Dry powder medicament formulations

• US 20040241232A1
• Filed: 03/12/2004
• Published: 12/02/2004
• Est. Priority Date: 09/17/2001
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Brown, Andrew Bruce, Va Oort, Michael Mary
• Granted Patent: US 8,337,816 B2
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14

Abstract

A dry powder pharmaceutical composition comprising (i) a medicament particle fraction comprising medicament particles with an aerodynamic diameter no greater than 10 μm; and (ii) at least 50% of a non-respirable excipient fraction comprising low density excipient particles with an aerodynamic diameter greater than 10 μm and a geometric diameter greater than 30 μm. In additional embodiments of the invention, the pharmaceutical composition includes a respirable excipient fraction comprising excipient particles with an aerodynamic diameter no greater than 10 μm. In a preferred embodiment of the invention, the non-respirable excipient particles include pores adapted to receive a portion of the respirable excipient fraction and/or the medicament fraction.

Claims

1. A pharmaceutical composition, comprising:

a medicament fraction, said medicament fraction comprising medicament particles having a mass median aerodynamic diameter no greater than approximately 10 μ

m; and

at least 50% of a non-respirable excipient fraction, said non-respirable excipient fraction comprising low density excipient particles having an aerodynamic diameter greater than approximately 10 μ

m and a geometric diameter greater than approximately 30 μ

m.

2. The pharmaceutical composition of claim 1, wherein said medicament fraction comprises a medicament selected from the group consisting of an analgesic, anginal preparation, antiallergic, antibiotic, antiinfective, antihistamine, anti-inflammatory, antitussive, bronchodilator, α

₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof.

3. The pharmaceutical composition of claim 2, wherein said medicament fraction comprises a medicament selected from the group consisting of codeine, dihydromorphine, ergotamine, fentanyl, morphine, diltiazem, cromoglycate, ketotifen, nedocromil;

cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines pentamidine;

methapyrilene, beclomethasone, fluticasone, flunisolide, budesonide, rofleponide, mometasone, ciclesonide, triamcinolone, noscapine, albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone, 2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol, (2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid, amiloride;

ipratropium, tiotropium, atropine, oxitropium;

cortisone, hydrocortisone, prednisolone, aminophylline, choline theophyllinate, lysine theophyllinate, theophylline, insulin or glucagon, and salts, esters, and derivatives and combinations thereof.

4. The pharmaceutical composition of claim 2, wherein said medicament fraction comprises a medicament selected from the group consisting of fluticasone, fluticasone propionate, fluticasone furoate, salmeterol, salmeterol xinafoate, albuterol base and sulfate, and combinations thereof.

5. The pharmaceutical composition of claim 1, wherein said medicament particles have an aerodynamic diameter in the range of approximately 0.5 to 6 μ

m.

6. The pharmaceutical composition of claim 5, wherein said medicament particles have an aerodynamic diameter in the range of approximately 2 to 6 μ

m.

7. The pharmaceutical composition of claim 5, wherein said medicament particles have an aerodynamic diameter in the range of approximately 0.5 to 3 μ

m.

8. The pharmaceutical composition of claim 1, wherein said medicament fraction comprises approximately 0.01 to 50% by weight of said pharmaceutical composition.

9. The pharmaceutical composition of claim 8, wherein said medicament fraction comprises approximately 0.01 to 30% by weight of said pharmaceutical composition.

10. The pharmaceutical composition of claim 8, wherein said medicament fraction comprises approximately 0.01 to 20% by weight of said pharmaceutical composition.

11. The pharmaceutical composition of claim 1, wherein said medicament particles are produced by micronization.

12. The pharmaceutical composition of claim 1, wherein said medicament particles are produced by milling.

13. The pharmaceutical composition of claim 1, wherein said medicament particles are produced by spray drying.

14. The pharmaceutical composition of claim 1, wherein said medicament particles are coated with an additional excipient.

15. The pharmaceutical composition of claim 1, wherein said medicament particles are co-precipitated with an additional excipient.

16. The pharmaceutical composition of claim 15, wherein said additional excipient comprises a surfactant.

17. The pharmaceutical composition of claim 15, wherein said additional excipient comprises a polymer.

18. The pharmaceutical composition of claim 15, wherein said additional excipient comprises a polylactide.

19. The pharmaceutical composition of claim 15, wherein said additional excipient comprises a polysaccharide.

20. The pharmaceutical composition of claim 1, wherein said medicament particles have a geometric diameter in the range of approximately 5 to 30 μ

m and a tap density less than 0.4 g/cm³.

21. The pharmaceutical composition of claim 1, wherein said non-respirable excipient fraction comprises an excipient selected from the group consisting of a polysaccharide, amino acid, bio-compatible polymer, inorganic salt and combinations thereof.

22. The pharmaceutical composition of claim 21, wherein said non-respirable excipient fraction comprises an excipient selected from the group consisting of lactose, mannitol, maltose, maltodextrins, dextrose, phenylalanine, leucine, glycine, polylactic acid (PLA), polylactic-coglycolic acid (PLGA), calcium salt and combinations thereof.

23. The pharmaceutical composition of claim 1, wherein said low density excipient particles have a tap density less than 0.8 g/cm³.

24. The pharmaceutical composition of claim 1, wherein greater than 70% of said non-respirable excipient particles have a geometric diameter greater than 50 μ

m.

25. The pharmaceutical composition of claim 1, wherein greater than 90% of said non-respirable excipient particles have a geometric diameter in the range of approximately 30 to 300 μ

m.

26. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition includes a respirable excipient fraction, said respirable excipient fraction comprising respirable excipient particles having an aerodynamic diameter no greater than 10 μ

m.

27. The pharmaceutical composition of claim 26, wherein said respirable excipient particles are formed by micronization.

28. The pharmaceutical composition of claim 26, wherein said respirable excipient particles are formed by milling.

29. The pharmaceutical composition of claim 26, wherein said respirable excipient particles are formed by spray drying.

30. The pharmaceutical composition of claim 26, wherein said respirable excipient fraction comprises an excipient selected from the group consisting of a polysaccharide, amino acid, calcium salt, biocompatible polymer and combinations thereof.

31. The pharmaceutical composition of claim 26, wherein said respirable excipient fraction comprises an excipient selected from the group consisting of mannitol, lactose, phenylalanine, glycine, leucine, dibasic calcium phosphate, tribasic calcium phosphate, polylactic acid (PLA), polylactic-coglycolic acid (PLGA), magnesium strearate and combinations thereof.

32. The pharmaceutical composition of claim 26, wherein said respirable excipient fraction comprises approximately 5% to 50% by weight of said pharmaceutical composition.

33. The pharmaceutical composition of claim 26, wherein greater than 50% of said respirable excipient particles have an aerodynamic diameter in the range of approximately 1 to 8 μ

m.

34. The pharmaceutical composition of claim 1, wherein said non-respirable excipient particles include defining pores, said non-respirable particles having sufficient porosity to receive a portion of said respirable excipient fraction.

35. The pharmaceutical composition of claim 34, wherein said non-respirable excipient particles have sufficient porosity to receive a portion of said medicament fraction.

36. The pharmaceutical composition of claim 1, wherein said non-respirable excipient fraction comprises excipient particles that are fissured.

37. The pharmaceutical composition of claim 36, wherein said non-respirable excipient particles are sufficiently fissured to receive a portion of said respirable excipient fraction.

38. The pharmaceutical composition of claim 1, wherein said non-respirable excipient fraction comprises excipient particles that are hollow.

39. A method for delivering a dry powder pharmaceutical composition to the pulmonary system of a patient, comprising the steps of:

providing a pharmaceutical delivery device containing a dry powder pharmaceutical composition comprising at least a medicament fraction and at least 50% of a non-respirable excipient fraction, the medicament fraction comprising medicament particles having an aerodynamic diameter no greater than 10 μ

m and the non-respirable excipient fraction comprising excipient particles having an aerodynamic diameter greater than 10 μ

m and a geometric diameter greater than 30 μ

m;

introducing an air flow within said delivery device;

aerosolizing said dry powder pharmaceutical composition into said air flow;

dispersing said aerosolized pharmaceutical composition into a plume;

emitting said aerosolized pharmaceutical composition from said delivery device; and

delivering said plume to the pulmonary system of the patient.

40. The method of claim 39, wherein said delivery device further includes a source of aerosolization energy that is independent of patient inhalation effort.

41. The method of claim 39, wherein at least 40% of said pharmaceutical composition is emitted from said delivery device, said emitted pharmaceutical composition including a fine particle fraction.

42. The method of claim 41, wherein said fine particle fraction of said emitted pharmaceutical composition is at least 40%.

43. The method of claim 39, wherein said medicament fraction comprises a medicament selected from the group consisting of an analgesic, anginal preparation, antiallergenic, antibiotic, antiinfective, antihistamine, anti-inflammatory, antitussive, bronchodilator, α

₄ integrin inhibitor, diuretic, anticholinergic, adenosine 2a agonists, hormones, xanthine, vaccine, therapeutic protein, peptide, and combinations thereof.

44. The method of claim 39, wherein said medicament fraction comprises a medicament selected from the group consisting of codeine, dihydromorphine, ergotamine, fentanyl, morphine, diltiazem, cromoglycate, ketotifen, nedocromil;

cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines pentamidine;

methapyrilene, beclomethasone, fluticasone, flunisolide, budesonide, rofleponide, mometasone, ciclesonide, triamcinolone, noscapine, albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl] sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone, 2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol, (2S)-3-[4-( {[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid, amiloride;

ipratropium, tiotropium, atropine, oxitropium;

cortisone, hydrocortisone, prednisolone, aminophylline, choline theophyllinate, lysine theophyllinate, theophylline, insulin or glucagon, and salts, esters and derivatives and combinations thereof.

45. The method of claim 39, wherein said medicament fraction comprises a medicament selected from the group consisting of fluticasone, fluticasone propionate, fluticasone furoate, salmeterol, salmeterol xinafoate, albuterol base and sulfate, and combinations thereof.

46. The method of claim 39, wherein said medicament fraction comprises approximately 0.01 to 50% by weight of said pharmaceutical composition.

47. The method of claim 39, wherein said pharmaceutical composition includes a respirable excipient fraction, said respirable excipient fraction comprising respirable excipient particles having an aerodynamic diameter no greater than 10 μ

m.

48. The method of claim 39, wherein said respirable excipient fraction comprises an excipient selected from the group consisting of mannitol, lactose, phenylalanine, glycine, dibasic calcium phosphate, tribasic calcium phosphate, polylactic acid (PLA), polylactic-coglycolic acid (PLGA), magnesium stearate and combinations thereof.

49. The method of claim 39, wherein said non-respirable excipient fraction comprises an excipient selected from the group consisting of lactose, mannitol, maltose, dextrose, phenylalanine, leucine, glycine, polylactic acid (PLA), polylactic-coglycolic acid (PLGA), calcium salt and combinations thereof.

50. The method of claim 39, wherein greater than 90% of said non-respirable excipient particles have a geometric diameter in the range of approximately 30 to 300 μ

m.

51. The method of claim 39, wherein said non-respirable excipient particles include defining pores.

52. The method of claim 39, wherein said non-respirable excipient fraction comprises excipient particles that are fissured.

53. A process for producing a pharmaceutical composition, comprising the steps of:

providing medicament particles having an aerodynamic diameter no greater than 10 μ

m;

providing first excipient particles having an aerodynamic diameter no greater than 10 μ

m;

providing second excipient particles having an aerodynamic diameter greater than 10 μ

m and a geometric diameter greater than 30 μ

m;

preblending said first and second excipient particles to form an excipient composition; and

blending said medicament particles and said excipient composition.

54. The method of claim 53, wherein said second excipient particles include defining pores.

55. The method of claim 54, wherein a portion of said first excipient particles are disposed in said defining pores during said pre-blending step.

56. A process for producing a pharmaceutical composition, comprising the steps of:

providing medicament particles having an aerodynamic diameter no greater than 10 μ

m;

providing first excipient particles having an aerodynamic diameter no greater than 10 μ

m;

providing second excipient particles having an aerodynamic diameter greater than 10 μ

m and a geometric diameter greater than 30 μ

m;

preblending said medicament particles and said second excipient particles to form a medicament/excipient composition; and

blending said first excipient particles and said medicament/excipient composition.

57. The method of claim 56, wherein said second excipient particles include defining pores.

58. The method of claim 57, wherein a portion of said medicament particles are disposed in said defining pores during said pre-blending step.

59. A pharmaceutical composition obtained by providing medicament particles having an aerodynamic diameter no greater than 10 μ

m,

providing first excipient particles having an aerodynamic diameter no greater than 10 μ

m,

providing second excipient particles having an aerodynamic diameter greater than 10 μ

m and a geometric diameter greater than 30 μ

m,

preblending said medicament particles and said first excipient particles to form a medicament/excipient composition, and

blending said second excipient particles and said medicament/excipient composition.

60. The pharmaceutical composition of claim 59, wherein said second excipient particles include defining pores.

61. The pharmaceutical composition of claim 60, wherein a portion of said first excipient particles are disposed in said defining pores during said pre-blending step. composition.