Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems

• US 9,463,161 B2
• Filed: 05/28/2010
• Issued: 10/11/2016
• 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:
  US12/790,448
• Publication Number:
  US 20110023876A1
• Time in Patent Office: 2,328 Days
• US Class Current: 1/1
• 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 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:

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

a suspension medium consisting essentially of a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising a pharmaceutically acceptable salt, ester, or isomer of glycopyrrolate in crystalline form; and

a plurality of respirable suspending particles, wherein the plurality of 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

administering the co-suspension to the patient by actuating the metered dose inhaler at least once, wherein said administering of the co-suspension composition comprises delivering a dose of 80 μ

g, or less, of glycopyrrolate per actuation of the metered dose inhaler and results in an increase in forced expiratory volume in one second (FEV₁) in the patient of at least 70 mL.

2. The method of claim 1, wherein the pulmonary disease or disorder is COPD.

3. The method of claim 1, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 40 μ

g.

4. The method of claim 1, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate selected from one of the following two dose ranges:

a dose of no more than 10 μ

g per actuation of the metered dose inhaler; and

a dose of up to 20 μ

g per actuation of the metered dose inhaler.

5. The method of claim 1, wherein said administering of the co-suspension composition results in an increase in FEV₁ of at least 100 mL within 1.0 hour, or less.

6. The method of claim 1, wherein said administering of the co-suspension composition results in an increase in FEV₁ of at least 100 mL within 1.0 hour, or less, and the delivered dose of glycopyrrolate is selected from one of the following two dose ranges:

a dose of no more than 10 μ

g per actuation of the metered dose inhaler; and

a dose of up to 20 μ

g per actuation of the metered dose inhaler.

7. The method of claim 3, wherein said administering of the co-suspension composition results in an increase in FEV₁ of at least 100 mL within 1.0 hour, or less.

8. The method of claim 1, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 20 μ

g.

9. The method of claim 1, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 20 μ

g, and said administration results in an increase in FEV₁ of at least 100 mL within 1.0 hour, or less.

10. The method of claim 1, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 10 μ

g, and said administration results in an increase in FEV₁ of at least 100 mL within 1.0 hour, or less.

11. The method of claim 1, wherein said administering of the co-suspension composition results in an increase in FEV₁ of at least 100 mL within 0.5 hours, or less.

12. The method of claim 6, wherein said administering of the co-suspension composition results in an increase in FEV₁ of at least 100 mL within 0.5 hours, or less.

13. The method of claim 1, wherein said administering of the co-suspension composition comprises administering a delivered dose of glycopyrrolate of no more than 20 μ

g, and said administration results in an increase in FEV₁ of at least 100 mL within 0.5 hours, or less.

15. The pharmaceutical composition according to claim 4, wherein the suspending particles are included in the suspension medium at a concentration selected from about 0.5 mg/mL and up to about 25 mg/mL.

16. The pharmaceutical composition according to claim 5, wherein the plurality of suspending particles exhibit a density lower than the suspension medium.

17. The pharmaceutical composition according to claim 16, wherein the crystalline glycopyrrolate active agent particles exhibit a density higher than the suspension medium such that, in the absence of the suspending particles, the glycopyrrolate particles form a sediment layer within the suspension medium.

18. The pharmaceutical composition according to claim 17, wherein the suspending particles comprise perforated microstructures.

19. The pharmaceutical composition according to claim 18, further comprising active agent particles comprising a pharmaceutically acceptable salt, ester, or isomer of formoterol.

20. The pharmaceutical composition according to claim 18, wherein the concentration of glycopyrrolate included in the co-suspension is between about 0.04 mg/mL and about 2.25 mg/mL.

21. The method of claim 1, wherein providing a metered dose inhaler comprising a pharmaceutically acceptable co-suspension, comprises providing a co-suspension wherein the plurality of respirable suspending particles are included in the suspension medium at a weight ratio of total mass of suspending particles to active agent particles of between 10:

1-200;

1.

22. The method of claim 21, wherein providing a metered dose inhaler comprising a pharmaceutically acceptable co-suspension, comprises providing a co-suspension wherein the plurality of respirable suspending particles are included in the suspension medium at a weight ratio of total mass of suspending particles to active agent particles of between 15:

1-60;

1.

23. The method of claim 22, wherein the pulmonary disease or disorder is COPD.

25. The pharmaceutical composition according to claim 19, wherein the plurality of respirable suspending particles are included in the suspension medium at a weight ratio of total mass of suspending particles to active agent particles of between 15:

1-60;

1.

26. The method of claim 1, wherein the pharmaceutically acceptable salt, ester, or isomer of glycopyrrolate is a salt of glycopyrrolate selected from fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate, and benzenesulfonate salts.

27. The method of claim 26, wherein the pharmaceutically acceptable salt of glycopyrrolate is selected from fluoride, chloride, bromide, and iodide salts.

28. The method of claim 27, wherein the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

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

a suspension medium consisting essentially of a pharmaceutically acceptable HFA propellant;

a plurality of active agent particles comprising a pharmaceutically acceptable salt, ester, or isomer of glycopyrrolate in crystalline form; and

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

m and about 10 μ

m, wherein the plurality of suspending particles are formed separately from the plurality of active agent particles, are different than the active agent particles, are substantially insoluble in the suspension medium, comprise 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), are present in the suspension medium at a concentration of up to about 30 mg/mL, and are included in the suspension medium at a weight ratio of total mass of suspending particles to active agent particles of between 10;

1-200;

1.

24. The pharmaceutical composition according to claim 14, wherein the plurality of respirable suspending particles are included in the suspension medium at a weight ratio of total mass of suspending particles to active agent particles of between 15:

1-60;

1.

29. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable salt, ester, or isomer of glycopyrrolate is a salt of glycopyrrolate selected from fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate, and benzenesulfonate salts.

30. The pharmaceutical composition of claim 29, wherein the pharmaceutically acceptable salt of glycopyrrolate is selected from fluoride, chloride, bromide, and iodide salts.

31. The pharmaceutical composition of claim 30, wherein the pharmaceutically acceptable salt of glycopyrrolate is 3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.