Classifications

• • 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
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/282—Organic compounds, e.g. fats
  • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• the present invention relates to a nucleated type orally disintegrating tablet.
• the inner core is a powder with low moldability, and it has an outer layer that covers the periphery of the inner core, giving it an appropriate hardness and excellent disintegration in the oral cavity as the final molded tablet
• the present invention relates to a nucleated molded product (hereinafter sometimes referred to as “nucleated orally disintegrating tablet”). That is, the present invention relates to a nucleated type orally disintegrating tablet in which an outer layer rapidly disintegrates in the oral cavity even after taking a small amount of water or without water, and thereafter granules or powders of the inner core are dispersed in the oral cavity.
• Patent Document 1 discloses a nucleated type orally disintegrating tablet as a form of a tablet that has not been known so far.
• the nucleated tablet is a tablet having a double structure of an inner core and an outer layer of the tablet, and has attracted attention as a new tablet forming technique.
• the formulation design focuses on the solubility and disintegration of the inner core, and the inner core component is composed of components having moldability as well as the outer layer component ( For example, as can be seen from the results of Test Example 2 in which a tablet was produced only with the inner core component, the inner core component has moldability and is considered to have a certain hardness or more).
• the outer layer of the nucleated molded article disclosed in Patent Document 1 has a disclosure relating to a combination of crystalline cellulose and sugar or sugar alcohol, but a combination further including a specific component in the present invention has not been disclosed.
• specific components (carmellose, low-substituted hydroxypropylcellulose, natural starch, crospovidone), which are essential components of the outer layer of the present invention, are described in Patent Document 1 as a dissolution / disintegration accelerator for the inner core (9 Page, lines 17-26).
• the outer layer includes a component having high moldability, and preferably further includes a component having high solubility and / or disintegration.
• the inner core has solubility or / And a component that is rich in disintegration, and in some cases, further contains a dissolution / disintegration accelerator ”(page 8, lines 14 to 17), thereby making the structure of the molded article a double structure of an inner core and an outer layer.
• Patent Document 1 it is considered that the feature is found by adding a component such as a dissolution / disintegration accelerator to the inner core and not adding it to the outer layer.
• the specific component is an essential component of the outer layer, and the method of using the specific component is completely opposite between the present invention and Patent Document 1.
• Patent Document 2 discloses a trial in which microcapsule-like granules are applied to the inner core component of the nucleated molded product in Patent Document 1 described above. That is, Patent Document 2 discusses the application of microcapsule-like granules to the inner core of a nucleated molded product.
• the outer layer has a composition composed of a lactose / crystalline cellulose component, and a predetermined manufacturing method is used.
• a manufacturing example in which a nucleated molded product containing a granule-like granule in the inner core is completed is disclosed.
• Patent Document 2 only discloses the invention of the nucleated molded article containing the above microcapsule-like granules in the inner core, and further studies for applying the nucleated molded article here to the orally disintegrating tablet have not been made. There was no suggestion.
• the outer layer component the component applicable as a nucleated molded product containing the microcapsule-like granule in the inner core has not been studied other than the composition from the lactose / crystalline cellulose component. The essential component combination was not disclosed. Moreover, there is no disclosure regarding the component containing mannitol in the outer layer of the nucleated molded article.
• Patent Document 3 has a disclosure regarding an orally disintegrating tablet containing mannitol, but there is no specific disclosure regarding a nucleated molded product.
• International Publication No. 2003/028706 International Publication No. 2005/097041 JP 2001-58944 A
• Orally disintegrating tablets are tablets that disintegrate rapidly in the oral cavity.
• the hardness and disintegration of tablets are in a contradictory relationship. Increasing the hardness deteriorates the disintegration, and conversely improving the disintegration decreases the hardness.
• coexistence of hardness and disintegration is a major issue.
• orally disintegrating tablets containing various functional ingredients and particles when various functional ingredients and particles are uniformly dispersed in the tablet, especially when functional ingredients and particles that adversely affect moldability are blended, In order to compensate for this, other additives need to be blended, and further contrivances have been demanded due to adverse effects such as enlargement of tablets.
• the outer layer containing the inner core has a coreless tablet (ordinary tablet) or normal It became clear in the process of completing the present invention that a higher hardness should be imparted compared to the dry-coated tablets.
• Patent Document 1 and Patent Document 2 are interesting as a new tablet technology.
• Patent Document 2 discloses a production example in which microcapsule-like granules are applied to the inner core. Furthermore, application to further functional preparations such as orally disintegrating tablets was expected.
• a nucleated tablet having an outer layer similar to the formulation disclosed in Patent Document 2 was actually produced, the disintegration property in the oral cavity was extremely poor (see Comparative Example 1-4 of the present invention).
• the outer layer disclosed in Patent Document 1 that is regarded as a nucleated fast disintegrating tablet, it was found that sufficient hardness was not obtained when a nucleated tablet containing particles having no moldability was produced (this book) (See Comparative Example 1-5 of the invention).
• the object of the present invention is to newly develop a nucleated molded product characterized in that the inner core is a granular material having a low moldability, and has an excellent disintegration property and appropriate hardness as a whole tablet. It is to provide an orally disintegrating tablet of the type.
• nucleated molded article comprising an inner core and an outer layer covering the periphery of the inner core, the inner core is composed of a granular material having low moldability, and the outer layer is made of crystalline cellulose, sugar or sugar alcohol and the specific components shown below ( It was found that a nucleated orally disintegrating tablet containing c) and having appropriate hardness and disintegration as a whole tablet can be produced.
• the ratio of the thickness of the inner core to the whole tablet is 30 to 80%
• the outer layer components are (a) crystalline cellulose, (b) sugar or sugar alcohol, and (c) crospovidone, starches,
• the outer layer components are (a) crystalline cellulose, (b) sugar or sugar alcohol, and (c) crospovidone, starches,
• the present invention provides the following various aspects of the invention.
• An orally disintegrating tablet having an outer layer covering the periphery of the inner core, wherein the ratio of the thickness of the inner core to the whole tablet is 30 to 80%, and the outer layer is (a) crystalline cellulose, (b) A nucleated orally disintegrating tablet containing sugar or sugar alcohol and (c) one or more specific components selected from the group consisting of crospovidone, starches, low-substituted hydroxypropylcellulose and carmellose.
• Nucleated orally disintegrating tablets [Item 7]
• the specific component (c) in the outer layer contains one or more selected from the group consisting of crospovidone, low-substituted hydroxypropylcellulose, and carmellose, and the total of the components in 100% by weight of the outer layer Item 6.
• [Item 10] The nucleated orally disintegrating tablet according to any one of Items 1 to 9, wherein the ratio of the thickness of the inner core to the whole tablet is 30 to 70%.
• [Item 11] The nucleated orally disintegrating tablet according to any one of Items 1 to 10, wherein the porosity of the inner core is larger than the porosity of the outer layer.
• [Item 12] The nucleated orally disintegrating tablet according to any one of Items 1 to 11, wherein the inner core contains an active ingredient.
• a cored molded product characterized in that the inner core is a granular material having low moldability, and the cored type orally disintegrating tablet having excellent disintegration property and appropriate hardness as a whole tablet Can provide.
• the nucleated type orally disintegrating tablet in the present invention is suitable for an “inner core” composed of a low-formability powder such as microcapsule-like functional particles and a final molded tablet covering the periphery of the inner core. Consists of an “outer layer” that imparts hardness and disintegration.
• an inner core component other than microcapsule-like functional particles, it is possible to carry out powders, granules, powders, etc. having low formability, and have sufficient hardness and disintegration.
• a karyotype orally disintegrating tablet is provided.
• the “outer layer” is selected from the group consisting of (a) crystalline cellulose, (b) sugar or sugar alcohol, and (c) crospovidone, starches, low-substituted hydroxypropylcellulose, and carmellose. Contains two or more specific components. By combining these components, a cored type orally disintegrating tablet that maintains sufficient hardness as a final molded product (orally disintegrating tablet) and has good disintegration can be obtained even with an inner core composed of components having low moldability. . It is preferable that the inner core is a granular material having low moldability, and when it contains 30% or more with respect to the thickness of the whole tablet, good disintegration is obtained.
• Orally disintegrating tablet means a tablet that disintegrates rapidly in the oral cavity without ingesting water to take the tablet.
• the oral disintegration time of the “orally disintegrating tablet” is measured by a disintegration test in the human oral cavity or a disintegration test by a device.
• Examples of the orally disintegrating tablet tester used in the disintegration test include model ODT-101 manufactured by Toyama Sangyo Co., Ltd.
• Oral disintegration time means a tablet in which the inner core and outer layer disintegrate or disperse usually within 60 seconds, preferably within 45 seconds, more preferably within 30 seconds, and most preferably within 20 seconds.
• the oral disintegration time includes the tablet in the human oral cavity, and the time until the tablet completely disintegrates was measured. After the test, the contents were discharged and the oral cavity was washed with clean water.
• the average particle diameter is represented by a value measured by, for example, a laser diffraction particle size measuring device (HELOS & RODOS) manufactured by SYMPATEC or a laser diffraction particle size distribution measuring device (SALD3000) manufactured by Shimadzu Corporation.
• HELOS & RODOS laser diffraction particle size measuring device
• SALD3000 laser diffraction particle size distribution measuring device
• a bulk density is represented by the value measured by the constant mass method (1st method) described in Japanese Pharmacopoeia 15th revision. That is, it means a numerical value represented by the following formula when the bulk volume when a sample of about 30 g is usually put into a 100 mL (cm 3 ) glass graduated cylinder without being compacted is X cm 3 . However, if the specimen overflows from the graduated cylinder, the weight of the specimen should be reduced as appropriate.
• Bulk density (g / cm 3 ) weight of specimen (g) ⁇ X (cm 3 )
• the tablet hardness was measured using a tablet hardness tester (PORTABLE CHECKER PC-30 manufactured by Okada Seiko Co., Ltd.) to measure the force necessary for crushing in the diameter direction.
• “Absolute hardness” was calculated by the following formula using the value of the split hardness measured by the tablet hardness tester.
• “Absolute hardness” is a value obtained by dividing the hardness measured with a tablet hardness tester by the cross-sectional area (tablet diameter (mm) ⁇ tablet thickness (mm)) obtained by dividing the tablet in the longitudinal direction by the following formula: Desired.
• Absolute hardness (N / mm 2 ) Hardness (N) / Cross sectional area (mm 2 )
• HDBI Hardness and Disintegrating Balance Index
• the porosity is calculated
• Tablet porosity (%) (1 ⁇ Wt / ( ⁇ ⁇ V)) ⁇ 100 ⁇ : True density of tablets (mg / mm 3 ), V: Tablet volume (mm 3 ), Wt: Tablet weight (mg)
• the porosity can be measured as a porosity using, for example, a pore distribution measuring device (Micromeritics) manufactured by Shimadzu Corporation.
• the porosity of the outer layer is determined by the following equation.
• Porosity of outer layer (%) (1 ⁇ Wt / ( ⁇ ⁇ 3.14 ⁇ D 2 ⁇ T)) ⁇ 100 ⁇ : true density of outer layer (mg / mm 3 ), D: radius (mm) of outer layer (lower), T: thickness of outer layer (lower) (mm), Wt: weight of outer layer (lower) (mg)
• the thickness of the inner core was calculated by the following method.
• the thickness of the whole tablet was measured with a digital caliper (Mitutoyo).
• the dry coated tablet was divided in the diameter direction, the cross section was observed with a digital microscope (VHX-500 manufactured by Keyence), and the thicknesses of the upper and lower outer layers were measured.
• Inner core thickness (mm) Total tablet thickness (mm) ⁇ Total thickness of upper and lower outer layers (mm)
• “the ratio of the thickness of the inner core” means the ratio of the thickness occupied by the inner core to the thickness of the whole tablet. That is, the ratio of the thickness which an inner core occupies in the cross section parallel to the side surface of a tablet is meant.
• Ratio of inner core thickness (%) inner core thickness (mm) ⁇ total tablet thickness (mm) ⁇ 100
• the porosity of the outer layer is usually 1 to 20%, preferably 1 to 15%.
• the porosity of the inner core is usually 10 to 90%. Preferably, it is 20 to 80%.
• the porosity of the inner core is preferably larger than the porosity of the outer layer.
• Outer layer (a) Crystalline cellulose The crystalline cellulose used as an essential component of the outer layer of this invention will not be specifically limited if oral administration is possible. When the average particle size of the crystalline cellulose is large, it feels rough after disintegrating in the oral cavity. Therefore, the average particle size of the crystalline cellulose used as a raw material is preferably 150 ⁇ m or less, more preferably 130 ⁇ m or less. Preferably it is 120 micrometers or less.
• the orally disintegrating tablet of the present invention needs to impart hardness as a whole tablet only by the outer layer.
• the blending ratio of the crystalline cellulose used in the present invention is usually 10% by weight or more when the total weight of the outer layer is 100% by weight. .
• the blending proportion of crystalline cellulose used in the present invention is usually when the total weight of the outer layer is 100% by weight. 90% by weight or less.
• the blending ratio of the crystalline cellulose is 10 to 90% by weight, preferably 20 to 70% by weight when the total weight of the outer layer is 100% by weight.
• Examples of the crystalline cellulose used in the present invention include, for example, Theolas (CEOLUS, registered trademark, PH-101, PH-102, PH-301, PH-302, PH-F20J, KG-802, KG-1000, ST-02. : Asahi Kasei Chemicals), Avicel (AVICEL, registered trademark, PH-101, PH-102, PH-301, PH-302, FD-101, FD-301, FD-F20: manufactured by FMC BioPolymer) It is done. These crystalline celluloses may be used alone or in combination of two or more.
• the bulk density of the crystalline cellulose used in the present invention is preferably 0.1 to 0.5 g / cm 3 , more preferably 0.1 to 0.3 g / cm 3 .
• Examples of crystalline cellulose having a bulk density of 0.1 to 0.3 g / cm 3 include Theorus KG-802 and KG-1000.
• sugar or sugar alcohol used as an essential component of the outer layer of the present invention is not particularly limited as long as it can be administered orally, and is naturally derived from animals or plants, or chemically synthesized. Any of those obtained by a method or a fermentation method may be used.
• the blending ratio of the sugar or sugar alcohol used in the present invention is usually 0.5 to 84% by weight when the total weight of the outer layer is 100% by weight from the viewpoint of ingestion.
• the amount is preferably 20 to 80% by weight, more preferably 20 to 75% by weight.
• the sugar include glucose, fructose, sucrose, lactose (lactose), maltose, trehalose, palatinose and the like.
• lactose and trehalose are preferable, and lactose is most preferable.
• sugar alcohols include erythritol, mannitol, xylitol, sorbitol, maltitol, etc. Among them, erythritol and mannitol are preferable, and mannitol is most preferable from the viewpoint of a balance between hardness and disintegration.
• Lactose that can be used for the outer layer of the present invention is not particularly limited as long as it can be administered orally.
• ⁇ -lactose monohydrate There are ⁇ -lactose monohydrate, ⁇ -anhydrous lactose, and ⁇ -anhydrolactose, and ⁇ -lactose monohydrate is preferable in terms of handling.
• the average particle size of lactose used as a raw material from the viewpoint of taking feeling is preferably 150 ⁇ m or less, more preferably 120 ⁇ m or less.
• the mannitol that can be used in the outer layer of the present invention is not particularly limited as long as it can be administered orally, but D-mannitol is preferable.
• the crystal form is not particularly limited, and any of ⁇ -type, ⁇ -type, and ⁇ -type may be used, or an amorphous form obtained by spray drying may be used.
• mannitol having a high spherical density as described in JP-A-11-92403 may be used.
• the average particle size of mannitol to be blended is not particularly limited, but is preferably 10 to 300 ⁇ m, more preferably 10 to 250 ⁇ m, and still more preferably 30 to 200 ⁇ m.
• it may be appropriately pulverized as necessary. For example, it can grind
• the specific component used as an essential component of the outer layer of the present invention is at least one selected from the group consisting of crospovidone, starches, low-substituted hydroxypropylcellulose, and carmellose. .
• crospovidone starches
• low-substituted hydroxypropylcellulose and carmellose.
• these specific components are contained together with crystalline cellulose and sugar or sugar alcohol, it has been found that a desired effect can be obtained.
• the crospovidone that can be used in the present invention is not particularly limited, but those that are compatible with the Japanese Pharmacopoeia are usually used.
• the average particle size is not particularly limited, but if the average particle size of the crospovidone used is large, it feels rough after disintegrating in the oral cavity.
• the thickness is 10 to 200 ⁇ m, more preferably 10 to 150 ⁇ m, still more preferably 10 to 100 ⁇ m. In order to obtain a desired particle size, it may be appropriately pulverized as necessary. Examples of the pulverization method include a method using an airflow pulverizer or a hammer type pulverizer.
• the proportion of crospovidone in the outer layer is usually 3 to 20% by weight, preferably 5 to 10% by weight per 100% by weight of the outer layer.
• starches that can be used in the present invention are starches such as corn starch (corn starch), potato starch, rice starch, wheat starch, sweet potato starch, mung bean starch, tapioca starch, and partially pregelatinized starch.
• corn starch is preferable.
• completely pregelatinized starch cannot be applied because of its poor disintegration property.
• starches may be used alone or in combination of two or more.
• the average particle size is not particularly limited, but if the average particle size is large, it feels rough after disintegrating in the oral cavity. Therefore, the average particle size as a raw material is preferably 10 to 200 ⁇ m, more preferably from the viewpoint of ingestion.
• the thickness is 10 to 100 ⁇ m, more preferably 10 to 50 ⁇ m.
• it may be appropriately pulverized as necessary.
• the pulverization method include a method using an airflow pulverizer or a hammer type pulverizer.
• the total blending ratio of starches to be blended is usually 3 to 40% by weight, preferably 20 to 40% by weight per 100% by weight of the outer layer.
• the low-substituted hydroxypropyl cellulose that can be used in the present invention is not particularly limited to the substitution ratio of the hydroxypropoxy group, and can be used as long as it is compatible with the Japanese Pharmacopoeia.
• the substitution ratio is 7.0 to 12.9%.
• the average particle size is not particularly limited, but if the average particle size of the low-substituted hydroxypropylcellulose used is large, it feels rough after disintegrating in the oral cavity.
• the average particle size of cellulose is preferably 10 to 200 ⁇ m, more preferably 10 to 150 ⁇ m, and still more preferably 10 to 100 ⁇ m.
• the pulverization method include those using an airflow pulverizer or a hammer type pulverizer.
• the blending ratio is 3 to 20% by weight, preferably 5 to 10% by weight, per 100% by weight of the outer layer.
• C-4) Carmellose (CMC) Carmellose that can be used in the present invention is not particularly limited, but those that are compatible with the Japanese Pharmacopoeia are used.
• the average particle size is not particularly limited, but if the average particle size of carmellose used is large, it feels rough after disintegrating in the oral cavity, so that the average particle size of carmellose used as a raw material is preferably 10 to
• the thickness is 200 ⁇ m, more preferably 10 to 150 ⁇ m, still more preferably 10 to 100 ⁇ m. In order to obtain a desired particle size, it may be appropriately pulverized as necessary. Examples of the pulverization method include those using an airflow pulverizer or a hammer type pulverizer.
• the blending ratio when carmellose is blended is 3 to 20% by weight, preferably 5 to 10% by weight per 100% by weight of the outer layer.
• crospovidone, starches, and low-substituted hydroxypropylcellulose are preferable from the viewpoint of ingestion. More preferred are crospovidone and starches, and more preferred are crospovidone and corn starch. Most preferred is crospovidone from the viewpoint of the balance between hardness and disintegration.
• the total mixing ratio of the specific components is usually 6 to 43% by weight, preferably 25 to 40% by weight per 100% by weight of the outer layer. %.
• the total blending ratio of the specific components is usually 6 to 20% by weight, preferably 6 to 10% by weight, per 100% by weight of the outer layer. It is.
• formulation components can be added to the outer layer of the orally disintegrating tablet of the present invention for formulation.
• the “other formulation component” used in the present invention any component may be used as long as it has no or very little influence on the hardness and disintegration time of the drug and does not hinder formulation.
• other excipients, disintegrants, binders, sweeteners, flavoring agents, stabilizers, surfactants, fluidizing agents, antistatic agents, coating agents, lubricants, coloring agents, flavoring agents Etc. are mentioned as an example.
• the compounding amount of “other formulation ingredients” is 0.01 to 25% by weight per 100% by weight of the outer layer.
• Lubricant In the present invention, it is preferable to add a lubricant to the outer layer among the above other formulation ingredients.
• the lubricant include stearic acid, metal stearate, sodium stearyl fumarate, sucrose fatty acid ester, talc, hydrogenated oil, macrogol and the like.
• the metal stearate include magnesium stearate, calcium stearate, aluminum stearate and the like.
• stearic acid or a metal salt of stearic acid, particularly magnesium stearate is preferable in terms of manufacturability. From the viewpoint of the balance between hardness and disintegration and manufacturability, sodium stearyl fumarate is preferred.
• the average particle size before formulating the lubricant is 0.5 to 50 ⁇ m, preferably 1 to 30 ⁇ m.
• the blending ratio of the lubricant is usually 0.01 to 2.5% by weight, preferably 0.01 to 2% by weight, per 100% by weight of the outer layer. More preferably, the content is 0.01 to 1% by weight.
• the lubricant may be blended using any one of an external lubrication method and an internal lubrication method.
• the inner core is not particularly limited as long as it has good oral disintegration or dispersibility. Since the outer layer component of the present invention can impart sufficient hardness as a whole tablet even when the moldability of the inner core is low, the characteristics of the present invention can be exhibited when the inner core is a “powdery powder having low moldability”.
• the term “powders with low formability” means powders with low formability, such as powders, granulated products, etc., and when a compression molding is performed, no molded product is obtained or a molded product is obtained. Even so, the hardness is intended to be extremely low.
• the size of the “powders having low formability” used in the present invention is not particularly limited, but the average particle size is usually 3 mm or less, preferably 1 mm or less, more preferably 300 ⁇ m, from the viewpoint of ingestion in the oral cavity. Hereinafter, it is most preferably 150 ⁇ m or less.
• an active ingredient in the inner core for example, functional particles of microcapsules or coated granules containing the active ingredient, active ingredient powder itself, or microcapsules containing the active ingredient, functional particles or coated granules.
• liquidity, a dispersibility, and adhesiveness to component powder are contained.
• the granulated product is obtained by fluidized bed granulation method, extrusion granulation method, dry compaction granulation method, rolling granulation method, rolling fluidized bed granulation method, high-speed stirring granulation method, crushing granulation method, etc. Can be prepared.
• the microcapsules include microcapsules in a broad sense such as microcapsules, seamless capsules, mini soft capsules, microspheres, and the like.
• coated granules include polymer-coated granules, wax-coated granules, sugar-coated granules, and the like. Furthermore, it contains granules that may be inactivated by high-pressure tableting, such as enzyme-containing granules.
• the various coated particles are granules in which granular particles are coated with a coating film, granules in which nuclei are present in granular particles, granules in which nuclei are present in granular particles, and the like. It is a coated granule intended for enteric, gastric, heat resistance, light resistance, stability or bitterness improvement.
• coating includes covering all or part of the surface of the active ingredient with a coating component.
• the apparatus for coating include general fluidized bed granulators (including rolling fluidized bed granulators, Wurster type fluidized bed granulators, etc.).
• a fluidized bed granulator for example, SPC manufactured by POWREC Co., Ltd.
• a sizing / grinding mechanism for example, screen impeller system or blade stator system
• Wurster method equipped with a forced circulation device from the side , Cross screw, lamp breaker, etc.
• combined fluidized bed granulator for example, POWREC Co., Ltd., fine particle coating and granulator SFP-01
• rotary fluidized bed granulator for example, Nara Machinery Co., Ltd. Omnitex, etc.
• a general spray dryer for example, manufactured by Okawara Seisakusho, manufactured by Okawara Chemical Co., Ltd., manufactured by Yamato Co., Ltd., manufactured by Niro Co., Ltd.
• a general spray dryer for example, manufactured by Okawara Seisakusho, manufactured by Okawara Chemical Co., Ltd., manufactured by Yamato Co., Ltd., manufactured by Niro Co., Ltd.
• Examples of core components used in the production of the functional particles include commercially available crystalline cellulose granules, sucrose / starch spherical granules, purified sucrose spherical granules, lactose / crystalline cellulose spherical granules, D-mannitol, and anhydrous calcium hydrogen phosphate. , Magnesium oxide, magnesium hydroxide and the like.
• the active ingredient used in the orally disintegrating tablet of the present invention is not particularly limited as long as it is used as a pharmaceutically active ingredient for treatment and prevention of diseases and can be administered orally.
• nourishing tonic health drug antipyretic analgesic / anti-inflammatory drug; antipsychotic drug; hypnotic sedative drug; antispasmodic drug; central nervous system drug; cerebral metabolism improving drug; Agent; Anti-ulcer agent; Gastrointestinal motility improving agent; Antacid; Antitussive expectorant; Intestinal motility inhibitor; Antiemetic agent; Respiratory agent; Bronchodilator; Antiallergic agent; Cardiotonic agent; Arrhythmic agent; Vasoconstrictor; Coronary vasodilator; Vasodilator; Peripheral vasodilator; Hyperlipidemia agent; Biliate; Chemotherapeutic agent; Diabetes complication agent; Osteoporosis agent; Antirheumatic agent; Examples include muscle relaxants; therapeutic agents for gout; anti
• the active ingredient in the present invention may be in a salt or free form as long as it is pharmaceutically acceptable. Further, it may be in the form of a solvate such as an alcohol solvate or a hydrate. Furthermore, the active ingredients listed above may be used alone or in combination of two or more.
• the amount of the active ingredient in the inner core in the present invention is not particularly limited, but is 0.1 to 100% by weight, preferably 1 to 95% by weight with respect to 100% by weight of the inner core. %.
• the “mixing ratio of the active ingredient in the inner core” in the present invention is based on the form of “pharmaceutical active ingredient” which is generally employed as a drug. That is, in the case of a drug in the form of a salt, the amount of the salt is used as a reference.
• the above-mentioned active ingredients can be added to the outer layer within a range where the hardness and disintegration time of the final molded product are not affected or extremely small.
• the nucleated orally disintegrating tablet according to the present invention can be produced using a tableting machine capable of producing a nucleated molded product.
• a nucleated orally disintegrating tablet containing a large amount of microcapsule-like functional particles in the inner core is a tableting machine for a nucleated molded article disclosed in International Publication No. 2005/097041, etc.
• Examples of the method for producing a nucleated type orally disintegrating tablet according to the present invention in a laboratory include the following.
• the above components (a) to (c) are mixed, put in a mortar corresponding to the diameter of the inner core, and gently shaken to smooth the surface of the powder (outer layer (lower)).
• an appropriate amount of a powder having low formability corresponding to the inner core is added and temporarily compressed at a relatively low pressure using a hand press.
• the above components (a) to (c) are mixed, put into a mortar corresponding to the diameter of the tablet, and temporarily compressed at a relatively low pressure using a hand press.
• a powder having low formability corresponding to the inner core is put into a mortar corresponding to the diameter of the inner core, and temporarily compressed using a hand press machine at a relatively low pressure.
• granules before tableting may be prepared by a known method. For example, after the components (a) to (c) are uniformly mixed, a nucleated molded article can be produced by the above method using the mixture.
• each of the above components (a) to (c) may be granulated before tableting, a lubricant may be added thereto, and a mixture may be used to produce a nucleated molded product by the above method.
• a part of each of the above components (a) to (c) is granulated, and the remaining components (a) to (c) and a lubricant are added thereto, and a mixture thereof is used.
• a nucleated molded article may be produced by the above method.
• the granulation method include fluidized bed granulation method, extrusion granulation method, dry compaction granulation method, rolling granulation method, rolling fluidized bed granulation method, high-speed stirring granulation method, crushing granulation method, etc. Is mentioned.
• the orally disintegrating tablet of the present invention thus obtained means that rapidly disintegrating in the oral cavity without ingesting water to take the preparation.
• the orally disintegrating tablet of the present invention means a preparation that disintegrates within about 60 seconds mainly by saliva in the oral cavity, usually within 45 seconds, preferably within 30 seconds, more preferably within 20 seconds. Collapse.
• the orally disintegrating tablet of the present invention has a sufficient hardness that does not cause chipping or cracking during production, transportation, or medical practice.
• the orally disintegrating tablet of the present invention has a double structure and is more likely to be chipped or cracked compared to a normal orally disintegrating tablet, and it is desirable that the tablet has a higher hardness.
• the orally disintegrating tablet of the present invention the absolute hardness of 2.0 N / mm 2 or more, preferably 2.5 N / mm 2 or more.
• the shape of the nucleated type orally disintegrating tablet which is the final molded product of the present invention is not particularly limited, but may be any shape such as a circular tablet, a circular R tablet, a circular corner tablet, and various deformed tablets.
• the tablet diameter is usually 5 to 16 mm, preferably 7 to 10 mm.
• the “ratio of the thickness of the inner core” is usually 30 to 80%, preferably 30 to 70%, more preferably 30 to 60%.
• the thickness of the outer layer is usually 0.5 to 2.0 mm, preferably 0.5 to 1.5 mm, and more preferably 0.5 to 1.0 mm.
• the ratio of the volume occupied by the inner core is 10 to 60%, preferably 15 to 50% when the volume of the final molded product is 100%.
• the nucleated orally disintegrating tablet of the present invention must have disintegration property in the oral cavity and hardness sufficient to maintain the shape as a preparation when handled in the manufacturing process, distribution process, medical field, etc. .
• it is characterized by containing a low-moldability powder as an inner core, so that the outer layer needs to have sufficient strength, and compared with a normal orally disintegrating tablet that is not nucleated, the outer layer Hardness is required. It is preferable to make the porosity of the outer layer smaller than usual, and sufficient hardness can be achieved.
• the porosity of the outer layer of the tablet is preferably 1 to 20%, more preferably 1 to 15%.
• mannitol, lactose, sodium stearyl fumarate, corn starch, magnesium stearate, carmellose, low-substituted hydroxypropylcellulose (L-HPC), crystalline cellulose granules, crystalline cellulose and crospovidone are as follows unless otherwise specified. I used one.
• Mannitol Peritol 50C: manufactured by ROQUETTE
• lactose hydrate Pharmatose 200M: manufactured by DMV International
• sodium stearyl fumarate probe: Kimura Sangyo
• corn starch ((XX16) W: manufactured by Nippon Shokuhin Kako)
• Magnesium stearate light, vegetable: manufactured by Taihei Chemical Industry Co., Ltd.
• carmellose Nippon Shokuhin Kako
• NS-300 manufactured by Gotoku Pharmaceutical Co., Ltd.
• low-substituted hydroxypropyl cellulose LH-21: manufactured by Shin-Etsu Chemical Co., Ltd.
• SELFIA CP- 203: Asahi Kasei Chemicals Co., Ltd., crystalline cellulose (Ceorus PH-101 or Theolus PH-301, Theolas KG-802, Theolas KG-1000: Asahi Kasei Chemicals Co., Ltd.
• Examples 1-1 to 1-5 Examination of types of specific components ⁇ Production of nucleated orally disintegrating tablets> Five formulations containing different specific components in the outer layer were prepared according to the formulation shown in Table 1-1. First, each component of the outer layer was mixed. 40 mg of this was put into a 6 mm diameter mortar and lightly vibrated to smooth the surface of the powder (outer layer (lower)). On top of that, 50 mg of crystalline cellulose particles (Selfia CP-203) was added as an inner core component, and temporarily compressed using a hand press machine (manufactured by Riken, hydraulic press machine) at a low pressure of 3 kN.
• a hand press machine manufactured by Riken, hydraulic press machine
• This temporary compression product is placed concentrically with a diameter of 8 mm so that the outer layer (lower) faces downward, and is covered with a mortar with a diameter of 8 mm, and 140 mg of the mixture of the outer layer components above the temporary compression product (outer layer (side surface + side surface + The above)) was put into a final mold to produce a nucleated orally disintegrating tablet.
• the final molded product was tableted at 15 kN in Examples 1-2 and 1-5 and at 10 kN in others.
• the hardness of the compression molded product obtained by putting 50 mg of crystalline cellulose particles (Selfia CP-203) used in the present preparation into a 6 mm diameter die and compressing with a tableting pressure of 4 kN was less than 10N. .
• the disintegration time in the oral cavity, tablet hardness and thickness were measured, and the absolute hardness and HDBI were calculated.
• the tablet physical properties shown in Table 1-3 were obtained.
• any one of carmellose, corn starch, L-HPC, and crospovidone was included in the outer layer as in Examples 1-1 to 1-4, the disintegration time in the oral cavity was within 30 seconds, and the absolute hardness was 2.0 N / mm 2
• the absolute hardness was 2.0 N / mm 2
• HDBI which is an index of the balance between hardness and disintegration
• each of the prescriptions was good to take and there was no crispness in the mouth.
• the porosity of the outer layer (lower) part of these preparations was measured, all were 20% or less.
• HDBI is the largest. Also, as in Example 1-5, when mannitol of Example 1-2 was replaced with lactose, the oral disintegration time was similarly within 30 seconds and the absolute hardness satisfied 2.0 N / mm 2 or more. HDBI, which is an index of the balance between hardness and disintegration, was large.
• Comparative Examples 1-1 to 1-3 When no specific component or crystalline cellulose is contained (1) In the formulation shown in Table 2-1, a preparation containing no specific component in the outer layer was produced in the same manner as in Example 1-1. Mannitol S (manufactured by Towa Kasei Co., Ltd.) was used as mannitol. The final molded products were tableted at 4 kN and 15 kN in Comparative Examples 1-1 and 1-2, and 15 kN in Comparative Example 1-3.
• the obtained tablets were measured for oral disintegration time, tablet hardness and thickness, and the absolute hardness and HDBI were calculated, and the tablet physical properties shown in Table 2-3 were obtained.
• the oral disintegration time is within 30 seconds and the absolute hardness is 2.0 N / mm 2 or more.
• the criteria were barely satisfied in Comparative Example 1-1, the other comparative examples had low absolute hardness, and HDBI, which is an index of the balance between hardness and disintegration, was small in all comparative examples and less than 0.1.
• Comparative Example 1-4 No specific component (2) (Outer layer of Patent Document 2) A formulation having the formulation similar to the production example of Patent Document 2 shown in Table 2-4 and not containing the specific component of the present invention in the outer layer was produced in the same manner as in Example 1-1. The final molded product was tableted at 10 kN. However, the tool used a small amount of magnesium stearate applied. Cellactose 80 was manufactured by MEGGLE.
• the obtained tablets were measured for oral disintegration time, tablet hardness and thickness, and the absolute hardness and HDBI were calculated, and the tablet physical properties shown in Table 2-6 were obtained. It did not disintegrate in the oral cavity.
• Comparative Example 1-5 No specific component (3) (Outer layer of Patent Document 1) A formulation having the formulation shown in Table 2-7 and not containing the specific component of the present invention in the outer layer was produced in the same manner as in Example 1-1. The final molded product was tableted at 10 kN. The outer layer formulation was set to the same blending ratio as in Test Example 6 of Patent Document 2 (erythritol 60 mg, crystalline cellulose 19.5 mg, magnesium stearate 0.5 mg).
• the obtained tablets were measured for oral disintegration time, tablet hardness and thickness, and the absolute hardness and HDBI were calculated, and the tablet physical properties shown in Table 2-9 were obtained.
• the oral disintegration time was fast, but the absolute hardness was low, less than 1 N / mm 2 , and sufficient Hardness could not be obtained. That is, it was found that the outer layer component disclosed in Patent Document 1 cannot give sufficient hardness as a whole tablet when a dry-coated tablet having particles having no moldability as an inner core is produced.
• Examples 2-1 to 2-6 and Comparative Example 2-1 Ratio of crystalline cellulose
• Table 3-1 preparations having different amounts of crystalline cellulose in the outer layer were produced in the same manner as in Example 1-1. did.
• the final molded product was tableted at 15 kN in Comparative Example 2-1 and Examples 2-1 to 2-3, 10 kN in Example 2-4, and 4 kN in Examples 2-5 to 2-6.
• the obtained tablets were measured for oral disintegration time, tablet hardness and thickness, and the absolute hardness and HDBI were calculated, and the tablet physical properties shown in Table 3-3 were obtained.
• Comparative Example 2-1 when the amount of crystalline cellulose in the outer layer was 1%, the absolute hardness was less than 2.0 N / mm 2, and HDBI, which is an index of the balance between hardness and disintegration, was small.
• the amount of crystalline cellulose in the outer layer is 10 to 90% as in Examples 2-1 to 2-6, the disintegration time in the oral cavity is within 30 seconds, and the absolute hardness satisfies 2.0 N / mm 2 or more.
• HDBI which is an index of the balance between hardness and disintegration, was large.
• the amount of crystalline cellulose in the outer layer is too much, it becomes powdery, so the amount of crystalline cellulose in the outer layer is even better when it is 70% or less, and from the viewpoint of hardness, the amount of crystalline cellulose in the outer layer is 20%.
• the absolute hardness was 2.5 N / mm 2 or more, which was even better.
• HDBI which is an index of the balance between hardness and disintegration, was the largest.
• Examples 3-1 to 3-2 and Comparative Examples 3-1 to 3-2 Ratio of specific components (crospovidone) Preparations with different amounts of crospovidone in the outer layer with the formulation shown in Table 4-1 were produced in the same manner as in Example 1-1.
• the final molded product was tableted at 15 kN in Comparative Example 3-1 and Example 3-1, 10 kN in Example 3-2, and 4 kN in Comparative Example 3-2.
• the obtained tablets were measured for oral disintegration time, tablet hardness and thickness, and the absolute hardness and HDBI were calculated, and the tablet physical properties shown in Table 4-3 were obtained.
• Example 3-1 and Example 3-2 when the amount of crospovidone in the outer layer is 5% to 20%, the oral disintegration time is within 30 seconds and the absolute hardness satisfies 2.0 N / mm 2 or more. HDBI, which is an index of the balance between hardness and disintegration, was large.
• Comparative Example 3-1 and Comparative Example 3-2 when the amount of crospovidone in the outer layer was as small as 1% or as large as 40%, HDBI, which is an index of the balance between hardness and disintegration, was small. .
• Examples 4-1 to 4-2 and Comparative Example 4-1 Ratio of specific components (corn starch) Formulations with different amounts of corn starch in the outer layer having the formulation shown in Table 5-1 were produced in the same manner as in Example 1-1. The final molded product was tableted at 10 kN in Comparative Example 4-1 and Example 4-1, and at 15 kN in Example 4-2.
• Example 4-1 to Example 4-2 when the amount of corn starch in the outer layer is 5% to 40%, the oral disintegration time is within 30 seconds, and the absolute hardness satisfies 2.0 N / mm 2 or more. HDBI, which is an index of the balance between hardness and disintegration, was large.
• Examples 5-1 to 5-4 Types of crystalline cellulose Preparations having different types of crystalline cellulose in the outer layer were prepared in the same manner as in Example 1-1 with the formulation shown in Table 6-1. The final molded product was tableted at 15 kN.
• the disintegration time in the oral cavity, tablet hardness and thickness were measured, and the absolute hardness and HDBI were calculated.
• the tablet physical properties shown in Table 6-3 were obtained.
• the oral disintegration time is within 30 seconds, and the absolute hardness satisfies 2.0 N / mm 2 or more.
• HDBI which is an index of gender balance, was large.
• KG-802 or KG-1000 was used for the crystalline cellulose of the outer layer, HDBI, which is an index of the balance between hardness and disintegration, was 0.2 or more, and a tablet with a favorable balance was obtained.
• Examples 6-1 to 6-3 Types of lubricants In the formulation shown in Table 7-1, preparations having different types of lubricants in the outer layer were produced in the same manner as in Example 1-1. The final molded product was tableted at 15 kN.
• the disintegration time in the oral cavity was measured, and the absolute hardness and HDBI were calculated.
• the tablet physical properties shown in Table 7-3 were obtained.
• the disintegration time in the oral cavity is within 30 seconds, and the absolute hardness satisfies 2.0 N / mm 2 or more.
• HDBI which is an index of disintegration balance, was large.
• Examples 7-1 to 7-5 Combined use of specific components Preparations using two or more specific components in the outer layer in the formulation shown in Table 8-1 were produced in the same manner as in Example 1-1. The final molded product was tableted at 10 kN in Examples 7-1 and 7-3 and 15 kN in the others.
• the disintegration time in the oral cavity, tablet hardness and thickness were measured, and the absolute hardness and HDBI were calculated.
• the tablet physical properties shown in Table 8-3 were obtained. Even when two or more specific components of the outer layer are used in combination, the disintegration time in the oral cavity is within 30 seconds, the absolute hardness satisfies 2.0 N / mm 2 or more, and HDBI, which is an index of the balance between hardness and disintegration, is large. It was.
• the porosity of the outer layer was 9% in Example 7-1 and 10% in Example 7-3.
• Examples 8-1 to 8-2 Ratio of the thickness of the inner core According to the formulation shown in Table 9-1, preparations having different ratios of the thickness of the inner core were manufactured. First, the outer layer components were mixed. Take the powder mixture of the outer layer components shown in Table 7-1 (upper) weight, put it in a mortar with the diameter of the inner core shown in Table 7-1, and gently shake the powder surface. A predetermined amount of (Selfia CP-203) was added, and temporary compression was performed at a low pressure of 3 kN using a hand press machine (manufactured by Riken, hydraulic press machine).
• This temporary compression product is placed concentrically with a diameter of 8 mm so that the outer layer faces downward, and a mortar with a diameter of 8 mm is placed over the temporary compression product to the weight of the outer layer (side surface + upper) in Table 7-1.
• the outer layer component shown was put into final molding to produce a nucleated orally disintegrating tablet.
• the final molded product was tableted at 4 kN.
• the disintegration time in the oral cavity, tablet hardness and thickness were measured, and the absolute hardness and HDBI were calculated.
• the tablet physical properties shown in Table 9-3 were obtained.
• the ratio of the thickness of the inner core is 32 to 54%
• the oral disintegration time is within 30 seconds
• the absolute hardness satisfies 2.0 N / mm 2 or more
• HDBI which is an index of the balance between hardness and disintegration is large. It was.
• Example 9-1 Nucleated orally disintegrating tablet containing active ingredient (1) Production of acetaminophen-containing particles (Asahi Kasei Chemicals) Acetaminophen was coated so that the coating amount was 10% to obtain acetaminophen-containing particles.
• the coating component used was Aquacoat (manufactured by Asahi Kasei Chemicals), triacetin and mannitol 100: 25: 50% by weight.
• Table 10-1 a preparation containing an active ingredient was produced in the same manner as in Example 1-1. The final molded product was tableted at 4 kN.
• the disintegration time in the oral cavity, tablet hardness and thickness were measured, and the absolute hardness and HDBI were calculated.
• the tablet physical properties shown in Table 10-3 were obtained.
• the oral disintegration time was within 30 seconds, the absolute hardness satisfied 2.0 N / mm 2 or more, and HDBI, which is an index of the balance between hardness and disintegration, was large. Thus, it was found that a good nucleated orally disintegrating tablet can be obtained even when the active ingredient is contained.
• a solution obtained by dissolving 2.85 g of sodium hydroxide in 67.65 g of purified water was gradually added to 705 g of methacrylic acid copolymer LD (Polykid PA-30S: manufactured by Sanyo Chemical Industries, Ltd.) and stirred ( Second liquid).
• the second liquid was added to the first liquid, suspended, and sieved through a mesh screen having an opening diameter of 177 ⁇ m to obtain a coating coating dispersion.
• the supply air temperature is maintained at 80 to 90 ° C.
• the exhaust temperature is maintained at 26 to 30 ° C.
• the spray liquid flow rate is 10 to 12 g / min
• the spray air flow rate is 80 L / min
• the spray air pressure is 0.2 to 0.
• the production was carried out at 3 MPa, a side air pressure of 0.2 to 0.25 MPa, and an air supply amount of about 0.30 to 0.55 m 3 / min.
• the spray amount of the coating coating dispersion was about 1306 g
• the coating was completed and the coating was dried until the exhaust temperature reached 42 ° C.
• the obtained particles were sieved with a sieve of 32 mesh (aperture 500 ⁇ m) to obtain drug-containing particles having an average particle diameter of about 165 ⁇ m.
• Preparations containing active ingredient-containing particles in the inner core were prepared according to the formulation shown in Table 11-1.
• the inner core mixed particles of gasmotin-containing particles and crospovidone and talc were used.
• the outer layer components were mixed. 40 mg of this was put into a 6 mm diameter mortar and lightly vibrated to smooth the surface of the powder (outer layer (lower)).
• 50 mg of mixed particles of the inner core were added and temporarily compressed at a low pressure of 3 kN using a hand press machine (manufactured by Riken, hydraulic press machine).
• This temporary compression product is placed concentrically with a diameter of 8 mm so that the outer layer (bottom) faces down, and is covered with a mortar with a diameter of 8 mm, and the outer layer component 140 mg from the top of the temporary compression product (outer layer (side surface + upper)) And finally molded to produce a nucleated orally disintegrating tablet.
• the final molded product was tableted at 4 kN.
• the obtained tablets were measured for oral disintegration time, tablet hardness and thickness, and the absolute hardness and HDBI were calculated, and the tablet physical properties shown in Table 11-3 were obtained.
• the oral disintegration time was within 30 seconds, the absolute hardness satisfied 2.0 N / mm 2 or more, and HDBI, which is an index of the balance between hardness and disintegration, was large. Thus, it was found that a good nucleated orally disintegrating tablet can be obtained even when the active ingredient is contained.
• Comparative Examples 5-1 to 5-4 Normal tablets (nuclear-free tablets) Using the outer layer formulation of Example 1-1, ordinary tablets (core-free tablets containing no inner core) were produced. First, the raw materials were uniformly mixed so as to have the blending ratio shown in Table 12-1. 230 mg of this mixed powder was tableted at a diameter of 8 mm and a tableting pressure of 4, 10, 15 and 20 kN to produce ordinary tablets.
• the disintegration time in the oral cavity, tablet hardness and thickness were measured, and the absolute hardness and HDBI were calculated.
• the tablet physical properties shown in Table 12-3 were obtained.
• the tableting pressure was 15 kN or more
• the oral disintegration time was 30 seconds or more.
• the tableting pressure was 4 kN
• the absolute hardness was less than 1.0.
• HDBI which is an index of the balance between hardness and disintegration, was 0.15 or less.
• Comparative Example 6-1 Ordinary tablet uniformly containing non-moldable particles (core-free tablet) Using the mixture of the inner core formulation and the outer layer formulation of Example 1-1, ordinary tablets in which particles having no moldability were uniformly distributed in the tablets were produced. First, the raw materials were uniformly mixed so as to have the blending ratio shown in Table 13-1. Using this mixed powder, tableting was performed at a diameter of 8 mm and a tableting pressure of 10 kN to obtain ordinary tablets. This ordinary tablet is different from the dry-coated tablet obtained in Example 1-1 in that the amount of components contained in one tablet, tablet weight, tablet diameter, The tableting pressure was produced under the same conditions.
• nucleated type orally disintegrating tablet having an inner core with low moldability, and having a good balance between hardness and disintegration.

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