Aerosol pirfenidone and pyridone analog compounds and uses thereof
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Publication Number
US-11452718-B2
Publication Date
2022-09-27
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 relates to administering pirfenidone to a human by inhalation as an aqueous solution for the treatment of fibrotic lung disease. The aqueous solution has a concentration from about 5.0 mg/mL to about 19 mg/mL and an osmolality from about 50 mOsmol/kg to about 2000 mOsmol/kg, and the administration is structured to deliver a daily respirable delivered dose of at least 0.8 mg of pirfenidone.
The dosing regimen further requires that the administering step delivers less than 360 mg pirfenidone per day. The disclosed approach emphasizes inhalation delivery in a human with controlled solution concentration, osmolality, and pH as key parameters for achieving the respirable delivered dose.
Dependent aspects include administering the at least one dose per day at specific dosing frequencies and within a defined inhalation timing window. The aqueous solution can have a pH from about 4.0 to about 8.0, and the disclosure also describes high efficiency liquid nebulizer delivery of pirfenidone or a pyridone analog compound with quantitative measures for lung deposition and aerosol or droplet performance characteristics.
Claims Coverage
The claim set is directed to inhalation treatment of fibrotic lung disease in a human using an aqueous pirfenidone solution with specified concentration and osmolality to achieve a minimum daily respirable delivered dose while limiting total daily pirfenidone delivered. Dependent claims further refine dosing frequency and timing, solution pH, nebulizer performance parameters, and optional co-therapy.
Inhaled aqueous pirfenidone for fibrotic lung disease with constrained concentration, osmolality, and respirable dose
Administering by inhalation at least one dose per day of an aqueous solution of pirfenidone at a concentration from about 5.0 mg/mL to about 19 mg/mL and having an osmolality of from about 50 mOsmol/kg to about 2000 mOsmol/kg to deliver a daily respirable delivered dose of at least 0.8 mg of pirfenidone, wherein the administering step delivers less than 360 mg pirfenidone per day.
Dosing frequency and daily administration schedule
The method is carried out by administering the at least one dose per day of an aqueous solution of pirfenidone by inhalation once, twice, or three times per day.
Inhalation timing window
The method is carried out by administering the at least one dose through inhalation within 20 minutes.
Aqueous solution pH range
The method includes using an aqueous solution with a pH in the range from about pH 4.0 to about pH 8.0.
High efficiency liquid nebulizer delivery with aerosol performance targets
A high efficiency liquid nebulizer administers a pirfenidone or pyridone analog compound to a human via aqueous solution while achieving specified lung deposition, droplet size distribution parameters including GSD, MMAD, VMD, and MMD, fine particle fraction (FPF), output rate, and a specified fraction of solution delivered.
Optional co-administration of additional therapeutic agents
The method includes administering one or more additional therapeutic agents to a mammal selected from a specified set of interferons, other small molecules, and antibodies targeting various ligands or receptors.
Overall, the claim set is directed to inhalation-based treatment of fibrotic lung disease using an aqueous pirfenidone solution with specified concentration and osmolality to reach a daily respirable delivered dose while limiting total daily delivered pirfenidone. Dependent claims further constrain dosing frequency and inhalation timing, define a solution pH range, characterize high efficiency liquid nebulizer aerosol performance targets, and permit co-administration of enumerated therapeutic agents.
Stated Advantages
Delivers a daily respirable delivered dose of at least 0.8 mg of pirfenidone while limiting administration to less than 360 mg pirfenidone per day.
Supports aerosol performance and process-temperature stability of aqueous pirfenidone formulations for inhaled delivery.
The patent describes inhalation advantages for local deposition and reduced systemic metabolism versus oral dosing.
Improves lung exposure and tolerability while potentially enabling systemic exposure compared with oral administration.
Delivers higher lung levels at a lower dose and reduces gastrointestinal toxicity.
Reduces the need for dose escalation and food constraints associated with oral dosing.
Provides localized drug availability in lung tissue with potential downstream tissue systemic exposure.
Documented Applications
Treatment of fibrotic lung disease in a human using inhaled aqueous pirfenidone dosing with specified concentration, osmolality, and respirable delivered dose constraints.
Treatment of idiopathic pulmonary fibrosis (as narrowed disease scope in dependent claim context).
Delivery of pirfenidone or a pyridone analog compound to a human via aqueous solution using a high efficiency liquid nebulizer with specified lung deposition and aerosol performance parameters.
Treatment of fibrotic lung disease in a human, including pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF).
Prophylactic therapy for fibrotic lung disease using inhalation and topical delivery to lungs and downstream tissues such as heart, kidney, liver, and CNS.
Use of inhalation and topical delivery approaches for pirfenidone/pyridone-analog formulations, including delivery via nebulizer, metered-dose inhaler, and other discussed formulations.
Therapeutic use with potential co-administration ("cocktail therapy") with enumerated anti-fibrotic/anti-inflammatory/cancer/pulmonary hypertension agents delivered orally or by inhalation.
In vivo evaluation in a bleomycin model of pulmonary fibrosis, including measurement of hydroxyproline and fibrosis scoring based on histology staining.
Pharmacokinetic/pharmacodynamic characterization comparing oral administration and direct lung aerosol delivery, including rat tissue and plasma concentration assessment and modeled human pharmacokinetic and tissue distribution.
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