Pharmaceutical composition comprising sentanfardine

Abstract

The present invention relates to a pharmaceutical composition comprising (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo [3.1. 0] hexane (sentannalfane) or a pharmaceutically acceptable salt thereof as an active ingredient, and to a formulation comprising said pharmaceutical composition, which can be administered once a day.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, which comprises (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (centanafadine) or a pharmaceutically acceptable salt thereof as an active ingredient, and also relates to an oral solid preparation comprising the pharmaceutical composition, wherein the oral solid preparation can be administered once a day. Background Art

[0002] (1R,5S)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is able to inhibit the reuptake of three biogenic amines: norepinephrine, serotonin, and dopamine (PL1).

[0003] (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is most effective for norepinephrine (NE) reuptake, but 6 times less effective for dopamine (DA) reuptake and 14 times less effective for serotonin (5-HT) reuptake. Therefore, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is a compound that can be used as an unbalanced triple reuptake inhibitor (TRI). Based on these actions, the compounds of the present invention can be used as therapeutic agents for CNS disorders such as depression, anxiety and attention deficit hyperactivity disorder (ADHD).

[0004] Recently, for the use of drugs in the treatment of CNS disorders such as depression, anxiety and attention deficit hyperactivity disorder (ADHD), once-daily oral administration is recommended. Pharmaceutical compositions suitable for once-daily oral administration have been developed, for example, pharmaceutical preparations comprising a variety of drug-containing granules have been developed, which are prepared with delayed-release (enteric-coated) granules, sustained-release granules and / or immediate-release granules.

[0005] Citations

[0006] Patent Literature

[0007] [PL 1] JP 5184354 B Summary of the invention

[0008] Technical issues

[0009] One of the problems to be solved by the present invention is to provide a pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (sentanafidine, hereinafter also referred to as "compound (I)") or a salt thereof, which is suitable for once-daily oral administration.

[0010] Technical Solutions

[0011] The present inventors conducted extensive studies to solve the above problems and found that a pharmaceutical composition suitable for maintaining sustained absorption in the lower digestive tract can be prepared by coating core particles comprising compound (I) or a salt thereof with at least two types of polymers.

[0012] The present invention includes the following embodiments.

[0013] (Item 1)

[0014] A pharmaceutical composition comprising a core particle having a coating layer, wherein the core particle comprises (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a salt thereof as an active ingredient, and wherein the coating layer comprises at least two types of polymers.

[0015] (Item 2)

[0016] The pharmaceutical composition of item 1, wherein the two types of polymers are an enteric polymer and a sustained-release polymer.

[0017] (Item 3)

[0018] The pharmaceutical composition of item 2, wherein the enteric polymer is methacrylic acid copolymer LD.

[0019] (Item 4)

[0020] The pharmaceutical composition of item 2 or 3, wherein the sustained-release polymer comprises one or more polymers selected from the group consisting of alkyl cellulose, acrylic acid polymers, acrylic acid copolymers, vinyl acetate polymers and cellulose ethers.

[0021] (Item 5)

[0022] The pharmaceutical composition of item 4, wherein the sustained-release polymer comprises one or more polymers selected from the group consisting of alkyl cellulose and acrylic acid copolymers.

[0023] (Item 6)

[0024] The pharmaceutical composition of item 5, wherein the alkyl cellulose is ethyl cellulose.

[0025] (Item 7)

[0026] The pharmaceutical composition of Item 5, wherein the acrylic acid copolymer is an ethyl acrylate-methyl methacrylate copolymer.

[0027] (Item 8)

[0028] The pharmaceutical composition of item 2, wherein the enteric polymer is methacrylic acid copolymer LD, and wherein the sustained-release polymer is ethylcellulose.

[0029] (Item 9)

[0030] The pharmaceutical composition of item 2, wherein the enteric polymer is methacrylic acid copolymer LD, and wherein the sustained-release polymer is ethyl acrylate-methyl methacrylate copolymer.

[0031] (Item 10)

[0032] The pharmaceutical composition of any one of items 1 to 9, wherein the coating layer consists of multiple layers.

[0033] (Item 11)

[0034] The pharmaceutical composition of item 10, wherein the coating layer consists of two coating layers: a coating layer comprising an enteric polymer and a coating layer comprising a sustained-release polymer, wherein the coating layer of the enteric polymer covers the coating layer of the sustained-release polymer.

[0035] (Item 12)

[0036] The pharmaceutical composition of item 11, wherein in the case of multiple coating layers, the amount of the sustained-release polymer is from about 2 wt % to about 40 wt %, or from about 5 wt % to about 15 wt %, or from about 8 wt % to about 12 wt %, or about 10 wt %, based on the total weight of the core particle or the seal-coated core particle.

[0037] (Item 13)

[0038] The pharmaceutical composition of item 11 or 12, wherein in the case of a multi-layer coating layer, the amount of the enteric polymer is from about 10 wt % to about 50 wt %, or from about 10 wt % to about 40 wt %, or from about 15 wt % to about 30 wt %, or from about 15 wt % to about 25 wt %, based on the total weight of the core particle or the seal-coated core particle.

[0039] (Item 14)

[0040] The pharmaceutical composition of any one of items 1 to 9, wherein the coating layer consists of a single layer.

[0041] (Item 15)

[0042] The pharmaceutical composition of Item 14, wherein the single coating layer comprises a sustained-release polymer and an enteric polymer.

[0043] (Item 16)

[0044] The pharmaceutical composition of item 15, wherein in the case of a single coating layer, the amount of the sustained-release polymer is from about 2 wt % to about 40 wt %, or from about 5 wt % to about 15 wt %, or from about 6 wt % to about 13 wt %, based on the total weight of the core particle or the seal-coated core particle.

[0045] (Item 17)

[0046] The pharmaceutical composition of item 15 or 16, wherein in the case of a single coating layer, the amount of the enteric polymer is from about 10 wt % to about 50 wt %, or from about 15 wt % to about 40 wt %, or from about 20 wt % to about 40 wt %, based on the total weight of the core particle or the seal-coated core particle.

[0047] (Item 18)

[0048] The pharmaceutical composition of any one of items 15 to 17, wherein the weight ratio of the sustained release polymer to the enteric polymer in the coating layer is 1:1 to 1:5.

[0049] (Item 19)

[0050] The pharmaceutical composition of Item 18, wherein the weight ratio of the sustained-release polymer to the enteric polymer in the coating layer is 1:3.

[0051] (Item 20)

[0052] The pharmaceutical composition of any one of items 1 to 19, wherein the core particles are seal coated.

[0053] (Item 21)

[0054] The pharmaceutical composition of any one of items 1 to 20, wherein the core particles having the coating layer are delayed-release (enteric-coated) particles.

[0055] (Item 22)

[0056] The pharmaceutical composition of any one of items 1 to 21, wherein the active ingredient is (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

[0057] (Item 23)

[0058] The pharmaceutical composition of any one of items 1 to 22, which satisfies the following conditions:

[0059] When the pharmaceutical composition is tested according to the basket apparatus in the Japanese Pharmacopoeia dissolution test at 37°C ± 0.5°C at 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours and then in 900 mL of pH 7.4 buffer solution for 10 hours,

[0060] a) less than 10% of the active ingredient is released at 2 hours, and

[0061] b) 80% or more of the active ingredient is released between 4 and 12 hours.

[0062] (Item 24)

[0063] The pharmaceutical composition of any one of items 1 to 22, which satisfies the following conditions:

[0064] When the pharmaceutical composition is tested according to the basket apparatus in the Japanese Pharmacopoeia dissolution test at 37°C ± 0.5°C at 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours and then in 900 mL of pH 7.4 buffer solution for 10 hours,

[0065] a) less than 10% of the active ingredient is released at 2 hours,

[0066] b) at 4 hours, 30% to 70% of the active ingredient is released, and

[0067] c) At 12 hours, 80% or more of the active ingredient is released.

[0068] (Item 25)

[0069] The pharmaceutical composition of any one of items 1 to 24, which is used for preventing and / or treating central nervous system (CNS) disorders.

[0070] (Item 26)

[0071] The pharmaceutical composition of item 25, wherein the central nervous system (CNS) disorder is at least one CNS disease selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; mood disorders; psychotic disorders; mood disorders; bipolar disorder; mania; depression; endogenous depression; major depressive disorder; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; anxiety disorder; somatoform disorder; factitious disorder; dissociative disorder; sexual disorder; eating disorder; sleep disorder; adaptive disorder disorders; substance-related disorders; anhedonia; delirium; cognitive impairment; Alzheimer's disease; Parkinson's disease; cognitive impairment associated with other neurodegenerative diseases; BPSD associated with dementia; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette's disorder; tic disorder; attention deficit hyperactivity disorder; conduct disorder; borderline personality disorder; nicotine-related disorders; bulimia; Down syndrome.

[0072] (Item 27)

[0073] Use of the pharmaceutical composition of any one of items 1 to 24 in the manufacture of a medicament for preventing and / or treating a central nervous system (CNS) disorder.

[0074] (Item 28)

[0075] An oral solid preparation comprising the pharmaceutical composition of any one of items 1 to 26.

[0076] (Item 29)

[0077] The oral solid preparation of item 28, which is a granule or a capsule.

[0078] (Item 30)

[0079] The oral solid preparation of item 28 or 29 further comprises sustained-release granules containing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a salt thereof and / or immediate-release granules containing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a salt thereof.

[0080] Effects of the Invention

[0081] The pharmaceutical composition of the present invention comprising the core particles with a coating layer is designed as delayed-release (enteric-coated) particles suitable for maintaining sustained absorption of compound (I) or a salt thereof in the lower digestive tract. The oral solid preparation comprising the pharmaceutical composition of the present invention can be used in the form of capsules or granules.

[0082] In addition, the pharmaceutical composition of the present invention can be used in combination with another sustained-release granule containing compound (I) or a salt thereof and / or an immediate-release granule containing compound (I) or a salt thereof. In addition, the pharmaceutical composition of the present invention combined with other sustained-release granules and / or immediate-release granules can be used as a capsule or granule. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The results of the dissolution test conducted on the granules prepared in Example 4-1 and Example 4-2 in Example 5 are shown.

[0084] Figure 2 The results of the dissolution test conducted on the granules prepared in Example 7-1 and Example 7-2 in Example 8 are shown.

[0085] Figure 3 The results of the dissolution test conducted on the granules prepared in Example 9-1 and Example 9-2 in Example 10 are shown.

[0086] Figure 4The results of the dissolution test conducted in Comparative Example 2 on the granules prepared in Comparative Examples 1-1 to 1-3 are shown. DETAILED DESCRIPTION

[0087] The terms and the like used in this document are explained below.

[0088] The pharmaceutical composition comprising the core particles having a coating layer of the present invention is designed as delayed-release (enteric-coated) particles suitable for maintaining sustained absorption of Compound (I) or a salt thereof in the lower digestive tract.

[0089] The pharmaceutical composition encompassed by the present invention comprises (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane [compound (I)] or a salt thereof as an active ingredient, which is hereinafter referred to as compound (I). Compound (I) may be in any form, such as a free form or a pharmaceutically acceptable salt form. The salt of compound (I) is not limited as long as it is a pharmaceutically acceptable salt, and preferably includes, for example, its acid addition salt, and more preferably includes, for example, the hydrochloride of compound (I).

[0090] [Chemical formula 1]

[0091] .

[0092] As used herein, compound (I) or its salt should be understood to cover the compound in crystalline form or amorphous form, including polymorphs, solvates including hydrates, ansolvates, conformational polymorphs, and mixtures thereof. In the present invention, "crystalline form" and "polymorph" are sometimes used interchangeably, and unless otherwise specified, the present invention is intended to cover all compounds of compound (I) or its salt in free form or in the form of a pharmaceutically acceptable salt, including polymorphs, solvates including hydrates, ansolvates, conformational polymorphs, and mixtures thereof. In addition, compound (I) or its salt covers its isomers, such as geometric isomers, stereoisomers and optical isomers.

[0093] The pharmaceutical composition comprising core particles with a coating layer of the present invention is designed as delayed-release (enteric) particles, and the delayed-release (enteric) particles have an inner core and an outer layer, wherein the inner core is "core particles comprising compound (I) or a salt thereof", and the outer layer is "coating layer comprising at least two types of polymers". The core particles comprising compound (I) or a salt thereof may be seal-coated.

[0094] The core particle comprises compound (I) or a salt thereof as an active ingredient and additives. Preferably, the core particle comprises the hydrochloride salt of compound (I) as an active ingredient and additives.

[0095] The amount of compound (I) or a salt thereof in the core particles is from about 5 wt % to about 95 wt %, preferably from about 20 wt % to about 90 wt %, more preferably from about 30 wt % to about 90 wt %, even more preferably from about 40 wt % to about 85 wt %, and most preferably from about 50 wt % to about 80 wt %, based on the total weight of the core particles.

[0096] The additives in the core particles may include one or more materials selected from excipients, binders, glidants, surfactants, lubricants, disintegrants and plasticizers. Preferred additives are excipients and / or binders.

[0097] Excipients include, for example, lactose, sucrose, glucose, corn starch, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silicon dioxide and sodium chloride, but are not limited thereto. These ingredients may be used alone or in combination of two or more.

[0098] The amount of excipient in the core particle is about 5 wt % to about 95 wt %, preferably about 10 wt % to about 90 wt %, more preferably about 15 wt % to about 90 wt %, even more preferably about 20 wt % to about 90 wt %, and most preferably about 20 wt % to about 50 wt %, based on the total weight of the core particle.

[0099] Binders include cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, starch, pregelatinized starch, gum arabic, tragacanth, gelatin, polyvinylpyrrolidone (polyvidone, PVP), polyvinyl alcohol-polyethylene glycol graft copolymer, cross-linked polyvinylpyrrolidone, sodium alginate and microcrystalline cellulose, but are not limited thereto. These ingredients can be used alone or in combination of two or more.

[0100] Glidants include polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, silicon dioxide, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetyl alcohol, stearyl alcohol and talc, but are not limited thereto. These ingredients can be used alone or in combination of two or more.

[0101] Surfactants include anionic surfactants such as sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate; nonionic surfactants such as polyoxyethylene ether and polysorbate 80; and cationic surfactants such as quaternary ammonium compounds, but are not limited thereto. These components may be used alone or in combination of two or more.

[0102] Lubricants include stearic acid, magnesium stearate, calcium stearate, aluminum stearate, stearyl fumarate and silicified talc, but are not limited thereto. These ingredients may be used alone or in combination of two or more.

[0103] Disintegrants include starch, crosslinked sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, crosslinked calcium carboxymethylcellulose, crosslinked polyvinyl pyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose and hydroxypropyl starch, but are not limited thereto. These ingredients may be used alone or in combination of two or more.

[0104] Plasticizers include butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, PEG (eg, PEG 6000), acetyl triethyl citrate, and triacetin, but are not limited thereto. These ingredients may be used alone or in combination of two or more.

[0105] The core particles are uniform dry compositions, for example formed by compressing a mixture of compound (I) and additives. The core particles can be formed, for example, from particles of ground compound (I) or a salt thereof and additives. The core particles can be prepared using known techniques, including but not limited to granulation, spray drying, sieving, freeze drying, pulverization, grinding and micronization. The core particles can be prepared using the following equipment: for example, a stirred granulator, an extrusion granulator, a fluidized bed granulator, a spherical granulator and a roller compactor.

[0106] The core particles may be seal-coated. The purpose of seal coating is to make the surface of the core particles smooth, which is performed by coating the surface of the core particles with a coating component containing a water-soluble polymer, for example.

[0107] The seal coating method is not particularly limited, but can be performed by coating core particles comprising compound (I) or a salt thereof with a seal coating liquid in a coating machine such as a fluidized bed granulator.

[0108] As coating ingredients, known coating agents can be used, including, for example, hydrophilic polymers, more specifically, hydrophilic cellulose ethers, preferably hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR) and polyethylene glycol, but not limited thereto. These ingredients can be used alone or in combination of two or more, and the coating ingredients can also include a plasticizer or an anti-tacking agent. Preferably, hydroxypropyl methylcellulose (HPMC) can be used.

[0109] The amount of seal coating component used for the core particle is about 1 wt % to about 10 wt %, preferably about 2 wt % to about 8 wt %, more preferably about 2 wt % to about 6 wt %, based on the total weight of the core particle.

[0110] The delayed-release (enteric) granules are prepared by coating the above core granules or the above seal-coated core granules with a coating layer comprising at least two types of polymers, wherein the coating layer consists of a single layer or multiple layers (more than 2 layers).

[0111] The coating layer comprising two types of polymers may include an enteric polymer and a sustained-release polymer, wherein the coating layer may be a single layer or multiple layers.

[0112] The single-layer coated granules can be prepared by coating the core granules or the seal-coated core granules with a coating solution containing a sustained-release polymer and an enteric polymer, followed by drying.

[0113] The multi-layer coated particles include, for example, two-layer coated particles, three-layer coated particles, and four-layer coated particles, preferably two-layer coated particles, but not limited thereto. The two-layer coated particles can be prepared by coating the core particles or the seal-coated core particles with a coating solution containing a sustained-release polymer, followed by drying to obtain sustained-release coated particles, and then coating the sustained-release coated particles with a coating solution containing an enteric polymer, followed by drying.

[0114] For both the single-layer coated granules and the multi-layer coated granules, coating with a coating liquid can be performed according to a conventional method.

[0115] The conventional coating method is not particularly limited, but may be performed by coating the core granules or the seal-coated core granules using a coating machine such as a fluidized bed granulator.

[0116] Sustained-release polymers include alkylcelluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, vinyl acetate polymers, cellulose ethers, hydroxyalkylcelluloses, and carboxyalkylcelluloses. Preferably, ethylcellulose, ethyl acrylate-methyl methacrylate-trimethylaminoethyl chloride copolymers, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose (HPMC)), ethyl acrylate-methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, and polyvinyl acetate-polyvinyl pyrrolidone copolymers are included. More preferably, ethylcellulose and ethyl acrylate-methyl methacrylate copolymers are included. The ethylcellulose includes, for example, Aquacoat TMECD-30. The ethyl acrylate-methyl methacrylate copolymer is a copolymer of ethyl acrylate and methyl methacrylate, wherein the content ratio of ethyl acrylate to methyl methacrylate is about 2:1. The ethyl acrylate-methyl methacrylate copolymer includes, for example, Eudragit TM NE30D and Eudragit TM NM30D.

[0117] The enteric polymer herein is a polymer that dissolves at a pH of 4.5 or higher, and includes, for example, methacrylic acid copolymer LD and methacrylic acid-ethyl acrylate copolymer. The methacrylic acid-ethyl acrylate copolymer is a copolymer of methacrylic acid and ethyl acrylate, wherein the content ratio of methacrylic acid to ethyl acrylate is about 1:1. The methacrylic acid-ethyl acrylate copolymer includes, for example, Eudragit TM L30D-55.

[0118] In the case of both multilayer coatings and monolayer coatings, based on the gross weight of core particles or seal coated core particles, the amount of sustained release polymer is from about 2 wt % to about 40 wt %, preferably from about 4 wt % to about 30 wt %, more preferably from about 6 wt % to about 20 wt %, even more preferably from about 7 wt % to about 15 wt %. In the case of multilayer coatings, based on the gross weight of core particles or seal coated core particles, the amount of sustained release polymer is from about 2 wt % to about 40 wt %, preferably from about 5 wt % to about 15 wt %, more preferably from about 8 wt % to about 12 wt %, even more preferably from about 10 wt %, but not limited thereto. In the case of monolayer coatings, based on the gross weight of core particles or seal coated core particles, the amount of sustained release polymer is from about 2 wt % to about 40 wt %, preferably from about 5 wt % to about 15 wt %, more preferably from about 6 wt % to about 13 wt %, but not limited thereto.

[0119] In the case of both multilayer coatings and monolayer coatings, based on the total weight of core particles or seal coated core particles, the amount of enteric polymer is from about 10% by weight to about 50% by weight, preferably from about 10% by weight to about 40% by weight, more preferably from about 15% by weight to about 40% by weight. In the case of multilayer coatings, based on the total weight of core particles or seal coated core particles, the amount of enteric polymer is from about 10% by weight to about 50% by weight, preferably from about 10% by weight to about 40% by weight, more preferably from about 15% by weight to about 30% by weight, even more preferably from about 15% by weight to about 25% by weight, but not limited thereto. In the case of monolayer coatings, based on the total weight of core particles or seal coated core particles, the amount of enteric polymer is from about 10% by weight to about 50% by weight, preferably from about 15% by weight to about 40% by weight, more preferably from about 20% by weight to about 40% by weight, but not limited thereto.

[0120] When core particles are monolayer coated with a coating solution comprising a sustained-release polymer and an enteric polymer, ethyl acrylate-methyl methacrylate copolymer is ideally used as a sustained-release polymer, and methacrylic acid copolymer LD is used as an enteric polymer. Based on the gross weight of core particles or seal-coated core particles, the amount of a mixture of a sustained-release polymer and an enteric polymer is from about 20% by weight to about 75% by weight, preferably from about 25% by weight to about 70% by weight, more preferably from about 25% by weight to about 65% by weight. In the coating solution comprising a sustained-release polymer and an enteric polymer, the weight ratio of the sustained-release polymer to the enteric polymer is from about 1:1 to about 1:5, preferably from about 1:2 to about 1:4, more preferably from about 1:3.

[0121] The coating solution used herein (ie, a coating solution containing a sustained-release polymer, a coating solution containing an enteric polymer, a coating solution containing a sustained-release polymer and an enteric polymer) may include a surfactant, a pore former, a plasticizer, an anti-adhesive agent, and the like.

[0122] The surfactant herein includes the surfactant that may be contained in the above core particles. Preferably, the surfactant may include polysorbate 80.

[0123] The amount of the surfactant is about 1 wt % to about 25 wt %, preferably about 5 wt % to about 20 wt %, more preferably about 10 wt %, based on the weight of the sustained-release polymer.

[0124] The pore-forming agent includes a hydrophilic polymer, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, poloxamer 188, polyvinyl pyrrolidone, d-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer and sugars, but is not limited thereto. Preferably, it may include one or more selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, polyvinyl pyrrolidone and methylcellulose. More preferably, the pore-forming agent may include one or more selected from hydroxypropyl methylcellulose (HPMC) and methylcellulose.

[0125] The amount of the pore former is about 0.5 wt % to about 20 wt %, preferably about 1 wt % to about 18 wt %, more preferably about 2.5 wt % to about 16 wt %, based on the weight of the sustained release polymer.

[0126] The plasticizer herein includes the plasticizer that may be contained in the core particles mentioned above. Preferably, the plasticizer may include triethyl citrate.

[0127] The amount of plasticizer is about 5 wt % to about 40 wt %, preferably about 10 wt % to about 25 wt %, based on the weight of the polymer in each coating layer.

[0128] Anti-adhesive agents include, for example, talc, glyceryl monostearate, fumed silica (e.g., AEROSIL available from Evonik Industries), TM 200), precipitated silica (e.g., SIPERNAT TM PQ) and magnesium stearate. Preferably, the anti-adhesive agent may include talc.

[0129] The amount of the anti-adhesive agent is about 20% to about 150% by weight, preferably about 25% to about 100% by weight, based on the weight of the polymer in each coating layer.

[0130] The pharmaceutical composition of the present invention can be prepared by coating core particles comprising Compound (I) or a salt thereof with a seal coating solution, and then spraying a coating solution comprising at least two polymers onto the particles in a known manner.

[0131] After coating with the coating solution, the product can be dried as needed. Drying can be carried out by conventional drying methods for pharmaceutical preparations, such as vacuum drying, fluidized bed drying, and tray drying.

[0132] The core particles are characterized by having a particle size distribution.

[0133] In the present invention, the upper limit of the particle size of the core particles is 3 mm or less, preferably 2 mm or less, more preferably 1 mm or less, but it may be related to the average particle size of the core particles. And, in the preparation of the present invention, the lower limit of the particle size of the core particles includes but is not limited to preferably 0.3 mm or more, more preferably 0.5 mm or more.

[0134] At least a portion or all of the particles prepared by coating the core particles or the seal-coated core particles with a coating solution comprising at least two polymers have a size of about 0.2 mm to about 2 mm, preferably about 0.3 mm to about 1.5 mm, more preferably about 0.4 mm to about 1.0 mm, but should not be limited thereto.

[0135] The pharmaceutical composition of the present invention can also be characterized by evaluating the dissolution curve through a dissolution test, and the actual pharmacokinetics can be predicted by the dissolution curve. Examples of dissolution test conditions are shown below, but the conditions are not necessarily limited thereto.

[0136] The dissolution test of the pharmaceutical composition of the present invention comprising a salt of compound (I) can be conducted according to Test Method 1 (rotating basket method) in the 18th edition of the Japanese Pharmacopoeia, using 900 mL of 0.1 N hydrochloric acid as the dissolution medium, at 37°C ± 0.5°C and 100 rpm for 2 hours. After 2 hours, the dissolution medium is removed, and a pH 7.4 phosphate buffer at 37°C ± 0.5°C is added to the test container, and the dissolution test is immediately restarted. The test is conducted at 37°C ± 0.5°C and 100 rpm for 10 hours.

[0137] The preferred dissolution profile of the pharmaceutical composition of the present invention can be characterized by the following release rate, for example, optionally, less than about 10% of compound (1) is released 2 hours after the start of the test, and further optionally, about 80% or more is released at 4-12 hours.

[0138] Preferably, it can be characterized by the following release rate, for example, optionally, at 2 hours after the start of the test, the release of compound (1) is less than about 10%, further optionally, at 4 hours, the release is about 30% or more, further optionally, at or before 12 hours, the release is about 80% or more.

[0139] The oral solid preparation containing the pharmaceutical composition of the present invention can be used in the form of capsules or granules. Pharmaceutical formulation ingredients (additives) can be added to the pharmaceutical composition of the present invention as needed, and the mixture can be processed into solid oral preparations containing the pharmaceutical composition of the present invention, such as capsules and granules. The capsule used herein refers to a preparation containing the pharmaceutical composition of the present invention in a capsule.

[0140] The pharmaceutical composition of the present invention can be used in combination with other sustained-release granules and / or immediate-release granules comprising compound (I) or a salt thereof, and can be used as a solid oral preparation such as capsules and granules.

[0141] The oral solid preparation comprises the pharmaceutical composition of the present invention, and may further comprise additional sustained-release granules and / or immediate-release granules containing Compound (I) or a salt thereof, and additives.

[0142] The sustained-release particles containing compound (I) or a salt thereof are characterized by having an inner core and an outer layer, wherein the inner core is a "core particle containing compound (I) or a salt thereof" and the outer layer is a "coating layer containing a sustained-release polymer". Furthermore, the core particles containing compound (I) or a salt thereof may be seal-coated.

[0143] Furthermore, the sustained-release granules can be prepared according to the composition described in the description of the delayed-release (enteric-coated) granules, for example, by coating the core granules with a coating solution containing a sustained-release polymer. The components and amounts contained in the core granules and the components and amounts contained in the sustained-release polymer can be the components and amounts described in the delayed-release (enteric-coated) granules.

[0144] The immediate-release granules comprising compound (I) or a salt thereof are characterized by having only an inner core, wherein the inner core is a "core granule comprising compound (I) or a salt thereof".

[0145] The amount of compound (I) or a salt thereof in the immediate-release granules is about 5 wt % to about 95 wt %, preferably about 5 wt % to about 90 wt %, more preferably about 5 wt % to about 85 wt %, even more preferably about 10 wt % to about 80 wt %, and most preferably about 10 wt % to about 50 wt %, based on the total weight of the immediate-release granules.

[0146] Furthermore, the immediate-release granules may include the additives of the core granules contained in the above-mentioned delayed-release (enteric-coated) granules, and may contain such amounts.

[0147] The pharmaceutical composition of the present invention effectively prevents and / or treats diseases associated with target central nervous system disorders by inhibiting the reuptake of various biogenic amines, including the following:

[0148] (i) attention deficit hyperactivity disorder (ADHD, children and adults) and related behavioral disorders, as well as forms and symptoms of alcohol abuse, drug abuse, obsessive-compulsive disorder, learning disabilities, reading problems, gambling addiction, mania, phobias, panic attacks, oppositional defiant disorder, conduct disorder, disruptive behavior disorder, school academic problems, smoking, aberrant sexual behavior, schizophrenic behavior, somatization, depression (major depressive disorder, recurrent sexual behavior; dysthymic disorder; not otherwise specified (NOS) depressive disorder; major depressive disorder, single episode; depression associated with bipolar disorder, Alzheimer's disease, psychosis, or Parkinson's disease; postpartum depression; and seasonal affective disorder), sleep disorders, generalized anxiety disorder, stuttering, and tics (e.g., Tourette's syndrome);

[0149] (ii) ADHD, substance abuse, depression, anxiety disorders (including, but not limited to, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety disorder), autism, traumatic brain injury, cognitive impairment, schizophrenia (especially cognitive aspects), obesity, chronic pain disorders, personality disorders, and mild cognitive impairment;

[0150] (iii) anxiety disorders, panic disorders, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorders, intoxication, Parkinson's disease, and chronic pain;

[0151] (iv) substance abuse disorders (including, but not limited to, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, and opioid-related disorders);

[0152] (v) cognitive impairment, bipolar disorder, anorexia nervosa, bulimia nervosa, cyclothymia, chronic fatigue syndrome, chronic or acute stress, fibromyalgia and other somatoform disorders (e.g., somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, and somatoform NOS), incontinence (i.e., tonic incontinence, true stress incontinence, and mixed incontinence), aspiration disorder, mania, migraine, and peripheral neuropathy;

[0153] (vi) Addictive disorders (including, but not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, and opioid-related disorders)

[0154] (vii) Fragile X-related disorders;

[0155] (viii) autism spectrum disorder (ASD), for example, ASD in patients with fragile X-related disorder;

[0156] (ix) ADHD in patients with fragile X-related disorders;

[0157] (x) Comorbidity of ADHD and depression;

[0158] (xi) comorbidity of ADHD and substance abuse;

[0159] (xii) Comorbidity of ADHD and anxiety disorders.

[0160] In another embodiment, the pharmaceutical compositions of the present invention are effective in treating any of the following disorders.

[0161] - Attention Deficit Hyperactivity Disorder (ADHD) and related behavioral disorders, as well as forms and symptoms of substance abuse (e.g., alcohol and drug abuse), obsessive-compulsive behaviors, learning disabilities, reading problems, gambling addiction, mania, phobias, panic attacks, rebellious behavior, conduct disorders, school academic problems, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression, sleep disorders, generalized anxiety disorder, stuttering, and tics;

[0162] - depression, anxiety disorders, autism, traumatic brain injury, cognitive impairment, schizophrenia (especially cognitive impairment), obesity, chronic pain disorders, personality disorders, and mild cognitive impairment;

[0163] - Panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorders, and Parkinson's disease;

[0164] - Fragile X-related disorders;

[0165] - Patients with Fragile X-related disorder who have not responded to previous treatment for Fragile X-related disorder;

[0166] - Attention-deficit / hyperactivity disorder (ADHD), e.g., patients with Fragile X-related disorders also have anxiety and / or depressive disorders (e.g., depression);

[0167] - Autism Spectrum Disorder (ASD).

[0168] In another embodiment, the disorders that the pharmaceutical composition of the present invention attempts to prevent and / or treat include disorders described in the American Psychiatric Association's DSM-IV Diagnostic Criteria Quick Reference (Washington, DC, 1994). Target disorders include attention-deficit / hyperactivity disorder, mainly inattentive type; attention-deficit / hyperactivity disorder, mainly hyperactive-impulsive type; attention-deficit / hyperactivity disorder, mixed type; attention-deficit / hyperactivity disorder, not otherwise specified (NOS); conduct disorder; oppositional defiant disorder; and disruptive behavior disorder, not otherwise specified (NOS), but are not limited thereto.

[0169] Depressive disorders in the present invention include major depressive disorder, recurrent depression, dysthymic disorder, not otherwise specified (NOS) depressive disorder, major depressive disorder and single episode, but are not limited thereto.

[0170] Addictive disorders in the present invention include eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, marijuana-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders and opioid-related disorders, but are not limited thereto.

[0171] The dosage of the present pharmaceutical composition should not be particularly limited, but varies according to the subject of administration, route of administration and symptoms. For example, when orally administered to an adult patient of normal weight (weighing about 40 to 80 kg), the amount of the active ingredient compound (I) or a salt thereof is about 0.05-30 mg / kg body weight / day, preferably, it can be administered in a dosage range of about 0.2-20 mg / kg body weight. For example, in the case of oral administration to a pediatric patient (e.g., weighing less than 40 kg), the amount of the active ingredient compound (I) or a salt thereof is about 0.01-20 mg / kg body weight, preferably, it can be administered in a dosage range of about 0.2-10 mg / kg body weight / day.

[0172] The frequency of administration is once, twice or more times a day.

[0173] The specific regimen, ie, dosage, timing, and number of repetitions, will depend on the specific individual and the individual's medical history.

[0174] Example

[0175] Example 1

[0176] 3,200 g of compound (I) hydrochloride (micronized by a screen mill) and 800 g of microcrystalline cellulose (CEOLUS TM PH-301: AsahiKASEI) was placed in a stirring granulator (VG-25: POWREX), and then 1,020 g of purified water was added to the granulator while stirring and mixing. The resulting mixture was extruded and granulated with an extrusion granulator (TDG-80: DALTON) equipped with a dome die with an aperture of 0.6 mm, and then made into spherical particles with a spheronizer (QJ-700: Fuji Paudal). The resulting granules were dried with a fluidized bed granulator (Flo-5M: FREUND) and sieved with two sieves with mesh sizes of 0.71 mm and 0.5 mm to obtain core particles with a diameter of 0.5 to 0.71 mm.

[0177] Example 2

[0178] 15 g of Hydroxypropyl methylcellulose (Methocel TM E5 Premium LV: Du Pont) was dissolved in 285 g of purified water to prepare a coating solution. 400 g of the core particles prepared in Example 1 were placed in a fluidized bed granulator (MP-01: POWREX) and then coated with the coating solution prepared above until the coating component was 3% of the weight of the core particles. The coated particles were dried in the fluidized bed granulator to obtain seal-coated particles.

[0179] Example 3

[0180] 7.5 g of Hydroxypropyl methylcellulose (Methocel TM E5 Premium LV: Du Pont) and 5 g Polysorbate 80 (Tween TM 80: Merck) was dissolved in 445.8 g of purified water. 50 g of talc (Luzenac Pharma TM M: Imerys) was dispersed in the above prepared solution, and then 166.7 g of ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit TM NM30D: Evonik), stirred to prepare a coating dispersion. 400 g of the seal-coated granules prepared in Example 2 were placed in a fluidized bed granulator (MP-01: POWREX), and then coated with the coating dispersion prepared above until the coating component was 22.5% of the weight of the seal-coated granules. The coated granules were taken out of the fluidized bed granulator and dried in a tray oven at 50°C for 24 hours to obtain sustained-release coated granules.

[0181] Example 4

[0182] 333.3 g of methacrylic acid copolymer LD (Eudragit TM L30D-55: Evonik), 10 g triethyl citrate (Merck), and 50 g talc (Luzenac Pharma TM M: Imerys) was dispersed in 406.7 g of purified water to prepare a coating solution. 400 g of the sustained-release coated granules prepared in Example 3 were placed in a fluidized bed granulator (MP-01: POWREX), and then coated with the above-prepared coating solution until the coating component was 24% or 32% of the weight of the sustained-release coated granules to obtain two types of delayed-release (enteric) granules (Example 4-1 was a granule with a coating rate of 24%, and Example 4-2 was a granule with a coating rate of 32%).

[0183] [Table 1]

[0184]

[0185] Example 5

[0186] The release rate of the granules prepared in Example 4 was evaluated by a dissolution test including an acidic stage and a buffer stage. The dissolution test was conducted according to the test method 1 (rotating basket method) of the 18th edition of the Japanese Pharmacopoeia. The test was conducted for 2 hours in the acidic stage. After the completion of the acidic stage test, the dissolution medium was removed, and the dissolution medium was switched to the buffer stage, and the dissolution test was continued on the same sample in the buffer stage. The buffer stage test was conducted for 10 hours. 900 mL of 0.1 N hydrochloric acid was used as the dissolution medium in the acidic stage, and 900 mL of pH 7.4 phosphate buffer was used in the buffer stage, wherein the temperature of the dissolution medium was 37°C and the rotation speed was 100 rpm. Sampling was performed over time. The content of compound (I) (sentanafacil free base) in the sampled solution was measured using a UV detector (absorbance measurement wavelength: 276 nm and 350 nm). The dissolution rate (%) is defined as the ratio of the weight of the dissolved compound (I) to the total weight of the compound (I) initially contained in the preparation. The dissolution rate in the buffer phase was analyzed by accumulating the acid phase and the buffer phase. The results are shown in Figure 1 shown.

[0187] Example 6

[0188] 6.2 g of methylcellulose (Metolose TM SM-4: Shin-Etsu Chemical) and 10.3 g of triethyl citrate (Merck) were dissolved in 231.0 g of purified water, and 137.5 g of ethyl cellulose aqueous dispersion (Aquacoat TM ECD-30: Du Pont) was dispersed in the above-prepared solution to prepare a coating solution. 400 g of the seal-coated granules prepared in Example 2 were placed in a fluidized bed granulator (MP-01: POWREX) and then coated with the above-prepared coating solution until the coating component was 14% of the weight of the seal-coated granules. The coated granules were taken out of the fluidized bed granulator and dried in a rack dryer at 60°C for 18 hours to obtain sustained-release coated granules.

[0189] Example 7

[0190] 666.7 g of methacrylic acid copolymer LD (Eudragit TM L30D-55: Evonik), 20 g triethyl citrate (Merck), and 100 g talc (Luzenac Pharma TMM: Imerys) was dispersed in 813.3 g of purified water to prepare a coating solution. The sustained-release coated granules prepared in Example 6 were placed in a fluidized bed granulator (MP-01: POWREX), and then coated with the coating solution prepared above until the coating component was 24% or 31% of the weight of the sustained-release coated granules to obtain two types of delayed-release (enteric) granules (Example 7-1 is a granule with a coating rate of 24%, and Example 7-2 is a granule with a coating rate of 31%).

[0191] [Table 2]

[0192]

[0193] Example 8

[0194] Each granule in Table 2 was evaluated in a similar manner to the dissolution test described in Example 5. The results are shown in Table 2. Figure 2 shown.

[0195] Example 9

[0196] 10 g polysorbate 80 (Tween TM 80: Merck) was dissolved in 1,106.7 g of purified water. 1000 g of methacrylic acid copolymer LD (Eudragit TM L30D-55: Evonik), 333.3 g of ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit TM NM30D: Evonik), and 100 g talc (Luzenac Pharma TM M: Imerys) was dispersed in the above-prepared solution to prepare a coating dispersion. 400 g of the seal-coated granules prepared in Example 2 were placed in a fluidized bed granulator (MP-01: POWREX) and then coated with the above-prepared coating dispersion until the coating component was 38.3% or 63.8% by weight of the seal-coated granules. The coated granules were taken out of the fluidized bed granulator and dried in a rack dryer at 50°C for 24 hours to obtain two types of delayed-release (enteric) granules (Example 9-1 is a granule with a coating rate of 38.3%, and Example 9-2 is a granule with a coating rate of 63.8%).

[0197] [Table 3]

[0198]

[0199] Example 10

[0200] Each granule in Table 3 was evaluated in a similar manner to the dissolution test described in Example 5. The results are shown in Table 3. Figure 3 shown.

[0201] Comparative Example 1

[0202] 30 g polysorbate 80 (Tween TM 80: Merck) was dissolved in 1,986.7 g of purified water. 333.3 g of methacrylic acid copolymer LD (Eudragit TM L30D-55: Evonik), 1000 g ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit TM NM30D: Evonik), and 300 g talc (Luzenac Pharma TM M: Imerys) was dispersed in the above-prepared solution to prepare a coating dispersion. 400 g of the seal-coated granules prepared in Example 2 were placed in a fluidized bed granulator (MP-01: POWREX) and then coated with the above-prepared coating dispersion until the coating component was 36.5%, 45.63% or 54.8% by weight of the seal-coated granules. The coated granules were taken out of the fluidized bed granulator and dried in a rack dryer at 50°C for 24 hours to obtain three types of granules (Comparative Example 1-1 is a granule with a coating rate of 36.5%, Comparative Example 1-2 is a granule with a coating rate of 45.63%, and Comparative Example 1-3 is a granule with a coating rate of 54.8%).

[0203] [Table 4]

[0204]

[0205] Comparative Example 2

[0206] Each granule in Table 4 was evaluated in a similar manner to the dissolution test described in Example 5. The results are shown in Table 4. Figure 4 shown.

Claims

1. A pharmaceutical composition comprising a core particle having a coating layer, wherein the core particle comprises (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a salt thereof as an active ingredient, and wherein the coating layer comprises at least two types of polymers.

2. The pharmaceutical composition according to claim 1, wherein the two types of polymers are an enteric polymer and a sustained release polymer.

3. The pharmaceutical composition according to claim 2, wherein the enteric polymer is methacrylic acid copolymer LD.

4. The pharmaceutical composition according to claim 2 or 3, wherein the sustained-release polymer comprises one or more polymers selected from the group consisting of alkylcellulose, acrylic acid polymers, acrylic acid copolymers, vinyl acetate polymers and cellulose ethers.

5. The pharmaceutical composition according to claim 4, wherein the sustained release polymer comprises one or more polymers selected from the group consisting of alkyl cellulose and acrylic acid copolymers. The pharmaceutical composition according to claim 5 , wherein the alkyl cellulose is ethyl cellulose.

7. The pharmaceutical composition according to claim 5, wherein the acrylic acid copolymer is an ethyl acrylate-methyl methacrylate copolymer.

8. The pharmaceutical composition according to claim 2, wherein the enteric polymer is methacrylic acid copolymer LD, and wherein the sustained release polymer is ethylcellulose.

9. The pharmaceutical composition according to claim 2, wherein the enteric polymer is methacrylic acid copolymer LD, and wherein the sustained release polymer is ethyl acrylate-methyl methacrylate copolymer.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the coating layer consists of multiple layers.

11. The pharmaceutical composition according to claim 10, wherein the coating layer consists of two coating layers: The coating layer comprises an enteric polymer and a coating layer comprises a sustained-release polymer, wherein the coating layer of the enteric polymer covers the coating layer of the sustained-release polymer.

12. The pharmaceutical composition of claim 11, wherein in the case of multiple coating layers, the amount of the sustained release polymer is from about 2 wt % to about 40 wt %, or from about 5 wt % to about 15 wt %, or from about 8 wt % to about 12 wt %, or about 10 wt %, based on the total weight of the core particle or the seal-coated core particle.

13. The pharmaceutical composition according to claim 11 or 12, wherein in the case of multiple coating layers, the amount of enteric polymer is from about 10 wt % to about 50 wt %, or from about 10 wt % to about 40 wt %, or from about 15 wt % to about 30 wt %, or from about 15 wt % to about 25 wt %, based on the total weight of the core particle or the seal-coated core particle.

14. The pharmaceutical composition according to any one of claims 1 to 9, wherein the coating layer consists of a single layer.

15. The pharmaceutical composition according to claim 14, wherein the single coating layer comprises a sustained release polymer and an enteric polymer.

16. The pharmaceutical composition of claim 15, wherein in the case of a single coating layer, the amount of the sustained release polymer is from about 2 wt% to about 40 wt%, or from about 5 wt% to about 15 wt%, or from about 6 wt% to about 13 wt%, based on the total weight of the core particle or the seal-coated core particle.

17. The pharmaceutical composition according to claim 15 or 16, wherein in the case of a single coating layer, the amount of the enteric polymer is from about 10 wt % to about 50 wt %, or from about 15 wt % to about 40 wt %, or from about 20 wt % to about 40 wt %, based on the total weight of the core particle or the seal-coated core particle.

18. The pharmaceutical composition according to any one of claims 15 to 17, wherein the weight ratio of the sustained release polymer to the enteric polymer in the coating layer is 1:1 to 1:

5.

19. The pharmaceutical composition according to claim 18, wherein the weight ratio of the sustained-release polymer to the enteric polymer in the coating layer is 1:

3.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the core particles are seal coated.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the core particles having the coating layer are delayed-release (enteric-coated) particles.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the active ingredient is (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

23. A pharmaceutical composition according to any one of claims 1 to 22, which satisfies the following conditions: When the pharmaceutical composition is tested according to the basket apparatus in the Japanese Pharmacopoeia dissolution test at 37°C ± 0.5°C and 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours and then in 900 mL of pH 7.4 buffer solution for 10 hours, a) less than 10% of the active ingredient is released at 2 hours, and b) 80% or more of the active ingredient is released between 4 and 12 hours.

24. A pharmaceutical composition according to any one of claims 1 to 22, which satisfies the following conditions: When the pharmaceutical composition is tested according to the basket apparatus in the Japanese Pharmacopoeia dissolution test at 37°C ± 0.5°C and 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours and then in 900 mL of pH 7.4 buffer solution for 10 hours, a) less than 10% of the active ingredient is released at 2 hours, b) at 4 hours, 30% to 70% of the active ingredient is released, and c) At 12 hours, 80% or more of the active ingredient is released.

25. The pharmaceutical composition according to any one of claims 1 to 24, for use in the prevention and / or treatment of central nervous system (CNS) disorders.

26. The pharmaceutical composition of claim 25, wherein the central nervous system (CNS) disorder is at least one CNS disease selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; mood disorders; psychotic disorders; mood disorders; bipolar disorder; mania; depression; endogenous depression; major depressive disorder; melancholic and refractory depression; dysthymic disorder; cyclothymic disorder; anxiety disorder; somatoform disorder; factitious disorder; dissociative disorder; sexual disorder; eating disorder; sleep disorder ; adjustment disorder; substance-related disorder; anhedonia; delirium; cognitive impairment; Alzheimer's disease; Parkinson's disease; cognitive impairment associated with other neurodegenerative diseases; BPSD associated with dementia; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette's disorder; tic disorder; attention deficit hyperactivity disorder; conduct disorder; borderline personality disorder; nicotine-related disorder; bulimia; Down syndrome.

27. Use of the pharmaceutical composition according to any one of claims 1 to 24 in the manufacture of a medicament for preventing and / or treating central nervous system (CNS) disorders.

28. An oral solid dosage form comprising the pharmaceutical composition according to any one of claims 1 to 26. The oral solid preparation according to claim 28, which is a granule or a capsule.

30. The oral solid preparation according to claim 28 or 29, further comprising sustained-release particles containing (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a salt thereof and / or immediate-release particles containing (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a salt thereof.

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