Aerosol pirfenidone and pyridone analog compounds and uses thereof
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Publication Number
US-12023342-B2
Publication Date
2024-07-02
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 an aqueous solution of pirfenidone for treatment of interstitial lung disease in a subject using nebulized administration by inhalation from a nebulizer. The aqueous solution comprises water and pirfenidone at a concentration from about 3.0 mg/ml to about 16.0 mg/ml, together with a citrate buffer formulated with sodium citrate, sodium chloride, and a taste masking agent that is sodium saccharin.
The taste masking agent is sodium saccharin at a concentration between 0.1 mM and 0.9 mM, with the concentration tied to pirfenidone concentration from about 3.0 mg/ml to about 16.0 mg/ml. The solution is further defined by osmolality from about 250 mOsmol/kg to about 500 mOsmol/kg and pH from about 5.0 to about 6.0.
The disclosed formulation is defined to deliver a respirable delivered dose of between 4.2 and 15.5 mg per 2.0 ml of fill volume of the aqueous solution in the nebulizer. The description additionally characterizes suitable inhalation devices including jet, ultrasonic, vibrating mesh/plate, and high-efficiency liquid nebulizers, and discusses aerosol performance parameters including lung deposition and droplet size distribution metrics.
Claims Coverage
The document provides one independent claim defining an aqueous pirfenidone solution for nebulized inhalation treatment of interstitial lung disease, with multiple formulation constraints and delivery-performance conditions. Across the independent claim and dependent claims, there are at least three main inventive feature themes: composition with sodium citrate, sodium chloride, and sodium saccharin; solution property targeting for osmolality and pH; and respirable delivered dose and related nebulizer/aerosol constraints.
Aqueous pirfenidone solution for nebulized inhalation treatment of interstitial lung disease
An aqueous solution comprising water and pirfenidone at a concentration from about 3.0 mg/ml to about 16.0 mg/ml for treatment of interstitial lung disease in a subject using nebulized administration by inhalation from a nebulizer.
Citrate buffer, sodium chloride, and sodium saccharin formulation
The aqueous solution comprises a citrate buffer formulated with sodium citrate, sodium chloride at a concentration between 100 mM and 200 mM, and a taste masking agent that is sodium saccharin with a concentration between 0.1 mM and 0.9 mM.
Interdependent sodium saccharin concentration tied to pirfenidone concentration
The concentration of sodium saccharin is from between 0.1 mM and 0.4 mM at pirfenidone concentrations of about 3.0 mg/ml and between 0.5 mM and 0.9 mM at pirfenidone concentrations of about 16.0 mg/ml.
Solution osmolality and pH targets
The osmolality of the aqueous solution is from about 250 mOsmol/kg to about 500 mOsmol/kg, and the pH of the solution is about 5.0 to about 6.0.
Respirable delivered dose per nebulizer fill volume
The treatment delivers a respirable delivered dose of between 4.2 and 15.5 mg per 2.0 ml of fill volume of the aqueous solution in the nebulizer.
Nebulized treatment with specified output and device constraints
Dependent claims refine the delivery by specifying total pirfenidone output rate constraints, unit-dose presentation, use with a vibrating mesh nebulizer, and performance with jet, ultrasonic, vibrating mesh/plate, and high-efficiency liquid nebulizers.
Aerosol performance constraints
Dependent claims specify lung deposition of at least 7% of pirfenidone and emitted aqueous droplet characteristics using droplet size distribution metrics, fine particle fraction, output rate, and/or delivered fraction.
The claim coverage centers on an aqueous pirfenidone solution for nebulized inhalation treatment of interstitial lung disease, with defined composition, solution properties, and respirable delivered dose requirements. Dependent claims further narrow delivery configuration and aerosol performance using output rate constraints, unit-dose and vibrating mesh nebulizer use, and lung deposition and droplet metrics.
Stated Advantages
Inhalation can maintain lung levels at or above a minimally efficacious lung-tissue concentration for at least 4 hours.
May enable less frequent dosing.
May reduce systemic exposure.
May reduce oral GI/systemic toxicity.
Reduced systemic exposure compared with oral dosing, aiming to limit plasma and blood exposure.
Reduced systemic side effects associated with oral administration, including GI and photosensitivity, and liver enzyme abnormalities.
Pulmonary efficacy indicated by reduction of IL-1β in bronchial lavage fluid for pulmonary fibrosis.
Documented Applications
Treatment of interstitial lung disease in a subject using nebulized administration by inhalation of an aqueous pirfenidone solution.
Treatment of interstitial lung disease in a subject via nebulized administration by inhalation from a nebulizer.
Treatment of pulmonary fibrosis, with reduction of IL-1β in bronchial lavage fluid.
Broader therapeutic aims for pirfenidone/pyridone analogs via inhalation or nasal delivery for fibrotic/inflammatory indications, including pulmonary fibrosis/IPF/ILD and inflammasome/NLRP3/caspase-1/IL-1β/IL-18 pathway-related fibrosis, as well as other fibrosis indications including kidney, cardiac, and hepatic.
Discussion of organ toxicities, including heart and kidney toxicity (doxorubicin), and additional conditions mentioned in the broader discussion such as COPD and asthma, and multiple sclerosis.
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