TWI606847B - Tablet disintegrating in oral cavity - Google Patents

Description

Oral disintegration ingot

The present invention relates to an orally disintegrating ingot containing a proton pump inhibitor (hereinafter referred to as PPI) and acetaminosalicylic acid. More specifically, the present invention relates to an orally disintegrating ingot in which the stability of the active ingredient is superior, and the pharmacological effect after administration is stabilized and rapidly manifested.

When a low dose of acetyl salicylic acid is administered for the purpose of inhibiting the formation of thrombus/embolism in diseases of the cerebral blood vessels and circulators (antiplatelet therapy), it may cause gastric ulcer or duodenal ulcer. Since the thrombus/embolization may form if the administration of acetyl salicylic acid is stopped, it is considered that it is important to continue to administer a low dose of acetaminophen while suppressing the onset of ulceration. Further, it is known that acetaminophen salicylic acid is a non-steroidal anti-inflammatory drug (NSAIDs) mainly used for treating pain, fever, and inflammation, but NSAIDs may cause gastric ulcer or duodenal ulcer. In particular, when treating rheumatoid arthritis or osteoarthritis, the quality of life (QOL) is remarkably lowered, and it is difficult to stop the administration of NSAIDs. Therefore, it is considered that it is important to continue to invest in NSAIDs while suppressing the onset of ulcers.

On the other hand, since the PPI of a benzimidazole-based compound such as Lansoprazole or Omeprazole has a strong gastric acid secretion inhibitory action and a gastric mucosal defense effect, it is widely used as a therapeutic agent for peptic ulcer. Wait for use. In particular, lansalazole preparations have been recognized in Japan in recent years as "inhibiting the onset of gastric or duodenal ulcers when low-dose acetaminophen is administered" and "inhibiting the administration of non-steroidal anti-inflammatory drugs". The efficacy of the onset of gastric or duodenal ulcers has been shown to inhibit the clinical effects of gastric ulcer or duodenal ulcer caused by administration of acetaminosalicylic acid.

Patent Document 1 discloses a pharmaceutical composition comprising: (a) a therapeutically effective amount of at least one hydrogen ion pump inhibitor which is unstable to acid; (b) a sufficient amount of at least one buffer agent, Used to raise the pH of gastric juice to prevent acid decomposition of at least several hydrogen ion pump inhibitors in gastric juice; and (c) to treat a therapeutically effective amount of at least one non-steroidal anti-inflammatory drug.

Patent Document 2 discloses a pharmaceutical dosage form for oral administration which contains an acid-sensitive hydrogen ion pump inhibitor, at least one non-steroidal anti-inflammatory drug (NSAID), and a desired pharmaceutically acceptable excipient.

Patent Document 3 discloses a pharmaceutical composition suitable for a unit dosage form for oral administration of a patient, which comprises: (a) after administering one or more of the above unit dosage forms, the pH of the stomach of the patient is at least at least An acid inhibitor present in an effective amount to rise to 3.5; and (b) an effective amount of a non-steroidal anti-inflammatory agent that reduces or eliminates pain or inflammation of the above-mentioned patient after administration of one or more of the above unit dosage forms The above unit dosage form is characterized in that the above NSAID is coordinatedly released after the above acid inhibitor.

Further, PPI or acetaminosalicylic acid such as lansylazole has been commercially available as a single agent, but an orally disintegrating tablet (a mixture of laminated ingots) containing both PPI and acetyl salicylic acid is still unknown.

[Advanced technical literature]

[Patent Literature]

[Patent Document 1] International Publication No. 2005/076987

[Patent Document 2] International Publication No. 97/25064

[Patent Document 3] International Publication No. 2002/098352

It is clinically highly useful to provide a preparation (mixture) containing both PPI and acetyl salicylic acid as an active ingredient. However, it is not easy to put a preparation containing a plurality of active ingredients into a preparation which is composed of a single active ingredient. For example, since the rate of dissolution of the active ingredient from the preparation affects the time-dependent pharmacodynamic profile after administration, it is necessary to adjust the composition of the preparation to make the dissolution rate of the active ingredient optimum. However, in the case of a mixture, it is necessary to optimize the dissolution rate for each active ingredient, and the difficulty in preparation is high. Further, it is also necessary to suppress adverse effects caused by interaction of a plurality of active ingredients contained in the mixture (preservation such as decomposition or activity reduction of the active ingredient over time, reduction in chemical stability, change in dissolution profile of the active ingredient over time, etc.) Reduced dissolution stability, etc.).

In addition, as the population ages and the living environment changes, it is expected to develop an oral cavity that can maintain the handling convenience of the tablet, and that can be easily taken, and can be easily taken at any time and anywhere without water. Intrinsic disintegration.

As a result of intensive studies, the present inventors have found that a laminated orally disintegrating ingot has (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) an acetaminophen containing salicylic acid. a layer, the active ingredient of the orally disintegrating tablet has high stability, and the pharmacological effect of the active ingredient after administration is stable and The performance is quickly performed, thus completing the present invention.

That is, the present invention provides the following: [1] A laminated intraoral disintegrating tablet comprising: (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor; and (2) a layer B [2] The orally disintegrating tablet of the above-mentioned [1], wherein the layer containing the enteric fine particles contains an antacid in a portion other than the enteric fine particles; [3] The orally disintegrating tablet according to the above [2], wherein the antacid is at least one component selected from the group consisting of metal oxides, metal hydroxides, alkaline earth metal carbonates, and aluminum glycinate; [4] The orally disintegrating ingot according to [3] above, wherein the metal oxide is selected from the group consisting of magnesium oxide, magnesium citrate, dried aluminum hydroxide gel, and magnesium aluminometasilicate. [5] The orally disintegrating ingot according to the above [3], wherein the metal hydroxide is selected from the group consisting of magnesium hydroxide, aluminum hydroxide, hydritalcite, aluminum hydroxide and hydrogen. Coprecipitate of magnesium oxide, coprecipitate of aluminum hydroxide with magnesium carbonate and calcium carbonate, and aluminum hydroxide and carbon [6] The orally disintegrating ingot according to the above [3], wherein the alkaline earth metal carbonate is calcium carbonate or magnesium carbonate; [7] as described above [ (2) The orally disintegrating tablet of the present invention, wherein the antacid is a mixture of magnesium carbonate and aluminum sulphate; [8] the orally disintegrating tablet according to [2] above, wherein the antacid content The oral disintegrating tablet according to the above [1], wherein the hydrogen ion pump inhibitor is lansylazole, omeprazole, rabeprazole, The orally disintegrating tablet of the above-mentioned [1], wherein the content of acetyl salicylic acid is about 70 mg per ingot to the oral disintegrating tablet of the above [1]. [11] The orally disintegrating tablet according to the above [1], wherein the layer containing acetaminosalicylic acid contains carboxymethylcellulose; [12] in the oral cavity as described in [1] above. a disintegrating tablet, wherein, in a layer containing enteric fine particles containing a hydrogen ion pump inhibitor, a portion other than the enteric fine particles is selected from the group consisting of crospovidone and aluminum magnesium metasilicate. [13] The orally disintegrating tablet according to the above [1], wherein the layer containing the acetaminosalicylic acid contains a lubricant; [14] as described in the above [13] The orally disintegrating ingot, wherein the lubricant is a hardened oil; [15] the orally disintegrating ingot according to the above [1], which is a two-layer ingot; [16] the orally disintegrating as described in the above [1] Ingot And (1) having an intermediate layer between (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) a layer containing acetamidine salicylic acid; [17] an oral cavity as described in [1] above In the case of the orally disintegrating ingot, the orally disintegrating tablet of the above-mentioned [1] has a tablet weight of about 300 mg to about 800 mg, and (1) contains Enteric solution containing hydrogen ion pump inhibitor The weight ratio of the layer of the fine granules to (2) the layer containing acetamidine salicylic acid is from about 10:1 to about 1:10; [19] The orally disintegrating ingot according to the above [1], which is hitting [20] The orally disintegrating ingot according to the above [1], wherein the disintegration time in the oral cavity is within about 60 seconds; [21] orally disintegrating as described in [1] above. The ingot has a tablet hardness of from about 20 to about 100N.

The orally disintegrating tablet of the present invention contains a PPI having a strong inhibitory effect on acid secretion, and can be used as a prophylactic/therapeutic agent for diseases in the field of cerebrovascular and circulator, such as angina (chronic stability stenosis, Inhibition of thrombosis/embolic formation in myocardial infarction, prevention/therapeutic agent for ischemic cerebrovascular disease (temporary ischemic attack (TIA), cerebral infarction), coronary artery bypass surgery (in coronary artery bypass surgery) CABG) or an inhibitor of thrombus/embolization after percutaneous transluminal coronary angioplasty (PTCA) or a preventive/therapeutic agent for Kawasaki disease (including cardiovascular sequelae caused by Kawasaki disease) The acid can be administered to the orally disintegrating ingot of the present patent application for the purpose of continuing to administer acetyl salicylic acid while treating or inhibiting the onset of gastric ulcer or duodenal ulcer.

In addition, acetaminophen salicylic acid is one of non-steroidal anti-inflammatory drugs (NSAIDs), which can also be used to treat pain, fever, and inflammation. Therefore, it is intended to continue to administer NSAIDs while treating or inhibiting the onset of gastric ulcer or duodenal ulcer. Intraoral disintegration tablets of the present patent application can also be administered.

The orally disintegrating tablet active ingredient of the present invention has high stability and is administered The pharmacological effects of the post-active ingredients will be stable and rapid.

The orally disintegrating tablet of the present invention can be easily taken while ensuring handling convenience, and can be easily taken at any time and anywhere without water.

(Detailed description of the invention)

Hereinafter, the present invention will be described in detail.

The solid preparation of the present invention is formed by combining (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) a layer containing acetaminosalicylic acid, especially a laminated oral cavity. The intrinsic disintegration is characterized.

(1) "Layer containing enteric fine particles containing PPI" (1)-1: About PPI

The PPI is preferably a compound represented by the following formula (I) [hereinafter, also referred to as a compound (I)].

The compound (I) may, for example, be a compound represented by the formula (I), or an optically active substance thereof or a salt thereof: Wherein ring A represents a benzene ring which may have a substituent, R ¹ represents a hydrogen atom, an aralkyl group which may have a substituent, a fluorenyl group or a decyloxy group; and each of R ² , R ³ and R ⁴ may be the same or Different, it represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, or an amine group which may have a substituent, and Y represents a nitrogen atom or CH].

In the above-mentioned compound (I), the "substituent" of the "benzene ring which may have a substituent" represented by the ring A may, for example, be a halogen atom, a cyano group, a nitro group, an alkyl group which may have a substituent, a hydroxyl group, or may have a substitution. The alkoxy group, the aryl group, the aryloxy group, the carboxyl group, the decyl group, the decyloxy group, the 5- to 10-membered heterocyclic group, etc., may be substituted in the benzene ring by about 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. Among these substituents, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, etc. are preferable.

Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Among them, a fluorine atom is preferred.

The "alkyl group" of the "alkyl group which may have a substituent" may, for example, be a C _1-7 alkyl group (e.g., methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, second butyl group, Third butyl, pentyl, hexyl, heptyl, etc.). Examples of the "substituent" of the "alkyl group which may have a substituent" include a halogen atom, a hydroxyl group, a C _1-6 alkoxy group (e.g., a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc.), C. _An alkoxycarbonyl group (e.g., a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, etc.), an aminomethylcarbenyl group, etc., and the number of these substituents may be about 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

The "alkoxy group" of the "alkoxy group which may have a substituent" may, for example, be a C _1-6 alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, or different). Butoxy, pentyloxy, etc.). The "substituent" of the "alkoxy group which may have a substituent" is the same as the "substituent" of the above-mentioned "alkyl group which may have a substituent", and the substitution number of the substituent is also the same.

Examples of the "aryl group" include a C _6-14 aryl group (e.g., a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenyl group, a 2-indenyl group, etc.).

The "aryloxy group" may, for example, be a C _6-14 aryloxy group (for example, a phenyloxy group, a 1-naphthyloxy group or a 2-naphthyloxy group).

Examples of the "fluorenyl group" include a methyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an aminomethyl fluorenyl group, an alkylaminocarbamyl group, an alkylsulfinyl group, an alkylsulfonyl group, and the like.

Examples of the "alkylcarbonyl group" include a C _1-6 alkylcarbonyl group (e.g., an ethyl fluorenyl group, a propyl fluorenyl group, etc.).

The "alkoxycarbonyl group" may, for example, be a C _1-6 alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group or a butoxycarbonyl group).

The "alkylaminocarbamyl group" may, for example, be an NC _1-6 alkylaminocarboxamyl group (e.g., methylaminocarbinyl group, ethylaminomethylmercapto group, etc.), N,N-di-C _{1 -6} alkylaminocarbamyl (e.g., N,N-dimethylaminocarbamimidyl, N,N-diethylaminocarbamyl, etc.), and the like.

The "alkylsulfinyl" group may, for example, be a C _1-7 alkylsulfinyl group (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinonium). Base, etc.).

The "alkylsulfonyl group" may, for example, be a C _1-7 alkylsulfonyl group (for example, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfinyl group or the like).

Examples of the "decyloxy group" include an alkylcarbonyloxy group, an alkoxycarbonyloxy group, an aminomethylcarbonyloxy group, an alkylaminocarbyloxy group, an alkylsulfinyloxy group, and an alkyl group. Alkylsulfonyloxy and the like.

The "alkylcarbonyloxy group" may, for example, be a C _1-6 alkylcarbonyloxy group (e.g., an ethyl fluorenyloxy group or a propyl fluorenyloxy group).

The "alkoxycarbonyloxy group" may, for example, be a C _1-6 alkoxycarbonyloxy group (e.g., a methoxycarbonyloxy group, an ethoxycarbonyloxy group, a propoxycarbonyloxy group, a butoxycarbonyloxy group). and many more.

Examples of the "alkylaminomethylmercaptooxy group" include a C _1-6 alkylaminocarbyloxy group (e.g., a methylaminomethyl decyloxy group, an ethylaminomethyl decyloxy group, etc.). .

The "alkylsulfinyloxy group" may, for example, be a C _1-7 alkylsulfinyloxy group (e.g., methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyl). Alkoxy group, isopropylsulfinyloxy group, etc.).

The "alkylsulfonyloxy group" may, for example, be a C _1-7 alkylsulfonyloxy group (e.g., methylsulfonyloxy group, ethylsulfonyloxy group, propylsulfonyloxy group, or different). Propylsulfonyloxy, etc.).

The "5 to 10 membered heterocyclic group" may, for example, be 5 to 10 members (more preferably, one or more (for example, 1 to 3) hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. a 5- or 6-membered heterocyclic group, and specific examples thereof include 2- or 3-thienyl; 2-, 3- or 4-pyridyl; 2- or 3-furyl; 1-, 2- or 3-pyrrole; 2-; 3-, 3-, 4-, 5- or 8-quinolinyl; 1-, 3-, 4- or 5-isoquinolinyl; 1-, 2- or 3-indenyl and the like. Among them, a 5- or 6-membered heterocyclic group such as a 1-, 2- or 3-pyrrolyl group is preferred.

The ring A is preferably selected from a halogen atom may be, it may be substituted with a halogenated C _1-4 alkyl halogenated C _1-4 alkoxy group and the 5- or 6-membered heterocyclic group of 1 or 2 Base benzene ring.

The "aralkyl group" of the "aralkyl group which may have a substituent" represented by R ¹ may, for example, be a C _7-16 aralkyl group (e.g., a C _6-10 aryl C _1-6 such as a benzyl group or a phenethyl group). Alkyl, etc.). The "substituent" of the "aroyl group which may have a substituent" is exemplified by the same substituent as the "substituent" of the above-mentioned "alkyl group which may have a substituent", and the number of the substituents is about 1 to 4. When the number of the substituents is two or more, the respective substituents may be the same or different.

The "mercapto group" represented by R ¹ may, for example, be a "mercapto group" described as a substituent of the ring A.

The "mercaptooxy group" represented by R ¹ may, for example, be a "mercaptooxy group" described as a substituent of the above ring A.

Preferably, R ¹ is a hydrogen atom.

The "alkyl group which may have a substituent" represented by R ² , R ³ or R ⁴ is exemplified by the "alkyl group which may have a substituent" described as the substituent of the above ring A.

The "alkoxy group which may have a substituent" represented by R ² , R ³ or R ⁴ is exemplified by the "alkoxy group which may have a substituent" described as the substituent of the above ring A.

Examples of the "amino group which may have a substituent" represented by R ² , R ³ or R ⁴ may, for example, be an amine group, a mono-C _1-6 alkylamino group (e.g., a methylamino group, an ethylamino group, etc.), a mono-C. _6-14 arylamino (eg phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C _1-6 alkylamino (eg dimethylamino, diethyl) Amino group, etc.), a di-C _6-14 arylamine group (for example, a diphenylamino group, etc.), and the like.

Desirable R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkoxy group or a di-C _1-6 alkylamino group. More preferably, R ² is a C _1-3 alkyl group or a C _1-3 alkoxy group.

The preferred R ³ is a hydrogen atom, C _1-6 alkoxy -C _1-6 alkoxy, or the halogenated C _1-6 alkoxy group. More preferably, R ³ is a C _1-3 alkoxy group which may be halogenated or substituted with a C _1-3 alkoxy group.

Preferably, R ⁴ is a hydrogen atom or a C _1-6 alkyl group. More preferably, R ⁴ is a hydrogen atom or a C _1-3 alkyl group (especially a hydrogen atom).

Preferably Y is a nitrogen atom.

Preferably, the compound of the formula (I) is a ring A which may have a halogen atom, a halogenated C _1-4 alkoxy group, a halogenated C _1-4 alkoxy group and a 5 or 6 membered heterocyclic group. a benzene ring of a substituent, R ¹ is a hydrogen atom, and R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkoxy group or a di-C _{1 a -6} alkylamino group, R ³ is a hydrogen atom, a C _1-6 alkoxy-C _1-6 alkoxy group or a halogenated C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or C _{1- 6} alkyl, Y is a compound of a nitrogen atom.

In the compound (I), the compound represented by the formula (Ia): [Wherein, R ¹ is a hydrogen atom, R ² is C _1-3 alkyl or a C _1-3 alkoxy group, R ³ is substituted it may be halogenated by a C _1-3 alkoxy group or a C _1-3 alkoxy An oxy group, R ⁴ is a hydrogen atom or a C _1-3 alkyl group, and R ⁵ is a hydrogen atom, a halogenated C _1-3 alkoxy group or a pyrrolyl group (for example, 1-, 2- or 3-pyrrolyl)] .

In the formula (Ia), more preferably R ¹ is a hydrogen atom, R ² is a C _1-3 alkyl group, R ³ is a halogen-substituted C _1-3 alkoxy group, R ⁴ is a hydrogen atom, and R ⁵ is A hydrogen atom or a compound of a C _1-3 alkoxy group which may be halogenated.

Specific examples of the compound (I) include the following compounds.

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]- Sulfhydryl]-1H-benzimidazole, 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-5-A oxy-1H-benzimidazole (omeprazole), 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl -1H-benzimidazole (lapelaprazole) ‧ sodium salt, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfin Base]-1H-benzimidazole (pantoprazole) and the like.

Among these compounds, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H- is preferred. Benzimidazole (lansalazole).

The compound (I) may be a racemate or an optically active substance such as an R-body or an S-body. For example, the compound (I) may also be (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinium sulfonium The optically active substance such as -1H-benzimidazole is preferably the optically active substance.

The salt of the compound (I) or an optically active substance thereof is preferably a pharmaceutically acceptable salt, and examples thereof include a compound (I) or an optically active substance thereof, a salt with an inorganic base, a salt with an organic base, and a basic amino group. Salt of acid, etc.

Preferable examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; and an ammonium salt.

Preferable examples of the salt with an organic base include, for example, an alkylamine (trimethylamine, triethylamine, etc.), a heterocyclic amine (pyridine, methylpyridine, etc.), an alkanolamine (ethanolamine, diethanolamine). , triethanolamine, etc.), dicyclohexylamine, N, N'-diphenylmethylethylenediamine and the like.

Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, and ornithine.

Among these salts, an alkali metal salt or an alkaline earth metal salt is preferred. Especially sodium salts are preferred.

The compound (I) can be produced by a method known per se, for example, according to JP-A-61-50978, US Pat. No. 4,628,098, JP-A-10-195068, and International Publication No. 98/21201. The method is manufactured by the method based on the above.

The optically active substance of the compound (I) may be subjected to an optical separation method (recrystallization method, chiral column method, non-image isomer method, method using microorganisms or enzymes, etc.), asymmetric oxidation, or the like. The method is obtained. For example, when the lansinazole is the R body, the method described in the specification of International Publication No. 00/78745, International Publication No. 01/83473, International Publication No. 01/87874, and International Publication No. 02/44167 can be used. Manufacturing.

The PPI used in the present invention is preferably a benzimidazole compound having an antiulcer effect such as lansilerazole, omeprazole, lapelaprazole, and pantoprazole, and the optically active substance and the like. The pharmaceutically acceptable salt.

(1)-2: About "Enteric-coated fine particles containing PPI"

The "enteric-soluble fine particles containing PPI" means fine particles in which a composition containing PPI is coated with an enteric coating layer and an average particle diameter is about 400 μm or less.

The "coating" is not limited to the case where the surface of the object to be coated (for example, the core) is entirely covered, and the case where the surface is covered or adsorbed or absorbed. The "average particle diameter" means a volume-based median diameter (median particle diameter: a particle diameter corresponding to a cumulative distribution of 50%) unless otherwise specified. Its measuring side For example, a laser diffraction type particle size distribution measuring method can be cited, and a specific example thereof is a method using a laser diffraction type particle size distribution measuring apparatus HEROS RODOS (manufactured by Sympatec Co., Germany).

The "average particle size of a composition containing a PPI coated with an enteric coating layer and having an average particle diameter of about 400 μm or less" is used to prevent a person from feeling rough or uncomfortable in the mouth. It is below about 400 μm. A preferred average particle diameter is from 300 to 400 μm.

When the size of the largest particles is not the average particle diameter of the "fine particles", the particle diameter is substantially 425 μm or less, preferably 400 μm or less. A preferred range is a particle size of substantially 300 to 425 μm, more preferably substantially 300 to 400 μm.

The meaning of "substantially" such as "the particle size is substantially 425 μm or less" and "the particle diameter is substantially 400 μm or less" means that a small amount (about 5% by weight or less) is contained as long as it is inevitably mixed. Particles having a particle size in the above range.

In the present invention, the content of the PPI in the "composition containing PPI" (the composition before coating with the enteric coating layer) is, for example, about 5% by weight or more, preferably about 10 to 50% by weight. More preferably, it is from about 15 to 50% by weight, particularly preferably from about 20 to about 50% by weight.

The content of the PPI in the entire preparation is, for example, about 1% by weight or more, preferably about 1.5% by weight or more and 10.0% by weight or less, more preferably about 2.0% by weight or more and 8.0% by weight or less.

In the above "composition", in order to stabilize the physiologically active substance (PPI) in the preparation, it is preferred to formulate a basic inorganic salt.

The "basic inorganic salt" may, for example, be an alkali inorganic salt of sodium, potassium, magnesium and/or calcium. It is preferably an alkaline inorganic salt of magnesium and/or calcium. More preferably, it is an alkaline inorganic salt of magnesium.

Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogencarbonate and the like.

The basic inorganic salt of potassium may, for example, be potassium carbonate or potassium hydrogencarbonate.

Examples of the basic inorganic salt of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, aluminum magnesium niobate, magnesium niobate, magnesium aluminate, and synthetic hydrotalcite [Mg ₆ Al ₂ (OH) ₁₆ ‧CO ₃ ‧4H ₂ O] and aluminum hydroxide ‧ magnesium [2.5MgO‧Al ₂ O ₃ ‧xH ₂ O], preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, and the like.

Examples of the alkaline inorganic salt of calcium include precipitated calcium carbonate, calcium hydroxide and the like.

The "basic inorganic salt" is more preferably a heavy magnesium carbonate, magnesium carbonate, magnesium oxide or magnesium hydroxide.

The basic inorganic salt such as magnesium or calcium may be any one of a 1% aqueous solution or a suspension having a pH value indicating that it is alkaline (pH 7 or higher).

The basic inorganic salt (preferably an alkaline inorganic salt of magnesium or calcium) may be used singly or in combination of two or more kinds, and the amount of the compound may be appropriately selected depending on the type of the basic inorganic salt. The compounding amount is, for example, about 0.3 to 200% by weight, preferably about 1 to 100% by weight, more preferably about 10 to 50% by weight, most preferably about 20 to 40% by weight, based on the PPI.

The "composition" may also contain a water-soluble polymer, a binder, a lubricant, an excipient, or the like used in a preparation for general production to be described later. The amount added is the amount used in the usual preparation.

Examples of the "water-soluble polymer" include ethanol-soluble water-soluble polymers (for example, cellulose derivatives such as hydroxypropylcellulose (hereinafter also referred to as HPC), polyvinylpyrrolidone, etc.], and ethanol-insoluble water-soluble polymers. [For example, hydroxypropylmethylcellulose (hereinafter also referred to as HPMC), cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, and Guanhua beans Gum (Guar Gum), etc.].

When a water-soluble polymer is used, the dissolution property of the drug (PPI) can be controlled by using an ethanol-soluble water-soluble polymer in combination with an ethanol-insoluble water-soluble polymer or a water-soluble polymer having a different viscosity. .

In the present invention, preferred water-soluble polymers include cellulose derivatives such as HPC, HPMC, and methyl cellulose, and polyvinyl alcohol, and more preferably cellulose derivatives such as HPC and HPMC.

The HPC contains a hydroxypropoxy group, for example, from about 53.4 to 77.5 wt%, preferably from about 60 to 70 wt%. The viscosity of HPC's 2% by weight aqueous solution at 20 ° C is typically from about 1 to 150,000 cps (centipoise). Such HPC is a hydroxypropylcellulose of the Japanese Pharmacopoeia (hereinafter, the viscosity of HPC is a value of a 2% by weight aqueous solution at 20 ° C).

The HPMC is a mixed ether composed of a methoxy group and a hydroxypropoxy group. The content of the methoxy group in the HPMC is, for example, about 19 to 30% by weight, and the content of the hydroxypropoxy group is, for example, about 4 to 12% by weight. The viscosity of a 2% by weight aqueous solution of HPMC at 20 ° C is typically from about 1 to 40,000 centistokes. Such HPMC uses hydroxypropylmethylcellulose 2208 of the Japanese Pharmacopoeia, hydroxypropylmethylcellulose 2906 of the Japanese Pharmacopoeia, and hydroxypropylmethylcellulose 2910 of the Japanese Pharmacopoeia. Hydroxypropyl methylcellulose can make One type may be used in combination of two or more types.

The content of the water-soluble polymer such as HPC and/or HPMC is usually from about 0.1 to 50% by weight, preferably about 0.1 to 50% by weight, in order to control the dissolution of the PPI in the PPI-containing composition and maintain a high content. 1 to 30% by weight.

For example, the "enteric coating layer" coated with the "component containing PPI" may be, for example, cellulose acetate phthalate (CAP) or hydroxypropyl methylcellulose phthalate (hereinafter, described) It is HP-55), hydroxymethyl cellulose acetate succinate, methacrylic acid copolymer [for example, Eudragit L30D-55 (trade name; manufactured by Evonik), Klik Kollicoat MAE 30DP (trade name; manufactured by BASF), Polyquid PA30 (trade name; Sanyo Chemical Co., Ltd.), etc., carboxymethylethylcellulose, shellac, etc. Soluble polymer base; methacrylate copolymer [for example, Utech NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), Eudragit RS30D (trade name), etc. And other sustained release base; water-soluble polymer; triethyl citrate, polyethylene glycol, acetylated monoglyceride, triacetin, castor oil and other plasticizers. These may be used alone or in combination of two or more.

The aqueous enteric polymer base is preferably a methacrylic acid copolymer.

The sustained release base is preferably a methacrylate copolymer, especially a copolymer of ethyl acrylate and methyl methacrylate.

The sustained-release base is used in relation to the aqueous enteric polymer base. The agent is from about 5 to 30% by weight, preferably from about 5 to 15% by weight, based on 100% by weight. The plasticizer is preferably used in an amount of 5 to 30% by weight based on 100% by weight of the aqueous enteric polymer base.

The above "PPI-containing composition" can be produced by a known granulation method.

Examples of the "granulation method" include a rotary granulation method (for example, centrifugal granulation granulation method), a flow granulation method (for example, turbulent flow layer granulation, flow granulation, etc.), a stirring granulation method, and the like. Among them, the flow granulation method is preferred. Better granulation for rotating the flow layer.

Specific examples of the tumbling granulation method include a method using a "CF device" manufactured by Freund et (FREUND). Specific examples of the tumbling flow layer granulation method include, for example, "Multiplex" manufactured by POWREX, and Fuji Paudal. The company's "New Marume" and other methods. The spraying method of the mixed solution can be appropriately selected depending on the type of the granulating device, and may be, for example, any of a top spray method, a bottom spray method, a tangential spray method, and the like. Among them, a tangential spray method is preferred.

The "component containing PPI" can be produced, for example, by coating PPI on a core containing crystalline cellulose and lactose.

For example, the production method (coating method) described in JP-A-H05-092918, etc., for the nucleus containing crystalline cellulose and lactose, and the physiologically active substance which is unstable to acid and, if necessary, an alkaline inorganic salt A method of coating a binder, a lubricant, an excipient, a water-soluble polymer, or the like (hereinafter, simply referred to as a coating layer). For example, physiologically active substances that are unstable to acid and A method in which an alkaline inorganic salt is coated on a core and then coated with a binder, a lubricant, an excipient, a water-soluble polymer, or the like.

The average particle diameter of the "core" may be about 50 to 250 μm, preferably about 100 to 250 μm, more preferably about 100 to 200 μm, as long as it is about 250 μm or less. The core having such an average particle diameter comprises: all passing through a No. 50 (300 μm) sieve, and the particles remaining in the No. 60 (250 μm) sieve are below about 5 w/w% as a whole, and passed through a No. 282 (53 μm) sieve. The particles are particles of about 10 w/w% or less in total. The specific capacity of the "nucleus" is about 5 mL/g or less, preferably about 3 mL/g or less.

The "nucleus" may, for example, be: (1) spherical granulated product of crystalline cellulose and lactose, and (2) spherical granulated product of about 150 to 250 μm of crystalline cellulose (Avicel, manufactured by Asahi Kasei Co., Ltd., Avicel) (SP), (3) a stirred granulated product of about 50 to 250 μm made of lactose (9 parts) and α-starch (1 part), and (4) a microcrystal described in JP-A-61-213201 a processed product such as a fine particle of about 250 μm or less of cellulose spherical particles, (5) a processed product obtained by spray cooling or melt granulation to form a spherical wax, and (6) a gelatinous bead product of an oil component, (7) calcium citrate, (8) starch, (9) chitin, porous particles such as cellulose and chitosan, (10) fine granulated sugar, crystalline lactose, crystalline cellulose or sodium chloride Simple items and processed products of these preparations. Further, the cores can be produced by a known pulverization method or granulation method, and sieved to prepare particles having a desired particle diameter.

The "spherical granulated product of crystalline cellulose and lactose" may, for example, be (i) a spherical granulated product of about 100 to 200 μm made of crystalline cellulose (3 parts) and lactose (7 parts) (for example, the best product (for example) Nonpareil) 105 (70-140) 100 to 200 μm), manufactured by Freuned (FREUND), (ii) spherical granulated product of about 150 to 250 μm made of crystalline cellulose (3 parts) and lactose (7 parts) (for example, the best NP) -7:3, manufactured by Freund Corporation, (iii) spherical granulated product of about 100 to 200 μm made of crystalline cellulose (4.5 parts) and lactose (5.5 parts) (for example, the best product 105T (70-140) (particle size 100 to 200 μm), manufactured by Freund Corporation, etc., (iv) spherical granulated product of about 150 to 250 μm made of crystalline cellulose (5 parts) and lactose (5 parts) (for example, the best) NP-5: 5, manufactured by Freund Corporation).

In order to produce a preparation which maintains an appropriate strength and is also excellent in solubility, the "nucleus" is preferably a spherical granulated product made of crystalline cellulose and lactose, and more preferably, it is composed of crystalline cellulose and lactose. The spherical granulated product contains 50% by weight or more of lactose. It is preferably 40 to 50% by weight of crystalline cellulose and 50 to 60% by weight of lactose.

The core used in the present invention is preferably a spherical granulated product of crystalline cellulose and lactose, more preferably a spherical granulated product of about 100 to 200 μm made of crystalline cellulose (4.5 parts) and lactose (5.5 parts).

The "nucleus" may contain a PPI, but since the release of the PPI can be controlled via a coating layer containing the PPI, the core may not contain the PPI.

The "nucleus" may be in the form of fine particles, and in order to make the difference in the coating smaller, it is preferable to be as uniform as possible.

The ratio of the "coating layer" to the "core" may be selected within a range that can control the dissolution property of the physiologically active substance and the particle size of the composition, for example, usually about 50 to 400 parts by weight with respect to 100 parts by weight of the core. .

The "cladding layer" may be formed of a plurality of layers as long as the coating of the plurality of layers is There is one layer that contains PPI. A combination of a coating layer having no active component constituting the plurality of layer coating layers, a coating layer for a backing layer, and an enteric coating layer can be appropriately selected.

When the core is coated, for example, a PPI and a water-soluble polymer can be used as a mixed liquid. The mixed solution may be a solution or a dispersion, and may be prepared using an organic solvent such as water or ethanol or a mixture thereof.

The concentration of the water-soluble polymer in the mixed solution is maintained in accordance with the ratio of the PPI and the additive, in order to maintain the binding force of the PPI to the core and maintain the viscosity of the mixed solution at the same time. It is about 0.1 to 50% by weight, preferably about 0.5 to 10% by weight.

When the coating layer is formed by a plurality of layers, the blending ratio or viscosity gradient of the water-soluble polymer may be selected, or the mixture of the PPI or other additives may be sequentially coated to make the PPI concentration continuity of each layer or Change in stages. In this case, as long as the entire coating layer contains the water-soluble polymer in an amount of about 0.1 to 50% by weight, it may be coated with a mixed solution in a proportion exceeding the range of about 0.1 to 50% by weight. Further, an inert coating film may be formed by a known method to form a coating layer composed of a plurality of layers so as to block each layer containing PPI.

After drying the above-mentioned coating, a composition having a uniform particle size was obtained through a sieve. The shape of the composition generally corresponds to the core, so that a slightly spherical composition can also be obtained. The sieve can be obtained by using a circular sieve of, for example, No. 50 (300 μm), by picking particles passing through the No. 50 round sieve.

"Enteric-coated fine particles containing PPI" is a composition containing PPI for the purpose of protecting PPI or imparting enteric solubility according to the same granulation method as described above. The article was produced by coating with an enteric coating. Further, it may be further coated with a water-soluble sugar alcohol (preferably mannitol) as needed. When coated with a water-soluble sugar alcohol, the strength of the orally disintegrating ingot containing fine particles can be enhanced.

The enteric coating layer is preferably a layer which is coated with the entire surface of the PPI composition in a thickness of about 20 to 70 μm, preferably about 30 to 50 μm. Therefore, the smaller the particle diameter of the composition, the larger the weight % of the enteric coating layer as a whole of the fine particles. The enteric coating layer in the "enteric soluble fine particles containing PPI" is about 30 to 70% by weight, preferably about 50 to 70% by weight, based on the whole of the fine particles.

The enteric coating layer may be formed of a plurality of layers (for example, 2 to 3 layers). For example, the composition may be coated with an enteric coating layer containing polyethylene glycol, and coated with an enteric coating layer containing triethyl citrate, and further containing polyethylene glycol. A method of coating an enteric coating layer or the like.

(1)-3: About "layer containing enteric fine particles containing PPI"

In the layered orally disintegrating tablet of the present invention, the "layer containing enteric fine particles containing PPI" contains: 1) the PPI-containing composition is coated with an enteric coating layer, and the average particle diameter is about 400 μm. The following fine particles; and 2) additives. The additive is a component contained in a portion other than the enteric fine particles.

The blending amount of "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI" is about 20 to about 100 parts by weight with respect to 100 parts by weight of "layer containing enteric fine particles containing PPI". 80 parts by weight, preferably from about 30 to about 70 parts by weight.

The "additive" can be selected from, for example, an antacid, a water-soluble sugar alcohol, and a knot. Further, one or more of crystalline cellulose and low-substituted hydroxypropyl cellulose may further use a binder, a sour material, a foaming agent, a sweetener, a fragrance, a lubricant, a colorant, and a stabilizer. , excipients, disintegrators, etc.

The orally disintegrating tablet of the present invention preferably contains an antacid in a portion other than the enteric fine particles.

The antacid is preferably at least one selected from the group consisting of metal oxides, metal hydroxides, alkaline earth metal carbonates, and aluminum glycinates (more preferably 1 to 15 types, more preferably 1). Up to 10 types).

The metal oxide is preferably selected from the group consisting of magnesium oxide for medical use, magnesium citrate (2MgO‧3SiO ₂ ‧xH ₂ O), dried aluminum hydroxide gel (Al ₂ O ₃ ‧xH ₂ O), and metafluoric acid At least one group (more preferably 1 to 3 kinds) of aluminum magnesium (Al ₂ O ₃ ‧MgO‧2SiO ₂ ‧xH ₂ O) is grouped.

Among them, it is more preferably magnesium oxide. Magnesium oxide is preferred as a medical user and has excellent acid reactivity and neutralizing power. Such a magnesium oxide can be obtained by a usual production method or a commercial product, but is preferably a so-called light-burned magnesia which is fired at a low temperature. It is usually preferred to fire at a temperature of from about 500 to about 1000 ° C, especially from the viewpoint of neutralization, preferably from about 600 to 900 ° C, preferably from about 800 ° C. . In such magnesium oxide, the BET specific surface area is usually from 10 to 50 m ² /g, preferably from 20 to 50 m ² /g.

Here, the BET specific surface area means a specific surface area measured by a nitrogen gas adsorption method, and includes pores in a range of a predetermined amount of magnesium oxide and a range in which nitrogen gas enters, and the specific surface area is measured by the amount of adsorption of nitrogen.

Magnesium oxide may, for example, be a commercially available heavy magnesium oxide (Concord Chemical Industry) (manufactured by the company), heavy magnesium oxide (manufactured by Tomita Pharmaceutical Co., Ltd.), heavy 30 magnesia (manufactured by Kyowa Chemical Industry Co., Ltd.), light magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.), etc. It is preferably heavy magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.) or the like.

The metal hydroxide is preferably used, for example, from magnesium oxide, aluminum hydroxide, synthetic hydrotalcite (Mg ₆ Al ₂ (OH) ₁₆ CO ₃ ‧4H ₂ O), aluminum hydroxide and magnesium hydroxide. At least one (more preferably 1 to 3) of the precipitate, a coprecipitate of aluminum hydroxide and a mixture of magnesium carbonate and calcium carbonate, and a coprecipitate of aluminum hydroxide and sodium hydrogencarbonate. Among these, magnesium hydroxide is preferred from the viewpoints of disintegration properties and PPI elution properties.

The carbonate of the alkaline earth metal may, for example, be calcium carbonate or magnesium carbonate for medical use. It is preferably magnesium carbonate.

The metal oxide, the metal hydroxide, the alkaline earth metal carbonate, and the aluminum glycinate may be used singly or in combination of two or more (preferably two to three).

The antacid is preferably a mixture of an alkaline earth metal carbonate and an aluminum glycinate, and is preferably a mixture of magnesium carbonate and aluminum glycinate.

In metal oxides and metal hydroxides, the surface of the preparation machine is ground at the time of manufacture to blacken the surface of the tablet in whole or in part, or to cause black spots, black lines, and black spots, and to adhere to the ingot. The time is right. These physical properties are markedly impaired in manufacturability. Therefore, when metal oxides or metal hydroxides having abrasive properties and ruthenium adhesion properties are selected, metal oxides and metal hydroxides having no such properties can be used. Combination of things, or with The additive used in the pharmaceutical product (for example, an excipient, a binder, a disintegrator or the like described later) is subjected to wet or dry granulation together to suppress the polishing action or the adhesion of the crucible.

The antacid can be wet- or dry-granulated by pre-mixing with an additive (for example, an excipient, a binder, etc. described later), and the contact with acetaminosalicylic acid is minimized to contribute to the sulphur The acid is stabilized.

The content of the above antacids varies depending on the ability of each antacid to neutralize gastric acid, but is from 0 mg to about 200 mg, preferably from about 10 mg to about 100 mg, in the orally disintegrating tablet of the present invention.

The antacid is usually formulated in an amount of from 0 to 50 parts by weight, preferably from 10 to 100 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". 40 parts by weight of the formulation.

The above-mentioned "water-soluble sugar alcohol" means that 1 g of sugar alcohol is added to water, and the mixture is vigorously shaken at 30 ° C for 30 seconds for mixing for 30 seconds, and when it is dissolved within about 30 minutes, the required amount of water is less than 30 mL of sugar alcohol. .

Examples of the "water-soluble sugar alcohol" include sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced palatinose, erythritol, and the like. Two or more (preferably 2 to 3) may be used in an appropriate ratio.

The "water-soluble sugar alcohol" is preferably mannitol, xylitol or erythritol, more preferably mannitol or erythritol, and most preferably mannitol. The erythritol is usually produced by using glucose as a raw material, fermented by yeast or the like, and having a particle size of 50 or less. This erythritol is commercially available from a commercial product [manufactured by Nikko Chemical Co., Ltd., etc.].

In order to obtain sufficient formulation strength and sufficient in-oral disintegration, the water-soluble solution is 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". The "sugar alcohol" is usually used in an amount of about 5 to 97 parts by weight, preferably about 10 to 90 parts by weight.

The above "crystalline cellulose" may be obtained by partially depolymerizing and refining α-cellulose. Also, it is also known as microcrystalline cellulose. Specific examples of the crystalline cellulose include Ceolus KG801, Avicel PH101, Avicel PH102, Avicin PH301, Avicin PH302, and Avicin RC-591. (crystalline cellulose ‧ carboxymethyl cellulose sodium) and the like. Preferred examples are the Eurasian KG801, which is called high-formed Avicel. These crystalline celluloses may be used singly or in combination of two or more (preferably two to three). These crystalline celluloses are commercially available from the commercial product [made by Asahi Kasei Co., Ltd.].

The crystalline cellulose is usually used in an amount of about 3 to 50 parts by weight, preferably 100 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". It is preferably from 5 to 40 parts by weight, preferably from about 5 to 20 parts by weight.

The above "low-substituted hydroxypropyl cellulose" means a low-substituted hydroxypropyl group having a hydroxypropoxy group content (hereinafter, also referred to as HPC group content) in the hydroxypropyl cellulose of about 5.0 to 9.9% by weight. Cellulose, among them, particularly means about 5.0 to 7.0% by weight of low-substituted hydroxypropylcellulose and about 7.0 to 9.9% by weight of low-substituted hydroxypropylcellulose and the like.

The low-substituted hydroxypropyl fiber having an HPC group content of about 7.0 to 9.9% The vitamins may, for example, be LH-22, LH-32, and the like, and the like, which are commercially available from Shin-Etsu Chemical Co., Ltd. Further, it can be produced by a method known per se, for example, a method described in Japanese Patent Publication No. Sho 57-53100, or a method based on the above.

The low-substituted hydroxypropylcellulose having an HPC content of about 5.0 to 7.0% may, for example, be LH-23, LH-33, and the like, and the like may be a method known per se, for example, Japanese Patent Publication No. 57 A method described in the publication No. -53100 or a method based on the above.

The particle diameter of the "low-substituted hydroxypropylcellulose having a hydroxypropoxy group content of 5.0 to 7.0% by weight" is, for example, an average particle diameter of about 5 to 60 μm, preferably about 10 to 40 μm.

In such a range, if a large particle size L-HPC (for example, L-HPC having an average particle diameter of about 26 to 40 μm) is used, a formulation having excellent disintegration properties can be produced. On the other hand, if L-HPC having a small particle diameter (for example, L-HPC having an average particle diameter of about 10 to 25 μm) is used, a preparation excellent in the strength of the preparation can be produced.

Therefore, the particle diameter of L-HPC can be appropriately selected depending on the characteristics of the preparation for the purpose.

The low-substituted hydroxypropylcellulose having a HPC group content of 5.0 to 7.0% by weight and the HPC group content of 7.0 to 9.9%, in order to obtain sufficient oral disintegration and sufficient The strength of the preparation is usually from 0 to 50 parts by weight, preferably from 100 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". 0 to about 40 parts by weight, more preferably From 0 to about 20 parts by weight is used.

Examples of the above-mentioned "adhesive" include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, gelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, and pullulan. Low substitution hydroxypropyl cellulose and the like. When the binder is a crystalline cellulose, a solid preparation having a stronger preparation can be obtained while maintaining excellent disintegration in the oral cavity.

Examples of the above "acidulant" include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.

Examples of the "foaming agent" include an alkali metal carbonate (for example, sodium carbonate or potassium carbonate), an alkali metal hydrogencarbonate (for example, sodium hydrogencarbonate or potassium hydrogencarbonate), and ammonium carbonate.

Examples of the above-mentioned "population sweetener" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

The above-mentioned "fragrance" may be any of a composition and a natural product, and examples thereof include lemon, lime, orange, mint, strawberry, and the like.

Examples of the "lubricant" include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, and hardened oil.

Examples of the "coloring agent" include food coloring agents such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake coloring matter, iron oxide red, and the like.

Examples of the above-mentioned "stabilizing agent" include the above-mentioned basic inorganic salts and the like.

Examples of the "excipient" include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous citric acid, titanium oxide, and the like.

The above-mentioned "disintegrant" may be a disintegrator which is conventionally used in the field of preparation, and examples thereof include (1) crospovidone (for example, crospovidone CL-F) and (2) croscarmellose. Sodium (made by FMC-Asahi Kasei Co., Ltd.), carboxymethylcellulose calcium (manufactured by Wude Pharmaceutical Co., Ltd.), etc. is called a disintegrant of super disintegrant, and (3) sodium carboxymethyl starch (for example, Songgu Chemical Co., Ltd.) (manufacturing), (4) low-substituted hydroxypropyl cellulose (for example, manufactured by Shin-Etsu Chemical Co., Ltd.), (5) corn starch, (6) aluminum magnesium metasilicate (such as neusilin UFL2), and the like. More preferred disintegrants are, for example, crospovidone and/or aluminum magnesium metasilicate.

The "cross-linked povidone" also includes a polyvinyl polypyrrolidone (PVPP), 1-vinyl-2-pyrrolidone homopolymer, which may have a 1-vinyl-2 Any one of the chemical names of the pyrrolidone homopolymer and the crosslinked polymer, and specific examples thereof are Kollidon CL (manufactured by BASF Corporation), polyplasdone XL (manufactured by ISP), and poly Waxone XL-10 (manufactured by ISP), povidone INF-10 (manufactured by ISP), and the like. Usually the molecular weight exceeds 1,000,000.

These disintegrators may be used alone or in combination of two or more. For example, crospovidone may be used alone or crospovidone may be used in combination with other disintegrants.

The disintegrating agent is usually used in an amount of from about 3 to about 20 parts by weight, based on 100 parts by weight of the component other than "the enteric fine particles containing PPI" in the "layer containing enteric fine particles containing PPI". About 5 to about 18 parts by weight are used.

The "enteric soluble fine particles containing PPI" in the present invention may contain, for example, titanium oxide or the like as a concealing agent.

In the invention of the present application, a preferred embodiment of the "layer containing enteric fine particles containing PPI" is a fine particle containing 1) a composition containing PPI coated with an enteric coating layer (preferably A fine particle having an average particle diameter of about 400 μm or less), 2) a layer containing an acid generator and 3) the above additive in a portion other than the enteric fine particles.

In particular, it contains 1) fine particles (preferably fine particles having an average particle diameter of about 400 μm or less) coated with an enteric coating layer, and 2) contained in a portion other than the enteric fine particles. The antacid and the granulated product of the additive (i), and 3) a layer containing the additive (ii) in the portion other than the enteric fine particle and the granulated product.

Additives (i) and (ii) may be derived from the above-mentioned water-soluble sugar alcohols, crystalline cellulose, low-substituted hydroxypropyl cellulose, binders, sour materials, foaming agents, bulk sweeteners, perfumes, lubricants A colorant, a stabilizer, an excipient, a disintegrator or the like is appropriately selected.

Among them, the additive (i) is preferably a water-soluble sugar alcohol such as mannitol, an excipient such as crystalline cellulose, or a binder such as hydroxypropylcellulose.

The additive (ii) is preferably a disintegrant such as crospovidone or aluminum magnesium metasilicate; an excipient such as crystalline cellulose; a lubricant such as magnesium stearate or the like.

(2) "Layer containing acetyl salicylic acid"

The "layer containing acetamidine salicylic acid" in the laminated orally disintegrating tablet of the present invention contains: 1) acetamidine salicylic acid and 2) an additive.

The content of acetyl salicylic acid is from about 70 to about 400 mg per ingot. Regarding the content of acetyl salicylic acid per ingot, for non-steroidal anti-inflammatory drugs (NSAIDs), mainly for the purpose of treating pain, fever, inflammation, about 250 Up to about 400mg.

On the other hand, when it is intended to suppress thrombus/embolization (anti-platelet therapy) in diseases such as cerebral blood vessels and circulators, about 70 mg to about 120 mg is formulated.

The aforementioned "additives" are the above-mentioned water-soluble sugar alcohols, crystalline cellulose, low-substituted hydroxypropyl cellulose, binders, sour materials, foaming agents, pops, flavors, lubricants, colorants, and stability. As the agent, excipient or the like, it is preferred to use a water-soluble sugar alcohol, a sour material, a sweetener, a lubricant, an excipient or the like. In addition, carboxymethylcellulose (carmellose), croscarmellose sodium, crystalline cellulose, gelatinized starch, gelatin and other disintegrants or light anhydrous citric acid, aqueous cerium oxide, talcum powder may also be used. , liquefied agent such as stearic acid.

Among the above components, the water-soluble sugar alcohol may, for example, be mannitol, xylitol or erythritol, and more preferably mannitol.

The water-soluble sugar alcohol is formulated in an amount of from about 10 to about 100 parts by weight, preferably from about 25 to about 85 parts by weight, per 100 parts by weight of the "layer containing acetamidine salicylic acid".

From the viewpoint of suppressing the barging barrier, the lubricant is preferably a hardened oil. In particular, when magnesium stearate or the like is used as a lubricant, the stability of acetyl salicylic acid is lowered, and tableting failure occurs.

The lubricant is formulated in an amount of from about 0.5 to about 10 parts by weight, preferably from about 0.5 to about 7 parts by weight, per 100 parts by weight of the "layer containing acetamidine salicylic acid".

From the viewpoint of improving the stability of acetaminophen salicylic acid, the disintegrant is preferably Carmellose was used.

The disintegrant is formulated in an amount of from about 1 to about 20 parts by weight, preferably from about 5 to about 15 parts by weight, per 100 parts by weight of the "layer containing acetamidine salicylic acid".

Acetyl salicylic acid and additives may be mixed as they are, or may be premixed with acetaminosalicylic acid and excipients (for example, acetyl salicylic acid: corn starch = 90:10, dry granulated product). Mix well with other additives.

The acetaminosalicylic acid used in the orally disintegrating tablet of the present invention is preferably coated without enteric coating.

(3) laminated intraoral disintegration ingot

The tablet of the laminar orally disintegrating tablet has a weight of from about 300 mg to about 800 mg. The weight ratio of "layer containing enteric fine particles containing PPI" to "layer containing acetamidine salicylic acid" is from about 10:1 to about 1:10, preferably from about 5:1 to about 1:5. More preferably from about 3:1 to about 1:3 is preferred.

The "intraoral disintegration tablet" of the present invention is produced by a method conventionally used in the field of preparation.

[Manufacturing Method 1]

The composition for "construction of a layer containing enteric fine particles containing PPI" can be produced, for example, by mixing "insoluble fine particles containing PPI" and "additive" according to a known method. 1).

The composition for constructing the "layer containing acetamidine salicylic acid" can be mixed with the "additive" according to a method known per se, and can be passed as it is or as desired. a known method for granulation, And manufactured (composition 2).

A laminated intraoral disintegrating ingot can be produced by ingoting the composition 1 and the composition 2 by a known ingot method.

[Manufacturing Method 2]

In the "layer containing enteric fine particles containing PPI", when the acid agent is prepared in the "additive", the additives such as 1) antacid and 2) excipients, binders, disintegrators, etc. may be temporarily suspended. After mixing, granulation is carried out by a method such as a fluidized bed granulation method or a high-speed stirring granulation method, and dried as desired to produce fine particles (composition 3).

By mixing the composition 3, "the enteric fine particles containing PPI", and other additives (disintegrant, bulk sweetener, excipient, lubricant, etc.), it is manufactured to construct "the intestine containing the PPI. By laminating the composition of the layer of the soluble fine particles together with the above composition 2, a laminated orally disintegrating ingot can be produced.

The "mixing" is carried out according to a commonly used mixing method such as mixing, blending, granulation, and the like. The "mixing" is, for example, a vertical granulator VG10 (manufactured by Parek Corporation), a universal machine (manufactured by 畑铁工工), a fluidized layer granulator LAB-1, FD-3A ( It is carried out by a device such as a Parec company, a V-type mixer, and a tumbler mixer.

Examples of the "granulation method" in the above production method include a tumbling granulation method (for example, centrifugal granulation granulation method), a flow granulation method (for example, turbulent flow layer granulation, flow granulation, etc.), a stirring granulation method, and the like. Among them, the flow granulation method is preferred. Better granulation for rotating the flow layer.

Specific examples of the tumbling granulation method include, for example, the use of Freund The method of "CF device" manufactured by the company. Specific examples of the tumbling flow layer granulation method include, for example, "spiraflow", "multiplex" manufactured by Parek, and "Xinma" manufactured by Fujita. Ways such as New Marume. The spraying method of the mixed solution can be appropriately selected depending on the type of the granulating device, and may be any one of a top spray method, a bottom spray method, a tangential spray method, and the like. Among them, a tangential spray method is preferred.

"Ingot" is a single-shot tablet machine (manufactured by Kikusui Seisakusho Co., Ltd.), a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.), a rotary laminating ingot machine (manufactured by Nippon Iron Works Co., Ltd.), etc., at 1 to 80 kN/cm ^{2 .} , a pressure of 5 to 50kN / cm ^2, the pressure is preferably tableted 15 to 40kN / cm ² of. Further, in the case of a rotary type ingot machine, it is only necessary to perform ingot casting at a normal number of rotations, for example, 3 to 40 min ^-1 , preferably 3 to 30 min ^-1 , more preferably 5 to 25 min ^-1 .

In the form of the orally disintegrating ingot of the present invention, from the viewpoint of the strength of the tablet, the ingot surface has a curved surface, and a part thereof may have a flat surface.

"Drying" can be carried out by any of the methods usually used for drying, such as vacuum drying, fluidized bed drying, and the like. Drying is preferably carried out by vacuum drying.

The tableting method of the orally disintegrating tablet of the present invention can be carried out at room temperature, or can be carried out at a temperature exceeding room temperature. "Room temperature" means the room temperature at which the tableting is usually carried out at the time of manufacture of the tablet, and the temperature is usually from about 20 ° C to about 23 ° C. The "temperature exceeding room temperature" is a temperature exceeding the temperature, and preferably the lower limit is about 25 °C. The temperature varies depending on the raw material powder or fine particles used, but is usually preferably from about 25 ° C to about 50 ° C. The warm It is changed according to the quality of the desired tablet.

The orally disintegrating tablet of the present invention is preferably a double-layer ingot having "a layer containing enteric fine particles containing PPI" and "a layer containing acetyl salicylic acid", and "containing enteric fines containing PPI" There may be an intermediate layer between the "layer of particles" and the "layer containing acetamidine salicylic acid".

Through the intermediate layer, the stability of PPI and acetyl salicylic acid can be further improved by blocking the direct contact between "a layer containing enteric fine particles containing PPI" and "a layer containing acetamidine salicylic acid". .

The material for the above intermediate layer may, for example, be a low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (for example, TC-5, etc.), polyvinylpyrrolidone, or polyvinyl alcohol. , such as methyl cellulose, hydroxyethyl methyl cellulose and other polymer substrates, sucrose (refined white sugar (powdered sugar) or unsmashed), corn starch, starch sugar, lactose, etc. Honey and sugar alcohol (D-mannitol, erythritol, etc.) and other sugars. Further, as the intermediate layer, an excipient (for example, a concealing agent (titanium oxide or the like), an antistatic agent (titanium oxide, talc, etc.)) or the like may be appropriately added as necessary.

The amount of the intermediate layer in the tablet is usually from about 5 parts by weight to about 50 parts by weight, preferably from about 10 to about 45 parts by weight, per tablet.

The formation of the intermediate layer can be carried out according to the usual method.

Further, the intermediate layer may be not only one layer but also a plurality of layers (preferably 2 to 3 layers).

In the "oral disintegration tablet" of the present invention, the diameter of the tablet is preferably about 5 to 20 mm, preferably about 7 to 15 mm, more preferably about 8 to 13 mm, which is advantageous for the treatment.

The "oral disintegration tablet" of the present invention exhibits rapid disintegration or solubility in the oral cavity, and an appropriate formulation strength.

The intraoral disintegration time of the orally disintegrating tablet of the present invention (the time from the use of saliva in healthy adult males and female oral cavities until the disintegrating ingot in the oral cavity completely disintegrates) is within about 60 seconds, usually at about 50 Within seconds, preferably within about 40 seconds.

Further, the disintegration time of the orally disintegrating tablet of the present invention (using the disintegration test device described in the Pharmacopoeia, using water as a test solution, the liquid temperature is 37 ± 2 ° C, and the disintegration test is carried out until the orally disintegrating ingot The time until complete disintegration is within about 90 seconds, preferably within about 60 seconds, more preferably within about 50 seconds.

Further, the orally disintegrating tablet of the present invention has an appropriate hardness to such an extent that it is not damaged during the formulation step and the circulation, and the strength of the orally disintegrating tablet (the value measured by the tablet hardness meter) is usually about 20 to About 100N, more preferably from about 30 to about 90N.

The orally disintegrating tablet of the present invention may be used without water or with water. The method of administration may be exemplified by: (1) a method of taking it in the mouth without swallowing it, using a small amount of water or not using water to dissolve or disintegrate it in the oral cavity; or (2) swallowing it with water. How to take it. Further, the tablet may be dissolved or disintegrated in water and then taken.

Since the orally disintegrating tablet of the present invention contains PPI, it has an excellent anti-ulcer effect, inhibits gastric acid secretion, protects mucosa, and acts against Helicobacter pylori.

On the other hand, the orally disintegrating tablet of the present invention contains Ethylhydrazine Acid, it can be used as a disease inhibiting the formation of cerebrovascular and circulatory diseases, such as angina (chronic stability angina, restless angina), thrombosis / embolism in myocardial infarction; prevention / treatment of ischemic Cerebrovascular disorder (temporary ischemic attack (TIA), cerebral infarction); inhibition of thrombus/embolization after coronary artery bypass surgery (CABG) or percutaneous transluminal coronary angioplasty (PTCA); Kawasaki disease (including Use of preventive/therapeutic agents for cardiovascular sequelae caused by Kawasaki disease. Therefore, the orally disintegrating ingot of the present patent application can be administered for the purpose of continuing to administer acetaminosaliside while treating or inhibiting the onset of gastric ulcer or duodenal ulcer. For the purpose of preventing/treating a related disease, PPI is administered from about 10 mg to about 40 mg per day, and acetaminosalicylic acid is administered from about 70 mg to about 120 mg per day (low dose).

In addition, acetaminophen can also be used as a non-steroidal anti-inflammatory drug (NSAIDs) for the treatment of pain, fever, and inflammation. Since NSAIDs cause gastric ulcer or duodenal ulcer, especially when treating rheumatoid arthritis or deformed arthritis, QOL is lowered, so it is difficult to stop the administration of NSAIDs. In such cases, the orally disintegrating ingot of the present invention can be administered for the purpose of continuing to administer NSAIDs while treating or inhibiting the onset of gastric ulcer or duodenal ulcer.

For the purpose of such treatment, PPI is administered from about 10 mg to about 40 mg per day, and acetaminosalicylic acid is administered from about 240 mg to about 400 mg per day.

Therefore, the orally disintegrating ingot of the present invention can be used as a combination of PPI and acetaminosalicylic acid which are low in toxicity and safe.

For the orally disintegrating ingot of the present invention, for mammals (for example, humans, monkeys, sheep, horses, dogs, cats, rabbits, rats, mice) Etc., for the purpose of inhibiting the formation of thrombus/embolism in diseases in the field of cerebral blood vessels and circulators, and treating and preventing ulcers caused by non-steroidal anti-inflammatory agents, for oral administration.

Further, in addition to the above object, in order to sterilize or assist in sterilization of H. pylori, the orally disintegrating ingot of the present invention may be combined with penicillin-based antibiotics (for example, amoxicillin) and erythromycin-based antibiotics ( For example, clarithromycin is used in combination.

The dose of the solid preparation of the present invention for one day is not particularly limited depending on the degree of symptoms, the age, sex, body weight, administration period, interval, and type of active ingredient of the subject to be administered. Further, the orally disintegrating tablet of the present invention can be administered once a day or divided into two to three times.

[Examples]

Hereinafter, the present invention will be described in more detail based on Reference Examples, Examples, and Evaluations (Test Examples), but the present invention is not limited to the examples. Hereinafter, the formulation additives used in the reference examples and the examples are suitable for the Pharmacopoeia Applicables/Pharmaceutical Additives.

Reference example 1 Manufacture of lansprazole enteric fine granules Main drug fine

39.6 kg of nonpareil 105 (trade name) was placed in a rotary flow layer type coating granulator (manufactured by Parek, MP-400), and a pre-mixed main drug coating liquid of the following composition was sprayed. Coating. Pre-modulation The intermediate layer coating liquid of the following composition was spray-coated. After the coating was completed, it was dried to obtain 145.2 kg of main drug fine particles.

[main drug coating solution]

[Intermediate layer coating solution]

Lansalazole enteric fine granule

44.0 kg of the main drug fine particles were placed in a tumbling flow layer type coating granulator (manufactured by Parek, MP-400), and the enteric coating liquid 1 having the following composition prepared in advance was spray-coated. Next, the enteric coating liquid 2 of the following composition prepared previously was spray-coated. A pre-modulated overcoating solution was also spray coated. After coating is completed, drying is performed to obtain Lansalazole enteric fine particles 108kg.

[monostearic acid glycerin solution]

[Enteric coating liquid 1]

[Enteric coating liquid 2]

[Protective coating liquid]

Example 1

Weighing the yttrium salicylic acid premix (Ethyl salicylic acid: corn starch = 90:10, dry granulation, Rhoine 2312 by Rhodia) 1080g, mannitol (Pearlitol 200SD manufactured by Roquette Co., Ltd.) 924 g, 240 g of carboxymethylcellulose, 21.6 g of anhydrous citric acid, 24.0 g of aspartame, and 110.4 g of hardened oil were mixed as pellet A. 88.0 g of aluminum glycinate, 176.0 g of magnesium carbonate, 403.3 g of mannitol (Pearlitol 200SD manufactured by Rockford), and 47.7 g of crystalline cellulose were weighed in a fluidized bed dryer (LAB-1 manufactured by Parek). A solution of 540.8 g of a 5% hydroxypropylcellulose (HPC-L) solution was sprayed and granulated. It is then dried to obtain granules. Further, the particles obtained by the same operation in the same manner were mixed with the previously produced particles as the particles B. Weighing granule B 1113.0g, lansinazole, enteric fine granules 1620g, 179.4 g of videtone, 32.4 g of aspartame, 259.2 g of crystalline cellulose (Coordination KG-1000 manufactured by Asahi Kasei Co., Ltd.), and 66.0 g of Neusilin (trade name, manufactured by Fuji Chemical Co., Ltd.) 30.0 g of magnesium stearate was mixed and made into pellet C. The pellet A and the pellet C were subjected to tableting using a tableting machine (Piccola manufactured by RIVA Co., Ltd.) at a spindle pressure of 11 kN to obtain a laminated ingot having a diameter of 11 mm (formulation 1). The composition of each of the preparations 1 was shown in Table 1.

Example 2

Weighing the yttrium salicylic acid premix (Ethyl salicylic acid: corn starch = 90:10, dry granulated product, Rodi 2312 manufactured by Rodia) 1800g, mannitol (Pearlitol manufactured by Rockdale) 200 SD) 1540 g, 400 g of carboxymethylcellulose, 36.0 g of anhydrous citric acid, 40.0 g of aspartame, and 184.0 g of hardened oil were mixed as pellet D. 604.9 g of mannitol (Pearlitol 200SD manufactured by Rockford) and 71.5 g of crystalline cellulose were weighed in a fluidized bed dryer (MP-01 manufactured by Parek), and 5% hydroxypropylcellulose solution 811.2 g spray, granulation. It is then dried to obtain granule E. Weighing granules E 298.9 g, lansylazole enteric fine 675 g, crospovidone 74.75 g, aspartame 13.52 g, crystalline cellulose 108 g (Asahi Kasei Co., Ltd. Kia-KG-1000) 27.48 g of Nixil (manufactured by Fuji Chemical Co., Ltd., trade name) and 12.5 g of magnesium stearate were mixed and used as pellet F. The pellets D and the pellets F were tableted by a tableting machine (Piccola manufactured by RIVA Co., Ltd.) at a tableting pressure of 15 kN to obtain a laminated ingot having a diameter of 11 mm (formulation 2). The composition of each of the preparations 2 was shown in Table 2.

Example 3

Weighing the yttrium salicylic acid premix (acetonitrile salicylic acid: corn starch = 90:10, dry granulated product, Rodi 2312 manufactured by Rodia) 900 g, mannitol (Pearlitol manufactured by Rockdale) 200 SD) 760 g, carboxymethylcellulose 200 g, anhydrous citric acid 17.93 g, aspartame 20.0 g, light anhydrous citric acid 10.0 g, and hardened oil 91.99 g were mixed as granule G. 550.3 g of aluminum glycinate, 1100.2 g of magnesium carbonate, 2545.5 g of mannitol (Pearlitol 200SD manufactured by Rockford), and 298.0 g of crystalline cellulose were used in a fluidized bed dryer (FLO-5M manufactured by Freund Corporation). After weighing, 2414 g of a 7% hydroxypropylcellulose solution was sprayed and granulated. It is then dried to obtain granules. Further, the particles obtained by the same operation in the same manner were mixed with the previously produced particles as the particles H. Weighing 109 H of granule H, 2025.2 g of lansile-carbazole enteric-coated fine granules, 224.3 g of crospovidone, 40.5 g of aspartame, and 323.8 g of crystalline cellulose (Co-Olas KG-1000 manufactured by Asahi Kasei Corporation) ), button Xilin (manufactured by Fuji Chemical Co., Ltd., trade name) 82.5 g, magnesium stearate 37.5 g, and mixed as pellet I. The pellets G and pellets I were tableted using a tableting machine (Piccola manufactured by RIVA Co., Ltd.) at a tableting pressure of 8.6 kN to obtain a laminated ingot having a diameter of 10 mm (formulation 3). The composition of the preparation 3 per ingot is shown in Table 3.

Example 4

Weighed 1214.6 g of acetyl salicylic acid, 135.0 g of corn starch, 1140.2 g of mannitol (Pearlitol 200SD manufactured by Rockford), 300.0 g of carboxymethylcellulose, 27.0 g of anhydrous citric acid, and 30.0 g of aspartame. 14.93 g of light anhydrous citric acid and 138.2 g of hardened oil were mixed and used as granule J. The pellet J and the pellet I described above were tableted at a tableting pressure of 10 kN using a tableting machine (Piccola manufactured by RIVA Co., Ltd.) to obtain a laminated ingot (formulation 4) having a diameter of 10.5 mm (shape: two-stage R). The composition of the preparation 4 per ingot is shown in Table 4.

Example 5

Weighing the yttrium salicylic acid premix (acetonitrile salicylic acid: corn starch = 90:10, dry granulated product, Rodi 2312 manufactured by Rodia), 3,500 g, mannitol (Pearlitol, manufactured by Rockdale) 200SD) 28820g, carboxymethyl cellulose 7000g, anhydrous citric acid 630g, aspartame 700g, light anhydrous citric acid (Oxygen cerium oxide manufactured by Aerosil Co., Ltd.) 350g, hardened 1400 g of oil was mixed with a tumbler mixer as pellet K. 4840 g of aluminum glycinate, 9680 g of magnesium carbonate, 22180 g of mannitol (Pearlitol 200SD manufactured by Rockford), 2622 g of crystalline cellulose (Co-Olas PH-101 manufactured by Asahi Kasei Co., Ltd.), crospovidone 6576 g, 1188g of spartan, 9504g of crystalline cellulose (Co-Olas KG-1000 manufactured by Asahi Kasei Co., Ltd.), 2420g of Nisshin (manufactured by Fuji Chemical Co., Ltd.) in a fluidized layer dryer (WSG-60 manufactured by Parek) In the middle of the scale, 24,785 g of a 6% hydroxypropylcellulose solution was sprayed and granulated. It is then dried to obtain particles L. After the pellet L was granulated using a power mill, 34,380 g of the pellet L was weighed and mixed with lansalazole enteric fine granules 33,725 g and magnesium stearate 625 g together as a pellet M. The pellets K and the pellets M were subjected to tableting using a tableting machine (HT-CVX54LS-UW/C&3L manufactured by Nippon Steel Co., Ltd.) at a spindle pressure of 11 Kn to obtain a laminated ingot having a diameter of 10.5 mm. The laminated ingot was vacuum dried to obtain Formulation 5. The composition of the preparation 5 per ingot is shown in Table 5.

Evaluation Test example 1

The tablets obtained in Example 1 and Example 5 were placed in a desiccant, and they were tightly sealed, and after 1 month at 40 ° C, the content of acetaminosalicylic acid in the preparation was quantified by high-speed liquid chromatography. From the quantified value, the residual ratio of acetaminophenic acid was calculated as % (= the content of acetaminolic acid after the passage / the content of the initial hydrazine salicylic acid × 100). The residual rate of the acetaminophen acid was 95% or more and 100% or less was ○, and 90% or more and 95% was Δ, and less than 90% was ×. The results of the evaluation are shown in Table 6.

Test example 2

The intraoral disintegration time of the tablets obtained in Example 1 and Example 5 was measured. Further, the intraoral disintegration time refers to the time (n=2 of the average value) after the tablet is contained in the mouth of a healthy normal person, and the tooth is not bitten until dissolved. The results are shown in Table 7.

Test Example 3

Using a tablet measuring device (manufactured by Pharmatest), measurement was carried out Example 1, the tablet obtained in Example 5, the initial tablet hardness. The test was carried out 5 times for Example 1, and 10 times for Example 5, and the average value thereof is shown in Table 8.

[Possibility of industrial use]

The orally disintegrating tablet according to the present invention contains a PPI having a strong inhibitory effect on acid secretion and an acetyl salicylic acid belonging to one of NSAIDs, and is used for treating or inhibiting the onset of gastric ulcer or duodenal ulcer in order to continue administering NSAIDs. At the time, it can be administered. Further, the orally disintegrating tablet active ingredient of the present invention has high stability, and the pharmacological effect of the active ingredient after administration is stable and rapid. Further, the orally disintegrating tablet of the present invention also has the convenience of being easily taken at any time and anywhere at any time in the absence of water.

In the above, a plurality of specific aspects of the present invention will be described in detail, but as long as it is a person having ordinary knowledge in the technical field of the present invention, the specific aspects shown can be substantially eliminated from the teachings and advantages of the present invention. Various modifications and changes are made to the scope of the scope. Therefore, these modifications and variations are intended to be included within the spirit and scope of the invention as claimed.

Claims (16)

A laminated intraoral disintegrating tablet comprising: (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor; and (2) a layer containing acetaminophen salicylic acid; The enteric fine particle of the agent is a fine particle containing a composition of a hydrogen ion pump inhibitor coated with an enteric coating layer, and the hydrogen ion pump inhibitor is lansile or its optically active substance or Is a salt thereof, and in the layer containing the enteric fine particles, an acid generator is contained in a portion other than the enteric fine particles, and the content of the acid generator is from about 10 mg to about 100 mg, and the orally disintegrating ingot is in the oral cavity. The time for disintegration is within about 60 seconds, and the hardness of the orally disintegrating ingot is from about 20 to about 100N. The orally disintegrating tablet according to claim 1, wherein the antacid is at least one selected from the group consisting of metal oxides, metal hydroxides, alkaline earth metal carbonates, and aluminum glycinate. ingredient. The orally disintegrating tablet of claim 2, wherein the metal oxide is selected from the group consisting of magnesium oxide, magnesium citrate, dried aluminum hydroxide gel, and magnesium aluminometasilicate. At least one of the groups. The orally disintegrating ingot according to claim 2, wherein the metal hydroxide is selected from the group consisting of magnesium hydroxide, aluminum hydroxide, synthetic hydrotalcite, coprecipitate of aluminum hydroxide and magnesium hydroxide, and hydrogen. Alumina and At least one of a coprecipitate of magnesium carbonate and calcium carbonate, and a coprecipitate of aluminum hydroxide and sodium hydrogencarbonate. The orally disintegrating ingot according to claim 2, wherein the alkaline earth metal carbonate is calcium carbonate or magnesium carbonate. The orally disintegrating ingot according to claim 1, wherein the antacid is a mixture of magnesium carbonate and aluminum glycinate. The orally disintegrating tablet of claim 1, wherein the content of acetaminosalicylic acid is from about 70 mg to about 120 mg per ingot. The orally disintegrating tablet according to claim 1, wherein the layer containing acetaminosalicylic acid contains carboxymethylcellulose. The orally disintegrating ingot according to claim 1, which is contained in a layer containing enteric fine particles containing a hydrogen ion pump inhibitor, and is selected from the group consisting of cross-linked polycondensation in a portion other than the enteric fine particles. At least one disintegrant of ketene and aluminum magnesium metasilicate. The orally disintegrating ingot according to claim 1, which contains a lubricant in a layer containing acetyl salicylic acid. The orally disintegrating ingot according to claim 10, wherein the lubricant is a hardened oil. The orally disintegrating ingot according to claim 1, which is a two-layer ingot. The orally disintegrating ingot according to claim 1, which is characterized in that (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) a layer containing acetaminosalicylic acid. Between, with an intermediate layer. The orally disintegrating ingot according to claim 1, wherein Acetylsalicylic acid is not enteric coated. The orally disintegrating tablet according to claim 1, wherein the tablet has a weight of about 300 mg to about 800 mg, and (1) a layer containing enteric fine particles containing a hydrogen ion pump inhibitor and (2) The weight ratio of the layer containing acetyl salicylic acid is from about 10:1 to about 1:10. The orally disintegrating ingot according to claim 1, which has a curved surface on the ingot surface.