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Claims for Patent: 8,815,258

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Claims for Patent: 8,815,258

Title:Compositions, methods and systems for respiratory delivery of two or more active agents
Abstract: Compositions, methods and systems are provided for pulmonary or nasal delivery of two or more active agents via a metered dose inhaler. In one embodiment, the compositions include a suspension medium, active agent particles, and suspending particles, in which the active agent particles and suspending particles form a co-suspension within the suspension medium.
Inventor(s): Vehring; Reinhard (Edmonton, CA), Hartman; Michael Steven (Millbrae, CA), Lechuga-Ballesteros; David (San Jose, CA), Smith; Adrian Edward (Emerald Hills, CA), Joshi; Vidya B. (Redwood City, CA), Dwivedi; Sarvajna Kumar (Redwood City, CA)
Assignee: Pearl Therapeutics, Inc. (Redwood City, CA)
Application Number:13/109,884
Patent Claims: 1. A method for treating a pulmonary disease or disorder in a patient, the method comprising: providing metered dose inhaler containing a pharmaceutically acceptable co-suspension, the co-suspension comprising: a suspension medium comprising a pharmaceutically acceptable propellant free of co-solvents and solubilizing agents; two or more species of respirable active agent particles, wherein a first species of active agent particles comprises respirable particles of a pharmaceutically acceptable salt, ester, isomer of glycopyrrolate, and a second species of active agent particles comprises respirable particles of a pharmaceutically acceptable salt, ester, isomer of formoterol; and a plurality of respirable suspending particles different than the active agent particles and formed of a dry, particulate phospholipid material that is substantially insoluble in the suspension medium, wherein the suspending particles and the two or more species of active agent particles are co-suspended in the suspension medium at a weight ratio of total mass of the suspending particles to total mass of the two or more species of active agent particles that ranges from above 1:1 and up to 200:1; and administering the co-suspension to the patient as a respirable aerosol produced by actuating the metered dose inhaler, wherein said administering of the co-suspension comprises delivering therapeutically effective amounts of glycopyrrolate and formoterol to the patient.

2. The method of claim 1, wherein the pulmonary disease or disorder is selected from at least one of asthma, COPD, chronic bronchitis, emphysema, bronchiectasis, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, pulmonary inflammation experienced with cystic fibrosis, and pulmonary obstruction experienced with cystic fibrosis.

3. The method of claim 2, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a third species of respirable active agent particles comprising respirable particles of a pharmaceutically acceptable salt, ester, isomer of a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and trimacinolone.

4. The method of claim 3, wherein the third species of respirable active agent particles comprises respirable of a pharmaceutically acceptable salt, ester, isomer of budesonide.

5. The method of claim 2, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension wherein the ratio of the total mass of the suspending particles to the total mass of the two or more species of active agent particles is selected from above about 1.5:1, up to about 5:1, up to about 10:1, up to about 15:1, up to about 17:1, up to about 20:1, up to about 30:1, up to about 40:1, up to about 50:1, up to about 60:1, up to about 75:1, up to about 100:1, up to about 150:1, and up to about 200:1.

6. The method of claim 2, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension wherein the ratio of the total mass of the suspending particles to the total mass of the two or more species of active agent particles is selected from between about 10:1 and about 200:1, between about 60:1 and about 200:1, between about 15:1 and about 60:1, and between about 15:1 and about 170:1.

7. The method of claim 2, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension wherein the two or more species of active agent particles associate with the suspending particles such that there is no visible separation of the two or more species of active agent particles from the suspending particles within the suspension medium.

8. The method of claim 5, wherein the respirable suspending particles comprise perforated microstructures.

9. The method of claim 5, wherein the respirable suspending particles comprise 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC) and calcium chloride.

10. The method of claim 2, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension wherein the suspension medium comprises a pharmaceutically acceptable HFA propellant.

11. The method of claim 2, wherein administering the co-suspension to the patient results in a clinically significant increase in FEV.sub.1 in the patient.

12. The method of claim 11, wherein administering the co-suspension to the patient results in an increase in FEV.sub.1 of at least 150 mL within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1.5 hours, or less.

13. The method of claim 12, wherein administering the co-suspension to the patient results in an increase in FEV.sub.1 of at least 200 mL within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1.5 hours, or less.

14. The method of claim 13, wherein administering the co-suspension to the patient results in an increase in FEV.sub.1 of at least 250 mL within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1.5 hours, or less.

15. The method of claim 14, wherein administering the co-suspension to the patient results in an increase in FEV.sub.1 of at least 300 mL within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1.5 hours, or less.

16. The method of claim 15, wherein administering the co-suspension to the patient results in an increase in FEV.sub.1 of at least 350 mL within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1.5 hours, or less.

17. The method of claim 11, wherein the clinically significant increase in FEV.sub.1 achieved by administering the co-suspension to the patient remains clinically significant for a period of time selected from up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours, and up to 12 hours, or more.

18. The method of claim 11, wherein administering the co-suspension to the patient results in a 10% or greater increase in FEV.sub.1 within a period of time selected from 0.5 hours, or less, 1 hour, or less, 1.5 hours, or less, and 2 hours, in 50% or more of patients.

19. The method of claim 11, wherein administering the co-Suspension to the patient results in a 10% or greater increase in FEV.sub.1 within a period of time selected from 0.5 hours, or less, 1 hour, or less, 1.5 hours, or less, and 2 hours, in 60% or more of patients.

20. The method of claim 11, wherein administering the co-suspension to the patient results in a 10% or greater increase in FEV.sub.1 within a period of time selected from 0.5 hours, or less, 1 hour, or less, 1.5 hours, or less, and 2 hours, in 70% or more of patients.

21. The method of claim 11, wherein administering the co-suspension to the patient results in a 10% or greater increase in FEV.sub.1 within a period of time selected from 0.5 hours, or less, 1 hour, or less, 1.5 hours, or less, and 2 hours, in 80% or more of patients.

22. The method of claim 11, wherein administering the co-suspension to the patient results in the patient experiencing either an increase from baseline in FEV.sub.1 of at least 200 mL or a 12%, or greater, increase from baseline in FEV.sub.1 coupled with total increase in FEV.sub.1 of at least 150 mL.

23. The method of claim 11, wherein administering the co-suspension to the patient results in the patient experiencing either an increase from baseline in FEV.sub.1 of at least 200 mL or a 12%, or greater, increase from baseline in FEV.sub.1 coupled with total increase in FEV.sub.1 of at least 150 mL within a period of time selected from 1 hour, or less, 1.5 hours, or less, 2 hours, or less, and 2.5 hours, or less.

24. The method of claim 23, wherein either the increase from baseline in FEV.sub.1 of at least 200 mL or the 12%, or greater, increase from baseline in FEV.sub.1 coupled with total increase in FEV.sub.1 of at least 150 mL is experienced in at least 50% of patients within a period of time selected from 1 hour, or less, 1.5 hours, or less, 2 hours, or less, and 2.5 hours, or less.

25. The method of claim 24, wherein either the increase from baseline in FEV.sub.1 of at least 200 mL or the 12%, or greater, increase from baseline in FEV.sub.1 coupled with total increase in FEV.sub.1 of at least 150 mL is experienced in at least 60% of patients within a period of time selected from 1 hour, or less, 1.5 hours, or less, 2 hours, or less, and 2.5 hours, or less.

26. The method of claim 23, wherein either the increase from baseline in FEV.sub.1 of at least 200 mL or the 12%, or greater, increase from baseline in FEV.sub.1 coupled with total increase in FEV.sub.1 of at least 150 mL is experienced in at least 70% of patients within a period of time selected from 1 hour, or less, 1.5 hours, or less, 2 hours, or less, and 2.5 hours, or less.

27. The method of claim 23, wherein either the increase from baseline in FEV.sub.1 of at least 200 mL or the 12%, or greater, increase from baseline in FEV.sub.1 coupled with total increase in FEV.sub.1 of at least 150 mL is experienced in at least 80% of patients within a period of time selected from 1 hour, or less, 1.5 hours, or less, 2 hours, or less, and 2.5 hours, or less.

28. The method of claim 23, wherein administering the co-suspension to the patient results in a clinically significant increase in FEV.sub.1 in the patient and the clinically significant increase in FEV.sub.1 is a significant improvement over the increase provided by a composition delivering only one of the two or more active agents.

29. The method of claim 28, wherein the significant improvement in FEV.sub.1 is 70 mL, or greater.

30. The method of claim 29, wherein the significant improvement in FEV.sub.1 is 80 mL, or greater.

31. The method of claim 30, wherein the significant improvement in FEV.sub.1 is 90 mL, or greater.

32. The method of claim 28, wherein the significant improvement is measured as an improvement in peak FEV.sub.1.

33. The method of claim 28, wherein the significant improvement is measured as an improvement in FEV.sub.1 AUC.sub.0-12.

34. The method of claim 28, wherein administering the co-suspension to the patient results in a clinically significant increase in inspiratory capacity (IC).

35. The method according to claim 34, wherein the clinically significant increase in IC is an increase of 100 mL, or greater.

36. The method according to claim 35, wherein the clinically significant increase in IC is an increase of 200 mL, or greater.

37. The method according to claim 36, wherein the clinically significant increase in IC is an increase of 300 mL, or greater.

38. The method according to claim 37, wherein the clinically significant increase in IC is an increase of 350 mL, or greater.

39. The method of claim 34, wherein the clinically significant increase in IC is achieved in 2 hours, or less.

40. The method of claim 34, wherein the clinically significant increase in IC is achieved in 1 hour, or less.

41. The method according to claim 11, wherein the first species of active agent particles included in the pharmaceutically acceptable co-suspension contained within the metered dose inhaler comprises respirable, crystalline particles of 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

42. The method according to claim 11, wherein the second species of active agent particles included in the pharmaceutically acceptable co-suspension contained within the metered dose inhaler comprises respirable, crystalline particles of formoterol fumarate.

43. The method according to claim 42, wherein the first species of active agent particles included in the pharmaceutically acceptable co-suspension contained within the metered dose inhaler comprises respirable, crystalline particles of 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

44. The method of claim 11, wherein at least 50% by volume of the at least two species of active agent particles included in the co-suspension and administered as a respirable aerosol exhibit an optical diameter of 5 .mu.m, or less.

45. The method of claim 11, wherein the respirable suspending particles are included in the suspension medium at a concentration selected from between about 1 mg/mL and about 15 mg/mL, between about 3 mg/mL and about 10 mg/mL, between about 5 mg/mL and about 8 mg/mL, and about 6 mg/mL.

46. The method of claim 11, wherein the respirable suspending particles included in the co-suspension and administered as a respirable aerosol exhibit a mass median aerodynamic diameter (MMAD) selected from between about 10 .mu.m and about 500 nm, between about 5 .mu.m and about 750 nm, between about and 1 .mu.m and about 3 .mu.m.

47. The method of claim 11, wherein the respirable suspending particles included in the co-suspension and administered as a respirable aerosol exhibit a volume median optical diameter selected from between about 0.2 .mu.m and about 50 .mu.m, between about 0.5 .mu.m and about 15 .mu.m, between about 1.5 .mu.m and about 10 .mu.m, and between about 2 .mu.m and about 5 .mu.m.

48. The method of claim 7, wherein the two or more species of active agent particles remain associated with the suspending particles within the suspension medium such that there is no visible separation of the two or more species of active agent particles from the suspending particles even when the co-suspension is subjected to buoyancy forces amplified by centrifugation at an acceleration selected from accelerations of at least 1 g, at least 10 g, at least 50 g, and at least 100 g.

49. The method of claim 11, wherein administering the co-suspension to the patient as a respirable aerosol comprises administering the co-suspension to the patient up to two times daily, and each administration comprises delivering no more than 150 .mu.g of the salt, ester, isomer of glycopyrrolate and no more than 12 .mu.g of the salt, ester, isomer of formoterol.

50. The method of claim 11, wherein administering the co-suspension to the patient as a respirable aerosol comprises administering the co-suspension to the patient up to two times daily, and each administration comprises delivering no more than 100 .mu.g of the salt, ester, isomer of glycopyrrolate and no more than 12 .mu.g of the salt, ester, isomer of formoterol.

51. The method of claim 11, wherein administering the co-suspension to the patient as a respirable aerosol comprises administering the co-suspension to the patient up to two times daily, and each administration comprises delivering no more than 80 .mu.g of the salt, ester, isomer of glycopyrrolate and no more than 12 .mu.g of the salt, ester, isomer of formoterol.

52. The method of claim 11, wherein administering the co-suspension to the patient as a respirable aerosol comprises administering the co-suspension to the patient up to two times daily, and each administration comprises delivering no more than 50 .mu.g of the salt, ester, isomer of glycopyrrolate and no more than 12 .mu.g of the salt, ester, isomer of formoterol.

53. The method according to claim 1, wherein the first species of active agent particles included in the pharmaceutically acceptable co-suspension contained within the metered dose inhaler comprises a pharmaceutically acceptable salt, ester, or isomer of glycopyrrolate selected from fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate, and benzenesulfonate salts, and the second species of active agent particles comprises a pharmaceutically acceptable salt, ester, or isomer of formoterol selected from hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acid salts.

54. The method of claim 53, wherein the pharmaceutically acceptable salt of glycopyrrolate is selected from fluoride, chloride, bromide, and iodide salts and the pharmaceutically acceptable salt of formoterol is formoterol fumarate.

55. The method of claim 54, wherein the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

56. The method of any of claims 53-55, wherein the first species of active agent particles comprise respirable, crystalline particles of a pharmaceutically acceptable salt, ester, or isomer of glycopyrrolate.

57. The method of any of claims 53-56, wherein the second species of active agent particles comprise respirable, crystalline particles of a pharmaceutically acceptable salt, ester, or isomer of formoterol.
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