Aerosol pirfenidone and pyridone analog compounds and uses thereof
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Publication Number
US-10610536-B2
Publication Date
2020-04-07
Expiration Date
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.
Core Innovation
The disclosure presents methods for decreasing IL-1β levels in the lungs of a mammal diagnosed with pulmonary fibrosis by administering by inhalation an aqueous solution of pirfenidone. The aqueous solution includes sodium citrate, citric acid, sodium chloride, and sodium saccharin, with the molar ratio of sodium saccharin to pirfenidone specified. The pirfenidone concentration, osmolality, and pH are constrained to specified intervals, and administration decreases IL-1β levels in bronchial lavage fluid (BAL) by at least 20%.
The invention also provides a method for treatment of lung disease in a mammal by administering inhaled doses of an aqueous solution of pirfenidone on a continuous dosing schedule. The aqueous solution composition and physical properties are defined by a pirfenidone concentration range, sodium citrate, citric acid, sodium chloride, and sodium saccharin with a defined molar ratio to pirfenidone. The osmolality and pH are limited, and the administration is inhaled dosing for a mammal in need thereof.
In the described examples and delivery concepts, pirfenidone is administered to target lung compartments and secondary sites using inhalation delivery formats. The disclosed delivery systems include inhaled aerosol/nebulization, dry powder, metered-dose inhaler, and topical aerosol/drops, with the stated objective of achieving target drug levels in blood, epithelial lining fluid, bronchoalveolar lavage fluid, lung tissue, and secondary sites.
Claims Coverage
The independent claims are clm-00001 and clm-00003. Across these claims, the coverage centers on inhaled aqueous pirfenidone with defined composition and physicochemical properties, with clm-00001 additionally requiring a minimum IL-1β decrease in BAL and clm-00003 adding a continuous dosing schedule.
Inhaled aqueous pirfenidone solution with defined formulation constraints
Administering by inhalation an aqueous solution of pirfenidone comprising 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 molar ratio of sodium saccharin to pirfenidone is between 1 to 53.9 and 1 to 215.9, wherein the osmolality is from about 200 mOsmol/kg to about 500 mOsmol/kg, and wherein the pH is about 5 to about 6.
Decreasing IL-1β levels in bronchial lavage fluid for pulmonary fibrosis
Administering by inhalation the aqueous solution of pirfenidone to a mammal diagnosed with pulmonary fibrosis, wherein the administration decreases IL-1β levels in the bronchial lavage fluid (BAL) by at least 20%.
Continuous dosing schedule for treatment of lung disease with inhaled aqueous pirfenidone
Administering by inhalation a dose of the aqueous solution of pirfenidone to a mammal in need thereof on a continuous dosing schedule, wherein the pirfenidone has a concentration from about 0.1 mg/mL to about 20 mg/mL; sodium citrate; citric acid; sodium chloride; and sodium saccharin, wherein the molar ratio of sodium saccharin to pirfenidone is between 1 to 53.9 and 1 to 215.9; wherein the osmolality is from about 200 mOsmol/kg to about 500 mOsmol/kg; and wherein the pH is about 5 to about 6.
The independent claim set is directed to inhaled aqueous pirfenidone formulations with tightly defined composition and physicochemical constraints, used to achieve at least a 20% decrease in IL-1β in bronchial lavage fluid in pulmonary fibrosis or to treat lung disease using a continuous dosing schedule.
Stated Advantages
Decreases IL-1β levels in bronchial lavage fluid (BAL) by at least 20%.
Improved pharmacokinetics versus oral dosing, including lung tissue Cmax/AUC comparisons to oral dosing.
Mitigates adverse events associated with oral therapy, including gastrointestinal adverse events, phototoxicity, and liver function biomarkers.
Documented Applications
Decreasing IL-1β levels in the lungs of a mammal diagnosed with pulmonary fibrosis by administering inhaled aqueous pirfenidone.
Treatment of lung disease in a mammal on a continuous dosing schedule using inhaled aqueous pirfenidone, including pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis and pulmonary fibrosis associated with systemic sclerosis, radiation exposure, or transplant).
Delivery of pirfenidone to lungs using a liquid nebulizer with specified aerosol performance constraints (lung deposition, droplet size distribution, fine particle fraction, output rate, and/or fraction delivered).
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