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Details for Patent: 8,182,791

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Details for Patent: 8,182,791

Title:Formulations for use in inhaler devices
Abstract: A formulation for an inhaler device comprises carrier particles having a diameter of at least 50 .mu.m and a mass median diameter of at least 175 .mu.m; active particles; and additive material to which is able to promote release of the active particles from the carrier particles on actuation of the inhaler device. The formulation has excellent flowability even at relatively high fine particle contents.
Inventor(s): Staniforth; John Nicholas (Bath, GB), Morton; David Alexander Vodden (Bath, GB), Gill; Rajbir (Wiltshire, GB), Brambilla; Gaetano (Parma, IT), Musa; Rossella (Parma, IT), Ferrarini; Lorenzo (Parma, IT)
Assignee: Vectura Limited (Chippenham, GB)
Filing Date:Apr 17, 2001
Application Number:10/257,790
Claims:1. A formulation for use in an inhaler device, comprising: carrier particles in the form of an agglomerate consisting of a plurality of crystals fused to one another via solid bridges such that the particles have no tendency to disintegrate on expulsion from the inhaler device, wherein the carrier particles have a diameter of at least 50 .mu.m and a mass median diameter of at least 175 .mu.m and a fissured surface, wherein the fissures are at least 20 .mu.m wide and at least 20 .mu.m deep; pharmaceutically active particles; and composite particles comprising additive material and fine excipient material consisting of one or more crystalline sugars, prepared as a pre-blend prior to the addition of the active and carrier particles by milling or high-energy mixing the additive and fine excipient material; wherein the additive material includes one or more compounds selected from amino acids and derivatives thereof; peptides and polypeptides having a molecular weight from 0.25 to 1000 Kda, and derivatives thereof; phospholipids or a derivative thereof; fatty acids and derivatives thereof; or a surface active material.

2. A formulation according to claim 1, in which the mass median diameter of the carrier particles is at least 200 .mu.m.

3. A formulation according to claim 1, in which the carrier particles are of a crystalline sugar.

4. A formulation according to claim 3, in which the carrier particles are of dextrose or lactose.

5. A formulation according to claim 4, in which the carrier particles are of lactose.

6. A formulation according to claim 1, in which the carrier particles are of a crystalline sugar having a tapped density not exceeding 0.75 g/cm.sup.3.

7. A formulation according to claim 6, in which the carrier particles have a tapped density not exceeding 0.7 g/cm.sup.3.

8. A formulation according to claim 1, in which the carrier particles have a bulk density as measured by mercury intrusion porosimetry of not exceeding 0.6 g/cm.sup.3.

9. A formulation according to claim 1, in which the carrier particles are obtainable by a wet granulation process.

10. A formulation according to claim 1, in which the carrier particles are dendritic spherulites.

11. A formulation according to claim 1, in which the additive material is present in an amount of not more than 50% by weight based on the total weight of the formulation.

12. A formulation according to claim 11, in which the additive material is present in an amount of not more than 10% by weight based on the total weight of the formulation.

13. A formulation according to claim 12, in which the additive material is present in an amount of not more than 5% by weight based on the total weight of the formulation.

14. A formulation according to claim 1, in which the additive material includes one or more compounds selected from amino acids and derivatives thereof, and peptides and polypeptides having a molecular weight from 0.25 to 1000 Kda, and derivatives thereof.

15. A formulation according to claim 14, in which the additive material comprises an amino acid.

16. A formulation according to claim 15, in which the additive material consists essentially of leucine.

17. A formulation according to claim 1, in which the additive material comprises a phospholipid or a derivative thereof.

18. A formulation according to claim 17, in which the additive material comprises soya lecithin.

19. A formulation according to claim 1, in which the additive material comprises one or more compounds selected from the group consisting of magnesium stearate, calcium stearate, sodium stearate, lithium stearate, stearic acid, stearylamine, sodium stearyl fumarate, oleic acid, behenic acid, and glyceryl behenate.

20. A formulation according to claim 19, in which the additive is magnesium stearate.

21. A formulation according to claim 1, in which the additive material is selected from fatty acids and derivatives.

22. A formulation according to claim 1, in which the additive material is in particulate form.

23. A formulation according to claim 22, in which at least 90% by weight of the additive particles have an aerodynamic diameter of less than 100 .mu.m.

24. A formulation according to claim 22, in which the mass median aerodynamic diameter of the additive particles is not more than about 10 .mu.m.

25. A formulation according to claim 1, which comprises not less than 0.01% by weight of additive material based on the weight of the formulation.

26. A formulation according to claim 1, in which the additive material forms a discontinuous covering on the surfaces of the carrier particles.

27. A formulation according to claim 26, which contains up to 50% by weight of active particles, based on the total weight of active particles, additive material and carrier particles.

28. A formulation according to claim 1, which contains up to 90% by weight of active particles, based on the total weight of active particles, additive material and carrier particles.

29. A formulation according to claim 28, which contains up to 50% by weight of active particles, based on the total weight of active particles, additive material and carrier particles.

30. A formulation according to claim 29, which contains up to 20% by weight of active particles, based on the total weight of active particles, additive material and carrier particles.

31. A formulation according to claim 1, which comprises at least 50% by weight carrier particles, based on the total weight of the formulation.

32. A formulation according to claim 31, which comprises at least 70% by weight carrier particles, based on the total weight of the formulation.

33. A formulation according to claim 1, in which the active particles comprise one or more active agents selected from .beta..sub.2-agonists, ipratropium bromide, steroids, cromones and leukotriene receptor antagonists and heparin.

34. A formulation according to claim 1, in which the active particles comprise a therapeutically active agent having systemic activity, the active agent being selected from DNase, leukotrienes, insulin, cyclosporin, interleukins, cytokines, anti-cytokines, cytokine receptors, vaccines, growth hormone, leuprolide and related analogues, interferons, desmopressin, immunoglobulins, erythropoeitin, calcitonin, parathyroid hormone, non-opioid analgesic agents and opioid analgesic agents.

35. A formulation according to claim 1, in which the active particles comprise one or more agents selected from peptides, polypeptides, proteins and DNA fragments.

36. A formulation according to claim 35, in which the active particles comprise insulin.

37. A formulation according to claim 1, wherein the fine excipient material comprises particles of an aerodynamic diameter of not more than 50 .mu.m.

38. A formulation according to claim 37, in which the mass median aerodynamic diameter of the fine excipient particles is not more than 15 .mu.m.

39. A formulation according to claim 38, in which the mass median aerodynamic diameter of the excipient particles is not more than 10 .mu.m.

40. A formulation according to claim 37, which includes the fine excipient particles in an amount of not less than 4% by weight, based on the total weight of the formulation.

41. A formulation according to claim 37, including fine excipient particles in an amount of up to 20% by weight, based on the total weight of the formulation.

42. A formulation according to claim 41, in which the fine excipient particles are present in an amount of up to 15% by weight, based on the total weight of the formulation.

43. A formulation according to claim 37, in which the fine excipient particles are of dextrose or lactose.

44. A formulation according to claim 43, in which the fine excipient particles are of lactose.

45. A formulation according to claim 37, in which the carrier particles and the fine excipient particles are of the same material.

46. A formulation according to claim 37, comprising up to 20% by weight fine excipient particles and up to 10% by weight additive material, based on the total weight of the formulation.

47. A formulation according to claim 1, which comprises up to 10% by weight additive material, based on the total weight of the formulation.

48. A formulation according to claim 1, which comprises up to 5% by weight additive material, based on the total weight of the formulation.

49. A formulation according to claim 1, comprising more than 5%, by weight, based on the total weight of the formulation, of particles of aerodynamic diameter less than 20 .mu.m, the formulation having a flowability index of 12 mm or less.

50. A formulation according to claim 1, comprising: from 5 to 90% by weight carrier particles having a diameter of at least 50 .mu.m and a mass median diameter of at least 175 .mu.m; from 0.01 to 90% by weight of a therapeutically active agent; from 0.01 to 50% by weight of an additive material; in each case, by weight, based on the total weight of the carrier particles, active agent and additive material; and fine excipient material in an amount of not more than 50% by weight, based on the total weight of the formulation.

51. A formulation according to claim 50, in which the carrier particles are present in an amount not exceeding 70% by weight, based on the total weight of the formulation.

52. A formulation according to claim 50 in which the total content of therapeutically active agent, additive material and fine excipient is at least 10% by weight based on the total weight of the formulation.

53. A formulation according to claim 52, in which the total content of therapeutically active agent, additive material and fine excipient particles, is at least 20% by weight, based on the total weight of the formulation.

54. An inhaler device comprising a formulation according to claim 1.

55. A device according to claim 54, which is a dry powder inhaler.

56. A device according to claim 54, which is a pressurised metered dose inhaler.

57. A method of manufacturing a formulation according to claim 1, comprising milling or high energy mixing the additive material with the fine excipient material, and mixing the resultant composite particles with the carrier particles and the active particles.

58. A method of increasing the fine particle fraction obtainable from a formulation for an inhaler device comprising: pre-blending additive and fine excipient material consisting of one or more crystalline sugars by milling or high energy mixing to create composite particles, and then combining the composite particles with fissured carrier particles of mass median diameter of at least 175 .mu.m wherein the additive material includes one or more compounds selected from amino acids and derivatives thereof; peptides and polypeptides having a molecular weight from 0.25 to 1000 Kda, and derivatives thereof; phospholipids or a derivative thereof; fatty acids and derivatives thereof; or a surface active material, and wherein the carrier particles are in the form of an agglomerate consisting of a plurality of crystals fused to one another via solid bridges such that the particles have no tendency to disintegrate on expulsion from the inhaler device and have a fissured surface, wherein the fissures in the carrier particles are at least 20 .mu.m wide and at least 20 .mu.m deep.

59. A formulation according to claim 1, comprising more than 10% by weight, based on the total weight of the formulation, of particles of aerodynamic diameter less than 20 .mu.m, the formulation having a flowability index of 12 mm or less.

60. A method according to claim 58, in which the additive material comprises an amino acid.

61. A method according to claim 60, wherein the additive material consists essentially of leucine.

62. A method according to claim 58, in which the additive material comprises one or more compounds selected from the group consisting of magnesium stearate, calcium stearate, sodium stearate, lithium stearate, stearic acid, stearylamine, sodium stearyl fumarate, oleic acid, behenic acid, and glyceryl behenate.

63. A method according to claim 62, in which the additive material is magnesium stearate.
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