Orally disintegrating tablets

Abstract

To provide a tablet that quickly disintegrates orally but maintains practical hardness, containing brexpiprazole or its salt.SOLUTION: Provided is an orally disintegrating tablet comprising (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) a lubricant.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to an orally disintegrating tablet containing brexpiprazole or a salt thereof, a method for producing the same, etc. The contents of all documents described in this specification are incorporated herein by reference. [Background technology]

[0002] 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (also called brexpiprazole) or its salts has a dopamine D2 receptor partial agonist effect, a serotonin 5-HT 2A It is known to have receptor antagonist effects and adrenergic α1 receptor antagonist effects, and furthermore, in addition to these effects, it is known to have a serotonin uptake inhibitory effect (or a serotonin reuptake inhibitory effect) (Patent Document 1), and has a wide therapeutic spectrum for central nervous system disorders (especially schizophrenia). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2006-316052 A Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have conducted studies with the main object of providing a tablet containing brexpiprazole or a salt thereof which has a practical hardness and yet disintegrates quickly in the oral cavity. [Means for solving the problem]

[0005] The present inventors have found that by adding specific ingredients in addition to brexpiprazole or a salt thereof, it is possible to prepare an orally disintegrating tablet that has a practical hardness but disintegrates quickly in the oral cavity, and have made further improvements.

[0006] The present disclosure includes, for example, the subject matter described in the following sections: Section 1. (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) Lubricant An orally disintegrating tablet containing Section 2. (D) The orally disintegrating tablet according to item 1, wherein the lubricant comprises magnesium stearate and sodium stearyl fumarate. Section 3. Item 2. The orally disintegrating tablet according to Item 1, wherein the (D) lubricant comprises (D1) an internal lubricant and (D2) an external lubricant. Section 4. Item 4. The orally disintegrating tablet according to Item 3, wherein (D1) the internal lubricant comprises sodium stearyl fumarate, and (D2) the external lubricant comprises magnesium stearate. Section 5. Item 5. The orally disintegrating tablet according to any one of Items 1 to 4, wherein the 50% particle size of (B) D-mannitol is 10 μm to 100 μm, and (B) D-mannitol is present in the tablet in the form of non-acicular crystals. Section 6. (C) The orally disintegrating tablet according to any one of Items 1 to 5, wherein the partially pregelatinized starch is a partially pregelatinized starch having a proportion of water-soluble components of 10% or less. Section 7. Item 7. The orally disintegrating tablet according to any one of Items 1 to 6, further comprising (E) crystalline cellulose. Section 8. 8. The orally disintegrating tablet according to claim 7, comprising (E) 5 to 15% by weight of crystalline cellulose. Section 9. Item 9. The orally disintegrating tablet according to any one of Items 1 to 8, further comprising (F) low-substituted hydroxypropyl cellulose. Section 10. Item 10. The orally disintegrating tablet according to any one of Items 1 to 9, wherein the tablet hardness in the diameter direction of the tablet is 15N to 70N as measured using a tablet hardness tester, and the disintegration time is within 70 seconds as measured according to the test method for immediate release preparations (plain tablets) in Disintegration Test Method 6.09 of the Japanese Pharmacopoeia. Section 11. Item 11. The orally disintegrating tablet according to any one of Items 1 to 10, for preventing or treating a central nervous system disease. Section 12. Item 12. The orally disintegrating tablet according to Item 11, for preventing or treating a central nervous system disorder selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, ataxic affective disorder, psychotic disorder, mood disorder, bipolar disorder, depression, endogenous depression, major depression, melancholic and treatment-resistant 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, cognitive impairment associated with a neurodegenerative disease, cognitive impairment caused by a neurodegenerative disease, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down's syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. Section 13. (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) Lubricant An orally disintegrating tablet comprising: An orally disintegrating tablet manufactured by external lubrication compression. Section 14. (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) Lubricant A method for producing an orally disintegrating tablet comprising the steps of: (D) the lubricant comprises (D1) an internal lubricant and (D2) an external lubricant; The method includes a step of mixing (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D1) an internal lubricant, and a step of compressing the mixture into tablets; The method according to claim 1, wherein in the tableting step, (D2) an external lubricant is added by spraying. Section A-1. (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) Lubricant An orally disintegrating tablet comprising: An orally disintegrating tablet, comprising (A) brexpiprazole or a salt thereof, (B) D-mannitol, and (C) partially pregelatinized starch granulated by a wet granulation method. Section A-2. (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) Lubricant A method for producing an orally disintegrating tablet comprising the steps of: A method comprising the steps of granulating (A) brexpiprazole or a salt thereof, (B) D-mannitol, and (C) partially pregelatinized starch by a wet granulation method, further mixing (D) a lubricant with the granulated mixture, and compressing the resulting mixture into tablets. Section A-3. brexpiprazole, D-mannitol, Partially pregelatinized starch, Sodium stearyl fumarate and magnesium stearate, Crystalline cellulose, Partially pregelatinized starch, Sucralose, At least one colorant selected from red ferric oxide, yellow ferric oxide, and blue aluminum lake No. 2; and Corn starch 1. An orally disintegrating tablet comprising or preferably consisting of: Effect of the Invention

[0007] Provided is an orally disintegrating tablet containing brexpiprazole or a salt thereof, which has a practical hardness and yet disintegrates quickly in the oral cavity. [Brief description of the drawings]

[0008] [Figure 1] 1 shows the disintegration times of the orally disintegrating tablets of Examples 1-1 to 1-3. [Figure 2a] 1 shows the hardness retention rates of the orally disintegrating tablets of Examples 2-1 to 2-3. [Figure 2b] 1 shows the disintegration times of the orally disintegrating tablets of Examples 2-1 to 2-3. [Diagram 3] 1 shows the relationship between disintegration time and tablet hardness for the orally disintegrating tablets of Example 3-1 and Comparative Example 3-2. [Figure 4a] 1 shows the hardness of the orally disintegrating tablets of Examples 4-1 to 4-4. [Figure 4b] 1 shows the disintegration times of the orally disintegrating tablets of Examples 4-1 to 4-4. [Diagram 5] 1 shows the relationship between disintegration time and tablet hardness for the orally disintegrating tablets of Examples 4-2, 4-4, and 5-3. [Figure 6a] 1 shows the dissolution properties of the orally disintegrating tablets of Examples 6-1 to 6-3. [Figure 6b] FIG. 1 shows the relationship between tablet physical properties (hardness and disintegrability) of the orally disintegrating tablets of Examples 6-1 to 6-3. [Figure 7a] FIG. 1 shows electron microscope photographs before and after granulation in the production of orally disintegrating tablets in Examples 7-1 and 7-2, and electron microscope photographs of the cross sections of the produced orally disintegrating tablets. [Figure 7b] 7 shows a photograph of the punch surface of a tablet press used in the production of the orally disintegrating tablet of Example 7-1, and the tablet appearance of the orally disintegrating tablet. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Hereinafter, each embodiment included in the present disclosure will be described in more detail. The present disclosure preferably includes an orally disintegrating tablet containing brexpiprazole or a salt thereof and a method for producing the same, but is not limited thereto, and the present disclosure includes all that is disclosed in the present specification and that can be recognized by a person skilled in the art.

[0010] The orally disintegrating tablet included in the present disclosure contains (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) a lubricant. The orally disintegrating tablet included in the present disclosure may be referred to as the "orally disintegrating tablet of the present disclosure."

[0011] (Brexpiprazole or its salt) The salt of brexpiprazole is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), and the like; ammonium salts, salts of inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); and salts of inorganic bases such as tri(lower)alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, isopropylamine, butyl ... Examples of the salts include salts of organic bases such as midazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkyl-morpholines (e.g., N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and organic acid salts such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and glutamate.

[0012] The orally disintegrating tablet of the present disclosure may contain, for example, about 0.1 to 10% by weight, or about 0.3 to 5% by weight, of (A) brexpiprazole or a salt thereof, but is not particularly limited thereto. Also, the orally disintegrating tablet of the present disclosure may contain, for example, about 0.05 to 10 mg, 0.1 to 8 mg, or 0.5 to 5 mg of (A) brexpiprazole or a salt thereof, but is not particularly limited thereto.

[0013] (D-Mannitol) In one embodiment, the (B) D-mannitol in the orally disintegrating tablet of the present disclosure is not particularly limited, but may have a 50% particle size of 10 μm to 100 μm, preferably 15 μm to 80 μm, and more preferably 20 μm to 50 μm. The 50% particle size is also expressed as D50 or median size, and represents the particle size of 50% of the particles larger and 50% smaller than this size. The 50% particle size is determined by a laser diffraction scattering method.

[0014] In addition, (B)D-mannitol is known to have crystal polymorphs such as α (alpha), β (beta), and δ (delta) types, as well as different crystal shapes such as plate-like, needle-like, and porous. It is generally known that the crystal shape (crystal form, crystal habit) is determined by the ratio of the forward speed of each crystal face, and changes significantly under the influence of amorphous components and impurities in the solution. For example, if the growth of the crystal side is inhibited by some factor, the crystal will grow only in one direction and take on a needle-like shape. In addition, various crystal shapes such as plate-like, prism-like, cubic, dendritic, and bulky shapes have been reported (Masakuni Matsuoka, "Basics and Applications of Crystal Polymorphism," Popular Edition, CMC Publishing, 2010; Hiroshi Takiyama, "Strengthening Book of Crystallization," First Edition, S&T Publishing, 2013). Usually, commercially available beta-D-mannitol crystals are manufactured as plate-like crystalline powders. On the other hand, D-mannitol commercially available as delta crystals transitions from delta to beta during the granulation process, and at this time, the crystal shape changes from plate-like to needle-like. The crystal shape of D-mannitol in tablets and granulated granules can be determined, for example, by observation using a microscope. Any crystalline polymorph of D-mannitol may be used for the orally disintegrating tablet of the present disclosure, but it is preferable to use beta-type D-mannitol. In addition, in the production of orally disintegrating tablets, when D-mannitol that exists in a non-needle, preferably plate-like, crystalline form during tableting is used, the effect of suppressing the filming phenomenon described below is particularly high, and is preferable. Therefore, in one embodiment, (B) D-mannitol in the orally disintegrating tablet of the present disclosure exists in a non-needle, preferably plate-like, crystalline form in the tablet.

[0015] In one embodiment, (B) D-mannitol in the orally disintegrating tablet of the present disclosure has a 50% particle size of 10 μm to 100 μm and is present in the tablet in a non-acicular, preferably plate-like, crystalline form.

[0016] The orally disintegrating tablet of the present disclosure may contain, for example, about 20 to 90% by weight, 40 to 85% by weight, 55 to 85% by weight, or 60 to 80% by weight of (B) D-mannitol, which is not particularly limited, and may contain, for example, about 10 to 180 parts by weight, 20 to 160 parts by weight, or 30 to 140 parts by weight of (B) D-mannitol per part by weight of (A) brexpiprazole or a salt thereof.

[0017] (Partially pregelatinized starch) (C) Partially pregelatinized starch refers to starch that is partially pregelatinized, and when water is added, it swells and becomes a cloudy liquid. In contrast, pregelatinized starch refers to starch that becomes a viscous, pasty liquid when water is added. Partially pregelatinized starch can be prepared by heating starch (preferably corn starch) together with water under normal pressure or under pressure (and drying as necessary). Partially pregelatinized starch preferably has a water-soluble component ratio of 10% or less, more preferably 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, or 3% or less. The water-soluble component ratio in partially pregelatinized starch is measured by the test method described in the section "STARCH, PREGELATINISED" in European Pharmacopoeia 9.0 under "Cold-water-soluble matter".

[0018] The partially pregelatinized starch (C) contained in the orally disintegrating tablet of the present disclosure preferably has a degree of pregelatinization of 70% or less, more preferably 30% to 70%, 40% to 70%, or 50% to 70%. The degree of pregelatinization in the partially pregelatinized starch is a numerical value representing the gelatinization (gelatinization) state in starch as a percentage, and is measured, for example, by the glucoamylase method.

[0019] In addition, the orally disintegrating tablet of the present disclosure may contain, for example, about 1 to 15% by weight, 1.5 to 10% by weight, or 2 to 8% by weight of (C) partially pregelatinized starch, but is not particularly limited thereto. In addition, the orally disintegrating tablet of the present disclosure may contain, for example, about 0.5 to 30 parts by weight, 1 to 20 parts by weight, or 1 to 15 parts by weight of (C) partially pregelatinized starch, but is not particularly limited thereto, per part by weight of (A) brexpiprazole or a salt thereof.

[0020] (lubricant) (D) Examples of lubricants include stearic acid or its salts (e.g., aluminum stearate, calcium stearate, magnesium stearate, etc.); carnauba wax, glycerin fatty acid esters, hardened oils, beeswax, white beeswax, talc, fumaric acid, sodium stearyl fumarate, polyethylene glycol (macrogols such as macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, etc.). These lubricants may be used alone or in combination of two or more. Among these, stearates, sodium stearyl fumarate, sucrose fatty acid esters, and hardened oils are preferred, magnesium stearate and sodium stearyl fumarate are more preferred, and it is particularly preferred to use magnesium stearate and sodium stearyl fumarate in combination. As described below, the (D) lubricant includes an internal lubricant (D1) contained inside the tablet and an external lubricant (D2) contained outside the tablet. The orally disintegrating tablet of the present disclosure preferably contains both an internal lubricant (D1) and an external lubricant (D2) as the (D) lubricant. The term "exterior of the tablet" refers to the surface of the tablet, more specifically, the portion 0.1 mm from the tablet surface. When the orally disintegrating tablet of the present disclosure contains an internal lubricant and an external lubricant, the internal lubricant and the external lubricant may be the same or different components. In addition, one type of component or a combination of two or more components can be used as the internal lubricant. In addition, one type of component or a combination of two or more components can be used as the external lubricant. Moreover, the orally disintegrating tablet of the present disclosure preferably contains (D1) sodium stearyl fumarate as an internal lubricant and (D2) magnesium stearate as an external lubricant.

[0021] The lubricant (D) is not particularly limited in the orally disintegrating tablet of the present disclosure, and may be contained in an amount of, for example, about 0.1 to 5% by weight, about 0.2 to 3% by weight, or about 0.3 to 2% by weight. The lubricant (D) is not particularly limited in amount, and may be contained in an amount of, for example, about 0.05 to 2 parts by weight, or about 0.1 to 1.5 parts by weight, per part by weight of brexpiprazole (A) or a salt thereof.

[0022] The orally disintegrating tablet of the present disclosure may contain other ingredients (A) to (D) above.

[0023] (crystalline cellulose) For example, (E) crystalline cellulose may be contained. The crystalline cellulose is not particularly limited, but preferably has an average particle size of about 10 to 100 μm, about 20 to 80 μm, about 30 to 70 μm, or about 40 to 60 μm. For example, the bulk density is preferably 0.1 to 0.5 g / cm. 3 Low degree, 0.15~0.45g / cm 3 Degree, 0.2~0.4g / cm 3 or 0.25~0.35g / cm 3 It is preferable that the degree of

[0024] The values ​​of the average particle size and bulk density are values ​​measured in accordance with the general test methods (3.01 Bulk density measurement method, 3.04 Particle size measurement method) of the 17th Edition of the Japanese Pharmacopoeia. More specifically, the bulk density is measured using the method using a volumeter as in Method 2, and the particle size is measured using the mechanical shaking method as in the sieving method.

[0025] The orally disintegrating tablet of the present disclosure contains (E) crystalline cellulose in an amount of, for example, about 1 to 20% by weight, about 5 to 15% by weight, or about 7.5 to 12.5% ​​by weight. Also, the amount of (E) crystalline cellulose is, for example, about 0.1 to 40 parts by weight, about 1 to 30 parts by weight, or about 2 to 25 parts by weight per part by weight of (A) brexpiprazole or a salt thereof.

[0026] (Low-substituted hydroxypropyl cellulose) Also, for example, (F) low-substituted hydroxypropyl cellulose may be contained. As the low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose containing hydroxypropoxy groups of about 5 to 16% (by mass) is preferable. The upper or lower limit of the range may be about 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% (by mass). The content of hydroxypropoxy groups in low-substituted hydroxypropyl cellulose can be measured by a method listed in the 17th revised Japanese Pharmacopoeia. The low-substituted hydroxypropyl cellulose can be produced by a known production method, or a commercially available product can be used. Examples of commercially available low-substituted hydroxypropyl cellulose include, but are not limited to, the "LH series" and "NBD series" manufactured by Shin-Etsu Chemical Co., Ltd.

[0027] The orally disintegrating tablet of the present disclosure contains (F) low-substituted hydroxypropyl cellulose in an amount of, for example, about 1 to 20% by weight, 2 to 15% by weight, or 2 to 10% by weight, and (D) low-substituted hydroxypropyl cellulose in an amount of, for example, about 0.5 to 40 parts by weight, 1 to 30 parts by weight, or 2 to 25 parts by weight per part by weight of (A) brexpiprazole or a salt thereof.

[0028] (Other additives) In addition, for example, the composition may contain other components than those mentioned above that are known in the field of pharmaceutical tablets, so long as they do not impair the effect of the orally disintegrating tablet of the present disclosure. Examples of such components include excipients, binders, disintegrants, colorants, pH adjusters, preservatives, absorption enhancers, flavoring agents, antioxidants, buffers, chelating agents, abrasives, solvents, hardeners, surfactants, sweeteners, fluidizing agents, glossing agents, and flavoring agents. Such other components may be used alone or in combination of two or more.

[0029] More specifically, examples of the excipient include sugars such as fructose, sucrose, refined sucrose, powdered sugar, lactose, powdered reduced maltose syrup, and maltose; sugar alcohols such as D-sorbitol, xylitol, erythritol, and maltitol; starches such as wheat starch, corn starch, and potato starch; starch derivatives such as dextrin and β-cyclodextrin; cellulose or derivatives thereof such as ethyl cellulose, carboxymethyl cellulose (carmellose), and sodium carboxymethyl cellulose (carmellose sodium); silicic acid or salts thereof such as light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, calcium silicate, magnesium silicate, and magnesium aluminometasilicate; kaolin, titanium oxide, magnesium oxide, talc, precipitated calcium carbonate, and anhydrous calcium hydrogen phosphate. The excipients can be used alone or in combination of two or more. Examples of the binder include cellulose or its derivatives such as pregelatinized starch, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; other polysaccharides such as gum arabic, powdered gum arabic, agar, powdered agar, guar gum, tragacanth, powdered tragacanth, pullulan, and pectin; acrylic acid polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, and aminoalkyl methacrylate copolymer RS; sodium alginate; purified gelatin; hydrolyzed gelatin powder; carboxyvinyl polymer; copolyvidone; povidone; and polyvinyl alcohol. The binder can be used alone or in combination of two or more. Examples of the sweetener include aspartame, sucralose, and examples of the colorant include red ferric oxide, yellow ferric oxide, and blue aluminum lake No. 2, and each of these can be used alone or in combination of two or more.

[0030] (Manufacturing method) The present disclosure also relates to a method for producing the orally disintegrating tablet. The orally disintegrating tablet of the present disclosure can be produced, for example, by a step of preparing a mixture containing (A) to (D) (optionally (E) and / or (F), and further other ingredients can also be used), and a step of tableting (e.g., tableting) the obtained mixture.

[0031] In one embodiment, the step of preparing a mixture containing (A) to (D) (and, if necessary, (E), (F), and / or other components) can be carried out by granulating a mixture containing (A) to (C) and further mixing with a lubricant (D). In the above step, (E), (F), and / or other components can be added at an appropriate stage if necessary.

[0032] The method of granulation is not particularly limited, and examples thereof include dry granulation and wet granulation (e.g., fluidized bed granulation, kneading granulation, etc.). Among these, wet granulation (particularly fluidized bed granulation) is preferable because it allows the active ingredient and other ingredients to be mixed uniformly, and thus a tablet containing uniform ingredients can be obtained. Therefore, in one embodiment, the method for producing an orally disintegrating tablet of the present disclosure includes a step of granulating a mixture containing (A) to (C) (and, if necessary, (E), (F), and / or other ingredients) by wet granulation. In one embodiment, the orally disintegrating tablet of the present disclosure includes (A) to (C) granulated by wet granulation. In other words, the orally disintegrating tablet of the present disclosure can be preferably prepared from particles containing (A) to (C) produced by wet granulation.

[0033] The method for making the tablets includes, for example, a tableting method, and more specifically, examples thereof include a direct tableting method, a dry tableting method, a wet tableting method, and an external lubricant tableting method.

[0034] In addition, when tablets are manufactured by tableting, filming or sticking to the plate surface may occur in the tablet press as tablet production continues. Filming is a phenomenon in which powder adheres to the surface of the punch of the tablet press. When this occurs, tablets are pressed with a punch with powder attached, resulting in a rough surface and a lack of gloss (rough) tablet properties. As a result, problems occur in printing, such as ink seeping in, blurring and rubbing, and inability to read the markings of company emblems and product codes. In addition, tablets with rough surfaces are often worn down by impact during distribution, even if they are selected as normal products. Furthermore, when pushing out from a blister sheet or filling into a cassette of an automatic tablet packaging machine, worn powder adheres to the tablet, which is undesirable. Furthermore, if tableting continues while filming occurs, the powder attached to the punch itself will harden, and if tableting is performed using a punch with such hardened powder attached, the tablet surface will become dented or the marking will be damaged, a phenomenon called sticking will occur. Therefore, it is necessary to remove the powder attached to the punch every time filming occurs, which is troublesome. Furthermore, plate surface adhesion is a phenomenon in which powder adheres to the turntable (area where the mortar is set) of the tablet press. In this case, although the possibility of adversely affecting the obtained tablet itself is smaller than filming, it is still preferable to remove the attached powder, which is troublesome. Therefore, although filming and plate surface adhesion themselves do not cause a problem in the therapeutic efficacy of the orally disintegrating tablet of the present disclosure, it is preferable to adopt a manufacturing method that does not cause filming or plate surface adhesion (especially filming) from the viewpoints of handling by medical personnel, patient dosing, and manufacturing efficiency.

[0035] In the production of the orally disintegrating tablet of the present disclosure, it is preferable to adopt an external lubricated tableting method, since filming is suppressed. Therefore, in one embodiment, the orally disintegrating tablet of the present disclosure is produced by an external lubricated tableting method. More specifically, it is preferable to add a lubricant by spraying during the process of tableting (compressing) the above mixture (i.e., during tableting). In particular, it is preferable that the mixture also contains a lubricant. In this embodiment, the lubricant contained in the composition (preferably the mixture) subjected to tableting can be the (D1) internal lubricant, and the lubricant sprayed during tableting can be the (D2) external lubricant.

[0036] Therefore, in one embodiment, the orally disintegrating tablet of the present disclosure can be produced by a method comprising a step of mixing (A) to (C) and (D1) an internal lubricant and compressing the mixture into tablets, wherein in the tableting step, (D2) an external lubricant is added by spraying (external lubricated tableting).

[0037] Furthermore, in the manufacturing method of the present disclosure, the above granulation method and tabletting method can be combined. For example, the orally disintegrating tablet of the present disclosure is more preferably manufactured by a method including a step of granulating a mixture containing (A) to (C) ((E) and / or (F) as necessary, and further other components can also be used), further mixing with (D1) an internal lubricant, and tableting the obtained mixture, in which (D2) an external lubricant is further added by spraying during the tableting (external lubricated tableting).

[0038] When prepared by such an external lubricant compression method, the (D1) internal lubricant contained in the mixture and the (D2) external lubricant sprayed during compression may be the same or different. The total weight of (D1) and (D2) is the weight of the (D) lubricant contained in the orally disintegrating tablet, and the weight ratio (D1:D2) of (D1) to (D2) is, for example, about 10:0.5-15, about 10:1-10, or about 10:2-9. Alternatively, for example, about 10:1-7, about 10:1-6, about 10:1-5, or about 10:2-5 can also be mentioned.

[0039] Although not particularly limited, the (D1) internal lubricant is preferably sodium stearyl fumarate, and the (D2) external lubricant is preferably magnesium stearate and / or sodium stearyl fumarate. More preferably, the (D1) internal lubricant of the orally disintegrating tablet of the present disclosure is sodium stearyl fumarate, and the (D2) external lubricant is magnesium stearate.

[0040] (Dosage / Dosage) The dosage of the orally disintegrating tablet of the present disclosure is appropriately selected depending on, for example, the method of use, the age, sex and other conditions of the patient, the severity of the disease, and the like. For example, the amount of the active ingredient (A) brexpiprazole or a salt thereof per day can be about 0.05 to 6 mg of brexpiprazole.

[0041] (Tablet hardness) The orally disintegrating tablet of the present disclosure is not particularly limited, and may have a tablet hardness of about 15 to 70 N, about 20 to 60 N, or about 30 to 60 N. The orally disintegrating tablet of the present disclosure preferably has a disintegration time of 70 seconds or less, and more preferably 65 seconds or less, 60 seconds or less, 55 seconds or less, 50 seconds or less, 45 seconds or less, 40 seconds or less, 35 seconds or less, 30 seconds or less, 25 seconds or less, or 20 seconds or less.

[0042] The tablet hardness is a value measured by measuring the hardness of the tablet in the diametric direction using a tablet hardness tester (e.g., MultiTest 50 (Pharmatron)). The disintegration time is a value measured by the test method for immediate release preparations (plain tablets) in General Test Method 6.09 Disintegration Test Method of the 17th Edition of the Japanese Pharmacopoeia (temperature setting: 37°C ± 2.0°C, test liquid: water). For example, a disintegration tester NT-200 (Toyama Sangyo) can be used for the measurement.

[0043] (Indications) The orally disintegrating tablet of the present disclosure can be used, for example, to prevent or treat central nervous system diseases.

[0044] Specific examples of central nervous system disorders that can be prevented or treated using the orally disintegrating tablet of the present disclosure include, but are not limited to, schizophrenia, treatment-resistant, refractory or chronic schizophrenia, ataxic affective disorder, psychotic disorder, mood disorder, bipolar disorder (e.g., bipolar I disorder and bipolar II disorder), depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorder (e.g., panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatoform disorder (e.g., hysteria, somatization disorder, conversion disorder, pain disorder, hypochondriasis, etc.), factitious disorder, dissociative disorder, sexual disorder (e.g., sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.), eating disorder (e.g., anorexia nervosa, bulimia nervosa, etc.), sleep disorder, Adjustment disorder, substance-related disorder (e.g., alcohol abuse, intoxication and drug addiction, stimulant addiction, narcotic addiction, etc.), anhedonia (e.g., anhedonia, iatrogenic anhedonia, anhedonia due to psychological or mental causes, anhedonia associated with depression, anhedonia associated with schizophrenia, etc.), delirium, cognitive impairment, cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases, cognitive impairment caused by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and related disorders, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, intractable, or chronic schizophrenia, etc., vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder (autism), Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down's syndrome, impulsive symptoms associated with dementia (e.g., agitation associated with Alzheimer's dementia), borderline personality disorder, and various other disorders of the central nervous system.

[0045] In addition, in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes all arbitrary combinations of the constituent features described in this specification.

[0046] In addition, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter included in the present disclosure. In other words, the present disclosure includes all subject matter consisting of all combinations of each combinable characteristic described in this specification. EXAMPLES

[0047] Hereinafter, the embodiments of the present disclosure will be described more specifically with reference to examples, but the embodiments of the present disclosure are not limited to the following examples.

[0048] Unless otherwise specified below, brexpiprazole was synthesized according to a known method and then pulverized with a hammer mill before use.

[0049] The disintegration test was performed according to the general test method 6.09 Disintegration Test for immediate release preparations (plain tablets) in the 17th Edition of the Japanese Pharmacopoeia (temperature setting: 37°C ± 2.0°C, test liquid: water). NT-200 (Toyama Sangyo) was used as the disintegration tester.

[0050] The dissolution test was performed according to the General Test Method 6.10 Dissolution Test of the 17th Edition of the Japanese Pharmacopoeia (dissolution test medium: dissolution test medium 1 (2.0 g of sodium chloride dissolved in 7.0 mL of hydrochloric acid and water to make 1000 mL, pH approximately 1.2), paddle rotation speed: 50 rpm, test liquid volume: 900 mL, temperature setting: 37±0.5°C, measurement wavelengths: λ1=214 nm, λ2=380 nm). The dissolution tester used was an NTR-6200A (Toyama Sangyo).

[0051] The hardness of the tablets was measured in the diametric direction using a tablet hardness tester MultiTest 50 (Pharmatron).

[0052] Disintegrant study 1 [Example 1-1] According to the formulation shown in Table 1, a suspension of partially pregelatinized starch as a binder was sprayed and added to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, corn starch, low-substituted hydroxypropylcellulose (LH-11), and sucralose, and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant, and the granules were compressed (compression pressure 6 kN or 9 kN) to obtain orally disintegrating tablets. [Example 1-2] According to the formulation shown in Table 1, a suspension of partially pregelatinized starch as a binder was sprayed and added to the granulated powder components of brexpiprazole, D-mannitol, crystalline cellulose, corn starch, sodium starch glycolate (Primojel), and sucralose, and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant, and the granules were compressed (compression pressure 6 kN or 9 kN) to obtain orally disintegrating tablets. [Examples 1-3] According to the formulation shown in Table 1, a suspension of partially pregelatinized starch as a binder was sprayed and added to the granulated powder components of brexpiprazole, D-mannitol, crystalline cellulose, corn starch, croscarmellose sodium (Kicolate ND-2HS), and sucralose, and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant, and the granules were compressed (compression pressure 6 kN or 9 kN) to obtain orally disintegrating tablets.

[0053] [Table 1]

[0054] Immediately after compression, each orally disintegrating tablet was subjected to a disintegration test. The results are shown in Figure 1. No impractical disintegration delay was observed regardless of the disintegrant used. Among them, low-substituted hydroxypropyl cellulose was found to be preferable.

[0055] Consideration of hardness retention [Example 2-1] According to the formulation shown in Table 2, a suspension of partially pregelatinized starch as a binder was sprayed and added to the granulated powder components brexpiprazole, D-mannitol, low-substituted hydroxypropyl cellulose, and sucralose, and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant, and the granules were compressed (compression pressure 6 kN or 9 kN) to obtain orally disintegrating tablets. [Example 2-2] According to the formulation shown in Table 2, a suspension of partially pregelatinized starch as a binder was sprayed and added to the granulated powder components of brexpiprazole, D-mannitol, crystalline cellulose (Ceolas PH-101) 5 mg, low-substituted hydroxypropylcellulose, and sucralose, and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant, and the granules were compressed (compression pressure 6 kN or 9 kN) to obtain orally disintegrating tablets. [Example 2-3] According to the formulation shown in Table 2, a suspension of partially pregelatinized starch as a binder was sprayed and added to the granulated powder components of brexpiprazole, D-mannitol, crystalline cellulose (Ceolas PH-101) 10 mg, low-substituted hydroxypropylcellulose, and sucralose, and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant, and the granules were compressed (compression pressure 6 kN or 9 kN) to obtain orally disintegrating tablets.

[0056] [Table 2]

[0057] For each orally disintegrating tablet, the hardness and disintegration time were measured at the start of storage and after 3 days, 7 days, and 14 days under humidified storage at 25° C. / 75% RH (relative humidity). The hardness retention rate obtained from the hardness measurement results is shown in Figure 2a. The disintegration time measurement results are shown in Figure 2b. Regardless of the amount of crystalline cellulose used, a practical hardness was maintained. Among them, it was found that the example using 10 mg of crystalline cellulose (Example 2-3) was preferable.

[0058] Consideration of binders [Example 3-1] According to the formulation shown in Table 3, a suspension of partially pregelatinized starch (PCS PC-10) as a binder was sprayed and added to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and sucralose, and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant, and the granules were compressed (compression pressure 4 kN, 5 kN, or 6 kN) to obtain orally disintegrating tablets.

[0059] [Comparative Example 3-2] According to the formulation shown in Table 3, a suspension of pregelatinized starch (SWELSTAR WB-1) was sprayed and added to the granulated powder components (brexpiprazole, D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, and sucralose) and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate was then added to the granules as a lubricant and compressed (compression pressure 4 kN, 5 kN, or 6 kN) to obtain orally disintegrating tablets.

[0060] [Table 3]

[0061] The degree of pregelatinization of the partially pregelatinized starch used (PCS PC-10: Asahi Kasei Corporation) was 55 to 70%, and the degree of pregelatinization of the pregelatinized starch used (SWELSTAR WB-1: Asahi Kasei Corporation) was 90 to 100%. The water-soluble component content of the partially pregelatinized starch used was 3% or less.

[0062] The disintegrability and hardness of each orally disintegrating tablet were measured. The results are shown in Figure 4. It was found that the use of partially pregelatinized starch was more preferable because it maintained a suitable hardness while also having good disintegrability, and was able to maintain a good balance between the two. It can also be said that the use of partially pregelatinized starch broadened the range of tablet compression pressure conditions that simultaneously satisfied the desired hardness and disintegration time.

[0063] Lubricant Considerations [Example 4-1] According to the formulation shown in Table 4, the suspension of partially pregelatinized starch, which is a binder, was sprayed and added to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropylcellulose, and granulated to obtain granules (fluidized bed granulation method). After sieving the granules, a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder. As the green pigment dispersion, a pigment component, Pigment Blend PB-1543 Green, was triturated with corn starch of 5 times its weight. Sucralose was used as the sweetener. Then, 0.9 mg of sodium stearyl fumarate (PRUV) was added as a lubricant to the post-added mixed powder, and the mixture was compressed (compression pressure 3 kN, 5 kN, or 7 kN) to obtain an orally disintegrating tablet. [Example 4-2] According to the formulation shown in Table 4, the suspension of partially pregelatinized starch, which is a binder, was sprayed and added to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropylcellulose, and granulated to obtain granules (fluidized bed granulation method). After sizing the granules, a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder. As the green pigment dispersion, a pigment component, Pigment Blend PB-1543 Green, was triturated with corn starch of 5 times its weight. Sucralose was used as the sweetener. Then, 1.8 mg of sodium stearyl fumarate (PRUV) was added as a lubricant to the post-added mixed powder, and the mixture was compressed (compression pressure 3 kN, 5 kN, or 7 kN) to obtain an orally disintegrating tablet. [Example 4-3] According to the formulation shown in Table 4, the suspension of partially pregelatinized starch, which is a binder, was sprayed and added to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropylcellulose, and granulated to obtain granules (fluidized bed granulation method). After sieving the granules, a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder. As the green pigment dispersion, a pigment component, Pigment Blend PB-1543 Green, was triturated with corn starch of 5 times its weight. Sucralose was used as the sweetener. Then, 3.6 mg of sodium stearyl fumarate (PRUV) was added as a lubricant to the post-added mixed powder, and the mixture was compressed (compression pressure 3 kN, 5 kN, or 7 kN) to obtain an orally disintegrating tablet. [Example 4-4] According to the formulation shown in Table 4, the suspension of partially pregelatinized starch, which is a binder, was sprayed and added to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropylcellulose, and granulated to obtain granules (fluidized bed granulation method). After sieving the granules, a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder. As the green pigment dispersion, a pigment component, Pigment Blend PB-1543 Green, was triturated with corn starch of 5 times its weight. Sucralose was used as the sweetener. Then, 0.9 mg of magnesium stearate was added as a lubricant to the post-added mixed powder, and the mixture was compressed (compression pressure 3 kN, 5 kN, or 7 kN) to obtain an orally disintegrating tablet.

[0064] [Table 4]

[0065] The hardness of each orally disintegrating tablet immediately after tableting was measured, and the tablet was also subjected to a disintegration test. The results are shown in Figures 4a and 4b, respectively. All orally disintegrating tablets had practical hardness and disintegration properties. In particular, when sodium stearyl fumarate was used as a lubricant (e.g., Example 4-1 or 4-2), it was found that a particularly excellent orally disintegrating tablet having high hardness and short disintegration time was obtained.

[0066] Lubrication during tableting (external lubrication) When tableting production of the orally disintegrating tablets of the above Examples 4-1 to 4-4 was continued, filming occurred after about 5 to 30 minutes of tableting production in Examples 4-1 and 4-2, in which sodium stearyl fumarate was used as an internal lubricant. Filming also occurred in Example 4-3, although it was minor.

[0067] Filming is a phenomenon in which powder adheres to the surface of the punch of a tablet press. When this occurs, tablets are pressed with a punch that has powder attached to it, resulting in a rough (rough) surface. Furthermore, if tableting continues with filming occurring, the powder attached to the punch itself will harden, and tablets produced by pressing with a punch that has hardened and adhered to such powder will have a concave surface. Therefore, the powder attached to the punch must be removed every time filming occurs, which is disadvantageous for mass production.

[0068] Moreover, in Example 4-4 in which magnesium stearate was used as the internal lubricant, the tablet physical properties (balance between hardness and disintegration property) were poor.

[0069] Therefore, we investigated whether there was a way to prevent this filming, and found that it could be prevented by the external lubricant compression method, in which the lubricant is supplied from the outside, as shown below. More specifically, the external lubricant compression method is a method in which a small amount of lubricant is forcibly charged and sprayed directly onto the upper and lower punches and dies.

[0070] That is, according to the formulation shown in Example 5-3 of Table 5a, a suspension of partially pregelatinized starch as a binder was sprayed and added to the granulated powder components of brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropylcellulose, and granulated to obtain granules (fluidized bed granulation method). After sieving the granules, a yellow pigment dispersion, a blue pigment dispersion, and a sweetener were added and mixed to obtain a post-addition mixed powder. As the yellow pigment dispersion, yellow ferric oxide was dispersed with 5 times the weight of corn starch, and as the blue pigment dispersion, blue No. 2 aluminum lake was dispersed with 5 times the weight of corn starch, and sucralose was used as the sweetener. Then, sodium stearyl fumarate was added internally as a lubricant. Furthermore, an external lubricant compression method was adopted, and 0.21 mg of magnesium stearate was sprayed during compression (compression pressure 3 to 8 kN) to obtain an orally disintegrating tablet. That is, sodium stearyl fumarate was used as an internal lubricant and magnesium stearate was used as an external lubricant.

[0071] Table 5a also shows the compositions of Examples 4-2 and 4-4.

[0072] [Table 5a]

[0073] The tablet physical properties (balance between hardness and disintegration property) and filming of the tablets of Examples 4-2, 4-4, and 5-3 were examined, and the results are shown in Table 5b and FIG.

[0074] [Table 5b]

[0075] Furthermore, orally disintegrating tablets were obtained in the same manner as in Example 5-3, except that an external lubricant compression method was used and 0.05, 0.10, or 0.38 mg of magnesium stearate was added by spraying during tableting (tabletting pressure 3 to 8 kN) according to the formulation shown in Table 5c (Examples 5-1, 5-2, and 5-4). The composition of Example 5-3 is also shown in Table 5c.

[0076] [Table 5c]

[0077] The total amount of solid components in the tablets of each Example differs slightly due to the difference in the amount of magnesium stearate added as an external lubricant.

[0078] No filming was observed when any of the orally disintegrating tablets (Examples 5-1 to 5-4) were compressed. All of the orally disintegrating tablets exhibited good hardness and disintegration time, and were able to achieve both tableting suitability and oral disintegrability. When comparing the pushing pressure during each orally disintegrating tablet production process when compressed at a compression pressure of 6 kN, Example 5-1 exhibited a slightly high pushing pressure, but the other Examples had low values, allowing continuous compression.

[0079] Examination of particle size of D-mannitol According to the formulations shown in Table 6, orally disintegrating tablets of Examples 6-1 to 6-3 were produced using D-mannitol having different particle sizes. [Example 6-1] to [Example 6-3] According to the formulation shown in Table 6, the suspension of partially pregelatinized starch, which is a binder, was sprayed and added to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropylcellulose, and granulated to obtain granules (fluidized bed granulation method). As D-mannitol, Pearitol 50C (Rocket Co., Ltd.) was used in Example 6-1, Pearitol 160C (Rocket Co., Ltd.) in Example 6-2, and Pearitol 300DC (Rocket Co., Ltd.) in Example 6-3. After the granules were sized, a yellow pigment dispersion, a blue pigment dispersion, and a sweetener were added and mixed to obtain a post-addition mixed powder. As the yellow pigment dispersion, yellow ferric oxide was dispersed with 5 times the weight of corn starch, and as the blue pigment dispersion, blue No. 2 aluminum lake was dispersed with 5 times the weight of corn starch, and sucralose was used as the sweetener. Then, sodium stearyl fumarate was added internally as a lubricant. Furthermore, an external lubricant tableting method was adopted, and magnesium stearate was added by spraying during tableting (tabletting pressure 4 kN, 6 kN, or 8 kN) to obtain orally disintegrating tablets.

[0080] [Table 6]

[0081] The dissolution and tablet physical properties (balance between hardness and disintegration) of the tablets of Examples 6-1 (Pearitol 50C: 50% particle size 35 μm), 6-2 (Pearitol 160C: 50% particle size 70 μm), and 6-3 (Pearitol 300DC: 50% particle size 250 μm) were evaluated. The results are shown in FIG. 6a for dissolution and in FIG. 6b for tablet physical properties. Examples 6-1 to 6-3 use D-mannitol with different particle sizes. Practical dissolution and tablet physical properties were achieved regardless of the particle size of D-mannitol used. Among them, it was found that the example (Example 6-1) using D-mannitol with a 50% particle size of 35 μm was preferable. All tablets had an appearance that was practically acceptable, but it was found that the tablet using D-mannitol with a small particle size had a uniform color tone on the tablet surface and was more preferable.

[0082] Examination of the crystal shape of D-mannitol According to the formulations shown in Table 7, orally disintegrating tablets of Examples 7-1 and 7-2 were produced. [Example 7-1] and [Example 7-2] According to the formulation shown in Table 7, the suspension of partially pregelatinized starch, which is a binder, was sprayed and added to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropylcellulose, and granulated to obtain granules (fluidized bed granulation method). As D-mannitol, Pearitol 50C (Rocket Co., Ltd.) was used in Example 7-1, and Parteck Delta M (Merck Co., Ltd.) was used in Example 7-2. After the granules were sized, a yellow pigment dispersion, a blue pigment dispersion, and a sweetener were added and mixed to obtain a post-addition mixed powder. As the yellow pigment dispersion, yellow ferric oxide was dispersed with 5 times the weight of corn starch, and as the blue pigment dispersion, blue No. 2 aluminum lake was dispersed with 5 times the weight of corn starch, and as the sweetener, sucralose was used. Thereafter, sodium stearyl fumarate was added as a lubricant to the post-added mixed powder, and the mixture was compressed (compression pressure 8 kN) to obtain orally disintegrating tablets.

[0083] [Table 7]

[0084] First, the crystal shape of D-mannitol was evaluated before and after granulation and after tableting for Example 7-1 (Pearitol 50C) and Example 7-2 (Parteck Delta M). The crystal shape of D-mannitol was evaluated by observing the cross section of the granulated product or tablet at a magnification of 500 times or 2000 times using an electron microscope (KEYENCE Real Surface View Microscope VE-7800). The results are shown in Figure 7a. Pearitol 50C (Example 7-1) consistently showed a plate-like crystal shape before and after granulation. On the other hand, Parteck Delta M (Example 7-2) showed a plate-like crystal shape before granulation, but the crystal shape changed from plate-like to needle-like after granulation. When the subsequent manufacturing process was carried out using the obtained granulated product, orally disintegrating tablets could be produced in all Examples. The difference between the plate-like and needle-like crystal shapes observed in the granulated product could also be clearly confirmed in the cross section of the tablet after tableting.

[0085] Next, for Example 7-1 (Pearitol 50C), the tableting suitability (presence or absence of filming) and tablet appearance were evaluated. The tablet appearance was evaluated using a digital camera and a digital microscope (Keyence VHX-500). The results are shown in Figure 7b. When Pearitol 50C was used as D-mannitol (Example 7-1), no filming was observed even 30 minutes after the start of tableting, indicating a high filming suppression effect. In addition, the obtained tablets had a glossy surface.

Claims

1. (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) Lubricant Contains The partially pregelatinized starch has a degree of pregelatinization of 70% or less. Orally disintegrating tablet.

2. 2. The orally disintegrating tablet according to claim 1, wherein (D) the lubricant comprises magnesium stearate and sodium stearyl fumarate.

3. 2. The orally disintegrating tablet according to claim 1, wherein the lubricant (D) comprises an internal lubricant (D1) and an external lubricant (D2).

4. 4. The orally disintegrating tablet according to claim 3, wherein (D1) the internal lubricant comprises sodium stearyl fumarate and (D2) the external lubricant comprises magnesium stearate.

5. The orally disintegrating tablet according to any one of claims 1 to 4, wherein the 50% particle size of the D-mannitol (B) is 10 µm to 100 µm, and the D-mannitol (B) is present in the tablet in a non-acicular crystalline form.

6. The orally disintegrating tablet according to any one of claims 1 to 5, wherein the partially pregelatinized starch (C) is a partially pregelatinized starch having a proportion of water-soluble components of 10% or less.

7. The orally disintegrating tablet according to any one of claims 1 to 6, further comprising (E) crystalline cellulose.

8. The orally disintegrating tablet according to claim 7, containing 5 to 15% by weight of (E) crystalline cellulose.

9. The orally disintegrating tablet according to any one of claims 1 to 8, further comprising (F) low-substituted hydroxypropyl cellulose.

10. The orally disintegrating tablet according to any one of claims 1 to 9, wherein the tablet hardness in the diameter direction of the tablet measured using a tablet hardness tester is 15N to 70N, and the disintegration time measured by the test method for immediate release preparations (plain tablets) in the Japanese Pharmacopoeia General Test Method 6.09 Disintegration Test is 70 seconds or less.

11. The orally disintegrating tablet according to any one of claims 1 to 10, for preventing or treating a central nervous system disease.

12. The orally disintegrating tablet according to claim 11, for preventing or treating a central nervous system disorder selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, ataxic affective disorder, psychotic disorder, mood disorder, bipolar disorder, depression, endogenous depression, major depression, melancholic and treatment-resistant 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 disorder, cognitive disorder associated with neurodegenerative disease, cognitive disorder caused by neurodegenerative disease, cognitive disorder of schizophrenia, cognitive disorder caused by treatment-resistant, refractory or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down's syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

13. (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) Lubricant wherein the partially pregelatinized starch has a degree of pregelatinization of 70% or less, (D) the lubricant comprises (D1) an internal lubricant and (D2) an external lubricant; The method includes a step of mixing (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D1) an internal lubricant, and a step of compressing the mixture into tablets, wherein in the tableting step, an external lubricant (D2) is added by spraying.

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