COMPOSITIONS FOR RESPIRATORY DELIVERY OF ACTIVE AGENTS AND ASSOCIATED METHODS AND SYSTEMS

• US 20110135737A1
• 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
• Application Number:
  US12/790,671
• Publication Number:
  US 20110135737A1
• Time in Patent Office: Days
• US Class Current: 424/489
• 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 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 co-suspension deliverable from a metered dose inhaler, the stable co-suspension comprising:

a suspension medium comprising a pharmaceutically acceptable propellant;

a plurality of active agent particles; and

a plurality of respirable suspending particles, wherein the plurality of active agent particles associate with the plurality of suspending particles despite buoyancy differences between the active agent particles and the suspending particles within the suspension medium.

2. A co-suspension according to claim 1, wherein at least 90% of the active agent particles by volume exhibits an optical diameter of 7 μ

m or less.

3. A co-suspension according to claim 1, wherein at least 50% of the active agent particles by volume exhibits an optical diameter of 5 μ

m or less

4. A co-suspension according to claim 1, wherein the active agent particles comprise particles of active agent in crystalline form.

5. A co-suspension according to claim 1, wherein the active agent particles comprise particles of active agent in amorphous form.

6. A co-suspension according to claim 1, wherein the active agent exhibits measurable solubility that results in dissolution selected from as much as 1% of the total active agent mass in the suspension medium, as much as 0.5% of the total active agent mass in the suspension medium, as much as 0.05% of the total active agent mass in the suspension medium, and as much as 0.025% of the total active agent mass in the suspension medium.

7. A co-suspension according to claim 1, wherein the total mass of the active agent that dissolves in the suspension medium is less than 5% of the total active agent mass in the suspension medium.

8. A co-suspension according to claim 1, wherein the plurality of active agent particles includes two or more different active agents.

9. A co-suspension according to claim 1, wherein the active agent particles comprise an active agent selected from short-acting beta agonists, such as bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, salbutamol (albuterol), terbutaline, tulobuterol, reproterol and epinephrine, long-acting beta agonists, such as bambuterol, clenbuterol, formoterol, and salmeterol, ultra long-acting beta agonists, such as carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β

₂ agonists, corticosteroids, such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, anti-inflammatories, such as fluticasone propionate, beclomethasone dipropionate, flunisolide, budesonide, tripedane, cortisone, prednisone, prednisilone, dexamethasone, betamethasone, or triamcinolone acetonide, antitussives, such as noscapine, bronchodilators, such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, salbutamol, albuterol, salmeterol, terbutaline, anticholinergics, such as glycopyrrolate, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium, atropine, benzatropin, or oxitropium, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

10. A co-suspension according to claim 1, wherein two or more active agents are included in the active agent particles and the two or more active agents are selected from a combination of formoterol and budesonide, a combination of glycopyrrolate and formoterol, a combination of ciclesonide and formoterol, a combination of salmeterol and fluticasone, a combination of glycopyrrolate, formoterol, and budesonide, and a combination of glycopyrrolate, formoterol, and mometasone, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

11. A co-suspension according to claim 1, wherein the active agent is selected from potent and highly potent active agents.

12. A co-suspension according to claim 1, wherein the target delivered dose of active agent is selected from between about 100 μ

g and about 100 mg per dose, between about 100 μ

g and about 10 mg per dose, and between about 100 μ

g and 1 mg per dose.

13. A co-suspension according to claim 1, wherein the target delivered dose of active agent is selected from up to about 80 μ

g per dose, up to about 40 μ

g per dose, up to about 20 μ

g per dose, or between about 10 μ

g and about 100 μ

g per dose.

14. A co-suspension according to claim 1, wherein the target delivered dose of active agent is selected from between about 0.1 and about 2 μ

g per dose, about 0.1 and about 1 μ

g per dose, and about 0.1 and about 0.5 μ

g per dose.

15. A co-suspension according to claim 1, wherein the suspending particles exhibit an MMAD selected from between about 10 μ

m and about 500 nm, between about 5 μ

m and about 750 nm, and 1 μ

m and about 3 μ

m.

16. A co-suspension according to claim 1, wherein the suspending particles exhibit a volume median optical diameter selected from between about 0.2 μ

m and about 50 μ

m, between about 0.5 μ

m and about 15 μ

m, between about 1.5 μ

m and about 10 μ

m, and between about 2 μ

m and about 5 μ

m.

17. A co-suspension according to claim 1, 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.

18. A co-suspension according to claim 17, wherein the suspending particles are included in the suspension medium at a concentration selected from between about 1 mg/mL to about 15 mg/mL, about 3 mg/mL to about 10 mg/mL, about 1.5 mg/mL to about 10 mg/mL.

19. A co-suspension according to claim 17, wherein the active agent particles comprise glycopyrrolate, and the suspending particles are included in the suspension medium at a concentration selected from about 6 mg/mL, between about 3 mg/mL and about 10 mg/mL, and between about 1 mg/mL and about 15 mg/mL.

20. A co-suspension according to claim 17, wherein the active agent particles comprise formoterol, and the suspending particles are included in the suspension medium at a concentration selected from about 3 mg/mL, between about 1.5 mg/mL and about 5 mg/mL, and between about 0.5 mg/mL and about 7.5 mg/mL.

21. A co-suspension according to claim 17, wherein the active agent particles comprise formoterol, and the suspending particles are included in the suspension medium at a concentration selected from about 6 mg/mL, between about 3 mg/mL and about 10 mg/mL, and between about 1 mg/mL and about 15 mg/mL.

22. A co-suspension according to claim 17, wherein the active agent particles comprise salmeterol, and the suspending particles are included in the suspension medium at a concentration selected from about 5 mg/mL, between about 3 mg/mL and about 10 mg/mL, and between about 1 mg/mL and about 15 mg/mL.

23. A co-suspension according to claim 17, wherein the active agent particles comprise budesonide, and the suspending particles are included in the suspension medium at a concentration selected from about 8 mg/mL, between about 5 mg/mL and about 20 mg/mL, and between about 0.5 mg/mL and about 30 mg/mL.

24. A co-suspension according to claim 17, wherein the active agent particles comprise fluticasone, and the suspending particles are included in the suspension medium at a concentration selected from about 6 mg/mL, between about 3 mg/mL and about 10 mg/mL, and between about 1 mg/mL and about 15 mg/mL.

25. A co-suspension according to claim 1, wherein the total mass of the suspending particles exceeds the total mass of the active agent particles.

26. A co-suspension according to claim 25, wherein the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from above about 1.5, up to about 5, up to about 10, up to about 15, up to about 20, up to about 30, up to about 50, up to about 75, up to about 100, up to about 150, and up to about 200.

27. A co-suspension according to claim 25, wherein at least one of the active agents included in the active agent particles is a highly potent active agent and the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 5 and about 175, between about 10 and about 150, between about 15 and about 125, and between about 25 and about 75.

28. A co-suspension according to claim 25, wherein the active agent particles include one or more of glycopyrrolate, fluticasone, mometasone, and budesonide, and the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 1 and about 20, between about 5 and about 15, and about 10.

29. A co-suspension according to claim 25, wherein the active agent particles include one or more of fluticasone, mometasone, and budesonide, and the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 1 and about 15, between about 1.5 and about 10, and between about 2.5 and about 5.

30. A co-suspension according to claim 25, wherein the active agent particles include salmeterol, and the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 10 and about 30, between about 15 and about 25, and about 20.

31. A co-suspension according to claim 25, wherein the active agent particles include formoterol, and the ratio of the total mass of the suspending particles to the total mass of the active agent particles is selected from between about 10 and about 200, between about 50 and about 125, and about 75.

32. A co-suspension according to claim 1, wherein the suspending particles remain associated with 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.

33. A co-suspension according to claim 1, wherein the suspending particles comprise an excipient selected from the group consisting of lipids, phospholipids, nonionic detergents, polymers, such as nonionic block copolymers, surfactants, such as non-ionic surfactants and biocompatible fluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof.

34. A co-suspension according to claim 1, wherein the suspending particles comprise active agent particles comprising an excipient selected from the group consisting of lipids, phospholipids, nonionic detergents, polymers, such as nonionic block copolymers, surfactants, such as non-ionic surfactants and biocompatible fluorinated surfactants, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, and combinations thereof.

35. A co-suspension according to claim 1, wherein one or more of said plurality of suspending particles comprises an active agent.

36. A co-suspension according to claim 1, wherein the suspension medium comprises propellant substantially free of additional constituents.

37. The co-suspension according to claim 36, wherein the propellant comprises a propellant selected from an HFA propellant, a PFC propellant and combinations thereof.

38. A co-suspension according to claim 1, wherein the suspension medium comprises propellant in combination with one or more constituents selected from antisolvents, solubilizing agents, cosolvents, adjuvants, PVP and PEG.

39. A co-suspension according to claim 1, wherein the active agent particles are prepared by a micronization process selected from milling, grinding, crystallization, recrystallization, and supercritical or near-supercritical precipitation processes, and the suspending particles are prepared using a spray drying process.

40. A metered dose inhaler comprising a canister with an outlet valve including an actuator for dispensing a metered volume said canister containing a co-suspension as defined in claim 1, wherein the metered dose inhaler exhibits a delivered dose uniformity (“

DDU”

) for the co-suspension formulation selected from a DDU of ±

30%, or better, a DDU of ±

25%, or better, and a DDU of ±

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

41. A metered dose inhaler according to claim 40, wherein the metered dose inhaler dispenses the co-suspension at an initial fine particle fraction and the initial fine particle fraction dispensed 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.

42. A metered dose inhaler according to claim 41, wherein the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction.

43. A metered dose inhaler according to claim 41, wherein the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction.

44. A metered dose inhaler according to claim 40, wherein the co-suspension formulation contained within the canister of the metered dose inhaler is storage stable for at least six months.

45. A metered dose inhaler according to claim 40, wherein the metered dose inhaler exhibits a delivered dose uniformity (“

DDU”

) for the co-suspension formulation selected from a DDU of ±

30%, or better, a DDU of ±

25%, or better, and a DDU of ±

20%, or better, throughout emptying of the canister, after said canister is subjected to temperatures alternating between −

5°

C. and 40°

C. every 6 hours for a period of six weeks.

46. A metered dose inhaler according to claim 41, wherein the fine particle fraction is substantially maintained throughout emptying of the canister, after said canister is subjected to temperatures alternating between −

5°

C. and 40°

C. every 6 hours for a period of six weeks.

47. A method of preparing a metered dose inhaler containing a stable co-suspension formulation, the method comprising:

loading a canister with suspending particles and active agent particles containing at least one active agent;

attaching an actuator valve to an end of said canister and sealing said canister, said actuator valve adapted for dispensing a metered amount of the co-suspension formulation per actuation; and

charging the canister with a pharmaceutically acceptable suspension medium comprising a propellant, wherein the active agent particles, suspending particles and suspension medium are selected such that said loading of the active agent particles and suspending particles and said charging of the canister with a pharmaceutically acceptable suspension medium provides a co-suspension formulation as defined in claim 1.

48. A method of preparing a metered dose inhaler containing a stable co-suspension formulation, the method comprising:

loading a canister with active agent particles containing at least one active agent and suspending particles;

attaching an actuator valve to an end of said container and sealing said canister, said actuator valve adapted for dispensing a metered amount of the co-suspension formulation per actuation; and

charging the canister with a pharmaceutically acceptable suspension medium comprising a propellant, wherein the active agent particles, suspending particles and suspension medium are selected such that said loading of the active agent particles and suspending particles and said charging of the canister with a pharmaceutically acceptable suspension medium provides a metered dose inhaler as defined in claim 40.

49. A method of respiratory delivery of an active agent to a patient, the method comprising:

providing a metered dose inhaler comprising a canister containing a co-suspension as defined in claim 1; and

delivering the co-suspension to the patient using the metered dose inhaler.

50. The method of claim 49, wherein delivering the co-suspension formulation to the patient comprises delivering the co-suspension formulation at a DDU selected from a DDU of ±

30%, or better, a DDU of ±

25%, or better, and a DDU of ±

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

51. A method of respiratory delivery of an active agent to a patient, the method comprising:

providing a metered dose inhaler as defined in claim 40; and

delivering the co-suspension to the patient using the metered dose inhaler.

52. A method for treating a patient suffering from an inflammatory or obstructive pulmonary disease or condition, the method comprising administering to the patient via an MDI a therapeutically effective amount of co-suspension as defined in claim 1.

53. The method of claim 52, wherein the disease or condition is selected from asthma, COPD, exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, and pulmonary inflammation and obstruction associated with cystic fibrosis.

54. The method of claim 53, wherein administering the therapeutically effective amount of the co-suspension comprises:

providing a metered dose inhaler comprising a canister containing the co-suspension; and

delivering the co-suspension to the patient using the metered dose inhaler such that a DDU selected from a DDU of ±

30%, or better, a DDU of ±

25%, or better, and a DDU of ±

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