WO2011019043A1 - 2種以上の粒子を含有する口腔内速崩壊錠 - Google Patents
2種以上の粒子を含有する口腔内速崩壊錠 Download PDFInfo
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- WO2011019043A1 WO2011019043A1 PCT/JP2010/063599 JP2010063599W WO2011019043A1 WO 2011019043 A1 WO2011019043 A1 WO 2011019043A1 JP 2010063599 W JP2010063599 W JP 2010063599W WO 2011019043 A1 WO2011019043 A1 WO 2011019043A1
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- disintegrating tablet
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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
- A61K9/20—Pills, tablets, discs, rods
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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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
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- 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
-
- 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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
Definitions
- the present invention relates to an intraoral quick disintegrating tablet characterized by containing two or more kinds of particles. Specifically, the present invention relates to a preparation that maintains the same hardness as a normal tablet, maintains sufficient hardness after opening, and can rapidly disintegrate in the oral cavity without water.
- the intraoral rapidly disintegrating tablet When the intraoral rapidly disintegrating tablet is used like a normal tablet, it is the maintenance of the hardness after opening. In the prior art, there is no description about the hardness, or the initial hardness necessary for satisfying the hardness at the time of taking out is described, but what is mentioned about the hardness reduction after opening is known. Absent.
- the intraoral rapidly disintegrating tablet needs to have a hardness that prevents the tablet from being chipped or powdered during tablet production or transportation while having an early disintegration time in the oral cavity. However, the hardness and the disintegration time are contradictory elements. Generally, when the disintegration time is shortened, the hardness decreases, and when the hardness is increased, the disintegration time increases.
- Patent Document 1 discloses a pharmaceutical composition obtained by spray drying a suspension in which an inorganic compound and a saccharide are uniformly dispersed.
- Patent Document 2 discloses a composition obtained by spray-drying a suspension of a saccharide, an inorganic excipient, a disintegrant composed of a combination of mannitol and xylitol, and an intraoral rapidly disintegrating tablet containing the same
- Patent Document 3 discloses an orally rapidly disintegrating tablet using a disintegration aid at the final formulation stage.
- orally disintegrating tablets disintegrate tablets with a small amount of saliva. Therefore, it is usually easy to reduce the hardness due to humidity, and it is considered difficult to develop an orally rapidly disintegrating tablet that stably maintains the hardness. .
- an orally rapidly disintegrating tablet that has a sufficiently short oral disintegration time and that retains the hardness after opening while satisfying the initial hardness.
- the present inventors obtained drug-containing particles obtained by granulating a mixture containing a drug, a water-soluble polymer and sugar or a sugar alcohol, and specific spray-dried particles obtained by previously spray-drying.
- a preparation having excellent oral disintegration and initial hardness could be produced.
- the present invention provides the following various aspects of the invention.
- An intraoral quick disintegrating tablet comprising the following particles (1) and (2): (1) Drug-containing particles comprising the following components (a) to (c), and granulating each component into particles: (A) drugs, (B) a water-soluble polymer, and (C) sugar or sugar alcohol, and (2) Spray-dried particles comprising the following components (d) to (f), each component being dispersed in a dispersion solvent and spray-dried; (D) mannitol, or mannitol and xylitol, (E) carboxymethylcellulose, and (F) Disintegrant.
- Drug-containing particles comprising the following components (a) to (c), and granulating each component into particles: (A) drugs, (B) a water-soluble polymer, and (C) sugar or sugar alcohol, and (2) Spray-dried particles comprising the following components (d) to (f), each component being dispersed in a dispersion solvent and spray-dried; (D) mannitol, or mannitol and x
- disintegrant (f) is at least one selected from the group consisting of low-substituted hydroxypropylcellulose, croscarmellose sodium, crystalline cellulose, carmellose calcium, hydroxypropyl starch, and rice starch.
- the intraorally rapidly disintegrating tablet according to any one of 1 to 5.
- the inorganic compound (g) is at least one selected from the group consisting of magnesium aluminate metasilicate, magnesium aluminate silicate, anhydrous silicic acid, light anhydrous silicic acid, calcium silicate, and calcium hydrogen phosphate.
- a drug having an unpleasant taste With respect to a drug having an unpleasant taste, it has a sufficient hardness so as not to hinder the handling from the manufacture of the tablet to the dose, and is characterized in that the hardness after storage is maintained particularly under humidified conditions, It is possible to mass-produce tablets that are small and do not feel unpleasant taste, have a good feeling of administration, and are excellent in disintegration in the oral cavity and dissolution in the digestive tract.
- “orally disintegrating tablet in the oral cavity” means that it is within about 60 seconds in the oral cavity mainly in the test with saliva or in the apparatus test, without ingesting water in order to take a preparation such as a tablet. A formulation that disintegrates within 40 seconds.
- an oral disintegration tester manufactured by Toyama Sangyo Co., Ltd., ODT-101 can be used.
- the “average particle diameter” is represented by a value measured by, for example, a laser diffraction particle size analyzer [HELOS & RODOS] manufactured by Sympatech.
- % by weight means% by weight when the total weight per tablet of the final preparation is 100% by weight. Further, among the components in the drug-containing particles and the spray-dried particles, what is indicated by “% by weight” with respect to 100% by weight of the total amount of the composition in each particle means the blending ratio at the time of manufacturing each particle.
- the intraoral quick disintegrating tablet of the present invention is Orally rapidly disintegrating tablets characterized by containing the following particles (1) and (2): (1) Drug-containing particles comprising the following components (a) to (c), and granulating each component into particles: (A) drugs, (B) a water-soluble polymer, and (C) sugar or sugar alcohol, and (2) Spray-dried particles comprising the following components (d) to (f), each component being dispersed in a dispersion solvent and spray-dried; (D) mannitol, or mannitol and xylitol, (E) carboxymethylcellulose, and (F) Disintegrant, and each component and each particle will be described below.
- Drug-containing particles comprising the following components (a) to (c), and granulating each component into particles: (A) drugs, (B) a water-soluble polymer, and (C) sugar or sugar alcohol, and (2) Spray-dried particles comprising the following components (d) to (f), each component being dispersed in a dispersion
- Drug-containing particle (a) drug As an active ingredient used as a drug in the intraoral quick disintegrating tablet of the present invention, it can be used as a pharmaceutical active ingredient for treatment or 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
- 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. Moreover, you may use what masked the unpleasant taste, such as a bitter taste of a drug.
- the present invention applies to 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof as a drug. it can.
- the compound (or an acid addition salt thereof or a hydrate thereof) is a selective serotonin 4 receptor agonist and exhibits a good gastrointestinal motility promoting action.
- Patent Document 4 discloses particles obtained by combining mannitol and methylcellulose with respect to particles containing the compound, but the examples do not disclose combinations with particles obtained by spray drying and the effects thereof. .
- This 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide is one of the optically active substances, even if it is a racemate. However, a racemate is preferable.
- the compound may be a free form or a physiologically acceptable salt thereof.
- the salt is preferably an acid addition salt. Examples of organic acid addition salts include, but are not limited to, formate, acetate, lactate, adipate, citrate, tartrate, fumarate, methanesulfonate, maleate, and the like. .
- inorganic acid addition salts include, but are not limited to, hydrochlorides, sulfates, nitrates, phosphates, and the like. Of these, citrate is particularly preferable. Furthermore, the compound or a physiologically acceptable salt thereof may be a solvate, a hydrate or a non-hydrate. Citrate hydrate is preferred, and citrate dihydrate is particularly preferred.
- the amount of the drug is usually 1 to 30% by weight, preferably 4 to 25% by weight, more preferably 5 to 20% by weight, and still more preferably 9% to 100% by weight of the total composition of the drug-containing particles. ⁇ 20% by weight.
- the drug in order to prepare particles obtained by mixing a drug-containing component and a solvent before tableting, the drug has an average particle size of 1 ⁇ m to 30 ⁇ m, preferably 1 ⁇ m to 15 ⁇ m, more preferably 1 ⁇ m to 10 ⁇ m. More preferably, it is recommended to pulverize to 5 to 10 ⁇ m.
- the “active ingredient blending amount” in the present invention is based on the form of “pharmaceutical active ingredient” generally employed as a drug.
- a drug in the form of a salt it is based on the amount of acid or base added to form the salt.
- the amount obtained by subtracting the amount corresponding to the water of crystallization is the standard.
- the water-soluble polymer used in the present invention includes one selected from polyvinyl pyrrolidone, methyl cellulose, pullulan, polyvinyl alcohol, hydroxypropyl methylcellulose and hydroxypropylcellulose, or a combination of two or more thereof. However, it is not limited to these. Preferred are methyl cellulose, pullulan, polyvinyl alcohol and hydroxypropyl cellulose, and more preferred is methyl cellulose. When the viscosity of a 2% by weight aqueous solution is measured at 0 ° C. according to the 14th revision of the Japanese Pharmacopoeia, it is usually 1 to 100 mm.
- the blending amount of the water-soluble polymer is usually 3 to 45% by weight, preferably 3 to 40% by weight, more preferably 5 to 30% by weight, more preferably 100% by weight of the total composition of the drug-containing particles. Is from 10 to 30% by weight.
- sugar or sugar alcohol used in the present invention includes one or a combination of two or more selected from mannitol, xylitol, lactose, erythritol, trehalose, sucrose, maltitol, lactitol, and the like.
- mannitol xylitol
- lactose erythritol
- trehalose sucrose
- maltitol lactitol
- lactitol and the like.
- Preferred are mannitol, xylitol, lactose, erythritol and lactitol, more preferred is mannitol, and even more preferred is D-mannitol.
- the amount of sugar or sugar alcohol is such that fast solubility can be achieved, and usually 40 to 90% by weight, preferably 60 to 90% by weight, more preferably 100% by weight of the total composition of the drug-containing particles. 60 to 85% by weight, more preferably 60 to 75% by weight.
- the drug-containing particles include the components (a) to (c) described above, and are formed by granulating each component into particles.
- each of the components (a) to (c) above Are mixed, granulated, and granulated. More specifically, for example, particles obtained by mixing the components (a) to (c) described above, adding a solvent, and granulating.
- the method includes mixing each component and then granulating by adding a solvent, or dissolving or suspending a part or all of each component in a solvent and adding it to the mixture and granulating. It is. Furthermore, it can also be granulated by adding formulation ingredients such as a binder and a corrigent which will be described later within a range that does not affect the effects of the present invention.
- the solvent may be any solvent that does not affect the properties of the composition and is acceptable in terms of stability and safety even when used in pharmaceuticals and foods, and is selected from, for example, water, ethanol, methanol, and the like. Although the mixed solvent of 1 type or those 2 or more types of combinations is mentioned, It is not limited to these.
- the drug is not present in a state where the water-soluble polymer is completely coated around the drug, but the drug is also present on the particle surface.
- the amount of the drug-containing particles is usually 5 to 37% by weight, preferably 10 to 30% by weight, more preferably 10 to 25% by weight, and even more preferably, per 100% by weight of the orally rapidly disintegrating tablet. It is 10 to 20% by weight, most preferably 10 to 15% by weight.
- the average particle size of the particles before formulation is usually about 500 ⁇ m or less, for example, 50 to 500 ⁇ m, preferably 50 to 400 ⁇ m, more preferably 100 to 300 ⁇ m, more preferably 100 to 200 ⁇ m, and most preferably 100 ⁇ 150 ⁇ m.
- the amount of mannitol, or mannitol and xylitol mannitol, or mannitol and xylitol is usually 65 to 95% by weight with respect to 100% by weight of the total composition of the spray-dried particles.
- the mannitol alone or the total amount of mannitol and xylitol is 70 to 90% by weight, more preferably 70 to 85% by weight, and still more preferably 75 to 85% by weight.
- the blending amount is usually 0.01 to 5% by weight, preferably 2 to 5% by weight, more preferably 2 to 2% with respect to 100% by weight of the total composition of spray-dried particles. It is 4% by weight, more preferably 2-3% by weight.
- carboxymethylcellulose used in the present invention (sometimes referred to herein as carmellose) is usually 1 to 20% by weight, preferably 3 to 15% by weight, more It is preferably 3 to 12% by weight, more preferably 5 to 12% by weight, and most preferably 5 to 10% by weight.
- the disintegrant used in the present invention is one selected from low-substituted hydroxypropylcellulose, croscarmellose sodium, crystalline cellulose, carmellose calcium, hydroxypropyl starch, rice starch, carmellose sodium, and the like. Or the combination of 2 or more types thereof is mentioned, but it is not limited to these. Preferred are low-substituted hydroxypropylcellulose, croscarmellose sodium, crystalline cellulose, carmellose calcium, hydroxypropyl starch and rice starch, and most preferred is low-substituted hydroxypropylcellulose.
- the low-substituted hydroxypropyl cellulose refers to hydroxypropyl cellulose having a hydroxypropoxyl group content of 5 to 16% by weight.
- the amount of the disintegrant is usually 1 to 20% by weight, preferably 3 to 15% by weight, more preferably 3 to 12% by weight, and still more preferably 100% by weight of the total composition of spray-dried particles. 5 to 12% by weight, most preferably 5 to 10% by weight.
- the spray-dried particles in the present invention may contain an inorganic compound.
- an inorganic compound By blending an inorganic compound, there is an effect that the disintegration time is further shortened.
- the inorganic compound used in the present invention one or two kinds selected from magnesium aluminate metasilicate, magnesium aluminate silicate, anhydrous silicic acid, light anhydrous silicic acid, calcium silicate, calcium hydrogen phosphate and the like. Although the above combination is mentioned, it is not limited to these.
- Preferred inorganic compounds are magnesium aluminate metasilicate and calcium silicate, and the compounding amount of the inorganic compound is usually 0.01 to 15% by weight with respect to 100% by weight of the total composition of the spray-dried particles, It is preferably 3 to 12% by weight, more preferably 3 to 10% by weight, still more preferably 4 to 8% by weight, and most preferably 4 to 5% by weight.
- the spray-dried particles include the components (d) to (f) and the component (g) as appropriate, and each component is dispersed in a dispersion solvent and spray-dried.
- each component is dispersed in a dispersion solvent and spray-dried.
- the components (d) to (f) and the component (g) as appropriate are combined or individually added to the dispersion solvent and mixed and spray-dried.
- each component can be dissolved or dispersed in a solvent, adjusted to an aqueous solution or a water-soluble dispersion, and then spray dried.
- the dispersion solvent may be any solvent that does not affect the properties of the composition and is acceptable in terms of stability and safety even when used in pharmaceuticals and foods.
- it is selected from water, ethanol, methanol, and the like. Examples thereof include, but are not limited to, mixed solvents of one kind or a combination of two or more kinds thereof.
- the conditions of spray drying are not particularly limited, but it is preferable to use disk type or nozzle type spray drying as the spray drying.
- the temperature at the time of spray drying is preferably about 120 to 220 ° C. at the inlet temperature and about 80 to 130 ° C. at the outlet temperature.
- the dispersion can be prepared by a known method, for example, normal stirring, colloid mill, high-pressure homogenizer, ultrasonic irradiation, etc., but any method that can uniformly disperse particles in an aqueous dispersion good.
- the content ratio in the dispersion may be in a range that can be spray-dried depending on the viscosity of the dispersion, that is, 5 to 50% by weight, preferably 10 to 45% by weight.
- the amount of the spray-dried particles is usually 15 to 90% by weight, preferably 30 to 85% by weight, more preferably 40 to 85% by weight, and still more preferably 40% per 100% by weight of the orally rapidly disintegrating tablet. It is ⁇ 80% by weight, most preferably 60 ⁇ 80% by weight. When the amount of the drug-containing particles is large, the amount can be appropriately reduced.
- the average particle diameter of the particles before formulation is usually about 400 ⁇ m or less, for example, 1 to 400 ⁇ m, preferably 5 to 300 ⁇ m.
- the orally disintegrating tablet of the present invention it is essential to contain the particles of (1) and (2) above, but usually formulated by adding other formulated components. To do. These formulation ingredients may be added to the particles of (1) or (2) as necessary, or may be used as formulation ingredients other than (1) and (2), or any of them. You may use as a combination in the case of.
- the “other formulation component” that may be used in the present invention may be any component as long as there is no problem in the stability of the drug even if it is blended and there is no problem in formulation.
- the “other formulation component” that may be used in the present invention may be any component as long as there is no problem in the stability of the drug even if it is blended and there is no problem in formulation.
- lubricants for example, one or a combination of two or more selected from lubricants, flavoring agents, binders, excipients, stabilizers, surfactants, fluidizing agents, colorants, fragrances and the like can be mentioned. However, it is not limited to these.
- the amount of “other formulation ingredients” is 0.01 to 25% by weight, preferably 0.1 to 25% by weight, more preferably 0.1 to 10% by weight, and still more preferably 0.1 to 1%. % By weight.
- Lubricant Lubricant used in the present invention is a lubricant that may be blended inside the tablet.
- Specific examples thereof include stearic acid, metal stearate, sucrose fatty acid ester, talc, Although 1 type chosen from hydrogenated oil, macrogol, etc. or those 2 or more types of combinations is mentioned, it is not limited to these.
- the metal stearate include, but are not limited to, magnesium stearate, calcium stearate, and aluminum stearate. Of these, magnesium stearate is preferred.
- the average particle size before formulating the lubricant is 0.5 to 50 ⁇ m, preferably 1 to 30 ⁇ m, more preferably 1 to 10 ⁇ m.
- the amount of stearic acid or stearic acid metal salt is usually 0.01 to 2.0% by weight in the preparation, preferably 0.1 to 1.0% by weight, more preferably 0.1 to 0.8%. % By weight, more preferably 0.2 to 0.5% by weight.
- a corrigent In this invention, you may mix
- Specific examples include neotame, thaumatin (thaumatin), aspartame, stevia, sodium saccharin, sodium glutamate, and the like, but are not limited thereto. These may be used alone or in combination of two or more.
- binder binders are acacia, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, pullulan, gelatin, ethylcellulose, methylcellulose, carmellose sodium, dextrin, although povidone and the like are not limited to .
- the blending amount of the binder may be an amount that maintains the hardness of the tablet and does not hinder disintegration in the oral cavity.
- excipient excipients include lactose, sucrose, mannitol, starch, crystalline cellulose (eg, Theolas KG-802), erythritol, trehalose, anhydrous calcium hydrogen phosphate, calcium sulfate, etc. It is not limited to.
- stabilizing agent stabilizer sodium edetate, but tocopherol, and the like without limitation.
- surfactant surfactants are sodium lauryl sulfate, polysorbates, but hardened oil, and the like without limitation.
- fluidizing agent fluidizing agent examples include, but are not limited to, light anhydrous silicic acid, magnesium aluminate metasilicate and the like.
- colorant colorant examples include food dyes, red ferric oxide, but carmine etc. without limitation.
- fragrances and fragrances include, but are not limited to, various fruit fragrances including strawberry and yogurt, mint, menthol and the like.
- Intraoral rapidly disintegrating tablet and method for producing the same The intraoral rapidly disintegrating tablet of the present invention can be produced by a method commonly used in the field of pharmaceutical preparations.
- the above-described formulation ingredients can be uniformly mixed with the drug-containing particles and spray-dried particles of the present invention, and then the mixture can be formulated by known means.
- it can be formulated into various solid preparations suitable for oral administration such as tablets, granules, pills, powders, fine granules and the like.
- a tablet it can be produced by tableting the above-mentioned spray-dried particles and drug-containing particles together with the above-mentioned formulation ingredients with a normal tableting machine.
- it may be produced by tableting the above-mentioned spray-dried particles and drug-containing particles together with the above-mentioned formulation ingredients with a tableting machine in which stearic acid or a stearic acid metal salt is attached to the punch and mortar.
- the intraoral rapidly disintegrating tablet of the present invention exhibits quick disintegration and moderate hardness in the oral cavity.
- the disintegration time of the orally rapidly disintegrating tablet of the present invention is usually within about 60 seconds, preferably within 40 seconds, in an oral disintegration tester (manufactured by Toyama Sangyo Co., Ltd., ODT-101) described later.
- the hardness using a tablet hardness tester (Toyama Sangyo, TH-203MP), which will be described later, is usually 30 to 70 N, preferably 40 to 60 N.
- the hardness after one day has passed after storage at 25 ° C. and 75% RH is usually 30 to 60 N, preferably 35 to 55 N. This hardness is measured by a usual method using a tablet hardness tester (TH-203MP, manufactured by Toyama Sangyo).
- Mosapride citrate dihydrate is ( ⁇ ) 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate A dihydrate is used from Dainippon Sumitomo Pharma Co., Ltd. (average particle size of about 5 ⁇ m).
- Methyl cellulose uses Shin-Etsu Chemical's Metrows SM-25 (viscosity 2.53 mm 2 / S (2% water-soluble viscosity at 20 ° C. (Japanese Pharmacopoeia))), and mannitol is D-mannitol (ROQUETTE). ) MANITIOL 60 (average particle size 60 ⁇ m).
- Pullulan uses Hayashibara's Pullulan PI-20
- polyvinyl alcohol (PVA) uses Shin-Etsu Chemical's Shin-Etsu Poval.
- Hydroxypropylcellulose uses Nippon Soda's HPC L
- hydroxypropylmethylcellulose HPMC
- HPMC hydroxypropylmethylcellulose
- PVP polyvinylpyrrolidone
- Xylitol uses Towa Kasei's xylit
- trehalose uses Asahi Kasei's trehalose P.
- Erythritol uses Nikken Chemical's erythritol fine powder, and maltitol uses Towa Kasei's amalty. Lactose uses DMV 200M lactose, lactitol uses Towa Kasei's milhen, and sucrose uses Nissin Sugar's high-grade powder sugar.
- Cornstarch uses cornstarch (XX16) W of Nippon Food & Chemicals, rice starch uses Shimada Chemical's micropearl, crystalline cellulose PH-101 uses Asahi Kasei's Theorus PH-101, crystalline cellulose KG-802 Asahi Kasei's Theorus KG-802 is used, and Fuji Chemical's Fujicalin is used as the anhydrous calcium phosphate.
- Low-substituted hydroxypropylcellulose uses LH-21 from Shin-Etsu Chemical
- carboxymethylcellulose uses carboxymethylcellulose NS-300 from Gotoku Pharmaceutical Co., Ltd.
- calcium silicate uses Eisai Food Chemical's Florite RE
- metasilicate aluminate Magnesium uses Neusilin URF2 from Fuji Chemical Industry, and crospovidone uses BASF Takeda vitamin Kollidon CL.
- Magnesium stearate uses magnesium stearate (vegetable) from Taihei Chemical Industry.
- each component constituting the drug-containing particle 1 was granulated by spraying 130 g of purified water with a stirring granulator (manufactured by Paulec, FM-VG-05), and subsequently dried with a shelf dryer.
- the obtained particles were sieved with a 32 mesh (aperture 500 ⁇ m) sieve to obtain drug-containing particles 1 having an average particle diameter of about 150 ⁇ m.
- Spray-dried particles 1 were produced according to the formulation shown in Table 2. That is, after each component constituting the spray-dried particles is uniformly dispersed in water (186 g), it is spray-dried at an outlet temperature of 80 ° C. using a spray dryer (manufactured by Okawara Kako Co., Ltd., L-8) White spherical spray-dried particles 1 having good fluidity were obtained.
- Example 1 Production of intraoral quick disintegrating tablet
- the drug-containing particles 1 obtained in Reference Example 1, the spray-dried particles 1 obtained in Reference Example 2, and magnesium stearate are mixed according to the formulation shown in Table 3, and tableting pressure Tableting was performed at 0 MPa to obtain a tablet having a tablet weight of 240 mg and a diameter of 8.5 mm.
- Example 2 According to the formulations shown in Tables 4 and 5 below, each component was mixed in the same manner as in Example 1 to produce an intraorally rapidly disintegrating tablet (1 tablet weight: 240 mg tablet).
- each component was mixed in the same manner as in Reference Example 1 to produce drug-containing particles having an average particle size of 150 to 250 ⁇ m.
- the obtained spray-dried particles 1 were mixed to produce an intraoral rapidly disintegrating tablet (1 tablet weight: 240 mg tablet).
- the drug-containing particles shown in the upper part of Tables 6 to 15 indicate the formulation in the particles, and the lower part indicates the formulation in the tablet.
- the prescription (mixing amount) in each table indicates the mixing amount of each component, and the subtotal indicates the total component amount of each drug-containing particle.
- the content ratio indicates the content ratio relative to 100% by weight of the total composition in the tablet, and the subtotal indicates the content ratio (100% by weight) of each drug-containing particle.
- Reference example 3 Production of drug-containing particles 2 This particle was produced by mixing each component in the same manner as in Reference Example 1 according to the formulation shown in Table 16 (including methylcellulose as a water-soluble polymer), and the resulting particles were 32 mesh (apertures) 500 ⁇ m) to obtain drug-containing particles 2 having an average particle size of 150 to 250 ⁇ m.
- Example 27 and Comparative Example 1 According to the formulations shown in Tables 17 and 18 below, each component was mixed to produce spray-dried particles in the same manner as in Reference Example 2, and each component was mixed in the same manner as in Example 1 to rapidly disintegrate the oral cavity (1 tablet weight). : 240 mg tablet).
- the blending amount of the spray-dried particles shown in Table 17 indicates the formulation of the particles
- the content ratio shown in Table 18 indicates the content ratio with respect to 100% by weight of the total composition of the particles
- the subtotal is the total component amount of the particles. Or a content rate (100 weight%) is shown.
- each component was mixed to produce spray-dried particles in the same manner as in Reference Example 2, and each component was mixed in the same manner as in Example 1 to rapidly disintegrate the oral cavity (1 tablet weight). : 240 mg tablet).
- Test example 1 The characteristics of the tablets produced in each Example and Comparative Example were examined, and the results shown in Table 27 and Table 28 were obtained. Specifically, the disintegration time was measured under the standard conditions of a commercially available oral disintegration tester (manufactured by Toyama Sangyo). Moreover, it measured also about the hardness immediately after manufacture and after humidification. As a result, as shown in the following table, the intraoral quick disintegrating tablet obtained in each example has an appropriate hardness of 30 N or more, and the disintegration time is within 40 seconds, and has sufficient oral disintegration. It was.
- the hardness retention rate was 49%, and in the case of the rapidly disintegrating tablet in the present example, at least 60% or more. In many cases, a hardness retention rate of a significant magnitude of 70% or more and 80% or more was exhibited.
- * 1 The pressure applied to the entire punch during tableting was read from the pressure gauge installed in the tableting machine (Riken, hydraulic press).
- * 2 Using an intraoral disintegration tester (manufactured by Toyama Sangyo Co., Ltd., ODT-101), the time until a weight of 15 mm in diameter and 15 g in weight collapsed the tablet and reached the mesh was measured.
- * 3 Hardness was measured using a tablet hardness meter (TH-203MP, manufactured by Toyama Sangyo).
- * 4 Using a tablet hardness meter (TH-203MP, manufactured by Toyama Sangyo Co., Ltd.), the hardness after 1 day from storage at 25 ° C. and 75% RH was measured.
- * 5 Calculated by hardness after humidification / hardness ⁇ 100 (%), and the hardness retention rate was calculated.
- a drug having an unpleasant taste has a sufficient hardness (fastness) so as not to hinder the handling from the manufacture of a tablet to its administration, and particularly the hardness after humidification is maintained.
- fastness so as not to hinder the handling from the manufacture of a tablet to its administration, and particularly the hardness after humidification is maintained.
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Abstract
Description
本発明は下記の各種の態様の発明を提供するものである。
(1)下記(a)~(c)の成分を含み、各成分を造粒して、粒子化してなる薬物含有粒子;
(a)薬物、
(b)水溶性高分子、及び、
(c)糖又は糖アルコール、並びに、
(2)下記(d)~(f)の成分を含み、各成分を分散溶媒に分散させ、噴霧乾燥してなる噴霧乾燥粒子;
(d)マンニトール、又はマンニトールとキシリトール、
(e)カルボキシメチルセルロース、及び、
(f)崩壊剤。
(a)薬物を1~30重量%、
(b)水溶性高分子を3~45重量%、及び、
(c)糖又は糖アルコールを40~90重量%、
の割合で含む項1に記載の口腔内速崩壊錠。
(d)マンニトール、又はマンニトールとキシリトールを65~95重量%、
(e)カルボキシメチルセルロースを1~20重量%、及び、
(f)崩壊剤を1~20重量%、
の割合で含む項1に記載の口腔内速崩壊錠。
下記(1)及び(2)の粒子を含有することを特徴とする口腔内速崩壊錠:
(1)下記(a)~(c)の成分を含み、各成分を造粒して、粒子化してなる薬物含有粒子;
(a)薬物、
(b)水溶性高分子、及び、
(c)糖又は糖アルコール、並びに、
(2)下記(d)~(f)の成分を含み、各成分を分散溶媒に分散させ、噴霧乾燥してなる噴霧乾燥粒子;
(d)マンニトール、又はマンニトールとキシリトール、
(e)カルボキシメチルセルロース、及び、
(f)崩壊剤
であり、以下に各成分及び各粒子について説明する。
(a)薬物
本発明の口腔内速崩壊錠において薬物として使用される活性成分としては、医薬活性成分として疾患の治療や予防に供され、経口投与可能なものであれば特に限定されない。例えば、滋養強壮保健薬;解熱鎮痛消炎薬;抗精神病薬;催眠鎮静薬;鎮痙薬;中枢神経作用薬;脳代謝改善薬;脳循環改善薬;抗てんかん薬;交感神経興奮剤;健胃消化剤;抗潰瘍剤;消化管運動機能改善剤;制酸剤;鎮咳去痰剤;腸運動抑制薬;鎮吐剤;呼吸促進剤;気管支拡張剤;抗アレルギー剤;強心剤;不整脈用剤;利尿剤;血管収縮剤;冠血管拡張剤;血管拡張薬;末梢血管拡張薬;高脂血症用剤;利胆剤;化学療法剤;糖尿病合併症治療薬;骨粗しょう症治療剤;抗リウマチ剤;骨格筋弛緩剤;痛風治療剤;血液凝固阻止剤;抗悪性腫瘍剤等が挙げられる。本発明における活性成分は、薬学上許容される限り、塩またはフリー体の形であってもよい。また、アルコール和物等の溶媒和物、または水和物等の形であってもよい。さらに、上記に挙げた活性成分は、単独で用いても、または2種以上を組み合わせて用いてもよい。また、薬物の苦味等の不快な味をマスキング処理したものを用いてもよい。
本発明で用いられる水溶性高分子としてはポリビニルピロリドン、メチルセルロース、プルラン、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースから選ばれる1種又はそれらの2種以上の組み合わせが挙げられるが、これらに限定されない。好ましくは、メチルセルロース、プルラン、ポリビニルアルコール及びヒドロキシプロピルセルロースであり、さらに好ましくは、メチルセルロースであり、0℃においてその2重量%水溶液の粘度を日本薬局方第14改正に従って測定したとき、通常1~100mm2/秒であり、好ましくは5~60mm2/秒、より好ましくは当該粘度が10~40mm2/秒、一層好ましくは当該粘度が20~30mm2/秒である。水溶性高分子の配合量としては、通常、薬物含有粒子の組成物全量100重量%に対して3~45重量%、好ましくは3~40重量%、より好ましくは5~30重量%、一層好ましくは10~30重量%である。
本発明で用いられる糖又は糖アルコールとしてはマンニトール、キシリトール、乳糖、エリスリトール、トレハロース、ショ糖、マルチトール及びラクチトール等から選ばれる1種又はそれらの2種以上の組み合わせが挙げられるが、これらに限定されない。好ましくは、マンニトール、キシリトール、乳糖、エリスリトール及びラクチトールであり、より好ましくはマンニトールであり、さらに好ましくはD-マンニトールである。糖又は糖アルコールの配合量は、速溶性が達成できる量であり、通常、薬物含有粒子の組成物全量100重量%に対し、40~90重量%、好ましくは60~90重量%、より好ましくは60~85重量%、一層好ましくは60~75重量%である。
(d)マンニトール、又はマンニトールとキシリトール
マンニトール、又はマンニトールとキシリトールの配合量は、通常、噴霧乾燥粒子の組成物全量100重量%に対し65~95重量%であるが、好ましくはマンニトールの単独量又はマンニトールとキシリトールの合計量が70~90重量%、より好ましくは70~85重量%、一層好ましくは75~85重量%である。キシリトールを配合するとき、その配合量は、通常、噴霧乾燥粒子の組成物全量100重量%に対して、0.01~5重量%であり、好ましくは2~5重量%、より好ましくは2~4重量%、一層好ましくは2~3重量%である。
本発明で用いられるカルボキシメチルセルロース(本明細書中、カルメロースと呼ぶこともある)の配合量は、通常、1~20重量%であるが、好ましくは3~15重量%、より好ましくは3~12重量%、一層好ましくは5~12重量%、最も好ましくは5~10重量%である。
本発明に用いられる崩壊剤としては、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、結晶セルロース、カルメロースカルシウム、ヒドロキシプロピルスターチ、ライススターチ、カルメロースナトリウム等から選ばれる1種又はそれらの2種以上の組み合わせが挙げられるが、これらに限定されない。好ましくは、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、結晶セルロース、カルメロースカルシウム、ヒドロキシプロピルスターチ及びライススターチであり、最も好ましくは、低置換度ヒドロキシプロピルセルロースである。ここで、低置換度ヒドロキシプロピルセルロースとは、ヒドロキシプロポキシル基の含有量が5~16重量%のヒドロキシプロピルセルロースをいう。崩壊剤の配合量は、通常、噴霧乾燥粒子の組成物全量100重量%に対し、1~20重量%であり、好ましくは3~15重量%、より好ましくは3~12重量%、一層好ましくは5~12重量%、最も好ましくは5~10重量%である。
本発明における噴霧乾燥粒子においては無機化合物を配合してもよい。無機化合物を配合することで崩壊時間がさらに短くなるという効果がある。本発明に用いられる無機化合物としては、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム、無水ケイ酸、軽質無水ケイ酸、ケイ酸カルシウム、リン酸水素カルシウム等から選ばれる1種又はそれらの2種以上の組み合わせが挙げられるが、これらに限定されない。好ましい無機化合物としては、メタケイ酸アルミン酸マグネシウム及びケイ酸カルシウムであり、無機化合物の配合量は、通常、噴霧乾燥粒子の組成物全量100重量%に対し、0.01~15重量%であり、好ましくは3~12重量%、より好ましくは3~10重量%、一層好ましくは4~8重量%、最も好ましくは4~5重量%である。
本発明の口腔内崩壊錠においては、上記(1)及び(2)の粒子を含有することを必須とするが、通常、その他の製剤化成分を加えて製剤化する。これら製剤化成分は、また必要に応じて(1)又は(2)の粒子中に加えてもよく、又は(1)及び(2)以外の製剤化成分として用いても良く、あるいはそれらのいずれの場合の組み合わせとして用いても良い。本発明で用いられることもある「その他の製剤化成分」としては、配合しても薬剤の安定性に問題が無く、製剤化するのに問題の無い成分であればいずれでもよい。本発明で用いられることもある「その他の製剤化成分」としては、配合しても薬剤の安定性に問題が無く、製剤化するのに問題の無い成分であればいずれでもよい。例えば、滑沢剤、矯味剤、結合剤、賦形剤、安定化剤、界面活性剤、流動化剤、着色剤、香料等から選ばれる1種又はそれらの2種以上の組み合わせが挙げられるが、これらに限定されない。「その他の製剤化成分」の配合量は0.01~25重量%であり、好ましくは0.1~25重量%、より好ましくは0.1~10重量%、一層好ましくは0.1~1重量%である。
本発明で用いられる滑沢剤とは、錠剤の内部に配合してもよい滑沢剤であり、その具体例としては、ステアリン酸、ステアリン酸金属塩、ショ糖脂肪酸エステル、タルク、硬化油、マクロゴール等から選ばれる1種又はそれらの2種以上の組み合わせが挙げられるが、これらに限定されない。ステアリン酸金属塩としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸アルミニウム等が挙げられるがこれらに限定されない。この中でステアリン酸マグネシウムが好ましい。滑沢剤の製剤化する前の平均粒子径は0.5~50μmであり、好ましくは1~30μm、より好ましくは1~10μmである。ステアリン酸又はステアリン酸金属塩の配合量は、通常製剤中に0.01~2.0重量%であり、好ましくは0.1~1.0重量%、より好ましくは0.1~0.8重量%、一層好ましくは0.2~0.5重量%である。
本発明においては、矯味剤を配合してもよい。具体的には、ネオテーム、ソーマチン(タウマチン)、アスパルテーム、ステビア、サッカリンナトリウム、グルタミン酸ナトリウム等が挙げられるがこれらに限定されない。これらは単品で使用してもよいが、2種又は数種の併用であってもよい。
結合剤の具体例としては、アラビアゴム、デンプン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、プルラン、ゼラチン、エチルセルロース、メチルセルロース、カルメロースナトリウム、デキストリン、ポビドン等が挙げられるがこれらに限定されない。結合剤の配合量は、錠剤の硬度を維持し、且つ口腔内での崩壊に支障のない量であればよい。
賦形剤の具体例としては、乳糖、ショ糖、マンニトール、デンプン、結晶セルロース(例えば、セオラスKG-802)、エリスリトール、トレハロース、無水リン酸水素カルシウム、硫酸カルシウム等が挙げられるがこれらに限定されない。
安定化剤の具体例としては、エデト酸ナトリウム、トコフェロール等が挙げられるがこれらに限定されない。
界面活性剤の具体例としては、ラウリル硫酸ナトリウム、ポリソルベート、硬化油等が挙げられるがこれらに限定されない。
流動化剤の具体例としては、軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウム等が挙げられるがこれらに限定されない。
着色剤の具体例としては、食用色素、三二酸化鉄、カルミン等が挙げられるがこれらに限定されない。
香料の具体例としては、ストロベリーを含む種々の果実香料並びにヨーグルト、ミント、メントール等が挙げられるがこれらに限定されない。
本発明の口腔内速崩壊錠は、製剤分野において慣用の方法を用いて製造することができる。例えば本発明の薬物含有粒子及び噴霧乾燥粒子に上述のような製剤化成分を均一に混合した後、その混合物を公知手段で製剤化することができる。例えば錠剤、顆粒剤、丸剤、散剤、細粒剤等の経口投与に適した各種固形製剤に製剤化することができる。例えば、錠剤の場合は、通常の打錠機により、上述の噴霧乾燥粒子及び薬物含有粒子を前述の製剤化成分とともに打錠することにより製造できる。また、ステアリン酸又はステアリン酸金属塩を杵及び臼に付着させた打錠機により、上述の噴霧乾燥粒子及び薬物含有粒子を前述の製剤化成分とともに打錠することにより製造してもよい。
薬物含有粒子1の製造
本粒子は、表1に示す処方(水溶性高分子としてポリビニルピロリドンを含む)に従って製造した。すなわち、薬物含有粒子1を構成する各成分を攪拌造粒機(パウレック製、FM-VG-05)で精製水130gを噴霧して造粒し、引き続き棚型乾燥機で乾燥した。得られる粒子を32メッシュ(目開き500μm)の篩で篩過し、平均粒子径が約150μmの薬物含有粒子1を得た。
噴霧乾燥粒子1の製造
噴霧乾燥粒子1は、表2に示す処方に従って製造した。すなわち、噴霧乾燥粒子を構成する各成分を水(186g)に均一に分散させたのち、噴霧乾燥機(大川原化工機社製、L-8)を用いて、出口温度80℃で噴霧乾燥し、流動性の良い白色球状の噴霧乾燥粒子1を得た。
口腔内速崩壊錠の製造
参考例1で得られた薬物含有粒子1、参考例2で得られた噴霧乾燥粒子1、およびステアリン酸マグネシウムを表3に示す処方に従って混合し、打錠圧2.0MPaで打錠し、1錠重量240mg、直径8.5mmの錠剤を得た。
下記表4及び5の処方に従って、実施例1と同様に各成分を混合して口腔内速崩壊錠(1錠重量:240mg錠)を製造した。
下記表6~15の処方に従って、参考例1と同様に各成分を混合して平均粒子径が150~250μmの薬物含有粒子を製造し、また実施例1と同様に各成分を参考例2で得られた噴霧乾燥粒子1と混合して口腔内速崩壊錠(1錠重量:240mg錠)を製造した。ただし、表6~15の上部に示す薬物含有粒子の標記は粒子内の処方を示し、下部には錠剤中の処方を示す。各表の処方(配合量)は各々の成分の配合量を示し、小計は各薬物含有粒子の全成分量を示す。含有割合は錠剤中の組成物全量100重量%に対する含有割合を示し、小計は各薬物含有粒子の含有割合(100重量%)を示す。
薬物含有粒子2の製造
本粒子は、表16に示す処方(水溶性高分子としてメチルセルロースを含む)に従い、参考例1と同様に各成分を混合し製造し、得られる粒子を32メッシュ(目開き500μm)の篩で篩過し、平均粒子径が150~250μmの薬物含有粒子2を得た。
下記表17及び18の処方に従って、参考例2と同様に各成分を混合して噴霧乾燥粒子を製造し、また実施例1と同様に各成分を混合して口腔内速崩壊錠(1錠重量:240mg錠)を製造した。ただし、表17に示す噴霧乾燥粒子の配合量は該粒子の処方を示し、表18に示す含有割合は該粒子の組成物全量100重量%に対する含有割合を示し、小計は該粒子の全成分量又は含有割合(100重量%)を示す。
下記表19~26の処方に従って、参考例2と同様に各成分を混合して噴霧乾燥粒子を製造し、また実施例1と同様に各成分を混合して口腔内速崩壊錠(1錠重量:240mg錠)を製造した。
各実施例及び比較例で製造された錠剤の特性を調べ、表27および表28の結果を得た。
具体的には、市販されている口腔内崩壊試験器(富山産業製)の標準条件で、崩壊時間を測定した。また、製造直後及び加湿後の硬度についても測定した。
結果、下記表中に示す通り、各実施例で得られる口腔内速崩壊錠は30N以上の適度な硬度を有し、且つ崩壊時間は40秒以内であり、十分な口腔内崩壊性を有していた。また、噴霧乾燥粒子中にカルボキシメチルセルロースを含有しない比較例の場合には硬度維持率は49%であったのに比べて、本実施例の口腔内速崩壊錠の場合には、少なくとも60%以上、多くの場合には70%以上及び80%以上の有意な大きさの硬度維持率を示した。
*2:口腔内崩壊試験器(富山産業製、ODT-101)を用いて、直径15mm、重さ15gのおもりが、錠剤を崩壊してメッシュに到達するまでの時間を測定した。
*3:錠剤硬度計(富山産業製、TH-203MP)を用いて硬度を測定した。
*4:錠剤硬度計(富山産業製、TH-203MP)を用いて、25℃75%RH保存後1日経過後の硬度を測定した。
*5:加湿後硬度/硬度×100(%)で算出し、硬度維持率を算出した。
Claims (14)
- 下記(1)及び(2)の粒子を含有することを特徴とする口腔内速崩壊錠:
(1)下記(a)~(c)の成分を含み、各成分を造粒して、粒子化してなる薬物含有粒子;
(a)薬物、
(b)水溶性高分子、及び、
(c)糖又は糖アルコール、並びに、
(2)下記(d)~(f)の成分を含み、各成分を分散溶媒に分散させ、噴霧乾燥してなる噴霧乾燥粒子;
(d)マンニトール、又はマンニトールとキシリトール、
(e)カルボキシメチルセルロース、及び、
(f)崩壊剤。 - 水溶性高分子(b)が、ポリビニルピロリドン、メチルセルロース、プルラン、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースからなる群から選択される少なくとも1種である請求項1に記載の口腔内速崩壊錠。
- 水溶性高分子(b)が、メチルセルロース、プルラン、ポリビニルアルコール及びヒドロキシプロピルセルロースからなる群から選択される少なくとも1種である請求項2に記載の口腔内速崩壊錠。
- 糖又は糖アルコール(c)が、マンニトール、キシリトール、乳糖、エリスリトール、トレハロース、ショ糖、マルチトール及びラクチトールからなる群から選択される少なくとも1種である請求項1~3のいずれか一項に記載の口腔内速崩壊錠。
- 糖又は糖アルコール(c)が、マンニトール、キシリトール、乳糖、エリスリトール及びラクチトールからなる群から選択される少なくとも1種である請求項4に記載の口腔内速崩壊錠。
- 崩壊剤(f)が、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、結晶セルロース、カルメロースカルシウム、ヒドロキシプロピルスターチ及びライススターチからなる群から選択される少なくとも1種である請求項1~5のいずれか一項に記載の口腔内速崩壊錠。
- 崩壊剤(f)が、低置換度ヒドロキシプロピルセルロースを含む請求項6に記載の口腔内速崩壊錠。
- 噴霧乾燥粒子(2)が、無機化合物(g)の成分を含み、(d)~(g)の各成分を分散溶媒に分散させ、噴霧乾燥してなる請求項1~7のいずれか一項に記載の口腔内速崩壊錠。
- 無機化合物(g)が、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム、無水ケイ酸、軽質無水ケイ酸、ケイ酸カルシウム及びリン酸水素カルシウムからなる群から選択される少なくとも1種である請求項8に記載の口腔内速崩壊錠。
- 薬物含有粒子(1)の組成物全量100重量%に対して、
(a)薬物を1~30重量%、
(b)水溶性高分子を3~45重量%、及び、
(c)糖又は糖アルコールを40~90重量%、
の割合で含む請求項1に記載の口腔内速崩壊錠。 - 噴霧乾燥粒子(2)の組成物全量100重量%に対して、
(d)マンニトール、又はマンニトールとキシリトールを65~95重量%、
(e)カルボキシメチルセルロースを1~20重量%、及び、
(f)崩壊剤を1~20重量%、
の割合で含む請求項1に記載の口腔内速崩壊錠。 - 噴霧乾燥粒子(2)の組成物全量100重量%に対して、(g)無機化合物の成分を0.01~15重量%の割合で更に含む請求項11に記載の口腔内速崩壊錠。
- 薬物が、4-アミノ-5-クロロ-2-エトキシ-N-[[4-(4-フルオロベンジル)-2-モルホリニル]メチル]ベンズアミドである請求項1~12のいずれか一項に記載の口腔内速崩壊錠。
- 口腔内速崩壊錠100重量%あたり、(1)の薬物含有粒子を5~37重量%、および(2)の噴霧乾燥粒子を15~90重量%の割合で含む請求項1~13のいずれか一項に記載の口腔内速崩壊錠。
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EP10808226A EP2465495A4 (en) | 2009-08-11 | 2010-08-11 | TABLET WITH FAST DECOMPOSITION IN THE MOUTH AND TWO OR MORE TYPES OF PARTICLES |
JP2011526772A JP4920798B2 (ja) | 2009-08-11 | 2010-08-11 | 2種以上の粒子を含有する口腔内速崩壊錠 |
CN2010800457816A CN102548542B (zh) | 2009-08-11 | 2010-08-11 | 含有两种以上粒子的口腔速崩片 |
US13/389,280 US8591955B2 (en) | 2009-08-11 | 2010-08-11 | Orally rapidly disintegrating tablet that contains two or more types of particles |
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4870074A (en) | 1986-04-30 | 1989-09-26 | Dainippon Pharmaceutical Co., Ltd. | Substituted benzamide derivatives, for enhancing gastrointestinal motility |
JP2000086537A (ja) | 1998-09-11 | 2000-03-28 | Fuji Chem Ind Co Ltd | 無機化合物糖類組成物、賦形剤、速崩壊性圧縮成型物及びその製造方法 |
WO2005037254A1 (ja) * | 2003-10-15 | 2005-04-28 | Fuji Chemical Industry Co., Ltd. | 口腔内速崩壊性錠剤 |
JP2005139168A (ja) | 2003-10-15 | 2005-06-02 | Fuji Chem Ind Co Ltd | 口腔内速崩壊性錠剤用の組成物 |
WO2005055989A1 (ja) | 2003-12-09 | 2005-06-23 | Dainippon Sumitomo Pharma Co., Ltd. | 薬物含有粒子および該粒子を含む固形製剤 |
WO2007029376A1 (ja) | 2005-09-02 | 2007-03-15 | Fuji Chemical Industry Co., Ltd. | 口腔内速崩壊性錠剤 |
WO2009066773A1 (ja) * | 2007-11-21 | 2009-05-28 | Dainippon Sumitomo Pharma Co., Ltd. | 口腔内崩壊錠 |
WO2009102038A1 (ja) * | 2008-02-13 | 2009-08-20 | Dainippon Sumitomo Pharma Co., Ltd. | 口腔内崩壊錠 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7510728B2 (en) | 2000-10-06 | 2009-03-31 | Takeda Pharmaceutical Company Limited | Solid preparations |
CN100438914C (zh) | 2003-10-15 | 2008-12-03 | 富士化学工业株式会社 | 用于口腔内快速崩解的片剂的组合物 |
DE602004031144D1 (de) * | 2003-11-14 | 2011-03-03 | Ajinomoto Kk | Feste dispersion oder medizinisches festes dispersionspräparat eines phenylalanin-derivats |
US7465864B2 (en) | 2006-10-17 | 2008-12-16 | Clarflupet, Llc | Musical instrument training device with multiple mouthpieces |
-
2010
- 2010-08-11 JP JP2011526772A patent/JP4920798B2/ja active Active
- 2010-08-11 KR KR1020127005982A patent/KR20120046766A/ko not_active Application Discontinuation
- 2010-08-11 WO PCT/JP2010/063599 patent/WO2011019043A1/ja active Application Filing
- 2010-08-11 US US13/389,280 patent/US8591955B2/en not_active Expired - Fee Related
- 2010-08-11 CN CN2010800457816A patent/CN102548542B/zh not_active Expired - Fee Related
- 2010-08-11 EP EP10808226A patent/EP2465495A4/en not_active Withdrawn
-
2012
- 2012-10-24 HK HK12110591.8A patent/HK1169811A1/xx not_active IP Right Cessation
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4870074A (en) | 1986-04-30 | 1989-09-26 | Dainippon Pharmaceutical Co., Ltd. | Substituted benzamide derivatives, for enhancing gastrointestinal motility |
JP2000086537A (ja) | 1998-09-11 | 2000-03-28 | Fuji Chem Ind Co Ltd | 無機化合物糖類組成物、賦形剤、速崩壊性圧縮成型物及びその製造方法 |
WO2005037254A1 (ja) * | 2003-10-15 | 2005-04-28 | Fuji Chemical Industry Co., Ltd. | 口腔内速崩壊性錠剤 |
JP2005139168A (ja) | 2003-10-15 | 2005-06-02 | Fuji Chem Ind Co Ltd | 口腔内速崩壊性錠剤用の組成物 |
WO2005055989A1 (ja) | 2003-12-09 | 2005-06-23 | Dainippon Sumitomo Pharma Co., Ltd. | 薬物含有粒子および該粒子を含む固形製剤 |
WO2007029376A1 (ja) | 2005-09-02 | 2007-03-15 | Fuji Chemical Industry Co., Ltd. | 口腔内速崩壊性錠剤 |
WO2009066773A1 (ja) * | 2007-11-21 | 2009-05-28 | Dainippon Sumitomo Pharma Co., Ltd. | 口腔内崩壊錠 |
WO2009102038A1 (ja) * | 2008-02-13 | 2009-08-20 | Dainippon Sumitomo Pharma Co., Ltd. | 口腔内崩壊錠 |
Non-Patent Citations (1)
Title |
---|
See also references of EP2465495A4 * |
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US20120135991A1 (en) | 2012-05-31 |
KR20120046766A (ko) | 2012-05-10 |
EP2465495A4 (en) | 2013-01-23 |
EP2465495A1 (en) | 2012-06-20 |
CN102548542B (zh) | 2013-11-20 |
HK1169811A1 (en) | 2013-02-08 |
JPWO2011019043A1 (ja) | 2013-01-17 |
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US8591955B2 (en) | 2013-11-26 |
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