Centanafadine Pharmaceutical Composition

Abstract

The present invention relates to a pharmaceutical composition containing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (centanafadine) or a pharmaceutically acceptable salt thereof as an active ingredient, and to a preparation containing the pharmaceutical composition that allows for once-daily administration.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (centanafadine) or a pharmaceutically acceptable salt thereof as an active ingredient, and to an oral solid formulation containing the pharmaceutical composition and capable of being administered once a day. [Background technology]

[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, inhibits the reuptake of three biogenic amines: norepinephrine, serotonin, and dopamine (Patent Document 1). (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is most effective against norepinephrine (NE) reuptake, six times less effective against dopamine (DA) reuptake, and 14 times less effective against serotonin (5-HT) reuptake. Therefore, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is a useful compound as an unbalanced triple reuptake inhibitor (TRI). Based on these effects, the compound is useful as a therapeutic agent for CNS disorders such as depression, anxiety, and attention-deficit hyperactivity disorder (ADHD).

[0003] Today, the use of drugs in the treatment of CNS disorders such as depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) is recommended as a once-daily oral administration. Pharmaceutical compositions suitable for once-daily oral administration have been developed, for example, as pharmaceutical formulations containing multiple drug-containing granules, prepared from delayed (enteric)-release granules, sustained-release granules, and / or immediate-release granules. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 5184354 Summary of the Invention [Problem to be solved by the invention]

[0005] One of the problems to be solved by the present invention is to provide a pharmaceutical composition containing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (hereinafter also referred to as "compound (I)") or a salt thereof, which is suitable for once-daily oral administration. [Means for solving the problem]

[0006] The present inventors have conducted extensive research to solve the above problems and have discovered a pharmaceutical composition suitable for maintaining sustained absorption in the lower gastrointestinal tract by coating core granules containing compound (I) or a salt thereof with at least two types of polymers.

[0007] The present invention includes the following aspects. [Section 1] A pharmaceutical composition comprising a core granule containing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a salt thereof as an active ingredient, and further having a coating layer containing at least two types of polymers.

[0008] [Section 2] Item 1. The pharmaceutical composition according to Item 1, wherein the two polymers are an enteric polymer and a sustained-release polymer.

[0009] [Section 3] Item 3. The pharmaceutical composition according to Item 2, wherein the enteric polymer is methacrylic acid copolymer LD.

[0010] [Section 4] Item 4. The pharmaceutical composition according to Item 2 or 3, wherein the sustained-release polymer comprises one or more polymers selected from alkylcelluloses, acrylic acid polymers, acrylic acid copolymers, vinyl acetate polymers, and cellulose ethers.

[0011] [Section 5] Item 5. The pharmaceutical composition according to Item 4, wherein the sustained-release polymer comprises one or more polymers selected from alkylcelluloses or acrylic acid copolymers.

[0012] [Section 6] Item 6. The pharmaceutical composition according to Item 5, wherein the alkyl cellulose is ethyl cellulose.

[0013] [Section 7] Item 6. The pharmaceutical composition according to Item 5, wherein the acrylic acid copolymer is an ethyl acrylate-methyl methacrylate copolymer.

[0014] [Section 8] Item 3. The pharmaceutical composition according to Item 2, wherein the enteric polymer is methacrylic acid copolymer LD and the sustained-release polymer is ethyl cellulose.

[0015] [Section 9] Item 3. The pharmaceutical composition according to Item 2, wherein the enteric polymer is methacrylic acid copolymer LD and the sustained-release polymer is ethyl acrylate-methyl methacrylate copolymer.

[0016] [Section 10] Item 10. The pharmaceutical composition according to any one of Items 1 to 9, wherein the coating layer comprises a multi-layer coating.

[0017] [Section 11] Item 11. The pharmaceutical composition according to Item 10, wherein the coating layer comprises two coating layers, one containing an enteric polymer and the other containing a sustained-release polymer, and the coating layer containing the enteric polymer is coated on top of the coating layer containing the sustained-release polymer.

[0018] [Section 12] Item 12. The pharmaceutical composition according to Item 11, wherein the amount of the sustained-release polymer in the multi-coating layer is about 2% by mass to about 40% by mass, or about 5% by mass to about 15% by mass, or about 8% by mass to about 12% by mass, or about 10% by mass, based on the total mass of the core granule or the seal-coated core granule.

[0019] [Section 13] Item 13. The pharmaceutical composition according to Item 11 or 12, wherein the amount of the enteric polymer in the multi-coating layer is about 10% by mass to about 50% by mass, or about 10% by mass to about 40% by mass, or about 15% by mass to about 30% by mass, or about 15% by mass to about 25% by mass, based on the total mass of the core granule or the seal-coated core granule.

[0020] [Section 14] Item 10. The pharmaceutical composition according to any one of Items 1 to 9, wherein the coating layer is a single-layer coating.

[0021] [Section 15] Item 15. The pharmaceutical composition according to Item 14, wherein the single coating layer contains a sustained-release polymer and an enteric polymer.

[0022] [Section 16] Item 16. The pharmaceutical composition according to Item 15, wherein the amount of the sustained-release polymer in the single coating layer is about 2% by mass to about 40% by mass, or about 5% by mass to about 15% by mass, or about 6% by mass to about 13% by mass, based on the total mass of the core granules or seal-coated core granules.

[0023] [Section 17] Item 17. The pharmaceutical composition according to Item 15 or 16, wherein the amount of the enteric polymer in the single coating layer is about 10% by mass to about 50% by mass, about 15% by mass to about 40% by mass, or about 20% by mass to about 40% by mass, based on the total mass of the core granules or seal-coated core granules.

[0024] [Section 18] Item 18. The pharmaceutical composition according to any one of Items 15 to 17, wherein the mass ratio of the sustained-release polymer to the enteric polymer in the coating layer is 1:1 to 1:5.

[0025] [Section 19] Item 19. The pharmaceutical composition according to Item 18, wherein the weight ratio of the sustained-release polymer to the enteric polymer in the coating layer is 1:3.

[0026] [Section 20] Item 20. The pharmaceutical composition according to any one of Items 1 to 19, wherein the core granules are seal-coated.

[0027] [Section 21] 21. The pharmaceutical composition according to any one of Items 1 to 20, wherein the core granules having a coating layer are delayed (enteric) release granules.

[0028] [Section 22] 22. The pharmaceutical composition according to 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.

[0029] [Section 23] Item 23. The pharmaceutical composition according to any one of Items 1 to 22, when tested according to the Japanese Pharmacopoeia dissolution test using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours, and then in 900 mL of pH 7.4 buffered water for 10 hours, has the following characteristics: a) releases less than 10% of the active ingredient at 2 hours; b) Release of 80% or more of the active ingredient at 4 to 12 hours.

[0030] [Section 24] Item 23. The pharmaceutical composition according to any one of Items 1 to 22, when tested according to the Japanese Pharmacopoeia dissolution test using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours, and then in 900 mL of pH 7.4 buffered water for 10 hours, has the following characteristics: a) releases less than 10% of the active ingredient at 2 hours; b) Releases 30% to 70% of the active ingredient at 4 hours; c) Release of at least 80% of the active ingredient at 12 hours.

[0031] [Section 25] 25. The pharmaceutical composition according to any one of items 1 to 24, for use in the prevention and / or treatment of central nervous system (CNS) disorders.

[0032] [Section 26] Central nervous system (CNS) disorders include schizophrenia, treatment-resistant, refractory or chronic schizophrenia, affective disorders, psychotic disorders, mood disorders, bipolar disorders, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorders, cyclothymic disorders, anxiety disorders, somatoform disorders, factitious disorder, dissociative disorders, sexual disorders, eating disorders, sleep disorders, adjustment disorders, substance-related disorders, anhedonia, delirium, cognitive disorders, Alzheimer's disease, Parkinson's disease, and others. Item 26. The pharmaceutical composition or oral solid formulation according to Item 25, wherein the central nervous system disorder is at least one selected from the group consisting of cognitive impairment associated with neurodegenerative diseases, BPSD associated with dementia, cognitive impairment due to schizophrenia, cognitive impairment due to treatment-resistant, intractable or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, borderline personality disorder, nicotine-related disorder, hyperphagia and Down's syndrome.

[0033] [Section 27] Use of the pharmaceutical composition according to any one of items 1 to 24 in the manufacture of a medicament for the prevention and / or treatment of a central nervous system (CNS) disorder.

[0034] [Section 28] 27. An oral solid formulation comprising the pharmaceutical composition according to any one of Items 1 to 26.

[0035] [Section 29] Item 29. The oral solid formulation according to Item 28, which is a granule or capsule.

[0036] [Section 30] Item 28 or 29. The oral solid dosage form of item 28 or 29, further comprising 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. [Effects of the Invention]

[0037] The pharmaceutical composition containing the core granules having a coating layer of the present invention is designed as a delayed (enteric) release granule suitable for maintaining sustained absorption of Compound (I) or a salt thereof in the lower gastrointestinal tract. The oral solid formulation containing the pharmaceutical composition of the present invention can be used in the form of a capsule or granules. The pharmaceutical composition of the present invention can also be used in combination with other sustained-release granules and / or immediate-release granules containing Compound (I) or a salt thereof. Furthermore, 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 explanation of the drawings]

[0038] [Figure 1] In Example 5, the results of the dissolution test of the granules prepared in Example 4-1 and Example 4-2 are shown. [Figure 2] In Example 8, the results of the dissolution test of the granules prepared in Example 7-1 and Example 7-2 are shown. [Figure 3] In Example 10, the results of the dissolution test of the granules prepared in Example 9-1 and Example 9-2 are shown. [Figure 4] 1 shows the results of the dissolution test of the granules prepared in Comparative Example 2 from Comparative Example 1-1 to Comparative Example 1-3. DETAILED DESCRIPTION OF THE INVENTION

[0039] The terms used in the present invention will be explained below.

[0040] The pharmaceutical composition containing the core granules having a coating layer of the present invention is designed as a delayed (enteric) release granule suitable for maintaining sustained absorption of Compound (I) or a salt thereof in the lower gastrointestinal tract.

[0041] The pharmaceutical composition of the present invention contains, as an active ingredient, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane [Compound (I)], shown below as Compound (I), or a salt thereof. Compound (I) may take any form, for example, a free form or a pharmaceutically acceptable salt form. The salt of Compound (I) is not particularly limited as long as it is a pharmaceutically acceptable salt, and preferred examples include acid addition salts. More preferred examples include the hydrochloride salt of Compound (I). [ka]

[0042] As used herein, Compound (I) or a salt thereof is also understood to encompass the compound in crystalline and non-crystalline forms, including, for example, polymorphs, solvates (including hydrates), non-solvates, conformational polymorphs, and mixtures thereof of the compound. In the present invention, the terms "crystalline form" and "polymorph" may be used interchangeably and are intended to include all compounds of Compound (I) or a salt thereof in free or pharmaceutically acceptable salt form, including, for example, polymorphs, solvates (including hydrates), non-solvates, conformational polymorphs, and mixtures thereof, unless a specific crystalline form is specified. Compound (I) or a salt thereof also includes its isomers such as geometric isomers, stereoisomers, and optical isomers.

[0043] The pharmaceutical composition containing the core granules having a coating layer of the present invention is designed as a delayed (enteric) release granule, and the delayed (enteric) release granules are characterized in that they have an inner core and an outer layer, the inner core being a "core granule containing Compound (I) or a salt thereof" and the outer layer being a "coating layer containing at least two types of polymers." In addition, the core granules containing Compound (I) or a salt thereof may be seal-coated.

[0044] The core granules contain Compound (I) or a salt thereof as an active ingredient and an additive, preferably the hydrochloride salt of Compound (I) as an active ingredient and an additive.

[0045] The amount of compound (I) or a salt thereof contained in the core granules is about 5% by mass to about 95% by mass, preferably about 20% by mass to about 90% by mass, more preferably about 30% by mass to about 90% by mass, even more preferably about 40% by mass to about 85% by mass, and most preferably about 50% by mass to about 80% by mass, based on the total mass of the core granules.

[0046] The additives contained in the core granules include one or more materials selected from a filler, a binder, a glidant, a surfactant, a lubricant, a disintegrant, and a plasticizer. Preferably, the additive is a filler and / or a binder.

[0047] Examples of excipients include, but are not limited to, lactose, refined sucrose, glucose, cornstarch, crystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, which may be used singly or in combination of two or more.

[0048] The amount of excipient contained in the core granules is, based on the total mass of the core granules, about 5% by mass to about 95% by mass, preferably about 10% by mass to about 90% by mass, more preferably about 15% by mass to about 90% by mass, even more preferably about 20% by mass to about 90% by mass, and most preferably about 20% by mass to about 50% by mass.

[0049] Examples of binders include, but are not limited to, cellulose ether, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hypromellose (HPMC), carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinylpyrrolidone (povidone, PVP), polyvinyl alcohol-polyethylene glycol graft copolymer, cross-linked polyvinylpyrrolidone, sodium alginate, and microcrystalline cellulose. These may be used alone or in combination.

[0050] Glidants include, but are not limited to, polyethylene glycols 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, which may be used singly or in combination.

[0051] Examples of surfactants include, but are not limited to, anionic surfactants such as sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate; nonionic surfactants such as polyoxyethylene ethers and polysorbate 80; and cationic surfactants such as quaternary ammonium compounds. These surfactants can be used singly or in combination of two or more.

[0052] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, stearyl alcohol fumarate, and siliconized talc, which may be used singly or in combination of two or more.

[0053] Disintegrants include, but are not limited to, starch, cross-linked sodium carboxymethylcellulose, croscarmellose sodium, croscarmellose calcium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch, which may be used singly or in combination of two or more.

[0054] Examples of plasticizers include, but are not limited to, butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, PEG (e.g., PEG6000), acetyltriethyl citrate, and triacetin. These can be used alone or in combination of two or more.

[0055] The core granules are, for example, homogeneous dry compositions formed by compressing a mixture of Compound (I) and additives. The core granules can be formed, for example, from pulverized particles of Compound (I) or a salt thereof and additives. The core granules can be prepared using known techniques, including, but not limited to, granulation, spray drying, sieving, freeze-drying, crushing, grinding, and shredding. The preparation of the core granules can be carried out using the following equipment: agitator granulator, extrusion granulator, fluidized bed granulator, spherical granulator, roller compactor, and the like.

[0056] The core granules may be subjected to seal coating. Seal coating refers to coating the surface of the core granules with a coating component containing, for example, a water-soluble polymer, for the purpose of smoothing the surface of the core granules. The seal coating method is not particularly limited, but for example, the seal coating solution can be applied to core granules containing compound (I) or a salt thereof using a coating machine such as a fluidized bed granulator. Known coating agents can be used as coating components, such as hydrophilic polymers. Specific examples include, but are not limited to, hydrophilic cellulose ethers, preferably hypromellose (HPMC), hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR), and polyethylene glycol. These can be used alone or in combination of two or more, and may further contain a plasticizer or anti-aggregating agent. Preferably, hypromellose (HPMC) can be used.

[0057] The amount of the seal coating component relative to the core granules is about 1% by mass to about 10% by mass, preferably about 2% by mass to about 8% by mass, and more preferably about 2% by mass to about 6% by mass, based on the total mass of the core granules.

[0058] The delayed (enteric) release granules, which are the pharmaceutical composition of the present invention, are characterized in that the core granules or seal-coated core granules are coated with a coating layer containing at least two types of polymers, and the coating layer is a single layer or multiple layers (two or more layers). The coating layer containing two kinds of polymers contains an enteric polymer and a sustained-release polymer, and the coating layer may be a single layer or multiple layers. The single-layer coated granules can be produced by coating a coating liquid containing a sustained-release polymer and an enteric polymer onto a core granule or a seal-coated core granule, followed by drying. The multi-layer coated granules are not particularly limited, but examples thereof include double-layer coated granules, triple-layer coated granules, and quadruple-layer coated granules, and preferably double-layer coated granules. Double-layer coated granules can be produced by coating core granules or seal-coated core granules with a coating liquid containing a sustained-release polymer, drying them to form sustained-release coated granules, and then further coating these sustained-release coated granules with a coating liquid containing an enteric polymer, and drying them. For both single-layer coated granules and multi-layer coated granules, the coating liquid can be applied by a conventional coating method. The conventional coating method is not particularly limited, but for example, a coating machine such as a fluidized bed granulator can be used to coat core granules or seal-coated core granules.

[0059] Examples of 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. Preferred examples include ethylcellulose, ethyl acrylate-methyl methacrylate-trimethylammonioethyl chloride copolymer, hydroxypropylmethylcellulose (hypromellose (HPMC)), ethyl acrylate-methyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, and polyvinyl acetate-polyvinylpyrrolidone copolymer. More preferred examples include ethylcellulose and ethyl acrylate-methyl methacrylate copolymer. Examples of ethylcellulose include Aquacoat™ ECD-30. Ethyl acrylate-methyl methacrylate copolymer is a copolymer of ethyl acrylate and methyl methacrylate, with the ethyl acrylate to methyl methacrylate ratio being approximately 2:1. Ethyl acrylate-methyl methacrylate copolymers include, for example, Eudragit™ NE30D or Eudragit™ NM30D.

[0060] The enteric polymer is a polymer that dissolves at pH 4.5 or higher, and is specifically selected from methacrylic acid copolymer LD and methacrylic acid-ethyl acrylate copolymer. Methacrylic acid-ethyl acrylate copolymer is a copolymer of methacrylic acid and ethyl acrylate, and the ratio of methacrylic acid to ethyl acrylate is about 1:1. Examples of methacrylic acid-ethyl acrylate copolymers include Eudragit™ L30D-55.

[0061] The amount of sustained-release polymer, whether multi-layer coated or single-layer coated, is about 2% to about 40% by mass, preferably about 4% to about 30% by mass, more preferably about 6% to about 20% by mass, and even more preferably about 7% to about 15% by mass, based on the total mass of the core granule or seal-coated core granule. Although not particularly limited, the amount of sustained-release polymer contained in the multi-layer coated formulation is about 2% to about 40% by mass, preferably about 5% to about 15% by mass, more preferably about 8% to about 12% by mass, and even more preferably about 10% by mass, based on the total mass of the core granule or seal-coated core granule. Although not particularly limited, the amount of sustained-release polymer contained in the single-layer coated formulation is about 2% to about 40% by mass, preferably about 5% to about 15% by mass, and even more preferably about 6% to about 13% by mass, based on the total mass of the core granule or seal-coated core granule.

[0062] The amount of enteric polymer is about 10% to about 50% by mass, preferably about 10% to about 40% by mass, and more preferably about 15% to about 40% by mass, based on the total mass of the core granule or seal-coated core granule, in either the multi-layer or single-layer coating. Although not particularly limited, the amount of enteric polymer contained in the multi-layer coating is about 10% to about 50% by mass, preferably about 10% to about 40% by mass, more preferably about 15% to about 30% by mass, and even more preferably about 15% to about 25% by mass, based on the total mass of the core granule or seal-coated core granule. Although not particularly limited, the amount of sustained-release polymer contained in the single-layer coating is about 10% to about 50% by mass, preferably about 15% to about 40% by mass, and more preferably about 20% to about 40% by mass, based on the total mass of the core granule or seal-coated core granule.

[0063] When core granules are coated with a single layer using a coating solution containing a sustained-release polymer and an enteric polymer, it is desirable to use ethyl acrylate-methyl methacrylate copolymer as the sustained-release polymer and methacrylic acid copolymer LD as the enteric polymer. The amount of the mixture of sustained-release polymer and enteric polymer is about 20% to about 75% by mass, preferably about 25% to 70% by mass, and more preferably about 25% to about 65% by mass, based on the total mass of the core granules or seal-coated core granules. The mass ratio of the sustained-release polymer to the enteric polymer in the coating solution containing the sustained-release polymer and the enteric polymer is about 1:1 to about 1:5, preferably about 1:2 to about 1:4, and more preferably about 1:3.

[0064] The coating liquid used in the present invention (a coating liquid containing a sustained-release polymer, a coating liquid containing an enteric polymer, or a coating liquid containing a sustained-release polymer and an enteric polymer) may contain surfactants, pore-forming agents, plasticizers, anti-aggregating agents, etc.

[0065] The surfactant may be any of those that can be contained in the core granules. Preferably, polysorbate 80 can be contained as the surfactant.

[0066] The amount of the surfactant is about 1% by mass to about 25% by mass, preferably about 5% by mass to about 20% by mass, and more preferably about 10% by mass, based on the mass of the sustained-release polymer.

[0067] Pore formers include hydrophilic polymers, including, but not limited to, hydroxypropyl cellulose, hypromellose (HPMC), polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, d-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymers, and saccharides. Preferably, the pore former may include one or more selected from hypromellose (HPMC), hydroxypropyl cellulose, polyvinylpyrrolidone, and methylcellulose. More preferably, the pore former may include one or more selected from hypromellose (HPMC) and methylcellulose.

[0068] The amount of the pore-forming agent is about 0.5% by mass to about 20% by mass, preferably about 1% by mass to about 18% by mass, and more preferably about 2.5% by mass to about 16% by mass, based on the mass of the sustained-release polymer.

[0069] The plasticizer includes those that can be contained in the core granules, and preferably triethyl citrate.

[0070] The amount of the plasticizer is about 5% by mass to about 40% by mass, and preferably about 10% by mass to about 25% by mass, based on the mass of the polymer contained in each coating layer.

[0071] Examples of anti-agglomerating agents include talc, glyceryl monostearate, fumed silica (e.g., AEROSIL® 200 available from Evonik Industries), precipitated silica (e.g., SIPERNAT® PQ), and magnesium stearate. Talc is preferred.

[0072] The amount of the anti-agglomerating agent is about 20% by mass to about 150% by mass, and preferably about 25% by mass to about 100% by mass, based on the mass of the polymer contained in each coating layer.

[0073] The pharmaceutical composition of the present invention can be produced by coating core granules containing compound (I) or a salt thereof with a seal coating liquid, if desired, and then spraying a coating liquid containing at least two types of polymers by a known method. After coating with the coating liquid, the coated product may be subjected to "drying" if necessary. Drying may be performed by any method generally used for drying pharmaceutical preparations, such as vacuum drying, fluidized bed drying, or tray drying.

[0074] The core granules can be characterized by having a distribution of particle sizes. In the present invention, the upper limit of the particle size of the core granule is 3 mm or less, preferably 2 mm or less, and more preferably 1 mm or less, although this depends on the average particle size of the core granule. On the other hand, in the formulation of the present invention, the lower limit of the particle size of the core granule is not particularly limited, but is preferably 0.3 mm or more, and more preferably 0.5 mm or more. At least a portion or all of the granules obtained by coating the core granules or the seal-coated core granules with a coating liquid containing at least two types of polymers have a size of, but not limited to, about 0.2 mm to about 2 mm, preferably about 0.3 mm to about 1.5 mm, and more preferably about 0.4 mm to about 1.0 mm.

[0075] The pharmaceutical composition of the present invention can be specified by a dissolution profile evaluated by a dissolution test, and the actual pharmacokinetics can be predicted based on the dissolution profile. Examples of conditions for the dissolution test are shown below, but the conditions are not necessarily limited to these. The dissolution test for the pharmaceutical composition of the present invention containing a salt of Compound (I) is conducted according to the Japanese Pharmacopoeia, 18th Edition, Test Method 1 (rotating basket method), using 900 mL of 0.1 N hydrochloric acid as the test solution, at 37°C ± 0.5°C and 100 rpm for 2 hours. After 2 hours, the test solution is removed, and pH 7.4 phosphate buffer at 37°C ± 0.5°C is added, and the test is immediately resumed. The test is conducted for 10 hours at 37°C ± 0.5°C and 100 rpm. A preferred dissolution profile of the pharmaceutical composition of the present invention can optionally be characterized by a release rate such as less than about 10% release of Compound (1) at 2 hours after the start of the test, and further optionally, greater than about 80% release of Compound (1) at 4 to 12 hours. Preferably, the dissolution profile can optionally be characterized by a release rate such as less than about 10% release of Compound (1) at 2 hours after the start of the test, and further optionally, greater than about 30% release of Compound (1) at 4 hours, and further optionally, greater than about 80% release of Compound (1) at least at 12 hours.

[0076] Oral solid preparations containing the pharmaceutical composition of the present invention can be used as capsules or granules. Pharmaceutical formulation ingredients (additives) can be added to the pharmaceutical composition of the present invention as needed, followed by a formulation process to produce oral solid preparations such as capsules or granules containing the pharmaceutical composition of the present invention. Here, capsules refer to preparations in which the pharmaceutical composition of the present invention is contained within a capsule. The pharmaceutical composition of the present invention can also be used in combination with other sustained-release granules and / or immediate-release granules containing Compound (I) or a salt thereof, and can also be used as an oral solid formulation such as capsules or granules.

[0077] The oral solid formulation comprises the pharmaceutical composition of the present invention, and may further comprise other sustained-release granules and / or immediate-release granules containing Compound (I) or a salt thereof, and / or additives.

[0078] Here, the sustained-release granules containing Compound (I) or a salt thereof are characterized by having an inner core and an outer layer, the inner core being a "core granule containing Compound (I) or a salt thereof" and the outer layer being a "coating layer containing a sustained-release polymer." Furthermore, the core granules containing Compound (I) or a salt thereof may be seal-coated. The sustained-release granules can be prepared according to the composition described above for the delayed (enteric) release granules, for example, by coating a core granule with a coating liquid containing a sustained-release polymer. Here, the components and amounts contained in the core granule and the components and amounts of the sustained-release polymer may be the same as those described above for the delayed (enteric) release granules.

[0079] Further, the immediate-release granules containing compound (I) or a salt thereof herein are characterized in that they have only an inner core, and the inner core is a "core granule containing compound (I) or a salt thereof."

[0080] The amount of Compound (I) or a salt thereof contained in the immediate-release granules is about 5% by mass to about 95% by mass, preferably about 5% by mass to about 90% by mass, more preferably about 5% by mass to about 85% by mass, even more preferably about 10% by mass to about 80% by mass, and most preferably about 10% by mass to about 50% by mass, based on the total mass of the immediate-release granules. The immediate-release granules may also contain the additives in the core granules contained in the delayed (enteric)-release granules, and may contain them in the same amounts.

[0081] The pharmaceutical compositions of the present invention are effective against diseases that can be prevented and / or treated by inhibiting the reuptake of multiple biogenic amines that are implicated as causative of target central nervous system disorders, such as those listed below: (i) Attention Deficit Hyperactivity Disorder (ADHD, both children and adults) and related behavioral disorders, including alcohol abuse, drug abuse, obsessive-compulsive disorder, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, oppositional defiant disorder, conduct disorder, disruptive behavior disorders, academic problems at school, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression (including, but not limited to, major depressive disorder, recurrent; dysthymic disorder; depressive disorder not otherwise specified (NOS); major depressive disorder, single episode; bipolar disorder, depression associated with Alzheimer's disease, psychosis, or Parkinson's disease; postpartum depression; and seasonal affective disorder), sleep disorders, generalized anxiety disorder, stuttering, and tic disorders (such as Tourette's syndrome); (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 regarding cognition), obesity, chronic pain disorders, personality disorders, and mild cognitive impairment; (iii) anxiety disorders, panic disorders, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorders, addiction, Parkinson's disease, and chronic pain; (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-related disorders, inhalant-related disorders, and opioid-related disorders); (v) cognitive impairment, bipolar disorder, anorexia nervosa, bulimia nervosa, cyclothymic disorder, chronic fatigue syndrome, chronic or acute stress, fibromyalgia and other somatoform disorders (such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, somatoform NOS), incontinence (i.e., stress urinary incontinence, true stress urinary incontinence, and mixed urinary incontinence), inhalation disorders, mania, migraine, peripheral neuropathy; (vi) Addiction 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-related disorders, inhalant-related disorders, and opioid-related disorders). (vii) fragile X syndrome-related disorders; (viii) autism spectrum disorder (ASD), e.g., ASD in patients with fragile X syndrome-related disorders; (ix) ADHD in patients with fragile X syndrome-related disorders; (x) comorbidity of ADHD and depression; (xi) comorbidity of ADHD and substance abuse; (xii) Comorbidity of ADHD and anxiety disorders.

[0082] In another embodiment, the pharmaceutical compositions of the present invention may be effective in treating any of the following disorders: Attention deficit hyperactivity disorder (ADHD) and related behavioral disorders, as well as types and symptoms of substance abuse (alcohol abuse, drug abuse), obsessive-compulsive behavior, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, oppositional behavior, conduct disorders, academic problems at school, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression, sleep disorders, generalized anxiety disorder, stuttering, and tic disorders; Depression, anxiety, autism, traumatic brain injury, cognitive impairment, schizophrenia (especially cognitive impairment), obesity, chronic pain disorders, personality disorders and mild cognitive impairment; Panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorders, Parkinson's disease; ·Fragile X syndrome-related disorders; Fragile X syndrome-related disorders in which the patient has failed prior treatment for the Fragile X syndrome-related disorder; · Attention-deficit / hyperactivity disorder (ADHD), which is comorbid with anxiety and / or depression (e.g., depression) in patients with fragile X syndrome-related disorders; · Autism spectrum disorder (ASD).

[0083] In yet another embodiment, disorders contemplated for prevention and / or treatment using the pharmaceutical compositions of the present invention include disorders described in the Quick Reference to Diagnostic Criteria of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) American Psychiatric Association, Washington, DC, 1994. These target disorders include, but are not limited to, attention-deficit / hyperactivity disorder, predominantly inattentive type; attention-deficit / hyperactivity disorder, predominantly hyperactive-impulsive type; attention-deficit / hyperactivity disorder, combined type; attention-deficit / hyperactivity disorder not otherwise specified (NOS); conduct disorder; oppositional defiant disorder; and disruptive behavior disorder not otherwise specified (NOS).

[0084] In the present invention, depressive disorders include, but are not limited to, major depressive disorder, recurrent; dysthymic disorder; depressive disorder not otherwise specified (NOS); and major depressive disorder, single episode.

[0085] In the present invention, addictive disorders include, but are 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.

[0086] The dosage of the pharmaceutical composition of the present invention varies depending on the subject, administration route, and symptoms, but is not particularly limited. For example, when orally administered to a normal adult patient (body weight: approximately 40 to 80 kg), the amount of the active ingredient, Compound (I) or a salt thereof, may be administered at a dose ranging from approximately 0.05 to 30 mg / kg body weight, preferably approximately 0.2 to 20 mg / kg body weight per day. For example, when orally administered to a pediatric patient (e.g., body weight less than 40 kg), the amount of the active ingredient, Compound (I) or a salt thereof, may be administered at a dose ranging from approximately 0.01 to 20 mg / kg body weight, preferably approximately 0.2 to 10 mg / kg body weight per day. Dosage frequency may be once, twice or more times daily. The particular dosing regimen, ie, dosage, timing, and repetition, will depend on the particular individual and that individual's medical history. [Example]

[0087] Example 1 3,200 g of Compound (I) hydrochloride (screen milled product) and 800 g of crystalline cellulose (Ceolas (registered trademark) PH-301: Asahi Kasei) were placed in an agitation granulator (VG-25: Powrex), and 1,020 g of purified water was added and mixed while stirring. The mixture was extruded and granulated using an extrusion granulator (TDG-80: Dalton) equipped with a dome die with a diameter of 0.6 mm, and then spherical particles were obtained using a spherical granulator (QJ-700: Fuji Paudal). The resulting granules were dried using a fluidized bed granulator (Flo-5M: Freund) and classified using sieves with openings of 0.71 mm and 0.5 mm to obtain core granules of 0.5 to 0.71 mm.

[0088] Example 2 A coating solution was prepared by dissolving 15 g of hypromellose (Methocel (registered trademark) E5 Premium LV: manufactured by DuPont) in 285 g of purified water. 400 g of the core granules obtained in Example 1 were placed in a fluidized bed granulator (MP-01: manufactured by Powrex), and the coating solution prepared above was applied until the coating component accounted for 3% of the core granule mass. The granules were then dried in the fluidized bed granulator to obtain seal-coated granules.

[0089] Example 3 7.5 g of hypromellose (Methocel® E5 Premium LV, manufactured by DuPont) and 5 g of polysorbate 80 (Tween® 80, manufactured by Merck) were dissolved in 445.8 g of purified water, and 50 g of talc (Luzenac Pharma M®, manufactured by Imerys) was dispersed therein. 166.7 g of ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit® NM30D, manufactured by Evonik) was then added and stirred to prepare a coating agent dispersion. 400 g of the seal-coated granules obtained in Example 2 were placed in a fluidized bed granulator (MP-01, manufactured by Powrex), and the coating agent dispersion prepared above was applied until the coating components accounted for 22.5% of the seal-coated granule mass. The granules were then removed from the fluidized bed granulator and heat-treated in a tray dryer at 50°C for 24 hours to obtain sustained-release coated granules.

[0090] Example 4 A coating solution was prepared by dispersing 333.3 g of methacrylic acid copolymer LD (Eudragit® L30D-55, manufactured by Evonik), 10 g of triethyl citrate (manufactured by Merck), and 50 g of talc (Luzenac Pharma M®, manufactured by Imerys) in 406.7 g of purified water. 400 g of the sustained-release coated granules obtained in Example 3 were placed in a fluidized-bed granulator (MP-01, manufactured by Powrex), and the coating solution prepared above was applied until the coating component accounted for 24% or 32% of the sustained-release coated granules' mass, yielding two types of delayed (enteric)-release granules (the granules with a coating component ratio of 24% are designated Example 4-1, and the granules with a coating component ratio of 32% are designated Example 4-2). TIFF2025527009000002.tif78163

[0091] Example 5 The release rate of the granules obtained in Example 4 was evaluated by the following dissolution test consisting of an acid stage and a buffer stage. The dissolution test was performed according to the Japanese Pharmacopoeia, 18th Edition, Test Method 1 (rotating basket method). The test was performed for 2 hours in the acid stage. After the completion of the acid stage, the test solution was promptly removed, and the same sample was used to move to the buffer stage, where the dissolution test was continued. The test was performed for 10 hours in the buffer stage. As the test solution, 900 mL of 0.1 N hydrochloric acid was used for the acid stage, and 900 mL of pH 7.4 phosphate buffer was used for the buffer stage. The test was performed at 37°C and a rotation speed of 100 rpm. Sampling was performed over time, and the amount of compound (I) (centanafadine free base) in the sample solution was quantified using a UV detector (absorbance measurement wavelengths: 276 nm and 350 nm). The dissolution rate was defined as the mass percentage (%) of compound (I) dissolved when the total mass of compound (I) contained in the formulation was taken as 100%. The dissolution rate in the buffer stage was analyzed by integrating the acid stage and buffer stage values. The results are shown in Figure 1.

[0092] Example 6 A coating solution was prepared by dissolving 6.2 g of methylcellulose (Metolose® SM-4, manufactured by Shin-Etsu Chemical Co., Ltd.) and 10.3 g of triethyl citrate (manufactured by Merck) in 231.0 g of purified water, and then dispersing 137.5 g of an aqueous ethylcellulose dispersion (Aquacoat® ECD-30, manufactured by DuPont) in the solution. 400 g of the seal-coated granules obtained in Example 2 were placed in a fluidized bed granulator (MP-01, manufactured by Powrex Corporation), and the coating solution prepared above was applied until the coating components accounted for 14% of the seal-coated granule mass. The granules were then removed from the fluidized bed granulator and heat-treated in a tray dryer at 60°C for 18 hours to obtain sustained-release coated granules.

[0093] Example 7 A coating solution was prepared by dispersing 666.7 g of methacrylic acid copolymer LD (Eudragit® L30D-55, manufactured by Evonik), 20 g of triethyl citrate (manufactured by Merck), and 100 g of talc (Luzenac Pharma M®, manufactured by Imerys) in 813.3 g of purified water. The sustained-release coated granules obtained in Example 6 were placed in a fluidized-bed granulator (MP-01, manufactured by Powrex) and coated with the coating solution prepared above until the coating components accounted for 24% or 31% of the mass of the sustained-release coated granules. Two types of delayed (enteric) release granules were obtained (the granules with a coating component ratio of 24% are designated Example 7-1, and the granules with a coating component ratio of 31% are designated Example 7-2). TIFF2025527009000003.tif67167

[0094] Example 8 Each granule in Table 2 was evaluated in the same manner as in the dissolution test described in Example 5. The results are shown in Figure 2.

[0095] Example 9 10 g of polysorbate 80 (Tween (registered trademark) 80: manufactured by Merck) was dissolved in 1,106.7 g of purified water, and 1,000 g of methacrylic acid copolymer LD (Eudragit (registered trademark) L30D-55: manufactured by Evonik), 333.3 g of an ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit (registered trademark) NM30D: manufactured by Evonik), and 100 g of talc (Luzenac Pharma M (registered trademark): manufactured by Imerys) were dispersed therein to prepare a coating agent dispersion. 400 g of the seal-coated granules obtained in Example 2 were placed in a fluidized bed granulator (MP-01, manufactured by Powrex) and coated with the coating agent dispersion prepared above until the coating component accounted for 38.3% or 63.8% of the mass of the seal-coated granules. The granules were then removed from the fluidized bed granulator and heat-treated at 50°C for 24 hours in a tray dryer to obtain two types of delayed (enteric) release granules (the granules with a coating component ratio of 38.3% are designated Example 9-1, and the granules with a coating component ratio of 63.8% are designated Example 9-2). TIFF2025527009000004.tif62169

[0096] Example 10 Each granule in Table 3 was evaluated in the same manner as in the dissolution test described in Example 5. The results are shown in Figure 3.

[0097] Comparative Example 1 30 g of polysorbate 80 (Tween (registered trademark) 80: manufactured by Merck) was dissolved in 1,986.7 g of purified water, and 333.3 g of methacrylic acid copolymer LD (Eudragit (registered trademark) L30D-55: manufactured by Evonik), 1,000 g of an ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit (registered trademark) NM30D: manufactured by Evonik), and 300 g of talc (Luzenac Pharma M (registered trademark): manufactured by Imerys) were dispersed therein to prepare a coating agent dispersion. 400 g of the seal-coated granules obtained in Example 2 were placed in a fluidized bed granulator (MP-01, manufactured by Powrex) and coated with the coating agent dispersion prepared above until the coating component accounted for 36.5%, 45.63%, or 54.8% of the mass of the seal-coated granules. The granules were then removed from the fluidized bed granulator and heat-treated at 50°C for 24 hours in a tray dryer to obtain three types of granules (the granules with a coating component ratio of 36.5% are designated Comparative Example 1-1, the granules with a coating component ratio of 45.63% are designated Comparative Example 1-2, and the granules with a coating component ratio of 54.8% are designated Comparative Example 1-3). TIFF2025527009000005.tif62152

[0098] Comparative Example 2 Each granule in Table 4 was evaluated in the same manner as in the dissolution test described in Example 5. The results are shown in FIG.

Claims

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

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

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

4. 4. The pharmaceutical composition of claim 2 or 3, wherein the sustained release polymer comprises one or more polymers selected from alkyl celluloses, acrylic acid polymers, acrylic acid copolymers, vinyl acetate polymers, and cellulose ethers.

5. 5. The pharmaceutical composition of claim 4, wherein the sustained release polymer comprises one or more polymers selected from alkylcelluloses or acrylic acid copolymers.

6. 6. The pharmaceutical composition of claim 5, wherein the alkyl cellulose is ethyl cellulose.

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

8. 3. The pharmaceutical composition of claim 2, wherein the enteric polymer is methacrylic acid copolymer LD and the sustained release polymer is ethyl cellulose.

9. 3. The pharmaceutical composition of claim 2, wherein the enteric polymer is methacrylic acid copolymer LD and 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 comprises a multi-layer coating.

11. 11. The pharmaceutical composition according to claim 10, wherein the coating layer comprises two coating layers, one containing an enteric polymer and the other containing a sustained-release polymer, and the other coating layer is coated on top of the other coating layer containing the sustained-release polymer.

12. The pharmaceutical composition according to claim 11, wherein the amount of the sustained-release polymer in the multi-coating layer is about 2% by weight to about 40% by weight, or about 5% by weight to about 15% by weight, or about 8% by weight to about 12% by weight, or about 10% by weight, based on the total weight of the core granule or the seal-coated core granule.

13. The pharmaceutical composition according to claim 11 or 12, wherein the amount of the enteric polymer in the multi-coating layer is about 10% by weight to about 50% by weight, or about 10% by weight to about 40% by weight, or about 15% by weight to about 30% by weight, or about 15% by weight to about 25% by weight, based on the total weight of the core granule or the seal-coated core granule.

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

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

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

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

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

5.

19. 19. The pharmaceutical composition of 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 granules are seal-coated.

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

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. The pharmaceutical composition according to any one of claims 1 to 22, which has the following characteristics when tested according to the Japanese Pharmacopoeia dissolution test using Apparatus 1 (basket) under the conditions of 37°C ± 0.5°C, 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours, and then in 900 mL of pH 7.4 buffered water for 10 hours: a) releases less than 10% of the active ingredient at 2 hours; b) Release of 80% or more of the active ingredient at 4 to 12 hours.

24. The pharmaceutical composition according to any one of claims 1 to 22, which has the following characteristics when tested according to the Japanese Pharmacopoeia dissolution test using Apparatus 1 (basket) under the conditions of 37°C ± 0.5°C, 100 rpm, first in 900 mL of 0.1 N HCl solution for 2 hours, and then in 900 mL of pH 7.4 buffered water for 10 hours: a) releases less than 10% of the active ingredient at 2 hours; b) releases 30% to 70% of the active ingredient at 4 hours; c) Release of 80% or more of the active ingredient at 12 hours.

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

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

28. An oral solid formulation comprising the pharmaceutical composition according to any one of claims 1 to 26.

29. 29. The oral solid formulation of claim 28, which is a granule or a capsule.

30. 30. The oral solid formulation of claim 28 or 29, further comprising 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.

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