et al.
6001336	December 1999	Gordon

Foreign Patent Documents


0 275 796	Jul., 1988	EP
0 347 779	Dec., 1989	EP
92/08446	May., 1992	WO
WO 95/27475	Oct., 1995	WO
WO 96/25918	Aug., 1996	WO
WO 98/35666	Aug., 1998	WO
WO 99/30687	Jun., 1999	WO
WO 99/38493	Aug., 1999	WO
WO 99/45779	Sep., 1999	WO

Other References

Folke Moren, Chapter 13, Aerosol Dosage Forms and Formulations, Aerosols in Medicine. Principles, Diagnosis and Therapy (Elsevier Science Publishers 1993). cited by examiner .
Remington's Pharmaceutical Sciences (Mack Publishing Company 1990). cited by examiner .
Serafin, W Drugs used in the treatment of asthma Goodman and Gilman's: the Pharmacological Basis of Therapeutics McGraw-Hill New York p. 666 1996. cited by examiner .
Godman & Gilman, The Pharmacological Basis of Therapeutics, 1996, McGaw-Hill, 9th ed, p. 666. cited by examiner .
Newman, "Therapeutic Aerosols", pp. 197-224, (1984). cited by other .
Prodi, et al., "Airborne Particles And Their Intrapulmonary Deposition", Scientific Foundations Of Respiratory Medicine, pp. 545-558, (1981). cited by other .
Heyder, "Mechanisms Of Aerosol Particle Deposition", Lung Mucociliary Clearance, vol. 80:(6)820-823, (1981). cited by other .
Fox et al., "Performance Of a Venturi Eductor As A Feeder In A Pneumatic Conveying System", Powder And Bulk Engineering, pp. 33-36, (1988). cited by other .
Soviet Union Abstract No. 628930, "Bulb-Actuated Ejector For Powdered Medicinal Substance", (1978). cited by other .
Tiano, "Functionality Testing Used To Rationally Assess Performance Of A Model Respiratory Solution Or Suspension In A Nebulizer (Performance Assessment)", vol. 56/12-B of Dissertation Abstracts International, (1995). cited by other .
Waldrep et al,, "Operating Characteristics of 18 Different Continuous-Flow Jet Nebulizers With Beclomethasone Dipropionate Liposome Aerosol", pp. 11-17, (1994). cited by other .
Byron, Aerosol Formulation, Generation, And Delivery Using Nonmetered Systems, pp. 143-151, (1989). cited by other.

Primary Examiner: Padmanabhan; Sreeni
Assistant Examiner: Alstrum-Acevedo; James H.
Attorney, Agent or Firm: Foley & Lardner LLP

Claims

We claim:

1. A dry powder aerosol composition for pulmonary or nasal delivery comprising spherically shaped aggregates formed from spray-drying aqueous dispersions of nanoparticulate drug particles, wherein: (a) the aqueous dispersions of nanoparticulate drug particles: (i) comprise a poorly soluble crystalline drug, wherein by "poorly soluble" it is meant that the drug has a solubility in at least one liquid dispersion medium of less than about 10 mg/ml, (ii) have an effective average particle size of less than about 1000 nm, meaning at least 50% of the drug particles have a particle size of less than about 1000 nm, and (iii) have a surface modifier adsorbed on the surface thereof; and (b) the aggregates of such spray-dried drug particle dispersions are less than or equal to about 100 microns in diameter; and (c) such aggregates return to nanoparticulate drug particle dispersions upon reconstitution in an aqueous liquid medium.

2. The aerosol composition of claim 1 further comprising a diluent.

3. The aerosol composition of claim 2, wherein essentially every diluent particle comprises at least one embedded nanoparticulate drug particle having a surface modifier adhered to the surface of the drug particle.

4. The aerosol composition of claim 1, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

5. The aerosol composition of claim 4, wherein the drug is selected from the group consisting of beclomethasone dipropionate, naproxen, triamcinolone acetonide, budesonide, and an anti-emetic.

6. The aerosol composition of claim 1, wherein the nanoparticulate drug particles have an effective average particle size of less than about 400 nm.

7. The aerosol composition of claim 1, wherein the aerosol comprises a concentration of a drug in an amount of from about 0.05 mg/g up to about 900 mg/g.

8. The aerosol composition of claim 7, wherein the aerosol comprises a concentration of a drug selected from the group consisting of about 10 mg/g or more, about 100 mg/g or more, about 200 mg/g or more, about 400 mg/g or more, about 600 mg/g or more, and about 900 mg/g.

9. The aerosol composition of claim 1, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 10 microns.

10. The aerosol composition of claim 9, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 6 microns.

11. The aerosol composition of claim 10, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

12. The aerosol composition of claim 10, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

13. The aerosol composition of claim 1, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of less than about 2 microns.

14. The aerosol composition of claim 13, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

15. The aerosol composition of claim 13, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

16. The aerosol composition of claim 1, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 5 to about 100 .mu.m.

17. The aerosol composition of claim 16, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 30 to about 60 .mu.m.

18. The aerosol composition of claim 17, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

19. The aerosol composition of claim 17, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

20. A method of administering the aerosol of claim 1 to a patient, wherein the aerosol comprises drug at a concentration of 10 mg/g or greater, and wherein the patient delivery time for the aerosol administration is about 15 seconds or less.

21. The aerosol composition of claim 1, wherein the nanoparticulate drug particles have an effective average particle size of less than about 300 nm.

22. The aerosol composition of claim 1, wherein the nanoparticulate drug particles have an effective average particle size of less than about 250 nm.

23. The aerosol composition of claim 1, wherein the nanoparticulate drug particles have an effective average particle size of less than about 100 nm.

24. The aerosol composition of claim 1, wherein the nanoparticulate drug particles have an effective average particle size of less than about 50 nm.

25. The aerosol composition of claim 1, wherein at least 70% of the drug particles have a particle size of less than about 1000 nm.

26. The aerosol composition of claim 1, wherein at least 90% of the drug particles have a particle size of less than about 1000 nm.

27. A dry powder aerosol composition for pulmonary or nasal delivery comprising spherically shaped aggregates formed from freeze-drying aqueous dispersions of nanoparticulate drug particles, wherein: (a) the aggregates of such freeze-dried drug particle dispersions are less than or equal to about 100 microns in diameter; (b) the aqueous dispersions of nanoparticulate drug particles: (i) comprise a poorly soluble crystalline drug, wherein by "poorly soluble" it is meant that the drug has a solubility in at least one liquid dispersion medium of less than about 10 mg/ml, (ii) have an effective average particle size of less than about 1000 nm, meaning at least 50% of the drug particles have a particle size of less than about 1000 nm, and (iii) have a surface modifier adsorbed on the surface thereof; and (c) such aggregates return to nanoparticulatre drug particle dispersions upon reconstitution in an aqueous liquid medium.

28. The aerosol composition of claim 27, further comprising a diluent.

29. The aerosol composition of claim 27, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

30. The aerosol composition of claim 29, wherein the drug is selected from the group consisting of beclomethasone dipropionate, naproxen, triamcinolone acetonide, budesonide, and an anti-emetic.

31. The aerosol composition of claim 27, wherein the nanoparticulate drug particles have an effective average particle size of less than about 400 nm.

32. The aerosol composition of claim 27, wherein the aerosol comprises a concentration of a drug in an amount of from about 0.05 mg/g up to about 900 mg/g.

33. The aerosol composition of claim 32, wherein the aerosol comprises a concentration of a drug selected from the group consisting of about 10 mg/g or more, about 100 mg/g or more, about 200 mg/g or more, about 400 mg/g or more, about 600 mg/g or more, and about 900 mg/g.

34. The aerosol composition of claim 27, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 10 microns.

35. The aerosol composition of claim 34, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 6 microns.

36. The aerosol composition of claim 35, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

37. The aerosol composition of claim 35, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

38. The aerosol composition of claim 27, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of less than about 2 microns.

39. The aerosol composition of claim 38, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

40. The aerosol composition of claim 38, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

41. The aerosol composition of claim 27, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 5 to about 100 .mu.m.

42. The aerosol composition of claim 41, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 30 to about 60 .mu.m.

43. The aerosol composition of claim 42, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

44. The aerosol composition of claim 42, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

45. The aerosol composition of claim 27, further comprising spray-dried nanoparticulate drug powder, wherein the drug of the freeze-dried nanoparticulate drug powder is either the same or different from the drug of the spray-dried nanoparticulate drug powder.

46. A method of administering the aerosol of claim 27 to a patient, wherein the aerosol comprises drug at a concentration of 10 mg/g or greater, and wherein the patient delivery time for the aerosol administration is about 15 seconds or less.

47. The aerosol composition of claim 27, wherein the nanoparticulate drug particles have an effective average particle size of less than about 300 nm.

48. The aerosol composition of claim 27, wherein the nanoparticulate drug particles have an effective average particle size of less than about 250 nm.

49. The aerosol composition of claim 27, wherein the nanoparticulate drug particles have an effective average particle size of less than about 100 nm.

50. The aerosol composition of claim 27, wherein the nanoparticulate drug particles have an effective average particle size of less than about 50 nm.

51. The aerosol composition of claim 27, wherein at least 70% of the drug particles have a particle size of less than about 1000 nm.

52. The aerosol composition of claim 27, wherein at least 90% of the drug particles have a particle size of less than about 1000 nm.

53. A dry powder nanoparticulate aerosol composition for use in a propellant-based pMDI comprising (a) spherically shaped aggregates of nanoparticulate poorly soluble crystalline drug particles, wherein by "poorly soluble" it is meant that the drug has a solubility in at least one liquid dispersion medium of less than about 10 mg/ml, wherein the aggregates are less than or equal to about 100 microns in diameter, wherein such aggregates return to nanoparticulate drug particles upon reconstitution in an aqueous liquid medium, and wherein the drug particles: (i) have a surface modifier adsorbed on the surface thereof, and (ii) have an effective average particle size of less than about 1000 nm, meaning at least 50% of the drug particles have a particle size of less than about 1000 nm, and (b) a non-aqueous propellant.

54. The aerosol composition of claim 53, wherein at least 70% of the drug particles have a particle size of less than about 1000 nm.

55. The aerosol composition of claim 53, wherein the propellant is a non-CFC propellant.

56. A method of administering the aerosol of claim 53 to a patient, wherein the aerosol comprises drug at a concentration of 10 mg/g or greater, and wherein the patient delivery time for the aerosol administration is about 15 seconds or less.

57. The aerosol composition of claim 53, wherein at least 90% of the drug particles have a particle size of less than about 1000 nm.

58. The aerosol composition of claim 53, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

59. The aerosol composition of any one of claims 4, 29, 11, 14, 18, 36, 39, 43, or 58 wherein the drug is selected from the group consisting of a bronchodilator, a corticosteroid, and an anti-fungal.

60. The aerosol composition of claim 53, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

61. The aerosol composition of claim 53, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 10 microns.

62. The aerosol composition of claim 61, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 6 microns.

63. The aerosol composition of claim 53, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of less than about 2 microns.

64. The aerosol composition of claim 53, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 5 to about 100 .mu.m.

65. The aerosol composition of claim 64, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 30 to about 60 .mu.m.

66. A method of making a dry powder nanoparticulate drug composition comprising: (a) forming an aqueous nanoparticulate dispersion of a poorly soluble drug, wherein: (i) the dispersion comprises poorly soluble crystalline drug particles and a surface modifier adsorbed on the surface thereof, wherein by "poorly soluble" it is meant that the drug has a solubility in the liquid dispersion medium of less than about 10 mg/ml, and (ii) the drug particles have an effective average particle size of less than about 1000 nm, meaning at least 50% of the drug particles have a particle size of less than about 1000 nm; and (b) spray-drying the nanoparticulate dispersion to form a dry powder of spherically shaped aggregates of the nanoparticulate drug and surface modifier particles, wherein the aggregates have a diameter of less than or equal to about 100 microns, and wherein such aggregates return to a nanoparticulate drug dispersion upon reconstitution in an aqueous liquid medium.

67. The method of claim 66, further comprising adding a diluent to the nanoparticulate dispersion prior to spray-drying, wherein following spray-drying essentially every diluent particle contains at least one embedded drug particle and a surface modifier.

68. The method of claim 66, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

69. The method of claim 66, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

70. The method of claim 66, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 10 microns.

71. The method of claim 70, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 6 microns.

72. The method of claim 66, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of less than about 2 microns.

73. The method of claim 66, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 5 to about 100 .mu.m.

74. The method of claim 73, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 30 to about 60 .mu.m.

75. A method of making a dry powder nanoparticulate drug aerosol formulation comprising: (a) milling under non-pressurized conditions in a non-aqueous medium having a high boiling point a dispersion comprising the following: (i) a poorly soluble crystalline drug, wherein by "poorly soluble" it is meant that the drug has a solubility in the non-aqueous medium of less than about 10 mg/ml, and (ii) a surface modifier, to obtain a nanoparticulate drug composition having an effective average particle size of less than about 1000 nm, meaning at least 50% of the drug particles have a particle size of less than about 1000 nm, and (b) evaporating the non-aqueous medium to obtain a dry powder of spherically shaped aggregates of drug and surface modifier particles, wherein the aggregates have a diameter of less than or equal to about 100 microns, and wherein such aggregates return to nanoparticulate drug particle dispersions upon reconstitution in an aqueous liquid medium.

76. The aerosol composition of claim 75, wherein at least 70% of the drug particles have a particle size of less than about 1000 nm.

77. The aerosol composition of claim 75, wherein at least 90% of the drug particles have a particle size of less than about 1000 nm.

78. The method of claim 75, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

79. The method of claim 75, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

80. The method of claim 75, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 10 microns.

81. The method of claim 80, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 6 microns.

82. The method of claim 75, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of less than about 2 microns.

83. The method of claim 75, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 5 to about 100 .mu.m.

84. The method of claim 83, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 30 to about 60 .mu.m.

85. A method of making an aerosol composition comprising: (a) milling under pressurized conditions in a non-aqueous medium a dispersion comprising the following: (i) a poorly soluble crystalline drug, wherein by "poorly soluble" it is meant that the drug has a solubility in the non-aqueous dispersion medium of less than about 10 mg/ml, and (ii) a surface modifier, to obtain a drug having an effective average particle size of less than about 1000 nm, meaning at least 50% of the drug particles have a particle size of less than about 1000 nm; (b) evaporating the non-aqueous medium to obtain a dry powder of spherically shaped aggregates of drug and surface modifier particles, wherein the aggregates have a diameter of less than or equal to about 100 microns, and wherein such aggregates return to nanoparticulate drug particle dispersions upon reconstitution in an aqueous liquid medium; and (c) formulating the dry powder spherically shaped aggregates into an aerosol composition.

86. The aerosol composition of claim 85, wherein at least 70% of the drug particles have a particle size of less than-about 1000 nm.

87. The aerosol composition of claim 85, wherein at least 90% of the drug particles have a particle size of less than about 1000 nm.

88. The method of claim 85, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

89. The method of claim 85, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

90. The method of claim 85, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 10 microns.

91. The method of claim 90, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 6 microns.

92. The method of claim 85, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of less than about 2 microns.

93. The method of claim 85, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 5 to about 100 .mu.m.

94. The method of claim 93, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 30 to about 60 .mu.m.

95. A method of making a dry powder nanoparticulate drug composition comprising: (a) forming an aqueous nanoparticulate dispersion of a poorly soluble drug, wherein: (i) the dispersion comprises poorly soluble crystalline drug particles, wherein by "poorly soluble" it is meant that the drug has a solubility in the liquid dispersion medium of less than about 10 mg/ml, and wherein the drug particles have an effective average particle size of less than about 1000 nm, meaning at least 50% of the drug particles have a particle size of less than about 1000 nm, and (ii) a surface modifier adsorbed on the surface thereof; and (b) freeze-drying the nanoparticulate dispersion to form a dry powder of spherically shaped aggregates of the nanoparticulate drug and surface modifier particles, wherein the aggregates have a diameter of less than or equal to about 100 microns, and wherein such aggregates return to nanoparticulate drug particle dispersions upon reconstitution in an aqueous liquid medium.

96. The method of claim 95, further comprising adding a diluent to the nanoparticulate dispersion prior to freeze-drying, wherein following freeze-drying essentially every diluent particle contains at least one embedded drug particle and a surface modifier.

97. The aerosol composition of claim 95, wherein at least 70% of the drug particles have a particle size of less than about 1000 nm.

98. The aerosol composition of claim 95, wherein at least 90% of the drug particles have a particle size of less than about 1000 nm.

99. The method of claim 95, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, fungal infection therapies, and respiratory illness therapies associated with acquired immune deficiency syndrome, an oncology drug, an anti-emetic, and a cardiovascular agent.

100. The method of any one of claims 68, 78, 88, and 96, wherein the drug is selected from the group consisting of a bronchodilator, a corticosteroid, and an anti-fungal.

101. The method of claim 95, wherein the nanoparticulate drug particles have an effective average particle size selected from the group consisting of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm.

102. The method of claim 95, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 10 microns.

103. The method of claim 102, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 2 to about 6 microns.

104. The method of claim 95, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of less than about 2 microns.

105. The method of claim 95, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 5 to about 100 .mu.m.

106. The method of claim 105, wherein the aggregates of the nanoparticulate drug particles have a mass median aerodynamic diameter of about 30 to about 60 .mu.m.

Description

FIELD OF THE INVENTION

The present invention is directed to aerosol formulations of nanoparticulate drug compositions, and methods of making and using such aerosol formulations.

BACKGROUND OF THE INVENTION

The route of administration of a drug substance can be critical to its pharmacological effectiveness. Various routes of administration exist, and all have their own advantages and disadvantages. Oral drug delivery of tablets, capsules, liquids, and the like is the most convenient approach to drug delivery, but many drug compounds are not amenable to oral administration. For example, modem protein drugs which are unstable in the acidic gastric environment or which are rapidly degraded by proteolytic enzymes in the digestive tract are poor candidates for oral administration. Similarly, poorly soluble compounds which do not dissolve rapidly enough to be orally absorbed are likely to be ineffective when given as oral dosage forms. Oral administration can also be undesirable because drugs which are administered orally are generally distributed to all tissues in the body, and not just to the intended site of pharmacological activity. Alternative types of systemic administration are subcutaneous or intravenous injection. This approach avoids the gastrointestinal tract and therefore can be an effective route for delivery of proteins and peptides. However, these routes of administration have a low rate of patient compliance, especially for drugs such as insulin which must be administered one or more times daily. Additional alternative methods of drug delivery have been developed including transdermal, rectal, vaginal, intranasal, and pulmonary delivery.

Nasal drug delivery relies on inhalation of an aerosol through the nose so that active drug substance can reach the nasal mucosa. Drugs intended for systemic activity can be absorbed into the bloodstream because the nasal mucosa is highly vascularized. Alternatively, if the drug is intended to act topically, it is delivered directly to the site of activity and does not have to distribute throughout the body; hence, relatively low doses may be used. Examples of such drugs are decongestants, antihistamines, and anti-inflammatory steroids for seasonal allergic rhinitis.

Pulmonary drug delivery relies on inhalation of an aerosol through the mouth and throat so that the drug substance can reach the lung. For systemically active drugs, it is desirable for the drug particles to reach the alveolar region of the lung, whereas drugs which act on the smooth muscle of the conducting airways should preferentially deposit in the bronchiole region. Such drugs can include beta-agonists, anticholinergics, and corticosteroids.

Devices Used For Nasal and Pulmonary Drug Delivery

Drugs intended for intranasal delivery (systemic and local) can be administered as aqueous solutions or suspensions, as solutions or suspensions in halogenated hydrocarbon propellants (pressurized metered-dose inhalers), or as dry powders. Metered-dose spray pumps for aqueous formulations, pMDIs, and DPIs for nasal delivery, are available from, for example, Valois of America or Pfeiffer of America.

Drugs intended for pulmonary delivery can also be administered as aqueous formulations, as suspensions or solutions in halogenated hydrocarbon propellants, or as dry powders. Aqueous formulations must be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization, propellant-based systems require suitable pressurized metered-dose inhalers (pMDIs), and dry powders require dry powder inhaler devices (DPIs) which are capable of dispersing the drug substance effectively. For aqueous and other non-pressurized liquid systems, a variety of nebulizers (including small volume nebulizers) are available to aerosolize the formulations. Compressor-driven nebulizers incorporate jet technology and use compressed air to generate the liquid aerosol. Such devices are commercially available from, for example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc. Ultrasonic nebulizers rely on mechanical energy in the form of vibration of a piezoelectric crystal to generate respirable liquid droplets and are commercially available from, for example, Omron Heathcare, Inc. and DeVilbiss Health Care, Inc.

A propellant driven inhaler (pMDI) releases a metered dose of medicine upon each actuation. The medicine is formulated as a suspension or solution of a drug substance in a suitable propellant such as a halogenated hydrocarbon. pMDIs are described in, for example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224 (Butterworths, London, England, 1984).

Dry powder inhalers (DPIs), which involve deaggregation and aerosolization of dry powders, normally rely upon a burst of inspired air that is drawn through the unit to deliver a drug dosage. Such devices are described in, for example, U.S. Pat. No. 4,807,814, which is directed to a pneumatic powder ejector having a suction stage and an injection stage; SU 628930 (Abstract), describing a hand-held powder disperser having an axial air flow tube; Fox et al., Powder and Bulk Engineering,pages 33-36 (March 1988), describing a venturi eductor having an axial air inlet tube upstream of a venturi restriction; EP 347 779, describing a hand-held powder disperser having a collapsible expansion chamber; and U.S. Pat. No. 5,785,049, directed to dry powder delivery devices for drugs.

Droplet/Particle Size Determines Deposition Site

In developing a therapeutic aerosol, the aerodynamic size distribution of the inhaled particles is the single most important variable in defining the site of droplet or particle deposition in the patient; in short, it will determine whether drug targeting succeeds or fails. See P. Byron, "Aerosol Formulation, Generation, and Delivery Using Nonmetered Systems," Respiratory Drug Delivery, 144-151, 144 (CRC Press, 1989). Thus, a prerequisite in developing a therapeutic aerosol is a preferential particle size. The deposition of inhaled aerosols involves different mechanisms for different size particles. D. Swift (1980); Parodi et al., "Airborne Particles and Their Pulmonary Deposition," in Scientific Foundations of Respiratory Medicine, Scaddings et al. (eds.), pp. 545-557 (W. B. Saunders, Philadelphia, 1981); J. Heyder, "Mechanism of Aerosol Particle Deposition," Chest, 80:820-823 (1981).

Generally, inhaled particles are subject to deposition by one of two mechanisms: impaction, which usually predominates for larger particles, and sedimentation, which is prevalent for smaller particles. Impaction occurs when the momentum of an inhaled particle is large enough that the particle does not follow the air stream and encounters a physiological surface. In contrast, sedimentation occurs primarily in the deep lung when very small particles which have traveled with the inhaled air stream encounter physiological surfaces as a result of random diffusion within the air stream. For intranasally administered drug compounds which are inhaled through the nose, it is desirable for the drug to impact directly on the nasal mucosa; thus, large (ca. 5 to 100 .mu.m) particles or droplets are generally preferred for targeting of nasal delivery.

Pulmonary drug delivery is accomplished by inhalation of an aerosol through the mouth and throat. Particles having aerodynamic diameters of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed. Particles having diameters of about 2 to about 5 microns are small enough to reach the upper- to mid-pulmonary region (conducting airways), but are too large to reach the alveoli. Even smaller particles, i. e., about 0.5 to about 2 microns, are capable of reaching the alveolar region. Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles may be exhaled.

Problems with Conventional Aerosol Compositions and Methods

Conventional techniques are extremely inefficient in delivering agents to the lung for a variety of reasons. Prior to the present invention, attempts to develop respirable aqueous suspensions of poorly soluble drugs have been largely unsuccessful. For example, it has been reported that ultrasonic nebulization of a suspension containing fluorescein and latex drug spheres, representing insoluble drug particles, resulted in only 1% aerosolization of the particles, while air-jet nebulization resulted in only a fraction of particles being aerosolized. Susan L. Tiano, "Functionality Testing Used to Rationally Assess Performance of a Model Respiratory Solution or Suspension in a Nebulizer," Dissertation Abstracts International, 56/12-B, pp. 6578 (1995). Another problem encountered with nebulization of liquid formulations prior to the present invention was the long (4-20 min) period of time required for administration of a therapeutic dose. Long administration times are required because conventional liquid formulations for nebulization are very dilute solutions or suspensions of micronized drug substance. Prolonged administration times are undesirable because they lessen patient compliance and make it difficult to control the dose administered. Lastly, aerosol formulations of micronized drug are not feasible for deep lung delivery of insoluble compounds because the droplets needed to reach the alveolar region (0.5 to 2 microns) are too small to accommodate micronized drug crystals, which are typically 2-3 microns or more in diameter.

Conventional pMDIs are also inefficient in delivering drug substance to the lung. In most cases, pMDIs consist of suspensions of micronized drug substance in halogenated hydrocarbons such as chlorofluorocarbons (CFCs) or hydrofluoroalkanes (HFAs). Actuation of the pMDI results in delivery of a metered dose of drug and propellant, both of which exit the device at high velocities because of the propellant pressures. The high velocity and momentum of the drug particles results in a high degree of oropharyngeal impaction as well as loss to the device used to deliver the agent. These losses lead to variability in therapeutic agent levels and poor therapeutic control. In addition, oropharyngeal deposition of drugs intended for topical administration to the conducting airways (such as corticosteroids) can lead to systemic absorption with resultant undesirable side effects. Additionally, conventional micronization (air-jet milling) of pure drug substance can reduce the drug particle size to no less than about 2-3 microns. Thus, the micronized material typically used in pMDIs is inherently unsuitable for delivery to the alveolar region and is not expected to deposit below the central bronchiole region of the lung.

Prior to the present invention, delivery of dry powders to the lung typically used micronized drug substance. In the dry powder form, micronized substances tend to have substantial interparticle electrostatic attractive forces which prevent the powders from flowing smoothly and generally make them difficult to disperse. Thus, two key challenges to pulmonary delivery of dry powders are the ability of the device to accurately meter the intended dose and the ability of the device to fully disperse the micronized particles. For many devices and formulations, the extent of dispersion is dependent upon the patient's inspiration rate, which itself may be variable and can lead to a variability in the delivered dose.

Delivery of drugs to the nasal mucosa can also be accomplished with aqueous, propellant-based, or dry powder formulations. However, absorption of poorly soluble drugs can be problematic because of mucociliary clearance which transports deposited particles from the nasal mucosa to the throat where they are swallowed. Complete clearance generally occurs within about 15-20 minutes. Thus, poorly soluble drugs which do not dissolve within this time frame are unavailable for either local or systemic activity.

The development of aerosol drug delivery systems has been hampered by the inherent instability of aerosols, the difficulty of formulating dry powder and aqueous aerosols of water-insoluble drugs, and the difficulty of designing an optimal drug particle size for an aerosol drug delivery system. There is a need in the art for aerosols that deliver an optimal dosage of essentially insoluble drugs throughout the respiratory tract or nasal cavity. The present invention satisfies these needs.

SUMMARY OF THE INVENTION

The present invention is directed to aqueous, propellant-based, and dry powder aerosols of nanoparticulate compositions, for pulmonary and nasal delivery, in which essentially every inhaled particle contains at least one nanoparticulate drug particle. The drug is highly water-insoluble. Preferably, the nanoparticulate drug has an effective average particle size of about 1 micron or less. This invention is an improvement of the nanoparticulate aerosol formulations described in pending U.S. application Ser. No. 08/984,216, filed on Oct. 9, 1997, for "Aerosols Containing Nanoparticulate Dispersions," specifically incorporated by reference. Non-aerosol preparations of submicron sized water-insoluble drugs are described in U.S. Pat. No. 5,145,684, specifically incorporated herein by reference.

A. Aqueous Aerosol Formulations

The present invention encompasses aqueous formulations containing nanoparticulate drug particles. For aqueous aerosol formulations, the drug may be present at a concentration of about 0.05 mg/mL up to about 600 mg/ML. Such formulations provide effective delivery to appropriate areas of the lung or nasal cavities. In addition, the more concentrated aerosol formulations (i.e., for aqueous aerosol formulations, about 10 mg/mL up to about 600 mg/mL) have the additional advantage of enabling large quantities of drug substance to be delivered to the lung in a very short period of time, e.g., about 1 to about 2 seconds (1 puff) as compared to the conventional 4-20 min. administration period.

B. Dry Powder Aerosol Formulations

Another embodiment of the invention is directed to dry powder aerosol formulations comprising drug particles for pulmonary and nasal administration. Dry powders, which can be used in both DPIs and pMDIs, can be made by spray-drying aqueous nanoparticulate drug dispersions. Alternatively, dry powders containing nanoparticulate drug can be made by freeze-drying nanoparticulate drug dispersions. Combinations of spray-dried and freeze-dried nanoparticulate drug powders can be used in DPIs and pMDIs. For dry powder aerosol formulations, the drug may be present at a concentration of about 0.05 mg/g up to about 990 mg/g. In addition, the more concentrated aerosol formulations (i.e., for dry powder aerosol formulations about 10 mg/g up to about 990 mg/g) have the additional advantage of enabling large quantities of drug substance to be delivered to the lung in a very short period of time, e.g., about 1 to about 2 seconds (1 puff).

1. Spray-Dried Powders Containing Nanoparticulate Drug

Powders comprising nanoparticulate drug can be made by spray-drying aqueous dispersions of a nanoparticulate drug and a surface modifier to form a dry powder which consists of aggregated drug nanoparticles. The aggregates can have a size of about 1 to about 2 microns which is suitable for deep lung delivery. The aggregate particle size can be increased to target alternative delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of drug in the spray-dried dispersion or by increasing the droplet size generated by the spray dryer.

Alternatively, the aqueous dispersion of drug and surface modifier can contain a dissolved diluent such as lactose or mannitol which, when spray dried, forms respirable diluent particles, each of which contains at least one embedded drug nanoparticle and surface modifier. The diluent particles with embedded drug can have a particle size of about 1 to about 2 microns, suitable for deep lung delivery. In addition, the diluent particle size can be increased to target alternate delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of dissolved diluent in the aqueous dispersion prior to spray drying, or by increasing the droplet size generated by the spray dryer.

Spray-dried powders can be used in DPIs or pMDIs, either alone or combined with freeze-dried nanoparticulate powder. In addition, spray-dried powders containing drug nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions having respirable droplet sizes, where each droplet contains at least one drug nanoparticle. Concentrated nanoparticulate dispersions may also be used in these aspects of the invention.

2. Freeze-Dried Powders Containing Nanoparticulate Drug

Nanoparticulate drug dispersions can also be freeze-dried to obtain powders suitable for nasal or pulmonary delivery. Such powders may contain aggregated nanoparticulate drug particles having a surface modifier. Such aggregates may have sizes within a respirable range, i.e., about 2 to about 5 microns. Larger aggregate particle sizes can be obtained for targeting alternate delivery sites, such as the nasal mucosa.

Freeze dried powders of the appropriate particle size can also be obtained by freeze drying aqueous dispersions of drug and surface modifier, which additionally contain a dissolved diluent such as lactose or mannitol. In these instances the freeze dried powders consist of respirable particles of diluent, each of which contains at least one embedded drug nanoparticle.

Freeze-dried powders can be used in DPIs or pMDIs, either alone or combined with spray-dried nanoparticulate powder. In addition, freeze-dried powders containing drug nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions having respirable droplet sizes, where each droplet contains at least one drug nanoparticle. Concentrated nanoparticulate dispersions may also be used in these aspects of the invention.

C. Propellant-Based Formulations

Yet another embodiment of the invention is directed to a process and composition for propellant-based systems comprising nanoparticulate drug particles and a surface modifier. Such formulations may be prepared by wet milling the coarse drug substance and surface modifier in liquid propellant, either at ambient pressure or under high pressure conditions. Alternatively, dry powders containing drug nanoparticles may be prepared by spray-drying or freeze-drying aqueous dispersions of drug nanoparticles and the resultant powders dispersed into suitable propellants for use in conventional pMDIs. Such nanoparticulate pMDI formulations can be used for either nasal or pulmonary delivery. For pulmonary administration, such formulations afford increased delivery to the deep lung regions because of the small (i.e., about 1 to about 2 microns) particle sizes available from these methods. Concentrated aerosol formulations can also be employed in pMDIs.

D. Methods of Making Aerosol Formulations

The invention also provides methods for making an aerosol of nanoparticulate compositions. The nanoparticulate dispersions used in making aqueous aerosol compositions can be made by wet milling or by precipitation methods known in the art. Dry powders containing drug nanoparticles can be made by spray drying or freeze-drying aqueous dispersions of drug nanoparticles. The dispersions used in these systems may or may not contain dissolved diluent material prior to drying. Additionally, both pressurized and non-pressurized milling operations can be employed to make nanoparticulate drug compositions in non-aqueous systems.

In a non-aqueous, non-pressurized milling system, a non-aqueous liquid which has a vapor pressure of 1 atm or less at room temperature is used as a milling medium and may be evaporated to yield dry nanoparticulate drug and surface modifier. The non-aqueous liquid may be, for example, a high-boiling halogenated hydrocarbon. The dry nanoparticulate drug composition thus produced may then be mixed with a suitable propellant or propellants and used in a conventional pMDI.

Alternatively, in a pressurized milling operation, a non-aqueous liquid which has a vapor pressure >1 atm at room temperature is used as a milling medium for making a nanoparticulate drug and surface modifier composition. Such a liquid may be, for example, a halogenated hydrocarbon propellant which has a low boiling point. The resultant nanoparticulate composition can then be used in a conventional pMDI without further modification, or can be blended with other suitable propellants. Concentrated aerosols may also be made via such methods.

E. Methods of Using Nanoparticulate Aerosol Formulations

In yet another aspect of the invention, there is provided a method of treating a mammal comprising: (1) forming an aerosol of a dispersion (either aqueous or powder) of nanoparticles, wherein the nanoparticles comprise an insoluble drug having a surface modifier on the surface thereof, and (2) administering the aerosol to the pulmonary or nasal cavities of the mammal. Concentrated aerosol formulations may also be used in such methods.

Another embodiment of the invention provides a method of diagnosing a mammal comprising: (1) forming an aerosol of a dispersion (either aqueous or dry) of nanoparticles, wherein the nanoparticles comprise an insoluble diagnostic agent having a surface modifier; (2) administering the aerosol to the pulmonary or nasal cavities of the mammal; and (3) imaging the diagnostic agent in the pulmonary or nasal system. Concentrated aerosol formulations can also be employed in such diagnostic methods.

Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Shows an in vitro deposition pattern of a concentrated aerosolized beclomethasone dipropionate dispersion from an ultrasonic nebulizer.

FIG. 2. Shows an in vitro deposition pattern of a concentrated aerosolized beclomethasone dipropionate dispersion from a jet nebulizer.

FIG. 3. Shows the aerodynamic volume distribution diameter of a spray-dried naproxen aerosol (2% (w/w) naproxen).

FIG. 4. Shows a scanning electron micrograph of spray-dried naproxen aerosol particles (aggregated naproxen/polyvinylpyrrolidone (surface modifier) nanoparticles, demonstrating the overall uniformity of size and the spherical nature of the particle