Orally disintegrating tablets

Abstract

To provide orally disintegrating tablets containing Brexpiprazole or a salt thereof that have practical hardness and disintegrate quickly in the oral cavity.SOLUTION: Provided is an orally disintegrating tablet containing (A) Brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D) a lubricant. The lubricant includes magnesium stearate and sodium stearyl fumarate. Preferably, the lubricant includes an internal lubricant and an external lubricant, more preferably, the internal lubricant includes sodium stearyl fumarate and the external lubricant includes magnesium stearate.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 known as brexpiprazole) or its salts has a dopamine D2 receptor partial agonist effect and a serotonin 5-HT 2A It is known to have receptor antagonistic effects and adrenaline α1 receptor antagonistic effects, and in addition to these effects, it also has a serotonin uptake inhibitory effect (or 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] Japanese Patent Application Laid-Open No. 2006-316052 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 that 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. Item 1. The orally disintegrating tablet according to Item 1, wherein the lubricant (D) comprises magnesium stearate and sodium stearyl fumarate. Section 3. Item 1. 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 oral administration method 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. Internally disintegrating tablet. Section 6. (C) The orally disintegrating tablet according to any one of Items 1 to 5, wherein the partially pregelatinized starch has a water-soluble component ratio of 10% or less. Section 7. Item 8. The orally disintegrating tablet according to any one of Items 1 to 6, further comprising (E) crystalline cellulose. 8. The orally disintegrating tablet according to claim 7, comprising 5 to 15% by weight of (E) 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 measured using a tablet hardness tester is 15 N to 70 N, and the disintegration time measured according to the test method for immediate-release preparations (uncoated tablets) in Japanese Pharmacopoeia General Test Method 6.09 Disintegration Test is 70 seconds or less. 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 neurodegenerative disease, cognitive impairment caused by 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: Orally disintegrating tablets manufactured by external lubrication tableting. 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: (D) the lubricant comprises (D1) an internal lubricant and (D2) an external lubricant; the method comprises the steps of mixing (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D1) an internal lubricant, and compressing the mixture into tablets; The method, wherein (D2) an external lubricant is added by spraying in the tableting step. 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: 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 no. 2 aluminum lake; and corn starch An orally disintegrating tablet comprising or preferably consisting of: [Effects 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 explanation 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. [Figure 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. [Figure 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] 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 section of the produced orally disintegrating tablets. [Figure 7b] 7 shows a photograph of the surface of the punch of the tablet press used in the production of the orally disintegrating tablets of Example 7-1, and the tablet appearance of the orally disintegrating tablets. DETAILED DESCRIPTION OF THE INVENTION

[0009] Each embodiment of the present disclosure will be described in more detail below. 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 encompassed by the present disclosure contains (A) brexpiprazole or a salt thereof, as well as (B) D-mannitol, (C) partially pregelatinized starch, and (D) a lubricant. The orally disintegrating tablet encompassed by 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.), 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.); salts of inorganic bases such as tri(lower)alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, isopropyl alcohol, methyl methyl amine ... Examples of the salt include salts of organic bases such as midazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkylmorpholines (e.g., N-methylmorpholine), 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, but is not limited to, for example, 0.1 to 10 wt % or 0.3 to 5 wt % of (A) brexpiprazole or a salt thereof. Furthermore, the orally disintegrating tablet of the present disclosure may contain, but is not limited to, for example, 0.05 to 10 mg, 0.1 to 8 mg, or 0.5 to 5 mg of (A) brexpiprazole or a salt thereof.

[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 referred to as D50 or median diameter, and represents the particle size of 50% of the particles larger and 50% smaller than this size. The 50% particle size is determined by laser diffraction scattering.

[0014] In addition, (B)D-mannitol is known to exist in various crystal polymorphs, such as α (alpha), β (beta), and δ (delta), as well as in various crystal shapes, such as plate-like, needle-like, and porous (hollow) shapes. It is generally known that the crystal shape (crystal form, crystal habit) is determined by the ratio of the forward speeds of each crystal face, and changes significantly depending on the influence of amorphous components and impurities in the solution. For example, if the growth of the crystal's sides is inhibited by some factor, the crystal will grow in only one direction and take on a needle-like shape. Various other crystal shapes have also been reported, including plate-like, prismatic, cubic, dendritic, and bulky shapes (Masakuni Matsuoka, "Fundamentals and Applications of Crystal Polymorphism," Popular Edition, CMC Publishing, 2010; Hiroshi Takiyama, "Intensifying Crystallization," First Edition, S&T Publishing, (2013). Commercially available beta D-mannitol crystals are usually produced as plate-shaped crystalline powder. On the other hand, commercially available delta D-mannitol crystals undergo a transition from delta to beta during the granulation process, during which the crystal shape changes from plate-shaped to needle-shaped. The crystalline shape of D-mannitol in tablets or granulated granules can be determined, for example, by observation using a microscope. The orally disintegrating tablet of the present disclosure may contain any crystalline polymorph of D-mannitol, but beta D-mannitol is preferred. Furthermore, in the production of orally disintegrating tablets, the use of D-mannitol that exists in a non-acicular, preferably plate-shaped, crystalline form during tableting is particularly effective in suppressing the filming phenomenon described below, and is therefore preferred. Therefore, in one embodiment, the (B) D-mannitol in the orally disintegrating tablet of the present disclosure exists in a non-acicular, preferably plate-shaped, crystalline form within the tablet.

[0015] In one embodiment, the (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 the form of non-acicular, preferably plate-like, crystals.

[0016] The orally disintegrating tablet of the present disclosure may contain, for example, about 20 to 90 wt. %, 40 to 85 wt. %, 55 to 85 wt. %, or 60 to 80 wt. Furthermore, the orally disintegrating tablet of the present disclosure may contain, for example, about 10 to 180 wt. %, 20 to 160 wt. %, or 30 to 140 wt. parts of (B) D-mannitol per part by weight of (A) brexpiprazole or a salt thereof, without any particular limitation.

[0017] (Partially pregelatinized starch) (C) Partially pregelatinized starch refers to starch that has been partially pregelatinized and that swells to form a cloudy liquid when water is added. In contrast, pregelatinized starch refers to starch that forms a viscous, pasty liquid when water is added. Partially pregelatinized starch can be prepared by heating starch (preferably corn starch) with water under normal or increased 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 according to the test method described in the "Cold-water-soluble matter" section of the "STARCH, PREGELATINIZED" section of European Pharmacopoeia 9.0.

[0018] Furthermore, 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 partially pregelatinized starch is a numerical value representing the proportion of the gelatinized (gelatinized) state in the starch, and is measured, for example, by the glucoamylase method.

[0019] 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. 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) Lubricants include, for example, stearic acid or a salt thereof (e.g., aluminum stearate, calcium stearate, magnesium stearate, etc.); carnauba wax, glycerin fatty acid ester, hardened oil, beeswax, white beeswax, talc, fumaric acid, sodium stearyl fumarate, polyethylene glycol (macrogol 400, macrogol Macrogol (e.g., Macrogol 600, Macrogol 1500, Macrogol 4000, Macrogol 6000, etc.) may be used alone or in combination of two or more. Among these, stearates, sodium stearyl fumarate, sucrose fatty acid esters, and hydrogenated oils are preferred, magnesium stearate and sodium stearyl fumarate are more preferred, and a combination of magnesium stearate and sodium stearyl fumarate is particularly preferred. As described below, (D) lubricants include (D1) internal lubricants contained inside the tablet and (D2) external lubricants contained outside the tablet. The orally disintegrating tablet of the present disclosure preferably contains both (D1) internal lubricants and (D2) external lubricants as (D) lubricants. The "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. Furthermore, a single component or a combination of two or more components may be used as the internal lubricant. Furthermore, a single component or a combination of two or more components may be used as the external lubricant. Furthermore, 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 orally disintegrating tablet of the present disclosure may contain, for example, about 0.1 to 5 wt. %, about 0.2 to 3 wt. %, or about 0.3 to 2 wt. The amount of (D) lubricant is not particularly limited, but may be, for example, about 0.05 to 2 wt. % or about 0.1 to 1.5 wt. % per part by weight of (A) brexpiprazole 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 to 0.35 g / 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 testing methods of the 17th edition of the Japanese Pharmacopoeia (3.01 Bulk Density Measurement Method, 3.04 Particle Size Measurement Method). More specifically, the bulk density was measured using the method using a volumeter (method 2), and the particle size was measured using the mechanical shaking method of 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. The amount of (E) crystalline cellulose is also, 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) Furthermore, for example, (F) low-substituted hydroxypropyl cellulose may be contained. As the low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose containing approximately 5 to 16% (by mass) of hydroxypropoxy groups is preferred. The upper or lower limit of this range may be approximately 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% (by mass). The hydroxypropoxy group content of low-substituted hydroxypropyl cellulose can be measured by the method described in the 17th edition of the Japanese Pharmacopoeia. The low-substituted hydroxypropyl cellulose can be produced by known production methods, and is also available as a commercially available product. Commercially available low-substituted hydroxypropyl cellulose products include, for example, the "LH series" and "NBD series" manufactured by Shin-Etsu Chemical Co., Ltd. However, the present invention is not limited to these.

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

[0028] (Other additives) In addition, for example, components other than those described above that are known in the field of pharmaceutical tablets may be contained within a range that does not impair the effects of the orally disintegrating tablet of the present disclosure. Such components include, for example, 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 excipients 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 its derivatives such as ethyl cellulose, carboxymethyl cellulose (carmellose), and sodium carboxymethyl cellulose (carmellose sodium); silicic acid or its salts 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 binders 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-based 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. Binders can be used alone or in combination. Sweeteners, such as aspartame and sucralose, and colorants, such as red ferric oxide, yellow ferric oxide, and blue No. 2 aluminum lake, can be used alone or in combination.

[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) includes preparing a mixture containing (A) to (C). This can be done by granulating the mixture and then mixing in (D) a lubricant. In the above process, (E), (F), and / or other ingredients can be added at an appropriate stage as needed.

[0032] The method for 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 preferred because it allows the active ingredient and other ingredients to be uniformly mixed, thereby obtaining tablets with a uniform ingredient content. Therefore, in one embodiment, the method for producing an orally disintegrating tablet of the present disclosure comprises a step of granulating a mixture containing (A) to (C) (and, if necessary, (E), (F), and / or other ingredients) by wet granulation. Furthermore, in one embodiment, the orally disintegrating tablet of the present disclosure comprises (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 tableting method includes, for example, tableting, and more specifically, direct tableting, dry tableting, wet tableting, external lubrication tableting, and the like.

[0034] When tablets are manufactured by tableting, continuous tablet production can cause filming and plate sticking in the tablet press. Filming is a phenomenon in which powder adheres to the surface of the punches of a tablet press. When this occurs, tablets are pressed using punches with powder attached, resulting in rough, dull (rough) tablets. As a result, problems occur, such as ink seeping in, blurring, and rubbing, making printing unclear, and making inscriptions such as company emblems and product codes illegible. Furthermore, tablets with rough surfaces often suffer wear and tear due to impacts during distribution, even if they are selected as normal products. Furthermore, worn powder adheres to the tablets when they are pushed out of blister sheets or loaded into cassettes of automatic tablet packaging machines, which is undesirable. Furthermore, if tableting continues while filming is occurring, the powder adhering to the punch itself will harden. When tableting is performed using a punch with such hardened powder, the tablet surface will become indented or the markings will be damaged, resulting in a phenomenon known as "sticking." Therefore, it is necessary to remove the powder adhering to the punch every time filming occurs, which is time-consuming. Furthermore, platen adhesion is a phenomenon in which powder adheres to the turntable (the area where the die is set) of a tablet press. In this case, although the possibility of adversely affecting the resulting tablet itself is smaller than with filming, it is still preferable to remove the adhering powder, which is time-consuming. Therefore, while filming and platen adhesion themselves do not pose a problem for the therapeutic efficacy of the orally disintegrating tablet of the present disclosure, it is preferable to adopt a manufacturing method that prevents filming and platen adhesion (especially filming) from the viewpoints of handling by medical professionals, patient dosing, and manufacturing efficiency.

[0035] In the production of the orally disintegrating tablet of the present disclosure, the externally lubricated tableting method is particularly preferred because filming is suppressed. Therefore, in one embodiment, the orally disintegrating tablet of the present disclosure is produced by the externally lubricated tableting method. More specifically, it is preferred to add a lubricant by spraying during the process of tableting (compressing) the above mixture (i.e., during tableting). In particular, it is preferred that a lubricant is also contained in the mixture. In this embodiment, the lubricant contained in the composition (preferably the mixture) subjected to tableting can be the (D1) internal lubricant, and the lubricant added by spraying 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 the steps 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-mentioned 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 comprising the steps of granulating a mixture containing (A) to (C) (optionally, (E) and / or (F), and further other ingredients can also be used), further mixing with (D1) an internal lubricant, and compressing the resulting mixture, wherein (D2) an external lubricant is further added by spraying during the tableting (externally lubricated tableting).

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

[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 selected appropriately depending on, for example, the method of use, the age, sex and other conditions of the patient, the severity of the disease, etc., but for example, the amount of the active ingredient (A) brexpiprazole or a salt thereof per day can be approximately 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. Furthermore, 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 the 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 the value measured by the test method for immediate-release preparations (uncoated tablets) in General Test Method 6.09 Disintegration Test of the Japanese Pharmacopoeia, 17th Edition (temperature setting: 37°C ± 2.0°C, test liquid: water). For example, a disintegration tester NT-200 (Toyama Sangyo) can be used for this 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 central nervous system disorders that may 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 disorders (e.g., panic attacks, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute sexual stress disorder, etc.), somatoform disorders (e.g., hysteria, somatization disorder, conversion disorder, pain disorder, hypochondria, etc.), factitious disorder, dissociative disorder, sexual disorders (e.g., sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.), eating disorders (e.g., anorexia nervosa, bulimia nervosa, etc.), sleep disorders, adjustment disorders, substance-related disorders (e.g., alcohol abuse, addiction 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, 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 (for example, agitation associated with Alzheimer's disease), borderline personality disorder, and various other disorders of the central nervous system.

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

[0046] Furthermore, 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 encompassed by the present disclosure, i.e., the present disclosure encompasses all subject matter consisting of any combination of the combinable characteristics described herein. [Example]

[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 in 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 (uncoated tablets) in the 17th edition of the Japanese Pharmacopoeia (temperature setting: 37°C ± 2.0°C, test liquid: water). The NT-200 (Toyama Sangyo) was used as the disintegration tester.

[0050] Dissolution tests were performed according to the General Test Method 6.10 Dissolution Test of the Seventeenth 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 medium 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, the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose (LH-11), and sucralose, were sprayed with a suspension of partially pregelatinized starch as a binder, and granulated to obtain granules (fluidized bed granulation method). Then, stearic acid fumarate was added as a lubricant. Orally disintegrating tablets were obtained by adding sodium methylpropional to the granules and compressing them (compression pressure 6 kN or 9 kN). [Example 1-2] According to the formulation shown in Table 1, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, corn starch, sodium starch glycolate (Primojel), and sucralose), followed by granulation to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate as a lubricant was then added to the granules, which were then 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 onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, corn starch, croscarmellose sodium (Kicolate ND-2HS), and sucralose), followed by granulation to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate as a lubricant was then added to the granules, which were then 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 delay in disintegration was observed with any of the disintegrants. Among them, low-substituted hydroxypropyl cellulose was found to be the most 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 of brexpiprazole, D-mannitol, low-substituted hydroxypropyl cellulose, and sucralose, followed by granulation to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate as a lubricant was then added to the granules, which were then compressed (compression pressure of 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 ingredients (brexpiprazole, D-mannitol, 5 mg of microcrystalline cellulose (Ceolus PH-101), low-substituted hydroxypropyl cellulose, and sucralose), followed by granulation to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate as a lubricant was then added to the granules, which were then compressed (compression pressure of 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 ingredients (brexpiprazole, D-mannitol, 10 mg of microcrystalline cellulose (Ceolus PH-101), low-substituted hydroxypropyl cellulose, and sucralose), followed by granulation to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate as a lubricant was then added to the granules, which were then compressed (compression pressure of 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, the example using 10 mg of crystalline cellulose (Example 2-3) was found to be 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 ingredients (brexpiprazole, D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and sucralose) and granulated to obtain granules (fluidized bed granulation method). Sodium stearyl fumarate as a lubricant was then added to the granules, which were then 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) binder was sprayed and added to the granulated powder ingredients (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 as a lubricant to the granules, which were then compressed (compression pressure 4 kN, 5 kN, or 6 kN) to obtain orally disintegrating tablets.

[0060] [Table 3]

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

[0062] The disintegration 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, as it maintained a moderate hardness while also providing good disintegration, maintaining a good balance between the two. In addition, the use of partially pregelatinized starch broadened the range of tableting pressure conditions that simultaneously satisfied the desired hardness and disintegration time. It is also possible.

[0063] Lubricant Considerations [Example 4-1] According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose), followed by granulation 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-addition mixed powder. The green pigment dispersion was prepared by triturating the pigment component, Pigment Blend PB-1543 Green, with corn starch in an amount five times its weight. Sucralose was used as the sweetener. Subsequently, 0.9 mg of sodium stearyl fumarate (PRUV) was added as a lubricant to the post-addition mixed powder, which was then compressed (compression pressure: 3 kN, 5 kN, or 7 kN) to obtain orally disintegrating tablets. [Example 4-2] According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose), followed by granulation 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-addition mixed powder. The green pigment dispersion was prepared by triturating the pigment component, Pigment Blend PB-1543 Green, with corn starch in an amount five times its weight. Sucralose was used as the sweetener. Subsequently, 1.8 mg of sodium stearyl fumarate (PRUV) was added as a lubricant to the post-addition mixed powder, which was then compressed (compression pressure: 3 kN, 5 kN, or 7 kN) to obtain orally disintegrating tablets. [Example 4-3] According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose), followed by granulation 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-addition mixed powder. The green pigment dispersion was prepared by triturating the pigment component, Pigment Blend PB-1543 Green, with corn starch in an amount five times its weight. Sucralose was used as the sweetener. Subsequently, 3.6 mg of sodium stearyl fumarate (PRUV) was added as a lubricant to the post-addition mixed powder, which was then compressed (compression pressure: 3 kN, 5 kN, or 7 kN) to obtain orally disintegrating tablets. [Example 4-4] According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose), followed by granulation 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-addition mixed powder. The green pigment dispersion was prepared by triturating the pigment component, Pigment Blend PB-1543 Green, with corn starch in an amount five times its weight. Sucralose was used as the sweetener. Subsequently, 0.9 mg of magnesium stearate as a lubricant was added to the post-addition mixed powder, which was then tableted (tabletting pressure: 3 kN, 5 kN, or 7 kN) to obtain orally disintegrating tablets.

[0064] [Table 4]

[0065] The hardness of each orally disintegrating tablet was measured immediately after tableting, 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 (for example, Example 4-1 or 4-2), it was found that particularly excellent orally disintegrating tablets were obtained, which had high hardness and short disintegration times.

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

[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 the punch to which the powder adheres, resulting in a rough (rough) surface. Furthermore, if tableting continues while filming is occurring, the powder adhering to the punch itself will harden, and tablets produced by pressing with a punch to which such hardened powder adheres will have a concave surface. Therefore, the powder adhering to the punch must be removed every time filming occurs, which is disadvantageous for mass production.

[0068] Furthermore, in Example 4-4, in which magnesium stearate was used as the internal lubricant, the tablet 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 filming could be prevented by the external lubricant compression method, in which a 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] Specifically, according to the formulation shown in Example 5-3 in Table 5a, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose), followed by granulation to obtain granules (fluidized bed granulation). After sizing the granules, a yellow pigment dispersion, a blue pigment dispersion, and a sweetener were added and mixed to obtain a post-addition mixed powder. The yellow pigment dispersion was prepared by triturating yellow ferric oxide with 5 times its weight of corn starch, and the blue pigment dispersion was prepared by triturating blue No. 2 aluminum lake with 5 times its weight of corn starch. Sucralose was used as the sweetener. Sodium stearyl fumarate was then internally added as a lubricant. Furthermore, an external lubrication tableting method was employed, and 0.21 mg of magnesium stearate was sprayed during tableting (tabletting pressure 3 to 8 kN) to obtain orally disintegrating tablets. 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 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 (Examples 5-1, 5-2, and 5-4), except that an external lubrication tableting method was employed 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. Table 5c also shows the composition of Example 5-3.

[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. Furthermore, all orally disintegrating tablets exhibited good hardness and disintegration time, achieving both tableting suitability and oral disintegrability. When comparing the pushing pressure during the manufacturing process of each orally disintegrating tablet when compressed at a compression pressure of 6 kN, Example 5-1 exhibited a slightly high pushing pressure, but the other Examples exhibited low values, enabling 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, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose) and granulated to obtain granules (fluidized bed granulation method). As D-mannitol, Pearitol 50C (Roquette) was used in Example 6-1, Pearitol 160C (Roquette) in Example 6-2, and Pearitol 300DC (Roquette) in Example 6-3. After sizing the granules, a yellow pigment dispersion, a blue pigment dispersion, and a sweetener were added and mixed to obtain a post-addition mixed powder. The yellow pigment dispersion was prepared by triturating yellow ferric oxide with 5 times its weight of corn starch, and the blue pigment dispersion was prepared by triturating blue No. 2 aluminum lake with 5 times its weight of corn starch. Sucralose was used as the sweetener. Sodium stearyl fumarate was then added internally as a lubricant, and then an external lubrication tableting method was employed, with magnesium stearate being 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 for dissolution are shown in Figure 6a, and the results for tablet physical properties are shown in Figure 6b. Examples 6-1 to 6-3 each used D-mannitol with a different particle size. Practical dissolution and tablet physical properties were achieved regardless of the particle size of D-mannitol used. Among them, the example using D-mannitol with a 50% particle size of 35 μm (Example 6-1) was found to be preferable. All tablets had an appearance that was practically acceptable, but the tablets using D-mannitol with a small particle size had a uniform color tone on the tablet surface and were found to be 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, a suspension of partially pregelatinized starch as a binder was sprayed onto the granulated powder components (brexpiprazole, D-mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose) and granulated to obtain granules (fluidized bed granulation method). As the D-mannitol, Pearitol 50C (Roquette) was used in Example 7-1, and Parteck Delta M (Merck) was used in Example 7-2. After sizing the granules, a yellow pigment dispersion, a blue pigment dispersion, and a sweetener were added and mixed to obtain a post-addition mixed powder. The yellow pigment dispersion was prepared by triturating yellow ferric oxide with 5 times its weight of corn starch, and the blue pigment dispersion was prepared by triturating blue No. 2 aluminum lake with 5 times its weight of corn starch. Sucralose was used as the sweetener. 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 for Example 7-1 (Pearitol 50C) and Example 7-2 (Parteck Delta M) before and after granulation and after tableting. The crystal shape of D-mannitol was evaluated by observing the cross section of the granules or tablets at a magnification of 500x or 2000x 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 both before and after granulation. On the other hand, Parteck Delta M (Example 7-2) had a plate-like crystalline shape before granulation, but after granulation, the crystalline shape changed from plate-like to needle-like. The resulting granules were used in the subsequent manufacturing process, and orally disintegrating tablets were produced in all Examples. The difference between the plate-like and needle-like crystalline shapes observed in the granules was also clearly visible in the cross-section of the tablets 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), the tablet appearance was evaluated from the start of tableting. No filming was observed even after 30 minutes, demonstrating a high filming prevention effect. The obtained tablets also had a glossy surface.

Claims

[Claim 1] The invention described in the specification.

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