Leboresen active pharmaceutical ingredient and pharmaceutical components containing it

Abstract

The present invention provides a pharmaceutical composition containing leboresen, which exhibits good dissolution distribution by using 90% of the powder particles with a cumulative diameter (D90) of less than 64 μm as the active pharmaceutical ingredient of leboresen.

Description

[Technical Field]

[0001] This invention relates to a raw material of Leemborexant and pharmaceutical compositions containing it. [Previous Technology]

[0002] Orexin receptors are G protein-coupled receptors that dominate the brain. Their endogenous ligands, orexin-A and orexin-B, are expressed by neurons located in the hypothalamus. Orexin-A is a peptide of 33 amino acids, and orexin-B is composed of 28 amino acids (Non-Patent Literature 1). There are two subtypes of orexin receptors: OX1 and OX2; OX1 preferentially binds to orexin-A, while OX2 binds to both orexin-A and orexin-B. Orexin stimulates feeding in rats, suggesting that orexin signaling can participate in central feedback mechanisms that regulate feeding behavior (Non-Patent Literature 1). Orexin has also been observed to control the wake-sleep state (Non-Patent Literature 2). Orexin is also involved in brain changes associated with opioid and nicotine dependence (Non-Patent Literature 3 and 4) and alcohol dependence (Non-Patent Literature 5). Furthermore, orexin participates 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)cyclopropylmethylmethamide (also known as "lebrosemide") are known to be potent orexin receptor antagonists, useful for treating sleep disorders such as insomnia and for other therapeutic purposes (Patent Documents 1 and 2). Dissolution tests of tablets containing 1 mg to 25 mg of lebrosemide have been reported (Patent Document 3). [Chemical 1] [Background Art Documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2012 / 039371 [Patent Document 2] International Publication No. 2013 / 123240 [Patent Document 3] International Publication No. 2016 / 063995 [Non-Patent Documents]

[0005] [Non-Patent Literature 1] Sakurai T. et al., Cell, 1998, Vol. 92, pp. 573-585 [Non-Patent Literature 2] Chemelli RM et al., Cell, 1999, Vol. 98, pp. 437-451 [Non-Patent Literature 3] SLBorgland et al., Neuron, 2006, Vol. 49, pp. 598-601 [Non-Patent Literature 4] CJWinrow et al., Neuropharmacology, 2010, Vol. 58, pp. 185-194 [Non-Patent Literature 5] JRShoblock et al., Psychopharmacology, 2011, Vol. 215, pp. 191-203 [Non-Patent Literature 6] T. Ida et al., Biochem. Biophys. Res. Commun. [Biochemical and Biophysical Research Communications], 2000, Vol. 270, pp. 318-323 [Summary of the Invention]

[0006] [The problem the invention aims to solve]

[0007] Pharmaceutical compositions are desirable for their good physicochemical properties. The object of this invention is to provide a pharmaceutical composition containing leboresen that exhibits good dissolution distribution. [Technical Means for Solving the Problem]

[0008] In order to solve the above problems, the inventors and others have made repeated efforts to conduct research and found that by using leboresen powder with a specified cumulative diameter (D90) as the active pharmaceutical ingredient, pharmaceutical compositions containing leboresen show good dissolution distribution.

[0009] That is, the present invention relates to the following [1] to

[15] . [1] A leboresen active pharmaceutical ingredient, which is a powder with a cumulative diameter (D90) of 90% or less of 64 μm. [2] A pharmaceutical composition containing leboresen and pharmaceutically acceptable additives, said pharmaceutical composition being manufactured using a leboresen active pharmaceutical ingredient, said leboresen being a powder with a cumulative diameter (D90) of 90% or less of 64 μm. [3] According to the pharmaceutical composition described in [2], when using a stirring paddle and a stirring device (speed: 50 rpm), in a test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen shows more than 50% within 15 minutes after the start of the dissolution test. [4] According to the pharmaceutical composition described in [2], using a stirring paddle method with a stirring paddle device (speed: 50 rpm), in a test solution (water, 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen showed more than 50% within 15 minutes after the start of the dissolution test. [5] According to the pharmaceutical composition described in [2], using a stirring paddle method with a stirring paddle device (speed: 100 rpm), in a test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen showed more than 50% within 15 minutes after the start of the dissolution test. [6] According to the pharmaceutical composition described in [2], the dissolution rate of leboresen in the test solution (0.1 mol / L hydrochloric acid, 900 mL, 37℃ ± 0.5℃) using a stirring paddle device (speed: 50 rpm) shows a dissolution rate of more than 80% within 15 minutes after the start of the dissolution test. [7] According to any one of [2] to [6], wherein the pharmaceutical composition is a tablet. [8] According to any one of [2] to [7], wherein it contains 2.5 mg to 10 mg of leboresen. [9] According to the pharmaceutical composition described in [8], wherein it contains 10 mg of leboresen.

[10] According to the pharmaceutical composition described in [8], wherein it contains 5 mg of leboresen.

[11] According to the pharmaceutical composition described in [8], wherein it contains 2.5 mg of leboresen.

[12] A pharmaceutical composition containing leboresen and pharmaceutically acceptable additives, wherein, by a paddle method using a paddle apparatus (speed: 50 rpm), the dissolution rate of leboresen is shown to be greater than 80% within 15 minutes after the start of the dissolution test in a test solution (0.1 mol / L hydrochloric acid, 900 mL, 37℃ ± 0.5℃), and in another test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen is shown to be greater than 50% within 15 minutes after the start of the dissolution test.

[13] According to the pharmaceutical composition described in

[12] , the active pharmaceutical ingredient of leboresen is a powder with a cumulative diameter (D90) of 90% or less of 64 μm.

[14] The pharmaceutical composition according to

[12] is manufactured using a leboresen active pharmaceutical ingredient, wherein the leboresen active pharmaceutical ingredient is a powder with a 90% cumulative diameter (D90) of 64 μm or less.

[15] A method for manufacturing a pharmaceutical composition comprising leboresen and pharmaceutically acceptable additives, the method comprising the step of mixing a leboresen active pharmaceutical ingredient with a pharmaceutically acceptable additive, wherein the leboresen active pharmaceutical ingredient is a powder with a 90% cumulative diameter (D90) of 64 μm or less. [Effects of the Invention].

[0010] The present invention can provide a pharmaceutical composition containing leboresen, which exhibits good dissolution distribution by using 90% of the powder particles with a cumulative diameter (D90) of less than 64 μm as the active pharmaceutical ingredient of leboresen.

Implementation Method

[0011] The following explains the meaning of the symbols, terms, etc. recorded in this specification, and provides a detailed description of this specification.

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

[0013] Leibores can be manufactured by known methods, such as those described in International Publication No. 2012 / 039371 and International Publication No. 2013 / 123240.

[0014] The particle size of the active pharmaceutical ingredient of Leboresen affects the dissolution distribution in certain test solutions. Therefore, in the cumulative distribution (volume distribution) of particles, it is preferable to have 90% cumulative diameter (D90) of less than 64 μm.

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

[0016] The active pharmaceutical ingredient of Leboresen, manufactured according to the desired method, is sometimes a powder with 90% cumulative diameter (D90) greater than 64 μm. Therefore, the active pharmaceutical ingredient of Leboresen can be pulverized by known methods. Pulverization is not particularly limited, and for example, a plate beater (100UPZ, 160UPZ) or a needle mill (100UPZ, 160UPZ) can be used.

[0017] In one embodiment of the present invention, by pulverizing the active pharmaceutical ingredient of Leboresen manufactured according to the desired method, as shown in Table 1, the active pharmaceutical ingredient of Leboresen can be made into powder particles with a cumulative diameter (D90) of 90% or less of 64 μm.

[0018] [Table 1] batch Particle size (D90 (μm)) 1 47 2 18 3 48 4 32 5 39 6 twenty three 7 40 8 35 9 34 average 35.1 Standard deviation 10.0 Average + upper limit of confidence interval a 65 a The upper limit of the confidence interval = 3 times the standard deviation of the batch analysis data

[0019] The particle size of the active pharmaceutical ingredient (API) of Leborex can be determined by laser diffraction scattering. The particle size determination can be performed under the following conditions: Approximately 30 mg of the API of Leborex is dispersed in 50 mL of a 0.1% polysorbate 20 aqueous solution to prepare a sample suspension. The sample suspension is then placed in a diffraction apparatus, and an appropriate amount of dispersing solvent is added. The particle size distribution of the sample suspension is determined, and the particle size values ​​are recorded as a cumulative diameter distribution. The particle size distribution determination conditions of the diffraction apparatus can be set as follows: Flow rate: 50%; Number of measurements: 3; Measurement time: 30 seconds; Shape: Non-spherical; Penetration: Penetrating particles; Refractive index: 1.81; Solvent refractive index: 1.33.

[0020] In one embodiment of the present invention, the pharmaceutical composition contains leboresen and one or more pharmaceutically acceptable additives, wherein the active pharmaceutical ingredient of leboresen is a powder with a 90% cumulative diameter (D90) of 64 μm or less. The pharmaceutical composition can be manufactured by mixing the pharmaceutically acceptable additive with the active pharmaceutical ingredient of leboresen, which is a powder with a 90% cumulative diameter (D90) of 64 μm or less. The pharmaceutical composition of the present invention can be manufactured, for example, by known methods such as those described in the General Principles of Formulations of the Sixteenth Revision of the Japanese Pharmacopoeia.

[0021] In one embodiment of the present invention, the additives include excipients, disintegrants, lubricants, surfactants, sweeteners, flavorings, stabilizers, fluidizing agents, etc., but are not limited to these.

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

[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 contains 2.5 mg to 10 mg of leboresen. The content of leboresen in the pharmaceutical composition may be set to 2.5 mg, 5 mg, or 10 mg.

[0025] In this specification, the dissolution test can be performed according to the stirred paddle method described in the Japanese Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia (e.g., the stirred paddle method specified in Section 6.10 Dissolution Test Method of the Sixteenth Revision of the Japanese Pharmacopoeia) under the following conditions: Apparatus: Stirred paddle apparatus; Test solution volume: 900 mL; Test solution temperature: 37℃ ± 0.5℃; Test solution: 0.1 mol / L hydrochloric acid, Dissolution Test Solution 1 of the Sixteenth Revision of the Japanese Pharmacopoeia (pH 1.2), diluted McIlvaine buffer (pH 5.0), Dissolution Test Solution 2 of the Sixteenth Revision of the Japanese Pharmacopoeia (pH 6.8), or water; Stirred paddle speed: 50 rpm or 100 rpm; Dissolution Test Solution 1 refers to a solution obtained by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to make 1000 mL of solution; Dissolution Test Solution 2 refers to a solution obtained by adding 1 volume of water to 1 volume of phosphate buffer at pH 6.8.

[0026] In one embodiment of the present invention, the pharmaceutical composition contains leboresen and one or more pharmaceutically acceptable additives. The pharmaceutical composition is manufactured using leboresen active pharmaceutical ingredient, which is a powder with a cumulative diameter (D90) of 90% or less. The pharmaceutical composition is prepared by stirring with a paddle device (speed: 50 rpm) in a test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃ ± 0.5℃). The dissolution rate of leboresen is shown to be 50% or more within 15 minutes after the start of the dissolution test.

[0027] In one embodiment of the present invention, the pharmaceutical composition contains leboresen and one or more pharmaceutically acceptable additives. The pharmaceutical composition is manufactured using leboresen active pharmaceutical ingredient, which is a powder with a cumulative diameter (D90) of less than 64 μm in 90% of its components. The pharmaceutical composition is prepared by a stirring paddle method using a stirring paddle device (speed: 50 rpm) in a test solution (water, 900 mL, 37℃ ± 0.5℃). The dissolution rate of leboresen is shown to be more than 50% within 15 minutes after the start of the dissolution test.

[0028] In one embodiment of the present invention, the pharmaceutical composition contains leboresen and one or more pharmaceutically acceptable additives. The pharmaceutical composition is manufactured using leboresen active pharmaceutical ingredient, which is a powder with a cumulative diameter (D90) of 90% or less. The pharmaceutical composition is prepared by stirring with a stirring device (speed: 100 rpm) in a test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃ ± 0.5℃). The dissolution rate of leboresen is shown to be 50% or more within 15 minutes after the start of the dissolution test.

[0029] In one embodiment of the present invention, the pharmaceutical composition contains leboresen and one or more pharmaceutically acceptable additives. The pharmaceutical composition is manufactured using leboresen active pharmaceutical ingredient, which is a powder with a cumulative diameter (D90) of less than 64 μm in 90% of its components. The pharmaceutical composition is tested using a stirring paddle method with a stirring paddle device (speed: 50 rpm) in a test solution (0.1 mol / L hydrochloric acid, 900 mL, 37℃ ± 0.5℃). The dissolution rate of leboresen is shown to be greater than 80% within 15 minutes after the start of the dissolution test.

[0030] In one embodiment of the present invention, the pharmaceutical composition contains leboresen and one or more pharmaceutically acceptable additives. Using a stirring paddle method with a stirring paddle device (speed: 50 rpm), in the test solution (0.1 mol / L hydrochloric acid, 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen shows more than 80% within 15 minutes after the start of the dissolution test, and in the test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃ ± 0.5℃), the dissolution rate of leboresen shows more than 50% within 15 minutes after the start of the dissolution test.

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

[0032] In one embodiment of the present invention, the dosage of leboresen varies depending on the severity of symptoms, age, sex, weight, form of administration / salt type, specific type of disease, etc. Typically, adults take 2.5 mg to 10 mg orally daily, or a choice of 2.5 mg, 5 mg, or 10 mg. [Embodiment]

[0033] Hereinafter, the present invention will be described in detail by way of embodiments. However, the present invention is not limited to these embodiments. In addition, the abbreviations used below are commonly used abbreviations known to those skilled in the art, and some abbreviations are shown below.

[0034] The chemical shifts in the proton nuclear magnetic resonance (1H-NMR) spectra are recorded in δ units (ppm) relative to tetramethylsilane, and the coupling constants are recorded in Hertz (Hz). Regarding the spectral type, s refers to a singlet, d to a doublet, br to a broad peak, and m to a multiplet.

[0035] The 1H-NMR spectrum and 13C-NMR spectrum were measured using a Varian 400 or 500 MHz spectrometer, or a JNM-AL400 nuclear magnetic resonance device (400 MHz) manufactured by Nippon Electronics Co., Ltd.

[0036] In the following embodiments, "room temperature" generally means about 10°C to about 35°C. Unless otherwise specified, % means weight percentage.

[0037] The Leiboresen of the present invention is manufactured using the methods described below. The compound of formula A can be manufactured, for example, using the manufacturing methods described in International Publication No. 2012 / 039371 or International Publication No. 2013 / 123240.

[0038] Preparation of (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropylmethylmethylamine (Leboresen) [Chemical 2] (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropylcarboxylic acid (62.4 kg, 197 mol, 1.00 equivalent), 5-fluoropyridin-2-amine (24.3 kg, 217 mol, 1.10 equivalent), ethyl acetate (499 L), N,N-diisopropylethylamine (53.5 kg, 414 mol, 2.10 equivalent), 1-propylphosphonic anhydride (50% ethyl acetate solution) (188 kg, 296 L) A mixture of 1 mol (1.50 equivalents) was heated at an external temperature of 70°C, and the reaction was confirmed to be complete by HPLC (High Performance Liquid Chromatography). After the reaction solution cooled, 312 L of purified water was added and stirred, then allowed to stand. After the aqueous layer was removed, an aqueous solution of sodium carbonate (68.9 kg sodium carbonate and 312 L of purified water) was added to the organic layer and stirred, then allowed to stand. After the aqueous layer was removed, 187 L of purified water was added to the organic layer and stirred, then allowed to stand. After the aqueous layer was removed, 187 L of purified water was added to the organic layer and stirred, then allowed to stand. After the aqueous layer was removed, the organic layer was filtered. The clarified filter line was rinsed with ethyl acetate, and a portion of the solvent was removed by distillation under reduced pressure. Ethyl acetate was added to the concentrated residue (containing 75.3 kg of leboresen) to bring the total volume to 256 L. The resulting mixture was heated and dissolved under stirring at an external temperature of 60 °C. Then, n-heptane (12.8 kg) was added, and the mixture was cooled to below 45 °C. Ethyl acetate (31 L) was added, and after cooling to below 35 °C, n-heptane (670 kg) was added. The suspension was then cooled to below 10 °C, filtered, and the solids in the mixture were removed and washed with a mixture of ethyl acetate and n-heptane. The obtained solids were dried under reduced pressure at an external temperature below 60 °C to obtain leboresen (70 kg) in 87% yield.

[0039] HPLC conditions used to confirm the above reaction: Reagents and mobile phase: • Purified water • Acetonitrile (Kanto Chemical Catalog No. 01031-2B for HPLC or equivalent) • Trifluoroacetic acid (Wako Pure Chemical Industries Catalog No. 208-02741, premium grade reagent or equivalent) • Mobile phase A: Water / trifluoroacetic acid mixture (1000 / 1, v / v) • Mobile phase B: Acetonitrile / trifluoroacetic acid mixture (1000 / 1, v / v) • Dissolving solution: Water / acetonitrile / trifluoroacetic acid mixture (500 / 500 / 1, v / v / v) • HPLC apparatus needle wash solution: Water / acetonitrile mixture (100 / 900, v / v) • Dissolving solution: Water / acetonitrile mixture (1 / 1, v / v) (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)cyclopropylcarboxylic acid) standard HPLC conditions Detector: Shimadzu SPD-20A UV spectrophotometer (measurement wavelength: 283 nm) or equivalent Column: A 3.5 μm octadecylsilylated silicone column packed in a 4.6 mm inner diameter, 15 cm length stainless steel tube, such as: SunFire C18 (Waters) (equivalent to USP packing L1) Column temperature: A constant temperature of approximately 40°C Mobile phase: Solution A: Water / trifluoroacetic acid mixture (1000 / 1, v / v) Solution B: Acetonitrile / trifluoroacetic acid mixture (1000 / 1, v / v) Flow rate: A constant flow rate gradient of approximately 1.0 mL / min Time (min) Ratio of mobile phase B (%) 0 5 > Linear gradient 7 30 20 30 > Linear gradient 34 100 39 100 39.01 5 50 Stop injection volume: 5 μL Sample rack temperature: a certain temperature around 10℃ Needle flushing solution: water / acetonitrile mixture (10 / 90, v / v) Area measurement range: approximately 34 minutes

[0040] NMR Data (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropylmethylamine: 1H NMR (500 MHz, DMSO-d6) 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); 13C NMR (125 MHz, DMSO-d6) 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] Implementation Method 1: Preparation of Leboresen Active Pharmaceutical Ingredients with Various Particle Sizes Using unground Leboresen active pharmaceutical ingredient, multiple Leboresen active pharmaceutical ingredients with different particle sizes were prepared by varying the rotation speed of a 160 UPZ (plate mill, needle mill). 1 kg of unground Leboresen active pharmaceutical ingredient was weighed in advance in a container and fed into a pulverizer (160 UPZ plate mill, 1 mm mesh screen) while timing with a stopwatch. The feeding was done manually with a shovel. The process was carried out at rotation speeds of 4000, 5600, 8000, and 9500 rpm and a feed rate of 10 kg / h (batches S1, S2, S3, S4, S6). However, batch S6 was prepared by first grinding (batch S5) at 5600 rpm and 60 kg / h, followed by grinding at 5600 rpm using a 160UPZ needle mill, and then further grinding at 10000 rpm. The grinding conditions and the obtained 90% cumulative diameter (D90) after grinding are summarized in Table 2. The 90% cumulative diameter (D90) was determined using a particle size analyzer (Microtrac MT3300EXII). Approximately 30 mg of leboresen active pharmaceutical ingredient was dispersed in 50 mL of a 0.1% polysorbate 20 aqueous solution to prepare a sample suspension. The sample suspension was added to the particle size analyzer, along with an appropriate amount of dispersing solvent. The particle size distribution of the sample suspension was measured, and the particle size values ​​were recorded as a cumulative diameter distribution. The particle size analyzer measurement conditions are as follows. Flow rate: 50% Number of measurements: 3 Measurement time: 30 seconds Shape: Non-spherical Penetration: Penetrating particles Refractive index: 1.81 Solvent refractive index: 1.33

[0042] [Table 2] batch Rotational 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] Effect 2: Manufacturing of Leboresen 2.5 mg and 10 mg tablets Using the batches (S1, S2, S3, S4, S6) obtained in Effect 1, Leboresen 2.5 mg and 10 mg tablets were manufactured. The composition and components of the manufactured tablets are shown in Table 3.

[0044] [Table 3] Composition, ingredients, and batch size of Leboresen 2.5 mg and 10 mg tablets Constituents Quantity 2.5 mg 10 mg mg / tablet g / batch mg / tablet g / batch Granulation section Leibo Reson 2.5 27.08 10.0 108.3 lactose hydrate 96.38 1044.12 88.88 962.87 Low-substitution hydroxypropyl cellulose 10.8 117.0 10.8 117.0 Hydroxypropyl cellulose 3.6 39.0 3.6 39.0 Purified water qs 163 qs 163 External additions Low-substitution degree hydroxypropyl cellulose 6.0 65.0 6.0 65.0 magnesium stearate 0.72 7.8 0.72 7.8 gross weight 120.0 1300.0 120.0 1300.0

[0045] Leboresen 2.5 mg and 10 mg tablets are manufactured via mixing, granulation, drying, sizing, mixing, and tableting steps. The active pharmaceutical ingredient of Leboresen, lactose hydrate, and low-substituted hydroxypropyl cellulose are added to a stirred granulator and mixed for 5 minutes. A liquid prepared by dissolving hydroxypropyl cellulose in purified water is added to the stirred granulator containing the obtained mixture, and granulation is carried out for 3 minutes. The resulting wet granules are dried using a fluidized bed dryer (feed temperature 70°C) until the exhaust temperature exceeds 38°C. The resulting dried granules are sizing using a granulator with a 1.0 mm sieve diameter. Low-substituted hydroxypropyl cellulose and magnesium stearate are weighed according to the granule yield. The dried granules, low-substituted hydroxypropyl cellulose, and magnesium stearate are added to a drum mixer and mixed for 16 minutes. The obtained mixture is tableted using a tableting machine at a tableting pressure of 1150 kgf to obtain tablets.

[0046] Implementation Method 3: Dissolution Test (1) Apparatus and Materials The apparatus and materials used for the dissolution test are listed in Table 4.

[0047] [Table 4] Equipment and materials project Equipment and materials device Dissolution system (device 2): Evolution 6100 (DISTEK) HPLC system: LC-2010C HT (Shimadzu Corporation) Chemical balance Material Acetonitrile (HPLC grade) 70% perchloric acid (analytical grade) 0.1 mol / L hydrochloric acid Dissolution test solution 1 (Japanese Pharmacopoeia, 16th revised edition) The diluted McIlvaine buffer (pH 5.0) listed in the Japanese guidelines for bioequivalence testing Dissolution test solution 2 (Japanese Pharmacopoeia, 16th revised edition) Purified water

[0048] (2) The dissolution test conditions are shown in Table 5. Each test was conducted using 6 or 12 tablets manufactured by the method described in Embodiment 2.

[0049] [Table 5] Dissolution test conditions device rotational speed test solution Liquid volume temperature Device 2 (Agitator) 50 rpm 0.1 mol / L hydrochloric acid 900 mL 37℃ ± 0.5℃ pH 1.2 (Dissolution test solution 1 (Japanese Pharmacopoeia 16th Revision)) pH 5.0 (diluted McIlvaine buffer) pH 6.8 (Dissolution test solution 2 (Japanese Pharmacopoeia 16th Revision)) water 100 rpm pH 6.8 (Dissolution test solution 2 (Japanese Pharmacopoeia 16th Revision))

[0050] (3) The dissolution test of the analytical procedure was performed using the stirring apparatus listed in the 16th revised edition of the Japanese Pharmacopoeia. For the tablets, 900 mL of 0.1 mol / L hydrochloric acid, dissolution test solution 1 (pH 1.2), diluted McIlvaine buffer, dissolution test solution 2 (pH 6.8), or water was used as the test solution, and the test was performed at a stirring speed of 50 rpm or 100 rpm. A certain amount of the test solution was filtered and removed at a specified time point. The standard solution was prepared to have a leboresen concentration corresponding to the usual concentration of the sample solution. The amount of leboresen released was determined by HPLC or UV-Vis absorbance determination. The HPLC conditions and UV-Vis absorbance determination conditions are as follows. <HPLC Conditions> Detector: UV spectrophotometer (measurement wavelength: 283 nm) Column: 4.6 mm inner diameter, 7.5 cm length (YMC-Triart C18 (YMC)) Packing material: 3 μm octadecylsilylated silica gel column for HPLC Temperature: 40℃ 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℃ Analysis time: 5 minutes <Conditions for UV-Vis absorbance determination (only for 0.1 mol / L hydrochloric acid)> Measurement wavelength: 233 nm and 400 nm Control: Test solution

[0051] (4) Results The test was conducted with 6 or 12 tablets, and their average values ​​are shown. The results of the dissolution test of Leborresen 2.5 mg and 10 mg tablets using 0.1 mol / L hydrochloric acid as the test solution are shown in Tables 6 and 7 and Figure 1. Regardless of the particle size and content of the Leborresen active pharmaceutical ingredient, all tablets were completely dissolved within 15 minutes in 0.1 mol / L hydrochloric acid.

[0052] [Table 6] Dissolution distribution of Leborex 2.5 mg tablets in 0.1 mol / L hydrochloric acid (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 20 minutes 30 minutes 98μm 81.0 95.8 96.9 97.1 97.0 79μm 79.4 95.2 97.5 97.6 97.4 64μm 82.4 97.6 99.8 100.0 100.7 56μm 82.3 96.8 98.5 98.3 98.3 20μm 81.8 97.8 100.0 100.1 100.5

[0053] [Table 7] Dissolution distribution of Leborex 10 mg tablets in 0.1 mol / L hydrochloric acid (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 20 minutes 30 minutes 98μm 80.3 95.3 96.8 96.7 96.7 79μm 79.1 94.8 96.8 96.7 96.7 64μm 82.7 97.6 99.9 99.8 99.8 56μm 78.8 94.3 97.1 97.0 96.9 20μm 82.1 98.4 101.0 100.9 100.9

[0054] The results of dissolution tests of Lebrex 2.5 mg tablets in different test solutions are shown in Tables 8-12 and Figures 2-4. Additionally, the results of dissolution tests of Lebrex 10 mg tablets in different test solutions are shown in Tables 13-17 and Figures 5-7. Furthermore, "N / T" in the following tables indicates Not Tested. Tablets with a particle size (D90) of 64 μm or less for both Lebrex 2.5 mg and 10 mg tablets showed good dissolution distribution in all test solutions. On the other hand, it was confirmed that tablets with a particle size (D90) of 79 μm and 98 μm for both Lebrex 2.5 mg and 10 mg tablets showed reduced dissolution rates (%) in diluted McIlvaine buffer, dissolution test solution 2 (pH 6.8), and water. Therefore, it is demonstrated that by reducing the particle size (D90) of the active pharmaceutical ingredient (API) of Leboresen to 64 μm or less, good dissolution distribution can be achieved, providing a homogeneous pharmaceutical composition. Furthermore, the dissolution test in Embodiment 3, as described in the <711> Dissolution section of the United States Pharmacopeia (USP42), is a standardized test method in the Japanese Pharmacopoeia, the United States Pharmacopeia, and the European Pharmacopoeia. Based on this test method, good dissolution distribution was confirmed for both 2.5 mg and 10 mg tablets. Since the 2.5 mg and 10 mg tablets are formulations that replace the difference in the amount of API in one tablet with lactose hydrate, it is expected that, according to the parenthesis, 2.5 mg to 10 mg tablets, such as 5 mg tablets, will also exhibit similarly good dissolution distribution.

[0055] [Table 8] Dissolution distribution of Leboresen 2.5 mg tablets at pH 1.2 (dissolution test solution 1 (Japanese Pharmacopoeia)) (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm N / T N / T N / T N / T N / T N / T 79μm N / T N / T N / T N / T N / T N / T 64μm 85.0 98.5 100.5 100.6 100.2 N / T 56μm 83.3 98.5 100.1 100.2 100.3 N / T 20μm 80.9 97.2 99.9 99.4 99.7 N / T

[0056] [Table 9] Dissolution profile of Leborex 2.5 mg tablets at pH 5.0 (diluted McIlvaine buffer) (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm 19.3 32.1 40.8 55.0 63.1 68.3 79μm 21.7 35.9 45.6 60.6 68.4 73.3 64μm 31.0 48.0 59.0 75.2 82.5 86.9 56μm 30.3 49.1 60.7 76.8 83.6 87.5 20μm 38.8 63.9 77.4 92.1 95.8 96.8

[0057] [Table 10] Dissolution distribution of Leboresen 2.5 mg tablets at pH 6.8 (dissolution test solution 2 (Japanese Pharmacopoeia)) (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm 22.0 34.2 42.3 55.8 63.5 68.6 79μm 24.0 38.5 47.7 62.6 70.6 75.8 64μm 32.9 50.8 61.6 77.1 84.1 88.1 56μm 34.6 53.5 64.3 78.7 84.8 88.3 20μm 41.8 67.0 79.7 92.9 96.3 97.3

[0058] [Table 11] Dissolution distribution of Leborex 2.5 mg tablets in water (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm 20.7 34.6 43.4 57.0 64.3 69.0 79μm 23.9 39.2 48.7 63.2 70.6 75.3 64μm 34.9 54.9 66.4 81.2 87.3 90.5 56μm 37.6 57.7 68.5 82.0 87.2 89.9 20μm 40.2 69.5 83.7 96.6 99.5 100.1

[0059] [Table 12] Dissolution distribution of Leboresen 2.5 mg tablets at pH 6.8 (dissolution test solution 2 (Japanese Pharmacopoeia)) (100 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm N / T N / T N / T N / T N / T N / T 79μm N / T N / T N / T N / T N / T N / T 64μm 43.4 59.5 68.9 83.0 89.3 92.8 56μm 45.9 61.8 70.9 84.1 89.8 92.9 20μm 55.0 76.3 86.0 96.9 99.6 100.4

[0060] [Table 13] Dissolution distribution of Leboresen 10 mg tablets at pH 1.2 (dissolution test solution 1 (Japanese Pharmacopoeia)) (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm N / T N / T N / T N / T N / T N / T 79μm N / T N / T N / T N / T N / T N / T 64μm 82.2 98.3 100.7 100.6 100.7 N / T 56μm 76.8 94.4 97.2 97.3 97.2 N / T 20μm 82.2 99.1 101.9 101.8 101.8 N / T

[0061] [Table 14] Dissolution profile of Leborex 10 mg tablets at pH 5.0 (diluted McIlvaine buffer) (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm 15.2 27.0 34.7 46.9 54.1 58.9 79μm 15.3 28.0 36.5 49.5 57.1 62.1 64μm 22.6 37.8 47.6 62.7 70.9 76.2 56μm 24.0 40.1 50.1 64.7 72.2 76.9 20μm 29.0 51.4 64.1 80.4 87.8 92.0

[0062] [Table 15] Dissolution distribution of Leboresen 10 mg tablets at pH 6.8 (dissolution test solution 2 (Japanese Pharmacopoeia)) (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm 18.2 29.9 37.4 50.0 57.4 62.1 79μm 20.1 32.4 40.2 53.0 60.3 65.4 64μm 24.8 41.3 51.7 66.7 74.6 79.7 56μm 25.6 43.2 53.4 67.7 75.0 79.4 20μm 29.3 54.6 68.2 84.2 90.2 94.1

[0063] [Table 16] Dissolution distribution of Leborex 10 mg tablets in water (50 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm N / T N / T N / T N / T N / T N / T 79μm N / T N / T N / T N / T N / T N / T 64μm 25.7 41.8 51.5 66.1 73.7 78.5 56μm 26.8 44.1 54.0 67.7 74.5 78.6 20μm 31.9 57.0 69.7 85.0 91.5 94.8

[0064] [Table 17] Dissolution distribution of Lebrrazan 10 mg tablets at pH 6.8 (dissolution test solution 2 (Japanese Pharmacopoeia)) (100 rpm) Particle size (D90) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 98μm N / T N / T N / T N / T N / T N / T 79μm N / T N / T N / T N / T N / T N / T 64μm 34.4 48.8 57.8 72.4 80.3 85.5 56μm 32.4 49.2 58.4 72.2 79.3 83.8 20μm 37.2 61.8 73.0 87.5 94.0 97.5

[0065] Implementation Method 4: Manufacturing of Leboresen 2.5 mg, 5 mg and 10 mg tablets The constituent components and composition of the manufactured tablets are shown in Table 18.

[0066] [Table 18] Composition, ingredients, and batch size of Leboresen 2.5 mg, 5 mg, and 10 mg tablets Constituents Quantity 2.5 mg 5 mg 10 mg mg / tablet kg / lot mg / tablet kg / lot mg / tablet kg / lot Granulation section Leibo Reson 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-substitution degree 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 qs 3.68 qs 2.88 qs 2.88 External additions Low-substitution degree 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 gross weight 120.0 120.0 120.0

[0067] Leboresen 2.5 mg, 5 mg and 10 mg tablets are manufactured by mixing, granulation, drying, sizing, mixing and tableting steps. The active pharmaceutical ingredient (32 μm (D90)) of Leboresen, lactose hydrate and low-substituted hydroxypropyl cellulose are added to a stirred granulator and mixed for 5 minutes. A solution of hydroxypropyl cellulose dissolved in purified water is added to the stirred granulator containing the obtained mixture, and granulation is carried out for 3 minutes. The resulting wet granules are dried using a fluidized bed dryer (supply air temperature 70°C) until the exhaust temperature is above 40°C. The resulting dried granules are sizing using a granulator with a sieve diameter of 0.8 mm. Low-substituted hydroxypropyl cellulose and magnesium stearate are weighed according to the granule yield. The dried granules, low-substituted hydroxypropyl cellulose and magnesium stearate are added to a drum mixer and mixed for 14 minutes. The obtained mixture was compressed into tablets using a tableting machine at compression pressures of 700 kgf, 1150 kgf, and 1600 kgf to obtain tablets.

[0068] Implementation 5: Dissolution test (1) Apparatus and materials The apparatus and materials used for the dissolution test are listed in Table 19.

[0069] [Table 19] project Equipment and materials device Dissolution system (device 2): Evolution 6100 (DISTEK) UV-1700 UV-Vis spectrophotometer (Shimadzu Corporation) Chemical balance Material Acetonitrile (HPLC grade) 0.1 mol / L hydrochloric acid

[0070] (2) The dissolution test conditions implemented are shown in Table 20. Each test was conducted using 6 tablets manufactured by the method described in Embodiment 4.

[0071] [Table 20] Dissolution test conditions device rotational speed test solution Liquid volume temperature Device 2 (stirring paddle) 50 rpm 0.1 mol / L hydrochloric acid 900 mL 37℃ ± 0.5℃

[0072] (3) The dissolution test of the analytical procedure was performed according to the stirring apparatus listed in the 16th revised edition of the Japanese Pharmacopoeia. For the tablets, 900 mL of 0.1 mol / L hydrochloric acid was used as the test solution, and the test was conducted at a stirring speed of 50 rpm. A certain amount of the test solution was filtered and removed at a specified time point. The standard solution was prepared to have a leboresen concentration corresponding to the usual concentration of the sample solution. The amount of leboresen released was determined by UV-Vis absorbance measurement. The conditions for UV-Vis absorbance measurement are as follows. <Conditions for UV-Vis absorbance measurement> Measurement wavelength: 233 nm and 400 nm Control: Test solution

[0073] (4) Results The test was conducted using 6 tablets, and their average values ​​are shown. The results of the dissolution test for 2.5 mg, 10 mg and 5 mg tablets of Leborraxen manufactured at different tableting pressures using 0.1 mol / L hydrochloric acid as the test solution are shown in Tables 21-23 and Figure 8.

[0074] [Table 21] Dissolution distribution of Leborexen 2.5 mg tablets manufactured under various compression pressures in 0.1 mol / L hydrochloric acid (50 rpm). Tableting pressure (kgf) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 20 minutes 30 minutes 45 minutes 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 distribution of Leborex 10 mg tablets manufactured under various compression pressures in 0.1 mol / L hydrochloric acid (50 rpm). Tableting pressure (kgf) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 20 minutes 30 minutes 45 minutes 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 distribution of Leborexin 5 mg tablets manufactured under various compression pressures in 0.1 mol / L hydrochloric acid (50 rpm). Tableting pressure (kgf) Dissolution rate (%) 5 minutes 10 minutes 15 minutes 20 minutes 30 minutes 45 minutes 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 the tableting pressure in the range of 700 kgf to 1600 kgf had no effect on the dissolution. [Simplified Explanation of the Diagram]

[0078] [Figure 1] Figures 1(a) and (b) show the results of the dissolution tests of Leborexin 2.5 mg and 10 mg tablets in 0.1 mol / L hydrochloric acid, as shown in Tables 6 and 7, respectively. [Figure 2] Figures 2(a) and (b) show the results of the dissolution tests of Leborexin 2.5 mg tablets in the test solution, as shown in Tables 8 and 9, respectively. [Figure 3] Figures 3(a) and (b) show the results of the dissolution tests of Leborexin 2.5 mg tablets in the test solution, as shown in Tables 10 and 12, respectively. [Figure 4] Figure 4 shows the results of the dissolution test of Leborexin 2.5 mg tablets in water, as shown in Table 11. [Figure 5] Figures 5(a) and (b) show the results of the dissolution tests of Leborexin 10 mg tablets in the test solution, as shown in Tables 13 and 14, respectively. [Figure 6] Figures 6(a) and (b) show the dissolution test results of Leborex 10 mg tablets in the test solution as shown in Tables 15 and 17, respectively. [Figure 7] Figure 7 shows the dissolution test results of Leborex 10 mg tablets in water as shown in Table 16. [Figure 8] Figures 8(a), (b), and (c) show the dissolution test results of Leborex 2.5 mg, 10 mg, and 5 mg tablets in the test solution as shown in Tables 21, 22, and 23, respectively.

Claims

1. A raw material for leboresen, wherein 90% of the cumulative diameter (D90) is granular material with a particle size of 20 μm or more and 64 μm or less.

2. A pharmaceutical composition comprising leboresen and pharmaceutically acceptable additives, said pharmaceutical composition being manufactured using a leboresen active pharmaceutical ingredient, said leboresen active pharmaceutical ingredient being 90% powder particles with a cumulative diameter (D90) of 20 μm to 64 μm.

3. For the pharmaceutical composition of claim 2, when using the stirrer method with a stirrer device (speed: 50 rpm) in the test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃±0.5℃), the dissolution rate of Leboresen is shown to be 50% or more within 15 minutes after the start of the dissolution test.

4. For the pharmaceutical composition of claim 2, when using the stir bar method with a stir bar device (speed: 50 rpm) in the test solution (water, 900 mL, 37℃±0.5℃), the dissolution rate of Leboresen is shown to be greater than 50% within 15 minutes after the start of the dissolution test.

5. For the pharmaceutical composition of claim 2, when using the stir bar method with a stir bar device (speed: 100 rpm) in the test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃±0.5℃), the dissolution rate of Leboresen is shown to be 50% or more within 15 minutes after the start of the dissolution test.

6. For the pharmaceutical composition of claim 2, when using the stir bar method with a stir bar device (speed: 50 rpm) in the test solution (0.1 mol / L hydrochloric acid, 900 mL, 37℃±0.5℃), the dissolution rate of Leboresen is shown to be above 80% within 15 minutes after the start of the dissolution test.

7. The pharmaceutical composition of any one of claims 2 to 6, wherein the pharmaceutical composition is a tablet.

8. Any pharmaceutical composition as described in any of claims 2 to 6, containing 2.5 mg to 10 mg of leboresen.

9. The pharmaceutical composition of claim 8 contains 10 mg of leboresen.

10. The pharmaceutical composition of claim 8 contains 5 mg of leboresen.

11. The pharmaceutical composition of claim 8 contains 2.5 mg of leboresen.

12. A pharmaceutical composition comprising leboresen and pharmaceutically acceptable additives, wherein the active pharmaceutical ingredient of leboresen is a powder with 90% cumulative diameter (D90) of 20 μm to 64 μm, and the dissolution rate of leboresen is greater than 80% within 15 minutes after the start of the dissolution test in a test solution (0.1 mol / L hydrochloric acid, 900 mL, 37℃ ± 0.5℃) using a stirring paddle device (speed: 50 rpm), and the dissolution rate of leboresen is greater than 50% within 15 minutes after the start of the dissolution test in another test solution (dissolution test solution 2 of the 16th revised edition of the Japanese Pharmacopoeia (pH 6.8), 900 mL, 37℃ ± 0.5℃).

13. A method for manufacturing a pharmaceutical composition, the pharmaceutical composition comprising leboresen and pharmaceutically acceptable additives, the method comprising the step of mixing a leboresen active pharmaceutical ingredient with pharmaceutically acceptable additives, wherein the leboresen active pharmaceutical ingredient is a powder with 90% cumulative diameter (D90) of 20 μm or more and 64 μm or less.

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