Particulate materials
View Patent ↗The present invention relates to active substances in particulate form, to methods for preparing them, to formulations containing them and to uses of such substances and formulations. A preferred embodiment is directed to particulate suspensions having improved flocculation behavior in a suspension vehicle, such as a hydrofluoroalkane propellant used in metered dose inhalers.
1. A composition of an aerosol formulation, comprising:
a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 μm, suspended in a nonsolvent hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v, which formulation exhibits a flocculation volume of about 85% or greater, about 1 minute after mixing the particulate active substance and the vehicle, wherein the particulate active substance comprises a compound selected from the group consisting of salmeterol xinafoate, budesonide, salbutamol sulfate, dihydroergotamine mesylate, risperidone-(9-hydroxy)-palmitate, bromocriptine mesylate, and derivatives thereof and the nonsolvent hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea).
2. The composition of claim 1 , wherein the vehicle is 1,1,1,2-tetrafluoroethane.
3. The composition of claim 2 , wherein the particulate active substance is suitable for delivery by inhalation.
4. The composition of claim 3 , consisting essentially of the particulate active substance and the vehicle.
5. The composition of claim 1 , wherein the particulate active substance is suspended in the vehicle at a concentration within a range from about 0.2% w/v to about 3% w/v.
6. The composition of claim 1 , wherein the particulate active substance is suspended in the vehicle at a concentration within a range from about 0.5% w/v to about 1.5% w/v.
7. The composition of claim 1 , wherein the relative standard deviation in a quantity of the particulate active substance delivered in each dose is no more than 15% over 100 successive equal volume doses.
8. The composition of claim 1 , wherein the relative standard deviation in a fine particle fraction of the delivered doses is no more than 15% over 100 successive equal volume doses.
9. The composition of claim 1 , wherein the relative standard deviation in a fine particle fraction contained in each dose is no more than 17% over 100 successive equal volume doses.
10. The composition of claim 1 , wherein the relative standard deviation in the mass median aerodynamic diameter of the particulate active substance contained in each dose is no more than 9.5% over 100 successive equal volume doses.
11. The composition of claim 1 , wherein a fine particle fraction contained in each dose is at least 25% over 100 successive equal volume doses.
12. The composition of claim 1 , wherein the mass median aerodynamic diameter of the particulate active substance delivered in each dose is 4 μm or less over 100 successive equal volume doses.
13. The composition of claim 1 , which is stable after storage at 25° C. and 60% relative humidity for a period of at least 12 months.
14. The composition of claim 1 , wherein the flocculation volume is about 35% or greater, about 5 minutes after mixing the particulate active substance and the vehicle.
15. The composition of claim 14 , wherein the flocculation volume is about 50% or greater, about 5 minutes after mixing the particulate active substance and the vehicle.
16. The composition of claim 15 , wherein the flocculation volume is about 50% or greater, about 10 minutes after mixing the particulate active substance and the vehicle.
17. The composition of claim 1 , wherein the particulate active substance further comprises a mass median diameter of less than 15 microns.
18. The composition of claim 17 , wherein the particulate active substance further comprises a mass median diameter of less than 10 microns.
19. The composition of claim 18 , wherein the particulate active substance comprises a mass median diameter of less than 5 microns.
20. The composition of claim 19 , wherein the particulate active substance comprises a mass median diameter of less than 3 microns.
21. The composition of claim 1 , wherein the particulate active substance is in a crystalline form.
22. The composition of claim 21 , wherein the crystalline form is significantly longer in one dimension than in at least one other dimension.
23. The composition of claim 1 , wherein the particulate active substance contains less than 200 ppm of a residual solvent.
24. The composition of claim 1 , wherein the particulate active substance is suitable for systemic delivery via the lung.
25. The composition of claim 1 , wherein the particulate active substance comprises budesonide.
26. A composition of an aerosol formulation, comprising:
a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 5 μm, suspended in a nonsolvent hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v, which formulation exhibits a flocculation volume of greater than 85%, about 60 seconds after mixing the particulate active substance and the vehicle, wherein the particulate active substance comprises a compound selected from the group consisting of salmeterol xinafoate, budesonide, salbutamol sulfate, dihydroergotamine mesylate, risperidone-(9-hydroxy)-palmitate, bromocriptine mesylate, and derivatives thereof and the nonsolvent hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea).
27. The composition of claim 26 , wherein the flocculation volume is greater than 50%, about 2 minutes after mixing the particulate active substance and the vehicle.
28. The composition of claim 27 , wherein the flocculation volume is greater than 85%, about 2 minutes after mixing the particulate active substance and the vehicle.
29. A composition of an aerosol formulation, comprising:
a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 μm; and
a suspension containing the particulate active substance suspended in a nonsolvent hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 3% w/v, wherein the suspension exhibits a flocculation volume of about 35% or greater, 5 minutes after mixing the particulate active substance and the vehicle, wherein the particulate active substance comprises a compound selected from the group consisting of salmeterol xinafoate, budesonide, salbutamol sulfate, dihydroergotamine mesylate, risperidone-(9-hvdroxv)-palmitate, bromocriptine mesylate, and derivatives thereof and the nonsolvent hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea).
30. A composition of an aerosol formulation, comprising:
a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 μm; and
a suspension containing the particulate active substance suspended in a nonsolvent hydrofluorocarbon fluid vehicle and having a flocculation volume of about 85% or greater, about 1 minute after mixing the particulate active substance and the vehicle, wherein the particulate active substance comprises a compound selected from the group consisting of salmeterol xinafoate, budesonide, salbutamol sulfate, dihydroergotamine mesylate, risperidone-(9-hydroxv)-palmitate, bromocriptine mesylate, and derivatives thereof and the nonsolvent hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea).
31. The composition of claim 30 , wherein the particulate active substance comprises salmeterol xinafoate or salbutamol sulfate.
32. The composition of claim 30 , wherein the particulate active substance comprises dihydroergotamine mesylate.
33. The composition of claim 1 , wherein the particulate active substance comprises salmeterol xinafoate or salbutamol sulfate.
34. The composition of claim 1 , wherein the particulate active substance comprises dihydroergotamine mesylate.
35. The composition of claim 26 , wherein the particulate active substance comprises salmeterol xinafoate or salbutamol sulfate.
36. The composition of claim 26 , wherein the particulate active substance comprises dihydroergotamine mesylate.
37. The composition of claim 29 , wherein the particulate active substance comprises salmeterol xinafoate or salbutamol sulfate.
38. The composition of claim 29 , wherein the particulate active substance comprises dihydroergotamine mesylate.
39. A composition of an aerosol formulation, comprising:
a particulate active substance of non-micronized, solid particles having a mass median diameter of less than 15 μm, suspended in a nonsolvent hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v, wherein the formulation exhibits a flocculation volume of 35% or greater, about 1 minute after mixing the particulate active substance and the vehicle, wherein the particulate active substance comprises a compound selected from the group consisting of salmeterol xinafoate. budesonide. salbutamol sulfate. dihydroergotamine mesylate, risperidone-(9-hydroxy)-palmitate, bromocriptine mesylate, and derivatives thereof and the nonsolvent hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea).
40. The composition of claim 39 , wherein the vehicle is 1,1,1,2-tetrafluoroethane.
41. The composition of claim 40 , wherein the particulate active substance is suitable for delivery by inhalation.
42. The composition of claim 39 , wherein the particulate active substance is suspended in the vehicle at a concentration within a range from about 0.2% w/v to about 3% w/v.
43. The composition of claim 42 , wherein the particulate active substance is suspended in the vehicle at a concentration within a range from about 0.5% w/v to about 1.5 % w/v.
44. The composition of claim 39 , wherein the flocculation volume is greater than 50%, about 1 minute after mixing the particulate active substance and the vehicle.
45. The composition of claim 43 , wherein the flocculation volume is greater than 75%, about 1 minute after mixing the particulate active substance and the vehicle.
46. The composition of claim 39 , wherein the flocculation volume is greater than 50%, about 90 seconds after mixing the particulate active substance and the vehicle.
47. The composition of claim 46 , wherein the flocculation volume is greater than 50%, about 2 minutes after mixing the particulate active substance and the vehicle.
48. The composition of claim 47 , wherein the flocculation volume is greater than 50%, about 4 minutes after mixing the particulate active substance and the vehicle.
49. The composition of claim 48 , wherein the flocculation volume is greater than 50%, about 5 minutes after mixing the particulate active substance and the vehicle.
50. The composition of claim 39 , wherein the flocculation volume is greater than 85%, about 1 minute after mixing the particulate active substance and the vehicle.
51. The composition of claim 47 , wherein the flocculation volume is greater than 85%, about 2 minutes after mixing the particulate active substance and the vehicle.
52. The composition of claim 47 , wherein the flocculation volume is greater than 85%, about 5 minutes after mixing the particulate active substance and the vehicle.
53. The composition of claim 47 , wherein the flocculation volume is greater than 85%, about 8 minutes after mixing the particulate active substance and the vehicle.
54. The composition of claim 47 , wherein the flocculation volume is greater than 85%, about 10 minutes after mixing the particulate active substance and the vehicle.
55. The composition of claim 39 , wherein the mass median diameter is less than 10 microns.
56. The composition of claim 55 , wherein the mass median diameter is less than 5 microns.
57. The composition of claim 39 , wherein the particulate active substance is in a crystalline form.
58. The composition of claim 39 , wherein the particulate active substance comprises salmeterol xinafoate or salbutamol sulfate.
59. The composition of claim 39 , wherein the particulate active substance comprises dihydroergotamine mesylate.
60. A composition of an aerosol formulation, comprising:
a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 5 μm, suspended in a nonsolvent hydrofluorocarbon fluid vehicle, wherein the formulation exhibits a flocculation volume of 50% or greater, 1 minute after mixing the particulate active substance and the vehicle, wherein the particulate active substance comprises a compound selected from the group consisting of salmeterol xinafoate, budesonide, salbutamol sulfate, dihydroergotamine mesylate, risperidone-(9-hydroxy)-palmitate, bromocriptine mesylate, and derivatives thereof and the nonsolvent hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea).
61. The composition of claim 60 , wherein the particulate active substance comprises salmeterol xinafoate or salbutamol sulfate.
62. The composition of claim 60 , wherein the particulate active substance comprises dihydroergotamine mesylate.