Aerosol pirfenidone and pyridone analog compounds and uses thereof
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Publication Number
US-11224592-B2
Publication Date
2022-01-18
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 invention provides a composition for clinically efficacious treatment of idiopathic pulmonary fibrosis in an adult human, using pirfenidone in an aqueous solution. The aqueous solution includes pirfenidone at a defined concentration and is formulated with a citrate or phosphate buffer, permeant ions comprising chloride ions, bromide ions, or combinations thereof, and a taste masking agent in a defined low concentration range.
The composition is packaged as a daily therapeutically effective dose for treating idiopathic pulmonary fibrosis by reducing a decline in forced vital capacity (FVC) in the lung of the adult human. The total daily dose of inhaled pirfenidone does not exceed 360 mg, and the formulation is directed to inhaled delivery to pulmonary targets.
The invention further defines inhaled delivery by aerosol formation from the aqueous, buffered solution using a nebulizer. Nebulization is characterized through aerosol and lung exposure relationships, including lung tissue pharmacokinetics such as lung Cmax and blood AUC0-24, and comparison criteria against orally administered pirfenidone using an oral benchmark dose.
Across exemplary implementations, the invention specifies how aerosol generation and lung deposition are characterized through droplet-size and aerosol performance metrics, and it also narrows formulation and device implementation to defined nebulizer types. The overall approach is aimed at improving clinically efficacious treatment by managing inhaled pirfenidone exposure while incorporating buffer, permeant ion, and taste masking components in the aqueous solution.
Claims Coverage
The claims cover a daily inhaled aqueous pirfenidone composition for idiopathic pulmonary fibrosis, with formulation, aerosol performance, and lung exposure features. The inventive features center on a specific aqueous buffered formulation with permeant ions and a taste masking agent, packaged as a daily inhaled regimen with a maximum total daily inhaled pirfenidone dose, and delivery characterized by aerosol metrics and lung exposure comparisons versus oral dosing.
A daily inhaled aqueous pirfenidone regimen capped for idiopathic pulmonary fibrosis
A composition for clinically efficacious treatment of idiopathic pulmonary fibrosis in an adult human packaged as a daily therapeutically effective dose, comprising a therapeutically effective dose of pirfenidone in an aqueous solution comprising water, where the total daily dose of inhaled pirfenidone does not exceed 360 mg and the treatment reduces a decline in forced vital capacity (FVC) in the lung.
Buffered aqueous pirfenidone formulation with permeant ions and taste masking
The composition includes pirfenidone at a concentration from about 5.0 to about 19.0 mg/mL, a permeant ion concentration of between about 30 mM and about 300 mM with permeant ions comprising chloride ions, bromide ions, or a combination thereof, a citrate or phosphate buffer, and a taste masking agent at a concentration of between 0.1 and 2.0 mM.
Nebulized aerosol performance characterized for liquid nebulization
The aqueous solution is nebulized to form an aerosol using a liquid nebulizer, where the aerosol includes pirfenidone and is characterized by defined droplet-size and aerosol performance metrics including MMAD/VMD range, geometric standard deviation, fine particle fraction (≤5 microns), and an output rate threshold.
Lung pharmacokinetics comparison versus an oral benchmark
Lung exposure from aerosol nebulization is defined by comparing lung Cmax and blood AUC0-24 of pirfenidone to exposure achievable with an orally administered dosage of pirfenidone using an oral benchmark dose.
Overall claim coverage is centered on a clinically efficacious, daily inhaled aqueous pirfenidone composition for idiopathic pulmonary fibrosis that uses a citrate/phosphate buffer, defined permeant ions, and a taste masking agent at a defined low concentration range, with an upper limit on total daily inhaled pirfenidone. Coverage further includes defining aerosol performance from a liquid nebulizer and specifying lung exposure using lung Cmax and blood AUC0-24 comparisons versus oral administration.
Stated Advantages
Reduces a decline in forced vital capacity (FVC) in the lung of the adult human.
Clinically efficacious treatment of idiopathic pulmonary fibrosis in an adult human.
Documented Applications
Treatment of idiopathic pulmonary fibrosis in an adult human by reducing a decline in forced vital capacity (FVC) in the lung using a daily inhaled pirfenidone composition.
Inhaled delivery of pirfenidone aerosol formed by nebulization from an aqueous solution, with evaluation using lung pharmacokinetics compared to oral administration.
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