MICRONIZED PARTICLES OF LOW-DOSAGE STRENGTH ACTIVE AGENTS FOR POWDER FORMULATIONS FOR INHALATION

• US 20100055192A1
• Filed: 07/09/2009
• Published: 03/04/2010
• Est. Priority Date: 01/10/2007
• Status: Active Grant

• Current Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Original Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Inventors: Catinella, Silvia, Musa, Rossella, Cocconi, Daniela
• Granted Patent: US 8,512,753 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• 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 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• 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

Abstract

Micronized particles of a low-dosage strength active ingredient, to be used in dry powder formulations for inhalation, with particular properties can easily and homogenously disperse in a dry powder formulation to be administered by means of a dry powder inhaler device.

Claims

1. A powder formulation, comprising

micronized particles of an active ingredient having a nominal dose delivered after an actuation of a dry powder inhaler equal to or lower than 4 μ

g, and

particles of a physiologically acceptable excipient having a mass median diameter (MMD) higher than 90 microns,

wherein agglomerates of micronized particles of said active ingredient are absent as determined by Near Infrared Spectrophotometer provided with a microscope.

2. A powder according to claim 1 wherein said active ingredient is carmoterol.

3. A powder according to claim 1. wherein the content uniformity of the active ingredient, expressed as relative standard deviation (RSD), is less than 5%.

4. Micronized particles of an active ingredient whose nominal dose delivered after an actuation of a dry powder inhaler is equal to or lower than 20 μ

g, wherein;

i) no more than 10% of said particles have a volume diameter lower than 0.8 microns;

ii) no more than 50% of said particles have a volume diameter lower than 1.7 microns; and

iii) at least 90% of said particles have a volume diameter lower than 10 microns.

5. Micronized particles according to claim 4, wherein said nominal dose of said active ingredient is lower than 12 μ

g.

6. Micronized particles according to claim 5, wherein said nominal dose of the active ingredient is equal to or lower than 6 μ

g

7. Micronized particles according to claim 6, wherein said nominal dose of the active ingredient is equal to or lower than 4 μ

g.

8. Micronized particles according to claim 4, wherein no more than 10% of said particles have a volume diameter lower than 1.0 microns.

9. Micronized particles according to claim 4, wherein no more than 50% of said particles have a volume diameter lower than 2.0 microns and higher than 3.0 microns.

10. Micronized particles according to claim 4, which are in crystalline form.

11. Micronized particles according to claim 10, wherein said active ingredient is 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl-2(1H)-quinolinone (carmoterol) or a salt thereof.

12. Micronized particles according to claim 11, wherein said salt is a hydrochloride salt.

13. Micronized particles according to claim 12, which have a specific surface area of between 8.5 and 10.5 m²/g.

14. Micronized particles according to claim 10, wherein said active ingredient is formoterol or a salt thereof.

15. Micronized particles according to claim 14, wherein said salt is a fumarate salt dihydrate.

16. Micronized particles according to claim 15, which have a specific surface area of between 5.2 and 6.5 m²/g.

17. A powder formulation, comprising

micronized particles according to claim 4, and

particles of a physiologically acceptable excipient having a mass median diameter (MMD) higher than 90 microns.

18. A powder according to claim 17, which is contained in a multidose dry powder inhaler.

19. A powder according to claim 17, further comprising

a fraction of microparticles having a MMD lower than 15 microns comprising a mixture of particles of a physiologically acceptable excipient and magnesium stearate.

20. A powder according to claim 19, wherein said physiologically acceptable material is:

one or more sugars selected from the group consisting of glucose, arabinose, maltose, saccharose, dextrose and lactose, or

one or more polyalcohols selected from the group consisting of mannitol, maltitol, lactitol or sorbitol.

21. A powder according to claim 20, wherein said physiologically acceptable material is alpha-lactose monohydrate.

22. A powder according to claim 17, further comprising a further active ingredient selected from the group consisting of a corticosteroid, an anticholinergic/antimuscarinic agent, a phosphodiesterase-4 (PDE-4) inhibitor, or a combination thereof.

23. A powder according to claim 22, wherein said corticosteroid is selected from the group consisting of budesonide and its epimers, beclometasone dipropionate, mometasone furoate, flunisolide, ciclesonide, rofleponide, fluticasone propionate, and triamcinolone acetonide.

24. A powder according to claim 23, wherein said anticholinergic/antimuscarinic agent is selected from the group consisting of ipratropium bromide, oxytropium bromide, tiotropium bromide, glycopyrrolate bromide, and its enantiomers.

25. A powder according to claim 17, wherein said micronised particles comprise carmoterol hydrochloride.

26. A powder according to claim 17, wherein said micronised particles comprise formoterol fumarate dihydrate.