JP2012036140A - Rapid disintegrating tablet with reduced bitterness - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a rapid disintegrating tablet or an intraoral rapid collapsing tablet for preventing deterioration of tablet hardness even when uncomfortable taste such as bitterness in a drug is masked and the tablet is preserved under a high humidity condition for a long period of time.SOLUTION: The rapid disintegrating tablet includes: a first granulated powder (A) containing (a-1) a powder drug including uncomfortable tastes, (a-2) a fluidizing agent preventing aggregation of the powder drug, and (a-3) a carrier for granulating or masking a mixture of the drug and the fluidizing agent; and a second granulated powder (B) containing (b-1) at least one granular base component having the average particle diameter of 10-500 μm that is selected from saccharide, sugar alcohol and amino acid, (b-2) a disintegrant having ≤1.3 swelling ratio in water absorption, and (b-3) a water-soluble binding agent, wherein the content of (b-3) the water-soluble binding agent is ≤1 pts.wt. based on 100 pts.wt. of tablets.

Description

  The present invention relates to main drug particles, a method for producing the same, and a fast disintegrating tablet. More specifically, the present invention relates to a method for producing main drug particles capable of masking bitterness and a fast disintegrating tablet including the orally disintegrating tablet.

In recent years, the proportion of the elderly in the population has increased rapidly, and accordingly, development of drugs for the elderly has been promoted. In order to facilitate drug intake by elderly people with various physiological functions and the like, fast disintegrating tablets including intraoral quick disintegrating tablets have attracted attention. Regarding such fast disintegrating tablets, for example, WO 2006/085497 (Patent Document 1) includes 10) a) active ingredient, b) sugar or sugar alcohol (lactose, D-mannitol, etc.), c) cold water soluble component. Orally disintegrating tablets are disclosed that contain 20% by weight partially pregelatinized starch and d) disintegrants (crospovidone, corn starch, etc.). WO 00/078292 (Patent Document 2) includes a) an active ingredient, b) a sugar or sugar alcohol having an average particle size of 30 μm to 300 μm, c) a disintegrant (carmellose calcium, sodium carboxymethyl starch, croscarmellose) A rapidly disintegrating solid preparation comprising sodium, crospovidone, etc.) and d) cellulose (crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, carmellose, etc.) is disclosed, based on 100 parts by weight of the solid preparation In addition, 40 to 95 parts by weight of sugar or sugar alcohol, 0.5 to 15 parts by weight of a disintegrant, and 0.5 to 40 parts by weight of celluloses are also disclosed. JP-A-2005-112861 (Patent Document 3) discloses a pharmacologically active ingredient having a solubility in water of 0.5 mg / mL or more, an average primary particle diameter of 30 μm or more, and a specific surface area of 0.4 m ² / Intraorally rapidly disintegrating tablets containing crystals or fine particles of D-mannitol and crospovidone that are not more than g are disclosed, and it is also disclosed that a lubricant is contained only on the surface of the tablets. However, these preparations easily swell due to moisture absorption, the hardness decreases with the passage of time, and the tablets are easily damaged.

  On the other hand, since the orally disintegrating tablet normally disintegrates within about 30 seconds in the oral cavity after taking, it can be taken without water. However, some orally disintegrating tablets make the bitter taste of the main drug uncomfortable when taken. Therefore, the development of a technique for masking the bitter taste of the main drug as well as a technique for facilitating absorption of the main drug in the stomach or intestine has been actively conducted. Among these techniques, as the simplest method, a technique of concealing the bitter taste by adding a sweetener such as aspartame, stevia, sugar alcohol and a fragrance such as L-menthol has been proposed (for example, patents). References 4-7). However, since these techniques hide the bitterness with other tastes, it is difficult to completely eliminate the bitterness of the drug.

  Therefore, a technique for coating the main agent with a coating agent has been proposed. For example, JP 2005-343800 A (Patent Document 8) discloses a coating formed by coating caffeine particles having a bitter taste with a primary average particle size of 200 to 600 μm with a coating agent containing a poorly water-soluble polymer and a plasticizer. Caffeine particles and solid preparations containing these coated caffeine particles as chewable tablets or orally disintegrating tablets are disclosed. Japanese Patent Application Laid-Open No. 2008-260712 (Patent Document 9) discloses a main agent particle in which basic or acidic main agent particles are coated with a water-insoluble coating film, and a base is formed inside the water-insoluble coating film. Disclosed are an active ingredient particle containing an acidic substance with respect to an active active ingredient and a basic substance with respect to an acidic active ingredient, and an orally disintegrating tablet using the same. JP 2007-524575 A (Patent Document 10) discloses an active substance-coated particle including a core part, wherein the core part contains the active substance and an acidic compound, and the core part is soluble at a pH of 5 or less. Also disclosed are coated particles coated with a taste masking coating based on polymers that are permeable above pH 5. JP 2004-339071 A (Patent Document 11) discloses a drug obtained by granulating or coating a drug having a bitter taste mixed with an excipient with a film-forming polymer that is insoluble in water but soluble in digestive fluid. An orally disintegrating tablet with reduced bitterness, which is a mixed compression molded product of granules, and sugar or sugar alcohol with drug-free granules that are granulated or coated with a hydrophilic granulation component that is insoluble in water Is disclosed.

  In these prior art documents, a drug alone or a drug and a sugar alcohol are flowed in a fluidized bed, and coating is performed with a solution containing a film-forming polymer that is insoluble in ethyl cellulose or water but soluble in digestive fluid. Therefore, fluid granulation is performed in a state where the drug is agglomerated, and even coating with a polymer cannot be expected. Further, when tableting is performed using such a coated granule, it may be considered that the granule is broken by the molding pressure and an uncoated surface appears, resulting in insufficient bitterness masking.

  Furthermore, in these documents, coated particles are prepared with a Wurster fluidized bed granulator equipped with a nozzle for spray coating from the bottom in the fluidized bed, or a rolling fluidized bed granulator in which the bottom of the fluidized bed rotates. An example is specifically disclosed, and the coated particles produced by such an apparatus are usually assumed to have an apparent specific gravity of 0.5 g / mL or more and a circularity of 0.7 or more. . Therefore, the difference in the apparent specific gravity between the excipient and the coated particles in the mixing and tableting process, even if the coated particles are simply mixed with the excipient for an intraoral quick disintegrating tablet and tableted. Segregation is likely to occur due to the difference in fluidity, and the uniformity of drug content cannot be improved. Here, “segregation” refers to a state in which the coated particles are not uniformly dispersed in the excipient, but are unevenly dispersed and uneven.

  Various problems arise due to this segregation. For example: The tableting pressure is directly transmitted to the coated particles due to the contact between the heel surface and the coated particles during tableting, and the contact between the coated particles. As a result, the coated particles are destroyed, and elution is promoted after tableting, resulting in a bitter taste. 2. 2. Since the degree of destruction of the coated particles varies depending on the degree of segregation, the target dissolution control cannot be realized with high reproducibility after tableting. Variations occur in the number of sustained-release fine particles contained in one tablet, resulting in problems such as inability to ensure drug content uniformity. In addition, an increase in apparent specific gravity and an increase in circularity suggest a decrease in tablet moldability and an increase in hardness after moisture absorption because the surface area of the coated particles themselves decreases. Furthermore, since the rapidly disintegrating granules contain crospovidone which easily swells due to moisture absorption, the hardness is further reduced after moisture absorption, and it cannot be said that the rapidly disintegrating granules have satisfactory characteristics as a rapidly disintegrating tablet.

WO2006 / 085497 (Claims) WO00 / 078292 (Claims) Japanese Patent Laying-Open No. 2005-112861 (Claims) JP-A-8-208517 JP-A-10-101582 JP 2001-302510 A JP 2001-106639 A JP-A-2005-343800 JP 2008-260712 A JP 2007-524575 A JP 2004-339071 A

  The present inventors have obtained the following knowledge in the formulation of drugs (for example, drugs having a bitter taste such as zonisamide). That is, according to the description in the prior art, (1) coating a drug alone or a mixed powder of a drug and an excipient (such as D-mannitol) with a water-insoluble polymer (such as ethyl cellulose) with a normal fluidized bed apparatus ( (Or granulation), the obtained granules have a drug-derived bitter taste and are insufficiently controlled. (2) When the obtained granules are orally disintegrating tablets, the smooth particle surface shape of the granules (3) The resulting coated granules have a large specific gravity and a high circularity, and do not contain a drug (hereinafter referred to as a drug). When mixing and compression molding with a non-containing granule), the uniformity of content in the tablet decreases due to the difference in specific gravity and fluidity with the drug-free granule, and (4) with the drug-free granule. Poor binding strength, moisture absorption (5) When a disintegrating agent widely used in solid preparations (such as a disintegrating agent called a super disintegrating agent) is blended with a drug-free granule, the hardness tends to further decrease after moisture absorption, etc. It was found that there are problems.

  Therefore, the object of the present invention is to mask an unpleasant taste (such as bitterness) of a drug and to rapidly disintegrate rapidly disintegrating tablets or disintegrating orally disintegrating tablets (or intraoral) It is to provide a fast-disintegrating tablet) and a production method thereof.

  Another object of the present invention is that the tablet hardness is high, and even when stored for a long time under high humidity, the decrease in tablet hardness can be suppressed, and it can be disintegrated in a short time with a small amount of water or a small amount of saliva in the oral cavity. An orally disintegrating tablet and a method for producing the same.

  Still another object of the present invention is to provide a rapidly disintegrating tablet including an orally disintegrating tablet having excellent drug content uniformity despite having drug particles capable of masking bitterness, and a method for producing the same. There is.

  Another object of the present invention is to provide a granule useful for preparing a tablet which is tableted by mixing with a predetermined granule and suppresses an unpleasant taste of a drug, and a method for producing the granule.

  As a result of intensive studies based on the above findings, the present inventors have found that the present invention is uncomfortable in the presence of a fluidizing agent that suppresses aggregation of a powdered drug (particularly, a pharmaceutical carrier having the aggregation suppressing function). When a powdery drug having a taste is granulated or coated with a water-insoluble carrier using an ordinary fluidized bed granulator, the unpleasant taste of the drug can be remarkably suppressed, and the apparent specific gravity and circularity are small. A granule is obtained, such a first granule, a saccharide as a base component, and a disintegrant having a low degree of water swelling instead of a disintegrant called a super disintegrant, and a small amount of a water-soluble solution having a low aqueous solution viscosity. Tablets mixed with the second granule granulated with a sex binder can suppress the unpleasant taste of the drug, while maintaining high hardness over a long period of time, significantly improving disintegration in the oral cavity Including orally disintegrating tablets with improved content uniformity It found that the disintegrating tablet can be obtained, and have completed the present invention.

  That is, the rapidly disintegrating tablet of the present invention comprises (a-1) a powdered drug having an unpleasant taste (for example, bitter taste), (a-2) suppressing aggregation of the powdered drug and is physiologically acceptable. Possible fluidizing agents or aggregation inhibitors (for example, pharmaceutical carriers), and (a-3) carriers for granulating or coating the mixture of the drug and the fluidizing agent (for example, granulating the mixture or A first granule (or a fluidized bed granulator combined with a fluidized bed dryer and a spray system) and granulated in a fluidized bed with a normal fluidized bed granulator (or a fluidized bed dryer and a spray system). (Drug containing granules) (A), (b-1) at least one granular base component having an average particle size of 10 to 500 μm and selected from sugar, sugar alcohol and amino acid, (b-2) at the time of water absorption A disintegrant having a swelling ratio of 1.3 or less, and (b-3) a water-soluble binder, and (b-3) the water The content of the functional binder is 1 part by weight or less with respect to 100 parts by weight of the tablet, and it is fluidized with an ordinary fluidized bed granulator (simple fluidized bed granulator combining a fluidized bed dryer and a spray system). And a second granulated granule (B). In such a fast disintegrating tablet, the taste (for example, bitterness) of the drug is suppressed.

  In such a fast disintegrating tablet, the first granule (A) may contain a bitter drug, and the second granule (B) may contain substantially no bitter drug. That is, the second granule (B) may be a drug-free granule. The carrier (a-3) may be at least one selected from water-insoluble carriers such as ethyl cellulose, methacrylic acid copolymers, and wax-like substances. The carrier (a-3) may be a carrier that is soluble in ethanol or hydrous ethanol. (A-2) The fluidizing agent or aggregation inhibitor is at least selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, sucrose fatty acid ester, light anhydrous silicic acid, and hydrous silicon dioxide. It may be a kind of pharmaceutical carrier. (A-2) The fluidizing agent or aggregation inhibitor is often at least one pharmaceutical carrier selected from light anhydrous silicic acid and hydrous silicon dioxide.

  The apparent specific gravity of the first granules (A) may be about 0.1 to 0.5 g / ml, and the circularity of the first granules (A) is about 0.2 to 0.7. May be.

Furthermore, in the second granule (B), (b-2) the disintegrant is at least one selected from crystalline cellulose and starch, for example, crystalline cellulose (crystalline cellulose having a bulk density of 0.23 g / cm ³ or less, etc. ). Moreover, about 1-30 weight part may be sufficient as content of (b-2) disintegrating agent with respect to 100 weight part of tablets. Furthermore, (b-3) the water-soluble binder may have a viscosity of 2% by weight aqueous solution of 3 mPa · s (20 ° C.) or less. (B-3) a water-soluble binder, 2.0 N / mm ² or more, may be particularly binding agent to give 2.5 N / mm ² or more tablet strength. (B-3) The water-soluble binder may be, for example, polyvinyl alcohol. The circularity ratio between the first granule (A) and the second granule (B) may be about 1: 3 to 3: 1.

  The quick disintegrating tablet usually contains a lubricant (C), and this lubricant (C) is contained in the first granules (A) and / or the second granules (B). Alternatively, it may be contained in a mixture of the first granules (A) and the second granules (B).

  More specifically, the quick disintegrating tablet of the present invention includes, for example, (a-1) a powdered drug having a bitter taste, (a-2) a pharmaceutical carrier that suppresses aggregation of the drug, and (a-3) ) Containing ethanol or water-insoluble polymer or wax-like substance soluble in water-containing ethanol for granulating or coating the mixture containing the mixture of drug and pharmaceutical carrier by fluidized bed granulation, and having an apparent specific gravity of 0 A first granule (A) having a circularity of 0.2 to 0.7, (b-1) an average particle size of 10 to 500 μm, and a sugar At least one granular base component selected from sugar alcohols and amino acids; (b-2) pre-gelatinized starch, carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone, selected from crystalline cellulose and starches Was less And (b-3) a water-soluble binder composed of polyvinyl alcohol having a viscosity of 3 mPa · s (20 ° C.) or less, and (b-3) a 2% by weight aqueous solution. The second granule (B) whose content is 0.5 parts by weight or less with respect to 100 parts by weight of the tablet, and the circularity ratio between the first granule (A) and the second granule (B) May be 1: 3 to 3: 1. This rapidly disintegrating tablet may contain (C) a lubricant, and even if the content of (C) the lubricant is about 0.5 to 1.0 part by weight with respect to 100 parts by weight of the tablet. Good. Such a fast disintegrating tablet has suppressed the bitterness of the drug.

  The rapidly disintegrating tablet may be an orally disintegrating tablet. Further, the rapidly disintegrating tablet contains the drug uniformly, and for example, the coefficient of variation of the drug content may be 3.5% or less. The drug may be, for example, various drugs having an unpleasant taste, for example, a drug having at least one bitter taste selected from zonisamide, rebamipide, olmesartan medoxomil, and the like.

  The present invention comprises (a-1) a powdered drug having an unpleasant taste, (a-2) a fluidizing agent that suppresses aggregation of the powdered drug and is physiologically acceptable, and (a-3) ) A first granule (A) comprising a carrier for granulating or coating the mixture of the drug and the fluidizing agent; and (b-1) having an average particle size of 10 to 500 μm, and sugar, sugar Containing at least one particulate base component selected from alcohol and amino acid, (b-2) a disintegrant having a swelling ratio of 1.3 or less upon water absorption, and (b-3) a water-soluble binder, (b- 3) The pharmaceutical composition containing the 2nd granule (B) whose content of the said water-soluble binder is 1 weight part or less with respect to 100 weight part of tablets, and a lubricant (C) is also included.

  Furthermore, the present invention provides a mixture of (a-1) a powdered drug having an unpleasant taste and (a-2) a physiologically acceptable fluidizing agent that suppresses aggregation of the powdered drug and is physiologically acceptable. (A-3) the first granules (A) granulated or coated with the simple fluid bed granulator using the carrier, and (b-1) having an average particle diameter of 10 to 500 μm, And at least one granular base component selected from sugar, sugar alcohol and amino acid, (b-2) a disintegrant having a swelling rate of 1.3 or less upon water absorption, and (b-3) a water-soluble binder And (b-3) a mixture containing the second granule (B) having a water-soluble binder content of 1 part by weight or less with respect to 100 parts by weight of the tablet and the lubricant (C). It also includes a method for producing a fast disintegrating tablet.

  Furthermore, the present invention relates to an uncomfortable presentation of a drug that is tableted by mixing with granules containing at least one granular base component selected from sugars, sugar alcohols and amino acids, a disintegrant, and a water-soluble binder. Also included are granules for preparing tablets with reduced taste (for example, fast disintegrating tablets such as orally disintegrating tablets). This granule corresponds to the first granule (A), (a-1) a powdered drug having an unpleasant taste, (a-2) suppressing aggregation of the powdered drug, and physiology And (a-3) a carrier for granulating or coating a mixture of the drug and the fluidizing agent (a carrier obtained by granulating or coating the mixture).

  In this specification, the simple fluidized bed granulator means a fluidized bed granulator that is a combination of a fluidized bed dryer and a spray system. In addition, it does not include a combined fluidized bed granulator to which forced circulation, granulating and / or rotating means are added. Tablet strength of the binder is tableting a mixture of 99 parts by weight of D-mannitol and 1 part by weight of binder (or a granulated product obtained by granulating 99 parts by weight of D-mannitol with an aqueous solution of 1 part by weight of binder). It can be defined as a value obtained by dividing the hardness of a tablet (diameter: 8 mm, weight: 200 mg) manufactured at a pressure of 5.0 kN by the fracture area of the tablet.

  “Drug coefficient of variation (CV%)” in this specification is an index of content uniformity. For example, a content uniformity test is performed according to the test method described in the 15th revised Japanese Pharmacopoeia, and is calculated by the following formula: To do.

CV% = (standard deviation of individual contents) / (average value of contents) × 100
When “CV% is 0 to 3.5%”, it can be considered that there is little variation in the drug content in the tablet and no segregation occurs, and “the drug content uniformity is ensured”. it can. On the other hand, when “CV% exceeds 3.5%”, the variation in drug content is large and it can be considered that segregation occurs, and it can be said that “content uniformity is poor”. The appropriate range of the coefficient of variation referred to in the present invention, that is, “CV% is 0 to 3.5%” is a numerical value considered necessary for quality assurance, and a composition containing a certain amount of drug is obtained. Is shown.

  The first granule can also be referred to as a drug-containing granule, and the second granule does not need to contain a drug, and thus can also be referred to as a drug-free granule. The “second granule” and the “drug-free granule” mean a granule that does not exhibit an unpleasant taste of the drug, and even a drug that exhibits an unpleasant taste is substantially unpleasant. If it is a small amount that does not give taste, it may contain a drug, and if it is a drug that does not give an unpleasant taste, it means that it may contain a drug. “Second granules” and “drug-free granules” usually do not contain a drug that exhibits an unpleasant taste.

  In the present invention, since the specific first granule and the specific second granule are included, unpleasant taste of the drug (bitter taste and the like) is suppressed, and the tablet is formed with a small amount of water or a small amount of saliva in the oral cavity. Can collapse quickly. In particular, the hardness of the tablet is high, and even when stored for a long period of time, a decrease in hardness can be suppressed, and the drug content uniformity is also excellent.

[Quick disintegrating tablets and pharmaceutical compositions]
The rapidly disintegrating tablet and the pharmaceutical composition contain the first granule (A) and the second granule (B), and the first granule (A) suppresses unpleasant taste of the drug. The above-mentioned components (A) to (C) improve the hardness of the tablet and the uniformity of the drug content while ensuring fast disintegration mainly by the granules (B). Fast disintegrating tablets and pharmaceutical compositions usually further contain a lubricant (C).

[First granule or drug-containing granule (A)]
The first granule (A) comprises (a-1) a powdery drug having an unpleasant taste (bitter taste etc.) and (a-2) suppresses aggregation of the powdery drug and is physiologically acceptable A fluidizing agent (for example, a pharmaceutical carrier); and (a-3) a carrier for granulating or coating a mixture of the drug and the fluidizing agent (a pharmaceutical carrier granulating or coating the mixture). The unpleasant taste of the drug is suppressed.

(A-1) Powdered drug having unpleasant taste The kind of the drug is not particularly limited as long as it has an unpleasant taste (bitter taste etc.), and includes pharmacologically active ingredients and physiologically active ingredients. Examples of the drugs include antiepileptic drugs, antiparkinsonian drugs, peptic ulcer drugs (such as gastric mucosal repair drugs), neuropsychiatric drugs (such as antipsychotic drugs), Alzheimer-type dementia therapeutic drugs, and digestive organs. Agents (antihyperlipidemic agents, antidiabetic agents, postprandial hyperglycemic agents, etc.), sleep inducers or hypnotic sedatives, hypotensive agents, antihypertensive agents, migraine treatment agents, antihistamines, allergic agents, Examples include bronchial asthma therapeutic agents, H2 receptor antagonists, arrhythmia agents and the like. These drugs can be used alone or in combination of two or more.

  Among drugs having an unpleasant taste, typical drugs having a bitter taste include, for example, zonisamide, rebamipide, olmesartan medoxomil, acetaminophen, meclofenoxate hydrochloride, chloramphenicol, aminophylline, erythromycin, josamycin , Indeloxazine hydrochloride, calcium hopate, phenobabital, cimetidine, ranitidine, famotidine, ethylephrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, flufenamic acid, digitoxin, theophylline, promethazine hydrochloride, quinine hydrochloride, sulpyrine, Ibuprofen, ambroxol hydrochloride, calcium carbonate, amlodipine besilate, pioglitazone hydrochloride, metformin hydrochloride, pravastatin sodium, clarithromycin , Cetirizine hydrochloride, allopurinol, phenoxyphenazine hydrochloride, olopatadine hydrochloride, imidapril hydrochloride, donepezil hydrochloride, zopiclone, nizatidine, tranexamic acid, risperidone, irsogladine maleate, selegiline hydrochloride, pranlukast hydrate These drugs can also be used alone or in combination of two or more.

  The upper limit of the average particle size of the drug before starting granulation or coating is an average particle size of 150 μm or less, preferably 100 μm or less, more preferably 50 μm or less, and most preferably 30 μm or less. When drug particles with a large particle size are included, the particle size of the granulated product becomes coarse and feels rough when it is contained in the mouth. On the other hand, if there are many drug particles smaller than the average particle size or the particle size of 0.3 μm, the amount of the carrier necessary for bitterness suppression increases, and accordingly, bioavailability decreases. Therefore, the average particle diameter of the drug particles is about 0.3 to 150 μm (for example, 0.5 to 100 μm, preferably 1 to 75 μm, more preferably 5 to 50 μm), and among the drug particles, the particle diameter is 0.3 μm. The proportion of the following particles is 10% or less, preferably 5% or less on a volume basis.

  The content of the drug can be selected from a wide range (for example, 0.001 to 50 parts by weight with respect to 100 parts by weight of the tablet) depending on the type of the drug, and is usually 0.01 to 100 parts by weight with respect to 100 parts by weight of the tablet. It may be about 50 parts by weight, preferably about 0.01 to 30 parts by weight, more preferably about 0.01 to 20 parts by weight.

(A-2) Fluidizing agent or aggregation inhibitor A fluidizing agent is a component that suppresses aggregation of the powdered drug (a-1) and is physiologically acceptable (particularly, a pharmaceutical carrier). Good. Examples of the fluidizing agent (a-2) include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, sucrose fatty acid ester, light anhydrous silicic acid, hydrous silicon dioxide and the like. These fluidizing agents can be used alone or in combination of two or more. A preferred (a-2) fluidizing agent is at least one pharmaceutical carrier selected from light anhydrous silicic acid and hydrous silicon dioxide. Granulation or coating of drug (a-1) with carrier (a-3) in the presence of fluidizing agent (a-2) such as light anhydrous silicic acid not only improves drug fluidity, Aggregated drugs are likely to become primary particles, and as a result, a coating (granulation) that suppresses bitterness more effectively can be achieved. The specific surface area of the fluidizing agent (e.g., light anhydrous silicic acid), for example, 30~1000m ² / g (e.g., 50~750m ² / g, preferably about 100 to 500 m ² / g. The The volume test of the fluidizing agent (for example, light anhydrous silicic acid) may usually be 70 ml / 5 g or more, and examples of the light anhydrous silicic acid include Adsolider 101 (Freund industry, average particle size: 3. 2 μm, specific surface area: 300 m ² / g, volume test: 90 ml / 5 g), Aerosil (Nippon Aerosil, primary particle size: 10-40 nm, specific surface area: 50-380 m ² / g), etc. Examples of the hydrous silicon dioxide include ADSOLIDER 102 (Freund Sangyo, average particle size: 5.0 μm). , Specific surface area: 700m ² / g, volume test:. 20 ml / 5 g), and others as fluidizing agents, light anhydrous silicic acid, in particular it is often used Adsolider.

  The amount of the fluidizing agent can be used within a range in which aggregation of the drug can be suppressed. For example, 0.1 part by weight or more (for example, 0.5 to 25 parts by weight), preferably 1 part by weight based on 100 parts by weight of the drug. Part or more (for example, 1 to 15 parts by weight), more preferably about 2 parts by weight or more (for example, 2 to 10 parts by weight), and 1.5 to 10 parts by weight (for example, 2.5 to 7.5 parts by weight). Part) degree.

(A-3) Carrier (or granulated carrier)
(A-3) As a carrier for granulating or coating the mixture of the drug and the fluidizing agent, various pharmaceutical carriers such as a water-soluble carrier and a water-insoluble carrier can be used. In order to enhance the properties, a water-insoluble carrier is used.

  The carrier (a-3) may be a low-molecular substance or a high-molecular substance, and usually includes a high-molecular substance (water-insoluble polymer, enteric polymer, gastric polymer), wax-like substance, and the like. . Examples of water-insoluble polymers include ethyl cellulose (trade name, etosel), water-insoluble cellulose ethers such as cellulose acetate, aminoalkyl methacrylate copolymer RS (ethyl acrylate / methyl methacrylate / trimethyl ammonium methacrylate copolymer, trade name Eudragit RL100, Water-insoluble acrylic copolymers such as Eudragit RL30D, Eudragit RSPO, Eudragit RS30D), ethyl acrylate / methyl methacrylate copolymer dispersion (trade name Eudragit NE30D), and vinyl acetate resins. Examples of the enteric polymer include hydroxypropyl methylcellulose acetate succinate, hypromellose phthalate (trade name HPMCP), methacrylic acid copolymer L (methacrylic acid-methyl methacrylate copolymer, trade name Eudragit L), and methacrylic acid copolymer. Methacrylic acid such as LD (methacrylic acid-ethyl acrylate copolymer, trade name Eudragit L30D-55), methacrylic acid copolymer S (methacrylic acid-methyl methacrylate copolymer, trade name Eudragit S), methacrylic acid-n-butyl acrylate copolymer A copolymer can be illustrated. Examples of gastric soluble polymers include gastric soluble polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, trade name: Eudragit E, Reem Co., Ltd.) Gastric soluble acrylic acid copolymers and the like. Examples of wax-like substances include solid fats such as hardened castor oil, hardened coconut oil, and beef tallow, higher fatty acids such as stearic acid, lauric acid, myristic acid, and palmitic acid (particularly saturated higher fatty acids), cetyl alcohol, stearyl alcohol, and the like. Of higher alcohols. These pharmaceutical carriers may be blended alone or in combination of two or more. Among these carriers, at least one selected from ethyl cellulose, methacrylic acid copolymers, and wax-like substances, particularly water-insoluble polymers that are soluble in ethanol or water-containing ethanol that are harmless to the environment and the human body (for example, ethyl cellulose, acrylic Preferred are ethyl acetate / methyl methacrylate / methyl methacrylate / trimethylammonium ethyl copolymer RS, methacrylic acid polymers L, LD, S, etc.) or waxy substances (higher fatty acids such as stearic acid).

  It is preferable to add a plasticizer to the pharmaceutical carrier used in the present invention. Examples of the plasticizer include triacetin, triethyl citrate, polyethylene glycol, stearic acid, and Eudragit NE30D.

  The amount of the carrier used can be adjusted depending on the degree of taste (bitterness etc.) of the drug, and usually 0.5 to 300 parts by weight, preferably 1 to 100 parts by weight, more preferably 3 to 100 parts by weight of the drug. It can be selected from a range of about 100 parts by weight, and depending on the type of drug (for example, zonisamide), it may be 5 to 50 parts by weight, preferably about 10 to 30 parts by weight with respect to 100 parts by weight of the drug.

  The first granule (A) further comprises pharmaceutically acceptable additives such as excipients, disintegrants, binders, lubricants, sweeteners, fragrances, stabilizers, plasticizers, colorants. It may contain a corrigent. These additives are added singly or in combination of two or more.

  The first granules (A) are characterized by a small apparent specific gravity and a small degree of circularity. The apparent specific gravity of the first granule (A) is, for example, 0.1 to 0.5 g / mL, preferably 0.15 to 0.45 g / mL, more preferably 0.2 to 0.45 g / mL (for example, 0.25 to 0.4 g / mL), or about 0.2 to 0.35 g / mL. The circularity of the first granules (A) is, for example, 0.2 to 0.7, preferably 0.3 to 0.6 (for example, 0.35 to 0.55), more preferably 0.37 to It is about 0.53 (for example, 0.4 to 0.5). When the circularity is less than 0.2, the specific surface area of the first granules increases, and the bitterness of the drug cannot be sufficiently suppressed. The first specific granule having an apparent specific gravity of 0.5 g / mL or more and a circularity of 0.7 or more was simply mixed with an excipient for a fast disintegrating tablet for tableting. However, there is a high possibility that segregation will occur due to the difference in apparent specific gravity and fluidity between the excipient and the coated particles in the tableting process. When the apparent specific gravity is large and the circularity is high, the surface area of the coated particle itself is reduced, which suggests that the tablet formability is lowered and the hardness is lowered after moisture absorption. Moreover, when the apparent specific gravity is reduced, the specific surface area of the first granules is increased, and the bitterness of the drug cannot be sufficiently suppressed.

In this specification, “apparent specific gravity” means the ratio (after tapping) of the mass of the powder and the volume occupied when put in the container. A smaller apparent specific gravity suggests that the particles are hollow or porous. The apparent specific gravity is determined by, for example, using a device for measuring apparent specific gravity (manufactured by Hosokawa Micron, powder tester), and performing a tapping operation a certain number of times (60 times per minute, 3 minutes) (powder weight per 1 cm ³ (g ).

  In this specification, “circularity” is a value obtained by photographing a granule with an optical microscope and multiplying the area of the granule by 4π by the square of the circumference of the granule. The circularity is a numerical value greater than 0 and less than or equal to 1, and the closer to 1, the closer the circle is to a perfect circle. The circularity can be measured using, for example, image processing integration software (Win ROOF ver 5.6, MITANI CORPORATION).

  If the average particle size of the first granules exceeds 300 μm, the amount added or spray solid content can be reduced, but there may be a feeling of roughness in the oral cavity or a feeling of foreign matter. Therefore, an average particle diameter is 300 micrometers or less, Preferably it is 250 micrometers or less, More preferably, it is 200 micrometers or less. On the other hand, when the number of particles having a small particle size is large, the specific surface area of the drug is large, so that the bitterness may not be sufficiently suppressed. Therefore, the average particle diameter is preferably 50 μm or more. From such a viewpoint, the average particle diameter of the first granules (A) may be, for example, about 50 to 250 μm, preferably about 70 to 200 μm, more preferably about 100 to 200 μm, and about 120 to 200 μm. May be.

  The first granules (A) can be obtained by ordinary fluidized bed granulation. The normal fluidized bed granulator is a simple fluidized bed granulator in which a fluidized bed dryer and a spray system are combined with this dryer. WSG "," FD type "," FLO type "manufactured by Freund Corporation," Flow coater "manufactured by Okawara Corporation, and the like. For example, the first granule (A) can be obtained by granulating or coating a mixture containing the mixture of the drug and the fluidizing agent by the fluidized bed granulation (a mixture in a form in which the powder is fluidized). it can. This granulation can be carried out using a normal fluidized bed granulator in which a carrier solution or suspension is sprayed onto a fluidized bed to granulate or coat. The solution or suspension of the carrier can be sprayed onto the fluidized bed by a conventional method such as bottom spray, top spray, or side spray, and is usually sprayed onto the fluidized bed by the top spray method in many cases. The first granule (A) can be obtained by spray granulation and drying the fluidized bed.

  Fluidized bed granulators other than normal fluidized bed granulators mean composite granulators that are spun, rolled, and stirred for granulation. Forced circulation from the side of the fluidized bed and sizing and pulverization This is a composite fluidized bed granulator in which the granulated material is jetted, rolled and stirred by the rotation of the blade rotor in the fluidized bed. Specifically, as the combined fluidized bed granulator, a rolling fluidized bed granulator equipped with a rotating disk in the fluidized bed (for example, “Multiplex” manufactured by Paulek, “Agromaster PJ type” manufactured by Hosokawa Micron, Inc. , "Spyra Coater" manufactured by Okada Seiko Co., Ltd.), fluidized bed granulator (for example, "SPC" manufactured by Paulec Co., Ltd.) with improved Wurster method equipped with a forced circulation device from the side, particle size crushing mechanism (screen impeller) Fluidized bed granulators (for example, “fine particle coating and granulating apparatus SFP-01” manufactured by POWREC), rotary fluidized bed granulators (for example, Nara) And “Omni-Tex” manufactured by Machine Manufacturing Co., Ltd.). When these composite fluidized bed granulators are used for granulation or coating, the granulated material is jetted, rolled, and stirred by forced circulation from the side, sizing and pulverization, and rotation of the blade rotor in the fluidized bed. The apparent specific gravity of the obtained granulated product (granules) is 0.5 g / mL or more and the circularity is 0.7 or more. Therefore, in order to obtain the first granule, it is effective to granulate or coat with a normal fluidized bed granulator other than the above granulator.

  As described above, the first granule (A) is mixed with a granule containing at least one granular base component selected from sugar, sugar alcohol and amino acid, a disintegrant, and a water-soluble binder, and compressed into tablets. It is useful for preparing a tablet with less drug aggregation, an unpleasant taste of the drug, and a uniform drug content. Also in this granule, the exemplified fluidizing agent (a-2), in particular, at least one pharmaceutical carrier selected from light anhydrous silicic acid and hydrous silicon dioxide is used, and the exemplified carrier (a-3), In particular, water-insoluble carriers selected from ethyl cellulose, methacrylic acid copolymers, wax-like substances and soluble in ethanol or hydrous ethanol are used.

[Second granule (B)]
The second granule (B) comprises (b-1) a granular base component mainly composed of sugars, (b-2) a disintegrant with a small degree of swelling, and (b-3) a water-soluble binder. Contains.

(B-1) Granular base component The base component of the second granule (B) is composed of a pharmacologically inert water-soluble granular material, and at least one selected from sugar, sugar alcohol and amino acid is used. The These particulate base components may be classified as excipients. Examples of the sugar include lactose, sucrose, glucose, fructose, maltose, trehalose, palatinose obtained by reacting an enzyme with sucrose (Mitsui Sugar Co., Ltd., trade name), and palatinose hydrogenated with palatinose (Mitsui Sugar Co., Ltd.) ) And trade names) and the like. Examples of the sugar alcohol include mannitol (D-mannitol), xylitol, sorbitol, erythritol, maltitol and the like. These sugars and sugar alcohols can be used alone or in combination of two or more. Of these sugars and sugar alcohols, lactose and sugar alcohols (such as mannitol) are often used.

  Examples of amino acids include glycine, alanine, arginine and the like. These amino acids can also be used alone or in combination of two or more, and may be used in combination with the sugar and / or sugar alcohol. Among these amino acids, glycine and alanine are preferable from the viewpoint of taking feeling.

  When a granular base component having a large particle size is used, the disintegration is improved, but the moldability tends to be lowered and the tablet becomes brittle. Therefore, the average particle size of the base component is preferably about 10 to 500 μm. The average particle diameter of the granular base component can be selected from the range of 10 to 500 μm, and is usually 15 to 300 μm, preferably 30 to 250 μm, more preferably 30 to 200 μm (for example, 30 to 150 μm), and about 30 to 80 μm. It may be. When the particle size of the granular base component is large, the permeability of water or saliva into the tablet is improved and the disintegration time is shortened.However, in the case of an orally disintegrating tablet, if the particle size is too large, the roughness in the oral cavity will be reduced. Impairs feeling, feeling of taking or eating. In the present invention, even if a granular base component having a large particle size is used, the powder contact surface can be obtained by spraying a predetermined disintegrant (such as crystalline cellulose) and a lubricant (in some cases, a small amount of lubricant on the upper and lower ridges and the die). And a tablet having high hardness and disintegration can be obtained. In addition, the average particle diameter of a granular base component can be measured, for example with the laser diffraction type | formula particle size measuring device [HELOS & RODOS] by a SYMPATEC company.

  The proportion of the granular base component can be selected according to the type of formulation component such as a disintegrant and the proportion of use, and is usually 40 to 98 parts by weight, preferably 45 to 95 parts by weight, and more preferably 100 to 100 parts by weight. Preferably it is 45-85 weight part.

(B-2) Disintegrant In the present invention, a disintegrant having a swelling ratio (water absorption swelling ratio) of 1.3 or less at the time of water absorption is used instead of a general-purpose disintegrant such as a super disintegrant. The water absorption swelling rate of the disintegrant is, for example, about 0.5 to 1.3, preferably about 0.6 to 1.2, and more preferably about 0.6 to 1.1. When a disintegrating agent having a swelling rate (water absorption swelling rate) exceeding 1.3 is incorporated, the hardness of the tablet is significantly reduced under high humidity (or humidification) conditions, or water penetrates into the center of the tablet. Decreases, the oral disintegration time is delayed, and the desired fast disintegrating tablet or orally disintegrating tablet cannot be obtained. In addition, the swelling rate at the time of water absorption can be measured as follows. At room temperature (15 to 25 ° C., particularly 20 ° C.), put 10 g of the sample into a graduated cylinder, measure the volume of the sample to obtain the volume before swelling, and further add water to make 100 mL. Volume of the disintegrant after 1 hour Is the volume after swelling. A value obtained by dividing the volume after swelling by the volume before swelling can be defined as the swelling ratio upon water absorption. Examples of such a disintegrant having a low swelling rate include crystalline cellulose and starches. Table 1 below shows the results of examining the swelling rate at the time of water absorption of various disintegrants.

  From Table 1 above, disintegrants having a water absorption swelling ratio of 1.3 or less include crystalline cellulose and starches (including hydroxypropyl starch), and at least one selected from these disintegrants is used. The crystalline cellulose is used in the form of fine particles, and may be fine particles that pass through most of a sieve having an opening of 38 μm or may be a granulated granular material. Crystalline cellulose is commercially available under trade names such as “Theoras”, “Avicel”, “Selfia”, “Pharmacel”. Starches include untreated or unprocessed starch such as potato starch, corn starch, rice starch and wheat starch, as well as hydroxyalkyl starch such as hydroxypropyl starch. These disintegrants can be used alone or in combination of two or more.

  Preferred disintegrants can consist of crystalline cellulose, untreated or raw starch (potato starch, corn starch, especially corn starch). Note that crystalline cellulose functions as a disintegrant and also as an excipient. Therefore, even if it is a composition with inferior moldability, moldability (or tabletability) can be improved by using crystalline cellulose as a disintegrant.

  As is clear from the above table, the disintegrant used in the present invention does not contain a general disintegrant (including a disintegrant called a super disintegrant). That is, pregelatinized starch (fully or partially pregelatinized starch), carboxymethyl starches (such as sodium carboxymethyl starch), carboxymethylcelluloses (carboxymethylcellulose such as carmellose, carmellose calcium, croscarmellose sodium, cross-linked products thereof or the like Alkali metal or alkaline earth metal salt), low-substituted hydroxypropylcellulose and crospovidone.

(B-2) The bulk density of the disintegrant (the bulk density of aggregates such as crystalline cellulose) also affects the disintegration property. The bulk density of the disintegrant (such as cellulose), for example, 0.23 g / cm ³ or less, preferably 0.18 g / cm ³ or less, still more preferably 0.15 g / cm ³ or less, typically 0.08 Often about 0.17 g / cm ³ .

  Content of a disintegrating agent can be selected according to the kind of disintegrating agent, 1-40 weight part (for example, 1-30 weight part) with respect to 100 weight part of tablets, Preferably it is about 3-30 weight part, Usually, it is about 10 to 35 parts by weight. More specifically, the ratio of crystalline cellulose is 1 to 30 parts by weight, preferably 3 to 25 parts by weight, and more preferably 5 to 15 parts by weight with respect to 100 parts by weight of the tablet. The ratio of starches is 1 to 40 parts by weight, preferably 5 to 30 parts by weight, more preferably about 7 to 25 parts by weight, and may be about 10 to 20 parts by weight with respect to 100 parts by weight of the tablet. . In addition, when there is too much total amount of a disintegrating agent, the ingestion feeling in an oral cavity will be impaired, and when too small, desired disintegration and tablet hardness will not be obtained.

  Crystalline cellulose and starches may be used alone, but two types are preferably used in combination. The weight ratio between the crystalline cellulose and the starch can be selected from a wide range of the former / the latter = about 5/95 to 95/5, usually 5/95 to 80/20, preferably 10/90 to 75/25, More preferably, it may be about 15/85 to 65/35.

(B-3) Water-soluble binder Water-soluble binders include polyvinyl alcohols, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), cellulose ethers [methyl cellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose. (HPC), hydroxypropyl methylcellulose (HPMC) and the like]. These water-soluble binders can be used alone or in combination of two or more. Preferred water-soluble binders can consist of polyvinyl alcohols and / or polyvinyl pyrrolidone (PVP), especially polyvinyl alcohols. Examples of the polyvinyl alcohols include polyvinyl alcohol (fully saponified polyvinyl alcohol, partially saponified polyvinyl alcohol), polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene / polyvinyl alcohol copolymer, and the like. As polyvinyl alcohols, fully saponified polyvinyl alcohol is often used. Polyvinyl alcohols can also be used alone or in combination of two or more. As the polyvinyl alcohol, a commercially available single product may be used, or a premix product (OPA DRY AMB (manufactured by Nippon Colorcon, premix product containing polyvinyl alcohol) or the like) may be used.

The water-soluble binder is preferably a binder that imparts high tablet hardness, and such a water-soluble binder comprises a mixture of 99 parts by weight of D-mannitol and 1 part by weight of a binder (or 99 parts by weight of D-mannitol). The hardness of a tablet (diameter: 8 mm, weight: 200 mg) made from a 1 part by weight aqueous solution of a binder and granulated by fluidized bed granulation at a tableting pressure of 5.0 kN is divided by the breaking area of the tablet. Value (tablet strength of the binder). It can be said that as the tablet strength of the binder increases, the binding strength of the binder increases. Water-soluble binders, tablet strength binders 2N / mm ² or more, preferably 2.3 N / mm ² or more, still more preferably not less 2.5 N / mm ² or more. The conditions of the fluidized bed granulation method can refer to the conditions of the examples described later. For example, 495 g of D-mannitol sieved with a No. 42 sieve is charged into a fluidized bed granulation dryer, and the supply temperature is 70 ° C. Then, an aqueous solution of 5 g of a water-soluble binder (for example, an aqueous solution having a concentration of 0.4% by weight) is sprayed and granulated, dried, and the resulting granule is granulated with a No. 22 sieve, thereby producing the granulated product. Can be obtained.

  Furthermore, in order to improve disintegration, the water-soluble binder is preferably a low-viscosity type binder, and the viscosity of a 2% by weight aqueous solution of the water-soluble binder is preferably 6 mPa · s or less at a temperature of 20 ° C., preferably May be 5 mPa · s or less, more preferably 4 mPa · s or less, and particularly 3 mPa · s or less. The aqueous solution viscosity of the binder can be measured using a rotational viscometer (B-type viscometer, Tokyo Keiki).

  In order to enhance the disintegration property in the oral cavity, the tablet of the present invention has a feature that the content of the water-soluble binder is small. The content of the water-soluble binder is 1 part by weight or less (for example, 0.05 to 0.8 part by weight), preferably 0.7 part by weight or less (for example, 0.05 to 0.7 parts by weight), more preferably 0.5 parts by weight or less (for example, 0.07 to 0.5 parts by weight), particularly 0.1 to 0.4 parts by weight, and 0.07 to 0.25. Part by weight may be used. If the proportion of the binder is too large, the tablet hardness increases, but the rapid disintegration property is lost. If the amount is too small, the tablet hardness decreases or a tableting failure occurs during tableting.

  In addition, when the usage-amount of a water-soluble binder is decreased, although the disintegration property of a tablet can be improved, the intensity | strength and hardness of a tablet will fall. Therefore, it is preferable to use a water-soluble binder that can improve the strength and hardness of the tablet even in a small amount. Such a water-soluble binder can be evaluated by the tablet strength, and compared with cellulose ethers such as HPC and HPMC, polyvinyl pyrrolidone (PVP), particularly polyvinyl alcohols, can improve tablet strength even in a small amount. . In particular, when a low-viscosity water-soluble binder is used, the strength and hardness of the tablet can be improved while maintaining rapid disintegration even in a small amount.

  If necessary, the second granule (B) may contain a drug (for example, a drug having no unpleasant taste). For example, the second granule (B) may contain vitamins, minerals and the like. Drugs that do not show unpleasant taste include, for example, phenytoin, cinnarizine, chlorpromazine / phenol phthalate, bitolterol mesylate, nifedipine, promethazine hydrochloride, sulfamethoxidine, ubidecarenone, pyromido acid, voglibose, acarbose, candesartan cilexetil And brotizolam. In many cases, the second granule (B) does not substantially contain a drug having an unpleasant taste (bitter taste or the like).

  The second granule (B) is the same as the first granule (A), and further includes pharmaceutically acceptable additives such as excipients, disintegrants, binders, lubricants, sweeteners, fragrances. , Stabilizers, plasticizers, coloring agents, and the like. These additives are added singly or in combination of two or more.

  The second granule (B) is prepared by using at least (b-1) a granular base component and (b-2) a mixture (a granular mixture) containing a disintegrant, and (b-3) an aqueous solution of a water-soluble binder. The fluidized bed granulation method similar to that for the first granule (A) can be used. For example, it can be obtained by granulating or coating a mixture containing a mixture of the drug and a fluidizing agent (a mixture in a form in which powder particles are fluidized) by fluidized bed granulation. This granulation can be performed using a normal fluidized bed granulator in which a solution or suspension containing a water-soluble binder is sprayed on the fluidized bed to granulate or coat. The solution or suspension of the water-soluble binder can be sprayed onto the fluidized bed by a conventional method such as bottom spray, top spray, or side spray, and is usually sprayed onto the fluidized bed by the top spray method in many cases. The second granule (B) can be obtained by spray granulation and drying the fluidized bed.

  The second granule (B) has the same apparent specific gravity, circularity, and average particle diameter as the first granule (A). That is, the apparent specific gravity of the second granule (B) is, for example, 0.1 to 0.5 g / mL, preferably 0.15 to 0.45 g / mL, and more preferably 0.2 to 0.45 g / mL. (For example, about 0.25 to 0.35 g / mL) or about 0.2 to 0.35 g / mL may be used. The circularity of the second granule (B) is, for example, 0.2 to 0.7, preferably 0.3 to 0.6 (for example, 0.35 to 0.55), more preferably 0.37 to It is about 0.53 (for example, 0.4 to 0.5). In addition, the average particle diameter of the second granule (B) may be, for example, about 50 to 300 μm, preferably 70 to 250 μm, and more preferably about 100 to 200 μm (for example, 100 to 200 μm).

  In the prior art document, for a preparation containing a drug having an unpleasant taste, a first granule (A) having a specific gravity, a specific circularity, and a second granule having a specific composition ( It is not disclosed about B), nor is it described that a rapidly disintegrating tablet or an orally disintegrating tablet is obtained by compression molding a mixture containing the first granule (A) and the second granule (B).

  The ratio of the circularity between the first granule (A) and the second granule (B) is 1: 3 to 3: 1, preferably 1: 2 to 2: 1, more preferably 1: 1.5 to 1. .About.5: 1 (for example, 1: 1.25 to 1.25: 1). When the ratio of circularity increases, there is a large difference in the fluidity of each granule, causing segregation of the contents, and due to insufficient bonding force between particles, it causes deterioration in moldability and a large decrease in hardness after moisture absorption. Become.

[(C) Lubricant]
The rapidly disintegrating tablet or orally disintegrating tablet (or pharmaceutical composition) of the present invention usually contains (C) a lubricant, and this lubricant contains the first granules (A) and / or the first granules. Although it may be contained in the second granule (B), it is usually contained in the tablet or composition as an external additive component added to the first granule (A) and the second granule (B).

  Examples of the lubricant include saturated higher fatty acids, metal salts thereof or esters with polyhydric alcohols (or esters of saturated higher alcohols with polycarboxylic acids or salts thereof), talc, and the like. More specifically, stearic acid, stearic acid metal salts (calcium salt, magnesium salt, aluminum salt, etc.), sucrose fatty acid ester, sodium stearyl fumarate and the like can be exemplified. These lubricants can also be used alone or in combination of two or more. A preferred lubricant is magnesium stearate.

  The content of the lubricant is 5.0 parts by weight or less, preferably 0.1 to 4 parts by weight, and more preferably 0.5 to 3 parts by weight with respect to 100 parts by weight of the tablet.

[Additive component]
The fast disintegrating tablet or orally disintegrating tablet of the present invention and the composition (or pharmaceutical composition) therefor are, in addition to the above-mentioned components, additives generally used in solid preparations such as excipients (crystalline cellulose). , Light silicic anhydride, etc.), a disintegrant with a small degree of water swelling, a fluidizing agent, a lubricant, a surfactant, a sweetening agent, a sour agent, a foaming agent, a fragrance, a coloring agent, and the like. . The amount of these additives used can be selected within a range that does not adversely affect the disintegration property and tablet hardness. The amount of the additive used is, for example, 0.01 to 5 parts by weight, preferably 0 with respect to 100 parts by weight of the tablet. It may be about 0.02 to 3 parts by weight, more preferably about 0.05 to 2 parts by weight.

  The tablet of the present invention is rapidly disintegrated by a small amount of water or a small amount of saliva in the oral cavity while suppressing an unpleasant taste (such as bitterness) of the drug. For example, when the time until the tablet completely disintegrates in the oral cavity without chewing the tablet and the bitterness of the drug at that time is evaluated, the disintegration time of the present invention is within 2 minutes according to the disintegration test method of the Japanese Pharmacopoeia. , Preferably within 1.5 minutes, more preferably within 1 minute. In addition, the disintegration time of the rapidly disintegrating tablet in the oral cavity of the oral disintegrating tablet is usually 10 to 50 seconds, preferably 10 to 40 seconds (for example, 15 to 35 seconds), more preferably 10 to 30 seconds ( For example, about 15 to 25 seconds). Therefore, it is useful as a fast disintegrating tablet or an orally disintegrating tablet.

  In the tablet of the present invention, unpleasant taste (bitterness etc.) of the drug is suppressed to such an extent that there is no problem in taking it, and preferably it is suppressed to such an extent that almost no bitterness is felt. Furthermore, the tablet of the present invention not only has high tablet hardness, but also can suppress a decrease in hardness even when stored under high humidity (humidification) conditions. The initial hardness of the tablet of the present invention may be, for example, about 20 N or more (for example, 25 to 80 N), preferably about 25 N or more (for example, 40 to 75 N), and the moisture absorption hardness is 25 ° C. and the relative humidity is 75%. And stored for 1 week at 10N or more (for example, 15 to 70N), preferably 15N or more (for example, 25 to 55N), more preferably 20N or more (for example, 30 to 45N), Usually, about 25-60N (for example, 30-50N) may be sufficient.

  Furthermore, the tablet of the present invention contains a drug uniformly and has a small coefficient of variation in drug content. That is, the tablet of the present invention has a coefficient of variation (CV%) of drug content of 3.5% or less (0 to 3.5%), usually 0.5 to 3%, preferably 1 to 2.5% ( For example, it is about 1.5 to 2.3%. The coefficient of variation (CV%) of the drug content indicates the degree of drug segregation, and can be obtained by measuring the drug content of a plurality of tablets and calculating the coefficient of variation.

[Method for producing rapidly disintegrating tablets]
The tablet of the present invention (fast disintegrating tablet including an orally disintegrating tablet) is a mixture containing the first granule (A), the second granule (B), the lubricant (C), and additives as necessary. Obtained by tableting. According to this method, an orally disintegrating tablet having excellent disintegration and high hardness can be industrially advantageously produced by a simple operation of tableting. In addition, since it is not necessary to use a wet powder, the productivity of tablets can be increased.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. In the following examples, the characteristics of the tablets were measured as follows.

[Oral disintegration time]
The oral disintegration time was determined by measuring the time until the tablets completely disintegrated without chewing the tablets in the oral cavity of four adult males, and taking the average value as the disintegration time.

[Evaluation of bitterness of drugs]
The evaluation of the bitterness of the drug was performed by 4 adult males based on the following criteria, and the average value was used as the bitterness score. When the average score was 1 or less, there was no problem in taking the bitter taste, and when it was 2 or more, it was judged that taking was difficult due to the bitter taste.

Score “0”: not bitter Score “1”: somewhat bitter Score “2”: bitter Score “3”: bitter but strong, score “4”: bitter and strong

[Hardness of rapidly disintegrating tablets in the oral cavity]
The hardness of the intraoral quick disintegrating tablet was measured with a digital hardness meter (PTB311E, Pharm Test GmbH Germany). The tablet hardness after moisture absorption (moisture absorption hardness) was measured for tablets stored at 25 ° C. and 75% relative humidity for 1 week.

[Tablet strength of binder]
Table 2 shows the viscosity (20 ° C.) of the 2 wt% aqueous solution of the binder used in each Example and Comparative Example and the tablet strength of the binder. The viscosity of the binder was measured using a rotational viscometer (B-type viscometer, manufactured by Tokyo Keiki Co., Ltd.). The specimen for measuring the tablet strength of the binder is a single-punch tableted granulation granulated by fluidized bed granulation of 99 parts by weight of β-type D-mannitol crystals (Rocket: Pearlitol 160C) with 4 parts by weight of 1 part by weight of binder. It was prepared by tableting with a machine (Tabflex, manufactured by Okada Seiko Co., Ltd.).

Reference example 1
The first granule raw material (zonisamide, light anhydrous silicic acid) shown in Table 3 is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.) to disperse talc. Granulation was performed by spraying a 4.0 wt% ethanol solution of ethyl cellulose. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain zonisamide-containing granules. The average particle diameter of the zonisamide-containing granule was 144 μm, the apparent specific gravity was 0.3 g / ml, the circularity was 0.48, and the bitterness score was 0. In the table, “part” indicates “part by weight” (the same applies hereinafter).

Example 1
Table 4 shows the formulation of the intraoral rapidly disintegrating tablet. The second granule raw material (D-mannitol crystals, corn starch, light anhydrous silicic acid) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.). Granulation was carried out by spraying a 0.4% by weight aqueous solution of alcohol. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. The first granule and the second granule produced in Example 1 and the externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid, aspartame, magnesium stearate) were mixed with a V-type mixer (VI-10, (stock) 3) for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at a number of uprights of 6 and a turntable of 30 rpm to obtain tablets (diameter φ8 mm and weight 200 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 50 N, the hardness after moisture absorption (moisture absorption hardness) was 35 N, the oral disintegration time was 20 seconds, and the bitterness score was 0. Further, as a result of evaluating the content uniformity, CV% = 2.1% was shown, and it was confirmed that the content uniformity was good. The result of the dissolution test of the obtained tablets was D15min (dissolution rate after 15 minutes) = 72.5% (paddle method 50 rpm, test solution: water, 900 mL), indicating good dissolution properties.

Example 2
Table 5 shows the formulation of the intraoral quick disintegrating tablet. The first granule raw material (olmesartan medoxomil, light anhydrous silicic acid) is sieved with a 42 mesh sieve and charged into a fluidized bed granulator / dryer (WSG-5, manufactured by Paulec Co., Ltd.) to disperse talc. A 4.0 wt% ethanol solution was sprayed to perform granulation. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain olmesartan-containing granules. The average particle diameter of the olmesartan-containing granule was 130 μm, the apparent specific gravity was 0.25 g / ml, and the circularity was 0.43. Separately, the second granule raw material (lactose, corn starch, light anhydrous silicic acid) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.). Granulation was performed by spraying a 0.4 wt% aqueous solution of acrylic acid / methyl methacrylate copolymer. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. V-type mixer (VI-10, manufactured by Tokusu Kosaku Co., Ltd.) with the first and second granules and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid, aspartame, magnesium stearate) And mixed for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at a number of uprights of 6 and a turntable of 30 rpm to obtain tablets (diameter φ8 mm and weight 200 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 50 N, the hardness after moisture absorption (moisture absorption hardness) was 33 N, the oral disintegration time was 22 seconds, and the bitterness score was 0. Moreover, as a result of evaluating the content uniformity, CV% = 1.8% was shown, confirming that the content uniformity was good. The result of the dissolution test of the obtained tablets was D15min = 81.3% (paddle method 50 rpm, test solution: water, 900 mL), and showed good dissolution properties.

Example 3
Table 6 shows the formulation of the intraoral quick disintegrating tablet. Methacrylic acid in which the first granule raw material (famotidine, light anhydrous silicic acid) is passed through a 42-mesh sieve and charged into a fluidized-bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.) to disperse talc. Granulation was carried out by spraying a 4.0 wt% ethanol solution of copolymer L. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a famotidine-containing granule. The average particle diameter of the famotidine-containing granules was 165 μm, the apparent specific gravity was 0.28 g / ml, and the circularity was 0.42. Separately, the second granule raw material (glycine, corn starch, light silicic acid anhydride) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.). Granulation was performed by spraying a 0.4 wt% aqueous solution. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. V-type mixer (VI-10, manufactured by Tokusu Kosaku Co., Ltd.) with the first and second granules and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid, aspartame, magnesium stearate) And mixed for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at a number of uprights of 6 and a turntable of 30 rpm to obtain tablets (diameter φ8 mm and weight 200 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 50 N, the hardness after moisture absorption (moisture absorption hardness) was 30 N, the oral disintegration time was 18 seconds, and the bitterness score was 0. Moreover, as a result of evaluating the content uniformity, it was confirmed that CV% = 2.0% and the content uniformity was good. The result of the dissolution test of the obtained tablets was D15min = 80.3% (paddle method 50 rpm, test solution: water, 900 mL), and showed good dissolution properties.

Example 4
Table 7 shows the formulation of the intraoral quick disintegrating tablet. The first granule raw material (rebamipide, light anhydrous silicic acid) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.), and ethyl cellulose with dispersed talc After spraying a 4.0 wt% ethanol solution, granulation was performed by spraying a 2.0 wt% ethanol solution of stearic acid. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain rebamipide-containing granules. The average particle size of the rebamipide-containing granules was 185 μm, the apparent specific gravity was 0.26 g / ml, and the circularity was 0.40. Separately, the second granule raw material (D-mannitol crystals, corn starch, light anhydrous silicic acid) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Pauleck Co., Ltd.) Granulation was carried out by spraying a 0.4% by weight aqueous solution of polyvinyl alcohol. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. V-type mixer (VI-10, manufactured by Tokusu Kosaku Co., Ltd.) with the first and second granules and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid, aspartame, magnesium stearate) And mixed for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at 6 ridges and a turntable rotating speed of 30 rpm to obtain tablets (diameter φ10 mm and weight 400 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 70 N, the hardness after moisture absorption (moisture absorption hardness) was 45 N, the oral disintegration time was 25 seconds, and the bitterness score was 1. Moreover, as a result of evaluating the content uniformity, it was confirmed that the CV% = 1.6% and the content uniformity was good. The result of the dissolution test of the obtained tablets was D15min = 68.3% (paddle method 50 rpm, test solution: water, 900 mL), and showed good dissolution properties.

Comparative Example 1
Only zonisamide shown in Table 8 is passed through a 42-mesh sieve and charged into a fluidized bed granulator / dryer (WSG-5, manufactured by Pauleck Co., Ltd.), and a 4.0 wt% ethanol solution of ethyl cellulose in which talc is dispersed. Was sprayed and granulated. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain zonisamide-containing granules. The average particle diameter of the zonisamide-containing granule was 144 μm, the apparent specific gravity was 0.3 g / ml, the circularity was 0.48, and the bitterness score was 2.

Comparative Example 2
The first granule raw material (zonisamide, D-mannitol) shown in Table 9 is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by POWREC Co., Ltd.) to disperse talc. Granulation was carried out by spraying a 4.0 wt% ethanol solution of ethyl cellulose. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain zonisamide-containing granules. The average particle diameter of the zonisamide-containing granule was 144 μm, the apparent specific gravity was 0.3 g / ml, the circularity was 0.48, and the bitterness score was 2.

Comparative Example 3
Table 10 shows the formulation of the intraoral rapidly disintegrating tablet. The second granule raw material (D-mannitol crystals, corn starch, light anhydrous silicic acid) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.). Granulation was carried out by spraying a 0.4% by weight aqueous solution of alcohol. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. The first granule obtained in Comparative Example 2, the second granule and the externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid, aspartame, magnesium stearate) are mixed into a V-type mixer (VI-10, (Made by Tokuju Kogakusho Co., Ltd.) for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at a number of uprights of 6 and a turntable of 30 rpm to obtain tablets (diameter φ8 mm and weight 200 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 52 N, the hardness after moisture absorption (moisture absorption hardness) was 37 N, the oral disintegration time was 21 seconds, and the bitterness score was 2. Moreover, as a result of evaluating the content uniformity, it was confirmed that CV% = 2.0% and the content uniformity was good. The result of the dissolution test of the obtained tablet was D15min = 98.8% (paddle method 50 rpm, test solution: water, 900 mL), indicating good dissolution properties.

Comparative Example 4
Table 11 shows the formulation of the intraoral quick disintegrating tablet. The first granule raw material (zonisamide, light anhydrous silicic acid) is sieved with a 42 mesh sieve, put into a fine particle coating / granulating apparatus (SFP-01, manufactured by Pauleck Co., Ltd.), and ethyl cellulose with dispersed talc. Granulation was performed by spraying a 4.0 wt% ethanol solution. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain zonisamide-containing granules. The average particle size of the zonisamide-containing granule was 130 μm, the apparent specific gravity was 0.80 g / ml, and the circularity was 0.85. Separately, the second granule raw material (D-mannitol crystal, light anhydrous silicic acid, corn starch) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.) Granulation was carried out by spraying a 0.4% by weight aqueous solution of polyvinyl alcohol. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. V-type mixer (VI-10, manufactured by Tokusu Kosaku Co., Ltd.) with the first and second granules and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid, aspartame, magnesium stearate) And mixed for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at a number of uprights of 6 and a turntable of 30 rpm to obtain tablets (diameter φ8 mm and weight 200 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 40 N, the hardness after moisture absorption (moisture absorption hardness) was 16 N, the oral disintegration time was 20 seconds, and the bitterness score was 0. Moreover, as a result of evaluating the content uniformity, it was confirmed that CV% = 3.8% and the content uniformity was low. The result of the dissolution test of the obtained tablets was D15min = 20.5% (paddle method 50 rpm, test solution: water, 900 mL), indicating a slow dissolution property.

Comparative Example 5
Table 12 shows the formulation of the intraoral rapidly disintegrating tablet. The first granule raw material (zonisamide, light anhydrous silicic acid) is sieved with a 42 mesh sieve, put into a fine particle coating / granulating dryer (SFP-01, manufactured by Pauleck Co., Ltd.), and ethyl cellulose in which talc is dispersed. A 4.0 wt% ethanol solution was sprayed to perform granulation. The supply air temperature was 50 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain zonisamide-containing granules. The average particle size of the zonisamide-containing granule was 130 μm, the apparent specific gravity was 0.8 g / ml, and the circularity was 0.90. Separately, the second granule raw material (D-mannitol crystals, crospovidone, light anhydrous silicic acid) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.) Granulation was carried out by spraying a 4.0% by weight aqueous solution of hydroxypropylcellulose. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. The first granule, the second granule and the externally added raw materials (light anhydrous silicic acid, aspartame, magnesium stearate) are mixed for 3 minutes with a V-type mixer (VI-10, manufactured by Tokuju Kogakusho Co., Ltd.) A tableting powder was obtained. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at a number of uprights of 6 and a turntable of 30 rpm to obtain tablets (diameter φ8 mm and weight 200 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 40 N, the hardness after moisture absorption (moisture absorption hardness) was 8 N, the oral disintegration time was 35 seconds, and the bitterness score was 0. Moreover, as a result of evaluating the content uniformity, it was confirmed that CV% = 4.2% and the content uniformity was low. The result of the dissolution test of the obtained tablets was D15min = 17.8% (paddle method 50 rpm, test solution: water, 900 mL), indicating a slow dissolution property.

Comparative Example 6
Table 13 shows the formulation of the intraoral rapidly disintegrating tablet. The first granule raw material (olmesartan medoxomil, light anhydrous silicic acid) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (WSG-5, manufactured by POWREC Co., Ltd.), and aqua dispersed with talc. Granulation was carried out by spraying a 4.0 wt% aqueous solution of a coat (trade name: Aquacoat ECD30, aqueous dispersion of ethyl cellulose). The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized with a 22 mesh sieve to obtain olmesartan-containing granules. The average particle size of the olmesartan-containing granule was 145 μm, the apparent specific gravity was 0.31 g / ml, and the circularity was 0.78. Separately, the second granule raw material (D-mannitol crystals, crospovidone, light anhydrous silicic acid) is sieved with a 42 mesh sieve and put into a fluidized bed granulator / dryer (WSG-5, manufactured by Powrec Co., Ltd.) Granulation was carried out by spraying a 4.0% by weight aqueous solution of hydroxypropylcellulose. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granule was sized with a 22 mesh sieve to obtain a second granule. The first granule, the second granule and the externally added raw materials (light anhydrous silicic acid, aspartame, magnesium stearate) are mixed for 3 minutes with a V-type mixer (VI-10, manufactured by Tokuju Kogakusho Co., Ltd.) A tableting powder was obtained. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tablet was tableted at a number of uprights of 6 and a turntable of 30 rpm to obtain tablets (diameter φ8 mm and weight 200 mg).

  The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 40 N, the hardness after moisture absorption (moisture absorption hardness) was 10 N, the oral disintegration time was 35 seconds, and the bitterness score was 3. Moreover, as a result of evaluating the content uniformity, it was confirmed that CV% = 4.4% and the content uniformity was low. As a result of the dissolution test of the obtained tablet, D15min = 52.5% (paddle method 50 rpm, test solution: water, 900 mL) was shown.

  The results of Examples and Comparative Examples are shown in Table 14 and Table 15.

  As is apparent from Tables 14 and 15, in the Examples, both the initial hardness and moisture absorption hardness of the tablet are higher than those in the Comparative Examples, and the hardness has no practical problem. In addition, the disintegration time in the oral cavity is about 25 seconds or less, the bitterness score is 1 or less, and the dissolution property is 60% or more at D15min. Furthermore, the coefficient of variation, which is an index of content uniformity, was 2.5% or less, which was a lower value than that of the comparative example.

  The tablet of the present invention has rapid disintegration in water or the oral cavity, and has high tablet hardness. Furthermore, the bitterness of the drug is suppressed while ensuring good dissolution properties, and the content uniformity is excellent. Therefore, even an elderly person can easily take it without water or with a small amount of water, and the quality of the tablet can be improved without the occurrence of chipping of the tablet in the production process, transport process and packaging process.

Claims (21)

  (A-1) a powdered drug having an unpleasant taste, (a-2) a fluidizing agent that suppresses aggregation of the powdered drug and is physiologically acceptable, and (a-3) the drug A first granule (A) comprising a carrier for granulating or coating a mixture with a fluidizing agent and fluidized bed granulated by a simple fluidized bed granulator combining a fluidized bed dryer and a spray system. And (b-1) at least one granular base component having an average particle size of 10 to 500 μm and selected from sugar, sugar alcohol and amino acid, and (b-2) a swelling ratio upon water absorption of 1.3. The following disintegrant and (b-3) a water-soluble binder, (b-3) the content of the water-soluble binder is 1 part by weight or less with respect to 100 parts by weight of the tablet, and the simple type A rapidly disintegrating tablet comprising a second granule (B) granulated by a fluidized bed granulator.   The fast disintegrating tablet according to claim 1, wherein the first granule (A) contains a drug having a bitter taste, and the second granule (B) contains substantially no drug having a bitter taste.   (A-2) For at least one preparation wherein the fluidizing agent is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, sucrose fatty acid ester, light anhydrous silicic acid, and hydrous silicon dioxide The rapidly disintegrating tablet according to claim 1 or 2, which is a carrier.   (A-2) The fast disintegrating tablet according to any one of claims 1 to 3, wherein the fluidizing agent is at least one pharmaceutical carrier selected from light anhydrous silicic acid and hydrous silicon dioxide.   The rapidly disintegrating tablet according to any one of claims 1 to 4, wherein the apparent specific gravity of the first granules (A) is 0.1 to 0.5 g / ml, and the circularity is 0.2 to 0.7. .   The rapidly disintegrating tablet according to any one of claims 1 to 5, wherein the circularity ratio between the first granules (A) and the second granules (B) is 1: 3 to 3: 1.   (A-3) The carrier is a water-insoluble carrier, The fast disintegrating tablet according to any one of claims 1 to 6.   (A-3) The rapidly disintegrating tablet according to any one of claims 1 to 7, wherein the carrier is at least one selected from ethyl cellulose, a methacrylic acid copolymer, and a wax-like substance.   (B-2) The rapidly disintegrating tablet according to any one of claims 1 to 8, wherein the disintegrant is at least one selected from crystalline cellulose and starches. (B-2) The rapidly disintegrating tablet according to any one of claims 1 to 9, wherein the disintegrant is crystalline cellulose having a bulk density of 0.23 g / cm ³ or less.   (B-2) The rapidly disintegrating tablet according to any one of claims 1 to 10, wherein the disintegrant is crystalline cellulose and the content of the disintegrant is 1 to 30 parts by weight with respect to 100 parts by weight of the tablet. (B-3) The water-soluble binder has a viscosity of 2% by weight aqueous solution of 3 mPa · s (20 ° C.) or less and gives a tablet strength of 2.5 N / mm ² or more. Quick disintegrating tablet according to crab.   (B-3) The water-soluble binder is polyvinyl alcohol, The fast disintegrating tablet according to any one of claims 1 to 12. (A-1) a powdery drug having a bitter taste, (a-2) a pharmaceutical carrier that suppresses the aggregation of the drug, and (a-3) a mixture of the drug and the pharmaceutical carrier by fluidized bed granulation. It contains ethanol for granulation or coating or a water-insoluble polymer or wax-like substance soluble in hydrous ethanol, has an apparent specific gravity of 0.1 to 0.5 g / ml, and a circularity of 0.2 to A first granule (A) which is 0.7;
(B-1) At least one granular base component having an average particle size of 10 to 500 μm and selected from sugar, sugar alcohol and amino acid, (b-2) pregelatinized starch, carboxymethyl starch, low substitution degree Consists of at least one disintegrant selected from crystalline cellulose and starches, and does not contain hydroxypropylcellulose and crospovidone, and (b-3) 2% by weight aqueous solution of polyvinyl alcohol having a viscosity of 3 mPa · s (20 ° C.) or less. And (b-3) a second granule (B) in which the content of the water-soluble binder is 0.5 parts by weight or less with respect to 100 parts by weight of the tablet,
A rapidly disintegrating tablet in which the roundness ratio of the first granule (A) and the second granule (B) is 1: 3 to 3: 1 and bitterness is suppressed.   The rapidly disintegrating tablet according to any one of claims 1 to 14, which is an orally disintegrating tablet.   The rapidly disintegrating tablet according to any one of claims 1 to 15, wherein the coefficient of variation of the drug content is 3.5% or less.   The rapidly disintegrating tablet according to any one of claims 1 to 16, wherein the drug is a drug having at least one bitter taste selected from zonisamide, rebamipide, and olmesartan medoxomil.   A tablet mixed with a granule containing at least one granular base component selected from sugar, sugar alcohol and amino acid, a disintegrant, and a water-soluble binder, and tableted with an unpleasant taste of the drug suppressed (A-1) a powdered drug having an unpleasant taste, (a-2) a physiologically acceptable fluidizing agent that suppresses aggregation of the powdered drug, and And (a-3) a granule comprising a carrier for granulating or coating a mixture of the drug and a fluidizing agent.   The fluidizing agent (a-2) is at least one pharmaceutical carrier selected from light anhydrous silicic acid and hydrous silicon dioxide, and the carrier (a-3) is selected from ethyl cellulose, a methacrylic acid copolymer, and a waxy substance. The granule according to claim 18, which is a water-insoluble carrier that is soluble in ethanol or hydrous ethanol.   (A-1) a powdered drug having an unpleasant taste, (a-2) a fluidizing agent that suppresses aggregation of the powdered drug and is physiologically acceptable, and (a-3) the drug A first granule (A) comprising a carrier for granulating or coating a mixture with a fluidizing agent, (b-1) having an average particle size of 10 to 500 μm, and from sugar, sugar alcohol and amino acid Containing at least one selected granular base component, (b-2) a disintegrant having a swelling ratio of 1.3 or less upon water absorption, and (b-3) a water-soluble binder, The pharmaceutical composition containing the 2nd granule (B) whose content of a sex binder is 1 weight part or less with respect to 100 weight part of tablets.   (A-1) a mixture of a powdered drug having an unpleasant taste and (a-2) a fluidizing agent that suppresses aggregation of the powdered drug and is physiologically acceptable (a-3 ) First granules (A) granulated or coated with a simple fluid bed granulator combining a fluid bed dryer and a spray system using a carrier, and (b-1) an average particle diameter of 10 to 500 μm And at least one granular base component selected from sugar, sugar alcohol and amino acid, (b-2) a disintegrant having a swelling rate of 1.3 or less upon water absorption, and (b-3) water-soluble A mixture containing (b-3) a second granule (B) having a water-soluble binder content of 1 part by weight or less with respect to 100 parts by weight of the tablet; A method for producing a disintegrating tablet.