KR102355128B1 - Dry powder formulation for inhalation comprising fine particle of nintedanib or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a dry powder formulation for inhalation comprising microparticles of nintedanib or a pharmaceutically acceptable salt thereof. Specifically, the microparticles of nintedanib or a pharmaceutically acceptable salt thereof according to the present invention have an inhalable size and particle shape, are thermodynamically stable, and exhibit high emitted dose (ED) and fine particle fraction (FPF) values. By dispensing, it can be easily used as a dry powder formulation for inhalation.

Description

DRY POWDER FORMULATION FOR INHALATION COMPRISING FINE PARTICLE OF NINTEDANIB OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF comprising microparticles of nintedanib or a pharmaceutically acceptable salt thereof

The present invention relates to a dry powder formulation for inhalation comprising microparticles of nintedanib or a pharmaceutically acceptable salt thereof.

Nintedanib is the first FDA-approved treatment for idiopathic pulmonary fibrosis as a TKI (tyrosine kinase inhibitor) class of targeted therapy. Nintedanib targets various growth factor receptors involved in the pathogenesis of pulmonary fibrosis, among them, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR). Inhibits fibrosis by blocking signal transduction.

On the other hand, fibrosis refers to a symptom in which tissue function is lost due to fibrosis in which normal tissue is destroyed and replaced with fibrous connective tissue, and fundamental treatment is difficult because the fibrosis process is chronically progressed.

Idiopathic pulmonary fibrosis, one of fibrosis, is a disease of unknown etiology characterized by chronically progressive fibrosis of the lungs. show opinion The prevalence of this disease is known to be 2 to 29 per 100,000 population, and it is designated as a rare intractable disease in Korea. The clinical course for idiopathic pulmonary fibrosis is diverse, and in general, it is a fatal disease that progresses to respiratory failure due to slowly progressive deterioration of lung function, and the average survival period after diagnosis is within 2 to 3 years.

Chemicals, smoking, fine dust, viral infection, and genetic factors have been mentioned as the cause of idiopathic pulmonary fibrosis, but the exact cause of the disease has not yet been identified, and basic research on the etiology is lacking. No therapeutic target has been discovered. In this regard, Korean Patent Laid-Open No. 10-2019-0064132 discloses that ornithine aminotransferase is involved in lung fibrosis due to collagen accumulation, and thus an inhibitor of ornithine aminotransferase is used to treat lung fibrosis. It is disclosed that it can be used for

Nintedanib has been used as such a treatment for idiopathic pulmonary fibrosis, and is currently administered in a soft capsule formulation for oral administration, but orally administered nintedanib has a problem in that the bioavailability is very low, about 5%.

Korean Patent Publication No. 10-2019-0064132

An object of the present invention is to provide a dry powder formulation for inhalation comprising microparticles of nintedanib or a pharmaceutically acceptable salt thereof, and a capsule for inhalation filled with the dry powder formulation for inhalation.

Another object of the present invention is to provide a method for preparing microparticles of nintedanib or a pharmaceutically acceptable salt thereof, and to provide microparticles of nintedanib or a pharmaceutically acceptable salt thereof prepared by the method.

In order to achieve the above object, the present invention provides a dry powder formulation for inhalation comprising microparticles of nintedanib or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a capsule for inhalation filled with the dry powder formulation for inhalation according to the present invention.

In addition, the present invention provides a primary grinding step of nintedanib or a pharmaceutically acceptable salt thereof at a pressure of 0.1 to 0.9 MPa; and a secondary grinding step of primary grinding nintedanib or a pharmaceutically acceptable salt thereof at a pressure of 0.4 to 1.5 MPa. Preparation of fine particles of nintedanib or a pharmaceutically acceptable salt thereof using a jet mill method provide a way

In addition, the present invention provides microparticles of nintedanib or a pharmaceutically acceptable salt thereof prepared by the above preparation method.

In addition, the present invention relates to a spray-drying method comprising spray-drying an aqueous solution of nintedanib or a pharmaceutically acceptable salt thereof at an intake temperature of 50 to 200° C. and an exhaust temperature of 30 to 100° C. Provided is a method for preparing microparticles of an acceptable salt.

Furthermore, the present invention provides microparticles of nintedanib or a pharmaceutically acceptable salt thereof prepared by the above method.

The microparticles of nintedanib or a pharmaceutically acceptable salt thereof according to the present invention have an inhalable size and particle shape, are thermodynamically stable, and exhibit high emitted dose (ED) and fine particle fraction (FPF) values. It can be easily used as a dry powder formulation for use.

1 is a view showing the results of observing the microparticle form of nintedanib esylate salt prepared in an embodiment of the present invention with a scanning electron microscope.
2 is a graph showing the results of analyzing the microparticles of the nintedanib esylate salt prepared in an embodiment of the present invention by the DSC method.
3 is a graph showing the results of XRD analysis of the microparticles of the nintedanib esylate salt prepared in an embodiment of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a dry powder formulation for inhalation comprising microparticles of nintedanib or a pharmaceutically acceptable salt thereof.

As used herein, the term "nintedanib" is a tyrosine kinase inhibitor that targets platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR). kinase inhibitor), and refers to a compound represented by the following formula (1). The nintedanib may be used for the treatment of idiopathic lung fibrosis or some non-small-cell lung cancer (NSCLC).

[Formula 1]

The nintedanib according to the present invention may include a pharmaceutically acceptable salt form thereof. Specifically, the pharmaceutically acceptable salts include addition salts with pharmaceutically acceptable non-toxic organic and inorganic acids such as acetic acid, citric acid, malic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; It may be a metal salt (eg, a sodium salt or potassium salt), an ammonium salt, an amine salt, an amino acid salt, and the like.

In addition to pharmaceutically acceptable salts, equivalents having the same or similar activity may be used. Examples of usable equivalents include solvates, hydrates, anhydrides, enantiomers, derivatives, polymorphs, prodrugs, etc. may be included.

According to an embodiment of the present invention, the nintedanib may be a nintedanib esylate salt.

The dry powder formulation for inhalation according to the present invention may contain microparticles of nintedanib or a pharmaceutically acceptable salt thereof. The fine particles have an average particle size of 20 μm or less, 0.1 to 10 μm, 0.1 to 7 μm, 0.1 to 5 μm, 0.5 to 10 μm, 0.5 to 7 μm, 0.5 to 5 μm, 1 to 10 μm, 1 to 7 μm, 1 to 5 μm, 2 to 10 μm, 2 to 7 μm, or 2 to 5 μm.

The fine particles of nintedanib or a pharmaceutically acceptable salt thereof may be pulverized by a method well known in the art. Specifically, the pulverization is performed by any one or more methods selected from the group consisting of a jet mill, a ball mill, a pin mill, spray drying, and supercritical fluid crystallization. can

In the method, nintedanib or a pharmaceutically acceptable salt thereof is 0.1 to 1.5 MPa, 0.1 to 1.0 MPa, 0.1 to 0.7 MPa, 0.2 to 1.5 MPa, 0.2 to 1.0 MPa, 0.2 to 0.7 MPa, 0.3 to 1.5 MPa, It can be pulverized by performing a jet mill at a pressure of 0.3 to 1.0 MPa or 0.3 to 0.7 MPa.

As an example, the preparation of nintedanib or a pharmaceutically acceptable salt thereof using the jet mill may include a primary grinding step performed at a pressure of 0.1 to 0.9 MPa; And it may be carried out through a secondary grinding step in which the primary grinding nintedanib or a pharmaceutically acceptable salt thereof is carried out at a pressure of 0.4 to 1.5 MPa. The primary grinding and secondary grinding may be performed as a series of processes, and the primary grinding and secondary grinding may be performed once or more, respectively. In addition, when a series of processes of performing the primary grinding step and the secondary grinding step are performed once, the process may be performed once or more.

Meanwhile, in the method, nintedanib or a pharmaceutically acceptable salt thereof may be pulverized by performing spray drying at an intake temperature of 50 to 200°C and an exhaust temperature of 70 to 200°C. Specifically, the intake air temperature is 50 to 200 ℃, 70 to 200 ℃, 80 to 200 ℃, 90 to 200 ℃, 100 to 200 ℃, 50 to 160 ℃, 70 to 160 ℃, 80 to 160 ℃, 90 to 160 ℃, 100 to 160 ℃, 50 to 130 ℃, 70 to 130 ℃, 80 to 130 ℃, 90 to 130 ℃ or may be 100 to 130 ℃. In addition, the exhaust temperature is 30 to 100 ℃, 40 to 100 ℃, 50 to 100 ℃, 30 to 90 ℃, 40 to 90 ℃, 50 to 90 ℃, 30 to 80 ℃, 40 to 80 ℃, 50 to 80 ℃ , 30 to 70 ℃, 40 to 70 ℃ or may be 50 to 70 ℃.

In the dry powder formulation for inhalation according to the present invention, the active ingredient, nintedanib or a pharmaceutically acceptable salt thereof, is filled in a capsule or cyst at an accurate dose, and an excipient may be further mixed to increase the delivery rate to the lungs upon inhalation. . The excipient may be any excipient known in the art, and may be appropriately modified by those skilled in the art.

In addition, the present invention provides a capsule for inhalation filled with the dry powder formulation for inhalation according to the present invention.

The dry powder formulation for inhalation may have the characteristics described above. For example, the dry powder formulation for inhalation may be microparticles of nintedanib or a pharmaceutically acceptable salt thereof. The fine particles have an average particle size of 20 μm or less, 0.1 to 10 μm, 0.1 to 7 μm, 0.1 to 5 μm, 0.5 to 10 μm, 0.5 to 7 μm, 0.5 to 5 μm, 1 to 10 μm, 1 to 7 μm, 1 to 5 μm, 2 to 10 μm, 2 to 7 μm, or 2 to 5 μm.

In addition, the fine particles may be pulverized by a method well known in the art. Specifically, the pulverization may be performed by any one or more methods selected from the group consisting of a jet mill and spray drying.

The capsule for inhalation according to the present invention is one in which the dry powder formulation for inhalation according to the present invention is filled in a capsule and cartridge such as gelatin or hypmellose used in an inhalation device, or a blister such as a layered aluminum thin film can

The capsule may have various internal capacities depending on the lake, for example, capsule No. 0 is about 0.68 ml, capsule No. 1 is about 0.47 ml, capsule No. 2 is about 0.37 ml, and capsule No. 2 is about 0.27 ml , No. 4 capsules may have an internal capacity of about 0.20 ml. The size of the capsule may be appropriately selected by a person skilled in the art and prepared as a capsule.

The capsule may be transparent in that it can be visually checked whether the patient inhales the dry powder formulation in the capsule after inhalation. In addition, in the transparent capsule, a decrease in stability or product defects such as aggregation and discoloration of the dry powder formulation in the capsule can be visually confirmed.

The inhalation capsule may be administered using any known dry powder inhalation device. The dry powder inhalation device may include means for rupturing, puncturing (puncturing) the capsule, or otherwise opening the capsule for delivery of the metered active ingredient in the capsule to the lungs of a patient. In addition, it may further include an inlet through which air enters to form a flow of air, an outlet through which the active ingredient is discharged through inhalation by the patient with mouth, and a sieve for filtering foreign substances. Examples of such devices are the commercially available ROTAHALER ^® from Glaxo-Smithkline, HANDIHALER ^® from Boehringer Ingelheim or AEROLIZER ^® from plastiape. The HANDIHALER ^® and AEROLIZER ^® have a flaw in the cap of the inhalation device, and when the button is pressed, a pin comes out and a hole is punched in the capsule.

In addition, the present invention provides a primary grinding step of nintedanib or a pharmaceutically acceptable salt thereof at a pressure of 0.1 to 0.9 MPa; and a secondary grinding step of primary grinding nintedanib or a pharmaceutically acceptable salt thereof at a pressure of 0.4 to 1.5 MPa. Preparation of fine particles of nintedanib or a pharmaceutically acceptable salt thereof using a jet mill method provide a way

In the preparation method, nintedanib or a pharmaceutically acceptable salt thereof may have the characteristics as described above, and specifically, the nintedanib may be a nintedanib esylate salt. Meanwhile, the fine particles have an average particle size of 20 μm or less, 0.1 to 10 μm, 0.1 to 7 μm, 0.1 to 5 μm, 0.5 to 10 μm, 0.5 to 7 μm, 0.5 to 5 μm, 1 to 10 μm, 1 to 7 μm, 1 to 5 μm, 2 to 10 μm, 2 to 7 μm, or 2 to 5 μm.

The pressure of the jet mill in the primary grinding step is 0.1 to 0.9 MPa, 0.1 to 0.7 MPa, 0.1 to 0.5 MPa, 0.2 to 0.9 MPa, 0.2 to 0.7 MPa, 0.2 to 0.5 MPa, 0.3 to 0.9 MPa, 0.3 to 0.7 MPa or It may be 0.3 to 0.5 MPa.

On the other hand, the pressure of the jet mill in the secondary grinding step is 0.4 to 1.5 MPa, 0.4 to 1.2 MPa, 0.4 to 0.9 MPa, 0.4 to 0.7 MPa, 0.5 to 1.5 MPa, 0.5 to 1.2 MPa, 0.5 to 0.9 MPa, or 0.5 to 0.7 may be MPa.

The manufacturing method according to the present invention may perform the primary grinding step and the secondary grinding step as a series of processes, and the primary grinding step and the secondary grinding step may be performed once or more, respectively. In addition, when a series of processes of performing the primary grinding step and the secondary grinding step are performed once, the process may be performed once or more.

In addition, the present invention provides microparticles of nintedanib or a pharmaceutically acceptable salt thereof prepared by the above preparation method. The fine particles may be manufactured by a manufacturing method including the characteristics as described above.

In addition, the present invention relates to a spray-drying method comprising spray-drying an aqueous solution of nintedanib or a pharmaceutically acceptable salt thereof at an intake temperature of 50 to 200° C. and an exhaust temperature of 70 to 200° C. Provided is a method for preparing microparticles of an acceptable salt.

In the preparation method, nintedanib or a pharmaceutically acceptable salt thereof may have the characteristics as described above, and specifically, the nintedanib may be a nintedanib esylate salt. Meanwhile, the fine particles have an average particle size of 20 μm or less, 0.1 to 10 μm, 0.1 to 7 μm, 0.1 to 5 μm, 0.5 to 10 μm, 0.5 to 7 μm, 0.5 to 5 μm, 1 to 10 μm, 1 to 7 μm, 1 to 5 μm, 2 to 10 μm, 2 to 7 μm, or 2 to 5 μm.

On the other hand, the intake air temperature in the above manufacturing method is 50 to 200 ℃, 70 to 200 ℃, 80 to 200 ℃, 90 to 200 ℃, 100 to 200 ℃, 50 to 160 ℃, 70 to 160 ℃, 80 to 160 ℃, 90 to 160 °C, 100 to 160 °C, 50 to 130 °C, 70 to 130 °C, 80 to 130 °C, 90 to 130 °C, or 100 to 130 °C.

In addition, the exhaust temperature is 30 to 100 ℃, 40 to 100 ℃, 50 to 100 ℃, 30 to 90 ℃, 40 to 90 ℃, 50 to 90 ℃, 30 to 80 ℃, 40 to 80 ℃, 50 to 80 ℃ , 30 to 70 ℃, 40 to 70 ℃ or may be 50 to 70 ℃.

Furthermore, the present invention provides microparticles of nintedanib or a pharmaceutically acceptable salt thereof prepared by the above method. The fine particles may be manufactured by a manufacturing method including the characteristics as described above.

Hereinafter, the present invention will be described in detail by the following examples, provided that the following examples are only for illustrating the present invention, and the present invention is not limited thereto. Anything that has substantially the same configuration as the technical idea described in the claims of the present invention and achieves the same operation and effect is included in the technical scope of the present invention.

Example 1. Preparation of nintedanib microparticles using jet mill-(1)

Fine particles of nintedanib esylate salt (MSN Laboratories Pvt. Ltd., India) were prepared using an A-O jet mill (JS-TECH) machine. Specifically, nintedanib was first pulverized at a pressure of 0.4 MPa using a G nozzle, and then secondary pulverization was performed at a pressure of 0.6 MPa using a P nozzle again. As a result, fine particles of nintedanib pulverized using a jet mill were obtained.

Example 2. Preparation of nintedanib microparticles using jet mill-(2)

Fine particles of nintedanib were obtained by grinding nintedanib under the same conditions and method as in Example 1, except that when the primary and secondary grinding were performed once, this was repeated twice.

Example 3. Preparation of nintedanib microparticles using spray drying-(1)

500 mg of nintedanib esylate salt was added to 100 ml of distilled water and dissolved well to obtain a nintedanib esylate salt solution, which was used to perform spray drying. Specifically, spray drying is performed by administering the obtained 0.5% (w/v) nintedanib esylate salt at an inlet temperature of 120° C., an outlet temperature of 65° C., and an atmospheric pressure of 0.36 m 3 / min. It was carried out under the conditions of a speed, a spraying rate of 4.6 ml/min, and an atomizing air pressure of 15×10 kPa. As a result, fine particles of pulverized nintedanib were obtained by spray drying. At this time, the yield of the obtained nintedanib microparticles was 19.7%.

Example 4. Preparation of nintedanib microparticles using spray drying-(2)

Fine particles of nintedanib were obtained by pulverizing nintedanib under the same conditions and methods as in Example 3, except that spray drying was performed at an intake temperature of 110°C and an exhaust temperature of 58°C. At this time, the yield of the obtained nintedanib microparticles was 36.7%.

Example 5. Preparation of nintedanib microparticles using spray drying-(3)

Fine particles of nintedanib were obtained by pulverizing nintedanib under the same conditions and method as in Example 3, except that spray drying was performed at an intake temperature of 150°C and an exhaust temperature of 85°C. At this time, the yield of the obtained nintedanib microparticles was 7.4%.

Example 6. Preparation of nintedanib microparticles using spray drying-(4)

Fine particles of nintedanib were obtained by pulverizing nintedanib in the same conditions and method as in Example 3, except that spray drying was performed at an intake temperature of 90°C, an exhaust temperature of 40°C, and a suction pressure of 20 × 10 kPa. obtained. At this time, the yield of the obtained nintedanib microparticles was 5.3%.

Experimental Example 1. Confirmation of size distribution of nintedanib microparticles

The fine particle size of nintedanib obtained in Examples 1 to 6 was confirmed by a conventional method using a mastersizer 3000 particle size analyzer (Malvern). In this case, unmilled nintedanib esylate salt was used as a control. As a result, the measured result values are shown in Table 1 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 1 Dv 50 (㎛) 2.57 2.12 2.45 2.68 3.06 - 53.1 Span 2.171 2.153 1.841 2.193 46.403 - -

As shown in Table 1, the pulverized nintedanib esylate salt exhibited a particle size of about 2.1 to 3.0 μm, whereas, in the control group, the fine particles of nintedanib obtained by showing a particle size of 53.1 μm were inhalable. was found to have been crushed. However, the fine particles of Examples 5 and 6 had a low yield during the manufacturing process, and the fine particles of Example 6 did not form appropriate particles, so that the particle size distribution could not be confirmed. On the other hand, the fine particles of Example 5 showed a particle size of 3 μm, but it was determined that the size distribution was too large to be used for inhalation.

Experimental Example 2. Confirmation of the morphology of nintedanib microparticles

The microparticle morphology of nintedanib obtained in Examples 1 to 6 was confirmed by a conventional method using an Ultra plus scanning electron microscope (Zeiss). In this case, unmilled nintedanib esylate salt was used as a control. As a result, the observed results are shown in FIG. 1 .

As shown in FIG. 1 , the pulverized fine particles of Examples 1 to 5 were different from the nintedanib esylate salt of Comparative Example 1, and the nintedanib esylate salts of Examples 1 and 2 pulverized with a jet mill were On the other hand, in the case of Examples 3 and 4 pulverized by spray drying, it was confirmed as amorphous particles.

In addition, in the case of Examples 3 to 5, there was a dent on the surface while exhibiting a spherical shape. It can be seen that such a shape reduces the surface area of the particles, thereby reducing the interaction between particles and promoting dispersion. On the other hand, in Example 5, it was confirmed that particles were not formed.

Experimental Example 3. Confirmation of inhalation efficiency of nintedanib microparticles

The inhalation efficiency of the nintedanib microparticles obtained in Examples 1 to 6 was confirmed by a conventional method using an Andesren cascade impactor (Copley), and as a result, the measured values are shown in Table 2 below.

MMAD±SD(㎛) GSD±SD ED±SD (%) FPF±SD (%) RF±SD (%) Example 1 2.97±0.33 1.72±0.11 91.11±4.41 40.30±7.84 92.46±2.97 Example 2 2.91±0.61 2.13±0.54 91.90±0.92 41.06±7.15 85.24±17.21 Example 3 2.74±0.03 1.60±0.02 77.99±3.58 47.09±4.87 93.12±1.81 Example 4 2.62±0.10 1.74±0.11 88.03±1.78 37.55±6.95 92.92±3.61 Example 5 - - - - - Example 6 3.73±0.14 2.06±0.13 91.44±1.85 28.05±5.47 71.97±4.02

As shown in Table 2, the nintedanib microparticles of Examples 1 to 4 and Example 6 exhibited a mass median aerodynamic diameter (MMAD) of 2.6 to 3.0 μm, and are generally used in formulations for inhalation. It was confirmed that it represents a possible size. In addition, the geometric standard deviation (GSD) indicating the aerodynamic particle size distribution also generally indicated a size that can be used in the formulation for inhalation.

On the other hand, the dry powders prepared in Examples 1 to 4 all showed high ED (emitted dose) and FPF (fine particle fraction) values, and thus it was confirmed that the inhalation efficiency was excellent. Moreover, all of the dry powders exhibited an RF (respirable fraction) value of 85% or more, indicating that the inhaled active ingredient reached the bronchi or alveoli with high efficiency. On the other hand, the nintedanib microparticles of Example 5 could not confirm the inhalation efficiency.

Therefore, from the above experimental results, it was determined that the nintedanib microparticles of Examples 5 and 6 were not suitable for use as a formulation for inhalation, and subsequent experiments were conducted using the nintedanib microparticles of Examples 1 to 4.

Experimental Example 4. Confirmation of chemical properties of nintedanib microparticles-(1)

Chemical properties of the nintedanib microparticles obtained in Examples 1 to 4 were confirmed by a conventional method using differential scanning calorimetry (DSC) analysis. In this case, unmilled nintedanib esylate salt was used as a control. As a result, the observed results are shown in FIG. 2 .

As shown in FIG. 2 , the nintedanib microparticles of Examples 1 and 2 showed a similar heat flow, whereas the nintedanib microparticles of Examples 3 and 4 showed a heat flow similar to Comparative Example 1. That is, from the above results, it was found that the nintedanib microparticles of Examples 1 and 2 showed a crystalline particle form, whereas the nintedanib microparticles of Examples 3 and 4 were amorphous.

Experimental Example 5. Confirmation of chemical properties of nintedanib microparticles-(2)

The chemical properties of the nintedanib microparticles obtained in Examples 1 to 4 were confirmed by a conventional method using X-ray diffraction (XRD) analysis. In this case, unmilled nintedanib esylate salt was used as a control. As a result, the observed results are shown in FIG. 3 .

As shown in FIG. 3 , the nintedanib microparticles of Examples 1 and 2 existed in a crystalline form having properties of a nintedanib esylate salt, whereas the nintedanib microparticles of Examples 3 and 4 were the same as in Comparative Example 1. It existed in an amorphous form. Therefore, from the above results, it was found that the microparticles of Examples 1 and 2 had higher stability than the microparticles of Examples 3 and 4, while the solubility was low.

Claims (4)

Using a spray drying method comprising spray drying an aqueous solution of nintedanib or a pharmaceutically acceptable salt thereof at an intake temperature of 100 to 130° C. and an exhaust temperature of 50 to 70° C. nintedanib or a pharmaceutically acceptable salt thereof A method for preparing microparticles of an acceptable salt, the method comprising:
The fine particles have an average particle size of 20 μm or less,
A pharmaceutically acceptable salt of nintedanib is a method for preparing microparticles of nintedanib or a pharmaceutically acceptable salt thereof, which is a nintedanib esylate salt.
delete delete A capsule for inhalation filled with fine particles prepared by the manufacturing method according to claim 1 .

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