Inhalable imatinib formulations

Abstract

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

Description

[Technical field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 134,336, filed January 6, 2021, and U.S. Provisional Patent Application No. 63 / 170,246, filed April 2, 2021, each of which is incorporated by reference in its entirety and for all purposes. [Background technology]

[0002] Imatinib is a small molecule kinase inhibitor that can inhibit Bcr-Abl tyrosine kinase, a constitutively abnormal tyrosine kinase generated by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML), and can be used to treat certain types of cancer. It is currently marketed by Novartis as its mesylate, imatinib mesilate (INN), in Gleevec (USA) or Glivec (Europe / Australia), and can inhibit proliferation and induce apoptosis in Bcr-Abl positive cell lines and fresh leukemia cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib can also inhibit the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF). There are also reports that injection (subcutaneous or intraperitoneal) or oral delivery of imatinib mesilate can have a therapeutic effect on pulmonary arterial hypertension in animal models and patients enrolled in clinical trials. Summary of the Invention [Means for solving the problem]

[0003]

[0003] In some embodiments, disclosed herein is a composition comprising an aqueous solution or suspension comprising (1) imatinib or a derivative thereof, (2) a solubility enhancer, and (3) a pH buffer, wherein the aqueous solution or suspension (a) has a concentration of imatinib or a derivative thereof from 20 to 500 mg / mL; (b) has a viscosity of up to 10 centipoise; and (c) has a pH of 3 to 8.

[0004] In some embodiments of the composition, the solubility enhancer is selected from the group consisting of a cyclodextrin, a lipid, a cosolvent, an organic acid, and a surfactant. In some embodiments of the composition, the solubility enhancer comprises a cyclodextrin. In some embodiments of the composition, the aqueous solution or suspension has a concentration of cyclodextrin from about 1% (w / v) to about 80% (w / v). In some embodiments of the composition, the solubility enhancer comprises a lipid or a fatty acid. In some cases of the composition, the lipid or fatty acid is selected from the group consisting of polyethoxylated castor oil, phospholipid, glycolipid, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol (PEG), chitin, hyaluronic acid, and polyvinylpyrrolidone; lipids with sulfonated monosaccharides, lipids with sulfonated disaccharides, lipids with sulfonated polysaccharides; 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 enhancer 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 enhancer comprises an organic acid. In some cases of the composition, the organic acid is selected from the group consisting of acetic acid, acid modified starch, aconitic acid, adipic acid, hexanedioic acid, L-ascorbic acid, benzoic acid, caprylic acid, octanoic acid, cholic acid, citric acid, deoxycholic acid, erythorbic acid (D-isoascorbic acid), formic acid, L-glutamic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, iron naphthenate, iron tartrate, iron stea ... tallate), D(-)-lactic acid, lactic acid, L(+)-lactic acid, linoleic acid, malic acid, L-malic acid, niacin (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, L(+)-potassium acid bitartrate, propionic acid, acid hydrolyzed proteins, sodium acid 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 enhancer comprises a surfactant, hi some cases, the surfactant comprises Tween, sodium lauryl sulfate (SLS), or dipalmitoylphosphatidylcholine (DPPC).

[0005]

[0005] In some embodiments, disclosed herein are compositions comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and cyclodextrin, wherein the aqueous solution or suspension has a concentration of cyclodextrin of about 1% (w / v) to about 80% (w / v).

[0006] In some cases of the composition, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin Dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, succinyl-α-cyclodextrin, succinyl-β-cyclodextrin, succinyl-γ-cyclodextrin, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, carboxymethyl-α-cyclodextrin, carboxymethyl The cyclodextrin may be selected from the group consisting of dimethyl-β-cyclodextrin, carboxymethyl-γ-cyclodextrin, 2-carboxyethyl-α-cyclodextrin, 2-carboxyethyl-β-cyclodextrin, 2-carboxyethyl-γ-cyclodextrin, phosphate-α-cyclodextrin, phosphate-β-cyclodextrin, phosphate-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin.In some cases of the composition, the cyclodextrin comprises succinyl-α-cyclodextrin, succinyl-β-cyclodextrin, succinyl-γ-cyclodextrin, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, carboxymethyl-α-cyclodextrin, carboxymethyl-β-cyclodextrin, carboxymethyl-γ-cyclodextrin, 2-carboxyethyl-α-cyclodextrin, 2-carboxyethyl-β-cyclodextrin, 2-carboxyethyl-γ-cyclodextrin, phosphate-α-cyclodextrin, phosphate-β-cyclodextrin, or phosphate-γ-cyclodextrin. In some cases of the composition, the cyclodextrin comprises an anionic cyclodextrin.

[0007]

[0007] In some embodiments, disclosed herein are compositions comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and a cyclodextrin, wherein the cyclodextrin comprises an anionic cyclodextrin.

[0008] In some cases, the aqueous solution or suspension further comprises a pH buffer. In some cases, 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 a phosphate buffer. In some cases, the pH buffer comprises a phosphate buffer.

[0009]

[0009] In some aspects, disclosed herein are compositions comprising an aqueous solution or suspension comprising imatinib or a derivative thereof, a cyclodextrin, a pH buffering agent, and a surfactant.

[0010] In some compositions, the aqueous solution or suspension comprises a salt of cyclodextrin. In some compositions, the salt of cyclodextrin is a salt selected from the group consisting of sodium salts, calcium salts, magnesium salts, iron salts, chromium salts, copper salts, zinc salts, lysine salts, arginine salts, and histidine salts. In some compositions, the cyclodextrin comprises sulfobutylether-β-cyclodextrin. In some compositions, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin. In some compositions, the aqueous solution or suspension comprises sulfobutylether-β-cyclodextrin sodium.

[0011] 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 lauryl sulfate (SLS), or dipalmitoylphosphatidylcholine (DPPC).

[0012] In some compositions, the aqueous solution or suspension has a viscosity of at most 10 centipoise. In some compositions, 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 4.8 ... In some embodiments, the viscosity of the composition may be at most 0.4 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 2.8 centipoise, at most 2.6 centipoise, at most 2.4 centipoise, at most 2.2 centipoise, at most 2.0 centipoise, at most 1.8 centipoise, at most 1.6 centipoise, at most 1.4 centipoise, at most 1.2 centipoise, at most 1.0 centipoise, at most 0.8 centipoise, at most 0.6 centipoise, at most 0.4 centipoise, or at most 0.2 centipoise.In some cases of the composition, the aqueous solution or suspension has a viscosity of about 0.1 centipoise, 0.2 centipoise, 0.3 centipoise, 0.4 centipoise, 0.5 centipoise, 0.6 centipoise, 0.7 centipoise, 0.8 centipoise, 0.9 centipoise, 1.0 centipoise, 1.1 centipoise, 1.2 centipoise, 1.3 centipoise, 1.4 centipoise, 1.5 centipoise, 1.6 centipoise, 1.7 centipoise, 1.8 centipoise, 1.9 centipoise, 2.0 centipoise, 2.1 centipoise, 2.2 centipoise, 2.3 centipoise, 2.4 centipoise, 2.5 centipoise, 2.6 centipoise, 2.8 centipoise, 3.0 centipoise, 3.2 centipoise, 3.5 centipoise, 3.8 centipoise, 4.0 centipoise, 4.2 centipoise, 4.5 centipoise, 4.8 centipoise, 5.0 centipoise, 5.5 centipoise, 6.0 centipoise, 6.5 centipoise, 7.0 centipoise, 7.5 centipoise, 8.0 centipoise, or 8.5 centipoise.

[0013] In some cases of the composition, the aqueous solution or suspension has 20-500 mg / mL of imatinib or its derivatives. In some cases of the composition, the aqueous solution or suspension has 20 mg / mL-400 mg / mL, 20 mg / mL-300 mg / mL, 20 mg / mL-200 mg / mL, 100 mg / mL-500 mg / mL, 200 mg / mL-500 mg / mL, 300 mg / mL-500 mg / mL, 400 mg / mL-500 mg / mL, 100 mg / mL-400 mg / mL, 100 mg / mL-300 mg / mL, 100 mg / mL-200 mg / mL, 200 mg / mL-400 mg / mL, 200 mg / mL-300 mg / mL, 20-100, 20 imatinib or a derivative thereof. In some cases of the composition, the aqueous solution or suspension has about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, or about 150 mg / mL of imatinib or a derivative thereof. In some cases of the composition, the aqueous solution or suspension has about 80 mg / mL of imatinib or a derivative thereof.

[0014] In some compositions, the aqueous solution or suspension has a pH of 3-8. In some compositions, the aqueous solution or suspension has a pH of 3-6, 4-6, 4.5-5.5, 5-6, 4-7, 5-7, or 6-7. In some compositions, the aqueous solution or suspension has a pH of 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 compositions, the aqueous solution or suspension has a pH of 7-8. In some compositions, the aqueous solution or suspension has a pH of about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0.

[0015] In some cases of the composition, the aqueous solution or suspension is from about 2% (w / v) to about 70% (w / v), from about 2% (w / v) to about 60% (w / v), from about 2% (w / v) to about 50% (w / v), from about 2% (w / v) to about 40% (w / v), from about 2% (w / v) to about 30% (w / v), from about 2% (w / v) to about 20% (w / v), from about 2% (w / v) to about 15% (w / v), from about 2% (w / v) to about 10% (w / v), from about 2% (w / v) to about Approximately 8% (w / v), approximately 2% (w / v) to approximately 5% (w / v), approximately 5% (w / v) to approximately 80% (w / v), approximately 5% (w / v) to approximately 70% (w / v), approximately 5% (w / v) to approximately 60% (w / v), approximately 5% (w / v) to approximately 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% (w / v) to about The cyclodextrin has a concentration of about 25% (w / v), about 20.5% (w / v) to about 25% (w / v), about 21% (w / v) to about 25% (w / v), about 21.5% (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 the composition, the aqueous solution or suspension has a cyclodextrin concentration of 5% (w / v) to 40% (w / v). In some compositions, the aqueous solution or suspension has a cyclodextrin concentration of 10% (w / v) to 20% (w / v). In some compositions, the aqueous solution or suspension has a cyclodextrin concentration of 25% (w / v) to 40% (w / v).In some cases of the composition, the aqueous solution or suspension has a cyclodextrin concentration of 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 aqueous solution or suspension has a cyclodextrin concentration of 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).

[0016] 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 the aqueous solution is negatively correlated with the pH of the aqueous solution. In some cases of the composition, the solubility of imatinib or a derivative thereof in the aqueous solution is positively correlated with the concentration of cyclodextrin in the aqueous solution.

[0017] In some cases, the composition comprises an aqueous suspension.

[0018] In some cases of the composition, the composition comprises less than 1 mg / mL, less than 0.5 mg / mL, less than 0.1 mg / mL, less than 0.05 mg / mL, less than 0.01 mg / mL, less than 0.005 mg / mL, less than 0.001 mg / mL, or less than 0.0001 mg / 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.

[0018]

[0019] In some embodiments, disclosed herein are pharmaceutical compositions comprising the compositions disclosed herein. In some cases, the pharmaceutical compositions are formulated for inhalatory administration. In some cases of the pharmaceutical compositions, the aqueous solution further comprises a pharma- ceutically acceptable excipient. In some cases, the pharma-ceutically acceptable excipient comprises a surfactant. In some cases of the pharmaceutical compositions, the surfactant comprises Tween, sodium lauryl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). In some cases, the pharma-ceutically acceptable excipient comprises a lipid. In some cases of the pharmaceutical compositions, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid. In some cases of the pharmaceutical compositions, the lipid comprises a polymeric lipid, a sulfonated polysaccharide, or a fatty acid. In some cases of the pharmaceutical compositions, the pharmaceutical compositions are organoleptically tolerated when inhaled by a human subject. In some cases of the pharmaceutical compositions, the pharmaceutical compositions do not induce a cough reflex when inhaled by a human subject. In some cases of the pharmaceutical compositions, the pharmaceutical compositions cause no or minimal irritation to the mouth or throat when inhaled by a human subject.

[0019]

[0020] In some embodiments, disclosed herein are pharmaceutical compositions comprising an aqueous solution comprising a cyclodextrin and a therapeutically effective amount of imatinib or a derivative thereof, wherein the aqueous solution is formulated for administration by inhalation.

[0020]

[0021] In some cases of the pharmaceutical composition, the aqueous solution has a viscosity of at most 10 centipoise. In some cases of the pharmaceutical composition, the aqueous solution has a viscosity of at most 2.5 centipoise.

[0021]

[0022] In some cases of the pharmaceutical composition, the aqueous solution has 20-500 mg / mL of imatinib or a derivative thereof. In some cases of the pharmaceutical composition, the aqueous solution has 20 mg / mL-400 mg / mL, 20 mg / mL-300 mg / mL, 20 mg / mL-200 mg / mL, 100 mg / mL-500 mg / mL, 200 mg / mL-500 mg / mL, 300 mg / mL-500 mg / mL, 400 mg / mL-500 mg / mL, 100 mg / mL-400 mg / mL, 100 mg / mL-300 mg / mL, 100 mg / mL-200 mg / mL, 200 mg / mL-400 mg / mL, 200 mg / mL-300 mg / mL, 20-100, 20 mg

[0036] In one embodiment, the present invention has imatinib or a derivative thereof of 60 mg / mL to 80 mg / mL, 20 mg / mL to 60 mg / mL, 20 mg / mL to 40 mg / mL, 20 mg / mL to 30 mg / mL, 30 mg / mL to 40 mg / mL, 40 mg / mL to 60 mg / mL, 40 mg / mL to 80 mg / mL, 40 mg / mL to 100 mg / mL, 40 mg / mL to 120 mg / mL, 40 mg / mL to 150 mg / mL, 60 mg / mL to 80 mg / mL, 60 mg / mL to 100 mg / mL, 60 mg / mL to 120 mg / mL, or 60 mg / mL to 150 mg / mL. In some cases of the pharmaceutical composition, the aqueous solution has about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, or about 150 mg / mL of imatinib or a derivative thereof. In some cases of the pharmaceutical composition, the aqueous solution has about 80 mg / mL of imatinib or a derivative thereof.

[0022]

[0023] In some cases of the pharmaceutical composition, the aqueous solution has a pH of 3-8. In some cases of the pharmaceutical composition, the pH of the aqueous solution is 3-6, 4-6, 4.5-5.5, 5-6, 4-7, 5-7, or 6-7. 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 the pharmaceutical composition, the pH of the aqueous solution or suspension is 7-8. 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 buffering agent 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.

[0023]

[0024] In some cases of the pharmaceutical composition, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin. Dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, succinyl-α-cyclodextrin, succinyl-β-cyclodextrin, succinyl-γ-cyclodextrin, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, carboxymethyl-α-cyclodextrin, carboxymethyl The cyclodextrin may be selected from the group consisting of dimethyl-β-cyclodextrin, carboxymethyl-γ-cyclodextrin, 2-carboxyethyl-α-cyclodextrin, 2-carboxyethyl-β-cyclodextrin, 2-carboxyethyl-γ-cyclodextrin, phosphate-α-cyclodextrin, phosphate-β-cyclodextrin, phosphate-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin.In some cases of the pharmaceutical composition, the cyclodextrin comprises succinyl-α-cyclodextrin, succinyl-β-cyclodextrin, succinyl-γ-cyclodextrin, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, carboxymethyl-α-cyclodextrin, carboxymethyl-β-cyclodextrin, carboxymethyl-γ-cyclodextrin, 2-carboxyethyl-α-cyclodextrin, 2-carboxyethyl-β-cyclodextrin, 2-carboxyethyl-γ-cyclodextrin, phosphate-α-cyclodextrin, phosphate-β-cyclodextrin, or phosphate-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 sulfobutylether-β-cyclodextrin. In some cases of the pharmaceutical composition, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin. In some cases of the pharmaceutical composition, 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 salt, calcium salt, magnesium salt, iron salt, chromium salt, copper salt, zinc salt, lysine salt, arginine salt, and histidine salt. In some cases of the pharmaceutical composition, the aqueous solution comprises sulfobutylether-β-cyclodextrin sodium.

[0024]

[0025] In some cases of the pharmaceutical composition, the aqueous solution is from about 1% (w / v) to about 80% (w / v), from about 2% (w / v) to about 70% (w / v), from about 2% (w / v) to about 60% (w / v), from about 2% (w / v) to about 50% (w / v), from about 2% (w / v) to about 40% (w / v), from about 2% (w / v) to about 30% (w / v), from about 2% (w / v) to about 20% (w / v), from about 2% (w / v) to about 15% (w / v), from about 2% (w / v) to about 10% (w / v), from about 2% (w / v) ~ approx. 8% (w / v), approx. 2% (w / v) ~ approx. 5% (w / v), approx. 5% (w / v) ~ approx. 80% (w / v), approx. 5% (w / v) ~ approx. 70% (w / v), approx. 5% (w / v) ~ approx. 60% (w / v), approximately 5% (w / v) ~50% (w / v), approximately 5% (w / v) ~ approximately 40% (w / v), approximately 5% (w / v) ~ approximately 30% (w / v), approximately 5% (w / v) ~ approximately 20% (w / v), approximately 5% (w / v) ~ approximately 15% (w / v), approximately 5% (w / v) ~ approximately 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 3 0% (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) The cyclodextrin has a concentration of about 25% (w / v), about 20.5% (w / v) to about 25% (w / v), about 21% (w / v) to about 25% (w / v), about 21.5% (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 the pharmaceutical composition, the aqueous solution has a cyclodextrin concentration of 5% (w / v) to 40% (w / v). In some cases of the pharmaceutical composition, the aqueous solution has a cyclodextrin concentration of 10% (w / v) to 20% (w / v). In some cases of the pharmaceutical composition, the aqueous solution has a cyclodextrin concentration of 25% (w / v) to 40% (w / v).In some cases of the pharmaceutical composition, the aqueous solution has a cyclodextrin concentration of 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 aqueous solution has a cyclodextrin concentration of 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).

[0025]

[0026] In some cases, the pharmaceutical composition is organoleptically tolerable when inhaled by a human subject. In some cases, the pharmaceutical composition does not induce a cough reflex when inhaled by a human subject. In some cases, the pharmaceutical composition causes no or minimal mouth or throat irritation when inhaled by a human subject.

[0026]

[0027] In some cases, the pharmaceutical composition comprises less than 1 mg / mL, less than 0.5 mg / mL, less than 0.1 mg / mL, less than 0.005 mg / mL, less than 0.001 mg / mL, or less than 0.0001 mg / mL of imatinib mesylate. In some cases, the pharmaceutical composition does not comprise imatinib mesylate. In some cases of the pharmaceutical composition, imatinib or a derivative thereof comprises imatinib free base. In some cases of the pharmaceutical composition, imatinib or a derivative thereof is imatinib free base.

[0027]

[0028] 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.

[0028]

[0029] In some cases of the pharmaceutical composition, the aqueous solution further comprises a pharma- ceutically acceptable excipient. In some cases of the pharmaceutical composition, the pharma- ceutically acceptable excipient comprises a surfactant. In some cases of the pharmaceutical composition, the surfactant comprises Tween, sodium lauryl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). In some cases of the pharmaceutical composition, the pharma- ceutically 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.

[0029]

[0030] In some cases of the pharmaceutical compositions, the solubility of imatinib or its derivatives in an aqueous solution is negatively correlated with the pH of the aqueous solution. In some cases of the pharmaceutical compositions, the solubility of imatinib or its derivatives in an aqueous solution is positively correlated with the concentration of cyclodextrin in the aqueous solution.

[0030]

[0031] In some embodiments, disclosed herein are aerosol compositions comprising atomized droplets of a pharmaceutical composition disclosed herein, or atomized droplets of a composition disclosed herein. In some cases, the atomized droplets have a mean 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.

[0031]

[0032] In some embodiments, a unit dose of a pharmaceutical composition disclosed herein, or a composition disclosed herein, or an aerosol composition disclosed herein, comprising about 10 mg to about 500 mg of imatinib or a derivative thereof is disclosed herein. In some cases, the unit dose comprises 20 mg to 180 mg, 20 mg to 150 mg, 20 mg to 120 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, 40 mg to 120 mg, 60 mg to 100 mg, or 60 mg to 80 mg of imatinib or a derivative thereof.

[0032]

[0033] Disclosed herein in some aspects is a method of treating a subject having a pulmonary disease, the method comprising administering to a subject in need thereof by inhalation a pharmaceutical composition disclosed herein.

[0033]

[0034] In some cases, the method includes administering to the subject about 10 mg to about 500 mg of imatinib or a derivative thereof by inhalation. In some cases, the method includes administering to the subject 20 mg to 180 mg, 20 mg to 150 mg, 20 mg to 120 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, 40 mg to 120 mg, 60 mg to 100 mg, or 60 mg to 80 mg of imatinib or a derivative thereof.

[0034]

[0035] 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 a day. In some cases, the method comprises administering the pharmaceutical composition to the subject 2, 3, 4, or 5 times a day. In some cases, the method comprises administering the pharmaceutical composition to the subject for at least 5, 10, 20, 30, 60, 100, or 300 days, at least 1, 2, 3, 4, or 5 years.

[0035]

[0036] In some cases of the method, the administering step is performed using a nebulizer. In some cases of the method, the nebulizer is a jet nebulizer, a vibrating mesh nebulizer, or an ultrasonic nebulizer. In some cases of the method, the administration of the single unit dose of the pharmaceutical composition is performed within 30 minutes. In some cases of the method, the administration of the single unit dose of the pharmaceutical composition is performed within 15 minutes, 10 minutes, or 5 minutes. In some cases of the method, the administration of the pharmaceutical composition does not induce a cough reflex in the subject. In some cases of the method, the pharmaceutical composition causes no or minimal irritation to the subject's mouth or throat.

[0036]

[0037] In some embodiments, disclosed herein is a kit comprising a pharmaceutical composition disclosed herein or a unit dose disclosed herein and instructions for using the pharmaceutical composition for the treatment of a pulmonary disease.

[0037]

[0038] In some embodiments, disclosed herein is a kit comprising: (a) a pharmaceutical composition disclosed herein; (b) a container containing the pharmaceutical composition; and (c) instructions for administering the pharmaceutical composition via a nebulizer to a subject in need thereof.

[0038]

[0039] In some embodiments, disclosed herein is a system comprising the pharmaceutical composition disclosed herein and a nebulizer. In some cases of the system, the nebulizer is a jet nebulizer, a vibrating mesh nebulizer, or an ultrasonic nebulizer.

[0039]

[0040] In some embodiments, disclosed herein is a method for producing a pharmaceutical composition comprising imatinib or a derivative thereof, the method comprising the steps of: preparing an aqueous solution comprising a solubility enhancer; dissolving imatinib or a derivative thereof, or a pharma- ceutically acceptable salt thereof, in the aqueous solution comprising the solubility enhancer to produce an aqueous solution containing imatinib or a derivative thereof; and adjusting the volume, pH, osmolality, or viscosity of the aqueous solution containing imatinib or a derivative thereof to produce a pharmaceutical composition comprising imatinib or a derivative thereof.

[0040]

[0041] In some methods, imatinib or its derivatives, or its pharma- ceutically acceptable salts, comprises imatinib free base. In some methods, imatinib or its derivatives, or its pharma- ceutically acceptable salts, is imatinib free base. In some methods, imatinib or its derivatives, or its pharma- ceutically acceptable salts, comprises an imatinib salt selected from the group consisting of acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate, and succinate. In some methods, imatinib or its derivatives, or its pharma- ceutically acceptable salts, 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 1 mg / mL, less than 0.5 mg / mL, less than 0.1 mg / mL, less than 0.005 mg / mL, less than 0.001 mg / mL, or less than 0.0001 mg / mL of imatinib mesylate. In some cases of the method, the imatinib or a derivative thereof, or a pharma- ceutically acceptable salt thereof, does not comprise imatinib mesylate. In some cases of the method, the pharmaceutical composition does not comprise imatinib mesylate. In some cases of the method, the solubility enhancer is selected from the group consisting of cyclodextrins, lipids, cosolvents, and organic acids.

[0041]

[0042] In some cases of the method, the solubility enhancer comprises a cyclodextrin. In some cases of the method, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin dimaltosyl-β-cyclodextrin, and 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin. In some embodiments of the method, the cyclodextrin comprises succinyl-α-cyclodextrin, succinyl-β-cyclodextrin, succinyl-γ-cyclodextrin, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, carboxymethyl-α-cyclodextrin, carboxymethyl-β-cyclodextrin, carboxymethyl-γ-cyclodextrin, 2-carboxyethyl-α-cyclodextrin, 2-carboxyethyl-β-cyclodextrin, 2-carboxyethyl-γ-cyclodextrin, phosphate-α-cyclodextrin, phosphate-β-cyclodextrin, phosphate-γ-cyclodextrin, sulfobutylether-γ-cyclodextrin, or sulfobutylether-γ-cyclodextrin. In some embodiments of the method, the cyclodextrin comprises an anionic cyclodextrin. In some cases of the method, 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 a cyclodextrin.In some cases of the method, the cyclodextrin salt is a salt selected from the group consisting of sodium salts, calcium salts, magnesium salts, iron salts, chromium salts, copper salts, zinc salts, lysine salts, arginine salts, and histidine salts. In some cases of the method, the aqueous solution comprises sulfobutylether-β-cyclodextrin sodium.

[0042]

[0043] In some instances of the method, the pharmaceutical composition is from about 1% (w / v) to about 80% (w / v), from about 2% (w / v) to about 70% (w / v), from about 2% (w / v) to about 60% (w / v), from about 2% (w / v) to about 50% (w / v), from about 2% (w / v) to about 40% (w / v), from about 2% (w / v) to about 30% (w / v), from about 2% (w / v) to about 20% (w / v), from about 2% (w / v) to about 15% (w / v), from about 2% (w / v) to about 10% (w / v), from about 2% (w / v) to about 3 ... w / v) ~ approx. 8% (w / v), approx. 2% (w / v) ~ approx. 5% (w / v), approx. 5% (w / v) ~ approx. 80% (w / v), approx. 5% (w / v) ~ approx. 70% (w / v), approx. 5% (w / v) ~ approx. 60% (w / v), approx. Approximately 50% (w / v), approximately 5% (w / v) to approximately 40% (w / v), approximately 5% (w / v) to approximately 30% (w / v), approximately 5% (w / v) to approximately 20% (w / v), approximately 5% (w / v) to approximately 15% (w / v), approximately 5% (w / v) to approximately 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 3 0% (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 21.5% (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 the method, the pharmaceutical composition comprises a cyclodextrin concentration of 5% (w / v) to 40% (w / v). In some embodiments of the method, the pharmaceutical composition comprises a cyclodextrin in a concentration of 10% (w / v) to 20% (w / v). In some embodiments of the method, the pharmaceutical composition comprises a cyclodextrin in a concentration of 25% (w / v) to 40% (w / v).In some embodiments of the method, the pharmaceutical composition comprises a cyclodextrin at a concentration of 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 embodiments of the method, the pharmaceutical composition comprises a cyclodextrin at a concentration of 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).

[0043]

[0044] In some cases of the method, the solubility enhancer comprises a lipid or a fatty acid. In some cases of the method, 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; lipids with sulfonated monosaccharides, lipids with sulfonated disaccharides, lipids with sulfonated polysaccharides; 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 enhancer comprises a co-solvent. In some cases of the method, the co-solvent comprises glycerol or ethanol.

[0044]

[0045] In some embodiments of the method, the solubility enhancer comprises an organic acid. In some embodiments of the method, the organic acid is selected from the group consisting of acetic acid, acid modified starch, aconitic acid, adipic acid, hexanedioic acid, L-ascorbic acid, benzoic acid, caprylic acid, octanoic acid, cholic acid, citric acid, deoxycholic acid, erythorbic acid (D-isoascorbic acid), formic acid, L-glutamic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, ferric naphthenate, ferric tartrate, D(-)-lactic acid, lactic acid, L(+)-lactic acid, linoleic ... In some embodiments, the acid is selected from the group consisting of oleic acid, malic acid, L-malic acid, niacin (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, potassium L(+)-acid bitartrate, propionic acid, acid hydrolyzed protein, sodium acid 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.

[0045]

[0046] In some embodiments of the method, the pharmaceutical composition comprises 20-500 mg / mL of imatinib or a derivative thereof. In some embodiments of the method, the pharmaceutical composition comprises 20 mg / mL-400 mg / mL, 20 mg / mL-300 mg / mL, 20 mg / mL-200 mg / mL, 100 mg / mL-500 mg / mL, 200 mg / mL-500 mg / mL, 300 mg / mL-500 mg / mL, 400 mg / mL-500 mg / mL, 100 mg / mL-400 mg / mL, 100 mg / mL-300 mg / mL, 100 mg / mL-200 mg / mL, 200 mg / mL-400 mg / mL, 200 mg / mL-300 mg / mL, 20-100, 20 mg

[0036] The present invention relates to imatinib or a derivative thereof, the amount of which is imatinib or a derivative thereof. In some cases of the method, the pharmaceutical composition comprises about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, or about 150 mg / mL of imatinib or a derivative thereof. In some cases of the method, the pharmaceutical composition comprises about 80 mg / mL of imatinib or a derivative thereof.

[0046]

[0047] In some cases of the method, the aqueous solution containing the solubility enhancer 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 a phosphate buffer. In some cases of the method, the pH buffer comprises a phosphate buffer. In some cases of the method, the pharmaceutical composition has a pH of 3-8. In some cases of the method, the pharmaceutical composition has a pH of 3-6, 4-6, 4.5-5.5, 5-6, 4-7, 5-7, or 6-7. In some cases of the method, 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. In some cases of the method, the pharmaceutical composition has a pH of 7-8. In some cases of the method, 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.

[0047]

[0048] In some cases of the method, the pharmaceutical composition has a viscosity of up to 10 centipoise. In some cases of the method, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient. In some cases of the method, the pharma- ceutical acceptable excipient comprises a surfactant. In some cases of the method, the surfactant comprises Tween, sodium lauryl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). In some cases of the method, the pharma- ceutical 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 the method, the solubility of imatinib or a derivative thereof in an aqueous solution is negatively correlated with the pH of the aqueous solution. In some cases of the 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 by Reference

[0049] 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.

[0048]

[0050] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure can be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings, in which: [Brief description of the drawings]

[0049] [Figure 1]

[0051] FIG. 1 shows a graph depicting the maximum concentration (mg / mL) of imatinib free base as a function of pH. [Diagram 2]

[0052] FIG. 2 shows a graph depicting the maximum concentration (mg / mL) of imatinib free base as a function of percent hydroxypropyl beta cyclodextrin (HPβCD or "HPBCD" in the figures) (w / v) at pHs of 5 and 7.5. [Figure 3A]

[0053] FIG. 3A shows a graph depicting the maximum concentration (mg / mL) of imatinib free base as a function of percent hydroxypropyl beta cyclodextrin (HPβCD or "HPBCD" in the figures) (w / v) at pHs of 5 and 7.5, and percent sulfobutyl ether beta cyclodextrin (SBEβCD or "SBEBCD" in the figures) (w / v) at a pH of 5. [Figure 3B]

[0054] FIG. 3B shows photographs of exemplary suspensions and solutions of about 30 mg / mL imatinib free base in aqueous solutions of 30% SBEβCD and 50 mM phosphate buffer at different pH levels. [Figure 4A]

[0055] FIG. 4A is a plot summarizing lung tissue concentrations of imatinib over time following IT (free base suspension) or IV (mesylate solution) administration. [Figure 4B]

[0056] FIG. 4B is a plot summarizing the plasma concentrations of imatinib over time following IT (free base suspension) or IV (mesylate solution) administration. [Figure 4C]

[0057] FIG. 4C is a plot summarizing lung tissue concentrations versus plasma concentrations of imatinib over time following IT administration of imatinib free base suspension. [Figure 4D]

[0058] FIG. 4D is a plot summarizing lung tissue concentrations of imatinib versus plasma concentrations of imatinib over time following IV administration of imatinib mesylate solution. [Figure 4E]

[0059] FIG. 4E is a plot summarizing lung tissue concentrations of imatinib versus plasma concentrations of imatinib over time following IT administration of imatinib free base suspension, plotted on a logarithmic scale. [Figure 4F]

[0060] FIG. 4F is a logarithmic scale plot summarizing lung tissue concentrations of imatinib versus plasma concentrations of imatinib over time following IV administration of imatinib mesylate solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050]

[0061] In some embodiments, the present disclosure provides compositions (e.g., pharmaceutical compositions), methods (e.g., methods of treatment, methods of making compositions), kits, and systems related to aqueous solutions or suspensions of imatinib. The aqueous solutions or suspensions of imatinib disclosed herein can be used as inhalable formulations for use in human patients, for example, by aerosolization with a nebulizer. In some embodiments, the pharmaceutical compositions and methods of treatment provided herein are advantageous in providing a fast, efficient, and safe therapeutic solution for treating pulmonary conditions. In some embodiments, the present disclosure relates to administration by inhalation of pharmaceutical compositions in the form of aqueous solutions or suspensions comprising imatinib and a solubility enhancer.

[0051]

[0062] In some embodiments, the pharmaceutical compositions or formulations provided herein allow for the delivery of more pharma- ceutical active ingredients, 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 enhancer. In some embodiments, the solubility enhancer comprises a cyclodextrin, a pH buffer, a lipid, a fatty acid, a cosolvent, or an organic solvent. In some cases, the pharmaceutical compositions described herein have variable concentrations of solubility enhancers to increase the solubility of imatinib or a derivative thereof, or a pharma- ceutical acceptable salt thereof. As used herein, the term "solubility" in reference to a specified solute in a solution can mean the maximum amount of solute that can be dissolved in a unit amount of a specified solvent 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" can mean the maximum amount of imatinib or a derivative thereof that can be dissolved in a unit amount of water present in the aqueous solution. In some embodiments, the amount of imatinib relative to the solubility enhancer in the aqueous solution or suspension provided herein can shorten the inhalation time, for example, because a given dose can be delivered at a faster rate compared to a comparable formulation that does not have a solubility enhancer and therefore has a relatively much lower concentration of imatinib.A shorter inhalation time can improve subject compliance, which can further increase the delivery efficiency of the drug.

[0052]

[0063] In some embodiments, the pharmaceutical compositions or formulations provided herein reduce the subject's unpleasant coughing upon inhalation, have improved organoleptic properties, and improve the overall patient inhalation experience. In some embodiments, the improved overall inhalation experience results in better compliance with the entire inhalation program. In some embodiments, more effective drug delivery is achieved when the subject has better inhalation compliance, and therefore more drug is delivered. Some aqueous solutions of imatinib mesylate or other salts of imatinib may have poor organoleptic properties, for example, may be severely irritating to the respiratory tract and may induce significant unpleasant sensations in the mouth and throat when inhaled by a human subject, and / or may induce coughing or even violent coughing, resulting in continuous deep lung inhalation being impossible or impractical. In some cases, solutions of imatinib mesylate or certain other salts of imatinib are not inhalable, for example, because they are not organoleptically acceptable to human subjects to allow continuous deep lung inhalation of the atomized aerosol. In contrast, the formulations according to some embodiments of the present disclosure can have improved organoleptic properties suitable for deep lung inhalation of the nebulized aerosol. In some cases, the formulations provided herein, for example, aqueous solutions made of imatinib free base, are not irritating or minimally irritating to the mouth and throat when inhaled in the form of nebulized aerosol. For example, subjects will not experience any unpleasant or severely unpleasant organoleptic irritation when inhaling nebulized aerosol of some formulations provided herein. Some formulations provided herein do not induce a cough reflex or violent cough in subjects inhaling the formulation. Subjects inhaling some formulations provided herein may report that they are tolerable and can continue deep lung inhalation for a desired period of time.

[0053]

[0064] Without being bound by any particular theory, the mesylate form of imatinib contributes to the undesirable organoleptic properties of the mist aerosol of its aqueous solution. In some embodiments, the formulations provided herein avoid problems associated with undesirable organoleptic properties by preparing the formulation using imatinib free base or other salt forms of imatinib. The absence of the mesylate form of imatinib can contribute to the improved organoleptic properties of certain formulations provided herein.

[0054]

[0065] In one aspect of the present disclosure, provided herein is a unit dose of the pharmaceutical composition provided herein. In some embodiments, the unit dose comprises about 20 mg to about 500 mg of imatinib free base. In another aspect, provided herein is a kit comprising the pharmaceutical composition or unit dose provided herein and instructions for using the pharmaceutical composition to treat pulmonary disease.

[0055] composition

[0066] In some embodiments, provided 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 aqueous solution or suspension has a concentration of imatinib of 20-500 mg / mL. In some cases, the aqueous solution or suspension has a viscosity of up to 10 centipoise. In some cases, the aqueous solution or suspension has a pH of 3-8. In some cases, the aqueous solution or suspension has a concentration of imatinib or a derivative thereof of 20-500 mg / m, a viscosity of up to 10 centipoise, and a pH of 3-8.

[0056]

[0067] In some cases, provided herein is a composition comprising an aqueous solution or suspension comprising imatinib or a derivative thereof and a cyclodextrin. In some cases, the aqueous solution or suspension has a cyclodextrin concentration of about 1% (w / v) to about 80% (w / v). In some cases, the cyclodextrin is an anionic cyclodextrin.

[0057]

[0068] In some cases, the compositions provided herein include a dilution of 20 mg / mL to 400 mg / mL, 20 mg / mL to 300 mg / mL, 20 mg / mL to 200 mg / mL, 100 mg / mL to 500 mg / mL, 200 mg / mL to 500 mg / mL, 300 mg / mL to 500 mg / mL, 400 mg / mL to 500 mg / mL, 100 mg / mL to 400 mg / mL, 100 mg / mL to 300 mg / mL, 100 mg / mL to 200 mg / mL, 200 mg / mL to 400 mg / mL, 200 mg / mL to 300 mg / mL, 20 to 100, 20 imatinib or a derivative thereof.

[0058]

[0069] In some cases, the compositions provided herein have a viscosity of up to 10 centipoise, e.g., up to 9.5 centipoise, up to 9.0 centipoise, up to 8.5 centipoise, up to 8.0 centipoise, up to 7.6 centipoise, up to 7.4 centipoise, up to 7.2 centipoise, up to 7.0 centipoise, up to 6.8 centipoise, up to 6.6 centipoise, up to 6.4 centipoise, up to 6.2 centipoise, up to 6.0 centipoise, up to 5.8 centipoise, up to 5.6 centipoise, up to 5.4 centipoise, up to 5.2 centipoise, up to 5.0 centipoise, up to 4.8 centipoise, up to 4.6 centipoise, In some embodiments, the viscosity of the oleic acid or oleic acid derivative may be 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 2.8 centipoise, at most 2.6 centipoise, at most 2.4 centipoise, at most 2.2 centipoise, at most 2.0 centipoise, at most 1.8 centipoise, at most 1.6 centipoise, at most 1.4 centipoise, at most 1.2 centipoise, at most 1.0 centipoise, at most 0.8 centipoise, at most 0.6 centipoise, at most 0.4 centipoise, or at most 0.2 centipoise.For example, the compositions provided herein can be hydrated to about 0.1 centipoise, 0.2 centipoise, 0.3 centipoise, 0.4 centipoise, 0.5 centipoise, 0.6 centipoise, 0.7 centipoise, 0.8 centipoise, 0.9 centipoise, 1.0 centipoise, 1.1 centipoise, 1.2 centipoise, 1.3 centipoise, 1.4 centipoise, 1.5 centipoise, 1.6 centipoise, 1.7 centipoise, 1.8 centipoise, 1.9 centipoise, 2.0 centipoise, 2.1 centipoise, The viscosity of the composition may be 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, 8.0, or 8.5 centipoise.

[0059]

[0070] In some cases, the compositions provided herein have a pH of 3 to 7, e.g., 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 compositions provided herein have a pH of 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 compositions include an aqueous solution of imatinib or a derivative thereof and have a pH of 3 to 7.

[0060]

[0071] In some cases, the compositions provided herein have a pH of 7-8, e.g., about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, or about 8.0. In some cases, the compositions comprise an aqueous suspension of imatinib or a derivative thereof and have a pH of 3-8.

[0061]

[0072] In some cases, the compositions provided herein do not have imatinib mesylate.In some cases, the compositions provided herein have a substantially low amount of imatinib mesylate, such as less than 1 mg / mL, less than 0.5 mg / mL, less than 0.4 mg / mL, less than 0.3 mg / mL, less than 0.2 mg / mL, less than 0.1 mg / mL, less than 0.075 mg / mL, less than 0.05 mg / mL, less than 0.025 mg / mL, less than 0.01 mg / mL, less than 0.0075 mg / mL, less than 0.005 mg / mL, less than 0.0025 mg / mL, less than 0.001 mg / mL, less than 0.00075 mg / mL, less than 0.0005 mg / mL, less than 0.00025 mg / mL, or less than 0.0001 mg / mL of imatinib mesylate. In some cases, the compositions have 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 even less, of the total amount of imatinib contained in the composition.

[0062]

[0073] In some cases, the compositions provided herein comprise an aqueous solution of imatinib or a derivative thereof. The term "solution" as used herein can refer to a homogeneous mixture of one or more solutes dissolved in a solvent. The term "solvent" can refer to a substance in which a solute dissolves to form a homogeneous mixture, and the term "solute" can refer to a substance in which a solvent dissolves to form a homogeneous mixture. As used herein, the term "aqueous solution" can refer to a solution in which one or more solvents is water.

[0063]

[0074] In some cases, the composition provided herein is an aqueous suspension of imatinib or a derivative thereof. The term "suspension" as used herein can refer to a heterogeneous mixture in which at least some of the solute particles are not dissolved but are suspended throughout the solvent. The suspension disclosed herein can be one in which some of the solute (e.g., imatinib or a derivative thereof) is dissolved in a solvent (e.g., water) while the rest is suspended in water and floats freely therein. The term "aqueous suspension" as used herein can refer to a suspension in which one or more solvents are water. The suspension provided herein can be used for therapeutic treatment and can be prepared immediately prior to therapeutic use (e.g., mixing the components and suspending undissolved imatinib or a derivative thereof in a solution mainly composed of water).

[0064] Imatinib

[0075] In some embodiments, the compositions disclosed herein include imatinib or a derivative thereof. In some embodiments of the present disclosure, the pharmaceutical composition includes a pharmaceutical agent for treating pulmonary disease. In some embodiments, the pharmaceutical agent for treating 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 of imatinib, e.g., a pharmaceutically acceptable salt, includes imatinib mesylate. In some embodiments, the pharmaceutical agent for treating pulmonary disease is an imatinib derivative (e.g., nilotinib, sorafenib, dasatinib) or a pharmaceutically acceptable salt thereof. Exemplary imatinib derivatives can include those described in Skobridis K et al. ChemMedChem. 2010 January;5(1):130-9, A. Mortlock et al. Comprehensive Medicinal Chemistry II, Vol. 7, 2007, pp. 183-220, and Musumeci F et al. Expert Opin Ther Pat. 2015;25(12):1411-21, all of which are incorporated herein in their entireties.

[0065]

[0076] The chemical structure of imatinib is shown in Compound I: Compound I

[0066] [ka]

[0067]

[0077] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compositions described herein with a mineral acid, an organic acid, or an inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide. , 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.

[0068]

[0078] Additionally, the compositions (e.g., pharmaceutical compositions or formulations) described herein can comprise a compound in free base form, in the form of a pharma- ceutically acceptable inorganic or organic acid, such as, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and 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, benzoic ... It can be prepared as a pharma- ceutically acceptable salt formed by reaction with such organic acids as 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0069]

[0079] In some embodiments, the pharmaceutical compositions described herein that contain free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharma- ceutically acceptable metal cation, ammonia, or a pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium salts, and aluminum salts. Illustrative bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 Alkyl)4, etc.

[0070]

[0080] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is understood that the compounds described herein are also intended to include the quaternization of any basic nitrogen-containing groups contained therein. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0071]

[0081] In some embodiments, pharma- ceutically acceptable salts of imatinib include acetate, formate, citrate, phosphate, maleate, fumarate, tartrate, malonate, lactate, and succinate salts.

[0072] Solubility Enhancer

[0082] In some embodiments of the present disclosure, the solubility enhancer described herein provides increased solubility in aqueous solutions to pharmaceutical agents for treating pulmonary diseases, such as imatinib or its derivatives, or its pharma- ceutically acceptable salts. In some embodiments of the present disclosure, the solubility enhancer described herein is a cyclodextrin. In some embodiments of the present disclosure, the solubility enhancer described herein is a lipid or fatty acid. In some embodiments of the present disclosure, the solubility enhancer described herein is a cosolvent. In some embodiments of the present disclosure, the solubility enhancer described herein is an organic acid or a generally recognized as safe (GRAS) excipient acid. In some embodiments of the present disclosure, the solubility enhancer described herein is a surfactant, such as Tween, sodium lauryl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC).

[0073]

[0083] The lipid or fatty acid in the composition (e.g., pharmaceutical composition or formulation) provided herein can include, but is not limited to, polyethoxylated castor oil, phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains such as polyethylene glycol (PEG, PEG300, PEG400), propylene glycol (PG), chitin, hyaluronic acid, and polyvinylpyrrolidone; lipids with sulfonated monosaccharides, lipids with sulfonated disaccharides, lipids with sulfonated polysaccharides; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate. In some embodiments of the present disclosure, the lipid is polymeric. In some embodiments of the present disclosure, the polymeric lipid is polyvinylpyrrolidone (PVP). In some embodiments of the present disclosure, the polymeric lipid is polyethylene glycol (PEG). In some embodiments of the present disclosure, the lipid is a sulfonated polysaccharide. In some embodiments of the present disclosure, the lipid is a fatty acid. In some embodiments of the present disclosure, the fatty acid is steric acid or oleic acid. In some embodiments of the present disclosure, the fatty acid is a phospholipid. In some embodiments, the phospholipid is lecirhin or 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC).

[0074]

[0084] Cosolvents in the compositions (e.g., pharmaceutical compositions or formulations) provided herein can include, but are not limited to, glycol or ethanol. Organic acids in the compositions (e.g., pharmaceutical compositions or formulations) provided herein can include, but are not limited to, acetic acid, acid modified starch, aconitic acid, adipic acid, hexanedioic acid, L-ascorbic acid, benzoic acid, caprylic acid, octanoic acid, cholic acid, citric acid, deoxycholic acid, erythorbic acid (D-isoascorbic acid), formic acid, L-glutamic acid, L-glutamic acid hydrochloride, glycocholic acid, hydrochloric acid, ferric naphthenate, ferric tartrate, D(-)-lactic acid, lactate, lactic acid ... Acids, L(+)-lactic acid, linoleic acid, malic acid, L-malic acid, niacin (nicotinic acid), oleic acid, pectin, pectic acid, phosphoric acid, L(+)-potassium acid tartrate, propionic acid, acid hydrolyzed protein, sodium acid 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 the compositions (e.g., pharmaceutical compositions or formulations) provided herein can include, but are not limited to, acetic acid, formic acid, citric acid, tartaric acid, maleic acid, fumaric acid, tartaric acid, malonic acid, lactic acid, and succinic acid.

[0075] Cyclodextrin

[0085] In some embodiments of the present disclosure, cyclodextrins are used as solubility enhancers for imatinib or its derivatives. In some embodiments of the present disclosure, cyclodextrins are used as solubility enhancers for imatinib free base. In some embodiments of the present disclosure, cyclodextrins are used as solubility enhancers for imatinib salts. Cyclodextrins are cyclic hydrocarbons derived from starch. Unmodified cyclodextrins vary in the number of glucopyranose units joined together in a cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as α-, β-, and γ-cyclodextrin, respectively. Each cyclodextrin subunit can have secondary hydroxyl groups at positions 2 and 3 and a primary hydroxyl group at position 6. Cyclodextrins can be imagined as hollow truncated cones with a hydrophilic exterior surface and a hydrophobic interior cavity. In aqueous solution, these hydrophobic cavities can provide a home for hydrophobic organic compounds that can fit all or part of their structure into these cavities. This process, known as inclusion complexation, can result in increased apparent aqueous solubility and stability for the complexed drug.

[0076]

[0086] The cyclodextrin in the compositions (e.g., pharmaceutical compositions) provided herein can include, but is not limited to, α-cyclodextrin (αCD), β-cyclodextrin (βCD), γ-cyclodextrin (γCD), derivatized α-cyclodextrin, derivatized β-cyclodextrin, and derivatized γ-cyclodextrin.Non-limiting examples of cyclodextrins that may be used in a subject composition (e.g., a pharmaceutical composition or formulation) include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin (HPβCD), hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β ... Maltosyl-β-cyclodextrin, Maltosyl-γ-cyclodextrin, Maltotriosyl-β-cyclodextrin, Maltotriosyl-γ-cyclodextrin, Dimaltosyl-β-cyclodextrin, Methyl-β-cyclodextrin (MβCD), Succinyl-α-cyclodextrin (SαCD), Succinyl-β-cyclodextrin (SβCD), Succinyl-γ-cyclodextrin (SγCD), 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, Sulfobutylether-α-cyclodextrin (SBEαCD) Examples of cyclodextrins include sulfobutylether-β-cyclodextrin (SBEβCD), sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, sulfoalkylether-γ-cyclodextrin, carboxymethyl-α-cyclodextrin (CMαCD), carboxymethyl-β-cyclodextrin (CMβCD), carboxymethyl-γ-cyclodextrin (CMγCD), 2-carboxyethyl-α-cyclodextrin (CEαCD), 2-carboxyethyl-β-cyclodextrin (CEβCD), 2-carboxyethyl-γ-cyclodextrin (CEγCD), phosphate-α-cyclodextrin (PαCD), phosphate-β-cyclodextrin (PβCD), and phosphate-γ-cyclodextrin (PγCD). In some embodiments, the composition (e.g., pharmaceutical composition) comprises hydroxypropyl-β-cyclodextrin (HPβCD).In some embodiments, a composition (e.g., a pharmaceutical composition) comprises more than one cyclodextrin, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different types of cyclodextrins. In some embodiments, a composition (e.g., a pharmaceutical composition) comprises HPβCD and one or more other cyclodextrins, e.g., 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 the group consisting of α-cyclodextrin, 3-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized 3-cyclodextrin, and derivatized γ-cyclodextrin. In some cases, the cyclodextrin is selected from the group consisting of α-cyclodextrin, 3-cyclodextrin, γ-cyclodextrin, hydroxypropyl-3-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, and maltotriosyl-γ-cyclodextrin. Selected from the group consisting of dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin.

[0077]

[0087] In some cases, a salt of cyclodextrin is used to prepare the compositions disclosed herein. For example, metal salts of cyclodextrin, such as, but not limited to, sodium salt, calcium salt, magnesium salt, iron salt, chromium salt, copper salt, and zinc salt, can be used. Alternatively or in addition, amino acid salts of cyclodextrin, such as, but not limited to, lysine, arginine, and histidine salts, can be used. In some cases, the aqueous solution or suspension disclosed herein includes a salt of cyclodextrin, such as, for example, an anionic cyclodextrin salt, such as, for example, a salt of sulfobutylether-β-cyclodextrin. In some cases, the aqueous solution or suspension disclosed herein includes sulfobutylether-β-cyclodextrin sodium.

[0078]

[0088] In some embodiments, the concentration of cyclodextrin contributes to the viscosity of the solution, which can reduce the efficiency (or rate) of nebulization 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 such that the viscosity of the solution is about 0.1 centipoise (cP), 0.2 cP, 0.3 cP, 0.4 cP, 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, 2.0 cP, 2.1 cP, 2.2 cP, 2.3 cP, 2.4 cP, 2.5 cP, 2.6 cP, 2.7 cP, 2.8 cP, 2.9 cP, 3.0 cP, 3.2 cP, 3.3 cP, 3.4 cP, 3.5 cP, 3.6 cP, 3.7 cP, 3.8 cP, 3.9 cP, 4.0 cP, 4.1 cP, 4.2 cP, 4.3 cP, 4.4 cP, 4.5 cP, 4.6 cP, 4.7 cP, 4.8 cP, 4.9 cP, 5.0 cP, 5.1 cP, 5.2 cP, 5.3 cP, 5.4 cP, 5.5 cP, 5.6 cP, 5.7 cP, 5.8 cP, 5.9 cP, 6.0 cP, 6.1 cP, 6.2 cP, 6.3 cP, 6.4 cP, 6.5 cP, 6.6 cP, 6.7 cP, 6.8 cP, 6.9 cP, 7.0 c It is adjusted so as not to be higher than a standard value such as 4cP, 3.5cP, 3.6cP, 3.8cP, 4.0cP, 4.2cP, 4.4cP, 4.6cP, 4.8cP, 5.0cP, 5.2cP, 5.4cP, 5.6cP, 5.8cP, 6.0cP, 6.2cP, 6.4cP, 6.6cP, 6.8cP, 7.0cP, 7.2cP, 7.4cP, 7.6cP, 7.8cP, 8.0cP, 8.2cP, 8.4cP, 8.6cP, 8.8cP, 9.0cP, 9.2cP, 9.4cP, 9.6cP, 9.8cP, or 10.0cP. 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% (w / v) of solution.

[0079]

[0089] Without wishing to be bound by any particular theory, imatinib or its derivatives (e.g., imatinib free base) in acidic conditions may be protonated, leading to increased solubility of imatinib free base. Without wishing to be bound by any particular theory, cyclodextrins may increase the solubility of imatinib or its derivatives (e.g., imatinib free base) by stabilizing the positively charged piperazine ring in acidic conditions. Without wishing to be bound by any particular theory, anionic cyclodextrins may increase the stabilization of positively charged imatinib or its derivatives (e.g., positively charged imatinib free base), increasing solubility. In some embodiments, cyclodextrins may be anionic, such as succinyl-α-cyclodextrin (SαCD), succinyl-β-cyclodextrin (SβCD), succinyl-γ-cyclodextrin (SγCD), sulfobutylether-α-cyclodextrin (SBEαCD). Sulfobutylether-β-cyclodextrin (SBEβCD), sulfobutylether-γ-cyclodextrin (SBEγCD), carboxymethyl-α-cyclodextrin (CMαCD), carboxymethyl-β-cyclodextrin (CMβCD), carboxymethyl-γ-cyclodextrin (CMγCD), 2-carboxyethyl-α-cyclodextrin (CEαCD), 2-carboxyethyl-β-cyclodextrin (CEβCD), 2-carboxyethyl-γ-cyclodextrin (CEγCD), phosphate-α-cyclodextrin (PαCD), phosphate-β-cyclodextrin (PβCD), and γ-cyclodextrin (PγCD) may be used in the compositions and methods disclosed herein.

[0080]

[0090] In some embodiments of the present disclosure, cyclodextrins, such as SBEβCD, are used as solubility enhancers for imatinib or its derivatives. In some embodiments of the present disclosure, cyclodextrins, such as SBEβCD, are used as solubility enhancers for imatinib free base. In some embodiments of the present disclosure, cyclodextrins, such as SBEβCD, are used as solubility enhancers for imatinib salts. In some cases, the concentration of the cyclodextrin, e.g., SBEβCD, in a 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 a solution at a pH of about 3 to about 8. In some cases, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition (e.g., pharmaceutical composition) is up to about 20% (w / v) of a solution at a pH of about 3 to about 8. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 80% of a solution at a pH of about 5. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 60% of a solution at a pH of about 5. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 50% of a solution at a pH of about 5. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 5% to about 45% of a solution at a pH of about 5. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 10% to about 20% of a solution at a pH of about 4. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is from about 2% to about 80% of a solution at a pH of about 4. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is from about 2% to about 60% of a solution at a pH of about 4.In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 50% of the solution at a pH of about 4. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 5% to about 45% of the solution at a pH of about 4. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 10% to about 20% of the solution at a pH of about 4. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition (e.g., pharmaceutical composition or formulation) is about 2% to about 80% of the solution at a pH of about 3. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition (e.g., pharmaceutical composition or formulation) is about 2% to about 60% of the solution at a pH of about 3. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 50% of the solution at a pH of about 3. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 5% to about 45% of a solution at a pH of about 3. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 10% to about 20% of a solution at a pH of about 3. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 80% of a solution at a pH of about 6. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 60% of a solution at a pH of about 6. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 2% to about 50% of a solution at a pH of about 6. In some embodiments, the concentration of the cyclodextrin, e.g., SBEβCD, in the composition is about 5% to about 45% of a solution at a pH of about 6. In some embodiments, the concentration of cyclodextrin, eg, SBEβCD, in the composition is about 10% to about 20% of the solution at a pH of about 6.

[0081]

[0091] In some cases, the concentration of the cyclodextrin, e.g., SBEβCD, in a 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% of a solution or suspension at a pH of about 3 to about 8. %, 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) and the concentration of dissolved imatinib is about 0.0001 mg / mL to about 500 mg / mL. In some cases, the concentration of cyclodextrin, e.g., SBEβCD, in the composition is up to about 2% to about 80% (w / v) of the solution at a pH of about 5 and the concentration of dissolved imatinib is about 1 mg / mL to about 200 mg / mL.

[0082]

[0092] In some cases, formulations disclosed herein, such as formulations containing imatinib free base and a cyclodextrin, such as SBEβCD, in the acidic pH range, can result in low systemic absorption of imatinib and high pulmonary residence time of imatinib. In some cases, formulations disclosed herein, such as formulations containing imatinib free base and a cyclodextrin, such as SBEβCD, in the acidic pH range, can result in highly preferential retention of the pharma- ceutically active ingredient, such as imatinib or a derivative thereof, in the lungs compared to plasma. Without wishing to be bound by a particular theory, minimizing systemic exposure can result in reduced systemic side effects. In some cases, for example, an acidic solution of imatinib or a derivative thereof containing imatinib free base and a cyclodextrin (e.g., SBEβCD), when administered to the lungs, can cause precipitation of imatinib or a salt thereof upon contact with the lung lining fluid.

[0083]

[0093] The solubility of imatinib or a derivative thereof (e.g., imatinib free base) in an acidic solution according to some embodiments of the present disclosure may be negatively correlated with the pH of the solution, e.g., the higher the pH of the solution, the less likely imatinib free base will be dissolved in the solution (e.g., as shown in Examples 4 and 5 and Figures 2, 3A, and 3B). Additionally or alternatively, the solubility of imatinib or a derivative thereof (e.g., imatinib free base) in an acidic solution containing a cyclodextrin (e.g., SBE®CD) according to some embodiments of the present disclosure may be positively correlated with the concentration of cyclodextrin in the solution, e.g., the higher the concentration of SBE®CD, the more likely imatinib free base will be dissolved in the solution (e.g., as shown in Examples 5-7). Without wishing to be bound by a particular theory, in some cases, the lung coating fluid acts as a buffer that increases the pH to precipitate the imatinib or a derivative thereof delivered in the formulation. Without wishing to be bound by any particular theory, in some cases, the lung coating liquid acts as a diluent to precipitate the imatinib or its derivatives delivered in the formulation. Without wishing to be bound by any particular theory, in some cases, the lung coating liquid acts as a buffer to increase the pH and as a diluent to precipitate the imatinib or its derivatives delivered in the formulation. Without wishing to be bound by any particular theory, the solid precipitated imatinib can result in sustained release of imatinib to lung tissue over time, lower systemic absorption, and longer lung residence time.

[0084]

[0094] In some cases, within 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, or 10 hours after inhalation administration of an exemplary composition disclosed herein, the concentration of imatinib or a derivative thereof in the systemic circulation, e.g., the concentration of imatinib measured in a blood sample collected from a large vessel or the heart, is lower than the concentration of imatinib in lung tissue, e.g., the concentration of imatinib measured in a sample collected from the lung, within 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, or 10 hours after inhalation administration, the concentration ratio of imatinib measured in a blood sample compared to a sample collected 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. 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.

[0085]

[0095] In some cases, following inhalation administration of an exemplary imatinib composition disclosed herein, the concentration of imatinib in pulmonary tissue, e.g., the concentration of imatinib measured in a sample collected from the lung, declines at a slower rate compared to the concentration of imatinib in the systemic circulation, e.g., the concentration of imatinib measured in a blood sample collected from the great vessels or the heart.

[0086] pH Buffers

[0096] In some aspects of the present disclosure, the composition provided herein further comprises 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.

[0087]

[0097] In some embodiments, a pH buffer is present in a composition (e.g., pharmaceutical composition) described herein to provide an aqueous solution with a pH of about 3 to about 7. In some embodiments, a pH buffer is present in a composition (e.g., pharmaceutical composition) described herein to provide an aqueous suspension with 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 a composition described herein to provide an aqueous solution with 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.

[0088]

[0098] In some embodiments, the pH buffer is present in the aqueous composition at about 0.001 mg / mL to about 100 mg / mL, e.g., between about 0.1 mg / mL to about 100 mg / mL, about 0.5 mg / mL to about 50 mg / mL, about 0.5 mg / mL to about 20 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.5 mg / mL to 5 mg / mL, or about 1 mg / mL to about 5 mg / mL. In some embodiments, the pH buffer is present in the aqueous composition at about 0.1 mM to about 500 mM, e.g., about 1 mM to 500 mM, 1 mM to 200 mM, 1 mM to 100 mM, 1 mM to 80 mM, 1 mM to 50 mM, 1 mM to 25 mM, 1 mM to 10 mM, 1 mM to 5 mM, 5 mM to 200 mM, 5 mM to 100 mM, 5 mM to 80 mM, 5 mM to 50 mM, 5 mM to 25 mM, 5 mM to 10 mM, 20 mM to 200 mM, 20 mM to 100 mM, 20 mM to 80 mM, or 20 mM to 50 mM.

[0089] Pharmaceutically acceptable excipients

[0099] In one embodiment, the present invention provides a formulation for the treatment of pulmonary disease.The formulation can comprise the composition provided herein and pharmaceutically acceptable carrier, excipient, diluent, or other components suitable for intended administration route, such as oral or nasal inhalation.The examples of pharmaceutically acceptable excipients include, but are not limited to, lipids, metal ions, surfactants, amino acids, carbohydrates, buffers, salts, polymers, sweeteners, etc., and combinations thereof.

[0090]

[0100] Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides, and polysaccharides, such as monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose, etc.; disaccharides such as lactose, maltose, sucrose, trehalose, etc.; trisaccharides such as raffinose, etc.; and other carbohydrates such as starch (hydroxyethyl starch), and maltodextrins.

[0091]

[0101] Non-limiting examples of lipids include phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids having polymer chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids having sulfonated monosaccharides, disaccharides, and polysaccharides; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate.

[0092]

[0102] In some cases, the phospholipid comprises one or more saturated phospholipids such as phosphatidylcholine. Exemplary acyl chain lengths are 16:0 and 18:0 (e.g., palmitoyl and stearoyl). The phospholipid content can be determined by the active agent activity, delivery mode, and other factors.

[0093]

[0103] Phospholipids of both natural and synthetic origin can be used in various amounts.When phospholipids are present, the amount is usually sufficient to cover the active agent with at least a single molecular layer of phospholipids.In general, the phospholipid content ranges from about 5wt% to about 99.9wt%, for example, from about 20wt% to about 80wt%.

[0094]

[0104] In general, compatible phospholipids include those that have a gel to liquid crystalline phase transition above about 40° C., such as above about 60° C., or above about 80° C. The phospholipids to be incorporated can be relatively long-chain (e.g., C 16 ~C 22 Exemplary phospholipids useful in the present disclosure include, but are not limited to, phosphoglycerides such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol, short chain phosphatidylcholines, hydrogenated phosphatidylcholines, E-100-3 (available from Lipoid KG, Ludwigshafen, Germany), long chain saturated phosphatidylethanolamines, long chain saturated phosphatidylserines, long chain saturated phosphatidylglycerols, long chain saturated phosphatidylinositols, phosphatidic acid, phosphatidylinositols, and sphingomyelins.

[0095]

[0105] Examples of metal ions include divalent cations including, but not limited to, calcium, magnesium, zinc, iron, etc. For example, when phospholipids are used, the pharmaceutical composition can also include polyvalent cations as disclosed in U.S. Patent Nos. 8,709,484 and 7,871,598, which are incorporated by reference in their entireties. Polyvalent cations allow the pharmaceutical composition to retain its molecular weight at its storage temperature (T m ) at least about 20° C., e.g., at least about 40° C. higher than the melting temperature (T m ) as shown in the T mThe polyvalent cation can be present in an amount effective to increase the phospholipid. The molar ratio of polyvalent cation to phospholipid can be at least about 0.05:1, such as about 0.05:1 to about 2.0:1 or about 0.25:1 to about 1.0:1. An example of a molar ratio of polyvalent cation:phospholipid is about 0.50:1. When the polyvalent cation is calcium, it can be in the form of calcium chloride. Metal ions such as calcium are often included with the phospholipid, but are not required.

[0096]

[0106] The pharmaceutical composition may include one or more surfactants. For example, one or more surfactants may be in the liquid phase, and one or more may be associated with the solid droplets or liquid droplets of the composition. By "associated with" it is meant that the pharmaceutical composition may incorporate, adsorb, absorb, be coated with, or be formed by the surfactant. Surfactants include, but are not limited to, fluorinated and non-fluorinated compounds, such as saturated and unsaturated lipids, non-ionic detergents, non-ionic block copolymers, ionic surfactants, and combinations thereof. In addition to the above-mentioned surfactants, it should be emphasized that suitable fluorinated surfactants are compatible with the teachings herein and may be used to provide the desired preparation. In some embodiments, the surfactant in the pharmaceutical composition described herein includes Tween, sodium lauryl sulfate (SLS), or dipalmitoyl phosphatidylcholine (DPPC). Without wishing to be bound by a particular theory, in some cases, the surfactant also functions as a solubility enhancer in the composition.

[0097]

[0107] Examples of non-ionic detergents include, but are not limited to, sorbitan esters such as sorbitan trioleate (Span™ 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters. Other suitable non-ionic detergents can be readily identified using McCutcheon's Emulsifiers and Detergents (McPublishing Co., Glen Rock, NJ), which is incorporated herein by reference in its entirety.

[0098]

[0108] Examples of block copolymers include, but are not limited to, diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, such as poloxamer 188 (Pluronic™ F-68), poloxamer 407 (Pluronic™ 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 pharma- ceutically acceptable excipients is known in the art, as disclosed in U.S. Pat. Nos. 6,123,936, 6,358,530, and 6,921,527, which are incorporated herein by reference in their entireties.

[0099]

[0109] The pharmaceutical composition according to one or more embodiments of the present disclosure may optionally contain a combination of a pharmaceutical agent for the treatment of pulmonary disease (e.g., imatinib or a derivative thereof, e.g., imatinib free base or imatinib salt) and one or more additional active agents. Examples of additional active agents include, but are not limited to, agents that can be delivered via the lungs.

[0100]

[0110] Additional active agents include, for example, hypnotics and sedatives, psychostimulants, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, anti-Parkinson's drugs (dopamine antagonists), analgesics, anti-inflammatory drugs, anti-anxiety drugs (tranquilizers), appetite suppressants, anti-migraine drugs, muscle contraction drugs, additional anti-infective drugs (antivirals, antifungals, vaccines). These may include anti-arthritics, anti-malarials, anti-emetics, anti-epileptics, cytokines, growth factors, anti-cancer drugs, anti-thrombotic drugs, anti-hypertensive drugs, cardiovascular drugs, anti-arrhythmic drugs, antioxidants, anti-asthmatic drugs, hormonal drugs, such as contraceptives, sympathomimetics, diuretics, lipid regulating agents, anti-androgens, anti-parasitic drugs, anticoagulants, neoplasms, antineoplastic drugs, hypoglycemic drugs, nutritional agents and dietary supplements, growth supplements, anti-antienteritis agents, vaccines, antibodies, diagnostic agents, and imaging agents. The additional active agents, when administered by inhalation, may act locally or systemically.

[0101]

[0111] The additional active agent can fall into one of several structural classes, including, but not limited to, small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of producing a physiological effect, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

[0102]

[0112] Examples of additional active agents suitable for use in this disclosure include, but are not limited to, calcitonin, amphotericin B, erythropoietin (EPO), factor VIII, factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-1 protease inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LH), and the like. MWH), 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., mono-acylated insulin described in U.S. Pat. No. 5,922,675, which is incorporated by reference in its entirety), amylin, C-peptide, somatostatin, soma tostatin analogues, e.g. octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), tissue growth factor, epidermal growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factor, parathyroid hormone (PTH), glucagon-like peptide thymosin alpha 1, IIb / IIa inhibitors, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds substances, VLA-4 inhibitors, bisphosphonates, respiratory syncytial virus antibodies, cystic fibrosis transmembrane regulator (CFFR) gene, deoxyribonuclease (DNase), bactericidal / permeability-increasing protein (BPI), anti-CMV antibodies, 13-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin, clarithromycin, daversine, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin,miokamycin, rokitamycin, andazithromycin, and swinolide A; fluoroquinolines such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin, teicoplanin, ramoplanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymyxins, e.g. polymyxin B, capreomycin, bacitracin, penems; penicillins, e.g. penicillinase-susceptible drugs, e.g. penicillin G, penicillin V, penicillinase-resistant drugs, e.g. methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, naphthalene, cillin; gram-negative active agents such as ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins such as carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins such as cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cefaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cefacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefinetazole, ceftazidime, loracarbef, and moxalamatam, monobactams such as aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethionate, lidocaine, metaproterenol sulfate,These include one or more of beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate, and analogs, agonists, antagonists, inhibitors, and pharma- ceutically acceptable salt forms of the foregoing, as applicable. In relation to peptides and proteins, the present disclosure is intended to encompass synthetic, native, glycosylated, non-glycosylated, pegylated forms, as well as biologically active fragments, derivatives, and analogs thereof.

[0103]

[0113] Additional active agents for use in the present disclosure may further include nucleic acids such as naked nucleic acid molecules, vectors, associated viral droplets, plasmid DNA or RNA or other nucleic acid constructs suitable for transfection or transformation of cells, e.g., of the type suitable for gene therapy, including antisense. Additionally, active agents may include live attenuated or killed viruses suitable for use as vaccines. Other useful drugs include those listed in the Physician's Desk Reference (latest edition), which is incorporated herein by reference in its entirety.

[0104]

[0114] When a combination of active agents is used, the agents may be provided in combination in a single type of pharmaceutical composition or separately in separate types of pharmaceutical compositions.

[0115] The pharmaceutical compositions of one or more embodiments of the present disclosure may be tasteless. In this regard, although a flavoring agent may be optionally included in the composition, the compositions in some embodiments do not include a flavoring agent other than cyclodextrin, and are tasteless without the flavoring agent.

[0105]

[0116] In some embodiments, the pharmaceutical compositions provided herein include a sweetener to improve the organoleptic properties of the composition. The sweetener may be a natural sweetener, such as certain sugars, or an artificial sweetener. Without wishing to be bound by a particular theory, the presence of a sweetener in a pharmaceutical composition can improve the organoleptic properties of the composition. In some cases, the presence of a sweetener in a pharmaceutical composition can improve the compliance of a subject. The presence of a sweetener in a pharmaceutical composition can increase the delivery efficiency of the composition. In some embodiments, the presence of a sweetener in a pharmaceutical composition can enhance the therapeutic effect of the composition.

[0106]

[0117] Non-limiting examples of artificial sweeteners that may be used in the pharmaceutical composition include acesulfame potassium, aspartame, cyclamate, mogrosides, saccharin, stevia, 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' Low powdered sweetener, Truvia powdered sweetener, Equal (aspartame), Stevia powder sachet, Aspen Naturals liquid stevia, Now Better Stevia liquid sweetener, Sweet N' Low liquid sweetener, Quick Sweet: Neotame liquid sweetener, or Splenda powder sachet, or pharma- ceutically acceptable salts 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.

[0107]

[0118] Natural sweeteners that may be used in the pharmaceutical composition include, but are not limited to, sucrose, agave, brown sugar, powdered sugar (icing sugar), corn syrup, dextrose, fructose, concentrated fruit juice, glucose, high fructose corn syrup, honey, invert sugar, lactose, maltose, maltose, maple syrup, molasses, nectar, raw sugar, and syrup. Sugars can increase the viscosity of liquid solutions, and therefore the concentration of any sugar added to the pharmaceutical composition is tightly controlled below a certain threshold in some embodiments.

[0108]

[0119] In some embodiments, the pharma- ceutically acceptable excipient or carrier comprises lactose, mannitol, sorbitol, erythritol, raffinose, sucrose, xylitol, trehalose, dextrose, cyclodextrin, maltitol, maltose, glucose, hydroxyapatite, or any combination thereof.

[0109]

[0120] In addition to the above-mentioned pharmaceutically acceptable excipients, it may be desirable to add other pharmaceutically acceptable excipients to pharmaceutical compositions to improve droplet rigidity, production yield, emitted dose and deposition, shelf life, and patient acceptance.Such optional pharmaceutically acceptable excipients include, but are not limited to, coloring agents, flavoring agents, buffering agents, hygroscopic agents, antioxidants, and chemical stabilizers.In some embodiments, the composition may include one or more osmolality adjusters, such as sodium chloride.For example, sodium chloride may be added to the solution to adjust the osmolality of the solution.

[0110]

[0121] In one or more embodiments, the aqueous pharmaceutical composition described herein is essentially composed of a pharmaceutical agent for treating pulmonary disease (e.g., imatinib), water, a pH buffer, a solubility enhancer, and an osmolality adjuster. In some embodiments, the osmolality adjuster can provide stability to the aerosolized pharmaceutical composition, reduce undesirable effects (e.g., coughing) on ​​the inhaled aerosolized pharmaceutical composition, affect the efficiency of aerosolization, or droplet size. In some embodiments, the osmolality of the aqueous pharmaceutical composition described herein is acceptable for pharmaceutical use (e.g., isotonic, physiologically osmolal, hypotonic, physiologically hypotonic, hypertonic, physiologically hypertonic). In some embodiments, the osmolality of the aqueous pharmaceutical composition is about 0.001 mOsm to about 2,000 mOsm, e.g., about 0.1 mOsm to about 1,000 mOsm, about 1 mOsm to about 200 mOsm, about 100 mOsm to about 200 mOsm, about 100 mOsm to about 500 mOsm, about 200 mOsm to about 400 mOsm, about 250 mOsm to about 350 mOsm, about 300 mOsm to about 400 mOsm, about 300 mOsm to about 2,000 mOsm, or about 1,000 mOsm to 2,000 mOsm. In some cases, the osmolality adjusting agent is a salt, such as sodium chloride or sodium carbonate.

[0111] Aerosol mist droplet

[0122] The distribution of aerosol droplets of an inhalable formulation can be expressed in terms of either the median aerodynamic diameter (MMAD) - the size at which half of the aerosol mass is contained in droplets smaller than a certain value and half in larger droplets; the volume mean diameter (VMD); the mass median diameter (MMD); the fine droplet fraction (FDF) - the fraction of droplets with a diameter <5um. These measurements have been used to compare the in vitro performance of different nebulizers and drug combinations. In general, the higher the fine droplet fraction, the higher the fraction of the emitted dose that will be deposited in the lungs. In general, inhaled droplets will be deposited by one of two mechanisms: impaction usually predominates for larger droplets, and sedimentation dominates for smaller droplets. Impaction can occur when the momentum of the inhaled droplets is large enough that the droplets do not follow the air stream and encounter a physiological surface. In contrast, sedimentation can occur primarily in the deep lung when very small droplets traveling with the inhaled airstream encounter a physiological surface as a result of random diffusion within the airstream.

[0112]

[0123] For pulmonary administration, the upper airways are usually avoided over the middle and lower airways. Pulmonary drug delivery can be achieved by inhalation of an aerosol through the mouth and throat. Droplets having a mass median aerodynamic diameter (MMAD) greater than about 5 microns generally do not reach the lungs; instead, they tend to get stuck in the back of the throat and are swallowed and possibly absorbed orally. Droplets having a diameter of about 1 to about 5 microns are small enough to reach the upper to middle lung regions (the conducting airways) but are 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 smaller than about 0.5 microns can also be deposited in the alveolar region by settling, although very small droplets may be exhaled. A measure of droplet size can be referred to as the volume mean diameter (VMD), mass median diameter (MMD), or MMAD. These measurements can be made by impaction (MMD and MMAD) or by laser (VMD). For liquid particles, the VMD, MMD and MMAD may be the same if ambient conditions, e.g., standard humidity, are maintained. However, if humidity is not maintained, the MMD and MMAD determinations will be smaller than the VMD due to dehydration during the impactor measurement. For purposes of this specification, the VMD, MMD and MMAD measurements are considered to be made under standard conditions so that the descriptions of VMD, MMD and MMAD are comparable.

[0113]

[0124] The size of aerosol particles can be expressed in terms of median aerodynamic diameter (MMAD). Large droplets (e.g., MMAD-5um) can deposit in the upper airways because they are too large to pass through the bends of the upper airways. Small droplets (e.g., MMAD-2um) can deposit poorly in the lower airways and thus become exhaled, providing additional opportunities for upper airway deposition. Hence, intolerance (e.g., coughing and bronchospasm) can occur from upper airway deposition resulting from both inhalation impaction of large droplets and settling of small droplets during repeated inhalation and exhalation.

[0114]

[0125] Thus, in one embodiment, an optimal droplet size (e.g., MMAD=1-5 um) is used to maximize mid-lung deposition and minimize intolerance associated with upper airway deposition. Additionally, production of a limited geometric standard deviation (GSD) of a defined droplet size can optimize deposition and tolerability. A narrow GSD limits the number of droplets outside the desired MMAD size range. In one embodiment, an aerosol is provided that contains one or more compounds disclosed herein having an MMAD of about 1 micron to about 5 microns with a GSD of about 2.5 microns or less. In another embodiment, an aerosol is provided that has an MMAD of about 2.8 microns to about 4.3 microns with a GSD of 2 microns or less. In another embodiment, an aerosol is provided that has an MMAD of about 2.5 microns to about 4.5 microns with a GSD of 1.8 microns or less.

[0115]

[0126] 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 pulsating membrane nebulizer, a nebulizer that includes a vibrating mesh or plate with multiple holes, or a nebulizer that includes a vibration generator and an aqueous chamber.In some embodiments, the nebulizer used in any of the methods described herein is a nebulizer that includes a vibrating mesh or plate with multiple holes. In some embodiments, the liquid nebulizer achieves pulmonary deposition of imatinib or a derivative thereof, or a salt thereof administered to a mammal; provides a geometric standard deviation (GSD) of the emitted droplet size distribution of the aqueous solution of about 1.0 um to about 2.5 um; provides a median aerodynamic diameter (MMAD) of the droplet size of the aqueous solution emitted by the high efficiency liquid nebulizer of about 1 um to about 5 um; a volume mean diameter (VMD) of about 1 um to about 5 um; and / or a mass median diameter (MMD) of about 1 um to about 5 um; provides a fine droplet fraction (FDF=%s5 microns) of droplets emitted from the liquid nebulizer of at least about 30%; provides an output rate of at least 0.1 mL / min; and / or provides at least about 25% of the aqueous solution to the mammal.

[0116]

[0127] In some embodiments, a composition (e.g., a pharmaceutical composition or formulation) is aerosolized into a mist of 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.

[0117] Nebulizer

[0128] In one embodiment, the nebulizer is selected based on its ability to form an aerosol of the compositions described herein, in some embodiments, the MMAD of the nebulized or aerosolized composition has a predominantly MMAD of about 1 to about 5 microns.

[0118]

[0129] Efficient drug delivery by nebulizer to lungs depends on several factors including inhaler device, formulation, and inhalation maneuver. Pharmaceutical compositions can be administered using aerosolization devices. Aerosolization devices can be nebulizers, metered dose inhalers, or liquid dose infusion devices. Aerosolization devices can include the ejection of pharmaceutical preparations through micron or submicron sized holes followed by Rayleigh breakup into fine droplets. Pharmaceutical compositions can be delivered by nebulizers as described in WO99 / 16420, by metered dose inhalers as described in WO99 / 16422, and by liquid dose infusion devices as described in WO99 / 16421, which are incorporated herein by reference in their entirety. Thus, the inhaler can include a canister containing droplets or droplets and a propellant, and the inhaler includes a metering valve in communication with the interior of the canister. The propellant can be a hydrofluoroalkane.

[0119]

[0130] For example, the pharmaceutical composition may be a liquid solution and administered with a nebulizer, such as that disclosed in WO99 / 16420, the entire disclosure of which is incorporated herein by reference, to provide an aerosolized medicament that can be administered to the pulmonary airways of a patient in need thereof. Nebulizers known in the art can be readily used to administer the claimed formulations. Breath-activated or breath-actuated nebulizers, including other types of improvements that have been developed or are to be developed, are also contemplated as being compatible with and within the scope of the formulations of the present disclosure.

[0120]

[0131] In some cases, the nebulizer is a breath-activated or breath-actuated nebulizer. In some cases, the nebulizer is a hand-held inhaler device (e.g., AeroEclipse® Breath Actuated Nebulizer (BAN)). In some cases, the nebulizer has a compressed air source. In some cases, the nebulizer converts the liquid medicament into an aerosol. In some cases, the nebulizer converts the liquid medicament into an aerosol by forcing the pharmaceutical preparation through micron or submicron sized holes. In some cases, the nebulizer converts the liquid medicament 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, the aerosolized medicament is only generated when inhaled through the device. In some cases, the medicament is contained in a cup during exhalation or during breaks in the treatment. In some cases, the medicament is contained in the cup until just before inhalation.

[0121]

[0132] A nebulizer can impart energy to a liquid composition to aerosolize the liquid, allowing delivery to the patient's pulmonary system, e.g., the lungs. A nebulizer includes a liquid delivery system, such as a container having a reservoir that contains the liquid composition. A liquid composition generally includes an active agent in solution or suspended in a liquid medium.

[0122]

[0133] In one type of nebulizer that can be used in the method and kit, commonly referred to as a jet nebulizer, compressed gas is ejected through an orifice in a container. The compressed gas draws liquid through a nozzle, and the drawn liquid can mix with the flowing gas to form aerosol droplets. The cloud of droplets can then be administered to the patient's respiratory tract. In another type of nebulizer that can be used in the method and kit, commonly referred to as a vibrating mesh nebulizer, energy, such as mechanical energy, vibrates a mesh. The vibration of the mesh aerosolizes the liquid composition to create an aerosol cloud that is administered to the patient's lungs. In another type of nebulizer that can be used in the method and kit, nebulization involves ejection through micron or submicron sized holes followed by Rayleigh breakup into fine droplets. Alternatively or additionally, the composition may be in liquid form and aerosolized using a nebulizer as described in WO2004 / 071368, which is incorporated herein by reference in its entirety, and U.S. Patent Application Publication Nos. 2004 / 0011358 and 2004 / 0035413, both of which are incorporated herein by reference in their entirety. Other examples of nebulizers include, but are not limited to, Aeroneb® Go or Aeroneb® Pro nebulizers available from Aerogen Ltd. of Galway, Ireland; PARI eFlow and other PARI nebulizers available from PARI Respiratory Equipment, Inc. of Midlothian, Va.; Lumiscope® Nebulizer 6600 or 6610 available from Lumiscope Company, Inc. of East Brunswick, NJ; and Omron NE-U22 available from Omron Healthcare, Inc. of Kyoto, Japan. Other examples of nebulizers include devices produced by Medspray (Enschede, The Netherlands) and Pulmotree Medical GmbH (Munchen, Germany).

[0123]

[0134] Vibrating mesh type nebulizers that form droplets without compressed gas, such as Aeroneb® Pro, can provide unexpected improvements in dosing efficiency and consistency. By using a vibrating perforated or non-perforated membrane to generate fine droplets rather than introducing compressed air, aerosolized compositions can be introduced without substantially affecting flow characteristics. In addition, the droplets generated when using this type of nebulizer can be introduced at a low velocity, which reduces the possibility of the droplets being driven to undesired areas. The droplets generated when using a jet / Rayleigh jet breakup type nebulizer can also be introduced at a low velocity, which reduces the possibility of the droplets being driven to undesired areas.

[0124]

[0135] In some cases, the nebulizers that may be used in the methods and kits are vibrating mesh types. In some cases, the nebulizers that may be used in the methods and kits are pressurized jet types. In some cases, the nebulizers that may be used in the methods and kits are jet / Rayleigh breakup types. In some cases, the nebulizers are lightweight (up to 60g, up to 100g, up to 200g, up to 250g) and nearly silent. In some cases, the nebulizers have a sound level of less than 35 A-weighted decibels (dBA) at 1 meter. In some cases, the nebulizers have a medication cup capacity of 6 mL. In some cases, the nebulizers have a residual volume of less than 0.3 mL. In some cases, the nebulizers produce an average flow rate of 0.4 mL / min. In some cases, the nebulizers produce an average flow rate of 0.5 mL / min. In some cases, the nebulizers produce an average flow rate of 0.6 mL / min. In some cases, the nebulizer produces an average flow rate of 0.7 mL / min. In some cases, the nebulizer produces an average flow rate of 0.8 mL / min, and in some cases, the nebulizer produces an average flow rate of 0.9 mL / min. In some cases, the nebulizer produces an average flow rate of 1.0 mL / min. In some cases, the nebulizer produces an average flow rate of 1.1 mL / min. In some cases, the nebulizer produces an average flow rate of 1.2 mL / min. In some cases, the nebulizer produces 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 produces 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 produces 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 6.0 μm MMAD. In yet another type of nebulizer that may be used in the present methods and kits, ultrasound is generated to directly vibrate and aerosolize the composition. The compositions disclosed herein may also be administered to the patient's lungs via aerosolization, such as by a metered dose inhaler. The use of such formulations provides excellent dose reproducibility and improved lung deposition, as disclosed in WO99 / 16422, which is incorporated herein by reference in its entirety. Metered dose inhalers (MDIs) known in the art may be used to administer the claimed compositions. Breath-activated or breath-actuated MDIs and pressurized MDIs (pMDIs), including other types of improvements that have been developed or are to be developed, are also compatible with the formulations of the present disclosure and are therefore considered within their scope. It is understood that in conjunction with MDIs and nebulizers, the formulations of one or more embodiments of the present disclosure can be used in combination with liquid dose infusion or LDI technology, for example as disclosed in WO99 / 16421, the entirety of which is incorporated herein by reference. Liquid dose infusion includes direct administration of the formulation to the lungs. For LDI, the formulations are preferably used in conjunction with partial or total liquid ventilation. Additionally, one or more embodiments of the present disclosure can further include introducing a therapeutically effective amount of a physiologically acceptable gas (e.g., nitric oxide or oxygen) into the drug microdispersion before, during, or after administration.

[0125]

[0136] Aqueous formulations can be aerosolized by liquid nebulizers using hydraulic or ultrasonic atomization. Propellant-based systems can use a suitable pressurized metered dose inhaler (pMDI). The desired particle size and distribution can be obtained by choosing the appropriate device. In some embodiments, the nebulizer is a jet nebulizer, a vibrating mesh nebulizer, or an ultrasonic nebulizer.

[0126] Ready-to-use formulation

[0137] The pharmaceutical compositions provided herein are ready-to-use for the treatment of pulmonary diseases for immediate use.In contrast, other drug formulations including imatinib are in powder form for oral liquid suspension or concentrated liquid form / stock solution that requires dilution prior to use, requiring additional components and steps.The pharmaceutical compositions described herein are in aqueous liquid form that provides immediate use for pulmonary disease-related symptoms without the need for additional steps.The ready-to-use formulations of the pharmaceutical compositions described herein are suitable for use in invasive procedures such as intravenous administration.

[0127]

[0138] In some embodiments, the ready-to-use pharmaceutical composition is a single-use dose for treating a pulmonary disease or a symptom of a pulmonary disease. In some embodiments, the single-use dose is placed in a cartridge or container with a volume for single use. In some embodiments, the single-use dose is placed in a cartridge or container with a volume for additional application of the pharmaceutical composition. In some embodiments, the ready-to-use pharmaceutical composition is a multi-dose formulation. In some embodiments, a multi-dose formulation of the ready-to-use drug formulation is placed in a cartridge or container with a volume containing multiple doses. In some embodiments, a multi-dose formulation requires refilling the cartridge or container with the ready-to-use pharmaceutical composition for nebulization. In some embodiments, a metering device and / or transfer device for refilling the cartridge or container for multi-dose use is included in the kit.

[0128] Treatment methods Pulmonary disease

[0139] The methods, compositions, and kits provided herein can include administration of the pharmaceutical composition by inhalation, e.g., oral or nasal inhalation. Examples of pulmonary diseases include, but are not limited to, asthma, emphysema, chronic obstructive pulmonary disease (COPD), infectious diseases (e.g., pneumonia, tuberculosis, influenza), coccidioidomycosis, coronavirus, cytogenetic organizing pneumonia (COP), pulmonary arterial hypertension, respiratory syncytial virus (RSV), Hantavirus pulmonary syndrome (HPS), Mycobacterium avium complex pulmonary disease, Middle East respiratory syndrome (MERS), mesothelioma, nontuberculous mycobacterial pulmonary disease (NTM), severe acute respiratory syndrome (SARS), lung cancer, acute respiratory distress syndrome (ARDS), alpha-1 antitrypsin deficiency, and the like. pulmonary fibrosis (IPF), pulmonary fibrosis (PFC), pulmonary asbestosis, aspergillosis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, acute bronchitis, bronchopulmonary dysplasia, chronic bronchitis, chronic cough, coal workers' pneumoconiosis (black lung disease), cystic fibrosis, e-cigarette or vaping use associated lung injury (EVALI), eosinophilic granulomatosis with polyangiitis, histoplasmosis, human metapneumovirus (hMPV), hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), institial lung disease (ILD), sarcoidosis, legionnaires' disease, pertussis (whooping cough), primary ciliary dyskinesia (PCT), pulmonary arterial hypertension (PAH), silicosis, or pulmonary fibrosis. The pharmaceutical compositions described herein can be used to treat lung disorders, respiratory diseases, and diseases and symptoms related to tracheal or bronchial disorders.In some cases, lung disorders can be caused by inhalation and / or exposure to tobacco smoke, infections (e.g., bacteria, viruses, fungi), radon, asbestos, air pollution, particulates, and debris.In some cases, lung disorders or symptoms of lung disorders can be caused by lung damage, sleep apnea, lung collapse, or pulmonary embolism.

[0129]

[0140] Thus, the pharmaceutical composition according to some examples of the present disclosure can be used to treat and / or provide prophylaxis for a wide range of patients. The patient suitable for receiving the treatment and / or prophylaxis described herein is any mammalian patient in need thereof, and preferably such mammal is a human. Examples of subjects include, but are not limited to, pediatric patients, adult patients, and elderly patients. In some cases, the composition is intended only as a treatment for rapid resolution of symptoms and restoration of normal sinus rhythm, and is not considered prophylactic. For example, when the patient is healthy, there is no need for drugs, which increases the benefit-risk ratio and overall safety of treatment due to sporadic or intermittent dosing, and may allow greater emphasis to be placed on reducing symptoms that interfere with daily life and restoring sinus rhythm only when needed.

[0130]

[0141] The pharmaceutical compositions disclosed herein may be more effective in subjects with or without certain physiological or demographic factors, such as, for example, age at clinical presentation, certain hemodynamic criteria, electrophysiological characteristics, and prior treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure suffers from an onset of pulmonary disease that occurred within 48 hours prior to treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure suffers from an onset of pulmonary disease that occurred between 1 hour and 48 hours prior to treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure suffers from recurrent pulmonary disease. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has an ongoing prescription for pulmonary disease. In some embodiments, the oral pharmaceutical for treating pulmonary disease is imatinib, or a pharmaceutically acceptable salt thereof.

[0131]

[0142] In some embodiments, the subject treated with a pharmaceutical composition of the present disclosure is over 18 years of age. In some embodiments, the subject treated with a pharmaceutical composition of the present disclosure is under 18 years of age. In some embodiments, the subject treated with a pharmaceutical composition of the present disclosure is under 85 years of age. In some embodiments, the subject treated with a pharmaceutical composition of the present disclosure is between 18 and 85 years of age.

[0132]

[0143] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit severe renal dysfunction, and the subject's eGFR is greater than or equal to 30 mL / min / 1.73 m upon treatment. 2 In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure is not undergoing dialysis 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, abnormal liver function is biochemical evidence of liver disease or significant liver derangement. 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 serum potassium less than 3.6 mEq / L at the time of treatment.

[0133]

[0144] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit a confirmed pulmonary disease requiring inhaled medication during treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not have or have a history of hypersensitivity to imatinib or any of its active metabolites. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is not administered concomitantly with a systemic drug that is an inhibitor of CYP 2D6. 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 composition of the present disclosure is not administered concomitantly with a systemic drug that is a CYP 2D6 inducer. In some embodiments, the CYP 2D6 inducer is phenytoin, phenobarbital, or carbamazepine.

[0134]

[0145] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit congenital pulmonary 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.

[0135]

[0146] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit any severe or life-threatening medical condition other than pulmonary disease symptoms 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.

[0136]

[0147] In some embodiments, the subject treated with a pharmaceutical composition of the present disclosure has not exhibited drug or alcohol dependence within 12 months prior to administration of the pharmaceutical composition. In some embodiments, the subject treated with a pharmaceutical composition of the present disclosure has a blood glucose level of 40 Kg / m 2 does not have a body mass index greater than

[0137]

[0148] The treatment provided herein can include or be suitable for inhalation, for example, oral or nasal inhalation.In some cases, during administration by oral inhalation, the pharmaceutical agent is inhaled by the patient through the mouth and 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.

[0138]

[0149] Inhalation route can avoid first-pass hepatic metabolism, and therefore, dosage variability can be eliminated.Unlike oral tablets or pills, the metabolic rate of the patient is not an issue, since administration is independent of the metabolic pathway experienced when a drug is administered by oral route through the gastrointestinal tract, for example, as a tablet, pill, liquid, or suspension.Fast onset of action, potential improved efficacy, and / or reduced dosage can be achieved with fast absorption of the drug from the nasal mucosa and / or lungs.

[0139]

[0150] Rapid rates of absorption of drugs through the lungs can be achieved because of the large surface area of ​​the lungs available for aerosols small enough to penetrate the central and peripheral regions of the lungs. As a result, the rate and extent of absorption of drugs delivered by inhalation can produce plasma concentration versus time profiles comparable to IV routes of administration.

[0140]

[0151] In some cases, the treatment provided herein is provided to the subject more than once if necessary.For example, the treatment can be administered to the subject at least once a day, for example, 1, 2, 3, 4, 5, 6, 8, or 10 times a day, for example, the pharmaceutical composition is inhaled by the subject.In some cases, the treatment can be administered to the subject for an extended period of time, for example, 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 treatment every day, or every other day, or every 2, 3, 4, 5, 6, 7, or 10 days.Each day that the treatment is administered to the subject, the subject can receive the treatment at least once, for example, 1, 2, 3, 4, 5, 6, 8, or 10 times, for example, the pharmaceutical composition provided herein can be inhaled.

[0141] dose

[0152] The pharmaceutical composition may be administered to a patient when necessary.

[0153] In some embodiments, the unit dosage is about 20 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease. In some embodiments, the unit dosage is about 20 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease, and the pharmaceutical agent for treating pulmonary disease is imatinib or a pharma- ceutical acceptable salt thereof. In some embodiments, the unit dosage is about 30 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease. In some embodiments, the unit dosage is about 40 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease. In some embodiments, the unit dosage is about 50 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease. In some embodiments, the unit dosage is about 100 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease. In some embodiments, the unit dosage is about 120 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease. In some embodiments, the unit dosage is about 150 mg to about 500 mg of the pharmaceutical agent for treating pulmonary disease. In some embodiments, the unit dose is about 200 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 250 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 300 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 350 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 400 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 450 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 30 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 450 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 400 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is from about 20 mg to about 350 mg of a pharmaceutical agent for treating a pulmonary disorder.In some embodiments, the unit dose is about 20 mg to about 300 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 250 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 200 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 150 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 120 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 100 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 50 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 40 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 30 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 30 mg to about 450 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 40 mg to about 400 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 50 mg to about 350 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 100 mg to about 300 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 150 mg to about 250 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 100 mg to about 150 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 20 mg to about 200 mg of the pharmaceutical agent for treating a pulmonary disease. In some embodiments, the unit dose is about 200 mg to about 500 mg of the pharmaceutical agent for treating a pulmonary disease.In some embodiments, the unit dose is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, or about 500 mg of a pharmaceutical agent for treating a pulmonary disease.

[0142]

[0154] In some cases, the unit dose of the pharmaceutical compositions described herein in aqueous solution is 20 mg / mL to 500 mg / mL of imatinib. In some cases, the unit dose is 20 to 500 mg / mL, 2 to 450 mg / mL, 20 to 400 mg / mL, 20 to 350 mg / mL, 20 to 300 mg / mL, 20 to 250 mg / mL, 20 to 200 mg / mL, 20 to 150 mg / mL, 20 to 120 mg / mL, 20 to 100 mg / mL, 20 mg / mL to 80 mg / mL, 20 mg / mL to 60 mg / mL, 20 mg / mL to 40 mg / mL, 20 mg / mL to 30 mg / mL, 30 mg / mL to 40 mg / mL, 40 mg / mL to 60 mg / mL, 40 mg / mL to 50 mg / mL, 50 mg / mL to 60 mg / mL, 60 mg / mL to 80 mg / mL, 70 mg / mL to 80 mg / mL, 80 mg / mL to 90 mg / mL, 90 mg / mL to 100 mg / mL, 100 mg / mL to 120 mg / mL, 100 mg / mL to 140 mg / mL, 100 mg / mL to 160 mg / mL, 100 mg / mL to 180 mg / mL, 100 mg / mL to 200 mg / mL, 100 mg / mL to 200 mg / mL, 100 mg / mL to 300 mg / mL, 100 mg / mL to 200 mg / mL, 100 mg / mL to 300 mg / mL, 100 mg / mL to 300 mg / mL, 100 mg / mL to 200 mg / mL, 1 mg / mL~80mg / mL, 40mg / mL~100mg / mL, 40mg / mL~120mg / mL, 40mg / mL~150mg / mL, 40mg / mL~200mg / mL, 40mg / mL~250mg / mL, 40mg / mL~300mg / mL, 4 0mg / mL~350mg / mL, 40mg / mL~400mg / mL, 40mg / mL~450mg / mL, 40mg / mL~500mg / mL, 60mg / mL~80mg / mL, 60mg / mL~100mg / mL, 60mg / mL~120mg / mL, 60mg / mL~150mg / mL, 60mg / mL~200mg / mL, 60mg / mL~250mg / mL, 60mg / mL~300mg / mL, 60mg / mL~350mg / mL, 60mg / mL~400mg / mL, 60mg / mL~450mg / m L, 60mg / mL~500mg / mL, 80mg / mL~100mg / mL, 80mg / mL~120mg / mL, 80mg / mL~150mg / mL, 80mg / mL~200mg / mL, 80mg / mL~250mg / mL, 80mg / mL~300mg / mL, 80mg / mL~350mg / mL, 80mg / mL~400mg / mL, 80mg / mL~450mg / mL, 80mg / mL~500mg / mL, 100mg / mL~120mg / mL, 100mg / mL~150mg / mL, 100mg / mL~ 200mg / mL, 100mg / mL~250mg / mL, 100mg / mL~300mg / mL, 100mg / mL~350mg / mL, 100mg / mL~400mg / mL, 100mg / mL~450mg / mL, 100mg / mL~500mg / mL,120mg / mL~150mg / mL、120mg / mL~200mg / mL、120mg / mL~250mg / mL、120mg / mL~300m g / mL、120mg / mL~350mg / mL、120mg / mL~400mg / mL、120mg / mL~450mg / mL、120mg / mL ~500mg / mL、150mg / mL~200mg / mL、150mg / mL~250mg / mL、150mg / mL~300mg / mL、150 mg / mL~350mg / mL、150mg / mL~400mg / mL、150mg / mL~450mg / mL、150mg / mL~500mg / mL 、200mg / mL~250mg / mL、200mg / mL~300mg / mL、200mg / mL~350mg / mL、200mg / mL~400 mg / mL、200mg / mL~450mg / mL、200mg / mL~500mg / mL、250mg / mL~300mg / mL、250mg / mL ~350mg / mL、250mg / mL~400mg / mL、250mg / mL~450mg / mL、250mg / mL~500mg / mL、300 mg / mL~350mg / mL、300mg / mL~400mg / mL、300mg / mL~450mg / mL、300mg / mL~500mg / mL 350mg / mL~400mg / mL、350mg / mL~450mg / mL、350mg / mL~500mg / mL、400mg / mL~ 450mg / mL、400mg / mL~500mg / mL、mg / mL、または450mg / mL~500mg / mLのイマチニブである。、

[0143]

[0155] The pharmaceutical composition of one or more embodiments of the present disclosure may have improved emitted dose efficiency. The emitted dose (ED) of the aerosolized 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 the treatment of pulmonary disease may be administered during a single inhalation or may be administered during several inhalations. The variability of the pharmaceutical agent may be reduced by administering the pharmaceutical composition more frequently or may be increased by administering the pharmaceutical composition less frequently. Thus, the pharmaceutical composition provided herein may be administered about 4 times a day to about once a month, for example, about once a day to about once every two weeks, about once every two days to about once a week, and about once every week.

[0144]

[0156] In some cases, the pharmaceutical agent for treating pulmonary disease is delivered by two or more inhalations. In some cases, the time for the two or more inhalations is about 0.1 to 10 minutes. The pharmaceutical agent for treating pulmonary disease is administered at the described dose in 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 required dose of the pharmaceutical agent for treating pulmonary disease (e.g., imatinib) is completed in 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 more than 5 minutes. In some cases, each inhalation is performed for up to 4.5 minutes. In some cases, each inhalation includes at least 60 inhalation breaths, 50 inhalation breaths, 40 inhalation breaths, 30 inhalation breaths, 20 inhalation breaths, 10 inhalation breaths, 8 inhalation breaths, 6 inhalation breaths, 4 inhalation breaths, 3 inhalation breaths, 2 inhalation breaths, or 1 inhalation breath. In some cases, each inhalation includes 100 or less inhalation breaths, 90 or less inhalation breaths, 80 or less inhalation breaths, 70 or less inhalation breaths, 60 or less inhalation breaths, 50 or less inhalation breaths, 40 or less inhalation breaths, 30 or less inhalation breaths, or 20 or less inhalation breaths. In some cases, inhalation of the antiarrhythmic pharmaceutical agent is performed by deep breathing through the lungs lasting more than 1 second, 2 seconds, 3 seconds, or 4 seconds. In some cases, inhalation of a pharmaceutical agent for the treatment of a pulmonary disease is accomplished by taking a deep lung breath lasting about 1, 2, 3, or 4 seconds.

[0145]

[0157] In some embodiments, during the inhalation delivery of the pharmaceutical agent for treating pulmonary disease, the subject takes a breath or is instructed to take a breath between two inhalations.In such embodiments, the breath between two inhalations lasts about 0.1-10 minutes, for example, 0.2-5, 1-5, 1.5-5, 2-5, 3-5, 4-5, 1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1.5-2, 1.5-2.5, or 1.5-3 minutes.In some cases, the subject takes a breath or is instructed to take a breath between two inhalations for about 1 minute. In some cases, the inhalation pattern for delivery of a single dose is as follows: first inhalation for about 4-4.5 minutes, a breath for about 1 minute, and a second inhalation for about 4-4.5 minutes; first inhalation for about 4-4.5 minutes, a breath for about 30 seconds, and a second inhalation for about 4-4.5 minutes; first inhalation for about 4-4.5 minutes, a first breath for about 1 minute, and a second inhalation for about 4-4.5 minutes; a second breath for about 1 minute, and a third inhalation for about 4-4.5 minutes; or first inhalation for about 4-4.5 minutes, a first breath for about 30 seconds, and a second inhalation for about 4-4.5 minutes; a second breath for about 30 seconds, and a third inhalation for about 4-4.5 minutes.

[0146]

[0158] In one version, the pharmaceutical compositions described herein can be administered daily, in which case the daily dose of imatinib ranges from about 0.1 mg to about 600 mg, such as about 0.5 mg to about 500 mg, about 1 mg to about 400 mg, about 2 mg to about 300 mg, and about 3 mg to about 200 mg.

[0147]

[0159] In some cases, the treatment provided herein can be provided to the subject more than once if necessary.For example, the present disclosure can include follow-up inhalation if the symptoms of pulmonary disease do not subside and occur after the first inhalation.In some cases, if the symptoms of pulmonary disease do not subside within 30 minutes of the first inhalation, the follow-up dose is higher than or the same as the first dose.

[0148]

[0160] In another version, the pharmaceutical composition is administered prophylactically to a subject susceptible to developing pulmonary disease. For example, a patient with a history of pulmonary disease can be prophylactically treated with a pharmaceutical composition comprising imatinib to reduce the likelihood of developing pulmonary disease.

[0149]

[0161] The pharmaceutical compositions can be administered to a patient in any regimen effective to prevent pulmonary disease. An illustrative prophylactic regimen includes 1 to 21 weekly doses of a pharmaceutical agent for treating pulmonary disease described herein.

[0150]

[0162] The amount of imatinib delivered to a subject for treatment of a pulmonary disease (e.g., the approximate amount of imatinib free base that leaves the mouthpiece when inhaled by a subject) may be from about 20 mg to about 500 mg, e.g., 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 20 mg to 60 mg, 20 mg to 70 mg, 20 mg to 80 mg, 20 mg to 90 mg, 20 mg to 100 mg, 20 mg to 110 mg, 20 mg to 120 mg, 20 mg to 130 mg, 20 mg to 140 mg, 20 mg to 150 mg, 20 mg to 160 mg, 20 mg to 200 mg, 20 mg to 220 mg, 20 mg to 240 mg, 20 mg to 260 mg, 20 mg to 280 mg, 20 mg to 290 mg, 20 mg to 300 mg, 20 mg to 310 mg, 20 mg to 320 mg, 20 mg to 330 mg, 20 mg to 340 mg, 20 mg to 350 mg, 20 mg to 360 mg, 20 mg to 370 mg, 20 mg to 380 mg, 20 mg to 390 mg, 20 mg to 400 mg, 20 mg to 410 mg, 20 mg to 420 mg, 20 mg to 430 mg, 20 mg to 440 mg, 20 mg to 450 mg, 20 mg to 460 mg, 20 mg to 470 mg, 20 mg to 480 mg, 20 mg to 490 mg, 20 mg to 500 mg mg~170mg, 20mg~180mg, 20mg~200mg, 20mg~250mg, 20mg~300mg, 20mg~350mg, 20mg~400mg, 20mg~500mg, 50mg~60mg, 50mg~70mg, 50mg~80mg, 50mg~90mg, 50mg~100mg, 50mg~120mg, 50mg~150mg, 50mg~200mg, 50mg~250mg, 50mg~300mg, 50mg~350mg, 50mg~400mg, 50mg~450mg, 50mg~500 mg, 100mg~120mg, 100mg~150mg, 100mg~200mg, 100mg~250mg, 100mg~300mg, 100mg~350mg, 100mg~400mg, 100mg~450mg, 100mg~500mg, 150mg ~200mg, 150mg~250mg, 150mg~300mg, 150mg~350mg, 150mg~400mg, 150mg~450mg, 150mg~500mg, 200mg~250mg, 200mg~300mg, 200mg~350mg, 20 In one embodiment, the amount of the active ingredient may be 0 mg to 400 mg, 200 mg to 450 mg, 200 mg to 500 mg, 40 mg to 150 mg, 50 mg to 150 mg, 60 mg to 150 mg, 70 mg to 150 mg, 80 mg to 150 mg, 90 mg to 150 mg, 100 mg to 150 mg, 110 mg to 150 mg, 120 mg to 150 mg, 130 mg to 150 mg, 140 mg to 150 mg, 30 mg to 140 mg, 40 mg to 130 mg, 50 mg to 120 mg, 60 mg to 110 mg, 70 mg to 110 mg, or 80 mg to 100 mg.

[0151]

[0163] In one version, the amount of imatinib delivered to a subject for treatment of a pulmonary disease (e.g., the approximate amount of imatinib that exits an aerosolization device when inhaled by a subject) is at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, at least about 220 mg, at least about 230 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 270 mg, at least about 280 mg, at least about 290 mg, at least about 300 mg, at least about 310 mg, at least about 320 mg, at least about 330 mg, at least about 340 mg, at least about 350 mg, at least about 360 mg, at least about 370 mg, at least about 380 mg, at least about 390 mg, at least about 400 mg, at least about 410 mg, at least about 420 mg, at least about 430 mg, at least about 440 mg, at least about 450 mg, at least about 460 mg, at least about 470 mg, at least about 480 mg, at least about 490 mg, at least about 500 mg, at least about 510 mg, at least about 520 mg, at least about 53 0 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 225 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 470 mg, or at least about 500 mg.

[0152]

[0164] In one version, the amount of imatinib delivered to a subject for treating a pulmonary disease (e.g., the approximate amount of imatinib that exits the mouthpiece when inhaled by a subject) is at most about 20 mg, at most about 30 mg, at most about 40 mg, at most about 50 mg, at most about 60 mg, at most about 70 mg, at most about 80 mg, at most about 90 mg, at most about 100 mg, at most about 110 mg, at most about 120 mg, at most about 130 mg, at most about about 140 mg, up to about 150 mg, up to about 160 mg, up to about 170 mg, up to about 180 mg, up to about 190 mg, up to about 200 mg, up to about 225 mg, up to about 250 mg, up to about 275 mg, up to about 300 mg, up to about 325 mg, up to about 350 mg, up to about 375 mg, up to about 400 mg, up to about 425 mg, up to about 450 mg, up to about 475 mg, or up to about 500 mg.

[0153]

[0165] In some cases, the amount of imatinib delivered to a subject for treatment of a pulmonary disease (e.g., the approximate amount of imatinib that leaves the mouthpiece when inhaled by a subject) is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

[0154] Kits and Systems

[0166] In one embodiment, a kit for treating pulmonary disease by inhalation is also provided herein.The kit can include one or more pharmaceutical agents, such as a salt of imatinib, or some additional active agents as described herein.In some cases, the kit includes a container for the pharmaceutical agent or composition.In some cases, a unit dose of the pharmaceutical agent described above is provided in the kit.In some cases, the kit also includes a container / receptacle for containing the pharmaceutical agent.

[0155]

[0167] The pharmaceutical composition according to one or more embodiments of the present disclosure may contain a combination of a pharmaceutical agent (e.g., imatinib free base, imatinib salt) and one or more additional active agents for the treatment of pulmonary disease, if desired. The pharmaceutical composition may be aerosolized prior to administration or may be presented to the user in the form of an aerosol.

[0156]

[0168] In some cases, all starting materials are sterilized by established techniques that meet the standards for medical use. Typically, manufacturing equipment is sterilized before use. Some or all of the other additional pharma- ceutically acceptable carriers or excipients, solubilizers, or other additional components of the pharmaceutical composition (e.g., cyclodextrin, e.g., SBEβCD or HPβCD; e.g., acids, 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., cosolvents) can be added to a suitable container.

[0157]

[0169] In some cases, the kit includes separate containers / receptacles for containing the pharmaceutical compositions described herein. In some other cases, the kit includes a single container for containing the pharmaceutical composition. The kit may further include instructions on how to use the kit. The instructions may be presented in the form of a data sheet, manual, a sheet of paper, printed on one or more containers or devices of the kit. Alternatively, the instructions may be provided in electronic form, for example available on a disk, or online with a web link available from the kit. The instructions for use of the kit may include instructions for use of the pharmaceutical composition and the aerosolization device (e.g., nebulizer) for treating any applicable condition, for example, pulmonary disease. The instructions for use of the kit may include instructions for use of the pharmaceutical composition and the aerosolization device (e.g., nebulizer) for treating pulmonary disease. In some cases, the kit includes a nose clip. The nose clip may be used to block the passage of air through the subject's nose during inhalation, increasing the percentage of the total inhaled volume of aerosol exiting the nebulizer.

[0158]

[0170] A unit dose of the pharmaceutical composition can be placed in a container. The container can be inserted into an aerosolization device. The container can be of a suitable shape, size, and material to contain the pharmaceutical composition and provide the pharmaceutical composition in a usable state. For example, the container can include a wall that includes a material that does not adversely react with the pharmaceutical composition. In addition, the wall can include a material that allows the capsule to be opened and the pharmaceutical composition to be aerosolized.

[0159]

[0171] In some cases, the pharmaceutical composition within the container may be stable for extended periods at reduced temperatures (eg, 2-8° C.), extending the stability of the pharmaceutical composition. terminology

[0172] As used herein, the singular forms "a," "an," and "the" can include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "pharmaceutical agent for the treatment of pulmonary disease" can include not only a single active agent but also a combination or mixture of two or more different active agents.

[0160]

[0173] References herein to "one embodiment," "one version," or "one aspect" can include one or more such embodiments, versions, or aspects, unless otherwise clear from the context.

[0161]

[0174] As used herein, the term "pharmaceutical acceptable solvate" can refer to a solvate that retains one or more of the biological activities and / or properties of a pharmaceutical agent and is not biologically or otherwise undesirable. Examples of pharmaceutical acceptable solvates include, but are not limited to, a pharmaceutical agent for the treatment of pulmonary disease in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or a combination thereof.

[0162]

[0175] As used herein, the term "salt" is equivalent to the term "pharmaceutical acceptable salt" and can refer to salts that retain one or more of the biological activities and properties of the free acids and bases and are not biologically or otherwise undesirable. Examples of pharmaceutical acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioxide, hexyne-1, These include 6-diacidote, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate salts.

[0163]

[0176] The term "about" with respect to a reference numerical value can include values ​​in a range of plus or minus 10% from that value. For example, the amount "about 10" includes amounts from 9 to 11, including the reference numbers 9, 10, and 11. The term "about" with respect to a reference numerical value can also include values ​​in a range of plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

[0164]

[0177] As used herein, the terms "treating" and "treatment" can refer to reducing the severity and / or frequency of symptoms, eliminating symptoms and / or underlying causes, reducing the likelihood of occurrence of symptoms and / or underlying causes, and / or ameliorating damage. Thus, "treating" a patient with an active agent provided herein can include prevention of a particular condition, disease, or disorder in susceptible individuals as well as treatment of clinically symptomatic individuals.

[0165]

[0178] As used herein, a "nominal amount" can mean the amount contained within a unit dose container to be administered.

[0179] As used herein, an "effective amount" can refer to an amount encompassing both a therapeutically effective amount and a prophylactically effective amount.

[0166]

[0180] As used herein, a "therapeutically effective amount" of an active agent can mean an amount that is effective to achieve a desired therapeutic result. The therapeutically effective amount of a given active agent can vary with factors such as the type and severity of the disorder or disease being treated, as well as the age, sex, and weight of the patient. In some cases, "inhalation" (e.g., "oral inhalation" or "nasal inhalation") refers to the inhalation delivery of a therapeutically effective amount of a pharmaceutical agent contained in one unit dose container, which may require one or more exhalations, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or more exhalations in some cases. For example, if the effective amount is 90 mg and each unit dose container contains 30 mg, delivery of the effective amount may require three inhalations.

[0167]

[0181] Unless otherwise indicated, the term "therapeutically effective amount" can include a "prophylactically effective amount," e.g., an amount of an active agent effective to prevent the occurrence or recurrence of a particular condition, disease, or disorder in a susceptible individual.

[0168]

[0182] As used herein, the phrase "minimum effective amount" can mean the minimum amount of a pharmaceutical agent required to achieve an effective dose.

[0183] As used herein, "mass median diameter" or "MMD" can refer to the median diameter of multiple droplets of a polydisperse droplet population, typically consisting of, for example, a range of droplet sizes.

[0169]

[0184] As used herein, "particles" can refer to the "droplets" of an aerosolized pharmaceutical composition.

[0185] As used herein, "geometric diameter" may mean the diameter of a single droplet as determined by microscopic examination, unless the context indicates otherwise.

[0170]

[0186] As used herein, "mass median aerodynamic diameter" or "MMAD" can refer to the median aerodynamic size of a plurality of droplets or droplets, usually of a polydisperse population. "Aerodynamic diameter" can be the diameter of a unit density sphere that generally has the same settling velocity in air as a powder, and is therefore a useful means of characterizing an aerosolized powder or other dispersed droplet or droplet formulation in terms of its settling behavior. Aerodynamic diameter includes droplet or droplet shape, density, and physical size of the droplet or droplet. As used herein, MMAD refers to the median aerodynamic droplet or droplet size distribution of aerosolized droplets as determined by cascade impaction, unless the context indicates otherwise.

[0171]

[0187] A "pharmaceutically acceptable" ingredient means an ingredient that is not biologically or otherwise undesirable, e.g., an ingredient may be incorporated into a pharmaceutical composition of the present disclosure and administered to a patient as described herein without causing any significant undesirable biological effects or interacting adversely with any other ingredients of the formulation in which it is contained. When the term "pharmaceutically acceptable" is used with respect to an excipient, it may imply that the ingredient meets the desired standards of toxicology and manufacturing testing or is included in the Inactive Ingredient Guide prepared by the US Food and Drug Administration.

[0172]

[0188] As used herein, "active nebulizer" or "nebulizer" refers to an inhalation device that does not rely exclusively on the patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or unit dose form, and includes inhaler devices that contain pressurized gas and a means for providing energy to disperse and aerosolize the drug composition, such as a vibrating or rotating element.

[0173]

[0189] As used herein, "room temperature" may mean a temperature between 18°C ​​and 25°C. EXAMPLES

[0174]

[0190] The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the disclosure; it will be understood that by their illustrative nature, other procedures, methodologies, or techniques known to those skilled in the art may be substituted.

[0175] Example 1: Organoleptic testing of formulations in solution.

[0191] This example illustrates the organoleptic properties of certain exemplary formulations of imatinib in liquid solution.

[0176]

[0192] In one experiment, exemplary formulations of imatinib according to some embodiments of the present disclosure were prepared as shown in Table 1 and tested for their organoleptic properties in minimal volumes by volunteer subjects.

[0177]

[0193] To prepare the exemplary formulations, imatinib mesylate or imatinib free base was dissolved directly in sterile water or a sterile aqueous solution containing the specified excipient (e.g., propylene glycol, sodium saccharin, sodium chloride, lactose monohydrate, phosphate, anhydrous dextrose, or hydroxypropyl-β-cyclodextrin). The pH of the resulting solution was measured, and water was added, if necessary, 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.

[0178]

[0194] Four individuals were instructed to perform deep lung inhalations of one or more exemplary formulations of minimal volume (<1.5 mL) at intervals of 1-2 minutes. Each individual was asked to describe the taste of the inhaled solution and to record their cough reflex, if any, and the sensation of the solution in the throat and mouth both during and after inhalation. Table 2 summarizes the observations made by the individuals. Of the formulations tested, it was found that most of the formulations made with imatinib mesylate elicited a cough reflex in the individuals tested and were reported to be irritating. In some cases, testers were unable to complete the inhalation due to a strong cough reflex or irritation. In contrast, exemplary formulation 13 made with imatinib free base did not elicit a cough reflex or elicited only a very slight cough or irritating sensation in the mouth.

[0179] Example 2: Exemplary Imatinib Formulations

[0195] Table 3 lists exemplary imatinib formulations with various solubility enhancers according to certain embodiments of the present disclosure.

[0180] [Table 1]

[0181]

Table 2-1

[0182]

Table 2-2

[0183]

Table 2-3

[0184]

Table 3-1

[0185]

Table 3-2

[0186]

Table 3-3

[0187]

Table 3-4

[0188]

Table 3-5

[0189]

Table 3-6

[0190]

Table 3-7

[0191]

Table 3-8

[0192]

Table 3-9

[0193]

Table 3-10

[0194]

Table 3-11

[0195]

Table 3-12

[0196]

Table 3-13

[0197]

Table 3-14

[0198]

Table 3-15

[0199]

Table 3-16

[0200]

Table 3-17

[0201]

Table 3-18

[0202]

Table 3-19

[0203]

Table 3-20

[0204]

Table 3-21

[0205]

Table 3-22

[0206]

Table 3-23

[0207]

Table 3-24

[0208]

Table 3-25

[0209]

Table 3-26

[0210]

Table 3-27

[0211]

Table 3-28

[0212]

Table 3-29

[0213]

Table 3-30

[0214]

Table 3-31

[0215]

Table 3-32

[0216]

Table 3-33

[0217]

Table 3-34

[0218]

Table 3-35

[0219]

Table 3-36

[0220]

Table 3-37

[0221]

Table 3-38

[0222]

Table 3-39

[0223] [Table 3-40]

[0224] [Table 3-41]

[0225] [Table 3-42]

[0226] [Table 3-43]

[0227] [Table 3-44]

[0228] [Table 3-45]

[0229] [Table 3-46]

[0230] [Table 3-47]

[0231] Example 3: Solubility studies with hydroxypropyl beta cyclodextrin (HPβCD)

[0196] This example illustrates the dissolution characteristics of certain formulations of imatinib free base in liquid solution.

[0232] Imatinib free base was poorly soluble in water over the physiologically relevant pH range of 4 to 8 (Figure 1). Figure 1 shows the maximum concentration (mg / mL) of imatinib free base as a function of pH. As can be seen in Figure 1, lower pH improved the solubility of imatinib free base. At pH 3, the concentration of imatinib free base was approximately 0.30 mg / mL. At pH 6, the concentration of imatinib free base was <0.01 mg / mL.

[0233] Example 4: Solubility Studies with HPβCD and pH

[0198] This example illustrates the dissolution characteristics of certain formulations of imatinib free base in liquid solution.

[0234] FIG. 2 shows the maximum concentration of imatinib free base as a function of percent HPβCD at pH 5 and 7.5. Improved solubility of imatinib free base was shown at pH 7.5. At 45% HPβCD (w / v), the amount of dissolved imatinib free base was 8.7 mg / mL. Addition of HPβCD improved solubility, e.g., the maximum concentration of imatinib free base increased from <0.01 mg / mL at 0% HPβCD to 8.7 mg / mL at 45% HPβCD, respectively. At pH 5 and about 5% HPβCD (w / v), the concentration of dissolved imatinib free base was approximately 2 mg / mL. At pH 5 and 25-30% HPβCD (w / v), the concentration of dissolved imatinib free base was 9.5 mg / mL. Lowering the pH improved the solubility of imatinib free base at all concentrations tested. Decreasing the pH from 7.5 to 5.0 provided a concentration increase of 2.5-5.8 mg / mL for HPβCD. The maximum imatinib free base concentration observed was 9.5 mg / mL.

[0235] Example 5: Solubility studies with HPβCD or sulfobutyl ether β-cyclodextrin (SBEβCD) and pH

[0200] This example illustrates the dissolution characteristics of certain exemplary formulations of imatinib free base in liquid solution.

[0236] FIG. 3A shows the maximum concentration of imatinib free base as a function of percent cyclodextrin (HPβCD or sulfobutyl ether β-cyclodextrin (SBEβCD)) at different pH levels. The relationship between the solubility of imatinib free base in solution and the concentration of HPβCD (w / v) was examined at pH 5 and 7.5. The relationship between the solubility of imatinib free base in solution and the concentration of SBEβCD (w / v) was examined at pH 5. At pH 5 and about 5% HPβCD (w / v), the maximum concentration of dissolved imatinib free base was approximately 2 mg / mL. At pH 5 and between 25-30% HPβCD (w / v), the concentration of dissolved imatinib free base was 9.5 mg / mL. At pH 5 and 10% SBEβCD (w / v), the concentration of dissolved imatinib free base was approximately 70 mg / mL. The results showed an approximately 3500-fold increase in solubility compared to imatinib free base in water at pH 5, which was 0.02 mg / mL. The data showed an approximately 16-fold increase in solubility compared to 10% HPβCD (w / v), which was 4.4 mg / mL at pH 5. The molar ratio of (imatinib / SBEβCD) in the solution was 3.1. At pH 5 and 20% SBEβCD (w / v), the concentration of dissolved imatinib free base was approximately 160 mg / mL. The results showed at least an approximately 8000-fold increase in solubility compared to imatinib free base in water at pH 5. The data showed an approximately 25-fold increase in solubility compared to 20% HPβCD (w / v) at pH 5, which was 6.8 mg / mL. The molar ratio of (imatinib / SBEβCD) in the solution was 3.5.

[0237]

[0202] Furthermore, at pH 5 and 25% SBEβCD (w / v), the concentration of dissolved imatinib free base was approximately 200 mg / mL. At pH 5 and 30% SBEβCD (w / v), the concentration of dissolved imatinib free base was approximately 225 mg / mL.

[0238]

[0203] Figure 3B shows photographs of exemplary imatinib solutions and suspensions at different pH conditions. Approximately 30 mg / mL of imatinib free base was mixed with three different vehicles (30% SBEβCD in 50 mM phosphate buffer adjusted to three different pH levels: 7, 5, and 3). As shown by the photographs, at pH=7, a white suspension was obtained, and at pH 5 and pH 3, clear solutions were obtained. This data indicates that the solubility of imatinib free base in aqueous solutions containing SBEβCD may be pH dependent, for example, the lower the pH of the SBEβCD aqueous solution, the higher the solubility of imatinib free base in the solution.

[0239] Example 6: Solubility studies using SBEβCD and dilution in water

[0204] This example illustrates the effect of dilution with water on the solubility of imatinib free base in a cyclodextrin-based formulation.

[0240] In one experiment, the solubility of imatinib free base in an exemplary imatinib free base formulation upon dilution with water was examined. Briefly, an exemplary imatinib free base solution (50 mg / mL imatinib free base, 10% SBEβCD, pH 5.1) was diluted 40-fold in water for injection (WFI). Upon dilution, imatinib precipitated. The pH of the final suspension after dilution was measured to be 5.4. Since imatinib is still primarily protonated at pH 5.4, the observed precipitation of imatinib may not be a pH-dependent effect.

[0241] In another experiment, another exemplary imatinib solution (100 mg / mL imatinib free base, 15% w / v SBEβCD, 50 mM phosphate buffer, pH 5.0) was diluted 20-fold with water. Upon dilution, imatinib also precipitated. The resulting suspension was used in the intratracheal (IT) arm of the rat pharmacokinetic study shown in Example 9 below.

[0242] Example 7: Solubility Studies with SBEβCD and Dilution

[0207] This example examines the effect of dilution at constant pH on the solubility of imatinib free base in a cyclodextrin-based formulation.

[0243] In one experiment, the solubility of imatinib free base in exemplary imatinib free base formulations upon dilution while keeping pH constant is tested. Briefly, various exemplary imatinib free base solutions (volume 100 mL, saturated imatinib free base, different SBEβCD concentrations, pH 5) are each diluted with phosphate buffer (50 mM, pH 5) to a formulation with a final SBEβCD concentration of 1.5% (w / v). The solubility of imatinib free base in SBEβCD solutions is predicted to decrease upon dilution despite keeping pH constant, based on the measurements shown in Example 5 and FIG. 3A. Table 4 summarizes the predicted precipitation of imatinib free base in each solution upon dilution to obtain a final SBEβCD concentration of 1.5% (w / v).

[0244] [Table 4]

[0245] Example 8: Taste testing of sulfobutyl ether beta cyclodextrin (SBEβCD) based formulations

[0209] This example illustrates the organoleptic properties of certain exemplary formulations of imatinib free base in liquid solution.

[0246]

[0210] Test subject 5 (T5) was tested inhaling the following two formulations: a. 40 mg / mL imatinib, 10% w / v SBEBCD, 50 mM phosphate buffer (pH 5) b. 80 mg / mL imatinib, 20% w / v SBEBCD, 50 mM phosphate buffer (pH 5).

[0247]

[0211] T5 did not cough after inhaling each of the two formulations for approximately 2 minutes (continuous inhalation). T5 did not experience any coughing, desire to cough, or throat irritation.

[0212] T5 stated that the imatinib free base formulation with SBEβCD did not cause coughing (an adverse reaction). The same subject T5 also tasted the imatinib mesylate formulation and coughed violently when inhaling the imatinib mesylate formulation.

[0248] Example 9: Testing of exemplary formulations in rats

[0213] This example illustrates and compares the pharmacokinetics of an exemplary imatinib free base / cyclodextrin formulation ("imatinib free base") and imatinib mesylate formulation ("imatinib mesylate") in rats following intravenous (IV) and intratracheal (IT) administration, respectively.

[0249] A concentration of imatinib free base compatible with IT rat dosing was found to be 5 mg / mL. 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), 50 mM phosphate buffer, pH 5.0) precipitated upon dilution, therefore the 100 mg / mL imatinib free base formulation was diluted 20-fold with water immediately prior to dosing and administered IT as a 5 mg / mL suspension. A 6 mg / mL imatinib mesylate (equivalent to 5 mg / mL imatinib free base) solution formulation was used as a comparative standard in the IV arm of the study. Both groups received a single dose equivalent to a 1 mg / kg dose of imatinib free base. Four animals from each group were euthanized at six time points 1-3, 5, 10, 20, 30, or 60 minutes after dosing for sample collection. Lung tissue and blood were collected for analysis.

[0250] All animals survived to their scheduled necropsy. No abnormal clinical observations were noted during the study. No test article-related weight changes were observed during the study. Overall, animal necropsy results were unremarkable.

[0251] Materials and Methods

[0252] [Table 5]

[0253] [Table 6]

[0254] Test System: Seventy-two male, 8-week-old Sprague Dawley rats (Charles River Laboratories) were used in the study, with weights ranging from 245.8 to 317 g at the start of the study.

[0255] Experimental Design and Execution: Briefly, after animals were admitted to the study, all animals were randomly assigned to treatment groups according to the following study design: Animals were treated with test article formulation R1 administered intravenously (IV) or formulation R2 administered intratracheally (IT). Four animals per group were euthanized for sample collection at six time points post-dosing as outlined in Table 7.

[0256] [Table 7]

[0257]

[0219] Pharmacokinetics Plasma and lung concentration versus time data were analyzed using JMP version 15.2.0. The mean of each time point is reported for groups / time points with a minimum of 2 animals. The following PK parameters were estimated using a two-compartment IV bolus dosing model fit using the nonlinear model fit platform in JMP version 15.2.0: maximum observed concentration (C max ), C max The time at which the max ) and the area under the plasma concentration versus time curve from zero to the last measured concentration (AUC 60min ). AUC 60min was calculated from the model curve using the trapezoidal integration method, and the results are shown in Table 8 below.

[0258] [Table 8]

[0259] The therapeutic benefit (Rd) in Table 8 was calculated using the following formula:

[0260]

number

[0261]

[0222] The IV data suggest that based on the high LogP (lipophilicity) of imatinib, the observed volume of distribution of imatinib (calculated as the ratio of the amount of imatinib in the body to the plasma concentration of imatinib), and cardiac output to the lungs, the sample collection period represents a distribution phase of material that accumulates preferentially in the lungs. This observation indicates that direct administration of imatinib to the lungs may provide improved safety compared to systemic delivery by oral or IV routes. Since imatinib preferentially accumulates in lung tissue, direct delivery to the lungs by inhalation may minimize systemic exposure. Notably, direct delivery of imatinib to the lungs by IT administration of an imatinib free base / cyclodextrin formulation shows a four-fold therapeutic advantage (Rd=4) compared to IV administration of an imatinib mesylate formulation. This treatment benefit can also be seen in Figures 4A-4F, which show plots summarizing lung versus plasma imatinib concentrations over time following IT administration of the imatinib free base / cyclodextrin formulation or IV administration of the imatinib mesylate formulation.

[0262]

[0223] Although preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to one skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It is understood that various alternatives to the embodiments of the present disclosure may be used in carrying out the present disclosure. The following claims define the scope of the present disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

[Claim 1] The invention described herein.

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