Inhaled imatinib for pulmonary hypertension

Abstract

Methods for treating pulmonary hypertension are provided, including dry powder inhalation administration of imatinib, a pharmaceutically acceptable salt, or a derivative thereof. Dry powder inhalable compositions containing imatinib, a pharmaceutically acceptable salt, or a derivative thereof, as well as methods for their preparation are also provided.

Description

[Technical Field]

[0001] field This application claims priority to U.S. Provisional Patent Application No. 63 / 114,781, filed on 17 November 2020, which is incorporated herein by reference for all purposes.

[0002] This application relates to methods, compositions, and kits for therapeutic procedures, more specifically, therapeutic methods for treating pulmonary hypertension, which involve administering imatinib using an inhalation method such as a dry powder inhalation method. [Background technology]

[0003] background All blood passes through the lungs via the pulmonary circulation, primarily to replenish oxygen, which is then distributed to blood flow around other parts of the body via the systemic circulation. Under normal circumstances, the flow in both circulations is equal, but the resistance to the flow in the pulmonary circulation is generally much less than that in the systemic circulation. When resistance to pulmonary blood flow increases, the pressure in that circulation increases for any particular flow. This condition is called pulmonary hypertension (PH). Generally, pulmonary hypertension is defined by the observation of pressures exceeding the normal range appropriate for the majority of people living at the same altitude and engaging in similar activities.

[0004] Pulmonary hypertension can occur for a variety of reasons, and its various components have been classified into five categories based on clinical and pathological evidence, in accordance with the latest WHO agreement. See, for example, Simonneau G., et al. J. Am. Coll. Cardiol. 2004; 43(12 Suppl S):5S-12S. Pulmonary hypertension can be a sign of obvious or explainable increased resistance, such as impaired blood flow due to pulmonary embolism, dysfunction of heart valves or myocardium handling blood after it has passed through the lungs, reduced pulmonary vascular diameter as a reflex response to alveolar hypoxia due to lung disease or high altitude, or mismatch between vascular volume and essential blood flow, such as blood bypassing or surgical removal of lung tissue in congenital anomalies. In addition, certain infections such as HIV and liver disease with portal hypertension can also cause pulmonary hypertension. Autoimmune diseases such as collagen vascular disease also frequently cause pulmonary vascular stenosis and contribute to a significant number of pulmonary hypertension cases. The remaining cases of pulmonary hypertension where the cause of increased resistance cannot yet be explained are defined as idiopathic (primary) pulmonary hypertension (iPAH). Diagnosed after ruling out the causes of secondary pulmonary hypertension, the majority of cases are associated with gene mutations in the bone morphogenetic protein receptor-2 gene. Cases of idiopathic pulmonary hypertension tend to constitute a recognizable proportion, approximately 40%, of patients receiving care in large facilities specializing in pulmonary hypertension. While the most common patients (about 65%) are women and young adults, it has also occurred in children and those over 50. The average life expectancy from diagnosis is short, approximately 3-5 years without special treatment, although spontaneous remission and extended lifespan can occasionally be expected depending on the characteristics of the diagnostic process. However, generally, the disease progresses relentlessly, often with syncope, and right heart failure and death can occur suddenly.

[0005] Pulmonary hypertension refers to a condition associated with an elevated pulmonary artery pressure (PAP) level exceeding normal levels. In humans, the normal average PAP is approximately 12-15 mmHg. Pulmonary hypertension, on the other hand, can be defined as an average PAP exceeding 25 mmHg when assessed by right heart catheterization. In severe pulmonary hypertension, pulmonary artery pressure may reach or even exceed systemic pressure levels. When PAP increases significantly due to pulmonary venous congestion, i.e., in left heart failure or left valvular dysfunction, plasma can leak from the capillaries into the pulmonary interstitium and alveoli. As a result, fluid accumulation in the lungs (pulmonary edema) occurs, which can lead to a decline in lung function that can be fatal in some cases. However, pulmonary edema is not always characteristic of all other components of this disease, even in severe cases of pulmonary hypertension due to pulmonary vascular changes.

[0006] Pulmonary hypertension can be acute or chronic. Acute pulmonary hypertension is often a potentially reversible phenomenon caused by contraction of the smooth muscle of pulmonary blood vessels, which can be triggered by conditions such as hypoxia (as in high-altitude illness), acidosis, inflammation, or pulmonary embolism. Chronic pulmonary hypertension is characterized by significant structural changes in the pulmonary vascular system that lead to a decrease in the cross-sectional area of ​​the pulmonary blood vessels. Causes of this can include, for example, chronic hypoxia, thromboembolism, collagen vascular disease, excessive pulmonary circulation due to left-to-right shunts, HIV infection, portal hypertension, or a combination of unknown causes such as gene mutations and idiopathic pulmonary hypertension.

[0007] Pulmonary hypertension has been associated with several life-threatening clinical conditions such as adult respiratory distress syndrome ("ARDS") and persistent pulmonary hypertension of the newborn ("PPHN"). Zapol et al., Acute Respiratory Failure, p.241-273, Marcel Dekker, New York (1985); Peckham, J. Ped. 93: 1005 (1978). PPHN, a disease mainly affecting full-term infants, is characterized by increased pulmonary vascular resistance, pulmonary arterial hypertension, and left-to-right shunting of blood due to patent ductus arteriosus and patent foramen ovale in the neonatal heart. The fatality rate ranges from 12 to 50%. Fox, Pediatrics 59:205 (1977); Dworetz, Pediatrics 84:1 (1989). Pulmonary hypertension may ultimately lead to the development of a potentially fatal heart disease known as "cor pulmonale" or pulmonary heart disease. Fishman, “Pulmonary Diseases and Disorders” 2nd Ed., McGraw-Hill, New York (1988).

[0008] Imatinib functions as a specific inhibitor of many tyrosine kinase (TK) enzymes. It blocks the TK active site and leads to a decrease in activity. There are many TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domains of abl (Abelson oncogene), c-kit, and PDGH-R (platelet-derived growth factor receptor). Aberrant expression and signaling of the PDGH ligand and receptor are associated with several connective tissue disorders and lung diseases such as pulmonary arterial hypertension, lung cancer, and idiopathic pulmonary fibrosis (IPF) (PAH). SUMMARY OF THE INVENTION

[0009] Summary One embodiment includes administering a therapeutically effective amount of a composition comprising a tyrosine kinase inhibitor, such as imatinib, a pharmaceutically acceptable salt thereof, or a derivative, by inhalation to a subject that needs it, for treating pulmonary hypertension.

[0010] Another embodiment is a dry powder inhalable composition comprising a therapeutically effective amount of imatinib, a pharmaceutically acceptable salt thereof, or a derivative, and optionally one or more excipients. In an exemplary embodiment, the dry powder inhalable composition comprises crystalline particles of diketopiperazine as a pharmaceutically acceptable excipient.

[0011] In one embodiment, an inhaler such as a dry powder inhaler for delivering an inhalable pharmaceutical composition such as a dry powder composition comprising a therapeutically effective amount of imatinib, a pharmaceutically acceptable salt thereof, or a derivative, and optionally one or more excipients is provided. In some embodiments, the dry powder inhaler can be structurally configured to deliver the dry powder composition from a capsule or cartridge that can be adapted or attached to the inhaler.

[0012] In one embodiment, the dry powder inhaler can be breath-actuated or activated to initiate aerosolization of the powder within the inhaler during use and delivery of the dry powder pharmaceutical composition.

Brief Description of the Drawings

[0013] [Figure 1A] Figures 1A - 1C show how the imatinib content of the powder affects the geometric particle size distribution of the powder released from the inhaler. The plot tracks three cut points of the distribution: x50 (median) (Figure 1B) and the points corresponding to approximately ±1 standard deviation from the median of the lognormal distribution (x16 (Figure 1A) and x84 (Figure 1C)). [Figure 1B] Figures 1A - 1C show how the imatinib content of the powder affects the geometric particle size distribution of the powder released from the inhaler. The plot tracks three cut points of the distribution: x50 (median) (Figure 1B) and the points corresponding to approximately ±1 standard deviation from the median of the lognormal distribution (x16 (Figure 1A) and x84 (Figure 1C)). [Figure 1C]Figures 1A–1C show how the imatinib content in the powder affects the geometric particle size distribution of the powder released from the inhaler. The plots track three cut points in the distribution: x50 (median) (Figure 1B) and points corresponding to approximately ±1 standard deviation from the median of the log-normal distribution (x16 (Figure 1A), and x84 (Figure 1C)). [Figure 2] Figure 2 shows the estimated lung dose of imatinib as a function of the imatinib content in the crystalline carrier (XC) powder. [Figure 3] Figure 3 shows the concentration of imatinib in rat plasma samples as a function of time. [Figure 4] Figure 4 provides a schematic example of lung section identification. [Figure 5] Figure 5 shows a plot of imatinib concentrations in rat lung sections identified in Figure 4 as a function of time. Error bars are not shown. [Figure 6] Figure 6 shows the concentrations of imatinib in rat lung sections identified in Figure 4. [Figure 7] Figure 7 shows the concentrations of imatinib in rat lung sections identified in Figure 4. The scale was set to show lower concentrations. [Modes for carrying out the invention]

[0014] Detailed description of the present invention For example, therapeutically effective doses of tyrosine kinase inhibitors, including imatinib, gefitinib, erlotinib, and sunitinib, may be administered by inhalation using an inhalation device, which may be a compact inhalation device such as a dry powder inhaler, as an effective treatment for pulmonary hypertension. In some embodiments, imatinib is administered using a dry powder inhaler as a dry powder composition. Furthermore, such doses do not cause significant side effects, such as pulmonary edema or subdural hematoma.

[0015] Treatment method

[0016] Accordingly, one exemplary embodiment is a method for delivering a therapeutically effective amount of imatinib, its pharmaceutically acceptable salt, or derivative to a subject suffering from pulmonary hypertension, such as a human, by administering a composition comprising a composition comprising a therapeutically effective amount of imatinib, its derivative, or its pharmaceutically acceptable salt to a subject by inhalation. In some embodiments, the composition is a dry powder inhalable composition that can be administered by a dry powder inhaler to a subject suffering from a condition or disease such as pulmonary hypertension that can be treated with imatinib.

[0017] Another embodiment is a method for treating pulmonary hypertension, comprising administering imatinib, its derivatives, or a pharmaceutically acceptable salt thereof in the form of a dry powder composition to a subject in need, such as a human, using a dry powder inhaler.

[0018] Imatinib mesylate is also known as STI-571. The molecular weight of imatinib is 493.603, and its empirical formula is C 29 H 31 It is N7O. Imatinib, or 4-[(4-methylpiperazine-1-yl)methyl]-N-[4-methyl-3-[(4-pyridine-3-ylpyrimidine-2-yl)amino]phenyl]benzamide, has the following formula: [ka] It has.

[0019] Imatinib is a small molecule kinase inhibitor used to treat certain types of cancer. It is currently marketed by Novartis as imatinib mesylate (INN), its mesylate, under the name Gleevec® (USA) or Glivec® (Europe / Australia). It is used in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors (GIST), and many other malignancies.

[0020] Imatinib was first described in U.S. Patent No. 5,521,184. U.S. Patent Publication No. US20110190313A1 describes the use of imatinib for the treatment of pulmonary hypertension. U.S. Patent Publication No. US20150044288A1 describes the administration of imatinib by inhalation for the treatment of pulmonary hypertension and other conditions.

[0021] This disclosure also encompasses methods using imatinib, its derivatives, or pharmaceutically acceptable salts thereof. In one embodiment, the method uses imatinib mesylate, which is currently marketed under the trade name Gleevec®. The FDA has approved imatinib mesylate for the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors, relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), spinal cord dysplasia / myeloproliferative disorders associated with platelet-derived growth factor receptor gene rearrangements, invasive systemic mastocytosis with or without an unknown D816V c-KIT mutation, idiopathic eosinophilic syndrome and / or chronic eosinophilic leukemia, unresectable, relapsed and / or metastatic dermatofibrosarcoma protuberance in humans with or without FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion), or with or without FIP1L1-PDGFRα fusion kinase.

[0022] In certain embodiments, imatinib may be administered in combination with one or more additional activators. In some embodiments, such one or more additional activators may also be administered together with imatinib using a metered-dose inhaler or a dry powder inhaler. In some further embodiments, such one or more additional activators may be administered separately from imatinib. In some embodiments, separate administration may be selected from oral, nasal, sublingual, buccal, intravenous, intramuscular, transdermal, liquid or gas aerosol inhalation (i.e., via metered-dose or dry powder inhaler), rectal, or vaginal. The specific additional activators that may be administered in combination with imatinib may depend on the specific disease or condition for which imatinib is administered for the treatment or prevention, e.g., pulmonary hypertension. In some cases, additional activators include calcium channel blockers such as amlodipine; endothelin receptor antagonists such as ambrisentan, bosentan, or macitentan; phosphodiesterase type 5 inhibitors such as sildenafil or tadalafil; prostacyclin derivatives such as epoprostenol, iloprost, or treprostinil; or prostacyclin IP receptor agonists such as selexipag.

[0023] In certain embodiments, the disclosure also extends to methods using physiologically acceptable salts of imatinib, as well as physiologically unacceptable salts of imatinib, which may be used in the preparation of the pharmacologically active compounds of the present invention.

[0024] The term "pharmaceutically acceptable salt" refers to a salt of imatinib with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. In some embodiments, the salt of imatinib is a salt using an inorganic acid, organic acid, or acidic amino acid. In some embodiments, the counterions of the salt form of imatinib are acetate, acetonide, alanine, aluminum, arginine, ascorbate, asparagine, aspartic acid, benzathine, benzoate, besylate, bisulfate, bisulfite, bitartrate, bromide, calcium, carbonate, camphor sulfonate, cetylpyridinium, chloride, chlorotheophylline, corinate, citrate, cysteine, deoxycholate, dieta Nolamine, diethylamine, diphosphate, dipropionate, disalicylate, edetate, edisylate, estrate, ethylamine, ethylenediamine, ethane disulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamic acid, glutamine, glycine, hippurate, histidine, hydrobromide, hydrochloride, hydroxide, iodide, isethionate, isoleucine, lactate, lactobionate, lauryl sulfate, leucone Syn, lysine, magnesium, malate, maleate, mandelate, meglumine, mesylate, metabisulfate, metabisulfite, methionine, methyl bromide, methyl sulfate, methyl p-oxybenzoate, mucinate, naphthate, napsilate, nitrate, nitrite, octadecanoate, oleate, ornithine, oxalate, pamoate, pentetate, phenylalanine, phosphate, piperazine, polygalacturonate, potassium, proca These include yin, proline, propionate, p-hydroxybenzoate propyl, saccharin, salicylate, selenocysteine, serine, silver, sodium, sorbitan, stearate, succinate, sulfate, sulfite, sulfosalicylate, tartrate, threonine, tosylate, triethylamine, triethiozide, trifluoroacetate, trioleate, tromethamine, tryptophan, tyrosine, valerate, valine, xinafoate, or zinc. In some embodiments, the salt form of imatinib may be imatinib mesylate.In some embodiments, the salt of imatinib may be imatinib fumarate. In some embodiments, the salt of imatinib may be imatinib hydrochloride. In some embodiments, the salt of imatinib may be imatinib phosphate.

[0025] In some embodiments, the imatinib salt may be in crystalline form. For example, in some embodiments, imatinib mesylate may be in crystalline form. In some embodiments, imatinib fumarate may be in crystalline form. In some embodiments, imatinib hydrochloride may be in crystalline form. In some embodiments, imatinib phosphate may be in crystalline form.

[0026] In some embodiments, imatinib may be administered by an inhalation device, such as a pulse inhalation device, which may contain a solution, suspension, or powder containing imatinib or a salt thereof. For example, such a solution or suspension may be used for aerosolization or atomization by an inhalation device, such as a nebulizer and / or metered-dose inhaler. Pulse inhalation devices are disclosed, for example, in U.S. Patent Application Publication No. 20080200449, U.S. Patents No. 9,358,240; No. 9,339,507; No. 10,376,525; and No. 10,716,793, each of which is incorporated herein by reference.

[0027] In this context, a metered-dose inhaler refers to a device capable of delivering a metered or bolus dose of a respiratory drug, such as imatinib, to the lungs. An example of an inhalation device may be a pressurized metered-dose inhaler, i.e., a device that generates an inhalation aerosol fog from a solution and / or suspension of a respiratory drug. In some embodiments, the aerosol fog may be formed from a solution of a respiratory drug, such as imatinib or a salt thereof, in a solution of chlorofluorocarbons (CFCs) and / or hydrofluoroalkanes (HFAs).

[0028] In some embodiments, the inhalation device may be a single-dose inhalation device, which may be a unit dose container such as a capsule or cartridge containing a single or repeated dose of a respiratory drug such as imatinib or a salt thereof, for example, two or more doses. In some embodiments, such a device may be a dry powder inhaler.

[0029] In some embodiments, the inhalation device may be a dry powder inhaler. In some embodiments, the inhalation device, such as a pulse inhalation device, may be a dry powder inhaler, which may contain a dry powder composition or formulation comprising imatinib or a salt thereof, such as imatinib mesylate. In some embodiments, in addition to imatinib or a salt thereof, such as imatinib mesylate, the dry powder composition may contain diketopiperazine (FDKP), such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine. In even more specific embodiments, the dry powder composition may consist of imatinib or a salt thereof, such as imatinib mesylate, and diketopiperazine, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP). In particular embodiments, in addition to imatinib or a salt thereof, such as imatinib mesylate, and diketopiperazine, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP), the dry powder composition may further contain pharmaceutically acceptable carriers and / or excipients, such as amino acids, such as leucine, isoleucine, norleucine, methionine, and glycine; and sugars including trehalose, mannitol, and lactose. In one embodiment, the dry powder composition may further contain, before spray drying, one or more phospholipids, such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), in amounts ranging from about 1% (w / w) to about 25%, or 2.5% to 20% (w / w), or 5% to 15% (w / w), in amounts up to about 25% (w / w) and ranging from about 1% (w / w) to about 25%, or 2.5% to 20% (w / w), or 5% to 15% (w / w), to assist in aerosolizing the formulation by reducing the particle density.In certain embodiments, the dry powder composition may also contain a surfactant in addition to imatinib or a salt thereof, such as imatinib mesylate, and diketopiperazine, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP). In some embodiments, the dry powder composition may contain only imatinib or a salt thereof, such as imatinib mesylate, diketopiperazine, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP), and a surfactant.

[0030] In some embodiments, the dry powder inhaler may be, for example, a dry powder inhaler disclosed in WO2010 / 152477 (each of which is incorporated herein by reference as a whole) or U.S. Patent No. 8,636,001. The use of a dry powder inhaler for delivering compositions comprising diketopiperazine, for example, (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) is disclosed, for example, in WO2019 / 237028 (each of which is incorporated herein by reference as a whole) and U.S. Patent No. 8,508,732.

[0031] The dry powder composition may have a diameter of 10 micrometers; or an average particle size of less than 9 microns, less than 8 microns, less than 7 microns, less than 6 microns, less than 5 microns, less than 4 microns, or less than 3 microns. The particle size may be measured using many techniques, including laser diffraction techniques. In some embodiments, the dry powder composition may have an average particle size of 0.5 to 10 microns, 1 to 8 microns, 1 to 5 microns, 1 to 4 microns, 1.5 to 4 microns, or 2 to 3 microns, or any value or partial range within these ranges. In some embodiments, 50% of the particles in the dry powder composition may have a size of less than 10 microns, less than 8 microns, less than 7 microns, less than 6 microns, less than 5 microns, or less than 4 microns. In some embodiments, 90% of the particles in the dry powder composition may have a size of less than 10 microns, less than 8 microns, less than 7 microns, less than 6 microns, or less than 5 microns.

[0032] In some embodiments, 16% of the particles in a dry powder composition, when discharged from a dry powder inhaler such as the dry powder inhaler disclosed in WO2010 / 152477 or U.S. Patent No. 8,636,001, may have a size of less than 4 microns, less than 3.5 microns, less than 3 microns, less than 2.5 microns, or less than 2 microns. For example, 16% of the particles in a dry powder composition discharged from a dry powder inhaler may have a size of 0.5 to 4 microns, 0.5 to 3.5 microns, 0.5 to 3.0 microns, 0.5 to 2.5 microns, or 0.5 to 2 microns. In some embodiments, 50% of the particles in a dry powder composition discharged from a dry powder inhaler may have a size of less than 20 microns, less than 18 microns, less than 15 microns, less than 12 microns, less than 10 microns, less than 8 microns, less than 7 microns, less than 6 microns, or less than 5 microns. For example, 50% of the particles in the dry powder composition released from a dry powder inhaler may have a size of 0.5 to 20 microns, 0.5 to 15 microns, 0.5 to 10 microns, 0.5 to 8 microns, 0.5 to 7 microns, 0.5 to 6 microns, or 0.5 to 5 microns. In some embodiments, when released from a dry powder inhaler, 84% of the particles in the dry powder composition may have a size of less than 60 microns, less than 55 microns, less than 50 microns, less than 45 microns, less than 40 microns, less than 35 microns, less than 30 microns, less than 25 microns, less than 22 microns, less than 21 microns, or less than 20 microns. For example, when released from a dry powder inhaler, 84% of the particles in the dry powder composition may have sizes ranging from 0.5 to 60 microns, 0.5 to 50 microns, 0.5 to 45 microns, 0.5 to 40 microns, 0.5 to 35 microns, 0.5 to 30 microns, 0.5 to 25 microns, 0.5 to 22 microns, 0.5 to 21 microns, or 0.5 to 20 microns.

[0033] In some embodiments, the dry powder comprises amorphous powder, multiple crystalline particles, or substantially homogeneous crystalline composite particles. In some embodiments, the dry powder composition is of the following formula: [ka] It includes amorphous, crystalline, or crystalline composite particles made from diketopiperazines such as compounds having [specific properties].

[0034] (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine, or pharmaceutically acceptable salts thereof including disodium salt, magnesium salt, lithium and potassium salt.

[0035] In some embodiments, the composition, such as a dry powder composition, may be administered to a patient in need in amounts of about 1 mg to about 800 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, or about 0.15 mg to about 50 mg, where the total weight per dose is administered in one or more inhalations using an inhalation device such as a dry powder inhaler. In certain embodiments, the total weight of the composition, such as a dry powder composition, may range from about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 5 mg to about 80 mg, or about 1 mg to about 30 mg; 2 mg to 20 mg, or 3 mg to 10 mg of imatinib or a pharmaceutically acceptable salt thereof per single dose or single dose event. In some embodiments, imatinib or a pharmaceutically acceptable salt thereof administered using an inhalation device such as a dry powder inhaler may be a composition of about 1 mg to about 800 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, or imatinib or a pharmaceutically acceptable salt thereof. The daily dose may be one or more, for example, two, three, four, five, or a single dose event.

[0036] In some embodiments, a dry powder inhaler can deliver doses of imatinib ranging from 0.1 mg to 200 mg, 1 mg to 100 mg, 5 mg to 80 mg, or 0.2 mg to 30 mg; 0.3 mg to 20 mg, or 0.5 mg to 10 mg to the patient's lungs ("pulmonary dose"). The dose of imatinib delivered to the patient's lungs via the dry powder inhaler may be effective in treating pulmonary conditions such as pulmonary hypertension. For example, an effective dose may enable a subject with pulmonary hypertension to extend a distance of at least 5 m, at least 10 m, or at least 20 m during a 6-minute walking test. In some embodiments, after treatment, the subject may be able to walk at least 100 m during a 6-minute walking test.

[0037] In some embodiments, a dry powder inhaler can deliver doses of imatinib to the patient's lungs ("pulmonary dose") of 0.1 mg / kg (patient's body weight (mass)) to 50 mg / kg, 0.5 mg / kg to 25 mg / kg, 1 mg / kg to 20 mg / kg, 1 mg / kg to 10 mg / kg, or 2 mg / kg to 10 mg / kg, or any value or partial range within these ranges.

[0038] In some embodiments, a dry powder inhaler can deliver a dose of imatinib to a patient's lungs to provide a pulmonary concentration of imatinib of at least 20 ng / ml, at least 50 ng / ml, at least 100 ng / ml, at least 200 ng / ml, at least 300 ng / ml, at least 400 ng / ml, at least 500 ng / ml, at least 600 ng / ml, at least 700 ng / ml, at least 800 ng / ml, at least 1000 ng / ml, at least 1200 ng / ml, at least 1500 ng / ml, at least 1800 ng / ml, at least 2000 ng / ml, at least 2200 ng / ml, at least 2500 ng / ml, at least 2800 ng / ml, at least 3000 ng / ml, at least 3500 ng / ml, at least 4000 ng / ml, or at least 4500 ng / ml.

[0039] In some embodiments, a dry powder inhaler can deliver a dose of imatinib to a patient's lungs to provide a pulmonary concentration of at least 20 ng / ml, at least 50 ng / ml, at least 100 ng / ml, at least 200 ng / ml, at least 300 ng / ml, at least 400 ng / ml, at least 500 ng / ml, or at least 600 ng / ml of imatinib one hour after the administration event.

[0040] In some embodiments, a dry powder inhaler can deliver a dose of imatinib to the patient's lungs so as to provide a pulmonary concentration of at least 20 ng / ml, at least 30 ng / ml, at least 40 ng / ml, at least 50 ng / ml, or at least 60 ng / ml of imatinib 5 hours after the administration event.

[0041] In some embodiments, a dry powder inhaler can deliver a dose of imatinib to a patient's lungs so as to provide a pulmonary concentration of at least 10 ng / ml, at least 15 ng / ml, at least 20 ng / ml, at least 21 ng / ml, at least 22 ng / ml, at least 23 ng / ml, at least 24 ng / ml, at least 25 ng / ml, at least 26 ng / ml, or at least 27 ng / ml of imatinib 8 hours after the administration event.

[0042] In some embodiments, the dry powder composition may contain about 1 wt% to about 60 wt%, 2 wt% to 55 wt%, 2.5 wt% to 50 wt%, 5 wt% to 50 wt%, or 10 wt% to 40 wt%, or values ​​within these ranges or partial ranges of imatinib or its salts, such as imatinib mesylate. In some embodiments, the dry powder composition may contain about 5 wt% to about 50 wt%, about 5 wt% to about 30 wt%, or about 10 wt% to about 20 wt% of imatinib or its salts, such as imatinib mesylate, and particles of diketopiperazine, such as (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine. In some embodiments, the dry powder composition comprises crystalline composite carrier particles prepared by spray-drying a suspension of particles with imatinib or a salt thereof, such as imatinib mesylate. In some embodiments, such composition may contain up to about 800 μg, about 5 mg, about 10 mg, about 20 mg, about 40 mg, or about 80 mg of imatinib per dose, and may be supplied in capsules or cartridges for dry powder inhalers. In some embodiments, the dose of the composition or imatinib or a salt thereof, provided in a container for dry powder inhalers, such as a capsule or cartridge, may be 1 mg to 200 mg, 1 mg to 150 mg, 1 mg to 100 mg, or 5 mg to 80 mg.

[0043] A metered-dose inhaler may also be a soft mist inhaler (SMI), in which case an aerosol cloud containing a respiratory drug can be generated by passing a solution containing the respiratory drug through one nozzle or a series of nozzles. Aerosol generation in an SMI can be achieved, for example, by mechanical, electromechanical, or thermomechanical processes. Examples of soft mist inhalers include the Respimat® inhaler (Boeringer Ingelheim GmbH), the AERx® inhaler (Aradigm Corp.), the Mystic® inhaler (Ventaira Pharmaceuticals, Inc.), and the Aira® inhaler (Chrysalis Technologies Incorporated). For a review of soft mist inhaler technology, see, for example, M. Hindle, The Drug Delivery Companies Report, Autumn / Winter 2004, pp. 31-34. Aerosols for SMIs can be generated from a solution of a respiratory drug further containing pharmaceutically acceptable excipients. In this case, the respiratory drug is imatinib, its derivatives, or a pharmaceutically acceptable salt thereof, which can be formulated as a solution in SMI. The solution may be, for example, a solution of imatinib in water, ethanol, or a mixture thereof. The diameter of the imatinib-containing aerosol particles is preferably less than about 10 microns, less than about 5 microns, or less than about 4 microns.

[0044] The concentration of imatinib, its pharmaceutically acceptable salts, or derivatives in aerosolizable compositions such as dry powder used in metered-dose inhalers or dry powder inhalers may range from about 500 μg / g to about 2500 μg / g, about 800 μg / g to about 2200 μg / g, or about 1000 μg / g to about 2000 μg / g (concentration of imatinib in μg units / number of grams of dry powder). The concentration of imatinib, its pharmaceutically acceptable salts, or derivatives in aerosolizable compositions such as solutions used in metered-dose inhalers may range from about 500 μg / ml to about 2500 μg / ml, about 800 μg / ml to about 2200 μg / ml, or about 1000 μg / ml to about 2000 μg / ml.

[0045] In a single event, the dose (single pump or release of the inhaler) of imatinib, its pharmaceutically acceptable salts, or derivatives that can be administered using an inhalation device such as a dry powder inhaler may be up to about 1 mg to about 200 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg (of dry powder or imatinib) in total. In certain embodiments, the total weight of the dry powder composition administered in a single event may range from about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 5 mg to about 80 mg, about 1 mg to about 30 mg; about 2 mg to 20 mg, or 3 mg to 10 mg (of dry powder or imatinib) per dose.

[0046] The pharmaceutically effective amount of imatinib, its pharmaceutically acceptable salts, or derivatives in the method may be, for example, about 0.1 mg to about 1 mg, about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 50 mg, about 50 mg to about 100 mg, or more than about 100 mg. The effective amount of imatinib may be provided in one or more capsules or cartridges for use with the corresponding dry powder inhaler.

[0047] Of course, the dosage may be adjusted according to the age, weight, species, sensitivity, symptoms, or effectiveness of the treatment.

[0048] In a single-dose event, imatinib, its pharmaceutically acceptable salts, or derivatives may be administered with a limited number of breaths by the patient. For example, imatinib may be administered with 20 or fewer breaths (inhalation), 19 or fewer breaths, 18 or fewer breaths, 17 or fewer breaths, 16 or fewer breaths, 15 or fewer breaths, 14 or fewer breaths, 13 or fewer breaths, 12 or fewer breaths, 11 or fewer breaths, 10 or fewer breaths, 9 or fewer breaths, 8 or fewer breaths, 7 or fewer breaths, 6 or fewer breaths, 5 or fewer breaths, or 4 or fewer breaths. For example, imatinib may be administered with 3, 2, or 1 breath. The total duration of the single-dose event may be less than 5 minutes, less than 4 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute, or less than 45 seconds, less than 30 seconds, or less than 20 seconds. Imatinib, its pharmaceutically acceptable salts, or derivatives may be administered once daily (single-dose event) or several times daily (single-dose event), such as two, three, or four times.

[0049] In yet another embodiment, imatinib, its pharmaceutically acceptable salt or derivative may be administered approximately five times a day, approximately four times a day, approximately three times a day, approximately half a day, approximately once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In yet another embodiment, imatinib, its pharmaceutically acceptable salt or derivative may be administered once a day, once every other day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, every other week, or once every few days.

[0050] In some embodiments, the method may result in the reduction or elimination of one or more symptoms of pulmonary hypertension. The symptoms may be selected from dyspnea, fatigue, dizziness, chest pain, edema, cyanosis, and cardiac palpitations. The reduction may be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, as measured by one or more medically recognized techniques.

[0051] In some embodiments, the administration does not cause systemic side effects in the subject. In some embodiments, systemic side effects are reduced compared to administration of the same dose or amount of dry powder by means of inhalation. Systemic side effects may be selected from one or more of the following: subdural hematoma, edema, gastric discomfort, musculoskeletal pain, muscle spasms, dizziness, visual impairment, loss of appetite, vomiting, diarrhea, decreased hemoglobin, rash, and drowsiness.

[0052] In some embodiments, the reduction in systemic side effects compared to administration other than dry powder inhalation is approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% when measured by one or more medically recognized techniques. Administration other than dry powder may be selected from oral, nasal, sublingual, buccal, intravenous, intramuscular, transdermal, liquid or gas aerosol inhalation, rectal, or transvaginal.

[0053] Medically recognized techniques include the Borg scale, numerical rating scales, visual analog scales, Fatigue Severity Scale, Dizziness Assessment Rating Scale (DARS), SVEAT Chest Pain Scoring System, EKG, Holter monitor, Epworth Sleepiness Scale (ESS), computed tomography (CT scan), magnetic resonance imaging (MRI scan), Adult Diarrhea Status Score (ADSS), and Chronic Subdural The Hematoma grading system, or the evaluation of edema by methods 1-8, which consist of (1) clinical assessment of pit depth and recovery at three locations, (2) patient questionnaire, (3) ankle circumference, (4) figure-eight (ankle circumference using eight ankle / foot markers), (5) edema tester (plastic card with holes of various sizes that is pressed against the ankle using a blood pressure cuff), (6) modified edema tester (edema tester with a raised area), (7) indirect foot volume (by a series of ankle / foot circumferences), and (8) foot / ankle volume by water displacement method, may be selected.

[0054] In some embodiments, the treatment of pulmonary hypertension may further include administering at least one adjuvant selected from the group consisting of prostacyclins such as floran, iloprost, beraprost, or treprostinil; sildenafil; tadalafil; calcium channel blockers (diltiazem, amlodipine, nifedipine); bosentan; cytaxentan; ambrisentan; and pharmaceutically acceptable salts thereof. In some embodiments, the adjuvant may be included in the imatinib composition and therefore administered simultaneously with imatinib using an inhalation device such as a dry powder inhaler. In some embodiments, the adjuvant may be administered separately from imatinib. In some embodiments, in addition to imatinib administered by inhalation using a metered-dose inhaler, intravenous prostacyclin (floran), intravenous, subcutaneous, oral, or inhaled treprostinil, intravenous iloprost, or intravenous or subcutaneous imatinib may be administered.

[0055] Composition and method for preparing the same

[0056] In another embodiment, a dry powder inhalable composition is provided, which comprises imatinib, a pharmaceutically acceptable salt thereof, or a derivative thereof, and optionally one or more excipients.

[0057] With respect to the composition in its solid-dry form, the excipient also forms a solid matrix in which imatinib, a salt thereof, or a derivative thereof is dispersed. In a preferred embodiment, the main excipient is (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine, fumaryldiketopiperazine (FDKP), or a salt thereof. The excipient may be processed to obtain crystals of an appropriate size to form a crystalline powder, a crystalline composite powder, or dissolved to obtain an amorphous powder.

[0058] The composition may contain excipients such as lactose and corn starch, flow promoters such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. Sweeteners and / or flavorings may be added if desired. Typical excipients, though not limited to these, include polyethylene glycol (PEG), hydrogenated castor oil (HCO3), cremofor, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / bulks, surfactants, lubricants (e.g., calcium stearate, magnesium stearate), flow promoters such as talc, disintegrants, diluents, buffers, acids, bases, film coatings, and combinations thereof. Other examples of soluble excipients that may be used in the composition include alitame, acesulfame potassium, aspartame, saccharin, sodium saccharin, sodium cyclamate, sucralose, trehalose, xylitol, citric acid, tartaric acid, cyclodextrin, dextrin, hydroxyethylcellulose, gelatin, malic acid, maltitol, maltodextrin, maltose, polydextrose, tartaric acid, sodium or potassium bicarbonate, sodium or potassium chloride, sodium or potassium citrate, Phospholipids, lactose, sucrose, glucose, fructose, mannitol, sorbitol, natural amino acids, alanine, glycine, serine, cysteine, phenylalanine, tyrosine, tryptophan, histidine, methionine, threonine, valine, isoleucine, leucine, arginine, lysine, aspartic acid, glutamic acid, asparagine, glutamine, proline, their salts, and simple chemical modifications thereof, such as N-acetylcysteine ​​and carbocysteine.

[0059] Preferred soluble excipients include alkali metal salts such as sodium chloride or potassium chloride, and sugars such as lactose. Specific carbohydrate excipients include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as raffinose, meletitose, maltodextrin, dextran, and starch; and algitols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, and myo-inositol.

[0060] In some embodiments, the excipient includes a surfactant. The surfactant in the composition can be selected from a variety of pharmaceutical-grade surfactants.

[0061] Suitable surfactants for use are generally all substances with medium or low molecular weight that contain a hydrophobic moiety that is readily soluble in organic solvents but weakly soluble or insoluble in water, and a hydrophilic (polar) moiety that is weakly soluble or insoluble in organic solvents but readily soluble in water. Surfactants are classified according to their polar moiety. Therefore, surfactants with a negatively charged moiety are called anionic surfactants, while cationic surfactants have a positively charged moiety. Uncharged surfactants are generally called nonionic, while surfactants that are both positively and negatively charged are called zwitterionic. Examples of anionic surfactants are fatty acid salts (better known as soaps), sulfates, sulfate ethers, and phosphate esters. Cationic surfactants are often based on polar groups containing amino groups. The most common nonionic surfactants are based on polar groups containing oligo-(ethylene-oxide) groups. Zwitterionic surfactants are generally characterized by polar groups formed by a quaternary amine and a sulfur or carboxyl group.

[0062] Specific examples of surfactants in this application are the following: benzalkonium chloride, cetrimide, sodium docusate, glyceryl monolaurate, sorbitan ester, sodium lauryl sulfate, polysorbate, phospholipids, and bile salts.

[0063] Nonionic surfactants such as polysorbates, polyethylene, and polyoxypropylene block copolymers known as "poloxama" may be used. Polysorbates are described in the CTFA International Cosmetic Ingredient Dictionary as a mixture of sorbitol and sorbitol anhydride fatty acid esters condensed with ethylene oxide. A series of nonionic surfactants known as "Tween," particularly "Tween 80," and surfactants known as polyoxyethylene sorbitan are especially preferred. Additional exemplary excipients include other polysorbates, e.g., "Tween 20" and pluronics such as F68 and F88 (both available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., lecithin and other phosphatidylcholines, and phospholipids such as phosphatidylethanolamine), fatty acids and fatty acid esters, steroids such as cholesterol, and chelating agents such as EDTA, zinc, and other suitable cations.

[0064] The presence of a surfactant, preferably Tween 80, may be essential to reduce the static charge, powder flow rate, and solid state maintenance in homogeneous methods without initial crystallization that are found in compositions without it. Phospholipids may be included in the surfactant or excipient as defined above.

[0065] Inhalation formulations may contain hydrophobic substances to reduce sensitivity to humidity. Such hydrophobic substances are preferably leucine, which facilitates the dissociation of particles.

[0066] In the case of producing solid products in powder form, this can be achieved using various well-established techniques in the pharmaceutical industry. Preparation of fine particles by spray drying can be an exemplary embodiment. For industrial production, this technique is certainly preferred over freeze-drying (which is currently the most expensive drying process in terms of both the equipment used and the yield and production time).

[0067] The pharmaceutical composition may contain other components such as pH buffers and preservatives. Examples of buffers, though not limited to these, include citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, monobasic sodium phosphate, dibasic sodium phosphate, and combinations thereof.

[0068] Furthermore, the compositions disclosed herein may optionally comprise one or more acids or bases. Examples of usable acids, which are not limited, include those selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Examples of suitable bases, which are not limited, include those selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.

[0069] The excipients may include antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

[0070] The term "dry powder" refers to a composition in the form of a powder, granules, tablet, or other solid having a moisture content that ensures the chemical stability of the composition over time. More precisely, the term "dry" refers to a solid composition having a moisture content of less than 10% w / w, typically less than 5%, and preferably less than 3%.

[0071] The amount of any excipient in a dry powder composition can be varied over a wide range. The amount of individual excipients in the composition depends on the role of the excipient, the dosage requirements of the active drug component, and the specific needs of the composition. However, generally, the amount of excipient in the composition is about 1% to about 99% by weight, preferably about 5% to about 98% by weight, and more preferably about 15% to about 95% by weight. Generally, the amount of excipient present in the compositions of this disclosure is selected from the following: at least about 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, and even 95% by weight.

[0072] This disclosure also provides a kit comprising a dry powder inhaler and a pre-filled unit dose cartridge containing a pharmaceutical composition comprising imatinib, its derivatives, or a pharmaceutically acceptable salt thereof. Such a kit further includes instructions for use relating to the use of the inhaler for inhaling imatinib. The kit can be used by subjects such as humans who have a disease or condition that can be treated with imatinib, such as asthma, pulmonary hypertension, peripheral vascular disease, or pulmonary fibrosis.

[0073] In some cases, the kit is a kit for treating pulmonary hypertension, comprising: (i) an inhalation device, such as a dry powder inhaler, and a pre-filled unit dose cartridge containing a pharmaceutical composition comprising imatinib, its derivatives, or a pharmaceutically acceptable salt; and (ii) instructions for using an inhalation device, such as a dry powder inhaler, containing imatinib when treating pulmonary hypertension. In certain embodiments, the kit may comprise a blister containing a plurality of pre-filled unit dose cartridges. definition

[0074] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless the relationship is explicitly indicated otherwise. It should also be noted that claims may be drafted to exclude any element whatsoever. Therefore, this statement is intended to serve as a basis for the use of exclusive terms such as “exclusively,” “solely,” or “negative” limitations in relation to the enumeration of elements of the claims.

[0075] Where used herein, the terms “contains” or “includes” are intended to mean that a composition or method contains the enumerated elements but does not exclude other elements. A composition or method “essentially consisting of” elements as defined herein does not exclude other materials or steps that do not materially affect the (one or more) fundamental and novel features of the claimed technology. “Consists of” means excluding other components beyond trace elements and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of this technology. When an embodiment is defined by these terms (e.g., “contains”), it should be understood that this disclosure also includes alternative embodiments, such as “essentially consisting of” and “consists of” with respect to the said embodiment.

[0076] "Pulmonary hypertension" refers to all forms of pulmonary hypertension, WHO Groups 1-5. Pulmonary artery hypertension is also called PAH and refers to WHO Group 1 pulmonary hypertension. PAH includes idiopathic, hereditary, drug or toxin-induced, and persistent pulmonary hypertension (PPHN) in the neonatal period.

[0077] "Subdural hematoma" or SDH, as used herein, refers to a type of hemorrhage in which blood accumulates between the inner layers of the dura mater and the arachnoid membrane of the meninges surrounding the brain.

[0078] As used herein, "edema" refers to, for example, a swelling of a part of the body in question.

[0079] "Administration other than inhalation of dry powder" as used herein refers to any route of administration other than inhalation of dry powder formulations. Examples include oral, nasal, sublingual, buccal, intravenous, intramuscular, transdermal, liquid or gas aerosol inhalation, rectal, or vaginal administration.

[0080] "Subject" refers to an animal, such as a mammal (including humans), that has been or will be the subject of treatment, observation, or experimentation. "Subject" and "patient" may be used interchangeably unless otherwise indicated. The methods described herein may be effective in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0081] The terms “therapeutic effective dose” and “effective dose” are used interchangeably and refer to the amount of a compound sufficient to achieve the treatment defined below when administered in one or more doses to a patient (e.g., a human) in need of such treatment. The therapeutic effective dose varies depending on the patient, the disease being treated, the patient’s weight and / or age, the severity of the disease, or the mode of administration, as determined by a qualified prescriber or caregiver.

[0082] The terms “treatment” or “to treat” mean the administration of any of the compounds disclosed herein for the purposes of: (i) delaying the onset of disease, i.e., delaying the onset of clinical symptoms of a disease that has not yet manifested; (ii) inhibiting disease, i.e., cessation of the onset of clinical symptoms; and / or (iii) alleviating disease, i.e., inducing a reduction in clinical symptoms or their severity.

[0083] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this existing art belongs. Any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the existing art, but representative example methods and materials are described herein.

[0084] As used herein, the term “Instructions for Use” means any label, instructions for use, or insert in the packaging relating to the administration of imatinib or its derivatives or pharmaceutically acceptable salts thereof by inhalation for the treatment of pulmonary hypertension. Instructions for Use may include, for example, but not limited to, signs of pulmonary hypertension, confirmation of individual symptoms associated with pulmonary hypertension that can be alleviated by imatinib, recommended dosages for subjects with pulmonary hypertension, and instructions for the use of inhalation devices such as dry powder inhalers and cartridges, or for operation with individual respiratory regulation and use of inhalation devices.

[0085] As used herein, “derivative” means a compound described in U.S. Patent No. 5,521,184 (the disclosure thereof is incorporated herein by reference), or a compound corresponding to imatinib, where: 1 or more aromatic Ns are CR 1 Substituted with; one or more aromatic CHs are substituted with N; one or more CHs are CR 1 Replaced by; one or more NHs are replaced by O, S, or NR 1 Substituted by; one or more third non-aromatic Ns are CR 1Substituted with; and / or one or more aryl groups of imatinib are substituted with different aryl or heteroaryl groups; where each R 1 This can independently refer to a hydroxyl, optionally substituted amino, halo, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C1-C6 alkoxy, optionally substituted aryl, acyloxy, acylamino, acyl, or optionally substituted heteroaryl.

[0086] "Substituted" can refer to a substitution in any of the bases defined below.

[0087] "Heterocyclic," "heterocyclic," "heterocycloalkyl," or "heterocyclyl" refers to a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocyclics include monocyclics or multiple fused rings, including fusion, bridging, or spirocyclic systems. In fusion ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the attachment point is via a non-aromatic ring. In one embodiment, the (one or more) nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N oxide, sulfinyl, or sulfonyl moiety.

[0088] "Substituted heterocyclic," "substituted heterocycloalkyl," or "substituted heterocyclyl" refers to a heterocyclyl group substituted with 1 to 5, or preferably 1 to 3, substituents, the same substituents defined for a substituted cycloalkyl.

[0089] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine.

[0090] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0091] A "heteroaryl" refers to an aromatic group comprising 1 to 10 carbon atoms in a ring and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such a heteroaryl group may have a monocyclic ring (e.g., pyridinyl or furyl) or a plurality of fused rings (e.g., indolidinyl or benzothienyl), where the fused ring may or may not be aromatic and / or contain heteroatoms, provided that the attachment point is via an atom of the aromatic heteroaryl group. In one embodiment, the (one or more) nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N oxide (N→O), sulfinyl, or sulfonyl moiety. Specific non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, tisolyl, and furyl.

[0092] "Substituted heteroaryl" refers to a heteroaryl group that is substituted with 1 to 5 substituents, preferably 1 to 3, or more preferably 1 to 2 substituents, selected from the same group as the substituents defined for the substituted aryl.

[0093] Examples of heterocyclic and heteroaryl compounds are not limited to these, but include azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, dihydroindole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthridine, acridine, phenanthroline, iso Examples include thiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinil, thiomorpholinil (also called thiamorpholinil), 1,1-dioxothiomorpholinil, piperidinil, pyrrolidine, and tetrahydrofuranil.

[0094] "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms and having one or more cyclic rings, including fusion, crosslinking, and spiro-ring systems. The fusion ring may be an aryl ring, provided that the non-aryl portion is bonded to the rest of the molecule. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0095] "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted This refers to a cycloalkyl or cycloalkenyl group having 1 to 5, preferably 1 to 3, substituents selected from the group consisting of substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0096] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a monocycle (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl), where the fused ring may or may not be aromatic (e.g., 2-benzoxazolinone, 2H1,4-benzoxazine3(4H)one7yl), but its attachment point is an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0097] "Replaced aryl" refers to an aryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl oxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0098] "Optionally substituted" refers to a group selected from the group and its substituted forms. Examples of substituents include any of the groups defined below. In one embodiment, the substituent is C1-C 10 or C1-C6 alkyl, substituted C1-C 10or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C8 cycloalkyl, C2-C 10 Heterocyclyl, C1-C 10 Heteroaryl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C6-C 10 Aryl, substituted C3-C8 cycloalkyl, substituted C2-C 10 Heterocyclyl, substituted C1-C 10 Selected from heteroaryl, halo, nitro, cyano, -CO2H, or their C1-C6 alkyl esters.

[0099] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Examples of this term include linear and branched hydrocarbyl groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2), and neopentyl ((CH3)3CCH2-).

[0100] "Alkenyl" refers to a monovalent linear or branched hydrocarbyl group having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms or preferably 2 to 4 carbon atoms, and having at least one, preferably 1 to 2 vinyl (>C=C<) unsaturated moieties. Such groups are exemplified by vinyl, allyl, and buta-3-en-1-yl. Cis and trans isomers or mixtures thereof are included within the scope of this term.

[0101] "Alkynyl" refers to a monovalent hydrocarbyl group, either linear or branched, having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms or preferably 2 to 3 carbon atoms, and having at least one, preferably 1 to 2, acetylene-type (-C≡C-) unsaturated moieties. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH).

[0102] "Substituted alkyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloal This refers to an alkyl group having 1 to 5 substituents, preferably 1 to 3, or more preferably 1 to 2 substituents, selected from the group consisting of lucenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0103] "Substituted alkenyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyl This refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of oxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein, except that none of the hydroxyl or thiol substitutions are attached to a vinyl (unsaturated) carbon atom.

[0104] "Substituted alkynyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyl This refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of ruoxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein, except that none of the hydroxyl or thiol substitutions are attached to an acetylene-type carbon atom.

[0105] "Alkoxy" refers to the group Oalkyl {wherein alkyl is as defined herein}. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0106] "Substituted alkoxy" refers to the group O(substituted alkyl) {wherein the formula, substituted alkyl is as defined herein}.

[0107] "Acyl" refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted This refers to heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are defined herein. Examples of acyls include the "acetyl" group CH3C(O).

[0108] "Acylamino" refers to the group -NR 47 C(O)alkyl, -NR 47 C(O)-substituted alkyl, -NR 47 C(O) cycloalkyl, -NR 47 C(O)-substituted cycloalkyl, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47 C(O) alkenyl, -NR 47 C(O)-substituted alkenyl, -NR 47 C(O)alkynyl, -NR 47 C(O)-substituted alkynyl, -NR 47 C(O)aryl, -NR 47 C(O) substituted aryl, -NR 47 C(O) heteroaryl, -NR 47C(O)-substituted heteroaryl, -NR 47 C(O) heterocycle, and NR 47 This refers to a C(O)-substituted heterogly, where R 47 is hydrogen or alkyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic formulas are as defined herein.

[0109] "Acyloxy" refers to groups such as alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, and This refers to substituted heteroaryl-C(O)O, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic formulas are defined herein.

[0110] "Amino" refers to the NH2 group.

[0111] "Substituted amino" refers to the group -NR 48 R 49 This refers to R 48 and R 49R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, SO2 alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl (cylcoalkyl), -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl (cylcoalkenyl), -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocycle, and -SO2-substituted heterocycle, and here, R 48 and R 49 These are optionally linked together with the nitrogen atoms bonded to them to form a heterocyclic group or a substituted heterocyclic group, however, R 48 and R 49 Both are not hydrogen, and here, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic formulas are as defined herein. 48 is hydrogen, and R 49 When is alkyl, the substituted amino group may also be referred to as alkylamino in this specification. 48 and R 49 When is alkyl, the substituted amino group may also be referred to as dialkylamino in this specification. When referring to monosubstituted amino, it is R 48 or R 49 This means that one of them is hydrogen, but not both are hydrogen. When referring to disubstituted amino acids, R 48 R 49 This also means it's not hydrogen.

[0112] Certain ranges are expressed herein using numbers preceded by the term “approximately.” The term “approximately” is used to provide literal support for the number it precedes, as well as for numbers that are close to or approximate to the number it precedes. When determining whether a number is close to or approximately the number specifically listed, the number that is close to or approximately the number listed may be a number that, in the context in which it is presented, provides a substantial equivalent to the number specifically listed.

[0113] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it is understood that each intervening value up to one-tenth of the lower limit unit between the upper and lower limits of that range, and any other stated or intervening values ​​within the stated range, are included within the scope of the invention. The upper and lower limits of these even smaller ranges may be independently included within their even smaller ranges and also included within the scope of the invention, subject to the limits specifically excluded in the stated values. Where a stated range includes one or both of the limits, the range excluding either or both of those included limits is also included within the invention.

[0114] The present invention can be illustrated in more detail by the following embodiments, but it should be understood that the present invention is not limited thereto.

[0115] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that can be readily separated from or combined with features of any of several other embodiments without departing from the scope or essence of the art. Any of the listed methods can be carried out in the order of the listed events, or in any other logically possible order. [Examples]

[0116] Example 1: Preparation of imatinib mesylate powder for inhalation

[0117] Imatinib inhalation powder was prepared as Technosphere® (T) powder or crystalline carrier (XC) powder. T particles were formed by crystallization of FDKP in the presence of the surfactant Tween20, followed by self-assembly, to form a suspension of particles with a diameter of approximately 2 to 2.5 μm. XC particles were formed by spray-drying a suspension of FDKP crystals that were formed under conditions where they did not self-assemble into particles in the suspension. A 25% solution of imatinib mesylate was prepared with deionized water and added to either the pre-formed T suspension or the XC suspension containing microcrystals to prepare particles containing 2.5 wt% to 50 wt% of imatinib on a dry weight basis (Table 1A). The T and XC suspensions containing imatinib mesylate were dried by either freeze-drying or spray-drying. The T suspension containing 10% to 20% imatinib mesylate was pelletized in liquid nitrogen and then freeze-dried. The freeze-dryer shelf temperature was increased from -45°C to 25°C at a rate of 0.2°C / min, and then maintained at 25°C under reduced pressure until the powder was completely dry. All other imatinib mesylate T and XC powders were prepared by spray drying using a Buchi B-290 spray dryer, operated at an inlet temperature of 180°C, an aspirator pump speed of 90%, a feed pump speed of 25%, and a nitrogen flow meter reading of 60 mm.

[0118] Table 1A: Preparation and composition of imatinib mesylate powder [Table 1] Example 2: Particle size and shape of imatinib powder

[0119] The geometric particle size distribution of the powder was evaluated using a Sympatec laser diffractometer fitted to either a RODOS® powder dispersion system or an inhaler adapter. Bulk powder was dispersed using a RODOS® powder dispersion system at either 0.5 bar or 3.0 bar. When using an inhaler adapter, a 10 mg powder sample was dispensed at 4 kPa from a Dreamboat Gen2C dry powder inhaler (MannKind Corp. - U.S. Patent No. 8,508,732 (as incorporated herein by reference)). Samples evaluated in anatomically correct airways were also dispensed at 4 kPa from a Gen2C inhaler filled with 10 mg of powder. These data are shown in Table 2. Figures 1A–1C show the 16th, 50th, and 84th percentiles (x) of the particle size distribution for imatinib XC powder from Table 2. 16 , x 50 , and x 84 ) Plot Sympatec inhaler data for this.

[0120] Table 2: Geometric particle size data for imatinib mesylate powder [Table 2]

[0121] Example 3: Aerodynamic performance test of imatinib powder

[0122] Aerodynamic performance was evaluated using MannKind's Anatomically Correct Airway (ACA, U.S. Patent No. 9,706,944, incorporated herein by reference), which simulates the inhalation efforts performed by the subject. The powder (10 mg) was filled into a cartridge, and the filled cartridge was weighed. The cartridge was inserted into a Dreamboat Gen2C inhaler and placed in the opening of an upper airway model of a male in his 20s. The powder was released into the airway using a 4 kPa pressure drop, and all powder that passed through the oropharynx on its way to the lungs was collected by a filter at the bottom of the airway. The released cartridge was weighed again to measure the percentage of powder released (%CE, cartridge evacuation). The filter was weighed to measure the amount of powder that reached the filter (MtF, mass reached by filter), and this result was normalized to the amount of powder filled in the cartridge (MtF / F, mass reached by filter divided by filling). The results are shown in Table 3, and the estimated lung dose as a function of imatinib content is presented in Figure 2. The estimated lung dose is the product of the cartridge content, MtF / F, and imatinib content. For example, powder 963-119 (30.08 wt% imatinib, 55.90% MtF / F) would provide an estimated lung dose of (10 mg)(0.3008)(0.5590) = 1.68 mg imatinib.

[0123] Table 3: Results of anatomically corrected airways [Table 3] Example 4 Measurement of in vivo pharmacokinetics of blown ImaT powder in rats overview

[0124] The pharmacokinetics of imatinib (ImaT) in a dry powder formulation were evaluated in this rat study. Blood samples and lungs were collected at specific time points throughout a 24-hour period after administration. The target dose was 1 mg of ImaT per rat, delivered as an inhalation dry powder.

[0125] The target dose of the test compound was based on information available at the time of planning this study. The selected dose reflects what is expected to exceed the therapeutic dose in humans. Methods and experimental design 1. Test System 1.1 species

[0126] The study used male Sprague Dawley rats (Charles River Laboratories) weighing between 225 and 275 grams at the time of enrollment. 1.2 Identification and Randomization of Study Systems

[0127] 1. The animals arrived at IPST at least three days before the planned experiment.

[0128] 2. The animals were identified upon arrival in accordance with CCAC guidelines.

[0129] 3. All animal care and maintenance of the ecological zoo were documented using records kept at the experimental facility.

[0130] 4. The animals were randomly assigned to one of the groups by the principal investigator before the experiment, and the principal investigator kept a record of each animal's identification number. 1.3 Basis for the Test System

[0131] We selected the Sprague-Dawley rat because it is recommended by various regulatory bodies and is frequently used in inhalation-dried powder testing. 2. Test substance and reference compound 2.1 Test substance Codename: ImaT Inhalation Powder (20% imatinib) Supplier: MannKind Corporation Lot number: 963-123 Date of retake exam: May 2021 Storage conditions: -20℃ At the end of the experiment, all remaining test substances were stored at -20±3°C. Rationale for dosage

[0132] The target dose of the test compound was based on information available at the time of planning this study. The selected dose reflects those that appeared to exceed the therapeutic dose in humans. ImaT was delivered to rats weighing approximately 250 grams at a target dose of 1 mg, leading to an average dose of 4 mg / kg. 3. Experimental Procedure

[0133] Male Sprague Dawley rats weighing 225–275 grams arrived at the facility the week before the start of the experiment. The animals were housed in pairs during the acclimatization period.

[0134] After the acclimatization period, each animal was randomly assigned to one dose-treatment group (see Table 4). Table 4: Experimental Design [Table 4]

[0135] Rats were anesthetized with a mixture of 1.5–3% isoflurane USP (Abbott Laboratories, Montreal Canada) in 100% oxygen, and then placed on a constant temperature heating pad to maintain a body temperature of 37±1°C.

[0136] In all groups, the test substance was administered using an automated inhalation device. The inhalation tip was inserted just above the tracheal bifurcation, and the release of the powder was timed to coincide with the animal's inhalation cycle. After administration, the animals were allowed to recover from anesthesia under supervision before being returned to their respective cages.

[0137] A 0.5 mL blood sample was collected from the jugular vein at the specified time (see Table 4).

[0138] Blood samples were centrifuged (3000 r.pm for 10 minutes, 2-8°C), and the plasma was transferred to Eppendorf tubes labeled with the test number, animal ID, dose group, and time point. The plasma samples were stored frozen (-80°C) until shipment for quantification of plasma imatinib content.

[0139] The lungs were also extracted at specified time points (see Table 4). To do so, the animals were anesthetized with a mixture of 1.5–3% isoflurane USP (Abbott Laboratories, Montreal Canada) in 100% oxygen and euthanized by bleeding. The lungs were then extracted. The left lobe was divided into three parts: upper, middle, and lower. Each section was cut into two equal pieces. Each piece was weighed and placed individually into appropriately labeled tubes. The lung samples were quenched and stored at -80°C. The lung samples were then homogenized in PBS, 0.1% Triton X-100 (200 mg tissue / mL). The homogenate samples were stored at -80°C.

[0140] Plasma samples and lung homogenates were shipped with dry ice for testing according to the sponsor's instructions. Controlling bias in a system

[0141] Any reported mishandling of the samples or animals led to their eventual exclusion from analysis. Data calculation

[0142] The results were analyzed using Microsoft Excel 2010 with the PK Solver Add-in, as described by Zhang et al. (2010), and Certara Phoenix WinNonLin 7.0. For each group, the data in this report are expressed as mean ± standard error. Results and Discussion

[0143] The results are summarized in Tables 5 to 7 and Figures 3 to 7. Table 5. Imatinib concentrations in rat plasma samples. [Table 5] Table 6. Non-compartmental analysis of plasma after ImaT infusion. [Table 6] Table 7. Imatinib concentrations in rat lung samples. [Table 7]

[0144] This study was conducted to evaluate the pharmacokinetic profile of inhaled imaT. The delivered dose produced measurable plasma concentrations of imatinib (see Table 5 and Figure 3). Plasma concentrations of imatinib were below the detection limit at 24 hours. A characteristic PK profile was observed at the first measurement time (5 minutes). max , and 2.63 hours of t 1 / 2 The final reduction was observed (see Table 6). In this study, some rats were excluded from data compilation due to incomplete drug administration in those animals. The ImaT powder tended to form several aggregates that could adhere to each other and not be delivered. These rats were excluded from the dataset before analysis.

[0145] The lung was also removed and cut into six sections (see Figure 4). Each section was homogenized, and the imatinib lung concentration was measured. The imatinib lung concentration was highest 5 minutes after ImaT inhalation. The maximum concentration varied from one lung section to another. Imatinib concentrations were higher in the lower and distal regions of the left lung lobe. Imatinib rapidly entered the bloodstream without adhering to the lung. Lung imatinib concentrations were below the detection limit at 24 hours. conclusion

[0146] In this study, the pharmacokinetic profile of imatinib was evaluated over 24 hours. A dose of 1 mg (4 mg / kg) of ImaT dry powder was administered by air inhalation to rats weighing approximately 250 grams, and the delivered imatinib rapidly moved from the lungs into the bloodstream. The results showed that plasma and pulmonary concentrations of imatinib were observed for up to 8 hours, with imatinib below the detection limit at 24 hours and having a plasma half-life of 2.63 hours. * * *

[0147] While the above describes specific preferred embodiments, it will be understood that the present invention is not so limited. It will be obvious to those skilled in the art that various modifications can be made to the disclosed embodiments, and that such modifications are intended to fall within the scope of the present invention.

[0148] All publications, patent applications, and patents cited herein are incorporated herein by reference as a whole.

Claims

1. A composition for treating pulmonary hypertension, administered to a subject by inhalation, The composition is a dry powder composition comprising imatinib or a pharmaceutically acceptable salt thereof and diketopiperazine, The aforementioned administration comprises a dry powder composition comprising one to three single-dose administration events per day.

2. The composition according to claim 1, wherein the administration is carried out using a dry powder inhaler.

3. The composition according to claim 2, wherein the dry powder inhaler comprises a container containing the composition comprising 1 mg to 200 mg of imatinib or a pharmaceutically acceptable salt thereof.

4. The composition according to any one of claims 1 to 3, wherein the single-dose event comprises administering a single dose of imatinib or a pharmaceutically acceptable salt thereof in an amount of 1 mg to 200 mg.

5. The composition according to claim 4, wherein the single dose is administered in 1 to 3 breaths.

6. The composition according to any one of claims 1 to 5, wherein the composition has a concentration of imatinib or a pharmaceutically acceptable salt thereof in a total dry weight of about 1% to about 60% by weight.

7. The composition according to any one of claims 1 to 6, wherein the composition comprises imatinib mesylate.

8. The composition according to any one of claims 1 to 7, wherein the subject is a human.

9. The composition according to any one of claims 1 to 8, further comprising one or more excipients.

10. The composition according to claim 9, wherein the composition has a concentration of imatinib or a pharmaceutically acceptable salt thereof in a total dry weight of about 1% to about 60% by weight.

11. The composition according to claims 1 to 10, wherein the composition comprises a particle size of about 0.1 to about 10 μm.

12. The composition according to any one of claims 1 to 11, wherein the composition comprises about 0.1% to about 99% by weight of diketopiperazine.

13. The composition according to claims 1 to 12, wherein the diketopiperazine is (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP).

14. A composition according to any one of claims 1 to 13, comprising imatinib mesylate.

15. A dry powder inhaler comprising the composition according to any one of claims 1 to 14.

16. A dry powder inhaler according to claim 15, comprising 1 mg to 200 mg of the composition.

17. A dry powder inhaler according to claim 15 or 16, comprising a container containing a single dose of the composition.

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