COMPOSITIONS, METHODS & SYSTEMS FOR RESPIRATORY DELIVERY OF TWO OR MORE ACTIVE AGENTS

• US 20110132357A1
• Filed: 05/28/2010
• Published: 06/09/2011
• Est. Priority Date: 05/29/2009
• Status: Abandoned Application

• 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, Lechuga-Ballesteros, David
• Application Number:
  US12/790,710
• Publication Number:
  US 20110132357A1
• 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 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.

Claims

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

a suspension medium comprising a pharmaceutically acceptable propellant;

two or more active agents;

one or more species of active agent particles; and

one or more species of respirable suspending particles, wherein the one or more species of active agent particles comprise at least one of the two or more active agents and the active agent particles and suspending particles associate to form a co-suspension.

2. A pharmaceutical composition according to claim 1, wherein the two or more active agents are selected from short-acting beta agonist, long-acting and ultra long-acting β

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, isomers or solvates thereof.

3. The pharmaceutical composition according to claim 2, wherein at least one of the at least one species of suspending particles comprises an active agent and the two or more active agents are selected from a LAMA active agent selected from glycopyrrolate, dexipirroium, 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 β

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, isomers or solvates thereof.

4. The pharmaceutical composition of claim 2, comprising at least two different species of active agent particles, wherein 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 β

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, isomers or solvates thereof.

5. The pharmaceutical composition of claim 4, comprising at least three different species of active agent particles, wherein 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 β

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, isomers or solvates thereof.

6. The pharmaceutical composition of claim 2, comprising at least two different species of active agent particles, wherein each of the at least two different species of active agent particles comprises a different active agent, at least one of the at least one species of suspending particles comprises a third 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 β

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, isomers or solvates thereof.

7. The pharmaceutical composition according to claim 2, wherein at least 50% of the active agent particles by volume exhibit an optical diameter of 5 μ

m or less.

8. The pharmaceutical composition according to claim 2, wherein at least one species of suspending particles comprise perforated microstructures.

9. The pharmaceutical composition according to claim 8, wherein the perforated microstructures are prepared using a spray drying process.

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

11. The pharmaceutical composition according to claim 2, wherein at least one species of 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.

12. The pharmaceutical composition according to claim 2, wherein the 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.

13. The pharmaceutical composition according to claim 2, wherein each of the at least one species of 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 each of the at least one species of 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 at least one species of suspending particles exceeds a total mass of the at least one species of active agent particles.

17. The pharmaceutical composition according to claim 16, wherein a ratio of the total mass of the at least one species of suspending particles to the total mass of at least one species of 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 at least one species of suspending particles to the total mass of the at least one species of 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 2, 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;

two or more active agents;

one or more species of active agent particles; and

one or more species of respirable suspending particles, wherein the one or more species of active agent particles comprise at least one of the two or more active agents and the active agent particles and suspending particles associate; 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 two or more active agents to the patient.

21. The method of claim 20, 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 β

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, isomers or solvates thereof.

22. The method of claim 21, 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 associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis.

23. The method of claim 22, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension wherein at least one of the at least one species of suspending particles comprises an active agent and the two or more 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 β

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, isomers or solvates thereof.

24. The method of claim 22, 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 β

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, isomers or solvates thereof.

25. The method of claim 24, 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 β

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, isomers or solvates thereof.

26. The method of claim 22, 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, at least one of the at least one species of suspending particles comprises a third 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 β

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, isomers or solvates thereof.

27. The method of claim 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient 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 β

₂ agonists, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

28. The method of claim 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient 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, isomers or solvates thereof.

29. The method of claim 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient 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 β

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, isomers or solvates thereof.

30. The method of claim 22, wherein delivering a therapeutically effective amount of the two or more active agents to the patient 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 β

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, isomers or solvates thereof.

31. A method for respiratory delivery of two or more active agents 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;

two or more active agents;

one or more species of active agent particles; and

one or more species of respirable suspending particles, wherein the one or more species of active agent particles comprise at least one of the two or more active agents and the active agent particles and suspending particles associate; and

actuating the metered dose inhaler to provide respiratory delivery of the two or more active agents to the patient.

32. The method of claim 31, 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 β

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, isomers or solvates thereof.

33. The method of claim 32, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension wherein at least one of the at least one species of suspending particles comprises an active agent and the two or more 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 β

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, isomers or solvates thereof.

34. The method of claim 32, 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 β

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, isomers or solvates thereof.

35. The method of claim 34, 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 β

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, isomers or solvates thereof.

36. The method of claim 32, 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, at least one of the at least one species of suspending particles comprises a third active agent, and the different active agents are selected from and the two or more 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 β

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, isomers or solvates thereof.

37. The method of claim 32, wherein actuating the metered dose inhaler to provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent and a LABA active agent to the patient, wherein each of the LAMA active agent and the LABA active agent are delivered to the patient at a DDU selected from a DDU of ±

25%, or better, a DDU of ±

20%, or better, and a DDU of ±

15%, or better, throughout emptying of the canister.

38. The method of claim 37, wherein the LAMA active agent is selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, and the LABA active agent is selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β

₂ agonists, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

39. The method of claim 38, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA and LABA active agents comprises delivering the LAMA and LABA active agents 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.

40. The method of claim 39, 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.

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 95% of the initial fine particle fraction.

42. The method of claim 32, wherein actuating the metered dose inhaler to provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent and a corticosteroid active agent to the patient, wherein each of the LAMA active agent and the corticosteroid active agent are delivered to the patient at a DDU selected from a DDU of ±

25%, or better, a DDU of ±

20%, or better, and a DDU of ±

15%, or better, throughout emptying of the canister.

43. The method of claim 42, wherein the LAMA active agent is selected from glycopyrrolate, dexipirronium, tiotropium, trospium, aclidinium, and darotropium, and the corticosteroid active agent is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

44. The method of claim 43, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA and corticosteroid active agents comprises delivering the LAMA and corticosteroid active agents 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.

45. The method of claim 44, 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.

46. The method of claim 45, 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.

47. The method of claim 32, wherein actuating the metered dose inhaler to provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LABA active agent and a corticosteroid active agent to the patient, wherein each of the LABA active agent and the corticosteroid active agent are delivered to the patient at a DDU selected from a DDU of ±

25%, or better, a DDU of ±

20%, or better, and a DDU of ±

15%, or better, throughout emptying of the canister.

48. The method of claim 47, wherein the LABA active agent is selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β

₂ agonists, and the corticosteroid active agent is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

49. The method of claim 48, wherein actuating the metered dose inhaler to provide respiratory delivery of the LABA and corticosteroid active agents comprises delivering the LABA and corticosteroid active agents 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.

50. The method of claim 49, 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.

51. The method of claim 50, 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.

52. The method of claim 32, wherein actuating the metered dose inhaler to provide respiratory delivery of the two or more active agents comprises simultaneously delivering therapeutically effective amounts of a LAMA active agent, a LABA active agent and a corticosteroid active agent to the patient, wherein each of the LAMA active agent, the LABA active agent and the corticosteroid active agent are delivered to the patient at a DDU selected from a DDU of ±

25%, or better, a DDU of ±

20%, or better, and a DDU of ±

15%, or better, throughout emptying of the canister.

53. The method of claim 52, wherein the LAMA active agent is selected from glycopyrrolate, tiotropium, trospium, aclidinium, and darotropium, the LABA active agent is selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β

₂ agonists, and the corticosteroid active agent is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

54. The method of claim 53, wherein actuating the metered dose inhaler to provide respiratory delivery of the LAMA, LABA and corticosteroid active agents comprises delivering the LAMA, LABA and corticosteroid active agents 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.

55. The method of claim 54, 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.

56. The method of claim 55, 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.

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

a suspension medium comprising a pharmaceutically acceptable HFA propellant;

a first species of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended 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;

a second species of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 μ

g and about 10 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, wherein the first and second species of active agent particles associate with the plurality of suspending particles to form a co-suspension.

58. The pharmaceutical composition according to claim 57, wherein a ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:

1 and about 15;

1 and between about 2;

1 and 8;

1.

59. 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 suspended 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 formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein the plurality of suspending particles exhibit a volume median optical diameter of between about 1.5 μ

m and about 10 μ

m, are included in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 μ

g and about 10 μ

g per actuation of the metered dose inhaler, and associate with the plurality of active agent particles to form a co-suspension.

60. The pharmaceutical composition according to claim 59, 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.

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

a suspension medium comprising a pharmaceutically acceptable HFA propellant;

a first species of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein at least 90% of the active agent particles by volume exhibit an optical diameter of 7 μ

m suspended 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;

a second species of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 μ

g and about 10 μ

g per actuation of the metered dose inhaler;

a third species of active agent particles comprising a corticosteroid selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof; 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, wherein the first, second and third species of active agent particles associate with the plurality of suspending particles to form a co-suspension.

62. The pharmaceutical composition according to claim 61, wherein a ratio of the total mass of the suspending particles to the total mass of the first, second and third species of active agent particles is selected from between about 3:

1 and about 15;

1 and between about 2;

1 and 8;

1.

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

a suspension medium comprising a pharmaceutically acceptable HFA propellant;

a first species of active agent particles comprising glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended 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;

a second species of active agent particles comprising formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol of between about 2 μ

g and about 10 μ

g per actuation of the metered dose inhaler; and

a plurality of respirable suspending particles comprising perforated microstructures and a corticosteroid selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein the suspending particles exhibit a volume median optical diameter of between about 1.5 μ

m and about 10 μ

m and associate with the first and second species of active agent particles to form a co-suspension.

64. The pharmaceutical composition according to claim 63, wherein a ratio of the total mass of the suspending particles to the total mass of the first and second species of active agent particles is selected from between about 3:

1 and about 15;

1 and between about 2;

1 and 8;

1.

65. A method for respiratory delivery of a combination of LAMA and LABA active agents 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 first species of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

a second species of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

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

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

20%, or better, throughout emptying of the canister.

66. The method of claim 65, wherein actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate and formoterol to the patient comprises delivering the glycopyrrolate and 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.

67. The method of claim 66, 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.

68. The method of claim 67, 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.

69. A method for respiratory delivery of a combination of LABA and LAMA active agents 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 comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof, 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 and formoterol to the patient at a DDU of ±

20%, or better, throughout emptying of the canister.

70. The method of claim 69, wherein actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate and formoterol to the patient comprises delivering the glycopyrrolate and 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.

71. The method of claim 70, 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.

72. The method of claim 71, 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.

73. A method for respiratory delivery of a combination of LAMA, LABA and corticosteroid active agents 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 first species of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

a second species of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

a third species of active agent particles comprising a corticosteroid selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

a plurality of respirable suspending particles, wherein the first, second and third species of active agent particles associate with the suspending particles; and

actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate, formoterol and the corticosteroid active agent to the patient at a DDU of ±

20%, or better, throughout emptying of the canister.

74. The method of claim 73, wherein actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate, formoterol and the corticosteroid active agent to the patient comprises delivering the glycopyrrolate, formoterol and corticosteroid 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.

75. The method of claim 74, 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.

76. The method of claim 75, 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.

77. A method for respiratory delivery of a combination of LAMA, LABA and corticosteroid active agents 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 first species of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

a second species of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

a plurality of respirable suspending particles comprising a corticosteroid selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, wherein the plurality of active agent particles associate with the first and second species of suspending particles; and

actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate, formoterol and the coroticosteroid active agent to the patient at a DDU of ±

20%, or better, throughout emptying of the canister.

78. The method of claim 77, wherein actuating the metered dose inhaler to provide respiratory delivery of glycopyrrolate, formoterol and the corticosteroid active agent to the patient comprises delivering the glycopyrrolate, formoterol and corticosteroid 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.

79. The method of claim 78, 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.

80. The method of claim 79, 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.

81. A method for preparing a composition suitable for respiratory delivery of a combination of LAMA and LABA active agents to a patient via an metered dose inhaler, the method comprising;

providing a suspension medium comprising a pharmaceutically acceptable HFA propellant;

providing a first species of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

providing a second species of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

providing a plurality of respirable suspending particles; and

combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the first and second species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

20% of those achieved by a comparable formulation including only one of glycopyrrolate or formoterol.

82. The method of claim 81, wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the first and second species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

15% of those achieved by a comparable formulation including only one of glycopyrrolate or formoterol.

83. The method of claim 81, wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the first and second species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

10% of those achieved by a comparable formulation including only one of glycopyrrolate or formoterol.

84. A method for preparing a composition suitable for respiratory delivery of a combination of LAMA and LABA active agents to a patient via an metered dose inhaler, the method comprising;

providing a suspension medium comprising a pharmaceutically acceptable HFA propellant;

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

providing a plurality of respirable suspending particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

combining the suspension medium, the active agent particles, and the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

20% of those achieved by a comparable formulation including only one of glycopyrrolate or formoterol.

85. The method of claim 84, wherein the method comprises combining the suspension medium, the active agent particles, and the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

15% of those achieved by a comparable formulation including only one of glycopyrrolate or formoterol.

86. The method of claim 84, wherein the method comprises combining the suspension medium, the active agent particles, and the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

10% of those achieved by a comparable formulation including only one of glycopyrrolate or formoterol.

87. A method for preparing a composition suitable for respiratory delivery of a combination of LAMA, LABA and corticosteroid active agents to a patient via an metered dose inhaler, the method comprising;

providing a suspension medium comprising a pharmaceutically acceptable HFA propellant;

providing a first species of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

providing a second species of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

providing a third species of active agent particles comprising a corticosteroid selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof;

providing a plurality of respirable suspending particles; and

combining the suspension medium, the first, second and third species of active agent particles, and the plurality of respirable suspending particles such that the first, second and third species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

20% of those achieved by a comparable formulation including only one of glycopyrrolate, formoterol, or the corticosteroid.

88. The method of claim 87, wherein the method comprises combining the suspension medium, the first, second and third species of active agent particles, and the plurality of respirable suspending particles such that the first, second and third species of active agent particles associate with the suspending particles to form a co-suspension and for each of active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

15% of those achieved by a comparable formulation including only one of glycopyrrolate or formoterol.

89. The method of claim 87, wherein the method comprises combining the suspension medium, the first, second and third species of active agent particles, and the plurality of respirable suspending particles such that the first, second and third species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the active agent particles, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

10% of those achieved by a comparable formulation including only one of glycopyrrolate, formoterol, or the corticosteroid.

90. A method for preparing a composition suitable for respiratory delivery of a combination of LAMA, LABA and corticosteroid active agents to a patient via an metered dose inhaler, the method comprising;

providing a suspension medium comprising a pharmaceutically acceptable HFA propellant;

providing a first species of active agent particles comprising glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

providing a second species of active agent particles comprising formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof;

providing a plurality of respirable suspending particles comprising a corticosteroid selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof; and

combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the first and second species of active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

20% of those achieved by a comparable formulation including only one of glycopyrrolate, formoterol, the corticosteroid.

91. The method of claim 90, wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

15% of those achieved by a comparable formulation including only one of glycopyrrolate, formoterol or the corticosteroid.

92. The method of claim 90, wherein the method comprises combining the suspension medium, the first and second species of active agent particles, and the plurality of respirable suspending particles such that the active agent particles associate with the suspending particles to form a co-suspension and for each of the active agents included in the co-suspension, one or more of the aerosol properties, the particle size distribution characteristics, the delivered dose uniformity, and the plasma concentration over time achieved by the co-suspension upon delivery to the patient from the metered dose inhaler are within ±

10% of those achieved by a comparable formulation including only one of glycopyrrolate, formoterol or the corticosteroid.