Particulate materials

• US 8,828,359 B2
• Filed: 06/03/2013
• Issued: 09/09/2014
• Est. Priority Date: 04/17/2002
• Status: Expired due to Term

• Current Assignee: Nektar Therapeutics
• Original Assignee: Nektar Therapeutics
• Inventors: Kordikowski, Andreas, Walker, Stephen Ernest, York, Peter
• Primary Examiner(s): Haghighatian, Mina
• Application Number:
  US13/908,540
• Publication Number:
  US 20140037697A1
• Time in Patent Office: 463 Days
• Field of Search: 424/46, 424/489, 424/499, 424/434, 424/45, 514/951
• US Class Current: 424/46
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 47/06 Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• CPC Class Codes: A61K 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• 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 9/12 Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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: B01J 2/04 : in a gaseous medium if combined with suspending the material in a gas, e.g. fluidised beds B01J2/16
• CPC Class Codes: Y10T 428/2982 : Particulate matter [e.g., sphere, flake, etc.]

Abstract

Embodiments of the invention relate to particles of active substances, methods for preparing the particles, formulations containing the particles, and metered dose inhalers containing such particles or formulations. In one embodiment, a composition of an aerosol formulation is provided and contains a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 μm suspended in a hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v. The aerosol formulation exhibits a flocculation volume of about 85% or greater about 1 minute after mixing the particulate active substance and the hydrofluorocarbon fluid vehicle. The particulate active substance contains an alkaloid ergotamine, pharmaceutically acceptable salts thereof, analogs thereof, or derivatives thereof. In some examples, the alkaloid ergotamine contains dihydroergotamine, such as dihydroergotamine mesylate and the hydrofluorocarbon fluid vehicle contains HFA 134a, HFA 227ea, or mixtures thereof.

Claims

1. Particles of an active substance, wherein the particles are non-micronized, solid, have a mass median aerodynamic diameter of less than 10 μ

m, and exhibit a flocculation volume of about 85% or greater about 1 minute after mixing the particles with a nonsolvent hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v,

wherein the active substance comprises an ergot alkaloid, pharmaceutically acceptable salts thereof, analogues thereof, or derivatives thereof.

2. The particles of claim 1, wherein the ergot alkaloid comprises dihydroergotamine, pharmaceutically acceptable salts thereof, analogues thereof, or derivatives thereof.

3. The particles of claim 2, wherein the ergot alkaloid is dihydroergotamine mesylate.

4. The particles of claim 1, wherein the hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea), or mixtures thereof.

5. The particles of claim 1, wherein the particles exhibit a flocculation volume of about 85% or greater about 5 minutes after mixing the particles and the hydrofluorocarbon fluid vehicle.

6. The particles of claim 5, wherein the particles exhibit a flocculation volume of about 85% or greater about 10 minutes after mixing the particles and the hydrofluorocarbon fluid vehicle.

7. The particles of claim 6, wherein the particles exhibit a flocculation volume of about 100% about 10 minutes after mixing the particles and the hydrofluorocarbon fluid vehicle.

8. The particles of claim 1, wherein the particles are mixed with the hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 3% w/v.

9. The particles of claim 8, wherein the particles are mixed with the hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.5% w/v to about 1.5% w/v.

10. The particles of claim 1, wherein the mass median aerodynamic diameter of the particles is about 5 μ

m or less.

11. The particles of claim 10, wherein the mass median aerodynamic diameter of the particles is about 3 μ

m or less.

12. The particles of claim 1, wherein the active substance is in a crystalline form.

13. Particles of an active substance, wherein the particles are non-micronized, solid, have a mass median aerodynamic diameter of less than 15 μ

m, and exhibit a flocculation volume of about 35% or greater about 1 minute after mixing the particles with a nonsolvent hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v,

wherein the active substance comprises an ergot alkaloid, pharmaceutically acceptable salts thereof, analogues thereof, or derivatives thereof.

14. The particles of claim 13, wherein the ergot alkaloid comprises dihydroergotamine, pharmaceutically acceptable salts thereof, analogues thereof, or derivatives thereof.

15. The composition of claim 14, wherein the ergot alkaloid is dihydroergotamine mesylate.

16. The particles of claim 13, wherein the hydrofluorocarbon fluid vehicle comprises 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea), or mixtures thereof.

17. The particles of claim 16, wherein the mass median diameter of the particles is about 10 μ

m or less.

18. The particles of claim 17, wherein the mass median diameter of the particles is about 5 μ

m or less.

19. The particles of claim 13, wherein the particles exhibit a flocculation volume of about 85% or greater about 10 minutes after mixing the particulate active substance and the hydrofluorocarbon fluid vehicle.

20. The particles of claim 13, wherein the particles are mixed with the hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 3% w/v.