RU2840786C1 - Lemborexant drug substance and medicinal composition containing same - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to the field of pharmaceutics, specifically to an active pharmaceutical ingredient of lemborexant, a pharmaceutical composition of lemborexant and a method for preparing a pharmaceutical composition of lemborexant containing lemborexant, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, water and magnesium stearate. Active pharmaceutical ingredient lemborexant which is a granular material having 90% cumulative diameter (D90) 20 mcm or more and 64 mcm or less. Pharmaceutical composition of lemborexant containing: 2.5 mg of lemborexant and 96.38 mg of lactose hydrate, or 5 mg of lemborexant and 93.88 mg of lactose hydrate, or 10 mg of lemborexant and 88.88 mg of lactose hydrate and 16.8 mg of low-substituted hydroxypropyl cellulose, 3.6 mg of hydroxypropyl cellulose, water and 0.72 mg of magnesium stearate, wherein lemborexant is said granulated material. Method of producing a pharmaceutical composition of lemborexant containing lemborexant, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, water and magnesium stearate, containing: a) a step of mixing said active pharmaceutical ingredient of lemborexant, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and water to produce granules; b) a step of mixing the granules obtained in step a), low-substituted hydroxypropyl cellulose and magnesium stearate to obtain a mixture; and c) a step of compressing the mixture obtained in step b) to obtain tablets.

EFFECT: said group of inventions makes it possible to produce a pharmaceutical composition of lemborexant, characterized by a favorable dissolution profile.

9 cl, 8 dwg, 23 tbl, 5 ex

Description

Field of technology

[0001] The present invention relates to the active pharmaceutical ingredient lemborexant and a pharmaceutical composition containing it.

State of the art

[0002] Orexin receptors are G protein-coupled receptors that are primarily present in the brain. The endogenous ligands of orexin receptors, orexin-A and orexin-B, are expressed by neurons located in the hypothalamic region. Orexin-A is a 33-amino acid peptide, and orexin-B is composed of 28 amino acids (Non-patent Literature 1). There are two subtypes of orexin receptors: OX1 and OX2, with OX1 preferentially binding to orexin-A, while OX2 binds to both orexin-A and orexin-B. Orexins have been suggested to stimulate food intake in rats, and orexin signaling may play a role in the underlying feedback mechanisms for regulating feeding behavior (Non-patent Literature 1). Orexins have also been found to control the sleep-wake state (Non-patent literature 2). Orexins may also play a role in the brain changes associated with opioid and nicotine addiction (Non-patent literature 3 and 4) and ethanol addiction (Non-patent literature 5). In addition, orexins have been suggested to play a role in some stress responses (Non-patent literature 6).

[0003] Compounds such as (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (also called "lemborexant") are known to be potent orexin receptor antagonists, and these compounds are useful for the treatment of sleep disorders such as insomnia and other therapeutic applications (Patent Literatures 1 and 2). The results of the "Dissolution" test of tablets containing 1 mg to 25 mg of lemborexant have been reported (Patent Literature 3).

List of references

Patent Literature Sources

[0004] [Patent Literature 1] WO 2012/039371.

[Patent Literature 2] WO 2013/123240.

[Patent Literature 3] WO 2016/063995.

Non-patent literature sources

[0005] [Non-patent Literature 1] Sakurai T. et al., Cell, 1998, Vol. 92, pp. 573 to 585.

[Non-patent literature 2] Chemelli R.M. et al., Cell, 1999, Vol. 98, pp. 437 to 451.

[Non-patent literature source 3] S.L. Borgland et al., Neuron, 2006, Vol. 49, pp. 598 to 601.

[Non-patent literature source 4] C.J. Winrow et al., Neuropharmacology, 2010, Vol. 58, pp. 185 to 194.

[Non-patent literature source 5] J.R. Shoblock et al., Psychopharmacology, 2011, Vol. 215, pp. 191 to 203.

[Non-patent Literature 6] T. Ida et al., Biochem. Biophys. Res. Commun., 2000, Vol. 270, pp. 318 to 323.

The essence of the invention

Technical task

[0006] It is desirable that the pharmaceutical composition has favorable physicochemical properties. The aim of the present invention is to provide a pharmaceutical composition containing lemborexant that exhibits a favorable dissolution profile.

Solution to the problem

[0007] The present inventors conducted extensive studies to solve the above-mentioned problems and, as a result, found that a pharmaceutical composition containing lemborexant exhibits an advantageous dissolution profile using a lemborexant granular material having a cumulative diameter (D90) of 90% as an active pharmaceutical ingredient.

[0008] In particular, the present invention relates to the following items [1] to [15].

[1] The active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 µm or less.

[2] A pharmaceutical composition comprising lemborexant and a pharmaceutically acceptable additive, obtained using the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 μm or less.

[3] The pharmaceutical composition according to [2], wherein the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the Dissolution test in the dissolution medium (2nd liquid for the Dissolution test (pH 6.8) in the Japanese Pharmacopoeia 16th edition, 900 ml, 37±0.5°C) using an apparatus with a paddle stirrer (rotation speed: 50 rpm) according to the method using a paddle stirrer.

[4] The pharmaceutical composition according to [2], wherein the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the “Dissolution” test in a dissolution medium (water, 900 ml, 37±0.5°C) using an apparatus with a paddle stirrer (rotation speed: 50 rpm) according to the method using a paddle stirrer.

[5] The pharmaceutical composition according to [2], wherein the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the Dissolution Test in the dissolution medium (2nd Dissolution Test Liquid (pH 6.8) in the Japanese Pharmacopoeia 16th Edition, 900 mL, 37±0.5°C) using a paddle stirrer apparatus (rotation speed: 100 rpm) according to the method using a paddle stirrer.

[6] The pharmaceutical composition according to [2], wherein the dissolution rate of lemborexant is 80% or more within 15 minutes from the start time of the “Dissolution” test in a dissolution medium (0.1 mol/L hydrochloric acid, 900 ml, 37±0.5°C) using an apparatus with a paddle stirrer (rotation speed: 50 rpm) according to the method using a paddle stirrer.

[7] A pharmaceutical composition according to any one of [2] to [6], wherein the pharmaceutical composition is a tablet.

[8] A pharmaceutical composition according to any one of [2] to [7], which contains from 2.5 mg to 10 mg of lemborexant.

[9] A pharmaceutical composition according to [8], which contains 10 mg of lemborexant.

[10] A pharmaceutical composition according to [8], which contains 5 mg of lemborexant.

[11] A pharmaceutical composition according to [8], which contains 2.5 mg of lemborexant.

[12] A pharmaceutical composition containing lemborexant and a pharmaceutically acceptable additive, wherein the dissolution rate of lemborexant is 80% or more within 15 minutes from the start time of the Dissolution Test in a dissolution medium (0.1 mol/L hydrochloric acid, 900 mL, 37±0.5°C) and the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the Dissolution Test in another dissolution medium (the 2nd Dissolution Test Liquid (pH 6.8) in the Japanese Pharmacopoeia 16th Edition, 900 mL, 37±0.5°C) using an apparatus with a paddle stirrer (rotational speed: 50 rpm) according to the method using a paddle stirrer.

[13] The pharmaceutical composition according to [12], wherein the active pharmaceutical ingredient lemborexant is a granular material having a 90% cumulative diameter (D90) of 64 μm or less.

[14] The pharmaceutical composition according to [12], obtained using the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 μm or less.

[15] A method for producing a pharmaceutical composition containing lemborexant and a pharmaceutically acceptable additive, comprising the step of mixing the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 μm or less, and the pharmaceutically acceptable additive.

Beneficial effects of the present invention

[0009] The present invention may provide a pharmaceutical composition containing lemborexant showing an advantageous dissolution profile, using a granular material having a 90% cumulative diameter (D90) of 64 μm or less as the active pharmaceutical ingredient lemborexant.

Brief description of graphic materials

[0010] Fig. 1(a) and 1(b) show the results of the “Dissolution” test of tablets containing 2.5 mg and 10 mg of lemborexant in 0.1 mol/L hydrochloric acid, shown in Table 6 and Table 7.

Fig. 2(a) and 2(b) show the results of the “Dissolution” test of tablets containing 2.5 mg lemborexant in the dissolution media shown in Table 8 and Table 9.

Fig. 3(a) and 3(b) show the results of the “Dissolution” test of tablets containing 2.5 mg lemborexant in the dissolution media shown in Table 10 and Table 12.

Fig. 4 shows the results of the “Dissolution” test of tablets containing 2.5 mg lemborexant in water, shown in Table 11.

Fig. 5(a) and 5(b) show the results of the “Dissolution” test of tablets containing 10 mg lemborexant in the dissolution media shown in Table 13 and Table 14.

Fig. 6(a) and 6(b) show the results of the “Dissolution” test of tablets containing 10 mg lemborexant in the dissolution media shown in Table 15 and Table 17.

Fig. 7 shows the results of the “Dissolution” test of tablets containing 10 mg lemborexant in water, shown in Table 16.

Fig. 8(a), 8(b) and 8(c) show the results of the “Dissolution” test of tablets containing 2.5 mg, 10 mg and 5 mg lemborexant in the dissolution media shown in Table 21, Table 22 and Table 23.

Description of embodiments

[0011] Next, the meanings of the items, terminology, etc. used in the present description will be described, and the present description will be described in detail.

[0012] In one embodiment of the present invention, the lemborexant is a free base.

[0013] Lemborexant can be obtained according to a known method, for example, the method described in WO 2012/039371 and WO 2013/123240.

[0014] Since the particle size of the active pharmaceutical ingredient lemborexant affects the dissolution profile in some dissolution media, a granular material having a 90% cumulative diameter (D90) of 64 μm or less in the cumulative distribution (volume distribution) of the particles is preferred.

[0015] In one embodiment of the present invention, the active pharmaceutical ingredient lemborexant is a granular material having a 90% cumulative diameter (D90) of 64 μm or less.

[0016] Since the active pharmaceutical ingredient lemborexant obtained according to the required method can be a granular material having a 90% cumulative diameter (D90) greater than 64 μm, the active pharmaceutical ingredient lemborexant can be ground according to a known method.

The crushing method is not particularly limited, and, for example, a hammer crusher (100UPZ, 160UPZ), a pin mill (100UPZ, 160UPZ), or the like can be used.

[0017] In one embodiment of the present invention, if the active pharmaceutical ingredient lemborexant obtained according to the required method is ground as shown in Table 1, the active pharmaceutical ingredient lemborexant may be a granular material having a 90% cumulative diameter (D90) of 64 μm or less.

[0018]

[Table 1]

Series Particle size (D90 (µm)) 1 47 2 18 3 48 4 32 5 39 6 23 7 40 8 35 9 34 Average 35.1 Standard deviation 10.0 Mean + upper limit of confidence interval ^a 65

^a upper limit of the confidence interval = 3 times the standard deviation of the batch analysis data

[0019] The particle size of the granular material, which is the active pharmaceutical ingredient lemborexant, can be measured by a laser diffraction/scattering method.

Particle size can be measured under the following conditions.

A sample suspension is prepared by dispersing approximately 30 mg of the active pharmaceutical ingredient lemborexant in 50 ml of a 0.1% aqueous solution of polysorbate 20 as a dispersing solvent. The sample suspension is placed in a diffractometer and an appropriate amount of the dispersing solvent is added. The particle size distribution of the sample suspension is measured and the particle size value of the sample is reported as a cumulative diameter distribution.

The conditions for measuring particle size distribution for a diffractometer can be as follows:

flow rate: 50%;

Number of measurements: 3 times;

measurement time: 30 seconds;

shape: non-spherical;

transparency: transparent;

refractive index of particles: 1.81;

refractive index of solvent: 1.33.

[0020] In one embodiment of the present invention, the pharmaceutical composition is a granular material containing lemborexant and one or more pharmaceutically acceptable additives, wherein the active pharmaceutical ingredient lemborexant has a 90% cumulative diameter (D90) of 64 μm or less. The pharmaceutical composition can be obtained by mixing the pharmaceutically acceptable additives with the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 μm or less. The pharmaceutical composition of the present invention can be obtained according to a known method, for example, the method described in the General Preparation Section of the Japanese Pharmacopoeia, 16th Edition.

[0021] In one embodiment of the present invention, additives include excipients, disintegrants, lubricants, surfactants, sweeteners, flavors, stabilizers, plasticizers, etc., but the present invention is not limited thereto.

[0022] In one embodiment of the present invention, the pharmaceutical composition is a solid preparation, and in one embodiment, the pharmaceutical composition is a solid oral preparation.

[0023] In one embodiment of the present invention, the pharmaceutical composition is a tablet.

[0024] In one embodiment of the present invention, the pharmaceutical composition comprises 2.5 mg to 10 mg of lemborexant. The content of lemborexant in the pharmaceutical composition may be 2.5 mg, 5 mg, or 10 mg.

[0025] In this specification, regarding the “Dissolution” test, the test can be carried out according to the method using a paddle stirrer described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia (e.g., the method using a paddle stirrer specified in 6.10 Test Method for “Dissolution” in the Japanese Pharmacopoeia 16th Edition) under the following conditions:

apparatus: apparatus with a paddle stirrer;

volume of dissolution medium: 900 ml;

temperature of dissolution medium: 37±0.5°C;

dissolution medium: 0.1 mol/L hydrochloric acid, the 1st test liquid of “Dissolution” (pH 1.2) in the Japanese Pharmacopoeia 16th edition, diluted McIlwain buffer solution (pH 5.0), the 2nd test liquid of “Dissolution” (pH 6.8) in the Japanese Pharmacopoeia 16th edition, or water;

blade rotation speed: 50 rpm or 100 rpm.

The 1st liquid for the Dissolution test is a solution obtained by dissolving 2.0 g of sodium chloride in 7.0 ml of hydrochloric acid and water to obtain 1000 ml.

The 2nd liquid for the Dissolution test is a solution obtained by adding 1 volume of water to 1 volume of phosphate buffer solution with pH 6.8.

[0026] In one embodiment of the present invention, a pharmaceutical composition comprises lemborexant and one or more pharmaceutically acceptable additives, and it is obtained using the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 μm or less, and for such a pharmaceutical composition, the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the "Dissolution" test in a dissolution medium (the 2nd liquid for the "Dissolution" test (pH 6.8) in the Japanese Pharmacopoeia 16th Edition, 900 ml, 37±0.5°C) using an apparatus with a paddle stirrer (rotational speed: 50 rpm) according to the method using a paddle stirrer.

[0027] In one embodiment of the present invention, a pharmaceutical composition comprises lemborexant and one or more pharmaceutically acceptable additives, and it is prepared using the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 μm or less, and for such a pharmaceutical composition, the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the "Dissolution" test in a dissolution medium (water, 900 ml, 37±0.5°C) using an apparatus with a paddle stirrer (rotational speed: 50 rpm) according to the paddle stirrer technique.

[0028] In one embodiment of the present invention, a pharmaceutical composition comprises lemborexant and one or more pharmaceutically acceptable additives, and it is prepared using an active pharmaceutical ingredient lemborexant that is a granular material having a 90% cumulative diameter (D90) of 64 μm or less, and for such a pharmaceutical composition, the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the "Dissolution" test in a dissolution medium (the 2nd "Dissolution" test liquid (pH 6.8) in the Japanese Pharmacopoeia 16th edition, 900 ml, 37±0.5°C) in the Japanese Pharmacopoeia 16th edition, 900 ml, 37±0.5°C) using a paddle stirrer apparatus (rotational speed: 100 rpm) according to the paddle stirrer method stirrers.

[0029] In one embodiment of the present invention, a pharmaceutical composition comprises lemborexant and one or more pharmaceutically acceptable additives, and it is obtained using the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 64 μm or less, and for such a pharmaceutical composition, the dissolution rate of lemborexant is 80% or more within 15 minutes from the start time of the "Dissolution" test in a dissolution medium (0.1 mol/L hydrochloric acid, 900 ml, 37±0.5°C) using an apparatus with a paddle stirrer (rotational speed: 50 rpm) according to the method using a paddle stirrer.

[0030] In one embodiment of the present invention, a pharmaceutical composition comprises lemborexant and one or more pharmaceutically acceptable additives, and the dissolution rate of lemborexant is 80% or more within 15 minutes from the start time of the Dissolution Test in a dissolution medium (0.1 mol/L hydrochloric acid, 900 mL, 37±0.5°C) and the dissolution rate of lemborexant is 50% or more within 15 minutes from the start time of the Dissolution Test in another dissolution medium (the 2nd Dissolution Test Liquid (pH 6.8) in the Japanese Pharmacopoeia 16th Edition, 900 mL, 37±0.5°C) using an apparatus with a paddle stirrer (rotational speed: 50 rpm) according to the method using a paddle stirrer.

[0031] In one embodiment of the present invention, the pharmaceutical composition can be suitably administered to patients according to its dosage form.

[0032] In one embodiment of the present invention, the dose of lemborexant varies depending on the severity of symptoms, age, sex, body weight, dosage form/salt type, specific type of disease, etc., but typically for adults, the oral daily dose is 2.5 mg to 10 mg or selected from 2.5 mg, 5 mg and 10 mg.

Examples

[0033] The present invention will now be described in detail using examples. However, the present invention is not limited to these examples. In addition, the abbreviations used in the following examples are common abbreviations well known to those skilled in the art, and several abbreviations are described below.

[0034] Chemical shifts in the proton nuclear magnetic resonance ( ¹ H-NMR) spectrum are reported in units of δ (ppm) relative to tetramethylsilane, and coupling constants are reported in hertz (Hz). In the spectra, s, d, br, and m denote singlet, doublet, broad, and multiplet, respectively.

[0035] ¹ H-NMR and ¹³ C-NMR spectra were measured using a Varian 400, 500 MHz spectrometer or a JNM-AL400 (400 MHz) nuclear magnetic resonance apparatus (commercially available from JEOL Ltd.).

[0036] “Room temperature” in the following examples generally means a temperature from about 10°C to about 35°C. Unless otherwise specified, “%” means weight percent.

[0037] The lemborexant of the present invention was prepared by the following method. The compound of formula A can be prepared, for example, by the preparation method described in WO 2012/039371 or WO 2013/123240.

[0038]

Preparation of (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (lemborexant)

A mixture of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid (62.4 kg, 197 mol, 1.00 equiv), 5-fluoropyridin-2-amine (24.3 kg, 217 mol, 1.10 equiv), ethyl acetate (499 L), N,N-diisopropylethylamine (53.5 kg, 414 mol, 2.10 equiv) and 1-propanephosphoric anhydride (50% ethyl acetate solution) (188 kg, 296 mol, 1.50 equiv) was heated at an external temperature of 70 °C and the completion of the reaction was confirmed by HPLC analysis. After cooling the reaction mixture, 312 L of purified water was added to it, and the mixture was stirred, and then left to stand. After removing the aqueous layer, an aqueous solution of sodium carbonate (68.9 kg of sodium carbonate and 312 L of purified water) was added to the organic layer, and the mixture was stirred, and then left to stand. After removing the aqueous layer, purified water (187 L) was added to the organic layer, and the mixture was stirred, and then left to stand. The aqueous layer was removed, purified water (187 L) was added to the organic layer, and the mixture was stirred, and then left to stand. The aqueous layer was removed, and the organic layer was filtered. The light filtration line was washed with ethyl acetate, and then the solvent was partially distilled off under reduced pressure. A mixture was obtained by adding ethyl acetate to the concentrated residue (containing essentially 75.3 kg of lemborexant) so that the total volume reached 256 L, and the mixture was heated and dissolved with stirring at an external temperature of 60°C. To the resultant was added n-heptane (12.8 kg), and the mixture was cooled to 45°C or lower. To the resultant was added ethyl acetate (31 L), the mixture was cooled to 35°C or lower, and then n-heptane (670 kg) was added thereto. Thereafter, the suspension was cooled to 10°C or lower, and the solid in the mixture was collected by filtration and washed with a mixture of ethyl acetate and n-heptane. The resulting solid was dried at an external temperature of 60°C or lower under reduced pressure, and thus lemborexant (70 kg) was obtained in a yield of 87%.

[0039] HPLC conditions for confirming the reaction described above:

reagents and mobile phases;

purified water;

acetonitrile (Kanto Chemical Co., Inc., Cat. No. 01031-2B, for high performance liquid chromatograph or equivalent product);

trifluoroacetic acid (Wako Pure Chemical Industries, Ltd., Cat. No. 208-02741, Specialty Reagent, or equivalent);

mobile phase A: mixture of water and trifluoroacetic acid (1000/1, v/v);

mobile phase B: mixture of acetonitrile and trifluoroacetic acid (1000/1, v/v);

solution: a mixture of water, acetonitrile and trifluoroacetic acid (500/500/1, v/v/v);

HPLC needle rinse: a mixture of water and acetonitrile (100/900, v/v);

solution: a mixture of water and acetonitrile (1/1, v/v);

standard sample of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropanecarboxylic acid.

HPLC conditions:

Detector: Shimadzu SPD-20A ultraviolet detector (measuring wavelength: 283nm) or similar product;

Column: 4.6 mm ID x 15 cm long stainless steel tube filled with 3.5 μm octadecylsilylated silica gel for liquid chromatography;

example: SunFire C18 (Waters) (equivalent to USP L1 packaging);

column temperature: constant temperature about 40°C;

mobile phases

A: mixture of water and trifluoroacetic acid (1000/1, v/v);

B: mixture of acetonitrile and trifluoroacetic acid (1000/1, v/v);

flow rate: constant flow rate approximately 1.0 ml/min;

gradient conditions:

time (minutes) percentage of mobile phase B (%)

[0040] NMR data

(1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide:

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 8.31 (d, J=3.0 Hz, 1H), 8.12 (s, 1H), 7.94-7.85 (m, 1H), 7.62 (tt, J=8.7, 3.1 Hz, 1H), 7.44 (dd, J=10.6, 1.5 Hz, 1H), 7.41-7.40 (m, 1H), 7.39 (s, 1H), 7.14-7.06 (m, 1H), 4.67 (d, J=10.2 Hz, 1H), 4.29 (t, J=9.9 Hz, 1H), 2.63 (t, J=7.0 Hz, 1H), 2.38 (s, 3H), 2.03 (s, 3H), 1.76-1.64 (m, 1H), 1.49 (dd, J=8.0, 4.8 Hz, 1H);

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ168.68, 161.98 (d, JCF= 242.3 Hz), 158.46,155.15, 155.38 (d, JCF=247.9 Hz), 148.90, 148.51, 145.00 (d, JCF=7.7 Hz), 139.37, 135.15 (d, JCF= 24.9 Hz), 130.06 (d, JCF=8.4 Hz), 125.05 (d, JCF=19.5Hz), 124.70 (d, JCF=2.6 Hz), 115.71 (d, JCF=21.7 Hz), 114.20 (d, JCF=4.1 Hz), 113.70 (d, JCF=20.9 Hz), 70.80, 34.09 (d, JCF=1.9 Hz), 26.90, 24.38, 18.37, 17.78.

[0041] Example 1. Obtaining the active pharmaceutical ingredient lemborexant, characterized by different particle sizes

A series of lemborexant active pharmaceutical ingredients characterized by different particle sizes were prepared using unmilled lemborexant active pharmaceutical ingredient product by varying the rotation speed of 160UPZ (hammer mill, pin mill).

A weighed portion of uncrushed active pharmaceutical ingredient lemborexant was taken in advance in an amount of one kg and put into a fine grinding mill (160UPZ hammer mill, sieve with a mesh size of 1 mm) while measuring the time with a stopwatch. The loading was carried out manually with a shovel. The rotating speed was 4000, 5600, 8000, 9500 rpm, and grinding was carried out under the condition of a feeding rate of 10 kg/h (S1, S2, S3, S4 and S6 series). However, S6 series was obtained by grinding once under the condition of a rotating speed of 5600 rpm and a feeding rate of 60 kg/h (S5 series), then grinding with a 160UPZ pin mill at 5600 rpm, and then continuously grinding at 10000 rpm. Table 2 shows the grinding conditions and the cumulative diameter (D90) obtained after grinding to 90%.

90% cumulative diameter (D90) was measured using a particle size analyzer (Microtrack MT3300EXII). A sample suspension was prepared by dispersing approximately 30 mg of the active pharmaceutical ingredient lemborexant in 50 ml of a dispersing solvent, which was a 0.1% aqueous solution of polysorbate 20. The sample suspension was placed in the particle size analyzer and an appropriate amount of the dispersing solvent was added thereto. The particle size distribution of the sample suspension was measured and the particle size value of the sample was recorded as the cumulative diameter distribution.

The measurement conditions for the particle size analyzer are as follows:

flow rate: 50%;

Number of measurements: 3 times;

measurement time: 30 seconds;

shape: non-spherical;

transparency: transparent;

refractive index of particles: 1.81;

refractive index of solvent: 1.33.

[0042] [Table 2]

Series Rotation speed (rpm) Feed rate (kg/h) D90 (µm) S1 4000 10 98 S2 5600 10 79 S3 8000 10 64 S4 9500 10 56 S5 5600 60 110 S6 10000 10 20

[0043] Example 2. Preparation of tablets containing 2.5 mg and 10 mg lemborexant

Tablets containing 2.5 mg and 10 mg lemborexant were prepared using each batch (S1, S2, S3, S4 and S6) obtained in Example 1.

Table 3 shows the components and compositions of the manufactured tablets.

[0044] [Table 3]

Components, composition and quantity of batches of tablets containing 2.5 mg and 10 mg lemborexant

Component Quantity 2.5 mg 10 mg mg/tablet g/batch mg/tablet g/batch Internal phase Lemborexant 2.5 27.08 10.0 108.3 Lactose hydrate 96.38 1044.12 88,88 962.87 Low substituted hydroxypropyl cellulose 10.8 117.0 10.8 117.0 Hydroxypropyl cellulose 3.6 39.0 3.6 39.0 Purified water In sufficient quantity 163 In sufficient quantity 163 External phase Low substituted hydroxypropyl cellulose 6.0 65.0 6.0 65.0 Magnesium stearate 0.72 7.8 0.72 7.8 Total weight 120,0 1300,0 120,0 1300,0

[0045] Tablets containing 2.5 mg and 10 mg of lemborexant were prepared by mixing, granulating, drying, grinding, compounding and tabletting processes. The active pharmaceutical ingredient lemborexant, lactose hydrate and low-substituted hydroxypropyl cellulose were charged into a high-shear wet granulator and mixed for 5 minutes. A solution obtained by dissolving hydroxypropyl cellulose in purified water was added to the high-shear wet granulator containing the resulting mixture, and the mixture was granulated for 3 minutes. The resulting wet granules were dried using a fluidized bed dryer (inlet air temperature of 70°C) until the outlet air temperature was above 38°C. The obtained dried granules were ground using a mill with a sieve hole diameter of 1.0 mm. A weighed portion of low-substitution hydroxypropyl cellulose and magnesium stearate was selected in accordance with the yield of granules. The dried granules, low-substitution hydroxypropyl cellulose and magnesium stearate were loaded into a drum mixer and mixed for 16 minutes. The resulting mixture was tableted using a tableting machine at a pressing force of 1150 kgf to obtain tablets.

[0046] Example 3. Dissolution Test

(1) Equipment and materials

The apparatus and materials used in the Dissolution test are listed in Table 4.

[0047] [Table 4]

Equipment and materials

Paragraph Equipment and materials The device Dissolution system (apparatus 2): Evolution 6100 (DISTEK) HPLC System: LC-2010C _HT (Shimadzu Corporation) Analytical balance Material Acetonitrile (HPLC grade) 70% perchloric acid (analytical grade) 0.1 mol/l hydrochloric acid 1st Dissolution Test Liquid (Japanese Pharmacopoeia 16th Edition) Diluted McIlwain's buffer solution (pH 5.0) specified in the Japanese Guidelines for Conducting Bioequivalence Studies 2nd Dissolution Test Liquid (Japanese Pharmacopoeia 16th Edition) Purified water

[0048] (2) Test conditions "Dissolution".

Table 5 shows the conditions for the Dissolution test.

Each test was carried out with 6 or 12 tablets prepared according to the method described in Example 2.

[0049] [Table 5]

Test conditions "Dissolution"

The device Rotation speed Dissolution media Volume of solution Temperature Apparatus 2 (paddle mixer) 50 rpm 0.1 mol/l hydrochloric acid 900 ml 37±
0.5°C pH 1.2 (1st Dissolution Test Liquid (Japanese Pharmacopoeia 16th Edition)) pH 5.0 (diluted McIlwain buffer solution) pH 6.8 (2nd Dissolution Test Liquid (Japanese Pharmacopoeia 16th Edition)) Water 100 rpm pH 6.8 (2nd Dissolution Test Liquid (Japanese Pharmacopoeia 16th Edition))

[0050] (3) Analysis procedure.

The Dissolution test was carried out in accordance with the paddle stirrer apparatus specified in The Japanese Pharmacopoeia, 16th Edition. The tablets were tested using 900 mL of 0.1 mol/L hydrochloric acid, the 1st Dissolution test liquid (pH 1.2), diluted McIlwain's buffer solution, the 2nd Dissolution test liquid (pH 6.8), or water as the dissolution medium at a paddle speed of 50 rpm or 100 rpm. A part of the dissolution medium was collected through a filter at a specified time. A standard solution whose concentration of lemborexant corresponded to the normal concentration of the sample solution was prepared. The amount of lemborexant released was determined by HPLC or an ultraviolet-visible absorption measurement method. The HPLC conditions and the conditions of the ultraviolet-visible absorption measurement method are shown below.

<HPLC conditions:>

Detector: Ultraviolet detector (measurement wavelength: 283nm);

column: with an internal diameter of 4.6 mm and a length of 7.5 cm (YMC-TriartC18(YMC));

filler: octadecylsilylated silica gel with a particle size of 3 μm for liquid chromatography;

column temperature: 40°C;

mobile phase: water/acetonitrile/70% perchloric acid (550:450:1, v/v/v);

flow rate: 1.2 ml/min;

injection volume: 50 µl;

sample rack temperature: 25°C;

Analysis time: 5 minutes.

<Conditions for the method of measuring absorption in the ultraviolet and visible region of the spectrum (measurement using this method is performed only in the case of 0.1 mol/l hydrochloric acid):>

measurement wavelength: 233 nm and 400 nm;

control: dissolution medium.

[0051] (4) Results

The test was performed with 6 or 12 tablets and their average value is shown. Table 6 and Table 7 and Fig. 1 show the results of the "Dissolution" test of 2.5 mg and 10 mg lemborexant tablets using 0.1 mol/L hydrochloric acid as a dissolution medium. All tablets were completely released in 0.1 mol/L hydrochloric acid within 15 minutes regardless of the particle size and the content of the active pharmaceutical ingredient lemborexant.

[0052] [Table 6]

Dissolution profiles of tablets containing 2.5 mg lemborexant in 0.1 mol/L hydrochloric acid (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 20 min 30 min 98 μm 81.0 95.8 96.9 97.1 97.0 79 μm 79.4 95.2 97.5 97.6 97.4 64 μm 82.4 97.6 99.8 100,0 100.7 56 μm 82.3 96.8 98.5 98.3 98.3 20 μm 81.8 97.8 100,0 100.1 100.5

[0053] [Table 7]

Dissolution profiles of tablets containing 10 mg lemborexant in 0.1 mol/L hydrochloric acid (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 20 min 30 min 98 μm 80.3 95.3 96.8 96.7 96.7 79 μm 79.1 94.8 96.8 96.7 96.7 64 μm 82.7 97.6 99.9 99.8 99.8 56 μm 78.8 94.3 97.1 97.0 96.9 20 μm 82.1 98.4 101,0 100.9 100.9

[0054] Tables 8-12 and Figs. 2-4 show the results of the "Dissolution" test of 2.5 mg lemborexant tablets in various dissolution media. In addition, Tables 13-17 and Figs. 5-7 show the results of the "Dissolution" test of 10 mg lemborexant tablets in various dissolution media. In this document, "N/T" in the following tables means "Not tested". Tablets in which the active pharmaceutical ingredient lemborexant had a particle size (D90) of 64 μm or less showed a favorable dissolution profile in all dissolution media for 2.5 mg and 10 mg lemborexant tablets. On the other hand, it was confirmed that in tablets in which the active pharmaceutical ingredient lemborexant had a particle size (D90) of 79 μm and 98 μm, the dissolution rate (%) was decreased in diluted McIlwain buffer solution, 2nd Dissolution Test Liquid (pH 6.8) and water in case of lemborexant 2.5 mg and 10 mg tablets.

Therefore, it was suggested that a homogeneous pharmaceutical composition exhibiting favorable dissolution profiles could be achieved by setting the particle size (D90) of the active pharmaceutical ingredient lemborexant to 64 μm or less.

In addition, the "Dissolution" test according to Example 3 is a test procedure according to the Japanese Pharmacopoeia, the United States Pharmacopoeia and the European Pharmacopoeia, as described in section <711> "Dissolution" in the United States Pharmacopoeia (USP42). Based on such a test procedure, it was confirmed that the 2.5 mg and 10 mg tablets exhibited a favorable dissolution profile. Since the 2.5 mg and 10 mg tablets were formulations in which the difference in the amount of active pharmaceutical ingredient in one tablet was replaced by lactose hydrate, it was expected that a similar favorable dissolution profile would be demonstrated in the case of tablets from 2.5 mg to 10 mg according to the method of selecting extreme options, for example, 5 mg tablets.

[0055] [Table 8]

Dissolution profiles of 2.5 mg lemborexant tablets at pH 1.2 (1st Dissolution Test Liquid (Japanese Pharmacopoeia)) (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns N/T N/T N/T N/T N/T N/T 79 microns N/T N/T N/T N/T N/T N/T 64 microns 85.0 98.5 100.5 100.6 100.2 N/T 56 microns 83.3 98.5 100.1 100.2 100.3 N/T 20 microns 80.9 97.2 99.9 99.4 99.7 N/T

[0056] [Table 9]

Dissolution profiles of tablets containing 2.5 mg lemborexant at pH 5.0 (diluted McIlwain buffer) (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns 19.3 32.1 40.8 55.0 63.1 68.3 79 microns 21.7 35.9 45.6 60.6 68.4 73.3 64 microns 31.0 48.0 59.0 75.2 82.5 86.9 56 microns 30.3 49.1 60.7 76.8 83.6 87.5 20 microns 38.8 63.9 77.4 92.1 95.8 96.8

[0057] [Table 10]

Dissolution profiles of 2.5 mg lemborexant tablets at pH 6.8 (2nd Dissolution Test Liquid (Japanese Pharmacopoeia)) (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns 22.0 34.2 42.3 55.8 63.5 68.6 79 microns 24.0 38.5 47.7 62.6 70.6 75.8 64 microns 32.9 50.8 61.6 77.1 84.1 88.1 56 microns 34.6 53.5 64.3 78.7 84.8 88.3 20 microns 41.8 67.0 79.7 92.9 96.3 97.3

[0058] [Table 11]

Dissolution profiles of tablets containing 2.5 mg lemborexant in water (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns 20.7 34.6 43.4 57.0 64.3 69.0 79 microns 23.9 39.2 48.7 63.2 70.6 75.3 64 microns 34.9 54.9 66.4 81.2 87.3 90.5 56 microns 37.6 57.7 68.5 82.0 87.2 89.9 20 microns 40.2 69.5 83.7 96.6 99.5 100.1

[0059] [Table 12]

Dissolution profiles of 2.5 mg lemborexant tablets at pH 6.8 (2nd Dissolution Test Liquid (Japanese Pharmacopoeia)) (rotation speed 100 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns N/T N/T N/T N/T N/T N/T 79 microns N/T N/T N/T N/T N/T N/T 64 microns 43.4 59.5 68.9 83.0 89.3 92.8 56 microns 45.9 61.8 70.9 84.1 89.8 92.9 20 microns 55.0 76.3 86.0 96.9 99.6 100.4

[0060] [Table 13]

Dissolution profiles of 10 mg lemborexant tablets at pH 1.2 (1st Dissolution Test Liquid (Japanese Pharmacopoeia)) (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns N/T N/T N/T N/T N/T N/T 79 microns N/T N/T N/T N/T N/T N/T 64 microns 82.2 98.3 100.7 100.6 100.7 N/T 56 microns 76.8 94.4 97.2 97.3 97.2 N/T 20 microns 82.2 99.1 101.9 101.8 101.8 N/T

[0061] [Table 14]

Dissolution profiles of 10 mg lemborexant tablets at pH 5.0 (diluted McIlwain buffer) (50 rpm rotation speed)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns 15.2 27.0 34.7 46.9 54.1 58.9 79 microns 15.3 28.0 36.5 49.5 57.1 62.1 64 microns 22.6 37.8 47.6 62.7 70.9 76.2 56 microns 24.0 40.1 50.1 64.7 72.2 76.9 20 microns 29.0 51.4 64.1 80.4 87.8 92.0

[0062] [Table 15]

Dissolution profiles of 10 mg lemborexant tablets at pH 6.8 (2nd Dissolution Test Liquid (Japanese Pharmacopoeia)) (rotation speed 50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns 18.2 29.9 37.4 50.0 57.4 62.7 79 microns 20.1 32.4 40.2 53.0 60.3 65.4 64 microns 24.8 41.3 51.7 66.7 74.6 79.7 56 microns 25.6 43.2 53.4 67.7 75.0 79.4 20 microns 29.3 54.6 68.2 84.2 90.2 94.1

[0063] [Table 16]

Dissolution profiles of 10 mg lemborexant tablets in water (50 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns N/T N/T N/T N/T N/T N/T 79 microns N/T N/T N/T N/T N/T N/T 64 microns 25.7 41.8 51.5 66.1 73.7 78.5 56 microns 26.8 44.1 54.0 67.7 74.5 78.6 20 microns 31.9 57.0 69.7 85.0 91.5 94.8

[0064] [Table 17]

Dissolution profiles of 10 mg lemborexant tablets at pH 6.8 (2nd Dissolution Test Liquid (Japanese Pharmacopoeia)) (rotation speed 100 rpm)

Particle size (D90) Dissolution rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 98 microns N/T N/T N/T N/T N/T N/T 79 microns N/T N/T N/T N/T N/T N/T 64 microns 34.4 48.8 57.8 72.4 80.3 85.5 56 microns 32.4 49.2 58.4 72.2 79.3 83.8 20 microns 37.2 61.8 73.0 87.5 94.0 97.5

[0065] Example 4. Preparation of tablets containing 2.5 mg, 5 mg and 10 mg of lemborexant

Table 18 shows the components and compositions of the manufactured tablets.

[0066] [Table 18]

Components, composition and quantity of batches of tablets containing 2.5 mg, 5 mg and 10 mg lemborexant

Component Quantity 2.5 mg 5 mg 10 mg mg/
tablet kg/
party mg/
tablet kg/
party mg/
tablet kg/
party Internal phase Lemborexant 2.5 0.271 5 0.542 10 1,083 Lactose hydrate 96.38 10,441 93.88 10.17 88,88 9,629 Low substituted hydroxypropyl cellulose 10.8 1.17 10.8 1.17 10.8 1.17 Hydroxypropyl cellulose 3.6 0.39 3.6 0.39 3.6 0.39 Purified water In sufficient quantity 3.68 In sufficient quantity 2.88 In sufficient quantity 2.88 External phase Low substituted hydroxypropyl cellulose 6 0.65 6 0.65 6 0.65 Magnesium stearate 0.72 0.078 0.72 0.078 0.72 0.078 Total weight 120,0 120,0 120,0

[0067] Tablets containing 2.5 mg, 5 mg and 10 mg of lemborexant were prepared by mixing, granulating, drying, grinding, compounding and tabletting processes. The active pharmaceutical ingredient lemborexant (32 μm (D90)), lactose hydrate and low-substituted hydroxypropyl cellulose were charged into a high-shear wet granulator and mixed for 5 minutes. A solution obtained by dissolving hydroxypropyl cellulose in purified water was added to the high-shear wet granulator containing the resulting mixture, and the mixture was granulated for 3 minutes. The resulting wet granules were dried in a fluidized bed dryer (inlet air temperature 70°C) until the outlet air temperature was above 40°C. The obtained dried granules were ground using a mill with a sieve hole diameter of 0.8 mm. A weighed portion of low-substituted hydroxypropyl cellulose and magnesium stearate was selected according to the yield of granules. The dried granules, low-substituted hydroxypropyl cellulose and magnesium stearate were loaded into a drum mixer and mixed for 14 minutes. The resulting mixture was tableted using a tableting machine at a pressing force of 700 kgf, 1150 kgf and 1600 kgf to obtain tablets.

[0068] Example 5. Dissolution Test

(1) Equipment and materials

The apparatus and materials used in the Dissolution test are listed in Table 19.

[0069] [Table 19]

Paragraph Equipment and materials The device Dissolution system (apparatus 2): Evolution 6100 (DISTEK) Ultraviolet-Visible Spectrophotometer: UV-1700 (Shimadzu Corporation) Analytical balance Material Acetonitrile (HPLC grade) 0.1 mol/l hydrochloric acid

[0070] (2) Test conditions "Dissolution"

Table 20 shows the conditions for performing the Dissolution test.

Each test was carried out with 6 tablets prepared according to the method described in Example 4.

[0071] [Table 20]

Test conditions "Dissolution"

The device Rotation speed Dissolution medium Volume of solution Temperature Apparatus 2 (paddle mixer) 50 rpm 0.1 mol/l hydrochloric acid 900 ml 37±0.5°C

[0072] (3) Analysis procedure

The "Dissolution" test was carried out in accordance with the paddle stirrer apparatus specified in the Japanese Pharmacopoeia, 16th Edition. The tablets were tested using 900 mL of 0.1 mol/L hydrochloric acid as the dissolution medium at a paddle rotation speed of 50 rpm. A part of the dissolution medium was collected through a filter at a certain time. A standard solution with a lemborexant concentration corresponding to the normal concentration of the sample solution was prepared. The amount of lemborexant released was determined by the ultraviolet-visible absorption measurement method. The conditions for the ultraviolet-visible absorption measurement method are shown below.

<Conditions for the method of measuring absorption in the ultraviolet and visible spectral region:>

measurement wavelength: 233 nm and 400 nm;

control: dissolution medium

[0073] (4) Results

The test was carried out with 6 tablets and their average value is shown. Tables 21-23 and Fig. 8 show the results of the "Dissolution" test of lemborexant tablets of 2.5 mg, 5 mg and 10 mg prepared with different pressing forces using 0.1 mol/L hydrochloric acid as the dissolution medium.

[0074] [Table 21]

Dissolution profiles of tablets containing 2.5 mg lemborexant, prepared at each compression force, in 0.1 mol/L hydrochloric acid (rotation speed 50 rpm)

Pressing force (kgf) Dissolution rate (%) 5 min 10 min 15 min 20 min 30 min 45 min 700 86.2 98.2 99.1 99.2 99.2 99.3 1150 83.8 96.8 97.3 97.5 97.5 97.4 1600 82.5 97.6 99.3 99.5 99.6 99.7

[0075] [Table 22]

Dissolution profiles of tablets containing 10 mg lemborexant, prepared at each compression force, in 0.1 mol/L hydrochloric acid (rotation speed 50 rpm)

Pressing force (kgf) Dissolution rate (%) 5 min 10 min 15 min 20 min 30 min 45 min 700 89 98.2 99.1 99.8 100.1 100.1 1150 88.2 97.8 98.4 98.5 98.7 98.8 1600 82.2 96.6 97.4 97.5 97.6 97.6

[0076] [Table 23]

Dissolution profiles of tablets containing 5 mg lemborexant, prepared at each compression force, in 0.1 mol/L hydrochloric acid (rotation speed 50 rpm)

Pressing force (kgf) Dissolution rate (%) 5 min 10 min 15 min 20 min 30 min 45 min 700 85.6 98.3 99.4 99.6 99.8 99.7 1150 82.8 97.5 99.1 99.1 99.1 99.3 1600 83.9 99.1 100.3 100.4 100.5 100.5

[0077] In the Dissolution Test of 2.5 mg tablets, 5 mg tablets and 10 mg tablets using 0.1 mol/L hydrochloric acid, it was confirmed that there was no effect on dissolution in the range of pressing force from 700 kgf to 1600 kgf.

Claims (19)

1. The active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 20 μm or greater and 64 μm or less. 2. A pharmaceutical composition of lemborexant containing: 2.5 mg lemborexant and 96.38 mg lactose hydrate, or 5 mg lemborexant and 93.88 mg lactose hydrate, or 10 mg lemborexant and 88.88 mg lactose hydrate, and 16.8 mg low substituted hydroxypropyl cellulose, 3.6 mg hydroxypropyl cellulose, water and 0.72 mg magnesium stearate, wherein the lemborexant is a granular material having a 90% cumulative diameter (D90) of 20 µm or greater and 64 µm or less. 3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is a tablet. 4. The pharmaceutical composition according to claim 3, wherein the tablet consists of an internal phase and an external phase, wherein the internal phase contains 10.8 mg of low-substituted hydroxypropylcellulose and the external phase contains 6.0 mg of low-substituted hydroxypropylcellulose. 5. A pharmaceutical composition according to any one of claims 2-4, which contains 10 mg of lemborexant. 6. A pharmaceutical composition according to any one of claims 2-4, which contains 5 mg of lemborexant. 7. A pharmaceutical composition according to any one of claims 2-4, which contains 2.5 mg of lemborexant. 8. A method for producing a pharmaceutical composition of lemborexant containing lemborexant, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, water and magnesium stearate, comprising: a) a step of mixing the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 20 μm or more and 64 μm or less, lactose hydrate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and water to obtain granules; b) a step of mixing the granules obtained in step a), low substituted hydroxypropyl cellulose and magnesium stearate to obtain a mixture; and c) a step of pressing the mixture obtained in step b) to obtain tablets. 9. The method according to item 8, including: a) a step of mixing the active pharmaceutical ingredient lemborexant, which is a granular material having a 90% cumulative diameter (D90) of 20 μm or more and 64 μm or less, lactose hydrate, 10.8 mg of low-substituted hydroxypropyl cellulose, 3.6 mg of hydroxypropyl cellulose and water to obtain granules, wherein the amounts of the active pharmaceutical ingredient lemborexant and the lactose hydrate are: 2.5 mg of the active pharmaceutical ingredient lemborexant and 96.38 mg of lactose hydrate; or 5 mg of the active pharmaceutical ingredient lemborexant and 93.88 mg of lactose hydrate; or 10 mg of the active pharmaceutical ingredient lemborexant and 88.88 mg of lactose hydrate; b) a step of mixing the granules obtained in step a), 6.0 mg of low-substituted hydroxypropyl cellulose and 0.72 mg of magnesium stearate to obtain a mixture; and c) a step of pressing the mixture obtained in step b) to obtain tablets, where the amount of each ingredient is indicated per tablet.