WO2021095779A1 - 口腔内崩壊錠 - Google Patents
口腔内崩壊錠 Download PDFInfo
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- WO2021095779A1 WO2021095779A1 PCT/JP2020/042114 JP2020042114W WO2021095779A1 WO 2021095779 A1 WO2021095779 A1 WO 2021095779A1 JP 2020042114 W JP2020042114 W JP 2020042114W WO 2021095779 A1 WO2021095779 A1 WO 2021095779A1
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- WIPO (PCT)
- Prior art keywords
- orally disintegrating
- disorder
- lubricant
- disintegrating tablet
- mannitol
- Prior art date
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Definitions
- the present disclosure relates to an orally disintegrating tablet containing brexpiprazole or a salt thereof, a method for producing the same, and the like.
- the contents of all documents described herein are incorporated herein by reference.
- the present inventors have studied for the main purpose of providing a tablet containing brexpiprazole or a salt thereof, which has a practical hardness but rapidly disintegrates in the oral cavity.
- the present inventors have the possibility of preparing an orally disintegrating tablet which has a practical hardness but rapidly disintegrates in the oral cavity by containing a specific component in addition to brexpiprazole or a salt thereof. Headed and further improved.
- Item 1 (A) Brexpiprazole or a salt thereof, (B) D-mannitol, An orally disintegrating tablet containing (C) partially pregelatinized starch and (D) a lubricant.
- Item 2. (D) The orally disintegrating tablet according to Item 1, wherein the lubricant contains magnesium stearate and stearyl sodium fumarate.
- Item 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.
- Item 2. The orally disintegrating tablet according to any one of Items 1 to 10, for preventing or treating a central nervous system disease.
- Schizophrenia refractory, refractory or chronic schizophrenia, ataxic emotional disorder, psychotic disorder, mood disorder, bipolar disorder, depression, intrinsic depression, major depression, melancholic and refractory depression , Mood disorder, Mood circulation disorder, Anxiety disorder, Physical expression disorder, False disorder, Dissociative disorder, sexual disorder, Eating disorder, Sleep disorder, Adaptation disorder, Material-related disorder, Numbness, Delusion, Cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment of schizophrenia, cognitive impairment due to treatment resistance, refractory or chronic schizophrenia, vomiting, vehicle sickness, obesity , Schizophrenia, pain, mental retardation, autism disorder, towlet disorder, tic disorder, attention deficit hyperactivity disorder, behavioral disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder Item 2.
- Item 13. (A) Brexpiprazole or a salt thereof, (B) D-mannitol, An orally disintegrating tablet containing (C) partially pregelatinized starch and (D) lubricant. An orally disintegrating tablet manufactured by the external sliding tableting method.
- Item 14. (A) Brexpiprazole or a salt thereof, (B) D-mannitol, A method for producing an orally disintegrating tablet containing (C) partially pregelatinized starch and (D) a lubricant.
- Lubricating agent contains (D1) internal lubricating agent and (D2) external lubricating agent.
- the method comprises mixing (A) brexpiprazole or a salt thereof, (B) D-mannitol, (C) partially pregelatinized starch, and (D1) an internal lubricant and tableting the mixture. , A method of spraying and adding (D2) an external lubricant in the step of locking. Item A-1. (A) Brexpiprazole or a salt thereof, (B) D-mannitol, An orally disintegrating tablet containing (C) partially pregelatinized starch and (D) lubricant.
- a step of granulating (A) brexpiprazole or a salt thereof, (B) D-mannitol, and (C) partially pregelatinized starch by a wet granulation method, and (D) a lubricant is further added to the granulated mixture.
- a method comprising a step of mixing and a step of tableting the resulting mixture. Item A-3.
- Brexpiprazole D-mannitol, Partially pregelatinized starch, Sodium stearyl fumarate and magnesium stearate, Crystalline cellulose, Partially pregelatinized starch, Sucralose, An orally disintegrating tablet containing or preferably consisting of at least one colorant selected from red iron sesquioxide, yellow iron sesquioxide, and blue No. 2 aluminum lake, and corn starch.
- an orally disintegrating tablet containing brexpiprazole or a salt thereof which has a practical hardness but rapidly disintegrates in the oral cavity.
- the disintegration time of the orally disintegrating tablets of Examples 1-1 to 1-3 is shown.
- the hardness retention rate of the orally disintegrating tablets of Examples 2-1 to 2-3 is shown.
- the disintegration time of the orally disintegrating tablets of Examples 2-1 to 2-3 is shown.
- the relationship between the disintegration time and the tablet hardness in the orally disintegrating tablets of Example 3-1 and Comparative Example 3-2 is shown.
- the hardness of the orally disintegrating tablets of Examples 4-1 to 4-4 is shown.
- the disintegration time of the orally disintegrating tablets of Examples 4-1 to 4-4 is shown.
- the relationship between the disintegration time and the tablet hardness of the orally disintegrating tablets of Examples 4-2, 4-2, and 5-3 is shown.
- the dissolution property of the orally disintegrating tablets of Examples 6-1 to 6-3 is shown.
- the tablet physical characteristics (relationship between hardness and disintegration) of the orally disintegrating tablets of Examples 6-1 to 6-3 are shown.
- the electron micrographs before and after granulation in the production of the orally disintegrating tablets of Examples 7-1 and 7-2 and the electron micrographs of the cross section of the produced orally disintegrating tablets are shown.
- the photograph of the punch surface of the tableting machine in the manufacture of the orally disintegrating tablet of Example 7-1 and the tablet appearance of the orally disintegrating tablet are shown.
- the present disclosure preferably includes, but is not limited to, an orally disintegrating tablet containing brexpiprazole or a salt thereof, a method for producing the same, and the like, and the present disclosure is all disclosed in the present specification and recognized by those skilled in the art. Including.
- the orally disintegrating tablets included in the present disclosure contain (A) brexpiprazole or a salt thereof, as well as (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 "orally disintegrating tablet of the present disclosure”.
- the salt of blexpiprazole is not particularly limited as long as it is a pharmacologically acceptable salt, and for example, an alkali metal salt (for example, sodium salt, potassium salt, etc.) and an alkaline earth metal salt (for example, calcium salt, magnesium salt, etc.).
- an alkali metal salt for example, sodium salt, potassium salt, etc.
- an alkaline earth metal salt for example, calcium salt, magnesium salt, etc.
- alkali metal carbonates eg, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.
- alkali metals hydrogen carbonate eg, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
- Salts of inorganic bases such as alkali metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); for example, tri (lower) alkylamines (eg, trimethylamine, triethylamine, N- Ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picolin, dimethylaminopyridine, dimethylaniline, N- (lower) alkyl-morpholin (eg, N-methylmorpholin, etc.), 1,5-diazabicyclo [4.3 .0] Nonen-5 (DBN), 1,8-diazabicyclo [5.4.0] Und
- Acid salt fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate
- organic acid salts such as salts.
- (A) Brexpiprazole or a salt thereof is not particularly limited in the orally disintegrating tablets of the present disclosure, but may be contained, for example, about 0.1 to 10% by weight or about 0.3 to 5% by weight.
- the amount of (A) brexpiprazole or a salt thereof is not particularly limited to one orally disintegrating tablet of the present disclosure, but is, for example, about 0.05 to 10 mg, 0.1 to 8 mg, or 0.5 to 5 mg. Can be contained.
- the (B) D-mannitol in the orally disintegrating tablet of the present disclosure is not particularly limited, but for example, the 50% particle size is 10 ⁇ m to 100 ⁇ m, preferably 15 ⁇ m to 80 ⁇ m, and more preferably 20 ⁇ m to 50 ⁇ m. Can be used.
- the 50% particle size is also expressed as D50 and the median diameter, and 50% of the particles are larger than this and 50% are smaller than this.
- the 50% particle size is determined by the laser diffraction / scattering method.
- D-mannitol has polymorphs such as ⁇ (alpha), ⁇ (beta), and ⁇ (delta) types, and different crystal shapes such as plate-like, needle-like, and poor (hollow) shapes. It is known to do. It is generally known that the crystal shape (crystal morphology, crystal habit) is determined by the ratio of the advancing speed of each surface of the crystal, and changes significantly under the influence of amorphizing components and impurities in the solution. .. For example, if the growth of the lateral sides of the crystal is inhibited by some factor, the crystal grows in only one direction and takes a needle-like morphology.
- the crystal shape of D-mannitol in tablets and granulated granules can be determined, for example, by observing with a microscope. Any crystalline polymorphic D-mannitol may be used for the orally disintegrating tablets of the present disclosure, but beta-type D-mannitol is preferably used. Further, in the production of an orally disintegrating tablet, when D-mannitol existing in a non-needle-like, preferably plate-like crystal form at the time of tableting is used, the effect of suppressing the filming phenomenon described later is particularly high, which is preferable. Therefore, in one embodiment, the (B) D-mannitol in the orally disintegrating tablet of the present disclosure is present in the tablet in a non-needle-like, preferably plate-like crystalline form.
- the (B) D-mannitol in the orally disintegrating tablet of the present disclosure has a 50% particle size of 10 ⁇ m to 100 ⁇ m and is present in the tablet in a non-needle-like, preferably plate-like crystalline form. To do.
- D-mannitol is not particularly limited in the orally disintegrating tablets of the present disclosure, but contains, for example, about 20 to 90% by weight, 40 to 85% by weight, 55 to 85% by weight, or 60 to 80% by weight. Can be done. Further, (B) D-mannitol is not particularly limited with respect to 1 part by weight of (A) brexpiprazole or a salt thereof, but is, for example, 10 to 180 parts by weight, 20 to 160 parts by weight, or 30 to 140 parts by weight. It can be contained in parts.
- Partially pregelatinized starch refers to a starch that is partially pregelatinized and swells to become a cloudy liquid when water is added. In contrast, pregelatinized starch refers to a viscous paste-like liquid when water is added. Partially pregelatinized starch can be prepared by heating starch (preferably corn starch) with water under normal pressure or pressure (drying if necessary). The partially pregelatinized starch preferably has a water-soluble component ratio of 10% or less, and is 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, or 3% or less. The one is more preferable. The ratio of the water-soluble component in the partially pregelatinized starch is measured by the test method described in "Cold-water-soluble matter" in the "STARCH, PREGELATINISED" section of European Pharmacopoeia 9.0.
- the partially pregelatinized starch (C) contained in the orally disintegrating starch of the present disclosure preferably has a degree of pregelatinization of 70% or less, preferably 30% to 70%, 40% to 70%, and 50%. More preferably, it is ⁇ 70%.
- the degree of pregelatinization in the partially pregelatinized starch is quantified as a ratio of the gelatinized (pregelatinized) state in the starch, and is measured by, for example, the glucoamylase method.
- the partially pregelatinized starch (C) is not particularly limited in the orally disintegrating tablets of the present disclosure, but is contained, for example, about 1 to 15% by weight, 1.5 to 10% by weight, or 2 to 8% by weight. obtain.
- the (C) partially pregelatinized starch is not particularly limited with respect to (A) 1 part by weight of brexpiprazole or a salt thereof, but is, for example, 0.5 to 30 parts by weight, 1 to 20 parts by weight, or 1 part. It can be contained in an amount of about 15 parts by weight.
- lubricant for example, stearic acid or a salt thereof (for example, aluminum stearate, calcium stearate, magnesium stearate, etc.); , Stearyl sodium fumarate, polyethylene glycol (macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, etc.) and the like. These lubricants may be used alone or in combination of two or more. Among these, stearate, sodium stearyl fumarate, sucrose fatty acid ester, and hydrogenated oil are preferable, magnesium stearate and sodium stearyl fumarate are more preferable, and magnesium stearate and sodium stearyl fumarate are particularly used in combination.
- the (D) lubricant includes an internal lubricant contained inside the tablet (D1) and an external lubricant contained outside the tablet (D2).
- the orally disintegrating tablets of the present disclosure preferably contain both (D1) internal lubricant and (D2) external lubricant as (D) lubricant.
- the “outside of the tablet” refers to the surface of the tablet, more specifically, the portion 0.1 mm from the surface of the tablet.
- the orally disintegrating tablets of the present disclosure preferably contain (D1) sodium stearyl fumarate as an internal lubricant and (D2) magnesium stearate as an external lubricant.
- the lubricant (D) is not particularly limited in the orally disintegrating tablets of the present disclosure, but is, for example, about 0.1 to 5% by weight, about 0.2 to 3% by weight, or 0.3 to 2% by weight. May be contained to some extent.
- the lubricant (D) is not particularly limited with respect to 1 part by weight of (A) brexpiprazole or a salt thereof, but is, for example, about 0.05 to 2 parts by weight or 0.1 to 1.5 parts by weight. It can be contained in parts.
- the orally disintegrating tablet of the present disclosure may contain other components (A) to (D) described above.
- (E) crystalline cellulose may be contained.
- the crystalline cellulose is not particularly limited, but is preferably one having an average particle size of, for example, about 10 to 100 ⁇ m, about 20 to 80 ⁇ m, about 30 to 70 ⁇ m, or about 40 to 60 ⁇ m.
- bulk density 0.1 ⁇ 0.5g / cm 3 low degree, about 0.15 ⁇ 0.45g / cm 3, 0.2 ⁇ 0.4g / cm 3 or so, or from 0.25 to 0 It is preferably about .35 g / cm 3.
- the average particle size and bulk density are measured in accordance with the 17th revised Japanese Pharmacy General Test Method (3.01 bulk density measurement method, 3.04 particle size measurement method). More specifically, the bulk density is a value measured by adopting the method using the volume meter of the second method, and the particle size measurement is a value measured by adopting the mechanical shaking method of the sieving method.
- (E) Crystalline cellulose is contained in the orally disintegrating tablet of the present disclosure, for example, about 1 to 20% by weight, about 5 to 15% by weight, or about 7.5 to 12.5% by weight. Further, (E) crystalline cellulose is contained, for example, about 0.1 to 40 parts by weight, 1 to 30 parts by weight, or 2 to 25 parts by weight with respect to 1 part by weight of (A) brexpiprazole or a salt thereof. ..
- (F) low-degree-of-substitution hydroxypropyl cellulose may be contained.
- the low degree of substitution hydroxypropyl cellulose hydroxypropyl cellulose containing about 5 to 16 (mass)% of hydroxypropoxy groups is preferable.
- the upper limit or the lower limit of the range may be about 6, 7, 8, 9, 10, 11, 12, 13, 14, or about 15 (mass)%.
- the content of hydroxypropoxy groups in low-degree-of-substitution hydroxypropyl cellulose can be measured by the method listed in the 17th revised Japanese Pharmacopoeia.
- the low-degree-of-substitution hydroxypropyl cellulose can be produced by a known production method, or a commercially available product can also be used.
- Examples of commercially available products of low-degree-of-substitution hydroxypropyl cellulose include, but are not limited to, "LH series” and "NBD series” manufactured by Shin-Etsu Chemical Co., Ltd.
- the low degree of substitution hydroxypropyl cellulose is contained in the orally disintegrating tablet of the present disclosure, for example, in an amount of about 1 to 20% by weight, 2 to 15% by weight, or 2 to 10% by weight. Further, (D) low-degree-of-substitution hydroxypropyl cellulose is, for example, 0.5 to 40 parts by weight, or 2 to 25 parts by weight, based on 1 part by weight of (A) brexpiprazole or a salt thereof. Degree of content.
- an ingredient other than the above and known in the field of pharmaceutical tablets may be contained as long as the effect of the orally disintegrating tablet of the present disclosure is not impaired.
- Such components include, for example, excipients, binders, disintegrants, colorants, pH regulators, preservatives, absorption enhancers, flavoring agents, antioxidants, buffers, chelating agents, abrasives, solvents. , Hardeners, surfactants, sweeteners, fluidizers, brighteners, fragrances and the like.
- Such other components may be used alone or in combination of two or more.
- the excipients include, for example, saccharides such as fructose, sucrose, purified sucrose, powdered sugar, lactose, powdered reduced starch syrup, maltose, etc .; sugars such as D-sorbitol, xylitol, erythritol, martitol, etc.
- Starches such as wheat starch, corn starch, potato starch; Starch derivatives such as dextrin and ⁇ -cyclodextrin; Cellulose or derivatives thereof such as ethyl cellulose, carboxymethyl cellulose (carmellose), 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, magnesium aluminometasilicate; kaolin, titanium oxide, magnesium oxide, talc, precipitated calcium carbonate, phosphoric acid anhydride Examples include calcium hydrogen hydrogen. Excipients can be used alone or in combination of two or more.
- binder examples include celluloses such as pregelatinized starch, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose or derivatives thereof; Other polysaccharides such as tragant powder, purulan, pectin; methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS Acrylic polymer such as; sodium alginate; purified gelatin; hydrolyzed gelatin powder; carboxyvinyl polymer; copolyvidone; povidone; polyvinyl alcohol and the like.
- celluloses such as pregelatinized starch, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxyprop
- the binder can be used alone or in combination of two or more. Further, aspartame, sucralose and the like can be used as the sweetener, and red iron sesquioxide, yellow sesquioxide, blue No. 2 aluminum lake and the like can be used as the colorant, and one type alone or two or more types can be used, respectively. Can be used in combination.
- the present disclosure also relates to the above-mentioned method for producing an orally disintegrating tablet.
- the orally disintegrating tablets of the present disclosure prepare a mixture containing, for example, (A) to (D) ((E) and / or (F) can be used as required, and other components may also be used). It can be produced by the step of tableting (for example, tableting) the obtained mixture.
- the steps of preparing a mixture containing the above (A) to (D) (and, if necessary, (E), (F), and / or other components) are (A) to (C). It can be carried out by granulating a mixture containing (D) and further mixing (D) a lubricant. In the above steps, (E), (F), and / or other components can be added at appropriate steps as needed.
- the method for performing the granulation is not particularly limited, and examples thereof include a dry granulation method and a wet granulation method (for example, a fluidized bed granulation method, a kneading granulation method, etc.).
- a wet granulation method particularly a fluidized bed granulation method
- the method for producing an orally disintegrating tablet of the present disclosure is a mixture containing (A) to (C) (and, if necessary, (E), (F), and / or other components).
- the orally disintegrating tablets of the present disclosure include (A) to (C) granulated by a wet granulation method.
- the orally disintegrating tablets of the present disclosure can be preferably prepared from particles containing (A) to (C) produced by a wet granulation method.
- Examples of the tableting method include a tableting method, and more specifically, a direct tableting method, a dry tableting method, a wet tableting method, an external sliding tableting method, and the like are exemplified.
- the worn powder adheres to the tablet, which is not preferable. Furthermore, if tableting is continued with filming occurring, the powder itself attached to the pestle will solidify, and if such powder is solidified and tableted with the pestle to be produced, the tablet surface will be hardened. A phenomenon called sticking occurs, such as dents or missing markings. Therefore, it is required to remove the powder adhering to the pestle every time filming occurs, which is troublesome. Further, the sticking to the board surface is a phenomenon in which powder adheres to the turntable (area in which the mortar is set) of the locking machine.
- filming and board sticking itself do not pose a problem of therapeutic effectiveness of the orally disintegrating tablets of the present disclosure, but from the viewpoint of handling by medical staff and patient's ingestibility and manufacturing efficiency, filming and board surface It is preferable to adopt a manufacturing method that does not cause sticking (particularly filming).
- the orally disintegrating tablets of the present disclosure are produced by an external sliding tableting method. More specifically, it is preferable to spray and add the lubricant during the step of tableting (tablet) the above mixture (that is, during tableting). In particular, it is preferable that the mixture also contains a lubricant.
- the lubricant contained in the composition (preferably a mixture) used for tableting is (D1) an internal lubricant, and the lubricant added by spraying during tableting is (D1). D2) Can be an external lubricant.
- the orally disintegrating tablets of the present disclosure include (A) to (C) and (D1) a step of mixing the internal lubricant and a step of tableting the mixture, and the tableting is performed.
- the above-mentioned granulation method and tableting method can be combined.
- the orally disintegrating tablets of the present disclosure make a mixture containing (A) to (C) (if necessary, (E) and / or (F), and further components can also be used). It comprises the steps of granulating and further mixing (D1) the internal lubricant and tableting the resulting mixture, where the (D2) external lubricant is further sprayed and added during the tableting. (External smooth tableting), more preferably produced by the method.
- the (D1) internal lubricant contained in the mixture and the (D2) external lubricant added by spraying during tableting are the same or different. You can.
- the sum of the weight of (D1) and the weight of (D2) is the weight of the (D) lubricant contained in the orally disintegrating tablet, and the weight ratio (D1) of (D1) and (D2).
- D2) may be, for example, about 10: 0.5 to 15, about 10: 1 to 10, or about 10: 2 to 9.
- about 10: 1 to 7, about 10: 1 to 6, about 10: 1 to 5, or about 10: 2 to 5 can be mentioned.
- the internal lubricant is preferably stearyl sodium fumarate
- the external lubricant is preferably magnesium stearate and / or sodium stearyl fumarate. More preferably, the (D1) internal lubricant of the orally disintegrating tablets of the present disclosure is stearyl sodium fumarate, and the (D2) external lubricant is magnesium stearate.
- the dose of the orally disintegrating tablet of the present disclosure is appropriately selected depending on, for example, usage, age, sex and other conditions of the patient, degree of disease, etc., and for example, the active ingredient (A) brexpiprazole per day.
- the amount of the salt thereof can be about 0.05 to 6 mg as brexpiprazole.
- the orally disintegrating tablet of the present disclosure is not particularly limited, but the tablet hardness may be 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, 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. Below, it is more preferably 30 seconds or less, 25 seconds or less, or 20 seconds or less.
- the tablet hardness is a value obtained by measuring the hardness in the diameter direction of the tablet using a tablet hardness tester (for example, MultiTest 50 (Pharmatron)).
- the disintegration time is the test method (temperature setting: 37 ° C ⁇ 2.0 ° C, test) related to the immediate release preparation (unlocked tablet) of the general test method 6.09 disintegration test method of the 17th revised Japanese Pharmacopoeia. It is a value measured by liquid: water).
- a collapse tester NT-200 Toyama Sangyo
- the orally disintegrating tablets of the present disclosure can be used, for example, to prevent or treat central nervous system diseases.
- Specific neurological disorders prevented or treated with the orally disintegrating tablets of the present disclosure include, but are not limited to: anhedonia, refractory, refractory or chronic schizophrenia.
- disorders of the central nervous system such as attention-deficient manic disorder, behavioral disorder, Down's syndrome, anhedonia associated with anhedonia (eg, anhedonia associated with Alzheimer-type dementia), borderline personality disorder, etc.
- the brexpiprazole used was synthesized according to a known method and then pulverized with a hammer mill.
- the disintegration test is a test method (temperature setting: 37 ° C ⁇ 2.0 ° C, test solution:) related to an immediate release preparation (unlocked tablet) of the general test method 6.09 disintegration test method of the 17th revision of the Japanese Pharmacopoeia. Water).
- NT-200 Toyama Sangyo was used as the decay tester.
- dissolution tester NTR-6200A (Toyama Sangyo) was used.
- the hardness of the tablet was measured in the radial direction using a tablet hardness tester MultiTest 50 (Pharmatron).
- disintegrant 1 [Example 1-1] According to the formulation shown in Table 1, the granulating powder components, brexpiprazole, D-mannitol, crystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose (LH-11), and sclarose, and the partial alpha which is a binder are added. A suspension of the gelatinized starch was spray-added and granulated to obtain granules (fluid layer granulation method). Then, stearyl sodium fumarate was added to the granules as a lubricant, and the granules were tableted (locking pressure 6 kN or 9 kN) to obtain an orally disintegrating tablet.
- Example 1-2 According to the formulation shown in Table 1, the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, corn starch, sodium starch glycolate (Primogel), and sclarose, and the binder partially pregelatinized starch are suspended. The turbid liquid was spray-added and granulated to obtain granules (fluid layer granulation method). Then, stearyl sodium fumarate was added to the granules as a lubricant, and the granules were tableted (locking pressure 6 kN or 9 kN) to obtain an orally disintegrating tablet.
- Example 1-3 Partial pregelatinization of the binders to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, corn starch, croscarmellose sodium (Kicolate ND-2HS), and sclarose, according to the formulation shown in Table 1.
- a suspension of starch was spray-added and granulated to obtain granules (fluid layer granulation method).
- stearyl sodium fumarate was added to the granules as a lubricant, and the granules were tableted (locking pressure 6 kN or 9 kN) to obtain an orally disintegrating tablet.
- Example 2-1 According to the formulation shown in Table 2, a suspension of partially pregelatinized starch as a binder was spray-added to the granulated powder components brexpiprazole, D-mannitol, low-substituted hydroxypropyl cellulose, and sucralose. Granulation was performed to obtain granules (fluidized bed granulation method). Then, stearyl sodium fumarate was added to the granules as a lubricant, and the granules were tableted (locking pressure 6 kN or 9 kN) to obtain an orally disintegrating tablet.
- Example 2-2 According to the formulation shown in Table 2, the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose (Theoras PH-101) 5 mg, low-substituted hydroxypropyl cellulose, sclarose, and partially pregelatinized starch as a binder. The suspension was spray-added and granulated to obtain granules (fluid layer granulation method). Then, stearyl sodium fumarate was added to the granules as a lubricant, and the granules were tableted (locking pressure 6 kN or 9 kN) to obtain an orally disintegrating tablet.
- Table 2 the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose (Theoras PH-101) 5 mg, low-substituted hydroxypropyl cellulose, sclarose, and partially pregelatinized starch as a binder. The
- Example 2-3 According to the formulation shown in Table 2, the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose (Theoras PH-101) 10 mg, low-substituted hydroxypropyl cellulose, sclarose, and partially pregelatinized starch as a binder. The suspension was spray-added and granulated to obtain granules (fluid layer granulation method). Then, stearyl sodium fumarate was added to the granules as a lubricant, and the granules were tableted (locking pressure 6 kN or 9 kN) to obtain an orally disintegrating tablet.
- Table 2 the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose (Theoras PH-101) 10 mg, low-substituted hydroxypropyl cellulose, sclarose, and partially pregelatinized starch as a binder.
- the hardness and disintegration time of the tablets stored at 25 ° C./75% RH (relative humidity) for 3 days, 7 days and 14 days at the start were measured.
- the hardness retention rate obtained from the hardness measurement result is shown in FIG. 2a.
- the results of the decay time measurement are shown in FIG. 2b.
- Practical hardness was maintained regardless of the amount of crystalline cellulose used. Above all, it was found that an example using 10 mg of crystalline cellulose (Example 2-3) is preferable.
- Binder Partially pregelatinized starch (PCS PC-10) as a binder to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and sclarose according to the formulation shown in Table 3.
- the suspension was spray-added and granulated to obtain granules (fluid layer granulation method).
- stearyl fumarate was added to the granules and tableted (locking pressure 4 kN, 5 kN, or 6 kN) to obtain an orally disintegrating tablet.
- the degree of pregelatinization of the partially pregelatinized starch (PCS PC-10: Asahi Kasei Co., Ltd.) used was 55 to 70%, and the degree of pregelatinization of the used pregelatinized starch (SWELSTAR WB-1: Asahi Kasei Co., Ltd.) was It is 90 to 100%.
- the content ratio of the water-soluble component of the partially pregelatinized starch used is 3% or less.
- Example 4-1 According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was spray-added to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropyl cellulose. , Granulation was performed to obtain granules (fluidized bed granulation method). After the granules were sized, a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder. As the green pigment-dispersed product, Pigment Blend PB-1543 Green, which is a pigment component, was doubled with 5 times the weight of corn starch.
- Pigment Blend PB-1543 Green which is a pigment component
- Sucralose was used as the sweetener. Then, 0.9 mg of stearyl fumarate (PRUV) was added as a lubricant to the post-added mixed powder, and the tablet was tableted to obtain an orally disintegrating tablet (locking pressure 3 kN, 5 kN, or 7 kN). It was.
- PRUV stearyl fumarate
- Example 4-2 According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was spray-added to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropyl cellulose. , Granulation was performed to obtain granules (fluidized bed granulation method).
- a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder.
- a green pigment-dispersed product Pigment Blend PB-1543 Green, which is a pigment component, was doubled with 5 times the weight of corn starch. Sucralose was used as the sweetener.
- PRUV stearyl fumarate
- Example 4-3 According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was spray-added to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropyl cellulose. , Granulation was performed to obtain granules (fluidized bed granulation method). After the granules were sized, a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder. As the green pigment-dispersed product, Pigment Blend PB-1543 Green, which is a pigment component, was doubled with 5 times the weight of corn starch.
- Pigment Blend PB-1543 Green which is a pigment component
- Sucralose was used as the sweetener. Then, 3.6 mg of stearyl fumarate (PRUV) was added as a lubricant to the post-added mixed powder, and the tablet was tableted to obtain an orally disintegrating tablet (locking pressure 3 kN, 5 kN, or 7 kN). It was.
- PRUV stearyl fumarate
- Example 4-4 According to the formulation shown in Table 4, a suspension of partially pregelatinized starch as a binder was spray-added to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropyl cellulose. , Granulation was performed to obtain granules (fluidized bed granulation method).
- a green pigment dispersion and a sweetener were added and mixed to obtain a post-added mixed powder.
- a green pigment-dispersed product Pigment Blend PB-1543 Green, which is a pigment component, was doubled with 5 times the weight of corn starch. Sucralose was used as the sweetener. Then, 0.9 mg of magnesium stearate was added as a lubricant to the post-additional mixed powder, and the tablet was tableted (tablet pressure 3 kN, 5 kN, or 7 kN) to obtain an orally disintegrating tablet.
- each orally disintegrating tablet immediately after tableting was measured and subjected to a disintegration test.
- the results are shown in FIGS. 4a and 4b, respectively.
- All orally disintegrating tablets had practical hardness and disintegration property.
- stearyl sodium fumarate for example, Example 4-1 or 4-2
- a particularly excellent orally disintegrating tablet having high hardness but short disintegration time can be obtained. I found out.
- filming is a phenomenon in which powder adheres to the surface of the punch of a tableting machine, and when this occurs, the tablet is locked with the punch to which the powder adheres, so that the surface of the produced tablet is rough (rough). Become. Furthermore, if tableting is continued with filming occurring, the powder itself attached to the pestle will solidify, and tablets produced by tableting with the pestle to which such powder has solidified will have a surface surface. Is dented. Therefore, it is disadvantageous for mass production because the powder adhering to the pestle must be removed every time filming occurs.
- the external lubrication tableting method is a method in which a small amount of lubricant is forcibly charged and sprayed directly onto the upper and lower pestle and mortar.
- the partially pregelatinized starch as a binder is added to the granulated powder components, brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropyl cellulose.
- Suspension was added by spraying and granulated to obtain granules (fluidized bed granulation method). After the granules were sized, a yellow pigment-dispersed product, a blue pigment-dispersed product, and a sweetener were added and mixed thereto to obtain a post-added mixed powder.
- yellow pigment dispersion product yellow sesquioxide was doubled with 5 times the weight of corn starch, and as the blue pigment dispersion product, blue No. 2 aluminum lake was doubled with 5 times the weight of corn starch.
- sucralose was used as the sweetener.
- stearyl sodium fumarate was internally added as a lubricant.
- an orally disintegrating tablet was obtained by spraying and adding 0.21 mg of magnesium stearate during tableting (locking pressure 3 to 8 kN) by adopting an external sliding tableting method. That is, stearyl sodium fumarate was used as an internal lubricant and magnesium stearate was used as an external lubricant.
- Table 5a also shows the compositions of Examples 4-2 and 4-2.
- Table 5b and FIG. 5 show the results of examining the tablet physical characteristics (balance between hardness and disintegration) and filming of the tablets of Examples 4-2, 4-2, and 5-3.
- Example 5c shows the composition of Example 5-3.
- Example 5-1 No filming was observed when any of the orally disintegrating tablets (Examples 5-1 to 5-4) was locked. In addition, all of the orally disintegrating tablets showed good hardness and disintegration time, and were able to achieve both tableting suitability and orally disintegrating property. Comparing the push-up pressures of each orally disintegrating tablet manufacturing process when the locks were locked at a locking pressure of 6 kN, Example 5-1 showed a slightly higher push-up pressure, but the other examples had low values and were continuous. It was possible to lock.
- Example 6-1 As D-mannitol, Pearitol 50C (Rocket Co., Ltd.) was used in Example 6-1, Pearitol 160C (Rocket Co., Ltd.) was used in Example 6-2, and Pearitol 300DC (Rocket Co., Ltd.) was used in Example 6-3.
- a yellow pigment-dispersed product As the yellow pigment dispersion product, yellow sesquioxide was doubled with 5 times the weight of corn starch, and as the blue pigment dispersion product, blue No. 2 aluminum lake was doubled with 5 times the weight of corn starch.
- Example 6-1 Dissolvability for tablets of Example 6-1 (Pearitol 50C: 50% particle size 35 ⁇ m), 6-2 (Pearitol 160C: 50% particle size 70 ⁇ m), and 6-3 (Pearitol 300DC: 50% particle size 250 ⁇ m). And the physical characteristics of the tablets (balance between hardness and disintegration) were evaluated. The results are shown in FIG. 6a for elution and in FIG. 6b for tablet physical characteristics. Examples 6-1 to 6-3 use D-mannitol having different particle sizes. Practical elution and tablet properties were achieved with any particle size of D-mannitol. Among them, it was found that an example using D-mannitol having a 50% particle size of 35 ⁇ m (Example 6-1) is preferable. Although all the tablets had an appearance without any problem in practical use, it was found that the tablet using D-mannitol having a small particle size had a uniform color tone on the tablet surface, which was more preferable.
- 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 spray-added to the granulated powder components brexpiprazole, D-mannitol, crystalline cellulose, and low-substituted hydroxypropyl cellulose. , Granulation was performed to obtain granules (fluidized bed granulation method).
- Example 7-1 As D-mannitol, Pairitol 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-dispersed product, a blue pigment-dispersed product, and a sweetener were added and mixed thereto to obtain a post-added mixed powder.
- yellow pigment dispersion product yellow sesquioxide was doubled with 5 times the weight of corn starch
- blue No. 2 aluminum lake was doubled with 5 times the weight of corn starch.
- sucralose was used as the sweetener.
- stearyl sodium fumarate was added as a lubricant to the post-added mixed powder, and the tablets were tableted to obtain an orally disintegrating tablet (locking pressure: 8 kN).
- Example 7-1 the crystal shape of D-mannitol before and after granulation and after tableting was evaluated.
- the crystal shape of D-mannitol was determined by observing the cross section of the granule or tablet at a magnification of 500 times or 2000 times using an electron microscope (real surface view microscope VE-7800 manufactured by KEYENCE). The results are shown in FIG. 7a.
- Pearitol 50C (Example 7-1) consistently showed a plate-like crystal shape before and after granulation.
- Parteck Delta M (Example 7-2) showed a plate-like crystal shape before granulation, but the crystal shape changed from a plate-like to a needle-like after granulation.
- an orally disintegrating tablet could be produced in any of the examples.
- the difference between the plate-shaped and needle-shaped crystal shapes observed in the granulated product could be clearly confirmed in the cross section of the tablet after tableting.
- Example 7-1 Tableting suitability (presence or absence of filming) and tablet appearance were evaluated.
- the appearance of the tablets was evaluated using a digital camera and a digital microscope (VHX-500 manufactured by KEYENCE).
- VHX-500 manufactured by KEYENCE
- FIG. 7b When Pearitol 50C was used as D-mannitol (Example 7-1), no filming was observed even 30 minutes after the start of tableting, and a high filming inhibitory effect was shown. In addition, the obtained tablet had a glossy surface.
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Abstract
Description
項1.
(A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠。
項2.
(D)滑沢剤が、ステアリン酸マグネシウム及びフマル酸ステアリルナトリウムを含む、項1に記載の口腔内崩壊錠。
項3.
(D)滑沢剤が(D1)内部滑沢剤及び(D2)外部滑沢剤を含む、項1に記載の口腔内崩壊錠。
項4.
(D1)内部滑沢剤がフマル酸ステアリルナトリウムを含み、(D2)外部滑沢剤がステアリン酸マグネシウムを含む、項3に記載の口腔内崩壊錠。
項5.
(B)D-マンニトールの50%粒子径が10μm~100μmであり、かつ(B)D-マンニトールが錠剤中に非針状の結晶形状で存在する、項1~4のいずれかに記載の口腔内崩壊錠。
項6.
(C)部分アルファー化デンプンが、水溶性成分の割合が10%以下の部分アルファー化デンプンである、項1~5のいずれかに記載の口腔内崩壊錠。
項7.
さらに、(E)結晶セルロースを含有する、項1~6のいずれかに記載の口腔内崩壊錠。
項8.
(E)結晶セルロースを、5~15重量%含有する、請求項7に記載の口腔内崩壊錠。
項9.
さらに、(F)低置換度ヒドロキシプロピルセルロースを含有する、項1~8のいずれかに記載の口腔内崩壊錠。
項10.
錠剤硬度計を用いて測定した錠剤の直径方向の錠剤硬度が15N~70Nであり、日本薬局方一般試験法6.09崩壊試験法の即放性製剤(素錠)に係る試験法により測定した崩壊時間が70秒以内である、項1~9のいずれかに記載の口腔内崩壊錠。
項11.
中枢神経疾患を予防または治療するための、項1~10のいずれかに記載の口腔内崩壊錠。
項12.
統合失調症、治療抵抗性、難治性または慢性統合失調症、失調感情障害、精神病性障害、気分障害、双極性障害、うつ病、内因性うつ病、大うつ病、メランコリー及び治療抵抗性うつ病、気分変調性障害、気分循環性障害、不安障害、身体表現性障害、虚偽性障害、解離性障害、性障害、摂食障害、睡眠障害、適応障害、物質関連障害、無快感症、せん妄、認知障害、神経変性疾患に伴う認知障害、神経変性疾患に起因した認知障害、統合失調症の認知障害、治療抵抗性、難治性または慢性統合失調症に起因する認知障害、嘔吐、乗物酔い、肥満、偏頭痛、疼痛、精神遅滞、自閉性障害、トウレット障害、チック障害、注意欠陥多動性障害、行為障害、ダウン症候群、認知症に伴う衝動性症状、並びに境界性人格障害からなる群より選ばれる中枢神経疾患を予防または治療するための、項11に記載の口腔内崩壊錠。
項13.
(A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠であって、
外部滑沢打錠法により製造される、口腔内崩壊錠。
項14.
(A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠の製造方法であって、
(D)滑沢剤が(D1)内部滑沢剤及び(D2)外部滑沢剤を含み、
前記方法が、(A)ブレクスピプラゾール又はその塩、(B)D-マンニトール、(C)部分アルファー化デンプン、及び(D1)内部滑沢剤を混合する工程及び混合物を打錠する工程を含み、
前記打錠する工程において、(D2)外部滑沢剤を噴霧添加する、方法。
項A-1.
(A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠であって、
(A)ブレクスピプラゾール又はその塩、(B)D-マンニトール、及び(C)部分アルファー化デンプンが湿式造粒法により造粒されている、口腔内崩壊錠。
項A-2.
(A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠の製造方法であって、
(A)ブレクスピプラゾール又はその塩、(B)D-マンニトール、及び(C)部分アルファー化デンプンを湿式造粒法により造粒する工程、前記造粒した混合物にさらに(D)滑沢剤を混合する工程、並びに得られた混合物を打錠する工程を含む、方法。
項A-3.
ブレクスピプラゾール、
D-マンニトール、
部分アルファー化デンプン、
フマル酸ステアリルナトリウム及びステアリン酸マグネシウム、
結晶セルロース、
部分アルファー化デンプン、
スクラロース、
赤色三二酸化鉄、黄色三二酸化鉄、及び青色二号アルミニウムレーキから選択される少なくとも一つの着色剤、並びに
トウモロコシデンプン
を含有するか、好ましくはこれらからなる、口腔内崩壊錠。
ブレクスピプラゾールの塩としては、薬理的に許容される塩であれば特に限定されず、例えば、アルカリ金属塩(例えばナトリウム塩、カリウム塩等)、アルカリ土類金属塩(例えばカルシウム塩、マグネシウム塩等)等の金属塩、アンモニウム塩、炭酸アルカリ金属(例えば、炭酸リチウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウム等)、炭酸水素アルカリ金属(例えば、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム等)、アルカリ金属水酸化物(例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化セシウム等)等の無機塩基の塩;例えば、トリ(低級)アルキルアミン(例えば、トリメチルアミン、トリエチルアミン、N-エチルジイソプロピルアミン等)、ピリジン、キノリン、ピペリジン、イミダゾール、ピコリン、ジメチルアミノピリジン、ジメチルアニリン、N-(低級)アルキル-モルホリン(例えば、N-メチルモルホリン等)、1,5-ジアザビシクロ[4.3.0]ノネン-5(DBN)、1,8-ジアザビシクロ[5.4.0]ウンデセン-7(DBU)、1,4-ジアザビシクロ[2.2.2]オクタン(DABCO)等の有機塩基の塩;塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸塩;ギ酸塩、酢酸塩、プロピオン酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、炭酸塩、ピクリン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、p-トルエンスルホン酸塩、グルタミン酸塩等の有機酸塩等が挙げられる。
一実施形態において、本開示の口腔内崩壊錠中の(B)D-マンニトールは、特に制限はされないが、例えば50%粒子径が10μm~100μm、好ましくは15μm~80μm、より好ましくは20μm~50μmのものを用いることができる。なお、50%粒子径とは、D50、メディアン径とも表記され、粒子の50%がこれより大きく、50%がこれより小さい粒径を表す。50%粒子径は、レーザー回折散乱法により求められる。
(C)部分アルファー化デンプンとは、デンプンを部分的にアルファー化したものであり、水を加えたときに、膨潤し、白濁した液となるものを指す。これに対し、アルファー化デンプンは、水を加えたときに、粘稠なのり状の液となるものを指す。部分アルファー化デンプンは、デンプン(好ましくはトウモロコシデンプン)を水と共に常圧下又は加圧下で加熱して(必要に応じて乾燥して)調製することができる。部分アルファー化デンプンとしては、水溶性成分の割合が10%以下のものが好ましく、9%以下、8%以下、7%以下、6%以下、5%以下、4%以下、又は3%以下のものがより好ましい。なお、部分アルファー化デンプンにおける水溶性成分の割合は、European Pharmacopoeia 9.0の「STARCH, PREGELATINISED」の項の「Cold-water-soluble matter」に記載の試験法により測定する。
(D)滑沢剤としては、例えば、ステアリン酸又はその塩(例えば、ステアリン酸アルミニウム、ステアリン酸カルシウム、ステアリン酸マグネシウム等);カルナウバロウ、グリセリン脂肪酸エステル、硬化油、ミツロウ、サラシミツロウ、タルク、フマル酸、フマル酸ステアリルナトリウム、ポリエチレングリコール(マクロゴール400、マクロゴール600、マクロゴール1500、マクロゴール4000、マクロゴール6000等のマクロゴール)等が挙げられる。これらの滑沢剤は、1種単独で使用してもよく、また、2種以上を併用して使用してもよい。これらの中でも、ステアリン酸塩、フマル酸ステアリルナトリウム、ショ糖脂肪酸エステル、硬化油が好ましく、ステアリン酸マグネシウム、及びフマル酸ステアリルナトリウムがより好ましく、ステアリン酸マグネシウム及びフマル酸ステアリルナトリウムを併用するのが特に好ましい。
(D)滑沢剤には、後述するように、錠剤内部に含有される(D1)内部滑沢剤と、錠剤外部に含有される(D2)外部滑沢剤とがある。本開示の口腔内崩壊錠は、好ましくは、(D)滑沢剤として(D1)内部滑沢剤と(D2)外部滑沢剤の両方を含有する。なお、「錠剤外部」とは、錠剤の表面、より具体的には錠剤表面から0.1mmの部分を指す。なお、本開示の口腔内崩壊錠が、内部滑沢剤及び外部滑沢剤を含有する場合、内部滑沢剤と外部滑沢剤とが同じ成分であっても異なる成分であってもよい。また、内部滑沢剤として1種単独の成分又は2種以上の成分を組み合わせて用いることができる。また、外部滑沢剤として1種単独の成分又は2種以上の成分を組み合わせて用いることができる。
また、本開示の口腔内崩壊錠は、好ましくは、(D1)内部滑沢剤としてフマル酸ステアリルナトリウムを含み、(D2)外部滑沢剤としてステアリン酸マグネシウムを含む。
例えば、(E)結晶セルロースを含有してもよい。結晶セルロースとしては、特に制限はされないが、例えば平均粒子径が10~100μm程度、20~80μm程度、30~70μm程度、又は40~60μm程度であるものが好ましい。また例えば、嵩密度が、0.1~0.5g/cm3低度、0.15~0.45g/cm3程度、0.2~0.4g/cm3程度、又は0.25~0.35g/cm3程度であるものが好ましい。
また例えば、(F)低置換度ヒドロキシプロピルセルロースを含有してもよい。低置換度ヒドロキシプロピルセルロースとしては、ヒドロキシプロポキシ基を約5~16(質量)%程度含有するヒドロキシプロピルセルロースが好ましい。当該範囲の上限又は下限は、6、7、8、9、10、11、12、13、14、又は15(質量)%程度であってもよい。低置換度ヒドロキシプロピルセルロースのヒドロキシプロポキシ基の含量は、第十七改正日本薬局方に収載されている方法により測定することができる。前記低置換度ヒドロキシプロピルセルロースは、公知の製造方法により製造することができ、また、市販品を用いることもできる。低置換度ヒドロキシプロピルセルロースの市販品としては、例えば、信越化学工業株式会社製の「LHシリーズ」、「NBDシリーズ」等が挙げられるが、これらに限定されるものではない。
また例えば、本開示の口腔内崩壊錠の効果を損なわない範囲で、上記以外の成分であって医薬錠剤の分野で公知の成分を含有してもよい。このような成分としては、例えば、賦形剤、結合剤、崩壊剤、着色剤、pH調整剤、保存剤、吸収促進剤、矯味剤、抗酸化剤、緩衝剤、キレート剤、研磨剤、溶剤、硬化剤、界面活性剤、甘味剤、流動化剤、光沢化剤、香料等を挙げることができる。このような他の成分は、1種単独で又は2種以上を組み合わせて用いることができる。
本開示は、また、上記の口腔内崩壊錠の製造方法にも関する。本開示の口腔内崩壊錠は、例えば、(A)~(D)(必要に応じて(E)及び/又は(F)、更には、その他成分をも用いることができる)を含む混合物を調製する工程、並びに得られた混合物を錠剤化する(例えば打錠する)工程によって製造することができる。
本開示の口腔内崩壊錠の投与量は、例えば用法、患者の年齢、性別その他の条件、疾患の程度等により適宜選択されるが、例えば、一日当り、有効成分である(A)ブレクスピプラゾール又はその塩の量を、ブレクスピプラゾールとして約0.05~6mg程度とすることができる。
本開示の口腔内崩壊錠は、特に制限はされないが、錠剤硬度が15~70N程度、20~60N程度、又は30~60N程度であり得る。また、本開示の口腔内崩壊錠は、崩壊時間が、70秒以下であることが好ましく、65秒以下、60秒以下、55秒以下、50秒以下、45秒以下、40秒以下、35秒以下、30秒以下、25秒以下、又は20秒以下であることがより好ましい。
本開示の口腔内崩壊錠は、例えば中枢神経疾患を予防又は治療するために用いることができる。
[実施例1-1]
表1に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、トウモロコシデンプン、低置換度ヒドロキシプロピルセルロース(LH-11)、及びスクラロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧6kN又は9kN)口腔内崩壊錠を得た。
[実施例1-2]
表1に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、トウモロコシデンプン、デンプングリコール酸ナトリウム(Primojel)、及びスクラロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧6kN又は9kN)口腔内崩壊錠を得た。
[実施例1-3]
表1に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、トウモロコシデンプン、クロスカルメロースナトリウム(Kicolate ND-2HS)、及びスクラロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧6kN又は9kN)口腔内崩壊錠を得た。
[実施例2-1]
表2に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、低置換度ヒドロキシプロピルセルロース、及びスクラロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧6kN又は9kN)口腔内崩壊錠を得た。
[実施例2-2]
表2に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース(セオラスPH-101)5mg、低置換度ヒドロキシプロピルセルロース、スクラロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧6kN又は9kN)口腔内崩壊錠を得た。
[実施例2-3]
表2に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース(セオラスPH-101)10mg、低置換度ヒドロキシプロピルセルロース、スクラロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧6kN又は9kN)口腔内崩壊錠を得た。
硬度測定結果から得られた硬度保持率を図2aに示す。また、崩壊時間測定結果を図2bに示す。いずれの量の結晶セルロースを用いても、実用的な硬度が保持された。中でも、結晶セルロースを10mg用いた例(実施例2-3)が好ましいことが分かった。
[実施例3-1]
表3に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、低置換度ヒドロキシプロピルセルロース、及びスクラロースに、結合剤である部分アルファー化デンプン(PCS PC-10)の懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧4kN、5kN、又は6kN)口腔内崩壊錠を得た。
表3に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、低置換度ヒドロキシプロピルセルロース、スクラロースに、結合剤であるアルファー化デンプン(SWELSTAR WB-1)の懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。その後、滑沢剤としてフマル酸ステアリルナトリウムを当該顆粒に添加し、打錠することで(打錠圧4kN、5kN、又は6kN)口腔内崩壊錠を得た。
[実施例4-1]
表4に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、及び低置換度ヒドロキシプロピルセルロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。当該顆粒を整粒後、緑色色素分散品及び甘味剤を添加して混合し、後添加混合末を得た。緑色色素分散品としては、色素成分であるPigment Blend PB-1543 Greenをその5倍重量のトウモロコシデンプンで倍散したものを用いた。甘味剤としては、スクラロースを用いた。その後、当該後添加混合末に、滑沢剤としてフマル酸ステアリルナトリウム(PRUV)0.9 mgを添加し、打錠することで(打錠圧3kN、5kN、又は7kN)口腔内崩壊錠を得た。
[実施例4-2]
表4に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、及び低置換度ヒドロキシプロピルセルロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。当該顆粒を整粒後、緑色色素分散品及び甘味剤を添加して混合し、後添加混合末を得た。緑色色素分散品としては、色素成分であるPigment Blend PB-1543 Greenをその5倍重量のトウモロコシデンプンで倍散したものを用いた。甘味剤としては、スクラロースを用いた。その後、当該後添加混合末に、滑沢剤としてフマル酸ステアリルナトリウム(PRUV)1.8 mgを添加し、打錠することで(打錠圧3kN、5kN、又は7kN)口腔内崩壊錠を得た。
[実施例4-3]
表4に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、及び低置換度ヒドロキシプロピルセルロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。当該顆粒を整粒後、緑色色素分散品及び甘味剤を添加して混合し、後添加混合末を得た。緑色色素分散品としては、色素成分であるPigment Blend PB-1543 Greenをその5倍重量のトウモロコシデンプンで倍散したものを用いた。甘味剤としては、スクラロースを用いた。その後、当該後添加混合末に、滑沢剤としてフマル酸ステアリルナトリウム(PRUV)3.6 mgを添加し、打錠することで(打錠圧3kN、5kN、又は7kN)口腔内崩壊錠を得た。
[実施例4-4]
表4に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、及び低置換度ヒドロキシプロピルセルロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。当該顆粒を整粒後、緑色色素分散品及び甘味剤を添加して混合し、後添加混合末を得た。緑色色素分散品としては、色素成分であるPigment Blend PB-1543 Greenをその5倍重量のトウモロコシデンプンで倍散したものを用いた。甘味剤としては、スクラロースを用いた。その後、当該後添加混合末に、滑沢剤としてステアリン酸マグネシウム0.9 mgを添加し、打錠することで(打錠圧3kN、5kN、又は7kN)口腔内崩壊錠を得た。
上記実施例4-1~4-4の口腔内崩壊錠の打錠生産を続けたところ、内部滑沢剤としてフマル酸ステアリルナトリウムを用いた実施例4-1及び4-2においては、5~30分ほど打錠生産を継続した時点で、フィルミングが生じた。実施例4-3でも軽微ではあるがフィルミングが生じた。
表6に示す配合に従い、粒子径の異なるD-マンニトールを用いて実施例6-1~6-3の口腔内崩壊錠を製造した。
[実施例6-1]~[実施例6-3]
表6に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、及び低置換度ヒドロキシプロピルセルロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。なお、D-マンニトールとして、実施例6-1ではペアリトール50C(ロケット社)、実施例6-2ではペアリトール160C(ロケット社)、実施例6-3ではペアリトール300DC(ロケット社)をそれぞれ用いた。当該顆粒を整粒後、これに黄色色素分散品、青色色素分散品、及び甘味剤を添加混合し、後添加混合末を得た。黄色色素分散品としては、黄色三二酸化鉄を5倍重量のトウモロコシデンプンで倍散したものを用い、青色色素分散品としては、青色二号アルミニウムレーキを5倍重量のトウモロコシデンプンで倍散したものを用い、甘味剤としては、スクラロースを用いた。その後、滑沢剤としてフマル酸ステアリルナトリウムを内部添加した。さらに、外部滑沢打錠法を採用し、打錠中(打錠圧4kN、6kN、又は8kN)にステアリン酸マグネシウムを噴霧添加することで口腔内崩壊錠を得た。
表7に示す配合に従い、実施例7-1及び7-2の口腔内崩壊錠を製造した。
[実施例7-1]及び[実施例7-2]
表7に示す配合に従い、造粒粉成分である、ブレクスピプラゾール、D-マンニトール、結晶セルロース、及び低置換度ヒドロキシプロピルセルロースに、結合剤である部分アルファー化デンプンの懸濁液を噴霧添加し、造粒して、顆粒を得た(流動層造粒法)。なお、D-マンニトールとして、実施例7-1ではペアリトール50C(ロケット社)、実施例7-2ではParteck Delta M(メルク社)をそれぞれ用いた。当該顆粒を整粒後、これに黄色色素分散品、青色色素分散品、及び甘味剤を添加混合し、後添加混合末を得た。黄色色素分散品としては、黄色三二酸化鉄を5倍重量のトウモロコシデンプンで倍散したものを用い、青色色素分散品としては、青色二号アルミニウムレーキを5倍重量のトウモロコシデンプンで倍散したものを用い、甘味剤としては、スクラロースを用いた。その後、当該後添加混合末に、滑沢剤としてフマル酸ステアリルナトリウムを添加し、打錠することで(打錠圧8kN)口腔内崩壊錠を得た。
Claims (14)
- (A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠。 - (D)滑沢剤が、ステアリン酸マグネシウム及びフマル酸ステアリルナトリウムを含む、請求項1に記載の口腔内崩壊錠。
- (D)滑沢剤が(D1)内部滑沢剤及び(D2)外部滑沢剤を含む、請求項1に記載の口腔内崩壊錠。
- (D1)内部滑沢剤がフマル酸ステアリルナトリウムを含み、(D2)外部滑沢剤がステアリン酸マグネシウムを含む、請求項3に記載の口腔内崩壊錠。
- (B)D-マンニトールの50%粒子径が10μm~100μmであり、かつ(B)D-マンニトールが錠剤中に非針状の結晶形状で存在する、請求項1~4のいずれかに記載の口腔内崩壊錠。
- (C)部分アルファー化デンプンが、水溶性成分の割合が10%以下の部分アルファー化デンプンである、請求項1~5のいずれかに記載の口腔内崩壊錠。
- さらに、(E)結晶セルロースを含有する、請求項1~6のいずれかに記載の口腔内崩壊錠。
- (E)結晶セルロースを、5~15重量%含有する、請求項7に記載の口腔内崩壊錠。
- さらに、(F)低置換度ヒドロキシプロピルセルロースを含有する、請求項1~8のいずれかに記載の口腔内崩壊錠。
- 錠剤硬度計を用いて測定した錠剤の直径方向の錠剤硬度が15N~70Nであり、日本薬局方一般試験法6.09崩壊試験法の即放性製剤(素錠)に係る試験法により測定した崩壊時間が70秒以内である、請求項1~9のいずれかに記載の口腔内崩壊錠。
- 中枢神経疾患を予防または治療するための、請求項1~10のいずれかに記載の口腔内崩壊錠。
- 統合失調症、治療抵抗性、難治性または慢性統合失調症、失調感情障害、精神病性障害、気分障害、双極性障害、うつ病、内因性うつ病、大うつ病、メランコリー及び治療抵抗性うつ病、気分変調性障害、気分循環性障害、不安障害、身体表現性障害、虚偽性障害、解離性障害、性障害、摂食障害、睡眠障害、適応障害、物質関連障害、無快感症、せん妄、認知障害、神経変性疾患に伴う認知障害、神経変性疾患に起因した認知障害、統合失調症の認知障害、治療抵抗性、難治性または慢性統合失調症に起因する認知障害、嘔吐、乗物酔い、肥満、偏頭痛、疼痛、精神遅滞、自閉性障害、トウレット障害、チック障害、注意欠陥多動性障害、行為障害、ダウン症候群、認知症に伴う衝動性症状、並びに境界性人格障害からなる群より選ばれる中枢神経疾患を予防または治療するための、請求項11に記載の口腔内崩壊錠。
- (A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠であって、
外部滑沢打錠法により製造される、口腔内崩壊錠。 - (A)ブレクスピプラゾール又はその塩、
(B)D-マンニトール、
(C)部分アルファー化デンプン、及び
(D)滑沢剤
を含有する口腔内崩壊錠の製造方法であって、
(D)滑沢剤が(D1)内部滑沢剤及び(D2)外部滑沢剤を含み、
前記方法が、(A)ブレクスピプラゾール又はその塩、(B)D-マンニトール、(C)部分アルファー化デンプン、及び(D1)内部滑沢剤を混合する工程及び混合物を打錠する工程を含み、
前記打錠する工程において、(D2)外部滑沢剤を噴霧添加する、方法。
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EP20887321.6A EP4059502A4 (en) | 2019-11-11 | 2020-11-11 | METAL TABLET |
US17/755,832 US20220387423A1 (en) | 2019-11-11 | 2020-11-11 | Orally disintegrating tablet |
JP2021556130A JP7395607B2 (ja) | 2019-11-11 | 2020-11-11 | 口腔内崩壊錠 |
CA3161119A CA3161119A1 (en) | 2019-11-11 | 2020-11-11 | Orally disintegrating tablet |
AU2020384456A AU2020384456A1 (en) | 2019-11-11 | 2020-11-11 | Orally disintegrating tablet |
JP2023201223A JP2024026205A (ja) | 2019-11-11 | 2023-11-29 | 口腔内崩壊錠 |
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WO2021095092A1 (ja) | 2021-05-20 |
US20220387423A1 (en) | 2022-12-08 |
TW202128167A (zh) | 2021-08-01 |
AU2020384456A1 (en) | 2022-06-09 |
CN114650821A (zh) | 2022-06-21 |
CA3161119A1 (en) | 2021-05-20 |
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