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Claims for Patent: 9,415,009

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Claims for Patent: 9,415,009

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:14/334,503
Patent Claims: 1. A method for treating a pulmonary disease or disorder in a patient, the method comprising: providing a pharmaceutically acceptable co-suspension deliverable from a metered dose inhaler, the co-suspension comprising: a suspension medium comprising a pharmaceutically acceptable propellant; one or more species of respirable active agent particles comprising two or more active agents; and a plurality of respirable suspending particles different than the active agent particles and comprising a particulate phospholipid material that is substantially insoluble in the suspension medium, wherein the active agent particles and suspending particles are co-suspended in the suspension medium at a weight ratio of total mass of the suspending particles to total mass of the one or more species of active agent particles that ranges from above 1:1 and up to 200:1; and administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension.

2. The method of claim 1, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising two or more active agents selected from short-acting beta agonist, long-acting and ultra long-acting .beta..sub.2 adrenergic receptor agonist (LABA), corticosteroid, anti-inflammatory, anti-tussive, bronchodilator, muscarinic antagonist, and long-acting muscarinic antagonist (LAMA) active agents, including any pharmaceutically acceptable salts, esters, or isomers thereof.

3. The method of claim 2, 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.

4. The method of claim 3, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising at least two different species of active agent particles, each of the at least two species of active agent particles comprises a different active agent, and the different active agents are selected from a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole- containing and adamantyl-derived .beta..sub.2 agonists, and a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.

5. The method of claim 4, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising at least three different species of active agent particles, each of the at least three species of active agent particles comprises a different active agent, and the different active agents are selected from a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole- containing and adamantyl-derived .beta..sub.2 agonists, and a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.

6. The method of claim 3, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, and a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole- containing and adamantyl-derived .beta..sub.2 agonists, including any pharmaceutically acceptable salts, esters, or isomers thereof.

7. The method of claim 3, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, and a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.

8. The method of claim 3, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension comprises simultaneously delivering therapeutically effective amounts of a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole- containing and adamantyl-derived .beta..sub.2 agonists, and a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.

9. The method of claim 3, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, a LABA active agent selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole- containing and adamantyl-derived .beta..sub.2 agonists, and a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, or isomers thereof.

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

11. The method of claim 10, wherein administering the co-suspension 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.

12. The method of claim 11, wherein administering the co-suspension 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.

13. The method of claim 12, wherein administering the co-suspension 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.

14. The method of claim 13, wherein administering the co-suspension 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.

15. The method of claim 14, wherein administering the co-suspension 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.

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

17. The method according to claim 1, wherein administering the co-suspension 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.

18. The method of claim 17, wherein the significant improvement in FEV.sub.1 is 70 mL or greater.

19. The method of claim 18, wherein the significant improvement in FEV.sub.1 is 80 mL or greater.

20. The method of claim 19, wherein the significant improvement in FEV.sub.1 is 90 mL or greater.

21. The method according to claim 18, wherein the significant improvement is measured as an improvement in peak FEV.sub.1 .

22. The method according to claim 18, wherein the significant improvement is measured as an improvement in FEV.sub.1 AUC.sub.0-12.

23. The method according to claim 1, wherein administering the co-suspension results in a clinically significant increase in inspiratory capacity (IC).

24. The method according to claim 23, wherein the clinically significant increase in IC is an increase of 100 mL or greater.

25. The method according to claim 24, wherein the clinically significant increase in IC is an increase of 200 mL or greater.

26. The method according to claim 25, wherein the clinically significant increase in IC is an increase of 300 mL or greater.

27. The method according to claim 26, wherein the clinically significant increase in IC is an increase of 350 mL or greater.

28. The method according to claim 23, wherein the clinically significant increase in IC is achieved in 2 hours, or less.

29. The method according to claim 23, wherein the clinically significant increase in IC is achieved in 1 hour, or less.

30. A method according to claim 4, wherein the one or more species of respirable active agent particles are substantially insoluble in the propellant.

31. The method of according to claim 4, wherein the respirable suspending particles comprise perforated microstructures.

32. The method according to claim 31, wherein the respirable suspending particles comprise DSPC and calcium chloride.

33. The method according to claim 4, wherein the respirable suspending particles included in the co-suspension 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.

34. The method according to claim 4, wherein the weight ratio of total mass of the suspending particles to total mass of the one 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.

35. The method according to claim 4, wherein the weight ratio of total mass of the suspending particles to total mass of the one or more species of active agent particles is selected from between about 3:1 and about 15:1 and between about 2:1 and 8:1.

36. The method according to claim 4, wherein the respirable suspending particles included in the co-suspension remain co-suspended with the active agent particles even when 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.

37. The method as in any one of claims 2, 3, 4, and 5, in which the active agent particles included in the co-suspension comprise a first species and a second species of active agent particles, with the first species of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, or isomers thereof, and the second species of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, or isomers thereof.

38. The method of claim 37, wherein the first species of active agent particles comprise crystalline glycopyrrolate and the second species of active agent particles comprise crystalline formoterol.

39. The method according to claim 37, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension 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 LAMA active agent and no more than 12 .mu.g of the LABA active agent.

40. The method according to claim 37, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension 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 LAMA active agent and no more than 12 .mu.g of the LABA active agent.

41. The method according to claim 37, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension 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 LAMA active agent and no more than 12 .mu.g of the LABA active agent.

42. The method according to claim 37, wherein administering a therapeutically effective amount of the pharmaceutically acceptable co-suspension 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 LAMA active agent and no more than 12 .mu.g of the LABA active agent.

43. The method as in any one of claims 1, 2, 3, 4, and 5, in which the weight ratio of total mass of the suspending particles to total mass of the one or more species of active agent particles is selected from the ranges of 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 170:1.

44. The method according to claim 37, wherein the pharmaceutically acceptable salt of glycopyrrolate is 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.

45. The method according to claim 44, wherein the pharmaceutically acceptable salt of glycopyrrolate is selected from fluoride, chloride, bromide, and iodide salts.

46. The method according to claim 45, wherein the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrroli dinium bromide.

47. The method according to claim 37, wherein the pharmaceutically acceptable salt of formoterol is 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.

48. The method according to claim 47, wherein the pharmaceutically acceptable salt, ester, or isomer of formoterol is formoterol fumarate.

49. A method according to claim 30, wherein the propellant is selected from an HFA propellant, a PFC propellant, and combinations thereof.
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