Rivaroxaban inhalation composition

Abstract

Disclosed is a method for preparing a rivaroxaban dry powder inhalation composition, the method comprising the steps of: (S1) placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads into a ball mill device and milling same to obtain bead-milled rivaroxaban dry powder; and (S2) placing the obtained bead-milled rivaroxaban dry powder into an air jet mill device and pulverizing same. Also, disclosed are: a rivaroxaban dry powder inhalation composition comprising rivaroxaban dry powder having a Dv50 diameter of 5 μm or less; and a dry powder inhaler comprising the composition.

Description

Rivaroxaban inhalation composition

[0001] The present invention relates to a composition for inhalation of rivaroxaban. Specifically, it relates to a method for producing fine particles containing rivaroxaban for inhalation, which have the property of agglomerating nano-sized particles with a bead mill and of being dispersed with an air jet mill, by combining a bead mill and an air jet mill, and a technology for producing dry powder fine particles containing a high drug content for inhalation using a hollow bead mill or hollow air jet mill based on a small amount of a dispersion stabilizer.

[0002] Venous thromboembolism, including pulmonary embolism and deep vein thrombosis, is the third most common cardiovascular disease. Untreated, pulmonary embolism has a mortality rate of up to 30%, making it the second-highest mortality rate after cancer. The risk of developing pulmonary embolism in cancer patients increases annually, reaching four to seven times higher than in non-cancer patients. The risk of pulmonary embolism has further increased recently due to complications from COVID-19.

[0003] According to the current guidelines for the treatment of pulmonary embolism (2019 ESC guidelines), low-molecular-weight heparin (LMWH) and novel oral anticoagulants (NOACs) are used as treatments for patients at intermediate or low risk of pulmonary embolism. Among NOACs, high-dose rivaroxaban, like LMWH, has proven clinically useful and is classified as a first-line treatment. LMWHs have a long history of use and extensive clinical experience, and the availability of protamine, a reversal agent, allows for mitigation of adverse effects. However, they can cause heparin-induced thrombocytopenia and have a relatively high recurrence rate compared to NOACs. Conversely, rivaroxaban offers significant clinical and maintenance benefits, including a low recurrence rate, and can be administered noninvasively orally. However, rivaroxaban also shares the inherent disadvantages of NOACs, namely a higher risk of bleeding compared to LMWHs.

[0004] For pulmonary diseases such as pulmonary embolism, pulmonary drug delivery allows for localized drug delivery directly to the lungs, and its large absorption surface area allows rapid drug entry even with low solubility. Therefore, pulmonary inhalation of rivaroxaban offers the advantage of treating pulmonary diseases with lower drug doses compared to formulations delivered through systemic circulation, while also reducing adverse drug effects such as bleeding. However, developing rivaroxaban as a dry powder inhalation formulation requires a sufficiently fine particle size to ensure deep lung delivery and particle characteristics that facilitate smooth aerosol formation.

[0005] [Prior Art Literature]

[0006] [Non-patent literature]

[0007] (Non-patent Document 1) Rashid, MA, Muneer, S., Mendhi, J., Sabuj, MZR, Alhamhoom, Y., Xiao, Y., ... & Islam, N. (2021). Inhaled Edoxaban dry powder inhaler formulations: Development, characterization and their effects on the coagulopathy associated with COVID-19 infection. International Journal of Pharmaceutics, 608, 121122.

[0008] The present invention provides a method for manufacturing inhalable fine particles of several to several tens of micrometers in size by combining a bead mill and an air jet mill. The combination of these two devices is expected to reduce the particle size of a dry powder inhalant to an inhalable size and improve dispersibility, thereby enhancing drug inhalation efficiency.

[0009] In addition, the absorption efficiency of the drug can be further maximized by using a bead mill or air jet mill, such as a dispersion stabilizer.

[0010] The present invention is to manufacture a dry powder inhaler of rivaroxaban with excellent inhalation efficiency through a bead mill and an air jet mill, and with a high content without a separate carrier, thereby enabling delivery of the drug to the deep lungs.

[0011] In order to solve the above problem, the present invention discloses the following means.

[0012] In one aspect, the present invention discloses a method for preparing a rivaroxaban dry powder inhalation composition, comprising the steps of (S1) placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads in a ball mill and milling to obtain a bead-milled rivaroxaban dry powder; and (S2) placing the obtained bead-milled rivaroxaban dry powder in an air jet mill and grinding it.

[0013] In another aspect, the present invention discloses a rivaroxaban dry powder inhalation composition comprising rivaroxaban dry powder having a Dv50 diameter of 5 μm or less.

[0014] In a final aspect, the present invention discloses a dry powder inhaler comprising the rivaroxaban dry powder inhalation composition.

[0015] The present invention has shown that it is possible to produce inhalable fine particles of several to several tens of micrometers in size with superior inhalation efficiency by combining a bead mill and an air jet mill, rather than by using a bead mill alone or an air jet mill alone, and additionally, it has been confirmed that the dispersibility of dry powder fine particles can be improved by adding a small amount of dispersion stabilizer, thereby achieving even better aerodynamic characteristics and maximizing inhalation efficiency.

[0016] This is a separate carrier up-production method for dry powder microparticles having a high drug content, and is expected to be used in dry powder inhalers that require a high drug content.

[0017] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0018] Figure 1 shows a process diagram for manufacturing bead mill dried powder fine particles according to Comparative Example 1-1.

[0019] Figure 2 shows a process diagram for manufacturing air jet mill dried powder according to Comparative Example 1-2.

[0020] Figure 3 shows a process diagram for manufacturing a dry powder using a combination of a bead mill and an air jet mill according to Example 1.

[0021] Figure 4 shows a process diagram for manufacturing a lysine-based hollow bead mill dry powder according to Comparative Example 2.

[0022] Figure 5 shows a process diagram for manufacturing a dry powder using a combination of a lysine-based hollow bead mill and an air jet mill according to Example 2.

[0023] Figure 6 shows a process diagram for manufacturing a simple mixed dry powder based on bead mill rivaroxaban and leucine according to Comparative Example 3.

[0024] Figure 7 shows a process diagram for manufacturing a combined dry powder using a bead mill rivaroxaban and a leucine-based co-air jet mill according to Example 3.

[0025] Figure 8 shows a process diagram for manufacturing a magnesium stearic acid-based bead mill dry powder according to Comparative Example 4.

[0026] Figure 9 shows a process diagram for manufacturing a combined dry powder of a magnesium stearic acid-based hollow bead mill and air jet mill according to Example 4.

[0027] Figure 10 shows a process diagram for manufacturing a simple mixed dry powder based on bead mill rivaroxaban and magnesium stearic acid according to Comparative Example 5.

[0028] Figure 11 shows a process diagram for manufacturing a combined dry powder of a co-air jet mill based on bead mill rivaroxaban and magnesium stearate according to Example 5.

[0029] Figure 12 shows a SEM image of the particle morphology of a dry powder containing a drug.

[0030] Figure 13 shows the absorption efficiency of the combined dry powder of the bead mill and air jet mill according to Experimental Example 3.

[0031] Figure 14 shows the absorption efficiency of the combined dry powder of the lysine-based hollow bead mill-air jet mill according to Experimental Example 3.

[0032] Figure 15 shows the absorption efficiency of the combined dry powder of the bead mill rivaroxaban and leucine-based co-air jet mill according to Experimental Example 3.

[0033] Figure 16 shows the absorption efficiency of the combined dry powder of a magnesium stearic acid-based hollow bead mill and air jet mill according to Experimental Example 3.

[0034] Figure 17 shows the absorption efficiency of the combined dry powder of the bead mill rivaroxaban and leucine-based co-air jet mill according to Experimental Example 3.

[0035] Hereinafter, the present specification will be described in more detail.

[0036] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0037] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0038] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0039] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0040] Expressions such as “comprising” as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0041] Hereinafter, the present invention will be described in detail.

[0042] Method for preparing a rivaroxaban dry powder inhalation composition

[0043] The present invention provides a method for preparing a rivaroxaban dry powder inhalation composition as follows.

[0044] Specifically, the present invention provides a method for preparing a rivaroxaban dry powder inhalation composition, comprising the steps of (S1) placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads in a ball mill and milling to obtain a bead-milled rivaroxaban dry powder; and (S2) placing the obtained bead-milled rivaroxaban dry powder in an air jet mill and grinding it.

[0045] Specifically, the present invention has an advantage in that it is possible to produce an inhalable rivaroxaban dry powder having a size of several to several tens of micrometers with excellent inhalation efficiency by combining a bead mill equipment and an air jet mill equipment, rather than producing a dry powder using a bead mill alone or an air jet mill alone.

[0046] In the present invention, rivaroxaban is represented by the following chemical formula 1 and is named 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide, and can be used for the prevention, secondary prevention and / or treatment of various thromboembolic diseases, and is used for the prevention, secondary prevention and / or treatment of various thromboembolic diseases, and is usually administered orally.

[0047] [Chemical Formula 1]

[0048]

[0049] However, the inventors of the present invention conducted research to solve the problem of not being able to secure the desired dissolution rate and bioavailability when administered orally due to the low solubility of rivaroxaban, and invented a method for preparing an optimal inhalation composition that can be delivered directly to the lungs. The rivaroxaban inhalation composition prepared by the manufacturing method of the present invention can be directly delivered to the lungs because the Dv50 diameter of the rivaroxaban dry powder is 5 μm or less. By controlling the diameter, even rivaroxaban with low solubility can be rapidly administered, and it is expected that diseases can be treated with a smaller amount of drug compared to a formulation that reaches the body through systemic circulation, and side effects of the drug, such as bleeding, can be reduced.

[0050] In the present invention, rivaroxaban may include all crystalline modifications and amorphous forms thereof, as well as hydrates, solvates and cocrystals thereof.

[0051] In the present invention, the pharmaceutically acceptable salt of rivaroxaban is an acid addition salt or a base addition salt. The acid addition salt includes a salt with an inorganic acid or an organic acid. Examples of the inorganic acid salt include a salt with hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid, and examples of the organic acid salt include, but are not limited to, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid (ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or naphthalenedisulfonic acid). The above-mentioned base addition salts include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), or ammonia salts or organic amine salts, for example, salts with diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, or dihydroabetylamine.

[0052] In the present invention, the step (S1) may be a step of placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads into a ball mill device and milling under conditions of repeating 3 to 8 times for 5 to 20 minutes at a speed of 500 to 800 rpm to obtain a bead-milled rivaroxaban dry powder, but is not limited thereto.

[0053] In the present invention, the step (S1) may further include a step of adding a dispersion stabilizer to obtain a dispersion stabilizer-based bead-milled rivaroxaban dry powder, or, after the step (S1), a step (S1-1) of mixing the bead-milled rivaroxaban dry powder and the dispersion stabilizer may be further included, but is not limited thereto.

[0054] Specifically, in step (S1), rivaroxaban or a pharmaceutically acceptable salt thereof, beads, and a dispersion stabilizer are placed in a ball mill and milled to obtain a dispersion stabilizer-based bead-milled rivaroxaban dry powder (obtaining a co-bead-milled dry powder), and then step (S2) of air jet milling is performed, or step (S1-1) of mixing the bead-milled rivaroxaban dry powder (simple bead-milled dry powder) obtained by step (S1) with a dispersion stabilizer is additionally performed, and then step (S2) of air jet milling is performed.

[0055] In the present invention, the dispersion stabilizer is used to control the dispersibility of the bead-milled dry powder of rivaroxaban.

[0056] In the present invention, the dispersion stabilizer may be included in an amount of 3 wt% or more based on the total weight of rivaroxaban, specifically, 5 wt% or more and less than 10 wt% based on the total weight of rivaroxaban, but is not limited thereto. By adding a small amount of the dispersion stabilizer based on the total weight of rivaroxaban in this way, the dispersibility of the dry powder fine particles is improved, thereby achieving a more excellent aerodynamic appearance and maximizing the inhalation efficiency.

[0057] In the present invention, the dispersion stabilizer may be at least one of amino acids or lipids, but is not limited thereto.

[0058] In the present invention, the amino acids may be at least one selected from the group consisting of leucine, trileucine, glycine, histidine, methionine, phenylalanine, valine, aspartame, arginine, and threonine, but are not limited thereto.

[0059] In the present invention, the lipid may be at least one selected from the group consisting of magnesium stearic acid, calcium stearic acid, sodium stearic acid, zinc stearic acid, and stearic acid, but is not limited thereto.

[0060] In the present invention, the step (S2) is a step of grinding using an air jet mill device, and the grinding step may be performed two or more times, but is not limited thereto.

[0061] In the present invention, the step (S1) may be a step of placing 1000 mg or more of rivaroxaban and beads into a ball mill and milling to obtain a bead-milled rivaroxaban dry powder, specifically, it may be a step of adding 1000 mg or more but less than 4000 mg, and more specifically, 2500 mg to 3000 mg of rivaroxaban, but is not limited thereto. Specifically, the method for preparing a rivaroxaban dry powder inhalation composition according to the present invention has the advantage of being applicable to a dry powder inhalation agent that must have a high drug content because it can contain a high content of rivaroxaban or a pharmaceutically acceptable salt thereof without a separate carrier.

[0062] Rivaroxaban dry powder inhalation composition

[0063] The present invention provides a rivaroxaban dry powder inhalation composition.

[0064] Specifically, the present invention provides a rivaroxaban dry powder inhalation composition comprising a rivaroxaban dry powder having a Dv50 diameter of 5 μm or less.

[0065] Specifically, the Dv50 diameter refers to the particle diameter corresponding to the cumulative particle size distribution percentage reaching 50%. This physically means that particles with a diameter larger than this account for 50%, and particles smaller than this also account for 50%. Dv50 is also called the median diameter or median particle size. At this time, if the Dv50 diameter of rivaroxaban dry powder exceeds 5 μm, it becomes difficult to inhale through an inhaler.

[0066] In the present invention, the dry powder inhalation composition may further include a dispersion stabilizer, but is not limited thereto.

[0067] In the present invention, the dispersion stabilizer may be included in an amount of 3 wt% or more based on the total weight of rivaroxaban or a pharmaceutically acceptable salt thereof, and specifically, may be included in an amount of 5 wt% or more and less than 10 wt% based on the total weight of rivaroxaban, but is not limited thereto.

[0068] In the present invention, the dispersion stabilizer may be at least one of amino acids or lipids, but is not limited thereto.

[0069] In the present invention, the amino acids may be at least one selected from the group consisting of leucine, trileucine, glycine, histidine, methionine, phenylalanine, valine, aspartame, arginine, and threonine, but are not limited thereto.

[0070] In the present invention, the lipid may be at least one selected from the group consisting of magnesium stearic acid, calcium stearic acid, sodium stearic acid, zinc stearic acid, and stearic acid, but is not limited thereto.

[0071] The above-described method for preparing a rivaroxaban dry powder inhalation composition can be applied to all of the above rivaroxaban dry powder inhalation compositions, unless they are contradictory.

[0072] dry powder inhaler

[0073] The present invention provides a dry powder inhaler comprising the above rivaroxaban dry powder inhalation composition.

[0074] The structure, components, etc. of the above dry powder inhaler are known to those skilled in the art to which the present invention pertains, and therefore, a detailed description thereof will be omitted below.

[0075] Information known to a person having ordinary skill in the art to which the present invention pertains regarding the structure and components of the above dry powder inhaler is incorporated into the content of the present invention.

[0076] The method for preparing a rivaroxaban dry powder inhalation composition and the description of the rivaroxaban dry powder inhalation composition described above can be applied to the above dry powder inhaler as long as they are not contradictory to each other.

[0077] Hereinafter, the present invention will be described in more detail using examples and comparative examples. It will be apparent to those skilled in the art that these examples and comparative examples are intended solely to illustrate the present invention more specifically and are not intended to limit the scope of the present invention.

[0078] In the following examples and comparative examples, the terms ‘simple’, ‘joint’, and ‘combination’ used can be defined as follows.

[0079] Specifically, 'simple' means that no dispersion stabilizer is added during bead milling or air jet milling (for example, it means that no dispersion stabilizer is added during bead milling or air jet milling), 'co-milling' means that the dispersion stabilizer leucine or magnesium stearate is added together during bead milling or air jet milling (for example, the addition of a dispersion stabilizer during bead milling or air jet milling means a co-bead mill or co-air jet milling), and 'combination' means that air jet milling (simple air jet milling or co-air jet milling) is performed after bead milling (simple bead milling or co-bead milling) (for example, the combination of bead milled rivaroxaban and leucine-based co-air jet milling means that bead-milled rivaroxaban and leucine, which is a dispersion stabilizer, are added together and air jet milling is performed).

[0080] Examples and comparative examples.

[0081] Comparative Example 1-1. Manufacturing of fine particle bead mill dried powder (simple bead mill)

[0082] As shown in Table 1, 3 g of rivaroxaban was weighed and placed in a ball mill (PM-100, Retsch GmbH, Germany) along with 750 g of 1 mm beads and 20 mL of distilled water, and the mixture was milled at 650 rpm for 12 minutes, repeated 5 times (interval 3 minutes) (see Table 2). Thereafter, the drug, rivaroxaban, and the beads were separated and dried in an oven at 60°C to obtain a bead-milled powder. The manufacturing process sequence for Comparative Example 1-1 is shown in Fig. 1.

[0083] Comparison Preliminary Comparison Example 1-1 Bigorivaroxaban (mg) 3000

[0084] Printing conditions Remarks Speed ​​(rpm)650Breadking time (min)12Interval (min)3Milling cycles (cycles)5

[0085] Comparative Example 1-2. Air Jet Mill Dry Powder Production (Simple Air Jet Mill)

[0086] Rivaroxaban is added in small amounts into the inlet of an air jet mill (AO JET MILL; JS Tech Co. Ltd., South Korea) (a total of 3 g of rivaroxaban is added). The grinding pressure of the air jet mill is 0.45 MPa, the pushing pressure is 0.5 MPa, and compressed air is injected to grind. The ground product is then added in small amounts into the inlet of the air jet mill for secondary grinding to obtain an air jet mill dried powder (see Table 3). The manufacturing process sequence for Comparative Examples 1-2 is shown in Fig. 2.

[0087] Factor conditions RemarksGrinding pressure (MPa)0.45Pushing pressure (MPa)0.5Milling cycles (cycles)2

[0088] Example 1. Production of dry powder using a combination of a bead mill and an air jet mill (simple bead mill followed by a simple air jet mill)

[0089] As shown in Table 1 above, 3 g of rivaroxaban is weighed and placed in a ball mill (PM-100, Retsch GmbH, Germany) together with 750 g of 1 mm beads and 20 mL of distilled water, and the mixture is milled 5 times at 650 rpm for 12 minutes (interval 3 minutes) (see Table 2). Thereafter, the drug rivaroxaban and the beads are separated and dried in an oven at 60°C to obtain bead-milled rivaroxaban (hereinafter referred to as “WB rivaroxaban”) dry powder. The obtained WB rivaroxaban dry powder is added in small portions to the inlet of an air jet mill (AO JET MILL; JS Tech Co. Ltd., South Korea). The air jet mill is ground with a grinding pressure of 0.45 MPa and a pushing pressure of 0.5 MPa by supplying compressed air. The crushed product is then fed back into the inlet of the air jet mill in small amounts for secondary crushing to obtain a combined dry powder of the bead mill and air jet mill (see Table 3). The manufacturing process sequence for Example 1 is shown in Fig. 3.

[0090] Comparative Example 2. Production of dry powder using a leucine-based hollow bead mill (leucine-based hollow bead mill)

[0091] As shown in Table 4 below, 3 g of rivaroxaban and 150 mg of leucine, a dispersion stabilizer, were weighed and placed in a ball mill (PM-100, Retsch GmbH, Germany) along with 750 g of 1 mm beads and 20 mL of distilled water, and the mixture was milled at 650 rpm for 12 minutes, repeated 5 times (interval 3 minutes) (see Table 2). The product and beads were then separated and dried in an oven at 60°C to obtain a leucine-based hollow bead mill dried powder. The manufacturing process sequence for Comparative Example 2 is shown in Fig. 4.

[0092] Comparison Preliminary Comparison Example 2-1 Bigorivaroxaban (mg) 3000 Leucine (mg) 150

[0093] Example 2. Production of dry powder using a combination of a hollow bead mill and an air jet mill based on leucine (combination of a hollow bead mill followed by a simple air jet mill)

[0094] As shown in Table 5 below, 3 g of rivaroxaban and 30, 150, and 300 mg of leucine as a dispersion stabilizer were each weighed and placed in a ball mill (PM-100, Retsch GmbH, Germany) together with 750 g of 1 mm beads and 20 mL of distilled water, and the mixture was ground five times at a speed of 650 rpm for 12 minutes (interval 3 minutes) (see Table 2). Afterwards, the product and beads were separated and dried in an oven at 60°C to obtain a leucine-based hollow bead mill dried powder. The obtained leucine-based hollow bead mill dried powder was added in small portions to the inlet of an air jet mill (AO JET MILL; JS Tech Co. Ltd., South Korea). The grinding pressure of the air jet mill was 0.45 MPa, and the pushing pressure was 0.5 MPa, and compressed air was used for grinding. The crushed product is then fed back into the inlet of the air jet mill in small amounts for secondary crushing to obtain a combined dry powder of a lysine-based hollow bead mill and air jet mill (see Table 3). The manufacturing process sequence for Example 2 is shown in Fig. 5.

[0095] Example Example 2-1 Example 2-2 Example 2-3 Bigorivaroxaban (mg) 3000 3000 3000 Leucine (mg) 30150 300

[0096] Comparative Example 3. Preparation of a simple mixed dry powder based on bead mill rivaroxaban and leucine.

[0097] As shown in Table 6 below, 3 g of bead-milled rivaroxaban (WB rivaroxaban) and 150 mg of leucine, a dispersion stabilizer, were weighed and mixed with a Turbular mixer (Turbular, WAB, Switzerland) at 49 rpm for 20 minutes to obtain a simply mixed dry powder based on bead-milled rivaroxaban and leucine. The manufacturing process sequence for Comparative Example 3 is shown in Fig. 6.

[0098] Comparison Preliminary Comparison Example 3-1 Bigobidemil Rivaroxaban (mg) 3000 Leucine (mg) 150

[0099] Example 3. Production of dry powder using a combination of a bead mill rivaroxaban and a leucine-based hollow air jet mill (combination of a simple bead mill followed by a hollow air jet mill)

[0100] As shown in Table 7 below, 3 g of bead-milled rivaroxaban (WB rivaroxaban) and 30, 150, and 300 mg of leucine, a dispersion stabilizer, were each weighed according to the method described in Comparative Example 1-1 and mixed with a Turbular mixer (Turbular, WAB, Switzerland) at 49 rpm for 20 minutes. Each resultant was added in small amounts to the inlet of an air jet mill (AO JET MILL; JS Tech Co. Ltd., South Korea). The air jet mill was ground with compressed air at a grinding pressure of 0.45 MPa and a pushing pressure of 0.5 MPa (see Table 2). The obtained ground resultant was again added in small amounts to the inlet of the air jet mill to perform secondary grinding to obtain a dry powder of a combination of bead-milled rivaroxaban and leucine-based co-air jet mill (WB / co-AJ). The manufacturing process sequence for Example 3 is shown in Fig. 7.

[0101] Example Example 3-1 Example 3-2 Example 3-3 Bigobidemil Rivaroxaban (mg) 3000 3000 3000 Leucine (mg) 30150 300

[0102] Comparative Example 4. Manufacturing of magnesium stearate-based bead mill dry powder (cavity bead mill)

[0103] As shown in Table 8 below, 3 g of rivaroxaban and 150 mg of magnesium stearate, a dispersion stabilizer, were weighed and placed in a ball mill (PM-100, Retsch GmbH, Germany) along with 750 g of 1 mm beads and 20 mL of distilled water, and the mixture was milled at 650 rpm for 12 minutes, repeated 5 times (interval 3 minutes) (see Table 2). The product and beads were then separated and dried in an oven at 60°C to obtain a magnesium stearate-based hollow bead mill dried powder. The manufacturing process sequence for Comparative Example 4 is shown in Fig. 8.

[0104] Comparison Preliminary Comparison Example 4-1 Bigorivaroxaban (mg) 3000 Magnesium stearate (mg) 150

[0105] Example 4. Preparation of dry powder using a combination of a hollow bead mill and an air jet mill based on magnesium stearate (combination of a hollow bead mill followed by a simple air jet mill)

[0106] As shown in Table 9 below, 3 g of rivaroxaban and 30, 150, and 300 mg of magnesium stearate as a dispersion stabilizer were each weighed and placed in a ball mill (PM-100, Retsch GmbH, Germany) together with 750 g of 1 mm beads and 20 mL of distilled water, and the mixture was ground five times at a speed of 650 rpm for 12 minutes (interval 3 minutes) (see Table 2). Afterwards, the product and beads were separated and dried in an oven at 60°C to obtain a magnesium stearate-based hollow bead mill rivaroxaban dry powder. The obtained magnesium stearate-based dry powder was added in small portions to the inlet of an air jet mill (AO JET MILL; JS Tech Co. Ltd., South Korea). The air jet mill was ground with a grinding pressure of 0.45 MPa and a pushing pressure of 0.5 MPa using compressed air. The crushed product is then fed in small amounts into the inlet of the air jet mill for secondary crushing to obtain a combined dry powder of a magnesium stearate-based hollow bead mill and air jet mill (see Table 2). The manufacturing process sequence for Example 4 is shown in Fig. 9.

[0107] Example Example 4-1 Example 4-2 Example 4-3 Bigorivaroxaban (mg) 3000 3000 3000 Magnesium stearate (mg) 30150 300

[0108] Comparative Example 5. Preparation of a simple mixed dry powder based on bead mill rivaroxaban and magnesium stearate.

[0109] As shown in Table 10 below, 3 g of bead-milled rivaroxaban (WB rivaroxaban) and 150 mg of magnesium stearate, a dispersion stabilizer, were weighed and mixed with a Turbular mixer (Turbular, WAB, Switzerland) at 49 rpm for 20 minutes to obtain a simply mixed dry powder based on bead-milled rivaroxaban and magnesium stearate. The manufacturing process sequence is shown in Fig. 10.

[0110] Comparison Preliminary Comparison Example 5-1 Bigobidemil Rivaroxaban (mg) 3000 Magnesium stearate (mg) 150

[0111] Example 5. Production of dry powder using a combination of bead mill rivaroxaban and magnesium stearate-based hollow air jet mill (combination of simple bead mill followed by hollow air jet mill)

[0112] As shown in Table 11 below, 3 g of rivaroxaban and 30, 150, or 300 mg of magnesium stearate, which were bead-milled according to the method described in Comparative Example 1-1, were each weighed and mixed with a Turbular mixer (Turbular, WAB, Switzerland) at 49 rpm for 20 minutes. Each resultant was added in small portions to the inlet of an air jet mill (AO JET MILL; JS Tech Co. Ltd., South Korea). The air jet mill was ground with a grinding pressure of 0.45 MPa and a pushing pressure of 0.5 MPa using compressed air. The obtained ground resultant was again added in small portions to the inlet of the air jet mill to perform a second grinding, thereby obtaining a combined dry powder of bead-milled rivaroxaban and a magnesium stearate-based co-air jet mill (see Table 2). The manufacturing process sequence for Example 5 is shown in Fig. 11.

[0113] Example Example 5-1 Example 5-2 Example 5-3 Bigobidemil Rivaroxaban (mg) 3000 3000 3000 Magnesium stearate (mg) 30150 300

[0114] Hereinafter, the present invention will be described in more detail using experimental examples. These experimental examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by them.

[0115] Experimental example.

[0116] Experimental Example 1. Confirmation of particle shape of dry powder containing drug

[0117] Evaluation method

[0118] In order to confirm the particle morphology of the dry powder containing the drug manufactured according to Comparative Example 1-1 (simple bead mill), Comparative Example 1-2 (simple air jet mill), and Example 1 (combination of simple bead mill and simple air jet mill), the particles of the dry powder manufactured according to Comparative Example 1-1, Comparative Example 1-2, and Example 1 were placed on a carbon tape and then coated with platinum using a coater. Thereafter, the particle morphology was observed using an electron scanning microscope (ZEISS-GEMINI LEO 1530, Zeiss, Germany) (observation was performed at magnifications of 1k and 10k).

[0119] Evaluation results

[0120] The particle morphology of the dry powder containing the drug manufactured according to Comparative Example 1-1, Comparative Example 1-2, and Example 1 was evaluated and is shown in Fig. 12. Referring to Fig. 12, the bead mill dried powder according to Comparative Example 1-1 showed a form in which nano-sized crystalline particles were aggregated, and the air jet mill dried powder according to Comparative Example 1-2 showed a form in which the particles were separated to form a single unit.

[0121] On the other hand, the combined dried powder of the bead mill-air jet mill according to Example 1 was observed to have nano-sized crystalline particles that were not aggregated as in Comparative Example 1-1, but formed a certain unit as in Comparative Example 1-2.

[0122] Experimental Example 2. Evaluation of particle size distribution of dry powder containing drug

[0123] Evaluation method

[0124] The particle size distribution of the manufactured dry powder is evaluated using a master sizer (Mastersizer 3000E, Malvern, UK).

[0125] Evaluation results

[0126] 1. Particle size distribution of dry powder produced by a combination of a bead mill and an air jet mill.

[0127] The particle size distributions of the dry powders according to Comparative Example 1-1 (simple bead mill), Comparative Example 1-2 (simple air jet mill), and Example 1 (combination of simple bead mill and simple air jet mill) were evaluated and shown in Table 12. Referring to Table 12, the dry powders according to Comparative Example 1-1 and Comparative Example 1-2 were evaluated as having a Dv50 of 45.9 and 6.12 μm, respectively, which were large enough to be inhaled, and the dry powder of the combination of the bead mill and the air jet mill of Example 1 was evaluated as having a Dv50 of 2.84 μm, which was enough to be inhaled to be 5 μm or less. However, the dry powder of the combination of the bead mill and the air jet mill of Example 1 was confirmed to have a Dv90 of 21.46 μm, which confirmed that some particles were aggregated (see Table 12).

[0128] Formulation (n=3) Dv 10 (μm) Dv 50 (μm) Dv 90 (μm) Span Comparative Example 1-14.82±0.1645.9±0.3686.88±0.131.78±0.01 Comparative Example 1-22.16±0.016.12±0.0413.94±0.201.92±0.02 Example 1-10.89±0.002.84±0.0821.46±1.757.21±0.39

[0129] 2. Particle size distribution of the dry powder produced by the combination of a lysine-based co-wetted bead mill and an air jet mill.

[0130] The particle size distributions of the combined dry powders of the leucine-based co-wetted bead mill-air jet mill according to Examples 2-1, 2-2, and 2-3 were evaluated and are shown in Table 13. Referring to Table 13, the dry powders according to Examples 2-1, 2-2, and 2-3 all showed Dv50 values ​​of 5 μm or less, which was evaluated as an inhalable size. Contrary to expectations, as the ratio of leucine increased, the Dv50 and Dv90 increased (see Table 13).

[0131] Formulation (n=3) Dv 10 (μm) Dv 50 (μm) Dv 90 (μm) Span Example 2-10.58±0.011.22±0.017.39±0.205.57±0.15 Example 2-20.87±0.012.58±0.019.25±0.083.23±0.03 Example 2-30.65±0.003.45±0.0822.73±1.386.39±0.24

[0132] 3. Particle size distribution of the dry powder produced by a combination of a bead mill, rivaroxaban, and a leucine-based co-air jet mill.

[0133] The particle size distributions of the combined dry powders of bead-milled rivaroxaban and leucine-based hollow air jet mill according to Examples 3-1, 3-2, and 3-3 were evaluated and shown in Table 14. Referring to Table 14, the combined dry powders of bead-milled rivaroxaban and leucine-based hollow air jet mill according to Examples 3-1, 3-2, and 3-3 all showed Dv50 values ​​of 5 μm or less, which was evaluated as an inhalable size. The results showed that the Dv90 decreased as the leucine ratio increased. This can be seen that the dispersibility of the hollow air jet milled leucine improved after the rivaroxaban was agglomerated after being ground by the bead mill (see Table 14).

[0134] Formulation (n=3) Dv 10 (μm) Dv 50 (μm) Dv 90 (μm) Span Example 3-10.71±0.003.23±0.0712.03±0.233.49±0.03 Example 3-20.81±0.012.26±0.098.21±0.023.27±0.15 Example 3-30.89±0.002.82±0.017.56±0.082.35±0.02

[0135] 4. Particle size distribution of dried powders prepared by a combination of a magnesium stearate-based hollow bead mill and an air jet mill.

[0136] The particle size distributions of the combined dry powders of the hollow bead mill-air jet mill based on magnesium stearate according to Examples 4-1, 4-2, and 4-3 were evaluated and are shown in Table 15. Referring to Table 15, the combined dry powders of the hollow bead mill-air jet mill based on magnesium stearate according to Examples 4-1, 4-2, and 4-3 all showed a Dv50 value of 5 μm or less, which was evaluated as an inhalable size. As the magnesium stearate ratio increased, the Dv50 and Dv90 decreased (see Table 15).

[0137] Formulation (n=3) Dv 10 (μm) Dv 50 (μm) Dv 90 (μm) Span Example 4-10.92±0.002.91±0.0718.66±0.926.10±0.15 Example 4-20.61±0.014.19±0.1527.60±1.356.44±0.43 Example 4-30.78±0.001.62±0.004.46±0.072.26±0.03

[0138] 5. Particle size distribution of the dry powder produced by a combination of a bead milled rivaroxaban and a magnesium stearate-based co-air jet mill.

[0139] The particle size distributions of the combined dry powders of bead milled rivaroxaban and magnesium stearate-based hollow air jet mill according to Examples 5-1, 5-2, and 5-3 were evaluated and are shown in Table 16. Referring to Table 16, the combined dry powders of bead milled rivaroxaban and magnesium stearate-based hollow air jet mill according to Examples 5-1, 5-2, and 5-3 all showed Dv50 values ​​of 5 μm or less, which was evaluated as an inhalable size. The particle sizes according to the magnesium stearate ratio were similar (see Table 16).

[0140] Formulation (n=3) Dv 10 (μm) Dv 50 (μm) Dv 90 (μm) Span Example 5-10.92±0.002.86±0.0411.86±0.413.81±0.08 Example 5-20.91±0.013.34±0.149.836±0.672.63±0.02 Example 5-30.88±0.002.76±0.0613.3±0.364.50±0.04

[0141] Experimental Example 3. Evaluation of the absorption efficiency of dry powder containing drugs.

[0142] Evaluation method

[0143] The dry powder prepared according to the above comparative examples and examples is filled into a No. 3 gelatin capsule at 20 mg, and the inhalation efficiency of the dry powder is evaluated using the Next generation impactor (Next generation impactor, Copley Scientific, UK). At this time, the dry powder inhalation equipment used is RS-01 (RS-01, Plastiape, Italy), and the flow rate is 60 L / sec for 4 seconds. The amount of drug distributed in each stage is quantified using HPLC to measure the inhalation efficiency.

[0144] <HPLC 분석조건>

[0145] -Equipment name: HPLC (Ultimate 3000, Thermoscientific)

[0146] -Column: Luna 5 μm C18 (4.6 x 250 mm, 100Å)

[0147] -Column temperature: 40℃

[0148] -Mobile phase: Acetonitrile: Distilled water = 55:45

[0149] -Flow rate: 1.2 ml / min

[0150] -Injection volume: 20 μl

[0151] -UV wavelength: 249 nm

[0152] Evaluation results

[0153] 1. Suction efficiency of dry powder produced by a combination of a bead mill and an air jet mill

[0154] The inhalation efficiency of the dry powder according to Comparative Example 1-1, Comparative Example 1-2, and Example 1 was evaluated in vitro. Specifically, the dry powder according to Example 1 was evaluated to have a higher inhalation efficiency than the dry powder according to Comparative Example 1-1 and Comparative Example 1-2 (see Fig. 13 and Table 17). A statistically more significant difference was observed in the FPF (Fine particle fraction) value, which is the drug fraction of the low stage representing the deep lung, and the FPD (Fine particle dose) value, which is the amount of the drug, which confirmed that the combination process of the bead mill and the air jet mill can actually work more advantageously in the deep lung than the process of only the bead mill or the air jet mill.

[0155] Parameter (n=3) Comparative Example 1-1 Comparative Example 1-2 Example 1-1 ED (%) 69.69±19.9 184.02±6.1 778.60±1.48 FPF (<4.46 μm) 15.69±1.9 127.71±2.49 45.55±4.90 ** / $$ FPD (μg)2211.77±747.614635.72±75.477151.71±656.10 ** / $$ MMAD (μm)N / A7.71±0.036.56±1.31GSDN / A1.66±0.022.61±0.18

[0156] (In Table 17, ** ANOVA, p-value < 0.005 compared to Comparative Example 1-1, and $$ ANOVA, p-value < 0.005 compared to Comparative Example 1-2)

[0157] 2. Suction efficiency of dry powder produced by a combination of a lysine-based co-bead mill and an air jet mill.

[0158] The inhalation efficiency of the dry powders according to Comparative Example 2-1, Example 2-1, Example 2-2, and Example 2-3 was evaluated in vitro. Specifically, the dry powder according to Example 2-2 was evaluated to have a higher inhalation efficiency than the dry powder of Comparative Example 2-1 (see Fig. 14 and Table 18). In addition, a statistically more significant difference was observed in the FPF and FPD values, which confirmed that the combination process of the leucine-based hollow bead mill and the air jet mill can actually work more advantageously in the deep lung than when the leucine-based hollow bead mill is performed alone.

[0159] In addition, as the ratio of leucine increased, the ED (Emitted dose) and FPD values, which are the amount of drug released from the capsule, increased, confirming that the increase in leucine contributed to improving the dispersion stability of rivaroxaban. However, in the case of leucine (Example 2-1) with a ratio of 1% (where % means the relative content ratio of leucine to the total content of the drug rivaroxaban and has the same meaning as weight %, and all parts indicating % of dispersion stabilizer hereinafter can be considered to have the same meaning), it was confirmed that the ratio of leucine should be 5% or more because it had a lower FPD value than Example 1 without leucine (see Table 19).

[0160] Parameter (n=3) Comparative Example 2-1 Example 2-2 ED (%) 84.21±1.55 267.77±1.62 ** FPF (<4.46 μm)27.67±2.53272.10±2.46 ** FPD (μg)4436.47±352.449306.22±315.75 ** MMAD (μm)N / A3.80±0.13GSDN / A2.00±0.06

[0161] (In Table 18, ** ANOVA, p-value < 0.005 compared to Comparative Example 2-1.)

[0162] Parameter (n=3) Example 2-1 Example 2-2 Example 2-3 ED (%) 51.43±3.46 67.77±1.62 ** 74.57±3.12 ** / $ FPF (<4.46 μm)46.89±12.2572.10±2.46 * 69.22±7.93 * FPD (μg)4831.10±1617.419306.22±315.75 ** 9366.71±898.04 ** MMAD (μm)4.91±2.363.80±0.133.13±0.39GSD3.02±0.822.00±0.062.13±0.30

[0163] (In Table 19, ** ANOVA, p-value < 0.005 compared to Example 2-1, and $ ANOVA, p-value < 0.05 compared to Example 2-2.)

[0164] 3. Intake efficiency of dry powder produced by a combination of a bead mill rivaroxaban and a leucine-based co-air jet mill.

[0165] The inhalation efficiency of the dry powders according to Comparative Example 3, Example 3-1, Example 3-2, and Example 3-3 was evaluated in vitro. Specifically, the dry powder according to Example 3-2 was evaluated to have a higher inhalation efficiency than the dry powder according to Comparative Example 3 (see Fig. 15 and Table 20). In addition, a statistically more significant difference was observed in the FPF and FPD values, which confirmed that the hollow air jet mill process can actually be more advantageous in the deep lung than simply mixing leucine into the bead-milled rivaroxaban.

[0166] In addition, as the ratio of leucine increased, the FPD value, which is the amount of drug released from the capsule, increased. However, since the FPD value was lower in the case of 1% leucine (Example 3-1) compared to Example 1 without leucine, it was confirmed that the ratio of leucine should be 5% or more (see Table 21).

[0167] Parameter (n=3) Comparative Example 3-1 Example 3-2 ED (%) 88.16±1.30 59.87±1.77 ** FPF (<4.46 μm)23.42±0.7575.09±1.88 ** FPD (μg)3934.25±173.368560.54±42.77 ** MMAD (μm)N / A3.43±0.11GSDN / A1.89±0.03

[0168] (In Table 20, ** ANOVA, p-value < 0.005 compared to Comparative Example 3.)

[0169] Parameter (n=3) Example 3-1 Example 3-2 Example 3-3 ED (%) 70.28±4.1359.87±1.77 ** 56.36±0.35 ** FPF (<4.46 μm)56.10±8.9575.09±1.88 ** 62.03±4.03FPD (μg)7845.94±1601.868560.54±42.776359.76±451.01MMAD (μm)4.41±0.073.43±0.114.02±0.40GSD2.06±0.101.89±0.032.43±0.33

[0170] (In Table 21, ** ANOVA, p-value < 0.005 compared to Example 3-1.)

[0171] 4. Suction efficiency of dry powder produced by a combination of a magnesium stearate-based hollow bead mill and an air jet mill.

[0172] The inhalation efficiency of the dry powders according to Comparative Example 4, Example 4-1, Example 4-2, and Example 4-3 was evaluated in vitro. Specifically, the dry powder according to Example 4-2 was evaluated to have a higher inhalation efficiency than the dry powder according to Comparative Example 4 (see Fig. 16 and Table 22). In addition, a statistically more significant difference was observed in the FPF and FPD values, which confirmed that the combined process of the magnesium stearate-based hollow bead mill and the air jet mill can actually work more advantageously in the deep lung than the process of using the magnesium stearate-based hollow bead mill alone.

[0173] In addition, as the proportion of magnesium stearate increased, the ED, FPF, and FPD values, which are the drug amounts released from the capsule, increased, confirming that increasing magnesium stearate contributed to improving the dispersion stability of rivaroxaban. However, since a 1% proportion of magnesium stearate (Example 4-1) had a lower FPD value than Example 1 without magnesium stearate, it was confirmed that the proportion of leucine should be 5% or more (see Table 23).

[0174] Parameter (n=3) Comparative Example 4-1 Example 4-2 ED (%) 91.59±1.25 68.32±0.45 ** FPF (<4.46 μm)26.03±5.1070.57±6.31 ** FPD (μg)4538.32±862.589186.70±856.23 ** MMAD (μm)N / A3.28±0.51GSD7.72±0.002.38±0.42

[0175] (In Table 22, ** ANOVA, p-value < 0.005 compared to Comparative Example 4.)

[0176] Parameter (n=3) Example 4-1 Example 4-2 Example 4-3 ED (%) 44.78±2.7 168.32±0.45 ** 72.75±2.38 **FPF (<4.46 μm)60.34±13.7870.57±6.3181.61±5.08FPD (μg)5308.14±989.039186.70±856.23 ** 10782.46±338.5 ** / $ MMAD (μm)4.09±1.943.28±0.512.67±0.27GSD2.79±0.822.38±0.421.79±0.13

[0177] (In Table 23, ** ANOVA, p-value < 0.005 compared to Example 4-1, and $ ANOVA, p-value < 0.05 compared to Example 4-2.)

[0178] 5. Intake efficiency of dry powder produced by a combination of a bead mill rivaroxaban and a leucine-based co-air jet mill.

[0179] The inhalation efficiency of the dry powders according to Comparative Example 5, Example 5-1, Example 5-2, and Example 5-3 was evaluated in vitro. Specifically, the dry powder according to Example 5-2 was evaluated to have a higher inhalation efficiency than the dry powder according to Comparative Example 5 (see Fig. 17 and Table 24). In addition, a statistically more significant difference was observed in the FPF and FPD values, which confirmed that the hollow air jet mill process can actually be more advantageous in the deep lung than simply mixing magnesium stearate into the bidmilled rivaroxaban.

[0180] In addition, as the proportion of magnesium stearic acid increased, the FPD value, which is the amount of drug released from the capsule, increased. However, since the 1% proportion of magnesium stearic acid (Example 5-1) had a lower FPD value than Example 1 without magnesium stearic acid, it was confirmed that the proportion of magnesium stearic acid should be 5% or more (see Table 25).

[0181] Parameter (n=3) Comparative Example 5-1 Example 5-2 ED (%) 93.08±1.05 67.34±2.87 **FPF (<4.46 μm)12.44±0.9171.80±2.47 ** FPD (μg)2205.59±139.619219.78±701.61 ** MMAD (μm)N / A3.90±0.01GSDN / A1.86±0.07

[0182] (In Table 24, ** ANOVA, p-value < 0.005 compared to Comparative Example 5.)

[0183] Parameter (n=3) Example 5-1 Example 5-2 Example 5-3 ED (%) 46.27±2.36 67.34±2.87 ** 65.90±1.14 ** FPF (<4.46 μm)41.82±8.4471.80±2.47 ** 86.32±1.98 ** / $ FPD (μg)3810.92±646.199219.78±701.61 ** 10341.66±60.32 ** / $ MMAD (μm)4.29±0.033.90±0.012.45±0.22GSD3.49±1.551.86±0.071.67±0.06

[0184] (In Table 25, ** ANOVA, p-value < 0.005 compared to Example 5-1, and $ ANOVA, p-value < 0.05 compared to Example 5-2.)

[0185] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. (S1) A step of placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads into a ball mill and milling to obtain a bead-milled dry powder of rivaroxaban; and (S2) A step of pulverizing the obtained bead-milled Rivaroxaban dry powder by putting it into an air jet mill equipment. A method for preparing a dry powder inhalation composition comprising rivaroxaban.

2. A method for producing a rivaroxaban dry powder composition for inhalation, wherein in the first paragraph, the step (S1) is a step of placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads into a ball mill and milling under conditions of repeating 3 to 8 times for 5 to 20 minutes at a speed of 500 to 800 rpm to obtain a bead-milled rivaroxaban dry powder.

3. A method for producing a rivaroxaban dry powder inhalation composition, wherein in the first paragraph, a dispersion stabilizer is additionally added to the step (S1) to obtain a dispersion stabilizer-based bead milled rivaroxaban dry powder.

4. A method for producing a rivaroxaban dry powder inhalation composition, wherein, after step (S1), the method further comprises a step (S1-1) of mixing the milled rivaroxaban dry powder and a dispersion stabilizer.

5. A method for producing a rivaroxaban dry powder inhalation composition according to claim 3 or 4, wherein the dispersion stabilizer is contained in an amount of 3 wt% or more based on the total weight of rivaroxaban.

6. A method for producing a rivaroxaban dry powder inhalation composition according to claim 3 or 4, wherein the dispersion stabilizer is at least one of amino acids or lipids.

7. A method for producing a rivaroxaban dry powder inhalation composition in claim 6, wherein the amino acids are at least one selected from the group consisting of leucine, trileucine, glycine, histidine, methionine, phenylalanine, valine, aspartame, arginine, and threonine.

8. A method for producing a rivaroxaban dry powder inhalation composition in claim 6, wherein the lipid is at least one selected from the group consisting of magnesium stearic acid, calcium stearic acid, sodium stearic acid, zinc stearic acid, and stearic acid.

9. A method for producing a rivaroxaban dry powder inhalation composition, wherein the step (S2) in paragraph 1 is performed twice or more.

10. A method for producing a rivaroxaban dry powder inhalation composition in the first paragraph, wherein the step (S1) is a step of placing 1000 mg or more of rivaroxaban and beads in a ball mill and milling them to obtain a bead-milled rivaroxaban dry powder.

11. A composition for inhalation comprising rivaroxaban dry powder having a Dv50 diameter of 5 μm or less.

12. A rivaroxaban dry powder inhalation composition further comprising a dispersion stabilizer according to claim 11.

13. A rivaroxaban dry powder inhalation composition according to claim 12, wherein the dispersion stabilizer is contained in an amount of 3 wt% or more based on the total weight of rivaroxaban or a pharmaceutically acceptable salt thereof.

14. A rivaroxaban dry powder inhalation composition in claim 12, wherein the dispersion stabilizer is at least one of amino acids and lipids.

15. A rivaroxaban dry powder inhalation composition in claim 12, wherein the amino acids are at least one selected from the group consisting of leucine, trileucine, glycine, histidine, methionine, phenylalanine, valine, aspartame, arginine, and threonine.

16. A rivaroxaban dry powder inhalation composition in claim 12, wherein the lipid is at least one selected from the group consisting of magnesium stearate, calcium stearate, sodium stearate, zinc stearate, and stearic acid.

17. A dry powder inhaler comprising the rivaroxaban dry powder inhalation composition of claim 11.

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