CN116897045A

CN116897045A - Inhalable imatinib formulations

Info

Publication number: CN116897045A
Application number: CN202280017463.1A
Authority: CN
Inventors: 卡洛斯·舒乐; 迈克尔·莱尔德·赫里; 格雷斯·E·科隆; 布莱恩·维斯特
Original assignee: Incarda Therapeutics Inc
Current assignee: Inaya Treatment Co.
Priority date: 2021-01-06
Filing date: 2022-01-06
Publication date: 2023-10-17

Abstract

A pharmaceutical composition comprising imatinib or a derivative thereof for treating a pulmonary disease by inhalation. A method of treating a pulmonary disease comprising administering to a patient in need thereof an effective amount of imatinib or a derivative thereof by inhalation. In various aspects, the pharmaceutical compositions provided herein comprise an aqueous solution or suspension of imatinib or a derivative thereof formulated for administration by inhalation.

Description

Inhalable imatinib formulations

Cross reference

The present application claims the benefit of U.S. provisional patent application No. 63/134,336 filed on 1 month 6 of 2021 and U.S. provisional patent application No. 63/170,246 filed on 2 month 4 of 2021, each of which is incorporated herein by reference in its entirety for all purposes.

Background

Imatinib is a small molecule kinase inhibitor that inhibits Bcr-Abl tyrosine kinase, a constitutive abnormal tyrosine kinase caused by philadelphia chromosome abnormalities in Chronic Myelogenous Leukemia (CML). It can be used to treat certain types of cancer. Currently, nova corporation (Novartis) sells its mesylate, imatinib mesylate (INN), as Gleevec (united states) or glicc (european/australia). It can inhibit proliferation and induce apoptosis in Bcr-Abl positive cell lines and fresh leukemia cells from Philadelphia chromosome positive chronic granulocytic leukemia. Imatinib also inhibits receptor tyrosine kinases for Platelet Derived Growth Factor (PDGF) and Stem Cell Factor (SCF). It has also been reported that injection (subcutaneous or intraperitoneal) or oral delivery of imatinib mesylate may have therapeutic effects on pulmonary arterial hypertension in animal models and in patients taking part in clinical trials.

Disclosure of Invention

In some aspects, disclosed herein is a composition comprising an aqueous solution or suspension comprising: (1) imatinib or a derivative thereof, (2) a solubility enhancing agent, and (3) a pH buffer, wherein the aqueous solution or suspension: (a) Imatinib or a derivative thereof having a concentration of 20 to 500 mg/mL; (b) has a viscosity of up to 10 centipoise; and (c) has a pH of 3 to 8.

In some embodiments of the composition, the solubility enhancing agent is selected from: cyclodextrin, lipid, co-solvent, organic acid and surfactant. In some cases of the composition, the solubility enhancing agent comprises cyclodextrin. In some cases of the composition, the cyclodextrin concentration of the aqueous solution or suspension is from about 1% (w/v) to about 80% (w/v). In some cases of the composition, the solubility enhancing agent comprises a lipid or fatty acid. In some cases of the composition, the lipid or fatty acid is selected from: polyethoxylated castor oil, phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol (PEG), chitin, hyaluronic acid and polyvinylpyrrolidone; a lipid-containing sulfonated monosaccharide, a lipid-containing sulfonated disaccharide, and a lipid-containing sulfonated polysaccharide; fatty acids such as palmitic acid, stearic acid and oleic acid; cholesterol, cholesterol esters and cholesterol hemisuccinate. In some cases of the composition, the solubility enhancing agent comprises a co-solvent. In some cases of the composition, the co-solvent comprises glycerol or ethanol. In some cases of the composition, the solubility enhancing agent comprises an organic acid. In some cases of the composition, the organic acid is selected from: acetic acid, acid modified starch, acrylic tricarboxylic acid, fatty acid, adipic acid, L-ascorbic acid, benzoic acid, caproic acid, caprylic acid, cholic acid, citric acid, deoxycholic acid, erythronic acid (D-isoascorbic acid), formic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, iron naphthenate, iron resinate, D (-) -lactic acid, L (+) -lactic acid, linoleic acid, malic acid, L-malic acid, nicotinic acid (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, L (+) -potassium hydrogen tartrate, propionic acid, acid hydrolyzed protein, disodium pyrophosphate, sodium aluminum acid phosphate, sorbic acid, stearic acid, succinic acid, sulfamic acid, sulfuric acid, tannic acid, L (+) -tartaric acid, taurocholic acid, and thiodipropionic acid. In some cases, the solubility enhancing agent comprises a surfactant. In some cases, the surfactant comprises Tween (Tween), sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

In some aspects, disclosed herein is a composition comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and a cyclodextrin, wherein the cyclodextrin concentration of the aqueous solution or suspension is from about 1% (w/v) to about 80% (w/v).

In some cases of the composition, the cyclodextrin is selected from: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin, methyl-beta-cyclodextrin 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin, succinyl-alpha-cyclodextrin, succinyl-beta-cyclodextrin, succinyl-gamma-cyclodextrin, sulfobutyl ether-alpha-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, carboxymethyl-alpha-cyclodextrin, carboxymethyl-beta-cyclodextrin, carboxymethyl-gamma-cyclodextrin, 2-carboxyethyl-alpha-cyclodextrin, 2-carboxyethyl-beta-cyclodextrin, 2-carboxyethyl-gamma-cyclodextrin, phosphoric acid-alpha-cyclodextrin, phosphoric acid-beta-cyclodextrin, phosphoric acid-gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin and sulfoalkyl ether-gamma-cyclodextrin. In some cases of the composition, the cyclodextrin comprises succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, succinyl- γ -cyclodextrin, sulfobutyl ether- α -cyclodextrin, sulfobutyl ether- β -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, carboxymethyl- α -cyclodextrin, carboxymethyl- β -cyclodextrin, carboxymethyl- γ -cyclodextrin, 2-carboxyethyl- α -cyclodextrin, 2-carboxyethyl- β -cyclodextrin, 2-carboxyethyl- γ -cyclodextrin, phosphoric acid- α -cyclodextrin, phosphoric acid- β -cyclodextrin, or phosphoric acid- γ -cyclodextrin. In some cases of the composition, the cyclodextrin comprises an anionic cyclodextrin.

In some aspects, disclosed herein is a composition comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and a cyclodextrin, wherein the cyclodextrin comprises an anionic cyclodextrin.

In some cases of the composition, the aqueous solution or suspension further comprises a pH buffer. In some cases of the composition, the pH buffer comprises an organic acid salt of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer. In some cases of the composition, the pH buffer comprises a phosphate buffer.

In some aspects, disclosed herein is a composition comprising an aqueous solution or suspension comprising imatinib or a derivative thereof, cyclodextrin, a pH buffer, and a surfactant.

In some cases of the composition, the aqueous solution or suspension comprises a salt of cyclodextrin. In some cases of the composition, the salt of cyclodextrin is a salt selected from the group consisting of: sodium, calcium, magnesium, iron, chromium, copper, zinc, lysine, arginine and histidine salts. In some cases of the composition, the cyclodextrin comprises sulfobutyl ether- β -cyclodextrin. In some cases of the composition, the cyclodextrin comprises hydroxypropyl-beta-cyclodextrin. In some cases of the composition, the aqueous solution or suspension comprises sodium sulfobutyl ether- β -cyclodextrin.

In some cases of the composition, the aqueous solution or suspension further comprises a surfactant. In some cases of the composition, the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

In some cases of the composition, the aqueous solution or suspension has a viscosity of up to 10 centipoise. In some cases of the composition, the aqueous solution or suspension has a viscosity of at most 9.5 centipoise, at most 9.0 centipoise, at most 8.5 centipoise, at most 8.0 centipoise, at most 7.6 centipoise, at most 7.4 centipoise, at most 7.2 centipoise, at most 7.0 centipoise, at most 6.8 centipoise, at most 6.6 centipoise, at most 6.4 centipoise, at most 6.2 centipoise, at most 6.0 centipoise, at most 5.8 centipoise, at most 5.6 centipoise, at most 5.4 centipoise, at most 5.2 centipoise, at most 5.0 centipoise, at most 4.8 centipoise, at most 4.6 centipoise, at most 4.4 centipoise, at most 4.2 centipoise, at most 4.0 centipoise, at most 3.8 centipoise, at most 3.6 centipoise, at most 3.4 centipoise, at most 3.2 centipoise, at most 3.0 centipoise, at most 2.6 centipoise, at most 2.4 centipoise, at most 2.0 centipoise, at most 1.8 centipoise, at most 1.0 centipoise. In some cases of the composition, the aqueous solution or suspension has a viscosity of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.8, 3.0, 3.2, 3.5, 3.8, 4.0, 4.2, 4.5, 4.8, 5, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 or 8.5.

In some cases of the composition, the aqueous solution or suspension has 20 to 500mg/mL of imatinib or a derivative thereof. In some cases of the composition, the aqueous solution or suspension has 20mg/mL to 400mg/mL, 20mg/mL to 300mg/mL, 20mg/mL to 200mg/mL, 100mg/mL to 500mg/mL, 200mg/mL to 500mg/mL, 300mg/mL to 500mg/mL, 400mg/mL to 500mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 200mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 300mg/mL, 20mg/mL to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 40mg/mL to 120mg/mL, 40mg/mL to 150mg/mL, 150mg to 60mg/mL, or 150mg to 150mg/mL of the derivatives thereof. In some cases of the composition, the aqueous solution or suspension has about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, or about 150mg/mL of imatinib or a derivative thereof. In some cases of the composition, the aqueous solution or suspension has about 80mg/mL of imatinib or a derivative thereof.

In some cases of the composition, the pH of the aqueous solution or suspension is from 3 to 8. In some cases of the composition, the pH of the aqueous solution or suspension is 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7. In some cases of the composition, the pH of the aqueous solution or suspension is about 4.5, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.4, about 5.5, or about 5.6. In some cases of the composition, the pH of the aqueous solution or suspension is 7 to 8. In some cases of the composition, the pH of the aqueous solution or suspension is about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0.

In some cases of the composition, the cyclodextrin concentration of the aqueous solution or suspension is about 2% (w/v) to about 70% (w/v), about 2% (w/v) to about 60% (w/v), about 2% (w/v) to about 50% (w/v), about 2% (w/v) to about 40% (w/v), about 2% (w/v) to about 30% (w/v), about 2% (w/v) to about 20% (w/v), about 2% (w/v) to about 15% (w/v), about 2% (w/v) to about 10% (w/v), about 2% (w/v) to about 8% (w/v), about 2% (w/v) to about 5% (w/v), about 5% (w/v) to about 80% (w/v), about 5% (w/v) to about 70% (w/v), about 5% (w/v) to about 60% (w/v), about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 40% (w/v) About 5% (w/v) to about 20% (w/v), about 5% (w/v) to about 15% (w/v), about 5% (w/v) to about 12% (w/v), about 5% (w/v) to about 10% (w/v), about 10% (w/v) to about 60% (w/v), about 10% (w/v) to about 50% (w/v), about 10% (w/v) to about 40% (w/v), about 10% (w/v) to about 30% (w/v), about 20% (w/v) to about 30% (w/v), about 10% (w/v) to about 25% (w/v), about 19% (w/v) to about 25% (w/v), about 19.5% (w/v) to about 25% (w/v), about 20% (w/v) to about 25% (w/v), about 20.5% (w/v) to about 25% (w/v), about 21% (w/v) to about 25% (w/v), about 25% (w/v) to about 25% (w/v) About 22.5% (w/v) to about 25% (w/v), about 23% (w/v) to about 25% (w/v), about 10% (w/v) to about 20% (w/v), or about 10% (w/v) to about 15% (w/v). In some cases of the composition, the cyclodextrin concentration of the aqueous solution or suspension is from 5% (w/v) to 40% (w/v). In some cases of the composition, the cyclodextrin concentration of the aqueous solution or suspension is from 10% (w/v) to 20% (w/v). In some cases of the composition, the cyclodextrin concentration of the aqueous solution or suspension is 25% (w/v) to 40% (w/v). In some cases of the composition, the cyclodextrin concentration of the aqueous solution or suspension is about 10% (w/v), about 12% (w/v), about 14% (w/v), about 15% (w/v), about 16% (w/v), about 18% (w/v), or about 20% (w/v). In some cases of the composition, the cyclodextrin concentration of the aqueous solution or suspension is about 22% (w/v), about 24% (w/v), about 26% (w/v), about 28% (w/v), about 30% (w/v), about 32% (w/v), about 34% (w/v), about 36% (w/v), about 38% (w/v), or about 40% (w/v).

In some cases of the composition, the composition comprises an aqueous solution. In some cases of the composition, the solubility of imatinib or a derivative thereof in an aqueous solution is inversely related to the pH of the aqueous solution. In some cases of the composition, the solubility of imatinib or a derivative thereof in an aqueous solution is positively correlated with the concentration of cyclodextrin in the aqueous solution.

In some cases, the composition comprises an aqueous suspension.

In some cases of the composition, the composition comprises less than 1mg/mL, less than 0.5mg/mL, less than 0.1mg/mL, less than 0.05mg/mL, less than 0.01mg/mL, less than 0.005mg/mL, less than 0.001mg/mL, or less than 0.0001mg/mL of imatinib mesylate. In some cases of the composition, the composition does not comprise imatinib mesylate. In some cases of the composition, the imatinib or derivative thereof comprises imatinib free base. In some cases of the composition, the imatinib or derivative thereof is imatinib free base. In some cases of the composition, the composition comprises a salt of imatinib or a derivative thereof selected from the group consisting of: acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate and succinate.

In some aspects, disclosed herein are pharmaceutical compositions comprising the compositions disclosed herein. In some cases, the pharmaceutical composition is formulated for administration by inhalation. In some cases of the pharmaceutical composition, the aqueous solution further comprises a pharmaceutically acceptable excipient. In some cases, the pharmaceutically acceptable excipient comprises a surfactant. In some cases of the pharmaceutical composition, the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). In some cases, the pharmaceutically acceptable excipient comprises a lipid. In some cases of the pharmaceutical composition, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid. In some cases of the pharmaceutical composition, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid. In some cases of the pharmaceutical composition, the pharmaceutical composition is organoleptically tolerable when inhaled by a human subject. In some cases of the pharmaceutical composition, the pharmaceutical composition does not cause a cough reflex when inhaled by a human subject. In some cases of the pharmaceutical composition, the pharmaceutical composition is not or minimally irritating to the oral cavity or throat when inhaled by a human subject.

In some aspects, disclosed herein is a pharmaceutical composition comprising an aqueous solution comprising cyclodextrin and a therapeutically effective amount of imatinib or a derivative thereof, wherein the aqueous solution is formulated for administration by inhalation.

In some cases of pharmaceutical compositions, the aqueous solution has a viscosity of up to 10 centipoise. In some cases of the pharmaceutical composition, the aqueous solution has a viscosity of up to 2.5 centipoise.

In some cases of the pharmaceutical composition, the aqueous solution has 20 to 500mg/mL of imatinib or a derivative thereof. In some cases of the pharmaceutical composition, the aqueous solution has 20mg/mL to 400mg/mL, 20mg/mL to 300mg/mL, 20mg/mL to 200mg/mL, 100mg/mL to 500mg/mL, 200mg/mL to 500mg/mL, 300mg/mL to 500mg/mL, 400mg/mL to 500mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 200mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 300mg/mL, 20mg/mL to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 60mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 40mg/mL to 120mg/mL, 40mg to 150mg/mL, 60mg to 60mg/mL, 150mg to 60mg/mL, or 150mg to 150mg/mL of the derivative thereof. In some cases of the pharmaceutical composition, the aqueous solution has about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, or about 150mg/mL of imatinib or a derivative thereof. In some cases of the pharmaceutical composition, the aqueous solution has about 80mg/mL of imatinib or a derivative thereof.

In some cases of the pharmaceutical composition, the pH of the aqueous solution is 3 to 8. In some cases of the pharmaceutical composition, the pH of the aqueous solution is 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7. In some cases of the pharmaceutical composition, the pH of the aqueous solution is about 4.5, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.4, about 5.5, or about 5.6. In some cases of pharmaceutical compositions, the pH of the aqueous solution or suspension is 7 to 8. In some cases of the pharmaceutical composition, the pH of the aqueous solution is about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0. In some cases of the pharmaceutical composition, the aqueous solution further comprises a pH buffer. In some cases of the pharmaceutical composition, the pH buffer comprises an organic acid salt of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer.

In some cases of the pharmaceutical composition, the cyclodextrin is selected from: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin, methyl-beta-cyclodextrin 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin, succinyl-alpha-cyclodextrin, succinyl-beta-cyclodextrin, succinyl-gamma-cyclodextrin, sulfobutyl ether-alpha-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, carboxymethyl-alpha-cyclodextrin, carboxymethyl-beta-cyclodextrin, carboxymethyl-gamma-cyclodextrin, 2-carboxyethyl-alpha-cyclodextrin, 2-carboxyethyl-beta-cyclodextrin, 2-carboxyethyl-gamma-cyclodextrin, phosphoric acid-alpha-cyclodextrin, phosphoric acid-beta-cyclodextrin, phosphoric acid-gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin and sulfoalkyl ether-gamma-cyclodextrin. In some cases of the pharmaceutical composition, the cyclodextrin comprises succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, succinyl- γ -cyclodextrin, sulfobutyl ether- α -cyclodextrin, sulfobutyl ether- β -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, carboxymethyl- α -cyclodextrin, carboxymethyl- β -cyclodextrin, carboxymethyl- γ -cyclodextrin, 2-carboxyethyl- α -cyclodextrin, 2-carboxyethyl- β -cyclodextrin, 2-carboxyethyl- γ -cyclodextrin, phosphoric acid- α -cyclodextrin, phosphoric acid- β -cyclodextrin, or phosphoric acid- γ -cyclodextrin. In some cases of the pharmaceutical composition, the cyclodextrin comprises an anionic cyclodextrin. In some cases of the pharmaceutical composition, the cyclodextrin comprises sulfobutyl ether- β -cyclodextrin. In some cases of the pharmaceutical composition, the cyclodextrin comprises hydroxypropyl- β -cyclodextrin. In some cases of pharmaceutical compositions, the aqueous solution comprises a salt of cyclodextrin. In some cases of the pharmaceutical composition, the salt of cyclodextrin is a salt selected from the group consisting of: sodium, calcium, magnesium, iron, chromium, copper, zinc, lysine, arginine and histidine salts. In some cases of the pharmaceutical composition, the aqueous solution comprises sodium sulfobutyl ether- β -cyclodextrin.

In some cases of the pharmaceutical composition, the cyclodextrin concentration of the aqueous solution is about 1% (w/v) to about 80% (w/v), about 2% (w/v) to about 70% (w/v), about 2% (w/v) to about 60% (w/v), about 2% (w/v) to about 50% (w/v), about 2% (w/v) to about 40% (w/v), about 2% (w/v) to about 30% (w/v), about 2% (w/v) to about 20% (w/v), about 2% (w/v) to about 15% (w/v), about 2% (w/v) to about 10% (w/v), about 2% (w/v) to about 8% (w/v), about 2% (w/v) to about 5% (w/v), about 5% (w/v) to about 80% (w/v), about 5% (w/v) to about 70% (w/v), about 5% (w/v) to about 60% (w/v), about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 40% (w/v) About 5% (w/v) to about 30% (w/v), about 5% (w/v) to about 20% (w/v), about 5% (w/v) to about 15% (w/v), about 5% (w/v) to about 12% (w/v), about 5% (w/v) to about 10% (w/v), about 10% (w/v) to about 60% (w/v), about 10% (w/v) to about 50% (w/v), about 10% (w/v) to about 40% (w/v), about 10% (w/v) to about 30% (w/v), about 20% (w/v) to about 30% (w/v), about 10% (w/v) to about 25% (w/v), about 19% (w/v) to about 25% (w/v), about 19.5% (w/v) to about 25% (w/v), about 20.5% (w/v) to about 25% (w/v), about 21% (w/v) to about 25% (w/v), about 22% (w/v) to about 25% (w/v), about 22.5% (w/v) to about 25% (w/v), about 23% (w/v) to about 25% (w/v), about 10% (w/v) to about 20% (w/v), or about 10% (w/v) to about 15% (w/v). In some cases of pharmaceutical compositions, the cyclodextrin concentration of the aqueous solution is from 5% (w/v) to 40% (w/v). In some cases of pharmaceutical compositions, the cyclodextrin concentration of the aqueous solution is from 10% (w/v) to 20% (w/v). In some cases of pharmaceutical compositions, the cyclodextrin concentration of the aqueous solution is 25% (w/v) to 40% (w/v). In some cases of the pharmaceutical composition, the cyclodextrin concentration of the aqueous solution is about 10% (w/v), about 12% (w/v), about 14% (w/v), about 15% (w/v), about 16% (w/v), about 18% (w/v), or about 20% (w/v). In some cases of the pharmaceutical composition, the cyclodextrin concentration of the aqueous solution is about 22% (w/v), about 24% (w/v), about 26% (w/v), about 28% (w/v), about 30% (w/v), about 32% (w/v), about 34% (w/v), about 36% (w/v), about 38% (w/v), or about 40% (w/v).

In some cases, the pharmaceutical composition is organoleptically tolerable when inhaled by a human subject. In some cases, the pharmaceutical composition does not cause a cough reflex when inhaled by a human subject. In some cases, the pharmaceutical composition is not or minimally irritating to the oral cavity or throat when inhaled by a human subject.

In some cases, the pharmaceutical composition comprises less than 1mg/mL, less than 0.5mg/mL, less than 0.1mg/mL, less than 0.005mg/mL, less than 0.001mg/mL, or less than 0.0001mg/mL of imatinib mesylate. In some cases, the pharmaceutical composition does not comprise imatinib mesylate. In some cases of the pharmaceutical composition, the imatinib or derivative thereof comprises imatinib free base. In some cases of the pharmaceutical composition, the imatinib or derivative thereof is imatinib free base.

In some cases, the pharmaceutical composition comprises a salt of imatinib or a derivative thereof selected from the group consisting of: acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate and succinate.

In some cases of the pharmaceutical composition, the aqueous solution further comprises a pharmaceutically acceptable excipient. In some cases of pharmaceutical compositions, the pharmaceutically acceptable excipient comprises a surfactant. In some cases of the pharmaceutical composition, the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). In some cases of the pharmaceutical composition, the pharmaceutically acceptable excipient comprises a lipid. In some cases of the pharmaceutical composition, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid. In some cases of the pharmaceutical composition, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid.

In some cases of pharmaceutical compositions, the solubility of imatinib or a derivative thereof in an aqueous solution is inversely related to the pH of the aqueous solution. In some cases of pharmaceutical compositions, the solubility of imatinib or a derivative thereof in an aqueous solution is positively correlated to the concentration of cyclodextrin in the aqueous solution.

In some aspects, disclosed herein are aerosol compositions comprising aerosolized droplets of a pharmaceutical composition disclosed herein or aerosolized droplets of a composition disclosed herein. In some cases, the atomized droplets have an average mass median aerodynamic diameter of 1 μm to 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 2 μm to 5 μm, 2 μm to 4 μm, 2 μm to 3 μm, or 3 μm to 4 μm.

In some aspects, disclosed herein is a unit dose of a pharmaceutical composition disclosed herein, or a composition disclosed herein, or an aerosol composition disclosed herein, comprising from about 10mg to about 500mg of imatinib or a derivative thereof. In some cases, the unit dose comprises 20mg to 180mg, 20mg to 150mg, 20mg to 120mg, 20mg to 100mg, 20mg to 80mg, 20mg to 60mg, 20mg to 40mg, 40mg to 120mg, 60mg to 100mg, or 60mg to 80mg of imatinib or a derivative thereof.

In some aspects, disclosed herein is a method of treating a subject having a pulmonary disease comprising administering to a subject in need thereof by inhalation of a pharmaceutical composition disclosed herein.

In some cases, the method comprises administering about 10mg to about 500mg of imatinib or a derivative thereof to the subject by inhalation. In some cases, the method comprises administering to the subject 20mg to 180mg, 20mg to 150mg, 20mg to 120mg, 20mg to 100mg, 20mg to 80mg, 20mg to 60mg, 20mg to 40mg, 40mg to 120mg, 60mg to 100mg, or 60mg to 80mg of imatinib or a derivative thereof.

In some cases, the pulmonary disease comprises pulmonary fibrosis, lung cancer, or pulmonary hypertension. In some cases, the pulmonary disease comprises pulmonary arterial hypertension. In some cases, the method comprises administering the pharmaceutical composition to the subject at least once per day. In some cases, the method comprises administering to the subject a pharmaceutical composition 2, 3, 4, or 5 times per day. In some cases, the method comprises administering the pharmaceutical composition to the subject for a period of 5, 10, 20, 30, 60, 100, or 300 days, at least 1, 2, 3, 4, or 5 years.

In some cases of this method, administration is performed using a nebulizer. In some cases of the method, the sprayer is a jet sprayer, a vibrating mesh sprayer, or an ultrasonic sprayer. In some cases of this method, the administration of a single unit dose of the pharmaceutical composition is performed within 30 minutes. In some cases of this method, the administration of a single unit dose of the pharmaceutical composition is performed within 15 minutes, 10 minutes, or 5 minutes. In some cases of this method, administration of the pharmaceutical composition does not cause cough reflex in the subject. In some cases of this method, the pharmaceutical composition is not or minimally irritating to the oral cavity or throat of the subject.

In some aspects, disclosed herein is a kit comprising: the pharmaceutical compositions disclosed herein or the unit doses disclosed herein, as well as instructions for use of the pharmaceutical compositions for treating pulmonary diseases.

In some aspects, disclosed herein is a kit comprising: (a) a pharmaceutical composition disclosed herein; (b) a vessel containing the pharmaceutical composition; and (c) instructions for administering the pharmaceutical composition to a subject in need thereof via a nebulizer.

In some aspects, disclosed herein is a system comprising: the pharmaceutical compositions and nebulizers disclosed herein. In some cases of the system, the sprayer is a jet sprayer, a vibrating mesh sprayer, or an ultrasonic sprayer.

In some aspects, disclosed herein is a method of preparing a pharmaceutical composition comprising imatinib or a derivative thereof, comprising: providing an aqueous solution comprising a solubility enhancing agent; dissolving imatinib or a derivative thereof, or a pharmaceutically acceptable salt thereof, in an aqueous solution comprising a solubility enhancing agent, thereby producing an aqueous solution comprising imatinib or a derivative thereof; and adjusting the volume, pH, osmolality or viscosity of the aqueous solution containing imatinib or derivative thereof, thereby producing a pharmaceutical composition comprising imatinib or derivative thereof.

In some cases of the method, the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, comprises imatinib free base. In some instances of the method, the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, is imatinib free base. In some cases of the method, the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, comprises a salt of imatinib selected from the group consisting of: acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate and succinate. In some cases of the method, the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, comprises less than 0.2%, less than 0.1%, less than 0.05%, less than 0.02%, less than 0.01%, or less than 0.001% imatinib mesylate. In some cases of the method, the pharmaceutical composition comprises less than 1mg/mL, less than 0.5mg/mL, less than 0.1mg/mL, less than 0.005mg/mL, less than 0.001mg/mL, or less than 0.0001mg/mL of imatinib mesylate. In some cases of this method, the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, does not comprise imatinib mesylate. In some cases of this method, the pharmaceutical composition does not comprise imatinib mesylate. In some cases of the method, the solubility enhancing agent is selected from the group consisting of: cyclodextrin, lipid, co-solvent and organic acid.

In some cases of the method, the solubility enhancing agent comprises cyclodextrin. In some cases of the method, the cyclodextrin is selected from: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin, 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin. In some cases of the method, the cyclodextrin comprises succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, succinyl- γ -cyclodextrin, sulfobutyl ether- α -cyclodextrin, sulfobutyl ether- β -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, carboxymethyl- α -cyclodextrin, carboxymethyl- β -cyclodextrin, carboxymethyl- γ -cyclodextrin, 2-carboxyethyl- α -cyclodextrin, 2-carboxyethyl- β -cyclodextrin, 2-carboxyethyl- γ -cyclodextrin, phosphoric acid- α -cyclodextrin, phosphoric acid- β -cyclodextrin, phosphoric acid- γ -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, or sulfobutyl ether- γ -cyclodextrin. In some cases of the method, the cyclodextrin comprises an anionic cyclodextrin. In some cases of the pharmaceutical composition, the cyclodextrin comprises hydroxypropyl- β -cyclodextrin. In some cases of the method, the cyclodextrin comprises hydroxypropyl- β -cyclodextrin. In some cases of the method, the aqueous solution comprises a salt of cyclodextrin. In some cases of the method, the salt of cyclodextrin is a salt selected from the group consisting of: sodium, calcium, magnesium, iron, chromium, copper, zinc, lysine, arginine and histidine salts. In some cases of the method, the aqueous solution comprises sodium sulfobutyl ether- β -cyclodextrin.

In some cases of this method, the pharmaceutical composition comprises cyclodextrin at the following concentrations: about 1% (w/v) to about 80% (w/v), about 2% (w/v) to about 70% (w/v), about 2% (w/v) to about 60% (w/v), about 2% (w/v) to about 50% (w/v), about 2% (w/v) to about 40% (w/v), about 2% (w/v) to about 30% (w/v), about 2% (w/v) to about 20% (w/v), about 2% (w/v) to about 15% (w/v), about 2% (w/v) to about 10% (w/v), about 2% (w/v) to about 8% (w/v), about 2% (w/v) to about 5% (w/v), about 5% (w/v) to about 80% (w/v), about 5% (w/v) to about 70% (w/v), about 5% (w/v) to about 60% (w/v), about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 5% (w/v), about 5% (w/v) to about 40% (w/v), about 40% (w/v) to about 30% (w/v), about 5% (w/v) to about 20% (w/v), about 5% (w/v) to about 15% (w/v), about 5% (w/v) to about 12% (w/v), about 5% (w/v) to about 10% (w/v), about 10% (w/v) to about 60% (w/v), about 10% (w/v) to about 50% (w/v), about 10% (w/v) to about 40% (w/v), about 10% (w/v) to about 30% (w/v), about 20% (w/v) to about 30% (w/v), about 10% (w/v) to about 25% (w/v), about 19% (w/v) to about 25% (w/v), about 19.5% (w/v) to about 25% (w/v), about 20% (w/v) to about 25% (w/v), about 20.5% (w/v) to about 25% (w/v), about 21% (w/v) to about 25% (w/v), about 25% (w/v) to about 25% (w/v) About 22.5% (w/v) to about 25% (w/v), about 23% (w/v) to about 25% (w/v), about 10% (w/v) to about 20% (w/v), or about 10% (w/v) to about 15% (w/v). In some cases of the method, the pharmaceutical composition comprises cyclodextrin at a concentration of 5% (w/v) to 40% (w/v). In some cases of the method, the pharmaceutical composition comprises cyclodextrin at a concentration of 10% (w/v) to 20% (w/v). In some cases of the method, the pharmaceutical composition comprises cyclodextrin at a concentration of 25% (w/v) to 40% (w/v). In some cases of this method, the pharmaceutical composition comprises cyclodextrin at the following concentrations: about 10% (w/v), about 12% (w/v), about 14% (w/v), about 15% (w/v), about 16% (w/v), about 18% (w/v), or about 20% (w/v). In some cases of this method, the pharmaceutical composition comprises cyclodextrin at the following concentrations: about 22% (w/v), about 24% (w/v), about 26% (w/v), about 28% (w/v), about 30% (w/v), about 32% (w/v), about 34% (w/v), about 36% (w/v), about 38% (w/v), or about 40% (w/v).

In some cases of the method, the solubility enhancing agent comprises a lipid or fatty acid. In some cases of the method, the lipid or fatty acid is selected from: polyethoxylated castor oil, phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol (PEG), chitin, hyaluronic acid and polyvinylpyrrolidone; a lipid-containing sulfonated monosaccharide, a lipid-containing sulfonated disaccharide, and a lipid-containing sulfonated polysaccharide; fatty acids such as palmitic acid, stearic acid and oleic acid; cholesterol, cholesterol esters and cholesterol hemisuccinate. In some cases of the method, the solubility enhancing agent comprises a co-solvent. In some cases of the method, the co-solvent comprises glycerol or ethanol.

In some cases of the method, the solubility enhancing agent comprises an organic acid. In some cases of the method, the organic acid is selected from: acetic acid, acid modified starch, acrylic tricarboxylic acid, fatty acid, adipic acid, L-ascorbic acid, benzoic acid, caproic acid, caprylic acid, cholic acid, citric acid, deoxycholic acid, erythronic acid (D-isoascorbic acid), formic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, iron naphthenate, iron resinate, D (-) -lactic acid, L (+) -lactic acid, linoleic acid, malic acid, L-malic acid, nicotinic acid (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, L (+) -potassium hydrogen tartrate, propionic acid, acid hydrolyzed protein, disodium pyrophosphate, sodium aluminum acid phosphate, sorbic acid, stearic acid, succinic acid, sulfamic acid, sulfuric acid, tannic acid, L (+) -tartaric acid, taurocholic acid, and thiodipropionic acid.

In some cases of the method, the pharmaceutical composition comprises 20 to 500mg/mL of imatinib or a derivative thereof. In some cases of the method, the pharmaceutical composition comprises imatinib or a derivative thereof: 20mg/mL to 400mg/mL, 20mg/mL to 300mg/mL, 20mg/mL to 200mg/mL, 100mg/mL to 500mg/mL, 200mg/mL to 500mg/mL, 300mg/mL to 500mg/mL, 400mg/mL to 500mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 200mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 300mg/mL, 20mg/mL to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 60mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 120mg/mL, 40mg/mL to 150mg/mL, 60mg to 60mg/mL, 60mg/mL or 60mg to 60 mg/mL. In some cases of the method, the pharmaceutical composition comprises imatinib or a derivative thereof: about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, or about 150mg/mL. In some cases of the method, the pharmaceutical composition comprises about 80mg/mL of imatinib or a derivative thereof.

In some cases of the method, the aqueous solution comprising the solubility enhancing agent further comprises a pH buffer. In some cases of the method, the pH buffer comprises an organic acid salt of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer. In some cases of the method, the pH buffer comprises a phosphate buffer. In some cases of this method, the pH of the pharmaceutical composition is from 3 to 8. In some cases of the method, the pH of the pharmaceutical composition is 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7. In some cases of the method, the pH of the pharmaceutical composition is about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.4, about 5.5, or about 5.6. In some cases of this method, the pH of the pharmaceutical composition is 7 to 8. In some cases of this method, the pH of the pharmaceutical composition is about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0.

In some cases of the method, the viscosity of the pharmaceutical composition is at most 10 centipoise. In some cases of the method, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some cases of the method, the pharmaceutically acceptable excipient comprises a surfactant. In some cases of the method, the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). In some cases of the method, the pharmaceutically acceptable excipient comprises a lipid. In some cases of the method, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid. In some cases of the method, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid. In some cases of this method, the solubility of imatinib or a derivative thereof in an aqueous solution is inversely related to the pH of the aqueous solution. In some cases of this method, the solubility of imatinib or a derivative thereof in an aqueous solution is positively correlated with the concentration of cyclodextrin in the aqueous solution.

Incorporation of reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure may be obtained by reference to the following detailed description that sets forth exemplary embodiments which utilize the principles of the disclosure, and the accompanying drawings, in which:

FIG. 1 shows a graph showing the maximum concentration (mg/mL) of imatinib free base as a function of pH.

FIG. 2 shows a graph showing the maximum concentration of imatinib free base (mg/mL) as a function of the percentage (w/v) of hydroxypropyl beta cyclodextrin (HP beta CD or "HPBCD" in the figures) at pH 5 and 7.5.

FIG. 3A shows a graph showing the maximum concentration of imatinib free base (mg/mL) as a function of the percentage of hydroxypropyl beta cyclodextrin (HP beta CD or "HPBCD" in the figures) at pH 5 and 7.5 (w/v) and the percentage of sulfobutyl ether beta cyclodextrin (SBE beta CD or "SBEBCD" in the figures) at pH 5 (w/v).

FIG. 3B shows photographs of exemplary suspensions and solutions of about 30mg/mL imatinib free base in aqueous solution of 30% SBE beta CD and 50mM phosphate buffer at different pH levels.

Fig. 4A is a graph summarizing lung tissue concentration of imatinib over time following IT (free base suspension) or IV (methanesulfonic acid solution) administration.

Fig. 4B is a graph summarizing the plasma concentration of imatinib over time after IT (free base suspension) or IV (methanesulfonic acid solution) administration.

Fig. 4C is a graph summarizing the lung tissue concentration of imatinib versus the plasma concentration of imatinib over time following IT administration of an imatinib free base suspension.

Fig. 4D is a graph summarizing the lung tissue concentration of imatinib mesylate versus the plasma concentration of imatinib over time following IV administration of imatinib mesylate.

Fig. 4E is a log scale plot summarizing the lung tissue concentration of imatinib versus the plasma concentration of imatinib over time following IT administration of an imatinib free base suspension.

Fig. 4F is a log scale plot summarizing lung tissue concentration of imatinib mesylate versus plasma concentration of imatinib following IV administration of imatinib mesylate.

Detailed Description

In some aspects, the present disclosure provides compositions (e.g., pharmaceutical compositions), methods (e.g., methods of treatment, methods of preparing compositions), kits, and systems relating to aqueous solutions or suspensions of imatinib. The aqueous solutions or suspensions of imatinib disclosed herein may be used as an inhalable formulation, for example, nebulized by a nebulizer, for use in human patients. In some embodiments, the pharmaceutical compositions and methods of treatment provided herein are advantageous in providing a rapid, effective, and safe therapeutic solution for treating pulmonary diseases. In some embodiments, the present disclosure relates to the administration of a pharmaceutical composition comprising imatinib and a solubility enhancing agent in the form of an aqueous solution or suspension by inhalation.

In some embodiments, the pharmaceutical compositions or formulations provided herein are capable of delivering more of a pharmaceutically active ingredient, such as imatinib, to a subject in a single dose or multiple doses over a period of time. In some embodiments, the subject pharmaceutical compositions or formulations have at least one solubility enhancing agent. In some embodiments, the solubility enhancing agent comprises cyclodextrin, a pH buffer, a lipid, a fatty acid, a co-solvent, or an organic solvent. In some cases, the pharmaceutical compositions described herein have a variable concentration of a solubility enhancing agent to increase the solubility of imatinib or a derivative thereof, or a pharmaceutically acceptable salt thereof. As used herein, the term "solubility" with respect to a specified solute in a solution may refer to the maximum amount of solute that is soluble in a specified solvent per unit amount in the solution. When used in reference to imatinib or a derivative thereof (e.g., imatinib free base) dissolved in an aqueous solution, the term "solubility" may refer to the maximum amount of imatinib or a derivative thereof that is capable of being dissolved in a unit amount of water present in the aqueous solution. In some embodiments, the amount of imatinib for the solubility enhancing agent in the aqueous solutions or suspensions provided herein shortens the duration of inhalation because, for example, a given dose can be delivered at a higher rate than a comparable formulation without the solubility enhancing agent and thus having a relatively much lower concentration of imatinib. Shorter inhalation times may improve subject compliance, which may further improve drug delivery efficiency.

In some embodiments, the pharmaceutical compositions or formulations provided herein reduce undesirable cough in a subject upon inhalation, have improved organoleptic properties, and improve the overall experience of inhalation by a patient. In some embodiments, the improved overall inhalation experience results in better compliance with the full inhalation procedure. In some embodiments, more efficient drug delivery, and thus more drug delivery, is achieved when the subject has better inhalation compliance. Some aqueous solutions of imatinib mesylate or other salts of imatinib may have poor organoleptic properties, e.g., they may have severe irritation to the respiratory tract, may cause severe unpleasant sensations in the mouth and throat when inhaled by a human subject, and/or may cause coughing or even severe coughing, thereby making continuous deep lung inhalation impossible or impractical. In some cases, solutions of imatinib mesylate or some other salt of imatinib are non-inhalable, e.g., because they are organoleptically intolerant to human subjects, and do not continue deep lung inhalation of nebulized aerosols. Conversely, formulations according to some embodiments of the present disclosure may have improved organoleptic properties and be suitable for deep lung inhalation of aerosol nebulization thereof. In some cases, the formulations provided herein, e.g., aqueous solutions made from imatinib free base, have no or minimal irritation to the oral cavity and throat when inhaled in the form of an aerosolized aerosol. For example, a subject may not experience any adverse or severely adverse sensory stimulus when inhaling an atomized aerosol of some of the formulations provided herein. Some formulations provided herein may not cause cough reflex or intense cough in subjects inhaling the formulation. Subjects inhaling some of the formulations provided herein may report that some of the formulations provided herein are tolerable and may continue their deep lung inhalation for a desired period of time.

Without being bound by some theory, imatinib in mesylate form may result in poor organoleptic properties of the aerosol atomized from its aqueous solution. In some embodiments, the formulations provided herein circumvent the problems associated with poor organoleptic properties by using either the imatinib free base or other forms of salts of imatinib to prepare the formulations. The absence of imatinib in mesylate form may help improve the organoleptic properties of certain formulations provided herein.

In one aspect of the present disclosure, provided herein are unit doses of the pharmaceutical compositions provided herein. In some embodiments, the unit dose comprises from about 20mg to about 500mg of imatinib free base. In another aspect, provided herein are kits comprising a pharmaceutical composition or unit dose provided herein and instructions for use of the pharmaceutical composition for treating a pulmonary disease.

Composition and method for producing the same

In some aspects, disclosed herein are compositions (e.g., pharmaceutical compositions or formulations) comprising an aqueous solution or suspension of imatinib or a derivative thereof. In some cases, the composition comprises an aqueous solution or suspension comprising: imatinib or a derivative thereof, a solubility enhancer, and a pH buffer. In some embodiments, the concentration of imatinib in the aqueous solution or suspension is from 20 to 500mg/mL. In some cases, the viscosity of the aqueous solution or suspension is up to 10 centipoise. In some cases, the pH of the aqueous solution or suspension is from 3 to 8. In some cases, the concentration of imatinib or derivative thereof in the aqueous solution or suspension is from 20 to 500mg/mL, a viscosity of up to 10 centipoise, and a pH of from 3 to 8.

In some cases, disclosed herein are compositions comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and a cyclodextrin. In some cases, the cyclodextrin concentration of the aqueous solution or suspension is from about 1% (w/v) to about 80% (w/v). In some cases, the cyclodextrin comprises an anionic cyclodextrin.

In some cases, the compositions provided herein have a specific value of 20mg/mL to 400mg/mL, 20mg/mL to 300mg/mL, 20mg/mL to 200mg/mL, 100mg/mL to 500mg/mL, 200mg/mL to 500mg/mL, 300mg/mL to 500mg/mL, 400mg/mL to 500mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 200mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 300mg/mL, 20mg/mL to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 40mg/mL to 120mg/mL, 40mg to 150mg/mL, 60mg to 60mg/mL, 150mg to 60mg/mL, 150mg/mL, or 150mg/mL of the derivatives thereof.

In some cases, the compositions provided herein have a viscosity of at most 10 centipoise, such as at most 9.5 centipoise, at most 9.0 centipoise, at most 8.5 centipoise, at most 8.0 centipoise, at most 7.6 centipoise, at most 7.4 centipoise, at most 7.2 centipoise, at most 7.0 centipoise, at most 6.8 centipoise, at most 6.6 centipoise, at most 6.4 centipoise, at most 6.2 centipoise, at most 6.0 centipoise, at most 5.8 centipoise, at most 5.6 centipoise, at most 5.4 centipoise, at most 5.2 centipoise, at most 5.0 centipoise, at most 4.8 centipoise, at most 4.6 centipoise, at most 4.4 centipoise, at most 4.2 centipoise, at most 4.0 centipoise, at most 3.8 centipoise, at most 3.4 centipoise, at most 3.2 centipoise, at most 3.0 centipoise, at most 2.8 centipoise, at most 2.4 centipoise, at most 2.2.2 centipoise, at most 2.0 centipoise, at most 1.8 centipoise, at most 1.0 centipoise, at most 1.0.0 centipoise. For example, the compositions provided herein have a viscosity of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.8, 3.0, 3.2, 3.5, 3.8, 4.0, 4.2, 4.8, 5, 5.5, 6.0, 7.0, 7.5, 8.0 or 8.5 centipoise.

In some cases, the pH of the compositions provided herein is from 3 to 7, such as from 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7. For example, the pH of the compositions provided herein is about 4.5, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.4, about 5.5, or about 5.6. In some cases, the composition comprises an aqueous solution of imatinib or a derivative thereof, and has a pH of 3 to 7.

In some cases, the pH of the compositions provided herein is from 7 to 8, such as about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0. In some cases, the composition comprises an aqueous suspension of imatinib or a derivative thereof, and has a pH of 3 to 8.

In some cases, the compositions provided herein do not have imatinib mesylate. In some cases, compositions provided herein have a substantially lower amount of imatinib mesylate, e.g., less than 1mg/mL, less than 0.5mg/mL, less than 0.4mg/mL, less than 0.3mg/mL, less than 0.2mg/mL, less than 0.1mg/mL, less than 0.075mg/mL, less than 0.05mg/mL, less than 0.025mg/mL, less than 0.01mg/mL, less than 0.0075mg/mL, less than 0.005mg/mL, less than 0.0025mg/mL, less than 0.001mg/mL, less than 0.00075mg/mL, less than 0.0005mg/mL, less than 0.00025mg/mL, or less than 0.0001mg/mL of imatinib mesylate, or less. In some cases, the composition has less than 0.2%, less than 0.15%, less than 0.1%, less than 0.075%, less than 0.05%, less than 0.025%, less than 0.02%, less than 0.015%, less than 0.01%, less than 0.0075%, less than 0.005%, less than 0.0025%, less than 0.002%, less than 0.0015%, or less than 0.001% imatinib mesylate, or less than the total amount of imatinib contained in the composition.

In some cases, the compositions provided herein comprise an aqueous solution of imatinib or a derivative thereof. The term "solution" as used herein may refer to a homogeneous mixture of one or more solutes dissolved in a solvent. The term "solvent" may refer to a substance in which a solute is dissolved to produce a homogeneous mixture, and the term "solute" may refer to a substance dissolved in a solvent to produce a homogeneous mixture. As used herein, the term "aqueous solution" may refer to a solution in which one of the one or more solvents is water.

In some cases, the compositions provided herein are aqueous suspensions of imatinib or a derivative thereof. The term "suspension" as used herein may refer to a heterogeneous mixture in which at least some of the solute particles are insoluble, but rather suspended throughout the bulk of the solvent. The suspensions disclosed herein may have some of the solute (e.g., imatinib or a derivative thereof) dissolved in a solvent (e.g., water) while the remainder is suspended in water, free-floating therein. The term "aqueous suspension" as used herein may refer to a suspension in which one of the one or more solvents is water. The suspensions provided herein are useful in therapeutic treatment and may be prepared immediately prior to therapeutic use (e.g., mixing the components and suspending undissolved imatinib or derivative thereof in an aqueous-based solution).

Imatinib

In some aspects, the compositions disclosed herein comprise imatinib or a derivative thereof. In some aspects of the disclosure, the pharmaceutical composition comprises a pharmaceutical agent for treating a pulmonary disease. In some embodiments, the pharmaceutical agent for treating a pulmonary disease is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically active ingredient in the composition (e.g., pharmaceutical composition or formulation) is imatinib free base. In some embodiments, the pharmaceutically active ingredient, such as a pharmaceutically acceptable salt of imatinib, comprises imatinib mesylate. In some embodiments, the pharmaceutical agent for treating a pulmonary disease is an imatinib derivative (e.g., nilotinib (Nilotinib), sorafenib, dasatinib) or a pharmaceutically acceptable salt thereof. Exemplary imatinib derivatives may include the imatinib derivatives described in the following: skobridis K et al ChemMedChem.2010 month 1; 5 (1) 130-9, A. Mortylock et al Comprehensive Medicinal Chemistry II, volume 7, 2007, pages 183-220, and Mus umeci F et al Expert Opin Ther Pat.2015;25 1411-21, which are incorporated herein in their entirety.

The chemical structure of imatinib is shown as compound I.

Compound I

Examples of pharmaceutically acceptable salts include those prepared by reacting the compositions described herein with: mineral acids, organic acids or inorganic bases, such salts include acetates, acrylates, adipates, alginates, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphorite, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentapropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, caproate, hexyne-1, 6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylene sulfonate.

Further, the compositions (e.g., pharmaceutical compositions or formulations) described herein may be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic or organic acids including, but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and hexadienedioic acid.

In some embodiments, those pharmaceutical compositions described herein that comprise a free acid group are reacted with a suitable base (e.g., a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium and magnesium, aluminum salts, and the like. Illustrative examples of the base include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C _1-4 Alkyl group ₄ Etc.

Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is to be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil soluble or dispersible products are obtained by such quaternization.

In some embodiments, the pharmaceutically acceptable salts of imatinib comprise acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate, and succinate.

Solubility enhancer

In some aspects of the disclosure, the solubility enhancers described herein provide increased solubility in aqueous solutions of pharmaceutical agents (e.g., imatinib or a derivative or pharmaceutically acceptable salt thereof) for treating pulmonary diseases. In some aspects of the disclosure, the solubility enhancing agent described herein is a cyclodextrin. In some aspects of the disclosure, the solubility enhancing agent described herein is a lipid or fatty acid. In some aspects of the disclosure, the solubility enhancing agent described herein is a co-solvent. In some aspects of the disclosure, the solubility enhancers described herein are organic acids or excipient acids commonly known as safety (GRAS). In some aspects of the disclosure, the solubility enhancing agent described herein is a surfactant, such as tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

The lipids or fatty acids in the compositions (e.g., pharmaceutical compositions or formulations) provided herein may include, but are not limited to: polyethoxylated castor oil, phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol (PEG, PEG300, PEG 400), propylene Glycol (PG), chitin, hyaluronic acid and polyvinylpyrrolidone; a lipid-containing sulfonated monosaccharide, a lipid-containing sulfonated disaccharide, and a lipid-containing sulfonated polysaccharide; fatty acids such as palmitic acid, stearic acid and oleic acid; cholesterol, cholesterol esters and cholesterol hemisuccinate. In some aspects of the disclosure, the lipid is polymeric. In some aspects of the disclosure, the polymeric lipid is polyvinylpyrrolidone (PVP). In some aspects of the disclosure, the polymeric lipid is polyethylene glycol (PEG). In some aspects of the disclosure, the lipid is a sulfonated polysaccharide. In some aspects of the disclosure, the lipid is a fatty acid. In some aspects of the disclosure, the fatty acid is stearic acid or oleic acid. In some aspects of the disclosure, the fatty acid is a phospholipid. In some aspects of the disclosure, the phospholipid is lecithin or 1, 2-dipalmitoyl-sn-glycerol-3-phosphorylcholine (DPPC).

Cosolvents in compositions (e.g., pharmaceutical compositions or formulations) provided herein may include, but are not limited to: ethylene glycol or ethanol. The organic acids in the compositions (e.g., pharmaceutical compositions or formulations) provided herein may include, but are not limited to: acetic acid, acid modified starch, acrylic tricarboxylic acid, fatty acid, adipic acid, L-ascorbic acid, benzoic acid, caproic acid, caprylic acid, cholic acid, citric acid, deoxycholic acid, erythronic acid (D-isoascorbic acid), formic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, iron naphthenate, iron resinate, D (-) -lactic acid, L (+) -lactic acid, linoleic acid, malic acid, L-malic acid, nicotinic acid (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, L (+) -potassium hydrogen tartrate, propionic acid, acid hydrolyzed protein, disodium pyrophosphate, sodium aluminum acid phosphate, sorbic acid, stearic acid, succinic acid, sulfamic acid, sulfuric acid, tannic acid, L (+) -tartaric acid, taurocholic acid, and thiodipropionic acid. GRAS excipient acids in compositions (e.g., pharmaceutical compositions or formulations) provided herein include, but are not limited to: acetic acid, formic acid, citrate, tartrate, maleate, fumarate, tartrate, malonate, lactate and succinate.

Cyclodextrin

In some aspects of the disclosure, cyclodextrin is used as a solubility enhancer for imatinib or a derivative thereof. In some aspects of the disclosure, cyclodextrin is used as a solubility enhancer for imatinib free base. In some aspects of the present disclosure, cyclodextrin is used as a solubility enhancer for the imatinib salt. Cyclodextrins are cyclic carbohydrates extracted from starch. Unmodified cyclodextrins differ in the number of glucopyranose units linked together in a cylindrical structure. The parent cyclodextrins contain 6, 7 or 8 glucopyranose units and are called α -cyclodextrin, β -cyclodextrin and γ -cyclodextrin, respectively. Each cyclodextrin subunit can have a secondary hydroxyl group in the 2 and 3 positions and a primary hydroxyl group in the 6 position. Cyclodextrin can be depicted as a hollow truncated cone with a hydrophilic outer surface and a hydrophobic inner cavity. In aqueous solution, these hydrophobic cavities may provide a port for hydrophobic organic compounds, which port may fit all or part of the structure of the hydrophobic organic compounds into these cavities. This process, known as inclusion complexation, can result in an increase in the apparent water solubility and stability of the complexed drug.

Cyclodextrin in the compositions provided herein (e.g., pharmaceutical compositions) can include, but are not limited to: alpha-cyclodextrin (αcd), beta-cyclodextrin (βcd), gamma-cyclodextrin (γcd), derivatized alpha-cyclodextrin, derivatized beta-cyclodextrin, and derivatized gamma-cyclodextrin. Non-limiting examples of cyclodextrins that can be used in the subject compositions (e.g., pharmaceutical compositions or formulations) include: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin (HP beta CD), hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin methyl-beta-cyclodextrin (MβCD), succinyl-alpha-cyclodextrin (SβCD), succinyl-beta-cyclodextrin (SβCD), succinyl-gamma-cyclodextrin (SγCD), 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin, sulfobutyl ether-alpha-cyclodextrin (SBEαCD), sulfobutyl ether-beta-cyclodextrin (SBEβCD), sulfobutyl ether-gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin, sulfoalkyl ether-gamma-cyclodextrin, carboxymethyl-alpha-cyclodextrin (CαCD), carboxymethyl-beta-cyclodextrin (CmβCD), and crystalline-beta-cyclodextrin, carboxymethyl-gamma-cyclodextrin (CM gamma CD), 2-carboxyethyl-alpha-cyclodextrin (CE alpha CD), 2-carboxyethyl-beta-cyclodextrin (CE beta CD), 2-carboxyethyl-gamma-cyclodextrin (CE gamma CD), phosphoric acid-alpha-cyclodextrin (palpha CD), phosphoric acid-beta-cyclodextrin (pbeta CD) and phosphoric acid-gamma-cyclodextrin (pgamma CD). In some embodiments, the composition (e.g., a pharmaceutical composition) comprises hydroxypropyl-beta-cyclodextrin (HP beta CD). In some embodiments, the composition (e.g., pharmaceutical composition) comprises more than one type of cyclodextrin, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different types of cyclodextrin. In some embodiments, the composition (e.g., a pharmaceutical composition) comprises hpβcd and one or more other cyclodextrins, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more other different types of cyclodextrins. In some cases, the cyclodextrin is selected from: alpha-cyclodextrin, 3-cyclodextrin, gamma-cyclodextrin, derivatized alpha-cyclodextrin, derivatized 3-cyclodextrin and derivatized gamma-cyclodextrin. In some cases, the cyclodextrin is selected from: alpha-cyclodextrin, 3-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-3-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin, succinyl-beta-cyclodextrin, 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin and sulfoalkyl ether-gamma-cyclodextrin.

In some cases, salts of cyclodextrins are used to prepare the compositions disclosed herein. For example, metal salts of cyclodextrins, such as, but not limited to, sodium, calcium, magnesium, iron, chromium, copper and zinc salts, may be used. Alternatively or additionally, amino acid salts of cyclodextrins, such as, but not limited to, lysine, arginine, and histidine salts, may be used. In some cases, the aqueous solutions or suspensions disclosed herein comprise a salt of a cyclodextrin, e.g., an anionic cyclodextrin salt, e.g., a sulfobutyl ether- β -cyclodextrin salt. In some cases, the aqueous solutions or suspensions disclosed herein comprise sodium sulfobutyl ether- β -cyclodextrin.

In some embodiments, the concentration of cyclodextrin contributes to the viscosity of the solution, which reduces the atomization efficiency (or rate) of the solution. For example, in some cases, the higher the concentration of cyclodextrin, the higher the viscosity of the solution. In some cases, the concentration of cyclodextrin in the composition is controlled such that the viscosity of the solution is not higher than a reference value, such as about 0.1 centipoise (cP), 0.2cP, 0.3cP, 0.4cP, 0.5cP, 0.6cP, 0.7cP, 0.8cP, 0.9cP, 1.0cP, 1.1cP, 1.2cP, 1.3cP, 1.4cP, 1.5cP, 1.6cP, 1.7cP, 1.8cP, 1.9cP, 2.0cP, 2.1cP, 2.2cP, 2.3cP, 2.4cP, 2.5cP, 2.6cP, 2.7cP, 2.8cP, 2.9cP, 3.0cP, 3.2cP, 3.4cP, 3.5cP, 3.6cP, 3.8cP, 4.0cP, 4.2cP, 5.4cP, 5.6cP, 5.8cP, 6.8cP, 6.6.6 cP, 6.7 cP, 6.8cP, 8.8cP, 8.7 cP, 8.8cP, 4.0cP, 8.7 cP, 8.8cP, 9cP, 4.0cP, 9.8cP, 9cP, 0.8cP, 9.8cP, 0.8cP, 9cP, and 9.8 cP. In some cases, the concentration of cyclodextrin in a composition (e.g., a pharmaceutical composition or formulation) is up to about 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 31%, 32%, 33%, 34%, 35%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% of the solution (w/v).

Without wishing to be bound by a theory, imatinib or a derivative thereof (e.g., imatinib free base) may be protonated under acidic conditions, resulting in an increase in solubility of the imatinib free base. Without wishing to be bound by a theory, cyclodextrin may increase the solubility of imatinib or a derivative thereof (e.g., imatinib free base) by stabilizing the positively charged piperazine ring under acidic conditions. Without wishing to be bound by a theory, anionic cyclodextrins may increase the stability and increase the solubility of positively charged imatinib or derivatives thereof (e.g., positively charged imatinib free base). In some embodiments, cyclodextrins that can be anionized can be used in the compositions and methods disclosed herein, e.g., succinyl- α -cyclodextrin (sαcd), succinyl- β -cyclodextrin (sβcd), succinyl- γ -cyclodextrin (sγcd), sulfobutyl ether- α -cyclodextrin (sbeαcd), sulfobutyl ether- β -cyclodextrin (sbeβcd), sulfobutyl ether- γ -cyclodextrin (sbeγcd), carboxymethyl- α -cyclodextrin (cmαcd), carboxymethyl- β -cyclodextrin (cmβcd), carboxymethyl- γ -cyclodextrin (cmγcd), 2-carboxyethyl- α -cyclodextrin (CE αcd), 2-carboxyethyl- β -cyclodextrin (CE βcd), 2-carboxyethyl- γ -cyclodextrin (CE γcd), phosphoric acid- α -cyclodextrin (pαcd), phosphoric acid- β -cyclodextrin (pβcd), and γ -cyclodextrin (pγcd).

In some aspects of the disclosure, cyclodextrin (e.g., SBE beta CD) is used as a solubility enhancer for imatinib or a derivative thereof. In some aspects of the disclosure, cyclodextrin (e.g., SBE beta CD) is used as a solubility enhancer for imatinib free base. In some aspects of the disclosure, cyclodextrin (e.g., SBE beta CD) is used as a solubility enhancer for the imatinib salt. In some cases, the concentration of cyclodextrin (e.g., SBE βcd) in the composition (e.g., pharmaceutical composition) is at most about 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 31%, 32%, 33%, 34%, 35%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% (w/v) of the solution at a pH of about 3 to about 8. In some cases, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition (e.g., pharmaceutical composition) is up to about 20% (w/v) of the solution at a pH of about 3 to about 8. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 80% of the solution at a pH of about 5. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 60% of the solution at a pH of about 5. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 50% of the solution at a pH of about 5. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 5% to about 45% of the solution at a pH of about 5. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is about 10% to about 20% of the solution at a pH of about 4. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 80% of the solution at a pH of about 4. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 60% of the solution at a pH of about 4. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 50% of the solution at a pH of about 4. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is about 5% to about 45% of the solution at a pH of about 4. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is about 10% to about 20% of the solution at a pH of about 4. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition (e.g., pharmaceutical composition or formulation) is from about 2% to about 80% of the solution at a pH of about 3. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition (e.g., pharmaceutical composition or formulation) is from about 2% to about 60% of the solution at a pH of about 3. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 50% of the solution at a pH of about 3. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is about 5% to about 45% of the solution at a pH of about 3. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is about 10% to about 20% of the solution at a pH of about 3. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 80% of the solution at a pH of about 6. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 60% of the solution at a pH of about 6. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is from about 2% to about 50% of the solution at a pH of about 6. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is about 5% to about 45% of the solution at a pH of about 6. In some embodiments, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is about 10% to about 20% of the solution at a pH of about 6.

In some cases, the concentration of cyclodextrin (e.g., SBE βcd) in the composition (e.g., pharmaceutical composition) is up to about 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 31%, 32%, 33%, 34%, 35%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% (w/v) of the solution and the concentration of dissolved imatinib is from about 0.0001mg/mL to about 500mg/mL at a pH of about 3 to about 8. In some cases, the concentration of cyclodextrin (e.g., SBE beta CD) in the composition is up to about 2% to about 80% (w/v) of the solution and the concentration of dissolved imatinib is about 1mg/mL to about 200mg/mL at a pH of about 5.

In some cases, the formulations disclosed herein (e.g., formulations containing imatinib free base and cyclodextrin such as SBE βcd) are in an acidic pH range, which can result in low systemic absorption of imatinib and high lung residence time of imatinib. In some cases, the formulations disclosed herein (e.g., formulations containing imatinib free base and cyclodextrin such as SBE beta CD) can result in a high preferential retention of the pharmaceutically active ingredient (e.g., imatinib or derivative thereof) in the lung over in the plasma at an acidic pH range. Without wishing to be bound by a theory, minimizing systemic exposure may result in reduced systemic side effects. In some cases, an acidic solution of imatinib or a derivative thereof (e.g., containing imatinib free base and a cyclodextrin such as SBE βcd) may cause precipitation of imatinib or a salt thereof upon contact with a lung lining fluid when administered to the lung.

According to some embodiments of the present disclosure, the solubility of imatinib or a derivative thereof (e.g., imatinib free base) in an acidic solution may be inversely related to the pH of the solution, e.g., the higher the pH of the solution, the lower the likelihood that the imatinib free base will dissolve in the solution (e.g., as shown in examples 4 and 5 and fig. 2, 3A and 3B). Additionally or alternatively, according to some embodiments of the present disclosure, imatinib or a derivative thereof (e.g., imatinib free base) is dissolved in a solvent (e.g., water) in the presence of cyclodextrin (e.g., waterCD) may be positively correlated with the concentration of cyclodextrin in the solution, e.g.>The higher the concentration of CD, the higher the likelihood that the imatinib free base will dissolve in solution (e.g., as shown in examples 5-7). Without wishing to be bound by a theory, in some cases, the lung lining fluid acts as a buffer to increase pH to precipitate the imatinib or derivative thereof delivered in the formulation. Without wishing to be bound by a theory, in some cases, the lung lining fluid acts as a diluent to precipitate the imatinib or derivative thereof delivered in the formulation. Without wishing to be bound by a theory, in some cases, the lung lining fluid acts as a buffer and diluent to increase pH to precipitate the imatinib or derivative thereof delivered in the formulation. Without wishing to be bound by a theory, solid precipitated imatinib may cause sustained release of imatinib to lung tissue over time, reduce systemic absorption, and prolong the lung Residence time.

In some cases, the concentration of imatinib or a derivative thereof in the systemic circulation (e.g., the concentration of imatinib measured in a blood sample taken from a large blood vessel or heart) is lower than the concentration of imatinib in lung tissue (e.g., the concentration of imatinib measured in a sample taken from the lung) within 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, or 10 hours after administration of an exemplary composition disclosed herein by inhalation. For example, the ratio of the concentration of imatinib in the blood sample to the concentration measured in the sample taken from the lung is less than 1, e.g., about 0.0001 to about 0.9, about 0.001 to about 0.9, about 0.01 to about 0.9, or about 0.1 to about 0.9, within 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, or 10 hours after administration by inhalation. In some embodiments, the concentration ratio is about 0.0001, about 0.0005, about 0.001, about 0.005, about 0.008, about 0.01, about 0.015, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, or about 0.9.

In some cases, after inhaled administration of the exemplary imatinib compositions disclosed herein, the concentration of imatinib in lung tissue (e.g., the concentration of imatinib measured in a sample taken from the lung) decreases at a lower rate than the concentration of imatinib in the systemic circulation (e.g., the concentration of imatinib measured in a blood sample taken from a large blood vessel or heart).

pH buffering agent

In some aspects of the disclosure, the compositions provided herein further comprise a pH buffer. In some cases, the pH buffer is an organic acid salt including, but not limited to, citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer. In some embodiments, the composition comprises more than one pH buffer.

In some embodiments, a pH buffer is present in a composition described herein (e.g., a pharmaceutical composition) to provide an aqueous solution at a pH of about 3 to about 7. In some embodiments, a pH buffer is present in a composition described herein (e.g., a pharmaceutical composition) to provide an aqueous suspension at a pH of about 3 to about 8. In some cases, the pH of the composition (e.g., pharmaceutical composition or formulation) is about 3, about 4, about 5, about 6, about 7, or about 8. In some embodiments, a pH buffer is present in the compositions described herein to provide an aqueous solution having a pH of 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7.

In some embodiments, the pH buffer is present in the aqueous composition from about 0.001mg/mL to about 100mg/mL, for example, between about 0.1mg/mL to about 100mg/mL, between about 0.5mg/mL to about 50mg/mL, between about 0.5mg/mL to about 20mg/mL, between about 0.5mg/mL to about 10mg/mL, between about 0.5mg/mL to 5mg/mL, or between about 1mg/mL to about 5 mg/mL. In some embodiments, the pH buffer is present in the aqueous composition at about 0.1mM to about 500mM, e.g., about 1mM to 500mM, 1mM to 200mM, 1mM to 100mM, 1mM to 80mM, 1mM to 50mM, 1mM to 25mM, 1mM to 10mM, 1mM to 5mM, 5mM to 200mM, 5mM to 100mM, 5mM to 80mM, 5mM to 50mM, 5mM to 25mM, 5mM to 10mM, 20mM to 200mM, 20mM to 100mM, 20mM to 80mM, or 20mM to 50mM.

Pharmaceutically acceptable excipients

In one aspect, provided herein are formulations for treating pulmonary diseases. The formulations may include the compositions provided herein and a pharmaceutically acceptable carrier, excipient, diluent, or any other suitable component for the intended route of administration (e.g., oral or nasal inhalation). Examples of pharmaceutically acceptable excipients include, but are not limited to, lipids, metal ions, surfactants, amino acids, carbohydrates, buffers, salts, polymers, sweeteners, and the like, and combinations thereof.

Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. For example, monosaccharides such as glucose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose, and the like; disaccharides such as lactose, maltose, sucrose, trehalose, and the like; trisaccharides such as raffinose and the like; and other carbohydrates such as starch (hydroxyethyl starch) and maltodextrin.

Non-limiting examples of lipids include phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol, chitin, hyaluronic acid or polyvinylpyrrolidone; lipids with sulfonated monosaccharides, disaccharides, and polysaccharides; fatty acids such as palmitic acid, stearic acid and oleic acid; cholesterol, cholesterol esters and cholesterol hemisuccinate.

In some cases, the phospholipid comprises a saturated phospholipid, such as one or more phosphatidylcholines. Exemplary acyl chain lengths are 16:0 and 18:0 (e.g., palmitoyl and stearoyl). The phospholipid content may be determined by the active agent activity, the mode of delivery, and other factors.

Phospholipids from natural and synthetic sources can be used in varying amounts. When present, the amount is generally sufficient to coat the active agent with at least one layer of phospholipid molecules. Typically, the phospholipid content ranges from about 5wt% to about 99.9wt%, for example from about 20wt% to about 80wt%.

Generally, compatible phospholipids may comprise those having a gel-to-liquid crystal phase transition of greater than about 40 ℃ (e.g., greater than about 60 ℃ or greater than about 80 ℃). The incorporated phospholipids may be relatively long chain (e.g., C ₁₆ -C ₂₂ ) Saturated lipids. Exemplary phospholipids for use in the present disclosure include, but are not limited to, phosphoglycerides such as dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, di-arachidonyl phosphatidylcholine (di-argidoyl phosphatidylcholine), di-behenyl phosphatidylcholine, di-phosphatidylglycerol, short chain phosphatidylcholine, hydrogenated phosphatidylcholine, E-100-3 (available from Lipoid KG, ludwigshafen, germany), long chain saturated phosphatidylethanolamine, long chain saturated phosphatidylserine, long chain saturated phosphatidylglycerol, long chain saturated phosphatidylinositol, phosphatidic acid, phosphatidylinositol, and sphingomyelin.

Examples of metal ions include, but are not limited to: divalent cations including calcium, magnesium, zinc, iron, and the like. For example, when phospholipids are used, the pharmaceutical compositions may also include multivalent cationsAs disclosed in U.S. patent nos. 8,709,484 and 7,871,598, the entire contents of which are incorporated herein by reference. The multivalent cations are present in an amount effective to raise the melting temperature (T) _m ) So that T of the pharmaceutical composition _m At a temperature (T) lower than the storage temperature (T) _m ) At least about 20 c higher, such as at least about 40 c higher. The molar ratio of multivalent cations to phospholipids may be at least about 0.05:1, for example about 0.05:1 to about 2.0:1 or about 0.25:1 to about 1.0:1. One example of a molar ratio of multivalent cations to phospholipids is about 0.50:1. When the multivalent cation is calcium, it may be in the form of calcium chloride. Although phospholipids often contain metal ions (e.g., calcium), there is no requirement.

The pharmaceutical composition may include one or more surfactants. For example, one or more surfactants may be in the liquid phase, with one or more being associated with a solid droplet or droplets of the composition. By "associated" is meant that the pharmaceutical composition may be incorporated, adsorbed, absorbed, coated with, or formed from a surfactant. Surfactants include, but are not limited to, fluorinated and non-fluorinated compounds such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof. It should be emphasized that suitable fluorinated surfactants are compatible with the teachings herein, in addition to the surfactants described above, and may be used to provide the desired formulation. In some aspects, the surfactant in the pharmaceutical compositions described herein comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). Without wishing to be bound by a theory, in some cases surfactants also act as solubility enhancers in the composition.

Examples of nonionic detergents include, but are not limited to: sorbitol esters, including sorbitol trioleate (Span ^TM 85 Sorbitol sesquioleate, sorbitol monooleate, sorbitol monolaurate, polyoxyethylene (20) sorbitol monolaurate and polyoxyethylene (20) sorbitol monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, dodecyl polyoxyethylene (4) ether, glycerol esters and sucrose esters. Other suitable nonionic detergentsCan be readily identified using McCutcheon's emulsifiers and detergents (McPublishing co., glen Rock, n.j.), the entire contents of which are incorporated herein by reference.

Examples of block copolymers include, but are not limited to: diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluronic ^TM F-68), poloxamer 407 (Pluronic) ^TM F-127) and poloxamer 338. Examples of ionic surfactants include, but are not limited to, sodium sulfosuccinate and fatty acid soaps. Examples of amino acids include, but are not limited to, hydrophobic amino acids. The use of amino acids as pharmaceutically acceptable excipients is known in the art, as disclosed in U.S. Pat. nos. 6,123,936, 6,358,530 and 6,921,527, the entire contents of which are incorporated herein by reference.

Pharmaceutical compositions according to one or more embodiments of the present disclosure may, if desired, comprise a combination of a pharmaceutical agent (e.g., imatinib or a derivative thereof, e.g., imatinib free base or an imatinib salt) and one or more additional active agents for treating a pulmonary disease. Examples of additional active agents include, but are not limited to, agents that can be delivered through the lung.

The additional active agent may comprise: for example, hypnotics and sedatives, heart potentiators, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinsonian agents (dopamine antagonists), analgesics, anti-inflammatory agents, anxiolytics (sedatives), appetite suppressants, antimigraine agents, muscle contractants, other antiinfectives (antiviral drugs, antifungal drugs, vaccines), anti-arthritic drugs, antimalarials, antiemetics, antiepileptics, cytokines, growth factors, anticancer agents, antithrombotics, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxidants, anti-asthmatic agents, hormonal agents (including contraceptives, sympathogenic drugs, diuretics, lipid regulating agents, antiandrogens, antiparasitics, anticoagulants, oncologics, antitumor drugs, hypoglycemic agents, nutritional agents and supplements), growth supplements, anti-enteritis agents, vaccines, antibodies, diagnostic agents and contrast agents. When administered by inhalation, the additional active agent may act locally or systemically.

The additional active agent may fall into one of a variety of structural categories including, but not limited to: small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of causing physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

Examples of additional active agents suitable for use in the present disclosure include, but are not limited to, one or more of the following: calcitonin, amphotericin B, erythropoietin (EPO), factor VIII, factor IX, cilicase, imisidase, cyclosporine, granulocyte Colony Stimulating Factor (GCSF), thrombopoietin (TPO), alpha-1 protease inhibitors, elcalcitonin, granulocyte-macrophage colony stimulating factor (GMCSF), growth hormone, human Growth Hormone (HGH), growth Hormone Releasing Hormone (GHRH), heparin, low Molecular Weight Heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-1 receptor, interleukin-2, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, luteinizing Hormone Releasing Hormone (LHRH), factor IX, insulin, proinsulin, insulin analogs (e.g., monoacylated insulin as described in U.S. Pat. No. 5,922,675, which is incorporated herein by reference in its entirety), pullulan, C-peptide, somatostatin analogs (including octreotide, vasopressin, follicle Stimulating Hormone (FSH), insulin-like growth factor (IGF), insulinotropic hormone (insulinotropic pin), macrophage colony stimulating factor (M-CSF), nerve Growth Factor (NGF), tissue growth factor, keratinocyte Growth Factor (KGF), glial Growth Factor (GGF), tumor Necrosis Factor (TNF), endothelial growth factor, parathyroid hormone (PTH), and, glucagon-like peptide thymosin alpha 1, IIb/IIa inhibitors, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosphonates, respiratory syncytial virus antibodies, cystic fibrosis transmembrane regulator (CFFR) genes, deoxyribonuclease (DNase), bactericidal/permeability increasing protein (BPI), anti-CMV antibodies, 13-cis-retinoic acid, oleandomycin acetate, roxithromycin, clarithromycin, cyclic erythromycin, azithromycin, fluoroerythromycin, dirithromycin, josamycin, spiramycin, midecamycin, leukomycin, melimycin, romycin and azithromycin and swinolide a; fluoroquinolones (e.g., ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, ara Qu Shaxing, moxifloxacin, norfloxacin, enoxacin, graminexacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amoxacin, fleroxacin, tosufloxacin, prulifloxacin, iloxacin, pazufloxacin, clinafloxacin, and sitafloxacin), teicoplanin, ramoplanin, melysin, colistin, daptomycin, gramicin, bacitracin, colistin mesylate, polymyxin (e.g., polymyxin B), frizzle, bacitracin, penicillins; penicillin (including penicillin sensitivity agents such as penicillin G, penicillin V), penicillin resistance agents (such as methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin); gram negative microbial agents (such as ampicillin, amoxicillin and oxacillin), and cilexetiln (galampicillin); anti-pseudomonas penicillins, such as carbenicillin, hydroxythiophene penicillins, azlocillin, mezlocillin, and piperacillin; cephalosporins (e.g. cefpodoxime, cefprozil, ceftizoxime, ceftriaxone, cefalotin, cefpiralin, cefalexin) cefradine, cefoxitin, cefadroxil, cefprozil, and cefprozil, wherein the cefprozil is preferably cefazolin, ceftiodine, cefaclor, cefadroxil, cefditoren, ceftazidime, ceftazi cefglycine, ceftriaxone, cefotaxime, ceftriaxone, cefacetonitrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, ceftazidime (cefinetazole), ceftazidime, chlorocarbon and moxalactam, monobactams such as aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isothiolate, lidocaine, oxacinnatine sulfate, beclomethasone dipropionate (beclomethasone diprepionate), triamcinolone acetonide, budesonide acetamide, fluticasone, ipratropium bromide, flunisone, cromolyn sodium, ergotamine tartrate, and, where applicable, analogs, agonists, antagonists, inhibitors and pharmaceutically acceptable salt forms of the above. With respect to peptides and proteins, the present disclosure is intended to encompass synthetic, natural, glycosylated, non-glycosylated, pegylated forms, and biologically active fragments, derivatives, and analogs thereof.

Additional agents for use in the present disclosure may further include nucleic acids, nucleic acid constructs that are naked nucleic acid molecules, vectors, related viral droplets, plasmid DNA or RNA, or other suitable transfected or transformed cell types, e.g., suitable for gene therapy including anti-transcription. In addition, the active agent may comprise an attenuated or killed live virus suitable for use as a vaccine. Other useful drugs include those listed in the Physician's Desk Reference (latest version), which is incorporated herein by Reference in its entirety.

When a combination of active agents is used, the agents may be provided in a single kind of pharmaceutical composition or in combination in different kinds of pharmaceutical compositions, respectively.

Pharmaceutical compositions of one or more embodiments of the present disclosure may lack taste. In this regard, while a taste-masking agent is optionally included in the composition, the composition in some embodiments does not include a taste-masking agent other than cyclodextrin, and lacks a taste even without a taste-masking agent.

In some embodiments, the pharmaceutical compositions provided herein comprise a sweetener to improve the organoleptic properties of the composition. The sweetener may be a natural sweetener (e.g., certain sugars) or an artificial sweetener. Without wishing to be bound by a theory, the presence of sweetener in the pharmaceutical composition may improve the organoleptic properties of the composition. In some cases, the presence of sweetener in the pharmaceutical composition may improve compliance of the subject. The presence of sweetener in the pharmaceutical composition may increase the delivery efficiency of the composition. In some embodiments, the presence of a sweetener in the pharmaceutical composition may enhance the therapeutic effect of the composition.

Non-limiting examples of artificial sweeteners that may be used in the pharmaceutical compositions include potassium acetyl sulfonamide, aspartame, cyclamate, mogrosides, saccharin, steviol, sucralose, neotame, and sugar alcohols (e.g., erythritol, hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol), such as those used in commercial products, such as Sweet N's low-powder sweetener, trusia powder sweetener, equal (aspartame), stevia powder sachets, aspen natural liquid steviol, now Better Stevia liquid sweetener, sweet N' low-liquid sweetener, quick Sweet: a Neotame liquid sweetener or a Splenda powder sachet, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises saccharin. In some embodiments, the pharmaceutical composition comprises a salt of saccharin. In some embodiments, the pharmaceutical composition comprises sodium saccharin.

Natural sweet substances that may be used in the pharmaceutical compositions include, but are not limited to, sucrose, agave, brown sugar, candy (powdered) sugar, corn syrup, dextrose, fructose, concentrated juice, glucose, high fructose corn syrup, honey, invert sugar, lactose, maltose syrup, maple syrup, molasses, honey, raw sugar and syrup. The sugar may increase the viscosity of the liquid solution, and thus in some embodiments, the concentration of any sugar added to the pharmaceutical composition is tightly controlled below a particular threshold.

In some embodiments, the pharmaceutically acceptable excipient or carrier comprises lactose, mannitol, sorbitol, erythritol, raffinose, sucrose, xylitol, trehalose, dextrose, cyclodextrin, maltitol, maltose, glucose, hydroxyapatite, or any combination thereof.

In addition to the pharmaceutically acceptable excipients described above, it may be desirable to add other pharmaceutically acceptable excipients to the pharmaceutical composition to improve drop hardness, production yield, shot dose and deposition, shelf life and patient acceptance. Such optional pharmaceutically acceptable excipients include, but are not limited to: colorants, taste masking agents, buffers, moisture absorbing agents, antioxidants, and chemical stabilizers. In some embodiments, the composition may include one or more osmolarity adjusting agents, such as sodium chloride. For example, sodium chloride may be added to the solution to adjust the osmolarity of the solution.

In one or more embodiments, the aqueous pharmaceutical compositions described herein substantially comprise an agent (e.g., imatinib), water, a pH buffer, a solubility enhancer, and an osmolarity adjusting agent for treating a pulmonary disease. In some embodiments, osmolarity adjusting agents can provide stability of the aerosolized pharmaceutical composition, reduce adverse effects (e.g., cough) on inhaled aerosolized pharmaceutical composition, aerosolization efficiency, or affect droplet size. In some embodiments, the osmolarity of the aqueous pharmaceutical compositions described herein is acceptable for pharmaceutical use (e.g., isotonic, physiological osmolarity, hypotonic, physiological hypotonic, hypertonic, physiological hypertonic). In some embodiments, the osmolality of the aqueous pharmaceutical composition is about 0.001 to about 2000mOsm, e.g., between about 0.1 to about 1000, about 1 to about 200, about 100 to about 500, about 200 to about 400, about 250 to about 350, about 300 to about 400, about 300 to about 2000, or about 1000 to 2000 mOsm. In some cases, the osmolality adjusting agent is a salt, such as sodium chloride or sodium carbonate.

Atomized aerosol

Liquid drop

The distribution of aerosol droplets of the inhalable formulation may be represented by any of the following: mass Median Aerodynamic Diameter (MMAD) -the size of half of the aerosol mass contained in smaller droplets and half contained in larger droplets; volume average diameter (VMD); mass Median Diameter (MMD); fine Drop Fraction (FDF) -percentage of drops with a diameter <5 um. These measurements have been used to compare the in vitro performance of different nebulizers and drug combinations. In general, the higher the fraction of fine droplets, the higher the proportion of the shot dose that may be deposited in the lungs. Typically, the aspirated droplets will deposit by one of two mechanisms: impingement, which is generally primarily used for larger droplets, and deposition, which is commonly used for smaller droplets. Impingement occurs when the momentum of the aspirated droplets is large enough that the droplets do not follow the airflow and encounter physiological surfaces. Conversely, deposition may occur primarily in the deep lung when very small droplets traveling with the inhaled air stream encounter physiological surfaces due to random diffusion within the air stream.

For pulmonary administration, the upper respiratory tract is generally avoided, while the middle and lower respiratory tracts are selected. Pulmonary drug delivery can be accomplished by inhalation of aerosols through the mouth and throat. Droplets having Mass Median Aerodynamic Diameters (MMAD) greater than about 5 microns typically do not reach the lungs; instead, they tend to strike the back of the throat and be swallowed, and may be absorbed orally. Droplets having diameters of about 1 micron to about 5 microns are small enough to reach the upper to middle lung regions (conductive airways), but too large to reach the alveoli. Smaller droplets, i.e., about 0.5 to about 2 microns, can reach the alveolar region. Droplets having a diameter of less than about 0.5 microns may also be deposited in the alveolar region by deposition, although very small droplets may be exhaled. The measurement of droplet size may be referred to as volume average diameter (VMD), mass Median Diameter (MMD), or MMAD. These measurements may be made by collision (MMD and MMAD) or laser (VMD). For liquid particles, the VMD, MMD, and MMAD may be the same if ambient conditions, such as standard humidity, are maintained. However, if moisture is not maintained, MMD and MMAD measurements will be smaller than VMD due to dehydration during impact measurements. For purposes of this description, VMD, MMD, and MMAD measurements are considered to be made under standard conditions, such that descriptions of VMD, MMP, and MMAD will be comparable.

Aerosol particle size may be expressed in terms of Mass Median Aerodynamic Diameter (MMAD). Large droplets (e.g., MMAD-5 um) may settle in the upper respiratory tract because they are too large to bypass the curvature of the upper respiratory tract. Small droplets (e.g., MMAD-2 um) may be difficult to settle in the lower respiratory tract and thus exhaled, providing additional opportunities for upper respiratory tract settling. Thus, during repeated inhalation and exhalation, inhalation collisions of large droplets and sedimentation of small droplets can lead to upper respiratory tract deposits, leading to intolerance (e.g. coughing and bronchospasm).

Thus, in one embodiment, to maximize deposition in the middle of the lung and minimize intolerance associated with upper respiratory tract deposition, an optimal droplet size (e.g., mmad=1-5 um) is used. Furthermore, generating a defined droplet size with a limited Geometric Standard Deviation (GSD) may optimize precipitation and tolerability. The narrow GSD limits the number of droplets to be outside the desired MMAD size range. In one embodiment, an aerosol is provided containing one or more compounds disclosed herein having an MMAD of about 1 micron to about 5 microns of GSD of less than or equal to about 2.5 microns. In another embodiment, an aerosol of MMAD having a GSD of less than or equal to 2 microns is provided from about 2.8 microns to about 4.3 microns. In another embodiment, an aerosol of MMAD of about 2.5 microns to about 4.5 microns having a GSD of less than or equal to 1.8 microns is provided.

In some embodiments, the nebulizer used in any of the methods described herein is a liquid nebulizer. In some embodiments, the nebulizer used in any of the methods described herein is a jet nebulizer, an ultrasonic nebulizer, a pulsed film nebulizer, a nebulizer comprising a vibrating mesh or plate having a plurality of holes, or a nebulizer comprising a vibration generator and a water chamber. In some embodiments, the nebulizer used in any of the methods described herein is a nebulizer comprising a vibrating mesh or plate having a plurality of holes. In some embodiments, the liquid nebulizer achieves lung precipitation of the mammal administered imatinib or derivative or salt thereof; providing a Geometric Standard Deviation (GSD) of the emission drop size distribution of the aqueous solution of about 1.0um to about 2.5 um; providing a Mass Median Aerodynamic Diameter (MMAD) of about 1um to about 5um of droplet size of the aqueous solution emitted with the high efficiency liquid atomizer; a volume average diameter (VMD) of about 1um to about 5um; and/or a Mass Median Diameter (MMD) of about 1um to about 5um; providing a fine droplet fraction (fdf=% s5 microns) of at least about 30% of the droplets emitted from the liquid atomizer; providing an output rate of at least 0.1 mL/min; and/or providing at least about 25% aqueous solution to the mammal.

In some embodiments, the composition (e.g., pharmaceutical composition or formulation) is atomized with atomized droplets having an average mass median aerodynamic diameter of 1 μm to 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 2 μm to 5 μm, 2 μm to 4 μm, 2 μm to 3 μm, or 3 μm to 4 μm.

Sprayer

In one embodiment, the nebulizer is selected on the basis of allowing an aerosol of the composition described herein to be formed. In some embodiments, the MMAD of the aerosolized or aerosolized composition has predominantly MMAD between about 1 and about 5 microns.

Effective delivery of drugs to the lungs by nebulizers depends on several factors, including inhaler device, formulation, and inhalation operation. The pharmaceutical composition may be administered using an aerosolization device. The nebulizing device may be a nebulizer, a metered dose inhaler or a liquid dose instillation device. The aerosolization device may comprise extruding the pharmaceutical formulation through micron or submicron sized pores, followed by Rayleigh (Rayleigh) break down into fine droplets. The pharmaceutical composition may be delivered by a nebulizer as described in WO 99/16420, a metered dose inhaler as described in WO 99/16422, a liquid dose instillation device as described in WO 99/16421, the entirety of which is incorporated herein by reference. Thus, the inhaler may comprise a canister containing droplets or droplets and a propellant, and wherein the inhaler comprises a metering valve in communication with the interior of the canister. The propellant may be a hydrofluoroalkane.

For example, the pharmaceutical composition may be a liquid solution and may be administered with a nebulizer, as disclosed for example in WO 99/16420, the disclosure of which is incorporated herein by reference in its entirety, to provide an aerosolized medicament that may be administered to the lung-air channel of a patient in need thereof. Nebulizers known in the art can be readily used for administration of the claimed formulations. Breath activated or breath actuated nebulizers, as well as those that have or will be developed that include other types of modifications, are also compatible with the formulations of the present disclosure and are considered to be within the scope of the present disclosure.

In some cases, the nebulizer is a breath-activated or breath-actuated nebulizer. In some cases, the nebulizer is a handheld inhaler device (e.g.Breath-actuated nebulizer (BAN)). In some cases, the sprayer has a source of compressed air. In some cases, the nebulizer converts the liquid drug into an aerosol. In some of the cases, in which the liquid is a liquid,nebulizers convert liquid drugs into aerosols by squeezing the drug formulation out of micron or submicron sized pores. In some cases, the nebulizer converts the liquid drug into an aerosol so that it can be inhaled into the lungs. In some cases, the nebulizer is a small volume nebulizer. In some cases, the nebulizer is a small volume jet nebulizer. In some cases, aerosolized drug is only produced upon inhalation through the device. In some cases, the medicament may be contained in the cup during the breath or during the treatment interval. In some cases, the medicament is contained in the cup until inhalation is ready.

The nebulizer may transfer energy into the liquid composition to nebulize the liquid and allow delivery to the pulmonary system, e.g., the lungs, of the patient. The sprayer includes a liquid delivery system, such as a container having a reservoir containing a liquid composition. Liquid compositions typically contain an active agent in solution or suspended in a liquid medium.

In one type of nebulizer that can be used in the methods and kits involved, commonly referred to as a jet nebulizer, compressed gas is forced through an orifice in a container. The compressed gas forces the liquid out through the nozzle and the expelled liquid may mix with the flowing gas to form aerosol droplets. A bolus of droplets may then be administered to the respiratory tract of the patient. In another type of nebulizer (commonly referred to as a vibrating mesh nebulizer) that can be used in the methods and kits involved, energy (e.g., mechanical energy) vibrates the mesh. This vibration of the mesh atomizes the liquid composition to produce an aerosol bolus for pulmonary administration to the patient. In another type of nebulizer that can be used in the methods and kits involved, the nebulization involves extrusion through micron or submicron sized orifices, followed by Rayleigh (Rayleigh) break down into fine droplets. Alternatively or additionally, the composition may be in liquid form and may be atomized using an atomizer as described in WO 2004/071368 (the entire contents of which are incorporated herein by reference), and U.S. published application nos. 2004/0011358 and 2004/0035413 (the entire contents of which are incorporated herein by reference). Examples of other atomizers include, but are not limited to: Or->Nebulizers, available from Aerogen limited of Galway, ireland; PARI eFlow and other PARI nebulizers available from PARI breathing apparatus company of Midlothian, va.; l->Nebulizers 6600 or 6610, available from L umiscope corporation of East Brunswick, n.j.; and Omron NE-U22, available from Omron health corporation of tokyo, japan. Other examples of nebulizers include devices manufactured by Medspray (encched, the Netherlands) and Pulmotree Medical GmbH (Miinchen, germany).

Vibrating mesh sprayers, e.g. sprayers forming droplets without the use of compressed gas, e.g.Unexpected improvements in metering efficiency and consistency may be provided. By using a vibrating perforated or unperforated film to generate fine droplets rather than by introducing compressed air, the atomized composition may be introduced without substantially affecting flow characteristics. Furthermore, when using this type of atomizer, the droplets produced can be introduced at a low rate, thereby reducing the likelihood of the droplets being driven into undesired areas. When using an extrusion/Rayleigh (Rayleigh) jet break-up atomizer, the generated droplets can also be introduced at low speeds, thereby reducing the likelihood of the droplets being driven into undesired areas.

In some cases, the nebulizers that can be used in the subject methods and kits are of the vibrating mesh type. In some cases, the nebulizers that may be used in the subject methods and kits are of the pressurized jet type. In some cases, the nebulizers that may be used in the subject methods and kits are of the extrusion/Rayleigh (Rayleigh) break-up type. In some cases, the nebulizer is lightweight (up to 60g, up to 100g, up to 200g, up to 250 g) and almost silent. In some cases, the sound level of the nebulizer at 1 meter is less than 35A weighted decibels (dBA). In some cases, the cup capacity of the nebulizer is 6mL. In some cases, the nebulizer remaining volume is less than 0.3mL. In some cases, the nebulizer produces an average flow rate of 0.4mL/min. In some cases, the nebulizer produces an average flow rate of 0.5mL/min. In some cases, the nebulizer produces an average flow rate of 0.6mL/min. In some cases, the nebulizer produces an average flow rate of 0.7mL/min. In some cases, the nebulizer produces an average flow rate of 0.8mL/min. In some cases, the nebulizer produces an average flow rate of 0.9mL/min. In some cases, the nebulizer produces an average flow rate of 1.0mL/min. In some cases, the nebulizer produces an average flow rate of 1.1mL/min. In some cases, the nebulizer produces an average flow rate of 1.2mL/min. In some cases, the nebulizer produced an average droplet size of 3.0 μm MMAD. In some cases, the nebulizer produces an average droplet size between 3.0 μm MMAD and 4.0 μm MMAD. In some cases, the nebulizer produced an average droplet size of 3.0 μm MMAD. In some cases, the nebulizer produces an average droplet size between 3.0 μm MMAD and 5.0 μm MMAD. In some cases, the nebulizer produced an average droplet size of 3.0 μmmad. In some cases, the nebulizer produces an average droplet size between 3.0 μm MMAD and 6.0 μm MMAD. In another type of nebulizer that can be used in the methods and kits involved, ultrasound is generated to vibrate and atomize the composition directly. The compositions disclosed herein may also be administered to the lungs of a patient by nebulization (e.g., with a metered dose inhaler). The use of such a formulation provides superior dose reproducibility and improved lung precipitation as disclosed in WO99/16422, which is incorporated herein by reference in its entirety. Metered Dose Inhalers (MDI) known in the art can be used for administration of the claimed compositions. Breath activated or breath driven MDI and pressurized MDI (pMDI), as well as those containing other types of modified MDI that have been or will be developed, are also compatible with the formulations of the present disclosure and are therefore considered to be within the scope of the present disclosure. Along with MDI and nebulizers, it will be appreciated that the formulations of one or more embodiments of the present disclosure may be used in conjunction with liquid dose instillation or LDI techniques, as disclosed, for example, in WO 99/16421, which is incorporated herein by reference in its entirety. Liquid dose instillation involves the administration of the formulation directly to the lungs. With respect to LDI, the formulation is preferably used in combination with partial or total liquid aeration. In addition, one or more embodiments of the present disclosure may further comprise introducing a therapeutically beneficial amount of a physiologically acceptable gas (e.g., nitric oxide or oxygen) into the drug microdispersion before, during, or after administration.

The aqueous formulation may be atomized by a liquid atomizer employing hydraulic or ultrasonic atomization. Propellant-based systems may use a suitable pressurized metered dose inhaler (pMDI). The desired particle size and distribution can be obtained by selecting an appropriate device. In some embodiments, the nebulizer is a jet nebulizer, a vibrating mesh nebulizer, or an ultrasonic nebulizer.

Instant preparation

The pharmaceutical compositions provided herein are ready-to-use and are ready-to-use for the treatment of pulmonary diseases. In contrast, other pharmaceutical formulations containing imatinib are in powder form as a liquid suspension for oral administration, or in concentrated form/stock solution requiring dilution, before additional components and steps are required. The pharmaceutical compositions described herein are in aqueous liquid form and provide immediate use for current symptoms associated with pulmonary disease without the need for additional steps. The ready-to-use formulation of the pharmaceutical compositions described herein is an invasive procedure (e.g., intravenous administration).

In some embodiments, the ready-to-use pharmaceutical composition is a single-use dose for treating a pulmonary disease or symptoms of a pulmonary disease. In some embodiments, the single use dose is in a cartridge or container having a volume for single use. In some embodiments, the single use dose is in a cartridge or container having a volume for additional administration of the pharmaceutical composition. In some embodiments, the ready-to-use pharmaceutical composition is a multi-dose formulation. In some embodiments, the multi-dose formulation of the ready-to-use pharmaceutical formulation is in a cartridge or container containing a multi-dose volume therein. In some embodiments, the multi-dose formulation requires refilling of the cartridge or container with the ready-to-use pharmaceutical composition for aerosolization. In some embodiments, a measuring means and/or a transfer means is included in the kit for refilling the cartridge or container for multiple dose use.

Therapeutic method

Pulmonary disease

Methods, compositions, and kits provided herein can include administration of a pharmaceutical composition by inhalation (e.g., oral or nasal inhalation). Examples of pulmonary diseases may include, but are not limited to: asthma, emphysema, chronic Obstructive Pulmonary Disease (COPD), infectious diseases (e.g. pneumonia, tuberculosis, influenza), coccidioidomycosis, coronavirus, cytogenetic Organized Pneumonia (COP), pulmonary arterial hypertension, respiratory Syncytial Virus (RSV), hantavirus Pulmonary Syndrome (HPS), avian mycobacterial compound lung disease, middle Eastern Respiratory Syndrome (MERS), mesothelioma, nontuberculous mycobacterial lung disease (NTM), severe Acute Respiratory Syndrome (SARS), lung cancer, acute Respiratory Distress Syndrome (ARDS), alpha-1 antitrypsin deficiency (AAT), asbestosis, aspergillosis, bronchiectasis, bronchiolitis, bronchopulmonary dysplasia, chronic bronchitis, chronic cough, coal dust (black lung), cystic fibrosis, electronic cigarette or electronic cigarette use-related lung injury (ali), eosinophilic granulomatosis with polyangitis, histoplasmosis, human metapneumovirus (hmv), hyperpneumonic fibrosis (pulmonary), idiopathic fibrosis (ILD), pulmonary fibrosis (ILD), sarcoidosis (pang), pertussis (PAH), pertussis, pulmonary disease (PAH), pertussis, or pulmonary disorder (panosis). The pharmaceutical compositions described herein are useful for treating diseases and conditions associated with pulmonary diseases, respiratory diseases, and tracheal or bronchial diseases. In some cases, lung disease may be caused by inhalation and/or exposure to tobacco smoke, infection (e.g., bacteria, viruses, fungi), radon, asbestos, air pollution, particulate matter, and debris. In some cases, the pulmonary disease or symptoms of the pulmonary disease may be caused by lung injury, sleep apnea, atelectasis, or pulmonary embolism.

Thus, pharmaceutical compositions according to some examples of the present disclosure may be used for treatment and/or to provide prophylaxis for a wide range of patients. Suitable patients to receive the treatment and/or prophylaxis described herein are any mammalian patients in need thereof, preferably such mammals are humans. Examples of subjects include, but are not limited to, pediatric patients, adult patients, and geriatric patients. In some cases, the composition is intended only for treatment that rapidly relieves symptoms and restores normal sinus rhythm, not as a precautionary measure, e.g., when the patient is healthy, no medication is needed-this may increase the risk ratio of treatment and overall safety due to occasional or intermittent dosing, and the emphasis is on reducing disabling symptoms and restoring sinus rhythm when needed.

The pharmaceutical compositions disclosed herein may be more effective in subjects that include or lack certain physiological or demographic factors, such as age at the time of clinical presentation, certain hemodynamic criteria, electrophysiological characteristics, and previous treatments. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a lung disease, the onset of which occurs within 48 hours prior to treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a lung disease, the onset of which occurs 1 hour to 48 hours prior to treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has recurrent pulmonary disease. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a continuously prescribed drug for pulmonary disease. In some embodiments, the oral drug for treating a pulmonary disease is imatinib or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure is over 18 years old. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure is less than 18 years old. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure is no older than 85 years. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is 18 to 85 years old.

In some embodiments, with the present disclosureThe subject treated with the pharmaceutical composition of (2) does not exhibit severe kidney damage, wherein the subject has an eGFR of less than 30mL/min/1.73m at the time of treatment ² . In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure is not dialyzed at the time of treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit abnormal liver function at the time of treatment. In some embodiments, the abnormal liver function is biochemical evidence of liver disease or significant liver disorder. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit uncorrected hypokalemia at the time of treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit less than 3.6mEq/L of serum potassium at the time of treatment.

In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit a positive diagnosis of a pulmonary disease requiring inhalation of the drug at the time of treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not have a hypersensitivity reaction to imatinib or any of its active metabolites or a medical history thereof. In some embodiments, the subject treated with the pharmaceutical compositions of the present disclosure is not concurrently administered a systemic drug (which is a CYP 2D6 inhibitor). In some embodiments, the inhibitor of CYP 2D6 is an antidepressant, a neuroleptic, or an antihistamine. In some embodiments, the inhibitor of CYP 2D6 is propranolol or ritonavir. In some embodiments, the subject treated with the pharmaceutical compositions of the present disclosure is not concurrently administered a systemic drug (which is a CYP 2D6 inducer). In some embodiments, the CYP 2D6 inducer is phenytoin, phenobarbital, or carbamazepine.

In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit congenital lung disease at the time of treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit syncope at the time of treatment.

In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit any serious or life threatening medical condition other than symptoms of a pulmonary disease at the time of treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit an acute pathogenic infection at the time of treatment.

In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit drug or alcohol dependence within 12 months prior to administration of the pharmaceutical composition. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit greater than 40Kg/m at the time of treatment ² Is a body mass index of (c).

The treatments provided herein may comprise or be suitable for inhalation, such as oral or nasal inhalation. In some cases, during administration by oral inhalation, the pharmaceutical agent is inhaled by the patient through the mouth and is absorbed by the lungs. In some cases, during administration by nasal inhalation, the pharmaceutical agent is inhaled by the patient through the nose and absorbed by the nasal mucosa and/or lungs.

The inhalation route avoids first pass liver metabolism and thus eliminates dose variability. Unlike the case of oral tablets or pills, the metabolic rate of the patient may not be critical because the administration is independent of the metabolic pathways experienced when taking the drug via the gastrointestinal tract (e.g., tablet, pill, solution or suspension) oral route. By rapid absorption of the drug from the nasal mucosa and/or lungs, a rapid onset of action, potential improvement in efficacy and/or reduction in dosage can be achieved.

Rapid absorption of the drug through the lungs is achievable because large surface area lungs are available for aerosols small enough to penetrate central and peripheral lung regions. Thus, the rate and extent of absorption of the drug delivered by inhalation can produce a plasma concentration versus time profile comparable to the IV route of administration.

In some cases, the treatment provided herein is provided to the subject more than once as needed. For example, a treatment may be administered to a subject, e.g., the pharmaceutical composition is inhaled by the subject at least once a day, e.g., 1, 2, 3,4, 5, 6, 8, or 10 times a day. In some cases, the subject may be administered the treatment for an extended period of time, such as for a period of at least 5, 10, 20, 30, 60, 100, or 300 days, at least 1, 2, 3,4, or 5 years, during which the subject receives the administration treatment every day or every other day, or every 2, 3,4, 5, 6, 7, or 10 days. On each day of treatment administration to a subject, the subject may receive administration of the treatment, e.g., inhalation of a pharmaceutical composition provided herein at least once, e.g., 1, 2, 3,4, 5, 6, 8, or 10 times.

Dosage of

The pharmaceutical composition may be administered to a patient as desired.

In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 500mg, wherein the pharmaceutical agent for treating a pulmonary disease is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 30mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 40mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 50mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 100mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 120mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 150mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 200mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 250mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 300mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 350mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 400mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 450mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 30mg to about 500mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 450mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 400mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 350mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 300mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 250mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 200mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 150mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 120mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 100mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 50mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 40mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 30mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 30mg to about 450mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 40mg to about 400mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 50mg to about 350mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 100mg to about 300mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 150mg to about 250mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 100mg to about 150mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 20mg to about 200mg. In some embodiments, the unit dose of the pharmaceutical agent for treating a pulmonary disease is from about 200mg to about 500mg. In some embodiments, the unit dose of a pharmaceutical agent for treating a pulmonary disease is about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, or about 500mg.

In some cases, the pharmaceutical compositions described herein have a unit dose of imatinib in aqueous solution of 20mg/mL to 500 mg/m. In some of the cases, in which the liquid is a liquid, the unit dosage is 20 to 500mg/mL, 20 to 450mg/mL, 20 to 400mg/mL, 20 to 350mg/mL, 20 to 300mg/mL, 20 to 250mg/mL, 20 to 200mg/mL, 20 to 150mg/mL, 20 to 120mg/mL, 20 to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 60mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 40mg/mL to 120mg/mL, 40mg/mL to 150mg/mL, 40mg/mL to 200mg/mL, 40mg/mL to 250mg/mL, 40mg/mL to 300mg/mL, 40mg/mL, 350mg/mL, 40mg/mL, 100mg/mL, and 40mg/mL to 400mg/mL, 40mg/mL to 450mg/mL, 40mg/mL to 500mg/mL, 60mg/mL to 80mg/mL, 60mg/mL to 100mg/mL, 60mg/mL to 120mg/mL, 60mg/mL to 150mg/mL, 60mg/mL to 200mg/mL, 60mg/mL to 250mg/mL, 60mg/mL to 300mg/mL, 60mg/mL to 350mg/mL, 60mg/mL to 400mg/mL, 60mg/mL to 450mg/mL, 60mg/mL to 500mg/mL, 80mg/mL to 100mg/mL, 80mg/mL to 120mg/mL, 80mg/mL to 150mg/mL, 80mg/mL to 200mg/mL, 80mg/mL to 250mg/mL, 80mg/mL to 300mg/mL, 80mg/mL to 350mg/mL, 80mg/mL to 400mg/mL, 60mg/mL, and 400mg/mL, 80mg/mL to 450mg/mL, 80mg/mL to 500mg/mL, 100mg/mL to 120mg/mL, 100mg/mL to 150mg/mL, 100mg/mL to 200mg/mL, 100mg/mL to 250mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 350mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 450mg/mL, 100mg/mL to 500mg/mL, 120mg/mL to 150mg/mL, 120mg/mL to 200mg/mL, 120mg/mL to 250mg/mL, 120mg/mL to 300mg/mL, 120mg/mL to 350mg/mL, 120mg/mL to 400mg/mL, 120mg/mL to 450mg/mL, 120mg/mL to 500mg/mL, 150mg/mL to 200mg/mL, 150mg/mL to 300mg/mL 150mg/mL to 350mg/mL, 150mg/mL to 400mg/mL, 150mg/mL to 450mg/mL, 150mg/mL to 500mg/mL, 200mg/mL to 250mg/mL, 200mg/mL to 300mg/mL, 200mg/mL to 350mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 450mg/mL, 200mg/mL to 500mg/mL, 250mg/mL to 300mg/mL, 250mg/mL to 350mg/mL, 250mg/mL to 400mg/mL, 250mg/mL to 450mg/mL, 250mg/mL to 500mg/mL, 300mg/mL to 350mg/mL, 300mg/mL to 400mg/mL, 300mg/mL to 450mg/mL, 300mg/mL to 500mg/mL, from 350mg/mL to 400mg/mL, 350mg/mL, 450mg/mL, 350mg/mL to 500mg/mL, 400mg/mL to 450mg/mL, 400mg/mL to 500mg/mL, or 450mg/mL to 500mg/mL of imatinib.

Pharmaceutical compositions of one or more embodiments of the present disclosure may have improved emission dose efficiency. The Emitted Dose (ED) of the atomized droplets of the present disclosure may be greater than about 30%, such as greater than about 40%, greater than about 50%, greater than about 60%, or greater than about 70%. The dose of the pharmaceutical agent (e.g., imatinib free base, imatinib salt, imatinib mesylate, imatinib derivative) for treating a pulmonary disease may be administered during a single inhalation or the agent may be administered during multiple inhalations. The fluctuation of the pharmaceutical agent may be reduced by more frequent administration of the pharmaceutical composition or may be increased by less frequent administration of the pharmaceutical composition. Thus, the pharmaceutical compositions provided herein may be administered from about 4 times per day to about 1 time per month, such as from about 1 time per day to about once every two weeks, from about 1 time per two days to about 1 time per week, and about 1 time per week.

In some cases, the pharmaceutical agent for treating a pulmonary disease is delivered by two or more inhalations. In some cases, the time between two or more inhalations is about 0.1 to 10 minutes. The pharmaceutical agent for treating a pulmonary disease is administered at the dose within less than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute. In some cases, the delivery of the desired dose of the pharmaceutical agent (e.g., imatinib) for treating a pulmonary disease is accomplished by 1, 2, 3, 4, 5, or 6 inhalations. In some cases, each inhalation is performed for about 0.5, 1, 1.2, 1.5, 1.8, 2, 2.2, 2.5, 2.8, 3, 3.2, 3.5, 3.8, 4, 4.2, 4.5, 4.8, or 5 minutes. In some cases, each inhalation is performed for longer than 5 minutes. In some cases, each inhalation is performed for up to 4.5 minutes. In some cases, each inhalation comprises at least 60 inhaled breaths, 50 inhaled breaths, 40 inhaled breaths, 30 inhaled breaths, 20 inhaled breaths, 10 inhaled breaths, 8 inhaled breaths, 6 inhaled breaths, 4 inhaled breaths, 3 inhaled breaths, 2 inhaled breaths, or 1 inhaled breath. In some cases, each inhalation comprises no more than 100 inhalation breaths, 90 inhalation breaths, 80 inhalation breaths, 70 inhalation breaths, 60 inhalation breaths, 50 inhalation breaths, 40 inhalation breaths, 30 inhalation breaths, or 20 inhalation breaths. In some cases, inhalation of the antiarrhythmic drug is performed with deep lung breathing lasting longer than 1 second, 2 seconds, 3 seconds, or 4 seconds. In some cases, inhalation of the pharmaceutical agent for pulmonary disease treatment is performed with deep lung breathing lasting about 1, 2, 3, or 4 seconds.

In some embodiments, during inhalation delivery of a pharmaceutical agent for treating a pulmonary disease, the subject is at rest or instructed to rest between inhalations. In such embodiments, the interval between inhalations lasts about 0.1 to 10 minutes, for example 0.2 to 5, 1 to 5, 1.5 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 1.5, 1 to 2, 1 to 2.5, 1 to 3, 1 to 3.5, 1 to 4, 1.5 to 2, 1.5 to 2.5 or 1.5 to 3 minutes. In some cases, the subject is at rest or instructed to rest for about 1 minute between inhalations. In some cases, the single dose delivery inhalation pattern proceeds as follows: the first inhalation is for about 4 to 4.5 minutes, rest for about 1 minute, and the second inhalation is for about 4 to 4.5 minutes; the first inhalation is for about 4 to 4.5 minutes, rest for about 30 seconds, and the second inhalation is for about 4 to 4.5 minutes; the first inhalation is for about 4 to 4.5 minutes, the first rest is for about 1 minute, and the second inhalation is for about 4 to 4.5 minutes; the second rest is about 1 minute and the third inhalation is about 4 to 4.5 minutes; or about 4 to 4.5 minutes for the first inhalation, about 30 seconds for the first rest, and about 4 to 4.5 minutes for the second inhalation; the second rest is about 30 seconds and the third inhalation is about 4 to 4.5 minutes.

In one version, the pharmaceutical compositions described herein may be administered daily. In this case, the daily dose of imatinib ranges from about 0.1mg to about 600mg, for example from about 0.5mg to about 500mg, from about 1mg to about 400mg, from about 2mg to about 300mg, and from about 3mg to about 200mg.

In some cases, the treatment provided herein is provided to the subject more than once as needed. For example, if symptoms of lung disease have not resolved and occur after an initial inhalation, the present disclosure may involve a subsequent inhalation. In some cases, the subsequent dose is higher than or equal to the initial dose if the symptoms of the pulmonary disease have not resolved within 30 minutes of the initial inhalation.

In another version, the pharmaceutical composition is administered prophylactically to a subject who may develop a lung disease. For example, a patient having a history of pulmonary disease may be prophylactically treated with a pharmaceutical composition comprising imatinib to reduce the likelihood of having pulmonary disease.

The pharmaceutical composition may be administered to the patient in any regimen effective to prevent lung disease. Exemplary prophylactic regimens include 1 to 21 administrations per week of a pharmaceutical agent described herein for treating a pulmonary disease.

The amount of imatinib delivered to a subject to treat a pulmonary disorder (e.g., about the amount of imatinib free base leaving the throat when the subject is inhaled) can be from about 20mg to about 500mg, for example, 20mg to 30mg, 20mg to 40mg, 20mg to 50mg, 20mg to 60mg, 20mg to 70mg, 20mg to 80mg, 20mg to 90mg, 20mg to 100mg, 20mg to 110mg, 20mg to 120mg, 20mg to 130mg, 20mg to 140mg, 20mg to 150mg, 20mg to 160mg, 20mg to 170mg, 20mg to 180mg, 20mg to 200mg, 20mg to 250mg, 20mg to 300mg, 20mg to 350mg, 20mg to 400mg, 20mg to 500mg, 50mg to 60mg, 50mg to 70mg, 50mg to 80mg, 50mg to 90mg, 50mg to 100mg, 50mg to 120mg, 50mg to 150mg, 50mg to 200mg, 50mg to 250mg, 50mg to 300mg, 50mg to 350mg, 50mg to 400mg, 50mg to 450mg, 50mg to 500mg, 100mg to 120mg, 100mg to 150mg, 100mg and 150mg 100mg to 200mg, 100mg to 250mg, 100mg to 300mg, 100mg to 350mg, 100mg to 400mg, 100mg to 450mg, 100mg to 500mg, 150mg to 200mg, 150mg to 250mg, 150mg to 300mg, 150mg to 350mg, 150mg to 400mg, 150mg to 450mg, 150mg to 500mg, 200mg to 250mg, 200mg to 300mg, 200mg to 350mg, 200mg to 400mg, 200mg to 450mg, 200mg to 500mg, 40mg to 150mg, 50mg to 150mg, 60mg to 150mg, 70mg to 150mg, 80mg to 150mg, 90mg to 150mg, 100mg to 150mg, 110mg to 150mg, 120mg to 150mg, 130mg to 150mg, 140mg to 150mg, 30mg to 140mg, 40mg to 130mg, 50mg to 120mg, 60mg to 110mg, 70mg to 110mg, or 80mg to 100mg.

In one version, the amount of imatinib delivered to a subject to treat a pulmonary disease (e.g., about the amount of imatinib exiting an aerosolization device when inhaled by the subject) is at least about 20mg, at least about 30mg, at least about 40mg, at least about 50mg, at least about 60mg, at least about 70mg, at least about 80mg, at least about 90mg, at least about 100mg, at least about 110mg, at least about 120mg, at least about 130mg, at least about 140mg, at least about 150mg, at least about 160mg, at least about 170mg, at least about 180mg, at least about 190mg, at least about 200mg, at least about 225mg, at least about 250mg, at least about 275mg, at least about 300mg, at least about 325mg, at least about 350mg, at least about 375mg, at least about 400mg, at least about 425mg, at least about 450mg, at least about 470mg, or at least about 500mg.

In one version, the amount of imatinib delivered to a subject to treat a pulmonary disease (e.g., about the amount of imatinib exiting the throat when inhaled by the subject) is at most about 20mg, at most about 30mg, at most about 40mg, at most about 50mg, at most about 60mg, at most about 70mg, at most about 80mg, at most about 90mg, at most about 100mg, at most about 110mg, at most about 120mg, at most about 130mg, at most about 140mg, at most about 150mg, at most about 160mg, at most about 170mg, at most about 180mg, at most about 190mg, at most about 200mg, at most about 225mg, at most about 250mg, at most about 275mg, at most about 300mg, at most about 325mg, at most about 350mg, at most about 375mg, at most about 400mg, at most about 425mg, at most about 450mg, at most about 475mg, or at most about 500mg.

In some cases, the amount of imatinib delivered to a subject to treat a pulmonary disorder (e.g., about the amount of imatinib exiting the throat when inhaled by the subject) is about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 475mg, or about 500mg.

Kit and system

In one aspect, provided herein is also a kit for treating a pulmonary disease by inhalation. The kit may include one or more pharmaceutical agents, such as salts of imatinib or some of the additional active agents described herein. In some cases, the kit includes a container of pharmaceutical agent or composition. In some cases, a unit dose of a pharmaceutical agent as described above is provided in a kit. In some cases, the kit further comprises a container/vessel containing the pharmaceutical agent.

If desired, pharmaceutical compositions according to one or more embodiments of the present disclosure may comprise a combination of a pharmaceutical agent (e.g., imatinib free base, imatinib salt) and one or more additional active agents for treating a pulmonary disease. The pharmaceutical composition may be nebulized prior to administration or may be presented to the user in aerosol form.

In some cases, all raw materials are sterilized by established techniques that meet medical use standards. Typically, the manufacturing equipment is sterilized prior to use. Some or all of the other additional pharmaceutically acceptable carriers or excipients, solubilizing agents, or other additional ingredients (e.g., cyclodextrin, e.g., SBE beta CD or HP beta CD; e.g., acid, e.g., acetic acid, hydrochloric acid, nitric acid, or citric acid; e.g., saccharin, e.g., sodium saccharin, e.g., lipids or fatty acids, e.g., co-solvents) of the pharmaceutical composition may be added to a suitable container.

In some cases, the kit comprises a separate container/vessel for containing the pharmaceutical composition described herein. In some other cases, the kit comprises a single container containing the pharmaceutical composition. The kit may also include instructions for methods of using the kit. The instructions may be presented in the form of a data sheet, a manual, paper, printed on one or more containers or devices of the kit. Alternatively, the instructions may be provided in electronic form, e.g. may be provided from a kit in an optical disc or provided online with a network link. The instructions for use of the kit may comprise instructions for use of the pharmaceutical composition and the aerosolization device (e.g., nebulizer) for treating any suitable indication (e.g., lung disease). Instructions for use of the kit may comprise pharmaceutical compositions and instructions for use of the aerosolization device (e.g., nebulizer) for treating a pulmonary disease. In some cases, the kit includes a nose clip. The nose clip may be used to block air from passing through the subject's nose during inhalation and increase the proportion of the total inhaled volume of aerosol released by the nebulizer.

The unit dose of the pharmaceutical composition may be placed in a container. The container may be inserted into the atomizing device. The container may be of suitable shape, size and material to contain the pharmaceutical composition and provide the pharmaceutical composition in a usable condition. For example, the container may comprise a wall comprising a material that does not react adversely with the pharmaceutical composition. Furthermore, the wall may comprise a material that allows the capsule to be opened to allow the pharmaceutical composition to be nebulized.

In some cases, the pharmaceutical composition in the container is stable at reduced temperatures (e.g., 2-8 ℃) for an extended period of time and may extend the stability of the pharmaceutical composition.

Terminology

As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical formulation for treating a pulmonary disorder" can include not only a single active agent, but also a combination or mixture of two or more different active agents.

Reference herein to "one embodiment," "a version," or "an aspect" may include one or more of such embodiments, versions, or aspects unless the context indicates otherwise.

As used herein, the term "pharmaceutically acceptable solvate" may refer to a solvate that retains one or more biological activities and/or properties of a pharmaceutical agent and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable solvates include, but are not limited to, pharmaceutical agents for use in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof, in the treatment of pulmonary diseases.

As used herein, the term "salt" is equivalent to the term "pharmaceutically acceptable salt" and may refer to those salts that retain one or more of the biological activity and properties of the free acid and base and are not biologically or otherwise undesirable. Illustrative examples of pharmaceutically acceptable salts include, but are not limited to: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, benzoate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

The term "about" in relation to a reference value may include a range of values plus or minus 10% of that value. For example, the number "about 10" includes numbers of 9 to 11, including reference numerals of 9, 10, and 11. The term "about" in relation to a reference value may also include a range of values from which 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% is added or subtracted.

As used herein, the terms "treatment" and "treatment" may refer to a reduction in the severity and/or frequency of symptoms, elimination of symptoms and/or underlying causes, a reduction in the likelihood of occurrence of symptoms and/or underlying causes, and/or remediation of lesions. Thus, "treating" a patient with an active agent provided herein may include preventing the treatment of a subject with a particular condition, disease or disorder, and clinical symptoms in a subject susceptible to such a condition.

As used herein, "nominal amount" may refer to the amount contained in a unit dose vessel for administration.

As used herein, "effective amount" may refer to an amount that covers both a therapeutically effective amount and a prophylactically effective amount.

As used herein, a "therapeutically effective amount" of an active agent may refer to an amount effective to achieve a desired therapeutic result. The therapeutically effective amount of a given active agent may vary depending on factors such as the type and severity of the condition or disorder being treated, and the age, sex, and weight of the patient. In some cases, "inhalation" (e.g., "oral inhalation" or "nasal inhalation") refers to the delivery of a therapeutically effective amount of an inhaled pharmaceutical agent contained in one unit dose vessel, wherein in some cases one or more breaths, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or more breaths, may be required. For example, if the effective amount is 90mg and each unit dose vessel contains 30mg, delivery of the effective amount may require 3 inhalations.

The term "therapeutically effective amount" may include, unless otherwise specified, a "prophylactically effective amount," e.g., an amount of active agent effective to prevent onset or recurrence of a particular condition, disease, or disorder in a susceptible individual.

As used herein, the phrase "minimum effective amount" may refer to the amount of pharmaceutical agent necessary to achieve an effective amount.

As used herein, "mass median diameter" or "MMD" may refer to the median diameter of a plurality of droplets (typically in a polydisperse population of droplets, e.g., consisting of a range of droplet sizes).

As used herein, "particles" may refer to "droplets" of an aerosolized pharmaceutical composition.

As used herein, unless the context dictates otherwise, "geometric diameter" may refer to the diameter of an individual droplet as determined by microscopic examination.

As used herein, "mass median aerodynamic diameter" or "MMAD" may refer to the median aerodynamic size of a plurality of droplets or droplets (typically in a polydisperse population). An "aerodynamic diameter" may be the diameter of a sphere of unit density, which generally has the same sedimentation velocity in air as the powder, and is therefore a useful method of characterizing the sedimentation behavior of an atomized powder or other dispersed droplet or droplet formulation. Aerodynamic diameter includes droplet or droplet shape, density, and physical size of the droplet or droplet. As used herein, MMAD refers to the median of the aerodynamic drop or size distribution of an atomized drop as determined by cascade collisions, unless the context indicates otherwise.

By "pharmaceutically acceptable" component is meant a component that is biologically or otherwise undesirable, e.g., the component may be incorporated into the pharmaceutical compositions of the present disclosure and administered to a patient as described herein without causing any significant adverse biological effects or interacting in a deleterious manner with any of the other components contained in the formulation. When the term "pharmaceutically acceptable" is used to refer to an excipient, it may mean that the component has reached the required standards for toxicology and manufacturing testing, or that it has been included in inactive ingredient guidelines established by the U.S. food and drug administration.

As used herein, "active nebulizer" or "nebulizer" refers to an inhalation device that does not rely solely on the autonomous inspiratory effort of the patient to disperse and aerosolize a pharmaceutical composition contained in a reservoir or in a unit dosage form device, and does include inhalation devices that include means for providing energy to disperse and aerosolize a pharmaceutical composition, such as compressed gas and vibrating or rotating elements.

As used herein, "room temperature" may refer to a temperature of 18 ℃ to 25 ℃.

Examples

The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the present disclosure; it will be appreciated by their exemplary nature that steps, methods or techniques thereof known to those skilled in the art may alternatively be used.

Example 1: sensory testing of formulations in solution

This example illustrates the organoleptic properties of certain exemplary formulations of imatinib in liquid solutions.

In one experiment, exemplary imatinib formulations according to some embodiments of the present disclosure were prepared as shown in table 1 and tested for organoleptic properties at minimal volume by volunteer subjects.

To prepare the exemplary formulations, imatinib mesylate or imatinib free base is dissolved directly in sterile water or a sterile aqueous solution containing the indicated excipients (e.g., propylene glycol, sodium saccharin, sodium chloride, lactose monohydrate, phosphate, dextrose anhydrate, or hydroxypropyl-beta-cyclodextrin). The pH of the resulting solution is measured and water is added as needed to produce the final solution. Each solution was filtered through a 0.22 μm filter and the osmolality of the final solution was measured and determined.

Four persons were instructed to perform deep lung inhalation of one or more exemplary formulation minimum volumes (< 1.5 mL) at 1 to 2 minute intervals. Each individual was asked to describe the taste of the inhaled solution and record their cough reflex (if any) and their sensory perception of the solution in the throat and mouth during and after inhalation. Table 2 is a summary of observations made by these persons. It was found that most of the formulations made of imatinib mesylate among the tested formulations caused cough reflex in the tested subjects and were reported to be irritating. In some cases, the test person cannot complete inhalation due to strong cough reflex or stimulus. In contrast, the exemplary formulation 13 made from imatinib free base did not cause a cough reflex or caused little cough or irritation in the throat or mouth.

Example 2: exemplary imatinib formulations

Table 3 is a list of exemplary imatinib formulations listing different solubility enhancers according to certain embodiments of the present disclosure.

Example 3: solubility studies related to hydroxypropyl beta cyclodextrin (HP beta CD)

This example illustrates the solubility characteristics of certain formulations of imatinib free base in liquid solutions.

Imatinib free base is poorly soluble in water at pH ranges of 4-8 that are physiologically relevant (fig. 1). FIG. 1 shows the maximum concentration (mg/mL) of imatinib free base as a function of pH. As shown in fig. 1, lower pH improved solubility of imatinib free base. At pH 3, the concentration of imatinib free base is about 0.30mg/mL. At pH 6, the concentration of imatinib free base is <0.01 mg/mL.

Example 4: solubility studies relating to HP beta CD and pH

Figure 2 shows the maximum concentration of imatinib free base as a function of percentage of HP beta CD at pH 5 and 7.5. At pH 7.5, improved solubility of the imatinib free base was shown. The dissolved amount of imatinib free base was 8.7mg/mL at 45% HP beta CD (w/v). The addition of HP beta CD improves solubility, e.g., the maximum concentration of imatinib free base increases from <0.01mg/mL at 0% HP beta CD to 8.7mg/mL at 45% HP beta CD, respectively. At pH 5 and about 5% HP beta CD (w/v), the concentration of dissolved imatinib free base is about 2mg/mL. At pH 5 and between 25-30% HP beta CD (w/v), the concentration of dissolved imatinib free base was 9.5mg/mL. Lowering the pH improves the solubility of imatinib free base at all concentrations tested. The decrease in pH from 7.5 to 5.0 provided a concentration increase of 2.5 to 5.8mg/mL with HP beta CD. The maximum concentration of imatinib free base was observed to be 9.5mg/mL.

Example 5: solubility studies in relation to HP beta CD or sulfobutyl ether beta cyclodextrin (SBE beta CD) and pH

Figure 3A shows the maximum concentration of imatinib free base as a function of the percentage of cyclodextrin (HP beta CD or sulfobutyl ether beta cyclodextrin (SBE beta CD)) at different pH levels. The solubility of imatinib free base in solution was tested at pH 5 and 7.5 as a function of HP beta CD concentration (w/v). At pH 5, the solubility of imatinib free base in solution was tested for relationship to SBE beta CD concentration (w/v). At pH 5 and about 5% HP beta CD (w/v), the maximum concentration of dissolved imatinib free base is about 2mg/mL. At a pH between 5 and 25-30% HP beta CD (w/v), the concentration of dissolved imatinib free base was 9.5mg/mL. At pH 5 and 10% SBE beta CD (w/v), the concentration of dissolved imatinib free base was about 70mg/mL. The results showed an increase in solubility of approximately 3500-fold (0.02 mg/mL) in water at pH 5 as compared to imatinib free base. The data show that at pH 5, the solubility is increased by about 16-fold (4.4 mg/mL) compared to 10% HP. Beta. CD (w/v). The molar ratio (imatinib/sbeβcd) in the solution was 3.1. At pH 5 and 20% SBE beta CD (w/v), the concentration of dissolved imatinib free base was about 160mg/mL. The results show at least about 8000-fold increase in solubility in water at pH 5 as compared to imatinib free base. The data show that at pH 5, the solubility is increased by about 25-fold (6.8 mg/mL) compared to 20% HP. Beta. CD (w/v). The molar ratio in solution (imatinib/sbeβcd) was 3.5.

Further, at pH 5 and 25% SBE beta CD (w/v), the concentration of dissolved imatinib free base is about 200mg/mL. At pH 5 and 30% SBE beta CD (w/v), the concentration of dissolved imatinib free base was about 225mg/mL.

Fig. 3B shows photographs of exemplary imatinib solutions and suspensions at different pH conditions. Approximately 30mg/mL imatinib free base was mixed with 3 different vehicles (50 mM phosphate buffer adjusted to 30% sbe beta CD at 3 different pH levels 7, 5 and 3). As shown in the photograph, a white suspension was obtained at ph=7, while a clear solution was obtained at pH 5 and pH 3. The data shows that the solubility of the imatinib free base in an aqueous solution containing SBE beta CD is pH dependent, e.g., the lower the pH of the aqueous SBE beta CD solution, the higher the solubility of the imatinib free base in the solution.

Example 6: solubility studies related to SBE beta CD and dilution with water

This example illustrates the effect of dilution with water on the solubility of imatinib free base in cyclodextrin-based formulations.

In one experiment, the solubility of imatinib free base upon dilution in water in an exemplary imatinib free base formulation was tested. Briefly, an exemplary imatinib free base solution (50 mg/mL imatinib free base, 10% sbe βcd, pH 5.1) was diluted 40-fold in water for injection (WFI). After dilution, imatinib precipitated. The pH of the final suspension after dilution was measured to be 5.4. Since imatinib remains predominantly protonated at pH 5.4, the observed precipitation of imatinib may not be a pH-dependent effect.

In another experiment, another exemplary imatinib solution (100 mg/mL imatinib free base, 15% w/v SBE. Beta. CD, 50mM phosphate buffer, pH 5.0) was diluted 20-fold in water. After dilution, imatinib also precipitated. The resulting suspension was used for the Intratracheal (IT) arm in a rat pharmacokinetic study as shown in example 9 below.

Example 7: solubility studies related to SBE beta CD and dilution

This example detects the effect of dilution on the solubility of imatinib free base in cyclodextrin-based formulations while maintaining a constant pH.

In one experiment, the solubility of imatinib free base in an exemplary formulation of imatinib free base upon dilution with the pH maintained constant was tested. Briefly, each of the various exemplary imatinib free base solutions (100 mL in volume, saturated imatinib free base, different SBE βcd concentrations, pH 5) was diluted with phosphate buffer (50 mM, pH 5) to achieve a final SBE βcd concentration of 1.5% (w/v). Based on the measurements shown in example 5 and fig. 3A, the solubility of imatinib free base in SBE beta CD solution is expected to decrease upon dilution, although the pH is constant. Table 4 summarizes the predicted precipitation of imatinib free base in each solution at dilution to give a final SBE beta CD concentration of 1.5% (w/v).

TABLE 4 predicted precipitation of imatinib free base after dilution

* Percent precipitate = 100 x (total imatinib-dissolved imatinib)/total imatinib

Example 8: taste testing of sulfobutyl ether beta cyclodextrin (SBE beta CD) based formulations

This example illustrates the organoleptic properties of certain exemplary imatinib free base formulations in liquid solutions.

Tester 5 (T5) tested inhalation of two formulations:

40mg/mL imatinib, 10% w/v SBEBCD, 50mM phosphate buffer (pH 5)

80mg/mL imatinib, 20% w/v SBEBCD, 50mM phosphate buffer (pH 5).

T5 had no cough after inhalation of each of the two formulations for a period of about 2 minutes (continuous inhalation). T5 did not experience any cough, any desire to cough or pharyngeal irritation.

T5 indicates that the imatinib free base formulation containing SBE beta CD does not cause cough (adverse reaction). The same test person T5 also tasted the imatinib mesylate formulation and severely couoked upon inhalation of the imatinib mesylate formulation.

Example 9: exemplary formulation test in rats

This example illustrates and compares the pharmacokinetics of exemplary imatinib free base/cyclodextrin formulations ("imatinib free base") and imatinib mesylate formulations ("imatinib mesylate") in rats after Intravenous (IV) and Intratracheal (IT) administration, respectively.

The imatinib free base concentration was found to be 5mg/mL compatible with IT rat dosing. However, IT was observed that the exemplary imatinib free base formulation (100 mg/mL imatinib free base, 15% w/v sulfobutyl ether beta cyclodextrin (sbeβcd), 50mM phosphate buffer, pH 5.0) precipitated upon dilution, thus diluting 100mg/mL imatinib free base formulation 20-fold in water immediately prior to dosing and administration of 5mg/mL suspension to IT. 6mg/mL of imatinib mesylate (equal to 5mg/mL of imatinib free base) solution formulation was used as a control for studying IV arms. Both groups received a single dose of imatinib free base equal to 1mg/kg dose. 4 animals in each group were euthanized at 6 time points 1-3, 5, 10, 20, 30 or 60 minutes after dosing at which time samples were taken. Lung tissue and blood were collected for analysis.

All animals survived to the scheduled necropsy. No abnormal clinical observations were found throughout the study. No subjects associated with weight change were observed during the study. Generally, the results of animal necropsy were not significant.

Materials and methods

Table 5. Test sample preparation R1: imatinib mesylate

Table 6. Test sample formulation R2: imatinib free base/cyclodextrin

And (3) a testing system: the study used 72 public Sprague (Sprague Dawley) rats (Charles River laboratory), 8 weeks old, with a body weight range of 245.8-317g at the beginning of the study.

Experimental design and implementation: briefly, after animals were transferred to the study, all animals were randomly assigned to treatment groups designed according to the study below. Animals are treated by Intravenous (IV) administration of formulation R1 or by Intratracheal (IT) administration of formulation R2 of the test article. 4 animals in each group were euthanized at the time point of 6 samples collected after dosing, as shown in table 7.

TABLE 7 design of experiments

Pharmacokinetics of

Plasma and lung concentrations versus time data were analyzed using JMP version 15.2.0. The average value for each time point for a group of at least 2 animals per time point is reported. Using the nonlinear model fitting platform in JMP version 15.2.0, the following PK parameters were estimated using a two-compartment IV single dose model fitting: maximum observed concentration (C) _max ) C is observed _max Time (T) _max ) And the area under the plasma concentration versus time curve (AUC) from zero to the last measured concentration _60min ). Calculation of AUC from modeling curves using trapezoidal integration _60min . The results are shown in Table 8 below.

TABLE 8 PK parameter results from pulmonary and plasma concentrations versus time data

The therapeutic benefit (Rd) in table 8 was calculated using the following equation:

IV data indicate that the sample collection phase exhibited a mass distribution phase that preferentially accumulated in the lungs based on the high LogP (lipophilicity) of imatinib, the observed imatinib distribution volume (calculated as the ratio of the amount of imatinib in vivo to the plasma concentration of imatinib), and cardiac output to the lungs. This observation suggests that direct pulmonary administration of imatinib may provide improved safety compared to systemic delivery via the oral or IV route. Since imatinib preferentially accumulates in lung tissue, delivery directly to the lungs by inhalation can minimize systemic exposure. Notably, the direct delivery of imatinib to the lungs by IT administration of the imatinib free base/cyclodextrin formulation has 4-fold therapeutic advantage compared to IV administration of the imatinib mesylate formulation (rd=4). This therapeutic advantage can also be seen in figures 4A-4F, which show graphs summarizing the changes over time in the concentration of imatinib in the lung versus plasma following IT administration of an imatinib free base/cyclodextrin formulation or IV administration of an imatinib mesylate formulation.

While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure may be employed in practicing the disclosure. The following claims define the scope of the present disclosure and methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims

1. A composition comprising an aqueous solution or suspension comprising:

(1) Imatinib or a derivative thereof,

(2) A solubility enhancer, and

(3) A pH buffering agent, wherein the pH buffering agent,

wherein the aqueous solution or suspension:

(a) The imatinib or derivative thereof having a concentration of 20 to 500 mg/mL;

(b) A viscosity of at most 10 centipoise; and is also provided with

(c) Having a pH of 3 to 8.

2. The composition of claim 1, wherein the solubility enhancing agent is selected from the group consisting of: cyclodextrin, lipid, co-solvent, organic acid and surfactant.

3. The composition of claim 1, wherein the solubility enhancing agent comprises cyclodextrin.

4. The composition of claim 3, wherein the cyclodextrin concentration of the aqueous solution or suspension is from about 1% (w/v) to about 80% (w/v).

5. The composition of claim 1, wherein the solubility enhancing agent comprises a lipid or fatty acid.

6. The composition of claim 5, wherein the lipid or fatty acid is selected from the group consisting of: polyethoxylated castor oil, phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol (PEG), chitin, hyaluronic acid and polyvinylpyrrolidone; a lipid-containing sulfonated monosaccharide, a lipid-containing sulfonated disaccharide, and a lipid-containing sulfonated polysaccharide; fatty acids such as palmitic acid, stearic acid and oleic acid; cholesterol, cholesterol esters and cholesterol hemisuccinate.

7. The composition of claim 1, wherein the solubility enhancing agent comprises a co-solvent.

8. The composition of claim 7, wherein the co-solvent comprises glycerol or ethanol.

9. The composition of claim 1, wherein the solubility enhancing agent comprises an organic acid.

10. The composition of claim 9, wherein the organic acid is selected from the group consisting of: acetic acid, acid modified starch, acrylic tricarboxylic acid, fatty acid, adipic acid, L-ascorbic acid, benzoic acid, caproic acid, caprylic acid, cholic acid, citric acid, deoxycholic acid, erythronic acid (D-isoascorbic acid), formic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, iron naphthenate, iron resinate, D (-) -lactic acid, L (+) -lactic acid, linoleic acid, malic acid, L-malic acid, nicotinic acid (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, L (+) -potassium hydrogen tartrate, propionic acid, acid hydrolyzed protein, disodium pyrophosphate, sodium aluminum acid phosphate, sorbic acid, stearic acid, succinic acid, sulfamic acid, sulfuric acid, tannic acid, L (+) -tartaric acid, taurocholic acid, and thiodipropionic acid.

11. The composition of claim 1, wherein the solubility enhancing agent comprises a surfactant.

12. The composition of claim 11, wherein the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

13. A composition comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and a cyclodextrin, wherein the cyclodextrin of the aqueous solution or suspension has a concentration of about 1% (w/v) to about 80% (w/v).

14. The composition of any one of claims 3, 4 or 13, wherein the cyclodextrin is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin, methyl-beta-cyclodextrin 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin, succinyl-alpha-cyclodextrin, succinyl-beta-cyclodextrin, succinyl-gamma-cyclodextrin, sulfobutyl ether-alpha-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, carboxymethyl-alpha-cyclodextrin, carboxymethyl-beta-cyclodextrin, carboxymethyl-gamma-cyclodextrin, 2-carboxyethyl-alpha-cyclodextrin, 2-carboxyethyl-beta-cyclodextrin, 2-carboxyethyl-gamma-cyclodextrin, phosphoric acid-alpha-cyclodextrin, phosphoric acid-beta-cyclodextrin, phosphoric acid-gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin and sulfoalkyl ether-gamma-cyclodextrin.

15. The composition of any one of claims 3, 4, or 13, wherein the cyclodextrin comprises succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, succinyl- γ -cyclodextrin, sulfobutyl ether- α -cyclodextrin, sulfobutyl ether- β -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, carboxymethyl- α -cyclodextrin, carboxymethyl- β -cyclodextrin, carboxymethyl- γ -cyclodextrin, 2-carboxyethyl- α -cyclodextrin, 2-carboxyethyl- β -cyclodextrin, 2-carboxyethyl- γ -cyclodextrin, phosphoric acid- α -cyclodextrin, phosphoric acid- β -cyclodextrin, or phosphoric acid- γ -cyclodextrin.

16. The composition of any one of claims 3, 4, or 13, wherein the cyclodextrin comprises an anionic cyclodextrin.

17. A composition comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and a cyclodextrin, wherein the cyclodextrin comprises an anionic cyclodextrin.

18. A composition comprising an aqueous solution or suspension comprising imatinib or a derivative thereof, cyclodextrin, a pH buffering agent, and a surfactant.

19. The composition of any one of claims 3, 4, or 13-18, wherein the aqueous solution or suspension comprises a salt of the cyclodextrin.

20. The composition of claim 19, wherein the salt of the cyclodextrin is a salt selected from the group consisting of: sodium, calcium, magnesium, iron, chromium, copper, zinc, lysine, arginine and histidine salts.

21. The composition of any one of claims 3, 4, or 13-18, wherein the cyclodextrin comprises sulfobutyl ether- β -cyclodextrin.

22. The composition of any one of claims 3, 4, or 13-18, wherein the aqueous solution or suspension comprises sodium sulfobutyl ether- β -cyclodextrin.

23. The composition of any one of claims 3, 4, or 13-18, wherein the cyclodextrin comprises hydroxypropyl- β -cyclodextrin.

24. The composition of any one of claims 13-17, 21, or 23, wherein the aqueous solution or suspension further comprises a pH buffer.

25. The composition of any one of claims 1-12 or 24, wherein the pH buffer comprises an organic acid salt of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer.

26. The composition of any one of claims 1-12 or 24, wherein the pH buffer comprises a phosphate buffer.

27. The composition of any one of claims 13-17 or 21-26, wherein the aqueous solution or suspension further comprises a surfactant.

28. The composition of any one of claims 18-27, wherein the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

29. The composition of any one of claims 13-28, wherein the aqueous solution or suspension has a viscosity of up to 10 centipoise.

30. The composition of any one of claims 13-28, wherein the aqueous solution or suspension has a viscosity of at most 9.5 centipoise, at most 9.0 centipoise, at most 8.5 centipoise, at most 8.0 centipoise, at most 7.6 centipoise, at most 7.4 centipoise, at most 7.2 centipoise, at most 7.0 centipoise, at most 6.8 centipoise, at most 6.6 centipoise, at most 6.4 centipoise, at most 6.2 centipoise, at most 6.0 centipoise, at most 5.8 centipoise, at most 5.6 centipoise, at most 5.4 centipoise, at most 5.2 centipoise, at most 5.0 centipoise, at most 4.8 centipoise, at most 4.6 centipoise, at most 4.4 centipoise, at most 4.2 centipoise, at most 4.0 centipoise, at most 3.8 centipoise, at most 3.6 centipoise, at most 3.4 centipoise, at most 3.2.0 centipoise, at most 2.8 centipoise, at most 2.6 centipoise, at most 2.4 centipoise, at most 2.2.2 centipoise, at most 2.0 centipoise, at most 1.0 centipoise.

31. The composition of any one of claims 13-28, wherein the aqueous solution or suspension has a viscosity of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.8, 3.0, 3.2, 3.5, 3.8, 4.0, 4.2, 4.5, 4.8, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8, or 8.5.

32. The composition of any one of claims 13-31, wherein the aqueous solution or suspension has 20 to 500mg/mL of the imatinib or derivative thereof.

33. The composition according to any one of claim 1 to 12 or 32, wherein the aqueous solution or suspension has a concentration of the drug of 20mg/mL to 400mg/mL, 20mg/mL to 300mg/mL, 20mg/mL to 200mg/mL, 100mg/mL to 500mg/mL, 200mg/mL to 500mg/mL, 300mg/mL to 500mg/mL, 400mg/mL to 500mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 200mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 300mg/mL, 20mg/mL to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 60mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 40mg/mL to 120mg/mL, 40mg to 150mg/mL, 60mg to 60mg/mL, or the derivative thereof.

34. The composition of any one of claims 1-12 or 32, wherein the aqueous solution or suspension has about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, or about 150mg/mL of the imatinib or derivative thereof.

35. The composition of any one of claims 1-12 or 32, wherein the aqueous solution or suspension has about 80mg/mL of the imatinib or derivative thereof.

36. The composition of any one of claims 13-35, wherein the aqueous solution or suspension has a pH of 3 to 8.

37. The composition of any one of claims 1-12 or 36, wherein the pH of the aqueous solution or suspension is 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7.

38. The composition of any one of claims 1-12 or 36, wherein the pH of the aqueous solution or suspension is about 4.5, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.4, about 5.5, or about 5.6.

39. The composition of any one of claims 1-12 or 36, wherein the pH of the aqueous solution or suspension is from 7 to 8.

40. The composition of any one of claims 1-12 or 36, wherein the pH of the aqueous solution or suspension is about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0.

41. The composition of any one of claims 3, 4, or 13-40, wherein the cyclodextrin is at a concentration of about 2% (w/v) to about 70% (w/v), about 2% (w/v) to about 60% (w/v), about 2% (w/v) to about 50% (w/v), about 2% (w/v) to about 40% (w/v), about 2% (w/v) to about 30% (w/v), about 2% (w/v) to about 20% (w/v), about 2% (w/v) to about 15% (w/v), about 2% (w/v) to about 10% (w/v), about 2% (w/v) to about 8% (w/v), about 2% (w/v) to about 5% (w/v), about 5% (w/v) to about 80% (w/v), about 5% (w/v) to about 70% (w/v), about 5% (w/v) to about 60% (w/v), about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 40% (w/v) About 5% (w/v) to about 30% (w/v), about 5% (w/v) to about 20% (w/v), about 5% (w/v) to about 15% (w/v), about 5% (w/v) to about 12% (w/v), about 5% (w/v) to about 10% (w/v), about 10% (w/v) to about 60% (w/v), about 10% (w/v) to about 50% (w/v), about 10% (w/v) to about 40% (w/v), about 10% (w/v) to about 30% (w/v), about 20% (w/v) to about 30% (w/v), about 10% (w/v) to about 25% (w/v), about 19% (w/v) to about 25% (w/v), about 19.5% (w/v) to about 25% (w/v), about 20.5% (w/v) to about 25% (w/v), about 21% (w/v) to about 25% (w/v), about 22% (w/v) to about 25% (w/v), about 22.5% (w/v) to about 25% (w/v), about 23% (w/v) to about 25% (w/v), about 10% (w/v) to about 20% (w/v), or about 10% (w/v) to about 15% (w/v).

42. The composition of any one of claims 3, 4, or 13-40, wherein the cyclodextrin concentration of the aqueous solution or suspension is 5% (w/v) to 40% (w/v).

43. The composition of any one of claims 3, 4, or 13-40, wherein the cyclodextrin concentration of the aqueous solution or suspension is 10% (w/v) to 20% (w/v).

44. The composition of any one of claims 3, 4, or 13-40, wherein the cyclodextrin concentration of the aqueous solution or suspension is 25% (w/v) to 40% (w/v).

45. The composition of any one of claims 3, 4, or 13-40, wherein the cyclodextrin concentration of the aqueous solution or suspension is about 10% (w/v), about 12% (w/v), about 14% (w/v), about 15% (w/v), about 16% (w/v), about 18% (w/v), or about 20% (w/v).

46. The composition of any one of claims 3, 4, or 13-40, wherein the cyclodextrin concentration of the aqueous solution or suspension is about 22% (w/v), about 24% (w/v), about 26% (w/v), about 28% (w/v), about 30% (w/v), about 32% (w/v), about 34% (w/v), about 36% (w/v), about 38% (w/v), or about 40% (w/v).

47. The composition of any one of claims 1-46, wherein the composition comprises the aqueous solution.

48. The composition of claim 47, wherein the solubility of the imatinib or derivative thereof in the aqueous solution is inversely related to the pH of the aqueous solution.

49. The composition of claim 47 or 48, wherein the solubility of the imatinib or derivative thereof in the aqueous solution is positively correlated to the concentration of the cyclodextrin in the aqueous solution.

50. The composition of any one of claims 1-46, wherein the composition comprises the aqueous suspension.

51. The composition of any one of claims 1-50, wherein the composition comprises less than 1mg/mL, less than 0.5mg/mL, less than 0.1mg/mL, less than 0.05mg/mL, less than 0.01mg/mL, less than 0.005mg/mL, less than 0.001mg/mL, or less than 0.0001mg/mL of imatinib mesylate.

52. The composition of any one of claims 1-50, wherein the composition does not comprise imatinib mesylate.

53. The composition of any one of claims 1-52, wherein the imatinib or derivative thereof comprises imatinib free base.

54. The composition of any one of claims 1-52, wherein the imatinib or derivative thereof is imatinib free base.

55. The composition of any one of claims 1-52, wherein the composition comprises a salt of the imatinib or derivative thereof selected from the group consisting of: acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate and succinate.

56. A pharmaceutical composition comprising the composition of any one of claims 1-55.

57. The pharmaceutical composition of claim 56, wherein the pharmaceutical composition is formulated for administration by inhalation.

58. The pharmaceutical composition of claim 56 or 57, wherein the aqueous solution further comprises a pharmaceutically acceptable excipient.

59. The pharmaceutical composition of claim 58, wherein the pharmaceutically acceptable excipient comprises a surfactant.

60. The pharmaceutical composition of claim 59, wherein the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

61. The pharmaceutical composition of claim 58, wherein the pharmaceutically acceptable excipient comprises a lipid.

62. The pharmaceutical composition of claim 61, wherein the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid.

63. The pharmaceutical composition of claim 61, wherein the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid.

64. The pharmaceutical composition of any one of claims 59-63, wherein the pharmaceutical composition is organoleptically tolerable when inhaled by a human subject.

65. The pharmaceutical composition of any one of claims 59-64, wherein the pharmaceutical composition does not cause a cough reflex when inhaled by a human subject.

66. The pharmaceutical composition of any one of claims 59-65, wherein the pharmaceutical composition is non-irritating or minimally irritating to the oral cavity or throat when inhaled by a human subject.

67. A pharmaceutical composition comprising an aqueous solution comprising cyclodextrin and a therapeutically effective amount of imatinib or a derivative thereof, wherein the aqueous solution is formulated for administration by inhalation.

68. The pharmaceutical composition of claim 67, wherein the aqueous solution has a viscosity of at most 10 centipoise.

69. The pharmaceutical composition of claim 67, wherein the aqueous solution has a viscosity of at most 2.5 centipoise.

70. The pharmaceutical composition of any one of claims 67-69, wherein the aqueous solution has 20 to 500mg/mL of the imatinib or derivative thereof.

71. The pharmaceutical composition of claim 70, wherein the aqueous solution has 20mg/mL to 400mg/mL, 20mg/mL to 300mg/mL, 20mg/mL to 200mg/mL, 100mg/mL to 500mg/mL, 200mg/mL to 500mg/mL, 300mg/mL to 500mg/mL, 400mg/mL to 500mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 200mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 300mg/mL, 20mg/mL to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 40mg/mL to 120mg/mL, 40mg/mL to 60mg/mL, 150mg/mL or 150mg/mL of the derivative thereof.

72. The pharmaceutical composition of claim 70, wherein the aqueous solution has about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, or about 150mg/mL of the imatinib or derivative thereof.

73. The pharmaceutical composition of claim 70, wherein the aqueous solution has about 80mg/mL of the imatinib or derivative thereof.

74. The pharmaceutical composition of any one of claims 67-73, wherein the aqueous solution has a pH of 3 to 8.

75. The pharmaceutical composition of claim 74, wherein the pH of the aqueous solution is 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7.

76. The pharmaceutical composition of claim 74, wherein the pH of the aqueous solution is about 4.5, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.4, about 5.5, or about 5.6.

77. The pharmaceutical composition of claim 74, wherein the pH of the aqueous solution or suspension is 7 to 8.

78. The pharmaceutical composition of claim 74, wherein the pH of the aqueous solution is about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0.

79. The pharmaceutical composition of any one of claims 67-78, wherein the aqueous solution further comprises a pH buffer.

80. The pharmaceutical composition of claim 79, wherein the pH buffer comprises an organic acid salt of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer.

81. The pharmaceutical composition of any one of claims 67-80, wherein the cyclodextrin is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin, methyl-beta-cyclodextrin 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin, succinyl-alpha-cyclodextrin, succinyl-beta-cyclodextrin, succinyl-gamma-cyclodextrin, sulfobutyl ether-alpha-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, carboxymethyl-alpha-cyclodextrin, carboxymethyl-beta-cyclodextrin, carboxymethyl-gamma-cyclodextrin, 2-carboxyethyl-alpha-cyclodextrin, 2-carboxyethyl-beta-cyclodextrin, 2-carboxyethyl-gamma-cyclodextrin, phosphoric acid-alpha-cyclodextrin, phosphoric acid-beta-cyclodextrin, phosphoric acid-gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin and sulfoalkyl ether-gamma-cyclodextrin.

82. The pharmaceutical composition of any one of claims 67-80, wherein the cyclodextrin comprises succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, succinyl- γ -cyclodextrin, sulfobutyl ether- α -cyclodextrin, sulfobutyl ether- β -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, carboxymethyl- α -cyclodextrin, carboxymethyl- β -cyclodextrin, carboxymethyl- γ -cyclodextrin, 2-carboxyethyl- α -cyclodextrin, 2-carboxyethyl- β -cyclodextrin, 2-carboxyethyl- γ -cyclodextrin, phosphoric acid- α -cyclodextrin, phosphoric acid- β -cyclodextrin, or phosphoric acid- γ -cyclodextrin.

83. The pharmaceutical composition of any one of claims 67-80, wherein the cyclodextrin comprises an anionic cyclodextrin.

84. The pharmaceutical composition of any one of claims 67-80, wherein the cyclodextrin comprises sulfobutyl ether- β -cyclodextrin.

85. The pharmaceutical composition of any one of claims 67-80, wherein the cyclodextrin comprises hydroxypropyl-beta-cyclodextrin.

86. The pharmaceutical composition of any one of claims 67-80, wherein the aqueous solution comprises a salt of the cyclodextrin.

87. The pharmaceutical composition of claim 86, wherein the salt of the cyclodextrin is a salt selected from the group consisting of: sodium, calcium, magnesium, iron, chromium, copper, zinc, lysine, arginine and histidine salts.

88. The pharmaceutical composition of any one of claims 67-80, wherein the aqueous solution comprises sodium sulfobutyl ether- β -cyclodextrin.

89. The pharmaceutical composition of any one of claims 67-88, wherein the cyclodextrin concentration of the aqueous solution is about 1% (w/v) to about 80% (w/v), about 2% (w/v) to about 70% (w/v), about 2% (w/v) to about 60% (w/v), about 2% (w/v) to about 50% (w/v), about 2% (w/v) to about 40% (w/v), about 2% (w/v) to about 30% (w/v), about 2% (w/v) to about 20% (w/v), about 2% (w/v) to about 15% (w/v), about 2% (w/v) to about 10% (w/v), about 2% (w/v) to about 8% (w/v), about 2% (w/v) to about 5% (w/v), about 5% (w/v) to about 80% (w/v), about 5% (w/v) to about 70% (w/v), about 5% (w/v) to about 60% (w/v), about 5% (w/v) to about 40% (w/v) About 5% (w/v) to about 30% (w/v), about 5% (w/v) to about 20% (w/v), about 5% (w/v) to about 15% (w/v), about 5% (w/v) to about 12% (w/v), about 5% (w/v) to about 10% (w/v), about 10% (w/v) to about 60% (w/v), about 10% (w/v) to about 50% (w/v), about 10% (w/v) to about 40% (w/v), about 10% (w/v) to about 30% (w/v), about 20% (w/v) to about 30% (w/v), about 10% (w/v) to about 25% (w/v), about 19% (w/v) to about 25% (w/v), about 19.5% (w/v) to about 25% (w/v), about 20.5% (w/v) to about 25% (w/v), about 21% (w/v) to about 25% (w/v), about 22% (w/v) to about 25% (w/v), about 22.5% (w/v) to about 25% (w/v), about 23% (w/v) to about 25% (w/v), about 10% (w/v) to about 20% (w/v), or about 10% (w/v) to about 15% (w/v).

90. The pharmaceutical composition of any one of claims 67-89, wherein the cyclodextrin concentration of the aqueous solution is 5% (w/v) to 40% (w/v).

91. The pharmaceutical composition of any one of claims 67-89, wherein the cyclodextrin concentration of the aqueous solution is 10% (w/v) to 20% (w/v).

92. The pharmaceutical composition of any one of claims 67-89, wherein the cyclodextrin concentration of the aqueous solution is 25% (w/v) to 40% (w/v).

93. The pharmaceutical composition of any one of claims 67-89, wherein the cyclodextrin concentration of the aqueous solution is about 10% (w/v), about 12% (w/v), about 14% (w/v), about 15% (w/v), about 16% (w/v), about 18% (w/v), or about 20% (w/v).

94. The pharmaceutical composition of any one of claims 67-89, wherein the cyclodextrin concentration of the aqueous solution is about 22% (w/v), about 24% (w/v), about 26% (w/v), about 28% (w/v), about 30% (w/v), about 32% (w/v), about 34% (w/v), about 36% (w/v), about 38% (w/v), or about 40% (w/v).

95. The pharmaceutical composition of any one of claims 67-94, wherein the pharmaceutical composition is organoleptically tolerable when inhaled by a human subject.

96. The pharmaceutical composition of any one of claims 67-95, wherein the pharmaceutical composition does not cause a cough reflex when inhaled by a human subject.

97. The pharmaceutical composition of any one of claims 67-96, wherein the pharmaceutical composition is non-irritating or minimally irritating to the oral cavity or throat when inhaled by a human subject.

98. The pharmaceutical composition of any one of claims 67-97, wherein the pharmaceutical composition comprises less than 1mg/mL, less than 0.5mg/mL, less than 0.1mg/mL, less than 0.005mg/mL, less than 0.001mg/mL, or less than 0.0001mg/mL of imatinib mesylate.

99. The pharmaceutical composition of any one of claims 67-97, wherein the pharmaceutical composition does not comprise imatinib mesylate.

100. The pharmaceutical composition of any one of claims 67-99, wherein the imatinib or derivative thereof comprises imatinib free base.

101. The pharmaceutical composition of any one of claims 67-99, wherein the imatinib or derivative thereof is imatinib free base.

102. The pharmaceutical composition of any one of claims 67-99, wherein the pharmaceutical composition comprises a salt of the imatinib or derivative thereof selected from the group consisting of: acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate and succinate.

103. The pharmaceutical composition of any one of claims 67-102, wherein the aqueous solution further comprises a pharmaceutically acceptable excipient.

104. The pharmaceutical composition of claim 103, wherein the pharmaceutically acceptable excipient comprises a surfactant.

105. The pharmaceutical composition of claim 104, wherein the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

106. The pharmaceutical composition of claim 103, wherein the pharmaceutically acceptable excipient comprises a lipid.

107. The pharmaceutical composition of claim 106, wherein the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid.

108. The pharmaceutical composition of claim 106, wherein the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid.

109. The pharmaceutical composition of claims 67-108, wherein the solubility of the imatinib or derivative thereof in the aqueous solution is inversely related to the pH of the aqueous solution.

110. The pharmaceutical composition of claims 67-109, wherein the solubility of the imatinib or derivative thereof in the aqueous solution is positively correlated to the concentration of the cyclodextrin in the aqueous solution.

111. An aerosol composition comprising aerosolized droplets of the pharmaceutical composition of any one of claims 56-110 or the composition of any one of claims 1-55.

112. The aerosol composition of claim 111, wherein the atomized droplets have an average mass median aerodynamic diameter of 1 μιη to 5 μιη, 1 μιη to 4 μιη, 1 μιη to 3 μιη, 1 μιη to 2 μιη, 2 μιη to 5 μιη, 2 μιη to 4 μιη, 2 μιη to 3 μιη, or 3 μιη to 4 μιη.

113. A pharmaceutical composition according to any one of claims 56-110 or a composition according to any one of claims 1-55 or a unit dose of the aerosol composition according to claim 111 or 112 comprising from about 10mg to about 500mg of imatinib or a derivative thereof.

114. The unit dose of claim 113, comprising 20mg to 180mg, 20mg to 150mg, 20mg to 120mg, 20mg to 100mg, 20mg to 80mg, 20mg to 60mg, 20mg to 40mg, 40mg to 120mg, 60mg to 100mg, or 60mg to 80mg of the imatinib or derivative thereof.

115. A method of treating a subject having a pulmonary disease comprising administering to the subject in need thereof the pharmaceutical composition of any one of claims 56-110 by inhalation.

116. The method of claim 115, comprising administering about 10mg to about 500mg of the imatinib or derivative thereof to the subject by inhalation.

117. The method of claim 115, comprising administering to the subject 20mg to 180mg, 20mg to 150mg, 20mg to 120mg, 20mg to 100mg, 20mg to 80mg, 20mg to 60mg, 20mg to 40mg, 40mg to 120mg, 60mg to 100mg, or 60mg to 80mg of the imatinib or derivative thereof.

118. The method of any one of claims 115-117, wherein the pulmonary disease comprises pulmonary fibrosis, lung cancer, or pulmonary hypertension.

119. The method of any one of claims 115-117, wherein the pulmonary disease comprises pulmonary arterial hypertension.

120. The method of any one of claims 115-119, comprising administering the pharmaceutical composition to the subject at least once daily.

121. The method of any one of claims 115-119, comprising administering the pharmaceutical composition to the subject at least 2, 3, 4, or 5 times per day.

122. The method of any one of claims 115-121, comprising administering the pharmaceutical composition to the subject over a period of 5, 10, 20, 30, 60, 100, or 300 days, at least 1, 2, 3, 4, or 5 years.

123. The method of any one of claims 115-122, wherein the administration is performed using a nebulizer.

124. The method of claim 123, wherein the nebulizer is a jet nebulizer, a vibrating mesh nebulizer, or an ultrasonic nebulizer.

125. The method of any one of claims 115-124, wherein administration of a single unit dose of the pharmaceutical composition occurs within 30 minutes.

126. The method of any one of claims 115-124, wherein administration of a single unit dose of the pharmaceutical composition occurs within 15 minutes, 10 minutes, or 5 minutes.

127. The method of any one of claims 115-126, wherein the administration of the pharmaceutical composition does not cause cough reflex in the subject.

128. The method of any one of claims 115-127, wherein the pharmaceutical composition is non-irritating or minimally irritating to the oral cavity or throat of the subject.

129. A kit, comprising: the pharmaceutical composition of any one of claims 56-110 or the unit dose of claim 113 or 114, and instructions for use of the pharmaceutical composition for treating a pulmonary disease.

130. A kit, comprising:

(a) The pharmaceutical composition of any one of claims 56-110;

(b) A vessel containing the pharmaceutical composition; and

(c) Instructions for administering the pharmaceutical composition to a subject in need thereof via a nebulizer.

131. A system, comprising: the pharmaceutical composition of any one of claims 56-110, and a nebulizer.

132. The system of claim 131, wherein the nebulizer is a jet nebulizer, a vibrating mesh nebulizer, or an ultrasonic nebulizer.

133. A method of preparing a pharmaceutical composition comprising imatinib or a derivative thereof, comprising:

providing an aqueous solution comprising a solubility enhancing agent;

dissolving the imatinib or a derivative thereof, or a pharmaceutically acceptable salt thereof, in the aqueous solution comprising the solubility enhancing agent, thereby producing an aqueous solution comprising imatinib or a derivative thereof; and

adjusting the volume, pH, osmolality, or viscosity of the aqueous solution containing imatinib or a derivative thereof, thereby producing the pharmaceutical composition comprising imatinib or a derivative thereof.

134. The method of claim 133, wherein the imatinib or derivative or pharmaceutically acceptable salt thereof comprises imatinib free base.

135. The method of claim 133, wherein the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, is imatinib free base.

136. The method of claim 133, wherein the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, comprises a salt of imatinib selected from the group consisting of: acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate and succinate.

137. The method of any of claims 133-136, wherein the imatinib or derivative or pharmaceutically acceptable salt thereof comprises less than 0.2%, less than 0.1%, less than 0.05%, less than 0.02%, less than 0.01%, or less than 0.001% imatinib mesylate.

138. The method of any of claims 133-137, wherein the pharmaceutical composition comprises less than 1mg/mL, less than 0.5mg/mL, less than 0.1mg/mL, less than 0.005mg/mL, less than 0.001mg/mL, or less than 0.0001mg/mL of imatinib mesylate.

139. The method of any of claims 133-136, wherein the imatinib or derivative thereof, or pharmaceutically acceptable salt thereof, does not comprise imatinib mesylate.

140. The method of any of claims 133-139, wherein the pharmaceutical composition does not comprise imatinib mesylate.

141. The method of any of claims 133-140, wherein the solubility enhancing agent is selected from the group consisting of cyclodextrins, lipids, co-solvents, and organic acids.

142. The method of claim 141, wherein the solubility enhancing agent comprises cyclodextrin.

143. The method of claim 142, wherein the cyclodextrin is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin, dimaltosyl-beta-cyclodextrin, 6A-amino-6A-deoxy-N- (3-hydroxypropyl) -beta-cyclodextrin.

144. The method of claim 142, wherein the cyclodextrin comprises succinyl-a-cyclodextrin, succinyl- β -cyclodextrin, succinyl- γ -cyclodextrin, sulfobutyl ether-a-cyclodextrin, sulfobutyl ether- β -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, carboxymethyl-a-cyclodextrin, carboxymethyl- β -cyclodextrin, carboxymethyl- γ -cyclodextrin, 2-carboxyethyl-a-cyclodextrin, 2-carboxyethyl- β -cyclodextrin, 2-carboxyethyl- γ -cyclodextrin, phosphoric acid-a-cyclodextrin, phosphoric acid- β -cyclodextrin, phosphoric acid- γ -cyclodextrin, sulfobutyl ether- γ -cyclodextrin, or sulfobutyl ether- γ -cyclodextrin.

145. The method of claim 142, wherein the cyclodextrin comprises an anionic cyclodextrin.

146. The method of claim 142, wherein the cyclodextrin comprises hydroxypropyl- β -cyclodextrin.

147. The method of claim 142, wherein the aqueous solution comprises a salt of the cyclodextrin.

148. The method of claim 147, wherein the salt of the cyclodextrin is a salt selected from the group consisting of: sodium, calcium, magnesium, iron, chromium, copper, zinc, lysine, arginine and histidine salts.

149. The method of claim 142, wherein the aqueous solution comprises sodium sulfobutyl ether- β -cyclodextrin.

150. The method of claim 142, wherein the cyclodextrin comprises hydroxypropyl- β -cyclodextrin.

151. The method of any one of claims 142-150, wherein the pharmaceutical composition comprises the cyclodextrin at the following concentrations: about 1% (w/v) to about 80% (w/v), about 2% (w/v) to about 70% (w/v), about 2% (w/v) to about 60% (w/v), about 2% (w/v) to about 50% (w/v), about 2% (w/v) to about 40% (w/v), about 2% (w/v) to about 30% (w/v), about 2% (w/v) to about 20% (w/v), about 2% (w/v) to about 15% (w/v), about 2% (w/v) to about 10% (w/v), about 2% (w/v) to about 8% (w/v), about 2% (w/v) to about 5% (w/v), about 5% (w/v) to about 80% (w/v), about 5% (w/v) to about 70% (w/v), about 5% (w/v) to about 60% (w/v), about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 5% (w/v), about 5% (w/v) to about 40% (w/v), about 40% (w/v) to about 30% (w/v), about 5% (w/v) to about 20% (w/v), about 5% (w/v) to about 15% (w/v), about 5% (w/v) to about 12% (w/v), about 5% (w/v) to about 10% (w/v), about 10% (w/v) to about 60% (w/v), about 10% (w/v) to about 50% (w/v), about 10% (w/v) to about 40% (w/v), about 10% (w/v) to about 30% (w/v), about 20% (w/v) to about 30% (w/v), about 10% (w/v) to about 25% (w/v), about 19% (w/v) to about 25% (w/v), about 19.5% (w/v) to about 25% (w/v), about 20% (w/v) to about 25% (w/v), about 20.5% (w/v) to about 25% (w/v), about 21% (w/v) to about 25% (w/v), about 25% (w/v) to about 25% (w/v) About 22.5% (w/v) to about 25% (w/v), about 23% (w/v) to about 25% (w/v), about 10% (w/v) to about 20% (w/v), or about 10% (w/v) to about 15% (w/v).

152. The method of any one of claims 142-150, wherein the pharmaceutical composition comprises the cyclodextrin in a concentration of 5% (w/v) to 40% (w/v).

153. The method of any one of claims 142-150, wherein the pharmaceutical composition comprises the cyclodextrin in a concentration of 10% (w/v) to 20% (w/v).

154. The method of any one of claims 142-150, wherein the pharmaceutical composition comprises the cyclodextrin in a concentration of 25% (w/v) to 40% (w/v).

155. The method of any one of claims 142-150, wherein the pharmaceutical composition comprises the cyclodextrin at the following concentrations: about 10% (w/v), about 12% (w/v), about 14% (w/v), about 15% (w/v), about 16% (w/v), about 18% (w/v), or about 20% (w/v).

156. The method of any one of claims 142-150, wherein the pharmaceutical composition comprises the cyclodextrin at the following concentrations: about 22% (w/v), about 24% (w/v), about 26% (w/v), about 28% (w/v), about 30% (w/v), about 32% (w/v), about 34% (w/v), about 36% (w/v), about 38% (w/v), or about 40% (w/v).

157. The method of claim 141, wherein the solubility enhancing agent comprises a lipid or fatty acid.

158. The method of claim 157, wherein the lipid or fatty acid is selected from the group consisting of: polyethoxylated castor oil, phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol (PEG), chitin, hyaluronic acid and polyvinylpyrrolidone; a lipid-containing sulfonated monosaccharide, a lipid-containing sulfonated disaccharide, and a lipid-containing sulfonated polysaccharide; fatty acids such as palmitic acid, stearic acid and oleic acid; cholesterol, cholesterol esters and cholesterol hemisuccinate.

159. The method of claim 141, wherein the solubility enhancing agent comprises a co-solvent.

160. The method of claim 159, wherein the co-solvent comprises glycerol or ethanol.

161. The method of claim 141, wherein the solubility enhancing agent comprises an organic acid.

162. The method of claim 161, wherein the organic acid is selected from the group consisting of: acetic acid, acid modified starch, acrylic tricarboxylic acid, fatty acid, adipic acid, L-ascorbic acid, benzoic acid, caproic acid, caprylic acid, cholic acid, citric acid, deoxycholic acid, erythronic acid (D-isoascorbic acid), formic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, iron naphthenate, iron resinate, D (-) -lactic acid, L (+) -lactic acid, linoleic acid, malic acid, L-malic acid, nicotinic acid (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, L (+) -potassium hydrogen tartrate, propionic acid, acid hydrolyzed protein, disodium pyrophosphate, sodium aluminum acid phosphate, sorbic acid, stearic acid, succinic acid, sulfamic acid, sulfuric acid, tannic acid, L (+) -tartaric acid, taurocholic acid, and thiodipropionic acid.

163. The method of any of claims 133-162, wherein the pharmaceutical composition comprises 20 to 500mg/mL of the imatinib or derivative thereof.

164. The method of any of claims 133-162, wherein the pharmaceutical composition comprises 20mg/mL to 400mg/mL, 20mg/mL to 300mg/mL, 20mg/mL to 200mg/mL, 100mg/mL to 500mg/mL, 200mg/mL to 500mg/mL, 300mg/mL to 500mg/mL, 400mg/mL to 500mg/mL, 100mg/mL to 400mg/mL, 100mg/mL to 300mg/mL, 100mg/mL to 200mg/mL, 200mg/mL to 400mg/mL, 200mg/mL to 300mg/mL, 20mg/mL to 100mg/mL, 20mg/mL to 80mg/mL, 20mg/mL to 60mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 30mg/mL, 30mg/mL to 40mg/mL, 40mg/mL to 80mg/mL, 40mg/mL to 100mg/mL, 40mg/mL to 60mg/mL, 60mg to 60mg/mL, 150mg to 150mg/mL, or the derivative thereof.

165. The method of any of claims 133-162, wherein the pharmaceutical composition comprises about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, or about 150mg/mL of the imatinib or derivative thereof.

166. The method of any of claims 133-162, wherein the pharmaceutical composition comprises about 80mg/mL of the imatinib or derivative thereof.

167. The method of any of claims 133-166, wherein the aqueous solution comprising the solubility enhancing agent further comprises a pH buffer.

168. The method of claim 167, wherein the pH buffer comprises an organic acid salt of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer.

169. The method of claim 167, wherein the pH buffer comprises a phosphate buffer.

170. The method of any of claims 133-169, wherein the pharmaceutical composition has a pH of 3 to 8.

171. The method of any of claims 133-169, wherein the pharmaceutical composition has a pH of 3 to 6, 4 to 6, 4.5 to 5.5, 5 to 6, 4 to 7, 5 to 7, or 6 to 7.

172. The method of any of claims 133-169, wherein the pharmaceutical composition has a pH of about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.4, about 5.5, or about 5.6.

173. The method of any of claims 133-169, wherein the pharmaceutical composition has a pH of 7 to 8.

174. The method of any of claims 133-169, wherein the pharmaceutical composition has a pH of about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0.

175. The method of any of claims 133-174, wherein the pharmaceutical composition has a viscosity of up to 10 centipoise.

176. The method of any of claims 133-174, wherein the pharmaceutical composition has a viscosity of up to 2.5 centipoise.

177. The method of any of claims 133-176, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

178. The method of claim 177, wherein the pharmaceutically acceptable excipient comprises a surfactant.

179. The method of claim 178, wherein the surfactant comprises tween, sodium dodecyl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

180. The method of claim 177, wherein the pharmaceutically acceptable excipient comprises a lipid.

181. The method of claim 180, wherein the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid.

182. The method of claim 180, wherein the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid.

183. The method of any of claims 133-182, wherein the solubility of the imatinib or derivative thereof in the aqueous solution is inversely related to the pH of the aqueous solution.

184. The method of any one of claims 142-183, wherein the solubility of imatinib or a derivative thereof in the aqueous solution is positively correlated to the concentration of the cyclodextrin in the aqueous solution.