COMPOSITIONS FOR PULMONARY DELIVERY OF LONG-ACTING MUSCARINIC ANTAGONISTS AND ASSOCIATED METHODS AND SYSTEMS

• US 20110023876A1
• Filed: 05/28/2010
• Published: 02/03/2011
• Est. Priority Date: 05/29/2009
• Status: Active Grant

• Current Assignee: Pearl Therapeutics Inc. (Astrazeneca PLC)
• Original Assignee: Pearl Therapeutics Inc. (Astrazeneca PLC)
• Inventors: Vehring, Reinhard, Dwivedi, Sarvajna Kumar, Joshi, Vidya B., Smith, Adrian Edward, Hartman, Michael Steven
• Granted Patent: US 9,463,161 B2
• Time in Patent Office: Days
• US Class Current: 128/203.15
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61M 15/0065 Inhalators with dosage or measuring devices A61M15/0028 takes precedence; dosage devices incorporated in aerosol cans B65D83/52
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/16 : Central respiratory analeptics
• 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 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

Compositions, methods and systems are provided for pulmonary delivery of long-acting muscarinic antagonists and long-acting β₂ 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.

Claims

1. A pharmaceutical composition deliverable from a metered dose inhaler, comprising:

a suspension medium comprising a pharmaceutically acceptable propellant;

a plurality of active agent particles comprising an active agent selected from a long-acting muscarinic antagonist (LAMA) active agent and a long-acting β

₂ adrenergic receptor agonist (LABA) active agent; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles to form a co-suspension.

2. A pharmaceutical composition according to claim 1, wherein the active agent included in the active agent particles is a LAMA active agent selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, darotropium, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

3. The pharmaceutical composition according to claim 2, wherein the active agent particles comprise glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

4. The pharmaceutical composition according to claim 3, wherein the active agent particles comprise crystalline glycopyrrolate.

5. The pharmaceutical composition according to claim 3, wherein the glycopyrrolate active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrolate per actuation of the metered dose inhaler selected from between about 2 μ

g and about 200 μ

g per actuation, between about 10 μ

g and about 150 μ

g per actuation, and between about 15 μ

g and about 80 μ

g per actuation.

6. The pharmaceutical composition according to claim 3, wherein the concentration of glycopyrrolate included in the co-suspension is between about 0.04 mg/ml and about 2.25 mg/ml.

7. The pharmaceutical composition according to claim 3, wherein at least 90% of the glycopyrrolate active agent particles by volume exhibit an optical diameter of 7 μ

m or less.

8. The pharmaceutical composition according to claim 3, wherein at least 50% of the glycopyrrolate active agent particles by volume exhibit an optical diameter of 5 μ

m or less.

9. The pharmaceutical composition according to claim 2, wherein the suspending particles 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 10, wherein the perforated microstructures comprise a spray dried emulsion of perfluorooctyl bromide, DSPC and calcium chloride in water.

12. The pharmaceutical composition according to claim 2, wherein the suspending particles comprise an excipient selected from at least one of lipids, phospholipids, nonionic detergents, polymers, nonionic block copolymers, surfactants, non-ionic surfactants, biocompatible fluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof.

13. The pharmaceutical composition according to claim 2, wherein the suspending particles exhibit an MMAD selected from between about 10 μ

m and about 500 nm, between about 5 μ

m and about 750 nm, between about and 1 μ

m and about 3 μ

m.

14. The pharmaceutical composition according to claim 2, wherein the suspending particles exhibit a volume median optical diameter selected from between about 0.2 μ

m and about 50 μ

m, between about 0.5 μ

m and about 15 μ

m, between about 1.5 μ

m and about 10 μ

m, and between about 2 μ

m and about 5 μ

m.

15. The pharmaceutical composition according to claim 2, wherein the propellant comprises a propellant selected from an HFA propellant, a PFC propellant and combinations thereof, and wherein the propellant is substantially free of additional constituents.

16. The pharmaceutical composition according to claim 2, wherein a total mass of the suspending particles exceeds a total mass of the active agent particles.

17. The pharmaceutical composition according to claim 16, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from above about 1.5, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200.

18. The pharmaceutical composition according to claim 16, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:

1 and about 15;

1 and between about 2;

1 and 8;

1.

19. The pharmaceutical composition according to claim 1, wherein the suspending particles remain associated 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.

20. 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 comprising a pharmaceutically acceptable propellant;

a plurality of active agent particles comprising an active agent selected from a LAMA active agent and a LABA active agent; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and

administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a therapeutically effective amount of the LAMA or LABA active agent to the patient.

21. The method of claim 20, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LAMA active agent.

22. The method of claim 21, wherein the LAMA active agent is selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, darotropium, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

23. The method of claim 22, wherein the pulmonary disease or disorder is selected from at least one of asthma, COPD, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis.

24. The method of claim 23, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

25. The method of claim 24, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the concentration of glycopyrrolate included in the co-suspension is between about 0.04 mg/ml and about 2.25 mg/ml

26. The method of claim 22, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV₁ in the patient within 1 hour, or less.

27. The method of claim 22, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV₁ in the patient within 0.5 hours, or less.

28. The method of claim 22, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in an increase of FEV₁ 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.

29. The method of claim 22, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV₁ in the patient within 0.5 hours, or less, and providing a clinically significant increase in FEV₁ for a time period 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.

30. The method of claim 23, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of LAMA active agent selected from 200 μ

g, or less, 150 μ

g, or less, 100 μ

g, or less, 75 μ

g, or less, 50 μ

g, or less, and 25 μ

g, or less, per actuation of the metered dose inhaler.

31. The method of claim 23, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of glycopyrrolate or a pharmaceutically acceptable salt, ester, isomer or solvate thereof, selected from about 150 μ

g, or less, about 80 μ

g, or less, about 40 μ

g, about 20 μ

g, or less, and about 10 μ

g, or less, per actuation of the metered dose inhaler.

32. The method of claim 26, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of LAMA active agent selected from 200 μ

g, or less, 150 μ

g, or less, 100 μ

g, or less, 75 μ

g, or less, 50 μ

g, or less, and 25 μ

g, or less, per actuation of the metered dose inhaler.

33. The method of claim 26, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of glycopyrrolate or a pharmaceutically acceptable salt, ester, isomer or solvate thereof, selected from about 150 μ

g, or less, about 80 μ

g, or less, about 40 μ

g, about 20 μ

g, or less, and about 10 μ

g, or less, per actuation of the metered dose inhaler.

34. The method of claim 22, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in inspiratory capacity.

35. A method for respiratory delivery of a LAMA or LABA 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 comprising a pharmaceutically acceptable propellant;

a plurality of active agent particles comprising an active agent selected from a LAMA active agent and a LABA active agent; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and

actuating the metered dose inhaler to provide respiratory delivery of the LAMA or LABA active agent to the patient.

36. The method of claim 35, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising a plurality of active agent particles comprising a LAMA active agent.

37. The method of claim 36, wherein the LAMA active agent is selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, darotropium, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

38. The method of claim 37, wherein the LAMA active agent is glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof.

39. The method of claim 36, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA active agent comprises delivering the LAMA active agent to the patient at a 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.

40. The method of claim 36, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA active agent comprises delivering the LAMA active agent 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.

41. The method of claim 40, 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.

42. The method of claim 40, 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.

43. A metered dose inhaler for delivery of a LAMA or a LABA active agent, the metered dose inhaler comprising:

a canister containing a pharmaceutically acceptable co-suspension comprising;

a suspension medium comprising a pharmaceutically acceptable propellant;

a plurality of active agent particles comprising an active agent selected from a LAMA active agent and a LABA active agent; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles;

wherein the LAMA or LABA active agent included in the pharmaceutically acceptable co-suspension is chemically stable over a period of at least 18 months when stored at 5°

C.

44. A pharmaceutical composition deliverable from a metered dose inhaler, comprising:

a suspension medium comprising a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, said active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrolate of between about 15 μ

g and about 80 μ

g per actuation of the metered dose inhaler; and

a plurality of respirable suspending particles comprising perforated microstructures exhibiting a volume median optical diameter of between about 1.5 μ

m and about 10 μ

m, said perforated microstructures associate with the plurality of active agent particles to form a co-suspension.

45. The pharmaceutical composition according to claim 44, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 3:

1 and about 15;

1 and between about 2;

1 and 8;

1.

46. A method for respiratory delivery of LAMA active agent to a patient, the method comprising;

providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprising;

a suspension medium comprising a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and

actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate to the patient at a DDU of ±

25%, or better, throughout emptying of the canister.

47. The method of claim 46, wherein actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate to the patient comprises delivering the glycopyrrolate 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.

48. The method of claim 47, 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.

49. The method of claim 48, 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.

50. 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 comprising a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and

administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 150 μ

g, or less, of glycopyrrolate per actuation of the metered dose inhaler and results in a clinically significant increase in FEV₁ in the patient.

51. The method of claim 50, wherein the pulmonary disease or disorder is selected from at least one of asthma, COPD, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis.

52. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g.

53. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g.

54. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g.

55. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g, and said administration results in an increase in FEV₁ of at least 150 mL within 0.5 hours, or less.

56. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g, and said administration results in an increase in FEV₁ of at least 150 mL within 0.5 hours, or less.

57. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g, and said administration results in an increase in FEV₁ of at least 150 mL within 0.5 hours, or less

58. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g, and said administration results in an increase in FEV₁ of at least 200 mL within 1.0 hour, or less.

59. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g, and said administration results in an increase in FEV₁ of at least 200 mL within 1.0 hour, or less.

60. The method of claim 50, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g, and said administration results in an increase in FEV₁ of at least 200 mL within 1.0 hour, or less.

70. 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 comprising a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and

administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 150 μ

g, or less, of glycopyrrolate per actuation of the metered dose inhaler and results clinically significant increase in FEV₁ in 0.5 hours, or less, and a clinically significant increase in FEV₁ is maintained for up to 12 hours.

71. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g.

72. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g.

73. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g.

74. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g, and said administration results in an increase in FEV₁ of at least 150 mL within 0.5 hours, or less, and a clinically significant increase in FEV₁ is maintained for at least 12 hours.

75. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g, and said administration results in an increase in FEV₁ of at least 150 mL within 0.5 hours, or less, and a clinically significant increase in FEV₁ is maintained for at least 10 hours.

76. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g, and said administration results in an increase in FEV₁ of at least 150 mL within 0.5 hours, or less, and a clinically significant increase in FEV₁ is maintained for at least 8 hours.

77. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g, and said administration results in an increase in FEV₁ of at least 200 mL within 1.0 hour, or less, and a clinically significant increase in FEV₁ is maintained for at least 12 hours.

78. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g, and said administration results in an increase in FEV₁ of at least 200 mL within 1.0 hour, or less, and a clinically significant increase in FEV₁ is maintained for at least 10 hours.

79. The method of claim 70, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g, and said administration results in an increase in FEV₁ of at least 200 mL within 1.0 hour, or less, and a clinically significant increase in FEV₁ is maintained for at least 8 hours.

80. A method for treating a pulmonary disease or disorder in a patient population, the method comprising:

providing metered dose inhalers comprising a pharmaceutically acceptable co-suspension, the co-suspension comprising;

a suspension medium comprising a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and

administering the co-suspension to the patient population by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 150 μ

g, or less, of glycopyrrolate per actuation of the metered dose inhaler and, in at least 50% of the patient population, results in an increase from baseline in FEV₁ selected from (i) an increase in baseline FEV₁ of at least 200 ml and (ii) a 12%, or greater, increase from baseline in FEV₁ coupled with total increase in FEV₁ of at least 150 ml.

81. The method of claim 80, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g.

82. The method of claim 80, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g.

83. The method of claim 80, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g.

84. The method of claim 80, wherein, for at least 60% of the patient population, said administering of the co-suspension composition results in an increase from baseline in FEV₁ selected from either (i) an increase in baseline FEV₁ of at least 200 ml and (ii) a 12%, or greater, increase from baseline in FEV₁ coupled with total increase in FEV₁ of at least 150 ml.

85. The method of claim 80, wherein, for at least 80% of the patient population, said administering of the co-suspension composition results in an increase from baseline in FEV₁ selected from either (i) an increase in baseline FEV₁ of at least 200 ml and (ii) a 12%, or greater, increase from baseline in FEV₁ coupled with total increase in FEV₁ of at least 150 ml.

86. 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 comprising a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles; and

administering the co-suspension to the patient by actuating the metered dose inhaler, wherein said administering of the co-suspension composition comprises delivering a dose of 150 μ

g, or less, of glycopyrrolate per actuation of the metered dose inhaler and results in a clinically significant increase in inspiratory capacity (IC) in the patient.

87. The method of claim 86, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g.

88. The method of claim 86, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 100 μ

g.

89. The method of claim 86, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 80 μ

g.

90. The method of claim 86, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g, and said administration results in an increase in IC of at least 300 ml within a period of time selected from 1 hour or less and 2 hours or less.

91. The method of claim 86, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g, and said administration results in an increase in IC of at least 150 ml within a period of time selected from 1 hour or less and 2 hours or less.

92. The method of claim 86, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 150 μ

g, and said administration results in an increase in IC of at least 100 ml within a period of time selected from 1 hour or less and 2 hours or less.