AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND USES THEREOF

• US 20150196543A1
• Filed: 01/09/2015
• Published: 07/16/2015
• Est. Priority Date: 01/10/2014
• Status: Active Grant

• Current Assignee: Avalyn Pharma Incorporated
• Original Assignee: Genoa Pharmaceuticals, Inc.
• Inventors: Surber, Mark William
• Granted Patent: US 9,770,443 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61M 11/001 Particle size control
• CPC Class Codes: A61M 11/005 using ultrasonics spraying or atomising liquids using ultrasonic vibrations in general B05B17/06
• CPC Class Codes: A61M 11/02 operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised sprayers for horticulture A01G, A01H; killing insects A01M; air humidifying by nozzles F24F6/14, F24F6/18; cooling by spraying F28B, F28C
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

Disclosed herein are formulations of pirfenidone or pyridone analog compounds for aerosolization and use of such formulations for aerosol administration of pirfenidone or pyridone analog compounds for the prevention or treatment of various fibrotic and inflammatory diseases, including disease associated with the lung, heart, kidney, liver, eye and central nervous system. In some embodiments, pirfenidone or pyridone analog compound formulations and delivery options described herein allow for efficacious local delivery of pirfenidone or pyridone analog compound. Compositions include all formulations, kits, and device combinations described herein. Methods include inhalation procedures, indications and manufacturing processes for production and use of the compositions described.

Claims

1. An aqueous solution for nebulized inhalation administration comprising:

water;

pirfenidone at a concentration from about 0.1 mg/mL to about 20 mg/mL;

sodium citrate;

citric acid;

sodium chloride; and

sodium saccharin;

wherein the pH is about 4.0 to about 7.0.

2. The aqueous solution of claim 1, comprising:

water;

pirfenidone at a concentration from about 1 mg/mL to about 20 mg/mL;

sodium citrate;

citric acid;

about 100-200 mM of sodium chloride; and

sodium saccharin.

3. The aqueous solution of claim 2, wherein the sodium citrate concentration and the citric acid concentration is in a range of 1-10 mM and the aqueous solution has a pH of about 5-6, wherein the pH is optionally achieved by addition of acid or base.

4. The aqueous solution of claim 2, comprising:

about 3.5 mM sodium citrate and about 1.5 mM citric acid.

5. The aqueous solution of claim 1, wherein:

the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 1000 mOsmol/kg.

6. The aqueous solution of claim 1, comprising:

about 150 mM of sodium chloride.

7. The aqueous solution of claim 1, comprising:

about 0.1 mM to about 1 mM of sodium saccharin.

8. The aqueous solution of claim 1, wherein:

the pH is about 5.5; and

the osmolality of the aqueous solution is from about 200 mOsmol/kg to about 500 mOsmol/kg.

9. A unit dosage adapted for use in a liquid nebulizer comprising from about 0.5 mL to about 6 mL of the aqueous solution of claim 1.

10. The unit dosage of claim 9, wherein the liquid nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, a nebulizer comprising a vibration generator and an aqueous chamber, or a nebulizer that uses controlled device features to assist inspiratory flow of the aerosolized aqueous solution to the lungs of the mammal.

11. The unit dosage of claim 10, wherein the liquid nebulizer:

(i) after administration of the inhaled dose, achieves lung deposition of at least 7% of the pirfenidone administered to the mammal;

(ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μ

m to about 2.5 μ

m;

(iii) provides droplets of the aqueous solution emitted with the high efficiency liquid with;

a) a mass median aerodynamic diameter (MMAD) of about 1 μ

m to about 5 μ

m;

b) a volumetric mean diameter (VMD) of about 1 μ

m to about 5 μ

m; and

/or

c) a mass median diameter (MMD) of about 1 μ

m to about 5 μ

m;

(iv) provides a fine particle fraction (FPF=%<

5 μ

m) of droplets emitted from the liquid nebulizer of at least about 30%;

(v) provides an output rate of at least 0.1 mL/min; and

/or

(vi) provides at least about 25% of the aqueous solution to the mammal.

12. A method of decreasing IL-1β

levels in the lungs of a mammal diagnosed with pulmonary fibrosis comprising administering by inhalation the aqueous solution of claim 1 to the mammal diagnosed with pulmonary fibrosis, wherein the administration of the aqueous solution to the mammal decreases IL-1β

levels in the bronchial lavage fluid (BAL) of the mammal by at least 20%.

13. The method of claim 12, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) or pulmonary fibrosis associated with systemic sclerosis, radiation exposure or transplant.

14. A method for the treatment of lung disease in a mammal comprising:

administering by inhalation a dose of the aqueous solution of claim 1 to the mammal in need thereof on a continuous dosing schedule.

15. The method of claim 14, wherein the lung disease is idiopathic pulmonary fibrosis, or pulmonary fibrosis associated with systemic sclerosis, radiation exposure or transplant, lung cancer or pulmonary hypertension.

16. The method of claim 15, wherein the lung disease is lung cancer and the treatment comprises inhibiting, reducing or slowing the growth of lung tumor stroma.

17. The method of claim 14, wherein the aqueous solution is administered by inhalation to the mammal in need thereof with a liquid nebulizer.

18. The method of claim 17, wherein the liquid nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, a nebulizer comprising a vibration generator and an aqueous chamber, or a nebulizer that uses controlled device features to assist inspiratory flow of the aerosolized aqueous solution to the lungs of the mammal.

19. The method of claim 18, wherein the liquid nebulizer:

(i) after administration of the inhaled dose, achieves lung deposition of at least 7% of the pirfenidone administered to the mammal;

(ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μ

m to about 2.5 μ

m;

(iii) provides droplets of the aqueous solution emitted with the high efficiency liquid with;

a) a mass median aerodynamic diameter (MMAD) of about 1 μ

m to about 5 μ

m;

b) a volumetric mean diameter (VMD) of about 1 μ

m to about 5 μ

m; and

/or

c) a mass median diameter (MMD) of about 1 μ

m to about 5 μ

m;

(iv) provides a fine particle fraction (FPF=%≦

5 μ

m) of droplets emitted from the liquid nebulizer of at least about 30%;

(v) provides an output rate of at least 0.1 mL/min; and

/or

(vi) provides at least about 25% of the aqueous solution to the mammal.

20. The method of claim 14, wherein the dose of the aqueous solution of pirfenidone is administered at least once a week.

21. The method of claim 14, wherein the dose of the aqueous solution of pirfenidone is administered on a continuous daily dosing schedule.

22. The method of claim 14, wherein the dose of the aqueous solution of pirfenidone is administered once a day, twice a day, three times a day, four times a day, five times a day, or six times a day.

23. The method of claim 14, wherein each dose of the aqueous solution of pirfenidone is administered within 20 minutes.

24. The method of claim 14, wherein the method further comprises administration of one or more additional therapeutic agents to the mammal.