Particulate materials

• US 10,251,881 B2
• Filed: 03/02/2017
• Issued: 04/09/2019
• Est. Priority Date: 04/17/2002
• Status: Active Grant

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Kordikowski, Andreas, Walker, Stephen Ernest, York, Peter
• Primary Examiner(s): Haghighatian, Mina
• Application Number:
  US15/448,271
• Publication Number:
  US 20170173006A1
• Time in Patent Office: 768 Days
• 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, analogues 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. An aerosol formulation comprised in an aerosol canister, the aerosol formulation comprising:

a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 μ

m, suspended in a hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v, wherein 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, and the particulate active substance is an ergot alkaloid, or a pharmaceutically acceptable salt analogue, or derivative thereof.

2. The aerosol formulation of claim 1, wherein the ergot alkaloid is an ergotamine or a pharmaceutically acceptable salt, analogue, or derivative thereof.

3. The aerosol formulation of claim 2, wherein the ergotamine is dihydroergotamine.

4. The aerosol formulation 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 a mixture thereof.

5. The aerosol formulation of claim 1, exhibiting a flocculation volume of about 85% or greater about 5 minutes after mixing the particulate active substance and the hydrofluorocarbon fluid vehicle.

6. The aerosol formulation of claim 5, exhibiting a flocculation volume of about 85% or greater about 10 minutes after mixing the particulate active substance and the hydrofluorocarbon fluid vehicle.

7. The aerosol formulation composition of claim 6, exhibiting a flocculation volume of about 100% about 10 minutes after mixing the particulate active substance and the hydrofluorocarbon fluid vehicle.

8. The aerosol formulation of claim 1, wherein the particulate active substance is suspended in the hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 3% w/v.

9. The aerosol formulation of claim 8, wherein the particulate active substance is suspended in the hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.5% w/v to about 1.5% w/v.

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

m or less.

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

m or less.

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

13. The aerosol formulation of claim 12, wherein the crystalline form is significantly longer in one dimension than in at least one other dimension.

21. The aerosol formulation of claim 3, wherein the dihydroergotamine is dihydroergotamine mesylate.

23. The aerosol formulation of claim 1, comprising less than 0.01% w/w surfactant.

24. The aerosol formulation of claim 1, wherein the aerosol canister is suitable for use in a metered dose inhaler.

14. An aerosol formulation comprised in an aerosol canister, the aerosol formulation comprising:

a particulate active substance of non-micronized, solid particles having a mass median diameter of less than 15 μ

m, suspended in a hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v, wherein 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, and the particulate active substance is an ergot alkaloid, or a pharmaceutically acceptable salt, analogue, or derivative thereof.

15. The aerosol formulation of claim 14, wherein the ergot alkaloid is an ergotamine, or a pharmaceutically acceptable salt, analogue, or derivative thereof.

16. The aerosol formulation of claim 15, wherein the ergotamine is dihydroergotamine.

17. The aerosol formulation of claim 14, wherein the hydrofluorocarbon fluid vehicle comprises 1, 1, 1, 2-tetrafluoroethane (HFA 134a), 1, 1, 1, 2, 3, 3, 3- heptafluoropropane (HFA 227ea), or a mixture thereof.

18. The aerosol formulation of claim 17, wherein the mass median diameter is about 3 μ

m or less.

19. The aerosol formulation of claim 14, exhibiting a flocculation volume of about 85% or greater about 10 minutes after mixing the particulate active substance and the hydrofluorocarbon fluid vehicle.

20. The aerosol formulation of claim 14, wherein the particulate active substance is suspended in the hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 3% w/v.

22. The aerosol formulation of claim 16, wherein the dihydroergotamine is dihydroergotamine mesylate.