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Claims for Patent: 8,808,713

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Claims for Patent: 8,808,713

Title:Compositions for pulmonary delivery of long-acting .beta..sub.2 adrenergic receptor agonists and associated methods and systems
Abstract: Compositions, methods and systems are provided for pulmonary delivery of long-acting muscarinic antagonists and long-acting .beta..sub.2 adrenergic receptor agonists via a metered dose inhaler. In particular embodiments, 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), Smith; Adrian Edward (Emerald Hills, CA), Joshi; Vidya B. (Redwood City, CA), Dwivedi; Sarvajna Kumar (Redwood City, CA)
Assignee: Pearl Thereapeutics, Inc. (Redwood City, CA)
Application Number:12/790,605
Patent Claims: 1. A pharmaceutical composition deliverable from a metered dose inhaler, comprising: a suspension medium substantially free of cosolvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of respirable active agent particles (AAP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol; and a plurality of respirable suspending particles (RSP) formed separately from the plurality of AAP, wherein the RSP comprise a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the RSP are present in the suspension medium at a concentration of up to about 30 mg/mL and at a weight ratio of total mass of RSP to total mass of AAP that ranges from above 1:1 up to 200:1.

2. A method for treating a pulmonary disease or disorder in a patient, the method comprising: providing metered dose inhaler comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising: a suspension medium substantially free of cosolvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of respirable active agent particles (AAP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol; and a plurality of respirable suspending particles (RSP) formed separately from the plurality of AAP, wherein the RSP comprise a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the RSP are present in the suspension medium at a concentration of up to about 30 mg/mL and at a weight ratio of total mass of RSP to total mass of AAP that ranges from above 1:1 up to 200:1; and administering the co-suspension to the patient by actuating the metered dose inhaler at least once, wherein said administering of the co-suspension composition comprises delivering a therapeutically effective amount of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol to the patient.

3. A method for respiratory delivery of a formoterol active agent to a patient, the method comprising; providing metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising: a suspension medium substantially free of cosolvents and solubilizing agents and comprising a pharmaceutically acceptable propellant; a plurality of respirable active agent particles (AAP) comprising a pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol; and a plurality of respirable suspending particles (RSP) formed separately from the plurality of AAP, wherein the RSP comprise a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and wherein the RSP are present in the suspension medium at a concentration of up to about 30 mg/mL and at a weight ratio of total mass of RSP to total mass of AAP that ranges from above 1:1 up to 200:1; and actuating the metered dose inhaler at least once to provide respiratory delivery of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol to the patient.

4. The pharmaceutical composition according to claim 1, wherein the AAP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol selected from between about 1 .mu.g and about 30 .mu.g, between about 0.5 .mu.g and about 10 .mu.g, between about 2 .mu.g and 5 .mu.g, between about 2 .mu.g and about 10 .mu.g, between about 5 .mu.g and about 10 .mu.g, and between 3 .mu.g and about 30 .mu.g per actuation of the metered dose inhaler.

5. The pharmaceutical composition according to claim 1, wherein the AAP are included in the composition in an amount sufficient to provide a delivered dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol selected from up to about 30 .mu.g, up to about 10 .mu.g, up to about 5 .mu.g, up to about 2.5 .mu.g, up to about 2 .mu.g, or up to about 1.5 .mu.g per actuation of the metered dose inhaler.

6. The pharmaceutical composition according claim 1, wherein the AAP are included in the co-suspension in an amount sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol selected from between about 0.01 mg/ml and about 1 mg/ml, between about 0.01 mg/ml and about 0.5 mg/ml, and between about 0.03 mg/ml and about 0.4 mg/ml.

7. The pharmaceutical composition according claim 1, wherein at least 90% of the AAP by volume exhibit an optical diameter of 5 .mu.m or less.

8. The pharmaceutical composition according to claim 1, wherein at least 50% of the AAP by volume exhibit an optical diameter of 2 .mu.m or less.

9. The pharmaceutical composition according to claim 1, wherein the RSP comprise perforated microstructures.

10. The pharmaceutical composition according to claim 9, wherein the perforated microstructures are prepared using a spray drying process.

11. The pharmaceutical composition according to claim 9, wherein the perforated microstructures comprise 1,2-disteroyl-sn-glycero-3-phosphocholine and calcium chloride.

12. The pharmaceutical composition according to claim 1, wherein the RSP exhibit a mass median aerodynamic diameter selected from between about 10 .mu.m and about 500 nm, between about 5 .mu.m and about 750 nm, and between about 1 .mu.m and about 3 .mu.m.

13. The pharmaceutical composition according to claim 1, wherein the RSP 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.

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

15. The method of claim 2, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising an amount of AAP sufficient to provide a concentration of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol within the co-suspension selected from between about 0.01 mg/ml and about 1 mg/ml, between about 0.01 mg/ml and about 0.5 mg/ml, and between about 0.03 mg/ml and about 0.4 mg/ml.

16. The method of claim 2, wherein administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in forced expiratory volume in one second (FEV.sub.1) in the patient within 1 hour, or less.

17. The method of claim 2, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV.sub.1 in the patient within 0.5 hours, or less.

18. The method of claim 2, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in an increase of FEV.sub.1 of 150 ml or greater within a period of time selected from 0.5 hours, or less, 1 hour, or less, and 1.5 hours, or less.

19. The method of claim 2, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV.sub.1 in the patient within 0.5 hours, or less, and providing a clinically significant increase in FEV.sub.1 for a time period selected from up to 4 hours, up to 6 hours, and up to 8 hours, or more.

20. The method of claim 2, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol selected from between about 1 .mu.g and about 50 .mu.g, between about 1 .mu.g and about 30 .mu.g, between about 2 .mu.g and 5 .mu.g, between about 2 .mu.g and about 10 .mu.g, between about 5 .mu.g and about 10 .mu.g, and between 3 .mu.g and about 30 .mu.g per actuation.

21. The method of claim 2, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of the pharmaceutically acceptable salt, ester, isomer or solvate of formoterol selected from up to about 30 .mu.g, up to about 10 .mu.g, up to about 5 .mu.g, up to about 2.5 .mu.g, up to about 2 .mu.g, and up to about 1.5 .mu.g per actuation.

22. The method of claim 2, wherein administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in inspiratory capacity.

23. The method of claim 3, wherein actuating the metered dose inhaler to provide respiratory delivery of the formoterol active agent comprises delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol to the patient at a delivered dose uniformity (DDU) selected from a DDU of .+-.30%, or better, a DDU of .+-.25%, or better, and a DDU of .+-.20%, or better, throughout emptying of the canister.

24. The method of claim 3, wherein actuating the metered dose inhaler to provide respiratory delivery of the formoterol active agent comprises delivering the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol at an initial fine particle fraction and the initial fine particle fraction delivered from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction.

25. The method of claim 24, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction.

26. The method of claim 25, wherein, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.

27. The pharmaceutical composition according to claim 1, wherein the RSP are included in the suspension medium at a weight ratio of total mass of RSP to total mass of AAP that ranges from 10:1 up to 200:1.

28. The pharmaceutical composition according to claim 1, wherein the RSP are included in the suspension medium at a weight ratio of total mass of RSP to total mass of AAP that ranges from 15:1 up to 60:1.

29. A method according to any one of claims 2 and 3, wherein the RSP are included in the suspension medium at a weight ratio of total mass of RSP to total mass of AAP that ranges from 10:1 up to 200:1.

30. A method according to any one of claims 2 and 3, wherein the RSP are included in the suspension medium at a weight ratio of total mass of RSP to total mass of AAP that ranges from 15:1 up to 60:1.

31. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol comprises a formoterol salt 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.

32. The pharmaceutical composition according to claim 31, wherein the formoterol salt is formoterol fumarate.

33. The pharmaceutical composition according to claim 32, wherein the formoterol fumarate comprises respirable crystalline particles of formoterol fumarate.

34. A method according to any one of claims 2 and 3, wherein the AAP comprise a formoterol salt 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.

35. The method of claim 34, wherein the formoterol salt is formoterol fumarate.

36. The method of claim 35, wherein the formoterol fumarate comprises respirable crystalline particles of formoterol fumarate.

37. A co-suspension composition deliverable from a metered dose inhaler for pulmonary administration of a pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol, the suspension composition prepared by a process comprising: providing a pharmaceutically acceptable propellant substantially free of cosolvents and solubilizing agents; providing respirable active agent particles (AAP) comprising the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol in crystalline form; providing respirable suspending particles (RSP), wherein the RSP are formed using a dry particulate phospholipid material that is substantially insoluble in the propellant and are free of the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol; and dispersing the AAP and the RSP within the pharmaceutically acceptable propellant to form a co-suspension composition wherein the RSP are included in the suspension medium at a weight ratio of total mass of the RSP to total mass of the AAP ranging from above 1:1 up to 200:1 and the RSP co-locate with the AAP in the pharmaceutically acceptable propellant.

38. The co-suspension composition of claim 37, wherein the weight ratio of total mass of the RSP to total mass of the AAP ranges from 10:1 up to 200:1.

39. The co-suspension composition of claim 38, wherein the weight ratio of total mass of the RSP to total mass of the AAP ranges from 15:1 up to 60:1.

40. The co-suspension composition of claim 37, wherein the RSP comprise perforated microstructures.

41. The co-suspension composition of claim 40, wherein the perforated microstructures are prepared using a spray drying process.

42. The co-suspension composition of claim 41, wherein the perforated microstructures comprise 1,2-disteroyl-sn-glycero-3-phosphocholine and calcium chloride.

43. The co-suspension composition of claim 37, wherein the pharmaceutically acceptable propellant comprises an hydrofluoroalkane propellant.

44. The co-suspension composition of claim 37, wherein the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol is chemically stable within the co-suspension composition over a period of at least 18 months when stored at 5.degree. C.

45. The co-suspension composition of claim 37, wherein a rate of formation of N-(2-hydroxy-5-(1-(2-hydroxy-5-(1-hydroxy-2-(1-(4-methoxyphenyl)propan-2-- ylamino)ethyl)phenylamino)-2-(1-(4-methoxyphenyl)propan-2-ylamino)ethyl)ph- enyl)acetamide within the suspension composition is not greater than about 0.15% after the suspension composition is sealed within a canister for use with a metered dose inhaler and the canister is subjected to a temperature of 40.degree. C. and a relative humidity of 75% for a period of one month.

46. The co-suspension composition of claim 45, wherein a rate of formation of N-(2-hydroxy-5-(1-(2-hydroxy-5-(1-hydroxy-2-(1-(4-methoxyphenyl)propan-2-- ylamino)ethyl)phenylamino)-2-(1-(4-methoxyphenyl)propan-2-ylamino)ethyl)ph- enyl)acetamide within the pharmaceutically acceptable co-suspension is not greater than about 0.5% after the suspension composition is sealed within a canister for use with a metered dose inhaler and the canister is subjected to a temperature of 40.degree. C. and a relative humidity of 75% for a period of one month.

47. The suspension composition of claim 37, wherein the pharmaceutically acceptable salt, ester, isomer, or solvate of formoterol comprises a formoterol salt 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 suspension composition of claim 47, wherein the formoterol salt is formoterol fumarate.

49. The suspension composition of claim 48, wherein the formoterol fumarate comprises respirable crystalline particles of formoterol fumarate.
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