Use of nintedanib and a combination dry powder composition of nintedanib

Abstract

The present invention includes a dry powder nintedanib formulation for dispersion and inhalation administration, comprising a salt of nintedanib, an indolinone derivative or a salt thereof, and a fixed dose combination with a carrier agent and other active ingredients. The aerosol delivery combination formulation can be administered as an inhaled aerosol over several actuations or by two or more actuations. Each dose can be administered one or more times a day on a regular or intermittent daily dosing schedule. Special formulation parameters of the present invention include the selection of the salt for complexing with the form of nintedanib used in the isolated dry powder and particle size distribution, and the combination with a force control agent to improve aerosol delivery. The methods of the present invention include the therapeutically effective doses of the present invention described for use in the treatment of interstitial lung disease.

Description

Background Art

[0001] Many pulmonary diseases, such as interstitial lung disease (ILD and its subclass diseases), cancer (lung cancer and its subclass diseases), fibrosis signs in the lungs, kidneys, heart, and eyes, viral infections, and central nervous system diseases, are currently areas where clinical needs are not met.

[0002] In fibrosis, scarring plays a valuable role in healing after injury. However, tissues may gradually scar and cause dysfunction after more chronic, repetitive, or idiopathic injuries. In the case of idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF), and other subclasses of ILD, when a sufficient portion of the lungs scars, respiratory failure may occur. In any case, progressive scarring may result from a series of recurrent injuries to different regions of the organ or the inability to stop the repair process after the injury has healed. In such cases, the scarring process becomes uncontrollable and unregulated. In some forms of fibrotic diseases, scarring is localized to limited areas, while in other forms, it is more diffuse and affects a wide area, potentially causing direct or related organ failure.

[0003] In epithelial injury, epithelial cells are triggered to release several fibrosis-promoting mediators, such as transforming growth factor beta (TGF-β), a potent fibroblast growth factor, tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), endothelin, other cytokines, metalloproteases, and tissue factor, a coagulation mediator. Importantly, it is clear that the triggered epithelial cells become vulnerable to apoptosis and cannot repair the epithelial cell layer, which is the most fundamental abnormality in fibrotic diseases.

[0004] In disease states such as diseases, physiological reactions characterized by the control of fibrosis-promoting factors by indolinone derivatives such as nintedanib are beneficial for the reduction and / or reversal of fibrosis and the treatment of cancer or central nervous system diseases. In this specification, treatment strategies that utilize the effects of such indolinone derivatives and / or nintedanib in these and other indications are being considered.

[0005] Despite the development of many promising therapies, many lung diseases, such as interstitial lung disease (ILD and its subclass diseases), cancer, vascular diseases, and many viral infections, still have unmet clinical needs. Furthermore, many extrapulmonary diseases may also benefit from the inhaled delivery of nintedanib or combinations between its agents, along with formulations specially designed to utilize the performance parameters of inhaler devices. However, the development of advanced nintedanib and combination formulations for inhaled delivery involves many challenges that have not yet been fully overcome.

Summary of the Invention

[0006] Special design considerations for nintedanib affect many parameters important for the development of inhaled therapeutic products. By selectively manipulating formulation parameters and aerosol device parameters, the dose administered to the target organ, the pharmacokinetic profile, and the safety profile can be improved, enhancing efficacy and safety and maximizing patient compliance. This specification describes compositions of nintedanib or its salts, indolinone derivatives or their salts, and methods of use suitable for inhaled delivery to the lung, central nervous system, and / or systemic compartments.

[0007] The present invention includes a dry powder formulation for dispersion and inhalation administration, comprising nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, and one or more carriers or diluents. The bulk powder composition may also contain one or more flow control agents in an amount of about 0.01% to about 20% of the bulk composition. Examples of the flow control agent may include leucine, trilucine, lecithin, magnesium stearate, sodium stearate, sucrose stearate, microcrystalline lactose, polyvinylpyrrolidone, ethyl cellulose, pluronic F-68, cremophor RH40, glyceryl monostearate, and polyethylene glycol 6000. Additionally, the bulk powder composition may contain inorganic salts in an amount of about 0.01% to about 20% of the bulk composition, such as sodium chloride, magnesium chloride, calcium chloride, potassium chloride, sodium bromide, potassium bromide, magnesium bromide and calcium bromide, and combinations thereof, as a stabilizer or secondary excipient. The bulk powder composition may contain anions in an amount of about 0.001% to about 10% of the bulk composition. The anion may be bromide or chloride. The bulk powder composition may contain a taste masking agent in an amount of about 0.001% to about 10% of the bulk composition. The taste masking agent may be saccharin or other agents commonly used in the art. The bulk powder composition may contain sugars such as lactose, mannitol, trehalose, dextrose, etc. as a diluent or stabilizer. The bulk powder composition may contain amino acids in an amount of about 0.01% to about 20% of the bulk composition.

[0008] The present invention also includes a dry powder formulation for dispersion and inhalation administration, comprising nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, in a fixed dose combination with pirfenidone or a pyridine analog. In this combination formulation, nintedanib or a salt thereof, or an indolinone derivative or a salt thereof is contained in an amount of about 0.0001 mg to about 200 mg, and pirfenidone or a pyridine analog is contained in an amount of about 1 mg to about 200 mg.

[0009] The present invention also includes dry powder formulations for dispersion and inhalation administration, comprising nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, in a fixed-dose combination with a PDE4 inhibitor. In this combination formulation, nintedanib or a salt thereof, or an indolinone derivative or a salt thereof is included in an amount of about 0.0001 mg to about 200 mg, and the PDE4 inhibitor is included in an amount of about 0.01 mg to about 40 mg.

[0010] The present invention also includes dry powder formulations for dispersion and inhalation administration, comprising nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, in a fixed-dose combination with a prostacyclin analog. In this combination formulation, nintedanib or a salt thereof, or an indolinone derivative or a salt thereof is included in an amount of about 0.0001 mg to about 200 mg, and the prostacyclin analog is included in an amount of about 0.001 mg to about 10 mg. The dry powder formulation can be administered as an inhalation aerosol produced from an amount of nintedanib or a salt thereof, or an indolinone derivative or a salt thereof in the range of about 0.0001 mg to about 200 mg, and a prostacyclin analog in the range of about 0.001 mg to about 10 mg per unit dose or per actuation. The dose of the combination formulation can be administered as an inhalation aerosol over several actuations or by two or more actuations. Each dose can be administered one or more times per day according to a regular or intermittent daily dosing schedule.

[0011] Special formulation parameters of the present invention include the selection of salts for complexing with the form of nintedanib used in the isolated dry powder. Preferred salts include esylate, mesylate, hydrochloride, and hydrobromide. The total delivery dose is about 0.0001 mg to about 200 mg of nintedanib in the dry powder formulation described herein.

[0012] The present invention includes a kit comprising a unit dose of a dry powder of nintedanib or a salt thereof as described herein, contained in a container suitable for use with a dry powder inhaler for dispersion and resulting powder aerosol inhalation. Such compositions may also include a combination with pirfenidone or a pyridine analog. Such compositions may also include a combination with a phosphodiesterase 4 (PDE4) inhibitor. Such compositions may also include a combination with a prostacyclin analog.

[0013] Furthermore, the physicochemical properties of the aerosols produced by the compositions and methods of the present invention are an important part of the therapeutic utility of the present invention, which is that specially selected formulation design parameters, together with dry powder dispersion by a dry powder inhaler structure as described below, produce an aerosol powder cloud with unique advantageous properties for the delivery of the active pharmaceutical ingredient to the lung compartments, tailored to the pharmacodynamic absorption of the active pharmaceutical ingredient in the lung organs. The dispersed dry powder forms a cloud consisting of particles of nintedanib or indolinone or a salt thereof, or having an average diameter of less than about 5.0 μm. The aerosol particles produced from the final bulk formulation placed in a dry powder inhaler are formulated as a specially designed powder containing from about 0.0001 mg to about 200 mg of nintedanib or indolinone or a salt thereof. Alternatively, the aerosol particles produced from the final bulk formulation placed in a dry powder inhaler are formulated as a specially designed powder containing from about 0.01 mg to about 100 mg of nintedanib or indolinone or a salt thereof. Alternatively, the aerosol particles produced from the final bulk formulation placed in a dry powder inhaler are formulated as a specially designed powder containing from about 0.01 mg to about 50 mg of nintedanib or indolinone or a salt thereof. Such compositions may also include a combination with 1 mg to 200 mg of pirfenidone or a pyridine analog within particles having an average diameter of less than about 5 μm. Such compositions may also include a combination with 0.01 mg to 40 mg of a PDE4 inhibitor within particles having an average diameter of less than about 5 μm. Such compositions may also include a combination with 0.001 mg to 10 mg of a prostacyclin analog within particles having an average diameter of less than about 5 μm.

[0014] These and other aspects of the invention will become apparent upon reference to the following detailed description. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to herein are hereby incorporated by reference in their entirety as if each were individually incorporated.

[0015] Specific Terms The term "mg" refers to milligram.

[0016] The term "μg" refers to microgram.

[0017] The term "microM" refers to micromole.

[0018] As used herein, the term "about" is used synonymously with the term "approximately". By way of example, the use of the term "about" with respect to a particular therapeutically effective pharmaceutical dosage indicates that values that deviate slightly from the recited value, for example, plus or minus 0.1% to 10%, are effective and safe.

[0019] As used herein, the terms "comprising", "including", "such as", and "for example" are used in an open and non-limiting sense.

[0020] The terms "administer" or "administering", and "deliver" or "delivery" refer to a method of administering to a human a dosage of a therapeutic or prophylactic formulation, such as a formulation of nintedanib or a salt thereof described herein, for example, as an anti-inflammatory, anti-fibrotic and / or anti-demyelinating pharmaceutical composition, or for other purposes. Preferred delivery or administration methods may vary depending on various factors, such as the components of the pharmaceutical composition, the desired site where the formulation is introduced, delivered or administered, the site where a therapeutic effect is sought, or the proximity to a diseased organ downstream from the initial delivery site (e.g., aerosol delivery to the lungs for absorption, and secondary delivery to the heart, kidneys, liver, central nervous system or other disease destinations).

[0021] The terms "pulmonary administration" or "inhalation" or "pulmonary delivery", and other related terms refer to a method of delivering to a human a dosage of a therapeutic or prophylactic formulation by a route such that the desired therapeutic or prophylactic agent is delivered to the lungs of the human.

[0022] The term "actuation" of "actuation" refers to triggering the device to release a measured amount of the pharmaceutical formulation.

[0023] The term "abnormal liver function" may manifest as an abnormality in the levels of biomarkers of liver function, including alanine transaminase, aspartate transaminase, bilirubin, and / or alkaline phosphatase, and serves as an indicator of drug-induced liver injury. See FDA Draft Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation, October 2007.

[0024] The term "base" refers to the active molecule itself, which may exist regardless of the presence or absence of the corresponding salt. The description "base within the salt form" refers to the active molecule itself within the corresponding salt form. The active molecule amounts and weight percentages described herein refer to the "base" or "base within the salt form" and can be readily adjusted to equivalents or weight percentages based on the individual salt species selected for the salt form of the base.

[0025] "Grade 2 abnormal liver function" includes an increase in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyl transferase (GGT) that exceeds 2.5 times the upper limit of normal (ULN) and is 5 times or less. Grade 2 abnormal liver function also includes an increase in bilirubin levels that exceeds 1.5 times the ULN and is 3 times or less.

[0026] "Gastrointestinal adverse events" include, but are not limited to, any one or more of dyspepsia, nausea, diarrhea, gastroesophageal reflux disease (GERD), and vomiting.

[0027] "Carrier" or "excipient" refers to a compound or material used to facilitate the administration of a compound, for example, to increase the solubility of the compound. Examples of solid carriers include starch, lactose, dicalcium phosphate, sucrose, and kaolin. In addition, various adjuvants, such as those commonly used in the art, may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds)(1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8 th Ed., Pergamon Press.

[0028] As used herein, "diagnostic" refers to a compound, method, system, or device that aids in the identification and characterization of a health or disease state. This diagnosis can be used in standard assays known in the art.

[0029] The term "bulking agent" refers to an excipient used in a pharmaceutical formulation to provide a matrix for carrying a drug and is usually present in small amounts.

[0030] The term "detackifier" refers to an excipient used in a pharmaceutical formulation to reduce the adhesion between a drug and carrier particles in an inhalation adhesive mixture, thereby increasing the detachment of the drug during inhalation.

[0031] The terms "D10, D50, and D90" refer to the volume-based diameters of particles at the 10, 50, and 90 percentiles.

[0032] The term "carrier-free blend" refers to a dry powder inhalation blend that does not use an inert excipient to aid in the dispersion of drug particles.

[0033] The term "carrier blend" refers to a dry powder inhalation blend that utilizes an inert excipient to reduce the cohesive forces between drug particles, thereby assisting in the dispersion of the drug particles.

[0034] The term "shell former" refers to an excipient used in the preparation of spray-dried powders to form an outer shell that enables the formation of hollow or porous particles.

[0035] The term "glass former" refers to an excipient used in the preparation of spray-dried powders to prevent the spray-dried particles from changing from an amorphous form to a crystalline form. The term "ex vivo" refers to an experiment or procedure conducted within or on a living tissue in an artificial environment outside of a living organism.

[0036] The term "low resistance" refers to a dry powder inhaler device that requires approximately 100 liters per minute to generate a pressure drop of 4 kPa necessary to operate and disperse the dry powder formulation contained therein.

[0037] The term "medium resistance" refers to a dry powder inhaler device that requires approximately 85 liters per minute to generate a pressure drop of 4 kPa necessary to operate and disperse the dry powder formulation contained therein.

[0038] The term "high resistance" refers to a dry powder inhaler device that requires approximately 60 liters per minute to generate a pressure drop of 4 kPa necessary to operate and disperse the dry powder formulation contained therein.

[0039] "Solvate" refers to a compound formed by the interaction of a solvent with nintedanib or an indolinone derivative compound, metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0040] "Therapeutically effective amount" or "pharmaceutically effective amount" means an amount of nintedanib or indolinone or a salt thereof that is therapeutically effective and useful for human treatment and provides the desired therapeutic effect as determined by clinical trial results and / or in model animals for pulmonary fibrosis, chronic lung allograft dysfunction (CLAD) associated with lung transplantation rejection and restrictive allograft syndrome (RAS), cardiac fibrosis, renal fibrosis, hepatic fibrosis, cardiac or renal toxicity, cancer, or diseases resulting from active, past, or latent viral infections.

[0041] "Therapeutic effect" reduces to some extent one or more symptoms associated with inflammation, fibrosis and / or demyelination. This includes slowing the progression of further inflammation, fibrosis and / or demyelination, or preventing or reducing further inflammation, fibrosis, and / or demyelination. In the case of idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF) and restrictive allograft syndrome (RAS), "therapeutic effect" is defined as a decrease in the level or rate of decline of forced vital capacity (FVC), and / or an improvement in the quality of life reported by the patient, and / or a statistically significant increase or stabilization in exercise tolerance and related blood oxygen saturation, a decrease in the decline of baseline forced vital capacity, a decrease in the incidence of acute exacerbations, an increase in the progression-free survival period, an increase in the time to death or disease progression, and / or a reduction in pulmonary fibrosis. In the case of CLAD, "therapeutic effect" is defined as a decrease in the decline of forced expiratory volume in one second (FEV1). In the case of cardiac fibrosis, "therapeutic effect" is defined as an improvement in the quality of life reported by the patient and / or a statistically significant improvement in cardiac function, a reduction in fibrosis, a reduction in cardiac stiffness, a reduction or recovery of valvular stenosis, a decrease in the incidence of arrhythmias, and / or a reduction in atrial or ventricular remodeling. In the case of renal fibrosis, "therapeutic effect" is defined as an improvement in the quality of life reported by the patient and / or a statistically significant improvement in glomerular filtration rate and related markers. In the case of liver fibrosis, "therapeutic effect" is defined as an improvement in the quality of life reported by the patient and / or a statistically significant decrease in elevated aminotransferases (such as AST and ALT), alkaline phosphatase, gamma-glutamyltransferase, bilirubin, prothrombin time, globulin, and / or a reversal of thrombocytopenia, leukopenia, neutropenia, and coagulation defects. Additionally, imaging, endoscopic, or other pathological findings may be reversed. In the case of diseases caused by active, past, or latent viral infections, "therapeutic effect" is defined as an improvement in the quality of life reported by the patient and / or a statistically significant decrease in viral load, an improvement in exercise capacity and related blood oxygen saturation, FEV1 and / or FVC, a delay or halt in progression during the same progression-free survival period, an increase in the time to death or disease progression, and / or a decrease in the incidence of neurological symptoms or an acute exacerbation or reduction.The term "preventive treatment" refers to treating patients who have not yet contracted a disease but are susceptible to or at risk of contracting a specific disease, or patients who have the disease but whose condition does not deteriorate while being treated with the pharmaceutical compositions described herein. The term "therapeutic treatment" refers to treating patients who already have a disease. Thus, in a preferred embodiment, treatment comprises administering a therapeutically effective amount of nintedanib or an indolinone derivative compound to a mammal (for either therapeutic or prophylactic purposes).

[0042] The term "fine particle fraction" is the proportion of aerosolized particles with a diameter of 5 microns or less.

[0043] The term "respirable delivered dose" or "fine particle dose" is the amount of drug particles of 5 microns or less that are inhaled into the inspiratory phase of a respiratory simulator.

[0044] As used herein, "lung deposition" refers to the proportion of the nominal dose of the active pharmaceutical ingredient (API) that deposits on the inner surface of the lungs.

[0045] The "nominal dose" or "loading dose" refers to the amount of drug placed in a dry powder inhaler before administration to a human. The amount of powder containing the nominal dose is called the "fill weight".

[0046] "Dispersion" refers to the process of scattering or diffusing a dry powder formulation fill weight into respirable drug fine particle fractions by aerodynamic means.

[0047] "Enhanced pharmacokinetic profile" means the improvement of several pharmacokinetic parameters. The pharmacokinetic parameters that can be improved include AUC last, AUC(0-∞), and optionally Cmax. The enhanced pharmacokinetic profile can be quantitatively measured by comparing the pharmacokinetic parameters obtained for the nominal dose of the pharmaceutical active ingredient (API) administered using one type of inhalation device with the same pharmacokinetic parameters obtained by oral administration of a composition of the same pharmaceutical active ingredient (API).

[0048] As used herein, "respiratory condition" refers to a disease or condition that physically appears in the airways, including but not limited to pulmonary fibrosis, cancer, diseases caused by active, past or latent viral infections, bronchitis, chronic bronchitis, or emphysema.

[0049] "Drug absorption" or simply "absorption" typically refers to the process by which a drug moves from the drug delivery site across a barrier to the blood vessels or site of action, e.g., the absorption of a drug into the alveolar capillary bed. BRIEF DESCRIPTION OF THE DRAWINGS

[0050]

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Mode for Carrying Out the Invention

[0051] Nintedanib and indolinone derivative compounds - therapeutic usefulness The indolinone derivatives for use in the indolinone derivative preparations described herein include nintedanib ((3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]phenylmethylene]-2-oxo-1H-indole-6-carboxylate) or a salt thereof.

[0052]

Chemical Formula

[0053] Other indolinone derivative compounds or salts thereof may be used in place of nintedanib. Examples of indolinone derivative compounds include, but are not limited to, compounds that are structurally similar to nintedanib and have the same type of biological activity as nintedanib. Indolinone derivative compounds include modifications to the nintedanib molecule that are predictable based on the interaction of nintedanib or the subject derivative as a specific and selective inhibitor of certain tyrosine kinases described below, or based on the substitution of chemical moieties that maintain the structure-activity relationship (SAR) of nintedanib. Examples of indolinone derivative compounds include, but are not limited to, the compounds described in U.S. Pat. Nos. 6,762,180 and 7,119,093.

[0054] Nintedanib inhibits a broad range of kinases at pharmacologically relevant concentrations. Examples of target kinases include all three subtypes of VEGFR (VEGFR-1, IC50 34 nM, VEGFR-2, IC50 21 nM, VEGFR-3, IC50 13 nM), FGFR types (FGFR-1, IC50 69 nM, FGFR-2, IC50 37 nM, FGFR-3, IC50 108 nM, FGFR-4, IC50 610 nM), PDGFR-α (IC50, 59 nM) and PDGFR-β (IC50, 65 nM). By being able to simultaneously target these three different angiogenesis-promoting receptor classes, the anti-tumor effect of nintedanib is enhanced and it may be possible to overcome resistance pathways to agents targeting VEGF and VEGFR-2. Nintedanib also inhibits Flt-3 and members of the Src family (Src, Lyn and Lek) and may have potential for the treatment of medical conditions such as blood disorders.

[0055] IPF and PPF are chronic and progressive fibrotic lung diseases associated with a short median survival of 2-3 years after diagnosis due to the lack of effective treatment. Both IPF and PPF are characterized by uncontrolled proliferation and differentiation of fibroblasts / myofibroblasts and excessive collagen deposition in the lung interstitium and alveolar space, causing symptoms of cough and dyspnea and ultimately leading to respiratory failure.

[0056] In some embodiments, administration of nintedanib or indolinone or a salt thereof by inhalation results in reduced gastrointestinal and liver side effects compared to oral administration. By reducing these side effects, patient safety is improved, patient compliance is maximized, dosing reduction and / or discontinuation protocols are avoided, and incremental increases in the local lung dose are possible to achieve additional efficacy not possible with oral products.

[0057] In some embodiments, administration of nintedanib or indolinone or a salt thereof by inhalation in combination with pirfenidone or a pyridine analog results in reduced gastrointestinal and liver side effects compared to additional oral administration of nintedanib and pirfenidone. By reducing these side effects, patient safety is improved, patient compliance is maximized, dosing reduction and / or discontinuation protocols are avoided, incremental increases in the local lung dose or optimization of the combination ratio are possible, and additional efficacy not possible with treatment with two oral products is obtained.

[0058] Nintedanib or indolinone dry powder specially formulated for dispersible and inhalable administration is used in a method for treating human lung diseases. This method is applicable to diseases including, but not limited to, pulmonary fibrosis, idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), sarcoidosis, usual interstitial pneumonia (UIP), cystic fibrosis, chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, bronchiolitis obliterans, chronic bronchitis, emphysema, pneumonia, lung cancer, Wegener's granulomatosis, scleroderma-associated pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease (SSc-ILD), silicosis, interstitial lung disease, asbestos-induced pulmonary fibrosis and / or pleural fibrosis. In some methods, the primary lung disease is pulmonary fibrosis (i.e., pulmonary fibrosis), while in other methods, the fibrosis is a complication of a separate disease such as cancer, or is the result of a previous infection or surgery, particularly including chronic lung allograft dysfunction (CLAD), and restrictive allograft syndrome (RAS).

[0059] Pirfenidone and pyridone analog compounds - Therapeutic usefulness In the invention described herein, pirfenidone or its pyridone analog is selected from 1-phenyl-2-(1H)pyridone, 5-methyl-1-phenyl-1,2-dihydropyridin-2-one, 5-methyl-1-(4-methylphenyl)-2-(1H)-pyridone, 5-methyl-1-(2'-pyridyl)-2-(1H)pyridone, 6-methyl-1-phenyl-3-(1H)pyridone, 6-methyl-1-phenyl-2-(1H)pyridone, 5-methyl-1-p-tolyl-3-(1H)pyridone, 5-methyl-1-phenyl-3-(1H)pyridone, 5-methyl-1-p-tolyl-2-(1H)pyridone, 5-ethyl-1-phenyl-2-(1H)pyridone, 5-ethyl-1-phenyl-3-(1H)pyridone, and 4-methyl-1-phenyl-3-(1H)pyridine, including deuterated forms.

[0060] In epithelial injury, epithelial cells are triggered to release several inflammatory and fibrosis-promoting mediators such as interleukin-1β, transforming growth factor beta (TGF-β), a potent fibroblast growth factor, tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), endothelin, other cytokines, metalloproteases, and tissue factor, a coagulation mediator. Importantly, it is clear that the triggered epithelial cells become vulnerable to apoptosis and are unable to repair the epithelial cell layer, which is the most fundamental abnormality in fibrotic diseases.

[0061] In medical conditions such as diseases, physiological responses characterized by the control of inflammatory and fibrosis-promoting factors by pyridone analogs such as pirfenidone are beneficial for the treatment or prevention of fibrosis, inflammation, or transplant rejection. The mechanism of action of pyridone analogs such as pirfenidone is to regulate the production of cytokines and growth factors. These effects may occur directly due to direct exposure to pirfenidone or may reflect secondary effects related to the regulation of a single molecular target. In either case, the regulation of cytokines, growth factors, and oxidative stress markers by pirfenidone is related to the regulation of pathways associated with the anti-fibrotic effect observed in vivo in ongoing fibrosis and demonstrates that it supports the observed anti-fibrotic effect. Pirfenidone is approved as an oral therapy for the treatment of idiopathic pulmonary fibrosis. See U.S. Pat. Nos. 10,092,552, 9,770,443, 10,028,966, 10,105,356, and 11,123,290, which are specifically incorporated herein by reference.

[0062] PDE4 Inhibitors and Subtype Compounds - Therapeutic Utility Phosphodiesterase (PDE) mediates the hydrolysis of the second messengers cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). PDE is encoded by 11 gene superfamilies that include multiple genes (encoding subtypes A, B, C, etc.), and alternative mRNA splicing variants that lead to approximately 100 PDE isoforms are also generated.

[0063] PDE4 subtypes A - D are encoded by different genes, PDE4A, B, C, and D, and post - translational processing generates N - terminal variant groups (long, short, and ultra - short) depending on the presence or absence of the upstream conserved regions 1 and 2 (UCR1 or UCR2) N - terminal domains. Since PDE4 subtypes can be incorporated into macromolecular complexes known as signalosomes, PDE signaling is highly compartmentalized.

[0064] PDE4 has traditionally been involved in the control of inflammation and the regulation of immune cells, and the three currently available selective PDE4 inhibitors support the beneficial role of PDE4 inhibitors in inflammatory and / or autoimmune diseases. The evidence indicates the involvement of various immune cells and inflammatory responses in pulmonary fibrosis.

[0065] The oral roflumilast (Daliresp®, Daxas®), the first - in - class PDE4 inhibitor, reduces the risk of COPD exacerbations in patients with chronic bronchitis and severe COPD with a history of exacerbations. Another compound, the oral apremilast (Otezla®), is effective in the treatment of psoriatic arthritis and plaque psoriasis. The third PDE4 inhibitor, crisaborole (Eucrisa®), is effective in the treatment of mild to moderate atopic dermatitis.

[0066] The general anti-inflammatory potential of PDE4 inhibition and its use in various inflammatory and immune-mediated diseases have been described. However, PDE4 may also play an important role in fibrosis. Roflumilast, apremilast, and crisaborole each hold the potential as PDE4 inhibitors effective in the treatment of fibrotic diseases. Additionally, BI 1015550 (a PDE4B inhibitor) has also shown promise. For the purposes of the present invention, PDE4 inhibitors include roflumilast, apremilast, crisaborole, BI 1015550, CHF6001, lonilast, oglemilast, GSK256066, YM976, GS5759, GPD-1116, MEM1414, RPL554, Asp3258, E6005, GW842470X, OPA-15406, Leo-29102, DRM02, percalcitol, HFP034, CBS3995, MK0873, levamisole, NCS 613, FCPR03, HT-0712, MK0952, API-4, ASP9831, including their deuterated forms.

[0067] Prostacyclin analogs and subtype compounds - Therapeutic utility Prostacyclin analogs promote vasodilation of the pulmonary and systemic arterial vascular beds and inhibit platelet aggregation. In addition to their effects on the pulmonary vasculature, the data indicate that prostacyclin analogs have antifibrotic properties. By way of non-limiting example, prostacyclin analogs include selexipag, epoprostenol, iloprost, treprostinil. Specifically, these prevent fibroblast proliferation in a dose-dependent manner to reduce extracellular matrix composition via TGF-β1 and PDGF-BB antagonism in human peripheral lung fibroblasts, inhibit extracellular matrix deposition by fibroblasts by both cyclic adenosine monophosphate (cAMP)-dependent and independent mechanisms in human peripheral lung fibroblasts, suppress the activity of profibrotic fibroblasts and the synthesis and deposition of collagen and fibronectin in mice by an anti-inflammatory process mediated by NK-κB signaling, and suppress the activity of profibrotic fibroblasts via inhibition of the transcription coactivator with PDZ-binding motif (TAZ) / Yes-associated protein (YAP) from prostacyclin (IP) receptor activation. Furthermore, clinical results indicate that prostacyclin analogs may be beneficial in patients with IPF. For the purposes of the present invention, and by way of non-limiting example, prostacyclin analogs include treprostinil, iloprost, epoprostenol, and verapost, including deuterated forms.

[0068] Idiopathic pulmonary fibrosis A method of treating or arresting the progression of a lung disease, comprising administering to the lower airways from the middle airways of a patient having or suspected of having a lung disease, by oral inhalation of a dry powder aerosol, nintedanib or indolinone or a salt thereof, or pirfenidone or a pyridone analog or a PDE4 inhibitor or a combination with a prostacyclin analog. A method of treating or arresting the progression of interstitial pulmonary fibrosis, including patients on mechanical ventilation.

[0069] A method for treating idiopathic pulmonary fibrosis (IPF) or suppressing its progression, which comprises administering, by oral inhalation of a dry powder aerosol containing nintedanib or a salt thereof, or a combination with pirfenidone, to the lower respiratory tract from the middle respiratory tract of a subject having or suspected of having IPF, a combination of nintedanib or indolinone or a salt thereof, or pirfenidone or a pyridone analog.

[0070] A method for treating progressive pulmonary fibrosis (PPF) or suppressing its progression, which comprises administering, by oral inhalation of a dry powder aerosol containing nintedanib or a salt thereof, or a combination with pirfenidone, to the lower respiratory tract from the middle respiratory tract of a subject having or suspected of having PPF, a combination of nintedanib or indolinone or a salt thereof, or pirfenidone or a pyridone analog.

[0071] A method for treating systemic sclerosis-related interstitial lung disease (SSc-ILD) or suppressing its progression, which comprises administering, by oral inhalation of a dry powder aerosol containing nintedanib or a salt thereof, or a combination with pirfenidone, to the lower respiratory tract from the middle respiratory tract of a subject having or suspected of having SSc-ILD, a combination of nintedanib or indolinone or a salt thereof, or pirfenidone or a pyridone analog.

[0072] A method for treating bronchiolitis obliterans or suppressing its progression, which comprises administering, by oral inhalation of a dry powder aerosol containing nintedanib or a salt thereof, or a combination with pirfenidone, to the lower respiratory tract from the middle respiratory tract of a patient having or suspected of having bronchiolitis obliterans, a combination of nintedanib or indolinone or a salt thereof, or pirfenidone or a pyridone analog.

[0073] A method for treating or suppressing the progression of chronic transplant lung dysfunction, comprising administering to the lower airway from the middle airway of a patient having or suspected of having chronic transplant lung dysfunction, by oral inhalation of a dry powder aerosol comprising nintedanib or a salt thereof, or a combination with pirfenidone, nintedanib or its indolinone salt, or a combination with pirfenidone or a pyridone analog.

[0074] A method for treating or suppressing the progression of restrictive graft syndrome, comprising administering to the lower airway from the middle airway of a patient having or suspected of having restrictive graft syndrome, by oral inhalation of a dry powder aerosol comprising nintedanib or a salt thereof, or a combination with pirfenidone, nintedanib or indolinone or a salt thereof, or a combination with pirfenidone or a pyridone analog.

[0075] As described herein, IPF refers to "idiopathic pulmonary fibrosis", and in some embodiments, it is a chronic disease that develops over several years in the absence of a known trigger and is characterized by scar tissue in the lungs. Shortness of breath during exercise and chronic dry cough may be prominent symptoms. IPF belongs to the family of lung disorders known as interstitial lung disease (ILD), or more precisely, diffuse parenchymal lung disease. Within this broad category of diffuse lung diseases, IPF belongs to a subgroup known as idiopathic interstitial pneumonia (IIP). There are seven different types of IIP, which are distinguished by specific clinical features and pathological patterns. IPF is the most common form of IIP. It is associated with a pathological pattern known as usual interstitial pneumonia (UIP), and thus IPF is often referred to as IPF / UIP. IPF is usually fatal, and the average survival period is about 3 years from the time of diagnosis. There is no single test for diagnosing pulmonary fibrosis, and several different tests, including chest X-ray, HRCT, pulmonary function tests, exercise stress tests, bronchoscopy, and lung biopsies, are used in combination with the methods described herein.

[0076] Idiopathic pulmonary fibrosis (also known as cryptogenic fibrosing alveolitis) is the most common form of interstitial lung disease and may be characterized by chronic progressive pulmonary parenchymal fibrosis. This is a progressive clinical syndrome of unknown cause, and the outcome is often fatal because there is no effective treatment. In some embodiments, nintedanib inhibits the proliferation and differentiation of fibroblasts associated with collagen synthesis, inhibits the production and activity of TGF-β, reduces the production of fibronectin and connective tissue growth factor, inhibits TNF-α and I-CAM, increases the production of IL-10, and / or decreases the levels of platelet-derived growth factor (PDGF) A and B in bleomycin-induced pulmonary fibrosis. The methods and compositions described herein may provide tolerability and utility to patients having advanced idiopathic pulmonary fibrosis and other lung diseases. In some embodiments, the methods and compositions of nintedanib described herein may provide tolerability and utility to patients with mild to moderate idiopathic pulmonary fibrosis. After treatment with the compositions of the invention, an increase in patient survival rate, enhancement of vital capacity, reduction in the episodes of acute exacerbation (compared to placebo), and / or delay in the progression of the disease are observed.

[0077] As used herein, PPF refers to "progressive pulmonary fibrosis." Similar to IPF, PPF is a chronic disease that develops over several years and is characterized by scar tissue in the lungs. Shortness of breath with exercise and chronic dry cough can be prominent symptoms. PPF also belongs to the family of interstitial lung diseases (ILDs) and more precisely to the category of diffuse parenchymal lung diseases. Idiopathic pulmonary fibrosis is specifically excluded from PPF. IPF is defined as an idiopathic ILD associated with the histological or radiological pattern of usual interstitial pneumonia (UIP). PPF has specific criteria, mainly consisting of worsening symptoms accompanied by radiographic fibrosis or increased impairment of respiratory physiology over time in non-IPF ILD. Despite the aforementioned histological and radiological differences from IPF, its natural history is similar. PPF is usually fatal, with an average survival period of about 3 to 5 years from the time of diagnosis. There is no single test for diagnosing PPF, and several different tests, including chest X-ray, HRCT, pulmonary function tests, exercise stress tests, bronchoscopy, and lung biopsy, are used in combination with the methods described herein.

[0078] Exemplary fibrotic lung diseases that can be treated or prevented using the methods described herein include, but are not limited to, idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis-related interstitial lung disease, pulmonary fibrosis secondary to transplant rejection such as bronchiolitis obliterans and constrictive allograft syndrome, systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, idiopathic pulmonary alveolitis, radiation-induced fibrosis, sarcoidosis, scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury, and acute respiratory distress (including that induced by bacterial pneumonia, trauma, viral pneumonia, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced).

[0079] When the methods of the present invention are applied to the treatment or suppression of the progression of lung cancer, the disorders include primary or secondary lung cancer resulting from metastatic diseases including pulmonary carcinoid tumors or bronchial carcinoids, non-small cell lung cancer, bronchioloalveolar carcinoma, sarcoma, and lymphoma.

[0080] The methods of the present invention include the treatment or prevention of patients identified as having gastrointestinal stromal tumors, relapsed or refractory Ph-positive acute lymphoblastic leukemia (ALL), myelodysplastic / myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangement, aggressive systemic mastocytosis (ASM) (without or unknown D816V c-KIT mutation), hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukemia (CEL), FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFR-α fusion kinase negative or unknown, or unresectable, relapsed and / or metastatic dermatofibrosarcoma protuberans, and combinations thereof.

[0081] Lung transplant rejection Lung transplant rejection initially presents as chronic lung allograft dysfunction (CLAD) and is a major cause of death. The main feature is bronchiolitis obliterans. The rate of decline in lung function in severe cases is on average about 7 times higher than that seen in patients with idiopathic pulmonary fibrosis (IPF). A subset of CLAD patients (about 30%) develop restrictive allograft syndrome (RAS), which has a poor prognosis. In these patients, both forced vital capacity (FVC) and forced expiratory volume are lost, resulting in restricted lung function. The pathophysiology is similar to that of IPF with progressive interstitial fibrosis.

[0082] A method of treating or arresting the progression of a lung disease, comprising administering nintedanib or indolinone or a salt thereof from the upper airway to the lower airway of a patient having or suspected of having a lung disease by oral inhalation of a dry powder aerosol. This method includes the treatment or arrest of the progression of chronic lung allograft dysfunction (CLAD) as a sign of lung transplant rejection. This method includes delivery to patients on mechanical ventilation. This method also includes administering nintedanib or indolinone or a salt thereof in combination with pirfenidone or a pyridone analog.

[0083] A method for treating or arresting the progression of a lung disease, comprising administering nintedanib or indolinone or a salt thereof from the upper airway to the lower airway of a patient having or suspected of having a lung disease by oral inhalation of a dry powder aerosol. This method includes treating or arresting the progression of bronchiolitis obliterans as a sign of lung transplant rejection. This method includes delivery to patients on a ventilator. This method also includes administering nintedanib or indolinone or a salt thereof in combination with pirfenidone or a pyridone analog.

[0084] A method for treating or arresting the progression of a lung disease, comprising administering nintedanib or indolinone or a salt thereof from the upper airway to the lower airway of a patient having or suspected of having a lung disease by oral inhalation of a dry powder aerosol. This method includes treating or arresting the progression of restrictive allograft syndrome (RAS) as a sign of lung transplant rejection. This method includes delivery to patients on a ventilator. This method also includes administering nintedanib or indolinone or a salt thereof in combination with pirfenidone or a pyridone analog.

[0085] Cardiac fibrosis A method of treating or arresting the progression of an extrapulmonary disorder, comprising administering nintedanib or indolinone or a salt thereof to the lower respiratory tract of a patient having or suspected of having cardiac fibrosis by oral inhalation of a dry powder aerosol, wherein cardiac fibrosis includes cardiac tissue remodeling observed in chronic hypertension and may also include cardiomyocyte hypertrophy and fibrosis, i.e., increased and heterogeneous deposition of extracellular matrix proteins. The extracellular matrix connects muscle cells, aligns contractile elements, prevents overstretching and destruction of muscle cells, transmits force, and provides tensile strength to prevent rupture. Fibrosis occurs in many models of hypertension and leads to increased diastolic stiffness, decreased cardiac function, increased risk of arrhythmia. If fibrosis rather than cardiomyocyte hypertrophy is an important factor in cardiovascular dysfunction, reversal of cardiac fibrosis promotes recovery of normal cardiac function. This method also includes administering nintedanib or indolinone or a salt thereof in combination with pirfenidone or a pyridone analog.

[0086] The term "cardiac fibrosis" refers, by way of non-limiting example, to remodeling associated with or resulting from viral or bacterial infection, surgery, Duchenne muscular dystrophy, radiation therapy, chemotherapy, transplant rejection, and chronic hypertension, and includes cardiomyocyte hypertrophy as well as fibrosis, with increased and heterogeneous deposition of extracellular matrix proteins occurring. Fibrosis occurs in many models of hypertension and causes increased diastolic stiffness, decreased cardiac function, increased risk of arrhythmia, and cardiovascular dysfunction.

[0087] Cancer A method for treating lung cancer or inhibiting its progression, comprising administering nintedanib or indolinone or a salt thereof to the airways of a patient having or suspected of having lung cancer by oral inhalation of a dry powder aerosol, wherein the lung cancer includes primary or secondary lung cancer resulting from metastatic diseases including pulmonary carcinoid tumors or bronchial carcinoids, non-small cell lung cancer, bronchioloalveolar carcinoma, sarcoma, and lymphoma. This method also includes administering a combination of nintedanib or indolinone or a salt thereof and pirfenidone or a pyridone analog.

[0088] The mortality rate due to lung cancer is high, and the annual number of deaths due to lung cancer is comparable to the total of prostate cancer, breast cancer, colon cancer, and rectal cancer. Despite the progress in knowledge of molecular mechanisms and the introduction of multiple new lung cancer therapeutics, the dismal 5-year survival rate (11 - 15%) has remained relatively unchanged. This reflects the limited available knowledge regarding factors that promote carcinogenic transformation into malignant cells and the proliferation of malignant cells.

[0089] It is now known that tumor growth is not determined solely by aggressive malignant cells because the interaction between cancer cells and the stromal compartment has a major impact on cancer growth and progression. Aggressive malignant cells skillfully utilize the tumor microenvironment: tumor cells can (1) exist within the stroma and transform the stroma, (2) change the surrounding connective tissue, (3) change the metabolism of resident cells, and form a permissive rather than defensive stroma.

[0090] In addition to overcoming host microenvironment control, an important feature of cancer cells is the ability to invade tissues and metastasize distantly. Invasion and metastasis require a coordinated interaction between fibroblasts, immune cells, and angiogenesis cells and factors.

[0091] The tumor stroma basically consists of (1) non-malignant cells of the tumor, such as cancer-associated fibroblasts (CAFs), specialized mesenchymal cell types specific to each tissue environment, innate and adaptive immune cells, and blood vessels including endothelial cells and pericytes, and (2) an extracellular matrix (ECM) composed of structural proteins (collagen and elastin), specialized proteins (fibrillin, fibronectin, elastin), and proteoglycans. Angiogenesis is central to the growth and survival of cancer cells and has been the most successful among stromal targets in anti-cancer therapy so far. The initiation of angiogenesis requires the degradation of the basement membrane, the sprouting of endothelial cells, and the induction of matrix metalloproteinases (MMPs) leading to the control of pericyte adhesion. However, CAFs play an important role in synchronizing these events through the expression of numerous ECM molecules and growth factors such as transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF2).

[0092] Normal tissue stroma is essential for the maintenance and integrity of epithelial tissues and contains numerous cells that cooperate to maintain the homeostasis of normal tissues. There is continuous and bidirectional molecular crosstalk between normal epithelial cells and stromal compartment cells, mediated either by direct cell-cell contact or secreted molecules. Thus, small changes in one compartment can cause dramatic changes throughout the system.

[0093] There are similarities between the stroma of wounds and tumors, as both tissues have active angiogenesis and numerous proliferative fibroblasts secreting a complex ECM, all of which exist against a background of fibrin deposition. Therefore, the tumor stroma is generally referred to as an activated or reactive stroma.

[0094] During cancer development, gene mutations result in malignant cells, which in turn cause changes in the stromal host compartment, establishing a permissive and supportive environment for cancer cells. At the initial stages of tumor development and invasion, the basement membrane is degraded, and the activated stroma, including fibroblasts, inflammatory infiltrates, and newly formed capillaries, comes into direct contact with tumor cells. The basement membrane matrix also alters cytokine interactions between cancer cells and fibroblasts. These cancer-inducing changes in the stroma contribute to cancer invasion. Animal studies have shown that both wounds and activated stroma provide carcinogenic signals that promote tumor formation. The normal stroma of most organs contains a minimal number of fibroblasts associated with the physiological ECM, while the activated stroma is associated with more ECM-producing fibroblasts, enhanced vascularization, and increased ECM production. The formation of this specific type of tumor stroma at the site of active tumor cell invasion is considered an essential part of tumor invasion and is called tumor stromagenesis.

[0095] The expansion of the tumor stroma with fibroblast proliferation and dense ECM deposition is called the fibrotic reaction. This follows malignant growth and can be separated from alveolar collapse that does not show activated fibroblasts or high-density collagen / ECM. Morphologically, this is called fibrosis and was initially thought to be a defense mechanism to prevent tumor growth, but data have shown that in established tumors, this process is instead involved in several aspects of tumor progression, such as angiogenesis, migration, invasion, and metastasis. Later studies have shown that fibroblasts and tumor cells can promote local tissue growth and cancer progression by secreting and degrading ECM components within the tumor stroma. This is partly related to the release of sequestered substances within the ECM, such as VEGF, and the cleavage of products from ECM proteins in response to the secretion of cancer-associated MMPs.

[0096] Fibrosis-promoting growth factors released by cancer cells, such as TGF-β, platelet-derived growth factor (PDGF), and FGF2, all govern the volume and composition of the tumor stroma because they are all important mediators of fibroblast activation and tissue fibrosis. PDGF and FGF2 also play important roles in angiogenesis.

[0097] In tumors, activated fibroblasts are called tumor-associated fibroblasts or cancer-associated fibroblasts (CAFs). CAFs are very heterogeneous, like activated fibroblasts, and are thought to be derived from the same sources as activated fibroblasts. The main progenitor cells are thought to be locally present fibroblasts, but perivascular cells and smooth muscle cells of the vasculature, bone marrow-derived mesenchymal cells, or those derived from epithelial or endothelial mesenchymal transition are also possible. The term CAF is quite ambiguous because the origins of these cells are diverse, similar to the differences between activated fibroblasts and CAFs. There is increasing evidence for epigenetic and perhaps genetic distinctions between CAFs and normal fibroblasts. CAFs can be recognized by the expression of α-smooth muscle actin, but due to heterogeneity, α-smooth muscle actin expression alone cannot identify all CAFs. Therefore, other CAF markers used are fibroblast-specific protein 1, fibroblast activation protein (FAP), and platelet-derived growth factor receptor (PDGFR) α / β.

[0098] In response to tumor growth, fibroblasts are mainly activated by TGF-β, chemokines such as monocyte chemoattractant protein 1, and ECM degrading agents such as MMPs. Some in vitro studies have demonstrated the effect of normal fibroblasts in inhibiting cancer progression, but today there is solid evidence that CAFs play a role in promoting cancer. In breast cancer, it is thought that 80% of stromal fibroblasts have this activated phenotype (CAF).

[0099] CAF promotes malignant tumors, angiogenesis, invasion, and metastasis. The role of CAFS and its potential as a target for cancer treatment have been studied in xenograft models, and translational research evidence has revealed the prognostic importance of CAF in several cancer types.

[0100] In the context of tumor growth, CAF is activated and highly synthesized, secreting, for example, type I and type IV collagens, extra domain A-fibronectin, heparan sulfate proteoglycan, acidic and cysteine-rich secreted protein, tenascin C, connective tissue growth factor, MMP, and plasminogen activator. In addition to secreting growth factors and cytokines that affect cell motility, CAF is also an important source of ECM-degrading proteases such as MMP, which play several important roles in tumor formation. MMP can promote tumor growth, invasion, angiogenesis, recruitment of inflammatory cells, and metastasis depending on the substrate through the degradation of ECM. Furthermore, many inflammation-inducing cytokines appear to be activated by MMP.

[0101] After injecting B16M melanoma cells into mice, the formation of liver metastases is associated with the early activation of stellate cells (fibroblast-like) in the liver, which is thought to be important because these cells form the metastatic niche and promote angiogenesis. MMP has also been associated with tumor angiogenesis in various in vivo models. CAF promoted the invasiveness of other non-invasive cancer cells when co-injected into mice. Furthermore, xenografts containing CAF grew significantly faster than xenografts injected with normal fibroblasts.

[0102] Upon recruitment and accumulation of CAF into the tumor stroma, these cells become actively communicative with cancer cells, epithelial cells, endothelial cells, pericytes, and inflammatory cells through the secretion of several growth factors, cytokines, and chemokines. CAF provides potent carcinogenic molecules such as TGF-β and hepatocyte growth factor (HGF).

[0103] TGF-β is a multifunctional growth factor expressed by both cancer cells and stromal cells. TGF-β is a tumor suppressor in normal cells and precancerous cells, but as cancer cells progress, the anti-proliferative effect is lost, and instead, TGF-β promotes tumorigenesis by inducing differentiation into an invasive phenotype. TGF-β may also induce cancer progression by escaping immune surveillance, and increased expression of TGF-β strongly correlates with the accumulation of fibrotic fibrous tissue and cancer progression. Recently, it has been reported that small molecule inhibitors of TGF-β receptor type I inhibit the production of connective tissue growth factor by hepatocellular carcinoma (HCC) cells, resulting in a decrease in the stromal components of HCC. Inhibition of the TGF-β receptor abrogates the crosstalk between HCC and CAF, and as a result, tumor growth, invasion, and metastasis are avoided. HGF belongs to the plasminogen family and binds to the ECM in its precursor form. It binds to the high-affinity receptor c-met, and overexpression or persistent oncogenic c-Met signaling causes proliferation, invasion, and metastasis.

[0104] PDGF is a regulator of fibroblasts and pericytes and plays an important role in tumor progression. It is a chemotactic and growth factor for mesenchymal cells and endothelial cells. It has a limited autocrine role in tumor cell replication but plays a potential role in a paracrine manner and in the development of the tumor stroma. It induces the proliferation of activated fibroblasts and may indirectly replenish CAFs by stimulating the release of TGF-β from macrophages.

[0105] Tumors do not occur without the parallel expansion of the tumor stroma. The exact mechanisms that control fibroblast activation and the accumulation of fibroblasts in cancer are not yet understood, but the available evidence indicates that the tumor stroma or CAFs may be potential targets for cancer therapy.

[0106] CAF and MMP are considered to be two of the major regulators of epithelial-derived tumors, representing potential new targets for combination therapies that affect both the transformed and non-transformed components of the tumor microenvironment. As previously commented, the experience with MMP inhibitors has not been successful to date. Evidence that CAFs are epigenetically and perhaps also genetically different from normal fibroblasts has led these cells to be defined as potential targets for anti-cancer therapies. FAP is expressed in over 90% of epithelial cancers and has emerged early as a promising candidate for targeting CAFs, and the potential therapeutic effects of its inhibition have recently been investigated. In preclinical studies, ablation of FAP attenuates tumor growth and significantly increases the uptake of anti-cancer agents by tumor tissue. In a phase I study of patients with FAP-positive advanced cancers (colorectal cancer and NSCLC) treated with an FAP antibody, the antibody specifically bound to the tumor site, but no objective response was observed.

[0107] Consistent and repeated findings regarding cancer cells that readily invade and metastasize in response to TGF-β have pointed to the need for new anti-cancer agents that target the carcinogenic activity of TGF-β. Over the past decade, numerous anti-TGF-β antibodies and TGF-β receptor I kinases have been preclinically tested. Due to lack of success, targeting the TGF-β signaling system remains elusive. It should be noted that both tumor-promoting and anti-tumor effects have been ascribed to TGF-β, and the multifunctionality of TGF-β represents the greatest barrier to effectively targeting this ligand, its receptor, or downstream effectors.

[0108] Combination As a non-limiting example, nintedanib or indolinone or a salt thereof is administered in a dosing regimen that includes a fixed combination, co-administration, sequential administration, or co-prescription with a PDE4 inhibitor for the treatment of interstitial lung disease.

[0109] As a non-limiting example, nintedanib or indolinone or a salt thereof is administered in a dosing regimen for the treatment of interstitial lung disease that includes a fixed combination, co-administration, sequential administration, or co-prescription with a prostacyclin analog.

[0110] As a non-limiting example, nintedanib or indolinone or a salt thereof is administered in a dosing regimen for the treatment of interstitial lung disease that includes a fixed combination, co-administration, sequential administration, or co-prescription with pirfenidone or a pyridine analog.

[0111] A promising approach for treating cancer is the administration of "cocktail therapy" or "cocktail prophylaxis", which involves co - administering or sequentially administering inhaled nintedanib or indolinone or a salt thereof with a cancer - targeting agent, such as gefitinib (Iressa, also known as ZD1839), erlotinib (Tarceva), bortezomib (initially coded as PS - 341, sold as Velcade® and Bortecad®), Janus kinase inhibitor, ALK inhibitor, PARP inhibitor (iniparib; BSI 201), PI3K inhibitor, apatinib (YN968D1), selumetinib, salinomycin, avitrexate (methotrexate), abraxane (paclitaxel albumin - stabilized nanoparticle formulation), afatinib dimaleate, alimta (pemetrexed disodium), avastin (bevacizumab), carboplatin, cisplatin, crizotinib, erlotinib hydrochloride, folrex (methotrexate), folrex PFS (methotrexate), gefitinib diotrif (afatinib maleate), gemcitabine hydrochloride, gemzar (gemcitabine hydrochloride), iressa (gefitinib), methotrexate, methotrexate LPF (methotrexate), mexate (methotrexate), mexate AQ (methotrexate), paclitaxel, paclitaxel albumin - stabilized nanoparticle formulation, paraplat (carboplatin), paraplat (carboplatin), pemetrexed disodium, platinol (cisplatin), platinol AQ (cisplatin), tarceva (erlotinib hydrochloride), taxol (paclitaxel), and xalkori (crizotinib), but not limited to these.

[0112] Approved combinations for non - small cell lung cancer include carboplatin - taxol and gemcitabine - cisplatin.

[0113] Drugs approved for small cell lung cancer include abtrexate (methotrexate), etopophos (etoposide phosphate), etoposide, etoposide phosphate, folrex (methotrexate), folrex PFS (methotrexate), hycamptin (topotecan hydrochloride), methotrexate, methotrexate LPF (methotrexate), mexate (methotrexate), mexate AQ (methotrexate), topsal (etoposide), topotecan hydrochloride, and vepecid (etoposide).

[0114] Dosage, formulation, and packaging of pharmaceuticals The selection of a particular nintedanib composition or indolinone or its salt involves the selection of the packaging and configuration of a specially designed product that maximizes the therapeutic utility of the particular composition. Elements to consider when selecting packaging include, for example, the stability inherent in the product, whether the formulation is subject to lyophilization, the choice of device (e.g., dry powder inhaler), and / or the packaging form (e.g., a dry powder formulation in a vial, capsule, or blister pack).

[0115] In a preferred embodiment, the composition will take the form of a unit dosage form such as a vial, capsule, or blister pack containing a dry powder or other composition, and thus the composition may include, along with the active ingredient, a carrier or diluent such as lactose, mannitol, a lubricant such as magnesium stearate, and / or a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc.

[0116] The compound formulations or combinations of nintedanib or indolinone or salts thereof described herein can be divided into two groups of simple or complex formulations that provide taste masking and improve properties such as tolerability, stability and tolerability, immediate or sustained release, and / or improvement in the shape of the area under the curve (AUC). Simple formulations can include dry powder inhaled nintedanib or indolinone formulations alone, or dry powder inhaled nintedanib or indolinone formulations containing water-soluble or organosoluble non-encapsulated excipients, with or without a carrier agent such as lactose.

[0117] Complex formulations containing the active ingredient can include nintedanib or indolinone alone, or the active ingredient encapsulated or complexed with a water-soluble excipient such as lipid, liposome, cyclodextrin, microencapsulation, etc., and an emulsion dry powder formulation administered using a dry powder inhaler of nintedanib or indolinone alone or the combinations described herein as a co-crystal / co-precipitate / spray-dried complex or mixture with a low water-soluble excipient / salt in dry powder form, with or without a carrier agent such as lactose. Specific methods for the preparation of simple and complex formulations are described herein.

[0118] The compositions of the present invention include each dosage consisting of from about 0.05 mg to about 100 mg of nintedanib or an indolinone compound. The dosage of the nintedanib base or indolinone compound base, or the nintedanib base or indolinone base within the nintedanib salt or indolinone salt, is in 0.01 mg units and may be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg of nintedanib or an indolinone compound. The compositions of the present invention may further include each dosage consisting of a particulate fraction from 10% to 100% in 1% increment units. As non-limiting examples, the particulate fraction may be greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, and about 100%. The compositions of the present invention may further include each dosage consisting of a particulate dosage of from about 0.001 mg to about 100 mg of the nintedanib base or indolinone compound base, or the nintedanib base or indolinone base within its nintedanib salt or indolinone salt. As non-limiting examples, in 0.01 mg units, they may be about 0.001 mg, about 0.005 mg, about 0.01 mg, and about 0.05 mg. As further examples, the particulate dosage may be in 0.1 mg units and may be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg.

[0119] As a non-limiting example, a preferred embodiment comprises micronized nintedanib or a salt thereof, comprising a hydrobromide salt in solid particles having a particle size distribution defined to have a D10 of about 0.1 μm to about 2 μm, a D50 of about 1 μm to about 3 μm, and a D90 of about 1.5 μm to about 5 μm at a formulation content of about 1% to about 20% on a weight-for-weight basis. A preferred embodiment may further comprise lactose having a particle size distribution defined to have a D10 of about 5 μm to about 15 μm, a D50 of about 50 μm to about 100 μm, and a D90 of about 120 μm to about 160 μm at a formulation content of about 60% to about 99% on a weight-for-weight basis. A preferred embodiment may further comprise lactose microparticles having a particle size distribution defined to have a D50 of less than about 5 μm and a D90 of less than about 10 μm at a formulation content of greater than 0% to about 20% on a weight-for-weight basis. The composition may further comprise one or more of a force control agent consisting of leucine, trilucine, magnesium stearate, sodium stearate and lecithin at about 0.1% to about 20% on a weight-for-weight basis. The composition can be packaged in a capsule, blister well, or metering device reservoir, each comprising a preferred dry powder formulation composition for administration using a dry powder inhaler, consisting of about 1 mg to about 40 mg. The preferred formulations described herein enable high dose release from medium and high resistance dry powder inhaler devices. For clarity, medium and high resistance devices are designed to require a lower inhalation flow rate to actuate and disperse the dose of the dry powder formulation, and are more suitable for persons suffering from lung diseases and reduced lung function where the inhalation flow rate may be insufficient to efficiently actuate and disperse the dry powder dose with inhalation administration from a low resistance device. Each dose can be administered in 1, 2, 3, 4, or up to 20 inhalation puffs per dose, each inhalation puff representing the administration of the contents from a single capsule, single blister well, or single metering device reservoir dose. Each dose can be provided once, twice, three times, or four times a day as the maximum daily dose of nintedanib of 200 mg.

[0120] The method of the present invention involves treating a person suffering from interstitial lung disease by administering an inhaled dry powder dosage consisting of from about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. The dosage of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in the nintedanib salt or indolinone salt, is in 0.01 mg units and may be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg of nintedanib or indolinone compound. The method of the present invention involves treating a person suffering from interstitial lung disease with an inhaled dry powder nintedanib or indolinone analog composition, and each dosage consists of a fine particle fraction of 10% to 100% in 1% increment units. As non-limiting examples, the fine particle fraction may be greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, and about 100%. The method of the present invention involves treating a person suffering from interstitial lung disease with an inhaled dry powder composition, and the fine particle dosage is from about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. As non-limiting examples, in 0.01 mg units, it may be about 0.001 mg, about 0.005 mg, about 0.01 mg, and about 0.05 mg.As a further example, the particulate dosage may be in 0.1 mg units and may be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg. The method of the present invention involves treating a person suffering from interstitial lung disease once a day, twice a day, three times a day, four times a day, or five times a day with inhaled dry powder nintedanib or an indolinone-like composition, each dosage consisting of about 0.05 mg to about 100 mg of nintedanib or an indolinone compound, and the particulate fraction being about 10% to 100%, delivering a particulate dosage of about 0.001 mg to about 100 mg of nintedanib or an indolinone analog.

[0121] The composition of the present invention also includes a combined dry powder of nintedanib or an indolinone analog and pirfenidone or a pyridone analog. As a non-limiting example, each dosage of nintedanib or an indolinone analog in the combination consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. The dosage of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt in the combination may be, in 0.01 mg units, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg of nintedanib or indolinone compound. As a non-limiting example, each dosage of pirfenidone or a pyridone analog in the combination consists of about 5 mg to about 100 mg of pirfenidone or pyridone analog compound. The dosage of pirfenidone or a pyridone analog in the combination may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of pirfenidone or pyridone analog. The composition of the combination of the present invention may further include each drug dosage consisting of a particulate fraction of 10% to 100% in 1% increment units. As a non-limiting example, the particulate fraction of each drug may be greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, and about 100%.The composition of the combination of the present invention may further comprise each dosage consisting of a particulate dosage of about 0.001 mg to about 100 mg of nintedanib or an indolinone analog and 5 mg to about 100 mg of pirfenidone or a pyridone analog compound. For example, the particulate dosage of nintedanib base or indolinone compound base from the combination, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, may be in 0.1 mg units of about 0.001 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. For example, the particulate dosage of pirfenidone or a pyridone analog compound from the combination may be about 0.5 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of pirfenidone or a pyridone analog.

[0122] The mg:mg composition ratio of nintedanib or an indolinone compound to pirfenidone or a pyridone analog is about 1:1000, about 1:900, about 1:800, about 1:700, about 1:600, about 1:500, about 1:400, about 1:300, about 1:250, about 1:200, about 1:100, about 1:75, about 1:50, about 1:25, about 1:20, about 1:10, about 1:5, about 1:2.5, about 1:1, about 2:1, about 3:1, and about 4:1.

[0123] The method of the present invention includes optimizing the ratio of the co-formulated combination of nintedanib or indolinone compound and pirfenidone or pyridone analog to avoid chemical interactions or physiological effects in co-formulation, where the rate of excretion of inhaled nintedanib or indolinone compound from the lung into plasma is increased compared to the rate of nintedanib or indolinone delivered without co-formulated pirfenidone or pyridone analog. As a non-limiting example, when the mg:mg ratio of nintedanib:pirfenidone is 2:100, the lung Cmax of nintedanib decreases by about 30 - 50% and the plasma Cmax of nintedanib increases by about 30 - 50%. To maximize the lung residence time of inhaled nintedanib co-formulated with pirfenidone, it is desirable to reduce this pharmacokinetic effect. As a non-limiting example, this undesirable pharmacokinetic effect can be minimized by reducing the pirfenidone content to less than 100 mg per single dose while setting the nintedanib:pirfenidone content ratio to 1:30 - 1:100. As another non-limiting example, this undesirable pharmacokinetic effect can be minimized by reducing the pirfenidone dose to less than 100 mg while setting the mg:mg nintedanib:pirfenidone content ratio to 1:20 - 1:50. As another non-limiting example, this undesirable pharmacokinetic effect can be minimized by increasing the nintedanib co-formulation content such that the resulting mg:mg nintedanib:pirfenidone content ratio is less than 1:50.

[0124] The method of the present invention includes optimizing a combination plan of the ratio of nintedanib or indolinone compound and pirfenidone or pyridone analog to improve therapeutic effects including efficacy, safety, tolerability, and compliance. As a non-limiting example, 100 mg of pirfenidone is at the upper limit range of the tolerability of pirfenidone as a sprayed single solution and is close to the upper limit threshold possible with a dry powder product with high compliance and high tolerability. As a non-limiting example, the efficacy of a dry powder product co-formulated with this nintedanib or indolinone compound and pirfenidone or pyridone analog is predicted to be greater than that of either active ingredient alone. To maximize the relationship between safety / tolerability / compliance and efficacy, compliance is improved by reducing the total amount of dry powder administered, and both the safety and tolerability of the combination product are improved. Utilizing the additional effect by co-formulation with a nintedanib or indolinone compound, the amount of pirfenidone or pyridone analog in the co-formulated dry powder product can be reduced while maintaining the overall additional advantage of administering both nintedanib or indolinone and pirfenidone or pyridone analog to the patient. As a non-limiting example, this desirable result is achieved by reducing the pirfenidone dosage to less than 100 mg while setting the nintedanib:pirfenidone content ratio at 1:25 to 1:500 on a mg:mg basis. The method of the present invention includes treating a person suffering from interstitial lung disease by administering a combination dry powder of a nintedanib or indolinone analog and a pirfenidone or pyridone analog, and each dosage of the nintedanib or indolinone analog consists of about 0.05 mg to about 100 mg of a nintedanib or indolinone compound and about 5 mg to about 100 mg of a pirfenidone or pyridone analog compound.The method of the present invention comprises treating a person suffering from interstitial lung disease with a combination composition of inhaled dry powder nintedanib or an indolinone analogue and pirfenidone or a pyridone analogue, each dosage consisting of a particulate fraction of 10% to 100%, and the resulting particulate dosage being such that the nintedanib or indolinone analogue is from about 0.001 mg to about 100 mg and the pirfenidone or pyridone analogue is from about 5 mg to about 100 mg. The method of the present invention comprises treating a person suffering from interstitial lung disease with a combination composition of inhaled dry powder nintedanib or an indolinone analogue and pirfenidone or a pyridone analogue once, twice, three times, four times or five times a day, each dosage consisting of from about 0.05 mg to about 100 mg of nintedanib or an indolinone compound and from about 5 mg to about 100 mg of a pirfenidone or pyridone analogue compound, the particulate fraction being about 10% to 100%, and delivering a particulate dosage of from about 0.001 mg to about 100 mg of nintedanib or an indolinone analogue and from about 5 mg to about 100 mg of a pirfenidone or pyridone analogue.

[0125] The composition of the present invention also includes a combined dry powder of nintedanib or an indolinone analog and a PDE4 inhibitor. As a non-limiting example, each dosage of nintedanib or an indolinone analog in the combination consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. The dosage in the combination of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in the nintedanib salt or indolinone salt, is in units of 0.01 mg and may be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg or about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in the nintedanib salt or its indolinone salt. As a non-limiting example, each dosage of the PDE4 inhibitor in the combination consists of about 0.01 mg to about 100 mg of the PDE4 inhibitor compound. The dosage of the PDE4 inhibitor in the combination may be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg of the PDE4 inhibitor compound. The composition of the combination of the present invention may further include each drug dosage consisting of 10% to 100% of the particulate fraction in 1% increment units.As a non-limiting example, the particulate fractions of each drug include more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 55%, more than about 60%, more than about 65%, more than about 70%, more than about 75%, more than about 80%, more than about 85%, more than about 90%, more than about 95%, and about 100%. The composition of the combination of the present invention may further include each dosage consisting of a particulate dosage of about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, and a PDE4 inhibitor compound of 0.001 mg to about 100 mg. As an example of nintedanib or an indolinone analog, the particulate dosage from the combination may be, in 0.1 mg units, about 0.001, about 0.01, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. As an example of a PDE4 inhibitor, the particulate dosage from the combination may be, in 0.1 mg units, about 0.001, about 0.01, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of a PDE4 inhibitor compound.

[0126] The composition of the present invention comprises an mg:mg ratio of nintedanib or indolinone compound to a PDE4 inhibitor of about 1:1000, about 1:900, about 1:800, about 1:700, about 1:600, about 1:500, about 1:400, about 1:300, about 1:250, about 1:200, about 1:100, about 1:75, about 1:50, about 1:25, about 1:20, about 1:10, about 1:5, about 1:2.5, about 1:1, about 2:1, about 3:1, and about 4:1.

[0127] The method of the present invention involves optimizing the ratio of the co-formulated nintedanib or indolinone compound and the PDE4 inhibitor in order to improve the therapeutic advantages. As a non-limiting example, the efficacy of a dry powder product co-formulated with this nintedanib or indolinone compound and the PDE4 inhibitor is expected to be greater than that of either active ingredient alone. To maximize the relationship between safety / tolerance / compliance and efficacy, compliance is improved by reducing the total amount of dry powder administered, and both the safety and tolerance of the combination product are improved. Utilizing the additional effect, while maintaining the overall additional advantages of administering both nintedanib or indolinone and the PDE4 inhibitor to the patient, both the amount of the nintedanib or indolinone compound and the amount co-formulated with the PDE4 inhibitor in the co-formulated dry powder product can be decreased. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:PDE4 inhibitor at 1:4 to 1:400 on a mg:mg basis and reducing the content of the PDE4 inhibitor to less than 40 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:PDE4 inhibitor at 1:4 to 1:400 on a mg:mg basis and reducing the content of the PDE4 inhibitor to less than 30 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:PDE4 inhibitor at 1:4 to 1:400 on a mg:mg basis and reducing the content of the PDE4 inhibitor to less than 20 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:PDE4 inhibitor at 1:4 to 1:400 on a mg:mg basis and reducing the content of the PDE4 inhibitor to less than 10 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:PDE4 inhibitor at 1:4 to 1:400 on a mg:mg basis and reducing the content of the PDE4 inhibitor to less than 5 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:PDE4 inhibitor at 1:4 to 1:400 on a mg:mg basis and reducing the content of the PDE4 inhibitor to less than 1 mg per single dose.

[0128] The method of the present invention includes treating a person suffering from interstitial lung disease by administering a combination dry powder of nintedanib or an indolinone analog and a PDE4 inhibitor, wherein each dosage of nintedanib or an indolinone analog consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, and about 0.01 mg to about 100 mg of a PDE4 inhibitor compound. The method of the present invention includes treating a person suffering from interstitial lung disease with a combined composition of inhaled dry powder nintedanib or an indolinone analog and a PDE4 inhibitor, wherein each dosage consists of 10% to 100% of the fine particle fraction, and the resulting fine particle dosage is about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, and about 0.001 mg to about 100 mg of a PDE4 inhibitor. The method of the present invention includes treating a person suffering from interstitial pneumonia once a day, twice a day, three times a day, four times a day, or five times a day with a combined composition of inhaled dry powder nintedanib or an indolinone analog and pirfenidone or a pyridone analog, wherein each dosage consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, and about 0.01 mg to about 100 mg of a PDE4 inhibitor compound, the fine particle fraction is about 10% to 100%, and delivers a fine particle dosage of about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, and about 0.001 mg to about 100 mg of a PDE4 inhibitor compound.

[0129] The composition of the present invention also includes a combined dry powder of nintedanib or an indolinone analog and a prostacyclin analog. As a non-limiting example, each dosage of nintedanib or an indolinone analog in the combination consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. The dosage of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, is in units of 0.01 mg, and may be about 0.01 mg, about 05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. As a non-limiting example, each dosage of each prostacyclin analog in the combination consists of about 0.001 mg to about 10 mg of a prostacyclin analog compound.The dosage of the prostacyclin analog in the combination may be a prostacyclin analog compound in units of 0.001 mg, such as about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, about 0.060 mg, about 0.065 mg, about 0.070 mg, about 0.075 mg, about 0.080 mg, about 0.085 mg, about 0.090 mg, about 0.095 mg, about 0.1 mg, about 0.15, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.1 mg, about 1.5 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, and about 10 mg. The composition of the combination of the present invention may further comprise a drug dosage consisting of a particulate fraction of 10% to 100% in 1% increment units. As non-limiting examples, the particulate fraction of each drug may be greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, and about 100%. The composition of the combination of the present invention may further comprise each dosage consisting of a particulate dosage of about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, and about 0.0001 mg to about 10 mg of a prostacyclin analog compound.For example, the particulate dosage of the nintedanib base or indolinone compound base from the combination, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt, may be, in 0.1 mg units, about 0.001, about 0.01, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of the nintedanib base or indolinone compound base, or the nintedanib base or indolinone base in its nintedanib salt or indolinone salt. As a non-limiting example, the dosage of the prostacyclin analog particulate from the combination may be, in 0.0001 mg units, about 0.0001 mg, about 0.0005 mg, about 0.001 mg, about 0.0015 mg, about 0.0020 mg, about 0.0025 mg, about 0.0030 mg, about 0.0035 mg, about 0.0040 mg, about 0.0045 mg, about 0.0050 mg, about 0.0055 mg, about 0.0060 mg, about 0.0065 mg, about 0.0070 mg, about 0.0075 mg, about 0.0080 mg, about 0.0085 mg, about 0.0090 mg, about 0.0095 mg, about 0.01 mg, about 0.015, about 0.02 mg, about 0.025 mg, about 0.03 mg, about 0.035 mg, about 0.04 mg, about 0.045 mg, about 0.05 mg, about 0.055 mg, about 0.06 mg, about 0.065 mg, about 0.07 mg, about 0.075 mg, about 0.08 mg, about 0.085 mg, about 0.09 mg, about 0.095 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, and about 10 mg of the prostacyclin analog compound.

[0130] The composition of the present invention comprises an mg:mg ratio of nintedanib or indolinone compound to prostacyclin analog at about 1,000,000:1, about 100,000:1, about 10,000:1, about 1,000:1, about 800:1, about 700:1, about 600:1, about 500:1, about 400:1, about 300:1, about 250:1, about 200:1, about 150:1, about 100:1, about 75:1, about 50:1, about 25:1, about 20:1, about 10:1, about 5:1, about 1:1, about 2:1, about 3:1 and about 10:1.

[0131] The method of the present invention involves optimizing the ratio of the co-formulated combination of nintedanib or indolinone compound and prostacyclin analog to improve therapeutic benefits. As a non-limiting example, the efficacy of a dry powder product co-formulated with this nintedanib or indolinone compound and prostacyclin analog is predicted to be greater than that of either active ingredient alone. To maximize the relationship between safety / tolerability / compliance and efficacy, compliance is improved by reducing the total amount of dry powder administered, and both the safety and tolerability of the combination product are improved. Utilizing the additional effect, while maintaining the overall additional benefits of administering both nintedanib or indolinone and the prostacyclin analog, the amounts of both the nintedanib or indolinone compound and the prostacyclin analog co-formulated in the co-formulated dry powder product can be reduced. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:prostacyclin analog on a mg:mg basis to 1:4 to 250:1 and reducing the content of the prostacyclin analog to less than 0.04 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:prostacyclin analog on a mg:mg basis to 1:4 to 250:1 and reducing the content of the prostacyclin analog to less than 0.02 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:prostacyclin analog on a mg:mg basis to 1:4 to 250:1 and reducing the content of the prostacyclin analog to less than 0.018 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:prostacyclin analog on a mg:mg basis to 1:4 to 250:1 and reducing the content of the prostacyclin analog to less than 0.015 mg per single dose. As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib:prostacyclin analog on a mg:mg basis to 1:4 to 250:1 and reducing the content of the prostacyclin analog to less than 0.01 mg per single dose.As a non-limiting example, this ratio is optimized by setting the content ratio of nintedanib: prostacyclin analog to 1:4 to 250:1 on a mg:mg basis and reducing the content of the prostacyclin analog to less than 0.005 mg per single dose.

[0132] The method of the present invention includes treating a person suffering from interstitial lung disease by administering a combined dry powder of nintedanib or indolinone analog and a prostacyclin analog. Each dose of nintedanib or indolinone analog in the combination consists of about 0.05 mg to about 100 mg of nintedanib or indolinone compound and about 0.001 mg to about 10 mg of prostacyclin analog compound. The method of the present invention includes treating a person suffering from interstitial lung disease with a combined composition of inhaled dry powder of nintedanib or indolinone analog and a prostacyclin analog. Each dose consists of 10% to 100% of the fine particle fraction, and the resulting fine particle dose is such that the nintedanib or indolinone analog is about 0.001 mg to about 100 mg and the prostacyclin analog compound is about 0.0001 mg to about 10 mg. The method of the present invention includes treating a person suffering from interstitial pneumonia once a day, twice a day, three times a day, four times a day, or five times a day with a combined composition of inhaled dry powder of nintedanib or indolinone analog and a pirfenidone or pyridone analog. Each dose consists of about 0.05 mg to about 100 mg of nintedanib or indolinone compound and about 0.001 mg to about 10 mg of prostacyclin analog compound, the fine particle fraction is about 10% to 100%, and delivers a fine particle dose of about 0.001 mg to about 100 mg of nintedanib or indolinone analog and about 0.0001 mg to about 10 mg of prostacyclin analog compound.

[0133] In other embodiments, the nintedanib or indolinone or combination described herein includes a taste masking agent that includes sugar, saccharin (e.g., sodium saccharin), a sweetener, or another compound or agent that beneficially affects taste, aftertaste, perceived unpleasant saltiness, sourness or bitterness, or that reduces the tendency of an oral or inhaled formulation to irritate the recipient (e.g., by causing other undesirable side effects that may cause coughing or throat pain or that may reduce the delivered dosage or negatively affect patient compliance with the prescribed treatment plan). Certain taste masking agents may be capable of forming a complex with nintedanib or indolinone or a salt thereof.

[0134] In another embodiment, the counterion salt form of nintedanib or indolinone in the salt form of nintedanib or indolinone is acetate, acetonide, alanine, aluminum, arginine, ascorbate, asparagine, aspartic acid, benzathine, benzoate, besylate, bisulfate, bisulfite, bitartrate, bromide (including bromide and hydrobromide), calcium, carbonate, camphorsulfonate, cetylpyridinium, chloride (including chloride and hydrochloride), chlorotheophyllinate, cholate, cysteine, deoxycholate, diethanolamine, diethylamine, diphosphate, dipropionate, disalicylate, edetate, edisylate, estolate, ethylamine, ethylenediamine, ethanedisulfonic acid, esylate, esilate, gluconate, glucuronate, glutamic acid, glutamine, glycine, hippuric acid, histidine, hydrobromide, hydrochloride, hydroxide, iodide, isethionate, isoleucine, lactate, lactobionate, lauryl sulfate, leucine, lysine, magnesium, mandelate, meglumine, mesylate, metabisulfate, metabisulfite, methionine, methyl bromide, methyl sulfate, methyl p-hydroxybenzoate, mucate, naphthoate, napsylate, nitrate, nitrite, octadecanoate, oleate, ornithine, oxalate, pamoate, pentetate, phenylalanine, phosphate, piperazine, polygalacturonate, potassium, procaine, proline, propionate, propyl p-hydroxybenzoate, saccharin, salicylate, selenocysteine, serine, silver, sodium, sorbitan, magnesium stearate, sodium stearate, succinate, sulfate, sulfite, sulfosalicylate, tartrate, threonine, tosylate, triethylamine, triethiodide, trifluoroacetate, trioleate, tromethamine, tryptophan, tyrosine, valerate, valine, xinafoate, or zinc.

[0135] The salt form of nintedanib or the salt form of indolinone is prepared as a chloride or bromide salt form.

[0136] In some embodiments, the kits described herein include unit dosages of a dry powder formulation of nintedanib, indolinone, or a salt thereof as described herein, contained in a container suitable for use with a dry powder inhaler device.

[0137] In some embodiments, the kits described herein include unit dosages of a dry powder formulation of nintedanib, indolinone, or a salt thereof in combination with pirfenidone as described herein, contained in a container suitable for use with a dry powder inhaler device.

[0138] In some embodiments, the kits described herein include unit dosages of a dry powder formulation of nintedanib, indolinone, or a salt thereof in combination with a PDE4 inhibitor as described herein, contained in a container suitable for use with a dry powder inhaler device.

[0139] In some embodiments, the kits described herein include unit dosages of a dry powder formulation of nintedanib, indolinone, or a salt thereof in combination with a prostacyclin analog as described herein, contained in a container suitable for use with a dry powder inhaler device.

[0140] An aerosol containing a plurality of dry powder particles has an aerodynamic mass median diameter (MMAD) of less than about 5.0 μm. In some embodiments, at least 20% of the dry powder particles in the aerosol have a diameter of less than about 5 μm.

[0141] The present invention includes a dry powder formulation containing nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, in a finely divided form at a concentration of 0.1% w / w to about 100% w / w and having a mass median diameter of 0.5 μm to 10 μm. By containing nintedanib or a salt thereof, or indolinone or a salt thereof, and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) in an amount of about 10% to about 99.99%, the handling, dispensing, dosing, and dispersion of the drug are improved. The formulation optionally contains one or more lubricants (e.g., L-leucine, trilucine, sodium stearate, magnesium stearate) at a concentration of about 0.1% w / w to about 10% w / w to reduce the adhesion between particles, improve the fluidity of the powder, and reduce the influence of moisture. The formulation can be prepared by physically mixing nintedanib or a salt thereof with the aforementioned excipients. Alternatively, the dry powder formulation may be formed by precipitation techniques including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification, or freeze drying. In these formulations, in addition to the excipients described above for the mixed dry powder formulation, phospholipids (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dilaidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol) may be included in an amount of 10% w / w to about 99.9% w / w to function as emulsifiers and bulking agents. Optionally, the formulations of the present invention may contain a biocompatible, preferably biodegradable, polymer, copolymer, or a blend or other combination thereof in an amount of about 0.1% w / w to 99.9% w / w. Examples of polymers include, but are not limited to, polylactic acid, polylactic glycolide, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinylpyrrolidone, polysaccharides (dextran, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.). The dry powder can be packaged as a unit dose in blister packs or capsules with a filling weight of 0.01 mg to 100 mg.Alternatively, the dry powder formulation can be packaged in a device reservoir that measures from 0.01 mg to 100 mg at the time of use.

[0142] The present invention includes a dry powder formulation containing nintedanib or a salt thereof, or an indolinone derivative or a salt thereof and pirfenidone in a combined drug concentration of 0.1% w / w to about 100% w / w and in a finely divided form having an aerodynamic mass median diameter of less than 5 microns. By including nintedanib or a salt thereof, or indolinone or a salt thereof, pirfenidone, and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) in an amount of about 10% to about 99.99%, the handling, delivery, dosing, and dispersion of the drug are improved. The formulation optionally includes one or more lubricants (e.g., L-leucine, trilucine, sodium stearate, magnesium stearate) at a concentration of about 0.1% w / w to about 10% w / w to reduce the adhesion between particles, improve the flowability of the powder, and reduce the effect of moisture. The formulation can be prepared by physically mixing nintedanib or a salt thereof and pirfenidone with the aforementioned excipients. Alternatively, the dry powder formulation may be formed by precipitation techniques including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification, or freeze drying. In these formulations, in addition to the excipients described above for the mixed dry powder formulation, phospholipids (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol) may be included in an amount of 10% w / w to about 99.9% w / w to function as emulsifiers and bulking agents. Optionally, the formulations of the present invention may include a biocompatible, preferably biodegradable, polymer, copolymer, or a blend or other combination thereof in an amount of about 0.1% w / w to 99.9% w / w. Examples of polymers include, but are not limited to, polylactic acid, poly(lactic-co-glycolic acid), cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, poly(lactam), polyvinylpyrrolidone, polysaccharides (dextran, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.).The dry powder can be packaged as a unit dose in blister packs or capsules with a fill weight of 0.01 mg to 100 mg. Alternatively, the dry powder formulation can be packaged in a device reservoir that measures 0.01 mg to 200 mg at the time of use.

[0143] The present invention includes a dry powder formulation containing nintedanib or a salt thereof, or an indolinone derivative or a salt thereof and a PDE4 inhibitor in a combined drug concentration of 0.1% w / w to about 100% w / w, in a finely divided form having an aerodynamic mass median diameter of less than 5 microns. By including nintedanib or a salt thereof, or indolinone or a salt thereof, a PDE4 inhibitor, and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) in an amount of about 10% to about 99.99%, the handling, delivery, dosing, and dispersion of the drug are improved. The formulation optionally contains one or more lubricants (e.g., L-leucine, trilucine, sodium stearate, magnesium stearate) at a concentration of about 0.1% w / w to about 10% w / w to reduce the adhesion between particles, improve the fluidity of the powder, and mitigate the effect of moisture. The formulation can be prepared by physically mixing nintedanib or a salt thereof and a PDE4 inhibitor with the aforementioned excipients. Alternatively, the dry powder formulation may be formed by precipitation techniques including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification, or freeze drying. In these formulations, in addition to the excipients described above for the mixed dry powder formulation, phospholipids (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dilaidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol) may be included in an amount of 10% w / w to about 99.9% w / w to function as emulsifiers and bulking agents. Optionally, the formulations of the present invention may contain a biocompatible, preferably biodegradable, polymer, copolymer, or a blend or other combination thereof in an amount of about 0.1% w / w to 99.9% w / w. Examples of polymers include, but are not limited to, polylactic acid, poly(lactic-co-glycolic acid), cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinylpyrrolidone, polysaccharides (dextran, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.).The dry powder can be packaged as a unit dose in blister packs or capsules with a filling weight of 0.01 mg to 100 mg. Alternatively, the dry powder formulation can be packaged in a device reservoir that measures 0.01 mg to 100 mg at the time of use.

[0144] The present invention includes a dry powder formulation containing nintedanib or a salt thereof, or an indolinone derivative or a salt thereof and a prostacyclin analog in a combined drug concentration of 0.1% w / w to about 100% w / w, in a finely divided form having an aerodynamic mass median diameter of less than 5 microns. By containing nintedanib or a salt thereof, or indolinone or a salt thereof, and a prostacyclin analog, and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) in an amount of about 10% to about 99.99%, the handling, delivery, dosing, and dispersion of the drug are improved. The formulation optionally contains one or more lubricants (e.g., L-leucine, trilucine, sodium stearate, magnesium stearate) at a concentration of about 0.1% w / w to about 10% w / w to reduce the adhesion between particles, improve the fluidity of the powder, and reduce the influence of moisture. The formulation can be prepared by physically mixing nintedanib or a salt thereof and a prostacyclin analog with the aforementioned excipients. Alternatively, the dry powder formulation may be formed by precipitation techniques including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification, or freeze drying. In these formulations, in addition to the excipients described above for the mixed dry powder formulation, phospholipids (e.g., dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dibehenoyl phosphatidylcholine, diphosphatidylglycerol) may be included in an amount of 10% w / w to about 99.9% w / w to function as emulsifiers and bulking agents. Optionally, the formulations of the present invention may contain a biocompatible, preferably biodegradable polymer, copolymer, or a blend or other combination thereof in an amount of about 0.1% w / w to 99.9% w / w. Examples of polymers include, but are not limited to, polylactic acid, poly(lactic-co-glycolic acid), cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinylpyrrolidone, polysaccharides (dextran, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.).The dry powder can be packaged as a unit dose in blister packs or capsules with a filling weight of 0.01 mg to 100 mg. Alternatively, the dry powder formulation can be packaged in a device reservoir that measures 0.01 mg to 100 mg at the time of use.

[0145] Method for treating or preventing a disease For the purposes of the methods described herein, indolinone, its salts or derivative compounds, most preferably nintedanib salts, are formulated and administered in a dry powder inhaler device that produces a particle size distribution optimized for the delivery of aerosol to the lung compartments. In some embodiments, nintedanib or an indolinone derivative compound or its salt is also formulated as a pharmaceutical composition suitable for aerosol formation, dosage for the indication, deposition location, therapeutic action in the lung or outside the respiratory tract, flavor, manufacturing and storage stability, and patient safety and tolerability. This method includes performing the mixing of solutions contained in a multi-container system that separates the active pharmaceutical ingredient (API) from other solutions before or immediately after placing it in a nebulizer for aerosol administration.

[0146] For the purposes of the methods described herein, indolinone, its salts or derivative compounds, most preferably nintedanib salts, are co-formulated and administered in combination with pirfenidone in a dry powder inhaler device that produces a particle size distribution optimized for the delivery of aerosol to the lung compartments. In some embodiments, nintedanib or an indolinone derivative compound or its salt and pirfenidone are formulated as a pharmaceutical composition suitable for dry powder dispersion and inhalation, dosage for the indication, deposition location, lung delivery for therapeutic action in the lung or outside the respiratory tract, flavor, manufacturing and storage stability, and patient safety and tolerability. This method includes performing the mixing of solutions contained in a multi-container system that separates the active pharmaceutical ingredient (API) from other solutions before or immediately after placing it in a nebulizer for aerosol administration.

[0147] For the purposes of the methods described herein, the compound of indolinone, its salts or derivatives, most preferably the nintedanib salt, is co-formulated and administered in combination with a PDE4 inhibitor in a dry powder inhaler device that generates a particle size distribution optimized for aerosol delivery to the lung compartment. In some embodiments, the nintedanib or indolinone derivative compound or its salt and the PDE4 inhibitor are formulated as a pharmaceutical composition suitable for dry powder dispersion and inhalation, dosage for the indication, deposition location, lung delivery for therapeutic effects in the lung or outside the respiratory tract, flavor, manufacturing and storage stability, and patient safety and tolerability. This method includes performing the mixing of solutions contained in a multi-container system that separates the pharmaceutical active ingredient (API) from other solutions before or immediately after placing it in a nebulizer for aerosol administration.

[0148] For the purposes of the methods described herein, the compound of indolinone, its salts or derivatives, most preferably the nintedanib salt, is co-formulated and administered in combination with a prostacyclin analog in a dry powder inhaler device that generates a particle size distribution optimized for aerosol delivery to the lung compartment. In some embodiments, the nintedanib or indolinone derivative compound or its salt and the prostacyclin analog are formulated as a pharmaceutical composition suitable for dry powder dispersion and inhalation, dosage for the indication, deposition location, lung delivery for therapeutic effects in the lung or outside the respiratory tract, flavor, manufacturing and storage stability, and patient safety and tolerability. This method includes performing the mixing of solutions contained in a multi-container system that separates the pharmaceutical active ingredient (API) from other solutions before or immediately after placing it in a nebulizer for aerosol administration. The dry powder administration step is performed with less than about 10 inhalation events, less than about 8 inhalation events, less than about 5 inhalation events, less than about 2 inhalation events, or 1 inhalation event.

[0149] In the method described herein, the aerosol contains particles having an aerodynamic mass median diameter of from about 1 micron to about 5 microns, from about 2 microns to about 5 microns, from about 3 microns to about 5 microns, or from about 4 microns to about 5 microns. The inhalation step delivers a dose of at least 0.0001 mg of nintedanib or indolinone or a salt thereof, at least 0.001 mg, at least 0.01 mg, at least 0.1 mg, at least 0.5 mg, at least 1.0 mg, at least 2.0 mg, at least 4.0 mg, at least 10 mg, at least 25 mg, at least 50 mg, or at least 100 mg of nintedanib or indolinone or a salt thereof. When nintedanib or indolinone or a salt thereof is co-formulated and administered with pirfenidone, the pirfenidone component contains a dose of at least 1 mg of pirfenidone, at least 5 mg of pirfenidone, at least 10 mg of pirfenidone, at least 15 mg of pirfenidone, at least 20 mg of pirfenidone, at least 25 mg of pirfenidone, at least 30 mg of pirfenidone, at least 40 mg of pirfenidone, at least 50 mg of pirfenidone, at least 60 mg of pirfenidone, at least 70 mg of pirfenidone, at least 80 mg of pirfenidone, at least 90 mg of pirfenidone, or at least 100 mg of pirfenidone. When nintedanib or indolinone or a salt thereof is co-formulated and administered in combination with a PDE4 inhibitor, the PDE4 inhibitor component is at least 0.1 mg of a PDE4 inhibitor, at least 0.5 mg of a PDE4 inhibitor, at least 1 mg of a PDE4 inhibitor, at least 2.5 mg of a PDE4 inhibitor, at least 5 mg of a PDE4 inhibitor, at least 7.5 mg of a PDE4 inhibitor, at least 10 mg of a PDE4 inhibitor, at least 15 mg of a PDE4 inhibitor, at least 20 mg of a PDE4 inhibitor, at least 30 mg of a PDE4 inhibitor, or at least 40 mg of a PDE4 inhibitor.When nintedanib or indolinone or a salt thereof is co-formulated and administered in combination with a prostacyclin analog, the prostacyclin analog component is at least 0.001 mg of a prostacyclin analog, at least 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, about 0.060 mg, about 0.065 mg, about 0.070 mg, about 0.075 mg, about 0.080 mg, about 0.080 mg, about 0.085 mg, about 0.090 mg, about 0.095 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 5 mg, about 10 mg of a prostacyclin analog.

[0150] In one aspect, the treatment method described herein includes administering nintedanib or indolinone or a salt thereof to a patient, and the patient avoids liver function abnormalities indicated by grade 2 or higher abnormalities in one or more biomarkers of liver function after oral administration of nintedanib or indolinone or a salt thereof. The administration includes administering nintedanib or indolinone or a salt thereof to the patient at a dose of less than 1056 mg per day. "Grade 2 liver function abnormalities" include that the increase in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyl transferase (GGT) exceeds 2.5 times the upper limit of normal (ULN) and is 5 times or less. Grade 2 liver function abnormalities also include that the increase in bilirubin level exceeds 1.5 times the ULN and is 3 times or less. One or more biomarkers of liver function are selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin, and alkaline phosphatase. This method further includes the step of measuring one or more biomarkers of liver function. The blood nintedanib or indolinone Cmax after inhalation administration of nintedanib or indolinone or a salt thereof is less than 40.0 ng / mL. The blood nintedanib or indolinone Cmax after administration of nintedanib or indolinone or a salt thereof is less than 20.0 ng / mL, less than 10.0 ng / mL, and less than 5.0 ng / mL.

[0151] The method of administering nintedanib or indolinone or a salt thereof includes avoiding nausea, diarrhea, headache, leg pain / cramps, fluid retention, visual impairment, itchy rash, reduced resistance to infection, bruising or bleeding, loss of appetite, weight gain, decrease in blood cell count (neutropenia, thrombocytopenia, anemia), headache, edema, and congestive heart failure observed after oral administration, and includes administering inhaled nintedanib or indolinone or a salt thereof to the patient at a dose of less than 100 mg per day.

[0152] The method of the present invention also includes a maximum dosage level of about 100 mg or less per day of nintedanib or a salt thereof to be delivered to a patient by inhalation. In some embodiments, about 50 mg or less, about 25 mg or less, about 10 mg or less, about 5 mg or less, about 2 mg or less, about 1 mg or less of nintedanib or indolinone per day is delivered to a patient by inhalation at a dosage of once a day, twice a day, three times a day, four times a day, five times a day, six times a day or more than six times a day, and can be administered daily, every other day, every three days, every four days, every five days, every six days or weekly, every other week, every three weeks or monthly.

[0153] The method of treatment includes preventing interstitial lung disease (ILD) by administering nintedanib or indolinone or a salt thereof to a subject having or suspected of having interstitial lung disease (ILD). Interstitial lung disease includes the above-mentioned diseases and all conditions of idiopathic interstitial pneumonia defined by the American Thoracic Society / European Respiratory Society's International Multidisciplinary Consensus Classification of Idiopathic Interstitial Pneumonia, i.e., AM. J. Respir. Crit. Care Med. 165, 277-304 (2002) (incorporated herein by reference).

[0154] The method of treatment may also include diagnostic steps such as identifying a subject having or suspected of having ILD. This method is further subclassified into idiopathic pulmonary fibrosis based on the degree of the disease, the progression of the disease, the rate of progression, or the response to existing therapies. The delivery amount of the aerosol nintedanib or indolinone or a salt thereof compound (or a salt thereof) formulation is sufficient to provide relief of acute, subacute, or chronic symptoms, delay the progression of fibrosis, halt the progression of fibrosis, reverse fibrotic damage, and / or improve subsequent survival rate and / or quality of life.

[0155] The treatment method may also include a diagnostic step of identifying a subject having or suspected of having fibrosis in other tissues, non-limiting examples of which include the heart, liver, kidney, or skin, and a therapeutic amount of dry powder aerosol nintedanib or indolinone or a salt thereof is sufficient to provide acute, subacute, or chronic symptom relief, delay in the progression of fibrosis, arrest of the progression of fibrosis, reversal of fibrotic damage, and / or subsequent improvement in survival rate and / or quality of life.

[0156] The treatment method may also include a diagnostic step of identifying a subject having or suspected of having multiple sclerosis, and the treatment method includes administering a dry powder aerosol nintedanib or indolinone or a salt thereof sufficient to provide acute, subacute, or chronic symptom relief, delay in the progression of demyelination, arrest of the progression of demyelination, reversal of demyelinating damage, and / or subsequent improvement in survival rate and / or quality of life.

[0157] The therapeutic treatment method includes administering to a patient a therapeutically effective aerosol dosage, which is calculated, titrated, or measured to establish or maintain a therapeutically effective threshold drug concentration in the lung and / or downstream tissues of the target, and this threshold drug concentration can be measured as the drug level in epithelial lining fluid (ELF), sputum, lung tissue, bronchoalveolar lavage fluid (BAL), or by deconvolution of blood concentration by pharmacokinetic analysis. One embodiment includes the use of aerosol administration to directly deliver a high or titrated concentration of drug exposure to the affected tissue to treat inflammation associated with pulmonary fibrosis and ILD (including idiopathic pulmonary fibrosis) in animals and humans. The peak level of lung ELF achieved after aerosol administration to the lung will be from 100 ng / mL of epithelial lining fluid to about 20,000 ng / mL of epithelial lining fluid of the nintedanib or indolinone compound.

[0158] As a non-limiting example, in a preferred embodiment, the indolinone derivative compounds provided herein (e.g., nintedanib) are formulated to enable dry powder inhaled aerosol administration to supply an effective concentration or amount to produce and maintain a threshold drug concentration in the blood and / or lung, which threshold drug concentration is measured as the drug level in epithelial lining fluid (ELF), sputum, lung tissue, bronchoalveolar lavage fluid (BAL), or can be measured by deconvolution of blood concentrations by pharmacokinetic analysis to absorb into the pulmonary vasculature to produce a drug level sufficient for extra-pulmonary treatment, maintenance, or prevention. Therapeutic treatment methods include the use of inhaled dry powder aerosol administration to deliver a high concentration of drug exposure to the pulmonary vasculature and associated vasculature of subsequent tissues for the treatment, maintenance, and / or prevention of, without limitation, cardiac fibrosis, renal fibrosis, hepatic fibrosis, cardiac toxicity or renal toxicity, or multiple sclerosis. The peak of tissue-specific plasma concentrations (e.g., heart, kidney, and liver) or cerebrospinal fluid concentrations (e.g., central nervous system) achieved after aerosol administration to the lung after oral inhalation or to the lung or nasal cavity after intranasal administration is from 0.01 ng / mL to about 50 ng / mL of nintedanib or indolinone or a salt thereof. The peak level of epithelial lining fluid achieved after inhaled dry powder administration to the lung is from 100 ng / mL of epithelial lining fluid to about 20,000 ng / mL of epithelial lining fluid of nintedanib or indolinone.

[0159] As a non-limiting example, the indolinone derivative compound remains at a therapeutically effective concentration at the lung lesion site, the site suspected of having a lung lesion, and / or the pulmonary absorption site into the pulmonary vasculature for at least about 10 seconds, at least 1 minute, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least 2 hours, at least about 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, or at least 1 week. The effective concentration of nintedanib or indolinone or a salt thereof is sufficient to cause a therapeutic effect, which effect can be localized at the lung lesion site or act more extensively therefrom.

[0160] For the pulmonary epithelial lining fluid, delivery sites such as the nasal cavity or paranasal sinuses, the compound formulations of nintedanib or indolinone or salts thereof provided herein are administered in one or more administrations to achieve a respirable delivery dose (RDD) per day of at least about 0.0001 mg to about 100 mg (including all integer values such as 0.0001, 0.001, 0.006, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 milligrams). The RDD level per day of the nintedanib or indolinone compound is consistent across the entire combination co-formulated at optimized doses and ratios with pirfenidone or pyridone analogs, or PDE4 inhibitors or prostacyclin analogs.

[0161] For delivery sites such as the lung, nasal cavity, or paranasal sinuses, the compound formulations of nintedanib or indolinone or salts thereof provided herein are administered in one or more administrations to achieve a respirable delivery amount of at least about 0.0001 mg to about 100 mg (including all integer values such as 0.0001, 0.001, 0.006, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 milligrams) of nintedanib or indolinone or salts thereof per day. Pirfenidone or pyridone analogs in combination co-formulated with the nintedanib or indolinone compounds described herein are administered in one or more administrations to achieve a respirable delivery dose of at least about 0.0001 mg to about 100 mg (including all integer values such as 0.0001, 0.001, 0.006, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 milligrams) of pirfenidone or pyridone analogs per day. PDE4 inhibitors in combination co-formulated with the nintedanib or indolinone compounds described herein are administered in one or more administrations to achieve a respirable delivery dose of at least about 0.0001 mg to about 100 mg (including all integer values such as 0.0001, 0.005, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 milligrams) of PDE4 inhibitors per day. Prostacyclin analogs in combination co-formulated with the nintedanib or indolinone compounds described herein are at least about 0.0001 mg to about 10 mg (0.0001, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.It is administered in one or more doses to achieve a respirable delivery dose per day of a prostacyclin analog (including all integer values such as 8, 2, 3, 4, 5, 6, 10 milligrams).

[0162] Manufacture For fixed-dose combination formulations of nintedanib or an indolinone derivative compound with pirfenidone or a pyridine analog, or a PDE4 inhibitor, or a prostacyclin analog, any suitable method is used. The fixed-dose combination formulation of nintedanib or an indolinone derivative compound with the above compounds can be in the form of an inhalation solution that can be used immediately upon delivery as an aerosol by a nebulizer, or in the form of a dry powder formulation that is delivered as an aerosol by a dry powder inhaler. The inhalation solution is prepared by dissolving the API and suitable excipients (e.g., buffer, osmotic pressure regulator, osmotic ion regulator, taste / tolerance modifier), sterile filtered, and can be aseptically filled into a suitable container closure system (e.g., low-density polyethylene, Type I glass ampoule). For the preparation of respirable dry powders and particles, many suitable methods conventional in the art are used, such as mixing micronized API, blending the API with carrier particles (e.g., lactose), spray drying, spray freezing, and methods involving the use of supercritical fluids (e.g., CO2) or perfluorocarbons (e.g., perfluorooctyl bromide). These methods can be used under conditions that result in the formation of respirable particles having the desired aerodynamic properties (e.g., aerodynamic mass median diameter, geometric standard deviation). Optionally, respirable dry particles with desired properties such as size and density may be selected using suitable methods such as sieving or cyclone separation.

[0163] Inhalation solution formulation for immediate use An inhalable solution that can be immediately used in a fixed-dose combination of nintedanib or an indolinone derivative compound and pirfenidone or a pyridine analog can be manufactured using a well-established mixing device. Excipients including a buffering agent, a pH adjuster, an osmotic pressure adjuster, and a taste masking agent are added in sequence, mixed, and dissolved one by one. Nintedanib or its salt is added to the solution, mixed, and dissolved. Nintedanib or its salt can also be pre-wetted with a wetting agent such as propylene glycol before being added to the solution to facilitate dissolution. Next, pirfenidone or a pyridone analog is added, mixed, and dissolved. To facilitate the dissolution of nintedanib or an indolinone derivative compound and pirfenidone or a pyridine analog, the solution may be heated at 40 - 50 °C for a certain period until the API is completely dissolved. The formulation is adjusted to the target pH, filtered into a holding tank for bioburden reduction, then sterile filtered and aseptically filled into suitable containers such as low-density polyethylene ampoules, clear cyclic olefin vials, and type I USP glass vials.

[0164] Carrier-free blend formulation In the simplest form of a dry powder inhalation formulation, the indolinone derivative compound, most preferably nintedanib as disclosed herein, can be formulated as a carrier-free dry powder in combination with pirfenidone by simply mixing the two APIs. Nintedanib or its salt and pirfenidone or a pyridone analog are first micronized to a desired size using one or a combination of milling, jet milling, ball milling, sieving, or any other suitable method. The mass median diameter in this embodiment can range from 0.5 to 10 microns, preferably from 1 to 5 microns, and most preferably from 2 to 3 microns. The micronized nintedanib or its salt and the micronized pirfenidone or pyridone analog can be blended together in a suitable ratio in the range of 1:2,000,000 to 200:1 using a low shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer) or a high shear mixer. The uniformity of the content is tested to ensure a uniform distribution of nintedanib or its salt and pirfenidone or a pyridine analog.

[0165] The present invention also includes micronizing nintedanib or a salt thereof, and blending the micronized indolinone derivative compound, most preferably nintedanib as disclosed herein, with a micronized PDE4 inhibitor. The mass median diameter of the micronized nintedanib or a salt thereof and the PDE4 inhibitor in this embodiment can be in the range of 0.5 to 10 microns, preferably 1 to 5 microns, and most preferably 2 to 3 microns. The micronized nintedanib or a salt thereof, and the micronized PDE4 inhibitor can be produced by any one or a combination of titration, jet milling, ball milling, sieving, or any other suitable method for reducing the particle size to the desired range. The micronized nintedanib or a salt thereof and the micronized PDE4 inhibitor are blended together at an appropriate ratio in the range of 1:400,000 to 20,000:1 using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer) or a high-shear mixer. The homogeneity of the content is tested to ensure a uniform distribution of nintedanib or a salt thereof and the PDE4 inhibitor.

[0166] The present invention also includes blending a micronized indolinone derivative compound, most preferably nintedanib as disclosed herein, with a micronized prostacyclin analog. The mass median diameter in this embodiment can range from 0.5 to 10 microns, preferably from 1 to 5 microns, and most preferably from 2 to 3 microns. The micronized nintedanib or its salt, and the micronized prostacyclin analog can be produced by any one or combination of titration, jet milling, ball milling, sieving, or any other suitable method to obtain the desired particle size range. The micronized nintedanib or its salt and the micronized prostacyclin analog are blended together at an appropriate ratio in the range of 1:100,000 to 20:1 using a low-shear mixer (e.g., conical screw mixer, tumble mixer, ribbon mixer) or a high-shear mixer. The uniformity of the content is tested to ensure a uniform distribution of nintedanib or its salt and the prostacyclin analog.

[0167] Carrier-based blend Another method for producing a dry powder for an indolinone derivative compound, most preferably nintedanib as disclosed herein, in combination with a second active compound is by blending with a carrier. Carriers include, but are not limited to, saccharides such as lactose, mannitol, sorbitol, erythritol, trehalose, cyclodextrin, dextrose, glucose monohydrate, maltitol, maltose, raffinose pentahydrate, and xylitol. Carrier particles are used to improve the fluidity of drug particles and provide a surface for smaller active drug particles to coat, thereby making it easier for drug particles to disperse into primary particles for inhalation. It is also used as a bulking agent to improve dosing accuracy and minimize dosing variation. The mass median diameter of the coarse carrier is about 10 to 200 μm, more preferably 25 to 150 μm, and most preferably 50 to 100 μm. The mass median diameter of the drug particles is about 0.5 to 10 μm, more preferably 1 to 5 μm, and most preferably 2 to 3 μm.

[0168] In one embodiment, the second active substance is pirfenidone or a pyridine analog. The ratio of nintedanib or a salt thereof to pirfenidone or a pyridine analog can range from 1:2,000,000 to 200:1. The two active compounds can be added directly to the coarse carrier or a premix can be formed using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer), and then added to the carrier at a ratio of 0.1% w / w, for a total of 99.9% w / w. The powder blend is mixed using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer) or a high-shear mixer. The homogeneity of the content is tested to ensure a uniform distribution of nintedanib or a salt thereof and pirfenidone or a pyridine analog.

[0169] In another embodiment, the second active substance is a PDE4 inhibitor. The ratio of nintedanib or a salt thereof to the PDE4 inhibitor can range from 1:400,000 to 20,000:1. The two active compounds can be added directly to the coarse carrier or a premix can be formed using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer), and then added to the carrier at a ratio of 0.1% w / w, for a total of 99.9% w / w. The carrier-based powder blend is obtained by mixing the active substance and the carrier using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer) or a high-shear mixer. The homogeneity of the content is tested to ensure that the final powder blend has a uniform distribution of nintedanib or a salt thereof and pirfenidone or a pyridine analog.

[0170] In yet another embodiment, the second active substance is a prostacyclin analogue. The ratio of nintedanib or its salt to the prostacyclin analogue can be in the range of 1:100,000 to 20:1, 1:400,000 to. The two active compounds can be added directly to the coarse carrier or a premix can be formed using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer), and then added to the carrier at a ratio of 0.1% w / w, 99.9% w / w in total. The carrier-based powder blend can be obtained by mixing the active substance and the carrier using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer) or a high-shear mixer. The homogeneity of the content is tested to ensure that the final powder blend has a uniform distribution of nintedanib or its salt and the pyrfenidone or pyridine analogue.

[0171] The present invention also includes micronizing nintedanib or its salt to a specific size and micronizing the PDE4 inhibitor, and then blending the indolinone derivative compound, most preferably nintedanib as disclosed herein, with the PDE4 inhibitor. The mass median diameter in this embodiment can be in the range of 0.5 to 10 μm, preferably 1 to 5 μm, most preferably 2 to 3 μm. The micronized nintedanib or its salt and the micronized PDE4 inhibitor are produced by a jet mill, a ball mill, or sieving, and a desired particle size range can be obtained. The micronized nintedanib or its salt and the micronized PDE4 inhibitor can be blended together at an appropriate ratio in the range of 1:400,000 to 20,000:1 using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer) or a high-shear mixer. The homogeneity of the content is tested to ensure a uniform distribution of nintedanib or its salt and the PDE4 inhibitor.

[0172] The present invention also includes micronizing nintedanib or a salt thereof to a specific size and micronizing a prostacyclin analog, and then blending an indolinone derivative compound, most preferably nintedanib as disclosed herein and a prostacyclin analog. The mass median diameter in this embodiment can range from 0.5 to 10 microns, preferably from 1 to 5 microns, and most preferably from 2 to 3 microns. The micronized nintedanib or a salt thereof and the micronized prostacyclin analog are produced by a jet mill, a ball mill, or sieving, and a particle size within the desired range can be obtained. The micronized nintedanib or a salt thereof and the micronized prostacyclin analog can be blended together at an appropriate ratio in the range of 1:400,000 to 20,000:1 using a low-shear mixer (e.g., a conical screw mixer, a tumble mixer, a ribbon mixer) or a high-shear mixer. The homogeneity of the content is tested to ensure a uniform distribution of nintedanib or a salt thereof and the prostacyclin analog.

[0173] Appropriate spray drying techniques are described in various references (e.g., Spray Drying Technology Review, R Wisniewski 2015; Spray Drying: An Overview, D Santos 2017). Briefly, the spray drying process involves continuously spraying a liquid feed containing a drug dissolved, emulsified, or suspended in a liquid into a hot gas such as heated air or nitrogen to evaporate the solvent from the sprayed droplets. The liquid feed is prepared in the form of a solution, emulsion, or suspension containing the components of the dry particles to be produced in a suitable solvent (e.g., an aqueous solvent, an organic solvent, an aqueous organic mixture, or an emulsion) and can be supplied to the atomizer by a pump. A nozzle atomizer or a rotary atomizer can be used to convert the feed solution into aerosol droplets. The spray drying conditions can vary depending on the composition and feed rate of the feed solution (or suspension or emulsion) and can be determined by those skilled in the art. Generally, depending on the flow direction of the sprayed droplets and the heated air flow, the inlet temperature to the spray dryer is about 100°C to about 400°C, preferably about 200°C to about 300°C. The outlet temperature of the spray dryer varies depending on factors such as the feed temperature, the direction of the air and the flow of the sprayed droplets, and the properties of the material being dried. Generally, the outlet temperature is about 50°C to about 150°C, preferably about 90°C to about 120°C, or about 95°C to about 105°C. Optionally, the collected dry particles can be further fractionated by using sieving or a cyclone and / or can be further separated according to density using techniques known to those skilled in the art.

[0174] To prepare spray-dried particles, typically a solution, emulsion, or suspension containing the desired components of the dry powder (i.e., the feedstock) is prepared and spray-dried under appropriate conditions. Preferably, the dissolved or suspended solid concentration in the feedstock is at least about 1 g / L, at least about 2 g / L, at least about 5 g / L, at least about 10 g / L, at least about 15 g / L, at least about 20 g / L, at least about 30 g / L, at least about 40 g / L, at least about 50 g / L, at least about 60 g / L, at least about 70 g / L, at least about 80 g / L, at least about 90 g / L, or at least about 100 g / L. The feedstock can be made into a solution or suspension by dissolving or suspending the appropriate components (e.g., one or more active drugs, excipients, other active ingredients) in an appropriate solvent. The solvent can be prepared from one or more liquids using a high-shear homogenizer to form a solution or emulsion. The resulting solution, emulsion, or suspension is preferably sprayed immediately after preparation into aerosol droplets and dried in a stream of hot air or nitrogen to form respirable fine particles.

[0175] Spraying can be done in various ways by pumping the feedstock through the nozzle or array of nozzles of an atomizer that produces fine droplets. The atomizer can be of rotary, single-fluid, two-fluid, or ultrasonic design. Different designs have different advantages, applicability, and drawbacks depending on the particular spray-drying process required. The hot drying gas can be introduced in the same (parallel) or opposite (countercurrent) flow as the direction of the atomizer. The parallel flow makes the flow of aerosol particles through the system and into a particle separator such as a cyclone faster and thus more efficient. The countercurrent mode allows for a longer residence time of the aerosol particles in the chamber before entering the separator.

[0176] Aerosol administration An indolinone derivative compound, most preferably nintedanib as disclosed herein, can be administered at a therapeutically effective dosage, for example, a dosage sufficient to treat the aforementioned disease states. For example, it is the daily aerosol dosage of nintedanib in a formulation of the nintedanib compound for a person weighing 70 kg.

[0177] An indolinone derivative compound, most preferably nintedanib as disclosed herein, can be administered at a therapeutically effective dosage, for example, a dosage sufficient to treat the aforementioned disease states. In some embodiments, for example, the daily aerosol dosage of nintedanib or indolinone in a formulation of nintedanib or indolinone compound for a person weighing 70 kg can be about 0.001 mg to about 1.0 mg of nintedanib per kg of body weight per dose. The amount of the active compound administered will, of course, depend on the subject being treated and the disease state, the severity of the disease, the method and schedule of administration, the site of the disease (e.g., whether delivery to the nasal cavity or upper airway, delivery to the pharynx or larynx, delivery to the bronchi, delivery to the lungs, and / or delivery to the lungs associated with systemic or central nervous system absorption is desired), and the judgment of the prescribing physician. For example, for the aerosol administration of nintedanib in a preferred embodiment, or of nintedanib or indolinone derivative compound in other embodiments, the possible dosage ranges may be from about 0.1 mg to 10 mg per dose to about 0.1 mg to about 100 mg per day. Similarly, if pirfenidone or pyridone analog, or PDE4 inhibitor or prostacyclin analog is included in the formulation, the daily aerosol dosage for a 70 kg person remains about 0.001 mg to about 1.0 mg of nintedanib per kg of body weight per dose.

[0178] Dry powder inhaler (DPI) Based on the relative growth scaling of animal efficacy data and human modeling, the dosage of nintedanib or its salt in humans has been observed to be low, in the range of about 0.04 mg to about 10 mg. If these low levels are supported by clinical observations, dry powder inhalation products may be selected as an alternative to aqueous spray products.

[0179] There are two main designs for dry powder inhalers. One design is a metering device where a reservoir of the drug is located within the device and the patient adds the dosage of the drug to the inhalation chamber. The second is a factory-metered device where individual dosages are manufactured in separate containers. Both systems rely on formulating the drug into small particles with a mass median diameter of about 1 micron to about 5 microns, usually including co-formulation with larger excipient particles (typically lactose particles with a diameter of 100 microns, although the particle size can be optimized). The drug powder is placed within the inhalation chamber (either by metering within the device or by crushing factory-metered dosages), and the patient's inspiratory flow accelerates the powder from the device into the oral cavity. The non-laminar flow characteristics of the powder path disperse aggregates of the excipient and the drug, and the larger excipient particles clog in the back of the throat by mass, while the smaller drug particles deposit deep in the lungs.

[0180] In a multiple-dose reservoir system, individual doses can be measured by volumetrically measuring the powder at a clearly defined opening of a disk (e.g., Turbuhaler®, AstraZeneca) or a slide (e.g., Novolizer®, Viatris). The metering compartment is mainly filled from the powder bulk reservoir by the action of gravity. Therefore, it is necessary to keep the inhaler in an upright position. In some special cases, for example, by passing compressed air through the powder bed in the bulk reservoir, forced metering is applied (e.g., Airmax™, Ivax Corporation). Generally, multiple-dose systems require specific properties of the powder formulation with respect to fluidity and uniformity. A different metering concept is the Ratiopharm® Jethaler® (Ratiopharm), which has a ring compact of a mixture of drug and excipient, and a small amount is scraped off by a scraper disk during inhalation. The concept is the same as that of the Ultrahaler® (Aventis).

[0181] The particle size of nintedanib or its salt, or an indolinone derivative or its salt can be optimized for aerosol administration. If the particle size is larger than the MMAD of about 5 microns, the particles will deposit in the upper airway. If the aerodynamic particle size of the aerosol is smaller than about 1 micron, the aerosol may be delivered to the alveoli and migrate into the systemic blood circulation.

[0182] As a non-limiting example, whether alone or co-formulated with pirfenidone or a pyridone analog, or a PDE4 inhibitor or a prostacyclin analog, the nintedanib or its salt, or an indolinone derivative or its salt disclosed herein is prepared at a dosage that disperses and delivers from about 0.01 mg to about 100 mg of nintedanib or indolinone compound from a dry powder formulation.

[0183] As a non-limiting example, dried powder nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, can be administered at the described respirable delivery dosage in 10 or fewer actuations and / or inhalations, or 8 or fewer actuations and / or inhalations, or 6 or fewer actuations and / or inhalations, or 4 or fewer actuations and / or inhalations, or 2 or fewer actuations and / or inhalations.

[0184] In some embodiments, a dry powder inhaler (DPI) is used to administer the nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, described herein. In a DPI, the drug substance is contained in the form of dry microparticles. Typically, when inhaled by a patient, the dry particles form an aerosol cloud that is drawn into the patient's lungs. The dry drug microparticles can be manufactured by any technique known in the art. Some well-known techniques include the use of a jet mill or other milling device, precipitation from a saturated or supersaturated solution, spray drying, on-site micronization (Hovione), particle engineering (Pulmosphere™, Technosphere®, PRINT®), or supercritical fluid methods. A typical powder formulation involves the manufacture of spherical pellets or an adhesive mixture. In an adhesive mixture, the drug particles adhere to larger carrier particles, such as lactose monohydrate, having a size of about 50 to about 100 microns in diameter. The larger the carrier particles, the lower the adhesive force to the carrier / drug aggregates and the better the dispersion of the drug. Turbulence and / or mechanical devices break down the aggregates into their components. The smaller drug particles are then drawn into the lungs, and the larger carrier particles deposit in the mouth or throat. Some examples of adhesive mixtures are described in U.S. Patent No. 5,478,578 and PCT Publication Nos. WO95 / 11666, WO87 / 05213, WO96 / 23485, and WO97 / 03649, all of which are incorporated herein by reference in their entirety. Additional excipients may also be included in the drug substance. Alternatively, porous particles can be used to deliver the drug without the need for larger carrier particles. Such porous particles can be manufactured using Pulmosphere™ or Technosphere® technology, which produces particles that are large in size but small in density and aerodynamic diameter. Further, using PRINT® technology to create drug particles having specific shapes and sizes reduces the dispersive forces and allows the drug particles to be delivered without the use of a carrier excipient.

[0185] There are three general types of DPIs, all of which can be used with the compounds of nintedanib or its salts, or indolinone derivatives or its salts described herein. In a single-dose DPI, a capsule containing a single dose of dry drug substance / excipient is loaded into an inhaler. When activated, the capsule is broken and the dry powder is dispersed, making it available for inhalation using a dry powder inhaler. To dispense additional doses, the old capsule needs to be removed and an additional capsule loaded. Examples of single-dose DPIs are described in U.S. Pat. Nos. 3,807,400, 3,906,950, 3,991,761, and 4,013,075, all of which are incorporated herein by reference in their entirety. In a multiple-unit dose DPI, a packaging containing multiple single-dose compartments is provided. For example, the packaging may include a blister pack where each blister compartment contains a single dose. Each dose can be dispersed as soon as the blister compartment is broken. Any of several arrangements of the compartments within the packaging can be used. For example, rotary or strip arrangements are common. Examples of multiple-unit dose DPIs are described in European Patent Application Publication Nos. 0211595A2, 0455463A1, and 0467172A1, all of which are incorporated herein by reference in their entirety. In a multi-dose DPI, a single reservoir of dry powder is used. A mechanism is provided for measuring a single dose from the reservoir to be aerosolized and inhaled, which is described, for example, in U.S. Pat. Nos. 5,829,434, 5,437,270, 2,587,215, 5,113,855, 5,840,279, 4,688,218, 4,667,668, 5,033,463, 4,805,811 and PCT Publication No. WO92 / 09322, all of which are incorporated herein by reference in their entirety.

[0186] In some embodiments, in addition to the patient's inhalation, or alternatively, auxiliary energy may be provided to facilitate the operation of the DPI. For example, pressurized air can be supplied to assist in the deaggregation of the powder, which is described, for example, in U.S. Patent Nos. 3,906,950, 5,113,855, 5,388,572, 6,029,662, PCT Publication Nos. WO93 / 12831, WO90 / 07351, and WO99 / 62495, all of which are incorporated herein by reference in their entirety. An electrically driven impeller can also be provided, which is described, for example, in U.S. Patent Nos. 3,948,264, 3,971,377, 4,147,166, 6,006,747, and PCT Publication No. WO98 / 03217, all of which are incorporated herein by reference in their entirety. Another mechanism is an electrically driven tapping piston, which is described, for example, in PCT Publication No. WO90 / 13327, which is incorporated herein by reference in its entirety. Other DPIs use a vibrator, which is described, for example, in U.S. Patent Nos. 5,694,920 and 6,026,809, both of which are incorporated herein by reference in their entirety. Finally, a scraper system can be used, which is described, for example, in PCT Publication No. WO93 / 24165, which is incorporated herein by reference in its entirety.

[0187] Further examples of DPIs for use herein are described in U.S. Patent Nos. 4,811,731, 5,113,855, 5,840,279, 3,507,277, 3,669,113, 3,635,219, 3,991,761, 4,353,365, 4,889,144, 4,907,538, 5,829,434, 6,681,768, 6,561,186, 5,918,594, 6,003,512, 5,775,320, 5,740,794, and 6,626,173, all of which are incorporated herein by reference in their entirety.

[0188] In some embodiments, a spacer or chamber can be used with any of the inhalers described herein to increase the amount of drug substance absorbed by the patient, which is described, for example, in U.S. Patent Nos. 4,470,412, 4,790,305, 4,926,852, 5,012,803, 5,040,527, 5,024,467, 5,816,240, 5,027,806, 6,026,807, all of which are incorporated herein by reference in their entirety. For example, the spacer may delay the time from aerosol generation until the aerosol enters the patient's mouth. Such a delay can improve the synchronization of the patient's inhalation and aerosol generation. A mask can also be incorporated for infants or other patients for whom it is difficult to use a conventional mouthpiece, which is described, for example, in U.S. Patent Nos. 4,809,692, 4,832,015, 5,012,804, 5,427,089, 5,645,049, and 5,988,160, all of which are incorporated herein by reference in their entirety.

[0189] Dry powder inhalers (DPIs) involve the deaggregation and aerosolization of dry powder particles and typically rely on the ejection of an inspiratory flow drawn through the unit to administer the drug. Such devices are described, for example, in U.S. Patent No. 4,807,814 for a pneumatic powder ejector having a suction stage and an ejection stage, SU628930 (abstract) describing a hand-held powder dispersion device with an axial air flow tube, Fox et al., Powder and Bulk Engineering, pages 33 - 36 (March 1988) describing a venturi duct having an axial air inlet tube upstream of the venturi restriction, European Patent No. 347,779 describing a hand-held powder dispersion device with a foldable expansion chamber, and U.S. Patent No. 5,785,049 directed to a dry powder delivery device for drugs.

[0190] Examples of commercially available capsule-based or blister-pack-based dry powder inhalers that can be used with the formulations of nintedanib or its salts, or indolinone derivatives or their salts described herein include Aerohaler, Aerolizer, Aspirair, Breezehaler, Diskhaler Forspiro, Exubera, Gyrohaler, Plastiape Monodose, Podhaler, Prohaler, Redihaler, Rotahaler, Turbohaler, Handihaler, and Discus. Examples of multiple-dose reservoir devices include E Flex, Jethaler, NEXThaler, Novolizer, PADD, Pulmojet, Spiromax, Swinghaler, Turbuhaler, and Ultrahaler. An example of a cassette-based dry powder inhaler available commercially is Spiros.

[0191] Solid lipid particles The preparation of solid lipid particles of nintedanib or an indolinone derivative compound or its salt can include dissolving the drug in a lipid melt maintained at at least the melting temperature of the lipid (phospholipids such as phosphatidylcholine and phosphatidylserine), followed by dispersing the drug-containing melt in an aqueous surfactant solution at elevated temperature (typically 1 - 5% w / v) maintained at at least the melting temperature of the lipid. The coarse dispersion is homogenized for 1 - 10 minutes using a Microfluidizer® to obtain a nanoemulsion. When the nanoemulsion is cooled to a temperature of 4 - 25°C, the lipid resolidifies to form solid lipid nanoparticles. Optimization of formulation parameters (type of lipid matrix, concentration of surfactant, manufacturing parameters) is carried out to achieve extended drug delivery. As a non-limiting example, this approach can also be used to isolate solid AUC-shape-enhanced formulations such as poorly soluble nintedanib or indolinone derivative compounds or their salts and improve their water solubility.

[0192] Coprecipitate A pharmaceutical formulation of a co-precipitate of nintedanib or an indolinone derivative compound or a salt thereof can be prepared by forming a co-precipitate with a pharmacologically inert polymeric material. It has been demonstrated that the in vitro dissolution rate and / or in vivo absorption can be significantly retarded by forming molecular solid dispersions or co-precipitates using various water-soluble polymers to create AUC-shape enhanced formulations. When preparing a powder product, the dissolution rate is greatly affected by the particle size, so milling is commonly used to reduce the particle size. Furthermore, applying strong forces (such as milling) can increase the surface energy and may cause distortion of the crystal lattice or a reduction in particle size. Co-milling the drug with hydroxypropyl methylcellulose, β-cyclodextrin, chitin and chitosan, crystalline cellulose, and gelatin improves the dissolution properties and may result in enhanced AUC shape for nintedanib or an indolinone derivative compound or a salt thereof that would otherwise be poorly bioavailable. As a non-limiting example, this approach can also be used to isolate and improve the water solubility of poorly soluble nintedanib or an indolinone derivative compound or a salt thereof, or a solid AUC-shape enhanced formulation such as a salt form, for nanoparticle-based formulations.

[0193] Dispersion-promoting peptide The composition may include one or more dipeptides or tripeptides containing two or more leucine residues. As a further non-limiting example, U.S. Patent No. 6,835,372, which discloses dispersion-promoting peptides, is hereby incorporated by reference in its entirety. This patent describes the discovery that dilucyl-containing dipeptides (e.g., dilucine) and tripeptides are excellent in their ability to enhance the dispersibility of powder compositions.

[0194] In another embodiment, highly dispersed particles containing amino acids are administered. Hydrophobic amino acids are preferred. Suitable amino acids include both naturally and non-naturally occurring hydrophobic amino acids. Some naturally occurring hydrophobic amino acids (including, but not limited to, non-naturally occurring amino acids) include, for example, beta amino acids. The D-form, L-form, and racemic forms of hydrophobic amino acids can all be used. Suitable hydrophobic amino acids also include amino acid analogs. As used herein, amino acid analogs include D-form or L-form configurations of amino acids having the formula -NH-CHR-CO-, where R is an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group, or a substituted aromatic group, where R does not correspond to the side chain of a natural amino acid. As used herein, aliphatic groups include straight-chain, branched, or cyclic C1-C8 hydrocarbons that are fully saturated and contain one or two heteroatoms such as nitrogen, oxygen, or sulfur, and / or contain one or more unsaturated units. Aromatic groups include carbocyclic aromatic groups such as phenyl and naphthyl, as well as heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, and acridinyl.

[0195] Suitable substituents for aliphatic, aromatic, or benzyl groups include -OH, halogen (-Br, -Cl, -I, and -F), -O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl, or substituted aryl group), -CN, -NO2, -COOH, -NH2, -NH(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl, or substituted aryl group), -N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl, or substituted aryl group)2, -COO(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl, or substituted aryl group), -CONH2, -CONH(aliphatic group, substituted aliphatic group), benzyl, substituted benzyl, aryl, or substituted aryl group)), -SH, -S(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic, or substituted aromatic group), and -NH-C(═NH)-NH2. The substituted benzyl group or aromatic group can also have an aliphatic group or substituted aliphatic group as a substituent. The substituted aliphatic group can also have a benzyl, substituted benzyl, aryl, or substituted aryl group as a substituent. The substituted aliphatic group, substituted aromatic group, or substituted benzyl group can have one or more substituents. Modifying an amino acid substituent can, for example, enhance the lipophilicity or hydrophobicity of a natural amino acid that is hydrophilic.

[0196] Many suitable amino acids, amino acid analogs, and their salts are commercially available. Others can be synthesized by methods known in the art.

[0197] Hydrophobicity is generally defined in terms of the partitioning of an amino acid between a nonpolar solvent and water. Hydrophobic amino acids are acids that prefer nonpolar solvents. The relative hydrophobicity of an amino acid can be represented on a hydrophobicity scale where the value for glycine is 0.5. On such a scale, amino acids that prefer water have values less than 0.5, and amino acids that prefer nonpolar solvents have values greater than 0.5. As used herein, the term hydrophobic amino acid refers to an amino acid that has a value of 0.5 or greater on the hydrophobicity scale, i.e., an amino acid that tends to partition into at least a nonpolar acid equivalent to glycine.

[0198] Examples of amino acids that can be used include, but are not limited to, glycine, proline, alanine, cysteine, methionine, valine, leucine, tyrosine, isoleucine, phenylalanine, and tryptophan. Preferred hydrophobic amino acids include leucine, isoleucine, alanine, valine, phenylalanine, and glycine. Combinations of hydrophobic amino acids can also be used. Furthermore, combinations of hydrophobic and hydrophilic (preferably distributed in water) amino acids, where the overall combination is hydrophobic, can also be used.

[0199] The amino acid can be present in the particles of the present invention in an amount of at least 10% by weight. Preferably, the amino acid can be present in the particles in an amount in the range of about 20% to about 80% by weight. The salt of a hydrophobic amino acid can be present in the particles of the present invention in an amount of at least 10 weight percent. Preferably, the amino acid salt is present in the particles in an amount in the range of about 20% to about 80% by weight. In a preferred embodiment, the particles have a tap density of less than about 0.4 g / cm3.

[0200] A method for forming and delivering particles containing an amino acid is described in U.S. Patent No. 6,586,008 entitled "Use of Simple Amino Acids for Forming Porous Particles During Spray Drying", the teachings of which are hereby incorporated by reference in their entirety.

[0201] Surface modifier The nintedanib or indolinone derivative compounds or salts thereof disclosed herein can be prepared in pharmaceutical compositions using suitable surface modifiers selected from known organic and inorganic pharmaceutical excipients. Such excipients include low molecular weight oligomers, polymers, surfactants, and natural products. Preferred surface modifiers include nonionic surfactants and ionic surfactants. Two or more surface modifiers can be used in combination.

[0202] Typical examples of surface modifiers include acetylpyridinium chloride, gelatin, casein, lecithin (phospholipid), dextran, glycerol, acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (e.g., macrogol ether such as cetomacrogol 1000), polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester (e.g., commercially available Tweens (trademark) such as Tween20 (trademark) and Tween80 (trademark) (ICI Specialty Chemicals)), polyethylene glycol (e.g., Carbowaxs3350 (trademark) and 1450 (trademark), Carbopol934 (trademark), (Union Carbide)), dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropylcellulose (HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 4-(1,1,3,3-tetramethylbutyl)phenol polymer containing ethylene oxide and formaldehyde (also known as tyloxapol, sperion, and triton), poloxamer (e.g., Pluronics F68 (trademark) and F108 (trademark) which are block copolymers of ethylene oxide and propylene oxide), poloxamine (e.g., tetronic 908 (trademark) also known as poloxamine 908 (trademark), a tetrafunctional block copolymer obtained by sequentially adding propylene oxide and ethylene oxide to ethylenediamine) (BASF Wyandotte Corporation, Parsippany, N.J.), charged phospholipids (DOSS) such as dimyristoyl phosphatidylglycerol, dioctyl sulfosuccinate, Tetronic 1508 (trademark) (T-1508) (BASF Wyandotte Corporation), dialkyl esters of sodium sulfosuccinate (e.g., Aerosol OT (trademark) (American Cyanamid), which is the dioctyl ester of sodium sulfosuccinate), Duponol P (trademark) (DuPont), which is sodium lauryl sulfate, Tritons X-200 (trademark) (Rohm and Haas), which is an alkylaryl polyether sulfonate, Crodestas F-110 (trademark) (Croda Inc.), which is a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), also known as Olin-log (trademark) or Surfactant10-G (trademark) (Olin Chemicals, Stanford, Connecticut), Crodestas SL-40 (trademark) (Croda, Inc.), and SA9OHCO (Eastman Kodak Co.), which is C18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2, decanoyl-N-methylglucamide, n-decyl β-D-glucopyranoside, n-decyl β-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl β-D-thioglucoside, n-hexyl β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl β-D-glucopyranoside, octanoyl-N-methylglucalimide, n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside, and the like can be mentioned.

[0203] Examples of surfactants for use in the solutions disclosed in this specification include, but are not limited to, ammonium lauryl sulfate, cetylamine oxide, cetrimonium chloride, cetyl alcohol, cetyl myristate, cetyl palmitate, cocoamide DEA, cocoamidopropyl betaine, cocoamidopropyl amine oxide, cocoamide MEA, lauryl sulfate DEA, ditallow phthalic amide, dicetyldimethylammonium chloride, diparotoyl ethyl hydroxymonium, disodium lauryl sulfosuccinate, di(hydrogenated)tallow phthalic acid, glyceryl dilaurate, glyceryl distearate, glyceryl oleate, glyceryl stearate, isopropyl myristate nf, isopropyl palmitate nf, lauramide DEA, lauramide MEA, lauramide oxide, myristamine oxide, octyl isononanoate, octyl palmitate, octyldodecyl neopentanoate, olealconium chloride, PEG-2 stearate, PEG-32 glyceryl caprylate / caprate, PEG-32 glyceryl stearate, PEG-4 and PEG-150 stearates and distearates, PEG-4 to PEG-150 laurates and dilaurates, PEG-4 to PEG-150 stearates and distearates, PEG-7 glyceryl cocoate, PEG-8 beeswax, propylene glycol stearate, sodium C14-16 olefin sulfonate, sodium lauryl sulfoacetate, sodium lauryl sulfate, sodium trideceth sulfate, stearalconium chloride, stearamide oxide, TEA-dodecylbenzene sulfonate, TEA lauryl sulfate.

[0204] Most of these surface modifiers are known pharmaceutical excipients and are described in detail in the "Handbook of Pharmaceutical Excipients" jointly published by the Pharmaceutical Manufacturers Association of the United States and the Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986), which is incorporated herein by reference in its entirety. The surface modifiers are commercially available and / or can be prepared by techniques known in the art. The relative amounts of the drug and the surface modifier can vary widely, and the optimal amount of the surface modifier depends on, for example, the particular drug and surface modifier selected, the critical micelle concentration when the surface modifier forms micelles, the hydrophilic-lipophilic balance (HLB) of the surface modifier, the melting point of the surface modifier, the water solubility of the surface modifier and / or the drug, the surface tension of the aqueous solution of the surface modifier, and the like.

[0205] In the present invention, the optimal ratio of the drug to the surface modifier is about 0.1% to about 99.9%, more preferably about 10% to about 90%, of the nintedanib or indolinone derivative compound or a salt thereof.

[0206] Microspheres The microspheres can be used for the delivery of nintedanib or indolinone derivative compounds or their salt compounds to the lung by first adding an appropriate amount of the drug compound solubilized in water. For example, an aqueous solution of a nintedanib or indolinone derivative compound or its salt can be dispersed in methylene chloride containing a predetermined amount (0.1 - 1% w / v) of poly(DL-lactide-co-glycolide) (PLGA) by probe sonication on an ice bath for 1 - 3 minutes. Separately, the nintedanib or indolinone derivative compound or its salt can be solubilized in methylene chloride containing PLGA (0.1 - 1% w / v). The resulting water-in-oil primary emulsion or polymer / drug solution is dispersed in an aqueous continuous phase consisting of 1 - 2% polyvinyl alcohol (pre-cooled to 4°C) by probe sonication on an ice bath for 3 - 5 minutes. The resulting emulsion is continuously stirred at room temperature for 2 - 4 hours to evaporate the methylene chloride. The microparticles thus formed are separated from the continuous phase by centrifugation at 8,000 - 10,000 rpm for 5 - 10 minutes. The precipitated particles are washed three times with distilled water and lyophilized. The lyophilized microparticles of the nintedanib or indolinone derivative compound or its salt are stored at -20°C.

[0207] As a non-limiting example, a spray-drying approach can be used to prepare microspheres of nintedanib or indolinone derivative compounds or their salt compounds. An appropriate amount of the nintedanib or indolinone derivative compound or its salt is solubilized in methylene chloride containing PLGA (0.1 - 1%). This solution is spray-dried to obtain microspheres.

[0208] Pharmacokinetics Inhalation therapy with aerosolized nintedanib or indolinone derivative compounds enables the direct deposition of sustained-release substances or active substances into the airways (intranasal or pulmonary), allowing for a therapeutic effect at the deposition site or systemic absorption into the region immediately downstream of the vascular absorption site.

[0209] Similar to the above-described applications to the nasal cavity and lungs, for the treatment or prevention of organs outside the respiratory tract, absorption into the systemic vascular compartment is required for transport to these extra-respiratory sites. When treating or preventing fibrotic or inflammatory diseases associated with the heart, liver, or kidneys, deposition of the drug in the respiratory tract, more specifically in the deep parts of the lungs, enables direct access to these organs via the carotid or coronary arteries from the left atrium. This direct delivery allows for the direct administration of high concentrations of nintedanib or indolinone derivative compounds without unnecessary systemic exposure. Similarly, this route enables dose titration to levels appropriate for these indications.

[0210] Pharmacokinetics is related to the uptake, distribution, metabolism, and excretion of drug substances. A pharmacokinetic profile includes one or more biological measurements designed to measure the absorption, distribution, metabolism, and excretion of a drug substance. One way to visualize a pharmacokinetic profile is to use a plasma concentration curve, which is a graph showing the mean plasma concentration of the active ingredient on the Y-axis and time (usually in units of time) on the X-axis. Pharmacokinetic parameters that can be visualized using a plasma concentration curve include the following. 1) Cmax: The maximum plasma concentration in a patient, 2) AUC: Area under the curve 3) TOE: Time of exposure 4) T1 / 2: The period until the amount of drug in the patient's body is reduced by half 5) Tmax: The time to reach the maximum plasma concentration in a patient

[0211] Pharmacokinetics (PK) is related to the time course of the in vivo concentration of therapeutic agents such as nintedanib or indolinone derivative compounds. Pharmacodynamics (PD) is related to the relationship between in vivo pharmacokinetics and efficacy. PK / PD parameters correlate with therapeutic agents such as exposure and effective activity. Thus, different PK / PD parameters can be used, for example, to predict the therapeutic effects of therapeutic agents with diverse mechanisms of action.

[0212] As used herein, the "peak period" of the in vivo concentration of a pharmaceutical is defined as the time of the dosing interval when the pharmaceutical concentration is 50% or more of its maximum plasma concentration or disease site concentration. The "peak period" is used to represent the dosing interval of nintedanib or an indolinone derivative compound. When considering the treatment of lung diseases, the methods or systems described herein improve the pharmacokinetic profile for the treatment of lung diseases by at least 2-fold. The methods and systems described herein improve the pharmacokinetic profile of lung tissue of nintedanib or indolinone or a salt compound thereof by at least 2-fold as compared to oral administration.

[0213] The amount of nintedanib or indolinone or a salt compound thereof administered to a human by inhalation can be calculated by measuring the amount of nintedanib or indolinone or a salt compound thereof and related metabolites found in urine. Approximately 80% of the administered nintedanib is excreted in urine. Calculations based on the compounds and metabolites in urine can be performed over a 48-hour urine collection (after a single dose), whereby the total amount of nintedanib or indolinone or a salt compound thereof delivered to the human is the sum of the measured nintedanib and its metabolites. As a non-limiting example, if it is known that 80% of nintedanib is excreted, a urinary measurement of a total of 50 mg of nintedanib and its metabolites would translate to a delivered dose of approximately 63 mg (50 mg divided by 80%). If the inhaled aerosol fine particle fraction (FPF) is 75%, it can be assumed that approximately 75% of the drug is deposited in the lung (approximately 25% is swallowed, then absorbed from the gut, and 80% is excreted in urine). Integrating these two calculations, of the 63 mg delivered dose (measured by urinary excretion), the amount of inhaled aerosol nintedanib delivered to the lung is approximately 47 mg (calculated as the product of the actual RDD, 63 mg, and 75% FPF). This RDD can be used for various calculations such as lung tissue concentration.

[0214] After administration of a single inhaled dose to a mammal, the pulmonary tissue Cmax and / or AUC of nintedanib or indolinone or a salt thereof is approximately the same as, or greater than, the pulmonary tissue Cmax and / or AUC of nintedanib or indolinone or a salt thereof obtained after a single oral administration at an oral dose that is about 80% to about 120% of the inhaled dose, and / or the plasma Cmax and / or AUC obtained after administration of a single inhaled dose to a mammal is less than the plasma Cmax and / or AUC obtained after a single oral administration of nintedanib or indolinone or a salt thereof at a dose that is about 80% to about 120% of the inhaled dose. The pulmonary tissue Cmax obtained after administration of a single inhaled dose to a mammal is greater than the pulmonary tissue obtained after a single oral administration of nintedanib or indolinone or a salt thereof at a dose that is about 80% to about 120% of the inhaled dose. The pulmonary tissue AUC of nintedanib or indolinone or a salt thereof obtained after administration of a single inhaled dose to a mammal is greater than the pulmonary tissue AUC obtained after a single oral administration of nintedanib or indolinone or a salt thereof at a dose that is about 80% to about 120% of the inhaled dose. The plasma Cmax of nintedanib or indolinone or a salt thereof obtained after administration of a single inhaled dose to a mammal is less than the plasma Cmax obtained after a single oral administration of nintedanib or indolinone or a salt thereof at a dose that is about 80% to about 120% of the inhaled dose. The plasma AUC of nintedanib or indolinone or a salt thereof obtained after administration of a single inhaled dose to a mammal is less than the plasma AUC obtained after a single oral administration of nintedanib or indolinone or a salt thereof at a dose that is about 80% to about 120% of the inhaled dose.

[0215] In one aspect, described herein is a method of achieving a lung tissue Cmax of a compound of nintedanib or indolinone or a salt thereof that is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 1.5-fold, at least 1.5-fold, at least 1.5-fold, at least 1.5-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, or at least 20-fold that of the Cmax of an orally administered dose of up to 200 mg of nintedanib or indolinone or a salt thereof. The method includes dispersing a dry powder formulation comprising nintedanib or indolinone or a salt thereof and administering the dry powder formulation to a human. Also described herein is a method of achieving a lung tissue Cmax of a compound of nintedanib or indolinone or a salt thereof that is at least equivalent to or greater than that of the Cmax of an orally administered dose of up to 200 mg of nintedanib or indolinone or a salt thereof. The method includes dispersing a dry powder formulation comprising nintedanib or indolinone or a salt thereof and administering the dry powder formulation to a human.

[0216] In one aspect, described herein is an AUC of an orally administered dose of up to 200 mg 0-24 that is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 1.5-fold, at least 1.5-fold, at least 1.5-fold, at least 1.5-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 1.5 to 20-fold, at least 1.5 to 15-fold, at least 1.5 to 10-fold, at least 1.5 to 5-fold, or at least 1.5 to 3-fold that of the lung tissue AUC of nintedanib or indolinone or a salt thereof. The method includes dispersing a dry powder formulation comprising nintedanib or indolinone or a salt thereof and administering the dry powder formulation to a human. The AUC of an orally administered dose of up to 600 mg of nintedanib or indolinone or a salt thereof 0-24 0-24and a lung tissue AUC of nintedanib or indolinone or a salt thereof that is at least equivalent to or greater than that 0-24 A method for achieving this, comprising dispersing a dry powder formulation containing nintedanib or indolinone or a salt thereof, and administering the dry powder formulation to a human.

[0217] This method includes a method of administering nintedanib or indolinone or a salt thereof to a human, which includes administering a dry powder formulation containing nintedanib or indolinone or a salt thereof. The lung tissue Cmax achieved by the dry powder formulation is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times that of the lung tissue Cmax achieved by orally administering nintedanib or indolinone or a salt thereof at a dose that is 80% - 120% of the dose of nintedanib administered by DPI.

[0218] This method includes a method of administering nintedanib or indolinone or a salt thereof to a human, which includes administering a dry powder formulation containing nintedanib or indolinone or a salt thereof. The lung tissue Cmax achieved by the dry powder formulation is at least equivalent to or greater than that of the lung tissue Cmax achieved by orally administering nintedanib or indolinone or a salt thereof at a dose that is 80% - 120% of the dose of nintedanib or indolinone or a salt thereof in the dry powder formulation of the administered nintedanib or indolinone or a salt thereof.

[0219] This method includes a method of administering nintedanib or indolinone or a salt thereof to a human, which includes administering a dry powder formulation containing nintedanib or indolinone or a salt thereof. The plasma AUC achieved by the dry powder formulation 0-24is the plasma AUC achieved by oral administration of nintedanib or indolinone or a salt thereof at a dose that is 80% to 120% of the dose of nintedanib or indolinone or a salt thereof in the dry powder formulation of the administered nintedanib or indolinone or a salt thereof 0-24 is less than.

[0220] The method includes a method of administering nintedanib or indolinone or a salt thereof, which includes administering a dry powder formulation containing nintedanib or indolinone or a salt thereof, and the lung tissue AUC achieved by the spray solution 0-24 is the lung tissue AUC achieved by the compound of nintedanib or indolinone or a salt thereof orally administered at a dose that is 80% to 120% of the dose of nintedanib or indolinone or a salt thereof in the dry powder formulation of nintedanib or indolinone or a salt thereof 0-24 is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5 to 20 times, at least 1.5 to 15 times, at least 1.5 to 10 times, at least 1.5 to 5 times, or at least 1.5 to 3 times. The method includes a method of administering nintedanib or indolinone or a salt thereof, which includes administering a dry powder formulation containing nintedanib or indolinone or a salt thereof, and the lung tissue AUC achieved by the dry powder formulation 0-24 is the lung tissue AUC achieved by the compound of nintedanib or indolinone or a salt thereof orally administered at a dose that is 80% to 120% of the dose of nintedanib or indolinone or a salt thereof in the dry powder formulation of the compound of nintedanib or indolinone or a salt thereof 0-24 is at least 1.5 times.

[0221] This method includes a method of improving the pharmacokinetic profile obtained in humans after administration of a single oral dose of nintedanib or indolinone or a salt thereof. The single oral dose includes up to about 200 mg of nintedanib or indolinone or a salt thereof. The method of improving the pharmacokinetic profile further includes comparing the pharmacokinetic parameters after inhaled administration with the same parameters obtained after oral administration, and may require multiple measurements over time in a single patient to compare the pharmacokinetic parameters of a single patient that vary depending on the dose, route of administration, form of the pharmaceutical active ingredient, and other parameters described herein. Long-term improvement of the pharmacokinetic profile is obtained by repeated and frequent administration of a dry powder formulation of nintedanib or indolinone or a salt thereof described herein by inhalation. Repeated administration of nintedanib or indolinone or a salt thereof by inhalation results in more frequent direct exposure to the lungs and provides an advantage to humans by repeating high Cmax levels. The dose of inhaled nintedanib or indolinone or a salt thereof is administered once a day, twice a day, three times a day, four times a day, every other day, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, or any combination thereof.

[0222] A small amount of intratracheal aerosol administration results in rapid elimination of high Cmax and low AUC in the lungs. Studies in humans, animals, and in vitro all show that the efficacy of nintedanib is dose-responsive (i.e., the higher the dose, the greater the efficacy), suggesting that Cmax is an important factor in the efficacy of nintedanib. Although the lung Cmax appears to be important for efficacy, more regular nintedanib exposure is important to enhance this effect. In the case of treating human lung diseases, administering the compound of nintedanib or indolinone or a salt thereof more frequently directly to the lungs may provide advantages through both repeated administration of high Cmax and more regular exposure to the active therapeutic agent.

[0223] The treatment methods include methods for treating lung diseases in mammals, which comprise directly administering nintedanib or a salt thereof, or an indolinone derivative compound or a salt thereof to the lungs of a mammal in need thereof according to a continuous dosing schedule, and the observed pulmonary tissue Cmax of the dose of nintedanib or an indolinone derivative or a salt thereof exceeds the pulmonary epithelial lining fluid of 10, 100, 1000 or 10,000 ng / mL. When co-formulated or combined with pirfenidone for administration, the resulting plasma pirfenidone Cmax is less than 10 μg / mL, less than 5 μg / mL, less than 2.5 μg / mL. When co-formulated with a PDE4 inhibitor and administered in combination, the resulting plasma PDE4 inhibitor Cmax is less than 10 μg / mL, less than 5 μg / mL, less than 2.5 μg / mL, less than 1.0 μg / mL, less than 0.5 μg / mL, less than 0.1 μg / mL. When co-formulated with a prostacyclin analog and administered in combination, the resulting plasma prostacyclin analog Cmax is less than 10 ng / mL, less than 5 ng / mL, less than 2.5 ng / mL, less than 1.0 ng / mL, less than 0.5 ng / mL, less than 0.1 ng / mL.

[0224] Administration Methods and Treatment Plans The term "continuous dosing schedule" refers to administering a specific therapeutic agent at regular intervals. A continuous dosing schedule refers to administering a specific therapeutic agent at regular intervals without drug withdrawal. A continuous dosing schedule refers to administering a specific therapeutic agent in a cycle in which drug administrations are alternated with a drug withdrawal period (e.g., a washout period) from the specific therapeutic agent. For example, in some embodiments, the therapeutic agent is administered once a day, twice a day, three times a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, every other day, every three days, every four days, daily for one week followed by no administration of the therapeutic agent for one week, daily for two weeks followed by no administration of the therapeutic agent for one week or two weeks, daily for three weeks followed by no administration of the therapeutic agent for one week, two weeks or three weeks, daily for four weeks followed by no administration of the therapeutic agent for one week, two weeks, three weeks or four weeks, no administration of the therapeutic agent for one week after administering the therapeutic agent weekly, or no administration of the therapeutic agent for two weeks after administering the therapeutic agent every two weeks.

[0225] A predetermined amount of nintedanib or an indolinone derivative compound is administered once a day. In some other embodiments, a predetermined amount of nintedanib or an indolinone derivative compound is administered twice a day. In some other embodiments, a predetermined amount of nintedanib or an indolinone derivative compound is administered three times a day.

[0226] If no improvement in the condition of a human disease or medical condition is observed, the daily dosage of the nintedanib or indolinone derivative compound is increased, for example, changing a once-daily dosing schedule to a twice-daily dosing schedule. A three-times-a-day dosing schedule is adopted to increase the dosage of the nintedanib or indolinone derivative compound. The frequency of administration by inhalation is increased to provide higher Cmax levels more regularly and repeatedly. The frequency of administration by inhalation is increased to maintain or perform more regular exposure to nintedanib. The frequency of administration by inhalation is increased to provide higher Cmax levels more regularly and repeatedly and to maintain or provide more regular exposure to nintedanib.

[0227] The high Cmax repeated dosage that provides more regular exposure to the active therapeutic agent administered to a human varies depending on factors such as the condition and severity of the disease or medical condition, the identity of the human (e.g., weight), and the specific additional therapeutic agent administered (if applicable), but is not limited thereto.

Example

[0228] Example 1. Proliferation of PDGF-induced fibroblasts The inhibitory effect of nintedanib on PDGF-induced fibroblast proliferation was determined in primary human fibroblasts. Briefly, fibroblasts were seeded at 2,500 cells / well in a 96-well clear-bottom Falcon plate with 10% FBS F12 / DMEM medium containing 1% Pen / Strep. These cells were left in an incubator at 37°C (5% CO2) for 24 hours to allow the cells to attach to the plate. Then, the medium was removed, the cells were washed with PBS, and the medium was replaced with 0.5% FBS F12 / DMEM medium containing 1% Pen / Strep, and left for a further 24 hours. To characterize the exposure period of each drug on growth inhibition, the cells were pretreated with the drug (0.5 - 50 nM) for 30 minutes, washed, and then replaced with 0.5% FBS F12 / DMEM medium containing 1% Pen / Strep + / - 20 ng / mL of PDGF-BB (short-term drug exposure mimicking pulmonary inhalation pharmacokinetics), or 0.5% FBS F12 / DMEM medium containing 1% Pen / Strep + / - 20 ng / mL of PDGF-BB and the initial drug concentration (long-term drug exposure mimicking oral pharmacokinetics). After 72 hours, the MTS assay was used to evaluate viable cells. The drug concentrations tested did not show cytotoxicity (data not shown).

[0229]

Table 1

[0230] The results in Table 1 show that nintedanib is dose-responsive in inhibiting PDGF-induced fibroblast proliferation. The data also show that only short-term nintedanib exposure (confirming pulmonary inhalation pharmacokinetics), with a 50 percent inhibitory concentration (IC50) of approximately 3 nM (approximately 1.6 ng / mL), is required for this activity.

[0231] Example 2. Formulations

[0232]

Table 2-1

[0233]

Table 2-2

[0234]

Table 2-3

[0235] Example 3. Nintedanib Dry Powder Formulation Five nintedanib hydrobromide formulations were manufactured by spray drying on a 25 g scale. The process parameters for all five spray-dried blends were kept constant. Each formulation was filled into size 3 HPMC capsules and stored in containers at 25°C / 60% RH and 40°C / 75% RH for 3 months, sealed in pouches for stabilization. Sufficient samples were set at two additional time points for each condition. One micronized nintedanib hydrobromide mixture was manufactured on a 2.5 g scale using pharmaceutical grade lactose monohydrate containing 10% fine particles. The formulation was filled into size 3 HPMC capsules and stored in containers at 25°C / 60% RH and 40°C / 75% RH for 1 month, sealed in pouches for stabilization. Sufficient samples were set at two additional time points for each condition. The physicochemical properties and aerosol performance of each formulation were evaluated. The details of the HPLC assay parameters for sample analysis are shown in Table 3.

[0236]

Table 3

[0237] For each assay, three assay measurements were performed and the average value was reported. The moisture content was measured by Karl Fischer coulometry using a Metrohm 851 Tritrando coulometer and a sample oven. 50 mg of each sample was heated to 80 °C. Lactose monohydrate was used as a bracketed standard. A single measurement was made for each sample. The delivery dose was measured at 100 L / min using a Dosing Unit Sampling Apparatus (DUSA). Samples were recovered using 50 mL of diluent. Ten measurements were performed and the average value was reported.

[0238] The particle size distribution of the delivery dose was measured at 100 L / min using a Next Generation Impactor (NGI). Three measurements were performed using one capsule each, and the average values of the fine particle dose and the fine particle fraction (less than 5 microns) were calculated. All aerosol performance evaluations were performed using a Plastiape RS01 monodose low resistance inhalation device.

[0239] The particle size distribution was measured using a Malvern Mastersizer 3000. The analytical sample (10 mg) was suspended in 0.1% lecithin (10 mL) in isooctane and sonicated to disperse the particles before measurement. One sample was prepared for each measurement.

[0240] The melting behavior of the formulation was measured using a Discovery DSC from TA Instruments. The sample (2 - 3 mg) was placed in a sample pan with a pierced lid and heated from 25 °C to 270 - 300 °C at 10 °C / min.

[0241] The effect of moisture absorption on the formulation was measured using a DVS Advantage from Surface Measurement Systems. The analytical sample (10 - 20 mg) was dried at 0% RH and then the RH was changed in 10% steps up to a maximum of 90% RH and then back to 0% RH. The step changes were triggered by mass changes with a limiting time of dm / dt = 0.01% / min.

[0242] Scanning electron microscopy and powder X-ray diffraction were performed at the University of Bath.

[0243] For the spray-dried nintedanib formulation, the following criteria were targeted. · PSD D90 < 5 µm · GSD < 1.8 · Fine particle dose (FPD) ≤ 2 mg For micronized drug substance: · PSD D90 ≤ 5 µm · For capsule filling, the weight range was 28.5 - 31.5 mg.

[0244] Spray drying was carried out (Table 4) and the batch yields were recorded (Table 5).

[0245]

Table 4

[0246]

Table 5

[0247] Capsule filling (spray-dried powder). HPMC size 3 capsules were filled using a 3Pi filling machine at 20% RH. A weight limit of 28.5 - 31.5 mg was used (Table 7).

[0248]

Table 6

[0249] The capsules were stored in plastic safety holding pots at 10 capsules per pot and each pot was sealed with an individual foil overlap before being placed in the stability chamber.

[0250] Micronization of API Nintedanib hydrobromide was micronized using a Hosokawa 50AS jet mill. Two batches were prepared and the particle size distribution was measured using a Mastersizer 3000 (Table 8).

[0251]

Table 7

[0252] Manufacture of lactose blend The micronized API was manually mixed with 10% fine particle lactose monohydrate (GRN4948) using a spatula to produce 2.5 g of nintedanib HBr: lactose monohydrate 10:90 wt%. 40 capsules were manually filled with 30.0 + / - 0.5 mg of the formulation under laboratory conditions (21°C, 50% RH).

[0253] Evaluation of micronized drug substance Micronized nintedanib HBr was placed in a glass snap cap vial sealed in an aluminum pouch and stored at 25°C / 60% RH and 40°C / 75% RH for 1 month, after which the PSD and moisture content were measured (Table 9). SEM images were recorded (Figures 1 and 2), and polymorphic stability was evaluated by XRPD (Figures 3 and 4) and DSC (Figure 6). Subsequently, after an additional 4 months under laboratory conditions, the characterization was repeated.

[0254]

Table 8

[0255] All results indicate that micronized nintedanib HBr did not change during the study. In the DSC traces after 1 month at both 25°C / 60% RH and 40°C / 75% RH, a higher and sharper melting point was shown compared to the initial, but this was not seen after an additional 4 months. No change in structure was shown by XRPD for any of the samples. The change in the DSC trace after 1 month may be due to a change in the hydration state of the sample.

[0256] There is a possibility of incompatibility between the active ingredient and glassware. This was not evaluated in this study. All future samples will be stored in plastic containers.

[0257] Formulation evaluation - assay

[0258]

Table 9

[0259] The initial nintedanib content of all formulations is lower than 8.7% of the expected maximum theoretical value. The theoretical value is derived by converting the hydrobromide salt to the free base, which requires a partial correction factor of 0.87, and thus a maximum theoretical value of 8.7% is obtained for a 10% w / w formulation.

[0260] Formulation evaluation - moisture content is shown in Table 11.

[0261]

Table 10

[0262] Formulation evaluation - release dose

[0263]

Table 11

[0264] The initial release dose data showed that all formulations were discharged from the capsules and at least 85% recovery was shown for all formulations. After storage, two of the spray-dried batches had insufficient release doses, so these studies were discontinued in combination with other data. Typical release dose data were observed for two spray-dried formulations evaluated after 3 months of storage (under both storage conditions), and for micronized formulations after 5 and 6 months of storage.

[0265] Formulation evaluation - fine particle dose and fine particle fraction (Table 13).

[0266]

Table 12

[0267] The initial data indicate that the FPF of the spray-dried formulations was in the range of 23 - 36%. The micronized drug / lactose formulations had higher performance, with an FPF of 60%. In further analysis after storage at 25°C / 60% RH and 40°C / 75% RH for 1 month, significant changes in aerosol performance were observed for 3 of the spray-dried formulations, so these were discontinued from further analysis. Of the 2 spray-dried formulations evaluated after storage at 25°C / 60% RH and 40°C / 75% RH for 2 and 3 months, trehalose:leucine:NHBr 80:10:10 wt% showed consistent performance (FPF after storage at 25°C / 60% RH and 40°C / 75% RH was 22 - 28% compared to an initial 32% FPF), and no clear trend was shown during storage under either condition. Lactose:leucine:NHBr 70:20:10 wt% had variable performance, with a significant difference in FPF depending on the storage condition. In particular, the FPF appears to be higher when stored at 25°C / 60% RH.

[0268] The micronized drug / lactose batches after storage at 25°C / 60% RH and 40°C / 75% RH for 5 and 6 months showed consistent physical performance compared to the initial stage, and the FPF remained at approximately 60%.

[0269] Table 14 shows the stability of the physical properties - particle size distribution by laser diffraction.

[0270]

Table 13

[0271] In the batches of trehalose:NHBr 90:10 wt% and lactose:NHBr 90:10 wt%, after storage at 25 °C / 60% RH for 1 month, changes in the particle size distribution due to particle aggregation were observed, and at 40 °C / 75% RH, the samples melted and became unmeasurable. After storage at 25 °C / 60% RH and 40 °C / 75% RH for 2 months, the samples under both conditions were completely aggregated. These batches did not contain leucine in the matrix known to form a hydrophobic surface layer.

[0272] In the batch of lactose:leucine:NHBr 80:10:10 wt%, an increase in size was shown under both storage conditions after 1 month. After 2 months, the samples under both conditions aggregated and became unmeasurable. Since this batch contains lactose, it is more susceptible to changes due to moisture than an equivalent trehalose batch (trehalose:leucine:NHBr 80:10:10 wt%).

[0273] Batches of trehalose:leucine:NHBr 80:10:10 wt% (containing trehalose and 10% leucine) and lactose:leucine:NHBr 70:20:10 wt% (containing lactose and 20% leucine) showed a similar small increase in particle size during the study period, and no signs of significant aggregation were observed.

[0274] The results of the DVS are shown in Figure 6.

[0275] Initially, the samples were amorphous and occupied 25 wt% of water, and there were no signs of crystallization. At all subsequent time points under both storage conditions, the samples were amorphous, but recrystallized when the RH exceeded 60% as indicated by the mass loss. After storage at 40 °C / 75% RH for 2 and 3 months, the samples showed an expected increase in the final mass because the amorphous trehalose formed crystalline trehalose dihydrate.

[0276] The sample was initially amorphous, but crystallized when the RH exceeded 30%, resulting in a significant mass loss. Similar behavior was observed after storage at 25°C / 60%RH for one month, but the sample was crystallized at 40°C / 75%RH. No further tests were conducted on this formulation.

[0277] The first sample had aggregated before analysis, so no test was conducted. The sample stored at 25°C / 60%RH became completely amorphous after one month, adsorbed 20% moisture, and no recrystallization was observed. However, the sample stored at 40°C / 75%RH was completely aggregated, so no test could be conducted. No further tests were conducted on this formulation.

[0278] Initially, the formulation was amorphous, 20% absorbed water, and no recrystallization occurred. After storage at 25°C / 60%RH for one month, the sample remained amorphous, but crystallized when the RH exceeded 60%, showing a large mass loss. The sample stored at 40°C / 75%RH was completely aggregated, so no test could be conducted. No further tests were conducted on this formulation.

[0279] Initially, the sample was amorphous, but crystallized when the RH exceeded 30%, resulting in a significant mass loss. Similar behavior was observed after storage for one month under both conditions, and after storage at 25°C / 60%RH for two and three months. After two and three months at 40°C / 75%RH, the sample was completely crystallized, absorbed only 2.5% water, and no signs of recrystallization were observed.

[0280] DSC The DSC thermogram shows multiple transitions, but there is no evidence of a crystalline substance. The thermogram is the same at all time points for each condition. Heating and cooling cycles are provided at the initial and one-month time points. Only the heating cycles for two and three months are shown.

[0281] The initial thermogram showed two broad events melting at 170 °C and 210 °C. A similar pattern was seen in samples stored at 25 °C / 60% RH for one month, but only two melts were shown in samples stored at 40 °C / 75% RH for one month, indicating that this sample had crystallized. No further tests were performed on this formulation.

[0282] The first sample was not analyzed because it had absorbed moisture and crystallized prior to testing. After one month at 25 °C / 60% RH, the sample showed a broad transition typical of an amorphous structure. Samples stored at 40 °C / 75% RH were crystalline and showed a distinct melting, presumably due to trehalose dihydrate. No further tests were performed on this formulation.

[0283] The thermograms of the first sample and the sample stored at 25 °C / 60% RH for one month showed complex and broad transitions. The sample stored at 40 °C / 75% RH showed a distinct melting at 215 °C, which could be due to crystalline anhydrous lactose. No further tests were performed on this formulation.

[0284] Initially, this formulation showed a broad moisture loss peak and a distinct melting around 170 - 175 °C. Similar thermograms were seen at each time point at 25 °C / 60% RH and after one month at 40 °C / 75% RH. After two and three months at 40 °C / 75% RH, the thermograms showed only a distinct melting around 175 °C, indicating that these samples had crystallized.

[0285] In the initial evaluation of five spray - dried formulations and micronized drug / lactose formulations, the FPF of the spray - dried batches was 20 - 30%, lower than the ideal for DPI formulations. In contrast, the FPF of the micronized formulations was 60%, which is more typical for DPI products.

[0286] Following the evaluation after 1 month of storage, 3 out of 5 spray-dried batches (lactose:L-leucine:nintedanib hydrobromide 80:10:10 wt%, trehalose:nintedanib hydrobromide 90:10 wt%, and lactose:nintedanib hydrobromide 90:10 wt%) contained a large number of aggregated particles, resulting in a decrease in aerosol performance being observed (maximum FPF < 25% at 25 / 60, less than this under accelerated stability conditions). No further analysis was performed on these batches.

[0287] In comparison, the micronized drug substance / lactose formulations evaluated after 5 and 6 months of storage (under ambient conditions) showed performance similar to the initial time point.

[0288] Example 4: Pharmacokinetics of inhaled (liquid nebulizer) nintedanib, inhaled (liquid nebulizer) fixed combination of nintedanib and pirfenidone, and single-dose oral (gavage) nintedanib in sheep In this study, Merino crossbred female sheep (ewes) aged 6 - 12 months and with a live weight of 30 - 40 kg were used. Optimization of oral dosing was performed on n = 4 animals, and another group of n = 10 sheep was selected for the main (drug dosing) study. All animals received standard vaccinations and were orally administered anthelmintics (in accordance with standard management practices) prior to arrival at the animal facility to remove parasites. The experimental animals alternated between indoor small-group cages and metabolic cages under controlled ambient conditions (20 - 22°C) and were maintained under a 12-hour light-dark cycle throughout the experimental period. The sheep in the main study were randomly assigned to one of three groups (Group 1 or Group 2, n = 5 / group).

[0289] Optimization of oral dosing The procedure for closing the reticular groove in sheep was optimized to enable direct oral drug delivery to the abomasum or true stomach. This procedure included the oral administration of a 10% copper sulfate solution (w / v, 20 mL) into the back of the throat using a dressing gun. Subsequently, 300 mL of glucose solution was delivered orally (via an esophageal feeding tube, delivering 75 g of glucose), and then blood glucose levels were monitored to confirm direct delivery to the abomasum after closure of the reticular groove. Blood samples taken before glucose administration (0 minutes), 15, 30, and 45 minutes after administration were immediately examined using standard glucose test strips and a digital blood glucose analyzer / reader.

[0290] Main study: Pharmacokinetics of nebulizer and oral delivery Nintedanib formulations, and nintedanib in fixed combination with pirfenidone for inhalation and oral dosing are shown in Table 15. All formulations used in this study were stored at room temperature (RT) and protected from light before use. Drugs were prepared on the day of use.

[0291]

Table 14

[0292] Sheep arrived at the facility as one group and were acclimated to the environment over 2 - 3 weeks prior to the experiment (housed in groups in indoor cages / enclosures). Sheep assigned to Group 1 (n = 5, sheep ID#11, 12, 13, 14, 16) or Group 2 (n = 5, sheep ID#2, 17, 18, 20, 21) received Treatments 1, 2, and 3. Sheep in Group 1 were also given Treatment 1b, an addition / amendment to the original study protocol. Treatments were conducted from Week 3 to Week 9 of the study. Each experimental treatment was conducted over one week in sheep from Group 1 or Group 2 (e.g., one group received treatment while the other group was rested).

[0293] Sheep in Group 1 and Group 2 were assigned separate sampling schedules for peripheral blood and bronchoalveolar lavage fluid (BALF) collection (Table 16).

[0294] In all drug administration procedures, the sheep were removed from the metabolic cages, their head and neck movements were restricted, and they were placed in a special restraint harness to facilitate drug administration and BALF sample collection.

[0295] Nebulizer inhalation dosing For nebulizer aerosol drug administration to the lungs (inhalation dosing), a cuffed endotracheal (ET) tube (Portex, inner diameter 7.0 - 8.0 mm) coated with lubricant was inserted into the trachea via the nasal passage (guided by a fiberoptic endoscope). Formulations of nintedanib (Treatments - 1 and - 1b) and a fixed combination of nintedanib and pirfenidone (Treatment 2) were aerosolized using an eFlow in - line nebulizer (PARI Pharma GmbH) placed in series with a biphasic volume - controlled ventilator / respirator (Harvard Apparatus, Massachusetts, USA) to provide a closed breathing loop.

[0296] Respiration was set at 20 breaths / min, 50% inspiration, and tidal volume of 350 mL. A filter (RCl, Hudson, North Carolina, USA) was placed in the expiratory line to collect the expired drug dose. After drug administration, all lines, filters, and nebulizer components were rinsed with 50 mL of sterile saline, and the remaining dose or expired dose was collected. An aliquot (500 μl) of the washed sample was frozen on dry ice in a 1.5 mL Eppendorf tube and stored at - 80 °C until shipment for drug content analysis.

[0297] The exact start and end times of the dose nebulizer and the final duration of the inhaled dose were accurately recorded.

[0298] Oral dosing Oral drug administration (Treatment 3) was carried out according to the procedure detailed below (optimization of oral dosing). A feeding tube (inner diameter 7 mm) was inserted into the upper region of the esophagus via the nasal passage (guided by a fiber optic endoscope). CuSO4 was administered into the back of the throat using a dropper gun, and 25 mL of a nintedanib solution (3 mg / mL) was delivered through the feeding tube 40 seconds later. Immediately after oral dosing of nintedanib, 300 mL of a glucose solution (“chaser”) was orally delivered through the same feeding tube over 20 - 25 seconds (including complete rinsing of a 50 mL Falcon™ tube containing the nintedanib formulation).

[0299] Peripheral blood collection Blood samples collected before and after drug administration (Table 16) were placed in tubes coated with K3EDTA. An aliquot (500 mcl) of the cell-free plasma sample was frozen on dry ice in a 1.5 mL Eppendorf tube and stored at -80 °C until shipment for drug content analysis.

[0300] Collection of bronchoalveolar lavage fluid (BALF) BALF samples were collected before and after drug administration (Table 2). Sampling was performed by injecting 25 ml of sterile saline into the lungs with a catheter through the biopsy port of the bronchoscope, and then immediately recovering the BALF sample into a collection syringe.

[0301] To avoid contamination between sampling time points, BALF was collected from separate lung segments / lobes. The right apical lobe (RA) was used for all pre-dose sampling, and post-dose samples were collected from the right middle (RM), right caudal (RC), left caudal (LC), left middle (LM), and left apical (LA) lobes. Details of BALF sampling (volume collected, exact time) were recorded, and the samples were immediately frozen on dry ice and stored at -80 °C before shipment for drug content analysis.

[0302]

Table 15

[0303] The results of the oral dosing optimization experiment are summarized in Figure 4. In all four sheep, an increase in blood glucose levels was detected at 15, 30, and 45 minutes after separate repeated CuSO4 administrations (Figures 16A and 16B). In contrast, in the absence of CuSO4 administration (glucose only), a sustained increase in blood glucose levels was not observed. The increase in blood glucose levels observed here supports the effective closure of the reticular groove after CuSO4.

[0304] Ten (10) sheep were assigned to the main study. Details of the sheep, live weight, and dosing data (time, volume, delivered dose) for all treatments are shown in Table 16.

[0305] Inhaled drug dosing (Treatments 1, 1b, and 2) was performed using a ventilator and a PARI nebulizer device within a closed breathing loop while the sheep were suspended in a custom harness. This procedure was well tolerated by all sheep. With an inhalation rate of 20 breaths per minute, the total lung dose could be delivered within 20 minutes (range 11.8 - 19.3 minutes). The average dosing time was similar across all treatments (Table 16): 15.5 ± 2.2 minutes (mean ± SD) for inhaled nintedanib (Treatments 1, 1b). With an inhalation rate of 20 breaths per minute, the total lung dose could be delivered within 20 minutes (range 12.3 - 18.2 minutes). The average dosing time was similar across all treatments (Table 16): 15.4 ± 2.2 minutes (mean ± SD) for inhaled nintedanib in combination with pirfenidone (Treatment 2).

[0306] Following the oral optimization study, to confirm effective closure of the reticular groove in each test sheep, CuSO4 followed by glucose was first administered during the week prior to nintedanib dosing. Oral dosing of nintedanib (Treatment 2) was administered with a "chaser" of glucose, and no side effects were observed. The dose of nintedanib delivered to all sheep was 75 mg (25 mL of a 3 mg / mL formulation), which corresponded to 2.07 ± 0.03 mg / kg of sheep live weight (Table 17).

[0307] [Table 16]

[0308] After oral administration of nintedanib, a continuous and significant increase in blood glucose levels was observed in all sheep, and it was confirmed that the orally administered drug passed directly through the abomasum (Figure 17).

[0309] Blood and BALF collection As shown in Table 2, blood was collected at 6 (six) time points for each of Treatments 1, 1b, and 2. BALF samples were collected at different time points for each of Treatments 1, 1b, 2, and 3 (Table 15). Samples were collected from separate lung lobes to avoid sample dilution between time points (Figure 3). The results are shown in Table 19.

[0310] Pharmacokinetic results A comparison of nebulizer inhalation and oral delivery of nintedanib is shown in Table 18 below.

[0311] [Table 17]

[0312] From the results in Table 17, it was found that although the amount of nebulizer-inhaled nintedanib was approximately 36-fold less than that of oral administration, the Cmax of the epithelial lining fluid (ELF) was approximately 100-fold higher and the AUC was approximately 5-fold higher than that of oral administration. In comparison, when nintedanib solution was inhaled using a nebulizer, the plasma AUC decreased by approximately 8-fold and the plasma Cmax increased by approximately 2-fold.

[0313] A comparison of nebulizer inhalation monotherapy of nintedanib and nebulizer inhalation of nintedanib administered in a fixed combination with pirfenidone is shown in Table 19.

[0314] [Table 18]

[0315] After nebulizer inhalation administration of nintedanib in a fixed combination with pirfenidone, the nintedanib concentration shows that the ELF Cmax is low (50% lower) and the ELF AUC is also low (12% lower). Conversely, the plasma Cmax and AUC increased (46% and 25% increase respectively). These results suggest a drug interaction that in the presence of the fixed combination pirfenidone, nintedanib may disappear more rapidly into the plasma (low ELF Cmax and AUC, high plasma Cmax and AUC). To support this hypothesis, formulation results show that pirfenidone stabilizes nintedanib in solution (Example 7). As a means to optimize these fixed combination interactions and reduce in vivo drug interactions, the amounts of both nintedanib and pirfenidone can be optimized (Example 7).

[0316] Example 5: Comparison of the Pharmacokinetics of Inhaled (Liquid Nebulizer) Nintedanib and Dry Powder (DPI) Nintedanib in Sheep DPI Bridging Study Using the same method as used in Example 4, an aqueous formulation of nintedanib HBr (nebulizer aqueous formulation) was compared with various dry powder nintedanib formulations. The formulations tested in this study were stored at room temperature (RT), protected from light, and prepared on the day of use (Table 20).

[0317] [Table 19]

[0318] Sheep arrived at the facility as a single group and were acclimated to the environment over 5 - 10 days prior to the experiment (group housed indoors in cages / enclosures). Sheep received Treatments 1 - 4 over a 3 - 4 week period of the study. After each experimental treatment in each sheep, a washout period of 72 - 96 hours ensued before the next scheduled treatment.

[0319] In all drug administration procedures, the sheep were removed from the metabolic cages and placed in a special restraint harness to limit head and neck movement and facilitate drug administration, measurement of lung function, and collection of BALF samples.

[0320] DPI and nebulizer inhalation dosing In all dosing procedures, an endotracheal (ET) tube with a cuff (Portex, inner diameter 7.0 - 8.0 mm) coated with a lubricant was inserted into the trachea via the nasal passage (guided by a fiberoptic endoscope). A nebulizer (for treatment 1) and a Penn Century (trademark) inhalation device (for treatments 2 - 4) were placed in the breathing line. Before all inhalation dosing procedures (treatments 1 - 4), the ventilator breaths were set to 20 breaths per minute (BPM), 50% inspiration, and a tidal volume of 350 mL.

[0321] The liquid nintedanib formulation (treatment 1) was nebulized using an eFlow (registered trademark) in - line nebulizer (PARI Pharma GmbH) placed in series with a two - phase controlled ventilator / respirator (Harvard Apparatus, Massachusetts, USA) to provide a closed breathing loop.

[0322] The micronized / spray - dried nintedanib formulation (treatments 2 - 4) was pre - weighed and placed in a Penn Century (trademark) inhalation device, which was then connected to an adjusted pressurized O2 gas source. Immediately before DPI dose delivery, the ventilation was reduced to 10 BPM and the powder dose was released in parallel with 2 - 3 actuations (for approximately 20 - 30 seconds). At the end of DPI dosing, the ventilation rate was returned to 20 BPM.

[0323] For all dosing treatments, a filter chamber (RCI, Hudson, NC, USA) was placed in the expiratory line to collect the exhaled drug dose. After drug administration, all lines, filters, and nebulizer (for treatment 1) components were rinsed with 50 mL of sterile MilliQ water to collect the remaining or exhaled dose. An aliquot of the washed sample (500 μL taken from a 50 mL post-wash volume) was frozen in dry ice (in an Eppendorf tube) and stored at -80 °C until shipment for drug content analysis.

[0324] The exact start and end times of the dose nebulizer and the final duration of the inhaled dose were accurately recorded (see Table 21).

[0325] Peripheral blood sampling Before and after each drug administration, blood samples (3 mL) were collected from all sheep into tubes coated with K3EDTA: before administration (t0), and at t2 minutes, t5 minutes, t10 minutes, t15 minutes, t30 minutes, t60 minutes, t120 minutes, t240 minutes, t480 minutes, and t720 minutes after completion of administration. An aliquot of the cell-free plasma sample (500 μL) was frozen on dry ice in a 1.5 mL Eppendorf tube and stored at -80 °C until shipment for drug content analysis.

[0326] Collection of bronchoalveolar lavage fluid (BALF) BALF samples were collected from three animals before and after drug administration. Sampling was performed by injecting 25 mL of sterile saline into the lungs with a catheter through the biopsy port of the bronchoscope and immediately recovering the BALF sample into a collection syringe.

[0327] BALF was collected from separate lung segments / lobes to avoid contamination between sampling time points. The right apical (RA) lobe was used for all pre-administration (t0) sampling, and post-administration samples were taken from the left caudal (LC) lobe at t2 minutes and the right caudal (RC) lobe at t10 minutes.

[0328] Recorded the details of BALF sampling (quantity, exact time of collection after dosing), immediately froze the samples on dry ice, and stored them at -80 °C before shipment for drug content analysis.

[0329] Lung function evaluation According to the established protocol, lung function measurements of awake and conscious breathing sheep were recorded. Lung measurements were evaluated during quiet breathing from 5 minutes before to 10 minutes after each drug administration. Lung parameters (dynamic compliance, transpulmonary pressure, lung volume, respiration, and flow) were derived from the average measurements of 5 epochs of 5 breaths, and the data were analyzed using LabChart™ software.

[0330] Dosing data for DPI bridging study Six (n = 6) sheep were assigned to this study. Details, live body weight, and dosing data (time, volume / delivery dose) of the sheep for Treatments 1 - 4 are shown in Table 21.

[0331] Inhaled nebulizer drug dosing (Treatment 1) was performed using a ventilator and a PARI eFlow in-line device within a closed breathing loop while suspending the sheep with a custom harness. This procedure was well tolerated by all sheep. In Treatment 1, with an inhalation rate of 20 BPM, the total lung dose could be delivered within 20 minutes (range: 17.98 - 20.00 minutes, mean ± SEM: 18.73 ± 0.23 minutes).

[0332] For the delivery of dry powder inhaled (DPI) formulations, the ventilation was reduced to 10 BPM, and 24 - 30 mg of powder was delivered in 2 - 3 actuations via a Penn Century device. The total dose of micronized powder delivered in Treatments 2 - 4 ranged from 14 - 26 mg, and the most efficient delivery was observed with DPI doses #2 and #3 (95% effective dose released / delivered). The DPI dose #1 formulation showed signs of aggregation / compression within the Penn Century device after dosing and exhibited variable powder dose release of 46 - 73%.

[0333]

Table 20

[0334] Blood and BALF collection Blood samples were collected from all animals at the 11 (11) time points for each of Treatments 1 - 4. For Treatments 1 - 4, BALF samples were collected from 3 (3) animals at 3 (3) time points from separate lung lobes. The mean BALF collection times at the "2 - minute" and "10 - minute" time points were 3.18 ± 0.35 minutes and 13.63 ± 0.82 minutes (mean ± SEM), respectively, with no significant differences across Treatments 1 - 4. No significant differences in BALF volume were observed between time points (0, 2, 10 minutes) or between Treatments 1 - 4 (range: 5.5 - 14.0 mL; mean ± SEM: 8.53 ± 0.31 mL).

[0335] Lung function analysis For all sheep, lung function was evaluated before (pre - treatment) and after (post - treatment) Treatments 1 - 4. The mean values of each evaluated lung function parameter are summarized in Figure 18. No significant changes (pre - treatment vs. post - treatment) were seen in the mean trans - pulmonary pressure (airway resistance) or dynamic compliance of the sheep after each of Treatments 1 - 4. During Treatment 4, the ventilation rate was slightly but significantly increased (Figure 18C) (from 7.23 ± 0.63 L / min to 8.96 ± 0.64 L / min, mean ± SEM), with no effect on other lung function parameters. This response may reflect a mild transient response to the dosing of Treatment 4 (90% lactose: 10% nintedanib - micronized).

[0336] Pharmacokinetic results Comparative inhaled dry powder (lactose monohydrate: micronized nintedanib (90:10 wt%)) and aqueous nebulizer - delivered inhaled nintedanib are shown in Figures 19 and 20.

[0337] Figure 19 shows that both inhaled delivered aqueous nebulizer nintedanib and dry powder nintedanib are removed from the lung at a similar rate. This data indicates that a simple micronized nintedanib dry powder formulation (90% lactose: 10% nintedanib) readily dissolves in the lung and provides a substantially bioavailable delivery dose in the lung. Importantly, by calculating the delivery dose (measuring the nintedanib remaining in the ventilator tubing after administration completion and subtracting it from the dose loaded into the device), the nebulizer formulation delivered 1.8 mg of nintedanib, while this dry powder formulation delivered 1.2 mg, and the dry powder ELF Cmax and AUC were approximately 61% and 44% of the nebulizer formulation, respectively. Adjusting for the fine particle fraction and delivery dose dry powder pharmacokinetic data, these curves overlap, corroborating the following: 1. The two formulations are actually similarly bioavailable, and 2. With additional particle engineering and device optimization, the delivery of the dry powder is improved.

[0338] Similar to that suggested in Figure 19, the parallel curves (same plasma Tmax and same plasma excretion rate) shown in Figure 20 further corroborate equivalent lung bioavailability and excretion between nebulizer nintedanib and dry powder nintedanib.

[0339] To corroborate these results, in vitro dissolution studies were conducted. Briefly, using a USP dissolution apparatus, the dissolution rate of nintedanib of each formulation in simulated lung fluid was measured.

[0340] Simulated Lung Fluid 4 (SLF4) was selected to perform the dissolution experiment. However, this buffer contains citrate and high concentrations of chloride, both of which are known to be incompatible with nintedanib hydrobromide. Therefore, the mixture was adjusted by replacing citrate with phosphate and reducing the total chloride concentration to less than 67 mmol. Calcium carbonate was omitted because it is known to cause pH drift. Additionally, DPPC was not added to the mixture. Studies were conducted to investigate the effects of chloride concentration and pH, and a total chloride concentration of 48 mmol and pH 6.0 were selected for performing the experiment. SLF was prepared as shown in Table 22.

[0341] All components except sodium chloride were added to 4.5 L of deionized water in the order shown. Sodium chloride was weighed into a separate beaker and dissolved in an additional 100 ml of deionized water with stirring. The pH of the components in 4.5 L of water was adjusted to pH 6.0 with 1 M NaOH, and then the sodium chloride solution was added. The resulting solution was transferred to a 5 L volumetric flask and made up to volume with deionized water.

[0342]

Table 21

[0343] Each container was filled with 500 mL of SLF at 37 °C, and 250 mg of the formulation was added while stirring at 125 rpm. Samples were taken at 0.5, 1, 2, 4, 6, 8, 10, 15, 30, and 60 minutes (2 mL was taken and 0.5 mL was discarded) using a 13 mm water-wettable PTFE syringe filter. Samples were diluted 1:4 with sample diluent and analyzed in duplicate using an HPLC assay method.

[0344] The dissolution results show that the micronized nintedanib dry powder formulation (90% lactose: 10% micronized nintedanib) studied in Figures 19 and 20 completely dissolved within 6 minutes (Table 23, formulation 6). In contrast, the spray-dried lactose: 10% nintedanib formulation with the same content otherwise (Table 23, formulation 4) dissolved only 62% in 10 minutes.

[0345]

Table 22

[0346] As further evidence of the pharmacokinetic results in sheep, Table 12 shows that formulation 6 of Table 23 (lactose monohydrate: micronized nintedanib (90:10 wt%)) exhibited a device release dose (93%) similar to that of other spray-dried formulations (Table 22, formulations 1 - 5), while showing a much larger fraction of fine particles (Table 13, in these spray-dried formulations in the range of 60% vs. 23% - 36%). Furthermore, the fraction of fine particles measured in vitro delivered a fine particle dose of 1.32 mg (from the 2.2 mg of nintedanib dose loaded into the device), and these characteristics were maintained for at least 6 months (Table 13). Combining this information, the data in Tables 12, 13, and 23 show that formulation 6 (lactose monohydrate: micronized nintedanib (90:10 wt%)) exhibited an acceptable fraction of fine particles, was stable in these characteristics for at least 6 months, and dissolved efficiently. Furthermore, the fine particle dose (1.32 mg) corresponds to the delivered dose of 1.2 mg measured in the sheep study (Figures 19 and 20). It has previously been shown that a nebulized, fully soluble aqueous solution of nintedanib is effective in animal models (Surber et al., 2020; Epstein-Shochet et al., 2020). Therefore, for the pharmacokinetic / pharmacodynamic relationship and maintenance of equivalent activity with an aqueous nebulizer product, it is important that the dry powder nintedanib formulation shows rapid dissolution to produce bioavailable drug. Considering that the dissolution rate and bioavailability of this lactose monohydrate: micronized nintedanib (90:10 wt%) formulation are equivalent to those delivered by inhalation of an aqueous solution (Figures 19 and 20), it is important to maintain a similar dissolution threshold. From the data in Table 23, it is clear that a successful dry powder nintedanib formulation must have a dissolution rate that dissolves more than 60% of the powder nintedanib within the first 10 minutes, and more preferably dissolves completely within the first 10 minutes.Furthermore, the particulate fraction, particulate dose, and actual delivered dose to sheep are reflective of consistency, and the modeled performance of dry powder nintedanib in humans compared to the approved oral therapy (Table 25) maintains substantial pharmacokinetic advantages, although it is clear that it is more efficient after inhalation of the nintedanib aqueous nebulizer formulation at the same loaded dose in the same device (Figure 19). More specifically, compared to the nebulizer formulation, the dry powder delivered dose is less efficient, and when adjusting the dry powder pharmacokinetic data for the particulate fraction and delivered dose, these curves overlap, indicating that while the two formulations are indeed similarly bioavailable, additional particle engineering and device optimization support further improvement in the delivery of the dry powder.

[0347] To characterize how dry powder nintedanib acts in humans, a clinical study comparing nebulizer inhaled nintedanib and oral nintedanib was first conducted in healthy volunteers. In this study, subjects were administered either 2 mg of aqueous nebulizer nintedanib using a PARI eFlow electronic nebulizer or 150 mg of oral pirfenidone (commercially available). The safety results of this study showed that inhaled nebulizer nintedanib had good tolerance, and only minimal grade 1 side effects such as mild reversible cough were observed. The pharmacokinetic results in humans are shown in Table 24.

[0348]

Table 23

[0349] Table 24 shows that inhaled aqueous nebulizer nintedanib at 2 mg delivered ELF Cmax and AUC levels that were approximately 64-fold and approximately 3-fold higher, respectively, than those of oral nintedanib at 150 mg. Furthermore, when 2 mg of aqueous nintedanib solution was inhaled, the plasma Cmax and AUC levels were approximately 5-fold and approximately 43-fold lower than those with oral administration. Collectively, these results support the hypothesis that inhaled nintedanib provides equivalent oral delivery with fewer side effects than those observed with oral products.

[0350] To understand how dry powder nintedanib acts in humans, comparable aqueous nebulizer inhalation and dry powder inhalation sheep data were extrapolated to the above human observations. Briefly, plasma and ELF nintedanib levels from aqueous nebulizer inhalation measured in sheep were bridged to the human data in Table 24. Next, the relationship between the collected sheep dry powder nintedanib pharmacokinetic data and the collected sheep aqueous nebulizer nintedanib data was directly compared to the measured human oral results. This extrapolated comparison is shown in Table 25.

[0351]

Table 24

[0352] Similar to the results observed in Table 23, the results in Table 24 indicate that inhaled nintedanib delivery results in superior lung levels with lower systemic exposure. Specifically, dry powder nintedanib at 2 mg had lung ELF Cmax and AUC levels that were approximately 40-fold and approximately 1.4-fold higher, respectively, than those of oral nintedanib at 150 mg. Furthermore, 2 mg of dry powder nintedanib had plasma Cmax and AUC levels that were approximately 8-fold and 66-fold lower than those with oral administration. Collectively, these results support the hypothesis that inhaled dry powder nintedanib also provides equivalent oral delivery with fewer side effects than those observed with oral products.

[0353] Example 6. Optimization of a Blend Formulation of Lactose Carrier and Nintedanib Formulation optimization studies were conducted to evaluate the effects of a force control agent, the particle size of nintedanib, the lactose carrier size, and device resistance on the aerodynamic properties of a nintedanib HBr dry powder formulation.

[0354] Nintedanib was first micronized to the target size and then a dry powder formulation was formulated by three-dimensional gravitational mixing with lactose and, where applicable, a force control agent. The prepared formulation was filled into capsules and the aerosol dispersion properties were tested using RS01® dry powder inhalers of various resistances (manufactured by Plastiape, Italy). The selected formulations were placed in a steady state at 25°C and 40°C and tested at regular intervals. The work completed so far is summarized below.

[0355] Micronized nintedanib HBr was ground so that D50 was 1.5 microns and D90 ≤ 5 microns. Micronization was carried out using a fluid energy jet mill in two passes to obtain coarse and fine materials. The grinding parameters are summarized below.

[0356] [Table 25]

[0357] The particle size distribution of micronized nintedanib HBr was measured using a Malvern Zetasizer Nano ZS particle size analyzer (Malvern, Pennsylvania) by suspending the powder in an isooctane solution containing 0.1% soy lecithin and sonicating it for dispersion before measurement. The measured values are shown in Table 27.

[0358] [Table 26]

[0359] Scanning electron microscopy (SEM) and powder X-ray diffraction were performed on micronized nintedanib HBr. From the SEM images, it was revealed that micronized nintedanib HBr had a tomahawk shape and the particle size was usually less than 3 µm (Figure 21).

[0360] The polymorphic form of micronized nintedanib HBr was determined by powder X-ray diffraction and was equivalent to the polymorphic form of micronized nintedanib HBr generated during the feasibility study of nintedanib powder (Figures 3 and 4), indicating that nintedanib HBr retained its polymorphic form after micronization (Figure 22).

[0361] Formulation blends. Micronized nintedanib HBr was blended with lactose carriers (Lactohale LH200, Respitose ML003) and force control agents (L-leucine, magnesium stearate [MgSt], Lactohale LH300) in various combinations shown in Table 28. Where applicable, the force control agent was added in layers to Lactohale 200, a lactose carrier, in a 50 mL metal container. The excipients were mixed in a Turbula tumble blender at 48 rpm for 15 minutes. Micronized nintedanib HBr was added in layers to the resulting powder and mixed in a Turbula blender at 48 rpm for 30 minutes.

[0362]

Table 27

[0363] Upon completion, samples were taken from various locations within the blend to test the uniformity of the content of the powder formulation (%RSD ≤ 15%), and the nintedanib content was analyzed with an ultraviolet-visible spectrophotometer at a wavelength of 390 nm. The results of the content uniformity are shown in Table 29.

[0364]

Table 28

[0365]

Table 29

[0366] The aerosol performance of formulations 101-04-45-1 to 101-04-45-3 and 101-04-45-5 was further evaluated. The test samples were placed in sealed glass vials and stored at 25°C / 60% RH and 40°C / 75% RH and tested after 1 month of storage (for formulation 101-04-45-05, only tested under the 25°C / 60% RH condition). A summary of the aerosol performance is shown in Table 31. Except for formulation 101-04-45-5, no substantial changes in aerosol performance were observed in the other three formulations. For formulation 101-04-45-5, after storage at 25°C / 60% RH for 1 month, the fine particle dose and fine particle fraction (>5%) decreased significantly.

[0367]

Table 30

[0368] Furthermore, formulations 101-04-45-1 to 101-04-45-3 and 101-04-45-5 were tested with devices of different flow resistances. Since many elderly patients with lung diseases are unable to inhale air at the high flow rates required by low-resistance devices, it is important to test the aerosol performance of these formulations with various flow resistance devices, and thus it is important to test medium- and high-resistance devices that require lower inhalation flow rates. The tests were performed using single-dose RS01 devices of low, medium, and high resistance (manufactured by Vali Global, Italy), with the NGI operating at 100 LPM, 85 LPM, and 60 RPM respectively, and a pressure drop of approximately 4 kPa occurred (as specified in USP <601>).

[0369] Test samples from the 1-month stability test at 25°C / 60% RH were used for the tests. One 24 mg filled capsule was inserted into the inhalation device and subsequently actuated in the NGI at the corresponding flow rates listed in the above paragraph. Nintedanib was collected and analyzed by HPLC method. The aerosol performance characteristics were determined using Inhalytics software (Copley, UK). The delivered dose mass, delivered dose fraction (relative to the nominal dose), fine particle dose and fine particle fraction, and the mass median aerodynamic diameter of the aerosol for each device resistance type are shown in Tables 32 and 33. It was found that the delivered dose and delivered dose fraction of formulations 101-04-45-3 and 101-04-45-5, which contain the force control agents microcrystalline lactose and leucine in that order, were not affected by the resistance of the device. On the other hand, formulations 101-04-45-1 and 101-04-45-2, which do not contain force control agents, were found to be lower compared to low- and medium-resistance devices.

[0370]

Table 31

[0371] The fine particle dose and fine particle fraction of all formulations tested with the medium resistance device increased slightly more than those of the low resistance device, while those of the high resistance device were substantially lower compared to those of the low and medium resistance devices. Of the four formulations tested, formulations 101-04-45-1 and 101-04-45-3 consistently showed high fine particle dose and fine particle fraction. On the other hand, formulation 101-04-45-5 consistently showed lower fine particle dose and lower fine particle fraction in medium and high resistance devices. The MMAD was found to be unaffected by the resistance of the device for all four formulations tested.

[0372]

Table 32

[0373] In summary, formulation 101-04-45-03 containing 5% fine lactose as a force control agent exhibits good aerosol performance, is stable through one-month storage under the conditions of 25°C / 60% RH and 40°C / 75% RH, and the influence due to the resistance of the device is minimized. Based on its overall aerosol performance characteristics, formulation 101-04-45-3 is a formulation favorable for further development. As a non-limiting example, a preferred embodiment contains a hydrobromide salt in solid particles having a particle size distribution defined to have a D10 of about 0.1 μm to about 1 μm, a D50 of about 1 μm to about 2.5 μm, and a D90 of about 1.5 μm to about 5 μm at a formulation content of about 1% to about 20% by weight, and contains micronized nintedanib or a salt thereof. A preferred embodiment may further contain lactose defined to have a D10 of about 5 μm to about 15 μm, a D50 of about 50 μm to about 100 μm, and a D90 of about 120 μm to about 160 μm at a formulation content of about 60% to about 99% by weight. A preferred embodiment may further contain lactose fine particles defined to have a particle size distribution having a D50 of less than about 5 μm and a D90 of less than about 10 μm at a formulation content of more than 0% to about 20% on a weight-to-weight basis. Further, the preferred formulations described herein enable high release doses from medium- and high-resistance dry powder inhalation devices. For clarity, medium- and high-resistance devices are designed to require a lower inhalation flow rate to actuate and disperse the dosage of the dry powder formulation, and are more suitable for persons suffering from lung diseases and reduced lung function who may have insufficient inhalation flow rates to efficiently actuate and disperse the dry powder dosage in an inhalation administration from a low-resistance device.

[0374] Example 7. Formulation of Fixed Dose Combination of Liquid Nintedanib and Pirofenidone Data from Example 5 indicate that nebulizer inhalation administration of pirfenidone and fixed-dose nintedanib delivers lower ELF levels and increases plasma levels. This observation suggests the potential for a drug-drug interaction with pirfenidone, whereby nintedanib may be removed from plasma more rapidly in the presence of fixed-dose pirfenidone. Consistent with this hypothesis, formulation results indicate that pirfenidone stabilizes nintedanib in solution. As a means to optimize these fixed-dose interactions and reduce drug-drug interactions in vivo, the amounts of both nintedanib and pirfenidone can be optimized.

[0375] As a first means of characterizing the interaction between pirfenidone and nintedanib, the physical stability of nintedanib in the presence of various concentrations of pirfenidone was investigated. Nintedanib (in various salt forms including esylate, hydrobromide, etc.) has previously been known to be physically unstable in solutions containing 30 mM or more of sodium chloride. It is also known that adding pirfenidone to such nintedanib solutions containing sodium chloride can physically stabilize nintedanib. As a surrogate for understanding the in vivo concentration limits and / or the ratio of undesirable drug-drug interactions in vivo, the chemical interaction between pirfenidone and nintedanib was investigated. In this study, the stability of a 0.25 mg / mL nintedanib solution in 67 mM sodium chloride at 0, 2.5, 5, 7.5, 10, and 12.5 mg / mL of pirfenidone was evaluated. By design, the stability limit was inferred as the limit of in vivo chemical or drug-drug interactions. First, a 67 mM sodium chloride solution was prepared by dissolving 0.8 g of sodium chloride in water and diluting to 200 mL. The 12.5 mg / mL solution was prepared by dissolving 1.25 g of pirfenidone in 100 mL of the physiological saline prepared above. An appropriate amount of nintedanib HBr was added to the 12.5 mg / mL solution and mixed with the 67 mM sodium chloride solution to produce a series of formulations shown in Table 34. The solution was heated to 40°C while mixing for 30 minutes, and upon completion, nintedanib in all formulations was completely dissolved.

[0376]

Table 33

[0377] The results of the interaction between pirfenidone and nintedanib are summarized in Table 35.

[0378]

Table 34

[0379] The results show that a ratio of approximately 30 parts of pirfenidone to 1 part of nintedanib (more than approximately 7.5 mg / mL of pirfenidone per 0.25 mg / mL of nintedanib) on a weight-for-weight basis stabilizes nintedanib in the presence of approximately 67 mM sodium chloride, which, as defined herein, is the limit of chemical interaction under these conditions. From these data, it is inferred that when the amount of pirfenidone is less than 30 parts per part of nintedanib on a weight basis, stability decreases and thus chemical interaction under these conditions decreases. When formulating together or administering in vivo to avoid the pharmacokinetic changes that exist when pirfenidone and nintedanib are administered in a fixed combination or co-administered by other means, a ratio of pirfenidone to nintedanib of 30 parts or less per part of nintedanib needs to be considered. However, under physiological conditions, the chloride content is close to 150 mM, and thus, to avoid the pharmacokinetic changes that exist when pirfenidone and nintedanib are administered in a fixed combination or co-administered by other means, this ratio can be extended such that it does not exceed 67 parts of pirfenidone per part of nintedanib on a weight basis.

[0380] As a means of optimizing the present invention, the ratio of the co-formulated combination of nintedanib and pirfenidone is optimized to avoid the in vivo physiological effects that may increase the rate of excretion of inhaled nintedanib from the lung to plasma compared to the co-formulated chemical interaction and nintedanib administered without the addition of co-formulated pirfenidone.

[0381] As a non-limiting example, when the nintedanib:pirfenidone ratio is 2:100 by weight, lung diseases are reduced and the Cmax of plasma nintedanib increases by about 30 - 50%. To maximize the lung residence time of inhaled nintedanib co-formulated with pirfenidone, it is desirable to mitigate this pharmacokinetic effect. According to non-limiting examples, this undesirable pharmacokinetic effect can be minimized by reducing the pirfenidone content to about 100 mg or less per dose while setting the nintedanib:pirfenidone content ratio to about 1:1 to about 1:67. According to another non-limiting example, this undesirable pharmacokinetic effect can be minimized by reducing the pirfenidone dose to about 100 mg or less while maintaining the nintedanib:pirfenidone content ratio at 1:20 to 1:67 by weight. According to another non-limiting example, this undesirable pharmacokinetic effect can be minimized by increasing the nintedanib co-formulation content such that the resulting nintedanib:pirfenidone content ratio is less than 1:67 by weight.

[0382] The method of the present invention involves optimizing the ratio of co-formulated nintedanib or indolinone compound to pirfenidone or pyridone analog to improve therapeutic effects including efficacy, safety, tolerability, and compliance. As a non-limiting example, 100 mg of pirfenidone is at the upper limit range of the tolerability of pirfenidone as a sprayed single solution and is close to the upper threshold possible with a dry powder product with high compliance and high tolerability. As a non-limiting example, the efficacy of a dry powder product co-formulated with this nintedanib or indolinone compound and pirfenidone or pyridone analog is predicted to be greater than that of either active ingredient alone. To maximize the relationship between safety / tolerability / compliance and efficacy, compliance is improved by reducing the total amount of dry powder administered, and both the safety and tolerability of the combination product are improved. Utilizing the additional effect by co-formulation with nintedanib or indolinone compound, the amount of pirfenidone or pyridone analog in the co-formulated dry powder product can be reduced while maintaining the overall additional advantage of administering both nintedanib or indolinone and pirfenidone or pyridone analog to the patient. According to a non-limiting example, this desirable result is achieved by reducing the pirfenidone dosage to about 100 mg or less while maintaining the nintedanib:pirfenidone content ratio on a weight basis from 1:20 to 1:67. The optimized nintedanib / pirfenidone formulation ratio and formulation are shown in Table 36.

[0383]

Table 35-1

[0384]

Table 35-2

[0385]

Table 35-3

[0386]

Table 35-4

[0387]

Table 35-5

[0388] Example 9. High-drug-loading fixed-dose combination of nintedanib HBr with controlled particle morphology and pirfenidone The high-drug-loading fixed-dose combination formulation of nintedanib HBr, its base or other salts with pirfenidone can be formulated by dissolving nintedanib and pirfenidone in hot water (50 °C) at the following ratios together with a shell-forming agent (L-leucine, trilucine, sodium stearate, magnesium stearate) and a glass-forming agent (sucrose and trehalose) as a stabilizer (Table 37).

[0389]

Table 36-1

[0390]

Table 36-2

[0391]

Table 36-3

[0392]

Table 36-4

[0393]

Table 36-5

[0394]

Table 36-6

[0395] The above formulation was spray-dried using Büchi's Mini Spray Dryer B-290 (Switzerland) under the following drying conditions: inlet temperature, 100 - 110°C; air flow rate, 450 - 500 L / h, aspirator, 90%, pump speed, 6.0 mL / min. Under these conditions, the outlet temperature was 45 - 50°C. The resulting powder was collected in a cyclone separator. These had a smooth spherical shape (particles formed without a shell-forming agent) or a wrinkled surface (with a shell-forming agent), as measured by a scanning electron microscope (SEM).

[0396] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulation was tested using a Next Generation Impactor (NGI). Up to 40 mg of the powder was filled into gelatin capsules (the exact amount varied depending on the required dose), dispersed at a flow rate of 100 L / min over 2.4 seconds using a low resistance Plastiape RS01 DPI device, and 4 L of air was inhaled. The amounts of nintedanib HBr and pirfenidone at each stage were collected and analyzed by HPLC. For some formulations, multiple runs may be required to collect sufficient amounts of the drug at the impactor stage. The fine particle fraction (FPF) and the mass median aerodynamic diameter (MMAD) are expected to be ≥50% and ≤5 μm, respectively. The formulation amounts for achieving the targets of nintedanib and pirfenidone, and the amounts filled into size 3 capsules.

[0397] Example 10. Optimization of the ratio of nintedanib to pirfenidone The formulations selected from the above formulations were filled into 3 - 4 capsules to produce fixed-dose combinations of nintedanib and pirfenidone in the ranges of 0.1 mg to 2 mg (free base) and 50 mg to 100 mg, respectively (Table 38).

[0398]

Table 37 - 1

[0399]

Table 37-2

[0400]

Table 37-3

[0401]

Table 37-4

[0402]

Table 37-5

[0403]

Table 37-6

[0404]

Table 37-7

[0405]

Table 37-8

[0406]

Table 37-9

[0407]

Table 37-10

[0408]

Table 37-11

[0409]

Table 37-12

[0410]

Table 37-13

[0411]

Table 37-14

[0412]

Table 37-15

[0413]

Table 37-16

[0414]

Table 37-17

[0415]

Table 37-18

[0416]

Table 37-19

[0417]

Table 37-20

[0418]

Table 37-21

[0419]

Table 37-22

[0420]

Table 37-23

[0421] Alternatively, a high drug-loading fixed-dose combination dry powder formulation of pirfenidone and nintedanib with highly porous particles having a high drug loading and high aerosol dispersibility is prepared from a perfluorocarbon emulsion. In this method, hollow particles of co-sprayed pirfenidone and nintedanib HBr, nintedanib base or other salts are prepared by spray drying technology using a Büchi mini spray dryer (Switzerland) or equivalent under the following spray conditions: suction: 100%, inlet temperature: 85 °C, outlet temperature: 61 °C, supply pump: 10%, N flow rate: 2,800 L / hour. The supply solution is prepared by dissolving pirfenidone and nintedanib in different ratios in 100 grams of water heated to 50 °C in the following various combinations. The formulated preparations of high drug-loading nintedanib or its salts and pirfenidone are shown in Table 39.

[0422]

Table 38

[0423] In another beaker, 5 g of distearoylphosphatidylcholine (DSPC) was homogenized in 750 g of hot water (50 °C) using a tabletop homogenizer. 125 grams of perfluorooctyl bromide was added dropwise to the solution while mixing. Next, this solution was homogenized with a high-pressure homogenizer. Then, this solution was mixed with a solution containing dissolved pirfenidone and nintedanib, and the resulting solution was passed through a high-pressure homogenizer to prepare a feedstock solution. This solution was fed to a spray dryer under the above conditions. A free-flowing white powder was collected with a cyclone separator. The hollow porous albuterol sulfate particles had a mass median aerodynamic diameter (MMAD) ≤ 5 μm as measured by the cascade impaction method. SEM analysis revealed that the powder was spherical and highly porous. The tapped density of the resulting powder was expected to be less than 0.2 g / cm3.

[0424] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulation was tested with a Next Generation Impactor (NGI). Approximately 20 - 30 mg of the powder was filled into gelatin or HPMC capsules and dispersed at a flow rate of 100 L / min for 2.4 seconds using a low-resistance Plastiape RS01 DPI device, and 4 L of air was inhaled. The amounts of nintedanib HBr and pirfenidone at each stage were collected and analyzed by HPLC. For some formulations, multiple runs may be required to collect sufficient amounts of the drug at the impactor stage. The fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) are expected to be ≥ 50% and ≤ 5 μm, respectively.

[0425] Example 12. Formulation of Nintedanib / PDE4 A fixed-dose dry powder formulation of nintedanib HBr, its base or other salts and a PDE4 inhibitor, such as roflumilast, apremilast, crisaborole, BI101555 and other PDE4 inhibitors, can be prepared with a lactose carrier blend. As a non-limiting example, nintedanib or its salt and roflumilast are micronized using a jet mill and reduced to a particle size of D90≤5μm and D50 1-2μm. The micronized nintedanib and roflumilast are mixed with a coarse lactose carrier (Lactohale 200) and fine lactose (Lactohale 300) and a lubricant (L-leucine, magnesium stearate) in various combinations shown in the following table. First, the lubricant (if applicable) was added layer by layer to Lactohale 200 in a metal container. The powder was mixed in a Turbula tumble blender at 48 rpm for 15 minutes. Roflumilast was added layer by layer to the resulting powder and mixed at 48 rpm for 15 minutes. Then, nintedanib was added layer by layer to the resulting powder mixture and mixed in a Turbula blender for 15 minutes. The finished powder formulation was tested for content uniformity with %RSD≤15% by sampling from various locations within the blend. The optimized formulation of nintedanib or its salt and a prostacyclin analog is shown in Table 40.

[0426]

Table 39

[0427] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulation is tested by a Next Generation Impactor (NGI). Approximately 20 mg of powder is filled into gelatin or HPMC capsules containing up to 2 mg of nintedanib and dispersed at a flow rate of 100 L / min over 2.4 seconds using a low resistance Plastiape RS01 DPI device, and 4 L of air is inhaled, which is considered the normal forced inspiratory volume of an average build male. The amount of nintedanib and roflumilast or other PDE4 inhibitor at each stage is recovered and analyzed by HPLC. For some formulations, multiple actuations may be required to collect a sufficient amount of drug at the impactor stage. The fine particle fraction (FPF) and the mass median aerodynamic diameter (MMAD) are expected to be 5 μm or less and 50% or more, respectively.

[0428] Example 13. Formulation of Nintedanib / Prostacyclin Analogue The fixed-dose dry powder formulation of nintedanib HBr, its base or other salts, and a prostacyclin analogue can be prepared with a lactose carrier blend. As a non-limiting example, the prostacyclin analogue may be selexipag, epoprostenol, iloprost, or treprostinil. Nintedanib and the prostacyclin analogue were micronized using a jet mill and reduced to a particle size of D90 ≤ 5 μm and D50 of 1 - 2 μm. The micronized nintedanib and prostacyclin analogue were mixed with a coarse lactose carrier (Lactohale 200), fine lactose (Lactohale 300), and glidants (L-leucine, magnesium stearate) in various combinations shown in the following table. First, the glidant (if applicable) was added to Lactohale 200 in two or three layers in a metal container. The powder was mixed in a Turbula tumble blender at 48 rpm for 15 minutes. The prostacyclin analogue was added to the resulting powder in two to three layers and mixed at 48 rpm for 15 minutes. Then, nintedanib or its salt was added layer by layer to the resulting powder mixture and mixed in the Turbula blender for 15 minutes. The finished powder formulation was tested for content uniformity with %RSD ≤ 15% by sampling from various locations within the blend. The optimized formulated products of nintedanib or its salt and the prostacyclin analogue are shown in Table 41.

[0429]

Table 40

[0430] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulations was tested by a Next Generation Impactor (NGI). Approximately 20 mg of the powder mixture was filled into each gelatin capsule. A low resistance Plastiape RS01 dry powder inhaler device was connected to the NGI and operated at 100 L / min for 2.4 seconds (to inhale 4 L of air) to measure the aerodynamic characteristics (MMAD and FPF) of the formulation. The amount of nintedanib HBr and selpercug in each stage was recovered and analyzed by HPLC. For some formulations, multiple actuations may be required to collect sufficient amounts of drug at the impactor stage. The fine particle fraction (FPF) and the aerodynamic mass median diameter (MMAD) are expected to be 5 μm or less and 50% or more, respectively.

[0431] Specific examples of the implementation of the present invention include the following.

[0432] The composition can be manufactured as a dry powder as described above and contains three important components to create a therapeutically effective dose. This dose contains 1 - 20% by weight of the nintedanib base molecule, which can also be provided in salt form using several different salt species as described above. Specific salt species include hydrobromide, esylate, and hydrochloride. The composition is provided in a defined portion based on a size range having a D90 of less than about 5 microns, 60 - 90% by weight of a carrier agent, and 0.01 - 20% by weight of a force control agent. In this unique formulation, the dry powder is designed for aerosol delivery to the adult lung by inhalation. When administered in the defined formulation, each therapeutically effective dose contains 0.005 - 10 mg of the nintedanib base or base within the salt form. Also, the therapeutically effective dose can be defined as an effective daily dose of 0.05 - 40 mg. The dry powder composition can also be defined as containing a nintedanib component having a fine particle fraction of 10% - 100%. The delivery of the above composition can also be defined as a fine particle dose of 0.005 mg or 0.05 mg to 10 mg of the nintedanib base or base within the salt form.

[0433] There are numerous indicators for measuring the health status of the lungs, and the therapeutic dosages of the present invention can improve various indicators for measuring the health status of the lungs. This includes slowing the progression of further inflammation, fibrosis, and / or demyelination, or preventing or reducing further inflammation, fibrosis, and / or demyelination. In the case of idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF), and restrictive allograft syndrome (RAS), the "therapeutic effect" is defined as a decrease in the level or rate of decline of forced vital capacity (FVC), and / or an improvement in the quality of life reported by the patient, and / or a statistically significant increase or stabilization of exercise tolerance and related blood oxygen saturation, a decrease in the decline of baseline forced vital capacity, a decrease in the incidence of acute exacerbation, an extension of the progression-free survival period, an extension of the time to death or disease progression, and / or a reduction in pulmonary fibrosis. In the case of CLAD, the "therapeutic effect" is defined as a decrease in the decline of forced expiratory volume in 1 second (FEV1).

[0434] The above disclosure describes the advantages of a dry powder composition having three important components for generating a therapeutically effective dosage. This dosage contains 1 to 20% by weight of the nintedanib base molecule, which can also be provided in salt form using several different salt species as described above. The composition is provided in a defined portion based on a size range having a D90 of less than about 5 microns, 60 to 90% by weight of a carrier agent, and 0.01 to 20% by weight of a force control agent. In this unique formulation, the dry powder is designed for aerosol delivery to the lungs of adults by inhalation. When administered in the defined formulation, each therapeutically effective dosage contains 0.005 to 10 mg of the nintedanib base or base within the salt form. Also, the therapeutically effective dosage can be defined as an effective daily dosage of 0.05 to 40 mg. In any of the desired formulations, the particle size of the nintedanib component is less than 5 microns, and in some cases, from 1 micron to 4 microns, and can be micronized.

[0435] Specifically, in the case of this formulation, delivery options include containment in a filled capsule, containment in a filled blister pack, or provision in a filled cassette for insertion into a dry powder inhaler device, or containment within the metering device reservoir of a dry powder inhaler.

[0436] The dry powder inhalers used in the present invention can have many performance parameters. The use of a medium-resistance or high-resistance dry powder inhalation device varies depending on the specific physiological functions or medical conditions of individual patients. The aforementioned formulation is particularly advantageous when used with a medium-resistance or high-resistance dry powder inhalation device and has unique advantages for the most difficult patients with interstitial lung disease.

[0437] As described above, one of the important components of the dry powder composition is the carrier agent. In one example, lactose is selected as the carrier agent, and even if other carrier agents can be modified to utilize the same physical and chemical properties of lactose, it provides specific advantages compared to other carrier agents.

[0438] As is well known in the art, nintedanib is typically delivered as an oral composition. One advantage of using a dry powder composition having three important components to generate a therapeutically effective dose as described above is that the dose has 1-20% by weight of nintedanib base molecules, can also be provided in the form of salts using several different salts, and is provided based on a defined size range or size range having a D90 of less than about 5 microns, 60-90% by weight of a carrier agent, and 0.01-20% by weight of a force control agent. The lung Cmax and / or AUC of nintedanib obtained after a single administration of the dry powder to a human using a dry powder inhaler is approximately the same as or higher than the lung Cmax and / or AUC of nintedanib obtained after a single oral administration of nintedanib to a human. The dose of orally administered nintedanib is about 80% to about 120% of the dose of the dry powder. This particular formulation can also be supplemented by adding other species useful for generating a dry powder composition having the parameters described above. In particular, additional components include bulking agents, surface modifiers, taste masking agents, sweeteners, salts, and combinations thereof.

[0439] By being able to provide a therapeutically effective dose of nintedanib, there is also an opportunity to add additional pharmaceutical active ingredients to address patients suffering from interstitial lung disease. A dry powder composition having three important components for creating a therapeutically effective dose as described above as part of a treatment regimen using multiple APIs, wherein the dose has 1-20% by weight of nintedanib base molecules, can also be provided in the form of salts using several different salt species, and is defined or provided in divided form based on a size range having a D90 of less than about 5 microns, 60-90% by weight of a carrier agent, and 0.01-20% by weight of a force control agent. It is used in a regimen including additional APIs in any of or combinations of dosing regimens including fixed combinations, simultaneous administration, sequential administration, or co-prescription with pirfenidone or pyridine analogs, PDE4 inhibitors or prostacyclin analogs.

[0440] For any of these species containing nintedanib as a pharmaceutical active ingredient, a number of specific formulations are contemplated. The nintedanib described in the previous paragraph can be provided as nanoparticles.

[0441] If the usefulness of a dry powder composition having three important components for generating a therapeutically effective dose is established, specific parameters of other elements other than the nintedanib composition can be defined. In particular, the bulking agent can be provided as lactose microparticles having a D50 of less than about 5 microns and a D90 of less than about 10 microns. Additional bulking agents for use with this nintedanib composition include leucine, trilucine, lecithin, magnesium stearate, sodium stearate, sucrose stearate, polyvinylpyrrolidone, ethyl cellulose, pluronic F-68, Cremophor RH40, glyceryl monostearate, and polyethylene glycol 6000, and combinations thereof. The bulking agent is defined as having a particle size distribution having a D50 of less than about 5 μm and a D90 of less than about 10 μm at a formulation content of more than 0.01% to about 20% on a weight-for-weight basis and containing lactose microparticles. The bulking agent may be about 0.1% to about 20% of leucine, trilucine, magnesium stearate, sodium stearate and lecithin, or combinations thereof.

[0442] In particularly preferred examples, the dry powder composition of the therapeutically effective dose has a particle size distribution of nintedanib of D10 of about 0.1 μm to about 2 μm, D50 of about 1 μm to about 3 μm, and D90 of about 1.5 μm to about 5 μm. In a preferred example, the carrier agent is lactose at a formulation content of about 60% to about 99% on a weight-for-weight basis, and the lactose carrier agent has a particle size distribution of D10 of about 5 μm to about 15 μm, D50 of about 50 μm to about 100 μm, and D90 of about 120 μm to about 160 μm.

Claims

1. A dry powder composition comprising therapeutically effective doses comprising 1% to 20% by weight of a nintedanib base or salt form having a particle size distribution defined to have a D90 of less than about 5 μm, 60% to 90% by weight of a carrier agent, and 0.01% to 20% by weight of a force control agent for aerosol delivery to the lungs of adults by inhalation, wherein each therapeutically effective dose comprises 0.05 to 10 mg of the nintedanib base or salt form, or a daily effective dose of 0.05 to 40 mg, for the treatment of interstitial lung disease.

2. The dry powder composition according to claim 1, wherein the therapeutically effective dose is contained in a pre-filled capsule, a pre-filled blister pack, or in a pre-filled cassette for insertion into a dry powder inhaler device, or contained in a metering device reservoir of a dry powder inhaler.

3. The dry powder composition according to claim 1, wherein the daily dose of the dry powder composition delivers approximately 0.05 mg to 40 mg of nintedanib base or a salt of the base per day.

4. The dry powder composition according to claim 1, which is delivered in combination with a dry powder inhaler device with medium or high resistance.

5. The dried powder composition according to claim 1, wherein the carrier agent is lactose.

6. The dry powder composition according to claim 1, wherein the unit dose of the dry powder composition has an amount and formulation that delivers each therapeutically effective dose in less than about 10 operations.

7. The dry powder composition according to claim 1, wherein the pulmonary Cmax and / or AUC of nintedanib obtained after a single administration of dry powder to a person using a dry powder inhaler is substantially the same as or greater than the pulmonary Cmax and / or AUC of nintedanib obtained after a single administration of orally administered nintedanib to a person at a dose that is approximately 80% to approximately 120% of the dry powder dose.

8. The dried powder composition according to claim 1, further comprising one or more additional components selected from bulking agents, surface modifiers, taste masking agents, sweeteners, salts, and combinations thereof.

9. The dried powder composition according to claim 1, wherein nintedanib is delivered in a dosage regimen including a fixed combination, co-administration, sequential administration, or simultaneous formulation with pirfenidone or a pyridine analog.

10. The dried powder composition according to claim 1, wherein nintedanib is delivered in a dosing regimen including a fixed combination, co-administration, sequential administration, or concurrent formulation with a PDE4 inhibitor or prostacyclin analog.

11. The dry powder composition according to claim 1, wherein the force control agent is lactose fine particles having a particle size distribution defined to have a D50 of less than about 5 μm and a D90 of less than about 10 μm.

12. The dried powder composition according to claim 1, wherein the nintedanib salt is hydrobromide.

13. The dried powder composition according to claim 1, wherein the nintedanib salt is esylate.

14. The dried powder composition according to claim 1, wherein the nintedanib salt is a hydrochloride.

15. The therapeutically effective dose of a dry powder composition according to claim 1, wherein the particle size distribution of nintedanib is defined to have D10 of about 0.1 μm to about 2 μm, D50 of about 1 μm to about 3 μm, and D90 of about 1.5 μm to about 5 μm.

16. Use of a therapeutically effective dose of a dry powder composition in the manufacture of a drug for treating interstitial lung disease, wherein the dry powder composition comprises 1% to 20% by weight of nintedanib base or nintedanib base in salt form having a particle size distribution defined to have a D90 of less than about 5 μm, 60% to 90% by weight of a carrier agent, and 0.01% to 20% by weight of a force control agent, wherein each therapeutically effective dose comprises 0.05 to 10 mg of nintedanib base or nintedanib base in salt form, or a daily effective dose of 0.05 to 40 mg.

17. The use according to claim 16, wherein the daily dose of the dried powder composition is approximately 0.05 mg to 40 mg of nintedanib base or nintedanib base in salt form per day.

18. The use according to claim 16, wherein aerosol delivery is achieved with a medium-resistance or high-resistance dry powder inhaler device.

19. The use according to claim 16, wherein the carrier agent is lactose.

20. The use according to claim 16, wherein the unit dose of the dry powder composition is delivered in less than about 10 operations.

21. The use according to claim 16, wherein the pulmonary Cmax and / or AUC of nintedanib obtained after a single dose of dry powder to a person using a dry powder inhaler is approximately the same as or greater than the pulmonary Cmax and / or AUC of nintedanib obtained after a single dose of orally administered nintedanib to a person at a dose that is approximately 80% to approximately 120% of the dry powder dose.

22. The use according to claim 16, wherein the dried powder composition further comprises one or more additional components selected from bulking agents, surface modifiers, taste masking agents, sweeteners, salts, and combinations thereof.

23. The use according to claim 16, wherein aerosol delivery is achieved by inhaling nintedanib from a single reservoir of a dry powder inhaler.

24. The use according to claim 16, wherein aerosol delivery is in accordance with a dosing plan including a fixed combination, simultaneous administration, sequential administration, or simultaneous prescription with pirfenidone or a pyridine analog.

25. The use according to claim 16, wherein aerosol delivery is in accordance with a dosing plan including a fixed combination, co-administration, sequential administration, or concurrent prescription with a PDE4 inhibitor or prostacyclin analog.

26. The use according to claim 16, wherein the force control agent is lactose microparticles having a particle size distribution defined to have a D50 of less than about 5 μm and a D90 of less than about 10 μm.

27. ​​The use according to claim 16, wherein the nintedanib salt is hydrobromide, and the weight percentage is equivalent to the amount of hydrobromide salt.

28. The use according to claim 16, wherein the nintedanib salt is esylate, and the weight percentage is equivalent to the amount of esylate salt.

29. The use according to claim 16, wherein the nintedanib salt is a hydrochloride, and the weight percentage is the equivalent amount of the hydrochloride salt.

30. The use according to claim 16, wherein the particle size distribution of nintedanib is defined to have D10 of about 0.1 μm to about 2 μm, D50 of about 1 μm to about 3 μm, and D90 of about 1.5 μm to about 5 μm.

31. The therapeutically effective dose is provided in multiple doses per day for administering at least 0.05 mg of nintedanib base or the salt form of nintedanib base, as per claim 16.

32. The use according to claim 31, wherein the therapeutically effective dose is administered in doses of 2 to 8 units, with each dose of 8 units containing 0.05 mg to 10 mg of nintedanib.

33. The use according to claim 16, wherein the therapeutically effective dose is delivered by a single dose once daily.

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