Dry Powder Drug Delivery Formulations, Methods of Use, and Devices Therefore

• US 20120111324A1
• Filed: 10/22/2008
• Published: 05/10/2012
• Est. Priority Date: 10/22/2007
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Kraft, Edward R., Enkhbaatar, Perenlei, Traber, Daniel L., Hoskins, Stephen L.
• Granted Patent: US 8,597,616 B2
• Time in Patent Office: Days
• US Class Current: 128/203.15
• 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 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 11/08 Bronchodilators

Abstract

The present disclosure relates to systems, methods, and formulations for the pulmonary administration of one or more therapeutic agents, in dry powder form, in a single, large dose quantity. These formulations, methods, and systems are useful in the treatment of patients suffering from toxic or harmful gas exposure, such as nerve gas exposure, as well as in the treatment of patients suffering from diseases of the pulmonary system, including tuberculosis, cystic fibrosis, and chronic obstructive pulmonary disease (COPD).

Claims

1. A method for the treatment of a pulmonary disorder, endotrachel event, bronchospasm, or for providing a rescue medication, wherein the method comprises administering to a patient in need of such treatment or medication, a medicament comprising epinephrine or an analogue thereof.

2. The method according to claim 1, wherein the medicament is a dry powder composition for pulmonary delivery, comprising microparticles of epinephrine.

3. The method according to claim 2, wherein the microparticles have a mean mass aerodynamic diameter of less than 10 μ

m.

4. The method according to claim 3, wherein the microparticles have a mean mass aerodynamic diameter of less than 5 μ

m.

5. The method, according to claim 1, wherein the patient is also treated with a therapeutic agent selected from steroids, mucolytics, MMP inhibitors, leukotrienes, antibiotics, antineoplastics, peptides, vaccines, antitussives, nicotine, sodium cromoglycate, PDR4 inhibitors, and elastase inhibitors.

6. The method, according to claim 1, wherein the medicament is in the form of a unit dosage comprising more than 20 mg epinephrine.

7. The method according to claim 6, wherein the unit dosage comprises more than 50 mg epinephrine.

8. The method according to claim 1, wherein the medicament is for use as a rescue medication following patient exposure to a nerve agent or a toxic chemical.

9. A method for the pulmonary delivery of a therapeutic agent in dry powder form to a patient, the method comprising:

micronizing one or more therapeutic agents in dry powder form;

preparing a therapeutic formulation comprising one or more therapeutic agents and a liquefied propellant, such that the therapeutic formulation is an admixture of the dry powder and liquefied propellant; and

delivering an aerosolized amount of the therapeutic formulation through a patients mouth and into the endotracheal region or lung region of the patient.

10. The method of claim 9, wherein the aerosolized amount of dry powder therapeutic agent delivered contains from about 20 mg to about 1,000 mg of the one or more therapeutic agents as a dry powder.

11. The method of claim 9, wherein the one or more therapeutic agents are selected from the group consisting of nerve-agent therapeutic agents, steroids, anticholinesterases, antioxidants, β

₂ agonists, anti-inflammatories, NSAIDs, bacterial protein synthesis inhibitors, interferons, oxazolidinones, epinephrine, combinations thereof, as well as pharmaceutically-acceptable salts, prodrugs, polymorphs, solvates, and derivatives thereof.

12. The method of claim 11, wherein the therapeutic agent is a pharmacologically effective amount of at least one adrenergic agonist selected from the group consisting of epinephrine, norepinephrine, α

-methylnorephedrine, isoproterenol, isoprenaline, albuterol, aminophylline, beclomethasone, dyphylline, flunisolide, isoetharine, metaproterenol, oxtriphylline, terbutaline, theophylline, pseudoephedrine, phenylephrine, and ephedrine.

13. A dry powder aerosol pharmaceutical formulation comprising:

at least one adrenergic agonist as active ingredient in a dosage amount of at least 20 mg;

wherein the at least one adrenergic agonist active ingredient is milled to an average particle size of less than about 10 μ

m.

14. The dry powder aerosol pharmaceutical formulation of claim 13, wherein the adrenergic agonist is milled to an average particle size of less than about 5 μ

m.

15. The pharmaceutical formulation of claim 13, further comprising one or more additional therapeutic agents selected from the group consisting of nerve-agent therapeutic agents, steroids, anticholinesterases, antioxidants, β

₂ agonists, anti-inflammatories, NSAIDs, bacterial protein synthesis inhibitors, interferons, oxazolidinones, epinephrine, combinations thereof, as well as pharmaceutically-acceptable salts, prodrugs, polymorphs, solvates, and derivatives thereof.

16. A metered dose dry powder aerosol inhaler comprising the dry powder formulation of claim 13 and a haloalkane propellant.

17. The metered dose dry powder aerosol inhaler of claim 16, wherein the haloalkane propellant is 1,1,2,2-tetrafluoroethane (R-134a).

18. A unit dosage form for pulmonary delivery of an interferon, comprising a unit dosage receptacle containing the dry powder composition of claim 13.

21. A method for aerosolizing a spray-dried, bioactive epinephrine-based dry powder composition, the method comprising:

dispersing an amount of the powder composition of claim 13 in a gas stream comprising a haloalkane propellant to form an aerosol; and

capturing the aerosol in a chamber of a delivery device for subsequent inhalation by a patient.

22. The pharmaceutical formulation of claim 13, wherein the adrenergic agonist is selected from the group consisting of epinephrine, epinephrine derivatives, epinephrine analogs, and pharmaceutically acceptable salts, solvates, hydrates, prodrugs, and polymorphs thereof.

19. A bioactive, spray-dried powder composition for pulmonary delivery into the endotracheal and lung regions of a patient, the composition comprising:

(i) a therapeutically effective amount of an adrenergic agonist;

(ii) a pharmaceutically acceptable carrier; and

(iii) a haloalkane propellant,

wherein the composition is substantially free from penetration enhancers.

20. A method for preparing the bioactive, spray-dried, adrenergic agonist-based dry powder composition claim 19, the method comprising spray-drying a gaseous solution of the adrenergic agonist and the carrier, under conditions to provide a respirable dry powder, which, when administered pulmonarily to a patient in need thereof in association with a propellent, is rapidly and systemically absorbed into the endotracheal and lung regions of the patient.