Pharmaceutical preparation for preventing or treating pulmonary fibrosis

Abstract

The present disclosure relates to the medical use of a compound of Formula 1 for the treatment or prevention of pulmonary fibrosis. The present disclosure also relates to the treatment with a combination of a compound of Formula 1 and nintedanib.

Description

Technical Field

[0001] This application claims priority to Korean Patent Application No. 10-2021-0071130, filed on June 1, 2021, the contents of which are disclosed in the specification and drawings of which are incorporated herein by reference.

[0002] This disclosure relates to pharmaceutical formulations for the treatment or prevention of pulmonary fibrosis. In other words, this disclosure relates to the medical use of compounds for the treatment or prevention of pulmonary fibrosis. This disclosure also relates to combination formulations for the treatment or prevention of pulmonary fibrosis, i.e., combination therapy. Background Technology

[0003] Pulmonary fibrosis is a disease in which the lungs become increasingly hard and their function deteriorates, leading to death from difficulty breathing. Causes include rheumatic diseases, radiation exposure, and fungal exposure, as well as idiopathic pulmonary fibrosis for which no specific cause has been identified.

[0004] Cases of lung tissue damage and fibrosis due to radiation exposure during chemotherapy or in industrial settings are very common. For example, 10% to 15% of patients receiving chest radiotherapy develop radiation pneumonitis after 2 to 3 months and fibrotic disease (a chronic side effect) after 6 months. Fibrosis that progresses in this way is irreversible and cannot be reversed.

[0005] The basic treatment for pulmonary fibrosis is to take medications that slow the progression of fibrosis as much as possible, and lung transplantation should be considered in severe cases. Currently, two prescription medications for pulmonary fibrosis are available in clinical use: pirfenidone and nintedanib.

[0006] Meanwhile, in combination therapy, where two drugs are administered together, the effects of using them together are practically unpredictable. However, such combination therapy has several advantages, such as reducing the dosage of each drug, thus warranting research into combination formulations. Summary of the Invention

[0007] Technical issues

[0008] This disclosure provides pharmaceutical preparations that can be used to prevent or treat pulmonary fibrosis. Another aspect of this disclosure is to provide methods for preventing or treating pulmonary fibrosis.

[0009] Technical solution

[0010] To achieve the above objectives, one embodiment of this disclosure provides a pharmaceutical preparation for the prevention or treatment of pulmonary fibrosis, comprising a pyrimidine-4-carboxamide compound of formula 1 as an active agent:

[0011] [Chemical Formula 1]

[0012]

[0013] In attempting to develop a drug for the prevention or treatment of pulmonary fibrosis, the inventors discovered that the compound represented by Chemical Formula 1 (2-((R)-4-(2-fluoro-4-(methanesulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R,2s,3S,5S,7S)-5-hydroxyadamantane-2-yl)pyrimidine-4-carboxamide) is highly effective in alleviating pulmonary fibrosis, and thus the present invention was completed.

[0014] The aforementioned compound is included in the chemical formula disclosed in PCT application publication WO2011-139107. This compound is known as an 11β-HSD1 (11β-hydroxysteroid dehydrogenase type 1) enzyme inhibitor and is currently being primarily investigated for the treatment of metabolic diseases such as diabetes and non-alcoholic steatohepatitis (PCT application publication WO2020-022708).

[0015] Compounds of Formula 1 can be prepared by the method disclosed in PCT application WO2011-139107.

[0016] This disclosure also provides methods for treating, improving, or preventing pulmonary fibrosis, characterized by applying a therapeutically or preventively effective amount of a compound of Formula 1 to a subject requiring treatment or prevention of pulmonary fibrosis. In other words, this disclosure provides the medical use of a compound of Formula 1 for the treatment or prevention of pulmonary fibrosis.

[0017] As used in this article, the term “prevention” includes preventing the recurrence, expansion, or occurrence of pulmonary fibrosis in patients.

[0018] As used herein, the term “treatment” includes eradicating, eliminating, or controlling pulmonary fibrosis and minimizing or delaying its spread.

[0019] In one embodiment of this disclosure, the pulmonary fibrosis is induced by drug treatment (e.g., anticancer drug treatment) or radiation exposure. In another embodiment of this disclosure, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0020] Another embodiment of this disclosure provides a pharmaceutical preparation for the prevention or treatment of pulmonary fibrosis, comprising a compound of formula 1 as an active agent, and further comprising nintedanib (CAS No.: 656247-17-5) or a pharmaceutically acceptable salt thereof as a second active agent. In other words, another embodiment of this disclosure provides a combination preparation of the above two active agents for the prevention or treatment of pulmonary fibrosis, i.e., combination therapy.

[0021] The compound of chemical formula 1, in synergy with nintedanib, enhances the therapeutic or preventative effects of pulmonary fibrosis.

[0022] Pharmaceutically acceptable salts of nintedanib can be acid addition salts and include salts of active compounds prepared from relatively non-toxic acids. Acid addition salts can be obtained by contacting a neutral compound with a sufficient amount of the desired acid and a pure or inert solvent. Suitable pharmaceutically acceptable acid addition salts include salts derived from non-toxic organic acids and non-toxic inorganic acids, including but not limited to acetic acid, propionic acid, isobutyl acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc., and non-toxic inorganic acids including but not limited to hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, phosphorous acid, etc. Pharmaceutically acceptable salts of nintedanib also include salts of amino acids, such as arginine salts or analogues of arginine salts, and also include analogues of organic acids such as glucuronic acid or galacturonic acid. For example, ethanesulfonic acid salts of nintedanib can be used.

[0023] As used herein, the terms “compound of Formula 1” or “nintedanib” refer to a compound of Formula 1 and nintedanib, respectively, and are intended to include its inclusion compounds, hydrates, solvates or polymorphs.

[0024] As used herein, the term "polymorph" refers to the solid crystalline form of the compound or its complexes disclosed herein. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (important in formulation and product preparation), and dissolution rate (which can affect bioavailability). Differences in stability can be caused by variations in chemical reactivity (e.g., differential oxidation, causing dosage forms to discolor more rapidly when containing one polymorph than when containing another) or mechanical properties (e.g., tablets crumble during storage as a kinetically favorable polymorph transforms into a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more prone to breakage at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate or may be more difficult to filter or wash without impurities (due to, for example, the shape or size distribution of its particles).

[0025] As used herein, the term "solvent" means a compound according to this disclosure that also comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and acceptable for use in trace doses administered to humans.

[0026] As used herein, the term "hydrate" means a compound according to this disclosure that also contains stoichiometric or nonstoichiometric amounts of water bound together by noncovalent intermolecular forces.

[0027] As used herein, the term "inclusion compound" means a compound according to this disclosure that contains, in lattice form, spaces (e.g., channels) in which guest molecules (e.g., solvents or water) are trapped.

[0028] Compounds (prodrugs) that decompose in vivo to produce the compounds of the present invention are also included within the scope of the invention. Unless otherwise stated, the term "prodrug" as used herein refers to a compound that, under biological conditions (in vitro or in vivo), is hydrolyzed, oxidized, and otherwise reacted to provide an active compound, particularly the compounds of the present invention. Some examples of prodrugs include, but are not limited to, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates / salts, biohydrolyzable carbonates / salts, and biohydrolyzable acylureas, as well as compounds containing a biohydrolyzable moiety, such as biohydrolyzable phosphate ester / salt analogs, which are biohydrolyzed to produce the compounds of the present invention. Preferably, prodrugs of compounds having a carboxyl functional group are lower alkyl esters of carboxylic acids. Carboxylic acid esters are typically formed by esterifying a portion of the carboxylic acid present in the molecule. Prodrugs can be readily prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0029] The compounds of the present invention are typically administered in therapeutically effective amounts.

[0030] The compounds of the present invention can be administered via any suitable route, in the form of a pharmaceutical composition suitable for such a route, and at a dose effective for the intended treatment. In a single dose or fractional dose, the effective dose is typically from about 0.01 to about 50 mg / kg body weight / day, preferably from about 0.05 to about 20 mg / kg / day. Dose levels below the lower limit of this range may be suitable depending on age, species, and the disease or condition being treated. In other cases, larger doses may be used without adverse side effects. Larger doses may also be divided into several smaller doses for administration throughout the day. Methods for determining appropriate doses are well known in the art.

[0031] When two active agents are administered in combination therapy according to this disclosure, the dose of each active agent may be the same as the dose when administered alone, or may be reduced by 10% to 30% by weight compared to single administration. In one embodiment of this disclosure, when used in combination, the compound of Formula 1 may be administered in an amount of 0.1 to 1 part by weight compared to the dose of nintedanib. The dosage of nintedanib is well known in the art (see [link to relevant documentation]). dose).

[0032] As previously stated, when two active agents are applied, they can be applied simultaneously (in the same formulation or in separate formulations) or sequentially. Therefore, in one embodiment, this disclosure provides a method for treating or preventing pulmonary fibrosis, comprising applying to a subject a therapeutically effective amount of a compound of formula 1 and a therapeutically effective amount of a second active agent, nintedanib or a pharmaceutically acceptable salt thereof.

[0033] In one implementation, one of the two active agents may be administered in multiple doses, or both may be administered in multiple doses. If not administered simultaneously, the intervals between the multiple doses may range from more than 0 weeks to at least 20 weeks.

[0034] Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents; multiple therapeutic combinations are also conceivable. Dosing regimens for treating, preventing, or improving pathological conditions can vary based on a variety of factors. These factors include an individual's age, weight, sex, diet, medical condition, and any medical conditions the individual may have.

[0035] Pharmaceutical formulations that achieve the combination therapies disclosed herein are either single dosage forms (optionally combined single dosage forms) or single dosage forms primarily intended for simultaneous administration. In this specification, the formulation may be a kit formulation containing two active agents separately. Pharmaceutical formulations that achieve the combination therapies of this disclosure may also be administered sequentially as any of the agents via a two-step administration regimen. The two-step administration regimen may require sequential administration of the active agents or intermittent administration of the individual active agents. The time interval between multiple administration steps can range from minutes to hours, depending on the characteristics of each active agent, such as its kinetic profile and potency, solubility, bioavailability, and plasma half-life. The diurnal variation of target molecule concentrations is used to determine the optimal dosing interval.

[0036] In another embodiment of this disclosure, a pharmaceutical preparation (combination preparation) comprising a compound of Formula 1 and a pharmaceutically acceptable carrier or additive is provided; or a pharmaceutical preparation (combination preparation) comprising a compound of Formula 1, nintedanib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

[0037] The term "medicinal" means that something is suitable for use as a pharmaceutical preparation, is generally considered safe for use as a pharmaceutical preparation, and has been officially approved for use as a pharmaceutical preparation by a national regulatory agency, or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0038] To treat the aforementioned diseases or conditions, one or more active agents described herein may be applied as follows: multiple active agents according to the invention may be contained together in one of the following formulations, or multiple active agents may be contained in separate formulations and taken together.

[0039] Intranasal application

[0040] The active agents according to the invention can be administered nasally, and intranasal administration may be particularly preferred for the medical uses of this disclosure. In this invention, such nasal administration includes conventional inhalation administration.

[0041] Such “intranasal administration” means delivery of the composition through one or both of the nose and nasal passages into the nose and nasal passages, including delivery by a spray mechanism or droplet mechanism, or delivery by atomization of the active agent. Inhalational application of the composition may be delivered through the nose or mouth via a spray or droplet mechanism.

[0042] For nasal or inhalation delivery, the compositions of the present invention can be formulated using methods known to those skilled in the art, such as, but not limited to, typical solubilizers, diluents, dispersants (e.g., saline), preservatives (e.g., benzyl alcohol), or absorption enhancers. The liquid pharmaceutical composition can be prepared using the same methods as the oral compositions described later.

[0043] Such intranasal administration can be performed using intranasal delivery devices known in the art to which this invention pertains, and in these devices propellants such as fluorocarbons and hydrofluoroalkanes can be used.

[0044] Oral application

[0045] The compounds of the present invention can be administered orally (including by swallowing) to allow the compounds to enter the digestive tract, or absorbed directly from the mouth (e.g., via the cheek or under the tongue) into the bloodstream.

[0046] Suitable compositions for oral administration include solid, liquid, gel, or powder formulations, and have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0047] Compositions for oral administration may optionally be enteric-coated and may exhibit delayed or sustained release through enteric coating. In other words, compositions for oral administration according to the invention may be formulations having an immediate release or a modulated release pattern.

[0048] Liquid formulations may include solutions, syrups, and suspensions, and may be used in soft capsules or hard capsules. Such formulations may contain pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also contain one or more emulsifiers and / or suspending agents.

[0049] In tablet dosage forms, the amount of the drug, the active ingredient, may be from about 0.05% to about 95% by weight of the dosage form, and more typically from about 2% to about 50% by weight. Additionally, the tablet may contain a disintegrant comprising from about 0.5% to about 35% by weight of the dosage form, and more typically from about 2% to about 25% by weight. Some examples of disintegrants include, but are not limited to, lactose, starch, sodium glycolate starch, crospovidone, crospovidone carboxymethyl cellulose, maltodextrin, or mixtures thereof.

[0050] Suitable lubricants for tablets may be present in amounts from about 0.1% to about 5% by weight, and include, but are not limited to, talc, silica, stearic acid, calcium stearate, zinc stearate or magnesium stearate, sodium stearate fumarate, etc.

[0051] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0052] Suitable solubilizers for tablets may be present in amounts from about 0.1% to about 3% by weight, and include, but are not limited to, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, and HCOR. TM (Nikkol), oil esters, Gelucire TM Caprylic acid / caprylic acid mono / diglycerides, sorbitan fatty acid esters and Solutol HS TM .

[0053] External application

[0054] The compounds disclosed herein can be directly applied to the bloodstream, muscles, or internal organs. Suitable routes of administration for parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, and intracranial administration. Suitable devices for parenteral administration include syringes (including needle-injectors and needle-free syringes) and infusion methods.

[0055] Compositions for parenteral administration can be formulated for immediate release or modulated release, including delayed release or sustained release.

[0056] Most parenteral preparations are liquid compositions, and liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, isotonic agent, etc., according to the present invention.

[0057] Parenteral preparations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These preparations can be used with suitable carriers such as sterile water. Solubility enhancers can also be used to prepare parenteral solutions.

[0058] Surface application

[0059] The compounds of this invention can be applied topically to the skin or transdermally. Formulations for such topical application may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical application formulations may include water, alcohols, mineral oils, glycerin, polyethylene glycol, etc. Topical application can also be performed via electroporation, iontophoresis, phonophoresis, etc.

[0060] Compositions for surface application can be formulated to release immediately or modulated release, including delayed release or sustained release.

[0061] Beneficial effects

[0062] This disclosure provides pharmaceutical preparations for the treatment or prevention of pulmonary fibrosis, comprising a compound of formula 1 as an active agent. In other words, this disclosure provides the medical use of a compound of formula 1 for the treatment or prevention of pulmonary fibrosis.

[0063] This disclosure also provides pharmaceutical formulations for the treatment or prevention of pulmonary fibrosis, comprising two active agents: a compound of formula 1 and nintedanib or a pharmaceutically acceptable salt thereof. In other words, the present invention provides a combination therapy exhibiting a synergistic effect, and it can be used to treat or prevent pulmonary fibrosis. Attached Figure Description

[0064] Figure 1 The results of Masson's trichrome staining of lung tissue at the irradiation site are shown when each test compound was orally administered to a mouse model of radiation-induced pulmonary fibrosis.

[0065] Figure 2 This is a graph that quantifies the degree of collagen deposition after the lung tissue at the irradiated site was photographed under a microscope when each test compound was orally administered to a mouse model of radiation-induced pulmonary fibrosis.

[0066] Figure 3 This is a graph showing the quantification of col1a1 gene mRNA expression using qPCR with RNA extracted from lung tissue when each test substance was orally administered to a bleomycin-induced pulmonary fibrosis mouse model.

[0067] Figure 4 This is a graph showing the quantification of TGFb gene mRNA expression using qPCR with RNA extracted from lung tissue when each test compound was orally administered to a bleomycin-induced pulmonary fibrosis mouse model.

[0068] Figure 5 This is a graph quantified by measuring the amount of hydroxyproline using an ELISA method after obtaining lysates by dissolving lung tissue when each test compound was orally administered to a bleomycin-induced mouse model of pulmonary fibrosis. Detailed Implementation

[0069] The invention is described in considerable detail below with the aid of embodiments to assist those skilled in the art in understanding it. However, the following embodiments are provided by way of example and are not intended to limit the scope of the invention. It will be apparent that various changes may be made without departing from the spirit and scope of the invention or sacrificing all its substantial advantages.

[0070] Refer to Example 1. Administration of an animal model in which pulmonary fibrosis was induced by radiation.

[0071] The test compound was orally administered to 8-week-old male C57BL / 6 mice, and one hour later, the chest was irradiated with 90 Gy (4 mm collimator) at a 3 mm diameter. The test compound was then administered orally twice daily for 14 days, followed by necropsy. Mouse lung tissue was fixed in 10% formalin, paraffin sections were prepared, and trichrome staining was used to determine the extent of collagen deposition in the tissue. The test groups are shown in Table 1 below.

[0072] [Table 1]

[0073]

[0074] Refer to Example 2. Administration of an animal model inducing pulmonary fibrosis by bleomycin injection.

[0075] C57BL / 6N mice were anesthetized with isoflurane. An incision was then made in the center of the neck to expose the airway. Bleomycin, dissolved in saline solution, was slowly injected into the exposed upper respiratory tract at a dose of 1.25 mg / kg using an insulin syringe. The insulin syringe was then removed and the incision sutured. The test compound was then administered orally twice daily for 14 days, followed by necropsy. Left lung tissue from the mice was fixed in 10% formalin, paraffin sections were prepared, and the degree of pulmonary fibrosis was assessed using H&E staining. Right lung tissue was lysed for qPCR and hydroxyproline measurements. These were subsequently used in each experiment to evaluate the expression of pulmonary fibrosis-related genes and the degree of collagen deposition in the lungs. The test groups are shown in Table 2 below.

[0076] [Table 2]

[0077]

[0078] Example 1. Antifibrotic efficacy of the compound of formula 1 in an animal model of pulmonary fibrosis.

[0079] Following Reference Example 1, the test compound was administered to a mouse model of radiation-induced pulmonary fibrosis, followed by necropsy. Mouse lung tissue was fixed in 10% neutral formalin for one day and paraffin sections were prepared. To remove paraffin from the tissue, it was sequentially reacted for 5 minutes each in xylene, 95%, 90%, and 70% ethanol solutions. To activate tissue antigens, the tissue was immersed in 0.1M citric acid (pH 6.0) solution and boiled for 20 minutes. It was then sequentially reacted with Bouin solution for 1 minute, with Weigert hematoxylin for 10 minutes, with phosphotungstic acid / phosphomolybdic acid for 10 minutes, with aniline blue for 5 minutes, and with 1% acetic acid for 1 minute. Following the dehydration process, the tissue was sealed with a coverslip and observed under a microscope (Carl Zeiss Vision).

[0080] As a test result, such Figure 1 and 2 As shown, compared to the carrier group (G1), all test compound application groups demonstrated anti-fibrotic effects by inhibiting collagen deposition. The test groups showing high significance were the group applying nintedanib alone (G2) and the group applying a combination of nintedanib and the compound of formula 1 (G4). In particular, the group applying a combination of nintedanib and the compound of formula 1 (G4) showed better efficacy compared to the group applying nintedanib alone (G2).

[0081] In summary, the compound of Formula 1 significantly inhibited collagen deposition, a major indicator of pulmonary fibrosis, and in particular, the combination of the compound of Formula 1 with nintedanib proved to be more effective than nintedanib alone.

[0082] Example 2. Antifibrotic efficacy of the compound of formula 1 in an animal model of pulmonary fibrosis.

[0083] Following Reference Example 2, the test compound was administered to a mouse model of bleomycin-induced pulmonary fibrosis, followed by necropsy. Left lung tissue from the mice was fixed in 10% neutral formalin for one day and paraffin sections were prepared. To remove paraffin from the tissue, it was sequentially reacted for 5 minutes each in xylene, 95%, 90%, and 70% ethanol solutions. Next, for trichrome staining, cells were sequentially reacted with Bouin solution for 1 minute, with Weigert hematoxylin for 10 minutes, with phosphotungstic acid / phosphomolybdic acid for 10 minutes, with aniline blue for 5 minutes, and with 1% acetic acid for 1 minute. Following the dehydration process, the tissue was sealed with coverslips and observed under a microscope (Carl Zeiss Vision). Half of the right lung tissue from the mice was lysed for qPCR, RNA was extracted, and cDNA was synthesized. Subsequently, gene expression analysis of Col1a1 (an extracellular matrix factor causing fibrosis) and TGFβ (an important cytokine causing fibrosis) was performed using qPCR. The other half of the tissue was lysed, and the lysate was analyzed using a hydroxyproline ELISA kit.

[0084] As a result of the test, Figure 3 In comparison of Col1a1 gene expression in lung tissue, no statistically significant differences were observed; however, a decreasing trend was confirmed in all administration groups compared to the load-administered group (G2). Additionally, in Figure 4 In comparison of TGFβ gene expression, significant differences were identified in all administration groups compared to the load-administered group (G2). Figure 5 As a result confirming the expression of hydroxyproline in lung tissue, significant differences were confirmed in all administration groups except for the nintedanib alone group (G7), compared to the carrier administration group (G2). Particularly good results were confirmed in the combination administration group of nintedanib and compound of formula 1 (G6).

[0085] In summary, the compound of Formula 1 significantly inhibited collagen deposition, a major indicator of pulmonary fibrosis, and in particular, its efficacy was shown to be superior to that of nintedanib alone when used in combination with nintedanib.

Claims

1. Use of compounds of formula 1 in the preparation of medicaments for the prevention or treatment of pulmonary fibrosis: [Chemical Formula 1] 。 2. The use according to claim 1, wherein the pulmonary fibrosis is caused by drug treatment or radiation exposure.

3. The use according to claim 1, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

4. The use according to any one of claims 1 to 3, wherein the medicament further comprises nintedanib or a pharmaceutically acceptable salt thereof as an active agent.

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