Compositions for pulmonary delivery of long-acting muscarinic antagonists or long-acting B2 adrenergic receptor agonists and associated methods and systems

• US 10,716,753 B2
• Filed: 11/02/2018
• Issued: 07/21/2020
• 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, Hartman, Michael Steven, Smith, Adrian Edward, Joshi, Vidya B., Dwivedi, Sarvajna Kumar
• Primary Examiner(s): Haghighatian, Mina
• Application Number:
  US16/179,712
• Publication Number:
  US 20190307676A1
• Time in Patent Office: 627 Days
• 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 a long-acting muscarinic antagonist (LAMA) active agent or a long-acting β

₂ adrenergic receptor agonist (LABA) active agent; and

a plurality of respirable suspending particles, wherein the respirable suspending particles are formed separately from and are different particles than the active agent particles and are formed of a dry particulate phospholipid material that is substantially insoluble in the suspension medium;

and wherein the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is from greater than 1;

1 up to 200;

1.

2. The pharmaceutical composition according to claim 1, wherein the suspending particles comprise perforated microstructures.

3. The pharmaceutical composition according to claim 2, wherein the perforated microstructures are prepared using a spray drying process.

4. The pharmaceutical composition according to claim 3, wherein the perforated microstructures comprise a spray dried emulsion of perfluorooctyl bromide, DSPC, and calcium chloride in water.

5. The pharmaceutical composition according to claim 1, wherein the suspending particles exhibit an MMAD selected from the group consisting of between about 10 μ

m and about 500 nm, between about 5 μ

m and about 750 nm, and between about 1 μ

m and about 3 μ

m.

6. The pharmaceutical composition according to claim 1, wherein the suspending particles exhibit a volume median optical diameter selected from the group consisting of 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.

7. The pharmaceutical composition according to claim 1, wherein the propellant comprises a propellant selected from the group consisting of an HFA propellant, a PFC propellant, and combinations thereof.

8. The pharmaceutical composition according to claim 1, wherein a ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from the group consisting of 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.

9. The pharmaceutical composition according to claim 1, wherein the active agent particles comprise crystalline active agent.

10. The pharmaceutical composition according to claim 1, wherein the active agent particles comprise micronized, crystalline active agent.

11. The pharmaceutical composition according to claim 1, wherein the active agent included in the active agent particles is a LAMA active agent selected from the group consisting of glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, and darotropium, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 11, wherein the active agent particles comprise glycopyrrolate, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 12, wherein the active agent particles comprise crystalline glycopyrrolate, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 12, wherein the active agent particles comprise micronized, crystalline glycopyrrolate, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 12, 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 of no more than 10 μ

g.

16. The pharmaceutical composition of claim 15, wherein the glycopyrrolate active agent particles comprise a pharmaceutically acceptable salt of glycopyrrolate selected from the group consisting of fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate, and benzenesulfonate salts.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutically acceptable salt of glycopyrrolate is selected from the group consisting of fluoride, chloride, bromide, and iodide salts.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

19. A pharmaceutical composition according to claim 1, wherein the active agent included in the active agent particles is a LABA active agent selected from the group consisting of bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β

2 agonists, or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 19, wherein the active agent particles comprise formoterol, or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition according to claim 19, wherein the active agent particles comprise crystalline formoterol, or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition according to claim 19, wherein the active agent particles comprise micronized, crystalline formoterol, or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition according to claim 19, wherein the formoterol active agent particles are included in the suspension medium at a concentration sufficient to provide a delivered dose of formoterol per actuation of the metered dose inhaler of no more than 5 μ

g.

24. The pharmaceutical composition according to claim 23, wherein the formoterol active agent particles comprise a pharmaceutically acceptable salt of formoterol selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic, oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic, and 3-hydroxy-2-naphthalene carboxylic acid salts.

25. The pharmaceutical composition according to claim 24, wherein the pharmaceutically acceptable salt of formoterol is formoterol fumarate.

26. A method for treating a pulmonary disease or disorder in a patient, wherein the pulmonary disease or disorder is selected from at least one of the group consisting of asthma, COPD, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, and pulmonary inflammation or obstruction resulting from cystic fibrosis, the method comprising administering a therapeutically effective amount of a pharmaceutical composition from a metered dose inhaler, the pharmaceutical composition comprising:

a suspension medium comprising a pharmaceutically acceptable propellant;

a plurality of active agent particles comprising a LAMA active agent or a LABA active agent; and

a plurality of respirable suspending particles, wherein the respirable suspending particles are formed separately from and are different particles than the active agent particles and are formed of a dry particulate phospholipid material that is substantially insoluble in the suspension medium;

and wherein the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is from greater than 1;

1 up to 200;

1.

27. The method of claim 26, wherein the active agent particles comprise crystalline active agent.

28. The method of claim 26, wherein the active agent particles comprise micronized, crystalline active agent.

29. The method of claim 26, wherein the active agent comprises a LAMA active agent selected from the group consisting of glycopyrrolate, dexpirronium, tiotropium, trospium, aclidinium, and darotropium, or a pharmaceutically acceptable salt thereof.

30. The method of claim 26, wherein the active agent comprises a LABA active agent selected from the group consisting of bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β

₂ agonists, or a pharmaceutically acceptable salt thereof.

31. The method of claim 29, wherein said administering the pharmaceutical composition comprises administering a delivered dose of glycopyrrolate, or a pharmaceutically acceptable salt thereof, of no more than 150 μ

g.

32. The method of claim 31, wherein the glycopyrrolate, or pharmaceutically acceptable salt thereof, comprises crystalline glycopyrrolate.

33. The method of claim 31, wherein the glycopyrrolate, or pharmaceutically acceptable salt thereof, comprises micronized, crystalline glycopyrrolate.

34. The method of claim 31, wherein the glycopyrrolate active agent particles comprise a pharmaceutically acceptable salt of glycopyrrolate and the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

35. The method according to claim 31, wherein said administering results in a clinically significant increase in inspiratory capacity (IC) in the patient.

36. The method of claim 29, wherein said administering the pharmaceutical composition comprises administering a delivered dose of glycopyrrolate, or a pharmaceutically acceptable salt thereof, of no more than 80 μ

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

37. The method according to claim 30, wherein said administering of the pharmaceutical composition comprises delivering a dose of 10 μ

g, or less, of formoterol, or a pharmaceutically acceptable salt thereof, per actuation of the metered dose inhaler.

38. The method of claim 37, wherein the formoterol, or pharmaceutically acceptable salt thereof, comprises crystalline formoterol.

39. The method of claim 37, wherein the formoterol, or pharmaceutically acceptable salt thereof, comprises micronized, crystalline formoterol.

40. The method of claim 37, wherein the active agent particles comprise a pharmaceutically acceptable salt of formoterol and the pharmaceutically acceptable salt of formoterol is formoterol fumarate.

41. The method according to claim 30, wherein said administering of the pharmaceutical composition comprises delivering a dose of 10 μ

g, or less, of formoterol, or a pharmaceutically acceptable salt thereof, per actuation of the metered dose inhaler, and said administering of the pharmaceutical composition results in a clinically significant increase in FEV₁ in the patient.