Compositions, methods and systems for respiratory delivery of two or more active agents

• US 8,324,266 B2
• Filed: 10/26/2011
• Issued: 12/04/2012
• 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, Lechuga-Ballesteros, David, Smith, Adrian Edward, Joshi, Vidya B., Dwivedi, Sarvajna Kumar
• Primary Examiner(s): Alstrum-Acevedo, James H.
• Application Number:
  US13/281,726
• Publication Number:
  US 20120039817A1
• Time in Patent Office: 405 Days
• Field of Search: 514/408, 424/45, 424/46, 424/489
• US Class Current: 514/408
• 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 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• 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 31/40 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 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/124 characterised by the propellant
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• 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 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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 method for treating a pulmonary disease or disorder in a patient, the method comprising:

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

a suspension medium comprising a pharmaceutically acceptable propellant free of additional constituents;

a first species of respirable active agent particles comprising a pharmaceutically acceptable salt, ester, or isomer of glycopyrrolate in crystalline form, as a first active agent;

one or more additional species of respirable active agent particles comprising one or more additional active agents selected from the group consisting of a short-acting beta agonist, a long-acting and ultra long-acting β

₂ adrenergic receptor agonist (LABA), a corticosteroid, an anti-inflammatory, an anti-tussive, a bronchodilator, and a muscarinic antagonist; and

a plurality of respirable suspending particles, wherein the total mass of the respirable suspending particles exceeds the total mass of the respirable active agent particles, the plurality of suspending particles are formed of a dry particulate phospholipid material that is substantially insoluble in the suspension medium, and the active agent particles associate with the plurality of suspending particles to form a co-suspension; and

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

g or less of glycopyrrolate per actuation of the metered dose inhaler and said delivery results in an increase in FEV₁ of at least 70 mL in 0.5 hours or less, and the at least 70 mL increase in FEV₁ remains for up to 12 hours or more.

2. The method of claim 1, 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, pulmonary inflammation experienced with cystic fibrosis, and pulmonary obstruction experienced with cystic fibrosis.

3. The method of claim 2, wherein administering the co-suspension to the patient further results in a clinically significant increase in inspiratory capacity (IC) in the patient.

4. The method of claim 3, wherein said administering of the co-suspension comprises administering a delivered dose of no more than 100 μ

g glycopyrrolate per actuation, 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.

5. The method of claim 4, wherein said administering of the co-suspension comprises administering a delivered dose of no more than 80 μ

g glycopyrrolate per actuation, 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.

6. The method of claim 4, wherein said administering of the co-suspension results in an increase in IC of at least 300 mL within 1 hour or less.

7. The method of claim 5, wherein said administering of the co-suspension results in an increase in IC of at least 150 mL within 1 hour or less.

8. The method of claim 4, wherein administering the co-suspension to the patient by actuating the metered dose inhaler comprises delivering glycopyrrolate to the patient at a delivered dose uniformity of ±

25% or better, throughout emptying of the canister.

9. The method of claim 1, wherein providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising suspending particles formed of 1,2-Distearoyl-sn-Glycero-3-Phosphocholine.

10. The method of claim 1, wherein providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprises providing a co-suspension exhibiting a ratio of total mass of the suspending particles to total mass of the active agent particles of between about 10:

1 and about 200;

1.

11. The method of claim 10, wherein the co-suspension contained within the canister comprises a second species of respirable active agent particles comprising a crystalline LABA active agent selected from the group consisting of bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, saligenin- or indole- containing and adamantyl-derived β

₂ agonists, and pharmaceutically acceptable salts, esters, or isomers thereof.

12. The method of claim 11, wherein the second species of respirable active agent particles comprises a pharmaceutically acceptable salt, ester, or isomer of formoterol in crystalline form.

13. The method of claim 12, 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, pulmonary inflammation experienced with cystic fibrosis, and pulmonary obstruction experienced with cystic fibrosis, and administering the co-suspension to the patient by actuating the metered dose inhaler comprises delivering a dose of glycopyrrolate of 10 μ

g or less per actuation of the metered dose inhaler.

14. The method of claim 13, wherein the pulmonary disease or disorder is COPD and the ratio of total mass of the respirable suspending particles to total mass of the respirable active agent particles is between about 15:

1 and about 60;

1.

15. The method of claim 1, wherein said increase in FEV₁ resulting from said administration of the co-suspension includes an increase in FEV₁ of at least 150 mL achieved within 0.5 hours, or less.

17. The method of claim 15, wherein actuating the metered dose inhaler to deliver each of the active agents from the metered dose inhaler in respirable form at a delivered dose uniformity of ±

20% or better throughout emptying of the canister.

16. A method for respiratory delivery of a therapeutically effective amount of at least two active agents to a patient, the method comprising:

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

a suspension medium comprising a pharmaceutically acceptable propellant free of additional constituents;

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

one or more additional species of respirable active agent particles comprising one or more additional active agents selected from the group consisting of a short-acting beta agonist, a long-acting and ultra long-acting β

₂ adrenergic receptor agonist (LABA), a corticosteroid, an anti-inflammatory, an anti-tussive, a bronchodilator, and a muscarinic antagonist; and

a plurality of respirable suspending particles, wherein the plurality of respirable suspending particles are formed of a dry particulate phospholipid material that is substantially insoluble in the suspension medium and the plurality of respirable active agent particles associate with the plurality of suspending particles to form a co-suspension; and

actuating the metered dose inhaler to deliver each of the active agents from the metered dose inhaler in respirable form at a delivered dose uniformity of ±

30% or better, throughout emptying of the canister.

18. The method of claim 16, wherein providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising sufficient active agent particles to provide a delivered dose of glycopyrrolate per actuation of the metered dose inhaler of between about 2 μ

g and about 200 μ

g and actuating the metered dose inhaler to deliver glycopyrrolate from the metered dose inhaler in respirable form further comprises expelling glycopyrrolate from the metered dose inhaler in an aerosol composition having an initial fine particle fraction and, throughout emptying of the canister, the aerosol composition expelled from the metered dose inhaler exhibits a fine particle fraction that is maintained within 80% of the initial fine particle fraction.

19. The method of claim 18, wherein providing a metered dose inhaler comprises providing a metered dose inhaler comprising a canister containing a co-suspension comprising sufficient active agent particles to provide a delivered dose of glycopyrrolate per actuation of the metered dose inhaler of between about 10 μ

g and about 150 μ

g, and wherein, throughout emptying of the canister the aerosol composition expelled from the metered dose inhaler exhibits a fine particle fraction that is maintained within 90% of the initial fine particle fraction.

20. The method of claim 19, wherein, throughout emptying of the canister, the aerosol composition expelled from the metered dose inhaler exhibits a fine particle fraction that is maintained within 95% of the initial fine particle fraction.

21. The method of claim 16, wherein providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprises providing a canister containing a co-suspension comprising suspending particles formed of 1,2-Distearoyl-sn-Glycero-3-Phosphocholine.

22. The method of claim 16, wherein providing a metered dose inhaler comprising a canister containing a pharmaceutically acceptable co-suspension comprises providing a canister containing a co-suspension exhibiting a ratio of total mass of the respirable suspending particles to total mass of the respirable active agent particles of between about 10:

1 and about 200;

1.

23. The method of claim 16, wherein the co-suspension contained within the canister comprises a second species ofb respirable active agent particles comprising a crystalline LABA active agent selected from the group consisting of bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, saligenin- or indole- containing and adamantyl-derived β

₂ agonists, and pharmaceutically acceptable salts, esters, or isomers thereof.

24. The method of claim 23, wherein the second species of respirable active agent particles comprises a pharmaceutically acceptable salt, ester, or isomer of formoterol in crystallinesolvate form.

25. The method of claim 24, wherein administering the co-suspension to the patient results in the patient experiencing either an increase from baseline in FEV₁ of at least 200 ml or a 12% or greater, increase from baseline in FEV₁ coupled with total increase in FEV₁ of at least 150 ml within a period of time selected from 1 hour or less, 1.5 hours or less, 2 hours or less, and 2.5 hours or less.

26. The method of claim 25, wherein administering the co-suspension to the patient results in the patient experiencing either an increase from baseline in FEV₁ of at least 200 ml or a 12% or greater, increase from baseline in FEV₁ coupled with total increase in FEV₁ of at least 150 ml within 1 hour or less.

27. The method of claim 25, wherein administering the co-suspension to the patient additionally results in a clinically significant increase in inspiratory capacity (IC).

28. The method of claim 27, wherein the clinically significant increase in IC is achieved in 1 hour or less.

29. The method of claim 16, wherein the co-suspension contained within the canister comprises a second species of respirable active agent particles comprising a crystalline LABA active agent selected from the group consisting of bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, saligenin- or indole- containing and adamantyl-derived β

₂ agonists, and pharmaceutically acceptable salts, esters, or isomers thereof, and a third species of respirable active agent particles comprising a crystalline corticosteroid active agent selected from the group consisting of beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, trimacinolone, and any pharmaceutically acceptable salts, esters, or isomers thereof.

30. The method of claim 29, wherein the second species of respirable active agent particles comprises a pharmaceutically acceptable salt, ester, or isomer of formoterol in crystalline form, and the third species of respirable active agent particles comprises a pharmaceutically acceptable salt, ester, or isomer of mometasone in crystalline form.