Nintedanib and nintedanib combined dry powder composition and application

Abstract

The present invention includes dry powder nintedanib formulations for dispersive and inhalation administration, including salts thereof, indolone derivatives or salts thereof, and in fixed dose combinations with a carrier agent and other active ingredients. The aerosol delivery combination formulation may be administered as an inhalation aerosol over several actuations or by two or more actuations. Each dose may be administered one or more times per day according to a regular or interval daily dosing regimen. Specific formulation parameters of the present invention include the selection of salts complexed with the nintedanib form for the isolated dry powder, as well as particle size distribution and in combination with force control agents to improve aerosol delivery. The methods of the invention comprise therapeutically effective doses of the described invention for the treatment of interstitial lung disease.

Description

Background of the Invention

[0002] Many lung diseases, such as interstitial lung disease (ILD; and its sub-groups), cancer (lung cancer; and its sub-groups), fibrotic indications of the lung, kidney, heart and eye, viral infections and diseases of the central nervous system are currently areas of unmet clinical need.

[0003] In fibrosis, scarring plays an important healing role in the healing after injury. However, after more chronic, repeated and or idiopathic injuries lead to dysfunction, the tissue may gradually become scarred. In the case of idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF); and other subclasses of ILD, if a sufficient proportion of the lungs become scarred, respiratory failure may occur. In any case, progressive scarring may be due to a series of repeated injuries in different areas of the organ, or failure to stop the repair process after the injury heals. In such cases, the scarring process becomes uncontrolled and deregulated. In some forms of fibrotic diseases, scarring is still confined to limited areas, but in other forms of fibrotic diseases, scarring may affect more diffuse and extensive areas, resulting in direct or related organ failure.

[0004] In epithelial injury, epithelial cells are triggered to release several profibrotic mediators, including the potent fibroblast growth factor transforming growth factor-β (TGF-β), tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), endothelin, other cytokines, metalloproteinases, and the coagulation mediator tissue factor. Importantly, the triggered epithelial cells become susceptible to apoptosis, and this, together with the apparent inability to restore the epithelial cell layer, is the fundamental abnormality in fibrotic diseases.

[0005] In cases such as diseases, physiological responses characterized by controlling profibrotic factors with indolinone derivatives (such as nintedanib) are beneficial for reducing and / or reversing fibrosis, treating cancer or central nervous system diseases. Therapeutic strategies that utilize the effects of such indolinone derivatives and / or nintedanib in these and other indications are contemplated herein.

[0006] Despite the development of many promising therapies, many pulmonary diseases, such as interstitial lung disease (ILD; and its sub-class diseases), cancer, vascular diseases and many viral infectious diseases still do not meet clinical needs. In addition, many extrapulmonary diseases may also benefit from nintedanib or drug-drug combinations therein, as well as inhalation delivery of formulations designed specifically to utilize inhalation device performance parameters. However, the development of advanced nintedanib and combination formulations for delivery by inhalation faces many challenges that have not yet been fully overcome. Summary of the invention

[0007] The special design considerations of nintedanib affect many parameters that are critical to the development of inhaled therapeutic products. By selectively manipulating formulation parameters and aerosol device parameters, target organ dose, pharmacokinetic profile, and safety profile can be improved to improve efficacy, safety, and maximize patient compliance. Compositions of nintedanib or its salts and indolinone derivatives or their salts suitable for inhaled delivery to the lungs, central nervous system, and / or systemic compartments and methods of use are described herein.

[0008] The present invention includes a dry powder formulation for dispersion and inhalation administration, which comprises nintedanib or its salt, or an indole derivative or its salt and one or more carriers or fillers. The bulk powder composition may also contain one or more force control agents accounting for about 0.01% to about 20% of the bulk composition. The force control agent can be leucine, trileucine, lecithin, magnesium stearate, sodium stearate, sucrose stearate, fine lactose, polyvinylpyrrolidone, ethylcellulose, Pluronic F-68, Cremophor RH 40, glyceryl monostearate and polyethylene glycol 6000. In addition, the bulk powder composition may contain inorganic salts, such as sodium chloride, magnesium chloride, calcium chloride, potassium chloride, sodium bromide, potassium bromide, magnesium bromide and calcium bromide and combinations thereof as stabilizers or auxiliary excipients, which account for about 0.01% to about 20% of the bulk composition. The bulk powder composition may also contain anions accounting for about 0.001% to about 10% of the bulk composition. The anion may be a bromide ion or a chloride ion. The bulk powder composition may also 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 also contain a sugar as a filler or stabilizer, such as lactose, mannitol, trehalose, dextrose. The bulk powder composition may also contain an amino acid in an amount of about 0.01% to about 20% of the bulk composition.

[0009] The present invention also includes a dry powder formulation for dispersion and inhalation administration, which contains 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 included in an amount of about 0.0001 mg to about 200 mg, and pirfenidone or a pyridine analog is included in an amount of about 1 mg to about 200 mg. Carrier

[0010] The present invention also includes a dry powder formulation for dispersion and inhalation administration, which contains 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. Carrier

[0011] The present invention also includes a dry powder formulation for dispersion and inhalation administration, which comprises nintedanib or its salt, or indolinone derivative or its salt, in a fixed dose combination with a prostacyclin analog. In this combination formulation, nintedanib or its salt, or indolinone derivative or its salt is included in an amount of about 0.0001mg to about 200mg, and a prostacyclin analog is included in an amount of about 0.001mg to about 10mg carrier. The dry powder formulation can be used as an inhalation aerosol, which is produced by nintedanib or its salt, or indolinone derivative or its salt (the range of dosage is about 0.0001mg to about 200mg) and a prostacyclin analog (the range is about 0.001mg to about 10mg per unit dose or single actuation). The combination formulation dosage can be used as an inhalation aerosol after several actuations or by two or more actuations. Each dose can be applied once or multiple times a day according to a regular or interval daily dosing regimen.

[0012] The special formulation parameters of the present invention include the selection of a salt complexed with the nintedanib form of the dry powder for separation. Preferred salts include ethanesulfonate, mesylate, hydrochloride and hydrobromide. In the dry powder formulation described herein, the total delivered dose is about 0.0001 mg to about 200 mg of nintedanib.

[0013] The present invention includes a kit comprising: a unit dose of a dry powder of nintedanib or a salt thereof as described herein, located in a container suitable for use with a dry powder inhaler for dispersion and inhalation of the resulting powder aerosol. 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.

[0014] In addition, the physicochemical properties of the resulting aerosol produced by the compositions and methods of the present invention are an important part of the therapeutic utility of the present invention, because the specially selected formulation design parameters, as well as the dry powder dispersion performed by the dry powder inhaler structure as described below, will produce an aerosol powder cloud having unique advantageous properties for delivering the active ingredient to the lung compartment, which is tailored for the pharmacodynamic absorption of the active pharmaceutical ingredient in the lung organ. The dispersed dry powder forms a cloud of nintedanib or its indolone salt, or nintedanib or its indolone salt particles with an average diameter of less than about 5.0 μm. The aerosol particles produced by the final bulk formulation placed in the dry powder inhaler are formulated as a specially designed powder containing about 0.0001 mg to about 200 mg of nintedanib or indolone or salt. Alternatively, the aerosol particles produced by the final bulk formulation placed in the dry powder inhaler are formulated as a specially designed powder containing about 0.01 mg to about 100 mg of nintedanib or indolone or its salt. Alternatively, the aerosol particles produced by the final bulk formulation placed in the dry powder inhaler are formulated as a specially designed powder containing about 0.01 mg to about 50 mg of nintedanib or indolinone or its salt. Such compositions may also include a combination of pirfenidone or pyridine analogs in an amount of 1 mg to 200 mg within particles with an average diameter of less than about 5 μm. Such compositions may also include a combination of a PDE4 inhibitor in an amount of 0.01 mg to 40 mg within particles with an average diameter of less than about 5 μm. Such compositions may also include a combination of a prostacyclin analog in an amount of 0.001 mg to 10 mg within particles with an average diameter of less than about 5 μm.

[0015] These and other aspects of the present invention will become apparent with 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 mentioned in this specification are incorporated herein by reference in their entirety, as if each patent was incorporated individually.

[0016] Certain terms

[0017] The term "mg" means milligrams.

[0018] The term "μg" means microgram.

[0019] The term "microM" refers to micromolar.

[0020] As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, use of the term "about" with respect to certain therapeutically effective drug doses indicates that the value is slightly outside the recited value, e.g., ±0.1% to 10%, which is also effective and safe.

[0021] As used herein, the terms "including," "comprising," "such as," and "for example" are used in their open, non-limiting sense.

[0022] The terms "administration" or "administering" and "delivery" or "delivery" refer to a method of administering a therapeutic or prophylactic formulation (such as nintedanib or a salt formulation thereof as described herein) to a human, for example as an anti-inflammatory, anti-fibrotic and / or anti-demyelinating pharmaceutical composition, or for other purposes. The preferred method of delivery or administration may vary depending on a variety of factors, such as the components of the pharmaceutical composition, the desired site to which the formulation is introduced, delivered or administered, the site where therapeutic benefit is sought, or the proximity of the initial delivery site to the downstream diseased organ (e.g., aerosol delivery to the lungs for absorption, and secondary delivery to the heart, kidneys, liver, central nervous system or other diseased destinations).

[0023] The terms "pulmonary administration" or "inhalation" or "pulmonary delivery" and other related terms refer to a method of delivering a dose of a therapeutic or prophylactic formulation to a human by a route such that the desired therapeutic or prophylactic agent is delivered to the lungs of the human.

[0024] The term "activation" refers to triggering the device to release a metered amount of the drug formulation.

[0025] The term "abnormal liver function" may be manifested as abnormal levels of biomarkers of liver function including alanine aminotransferase, aspartate aminotransferase, bilirubin and / or alkaline phosphatase, and is an indicator of drug-induced liver injury. See, FDA Draft Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation, October 2007.

[0026] The term "base" refers to the active molecule itself which may or may not be present with the corresponding salt. The description "base in salt form" refers to the active molecule itself in the corresponding salt form. The active molecular weights and weight percentages described herein refer to "base" or "base in salt form" and can be easily adjusted for equivalent weight or weight percentage based on the individual salt species selected for the salt form of the base.

[0027] "Grade 2 liver function abnormalities" include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) higher than 2.5 times the upper limit of normal (ULN) and less than or equal to 5 times. Grade 2 liver function abnormalities also include bilirubin levels increased to 1.5 times and less than or equal to 3 times the ULN.

[0028] "Gastrointestinal adverse events" include, but are not limited to, any one or more of the following: dyspepsia, nausea, diarrhea, gastroesophageal reflux disease (GERD), and vomiting.

[0029] A "carrier" or "excipient" is a compound or material used to facilitate the administration of a compound (e.g., to increase the solubility of the compound). Solid carriers include, for example, 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, in Merck Index, Merck & Company, Rahway, NJ. Considerations for including various components in a pharmaceutical composition are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th edition, Pergamon Press.

[0030] As used herein, a "diagnostic" is a compound, method, system, or device that aids in the identification and characterization of a health or disease state. Diagnostics can be used in standard assays as known in the art.

[0031] The term "filler" refers to an excipient used in a drug formulation to provide a matrix for the drug, usually present in small amounts.

[0032] The term "force control agent" refers to an excipient used in drug formulations to reduce the adhesion between the drug and carrier particles in a binder mixture for inhalation, and thereby increase the release of the drug during inhalation.

[0033] The terms "D10, D50, and D90" refer to the volume-based diameters of particles at the 10th, 50th, and 90th percentiles.

[0034] The term "carrier-free blend" refers to a dry powder inhalation blend that does not utilize inert excipients to aid in the dispersion of the drug particles.

[0035] The term "carrier blend" refers to a dry powder inhalation mixture that utilizes an inert excipient to reduce the cohesive forces between drug particles and thereby aid in the dispersion of the drug particles.

[0036] The term "shell forming agent" refers to an excipient used to form an outer shell in a spray-dried powder formulation, thereby enabling the formation of hollow or porous particles.

[0037] The term "glass former" refers to excipients used in spray-dried powder formulations to prevent the spray-dried particles from converting from an amorphous form to a crystalline form. The term "ex vivo" refers to experiments or procedures performed in or on living tissue in an artificial environment outside of an organism.

[0038] The term "low resistance" refers to dry powder inhalation devices where approximately 100 liters per minute are required to generate the 4 kPa pressure drop required to actuate and disperse the dry powder formulation contained therein.

[0039] The term "medium resistance" refers to a dry powder inhalation device in which approximately 85 liters per minute are required to generate the 4 kPa pressure drop required to actuate and disperse the dry powder formulation contained therein.

[0040] The term "high resistance" refers to dry powder inhalation devices wherein approximately 60 liters per minute are required to generate the 4 kPa pressure drop required to actuate and disperse the dry powder formulation contained therein.

[0041] "Solvate" refers to a compound formed by the interaction of a solvent with nintedanib or its indolinone derivative compound, metabolite or salt. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0042] "Therapeutically effective amount" or "pharmaceutically effective amount" means nintedanib or indolinone or salt, which is useful for treating humans in a therapeutically effective amount and produces the desired therapeutic effect, as judged based on clinical trial results and / or model animals for pulmonary fibrosis, chronic pulmonary allograft dysfunction (CLAD) associated with lung transplant rejection and restrictive allograft syndrome (RAS), cardiac fibrosis, renal fibrosis, liver fibrosis, cardiac or renal toxicity, cancer, or diseases caused by active, past or latent viral infection.

[0043] A "therapeutic effect" is a relief to some extent of one or more of the symptoms associated with inflammation, fibrosis, and / or demyelination. This includes slowing the progression of inflammation, fibrosis, and / or demyelination, or preventing or reducing additional inflammation, fibrosis, and / or demyelination. For idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF), and restrictive allograft syndrome (RAS), a "therapeutic effect" is defined as a reduction in the level or rate of decline in forced vital capacity (FVC) and / or an improvement in patient-reported quality of life and / or a statistically significant increase or stabilization in exercise tolerance and associated oxygen saturation, a reduction in the decline in baseline forced vital capacity, a reduction in the incidence of acute exacerbations, an increase in progression-free survival, an increase in time to death or disease progression, and / or a reduction in lung fibrosis. For CLAD, a "therapeutic effect" is defined as a reduction in the decline in forced expiratory volume in one second (FEV1). For cardiac fibrosis, "therapeutic effect" is defined as improvement in patient-reported quality of life and / or statistically significant improvement in cardiac function, reduction in fibrosis, reduction in cardiac stiffness, reduction or reversal of valvular stenosis, reduction in the incidence of arrhythmias, and / or reduction in atrial or ventricular remodeling. For renal fibrosis, "therapeutic effect" is defined as improvement in patient-reported quality of life and / or statistically significant improvement in glomerular filtration rate and related markers. For liver fibrosis, "therapeutic effect" is defined as improvement in patient-reported quality of life and / or statistically significant reduction in elevated transaminases (e.g., AST and ALT), alkaline phosphatase, gamma-glutamyl transferase, bilirubin, prothrombin time, globulin, and reversal of thrombocytopenia, leukopenia and neutropenia, and poor coagulability. Further, potential reversal of imaging, endoscopic or other pathological findings. For diseases caused by active, past or latent viral infections, "therapeutic effect" is defined as an improvement in patient-reported quality of life and / or a statistically significant reduction in viral load, an improvement in exercise capacity and related oxygen saturation, FEV1 and / or FVC, a slowing or cessation of its progression, an increase in progression-free survival, time to death or disease progression, and / or a reduction in the incidence or incidence of acute exacerbations or a reduction in neurological symptoms. The term "prophylactic treatment" refers to treating patients who are not yet ill but are susceptible to or at risk of a specific disease, or patients who are already ill but whose condition has not worsened when treated with the pharmaceutical composition described herein. The term "therapeutic treatment" refers to the administration of treatment to patients who already have a disease. Therefore, in a preferred embodiment, the treatment is the administration of a therapeutically effective amount of nintedanib or an indolinone derivative compound to a mammal (for therapeutic or preventive purposes).

[0044] The term "fine particle fraction" is the proportion of aerosolized particles having a diameter less than or equal to 5 microns.

[0045] The term "respirable delivered dose" or "fine particle dose" is the amount of drug particles equal to or smaller than 5 microns that are inhaled during the inhalation phase of the breathing simulator.

[0046] As used herein, "pulmonary deposition" refers to the fraction of a nominal dose of an active pharmaceutical ingredient (API) that is deposited on the inner surface of the lung.

[0047] The "nominal dose" or "loading dose" refers to the amount of medication placed in a dry powder inhaler prior to administration to humans. The amount of powder that contains the nominal dose is called the "fill amount."

[0048] "Dispersion" refers to the process of aerodynamically dispersing or spreading a dry powder formulation charge into a respirable fine drug particle fraction.

[0049] "Enhanced pharmacokinetic profile" means an improvement in some pharmacokinetic parameters. Pharmacokinetic parameters that may be improved include AUC last, AUC (0-∞) T max and optionally C max. The enhanced pharmacokinetic profile can be quantitatively measured by comparing the pharmacokinetic parameters obtained for a nominal dose of an active pharmaceutical ingredient (API) administered with one type of inhalation device with the same pharmacokinetic parameters obtained by oral administration of a composition of the same active pharmaceutical ingredient (API).

[0050] As used herein, "respiratory disorder" refers to a disease or condition that manifests physically in the respiratory tract, including but not limited to pulmonary fibrosis, cancer, disease caused by active, past or latent viral infection, bronchitis, chronic bronchitis, or emphysema.

[0051] "Drug absorption," or simply "absorption," generally refers to the process by which a drug moves from its site of delivery across a barrier into the blood vessels or site of action, for example, a drug is absorbed into the pulmonary capillary beds of the alveoli. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 is an initial scanning electron micrograph (SEM) of micronized nintedanib hydrobromide salt.

[0053] Figure 2 is a scanning electron micrograph (SEM) of micronized nintedanib hydrobromide after 5 months.

[0054] Figure 3 is the initial XRPD of micronized nintedanib HBr.

[0055] Figure 4 XRPD of nintedanib HBr – 1 month, 25° / 60RH and 40° / 75RH and after 5 months.

[0056] Figure 5 is the DSC of nintedanib HBr at initial, 1 month at 40° / 75RH and after 5 month intervals.

[0057] Figure 6 Figure 2 DVS adsorption / desorption cycles at initial, one month, two months, and three month intervals for trehalose:leucine:NHBr 80:10:10.

[0058] Figure 7 DVS adsorption / desorption cycles at initial and one month intervals with lactose:leucine:NHBr 80:10:10.

[0059] Figure 8 Figure 1 is a DVS adsorption / desorption cycle of trehalose:NHBr 90:10 at one month.

[0060] Fig. 9 Figure 2. DVS adsorption / desorption cycles of lactose:NHBr 90:10 at initial and one month intervals.

[0061] Fig.10 The DVS adsorption / desorption cycles were performed at 10 initial, one month, two months and three months intervals with lactose:leucine:NHBr ratio of 70:20:10.

[0062] Fig.11 DSC at 10 initial, one month, two months and three months intervals.

[0063] Fig.12 The DSC at 10 initial and one month intervals is lactose:leucine:NHBr 80:10:10 wt%.

[0064] Fig.13 DSC of trehalose:NHBr 90:10 wt % at one month interval.

[0065] Fig.14 DSC of lactose:NHBr 90:10 wt % at initial and one month intervals.

[0066] Fig.15 The DSC at 10 initial, one month, two months and three months intervals is lactose:leucine:NHBr 70:20:10 wt%.

[0067] Fig.16Shown are changes in blood glucose levels in sheep at two different times (A and B); sheep were given oral glucose in the absence of a previous dose of CuSO4 (glucose), or after CuSO4 administration (CuSO4+glucose). Data are mean ± SD of n = 4 sheep; **p < 0.01; ****p < 0.0001.

[0068] Fig.17 Peaks in blood glucose levels are shown, confirming effective closure of the sulcus reticularis following CuSO4 administration (CuSO4 + glucose). In the absence of CuSO4 (assessed at a separate time), no "peaks" in blood glucose levels were observed. Data are mean ± SD of n = 10 sheep; ****p < 0.0001.

[0069] Fig.18 Lung function assessments 1 to 4 are shown for sheep before and after treatment. (A) Transpulmonary pressure (index of airway resistance), (B) Dynamic Compliance Index, (C) Ventilation, (D) Tidal Volume, (E) Respiratory Rate, (F) Inspiratory Flow, and (G) Expiratory Flow. White bars = before dosing; grey bars = after dosing. Data shown: mean ± SEM of n = 6 sheep; *p < 0.05; one-way ANOVA with Sidak's multiple comparisons.

[0070] Fig.19 Sheep epithelial lining fluid (ELF) pharmacokinetics—dry powder versus nebulized inhaled nintedanib are shown.

[0071] Fig. 20 Sheep plasma pharmacokinetics - dry powder versus nebulized nintedanib are shown.

[0072] Fig.21 This is a scanning electron micrograph (SEM) of micronized nintedanib hydrobromide HBr.

[0073] Fig. 22 is the X-ray diffraction pattern of nintedanib hydrobromide. DETAILED DESCRIPTION

[0074] Nintedanib and indolone derivative compounds—therapeutic utility

[0075] The indolone derivative used in the indolone derivative formulations described herein includes nintedanib ((3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid methyl ester) or a salt thereof.

[0076]

[0077] Other indole derivative compounds or salts thereof can be used to replace nintedanib. Indole derivative compounds include but are not limited to those compounds having a structure similar to nintedanib and having the same type of biological activity as nintedanib. Indole derivative compounds include predictable modifications to nintedanib molecules based on substitutions of chemical moieties, which are based on the interaction of nintedanib to retain the structure activity relationship (SAR) of nintedanib, or as the subject derivatives of specific and selective inhibitors of certain tyrosine kinases, as described below. Indole derivative compounds include but are not limited to those compounds described in U.S. Patents 6,762,180 and 7,119,093.

[0078] Nintedanib inhibits a wide range of kinases at pharmacologically relevant concentrations. Examples of targeted kinases include all three VEGFR subtypes (VEGFR-1, IC50 34nM; VEGFR-2, IC50 21nM; VEGFR-3, IC50 13nM), FGFR types (FGFR-1, IC50 69nM; FGFR-2, IC50 37nM; FGFR-3, IC50 108nM; FGFR-4, IC50 610nM), and PDGFR-α (IC50, 59nM) and PDGFR-β (IC50, 65nM). The ability of Nintedanib to simultaneously target these three different angiogenic receptor classes can enhance its anti-tumor effects and overcome the pathways of resistance to VEGF-targeted agents and VEGFR-2-targeted agents. Nintedanib also inhibits Flt-3 and Src family members (Src, Lyn and Lck), which may have therapeutic potential for conditions such as blood disorders.

[0079] IPF and PPF are chronic and progressive fibrotic lung diseases with a short median survival of 2 to 3 years after diagnosis due to the lack of effective treatments. IPF and PPF are characterized by uncontrolled proliferation and differentiation of fibroblasts / myofibroblasts and excessive deposition of collagen in the lung interstitium and alveolar spaces, leading to symptoms of cough and dyspnea and ultimately respiratory failure.

[0080] In some embodiments, administration of nintedanib or indolone or a salt thereof by inhalation has reduced gastrointestinal and liver side effects compared to oral administration. Reducing these side effects increases patient safety, maximizes patient compliance, avoids dose reduction and / or discontinuation regimens, and enables increased local lung doses to achieve additional efficacy not possible with oral products.

[0081] In some embodiments, the combination of nintedanib or an indolone or a salt thereof and pirfenidone or a pyridine analog administered by inhalation has reduced gastrointestinal and hepatic side effects compared to additional oral administration of nintedanib and pirfenidone. Reducing these side effects increases patient safety, maximizes patient compliance, avoids dose reduction and / or discontinuation regimens, and enables increased local lung dose or optimization of the combination ratio to obtain additional efficacy not possible with treatment with two oral products.

[0082] Nintedanib or indolone dry powders specifically formulated for dispersion and inhalation administration are used in methods of treating human lung disease. These methods are applicable to diseases including, but not limited to, pulmonary fibrosis, idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, radiation-induced fibrosis, silicosis, asbestos-induced pulmonary 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, Kaplan syndrome, coal workers' pneumoconiosis, cryptogenic fibrosing alveolitis, bronchiolitis obliterans, chronic bronchitis, emphysema, pneumonia, lung cancer, Wegner's granulamatosis, scleroderma-associated pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease (SSc-ILD), silicosis, interstitial lung disease, asbestos-induced pulmonary and / or pleural fibrosis. In some methods, the primary lung disease is pulmonary fibrosis (i.e., pulmonary fibrosis), while in other methods, fibrosis is a comorbidity of a separate disease (such as cancer), or is a result of a previous infection or surgery, particularly including chronic lung allograft dysfunction (CLAD), and including restrictive allograft syndrome (RAS).

[0083] Pirfenidone and pyridone analog compounds—therapeutic utility

[0084] For 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-3-(1H)pyridone, 6-methyl-1-phenyl-1,2-dihydropyridin-2-one, 5-methyl-1-(4-methylphenyl)-2-(1H)-pyridone, 5-methyl-1-(2'-pyridyl)-2 ...1,2-dihydropyridin-2-one, 5-methyl-1-(4-methylphenyl)-2-(1H)-pyridone, 5-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)pyridone, including deuterated forms.

[0085] In epithelial injury, epithelial cells are triggered to release several pro-inflammatory and pro-fibrotic mediators, including interleukin-1β, the potent fibroblast growth factor transforming growth factor-β (TGF-β), tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), endothelins, other cytokines, metalloproteinases, and the coagulation mediator tissue factor. Importantly, the triggered epithelial cells become susceptible to apoptosis, and this, together with the apparent inability to restore the epithelial cell layer, is the fundamental abnormality in fibrotic diseases.

[0086] In diseases and other conditions, the physiological response characterized by controlling proinflammatory factors and profibrotic factors with pyridone analogs such as pirfenidone is beneficial to the treatment or prevention of fibrosis, inflammation or transplant rejection. The mechanism of action of pyridone analogs such as pirfenidone regulates the production of cytokines and growth factors. These effects may be directly caused by 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 proves that the anti-fibrotic effect observed in vivo is related to the regulation of ongoing fibrosis-related channels, and provides support for the observed anti-fibrotic effect. Pirfenidone has been approved as an oral therapy for the treatment of idiopathic pulmonary fibrosis. See U.S. Patents 10092552, 9770443, 10028966, 10105356 and 11123290, which are specifically incorporated herein by reference.

[0087] PDE4 inhibitors and isoform compounds—therapeutic utility

[0088] Phosphodiesterases (PDEs) mediate the hydrolysis of the second messengers cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). PDEs are encoded by 11 gene superfamilies containing multiple genes (encoding isoforms such as A, B, and C), which also produce alternative mRNA splicing variants, resulting in approximately 100 PDE isoforms.

[0089] PDE4 isoforms A to D are encoded by different genes PDE4A, B, C and D, where a set of N-terminal variants (long, short and ultrashort forms) are generated by post-translational processing depending on the presence or absence of the upstream conserved regions 1 and 2 (UCR1 or UCR2) N-terminal domains. PDE signaling is highly compartmentalized, as PDE4 isoforms can be integrated into macromolecular complexes called signalosomes.

[0090] PDE4 has traditionally been implicated in the regulation of inflammation and the modulation of immunocompetent cells, and the three selective PDE4 inhibitors currently available support a beneficial role for PDE4 inhibitors in inflammatory and / or autoimmune diseases. Evidence suggests that a range of immune cells and inflammatory responses are involved in pulmonary fibrosis.

[0091] The first PDE4 inhibitor, oral roflumilast Reducing the risk of COPD exacerbations in patients with severe COPD and a history of exacerbations associated with chronic bronchitis. Another compound, oral apremilast Effective in treating psoriatic arthritis and plaque psoriasis. The third PDE4 inhibitor, crisaborole Effective in treating mild to moderate atopic dermatitis.

[0092] 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 Clisborole each have the potential to be effective PDE4 inhibitors for the treatment of fibrotic diseases. In addition, BI 1015550 (PDE4B inhibitor) also shows promise. For the purposes of the present invention, PDE4 inhibitors include Roflumilast, Apremilast, Criborole, BI 1015550, CHF6001, Ronomilast, Oglemilast, GSK256066, YM976, GS5759, GPD-1116, MEM1414, RPL554, Asp3258, E6005, GW842470X, OPA-15406, Leo-29102, DRM02, Pefcalcitol, HFP034, CBS3995, MK0873, Revamilast, NCS 613, FCPR03, HT-0712, MK0952, API-4, ASP9831, including deuterated forms.

[0093] Prostacyclin analogs and isoforms—therapeutic utility

[0094] Prostacyclin analogs promote vasodilation of the pulmonary and systemic arterial vascular beds and inhibit platelet aggregation. In addition to the effects on the pulmonary vasculature, data show that prostacyclin analogs also have anti-fibrotic properties. By way of non-limiting example, prostacyclin analogs include Selexipag, Epoprostenol, Iloprost, Treprostinil. Specifically, these prostacyclin analogs have been shown to have a dose-dependent preventive effect on fibroblast proliferation, to reduce extracellular matrix compositions via TGF-β1 and PDGF-BB antagonism in human peripheral lung fibroblasts, to inhibit extracellular matrix deposition of fibroblasts by both cyclic adenosine monophosphate (cAMP)-dependent and -independent mechanisms in human peripheral lung fibroblasts, to inhibit the activity of profibrotic fibroblasts and the synthesis and deposition of collagen and fibronectin in mice by anti-inflammatory processes mediated by NK-κB signaling, and to inhibit the activation of prostaglandin (IP) receptors by Yes-associated protein (YAP) / transcription coactivator (TAZ) with PDZ binding motifs to inhibit the activity of profibrotic fibroblasts. Further, clinical results show that prostacyclin analogs may be beneficial to IPF patients. For the purposes of the present invention and by way of non-limiting example, prostacyclin analogs include treprostinil, iloprost, epoprostenol and treprostinil (Berapost), including deuterated forms.

[0095] Pulmonary fibrosis

[0096] A method for treating a pulmonary disease or preventing its progression, comprising administering nintedanib or an indolone or its salt or a combination with pirfenidone or a pyridone analogue or a PDE4 inhibitor or a prostacyclin analogue by oral inhalation of a dry powder aerosol to the middle and lower respiratory tract of a patient suffering from or suspected of suffering from a pulmonary disease. A method for treating interstitial pulmonary fibrosis or preventing its progression, and including a patient receiving mechanical ventilation.

[0097] A method for treating idiopathic pulmonary fibrosis (IPF) or preventing its progression, the method comprising administering nintedanib or an indolinone or a salt thereof or a combination thereof with pirfenidone or a pyridone analog to the middle and lower respiratory tract of a subject having or suspected of having IPF by oral inhalation of a dry powder aerosol comprising nintedanib or a salt thereof or a combination thereof with pirfenidone.

[0098] A method for treating progressive pulmonary fibrosis (PPF) or preventing its progression, the method comprising administering nintedanib or an indolinone or a salt thereof or a combination with pirfenidone or a pyridone analogue to the middle and lower respiratory tract of a subject having or suspected of having PPF by oral inhalation of a dry powder aerosol containing nintedanib or a salt thereof or a combination with pirfenidone.

[0099] A method for treating systemic sclerosis-related interstitial lung disease (SSc-ILD) or preventing its progression, the method comprising administering nintedanib or an indolinone or its salt or a combination with pirfenidone or a pyridone analog to the middle and lower respiratory tract of a subject having or suspected of having SSc-ILD by oral inhalation of a dry powder aerosol containing nintedanib or its salt or a combination with pirfenidone.

[0100] A method for treating bronchiolitis obliterans or preventing its progression, the method comprising administering nintedanib or an indolinone or a salt thereof or a combination with pirfenidone or a pyridone analogue to the middle and lower respiratory tract of a patient suffering from or suspected of suffering from bronchiolitis obliterans by oral inhalation of a dry powder aerosol comprising nintedanib or a salt thereof or a combination with pirfenidone.

[0101] A method for treating chronic pulmonary allograft dysfunction or preventing its progression, the method comprising administering nintedanib or its indolinone salt or a combination with pirfenidone or a pyridone analog to the middle and lower respiratory tract of a patient suffering from or suspected of suffering from chronic pulmonary allograft dysfunction by oral inhalation of a dry powder aerosol containing nintedanib or its salt or a combination with pirfenidone.

[0102] A method for treating restrictive allograft syndrome or preventing its progression, the method comprising administering nintedanib or its indolinone salt or in combination with pirfenidone or a pyridone analog by oral inhalation of a dry powder aerosol containing nintedanib or its salt or in combination with pirfenidone to the middle and lower respiratory tract of a patient suffering from or suspected of suffering from restrictive allograft syndrome.

[0103] As described herein, IPF refers to "idiopathic pulmonary fibrosis", and in some embodiments is a chronic disease that manifests itself for more than several years in the absence of known stimuli and is characterized by scar tissue within the lungs. Exercise-induced dyspnea and chronic dry cough may be prominent symptoms. IPF belongs to a 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 IIPs, which are distinguished according to specific clinical features and pathological patterns. IPF is the most common form of IIP. It is associated with a pathological pattern known as ordinary interstitial pneumonia (UIP); therefore, IPF is often referred to as IPF / UIP. IPF is usually fatal, with an average survival of about three years from the date of diagnosis. There is no single test for diagnosing pulmonary fibrosis; several different tests, including chest X-rays, HRCT, pulmonary function tests, exercise tests, bronchoscopy, and lung biopsy, are used in combination with the methods described herein.

[0104] 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 etiology; due to the absence of effective therapy, the results are often fatal. In some embodiments, nintedanib inhibits fibroblast proliferation and differentiation 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 reduces the level of platelet-derived growth factor (PDGF) A and B in bleomycin-induced pulmonary fibrosis. The methods and compositions described herein can provide tolerance and usefulness for patients with advanced idiopathic pulmonary fibrosis and other lung diseases. In some embodiments, the nintedanib methods and compositions described herein can provide tolerance and usefulness for patients with mild to moderate idiopathic pulmonary fibrosis. Increased patient survival, enhanced vital capacity, reduced acute exacerbations (compared to placebo) and / or slowed disease progression were observed after treatment with the composition of the present invention.

[0105] As described herein, PPF refers to "progressive pulmonary fibrosis". Like IPF, PPF is a chronic disease that manifests over several years and is characterized by scar tissue within the lungs. Exercise-induced dyspnea and chronic dry cough may be prominent symptoms. PPF also belongs to the family of interstitial lung disease (ILD), or more precisely, diffuse parenchymal lung disease. PPF explicitly excludes idiopathic pulmonary fibrosis. IPF is defined as an unexplained ILD associated with the histological or radiological pattern of usual interstitial pneumonia (UIP). PPF has specific criteria, mainly including worsening symptoms over time in non-IPF ILDs and increased radiofibrosis or respiratory physiology impairment. Despite the above-mentioned histological and radiological differences with IPF, its natural history is similar. PPF is usually fatal, with an average survival of approximately 3 to 5 years from the date of diagnosis. There is no single test for diagnosing PPF; several different tests, including chest X-ray, HRCT, pulmonary function tests, exercise tests, bronchoscopy and lung biopsy, are used in combination with the methods described herein.

[0106] Exemplary fibrotic lung diseases that are treated or prevented using the methods described herein include, but are not limited to, idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, pulmonary fibrosis secondary to transplant rejection (such as bronchiolitis obliterans and restrictive allograft syndrome), systemic inflammatory diseases (such as rheumatoid arthritis), scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, sarcoidosis, scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury, and acute respiratory distress (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced).

[0107] Where the methods of the invention are applied to treating lung cancer or preventing its progression, the conditions include lung carcinoid tumors or bronchial carcinoids, primary or secondary lung cancers arising from metastatic disease, including non-small cell lung cancer, bronchioloalveolar carcinoma, sarcomas, and lymphomas.

[0108] The methods of the invention include treating or preventing patients identified as having gastrointestinal stromal tumors, relapsed or refractory Ph-positive acute lymphoblastic leukemia (ALL), myelodysplasia / myeloproliferative disorders associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic macrocytosis (ASM) (without D816V c-KIT mutation or unknown), hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukemia (CEL), who have FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFR-α fusion kinase negative or unknown, or unresectable, recurrent and / or metastatic dermatofibrosarcoma protuberans, and combinations thereof.

[0109] Lung transplant rejection

[0110] Lung transplant rejection initially presents as chronic pulmonary allograft dysfunction (CLAD) and is a major cause of mortality. The main feature is bronchiolitis obliterans. In severe cases, the rate of decline in lung function is an average of about 7 times that observed in patients with idiopathic pulmonary fibrosis (IPF). Some patients with CLAD (approximately 30%) develop restrictive allograft syndrome (RAS) with a poor prognosis. These patients lose both FVC and forced vital capacity, resulting in restrictive lung function. Its pathophysiology is similar to that of IPF with progressive interstitial fibrosis.

[0111] A method for treating a pulmonary disease or preventing its progression, the method comprising administering nintedanib or indolinone or its salt to the middle and lower respiratory tract of a patient suffering from or suspected of having a pulmonary disease by oral inhalation of a dry powder aerosol. The method includes treating chronic pulmonary allograft dysfunction (CLAD) as a manifestation of lung transplant rejection or preventing its progression. The method includes delivery to a patient receiving mechanical ventilation. The method also includes combining nintedanib or indolinone or its salt with pirfenidone or a pyridone analog.

[0112] A method for treating a lung disease or preventing its progression, the method comprising administering nintedanib or indolinone or its salt to the middle and lower respiratory tract of a patient suffering from or suspected of having a lung disease by oral inhalation of a dry powder aerosol. The method includes treating bronchiolitis obliterans as a manifestation of lung transplant rejection or preventing its progression. The method includes delivery to a patient receiving mechanical ventilation. The method also includes administering nintedanib or indolinone or its salt in combination with pirfenidone or a pyridone analog.

[0113] A method for treating a lung disease or preventing its progression, the method comprising administering nintedanib or indolinone or its salt to the middle and lower respiratory tract of a patient suffering from or suspected of suffering from a lung disease by oral inhalation of a dry powder aerosol. The method includes treating a restrictive allograft syndrome (RAS) as a manifestation of lung transplant rejection or preventing its progression. The method includes delivery to a patient receiving mechanical ventilation. The method also includes combining administration of nintedanib or indolinone or its salt with pirfenidone or a pyridone analog.

[0114] Cardiac fibrosis

[0115] A method for treating extrapulmonary diseases or preventing their progression, the method comprising administering nintedanib or indolinone or its salt to the lower respiratory tract of a patient suffering from or suspected of suffering from cardiac fibrosis by oral inhalation of dry powder aerosol, wherein cardiac fibrosis includes cardiac tissue remodeling observed in chronic hypertension, and may involve myocyte hypertrophy and fibrosis, i.e., an increase and uneven deposition of extracellular matrix proteins. The extracellular matrix connects myocytes, arranges contractile elements, prevents myocytes from overstretching and destroying, transmits force and provides tensile strength to prevent rupture. Fibrosis occurs in many hypertension models, resulting in increased diastolic stiffness, decreased cardiac function and increased risk of arrhythmias. If fibrosis (rather than myocardial cell hypertrophy) is a key factor in impaired cardiovascular function, reversing cardiac fibrosis helps to restore normal cardiac function. The method also includes the combined administration of nintedanib or indolinone or its salt with pirfenidone or pyridone analogs.

[0116] By way of non-limiting example, the term "cardiac fibrosis" relates to remodeling associated with or caused by viral or bacterial infection, surgery, Duchenne muscular dystrophy, radiation therapy, chemotherapy, transplant rejection, and chronic hypertension, in which myocyte hypertrophy and fibrosis are involved, and increased and uneven deposition of extracellular matrix proteins occurs. Fibrosis occurs in many models of hypertension, leading to increased diastolic stiffness, decreased cardiac function, increased risk of arrhythmias, and impaired cardiovascular function.

[0117] cancer

[0118] A method for treating lung cancer or preventing its progression, the method comprising administering nintedanib or indolinone or its salt to the respiratory tract of a patient suffering from or suspected of having lung cancer by oral inhalation of a dry powder aerosol, wherein the lung cancer includes lung carcinoid tumors or bronchial carcinoids, primary or secondary lung cancer caused by metastatic disease, including non-small cell lung cancer, bronchioloalveolar carcinoma, sarcoma and lymphoma. The method also includes administering nintedanib or indolinone or its salt in combination with pirfenidone or a pyridone analog.

[0119] Lung cancer has a high mortality rate, and the number of deaths from lung cancer each year is equal to that of prostate cancer, breast cancer, colon cancer, and rectal cancer combined. Despite advances in knowledge of molecular mechanisms and the introduction of multiple new therapeutic lung cancer agents, the dismal 5-year survival rate (11% to 15%) remains relatively unchanged. This reflects the limited understanding of the factors that promote oncogenic transformation and proliferation of malignant cells.

[0120] We now know that tumor growth is not determined solely by malignant cells, as interactions between cancer cells and the stromal compartment have a major impact on cancer growth and progression. Aggressive malignant cells are adept at exploiting the tumor microenvironment: tumor cells can (1) reside in and transform the stroma, (2) alter the surrounding connective tissue, and (3) change the metabolism of resident cells, thereby creating a permissive rather than defensive stroma.

[0121] In addition to overcoming the host's microenvironmental control, a key property of cancer cells is their ability to invade tissues and metastasize to distant sites. For invasion and metastasis, the coordinated interaction between fibroblasts, immune cells, angiogenic cells, and factors is essential.

[0122] The tumor stroma is essentially composed of the following: (1) non-malignant cells of the tumor, such as CAFs, specialized mesenchymal cell types unique to each tissue environment, innate and adaptive immune cells, and a vasculature with endothelial cells and pericytes; and (2) the extracellular matrix (ECM), which is composed of structural proteins (collagen and elastin), specialized proteins (fibrillin, fibronectin and elastin), and proteoglycans. Angiogenesis is essential for cancer cell growth and survival and is the most successful matrix target in anticancer therapy to date. The initiation of angiogenesis requires matrix metalloproteinase (MMP) induction, resulting in basement membrane degradation, endothelial cell sprouting, and regulation of pericyte attachment. However, CAFs play an important role in synchronizing these events by expressing a large number of ECM molecules and growth factors, including transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF2).

[0123] The normal tissue stroma is essential for the maintenance and integrity of epithelial tissues and contains cells that collaborate to maintain normal tissue homeostasis. There is a continuous bilateral molecular crosstalk between normal epithelial cells and cells of the stromal compartment, mediated either by direct cell-cell contacts or through secreted molecules. Therefore, small changes in one compartment may result in large changes in the entire system.

[0124] There are similarities between stroma from wounds and tumors, as both entities have active angiogenesis and large numbers of proliferating fibroblasts that secrete a complex ECM, all against a background of fibrin deposition. Therefore, tumor stroma is often referred to as activated stroma or reactive stroma.

[0125] Genetic changes during cancer development (resulting in malignant cells) will therefore alter the matrix host compartment to establish a permissive and supportive environment for cancer cells. In the early stages of tumor development and invasion, the basement membrane degrades and an activated stroma containing fibroblasts, inflammatory infiltrates, and newly formed capillaries comes into direct contact with tumor cells. The basement membrane matrix also alters the cytokine interactions between cancer cells and fibroblasts. These cancer-induced matrix changes will contribute to cancer invasion. Animal studies have shown that both injured and activated stroma provide oncogenic signals to promote tumorigenesis. Although the normal stroma in most organs contains a minimal number of fibroblasts associated with the physiological ECM, the activated stroma is associated with more ECM-producing fibroblasts, enhanced vascularity, and increased ECM production. The formation of specific tumor stroma types at sites of active tumor cell invasion is considered a component of tumor invasion and is referred to as tumor stroma generation.

[0126] The expansion of the tumor stroma accompanied by the proliferation of fibroblasts and the dense deposition of ECM is called the desmoplastic reaction. It is secondary to malignant growth and can be distinguished from alveolar collapse, which shows neither activated fibroblasts nor dense collagen / ECM. Morphologically, this is called desmoplasia and was originally considered a defense mechanism to prevent tumor growth, but data show that in established tumors, this process is just the opposite and is involved in multiple aspects of tumor progression, such as angiogenesis, migration, invasion and metastasis. The latter studies have shown that fibroblasts and tumor cells can enhance local tissue growth and cancer progression by secreting ECM and degrading components of ECM within the tumor stroma. This is related to the release of substances (such as VEGF) sequestered in the ECM and the cleavage products from ECM proteins in response to the secretion of cancer-related MMPs.

[0127] Profibrotic growth factors released by cancer cells, such as TGF-β, platelet-derived growth factor (PDGF), and FGF2, control the volume and composition of the tumor stroma, as they are key mediators of fibroblast activation and tissue fibrosis. PDGF and FGF2 also play an important role in angiogenesis.

[0128] In tumors, activated fibroblasts are referred to as peritumoral fibroblasts or cancer-associated fibroblasts (CAFs). Like activated fibroblasts, CAFs are highly heterogeneous and are believed to originate from the same source as activated fibroblasts. The main progenitor cells appear to be locally resident fibroblasts, but they may also originate from pericytes and smooth muscle cells of the vasculature, bone marrow-derived mesenchymal cells, or through epithelial or endothelial-mesenchymal transition. The term CAF is rather vague because the origins of these cells vary and there are differences between activated fibroblasts and CAFs. There is increasing evidence that CAFs are epigenetically and possibly genetically distinct from normal fibroblasts. CAFs can be identified by their expression of α-smooth muscle actin, but due to heterogeneity, α-smooth muscle actin expression alone does not identify all CAFs. Therefore, other CAF markers used are fibroblast-specific protein 1, fibroblast activation protein (FAP), and PDGF receptor (PDGFR) α / β.

[0129] In response to tumor growth, fibroblasts are primarily activated by TGF-β, chemokines (such as monocyte chemoattractant protein 1), and ECM degraders (such as MMPs). Although several in vitro studies have demonstrated that normal fibroblasts have an inhibitory effect on cancer progression, there is now strong evidence that CAFs have a cancer-promoting role. In breast cancer, up to 80% of stromal fibroblasts are thought to have this activated phenotype (CAFs).

[0130] CAFs promote malignant growth, angiogenesis, invasion, and metastasis. The role of CAFs and their potential as targets for cancer therapy have been studied in xenograft models, and evidence from translational studies has revealed the prognostic significance of CAFs in several cancer types.

[0131] In the case of tumor growth, CAFs are activated and highly synthesized, thereby secreting, for example, type I and type IV collagen, extra-domain A-fibronectin, heparin sulfate proteoglycans, acidic and cysteine-rich secretory proteins, tenascin-C, connective tissue growth factor, MMPs and plasminogen activators. In addition to secreting growth factors and cytokines that affect cell motility, CAFs are also an important source of ECM-degrading proteases (such as MMPs), which play a variety of important roles in tumorigenesis. Through the degradation of ECM, MMPs can promote tumor growth, invasion, angiogenesis, recruitment and metastasis of inflammatory cells according to the substrate. In addition, many proinflammatory cytokines appear to be activated by MMPs.

[0132] Following injection of B16M melanoma cells in mice, the formation of liver metastases has been associated with early activation of stellate cells (fibroblast-like) in the liver, as these cells appear to be important for generating metastatic niches and promoting angiogenesis. MMPs have also been implicated in tumor angiogenesis in various in vivo models. When CAFs are co-injected into mice, they promote the invasiveness of otherwise non-invasive cancer cells. Furthermore, xenografts containing CAFs grow significantly faster than xenografts injected with normal fibroblasts.

[0133] When CAFs are recruited and accumulated in the tumor stroma, these cells will actively communicate with cancer cells, epithelial cells, endothelial cells, pericytes, and inflammatory cells by secreting a variety of growth factors, cytokines, and chemokines. CAFs provide potent oncogenic molecules such as TGF-β and hepatocyte growth factor (HGF).

[0134] TGF-β is a pleiotropic growth factor expressed by both cancer and stromal cells. In normal and precancerous cells, TGF-β is a suppressor of tumorigenesis, but as cancer cells progress, the antiproliferative effect disappears and, instead, TGF-β promotes tumorigenesis by inducing differentiation into an invasive phenotype. TGF-β may also trigger cancer progression by escaping immune surveillance, and increased TGF-β expression is closely associated with the accumulation of fibrotic desmoplastic tissue and cancer progression. Recently, it has been reported that small molecule inhibitors of the type I TGF-β receptor can inhibit the production of connective tissue growth factor by hepatocellular carcinoma (HCC) cells, leading to a decrease in the stromal components of HCC. Inhibition of the TGF-β receptor terminates the crosstalk between HCC and CAFs, thereby avoiding tumor proliferation, invasion, and metastasis. HGF belongs to the plasminogen family and is linked to the ECM in a precursor form. It binds to the high-affinity receptor c-Met, and overexpression or persistent oncogenic c-Met signaling leads to proliferation, invasion, and metastasis.

[0135] PDGF is a regulator of fibroblasts and pericytes and plays an important role in tumor progression. It is a chemokine and growth factor for mesenchymal and endothelial cells. It has limited autocrine effects in tumor cell replication but is a potential participant in a paracrine manner and in tumor stroma development. It induces proliferation of activated fibroblasts and may indirectly recruit CAFs by stimulating the release of TGF-β from macrophages.

[0136] Tumors cannot develop without the parallel expansion of the tumor stroma. Although we still do not understand the exact mechanisms regulating fibroblast activation and their accumulation in cancer, existing evidence suggests that the tumor stroma or CAFs may be candidate targets for cancer therapy.

[0137] CAFs and MMPs are considered two key regulators of epithelial-derived tumors, representing potential new targets for integrated therapies, affecting both the transformed and non-transformed components of the tumor environment. As reviewed previously, the experience with MMP inhibitors has not been successful so far. Evidence suggests that CAFs are epigenetically (and possibly genetically) different from normal fibroblasts, which begins to define these cells as potential targets for anticancer therapy. FAP, expressed in more than 90% of epithelial cancers, has long been a promising candidate for targeting CAFs, and the potential therapeutic benefits of its inhibition have recently been reviewed. In preclinical studies, abrogation of FAP attenuated tumor growth and significantly enhanced the uptake of anticancer drugs by tumor tissue. In a phase I study of patients with FAP-positive advanced cancers (colorectal cancer and NSCLC) treated with a FAP antibody, the antibody specifically bound to the tumor site, but no objective response was observed.

[0138] The consistent and repeated findings that cancer cells are susceptible to invasion and metastasis in response to TGF-β suggest the need for new anticancer drugs that target the oncogenic activity of TGF-β. Over the past decade, a large number of anti-TGF-β antibodies and TGF-β receptor I kinases have been preclinically tested. Due to the lack of success, targeting of the TGF-β signaling system remains elusive. It is noteworthy that TGF-β has both pro-tumor and anti-tumor effects, and the multifunctional nature of TGF-β clearly represents the greatest obstacle to effectively targeting this ligand, its receptor or downstream effectors.

[0139] combination

[0140] By way of non-limiting example, nintedanib or indolinone or a salt thereof is administered for the treatment of interstitial lung disease in a dosage regimen that includes a fixed combination, co-administration, sequential administration or co-prescription with a PDE4 inhibitor.

[0141] By way of non-limiting example, nintedanib or indolone or a salt thereof is administered for the treatment of interstitial lung disease in a dosage regimen that includes a fixed combination, co-administration, sequential administration or co-prescription with a prostacyclin analog.

[0142] By way of non-limiting example, nintedanib or an indolone or a salt thereof is administered for the treatment of interstitial lung disease in a dosage regimen that includes a fixed combination, co-administration, sequential administration or co-prescription with pirfenidone or a pyridine analog.

[0143] One promising approach to treating cancer is to administer "cocktail therapy" or "cocktail prevention," wherein the method comprises co-administering or sequentially administering inhaled nintedanib or indolone or its salt with a cancer-targeting agent, including but not limited to gefitinib (Iressa, also known as ZD1839), erlotinib (also known as Tarceva), bortezomib (originally codenamed PS-341; marketed as and ), Janus kinase inhibitors, ALK inhibitors, PARP inhibitors (Iniparib; BSI 201); PI3K inhibitors, Apatinib (YN968D1), Selumetinib, Salinomycin, Abitrexate (methotrexate), Abraxane (paclitaxel albumin-stabilized nanoparticle formulation), Afatinib Dimaleate, Alimta (pemetrexed disodium), Avastin (bevacizumab), Carboplatin, Cisplatin, Crizotinib, Erlotinib Hydrochloride, Folex (methotrexate), Folex PFS (methotrexate), Gefitinib, Afatinib (Afatinib Dimaleate), Gemcitabine Hydrochloride Hydrochloride), Gemcitabine (gemcitabine hydrochloride), Iressa (gefitinib), methotrexate, methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ (methotrexate), paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, Paraplat (carboplatin), Paraplatin (carboplatin), pemetrexed disodium, Platinol (cisplatin), Platinol-AQ (cisplatin), Tarceva (erlotinib hydrochloride), Taxol (paclitaxel), and Xalkori (crizotinib).

[0144] Combinations approved for NSCLC may include: carboplatin-paclitaxel and gemcitabine-cisplatin.

[0145] Drugs approved for small cell lung cancer may include: Abitrexate (methotrexate), Etopophos (etoposide phosphate), Etoposide (etoposide), Etoposide phosphate, Folex (methotrexate), Folex PFS (methotrexate), Hycamtin (topotecan hydrochloride), Methotrexate, Methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ (methotrexate), Toposar (etoposide), Topotecan hydrochloride, and VePesid (etoposide).

[0146] Drug Dosages, Formulations, and Packaging

[0147] When selecting a particular nintedanib composition or indolinone or salt thereof, a specially designed product packaging and configuration is selected to maximize the therapeutic utility of the particular composition. Factors to consider when selecting packaging may include, for example, intrinsic product stability, whether the formulation can be lyophilized, device selection (e.g., dry powder inhaler) and / or packaging format (e.g., dry powder formulation in vial, capsule or blister pack).

[0148] In a preferred embodiment, the composition will be in 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 contain a carrier or filler, such as lactose, mannitol, etc., together with the active ingredient; a lubricant, such as magnesium stearate, etc.; and / or a binder, such as starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose, cellulose derivatives, etc.

[0149] As described herein, the nintedanib or indolinone or its salt compound formulations or combinations can be divided into two groups; simple formulations or complex formulations, which provide taste masking to improve tolerance, stability and tolerability, immediate release or sustained release, and / or area under the curve (AUC) shape enhancement properties. Simple formulations may include dry powder inhalation nintedanib or indolinone formulations alone or together with water-soluble or organic-soluble non-encapsulating excipients, with or without a carrier agent (such as lactose).

[0150] Complex formulations containing active ingredients may include nintedanib or indolinone alone or in combination with active ingredients as described herein, encapsulated or complexed with water-soluble excipients such as lipids, liposomes, cyclodextrins, microencapsulation and emulsion dry powder formulations for administration of nintedanib or indolinone alone or in combination as described herein, as co-crystallized / co-precipitated / spray-dried complexes or mixtures in dry powder form with low water-soluble excipients / salts, with or without carrier agents such as lactose. Specific methods for the preparation of simple and complex formulations are described herein.

[0151] The compositions of the present invention comprise each dose consisting of about 0.05 mg to about 100 mg of nintedanib or indolone compound. The dose of nintedanib base or indolone compound base, or nintedanib salt or indolone salt thereof, can 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 indolone compound in increments of 0.01 mg. The composition of the present invention may further comprise each dose consisting of between 10% and 100% fine particle fraction, in increments of 1%. By way of non-limiting example, the fine particle fraction is 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 present invention may further comprise each dose consisting of a fine particle dose of about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib salt or its indolinone salt. By way of non-limiting example, about 0.001 mg, about 0.005 mg, about 0.01 mg, and about 0.05 mg, in increments of 0.01 mg. By way of further example, the fine particle dose can 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, in increments of 0.1 mg.

[0152] By way of non-limiting example, preferred embodiments contain micronized nintedanib or a salt thereof, including the hydrobromide salt in solid particles, whose particle size distribution is defined as having a D10 between about 0.1 μm and about 2 μm, a D50 between about 1 μm and about 3 μm, and a D90 between about 1.5 μm and about 5 μm, and whose formulation content is between about 1 wt% and about 20 wt% by weight. Preferred embodiments may further contain lactose, whose particle size distribution is defined as having 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, and whose formulation content is between about 60 wt% and about 99 wt% by weight. Preferred embodiments may further contain lactose fine powder, whose particle size distribution is defined as having a D50 of less than about 5 μm and a D90 of less than about 10 μm, and whose formulation content is between more than 0 wt% and about 20 wt% by weight. By weight, the composition may further contain about 0.1% to about 20% of one or more of the following force control agents: leucine, trileucine, magnesium stearate, sodium stearate and lecithin. The composition can be packaged in a capsule, a blister hole or a metering device reservoir, each of which is composed of a preferred dry powder formulation composition of about 1 mg to about 40 mg, for use with a dry powder inhaler. The preferred formulation described herein can emit a high dose from a medium resistance and high resistance dry powder inhalation device. For clarity, the medium resistance and high resistance devices are designed to require a lower inhalation flow rate to actuate and disperse the dry powder formulation dose, and are more suitable for people with lung disease and decreased lung function, whose inhalation flow rate may otherwise be insufficient to effectively actuate and disperse the dry powder dose from a low resistance device for inhalation application. Each dose can be administered in a manner of one, two, three, four or up to 20 inhalations per dose, wherein each inhalation represents the administration of the contents from a single capsule, a single blister hole or a single metering device reservoir dose. Each dose can be given once, twice, three times or four times daily, with a maximum daily dose of 200 mg nintedanib.

[0153] The methods of the present invention comprise treating a human suffering from an interstitial lung disease by administering an inhalable dry powder dose consisting of from about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base within a nintedanib salt or its indolinone salt. The dose of nintedanib base or indolinone compound base, or nintedanib salt or indolinone salt thereof, can 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 in increments of 0.01 mg. The methods of the present invention include treating a human with interstitial lung disease with an inhalable dry powder nintedanib or indolinone analog composition, wherein each dose consists of between 10% and 100% of the fine particle fraction, in increments of 1%. By way of non-limiting example, the fine particle fraction is 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 methods of the present invention include treating a human with interstitial lung disease with an inhalable dry powder composition, wherein the fine particle dose is from about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base within a nintedanib salt or its indolinone salt. By way of non-limiting example, about 0.001 mg, about 0.005 mg, about 0.01 mg, and about 0.05 mg, in increments of 0.01 mg. By way of further example, the fine particle dose can 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, in increments of 0.1 mg.The methods of the present invention comprise treating a human with interstitial lung disease with an inhaled dry powder nintedanib or indolinone analog composition once a day, twice a day, three times a day, four times a day, or five times a day, wherein each dose consists of about 0.05 mg to about 100 mg of nintedanib or indolinone compound, and the fine particle fraction is between about 10% and 100%, thereby delivering a fine particle dose of about 0.001 mg to about 100 mg of nintedanib or indolinone analog.

[0154] The composition of the present invention also comprises a dry powder combination of nintedanib or an indolinone analog and pirfenidone or a pyridone analog. By way of non-limiting example, each nintedanib or indolinone analog dose in the combination consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib salt or nintedanib base or indolinone base in its indolinone salt. The dose of nintedanib base or indolinone compound base, or nintedanib salt or its indolinone salt 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 nintedanib or indolinone compound in increments of 0.01 mg. By way of non-limiting example, each pirfenidone or pyridone analog dosage in combination is composed of about 5mg to about 100mg pirfenidone or pyridone analog compound. The pirfenidone or pyridone analog dosage in combination can be about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 35mg, about 40mg, about 45mg, about 50mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg or about 100mg pirfenidone or pyridone analog. The composition of the combined invention can further include each drug dosage consisting of a fine particle fraction between 10% and 100%, and the increment unit is 1%. By way of non-limiting example, the fine particle fraction of each drug is 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 invention may further comprise each dose consisting of a fine particle dose 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 fine particle dosage of nintedanib base or indolone base from the combined nintedanib base or indolone compound base, or nintedanib salt or its indolone salt can be 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 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 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 nintedanib base or indolinone base within a nintedanib salt or its indolinone salt, in increments of 0.1 mg. For example, the fine particle dose of pirfenidone or a pyridone analog compound from the combination can 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.

[0155] The mg:mg composition ratio of nintedanib or indolinone compound to pirfenidone or pyridone analog will be 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.

[0156] The method of the present invention includes optimizing the ratio of the co-prepared combination nintedanib or indolinone compound and pirfenidone or pyridone analogue, to avoid the chemical interaction or physiological effect of the co-preparation, compared with the nintedanib or indolinone delivered in the absence of the co-prepared pirfenidone or pyridone analogue, the chemical interaction or physiological effect increases the rate of the nintedanib or indolinone compound delivered by inhalation from the lung to plasma. By non-limiting example, 2:100 nintedanib: pirfenidone mg:mg ratio reduces lung nintedanib Cmax and increases plasma nintedanib Cmax by about 30-50%. In order to maximize the lung residence time of the co-prepared combination of inhaled nintedanib and pirfenidone, it is necessary to reduce this pharmacokinetic effect. By non-limiting example, this undesirable pharmacokinetic effect is minimized by reducing the pirfenidone content to less than 100mg per dose (wherein nintedanib: pirfenidone content ratio is between 1:30 and 1:100). By another non-limiting example, this undesirable pharmacokinetic effect is minimized by reducing the pirfenidone dose to less than 100 mg while maintaining a 1:20 to 1:50 mg:mg nintedanib:pirfenidone content ratio. By another non-limiting example, this undesirable pharmacokinetic effect is minimized by increasing the nintedanib co-formulation content such that the resulting mg:mg nintedanib:pirfenidone content ratio is less than 1:50.

[0157] The method of the present invention includes optimizing the ratio of the combination scheme of nintedanib or indolinone compound and pirfenidone or pyridone analog, to improve the therapeutic benefit, including efficacy, safety, tolerance and compliance. By non-limiting example, 100mg pirfenidone is present in the upper limit range of pirfenidone tolerance as an independent solution of atomization, and is close to the upper limit threshold of a compliant and well-tolerated dry powder product. By non-limiting example, it is expected that the efficacy of the dry powder product co-formulated with this nintedanib or indolinone compound and pirfenidone or pyridone analog will be greater than any active ingredient alone. In order to maximize the relationship between safety / tolerance / compliance and efficacy, reducing the total amount of dry powder application will improve compliance and increase the safety and tolerance of the combination product. Using the additional effect co-formulated 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 benefit of nintedanib or indolinone and pirfenidone or pyridone analog being applied to the patient. By way of non-limiting example, this desired result is produced by reducing the pirfenidone dose to less than 100 mg while maintaining a 1:25 to 1:500 mg:mg ratio of nintedanib:pirfenidone content. The methods of the present invention include treating a human with interstitial lung disease by administering a nintedanib or indolinone analog and pirfenidone or pyridone analog combination dry powder, wherein each nintedanib or indolinone analog dose within the combination consists of about 0.05 mg to about 100 mg of nintedanib or indolinone compound and about 5 mg to about 100 mg of pirfenidone or pyridone analog compound. The method of the present invention comprises treating a human suffering from interstitial lung disease with an inhaled dry powder nintedanib or an indolinone analog and pirfenidone or a pyridone analog combination composition, wherein each dose consists of between 10% and 100% of a fine particle fraction, wherein the resulting fine particle dose is from about 0.001 mg to about 100 mg of nintedanib or an indolinone analog and from about 5 mg to about 100 mg of pirfenidone or a pyridone analog. The methods of the present invention comprise treating a human with interstitial lung disease with an inhaled dry powder nintedanib or an indolinone analog and pirfenidone or a pyridone analog combination composition once a day, twice a day, three times a day, four times a day, or five times a day, wherein each dose consists of about 0.05 mg to about 100 mg of the nintedanib or indolinone compound and about 5 mg to about 100 mg of the pirfenidone or a pyridone analog compound, and the fine particle fraction is between about 10% and 100%, thereby delivering a fine particle dose of about 0.001 mg to about 100 mg of nintedanib or an indolinone analog and about 5 mg to about 100 mg of pirfenidone or a pyridone analog.

[0158] The composition of the present invention also comprises a combination dry powder of nintedanib or an indolinone analog and a PDE4 inhibitor. By way of non-limiting example, each nintedanib or indolinone analog dose in the combination consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base in a nintedanib salt or its indolinone salt. The dose of nintedanib base or indolinone compound base, or nintedanib salt or indolinone salt thereof, 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 nintedanib base or indolinone compound base, or nintedanib salt or indolinone salt thereof, in increments of 0.01 mg. By way of non-limiting example, each PDE4 inhibitor dose in the combination is composed of about 0.01 mg to about 100 mg of PDE4 inhibitor compound. The PDE4 inhibitor dose in the combination can 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 PDE4 inhibitor compound. The composition of the combined invention can further comprise each drug dose consisting of a fine particle fraction between 10% and 100%, with an increment unit of 1%. By way of non-limiting example, the fine particle fraction of each drug is 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 invention may further comprise each dose consisting of about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base within a nintedanib salt or its indolinone salt and 0.001 mg to about 100 mg of a fine particle dose of a PDE4 inhibitor compound.For example, for nintedanib or an indolinone analog, the fine particle dose from the combination can be 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 nintedanib base or indolinone base within a nintedanib salt or its indolinone salt, in increments of 0.1 mg. For example, for a PDE4 inhibitor, the fine particle dose from the combination can be 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 PDE4 inhibitor compound in increments of 0.1 mg.

[0159] The compositions of the present invention will comprise a mg:mg ratio of nintedanib or indolinone compound to 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.

[0160] The method of the present invention includes optimizing the ratio of the co-prepared combination nintedanib or indolinone compound and PDE4 inhibitor to improve the therapeutic benefit. By non-limiting examples, it is expected that the effect of the dry powder product co-prepared by this nintedanib or indolinone compound PDE4 inhibitor will be greater than any active ingredient alone. In order to maximize the relationship between safety / tolerance / compliance and efficacy, reducing the total amount of dry powder application can improve compliance and increase the safety and tolerance of the combination product. Utilizing the additional effect, the amount co-prepared with nintedanib or indolinone compound and PDE4 inhibitor in the co-prepared dry powder product can be reduced, while maintaining the overall additional benefit of nintedanib or indolinone and PDE4 inhibitor being applied to the patient. By non-limiting examples, the ratio is optimized by reducing the PDE4 inhibitor content to less than 40mg per dose (wherein based on mg:mg, nintedanib: PDE4 inhibitor content ratio is between 1:4 and 1:400). By non-limiting examples, the ratio is optimized by reducing the PDE4 inhibitor content to less than 30mg per dose (wherein based on mg:mg, nintedanib: PDE4 inhibitor content ratio is between 1:4 and 1:400). By non-limiting examples, the ratio is optimized by reducing the PDE4 inhibitor content to less than 20mg per dose (wherein based on mg:mg, nintedanib: PDE4 inhibitor content ratio is between 1:4 and 1:400). By non-limiting examples, the ratio is optimized by reducing the PDE4 inhibitor content to less than 10mg per dose (wherein based on mg:mg, nintedanib: PDE4 inhibitor content ratio is between 1:4 and 1:400). By non-limiting examples, the ratio is optimized by reducing the PDE4 inhibitor content to less than 5mg per dose (wherein based on mg:mg, nintedanib: PDE4 inhibitor content ratio is between 1:4 and 1:400). By way of non-limiting example, this ratio is optimized by reducing the PDE4 inhibitor content to less than 1 mg per dose (wherein the nintedanib:PDE4 inhibitor content ratio is between 1:4 and 1:400 on a mg:mg basis).

[0161] The methods of the present invention include treating a human with interstitial lung disease by administering a nintedanib or indolinone analog and PDE4 inhibitor combination dry powder, wherein each nintedanib or indolinone analog dose within the combination consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base within a nintedanib salt or its indolinone salt, and 0.01 mg to about 100 mg of the PDE4 inhibitor compound. The methods of the present invention include treating a human with interstitial lung disease with an inhalable dry powder nintedanib or indolinone analog and PDE4 inhibitor combination composition, wherein each dose consists of a fine particle fraction between 10% and 100%, wherein the resulting fine particle dose is between about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base within a nintedanib salt or its indolinone salt, and between about 0.001 mg to about 100 mg of the PDE4 inhibitor. The methods of the present invention comprise treating a human with interstitial lung disease with an inhaled dry powder nintedanib or an indolinone analog and pirfenidone or a pyridone analog combination composition once daily, twice daily, three times daily, four times daily, or five times daily, wherein each dose consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base within a nintedanib salt or its indolinone salt, and about 0.01 mg to about 100 mg of a PDE4 inhibitor compound, and the fine particle fraction is between about 10% and 100%, thereby delivering a fine particle dose of about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base within a nintedanib salt or its indolinone salt, and about 0.001 mg to about 100 mg of a PDE4 inhibitor compound.

[0162] The composition of the present invention also comprises a dry powder combination of nintedanib or an indolinone analog and a prostacyclin analog. By way of non-limiting example, each nintedanib or indolinone analog dose in the combination consists of about 0.05 mg to about 100 mg of nintedanib base or indolinone compound base, or nintedanib base or indolinone base in a nintedanib salt or its indolinone salt. The dose of nintedanib base or indolinone compound base, or nintedanib salt or indolinone salt thereof, can 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 nintedanib salt or indolinone salt thereof, in increments of 0.01 mg. By way of non-limiting example, each prostacyclin analog dosage in the combination consists of about 0.001 mg to about 10 mg of the prostacyclin analog compound. The prostacyclin analog dosage in the combination can be 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 0.096 mg, about 0.010 mg, about 0.011 mg, about 0.012 mg, about 0.013 mg, about 0.014 mg, about 0.015 mg, about 0.016 mg, about 0.017 mg, about 0.018 mg, about 0.019 mg, about 0.110 mg, about 0.111 mg, about 0.112 mg, about 0.113 mg, about 0.114 mg, about 0.115 mg, about 0.116 mg, about 0.117 mg 1mg, about 0.15, about 0.2mg, about 0.25mg, about 0.3mg, about 0.35mg, about 0.4mg, about 0.45mg, about 0.5mg, about 0.55mg, about 0.6mg, about 0.65mg, about 0.7mg, about 0.75mg, about 0.8mg, about 0.85mg, about 0.9mg, about 0.95mg, about 1.0mg, about 1.1mg, about 1.5mg, about 2mg, about 3mg, about 4mg, about 5mg and about 10mg prostacyclin analog compound, in increments of 0.001mg. The composition of the combined invention may further comprise each drug dose consisting of between 10% and 100% of the fine particle fraction, in increments of 1%.By way of non-limiting example, the fine particle fraction of each drug is 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 invention may further comprise each dose consisting of a fine particle dose of between about 0.001 mg to about 100 mg of nintedanib base or indolinone compound base, or a nintedanib salt or its indolinone salt, and about 0.0001 mg to about 10 mg of the prostacyclin analog compound. For example, the dosage of fine particles of nintedanib base or indolone base from the combined nintedanib base or indolone compound base, or nintedanib salt or indolone salt thereof can be 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 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 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 nintedanib base or indolinone base within a nintedanib salt or its indolinone salt, in 0.1 mg increments.By way of non-limiting example, the dosage of the prostacyclin analog fine particles from the combination can be 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 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 0.01 mg, about 0.015 mg, about 0.025 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 in increments of 0.0001 mg.

[0163] The compositions of the present invention will comprise a mg:mg ratio of nintedanib or indolinone compound to prostacyclin analog of 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.

[0164] The method of the present invention includes optimizing the ratio of the co-prepared combination of nintedanib or indolinone compound and prostacyclin analog to improve the therapeutic benefit. By non-limiting example, it is expected that the efficacy of the dry powder product co-prepared with this nintedanib or indolinone compound prostacyclin analog will be greater than any active ingredient alone. In order to maximize the relationship between safety / tolerance / compliance and efficacy, reducing the total amount of dry powder application will improve compliance and increase the safety and tolerance of the combination product. Utilizing the additive effect, the amount co-prepared with nintedanib or indolinone compound and prostacyclin analog in the co-prepared dry powder product can be reduced, while maintaining the overall additional benefit of nintedanib or indolinone and prostacyclin analog being applied to the patient. By non-limiting example, the ratio is optimized by reducing the prostacyclin analog content to less than 0.04mg per dose (wherein based on mg:mg, nintedanib: prostacyclin analog content ratio is between 1:4 and 250:1). By way of non-limiting example, the ratio is optimized by reducing the prostacyclin analog content to less than 0.02 mg per dose (wherein the ratio of nintedanib:prostacyclin analog content is between 1:4 and 250:1 on a mg:mg basis). By way of non-limiting example, the ratio is optimized by reducing the prostacyclin analog content to less than 0.018 mg per dose (wherein the ratio of nintedanib:prostacyclin analog content is between 1:4 and 250:1 on a mg:mg basis). By way of non-limiting example, the ratio is optimized by reducing the prostacyclin analog content to less than 0.015 mg per dose (wherein the ratio of nintedanib:prostacyclin analog content is between 1:4 and 250:1 on a mg:mg basis). By way of non-limiting example, the ratio is optimized by reducing the prostacyclin analog content to less than 0.01 mg per dose (wherein the ratio of nintedanib:prostacyclin analog content is between 1:4 and 250:1 on a mg:mg basis). By way of non-limiting example, the ratio is optimized by reducing the prostacyclin analog content to less than 0.005 mg per dose (wherein the ratio of nintedanib:prostacyclin analog content is between 1:4 and 250:1 on a mg:mg basis).

[0165] The methods of the invention include treating a human with interstitial lung disease by administering a nintedanib or indolinone analog and a prostacyclin analog combination dry powder, wherein each nintedanib or indolinone analog dose within the combination consists of about 0.05 mg to about 100 mg of the nintedanib or indolinone compound and about 0.001 mg to about 10 mg of the prostacyclin analog compound. The methods of the invention include treating a human with interstitial lung disease with an inhalable dry powder nintedanib or indolinone analog and prostacyclin analog combination composition, wherein each dose consists of a fine particle fraction between 10% and 100%, wherein the resulting fine particle dose is between about 0.001 mg to about 100 mg of the nintedanib or indolinone analog and between about 0.0001 mg to about 10 mg of the prostacyclin analog compound. The methods of the invention comprise treating a human with interstitial lung disease with an inhaled dry powder nintedanib or an indolinone analog and pirfenidone or a pyridone analog combination composition once a day, twice a day, three times a day, four times a day, or five times a day, wherein each dose consists of about 0.05 mg to about 100 mg of the nintedanib or indolinone compound and between about 0.001 mg to about 10 mg of the prostacyclin analog compound, and the fine particle fraction is between about 10% and 100%, thereby delivering a fine particle dose of between about 0.001 mg to about 100 mg of the nintedanib or indolinone analog and between about 0.0001 mg to about 10 mg of the prostacyclin analog compound.

[0166] In other embodiments, nintedanib or indolinone or combination described herein comprises a taste masking agent, which includes sugar, saccharin (e.g., sodium saccharin), sweeteners or other compounds or agents that beneficially affect the taste, aftertaste, perceived unpleasant salty, sour or bitter taste, or reduce the tendency of oral or inhaled formulations to irritate the recipient (e.g., by causing coughing or sore throat or other undesirable side effects, such as potentially reducing the delivered dose or adversely affecting the patient's compliance with the prescribed treatment regimen). Certain taste masking agents can form a complex with nintedanib or indolinone or a salt thereof.

[0167] In another embodiment, the counterion of the salt form of nintedanib or indolone is acetate, acetonide, alanine, aluminum, arginine, ascorbate, asparagine, aspartic acid, benzathine penicillin, benzoate, benzenesulfonate, bisulfate, bisulfite, bitartrate, bromide (including bromide and hydrobromide), calcium, carbonate, camphorsulfonate, cetylpyridinium, chloride (including chloride and hydrochloride), chlorophylline Acid, choline, cysteine, deoxycholate, diethanolamine, diethylamine, diphosphate, dipropionate, disalicylate, edetate, edisulphonate, etopoate, ethylamine, ethylenediamine, ethanedisulfonate, ethanesulfonate, ethanesulfonate hydroxide, glucoheptanoate, gluconate, glucuronide, glutamic acid, glutamine, glycine, hippurate, histidine, hydrobromide, hydrochloride, hydroxide, iodide, isethionate Acid, isoleucine, lactic acid, lactobionate, lauryl sulfate, leucine, lysine, magnesium, mandelate, meglumine, methanesulfonate, pyrosulfate, pyrosulfite, methionine, methyl bromide, methylsulfate, methylparaben, mucate, naphthoate, naphthosulfate, nitrate, nitrite, octadecanoate, oleate, ornithine, oxalate, pamoate, pentetate, phenylalanine, phosphate, piperazine, polygalacturon alanine, threonine, toluenesulfonate, triethylamine, triethyl iodide, trifluoroacetate, trioleate, tromethamine, tryptophan, tyrosine, valerate, valine, xinafoate, or zinc.

[0168] Nintedanib salt forms or indolone salt forms are prepared as chloride or bromide salt forms.

[0169] In some embodiments, described herein is a kit comprising: a unit dose of a dry powder formulation of nintedanib or an indolinone or a salt thereof, as described herein, in a container suitable for use in a dry powder inhalation device.

[0170] In some embodiments, described herein is a kit comprising: a unit dose of a dry powder formulation of nintedanib or an indolinone or a salt thereof in combination with pirfenidone, as described herein, in a container suitable for use in a dry powder inhalation device.

[0171] In some embodiments, described herein is a kit comprising: a unit dose of a dry powder formulation of nintedanib or an indolinone or a salt thereof in combination with a PDE4 inhibitor, as described herein, in a container suitable for use in a dry powder inhalation device.

[0172] In some embodiments, described herein is a kit comprising: a unit dose of a dry powder formulation of nintedanib or an indolinone or a salt thereof in combination with a prostacyclin analog, as described herein, in a container suitable for use in a dry powder inhalation device.

[0173] The aerosol comprising a plurality of dry powder particles has a mass median aerodynamic 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.

[0174] The present invention comprises a dry powder formulation comprising a finely divided form of nintedanib or a salt thereof, or an indolinone derivative or a salt thereof, in a concentration of 0.1% w / w to about 100% w / w, with a mass median diameter of 0.5 microns to 10 microns. About 10% to about 99.99% of nintedanib or a salt thereof, or an indolinone or a salt thereof and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) to improve the handling, distribution, metering and dispersion of the drug. The formulation may optionally contain one or more slip agents (e.g., L-leucine, trileucine, sodium stearate, magnesium stearate) in a concentration of about 0.1% w / w to about 10% w / w to reduce interparticle adhesion, improve powder flowability and reduce the effect of moisture. The formulation can be prepared by physically blending nintedanib or a salt thereof with the above excipients. Alternatively, dry powder formulations may be formed by precipitation techniques including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification or freeze drying. For these formulations, in addition to the excipients for the blended dry powder formulations described above, these formulations may also contain 10% w / w to about 99.9% w / w of phospholipids (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidonylphosphatidylcholine, dibehenylphosphatidylcholine, diphosphatidylglycerol) to act as emulsifiers and fillers. Optionally, the formulations of the present invention may also contain about 0.1% w / w 99.9% w / w of a biocompatible, preferably biodegradable polymer, copolymer, or blend or other combinations thereof. Examples of polymers include, but are not limited to, polylactide, polylactide-glycoside, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinylpyrrolidone, polysaccharides (glucan, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.). The dry powder can be packaged in a unit dose in a blister pack or capsule 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 100 mg when used.

[0175] The present invention comprises a dry powder formulation comprising a finely divided form of nintedanib or a salt thereof, or an indolinone derivative or a salt thereof and pirfenidone at a combined drug concentration of 0.1% w / w to about 100% w / w, with a mass median aerodynamic diameter of less than 5 microns. About 10% to about 99.99% of nintedanib or a salt thereof, or an indolinone or a salt thereof and pirfenidone and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) to improve the handling, distribution, metering and dispersion of the drug. The formulation may optionally contain one or more slip agents (e.g., L-leucine, trileucine, sodium stearate, magnesium stearate) at a concentration of about 0.1% w / w to about 10% w / w to reduce interparticle adhesion, improve powder flowability and reduce the effect of moisture. The formulation can be prepared by physically blending nintedanib or a salt thereof and pirfenidone with the above excipients. Alternatively, dry powder formulations can be formed by precipitation techniques, including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification or lyophilization. For these preparations, in addition to the excipients for mixed dry powder formulations described above, they can also contain 10% w / w to about 99.9% w of phospholipids (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidonylphosphatidylcholine, dibehenylphosphatidylcholine, diphosphatidylglycerol) to act as emulsifiers and fillers. Optionally, the formulations of the present invention can also include about 0.1% w / w 99.9% w / w of biocompatible, preferably biodegradable polymers, copolymers, or blends or other combinations thereof. Examples of polymers include, but are not limited to, polylactide, polylactide-glycoside, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinylpyrrolidone, polysaccharides (glucan, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.). The dry powder can be packaged in a unit dose in a blister pack or capsule 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 when used.

[0176] The present invention comprises a dry powder formulation comprising nintedanib or its salt, or indolinone derivative or its salt and PDE4 inhibitor in finely divided form at a combined drug concentration of 0.1% w / w to about 100% w / w, with a mass median aerodynamic diameter of less than 5 microns. About 10% to about 99.99% of nintedanib or its salt, or indolinone or its salt and PDE4 inhibitor and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) to improve drug handling, distribution, metering and dispersion. The formulation may optionally contain one or more slip agents (e.g., L-leucine, trileucine, sodium stearate, magnesium stearate) at a concentration of about 0.1% w / w to about 10% w / w to reduce interparticle adhesion, improve powder flowability and reduce the effect of moisture. The formulation can be prepared by physically blending nintedanib or its salt and PDE4 inhibitor with the above excipients. Alternatively, dry powder formulations may be formed by precipitation techniques including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification or freeze drying. For these formulations, in addition to the excipients for the blended dry powder formulations described above, these formulations may also contain 10% w / w to about 99.9% w / w of phospholipids (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidonylphosphatidylcholine, dibehenylphosphatidylcholine, diphosphatidylglycerol) to act as emulsifiers and fillers. Optionally, the formulations of the present invention may also contain about 0.1% w / w 99.9% w / w of a biocompatible, preferably biodegradable polymer, copolymer, or blend or other combinations thereof. Examples of polymers include, but are not limited to, polylactide, polylactide-glycolide, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydrides, polylactams, polyvinylpyrrolidone, polysaccharides (glucan, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.). The dry powder can be packaged in a blister pack or capsule with a fill weight of 0.01 mg to 100 mg in a unit dose. Alternatively, the dry powder formulation can be packaged in a device reservoir that measures 0.01 mg to 100 mg when in use.

[0177] The present invention comprises a dry powder formulation comprising a finely divided form of nintedanib or a salt thereof, or an indolinone derivative or a salt thereof and a prostacyclin analogue at a combined drug concentration of 0.1% w / w to about 100% w / w, with a mass median aerodynamic diameter of less than 5 microns. About 10% to about 99.99% of nintedanib or a salt thereof, or an indolinone or a salt thereof and a prostacyclin analogue and optionally one or more carrier excipients (e.g., lactose, mannitol, sucrose, glucose, trehalose) to improve drug handling, distribution, metering and dispersion. The formulation may optionally contain one or more slip agents (e.g., L-leucine, trileucine, sodium stearate, magnesium stearate) at a concentration of about 0.1% w / w to about 10% w / w to reduce interparticle adhesion, improve powder flowability and reduce the effect of moisture. The formulation may be prepared by physically blending nintedanib or a salt thereof and a prostacyclin analogue with the above excipients. Alternatively, dry powder formulations may be formed by precipitation techniques including spray drying, vacuum drying, solvent extraction, controlled precipitation, emulsification or freeze drying. For these formulations, in addition to the excipients for the blended dry powder formulations described above, these formulations may also contain 10% w / w to about 99.9% w / w of phospholipids (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidonylphosphatidylcholine, dibehenylphosphatidylcholine, diphosphatidylglycerol) to act as emulsifiers and fillers. Optionally, the formulations of the present invention may also contain about 0.1% w / w 99.9% w / w of a biocompatible, preferably biodegradable polymer, copolymer, or blend or other combinations thereof. Examples of polymers include, but are not limited to, polylactide, polylactide-glycolide, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydrides, polylactams, polyvinylpyrrolidone, polysaccharides (glucan, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.). The dry powder can be packaged in a blister pack or capsule with a fill weight of 0.01 mg to 100 mg in a unit dose. Alternatively, the dry powder formulation can be packaged in a device reservoir that measures 0.01 mg to 100 mg when in use.

[0178] Methods of treating or preventing disease

[0179] For the purposes of the methods described herein, indolone, its salt or derivative compound, most preferably nintedanib salt, is formulated and administered using a dry powder inhalation device that produces a particle size distribution optimized for aerosol delivery to the lung compartment. In some embodiments, nintedanib or an indolone derivative compound or its salt is formulated as a pharmaceutical composition suitable for aerosol formation, indication dosage, deposition location, pulmonary or extra-respiratory therapeutic effect, good taste, manufacturing and storage stability, and patient safety and tolerability. These methods include the step of mixing solutions contained in a multi-container system that separates the active pharmaceutical ingredient (API) from other solutions immediately before or after placement in a nebulizer for aerosol administration.

[0180] For the purposes of the methods described herein, indolone, its salt or derivative compound (most preferably nintedanib salt) and pirfenidone are co-formulated and administered using a dry powder inhalation device that produces a particle size distribution optimized for aerosol delivery to the lung compartment. In some embodiments, nintedanib or an indolone derivative compound or its salt and pirfenidone are formulated as pharmaceutical compositions suitable for dry powder dispersion and inhalation, indication dosage, deposition location, pulmonary delivery for pulmonary or extra-respiratory therapeutic effects, good taste, manufacturing and storage stability, and patient safety and tolerability. These methods include the step of mixing solutions contained in a multi-container system that separates the active pharmaceutical ingredient (API) from other solutions immediately before or after placement in a nebulizer for aerosol administration.

[0181] For the purposes of the methods described herein, indolone, its salt or derivative compound (most preferably nintedanib salt) and PDE4 inhibitor are co-formulated and administered using a dry powder inhalation device that produces a particle size distribution optimized for aerosol delivery to the lung compartment. In some embodiments, nintedanib or an indolone derivative compound or its salt and a PDE4 inhibitor are formulated as a pharmaceutical composition suitable for dry powder dispersion and inhalation, indication dosage, deposition location, pulmonary delivery for pulmonary or extra-respiratory therapeutic effects, good taste, manufacturing and storage stability, and patient safety and tolerability. These methods include the step of mixing solutions contained in a multi-container system that separates the active pharmaceutical ingredient (API) from other solutions immediately before or after being placed in a nebulizer for aerosol administration.

[0182] For the purposes of the methods described herein, indolinone, its salt or derivative compound (most preferably nintedanib salt) and prostacyclin analogs are co-formulated and administered using a dry powder inhalation device that produces a particle size distribution optimized for aerosol delivery to the lung compartment. In some embodiments, nintedanib or indolinone derivative compound or its salt and prostacyclin analog are formulated as pharmaceutical compositions suitable for dry powder dispersion and inhalation, indication dosage, deposition location, pulmonary delivery for pulmonary or extra-respiratory therapeutic effects, good taste, manufacturing and storage stability, and patient safety and tolerability. These methods include the step of mixing solutions contained in a multi-container system that separates the active pharmaceutical ingredient (API) from other solutions immediately before or after being placed in a nebulizer for aerosol administration. The dry powder administration step is performed in 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.

[0183] In the methods described herein, the aerosol comprises particles having a mass median aerodynamic diameter of about 1 micron to about 5 microns, about 2 microns to about 5 microns, about 3 microns to about 5 microns, 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, at least 100 mg of nintedanib or indolinone or a salt thereof. When nintedanib or an indolinone or a salt thereof is co-formulated with pirfenidone and administered in combination, the pirfenidone component contains a dosage of at least 1 mg pirfenidone, at least 5 mg pirfenidone, at least 10 mg pirfenidone, at least 15 mg pirfenidone, at least 20 mg pirfenidone, at least 25 mg pirfenidone, at least 30 mg pirfenidone, at least 40 mg pirfenidone, at least 50 mg pirfenidone, at least 60 mg pirfenidone, at least 70 mg pirfenidone, at least 80 mg pirfenidone, at least 90 mg pirfenidone or at least 100 mg pirfenidone. When nintedanib or indolinone or a salt thereof is co-formulated with a PDE4 inhibitor and administered in combination, the PDE4 inhibitor component is at least 0.1 mg PDE4 inhibitor, at least 0.5 mg PDE4 inhibitor, at least 1 mg PDE4 inhibitor, at least 2.5 mg PDE4 inhibitor, at least 5 mg PDE4 inhibitor, at least 7.5 mg PDE4 inhibitor, at least 10 mg PDE4 inhibitor, at least 15 mg PDE4 inhibitor, at least 20 mg PDE4 inhibitor, at least 30 mg PDE4 inhibitor or at least 40 mg PDE4 inhibitor. When nintedanib or indolone 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 prostacyclin analog.

[0184] On the one hand, a method of treatment is described herein, which includes administering nintedanib or indolinone or a salt thereof to treat a patient, wherein after administering nintedanib or indolinone or a salt thereof (including administering nintedanib or indolinone or a salt thereof to the patient at a dose of less than 1056 mg per day), the patient avoids abnormal liver function manifested by grade 2 or above abnormalities in one or more liver function biomarkers after oral administration. "Grade 2 abnormal liver function" includes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) higher than 2.5 times the upper limit of normal (ULN) and less than or equal to 5 times. Grade 2 abnormal liver function also includes bilirubin levels increased to 1.5 times of ULN and less than or equal to 3 times. One or more biomarkers of liver function are selected from the group consisting of alanine aminotransferase, aspartate aminotransferase, bilirubin and alkaline phosphatase. The method further includes the step of measuring one or more biomarkers of liver function. The blood Cmax of nintedanib or indolinone or its salt after inhalation administration is less than 40.0 ng / mL. The blood Cmax of nintedanib or indolinone or its salt after administration is less than 20.0 ng / mL, less than 10.0 ng / mL, less than 5.0 ng / mL.

[0185] The method of administering nintedanib or indolinone or a salt thereof includes avoiding nausea, diarrhea, headache, leg pain / cramps, fluid retention, visual disturbances, itchy rash, reduced resistance to infection, bruising or bleeding, loss of appetite, weight gain, decreased blood cell counts (neutropenia, thrombocytopenia, anemia), headache, edema, and congestive heart failure observed after oral administration (including administering inhaled nintedanib or indolinone or a salt thereof to the patient at a dose of less than 100 mg per day).

[0186] The methods of the present invention also include delivering to the patient by inhalation a maximum dose level of less than or equal to about 100 mg of nintedanib or a salt thereof per day. In some embodiments, less than or equal to about 50 mg, less than or equal to about 25 mg, less than or equal to about 10 mg, less than or equal to about 5 mg, less than or equal to about 2 mg, less than or equal to about 1 mg / day of nintedanib or indolone is delivered to the patient by inhalation as one dose per day, two doses per day, three doses per day, four doses per day, five doses per day, six doses per day, or more than six doses per 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.

[0187] Therapeutic methods include preventing interstitial lung disease by applying nintedanib or indolinone or its salt to a subject suffering from or suspected of suffering from interstitial lung disease (ILD). Interstitial lung disease includes the above-mentioned diseases and American Thoracic Society / European Respiratory Society idiopathic interstitial pneumonia international multidisciplinary consensus classification (American Thoracic Society / European Respiratory Society international multidisciplinary consensus classificationof the idiopathic interstitial pneumonias), AM.J.Respir.Crit.Care Med.165,277-304 (2002) (incorporated herein by reference) in the disease of all idiopathic interstitial pneumonias defined.

[0188] The method for treating can also include diagnostic step, such as identifying the experimenter suffering from or suspected suffering from ILD.The method is further subdivided into idiopathic pulmonary fibrosis according to disease extent, disease progression, progression rate or the response to any existing therapy.The delivery amount of aerosol nintedanib or indole or its salt compound (or its salt) formulation is enough to provide acute, subacute or chronic symptom relief, slow down fibrosis progression, stop fibrosis progression, reverse fibrosis damage and / or increase survival period and / or improve quality of life subsequently.

[0189] 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 are fibrosis in the heart, liver, kidney or skin), and a therapeutic amount of dry powder aerosol nintedanib or indolinone or salt thereof sufficient to provide acute, subacute or chronic symptom relief, slow fibrosis progression, halt fibrosis progression, reverse fibrotic damage and / or subsequently increase survival and / or improve quality of life.

[0190] The method of treatment may also include a diagnostic step of identifying a subject having or suspected of having multiple sclerosis, and the method of treatment comprises administering dry powder aerosol nintedanib or an indolinone or salt sufficient to provide acute, subacute or chronic symptom relief, slow the progression of demyelination, halt the progression of demyelination, reverse demyelinating damage and / or subsequently increase survival and / or improve quality of life.

[0191] Therapeutic treatment method comprises applying an effective aerosol dosage to the patient, wherein calculating, titrating or measuring dosage to establish or maintain the effective threshold drug concentration of the treatment in the lung and / or targeted downstream tissue, and the concentration can be measured as the drug level in epithelial lining fluid (ELF), sputum, lung tissue, bronchial lavage fluid (BAL), or by pharmacokinetic analysis, blood concentration is deconvoluted and measured. One embodiment comprises using aerosol to apply, so that the drug exposure of high concentration or titrated concentration is directly delivered to the affected tissue, to treat the pulmonary fibrosis of animals and humans and the inflammation (including idiopathic pulmonary fibrosis) associated with ILD. The peak lung ELF level reached after applying aerosol to the lung will be 100ng / mL epithelial lining fluid to about 20,000ng / mL epithelial lining fluid of nintedanib or indole one compound.

[0192] As a non-limiting example, in a preferred embodiment, the indolinone derivative compound provided herein (e.g., nintedanib) is formulated to allow the administration of a dry powder inhalation aerosol to provide an effective concentration or amount to produce and maintain a threshold drug concentration in the blood and / or lungs, which can be measured as the drug level in epithelial lining fluid (ELF), sputum, lung tissue, bronchial lavage fluid (BAL), or measured by deconvolution of the blood concentration by pharmacokinetic analysis, which is absorbed into the pulmonary vasculature, thereby producing a drug level sufficient for extrapulmonary treatment, maintenance or prevention. Therapeutic treatment methods include administration using an inhaled dry powder aerosol, thereby delivering high concentrations of drug exposure in the pulmonary vasculature and subsequent tissues and related vasculature, to treat, maintain and / or prevent but not limited to cardiac fibrosis, renal fibrosis, liver fibrosis, cardiac or renal toxicity, or multiple sclerosis. Peak tissue-specific plasma levels (e.g., heart, kidney, and liver) or cerebrospinal fluid levels (e.g., central nervous system) achieved after aerosol administration to the lungs following oral inhalation or after intranasal administration following aerosol administration to the lungs or nasal cavity will be between 0.01 ng / mL and about 50 ng / mL of nintedanib or indolone or its salt. Peak lung epithelial lining fluid levels achieved after administration of the inhaled dry powder to the lungs will be between 100 ng / mL of epithelial lining fluid and about 20,000 ng / mL of epithelial lining fluid of nintedanib or indolone.

[0193] As a non-limiting example, the indolinone derivative compound maintains a therapeutically effective concentration at the site of pulmonary pathology, suspected pulmonary pathology, and / or site of pulmonary absorption 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 about 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 one week. The effective concentration of nintedanib or indolinone or a salt thereof is sufficient to cause a therapeutic effect, and the effect may be local or widespread at or from the site of pulmonary pathology.

[0194] The delivery site is such as the lung epithelial lining fluid, the nasal cavity or the paranasal sinuses, and the nintedanib or indolinone or its salt compound formulation provided herein is administered in the form of one or more administrations so as to achieve a daily inhalable delivered dose (RDD) of nintedanib or indolinone or its salt of at least about 0.0001 mg to about 100 mg, including all integer values ​​therein, 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 mg. Daily RDD levels of nintedanib or indolinone compounds were maintained consistent with optimized doses and ratios of co-formulated combinations with pirfenidone or pyridone analogs, or PDE4 inhibitors or prostacyclin analogs.

[0195] The delivery site is such as the lungs, nasal cavity or sinus, and the nintedanib or indolinone or its salt compound formulation provided herein is administered in the form of one or more administrations so as to achieve a daily inhalable delivery dose of nintedanib or indolinone or its salt of at least about 0.0001 mg to about 100 mg, including all integer values ​​therein, 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, and administering the co-formulated combination of pirfenidone or a pyridone analog provided herein with nintedanib or an indolinone compound in one or more administrations to achieve a daily inhalable delivered dose of pirfenidone or a pyridone analog of at least about 0.0001 mg to about 100 mg, including all integer values ​​therein, 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 mg, and the co-formulated combination of the PDE4 inhibitor provided herein and nintedanib or an indolinone compound is administered in the form of one or more administrations so as to achieve a daily inhalable delivered dose of the PDE4 inhibitor of at least about 0.001 mg to about 100 mg, including all integer values ​​therein, such as 0.001, 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 mg, and the co-formulated combination of a prostacyclin analog provided herein and nintedanib or an indolinone compound is administered in the form of one or more administrations to achieve a daily inhalable delivered dose of the prostacyclin analog of at least about 0.0001 mg to about 10 mg, including all integer values ​​therein, such as 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, 1.8, 2, 3, 4, 5, 6, 10 mg.

[0196] manufacture

[0197] Using any suitable method, a fixed dose combination formulation of nintedanib or an indolinone derivative compound and pirfenidone or a pyridine analog, or a PDE4 inhibitor, or a prostacyclin analog. The fixed dose combination formulation of nintedanib or an indolinone derivative compound and the above-mentioned compound can be in the form of a ready-to-use inhalation solution delivered as an aerosol by a nebulizer, or in the form of a dry powder formulation delivered as an aerosol by a dry powder inhaler device. The inhalation solution can be prepared by dissolving the API and a suitable excipient (e.g., a buffer, an osmotic pressure regulator, an osmotic ion regulator, a taste / tolerance regulator), aseptically filtering, and aseptically filling into a suitable container closure system (e.g., a low-density polyethylene ampoule, a type I glass ampoule). In order to prepare inhalable dry powders and particles, many suitable methods conventional in the art such as mixing of micronized API, blending of 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 leading to the formation of inhalable particles with desired aerodynamic properties (e.g., mass median aerodynamic diameter, geometric standard deviation). If desired, suitable methods (such as sieving or cyclone separation) can be used to select inhalable dry particles with desired properties (such as size and density).

[0198] Ready-to-use inhalation solution formulations

[0199] A ready-to-use inhalation solution of a fixed dose combination of nintedanib or an indole derivative compound and pirfenidone or a pyridine analog can be manufactured using a complete mixing device. Excipients, including buffers, pH regulators, osmotic pressure regulators, and taste masking agents are added sequentially and mixed and dissolved one by one. Nintedanib or its salt is added to the solution and mixed and dissolved. Nintedanib or its salt can also be pre-moistened with a wetting agent (such as propylene glycol) before being added to the solution to promote its dissolution. Pirfenidone or a pyridone analog is then added and mixed and dissolved. In order to promote the dissolution of nintedanib or an indole derivative compound and pirfenidone or a pyridine analog, the solution can be heated to 40°C to 50°C for a limited period of time until the API is completely dissolved. The formulation is adjusted to the target pH value, then filtered into a storage tank to reduce bioburden, and then sterile filtered and aseptically filled into a suitable container (such as a low-density polyethylene ampoule or a transparent cyclic olefin vial or a Type I USP glass vial).

[0200] Carrier-free blending formulations

[0201] In the simplest form of dry powder inhalation formulations, indolone derivative compounds (most preferably nintedanib disclosed herein) can be formulated as carrier-free dry powders in combination with pirfenidone by simply blending two APIs. First, nintedanib or its salt and pirfenidone or pyridone analogs are micronized to the desired size using one or a combination of the following methods: grinding, 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 1 to 5 microns, and most preferably 2 to 3 microns. Micronized nintedanib or its salt and micronized pirfenidone or pyridone analogs can be blended together using a low shear mixer (e.g., a conical screw mixer, a drum mixer, a ribbon mixer) or a high shear mixer at an appropriate ratio in the range of 1:2,000,000 to 200:1. Test content uniformity to ensure uniform distribution of nintedanib or its salt and pirfenidone or pyridine analogs.

[0202] The present invention also includes blending micronized indole derivative compounds (most preferably nintedanib disclosed herein) with micronized PDE4 inhibitors by micronizing nintedanib or its salt. The mass median diameter of micronized nintedanib or its salt and PDE4 inhibitor in this embodiment can range from 0.5 to 10 microns, preferably 1 to 5 microns, and most preferably 2 to 3 microns. Micronized nintedanib or its salt and micronized PDE4 inhibitor can be produced by reducing the particle size to the desired range by one or combination of the following methods: titration, jet milling, ball milling, screening or any other suitable method. Micronized nintedanib or its salt and micronized PDE4 inhibitor are blended together using a low shear mixer (e.g., conical screw mixer, drum mixer, ribbon mixer) or a high shear mixer with an appropriate ratio in the range of 1:400,000 to 20,000:1. Test content uniformity to ensure uniform distribution of nintedanib or its salt and PDE4 inhibitor.

[0203] The present invention also includes blending micronized indole derivative compounds (most preferably nintedanib disclosed herein) with micronized prostacyclin analogs. The mass median diameter in this embodiment can range from 0.5 to 10 microns, preferably 1 to 5 microns, and most preferably 2 to 3 microns. Micronized nintedanib or its salt and micronized prostacyclin analogs can be produced by titration, jet milling, ball milling, screening or any other suitable method. Micronized nintedanib or its salt and micronized prostacyclin analogs are blended together using a low shear mixer (e.g., conical screw mixer, drum mixer, ribbon mixer) or a high shear mixer with an appropriate ratio in the range of 1: 100,000 to 20: 1. Test content uniformity to ensure uniform distribution of nintedanib or its salt and prostacyclin analogs.

[0204] Carrier-based blending

[0205] Another dry powder manufacturing method for combining an indole derivative compound (most preferably nintedanib disclosed herein) with a second active compound is by blending with a carrier. The carrier may include sugars such as, but not limited to, lactose, mannitol, sorbitol, erythritol, trehalose, cyclodextrin, dextrose, glucose monohydrate, maltitol, maltose, raffinose pentahydrate, and xylitol. The carrier particles are used to improve the fluidity of the drug particles and provide a coated surface for smaller active drug particles, thereby making it easier for the drug particles to be dispersed into primary particles for inhalation. It is also used as a filler to improve dosage accuracy and minimize dosage variability. The mass median particle size 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.

[0206] In one embodiment, the second active substance is pirfenidone or a pyridine analog. The ratio of nintedanib or its salt 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 a coarse carrier, or a premix is ​​formed using a low shear mixer (e.g., a conical screw mixer, a drum mixer, a ribbon mixer), and then added to the carrier at a ratio of 0.1% w / w to a total of 99.9% w / w. Powder blends are mixed using a low shear mixer (e.g., a conical screw mixer, a drum mixer, a ribbon mixer) or a high shear mixer. Content uniformity is tested to ensure uniform distribution of nintedanib or its salt and pirfenidone or a pyridine analog.

[0207] In another embodiment, the second active substance is a PDE4 inhibitor. The ratio of nintedanib or its salt to PDE4 inhibitor can range from 1:400,000 to 20,000:1. The two active compounds can be added directly to a coarse carrier, or a premix is ​​formed using a low shear mixer (e.g., conical screw mixer, drum mixer, ribbon mixer), and then added to the carrier at a ratio of 0.1% w / w totaling 99.9% w / w. A powder blend based on a carrier is obtained by mixing active substances and carrier using a low shear mixer (e.g., conical screw mixer, drum mixer, ribbon mixer) or a high shear mixer. Content uniformity is tested to ensure that the final powder blend has a uniform distribution of nintedanib or its salt and pirfenidone or pyridine analogs.

[0208] In another embodiment, the second active substance is a prostacyclin analog. The ratio of nintedanib or its salt to prostacyclin analog can range from 1:100,000 and 20:1 to 1:400,000. The two active compounds can be added directly to a coarse carrier, or a premix is ​​formed using a low shear mixer (e.g., a conical screw mixer, a drum mixer, a ribbon mixer), and then added to the carrier at a ratio of 0.1% w / w totaling 99.9% w / w. A powder blend based on a carrier is obtained by mixing active substances and carriers using a low shear mixer (e.g., a conical screw mixer, a drum mixer, a ribbon mixer) or a high shear mixer. Test content uniformity to ensure that the final powder blend has a uniform distribution of nintedanib or its salt and pirfenidone or pyridine analogs.

[0209] The present invention also includes blending indole derivative compounds (most preferably nintedanib disclosed herein) with PDE4 inhibitors by micronizing nintedanib or its salt and micronizing PDE4 inhibitors to a certain size. The mass median diameter in this embodiment can range from 0.5 to 10 μm, preferably 1 to 5 μm, and most preferably 2 to 3 μm. Micronized nintedanib or its salt and micronized PDE4 inhibitors can be produced by jet milling or ball milling or sieving to obtain a particle size within a desired range. Micronized nintedanib or its salt and micronized PDE4 inhibitors can be blended together using a low shear mixer (e.g., a conical screw mixer, a drum mixer, a ribbon mixer) or a high shear mixer with an appropriate ratio in the range of 1:400,000 to 20,000:1. Test content uniformity to ensure uniform distribution of nintedanib or its salt and PDE4 inhibitors.

[0210] The present invention also includes blending an indole derivative compound (most preferably Nintedanib disclosed herein) with a prostacyclin analog by micronizing Nintedanib or its salt and micronizing the prostacyclin analog to a certain size. The mass median diameter in this embodiment can range from 0.5 to 10 microns, preferably 1 to 5 microns, and most preferably 2 to 3 microns. Micronized Nintedanib or its salt and micronized prostacyclin analog can be produced by jet milling or ball milling or sieving to obtain a particle size within the desired range. Micronized Nintedanib or its salt and micronized prostacyclin analog can be blended together using a low shear mixer (e.g., a conical screw mixer, a drum mixer, a ribbon mixer) or a high shear mixer with an appropriate ratio in the range of 1:400,000 to 20,000:1. Test content uniformity to ensure uniform distribution of Nintedanib or its salt and prostacyclin analog.

[0211] Suitable spray drying techniques are described in various literature references (e.g., Spray Drying Technology Review, R Wisniewski 2015; Spray Drying: An Overview, D Santos 2017). In summary, the spray drying process involves continuous atomization of a liquid feed containing a drug dissolved or emulsified or suspended in a liquid into a hot gas (such as hot air or nitrogen) to evaporate the solvent from the atomized droplets. The liquid feed can be prepared in the form of a solution, an emulsion or a suspension containing components of dry particles to be produced in a suitable solvent (e.g., an aqueous solvent, an organic solvent, a water-organic mixture or an emulsion), and fed to an atomizer by a pump. A nozzle atomizer or a rotary atomizer can be used to convert the feed solution into aerosol droplets. Spray drying conditions can vary according to the composition and feed rate of the feed solution (or suspension or emulsion), and can be determined by those skilled in the art. Typically, the inlet temperature of the spray dryer is about 100°C to about 400°C, and preferably about 200°C to about 300°C, depending on the flow direction of the atomized droplets and the heated air flow. The outlet temperature of the spray dryer will vary depending on factors such as the feed temperature, the direction of the air and atomized droplet flow, and the nature of the material being dried. In general, 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 classified by sieving or using a cyclone separator, and / or further separated according to density using techniques known to those skilled in the art.

[0212] In order to prepare the spray-dried particles, the solution, emulsion or suspension containing the required dry powder component (that is, raw material) is usually prepared, and spray-dried under suitable conditions.Preferably, the solid concentration dissolved or suspended in the raw material is at least about 1g / L, at least about 2g / L, at least about 5g / L, at least about 10g / L, at least about 15g / L, at least about 20g / L, at least about 30g / L, at least about 40g / L, at least about 50g / L, at least about 60g / L, at least about 70g / L, at least about 80g / L, at least about 90g / L or at least about 100g / L.By dissolving or being suspended in a suitable solvent by suitable component (for example, one or more active drugs, excipients, other active ingredients), raw material can be solution or suspension.High shear homogenizer can be used to prepare solvent by one or more liquids to form liquid solution or emulsion. Preferably, the resulting solution, emulsion or suspension is atomized immediately after preparation into aerosol droplets, which are dried in a stream of hot air or nitrogen to form fine inhalable particles.

[0213] Atomization can be accomplished in a variety of ways, as the feedstock can be pumped into an atomizer nozzle or nozzle array to produce fine droplets. The atomizer can be a rotary, single-fluid, dual-fluid or ultrasonic design. Different designs have different advantages, applicability and disadvantages depending on the specific spray drying process required. The hot dry gas can be introduced in the same (co-current) or opposite (countercurrent) direction as the atomizer. Co-current makes the aerosol particles flow faster and therefore flow more effectively through the system into a particle separator, such as a cyclone separator. Countercurrent flow methods allow aerosol particles to have a longer residence time in the chamber before entering the separator.

[0214] Aerosol administration

[0215] Indole derivative compounds (most preferably nintedanib disclosed herein) can be administered in a therapeutically effective dose (e.g., a dose sufficient to provide treatment for the disease state described previously). For example, for a 70 kg person, a daily aerosol dose of nintedanib in a nintedanib compound formulation.

[0216] Indolinone derivative compounds (most preferably nintedanib disclosed herein) can be administered in a therapeutically effective dose (e.g., a dose sufficient to provide treatment for the disease state previously described). In some embodiments, for example, for a 70 kg person, the daily inhalable dry powder aerosol dose of nintedanib or indolinone in the nintedanib or indolinone compound formulation can be about 0.001 mg to about 1.0 mg nintedanib per kg body weight per dose. Of course, the amount of active compound administered will depend on the subject and the disease state being treated, the severity of the pain, the mode and schedule of administration, the location of the disease (e.g., whether it is necessary to achieve nasal or upper respiratory tract delivery, pharyngeal or laryngeal delivery, bronchial delivery, pulmonary delivery and / or pulmonary delivery and subsequent systemic or central nervous system absorption) and the judgment of the prescribing physician; for example, in preferred embodiments or in other embodiments of nintedanib or indolinone derivative compounds, the possible dose range of nintedanib aerosol administration is about 0.1 mg to 10 mg per dose to about 0.1 mg to about 100 mg per day. Similarly, if pirfenidone or a pyridone analog or a PDE4 inhibitor or a prostacyclin analog is included in the formulation, the daily aerosol dose for a 70 kg human is still about 0.001 mg to about 1.0 mg nintedanib per kg body weight per dose.

[0217] Dry powder inhaler (DPI)

[0218] Based on animal efficacy data and allometric scaling of human models, it is observed that human doses of nintedanib or its salts may be as low as a range between about 0.04 mg and about 10 mg. If clinical observations support these low levels, dry powder inhalation products may be a selected alternative to aqueous nebulized products.

[0219] There are two main designs for dry powder inhalers. One design is a metered device, in which a reservoir for the drug is placed within the device, and the patient adds a dose of the drug to the inhalation chamber. The second is a factory metered device, in which each individual dose is manufactured in a different container. Both systems rely on formulating the drug as small particles with a mass median diameter of about 1 to about 5 microns, and usually involve co-formulation with larger excipient particles (usually 100 micron diameter lactose particles, but the particle size can be optimized). The drug powder is placed in the inhalation chamber (either metered by the device or by breaking the factory metered dose), and the patient's inspiratory airflow accelerates the powder out of the device and into the mouth. The non-laminar nature of the powder path causes the excipient-drug aggregates to disperse, and the mass of the large excipient particles causes them to hit the back of the throat, while the smaller drug particles are deposited deep in the lungs.

[0220] In a multi-dose reservoir system, this can be accomplished by measuring the volume of powder onto a disk (e.g. AstraZeneca) or slides (e.g. Viatris) cavity. The measuring chamber is filled primarily by gravity from a bulk powder reservoir. This requires the inhaler to remain in an upright position. In some special cases, forced metering is applied, such as by bulk reservoirs (e.g., Airmax TM , Ivax Corporation). Typically, multi-dose systems require certain properties of the powder formulation, such as flowability and uniformity. A different metering concept is Jethaler (Ratiopharm), which has a ring-shaped compact of drug-excipient mixture, with a scraper disk to grind small amounts of drug during inhalation. (Aventis)Same.

[0221] The particle size of nintedanib or its salt, or indole derivative or its salt can be optimized for aerosol administration. If the particle size is greater than about 5 microns MMAD, the particles are deposited in the upper respiratory tract. If the aerodynamic particle size of the aerosol is less than about 1 micron, it will be delivered to the alveoli and may be transferred to the systemic blood circulation.

[0222] By way of non-limiting example, the nintedanib or salt thereof, or indolinone derivative or salt thereof disclosed herein, whether used alone or co-formulated with pirfenidone or a pyridone analog or a PDE4 inhibitor or a prostacyclin analog, is prepared to disperse and deliver a dose of about 0.01 mg to about 100 mg of the nintedanib or indolinone compound from a dry powder formulation.

[0223] By way of non-limiting example, dry powder nintedanib or a salt thereof, or an indolinone derivative or a salt thereof may be administered in said inhalable delivered dose with 10 actuations and / or inhaled breaths or less, or 8 actuations and / or inhaled breaths or less, or 6 actuations and / or inhaled breaths or less, or 4 actuations and / or inhaled breaths or less, or 2 actuations and / or inhaled breaths or less.

[0224] In some embodiments, a dry powder inhaler (DPI) is used to dispense nintedanib or a salt thereof, or an indole derivative or a salt thereof as described herein. The DPI contains the drug substance in the form of fine dry particles. Typically, the patient's inhalation causes the dry particles to form an aerosol cloud that is inhaled into the patient's lungs. The fine dry drug particles can be produced by any technique known in the art. Some well-known techniques include the use of a jet mill or other pulverizing equipment, precipitation from a saturated or supersaturated solution, spray drying, in situ micronization (Hovione), particle engineering (Pulmosphere TM , ) or supercritical fluid method. Typical powder formulations include the production of spherical granules or adhesive mixtures. In the adhesive mixture, the drug particles are attached to larger carrier particles, such as lactose monohydrate with a diameter size of about 50 to about 100 microns. The larger carrier particles reduce the adhesion on the carrier / drug agglomerates to improve drug dispersion. Turbulence and / or mechanical devices break the agglomerates into their components. Then, the smaller drug particles are inhaled into the lungs, while the larger carrier particles are deposited in the mouth or throat. Some examples of adhesive mixtures are described in U.S. Patent No. 5,478,578 and PCT Publication Nos. WO 95 / 11666, WO 87 / 05213, WO 96 / 23485 and WO 97 / 03649, all of which are incorporated by reference in their entirety. Additional excipients may also be included in the drug substance. Alternatively, porous particles may be used to deliver drugs without the need for larger carrier particles. Such porous particles may be used Pulmosphere TM or technology, producing particles that are larger in size but denser and have a smaller aerodynamic diameter. Technology to manufacture drug particles with specific shapes and sizes can reduce dispersion forces and enable drug particles to be delivered without the use of carrier excipients.

[0225] There are three common types of DPIs, all of which can be used with nintedanib or its salt, or indole derivative or its salt compound described herein. In a single-dose DPI, a capsule containing one dose of dry drug substance / excipient is loaded into an inhaler. Upon activation, the capsule ruptures, thereby dispersing the dry powder and inhaling it using a dry powder inhaler. In order to dispense additional doses, the old capsule must be removed and an additional capsule must be loaded. Examples of single-dose DPIs are described in U.S. Patent Nos. 3,807,400; 3,906,950; 3,991,761; and 4,013,075, all of which are hereby incorporated by reference in their entirety. In a multi-unit dose DPI, a package containing multiple single-dose compartments is provided. For example, the package may include a blister package, wherein each blister compartment contains one dose. Each dose may be dispensed when the blister compartment ruptures. Any of several arrangements of compartments in the package may be used. For example, a rotating or ribbon arrangement is common. Examples of multi-unit dose DPIs are described in EPO patent application publications Nos. 0211595A2, 0455463A1, and 0467172A1, all of which are hereby incorporated by reference in their entirety. In a multi-dose DPI, a single dry powder reservoir is used. A mechanism is provided for measuring a single dose amount to be atomized and inhaled from the reservoir, such as described 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; and 4,805,811 and PCT Publication No. WO 92 / 09322, all of which are hereby incorporated by reference in their entirety.

[0226] In some embodiments, in addition to or in addition to the patient's inhalation, auxiliary energy can also be provided to facilitate the operation of the DPI. For example, pressurized air can be provided to assist in powder deagglomeration, such as described in U.S. Patent Nos. 3,906,950; 5,113,855; 5,388,572; 6,029,662 and PCT Publication Nos. WO 93 / 12831, WO 90 / 07351 and WO 99 / 62495, all of which are hereby incorporated by reference in their entirety. An electrically driven impeller can also be provided, such as described in U.S. Patent Nos. 3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT Publication No. WO 98 / 03217, all of which are hereby incorporated by reference in their entirety. Another mechanism is an electric tapping piston, such as described in PCT Publication No. WO 90 / 13327, which is hereby incorporated by reference in its entirety. Other DPIs use vibrators, such as described in U.S. Patent Nos. 5,694,920 and 6,026,809, both of which are hereby incorporated by reference in their entirety. Finally, a scraper system may be employed, such as described in PCT Publication No. WO 93 / 24165, which is hereby incorporated by reference in its entirety.

[0227] Additional examples of DPIs for use herein are described in U.S. Pat. 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 hereby incorporated by reference in their entirety.

[0228] 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, such as in U.S. Pat. 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; and 6,026,807, all of which are hereby incorporated by reference in their entirety. For example, a spacer can delay the time from aerosol generation to aerosol entry into the patient's oral cavity. This delay can improve the synchronization between the patient's inhalation and aerosol generation. Infants or other patients for whom conventional mouthpieces are difficult to use may also be provided with masks such as those described 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 hereby incorporated by reference in their entirety.

[0229] Dry powder inhalers (DPIs) involve deagglomeration and atomization of dry powder particles, typically delivering a dose of medication by means of a burst of inhaled air drawn through the unit. Such devices are described, for example, in U.S. Pat. No. 4,807,814, which relates to a pneumatic powder injector having an aspiration stage and an injection stage; SU 628930 (Abstract), which describes a handheld powder disperser having an axial airflow tube; Fox et al., Powder and Bulk Engineering, pp. 33-36 (March 1988), which describes a venturi adductor having an axial air inlet tube upstream of the venturi throttle; EP 347779, which describes a handheld powder disperser having a collapsible expansion chamber; and U.S. Pat. No. 5,785,049, which relates to a dry powder delivery device for medication.

[0230] Commercial examples of capsule-based or blister-based dry powder inhalers that can be used with the formulations of nintedanib or its salt, or indolinone derivatives or their salts described herein include Aerohaler, Aerolizer, Aspirair, Breezehaler, Diskhaler Forspiro, Exubera, Gyrohaler, Plastiape Monodose, Podhaler, Prohaler, Redihaler, Rotahaler, Turbohaler, Handihalerand Discus. Multi-dose reservoir devices include E Flex, Jethaler, NEXThaler, Novolizer, PADD, Pulmojet, Spiromax, Swinghaler, Turbuhaler and Ultrahaler. A commercial example of a cartridge-based dry powder inhaler is Spiros.

[0231] Solid lipid particles

[0232] The preparation of solid lipid particles of nintedanib or indole derivative compounds or salt compounds thereof may involve dissolving the drug in a lipid melt (phospholipids, such as phosphatidylcholine and phosphatidylserine) maintained at least at the melting temperature of the lipid, and then dispersing the drug-containing melt in a hot aqueous surfactant solution (usually 1%-5% w / v) maintained at least at the melting temperature of the lipid. The crude dispersion is homogenized for 1-10 min to obtain a nanoemulsion. The nanoemulsion is cooled to a temperature between 4-25 ° C to resolidify the lipids, thereby causing the formation of solid lipid nanoparticles. The optimization of formulation parameters (type of lipid matrix, surfactant concentration and production parameters) will be carried out to achieve extended drug delivery. By way of non-limiting example, this method can also be used to isolate and improve the water solubility of solid AUC shape enhancement formulations (such as low solubility nintedanib or indole derivative compounds or their salts).

[0233] Coprecipitate

[0234] Coprecipitate nintedanib or indole derivative compound or its salt compound formulation can be prepared by forming a coprecipitate with a pharmacologically inert polymer material. It has been shown that forming a molecular solid dispersion or coprecipitate with various water-soluble polymers to produce an AUC shape enhancement formulation can significantly slow down their in vitro dissolution rate and / or in vivo absorption. When preparing a powdered product, grinding is usually used to reduce the particle size because the dissolution rate is greatly affected by the particle size. In addition, strong forces (such as grinding) may increase surface energy and cause lattice deformation and reduce particle size. Grinding the drug with hydroxypropyl methylcellulose, β-cyclodextrin, chitin and chitosan, crystalline cellulose and gelatin together can enhance dissolution properties, thereby making the originally easy bioavailable nintedanib or indole derivative compound or its salt compound obtain AUC shape enhancement. By way of non-limiting example, this method can also be used to isolate and improve the water solubility of solid AUC shape enhancement formulations (such as low solubility nintedanib or indole derivative compound or its salt compound or salt form of formulation based on nanoparticles).

[0235] Dispersion enhancing peptides

[0236] The composition may include one or more dipeptides or tripeptides containing two or more leucine residues. By way of further non-limiting example, U.S. Patent No. 6,835,372 discloses dispersion enhancing peptides, which is hereby incorporated by reference in its entirety. The patent describes the discovery that dipeptides (e.g., dileucine peptides) and tripeptides containing dileucine have excellent ability to increase the dispersibility of powdered compositions.

[0237] In another embodiment, highly dispersed particles comprising amino acids are administered. Preferred hydrophobic amino acids. Suitable amino acids include naturally occurring 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, β-amino acids. D, L and racemic configurations of hydrophobic amino acids can all be used. Suitable hydrophobic amino acids can also include amino acid analogs. As used herein, amino acid analogs include D or L configurations of amino acids with the following formula: --NH--CHR--CO--, wherein R is an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group, and wherein R does not correspond to the side chain of a naturally occurring amino acid. As used herein, an aliphatic group includes a fully saturated straight chain, branched chain or cyclic C1-C8 hydrocarbon containing one or two heteroatoms (such as nitrogen, oxygen or sulfur) and / or containing one or more desaturated units. Aromatic groups include carbocyclic aromatic groups such as phenyl and naphthyl, and heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl and acridinyl.

[0238] Suitable substituents on an aliphatic, aromatic or benzyl group include --OH, halogen (--Br, --Cl, --I and --F), --O (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl), --CN, --NO2, --COOH, --NH2, --NH (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl), --N (aliphatic, substituted aliphatic, benzyl, substituted substituted benzyl, aryl or substituted aryl)2, --COO(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl), --CONH2, --CONH(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl), --SH, --S(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl) and --NH--C(.dbd.NH)--NH2. Substituted benzyl or aromatic groups may also have aliphatic or substituted aliphatic groups as substituents. Substituted aliphatic groups may also have benzyl, substituted benzyl, aryl or substituted aryl as substituents. Substituted aliphatic, substituted aromatic or substituted benzyl may have one or more substituents. Modification of amino acid substituents may increase the lipophilicity or hydrophobicity of, for example, hydrophilic natural amino acids.

[0239] Many suitable amino acids, amino acid analogs and salts thereof are commercially available. Others can be synthesized by methods known in the art.

[0240] Hydrophobicity is usually defined based on the partitioning of an amino acid between non-polar solvents and water. Hydrophobic amino acids are those acids that show a preference for non-polar solvents. The relative hydrophobicity of an amino acid can be expressed on a hydrophobicity scale, on which glycine has a value of 0.5. On this scale, amino acids that prefer water have values ​​below 0.5, while amino acids that prefer non-polar solvents have values ​​above 0.5. As used herein, the term hydrophobic amino acid refers to an amino acid that has a value greater than or equal to 0.5 on the hydrophobicity scale, in other words, its partitioning tendency in non-polar acids is at least equal to that of glycine.

[0241] Examples of amino acids that can be used include, but are not limited to, glycine, proline, alanine, cysteine, methionine, valine, leucine, tyrosine, isoleucine, phenylalanine, tryptophan. Preferred hydrophobic amino acids include leucine, isoleucine, alanine, valine, phenylalanine, and glycine. Combinations of hydrophobic amino acids can also be used. In addition, combinations of hydrophobic and hydrophilic (preferentially distributed in water) amino acids can also be used, wherein the overall combination is hydrophobic.

[0242] The amino acid may be present in the particles of the present invention in an amount of at least 10% by weight. Preferably, the amino acid may be present in the particles in an amount ranging from about 20% by weight to about 80% by weight. The salt of a hydrophobic amino acid may be present in the particles of the present invention in an amount of at least 10% by weight. Preferably, the amino acid salt is present in the particles in an amount ranging from about 20% by weight to about 80% by weight. In a preferred embodiment, the particles have a tap density of less than about 0.4 g / cm3.

[0243] Methods of forming and delivering particles comprising amino acids are described in U.S. Pat. No. 6,586,008, entitled Use of Simple Amino Acids to Form Porous Particles During Spray Drying, the teachings of which are incorporated herein by reference in its entirety.

[0244] Surface modifiers

[0245] The nintedanib or indole derivative compound disclosed herein or its salt compound can be prepared in a pharmaceutical composition together with a suitable surface modifier, and the suitable surface modifier can be 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 and ionic surfactants. Two or more surface modifiers can be used in combination.

[0246] Representative examples of surface modifiers include acetylpyridinium chloride, gelatin, casein, lecithin (phospholipids), dextran, glycerol, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens TM , such as Tween 20 TM and Tween 80 TM (ICI Specialty Chemicals)); polyethylene glycol (e.g., Carbowaxs 3350 TM and 1450 TM and Carbopol 934 TM (Union Carbide), dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphates, sodium lauryl sulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose (HPC, HPC-SL and HPC-L), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione and triton), poloxamers (e.g., Pluronics F68 TM and F108 TM , which are block copolymers of ethylene oxide and propylene oxide); poloxamnine (e.g., Tetronic 908 TM , also known as Poloxamine 908 TM , which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ); charged phospholipids such as dimyristoylphosphatidylglyceride, dioctyl sulfosuccinate (DOSS); Tetronic 1508 TM ; (T-1508) (BASF Wyandotte Corporation), dialkyl esters of sodium sulfosuccinate (e.g., Aerosol OT TM , which is the dioctyl ester of sodium sulfosuccinate (American Cyanamid); Duponol P TM, which is sodium dodecyl sulfate (DuPont); TritonsX-200 TM , which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-110 TM , which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxy poly-(glycidol), also known as Olin-log TM or surfactant 10-G TM (Olin Chemicals, Stamford, Conn.); Crodestas SL-40 TM (Croda, Inc.); and SA9OHCO, which is C18 H37 CH2(CON(CH3)-CH2(CHOH)4(CH2 OH)2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-pyranoglucoside; n-decyl β-D-pyranoglucoside; n-dodecyl β-D-pyranoglucoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-pyranoglucoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-pyranoglucoside; nonanoyl-N-methylglucamide; n-nonanoyl β-D-pyranoglucoside; octanoyl-N-methylglucamide; n-octyl-β-D-pyranoglucoside; octyl β-D-thioglucoside; etc.

[0247] Examples of surfactants for use in the solutions disclosed herein include, but are not limited to, ammonium laureth sulfate, hexadecylamine oxide, hexadecyltrimethylammonium chloride, cetyl alcohol, cetyl myristate, cetyl palmitate, cocamide DEA, cocamidopropyl betaine, cocamidopropylamine oxide, cocamide MEA, DEA lauryl sulfate, distearyl phthalamide, dicetyl dimethyl ammonium chloride, dipalmitoylethyl hydroxyethyl ammonium, disodium laureth 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, myristic amine oxide, octyl isononanoate, octyl palmitate, octyldodecyl neopentanoate, oleylbenzyldimethylammonium chloride (olealkonium chloride), PEG-2 Stearate, PEG-32 Caprylic / Capric Glycerides, PEG-32 Stearic Acid Glycerides, PEG-4 and PEG-150 Stearates and Distearates, PEG-4 to PEG-150 Laurates and Dilaurates, PEG-4 to PEG-150 Oles and Dioleates, PEG-7 Glyceryl Cocoate, PEG-8 Beeswax, Propylene Glycol Stearate, Sodium C14-16 Olefin Sulfonate, Sodium Lauryl Sulfoacetate, Sodium Lauryl Sulfate, Sodium Tridecyl Sulfate, Stearalkonium Chloride, Stearamide Oxide, TEA Dodecylbenzene Sulfonate, TEA Lauryl Sulfate

[0248] Most of these surface modifiers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients (The Pharmaceutical Press, 1986), jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society, which is specifically incorporated by reference. Surface modifiers are commercially available and / or can be prepared by techniques known in the art. The relative amounts of drug and surface modifier can vary widely, and the optimal amount of surface modifier can depend on, for example, the specific drug and surface modifier selected, the critical micelle concentration of the surface modifier (if it 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, etc.

[0249] In the present invention, the optimal ratio of drug to surface modifier is from about 0.1% to about 99.9% of nintedanib or indolinone derivative compound or salt thereof, more preferably from about 10% to about 90%.

[0250] Microspheres

[0251] Microspheres can be used for pulmonary delivery of nintedanib or indolinone derivative compounds or their salt compounds by first adding an appropriate amount of the drug compound to be dissolved in water. For example, nintedanib or indolinone derivative compounds or their salt compound aqueous solutions can be dispersed in dichloromethane containing a predetermined amount (0.1-1% w / v) of poly (DL-lactide-co-glycolide) (PLGA) by performing 1-3min probe ultrasound on an ice bath. Separately, nintedanib or indolinone derivative compounds or their salt compounds can be dissolved in dichloromethane containing PLGA (0.1-1% w / v). By performing 3-5min probe ultrasound on an ice bath, 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). The resulting emulsion will be continuously stirred at room temperature for 2-4 hours to evaporate dichloromethane. The microparticles thus formed will be separated from the continuous phase by centrifugation at 8000-10000rpm for 5 to 10min. The precipitated particles will be washed three times with distilled water and freeze-dried. The freeze-dried nintedanib or indolinone derivative compound or its salt compound microparticles will be stored at -20°C.

[0252] By way of non-limiting example, a spray drying method can be used to prepare microspheres of nintedanib or an indole derivative compound or a salt thereof. An appropriate amount of nintedanib or an indole derivative compound or a salt thereof is dissolved in dichloromethane containing PLGA (0.1-1%). The solution is spray dried to obtain microspheres.

[0253] Pharmacokinetics

[0254] Inhalation therapy of aerosolized nintedanib or indolinone derivative compounds enables sustained release or direct deposition of the active substance in the respiratory tract (intranasal or lungs) to exert therapeutic effects at the site of deposition or systemic absorption to areas immediately downstream of vascular absorption sites.

[0255] Similar to the above-mentioned intranasal and pulmonary applications, the treatment or prevention of organs outside the respiratory tract needs to be absorbed into the systemic vascular department to be transported to these external respiratory locations. In the case of treating or preventing fibrosis or inflammatory diseases associated with the heart, liver and kidney, the deposition of the drug in the respiratory tract (more specifically, deep lung) will be able to enter these organs directly through the left atrium, reaching the carotid artery or coronary artery. This direct delivery will allow the direct administration of high concentrations of nintedanib or indole derivative compounds without unnecessary systemic exposure. Similarly, this approach allows the dose to be titrated to the level for these indications.

[0256] Pharmacokinetics is concerned with the uptake, distribution, metabolism, and excretion of a drug substance. A pharmacokinetic profile includes one or more biometric measurements designed to measure the absorption, distribution, metabolism, and excretion of a drug substance. One way to visualize a pharmacokinetic profile is with a plasma concentration curve, which is a graph that plots the mean active ingredient plasma concentration on the Y-axis and time (usually in hours) on the X-axis. Some pharmacokinetic parameters that can be visualized with a plasma concentration curve include:

[0257] 1) Cmax: maximum plasma concentration in the patient;

[0258] 2) AUC: Area Under the Curve

[0259] 3) TOE: Time of Exposure

[0260] 4) T1 / 2: The time it takes for the amount of drug in the patient's body to be reduced by half

[0261] 5) Tmax: The time when the plasma concentration in the patient reaches the maximum value

[0262] Pharmacokinetics (PK) is related to the concentration of therapeutic agents (such as nintedanib or indole derivative compounds) in vivo. Pharmacodynamics (PD) is related to the relationship between pharmacokinetics and in vivo efficacy. PK / PD parameters associate therapeutic agents (such as exposure) with effective activity. Therefore, in order to predict the therapeutic efficacy of therapeutic agents (such as therapeutic agents with different mechanisms of action), different PK / PD parameters can be used.

[0263] As used herein, the "peak phase" of the drug concentration in vivo is defined as the drug administration interval when the drug concentration is not less than 50% of its maximum plasma or disease site concentration. "Peak phase" is used to describe the interval between administrations of nintedanib or indolinone derivative compounds. When considering the treatment of lung disease, the methods or systems described herein can provide at least two times the pharmacokinetic enhancement for the treatment of lung disease. Compared to oral administration, the methods and systems described herein provide at least two times the lung tissue pharmacokinetic enhancement of nintedanib or indolinone or its salt compound.

[0264] The amount of nintedanib or indolinone or its salt compound applied to humans by inhalation can be calculated by measuring the amount of nintedanib or indolinone or its salt compound and related metabolites found in urine. About 80% of the nintedanib applied is discharged through urine. The calculation based on the compound and metabolite in urine can be completed by 48 hours of urine collection (after a single administration), and the total amount of nintedanib or indolinone or its salt compound delivered to humans is the sum of the measured nintedanib and its metabolites. By non-limiting example, if it is known that 80% of nintedanib is discharged, the 50mg total urine measurement of nintedanib and its metabolites will be converted into a delivery dose of about 63mg (50mg divided by 80%). If the inhaled aerosol fine particle fraction (FPF) is 75%, it can be assumed that about 75% of the drug is deposited in the lungs (and about 25% is swallowed, then absorbed from the intestine, and 80% is discharged through urine). Combining these two calculations, of the 63 mg delivered dose (as measured by urinary excretion), approximately 47 mg is the amount of inhaled aerosol nintedanib delivered to the lungs (actual RDD; calculated as the product of 63 mg and 75% FPF). This RDD can then be used for various calculations, including lung tissue concentration.

[0265] The lung tissue Cmax and / or AUC of nintedanib or indolinone or a salt thereof obtained after a single inhaled dose to a mammal is about equal to or greater than the lung tissue Cmax and / or AUC of nintedanib or indolinone or a salt thereof obtained after a single orally administered dose of about 80% to about 120% of the inhaled dose; and / or the plasma Cmax and / or AUC obtained after a single inhaled dose to a mammal is less than the plasma Cmax and / or AUC obtained after a single orally administered dose of nintedanib or indolinone or a salt thereof at a dose of about 80% to about 120% of the inhaled dose. The lung tissue Cmax obtained after a single inhaled dose to a mammal is greater than the lung tissue obtained after a single orally administered dose of nintedanib or indolinone or a salt thereof at a dose of about 80% to about 120% of the inhaled dose. The lung 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 lung tissue AUC obtained after a single dose of nintedanib or indolinone or a salt thereof administered orally at a dose of 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 dose of nintedanib or indolinone or a salt thereof administered orally at a dose of 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 dose of nintedanib or indolinone or a salt thereof administered orally at a dose of about 80% to about 120% of the inhaled dose.

[0266] In one aspect, described herein is a method of causing a lung tissue Cmax of a nintedanib or indolinone or salt thereof compound to be 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 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times greater than the Cmax of an orally administered dose of nintedanib or indolinone or salt thereof at most 200 mg, the method comprising dispersing a dry powder formulation comprising nintedanib or indolinone or salt thereof and administering the dry powder formulation to a human being. Described herein is a method of causing a lung tissue Cmax of a nintedanib or indolinone or salt thereof compound to be at least equal to or greater than the Cmax of an orally administered dose of nintedanib or indolinone or salt thereof at most 200 mg, the method comprising dispersing a dry powder formulation comprising nintedanib or indolinone or salt thereof and administering the dry powder formulation to a human being.

[0267] In one aspect, described herein is a method for increasing the lung tissue AUC of nintedanib or indolinone or a salt thereof. 0-24 AUC for oral doses up to 200 mg 0-24 A method of increasing the lung tissue AUC of nintedanib or an indolinone or a salt thereof by 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 1.5-20 times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times, the method comprising dispersing a dry powder formulation comprising nintedanib or an indolinone or a salt thereof compound and administering the dry powder formulation to a human. A method of increasing the lung tissue AUC of nintedanib or an indolinone or a salt thereof compound by 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 1.5-20 times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times 0-24 At least equal to or greater than the AUC of nintedanib or indole or a salt thereof for an orally administered dose of up to 600 mg 0-24 A method of treating a human being comprising dispersing a dry powder formulation comprising nintedanib or an indolinone or a salt thereof and administering the dry powder formulation to a human being.

[0268] These methods include a method of administering nintedanib or an indolinone or a salt thereof to a human, the method comprising administering a dry powder formulation containing nintedanib or an indolinone or a salt thereof, wherein the lung tissue Cmax achieved with 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 the lung tissue Cmax achieved with orally administered nintedanib or an indolinone or a salt thereof at a dose of 80% to 120% of the dose amount of nintedanib administered by DPI.

[0269] These methods include a method of administering nintedanib or an indolinone or a salt thereof to a human, the method comprising administering a dry powder formulation containing nintedanib or an indolinone or a salt thereof, wherein the lung tissue Cmax achieved with the dry powder formulation is at least equal to or greater than the lung tissue Cmax achieved with orally administered nintedanib or an indolinone or a salt thereof at a dose of 80% to 120% of the dose of nintedanib or an indolinone or a salt thereof in the administered dry powder formulation of nintedanib or an indolinone or a salt thereof.

[0270] These methods include a method of administering nintedanib or an indolinone or a salt thereof to a human, the method comprising administering a dry powder formulation containing nintedanib or an indolinone or a salt thereof, wherein the plasma AUC achieved with the dry powder formulation is 0-24 Less than the plasma AUC achieved with orally administered nintedanib or indolinone or its salt at a dose of 80% to 120% of the dose of nintedanib or indolinone or its salt administered in a dry powder formulation of nintedanib or indolinone or its salt 0-24 .

[0271] These methods include a method of administering nintedanib or an indolinone or a salt thereof, the method comprising administering a dry powder formulation containing nintedanib or an indolinone or a salt thereof, wherein the lung tissue AUC achieved with the nebulized solution is 0-24 The lung tissue AUC achieved with orally administered nintedanib or indolinone or its salt compound at a dose of 80% to 120% of the dose of nintedanib or indolinone or its salt in the dry powder formulation of nintedanib or indolinone or its salt 0-24 The methods include a method of administering nintedanib or an indolinone or a salt thereof to a human, the method comprising administering a dry powder formulation containing nintedanib or an indolinone or a salt thereof, wherein the lung tissue AUC achieved with 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 1.5-20 times, at least 1.5-15 times, at least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times. 0-24 The lung tissue AUC achieved with orally administered nintedanib or indolinone or its salt at a dose of 80% to 120% of the dose of nintedanib or indolinone or its salt in the dry powder formulation of the nintedanib or indolinone or its salt compound 0-24 At least 1.5 times of.

[0272] These methods include a method for improving the pharmacokinetic characteristics obtained in humans after a single oral dose of nintedanib or indolinone or its salt is administered. A single oral dose contains up to about 200 mg of nintedanib or indolinone or its salt. The method for improving pharmacokinetic characteristics further includes comparing the pharmacokinetic parameters after inhalation administration with the same parameters obtained after oral administration, and may require multiple measurements of a single patient over time to compare the pharmacokinetic parameters that vary due to dosage, route of administration, form of active pharmaceutical ingredient, and other parameters described herein in a single patient. Long-term improvement of pharmacokinetic characteristics is obtained by repeatedly and frequently administering a dry powder formulation of nintedanib or indolinone or its salt by inhalation as described herein. Repeated administration of nintedanib or indolinone or its salt by inhalation can provide more frequent direct lung exposure, thereby benefiting humans by repeated high Cmax levels. The inhaled dose of nintedanib or indolone 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.

[0273] Aerosol dose delivery in the small airways quickly eliminates high lung Cmax and low AUC. Human, animal and in vitro studies have shown that the efficacy of nintedanib is dose-responsive (i.e., the larger the dose, the better the efficacy), and show that Cmax is the key driving factor of the efficacy of nintedanib. Although lung Cmax seems to be important for efficacy, more regular nintedanib exposure is also important for enhancing this effect. In the case of treating human lung disease, more frequent direct pulmonary administration of nintedanib or indolinone or its salt compound can provide benefits by repeated high Cmax administration and providing more regular active therapeutic agent exposure.

[0274] The treatment methods include a method for treating a lung disease in a mammal, the method comprising administering nintedanib or a salt thereof, or an indolinone derivative compound or a salt thereof, directly to the lungs of a mammal in need thereof on a continuous dosing schedule, wherein the observed lung tissue Cmax for the dose of nintedanib or an indolinone derivative or a salt thereof is greater than 10, 100, 1000, or 10,000 ng / mL of lung epithelial lining fluid. When co-formulated or administered in combination with pirfenidone, the resulting blood pirfenidone Cmax is less than 10 μg / mL, less than 5 μg / mL, less than 2.5 μg / mL. When co-formulated and administered in combination with a PDE4 inhibitor, the resulting blood 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 blood 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.

[0275] Dosage and treatment regimen

[0276] The term "continuous dosing schedule" refers to the use of a specific therapeutic agent at regular intervals. A continuous dosing schedule refers to the use of a specific therapeutic agent at regular intervals, and this specific therapeutic agent does not have any drug holiday. A continuous dosing schedule refers to the use of a specific therapeutic agent in the alternating cycle of drug administration, followed by a drug holiday (such as a clearance period) of a 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, once every other day, once every two days, once every three days, once every four days, daily administration for one week, followed by no therapeutic agent in one week, daily administration for two weeks, followed by no therapeutic agent in one or two weeks, daily administration for three weeks, followed by no therapeutic agent in one week, two weeks or three weeks, daily administration for four weeks, followed by no therapeutic agent in one week, two weeks, three weeks or four weeks, weekly administration for four weeks, once a week, followed by no therapeutic agent in one week, or once a week, followed by no therapeutic agent in two weeks.

[0277] The amount of nintedanib or indolinone derivative compound is administered once a day. In some other embodiments, the amount of nintedanib or indolinone derivative compound is administered twice a day. In some other embodiments, the amount of nintedanib or indolinone derivative compound is administered three times a day.

[0278] If no improvement in the human disease or condition is observed, the daily dose of nintedanib or indolinone derivative compound is increased, for example, a once-a-day dosing schedule is changed to a twice-a-day dosing schedule. The administration of nintedanib or indolinone derivative compound is increased by a three-times-a-day dosing schedule. Increase the frequency of administration by inhalation to provide repeated high Cmax levels more regularly. Increase the frequency of administration by inhalation to provide maintained or more regular nintedanib exposure. Increase the frequency of administration by inhalation to provide repeated high Cmax levels more regularly and provide maintained or more regular nintedanib exposure.

[0279] The amount of repeated high Cmax dosing that provides more regular exposure of the active therapeutic agent to a human depends on various factors such as, but not limited to, the condition and severity of the disease or disorder, and the characteristics of the human (e.g., body weight), as well as the specific additional therapeutic agent being administered (if applicable).

[0280] Examples

[0281] Example 1. PDGF-induced fibroblast proliferation

[0282] The effect of nintedanib on the inhibition of PDGF-induced fibroblast proliferation was determined in primary human fibroblasts. Briefly, fibroblasts were seeded in 96-well flat transparent bottom Falcon plates at 2,500 cells / well and placed in 10% FBS F12 / DMEM medium containing 1% Pen / Strep. These cells were placed in a 37 degree incubator (5% CO2) for 24 hours to allow the cells to adhere to the plate. The medium was then removed, washed with PBS, and replaced with 0.5% FBSF12 / DMEM medium containing 1% Pen / Strep for another 24 hours. In order to characterize the effect of exposure duration of each drug on inhibition of proliferation, cells were pretreated with or without drugs (0.5 to 50 nM) for 30 minutes, washed and replaced with 0.5% FBS F12 / DMEM medium containing 1% Pen / Strep+ / -20 ng / mL PDGF-BB (simulating short-duration drug exposure of pulmonary inhalation pharmacokinetics) or 0.5% FBS F12 / DMEM medium containing 1% Pen / Strep+ / -20 ng / mL PDGF-BB and initial drug concentration (simulating long-duration drug exposure of oral pharmacokinetics). After 72 hours, MTS was used to assess viable cells. The drug concentration tested had no cytotoxicity (data not shown).

[0283] Table 1. Effects of nintedanib and duration of exposure on PDGF-induced fibroblast differentiation.

[0284]

[0285] The results in Table 1 show that nintedanib has a dose-responsive effect in inhibiting PDGF-induced fibroblast proliferation. The data also show that this activity requires only short-term nintedanib exposure (supporting inhaled lung pharmacokinetics), with a 50% inhibitory concentration (IC50) of approximately 3 nM (approximately 1.6 ng / mL).

[0286] Example 2. Formulation

[0287] Table 2. Exemplary Nintedanib dry powder formulations

[0288]

[0289]

[0290] a. Nintedanib salt is any salt form described herein

[0291] Example 3. Nintedanib dry powder formulation

[0292] Five nintedanib hydrobromide formulations were manufactured by spray drying at a scale of 25 g; the process parameters for all five spray-dried blends were kept constant. Each formulation was filled into HPMC capsules No. 3 and stability was set at 25°C / 60% RH and 40°C / 75% RH, stored in containers and sealed in bags for three months. Sufficient samples for two additional time points were set under each condition. A micronized nintedanib hydrobromide mixture was made at a scale of 2.5 g with pharmaceutical grade lactose monohydrate containing 10% fine powder. The formulation was filled into HPMC capsules No. 3 and stability was set at 25°C / 60% RH and 40°C / 75% RH, stored in containers and sealed in bags for one month. Sufficient samples for two additional time points were set under each condition. The physicochemical properties and aerosol performance of each formulation were evaluated. The HPLC assay parameters for sample analysis are detailed in Table 3.

[0293] Table 3. HPLC assay parameters

[0294]

[0295] Three determinations were made for each determination and the average was reported. Moisture content was measured by Karl Fischer coulometer using Metrohm 851Tritrando coulometer and sample oven. 50 mg of each sample was heated to 80°C. Lactose monohydrate was used as a graded standard. A single measurement was made for each sample. The emission dose was measured using a dose unit sampling apparatus (DUSA) at 100 L / min. The sample was recovered using 50 mL of diluent. Ten determinations were made and the average was reported

[0296] The particle size distribution of the emitted dose was measured using a Next Generation Impactor (NGI) at 100 L / min. Three determinations were made using one capsule each time, and the average values ​​of fine particle dose and fine particle fraction (less than 5 microns) were calculated. All aerosol performance evaluations were performed using a Plastiape RS01 Monodose low-resistance inhalation device.

[0297] The particle size distribution was measured using a Malvern Mastersizer 3000. Prior to measurement, the analytical sample (10 mg) was suspended in a 0.1% lecithin solution in isooctane (10 mL) and sonicated to disperse the particles. A single sample was prepared for each measurement.

[0298] The melting behavior of the formulations was measured using a TA Instrument Discovery DSC. The sample (2-3 mg) was placed in a sample pan with a perforated lid and heated from 25°C to 270-300°C at 10°C / min.

[0299] The effect of moisture adsorption on the formulations was measured using the surface measurement system DVS Advantage. The samples for analysis (10-20 mg) were dried at 0% RH and then the RH was varied in steps of 10% to a maximum of 90% RH and then back to 0% RH. The step size change was triggered by the change in mass over time: dm / dt=0.01% / min.

[0300] Scanning electron microscopy and X-ray powder diffraction were performed at the University of Bath.

[0301] The target specifications for spray-dried nintedanib formulations were as follows:

[0302] PSD D90<5mcm

[0303] GSD < 1.8

[0304] Fine particle dose (FPD) ≤ 2 mg

[0305] For micronized APIs:

[0306] ·PSD D90≤5mcm

[0307] For capsule filling, the weight range is 28.5-31.5 mg

[0308] Spray drying was performed (Table 4) and batch yields were recorded (Table 5).

[0309] Table 4. Spray drying conditions and parameters

[0310] Spray drying conditions / parameters value Solid content (%w / v) 4 Raw material feed rate (ml / min) 2 Outlet temperature(℃) 75 Atomizing gas pressure (bar) 2.5 Atomizing gas flow rate (L / min) 17 Dry gas pressure (bar) 2.5 Drying gas flow rate (kg / hr) 17

[0311] Table 5. Yield (spray drying batch)

[0312]

[0313]

[0314] Capsule filling (spray dried powder). HPMC size 3 capsules were filled at 20% RH using a 3Pi gravimetric filler. Weight limits of 28.5 to 31.5 mg were used (Table 7).

[0315] Table 7. Capsule fill weight and fill quantity

[0316]

[0317] The capsules were stored in plastic safety jars of 10 capsules per jar and each jar was sealed with an individual foil overwrap prior to placement in the stability chamber.

[0318] API Micronization

[0319] 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).

[0320] Table 8. Micronization parameters and PSD of micronized API.

[0321] Parameters / Results Batch 1 Batch 2 Feed rate g / min Approx. 1 Approx. 2 Feed pressure bar 5 5 Grinding pressure bar 3 3 Yield (g / %) 3.3 / 55.6 3.9 / 65.7 PSD D10μm 0.04 0.60 PSD D50μm 1.03 1.51 PSD D90μm 2.66 2.87

[0322] Manufacturing of Lactose Blends

[0323] Micronized API was manually mixed with lactose monohydrate, 10% fine powder (GRN4948) using a spatula to prepare 2.5 g of nintedanib HBr:lactose monohydrate 10:90 wt %. 40 capsules were manually filled with 30.0 + / - 0.5 mg formulation under laboratory conditions (21 °C, 50% RH).

[0324] Evaluation of Micronized APIs

[0325] Micronized nintedanib HBr was stored in glass snap-top vials sealed in aluminum bags at 25°C / 60% RH and 40°C / 75% RH for one month, and then PSD and moisture content were measured (Table 9). SEM images were recorded ( Figure 1 and Figure 2 ), and through XRPD( Figure 3 and Figure 4 ) and DSC( Figure 6 ) to assess polymorph stability. The characterization was then repeated after another four months under laboratory conditions.

[0326] Table 9. HBr PSD and moisture analysis of micronized nintedanib

[0327] sample D10(mcm) D50(mcm) D90(mcm) Water content (%) T0 0.5 1.5 2.8 5.3 1 month 25 / 60 0.6 1.6 3.0 5.3 1 month 40 / 75 0.6 1.5 2.6 5.2 +4 months 0.6 1.5 2.9 4.7

[0328] All results indicate that micronized nintedanib HBr did not change during the study period. The DSC traces at both 25°C / 60% RH and 40°C / 75% RH after one month showed a higher and sharper melting point than at the beginning, but this was not seen after another four months. XRPD showed no structural changes in any of the samples. The changes in the DSC traces at 1 month may be due to changes in the hydration state of the samples.

[0329] It is believed that there may be incompatibility between the drug substance and glassware; this was not evaluated in this study. Going forward, all samples will be stored in plastic containers.

[0330] Formulation Evaluation-Assay

[0331] Table 10. Average assays for Nintedanib (n=3)

[0332]

[0333] *Only once confirmed at the beginning

[0334] All formulations initially contained less than the maximum expected theoretical value of 8.7%. The theoretical value is derived from the conversion of the hydrobromide salt to the free base, which requires a partial correction factor of 0.87, thus giving a maximum theoretical value of 8.7% in the 10% w / w formulation.

[0335] Formulation Evaluation - Moisture Content is shown in Table 11.

[0336] Table 11. Moisture content (n=1)

[0337]

[0338] Formulation Evaluation – Emission Dose

[0339] Table 12. Average emission dose (n=10)

[0340]

[0341] *Emission dose results generated by NGI testing

[0342] Initial emission dose data indicated that all formulations were discharged from the capsules with a recovery of at least 85% for all formulations. After storage, two spray-dried batches had poor emission doses, which combined with other data led to the discontinuation of studies on these batches. Typical emission dose data were observed for the two spray-dried formulations evaluated after 3 months of storage (under both storage conditions), and for the micronized formulations evaluated after 5 and 6 months of storage.

[0343] Formulation Evaluation - Fine Particle Dose and Fine Particle Fraction (Table 13).

[0344] Table 13 Average fine particle dose (n=3)

[0345]

[0346] Initial data showed that the FPF of the spray dried formulations ranged from 23-36%. The micronized drug / lactose formulation had higher performance and an FPF of 60%. Further analysis after storage for 1 month at 25°C / 60% RH and 40°C / 75% RH showed that the aerosol performance of the three spray dried formulations changed significantly, resulting in the formulations not being further analyzed. Two spray dried formulations were evaluated after 2 and 3 months of storage at 25°C / 60% RH and 40°C / 75% RH, and Trehalose:Leucine:NHBr 80:10:10wt% showed consistent performance (22-28% FPF after storage at 25°C / 60% RH and 40°C / 75% RH compared to 32% FPF at the beginning), with no clear trend in storage under any one condition. Lactose:Leucine:NHBr 70:20:10wt% performed differently, with significant differences in FPF under different storage conditions. It is noteworthy that the FPF appears to be larger when stored at 25°C / 60% RH.

[0347] After storage for 5 and 6 months at 25°C / 60% RH and 40°C / 75% RH, the micronized drug / lactose batches showed consistent physical properties compared to the initial batches, with the FPF remaining at approximately 60%.

[0348] Physical Properties - The stability of the particle size distribution as determined by laser diffraction is shown in Table 14.

[0349] Table 14. Particle size measured by laser diffraction

[0350]

[0351] After 1 month storage at 25°C / 60% RH for the trehalose:NHBr 90:10wt% and lactose:NHBr 90:10wt% batches, the particle size changed due to particle agglomeration, while at 40°C / 75% RH, the samples were fused and therefore could not be measured. After 2 months storage at 25°C / 60% RH and 40°C / 75% RH, the samples had completely agglomerated in both conditions. These batches do not contain leucine in the matrix, which is known to form a hydrophobic surface layer.

[0352] The Lactose:Leucine:NHBr 80:10:10wt% batch showed an increase in size after 1 month under both storage conditions. After 2 months, samples from both conditions had agglomerated and therefore could not be measured. This batch contains lactose and is therefore more susceptible to moisture driven changes than the equivalent trehalose batch (trehalose:Leucine:NHBr 80:10:10wt%).

[0353] The trehalose:leucine:NHBr 80:10:10 wt % batch containing trehalose and 10% leucine and the lactose:leucine:NHBr 70:20:10 wt % batch containing lactose and 20% leucine showed a similar small increase in particle size over the course of the study and neither showed signs of significant agglomeration.

[0354] DVS results are as follows Figure 6 shown.

[0355] Initially, the sample was amorphous, absorbed 25 wt% water, and showed no signs of crystallization. At all subsequent time points under both storage conditions, the sample was amorphous, but recrystallization occurred above 60% RH, manifested by mass loss. After 2 and 3 months of storage at 40°C / 75% RH, the sample showed the expected final mass increase, which is expected to be due to the formation of crystalline trehalose dihydrate from amorphous trehalose.

[0356] The sample was initially amorphous and crystallized above 30% RH, resulting in a significant mass loss. After storage for 1 month at 25°C / 60% RH, the same behavior was observed, but at 40°C / 75% RH the sample had crystallized. No further testing was performed on this formulation.

[0357] The initial sample had agglomerated prior to analysis and therefore was not tested. At 1 month, the sample stored at 25°C / 60% RH was completely amorphous, had absorbed 20% of water, and no recrystallization occurred. However, the sample stored at 40°C / 75% RH had completely agglomerated and therefore could not be tested. No further testing was performed on this formulation.

[0358] Initially, the formulation was amorphous, absorbed 20% of water, and did not recrystallize. After 1 month storage at 25°C / 60% RH, the sample remained amorphous, but crystallized above 60% RH and showed a large mass loss. The sample stored at 40°C / 75% RH had completely agglomerated and therefore could not be tested. No further testing was performed on this formulation.

[0359] Initially, the sample was amorphous, but crystallized above 30% RH with a significant loss of mass. Similar behavior was observed after 1 month of storage under both conditions and after 2 and 3 months at 25°C / 60% RH. After 2 and 3 months at 40°C / 75% RH, the sample was completely crystallized, absorbing only 2.5% of water, and showed no signs of recrystallization.

[0360] DSC

[0361] The DSC thermograms show multiple transitions with no evidence of crystalline material. The thermograms for all time points are identical under each condition. The heating and cooling cycles at initial and one month are provided. Only the heating cycles for 2 and 3 months are shown.

[0362] Initially, the thermogram showed two broad events with melts at 170°C and 210°C. A similar pattern was also observed for the sample stored at 25°C / 60%RH for 1 month, but the sample stored at 40°C / 75%RH for 1 month showed only two melts, indicating that the sample had crystallized. No further testing was performed on this formulation.

[0363] The initial sample was not analyzed because it had absorbed water and crystallized before testing. After 1 month at 25°C / 60% RH, the sample showed a broad transition typical of an amorphous structure. The sample stored at 40°C / 75% RH had crystallized, showing a sharp melt, which may be due to trehalose dihydrate. No further testing was performed on this formulation.

[0364] Thermograms of the initial sample and the sample stored at 25°C / 60% RH for 1 month showed complex, broad transitions. The sample stored at 40°C / 75% RH melted sharply at 215°C, which may be due to crystallized anhydrous lactose. No further testing was performed on this formulation.

[0365] Initially, the formulation showed a broad water loss peak with a sharp melt at about 170-175°C. Similar thermograms were observed at each time point at 25°C / 60% RH and after 1 month at 40°C / 75% RH. After 2 and 3 months at 40°C / 75% RH, the thermograms showed only a sharp melt at about 175°C, indicating that these samples had crystallized.

[0366] Initial evaluation of five spray-dried formulations and one micronized API / lactose formulation showed that the FPF of the spray-dried batches was 20-30%, which is lower than the ideal value for DPI formulations. In contrast, the FPF of the micronized formulation was 60%, which is more typical for DPI products.

[0367] After evaluation after 1 month of storage, it was determined that three of the five spray-dried batches (lactose:L-leucine:nintedanib HBr 80:10:10 wt%, trehalose:nintedanib HBr 90:10 wt% and lactose:nintedanib HBr 90:10 wt%) contained a large amount of agglomerated particles and, as a result, reduced aerosol performance was observed (maximum FPF <25% at 25 / 60, less under accelerated stability conditions). No further analysis was performed on these batches.

[0368] In contrast, the micronized drug substance / lactose formulations evaluated after 5 and 6 months of storage (under ambient conditions) showed similar performance to the initial time point.

[0369] Example 4: Pharmacokinetics of inhaled (liquid nebulization) nintedanib, inhaled (liquid nebulization) nintedanib plus pirfenidone fixed combination, and single oral (gavage) dose of nintedanib in sheep

[0370] Merino cross female sheep (ewes) aged 6-12 months and 30-40 kg live weight were used in this study; n = 4 animals were optimized for oral dosing, while another group of n = 10 sheep were selected for the main (drug dosing) study. All animals received standard vaccinations before arrival at the animal farm and oral anthelmintics (in line with standard management practices) to eliminate any helminth parasites before the experiment. The experimental animals were rotated between indoor small group pens and metabolic cages under controlled environmental conditions (20-22°C) and maintained on 12 hours of light / darkness throughout the experiment. The sheep in the main study were randomly assigned to one of three groups (Group 1 or Group 2, n = 5 / group).

[0371] Oral drug delivery optimization

[0372] The sheep reticular sulcus closure surgery was optimized to enable oral drug delivery directly into the abomasum or abomasum. The surgery involved oral administration of 10% copper sulfate solution (w / v, 20 mL) into the back of the throat using a douche gun. This was followed by oral administration of 300 mL of glucose solution (delivering 75 g of glucose) (via an esophageal feeding tube) and subsequent monitoring of blood glucose levels to confirm direct delivery into the abomasum after reticular sulcus closure. Blood samples collected immediately before glucose administration (0 min) and 15 min, 30 min, and 45 min after glucose administration were tested using standard glucose test strips and a digital blood glucose analyzer / reader.

[0373] Main research: Pharmacokinetics of aerosolized and oral delivery

[0374] Nintedanib salt formulations and fixed combinations of nintedanib and pirfenidone for inhaled and oral administration are listed in Table 15. All formulations used in this study were stored at room temperature (RT) and protected from light until use; drugs were prepared on the day of use.

[0375] Table 15: Drug formulation and treatment assignment

[0376]

[0377]

[0378] Sheep entered the facility as a group and were acclimatized for 2-3 weeks prior to the experiment (group housed in indoor cages / pens). Sheep assigned to Group 1 (n=5; sheep ID#11, 12, 13, 14, 16) or to Group 2 (n=5; sheep ID#2, 17, 18, 20, 21) received treatments 1, 2, and 3. Group 1 sheep also received treatment 1b, which was an addition / modification to the original study protocol. Treatments were administered during weeks 3-9 of the study; each experimental treatment was administered for a one-week period in either Group 1 or Group 2 sheep (e.g., one group received treatment while the other rested).

[0379] Group 1 and Group 2 sheep were assigned different sampling schedules for the collection of peripheral blood and bronchoalveolar lavage fluid (BALF) (Table 16).

[0380] For all drug administration procedures, sheep were removed from metabolic cages and placed in specialized restraints to restrict movement of the head and neck to facilitate drug administration and BALF sample collection.

[0381] Nebulized inhalation drug delivery

[0382] For pulmonary aerosol drug administration (inhalation administration), a lubricated cuffed endotracheal (ET) tube (Portex, inner diameter 7.0-8.0 mm) was inserted into the trachea via the nasal passages (guided by a fiberoptic endoscope). Nintedanib (treatments 1 and 1b) and the fixed combination of nintedanib and pirfenidone (treatment 2) formulations were nebulized via an eFlow Inline nebulizer (PARIPharma GmbH), which was placed in conjunction with a biphasic controlled ventilator / respirator (Harvard Apparatus, MA, USA) to provide a closed breathing circuit.

[0383] Breathing is set to 20 breaths / min, inspiration 50%, and tidal volume is 350mL. A filter (HudsonRCl, NC, USA) is placed in the expiratory circuit to collect any exhaled drug dose. After drug administration, all pipelines, filters and nebulizer components are rinsed with 50mL sterile saline to collect any remaining or exhaled dose. Rinse sample aliquots (500 μl) are frozen on dry ice in 1.5mL Eppendorf tubes and then stored at -80°C before shipment to analyze drug content.

[0384] Accurately record the precise start and end times of dose nebulization, as well as the final duration of the inhaled dose.

[0385] Oral administration

[0386] Oral drug administration (treatment 3) follows the procedure (oral administration optimization) described in detail below. A feeding tube (internal diameter 7mm) is inserted into the upper esophageal region via the nasal passage (guided by a fiberoptic endoscope). CuSO4 is injected into the back of the throat using a rinsing gun, and 25mL of nintedanib solution (3mg / mL) is delivered by a feeding tube after 40 seconds. After oral administration of nintedanib, 300mL of glucose solution ("chaser") is delivered orally by the same feeding tube (including thoroughly flushing the 50mL FalconTM tube containing the nintedanib preparation) through the period of 20-25 seconds.

[0387] Peripheral blood collection

[0388] Blood samples collected before and after administration (Table 16) were placed into K3EDTA coated tubes. Cell-free plasma sample aliquots (500 mcl) were frozen on dry ice in 1.5 mL Eppendorf tubes and then stored at -80°C prior to shipment for drug content analysis.

[0389] Bronchoalveolar lavage fluid (BALF) collection

[0390] BALF samples were collected before and after administration (Table 2).Sampling was performed by infusing 25 ml of sterile saline into the lungs via the catheter through the biopsy port of the bronchoscope, and the BALF sample was immediately recovered into the collection syringe.

[0391] BALF was collected from different lung segments / lobes to avoid contamination between sampling time points: the right apical lobe (RA) was used for all pre-dose sampling, and post-dose samples were collected from the right middle lobe (RM); right caudal lobe (RC); left caudal lobe (LC); left middle lobe (LM); and apical lobe (LA) lobes. BALF sampling details (volume, exact collection time) were recorded and samples were immediately frozen on dry ice and then stored at -80°C before shipment for drug content analysis.

[0392] Table 16: Blood and BALF sampling schedule for Group 1 and Group 2 sheep

[0393]

[0394]

[0395] 1 Highlight blood and BALF collection times; 2 Sampled lobes: RA = right apical lobe; LM = left middle lobe; RC = right caudal lobe; LC = left caudate lobe; RM = right middle lobe; LA = left apical lobe.

[0396] The results of the oral administration optimization experiments are summarized in Figure 4 In all four sheep, elevated blood glucose levels were detected at 15 min, 30 min, and 45 min after repeated administration of CuSO4 ( Fig.16 A and Fig.16 B). In contrast, in the absence of CuSO4 administration (only glucose administration), no sustained increase in blood glucose was observed. The increase in blood glucose levels observed here confirms the effective closure of the reticular sulcus after CuSO4.

[0397] Ten (10) sheep were allocated to the main study. Details of all treated sheep, live weights and dosing data (time, volume, delivered dose) are shown in Table 16.

[0398] Inhaled medication administration (Treatment 1, Treatment 1b, and Treatment 2) was performed in a closed breathing circuit using a ventilator and PARI nebulizer device while the sheep were suspended in a custom-made harness. All sheep tolerated this procedure well. An inhalation rate of 20 breaths / min allowed the delivery of the entire pulmonary dose within 20 min (range 11.8-19.3 min). The mean dosing time was similar for each treatment (Table 16): 15.5±2.2 min (mean±SD) for inhaled nintedanib (Treatment 1, Treatment 1b). An inhalation rate of 20 breaths / min allowed the delivery of the entire pulmonary dose within 20 min (range 12.3–18.2 min). The mean dosing time was similar for each treatment (Table 16): 15.4±2.2 min (mean±SD) for the fixed combination of inhaled nintedanib and pirfenidone (Treatment 2).

[0399] Following the oral optimization study, CuSO4 and glucose were tested for the first time one week before the administration of Nintedanib to confirm that the reticular sulcus of each test sheep was effectively closed. Nintedanib (treatment 2) was orally administered with glucose "chaser", and no adverse reactions were observed. The Nintedanib dose delivered in all sheep was 75mg (25mL of 3mg / mL preparation), which was equivalent to 2.07±0.03mg / kg sheep live weight (Table 17).

[0400] Table 17: Details of drug administration in sheep

[0401]

[0402]

[0403] a Treatment 2, nintedanib component; b Treatment 2, pirfenidone component;

[0404] c Treatment 3 oral dose (25mL x 3mg / mL nintedanib) shown as mg / kg sheep live weight

[0405] 1 SD = standard deviation; 2 SEM = standard error of the mean

[0406] After oral administration of nintedanib, blood glucose levels in all sheep remained significantly elevated, confirming that the orally administered drug enters the abomasum directly ( Fig.17 ).

[0407] Blood and BALF collection

[0408] For each of Treatment 1, Treatment 1b, and Treatment 2, blood was collected at six (6) time points, as shown in Table 2. For each of Treatment 1, Treatment 1b, Treatment 2, and Treatment 3, BALF samples were collected at different time points (Table 15); samples were taken from different lobes ( Figure 3 ) to avoid sample dilution between time points. The results are shown in Table 19.

[0409] Pharmacokinetic results

[0410] A comparison of nebulized inhaled nintedanib and orally delivered nintedanib is shown in Table 18 below.

[0411] Table 18. Pharmacokinetics of nintedanib in sheep - nebulized inhaled nintedanib versus oral nintedanib

[0412]

[0413]

[0414] a. Pulmonary epithelial lining fluid; b. Immediately after dose

[0415] The results in Table 17 show that compared with oral administration, inhalation of about 1 / 36 of the aerosolized nintedanib can deliver about 100 times the epithelial lining fluid (ELF) Cmax and about 5 times the AUC. In contrast, inhalation of aerosolized nintedanib solution resulted in an approximately 8-fold decrease in plasma AUC and an approximately 2-fold increase in plasma Cmax.

[0416] Comparison of nebulized inhaled nintedanib monotherapy and nebulized inhaled nintedanib and pirfenidone fixed combination delivery is shown in Table 19.

[0417] Table 19. Pharmacokinetics in sheep - comparison of nebulized nintedanib with oral nintedanib and fixed combination

[0418]

[0419] a. Pulmonary epithelial lining fluid; b. Immediately after dose

[0420] After the aerosol inhalation administration of the fixed combination of nintedanib and pirfenidone, the nintedanib level showed a lower ELF Cmax (reduced by 50%) and a lower ELF AUC (reduced by 12%). On the contrary, plasma Cmax and AUC increased (increased by 46% and 25% respectively). These results show that there may be drug interactions, and in the presence of fixed combination pirfenidone, nintedanib may be eliminated faster into plasma (ELF Cmax and AUC are lower, plasma Cmax and AUC are higher). In order to support this hypothesis, the formulation results show nintedanib in pirfenidone stable solution (Example 7). As a means of optimizing these fixed combination interactions and reducing drug-drug interactions in vivo, the amount of nintedanib and pirfenidone can be optimized (Example 7).

[0421] Example 5: Comparative pharmacokinetics of inhaled (liquid aerosol) and dry powder (DPI) nintedanib in sheep DPI bridging study

[0422] Nintedanib HBr aqueous (nebulized aqueous formulation) was compared to various dry powder nintedanib formulations in a manner similar to that employed in Example 4. The formulations tested in this study were stored at room temperature (RT), protected from light, and prepared on the day of use (Table 20).

[0423] Table 20: Drug formulation and therapeutic allocation

[0424]

[0425] Sheep arrived at the facility as a group and were acclimatized (housed in groups in indoor cages / pens) for 5-10 days prior to experimentation. Sheep received treatments 1-4 during weeks 3-4 of the study. After each sheep received an experimental treatment, a washout period of 72-96 hours was followed before the next scheduled treatment.

[0426] For all drug administration procedures, sheep were removed from metabolic cages and placed in specialized restraints to restrict movement of the head and neck to facilitate drug administration, lung function measurements, and BALF sample collection.

[0427] DPI and nebulized inhalation

[0428] For all dosing procedures, a lubricated cuffed endotracheal (ET) tube (Portex, 7.0-8.0 mm inner diameter) was inserted into the trachea via the nasal passages (guided by a fiberoptic endoscope). A nebulizer (for treatment 1) and a Penn Century™ insufflator device (treatments 2-4) were placed in the breathing tube. Prior to all inhaled dosing procedures (treatments 1-4), ventilator ventilation was set to 20 breaths per minute (BPM), 50% inspiration, and 350 mL tidal volume.

[0429] Use liquid nintedanib formulation (treatment 1) Nebulization was performed using an inline nebulizer (PARIPharma GmbH) placed in conjunction with a biphasic controlled ventilator / respirator (Harvard Apparatus, MA, USA) to provide a closed breathing circuit.

[0430] Micronized / spray-dried nintedanib formulations (treatments 2-4) were pre-weighed into a Penn Century™ insufflator device, which was then connected to a controlled pressurized O2 source. Prior to DPI dose delivery, ventilation rate was reduced to 10 BPM, and the powder dose was fired simultaneously with 2-3 actuations (lasting approximately 20-30 seconds). At the completion of DPI dosing, ventilation rate was restored to 20 BPM.

[0431] For all dosing treatments, a filter chamber (Hudson RCl, NC, USA) was placed in the expiratory line to collect any exhaled drug dose. After drug administration, all lines, filters, and nebulizer (for treatment 1) components were flushed with 50 mL of sterile MilliQ water to collect any remaining or exhaled dose. The flush sample aliquots (500 mcl taken from 50 mL flush volume) were frozen on dry ice (in Eppendorf tubes) and then stored at -80 ° C before shipment for drug content analysis.

[0432] Accurately record the precise start and end times of dose nebulization, as well as the final duration of the inhaled dose (see Table 21).

[0433] Peripheral blood collection

[0434] Blood samples (3 mL) were collected from all sheep into K3EDTA-coated tubes before and after each drug administration: before dose (t0), and at t2 min, t5 min, t10 min, t15 min, t30 min, t60 min, t120 min, t240 min, t480 min, t720 min after dose completion. Cell-free plasma sample aliquots (500 mcl) were frozen on dry ice in 1.5 mL Eppendorf tubes and then stored at -80 °C before shipment for drug content analysis. Bronchoalveolar lavage fluid (BALF) collection

[0435] BALF samples were collected from 3 animals before and after administration. Sampling was performed by infusing 25 ml of sterile saline into the lungs via the catheter through the biopsy port of the bronchoscope, and the BALF sample was immediately recovered into the collection syringe.

[0436] BALF was collected from different lung segments / lobes to avoid contamination between sampling time points. The right apical (RA) lobe was used for all pre-dose (t0) sampling, and post-dose samples were collected from the left caudal (LC) lobe at t2 min and the right caudal (RC) lobe at t10 min.

[0437] BALF sampling details (volume, exact post-dose collection time) were recorded and samples were immediately frozen on dry ice and then stored at -80°C prior to shipment for drug content analysis.

[0438] Pulmonary function assessment

[0439] Lung function measurements were recorded in awake, conscious breathing sheep according to established protocols. Lung measurements were assessed during quiet breathing 5 min before each drug administration and up to 10 min after each drug administration. Lung parameters (dynamic compliance, transpulmonary pressure, lung volume, respiration and flow rate) were derived from the average measurements of five breaths over five periods and data analysis was performed using LabChart™ software.

[0440] DPI Bridging Study Dosing Data

[0441] Six (n=6) sheep were allocated to this study. Sheep details, live weights and dosing data (time, delivered volume / dose) for treatments 1-4 are shown in Table 21.

[0442] Inhaled nebulized medication was administered in a closed breathing circuit using a ventilator and the PARI eFlow inline device (Treatment 1) while the sheep were suspended in a custom-made harness. All sheep tolerated this procedure well. For Treatment 1, an inhalation rate of 20 BPM allowed the delivery of the entire lung dose within 20 min (range: 17.98-20.00 min; mean ± SEM: 18.73 ± 0.23 min).

[0443] For delivery of dry powder inhalation (DPI) formulations, ventilation rate was reduced to 10 BPM, with 24-30 mg powder delivered in 2-3 actuations via the PennCentury device. The total dose of micronized powder delivered for treatments 2-4 ranged from 14-26 mg, with the most effective delivery (95% effective dose emission / delivery) observed in DPI doses #2 and #3. DPI dose #1 formulation showed signs of aggregation / compaction within the Penn Century device after administration, with powder dose emission varying from 46-73%.

[0444] Table 21: Details of drug administration in sheep

[0445]

[0446] 1 Treatment 1, 8 mL, loaded into eFlow (PARI) inline nebulizer; 2 Treatment 2: Fill with 30 mg powder; 3 Treatment 3: Fill with 24-27 mg powder; 4 Treatment 4: Fill with 24-26 mg powder; 5 SEM: Standard error of the mean Blood and BALF collection

[0447] For each of treatments 1-4, blood samples were collected from all animals at eleven (11) time points. For treatments 1-4, BALF samples were collected from three (3) animals at three (3) time points from different lobes. The average BALF collection times for the "2min" and "10min" time points were 3.18±0.35min and 13.63±0.82min (mean±SEM), respectively, with no significant differences between treatments 1-4. BALF volumes did not differ significantly between time points (0, 2, 10min) or between treatments 1-4 (range: 5.5–14.0mL; mean±SEM: 8.53±0.31mL).

[0448] Lung function analysis

[0449] Lung function was assessed in all sheep before (Pre) and after (Post) treatments 1-4. Fig.18 The mean values ​​for each lung function parameter assessed were summarized. No significant changes were observed in mean transpulmonary pressure (airway resistance) or dynamic compliance in sheep after each of treatments 1-4 (pre-treatment vs. post-treatment). During treatment 4, there was a small but significant increase in ventilation rate ( Fig.18 C) (mean ± SEM from 7.23 ± 0.63 L / min to 8.96 ± 0.64 L / min), with no effect on other lung function parameters. This response may reflect a mild, transient response to treatment 4 dosing (90% lactose:10% nintedanib-micronized).

[0450] Pharmacokinetic results

[0451] Comparison of inhaled dry powder nintedanib (lactose monohydrate: micronized nintedanib (90:10 wt%)) and aqueous nebulized inhalation delivery of nintedanib Fig.19 and Fig. 20 shown.

[0452] Fig.19It is shown that the aqueous atomized nintedanib and dry powder nintedanib delivered by inhalation are eliminated from the lungs at a similar rate. The data show that a simple micronized nintedanib dry powder formulation (90% lactose: 10% nintedanib) is easily dissolved in the lungs and provides a large amount of bioavailable lung delivery dose. Importantly, the delivery dose calculation (measuring the remaining nintedanib in the ventilator circuit after the administration is completed and subtracted from the device loading dose) shows that the atomized formulation delivers 1.8mg nintedanib, and the dry powder formulation delivers 1.2mg, so that the dry powder ELF Cmax and AUC are respectively about 61% and 44% of the atomized formulation. Adjusting the dry powder pharmacokinetic data of fine particle fractions and delivery doses causes these curves to overlap, thereby supporting the following: 1. The two formulations do have similar bioavailability; and 2. Additional particle engineering and device optimization will improve dry powder delivery.

[0453] and Fig.19 Similar to what is shown in Fig. 20 The parallel curves shown in (same plasma Tmax and same plasma elimination rate) further support equivalent lung bioavailability and elimination between nebulized nintedanib and dry powder nintedanib.

[0454] To support these results, in vitro dissolution studies were performed. Briefly, the dissolution rate of nintedanib for each formulation was determined in simulated lung fluid using a USP dissolution apparatus.

[0455] Simulated lung fluid 4 (SLF 4) was selected for dissolution experiments. However, this buffer contains citrate and high levels of chloride, both of which are known to be incompatible with nintedanib hydrobromide. Therefore, the mixture was adjusted to replace citrate with phosphate and reduce the total chloride concentration to less than 67 mmol. Calcium carbonate was omitted because it is known to cause pH drift. In addition, DPPC was not added to the mixture. A study was conducted to investigate the effects of chloride concentration and pH, and ultimately a total chloride concentration of 48 mmol and pH 6.0 were selected for the experiment. SLF was prepared as shown in Table 22.

[0456] Add all components except sodium chloride to 4.5 L of deionized water in the order shown. Measure sodium chloride into a separate beaker and dissolve in an additional 100 ml of deionized water with stirring. Adjust the pH of each component in 4.5 L of water to pH 6.0 with 1 M NaOH, then add the sodium chloride solution. Transfer the resulting solution to a 5 L volumetric flask and make up to volume with deionized water.

[0457] Table 22. Composition of simulated lung fluid (SLF)

[0458]

[0459]

[0460] Each container was filled with 500 mL of SLF at 37°C and 250 mg of formulation was added under stirring at 125 rpm. Samples were collected using a 13 mm water-wet PTFE syringe filter - 2 mL, with 0.5 mL discarded (at 0.5, 1, 2, 4, 6, 8, 10, 15, 30 and 60 minutes). Samples were diluted 1:4 with sample diluent and analyzed in duplicate using the HPLC assay.

[0461] The dissolution results showed Fig.19 and Fig. 20 The micronized nintedanib dry powder formulation studied in (90% lactose: 10% micronized nintedanib) was completely dissolved within 6 minutes (Table 23; Formulation 6). In contrast, the spray-dried lactose: 10% nintedanib formulation (Table 23; Formulation 4) at the same level was only 62% dissolved at 10 min.

[0462] Table 23. Content of Nintedanib dry powder formulation

[0463]

[0464] To further support the ovine pharmacokinetic results, Table 12 shows that while Formulation 6 (Lactose monohydrate: micronized nintedanib (90:10 wt%)) of Table 23 exhibited a similar emitted device dose (93%) to the other spray-dried formulations (Table 22, Formulations 1-5), the fine particle fraction was much larger (Table 13; 60% compared to the range of 23% to 36% for these spray-dried formulations). In addition, this in vitro measured fine particle fraction delivered a fine particle dose of 1.32 mg (from a 2.2 mg device loaded nintedanib dose), and these properties were maintained for at least 6 months (Table 13). Combined with this information, the data from Tables 12, 13, and 23 show that Formulation 6 (Lactose monohydrate: micronized nintedanib (90:10 wt%)) exhibited an acceptable fine particle fraction, was stable in these properties for at least 6 months, and was effectively dissolved. Furthermore, the fine particle dose (1.32 mg) was equivalent to the 1.2 mg delivered dose measured in the sheep study ( Fig.19 and Fig. 20). Completely dissolved nebulized aqueous solutions of nintedanib have previously been shown to be effective in animal models (Surber et al., 2020; Epstein-Shochet et al., 2020). Therefore, it is critical that the dry powder nintedanib formulation exhibits rapid dissolution to produce bioavailable drug in order to maintain pharmacokinetic / pharmacodynamic relationships and equivalent activity to aqueous nebulized products. Given that the solubility and bioavailability of this lactose monohydrate: micronized nintedanib (90:10 wt%) formulation are comparable to those delivered by inhalation of aqueous solutions ( Fig.19 and Fig. 20 ), therefore maintaining a similar dissolution threshold is critical. As can be seen from the data in Table 23, a successful dry powder nintedanib formulation must have a dissolution rate of more than 60% of the powder nintedanib dissolved within the first 10 minutes, and more preferably provide complete dissolution within the first 10 minutes. Further, although the fine particle fraction, fine particle dose, and actual sheep delivered dose reflect consistency, and the performance of dry powder nintedanib simulated in humans maintains a significant pharmacokinetic advantage compared to the approved oral therapy (Table 25), the delivered dose after inhalation of the same device loaded dose of aqueous nintedanib aerosol formulation is clearly more effective ( Fig.19 ). More specifically, dry powders were less efficient in delivering doses compared to nebulized formulations, and adjustment of dry powder pharmacokinetic data for fine particle fraction and delivered dose resulted in these curves overlapping, supporting the view that while both formulations do have similar bioavailability, additional particle engineering and device optimization will further improve dry powder delivery.

[0465] In order to characterize how dry powder nintedanib will perform in humans, a clinical study was first conducted to compare the inhaled nebulized nintedanib and oral nintedanib in healthy volunteers. In this study, 2 mg of aqueous nebulized nintedanib or 150 mg of oral pirfenidone (commercial source) were administered to subjects using the PARI eFlow electronic nebulizer. The safety results of this study showed that inhaled nebulized nintedanib was well tolerated, with only slight grade 1 side effects observed, such as mild reversible cough. The pharmacokinetic results are shown in Table 24.

[0466] Table 24. ELF and plasma pharmacokinetics in humans - inhaled nebulized nintedanib versus oral nintedanib

[0467]

[0468] Table 24 shows that 2 mg inhaled aqueous aerosolized nintedanib delivered ELF Cmax and AUC levels of approximately 64 times and approximately 3 times that of 150 mg oral nintedanib, respectively. In addition, 2 mg inhaled aqueous nintedanib resulted in plasma Cmax and AUC levels of approximately 1 / 5 and 1 / 43 of those of oral administration, respectively. Taken together, these results support the hypothesis that inhaled nintedanib will deliver oral administration comparable to nintedanib delivered by lung, with fewer side effects than observed with oral products.

[0469] In order to understand how dry powder nintedanib will perform in humans, the equivalent aqueous nebulization and dry powder inhalation sheep data were extrapolated to the above human observations. In short, the plasma and ELF nintedanib levels produced by aqueous nebulization inhalation measured in sheep were linked to the human data in Table 24. Next, the collected sheep dry powder nintedanib pharmacokinetic data and the collected sheep aqueous nebulization nintedanib data were directly compared with the measured human oral results. This extrapolated comparison is listed in Table 25.

[0470] Table 25. Human ELF and plasma pharmacokinetics - inhaled dry powder nintedanib versus oral nintedanib

[0471]

[0472] Similar to what was observed in Table 23, the results in Table 24 indicate that inhaled nintedanib delivery results in higher lung levels and lower systemic exposure. Specifically, the lung ELF Cmax and AUC levels delivered by 2 mg dry powder nintedanib will be about 40 times and about 1.4 times that of 150 mg oral nintedanib, respectively. In addition, 2 mg dry powder nintedanib results in plasma Cmax and AUC levels of about 1 / 8 and 1 / 66 of oral, respectively. Taken together, these results support the hypothesis that inhaled dry powder nintedanib will also deliver oral equivalents to nintedanib delivered by the lungs, and that side effects are less observed than with oral products.

[0473] Example 6. Lactose carrier-nintedanib blend formulation optimization

[0474] Formulation optimization studies were performed to evaluate the effects of force control agents, nintedanib particle size, lactose carrier size and device drag on the aerodynamic properties of nintedanib HBr dry powder formulations.

[0475] Nintedanib was first micronized to the target size and the dry powder formulation was then formulated with lactose and force control agents (if applicable) by three-dimensional gravity blending. The prepared formulation was filled into capsules and filled using different resistance Aerosol dispersion properties were tested using a dry powder inhaler (Plastiape, Italy). Stability testing was performed on selected formulations at 25C and 40C and periodically. The work completed to date is summarized below.

[0476] Micronization. Nintedanib HBr was ground to a target D50 of 1.5 μm and D90 ≤ 5 μm. Micronization was performed in two steps using a fluid energy jet mill to obtain a coarse material and a fine material. The grinding parameters are summarized below.

[0477] Table 26. Grinding parameters

[0478] pass# Feed rate (g / min) Grinding pressure (bar) Feed pressure (bar) 1 Approx. 2 7 5.5 2 Approx. 1 5 3

[0479] The particle size distribution of micronized nintedanib HBr was measured using a Malvern Zetasizer Nano-ZS particle size analyzer (Malvern, PA) by suspending the powder in an isooctane solution containing 0.1% soy lecithin and dispersing it by ultrasonic treatment before measurement. The measured values ​​are shown in Table 27.

[0480] Table 27. Particle size distribution

[0481] Ground Nintedanib D10(μm) D50(μm) D90(μm) thick 1.6 2.1 2.8 thin 1.0 1.3 1.7

[0482] Scanning electron microscopy (SEM) and X-ray powder diffraction were performed on the fine nintedanib HBr. SEM images revealed that the micronized nintedanib HBr had a battle-axe shape and its particle size was generally less than 3 μm ( Fig.21 ).

[0483] The polymorphic form of micronized nintedanib HBr was determined by X-ray powder diffraction and was comparable to the polymorphic form of micronized nintedanib HBr generated during the nintedanib powder feasibility study ( Figure 3 and Figure 4 ), which indicates that after micronization, nintedanib HBr retains its polymorphic form ( Fig. 22 ).

[0484] Formulation blending. 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 as shown in Table 28. When applicable, the force control agent was added to the lactose carrier Lactohale 200 in a 50mL metal container in layers. The excipients were mixed in a Turbula drum mixer at 48rpm for 15 minutes. Micronized nintedanib HBr was added to the resulting powder in layers and mixed in a Turbula mixer at 48rpm for 30 minutes.

[0485] Table 28. Micronized Nintedanib blends

[0486]

[0487] a LH200 from DFE Pharma, where D10: 5 -15 μm, D50: 50-100 μm, D90: 120-160 μm b Respitose ML003 from DFE Pharma, with D10: 1–6 μm, D50: 20–50 μm, D90: 65–140 μm

[0488] c Lactohale LH300 from DFE Pharma, with D50 ≤ 5 μm, D90 ≤ 10 μm

[0489] After completion, the powder formulation was tested for content uniformity (%RSD≤15%) by taking samples from different locations in the blend and analyzed for nintedanib content by UV-vis spectrophotometer at a wavelength of 390 nm. The content uniformity results are shown in Table 29.

[0490] Table 29. Content uniformity of dry powder formulations

[0491]

[0492] The in vitro aerosol performance (fine particle fraction and MMAD) of the above-mentioned formulations was tested by the next generation impactor (NGI). About 24 mg of powder was filled into a gelatin capsule and dispersed through 2.4 seconds with a flow rate of 100 L / min using a low-resistance Plastiape RS01 DPI device to inhale 4 L of air, which is generally considered to be the normal forced inhalation amount of an average-sized male. The amount of nintedanib HBr in each stage was recovered and analyzed by HPLC. Each NGI collected an actuation. Emission dose (the amount of nintedanib emitted from the device), fine particle dose and fine particle fraction (respectively the amount and fraction of nintedanib with a mass ≤5 μm in aerosol particles) and mass median aerodynamic diameter (MMAD) are as shown in Table 30. Formulations 101-04-45-1 to 101-04-45-3 and 101-04-45-5 have higher emitted dose, fine particle dose, fine particle fraction compared to formulations 101-04-45-4 and 101-04-45-6. The aerosol performance attributes of the aforementioned formulations are comparable.

[0493] Table 30. Aerosol properties of nintedanib dry powder formulations

[0494]

[0495] 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 bottles 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 25°C / 60% RH conditions were tested). The aerosol performance summary 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. After storage for one month at 25°C / 60% RH, the fine particle dose and fine particle fraction (>5%) of formulation 101-04-45-5 were significantly reduced.

[0496] Table 31. Stability of nintedanib dry powder formulation at 1 month

[0497]

[0498] In addition, formulations 101-04-45-1 to 101-04-45-3 and 101-04-45-5 were tested in devices with different flow resistances. It is very important to test the aerosol performance of these formulations in devices with different flow resistances because many elderly patients with lung disease are unable to inhale air at the high flow rates required for low-resistance devices. Therefore, it is crucial to test medium-resistance and high-resistance devices that require lower inhalation flow rates. Single-dose RS01 devices (Berry Global, Italy) with low, medium and high resistances were used for testing, and NGI was operated at 100 LPM, 85 LPM and 60 RPM, respectively, producing a pressure drop of approximately 4 kPa (as USP <601> specified).

[0499] The test samples from 1 month, 25 ℃ / 60% RH stability tension were tested. A 24mg filled capsule was inserted into the inhalation device and then actuated into the NGI at the corresponding flow rate listed in the above paragraph. Nintedanib was collected and analyzed by HPLC method. Aerosol performance characteristics were determined using Inhalytix software (Copely, UK). The emission dose mass, emission dose fraction (relative to the nominal dose), fine particle dose and fine particle fraction, and aerosol mass median aerodynamic diameter of each device resistance type are shown in Table 32 and Table 33. The study found that the emission dose and emission dose fraction of the formulations 101-04-45-3 and 101-04-45-5 containing force control agents fine lactose and leucine in the corresponding order were not affected by the device resistance. On the other hand, the study found that the emission dose and emission dose fraction of the formulations 101-04-45-1 and 101-04-45-2 without force control agent were lower than those of the low resistance and medium resistance devices.

[0500] Table 32. Effect of device resistance on emitted dose and emitted dose fraction of nintedanib dry powder formulations

[0501]

[0502] The fine particle dose and fine particle fraction of all formulations tested using the medium resistance device were slightly higher than those of the low resistance device, while the fine particle dose and fine particle fraction of the high resistance device were significantly lower than 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 higher fine particle dose and fine particle fraction. On the other hand, formulation 101-04-45-5 consistently showed lower fine particle dose and fine particle fraction in the medium and high resistance devices. The study found that for all four tested formulations, MMAD was not affected by device resistance.

[0503] Table 33. Effect of device resistance on fine particle dose and fine particle fraction of nintedanib dry powder formulations

[0504]

[0505] In summary, formulation 101-04-45-03 formulated with 5% fine lactose as a force control agent exhibited good aerosol performance, remained stable after 1 month of storage at 25°C / 60% RH and 40°C / 75% RH, and was minimally affected by device resistance. Based on its overall aerosol performance properties, formulation 101-04-45-3 is a preferred formulation for further development. By way of non-limiting example, a preferred embodiment contains micronized nintedanib or a salt thereof, including the hydrobromide salt in solid particles, whose particle size distribution is defined as having a D10 between about 0.1 μm and about 1 μm, a D50 between about 1 μm and about 2.5 μm, and a D90 between about 1.5 μm and about 5 μm, and whose formulation content by weight is between about 1 wt% and about 20 wt%. Preferred embodiments may further contain lactose, whose particle size distribution is defined as having 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, and whose formulation content is between about 60 wt% and about 99 wt% by weight. Preferred embodiments may further contain lactose fine powder, whose particle size distribution is defined as having a D50 of less than about 5 μm and a D90 of less than about 10 μm, and whose formulation content is between more than 0 wt% and about 20 wt% by weight. In addition, the preferred formulations described herein are capable of emitting high doses from medium-resistance and high-resistance dry powder inhalation devices. For clarity, medium-resistance and high-resistance devices are designed to require lower inhalation flow rates to actuate and disperse dry powder formulation doses, and are more suitable for people with lung disease and decreased lung function, whose inhalation flow rates may otherwise be insufficient to effectively actuate and disperse dry powder doses from low-resistance devices for inhalation administration.

[0506] Example 7. Liquid nintedanib and pirfenidone fixed dose combination formulation

[0507] Data from Example 5 show that the aerosol inhalation administration of the fixed combination of nintedanib and pirfenidone delivers lower ELF levels and increased plasma levels. This observation indicates that there may be drug-drug interactions with pirfenidone, so in the presence of a fixed combination of pirfenidone, nintedanib can be eliminated faster into plasma. In order to support this hypothesis, the formulation results show nintedanib in pirfenidone stable solution. As a means of optimizing these fixed combinations to interact and reduce drug-drug interactions in vivo, the amount of nintedanib and pirfenidone can be optimized.

[0508] As a preliminary means of characterizing the pirfenidone-nintedanib interaction, the physical stability of nintedanib in the presence of different concentrations of pirfenidone was studied. It was previously known that nintedanib (various salt forms, including ethanesulfonate, hydrobromide, etc.) is physically unstable in solutions containing 30mM or higher sodium chloride. It was also previously known that when pirfenidone is added to such nintedanib solutions containing sodium chloride, nintedanib can be physically stabilized. As an alternative to understanding the in vivo concentration limit and or undesirable in vivo drug-drug interaction ratio, the chemical-chemical interaction between pirfenidone and nintedanib was explored. In this study, the stability of 0.25mg / mL nintedanib in 67mM sodium chloride solution at 0, 2.5, 5, 7.5, 10 and 12.5mg / mL pirfenidone concentrations was evaluated. According to the design, the stability limit is inferred as the limit of chemical-chemical or drug-drug interaction in vivo. First, a 67 mM sodium chloride solution was prepared by dissolving 0.8 g of sodium chloride in water and diluting to 200 mL. A 12.5 mg / mL solution was prepared by dissolving 1.25 g of pirfenidone in the saline solution prepared above to 100 mL. 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 as shown in Table 34. The solution was heated to 40°C while mixing for 30 minutes, and when completed, the nintedanib in all formulations was completely dissolved.

[0509] Table 34. Preparation of test solutions for pirfenidone-nintedanib interaction studies

[0510]

[0511] The pirfenidone-nintedanib interaction results are summarized in Table 35.

[0512] Table 35. Preparation of test samples for pirfenidone-nintedanib interaction studies

[0513]

[0514] The results show that, by weight, the ratio of more than about 30 parts of pirfenidone to 1 part of nintedanib (greater than about 7.5 mg / mL pirfenidone per 0.25 mg / mL nintedanib) stabilizes nintedanib in the presence of about 67 mM sodium chloride, and, as defined herein, is the limit of chemical-chemical interaction under such conditions. According to these data, by weight, each part of nintedanib is less than 30 parts of pirfenidone, which reduces stability and thus reduces chemical-chemical interaction under these conditions. In order to avoid the pharmacokinetic changes present when pirfenidone and nintedanib are administered in a fixed combination or otherwise co-administered, when formulated together or administered in vivo, less than 30 parts of pirfenidone to 1 part of nintedanib should be considered. However, under physiological conditions, the chloride content is close to 150 mM, so this ratio may be extended to no more than 67 parts of pirfenidone per part of nintedanib by weight to avoid altered pharmacokinetic profiles that exist when pirfenidone and nintedanib are administered as a fixed combination or otherwise co-administered.

[0515] As a means of optimizing the present invention, the ratio of the co-formulated combination nintedanib and pirfenidone is optimized to avoid chemical interactions of the co-formulation and possible in vivo physiological effects that increase the rate of elimination of inhaled delivered nintedanib from the lung to plasma compared to nintedanib without co-formulated pirfenidone.

[0516] By non-limiting example, 2:100 nintedanib by weight: pirfenidone ratio reduces lung nintedanib Cmax and increases plasma nintedanib Cmax by about 30-50%. In order to maximize the lung residence time of the co-formulated combination of inhaled nintedanib and pirfenidone, it is necessary to reduce this pharmacokinetic effect. By non-limiting example, by reducing pirfenidone content to less than or equal to about 100mg per dose (wherein nintedanib: pirfenidone content ratio is between about 1:1 to about 1:67) this undesirable pharmacokinetic effect is minimized. By another non-limiting example, by reducing pirfenidone dosage to less than or equal to about 100mg, while maintaining 1:20 to 1:67 nintedanib by weight: pirfenidone content ratio this undesirable pharmacokinetic effect is minimized. By way of another non-limiting example, this undesirable pharmacokinetic effect is minimized by increasing the nintedanib co-formulation content such that the resulting nintedanib:pirfenidone content ratio is less than 1 :67 by weight.

[0517] The method of the present invention includes optimizing the ratio of the co-formulated combination of nintedanib or indolinone compound and pirfenidone or pyridone analogue to improve therapeutic benefits, including efficacy, safety, tolerability and compliance. By non-limiting example, 100mg pirfenidone is present in the upper limit range of pirfenidone tolerance as an independent solution of atomization, and is close to the upper limit threshold of a compliant and well-tolerated dry powder product. By non-limiting example, it is expected that the efficacy of the dry powder product co-formulated with this nintedanib or indolinone compound and pirfenidone or pyridone analogue will be greater than any active ingredient alone. In order to maximize the relationship between safety / tolerance / compliance and efficacy, reducing the total amount of dry powder application will improve compliance and increase the safety and tolerability of the combination product. Using the additional effect of co-formulating with nintedanib or indolinone compound, the amount of pirfenidone or pyridone analogue in the co-formulated dry powder product can be reduced, while maintaining the overall additional benefit of applying both nintedanib or indolinone and pirfenidone or pyridone analogue to the patient. By way of non-limiting example, this desired result is produced by reducing the pirfenidone dose to less than or equal to about 100 mg while maintaining a nintedanib: pirfenidone content ratio of 1:20 to 1:67 by weight. The optimized nintedanib / pirfenidone combination ratios and formulations are shown in Table 36.

[0518] Table 36. Optimized nintedanib / pirfenidone combination ratios and formulations

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525] a. Amount of nintedanib in nintedanib base or nintedanib salt thereof

[0526] Example 9. High drug loading fixed dose combination of nintedanib HBr and pirfenidone with controlled particle morphology

[0527] High drug loading fixed dose combination formulations of nintedanib HBr, its base or other salts of pirfenidone can be formulated by dissolving nintedanib and pirfenidone in hot water (50°C), to which shelf formers (L-leucine, trileucine, sodium stearate, magnesium stearate) and glass formers (sucrose and trehalose) as stabilizers are added in the following ratios (Table 37).

[0528] Table 37. High drug loading fixed dose combination formulations of nintedanib and pirfenidone

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535] a. Sodium stearate can be replaced by magnesium stearate

[0536] The above formulations were spray dried using a Buchi MiniSpray dryer B-290 (Switzerland) under the following drying conditions: inlet temperature, 100-110°C; air flow rate, 450-500 L / h; aspirator, 90%, and pump rate, 6.0 mL / min. These conditions resulted in an outlet temperature of 45-50°C. The resulting powders were collected in a cyclone separator. As determined by scanning electron microscopy (SEM), they had a smooth spherical shape (particles formed in the absence of a shell forming agent) or a wrinkled surface (with a shell forming agent).

[0537] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulations was tested by the next generation impactor (NGI). Up to 40 mg of powder was filled into gelatin capsules (the exact amount depends on the desired dose) and dispersed over 2.4 seconds at a flow rate of 100 L / min using a low-resistance Plastiape RS01 DPI device to inhale 4 L of air. The amount of nintedanib HBr and pirfenidone in each stage was recovered and analyzed by HPLC. Depending on the formulation, multiple actuations may be required to collect sufficient amounts of drugs in the impactor stage. It is expected that the fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) are ≥50% and ≤5 μm, respectively. The target amount of nintedanib and pirfenidone formulations, as well as the amount filled into No. 3 capsules, were achieved.

[0538] Example 10. Optimization of the ratio of nintedanib and pirfenidone

[0539] Selected formulations from the above can be filled into three to four capsules to produce fixed dose combinations of nintedanib and pirfenidone ranging from 0.1 mg to 2 mg (free base) and 50 mg to 100 mg, respectively (Table 38).

[0540] Table 38. Optimized combination formulations of nintedanib or its salt and pirfenidone

[0541] a. Sodium stearate can be replaced by magnesium stearate

[0542] Table 38. High drug loading fixed dose combinations of nintedanib HBr and pirfenidone with hollow porous particles

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560] a. Amount of nintedanib in nintedanib base or nintedanib salt thereof

[0561] Alternatively, high drug loading fixed dose combination dry powder formulations of pirfenidone and nintedanib with high drug loading and porous particles for high aerosol dispersion were prepared from perfluorocarbon emulsions. In this method, co-sprayed hollow particles of pirfenidone and nintedanib HBr, nintedanib base or other salts thereof were prepared by spray drying technology with a Buchi MiniSpray dryer (Switzerland) or equivalent under the following spray conditions: inhalation: 100%, inlet temperature: 85°C; outlet temperature: 61°C; feed pump: 10%; N flow rate: 2,800 L / hr. The feed solution was prepared by dissolving pirfenidone and nintedanib in 100 grams of water heated to 50°C at different ratios in various combinations as follows. High drug loading nintedanib or its salt and pirfenidone combination formulations are shown in Table 39.

[0562] Table 39. High drug loading combination formulations of nintedanib or its salt and pirfenidone

[0563]

[0564] In different beakers, 5 g of distearoylphosphatidylcholine (DSPC) was homogenized in 750 g of hot water (50 ° C) using a benchtop homogenizer. 125 g of perfluorooctyl bromide was added dropwise to the solution while mixing. The solution was then homogenized by a high-pressure homogenizer. The solution was then combined with a solution containing dissolved pirfenidone and nintedanib, and the resulting solution was fed through a high-pressure homogenizer to prepare a raw material solution. The solution was fed into a spray dryer under the above conditions. Free-flowing white powder was collected at a cyclone separator. As determined by the cascade impact method, the MMAD of the hollow porous salbutamol sulfate particles was ≤5 μm. SEM analysis showed that the powder was spherical and highly porous. The tap density of the resulting powder is expected to be less than 0.2 g / cm3.

[0565] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulations was tested by the next generation impactor (NGI). About 20-30 mg of 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 RS01DPI device to inhale 4 L of air. The amount of nintedanib HBr and pirfenidone in each stage was recovered and analyzed by HPLC. Depending on the formulation, multiple actuations may be required to collect sufficient amounts of drugs in the impactor stage. It is expected that the fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) are ≥50% and ≤5 μm, respectively.

[0566] Example 12. Nintedanib / PDE4 combination

[0567] The fixed dose dry powder combination of nintedanib HBr, its alkali or other salts and PDE4 inhibitors (e.g., roflumilast, apremilast, criborol, BI 101555 and other PDE4 inhibitors) can be prepared by a lactose carrier blend. By way of non-limiting example, nintedanib or its salt and roflumilast are micronized using a jet mill to reduce the particle size to D90≤5 μm and D50 to 1-2 μm. Micronized nintedanib and roflumilast are mixed with various combinations of coarse lactose carrier (Lactohale 200) and lactose fine powder (Lactohale 300) and force control agents (L-leucine, magnesium stearate) as shown in the table below. First, the force control agent (if applicable) is added to Lactohale 200 in a metal container in layers. The powder is mixed at 48 rpm for 15 minutes in a Turbula drum mixer. Roflumilast is added to the resulting powder in layers and mixed at 48 rpm for 15 minutes. Nintedanib was then added to the resulting powder blend in layers and mixed in a Turbula blender for 15 minutes. Upon completion, the powder formulation was tested for content uniformity by taking samples from different locations in the blend, with %RSD≤15%. The optimized formulation of the combination of Nintedanib or its salt with a prostacyclin analog is shown in Table 40.

[0568] Table 40. Optimized combination formulations of nintedanib or its salt and PDE4 inhibitors

[0569]

[0570]

[0571] a. Amount of nintedanib in nintedanib base or nintedanib salt thereof

[0572] b. Magnesium stearate can be replaced by sodium stearate

[0573] Lactohale 200 from DFE Pharma with 9μm D10, 72μm D50 and 150μm D90 Respitose ML003 from DFE Pharma with 4μm D10, 38μm D50 and 112μm D90 Lactohale 300 from DFE Pharma with 5μm D50 and 10μm D90

[0574] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulations was tested by the next generation impactor (NGI). Approximately 20 mg of powder was filled into a gelatin or HPMC capsule containing up to 2 mg of nintedanib and up to 100 L / min, and dispersed over 2.4 seconds using a low-resistance Plastiape RS01 DPI device at a flow rate of 100 L / min to inhale 4 L of air, which is generally considered to be the normal forced inhalation volume of an average-sized male. The amount of nintedanib and roflumilast or other PDE4 inhibitors in each stage was recovered and analyzed by HPLC. Depending on the formulation, multiple actuations may be required to collect sufficient amounts of drugs in the impactor stage. It is expected that the fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) are ≤5 μm and ≥50%, respectively.

[0575] Example 13. Nintedanib / prostacyclin analog combination

[0576] The fixed dose dry powder combination of nintedanib HBr, its alkali or other salts and prostacyclin analogs can be prepared by lactose carrier blends. By way of non-limiting example, the prostacyclin analog can be selexipag, epoprostenol, iloprost or treprostinil. Nintedanib and prostacyclin analogs are micronized using a jet mill to reduce the particle size to D90≤5 μm and D50 to 1-2 μm. Micronized nintedanib and prostacyclin analogs are mixed with coarse lactose carrier (Lactohale 200), lactose fine powder (Lactohale 300) and force control agent (L-leucine, magnesium stearate) according to various combinations shown in the table below. First, the force control agent (if applicable) is added to Lactohale 200 in 2 or 3 layers in a metal container. The powder is mixed for 15 minutes at 48 rpm in a Turbula drum mixer. The prostacyclin analog was added to the resulting powder in 2-3 layers and mixed at 48 rpm for 15 minutes. Then nintedanib or its salt was added to the resulting powder blend in layers and mixed in a Turbula blender for 15 minutes. After completion, the content uniformity of the powder formulation was tested by taking samples from different locations in the blend, with %RSD≤15%. The optimized nintedanib or its salt and prostacyclin analog combination formulations are shown in Table 41.

[0577] Table 41. Optimized combination formulations of nintedanib or its salt and prostacyclin analogs

[0578]

[0579]

[0580] a. Amount of nintedanib in nintedanib base or nintedanib salt thereof

[0581] Lactohale 200 from DFE Pharma with 9μm D10, 72μm D50 and 150μm D90 Respitose ML003 from DFE Pharma with 4μm D10, 38μm D50 and 112μm D90 Lactohale 300 from DFE Pharma with 5μm D50 and 10μm D90

[0582] The in vitro aerosol performance (fine particle fraction and MMAD) of the above formulations was tested by the next generation impactor (NGI). Approximately 20 mg of powder blends were filled in each gelatin capsule. The low-resistance Plastiape RS01 dry powder inhaler device connected to NGI was run at 100 L / min for 2.4 seconds (to inhale 4 L of air) to determine the aerodynamic properties (MMAD and FPF) of the formulations. The amount of nintedanib HBr and selexipag in each stage was recovered and analyzed by HPLC. Depending on the formulation, multiple actuations may be required to collect sufficient amounts of medicine in the impactor stage. It is expected that the fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) are ≤5 μm and ≥50% respectively.

[0583] Specific examples for implementing the present invention include:

[0584] The composition can be prepared as a dry powder as described above, and has 3 important components to produce a therapeutically effective dose. The dose has 1% to 20% by weight of the nintedanib base molecule, which can also be provided in salt form using several different salt species described. Specific salt species include hydrobromide, ethanesulfonate and hydrochloride. The composition is provided with a prescribed or based on a size range of less than about 5 microns of D90, 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 to deliver an aerosol to the lungs of adults by inhalation. When applied in the form of a prescribed formulation, each therapeutically effective dose contains 0.005 to 10 mg of nintedanib base or base in salt form. In addition, a therapeutically effective dose can be defined as an effective daily dose of 0.05 to 40 mg. The dry powder composition can also be defined as a nintedanib component with a fine particle fraction between 10% and 100%. Delivery of the above composition may also be defined as a fine particle dose of between 0.005 mg or 0.05 mg and 10 mg of nintedanib base or salt form.

[0585] While there are many measures of lung health, the therapeutic doses of the invention can improve many different measures of lung health. This includes slowing the progression of inflammation, fibrosis, and / or demyelination, or preventing or reducing additional inflammation, fibrosis, and / or demyelination. For idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF), and restrictive allograft syndrome (RAS), a "therapeutic effect" is defined as a reduction in the level or rate of decline in forced vital capacity (FVC) and / or an improvement in patient-reported quality of life and / or a statistically significant increase or stabilization in exercise tolerance and associated oxygen saturation, a reduction in the decline in baseline forced vital capacity, a reduction in the incidence of acute exacerbations, an increase in progression-free survival, an increase in time to death or disease progression, and / or a reduction in lung fibrosis. For CLAD, a "therapeutic effect" is defined as a reduction in the decline in forced expiratory volume in one second (FEV1).

[0586] The above disclosure describes the advantages of dry powder compositions with 3 important components to produce a therapeutically effective dose. The dose has 1% to 20% by weight of nintedanib base molecules, which can also be provided in salt form using the above-mentioned several different salt species. The composition is provided with a prescribed or based on a size range of less than about 5 microns of D90, 60% to 90% by weight of a carrier agent and 0.01% to 20% by weight of a force control agent, and in this unique formulation, the dry powder is designed to be delivered to the lungs of adults by inhalation by aerosol. When applied in the form of a prescribed formulation, each therapeutically effective dose contains 0.005 to 10mg of nintedanib base or base in salt form. In addition, the therapeutically effective dose can be defined as an effective daily dose of 0.05 to 40mg. In any desired formulation, the particle size of the nintedanib component is less than 5 microns, sometimes between 1 and 4 microns, and can be micronized.

[0587] Specifically, for this formulation, delivery options include inclusion in a pre-filled capsule, pre-filled blister pack, or provided in a pre-filled cartridge for insertion into a dry powder inhaler device, or inclusion within a metering device reservoir of a dry powder inhaler.

[0588] The dry powder inhaler used by the present invention can have many performance parameters. The use of medium resistance or high resistance dry powder inhaler device depends on the specific physiology or disease state of individual patients. When used together with medium resistance or high resistance dry powder inhaler device, the aforementioned formulation has specific advantages and has unique advantages for the most challenging interstitial lung disease patients.

[0589] As mentioned above, one of the key components of the dry powder composition is a carrier. In one example, lactose is selected as a carrier, and lactose provides specific advantages compared to other carriers, even though other carriers can be modified to take advantage of the same physical and chemical properties of lactose.

[0590] As is well known in the art, nintedanib is typically delivered in the form of an oral composition. One advantage of using a dry powder composition having three important components to produce a therapeutically effective dose as described above, wherein the dose has 1 wt% to 20 wt% of nintedanib base molecules, which may also be provided in salt form using several different salt species, and provided in portions specified or based on a size range of D90 less than about 5 microns, 60 wt% to 90 wt% of a carrier agent, and 0.01 wt% to 20 wt% of a force control agent, is that the lung Cmax and / or AUC of nintedanib obtained after a single dose of dry powder is administered to a human using a dry powder inhaler is approximately equal to or greater than the lung Cmax and / or AUC of nintedanib obtained after a single dose of orally administered nintedanib is administered to a human at a dose of about 80% to about 120% of the dry powder dose. This particular formulation may also be supplemented by the addition of other substances that can be used to produce a dry powder composition having the above parameters. In particular, additional ingredients include fillers, surface modifiers, taste masking agents, sweeteners, salts, and combinations thereof.

[0591] The ability to provide a therapeutically effective dose of nintedanib also creates an opportunity to add additional active pharmaceutical ingredients to treat patients with interstitial lung disease. As part of a treatment regimen using multiple APIs, a dry powder composition having three important components to produce a therapeutically effective dose as described above (wherein the dose has 1 wt% to 20 wt% of nintedanib base molecules, which may also be provided in salt form using several different salt species, and provided in a specified or based on a size range of D90 less than about 5 microns, 60 wt% to 90 wt% of a carrier agent, and 0.01 wt% to 20 wt% of a force control agent) can be used in a regimen including an additional API in any dosage regimen or combination thereof, including fixed combination, co-administration, sequential administration, or co-prescription with pirfenidone or a pyridine analog, a PDE4 inhibitor, or a prostacyclin analog.

[0592] For any of these classes containing nintedanib as an active pharmaceutical ingredient, a number of specific formulations are contemplated. Nintedanib described in the preceding paragraphs may be provided in the form of nanoparticles.

[0593] Once the utility of a dry powder composition having three important components to produce a therapeutically effective dose is established. Specific parameters of other elements other than the nintedanib composition can be defined. In particular, the force control agent can be provided as a lactose fine powder having a D50 less than about 5 microns and a D90 less than about 10 microns. Additional force control agents used with the nintedanib composition include leucine, trileucine, lecithin, magnesium stearate, sodium stearate, sucrose stearate, polyvinylpyrrolidone, ethylcellulose, Pluronic F-68, Cremophor RH 40, glyceryl monostearate and polyethylene glycol 6000 and combinations thereof. The force control agent comprises lactose fine powder, and its particle size distribution is defined as having a D50 less than about 5 μm and a D90 less than about 10 μm, and its formulation content is between more than 0.01% by weight and about 20% by weight by weight. The force control agent may be from about 0.1% to about 20% of leucine, trileucine, magnesium stearate, sodium stearate, and lecithin, or a combination thereof.

[0594] In a particularly preferred example, the therapeutically effective dose of the dry powder composition has a particle size distribution of nintedanib, wherein D10 is between about 0.1 μm and about 2 μm, D50 is between about 1 μm and about 3 μm, and D90 is between about 1.5 μm and about 5 μm. In a preferred example, the carrier is lactose, the formulation content of which is between about 60% and about 99% by weight, and the lactose carrier has a particle size distribution, wherein D10 is between about 5 μm and about 15 μm, D50 is between about 50 μm and about 100 μm, and D90 is between about 120 μm and about 160 μm.

Claims

1. A dry powder composition comprising a therapeutically effective dose comprising: 1 wt% to 20 wt% of nintedanib base or base in salt form, the particle size distribution of which is defined as having a D90 of less than about 5 μm; 60 wt% to 90 wt% of a carrier agent; and 0.01 wt% to 20 wt% of a force control agent for aerosol delivery to the lungs of adults by inhalation, wherein each therapeutically effective dose contains 0.05 to 10 mg of the base in nintedanib base or salt form or an effective daily dose of 0.05 to 40 mg to treat interstitial lung disease.

2. The dry powder composition of claim 1, wherein the therapeutically effective dose of the dry powder composition treats interstitial lung disease by reducing the decline in forced vital capacity (FVC) of the lungs of the adult.

3. A 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 provided in a pre-filled box for insertion into a dry powder inhaler device, or contained in a metering device reservoir of a dry powder inhaler.

4. The dry powder composition of claim 1, wherein a daily dose of the dry powder composition delivers between approximately 0.05 mg and 40 mg of nintedanib base or base in salt form per day.

5. The dry powder composition according to claim 1, wherein the nintedanib has a fine particle fraction between 10% and 100%.

6. The dry powder composition according to claim 5, wherein the fine particle dose is between 0.005 mg and 10 mg of nintedanib base or base in salt form.

7. The dry powder composition of claim 1 delivered in combination with a medium resistance or high resistance dry powder inhaler device.

8. The dry powder composition according to claim 1, wherein the carrier agent is lactose.

9. The dry powder composition according to claim 1, wherein the average diameter of the nintedanib base or its salt is particles with a diameter between 1 and 5 microns.

10. The dry powder composition of claim 1, wherein a unit dose of the dry powder composition has an amount and formulation to deliver each therapeutically effective dose in less than about 10 actuations.

11. The dry powder composition of claim 1, wherein the lung Cmax and / or AUC of nintedanib obtained after administering a single dose of dry powder to the human using the dry powder inhaler is about equal to or greater than the lung Cmax and / or AUC of nintedanib obtainable after administering a single dose of orally administered nintedanib to the human at a dose of about 80% to about 120% of the dry powder dose.

12. The dry powder composition according to claim 1, further comprising one or more additional ingredients selected from the group consisting of fillers, surface modifiers, taste masking agents, sweeteners, salts, and combinations thereof.

13. The dry powder composition of claim 1 contained in a single reservoir of a dry powder inhaler.

14. The dry powder composition of claim 1, wherein nintedanib is delivered in a dosage regimen comprising a fixed combination, co-administration, sequential administration or co-prescription with pirfenidone or a pyridine analog.

15. The dry powder composition of claim 1, wherein nintedanib is delivered in a dosage regimen comprising a fixed combination, co-administration, sequential administration or co-prescription with a PDE4 inhibitor.

16. The dry powder composition of claim 1, wherein the nintedanib is delivered in a dosage regimen comprising a fixed combination, co-administration, sequential administration, or co-prescription with a prostacyclin analog.

17. The dry powder composition according to claim 1, wherein nintedanib is contained in nanoparticles.

18. The dry powder composition of claim 1, wherein the force control agent is a finely divided lactose powder having a particle size distribution defined as having a D50 of less than about 5 μm and a D90 of less than about 10 μm.

19. The dry powder composition according to claim 1, wherein the force control agent is leucine, trileucine, lecithin, magnesium stearate, sodium stearate, sucrose stearate, polyvinyl pyrrolidone, ethyl cellulose, Pluronic F-68, Cremophor RH 40, glyceryl monostearate and polyethylene glycol 6000 and combinations thereof.

20. The dry powder composition according to claim 1, wherein the nintedanib salt is a hydrobromide salt.

21. The dry powder composition according to claim 1, wherein the nintedanib salt is an esylate salt.

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

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

24. The dry powder composition of claim 1, wherein the carrier is lactose and its formulation content is between about 60 wt% and about 99 wt% by weight.

25. The dry powder composition of claim 1, wherein the carrier agent is lactose having a particle size distribution defined as having a D10 between about 5 μm and about 15 μm, a D50 between about 50 μm and about 100 μm, and a D90 between about 120 μm and about 160 μm.

26. The dry powder composition of claim 1, wherein the force control agent comprises lactose fine powder having a particle size distribution defined as having a D50 of less than about 5 μm and a D90 of less than about 10 μm, and having a formulation content of between greater than 0.01 wt% and about 20 wt% by weight.

27. The dry powder composition of claim 1, further comprising a force control agent of about 0.1 wt% to about 20 wt% by weight of leucine, trileucine, magnesium stearate, sodium stearate, and lecithin, or a combination thereof.

28. A method of treating an interstitial lung disease, the method comprising administering a therapeutically effective dose of a dry powder composition to treat the interstitial lung disease by aerosol delivery, the dry powder composition comprising: 1 wt% to 20 wt% of nintedanib base or nintedanib base in salt form having a particle size distribution defined as having a D90 of less than about 5 μm; 60 wt% to 90 wt% of a carrier agent; and 0.01 wt% to 20 wt% of a force control agent, wherein each therapeutically effective dose contains 0.05 to 10 mg of the nintedanib base or nintedanib base in salt form or an effective daily dose of 0.05 to 40 mg.

29. The method of claim 28, wherein the therapeutically effective dose of the dry powder composition treats interstitial lung disease by reducing the decline in forced vital capacity (FVC) of the lungs in the adult.

30. The method of claim 28, wherein the therapeutically effective dose is contained in a pre-filled capsule, pre-filled blister pack, or provided in a pre-filled cartridge for insertion into a dry powder inhaler device, or is contained within a metering device reservoir of a dry powder inhaler.

31. The method of claim 28, wherein the daily dose of the dry powder composition is administered daily between about 0.05 mg and 40 mg of nintedanib base or nintedanib base in salt form.

32. The method of claim 28, wherein the inhalable dry powder composition has a fine particle fraction of between 10% and 100% nintedanib.

33. The method of claim 28, wherein the fine particle dose is between 0.005 mg and 10 mg of nintedanib base or nintedanib base in salt form.

34. The method of claim 28, wherein the aerosol delivery is achieved via a medium resistance or high resistance dry powder inhaler device.

35. The method of claim 28, wherein the carrier agent is lactose.

36. The method of claim 28, wherein the average particle size of the nintedanib base or its salt is between 1 and 5 microns.

37. The method of claim 28, wherein a unit dose of the dry powder composition is delivered in less than about 10 actuations.

38. The method of claim 28, wherein the lung Cmax and / or AUC of nintedanib obtained after administering a single dose of dry powder to the human using the dry powder inhaler is about equal to or greater than the lung Cmax and / or AUC of nintedanib obtainable after administering a single dose of orally administered nintedanib to the human at a dose of about 80% to about 120% of the dry powder dose.

39. The method of claim 28, wherein the dry powder composition further comprises one or more additional ingredients selected from the group consisting of fillers, surface modifiers, taste masking agents, sweeteners, salts, and combinations thereof.

40. The method of claim 28, wherein the aerosol delivery is achieved by inhaling nintedanib from a single reservoir of a dry powder inhaler.

41. The method of claim 28, wherein the aerosol delivery follows a dosage regimen comprising a fixed combination, co-administration, sequential administration, or co-prescription with pirfenidone or a pyridine analog.

42. The method of claim 28, wherein the aerosol delivery follows a dosage regimen that includes a fixed combination, co-administration, sequential administration, or co-prescription with a PDE4 inhibitor.

43. The method of claim 28, wherein the aerosol delivery follows a dosage regimen comprising a fixed combination, co-administration, sequential administration, or co-prescription with a prostacyclin analog.

44. The method of claim 28, wherein nintedanib is contained in nanoparticles.

45. The method of claim 28, wherein the force control agent is a finely divided lactose powder having a particle size distribution defined as having a D50 of less than about 5 μm and a D90 of less than about 10 μm.

46. ​​The method of claim 28, wherein the force control agent is leucine, trileucine, lecithin, magnesium stearate, sodium stearate, sucrose stearate, polyvinylpyrrolidone, ethylcellulose, Pluronic F-68, Cremophor RH 40, glyceryl monostearate and polyethylene glycol 6000 and combinations thereof.

47. The method of claim 28, wherein the nintedanib salt is a hydrobromide salt and the weight percentage is the equivalent weight of the hydrobromide salt.

48. The method of claim 28, wherein the nintedanib salt is an ethanesulfonate salt and the weight percentage is the equivalent weight of the ethanesulfonate salt.

49. The method of claim 28, wherein the nintedanib salt is a hydrochloride salt and the weight percentage is the equivalent weight of the hydrochloride salt.

50. The method of claim 28, wherein the particle size distribution of nintedanib is defined as having a D10 between about 0.1 μm and about 2 μm, a D50 between about 1 μm and about 3 μm, and a D90 between about 1.5 μm and about 5 μm.

51. The method of claim 28, wherein the carrier agent is lactose and is present in an amount between about 60% and about 99% by weight of the formulation.

52. The method of claim 28, wherein the carrier agent is lactose having a particle size distribution defined as having a D10 between about 5 μm and about 15 μm, a D50 between about 50 μm and about 100 μm, and a D90 between about 120 μm and about 160 μm.

53. The method of claim 28, wherein the force control agent comprises lactose fine powder having a particle size distribution defined as having a D50 of less than about 5 μm and a D90 of less than about 10 μm, and having a formulation content of between greater than 0.01 wt% and about 20 wt% by weight.

54. The method of claim 28, further comprising a force control agent of about 0.1 wt% to about 20 wt% by weight of leucine, trileucine, magnesium stearate, sodium stearate, and lecithin, or a combination thereof.

55. The method of claim 28, wherein the therapeutically effective dose is provided as multiple doses within a single day to administer at least 0.05 mg of nintedanib base or nintedanib base in salt form.

56. The method of claim 55, wherein the therapeutically effective dose is administered in between two and eight unit doses, and each of the eight unit doses contains between 0.05 mg and 10 mg of the nintedanib.

57. The method of claim 28, wherein the therapeutically effective dose is delivered as a single dose once daily.

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