Aerosol pirfenidone and pyridone analog compounds and uses thereof

• US 10,105,356 B2
• Filed: 07/24/2013
• Issued: 10/23/2018
• Est. Priority Date: 01/31/2011
• Status: Active Grant

• Current Assignee: Avalyn Pharma Incorporated
• Original Assignee: Avalyn Pharma Incorporated
• Inventors: Surber, Mark William
• Primary Examiner(s): McMillian, Kara R
• Application Number:
  US13/950,110
• Publication Number:
  US 20130310424A1
• Time in Patent Office: 1,917 Days
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• 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 15/009 using medicine packages with incorporated spraying means, e.g. aerosol cans pocket atomiser of the injector type A61M11/08
• CPC Class Codes: A61M 2202/064 Powder

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. A method for the treatment of idiopathic pulmonary fibrosis in an adult human in need thereof, the method comprising:

administering one or more respirable delivered doses per day of an aqueous solution comprising pirfenidone, by a liquid nebulizer, to the human in need thereof;

the aqueous solution comprising water and pirfenidone at a concentration from about 5.0 mg/mL to about 19 mg/mL, the aqueous solution having an osmolality of from about 50 mOsmol/kg to about 2000 mOsmol/kg, wherein the daily respirable delivered dose is at least 0.8 mg of pirfenidone;

wherein the total daily respirable delivered dosage of pirfenidone administered to the human by the liquid nebulizer does not exceed 1.933 mg/kg body mass/day, wherein the respirable delivered dose is therapeutically effective to treat IPF by reducing decline in forced vital capacity (FVC) in the lung of the adult human.

2. The method of claim 1, wherein the aqueous solution further comprises:

an additional ingredient-selected from the group consisting of co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, salts, taste masking agents, and buffers and combinations thereof.

3. The method of claim 1, wherein the aqueous solution of each respirable delivered dose further comprises:

a buffer selected from a citrate buffer and a phosphate buffer, and one or more salts selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride and calcium bromide and combinations thereof.

4. The method of claim 1, wherein the aqueous solution of each respirable delivered dose comprises:

water;

one or more salts, wherein the total amount of the one or more salts is from about 0.01% to about 2.0% by weight of the weight of aqueous solution;

and

optionally a phosphate buffer or a citrate buffer that maintains the pH of the solution below about pH 8;

and

the osmolality of the of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg.

5. The method of claim 1, wherein the liquid nebulizer:

(i) after administration of each respirable delivered dose, achieves lung deposition of at least 5% of the pirfenidone administered to the human;

(ii) provides;

a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 0.5 μ

m to about 5 μ

m; and

/or

b) a volumetric mean diameter (VIVID) of about 0.5 μ

m to about 5 μ

m;

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

m to about 3.4 μ

m;

(iv) provides a fine particle fraction (FPF=% of aerosol particles≤

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 human.

6. The method of claim 5, wherein:

the blood AUC_0-24 of pirfenidone achieved upon administration of each respirable delivered dose to the lungs of the adult human is less than or equivalent to the blood AUC_0-24 achieved upon administration of an 801 mg orally administered dosage of pirfenidone to the adult human.

7. The method of claim 1, wherein the pirfenidone is administered on a continuous daily dosing schedule.

8. The method of claim 1, wherein the pirfenidone is administered once a day, twice a day, three times a day, or four times a day.

9. The method of claim 1, wherein the method further comprises administration of one or more additional therapeutic agents to the adult human.

10. The method of claim 5, wherein:

a) the lung tissue C_max of pirfenidone obtained in the human upon administration of each respirable delivered dose is at least equivalent to or greater than a lung C_max achievable upon administration of 801 mg of an orally administered dosage of pirfenidone to the human;

and/or

b) the blood AUC_0-24 of pirfenidone obtained in the human upon administration of each respirable delivered dose is less than a blood AUC_0-24 achievable upon administration of 801 mg of an orally administered dosage of pirfenidone to the adult human.

11. The method of claim 5, wherein:

each respirable delivered dose from the liquid nebulizer is delivered in less than about 30 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 microns.

12. The method of claim 4, wherein the administering step is comprised of inhaling the respirable delivered does within 20 minutes.

13. The method of claim 1, wherein the method further comprises administration of an additional therapeutic agents to the human, selected from the group consisting of interferon gamma, interferon beta-1a, pentraxin-2, N-acetyl-L-cysteine, GS-6624, IW001, PRM-151, STX-100, CC-930, QAX576, FG-3019, CNTO-888, ESBRIET®

(pirfenidone)™

, BIBF-1120, antibodies targeting IL-13 ligand or receptor, antibodies targeting alpha-v beta-6 integrin, antibodies targeting CTGF ligand or receptor, antibodies targeting CCL2 ligand or receptor, small molecules targeting vascular endothelial growth factor (VEGF) ligand or receptor, small molecules targeting platelet-derived growth factor (PDGF) ligand or receptor, small molecules targeting fibroblast growth factor (FGF) ligand or receptor, antibodies targeting LOXL2, small molecules targeting Jun kinase, and small molecules targeting TGF-beta and combinations thereof.

14. The method of claim 12, wherein each dose comprises has a volume of between about 0.5 mL and about 10 mL of the aqueous solution loaded into the liquid nebulizer and the aqueous solution comprises pirfenidone at a concentration of from about 5.0 mg/mL to about 19 mg/mL.