Inhaled imatinib for treatment of pulmonary arterial hypertension (PAH)
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Publication Number
US-11980689-B2
Publication Date
2024-05-14
Expiration Date
Abstract
Disclosed herein are formulations of imatinib or a phenylaminopyrimidine derivative compound for aerosolization and use of such formulations for inhaled aerosol administration of imatinib or a phenylaminopyrimidine derivative compound for the prevention or treatment of various fibrotic, carcinogenic, vascular and viral infectious diseases, including diseases associated with the lung, heart, kidney, liver, eye, central nervous system and surgical sites. In some embodiments, formulations and delivery options described herein allow for efficacious local delivery of imatinib or a phenylaminopyrimidine derivative compound or salt thereof. 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. Also included are methods for identifying compounds and indications that may benefit by reformulation and inhalation administration.
Core Innovation
The invention relates to treating pulmonary arterial hypertension in a human patient by inhaled delivery of an aerosolized imatinib compound. The aerosolized imatinib compound is not encapsulated and is contained in a device for aerosol delivery of particles having a mean volumetric diameter between about 2 and about 4 microns. The method administers a daily unit dose of an aerosol of the imatinib compound, including embodiments from 4 mg to 100 mg, to achieve a therapeutically effective amount that alleviates pulmonary arterial hypertension.
The method specifies obtaining a blood Cmax following aerosol delivery of the daily unit dose of less than 10 mcg/ml. Related embodiments target therapeutically effective lung and/or vascular exposure, including peak lung endothelial lining fluid concentration ranges, while limiting systemic plasma exposure. Specific imatinib salt forms suitable for aerosolized delivery are also described.
Additional embodiments include formulation and delivery parameters for the aerosolized imatinib compound. The imatinib compound can be formulated as a buffered aqueous solution within defined concentration and osmolality ranges, with an aqueous solution permeant ion concentration in a defined range. Optional taste masking agents and aerosol delivery using a nebulizer or other aerosol delivery device are also disclosed.
Claims Coverage
The claim coverage centers on inhaled treatment of pulmonary arterial hypertension with non-encapsulated aerosolized imatinib delivered in particles having a mean volumetric diameter of about 2 to about 4 microns and a daily inhaled dose of 4 mg to 100 mg, while achieving blood Cmax below 10 mcg/ml. Additional inventive features specify lung endothelial lining fluid concentration targets, selected imatinib salt forms, and buffered aqueous solution parameters such as concentration, osmolality, permeant ion concentration, taste masking with sodium saccharin, and use of a high efficiency nebulizer.
Inhaled aerosolized imatinib for pulmonary arterial hypertension with controlled particle size and dose
Administering to a human patient a daily unit dose of an aerosol of a non-encapsulated aerosolized imatinib compound contained in a device for aerosol delivery of particles having a mean volumetric diameter between about 2 and about 4 microns, wherein the daily inhaled dose of imatinib is from 4 mg to 100 mg, for treating pulmonary arterial hypertension.
Limiting blood Cmax after aerosol delivery for therapeutic effect
Obtaining a blood Cmax following aerosol delivery of the daily unit dose of less than 10 mcg/ml to achieve a therapeutically effective amount to alleviate pulmonary arterial hypertension.
Peak lung endothelial lining fluid concentration range
The daily dose achieves a peak lung endothelial lining fluid concentration of imatinib between 0.1 mcg/mL and about 50 mcg/mL.
Imatinib salt forms for aerosolized imatinib
The aerosolized imatinib is an imatinib salt selected from citrate, hydrobromide, hydrochloride, lactate, propionate, saccharin, and tartrate, or combinations thereof.
Buffered aqueous solution formulation with defined concentration and osmolality
The imatinib compound is formulated as a buffered aqueous solution at a concentration from about 0.001 mg/mL to about 200 mg/mL, wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg.
High efficiency nebulizer as aerosol delivery device
The administering step is comprised of the human patient using a high efficiency nebulizer as the aerosol delivery device.
Permeant ion concentration 30 to 300 mM
The aqueous solution has a permeant ion concentration of between 30-300 mM.
Taste masking agent sodium saccharin at defined concentration
The method uses a taste-masking agent comprising sodium saccharin at a concentration from 0.01 mM to 10 mM.
Overall, the claim coverage centers on inhaled delivery of a non-encapsulated aerosolized imatinib compound for pulmonary arterial hypertension using particles with a mean volumetric diameter about 2 to 4 microns and a daily inhaled dose of 4 to 100 mg, together with a blood Cmax below 10 mcg/ml to achieve therapeutic effect. Refinements further constrain lung concentration targets, imatinib salt forms, and specific formulation and device parameters.
Stated Advantages
Alleviates pulmonary arterial hypertension while achieving a therapeutically effective amount.
Achieves blood Cmax following aerosol delivery of the daily unit dose of less than 10 mcg/ml.
Provides defined peak lung endothelial lining fluid concentration ranges of imatinib.
Uses buffered aqueous formulations with defined concentration and osmolality ranges.
Supports selection of imatinib salt forms for inhalation.
Includes optional taste masking with sodium saccharin at a defined concentration.
Produces much higher lung Cmax and much lower plasma exposure for the intratracheal aerosol compared with oral dosing, supporting improved pulmonary efficacy.
Expands therapeutic index.
No acute toxicity observed in the reported rat study comparison.
Documented Applications
Treatment of pulmonary arterial hypertension in a human patient using inhaled delivery of aerosolized imatinib.
Treatment of pulmonary arterial hypertension in a human patient using inhaled delivery of aerosolized imatinib that is not encapsulated.
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