JP2016141630A - Orally disintegrating tablets - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide orally disintegrating tablets which can reduce the odor and bitter taste derived from olmesartan medoxomil.SOLUTION: An orally disintegrating tablet containing a fine granule having a nuclear containing an active pharmaceutical ingredient containing olmesartan medoxomil in the center, as well as a barrier layer containing at least one kind selected from polyvinyl alcohol and vinyl alcohol copolymer and a water-insoluble polymer layer containing a water-insoluble polymer without an amino group in order from a side of the active pharmaceutical ingredient; and an outer filler composition with respect to the fine granule.SELECTED DRAWING: None

Description

  The present invention relates to an orally disintegrating tablet.

  Some drugs used in medicines have an unpleasant odor or bitter taste. For example, olmesartan medoxomil having a (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group (hereinafter referred to as “medoxomil group”) is known as a drug exhibiting an unpleasant odor and bitterness. ing.

  On the other hand, the development of orally disintegrating tablets that can be taken without water is being promoted as an easier-to-take formulation to improve compliance, such as elderly patients, patients who have difficulty swallowing, and patients whose water intake is restricted. Yes. Orally disintegrating tablets are oral preparations that disintegrate rapidly in the oral cavity after administration. Therefore, when a drug that exhibits an unpleasant odor or bitter taste is used as the dosage form of an orally disintegrating tablet, the odor or bitterness derived from the drug. The technology to reduce is important.

  Conventionally, various techniques such as a technique using sugar coating or film coating, a technique using a component that adsorbs a substance causing odor, and the like have been proposed as techniques for reducing odors derived from drugs.

For example, Patent Document 1 discloses a film coating preparation containing olmesartan medoxomil in the formulation and one or more compounds selected from polyvinyl alcohol and a vinyl alcohol copolymer in the film layer. Has been.
Patent Document 2 discloses a pharmaceutical composition containing olmesartan medoxomil in the formulation and one or more compounds selected from polyvinyl alcohol and vinyl alcohol copolymers in the coating. .
Patent Document 3 discloses a film coating preparation containing olmesartan medoxomil in the formulation and dextrose in the film layer.
Patent Document 4 discloses a film coating preparation containing olmesartan medoxomil in the formulation and sodium carboxymethylcellulose in the film layer.
Patent Document 5 discloses a pharmaceutical composition containing a drug having a medoxomil group as an active ingredient and cyclodextrin as an additive.
Patent Document 6 discloses that by mixing an odor adsorbent with a packaging material for packaging tablets containing olmesartan medoxomil, the odor when taking out the preparation from the package can be reduced.

International Publication No. 2009/057569 Japanese Patent No. 5241511 Japanese Patent No. 497579 Japanese Patent No. 5000491 International Publication No. 2010/018777 Japanese Patent No. 5241503

It is possible to reduce the odor derived from the drug by sugar coating or the film coating technique as disclosed in Patent Documents 1 to 4. However, especially in dosage forms such as orally disintegrating tablets, disintegration in the oral cavity may be significantly delayed.
In the technique disclosed in Patent Document 5, in order to sufficiently reduce the odor, it is necessary to blend cyclodextrin in the same amount or more as the drug. However, in the case of a solid preparation such as an orally disintegrating tablet, the dosing property may be deteriorated due to an increase in the preparation. Moreover, the technique disclosed in Patent Document 5 does not reduce the bitterness derived from the drug.
In the technology disclosed in Patent Document 6, a special packaging material is used. However, oral preparations such as orally disintegrating tablets may be stored or prescribed without using a package, and in such cases, an odor is present. Can not be suppressed. Moreover, the technique disclosed in Patent Document 6 does not reduce the bitterness derived from the drug.

  This invention is made | formed in view of the above situations, and makes it a subject to provide the orally disintegrating tablet which can reduce the smell and bitterness derived from olmesartan medoxomil. Moreover, this invention makes it a subject to provide the orally disintegrating tablet which can reduce the smell and bitterness originating in olmesartan medoxomil, and can suppress disintegration delay.

Specific means for solving the above problems include the following embodiments.
<1> A barrier layer having an active ingredient-containing nucleus containing olmesartan medoxomil and having at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer in order from the active ingredient-containing nucleus, and an amino group An orally disintegrating tablet comprising a fine granule having a water-insoluble polymer layer containing a water-insoluble polymer which is not present, and an externally formed component to the fine granule.
<2> The formed component contained on the outside of the fine granules contains at least one selected from calcium silicate, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, and sodium carboxymethylcellulose, <1> Orally disintegrating tablets.
<3> The orally disintegrating tablet according to <1> or <2>, comprising at least one selected from magnesium salts and aluminum salts.
<4> The orally disintegrating tablet according to <3>, wherein the formed component contained on the outside of the fine granules contains at least one selected from a magnesium salt and an aluminum salt.
<5> Any of <1> to <4>, wherein the fine particles have an elution promoting layer containing at least one selected from a surfactant and a basic substance between the barrier layer and the water-insoluble polymer layer The orally disintegrating tablet according to any one of the above.
<6> At least one selected from polyvinyl alcohol and vinyl alcohol copolymers is polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, according to any one of <1> to <5>. Orally disintegrating tablets.
<7> The orally disintegrating tablet according to any one of <1> to <6>, wherein the water-insoluble polymer having no amino group is ethyl cellulose.
<8> At least one selected from magnesium salts and aluminum salts is at least one selected from magnesium oxide, magnesium hydroxide, magnesium carbonate, synthetic hydrotalcite, and aluminum hydroxide, <3> or The orally disintegrating tablet according to <4>.
<9> The orally disintegrating tablet according to <5>, wherein the surfactant is a sucrose fatty acid ester.
<10> The orally disintegrating tablet according to <5> or <9>, wherein the basic substance is at least one selected from synthetic hydrotalcite and meglumine.
<11> The orally disintegrating tablet according to any one of <1> to <10>, wherein the barrier layer further comprises hydroxypropylmethylcellulose.
<12> The drug substance-containing nucleus has the core particle as a center, and has an active drug layer containing olmesartan medoxomil on the outer side of the core particle. Disintegrating tablets.

In the present specification, a numerical range indicated using “to” means a range including the numerical values described before and after “to” as a minimum value and a maximum value, respectively.
In this specification, the amount of each component in the composition is the total amount of the plurality of substances present in the composition unless there is a specific indication when there are a plurality of substances corresponding to each component in the composition. Means.
In this specification, the “average particle size” means a volume average particle size (Mv), which is a value measured using a laser diffraction / scattering particle size distribution analyzer (product name: LS 13 320, Beckman Coulter, Inc.). However, the method for measuring the average particle size is not particularly limited.
In the present specification, the term “layer” includes not only a configuration covering the entire coating target but also a configuration covering a part of the coating target.

  ADVANTAGE OF THE INVENTION According to this invention, the orally disintegrating tablet which can reduce the smell and bitterness derived from olmesartan medoxomil can be provided. Moreover, according to another aspect of this invention, the orally disintegrating tablet which can reduce the smell and bitterness derived from olmesartan medoxomil and can suppress disintegration delay can be provided.

[Orally disintegrating tablets]
The orally disintegrating tablet of the present invention has a drug substance-containing nucleus containing olmesartan medoxomil as the center, and a barrier containing at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer in this order from the drug substance-containing nucleus side. An orally disintegrating tablet comprising a fine granule having a layer and a water-insoluble polymer layer containing a water-insoluble polymer having no amino group, and an externally formed component with respect to the fine granule. The orally disintegrating tablet of the present invention may contain other components other than the above-mentioned fine granules and formed ingredients, as necessary, within a range not impairing the effects of the present invention.

Olmesartan medoxomil is known as a drug that exhibits an unpleasant odor and bitter taste. The reason that olmesartan medoxomil exhibits an unpleasant odor is considered to be due to the decomposition of olmesartan medoxomil by hydrolysis or the like to generate 2,3-butanedione (hereinafter referred to as “diacetyl”) that exhibits an unpleasant odor. .
Therefore, when olmesartan medoxomil is used as a dosage form for orally disintegrating tablets, it is required to reduce the odor or bitterness derived from the drug.

  The orally disintegrating tablet of the present invention has a drug substance-containing nucleus containing olmesartan medoxomil as the center, and a barrier containing at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer in this order from the drug substance-containing nucleus side. And a fine granule having a water-insoluble polymer layer containing a water-insoluble polymer having no amino group, and an externally formed component with respect to the fine granule, thereby reducing the odor and bitterness derived from olmesartan medoxomil. It is possible to reduce the collapse delay.

  The reason why the odor and bitterness derived from olmesartan medoxomil can be reduced and the disintegration delay can be suppressed by the orally disintegrating tablet of the present invention is estimated as follows. That is, since the fine granules in the present invention have a barrier layer on the outer side of the drug substance-containing nucleus, it is possible to suppress permeation of diacetyl generated by the decomposition of olmesartan medoxomil. In addition, since the fine granules in the present invention have a water-insoluble polymer layer outside the barrier layer, the disintegration delay of the orally disintegrating tablet accompanying dissolution of polyvinyl alcohol or a vinyl alcohol copolymer is reduced by this water-insoluble polymer layer. Can be suppressed. Moreover, the bitter taste derived from olmesartan medoxomil can be reduced by this water-insoluble polymer layer.

  In the fine particles in the present invention, a barrier layer is interposed between the drug substance-containing nucleus containing olmesartan medoxomil and the water-insoluble polymer layer. However, even when the barrier layer is interposed between the drug substance-containing nucleus and the water-insoluble polymer layer, the present inventors have found that the water-insoluble polymer contained in the water-insoluble polymer layer has an amino group. Unexpectedly discovered that this polymer decomposes olmesartan medoxomil and exhibits an unpleasant odor. In the fine particles of the present invention, since the water-insoluble polymer contained in the water-insoluble polymer layer does not have an amino group, it is possible to prevent olmesartan medoxomil from being decomposed by the water-insoluble polymer.

  Hereinafter, each component of the orally disintegrating tablet of the present invention will be described in detail.

≪Fine grain≫
The fine particles in the present invention have a drug substance-containing nucleus containing olmesartan medoxomil as a center, and in order from the drug substance-containing nucleus side, a barrier layer containing at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer, And a water-insoluble polymer layer containing a water-insoluble polymer having no amino group. The fine particles in the present invention may have other layers other than the above-described barrier layer and water-insoluble polymer layer, if necessary, as long as the effects of the present invention are not impaired. For example, the fine particles in the present invention may have other layers such as an elution promoting layer and an overcoat layer described later. The fine granules in the present invention preferably further have an elution control layer for controlling elution from the fine granules of olmesartan medoxomil after taking the orally disintegrating tablet.
In addition, having the drug substance-containing nucleus at the center is intended to indicate the positional relationship between the drug substance-containing nucleus and other layers such as a barrier layer, and the drug substance-containing nucleus is located at the center of fine particles in a strict sense. It does not indicate what to do.

  Each layer such as the barrier layer and the water-insoluble polymer layer may be in a state where at least a part of the surface of the object to be coated is covered. For example, when the barrier layer covers the drug substance-containing nucleus, it is sufficient that at least a part of the surface of the drug substance-containing nucleus is covered with the barrier layer. Each layer such as the barrier layer and the water-insoluble polymer layer preferably covers 1/4 or more of the surface of the object to be coated, and more preferably covers 1/2 or more of the surface of the object to be coated. More preferably, the entire surface of the object to be coated is coated.

<Drug-containing nucleus>
The drug substance-containing nucleus in the present invention includes olmesartan medoxomil.
Olmesartan medoxomil may be a synthetic product or a commercial product. For example, olmesartan medoxomil can be produced according to the method described in Japanese Patent No. 2082519.

  Olmesartan medoxomil usually has a granular form. The average particle size of olmesartan medoxomil is preferably 20 μm or less, for example. By setting the average particle size of olmesartan medoxomil to 20 μm or less, the surface of the drug substance-containing nucleus is smoothed and it is easy to form other layers such as a barrier layer. The average particle size of olmesartan medoxomil is more preferably 10 μm or less. Moreover, it is preferable that the average particle diameter of olmesartan medoxomil is 1 micrometer or more.

  The content of olmesartan medoxomil is, for example, preferably 10 parts by mass or more, and more preferably 15 parts by mass or more with respect to 100 parts by mass of the drug substance-containing nucleus. In addition, the content of olmesartan medoxomil is preferably 75 parts by mass or less and more preferably 50 parts by mass or less with respect to 100 parts by mass of the drug substance-containing nucleus.

  In addition to olmesartan medoxomil, the drug substance-containing nucleus in the present invention may contain other components as necessary within the range not impairing the effects of the present invention.

  For example, the drug substance-containing nucleus in the present invention preferably contains at least one selected from a binder, a lubricant, and an excipient. As for the component selected from the binder, the lubricant, and the excipient, one component may be responsible for two or more functions.

The binder is a component that can contribute to improving the moldability of the drug substance-containing nucleus.
The binder is not particularly limited as long as it is a component that can function as a binder and is a pharmacologically acceptable component, and a known binder can be used. For example, examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxyvinyl polymer, sodium carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, gum arabic, gelatin, pregelatinized starch, and pullulan. As a binder, 1 type may be used independently and 2 or more types may be used together.
When the drug substance-containing nucleus contains a binder, the content of the binder is preferably 1 part by mass or more and more preferably 2 parts by mass or more with respect to 100 parts by mass of the drug substance-containing nucleus. Further, the content of the binder is preferably 40 parts by mass or less, and more preferably 30 parts by mass or less with respect to 100 parts by mass of the drug substance-containing nucleus.

Lubricants are components that can contribute to improving the productivity of drug substance-containing nuclei.
The lubricant is not particularly limited as long as it is a component that can function as a lubricant and is pharmacologically acceptable, and a known lubricant can be used. For example, examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, glyceryl monostearate, talc, and light anhydrous silicic acid. As the lubricant, one type may be used alone, or two or more types may be used in combination.
When the drug substance-containing nucleus contains a lubricant, the content of the lubricant is preferably 1 part by mass or more and more preferably 2 parts by mass or more with respect to 100 parts by mass of the drug substance-containing nucleus. preferable. Further, the content of the lubricant is preferably 20 parts by mass or less, more preferably 10 parts by mass or less, and 8 parts by mass or less with respect to 100 parts by mass of the drug substance-containing nucleus. Further preferred.

The excipient is a component that can contribute to improving the moldability of the drug substance-containing nucleus.
The excipient is not particularly limited as long as it is a component that can function as an excipient and is pharmacologically acceptable, and a known excipient can be used. The excipient may be an organic excipient or an inorganic excipient. As an excipient | filler, 1 type may be used independently and 2 or more types may be used together.
Examples of the organic excipient include mannitol, sorbitol, erythritol, lactose, purified sucrose, crystalline cellulose, ethyl cellulose and the like. Among these organic excipients, water-soluble mannitol, sorbitol, erythritol, lactose, and purified sucrose are preferable, and mannitol is more preferable.
Examples of the inorganic excipient include magnesium aluminate metasilicate, magnesium oxide, magnesium carbonate, magnesium phosphate, calcium silicate, anhydrous calcium phosphate, and the like.
When the drug substance-containing nucleus contains an excipient, the content of the excipient is preferably 10 parts by mass or more and more preferably 15 parts by mass or more with respect to 100 parts by mass of the drug substance-containing nucleus. preferable. Further, the content of the excipient is preferably 70 parts by mass or less, and more preferably 50 parts by mass or less, with respect to 100 parts by mass of the drug substance-containing nucleus.

  In addition, the drug substance-containing nucleus in the present invention may contain a disintegrant. In the disintegrant, one component may perform two or more functions.

The disintegrant is a component that can contribute to the promotion of the disintegration of the drug substance-containing nucleus.
The disintegrant is not particularly limited as long as it is a component that can function as a disintegrant and is pharmacologically acceptable, and a known disintegrant can be used. For example, as a disintegrating agent, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarboxymethylcellulose, crospovidone, low-substituted hydroxypropylcellulose, crystalline cellulose And hydroxypropyl starch. As a disintegrating agent, 1 type may be used independently and 2 or more types may be used together.

  Furthermore, the drug substance-containing nucleus in the present invention may contain an emulsifier, a surfactant, other active ingredients, and the like. Examples of other active ingredients include antihypertensive drugs, antidiabetic drugs, hyperlipidemia drugs, hyperuricemia drugs, and the like. Examples of antihypertensive drugs include calcium antagonists and diuretics. Examples of calcium antagonists include amlodipine, nifedipine, nicardipine, benidipine, varnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, efonidipine, cilnidipine, alanidipine, felodipine, nimodipine, clevidipine, lacidipine, lercanidipine and the like. Examples of diuretics include furosemide, torasemide, azosemide, piretanide, hydrochlorothiazide, trichlormethiazide, indapamide, chlorthalidone, triamterene, spironolactone, potassium canrenoate, eplerenone, acetazolamide, carperitide, tolvaptan and the like. The types and contents of components such as emulsifiers and surfactants can be appropriately set according to the purpose. As for components such as emulsifiers and surfactants, one component may be responsible for two or more functions.

  The average particle diameter of the drug substance-containing nucleus in the present invention is preferably 500 μm or less, for example. By setting the average particle size of the drug substance-containing nucleus to 500 μm or less, when the orally disintegrating tablet disintegrates in the oral cavity, roughness in the oral cavity can be further reduced. The average particle diameter of the drug substance-containing nucleus is more preferably 350 μm or less. In addition, the average particle size of the drug substance-containing nucleus is preferably 100 μm or more, and more preferably 150 μm or more.

In addition, the drug substance-containing nucleus in the present invention preferably has a high sphericity. By using a drug substance-containing nucleus having a high sphericity, it is possible to improve the uniformity when coating with a layer such as a barrier layer or a water-insoluble polymer layer. The sphericity of the drug substance-containing nucleus is preferably, for example, 0.7 or more.
In this specification, the sphericity is obtained by observing 10 particles under a microscope and using software (Image J, National Institutes of Health, USA) for a two-dimensional image of each particle {4π × (particle outline shape). ) / (The square of the perimeter of the contour shape of the particle)} is calculated and represented by an average value of 10, but the method of calculating the sphericity is not particularly limited. In the case of a true sphere, the sphericity is 1.0.

The drug substance-containing nucleus in the present invention is not particularly limited as long as it is a granulated product containing olmesartan medoxomil. For example, it may be a granulated product in which olmesartan medoxomil and, if necessary, other components such as a binder, a lubricant and an excipient are mixed. The drug substance-containing nucleus may be a granulated product having a multi-layer structure having a core drug particle as a center and a drug substance layer containing olmesartan medoxomil outside the core particle. When the drug substance-containing nucleus is a granulated product having a multilayer structure, the drug substance-containing nucleus may have an undercoat layer between the nucleus particle and the drug substance layer.
Note that having a core particle at the center is intended to indicate the positional relationship between the core particle and another layer such as a drug substance layer, and that the core particle is positioned at the center of the drug substance-containing core in a strict sense. It is not shown.

  Hereinafter, the case where the drug substance-containing nucleus is a granulated product having a multilayer structure will be further described.

(Nuclear particles)
The core particle in the present invention is a particle that becomes the core of the drug substance-containing nucleus. The component constituting the core particle is not particularly limited as long as it is a pharmacologically acceptable component. For example, as the core particles, the components described as excipients can be used.

As the core particles, the raw powder itself of the components described as the excipient may be used, a granulated product of the raw powder may be used, or a commercially available product may be used.
Examples of commercially available core particles include Florite (trade name, calcium silicate, Eisai Food Chemical Co., Ltd.), Nonparel (registered trademark) -105 (trade name, lactose / crystalline cellulose, Freund Sangyo Co., Ltd.) Nonparel (registered trademark) -108 (trade name, D-mannitol, Freund Sangyo Co., Ltd.), Selfia (registered trademark, crystalline cellulose, Asahi Kasei Chemicals Corporation) and the like. Among these, commercially available core particles are selected from Nonparel (registered trademark) -108 (trade name, D-mannitol, Freund Sangyo Co., Ltd.) and Selfia (registered trademark, crystalline cellulose, Asahi Kasei Chemicals Corporation). At least one kind is preferable, and Nonparel (registered trademark) -108 (trade name, D-mannitol, Freund Sangyo Co., Ltd.) is more preferable.

  The average particle diameter of the core particles is preferably, for example, 50 μm to 350 μm, and more preferably 100 μm to 300 μm. By making the average particle diameter of the core particles within the above range, the mouth of the orally disintegrating tablet is improved and it becomes easy to obtain a drug substance-containing core having a high sphericity.

  Further, the core particles in the present invention preferably have a high sphericity. By using the core particles having a high sphericity, it is possible to improve the uniformity when coating with a layer such as a drug substance layer. The sphericity of the core particle is preferably 0.8 or more, for example.

(Drug substance layer)
The drug substance layer in the present invention contains olmesartan medoxomil.
The drug substance layer in the present invention may further contain the above-described binder, lubricant, excipient, disintegrant, emulsifier, surfactant, other active ingredient, and the like. The kind and content of these components can be appropriately set according to the purpose.

(Undercoat layer)
The drug substance-containing nucleus in the present invention may have an undercoat layer between the core particle and the drug substance layer. When the drug substance-containing nucleus has an undercoat layer, damage to the core particles can be further suppressed. As a component constituting the undercoat layer, for example, the above binder and lubricant can be used.

  The proportion of the drug substance-containing nucleus in the fine particles in the present invention is preferably 40% by mass to 95% by mass and more preferably 45% by mass to 90% by mass with respect to the mass of the fine particles, for example. preferable.

<Barrier layer>
The barrier layer in the present invention contains at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer.
The vinyl alcohol copolymer is not particularly limited as long as it is a pharmacologically acceptable copolymer containing polyvinyl alcohol as a copolymerization component. The vinyl alcohol copolymer may be a random copolymer, a block copolymer, or a graft copolymer. From the viewpoint of further reducing the odor derived from olmesartan medoxomil, the content of polyvinyl alcohol in the vinyl alcohol copolymer is preferably 60% by mass to 90% by mass.

Examples of the vinyl alcohol copolymer include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer, and the like.
As for the copolymerization ratio of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, for example, the content of polyvinyl alcohol is 60 mass% to 90 mass%, the content of acrylic acid is 0.5 mass% to 12 mass%, It is preferable that the content rate of methyl methacrylate is 7 mass%-38 mass%.
The copolymerization ratio of the polyvinyl alcohol / polyethylene glycol graft copolymer is, for example, that the content of polyvinyl alcohol is 60% by mass to 90% by mass and the content of polyethylene glycol is 10% by mass to 40% by mass. preferable.

A commercially available product can also be used as the polyvinyl alcohol or the vinyl alcohol copolymer.
As a commercial item of polyvinyl alcohol, for example, Gohsenol (registered trademark, Nippon Synthetic Chemical Co., Ltd.), J-Poval (trade name, Nippon Vinegar Poval Co., Ltd.), Denkapoval (registered trademark, Electrochemical Industry ( Co., Ltd.), Kuraray Poval (trade name, Kuraray Co., Ltd.) and the like.
Examples of commercially available polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer include POVACOAT (registered trademark, Daido Kasei Kogyo Co., Ltd.). The copolymerization ratio of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in POVACOAT (registered trademark) is 80.0% by mass of polyvinyl alcohol, 2.5% by mass of acrylic acid, and methacrylic acid. The methyl content is 17.5% by mass.
Examples of commercially available polyvinyl alcohol / polyethylene glycol graft copolymers include Kollicoat (registered trademark) IR (trade name, BASF). As for the copolymerization ratio of the polyvinyl alcohol / polyethylene glycol graft copolymer in Kollicoat (registered trademark) IR, the content of polyvinyl alcohol is 75% by mass and the content of polyethylene glycol is 25% by mass.

  Among the polyvinyl alcohols or vinyl alcohol copolymers, vinyl alcohol copolymers are preferable and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymers are more preferable from the viewpoint of easy formation of the barrier layer.

  The content of at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer is preferably 10 parts by mass or more with respect to 100 parts by mass of the barrier layer, for example. By setting the content of at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer to 10 parts by mass or more with respect to 100 parts by mass of the barrier layer, the odor derived from olmesartan medoxomil can be further reduced. . As for content of at least 1 sort (s) selected from polyvinyl alcohol and a vinyl alcohol-type copolymer, it is more preferable that it is 15 mass parts or more with respect to 100 mass parts of barrier layers. Further, the content of at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer is preferably 70 parts by mass or less and 50 parts by mass or less with respect to 100 parts by mass of the barrier layer. More preferred.

  In addition to at least one selected from polyvinyl alcohol and vinyl alcohol copolymers, the barrier layer in the present invention may contain other components as necessary within the range not impairing the effects of the present invention. .

  For example, the barrier layer in the present invention preferably contains at least one selected from a lubricant, a plasticizer, and a binder.

As the lubricant, the components described in the section of drug substance-containing nucleus can be used. As the lubricant, one type may be used alone, or two or more types may be used in combination.
When the barrier layer contains a lubricant, the content of the lubricant is preferably 10 parts by mass or more, and more preferably 15 parts by mass or more with respect to 100 parts by mass of the barrier layer. Moreover, it is preferable that it is 70 mass parts or less with respect to 100 mass parts of barrier layers, and, as for content of a lubricant, it is more preferable that it is 50 mass parts or less.

The plasticizer is not particularly limited as long as it is a component that can function as a plasticizer and is pharmacologically acceptable, and a known plasticizer can be used. For example, examples of the plasticizer include triethyl citrate, triacetin, polyethylene glycol, polyoxyethylene sorbitan monooleate, acetyl triethyl citrate, tributyl citrate, and tributyl acetyl citrate. As a plasticizer, 1 type may be used independently and 2 or more types may be used together.
When the barrier layer contains a plasticizer, the content of the plasticizer is preferably 5 parts by mass or more and more preferably 10 parts by mass or more with respect to 100 parts by mass of the barrier layer. Moreover, it is preferable that it is 30 mass parts or less with respect to 100 mass parts of barrier layers, and, as for content of a plasticizer, it is more preferable that it is 20 mass parts or less.

As the binder, the components described in the section of drug substance-containing nucleus can be used. As a binder, 1 type may be used independently and 2 or more types may be used together.
The barrier layer in the present invention preferably contains hydroxypropyl methylcellulose among the binders. When the barrier layer contains hydroxypropylmethylcellulose, elution from the fine granules of olmesartan medoxomil after taking the orally disintegrating tablet can be promoted.
When the barrier layer contains a binder, the content of the binder is preferably 5 parts by mass or more and more preferably 10 parts by mass or more with respect to 100 parts by mass of the barrier layer. Moreover, it is preferable that it is 20 mass parts or less with respect to 100 mass parts of barrier layers, and, as for content of a binder, it is more preferable that it is 15 mass parts or less.

  In addition, the barrier layer in the present invention may contain an excipient, a disintegrant, a fluidizing agent, an emulsifier, a surfactant and the like. The types and contents of components such as excipients and disintegrants can be appropriately set according to the purpose.

  The ratio of the barrier layer to the fine particles in the present invention is, for example, preferably 2% by mass to 30% by mass and more preferably 4% by mass to 25% by mass with respect to the mass of the fine particles.

<Water-insoluble polymer layer>
The water-insoluble polymer layer in the present invention includes a water-insoluble polymer having no amino group. As used herein, “water-insoluble polymer” means a polymer having a solubility in water at 20 ° C. of less than 10 g / L.
Examples of the water-insoluble polymer having no amino group include water-insoluble cellulose ethers and water-insoluble acrylic acid copolymers. Examples of the water-insoluble cellulose ether include ethyl cellulose. Examples of the water-insoluble acrylic acid copolymer include ethyl acrylate / methyl methacrylate copolymer. As a water-insoluble polymer having no amino group, one type may be used alone, or two or more types may be used in combination.

A commercially available product can also be used as the water-insoluble polymer having no amino group.
Examples of commercially available water-insoluble cellulose ethers include ethyl cellulose aqueous dispersion (trade name: Aquacoat (registered trademark) ECD, FMC).
Examples of commercially available water-insoluble acrylic acid copolymers include ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit (registered trademark) NE30D, Evonik).

  Among water-insoluble polymers having no amino group, ethyl cellulose having a high glass transition point and low adhesion is preferable.

  The content of the water-insoluble polymer having no amino group is preferably 20 parts by mass or more with respect to 100 parts by mass of the water-insoluble polymer layer, for example. By setting the content of the water-insoluble polymer having no amino group to 20 parts by mass or more with respect to 100 parts by mass of the water-insoluble polymer layer, the orally disintegrating tablet accompanying dissolution of polyvinyl alcohol or the vinyl alcohol copolymer can be used. The decay delay can be further suppressed, and the bitterness derived from olmesartan medoxomil can be further reduced. The content of the water-insoluble polymer having no amino group is more preferably 30 parts by mass or more with respect to 100 parts by mass of the water-insoluble polymer layer. Further, the content of the water-insoluble polymer having no amino group is preferably 90 parts by mass or less, and more preferably 85 parts by mass or less, with respect to 100 parts by mass of the water-insoluble polymer layer.

  The water-insoluble polymer layer in the present invention may contain other components as necessary within the range not impairing the effects of the present invention, in addition to the water-insoluble polymer having no amino group.

  For example, the water-insoluble polymer layer in the present invention preferably contains at least one selected from a plasticizer and a lubricant.

As the plasticizer, the components described in the section of the barrier layer can be used. As a plasticizer, 1 type may be used independently and 2 or more types may be used together.
When the water-insoluble polymer layer contains a plasticizer, the content of the plasticizer is preferably 10 parts by mass or more, and more preferably 15 parts by mass or more with respect to 100 parts by mass of the water-insoluble polymer layer. Moreover, it is preferable that it is 35 mass parts or less with respect to 100 mass parts of water-insoluble polymer layers, and, as for content of a plasticizer, it is more preferable that it is 30 mass parts or less.

As the lubricant, the components described in the section of drug substance-containing nucleus can be used. As the lubricant, one type may be used alone, or two or more types may be used in combination.
When the water-insoluble polymer layer contains a lubricant, the content of the lubricant is preferably 20 parts by mass or more and more preferably 25 parts by mass or more with respect to 100 parts by mass of the water-insoluble polymer layer. preferable. Further, the content of the lubricant is preferably 40 parts by mass or less, and more preferably 35 parts by mass or less with respect to 100 parts by mass of the water-insoluble polymer layer.

  The water-insoluble polymer layer in the present invention may contain a binder, an excipient, a disintegrant, a fluidizing agent, an emulsifier, a surfactant and the like. The type and content of components such as a binder and an excipient can be appropriately set according to the purpose.

  The proportion of the water-insoluble polymer layer in the fine particles in the present invention is preferably 0.5% by mass to 20% by mass, and preferably 1% by mass to 15% by mass with respect to the mass of the fine particles. Is more preferable.

<Elution promotion layer>
The fine particles in the present invention may have an elution promoting layer containing at least one selected from a surfactant and a basic substance between the barrier layer and the water-insoluble polymer layer. When the fine granules have the dissolution promoting layer, dissolution of the olmesartan medoxomil from the fine granules after taking the orally disintegrating tablet can be promoted.

  The surfactant is not particularly limited as long as it is a pharmacologically acceptable component, and a known surfactant can be used. For example, surfactants include anionic surfactants such as sodium lauryl sulfate and calcium stearate, cationic surfactants such as benzalkonium chloride, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid Nonionic surfactants such as esters are exemplified. As the surfactant, one type may be used alone, or two or more types may be used in combination.

Of the surfactants, sucrose fatty acid esters are preferred.
Examples of the sucrose fatty acid ester include sucrose monofatty acid ester, sucrose difatty acid ester, sucrose trifatty acid ester, etc., selected from sucrose monofatty acid ester, sucrose difatty acid ester, sucrose trifatty acid ester, etc. It may be at least one kind or a mixture of two or more kinds.
When the sucrose fatty acid ester is a mixture of two or more selected from sucrose monofatty acid ester, sucrose difatty acid ester, sucrose trifatty acid ester, etc., the content of sucrose monofatty acid ester is the total amount of the mixture On the other hand, 20 mass% or more is preferable, 40 mass% or more is more preferable, and 50 mass% or more is still more preferable.
The number of carbon atoms of the fatty acid constituting the sucrose fatty acid ester is preferably 12 or more, and more preferably 12-20. Sucrose fatty acid esters include sucrose dioleate, sucrose distearate, sucrose dipalmitate, sucrose dimyristate, sucrose dilaurate, sucrose monooleate, sucrose monostearate Examples include acid esters, sucrose monopalmitate, sucrose monomyristate, and sucrose monolaurate.

  The basic substance is not particularly limited as long as it is a pharmacologically acceptable component, and a known basic substance can be used. The basic substance may be an inorganic basic substance or an organic basic substance. As a basic substance, 1 type may be used independently and 2 or more types may be used together.

  Inorganic basic substances include metal oxides such as magnesium oxide, calcium oxide and aluminum oxide, metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and aluminum hydroxide, sodium carbonate , Metal carbonates such as potassium carbonate, magnesium carbonate, calcium carbonate, metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate, trisodium phosphate, tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate, pyrolin Metal phosphates such as sodium phosphate, potassium pyrophosphate, sodium polyphosphate, potassium polyphosphate, metal hydrogen phosphates such as sodium monohydrogen phosphate, potassium monohydrogen phosphate, sodium silicate, magnesium silicate, silicic acid Calcium, synthetic aluminum silicate, synthetic ke Metal silicates such as magnesium silicate, talc, etc., composite silicate-aluminum compounds such as magnesium aluminate silicate, magnesium aluminum silicate and magnesium aluminate metasilicate, composite aluminum-magnesium compounds such as synthetic hydrotalcite, water Examples thereof include inorganic ammonium salts such as ammonium oxide, ammonium carbonate, ammonium hydrogen carbonate, and ammonium monohydrogen phosphate.

Examples of the organic basic substance include metal salts of organic acids, organic amines, basic amino acids and the like.
Examples of organic acid metal salts include sodium salts, potassium salts, magnesium salts, calcium salts, and the like of organic acids such as citric acid, succinic acid, tartaric acid, fumaric acid, maleic acid, malonic acid, and malic acid.
Organic amines include meglumine, monoethanolamine, diisopropanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, 2-amino-2-methyl-1-propanol, 2-amino-2-methyl -1,3-propanediol, polyoxyethylene alkylamine and the like.
Examples of basic amino acids include lysine, arginine, phenylalanine, tyrosine, histidine, proline, oxyproline, ornithine, hydroxylysine, and derivatives thereof.

  Among basic substances, at least one selected from synthetic hydrotalcite and meglumine is preferable.

The content of at least one selected from a surfactant and a basic substance is preferably 2 parts by mass or more with respect to 100 parts by mass of the elution promoting layer, for example. Fine granules of olmesartan medoxomil after taking orally disintegrating tablets by setting the content of at least one selected from a surfactant and a basic substance to 2 parts by mass or more with respect to 100 parts by mass of the dissolution promoting layer Elution from can be further promoted. As for content of at least 1 sort (s) selected from surfactant and a basic substance, it is more preferable that it is 4 mass parts or more with respect to 100 mass parts of elution promotion layers. Further, the content of at least one selected from a surfactant and a basic substance is preferably 60 parts by mass or less and more preferably 50 parts by mass or less with respect to 100 parts by mass of the elution promoting layer. preferable.
The content of at least one selected from a surfactant and a basic substance is preferably 1% by mass to 50% by mass and preferably 2% by mass to 30% by mass with respect to olmesartan medoxomil. Is more preferable.

  When the fine particles in the present invention have an elution promoting layer, the proportion of the elution promoting layer in the fine particles is not particularly limited.

<Overcoat layer>
The fine particles in the present invention may have an overcoat layer as a layer outside the water-insoluble polymer layer (for example, outermost layer). When the fine particles have an overcoat layer, adhesion or aggregation between the fine particles can be further suppressed. As a component constituting the overcoat layer, for example, mannitol can be used.

<Average particle size of fine particles>
The average particle diameter of the fine particles in the present invention is, for example, preferably 100 μm to 1000 μm, more preferably 100 μm to 750 μm, and still more preferably 150 μm to 500 μm. By making the average particle size of the fine particles within the above range, when the orally disintegrating tablet disintegrates in the oral cavity, it is possible to further reduce the roughness in the oral cavity, so avoiding a decrease in the feeling of dosing it can.

<Content ratio of fine particles>
The content ratio of the fine granules in the orally disintegrating tablet of the present invention is, for example, preferably 10% by mass to 50% by mass, and 20% by mass to 40% by mass with respect to the total mass of the orally disintegrating tablet. It is more preferable.

<Production method of fine particles>
Fine granules in the present invention can be obtained by sequentially coating a drug substance-containing nucleus with a barrier layer, a water-insoluble polymer layer, and the like.

  The drug substance-containing nucleus can be obtained by a general granulation method. Examples of the granulation method include a fluidized bed granulation method, a stirring granulation method, and a spray drying method.

  In the case where the drug substance-containing nucleus is a granulated product having a multi-layered structure having a drug substance layer including olmesartan medoxomil on the outer side of the core particle, for example, the components constituting the drug substance layer are mixed with water. It is possible to obtain a drug substance-containing nucleus by preparing a spray liquid for a drug substance layer dissolved in a solvent such as the above, spraying this spray liquid onto the core particles, and then evaporating the solvent contained in the sprayed spray liquid. it can.

  When the drug substance-containing nucleus has an undercoat layer between the core particles and the drug substance layer, the undercoat spray liquid may be sprayed before spraying the drug substance layer spray liquid.

Here, from the viewpoint of further suppressing the decomposition of olmesartan medoxomil, the drug substance layer spray liquid preferably does not contain olmesartan medoxomil. For example, in a state in which the core particles and olmesartan medoxomil are flowed, a spray solution for the drug substance layer in which components such as a binder and a lubricant are dissolved in a solvent such as water is sprayed and included in the sprayed spray solution The drug substance-containing nucleus can be obtained by evaporating the solvent.
In addition, from the viewpoint of enhancing the storage stability of olmesartan medoxomil during and after the manufacture of drug substance-containing nuclei, the addition of olmesartan medoxomil to the core particles and the spraying of the spray liquid for the drug substance layer are divided into several stages. Preferably it is done.

  Examples of granulators used in the production of drug substance-containing nuclei include fluidized bed granulators such as rolling fluidized bed granulators, spouted fluidized bed granulators, and mechanically stirred composite fluidized bed granulators It is done. Examples of the fluidized bed granulator include a rolling fluidized bed granulator (product name: FD-MP-01, Paulek Co., Ltd.), a flow coater (product name: FL-1, Freund Sangyo Co., Ltd.) and the like. It is done.

  As a method for removing the solvent contained in the drug substance layer spray liquid sprayed on the core particles, there is a method in which only drying is performed independently of the above method using the fluidized bed granulator. Examples of the method of performing only drying independently include a method using a vacuum dryer and a method using a hot air dryer.

  The spray rate, spraying time, solution temperature, drying conditions, etc. of the drug substance layer spray liquid when producing drug substance-containing particles are not particularly limited, and the composition, viscosity, etc. of the drug substance layer spray liquid Can be set as appropriate.

  As a method for coating a drug substance-containing nucleus with a barrier layer, a water-insoluble polymer layer, etc., a general granulation method can be employed. For example, a barrier layer spray solution in which the components constituting the barrier layer are dissolved in a solvent and a water insoluble polymer layer spray solution in which the components that constitute the water-insoluble polymer layer are dissolved in a solvent are prepared, and the particles to be coated are prepared. What is necessary is just to spray sequentially. The spraying speed, spraying time, liquid temperature, drying conditions and the like of the barrier layer spray liquid and the like are not particularly limited, and can be appropriately set according to the composition, viscosity, and the like of each spray liquid.

≪Formation amount≫
The orally disintegrating tablet of the present invention contains a formed component on the outside of the fine granules. The “formation component” referred to here is a component that can contribute to the improvement of moldability and dosage of tablets containing fine granules. Forming ingredients are pharmacologically acceptable additives for bitterness, odor adsorbent, excipient, disintegrant, lubricant, binder, fluidizer, sweetener, flavor, coloring A material or the like may be included as long as the effects of the present invention are not impaired. As for the additive for formulation, one component may perform two or more functions.

The orally disintegrating tablet of the present invention preferably contains at least one selected from calcium silicate, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, and sodium carboxymethyl cellulose outside the fine granules. By including at least one selected from calcium silicate, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, and cross-carboxymethylcellulose sodium, the bitterness derived from olmesartan medoxomil can be reduced.
Japanese Patent No. 5554699 describes that the dissolution property of olmesartan medoxomil from a pharmaceutical composition is improved by a calcium-containing additive such as calcium silicate and carboxymethylcellulose calcium. It is surprising that the bitterness derived from olmesartan medoxomil can be reduced by a component that was supposed to improve the dissolution property of olmesartan medoxomil.

  When the forming component contained outside the fine granules contains at least one selected from calcium silicate, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, and sodium carboxymethylcellulose, calcium silicate, carboxy The content of at least one selected from methyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose can be 1 to 8 parts by mass with respect to 100 parts by mass of the formed component.

The orally disintegrating tablet of the present invention preferably contains at least one selected from a magnesium salt and an aluminum salt outside the fine granules. By containing at least one selected from a magnesium salt and an aluminum salt, the odor derived from olmesartan medoxomil can be reduced.
Among the magnesium salts and aluminum salts, at least one selected from magnesium oxide, magnesium hydroxide, magnesium carbonate, synthetic hydrotalcite, and aluminum hydroxide is preferable from the viewpoint of odor adsorption. Examples of the aluminum hydroxide include dry aluminum hydroxide gel.
Note that Japanese Patent No. 5148296 describes the use of synthetic hydrotalcite as a fluidizing agent in tablets containing olmesartan medoxomil. It is surprising that the odor derived from olmesartan medoxomil can be reduced by magnesium salts and aluminum salts containing synthetic hydrotalcite and the like.

When the formed component contained outside with respect to the fine particles contains at least one selected from magnesium salt and aluminum salt, the content of at least one selected from magnesium salt and aluminum salt is 100% formed component. It can be 1 mass part-5 mass parts with respect to a mass part.
In addition, at least 1 sort (s) selected from magnesium salt and aluminum salt may be contained in the fine grain.

  The excipient is not particularly limited as long as it is a component that can function as an excipient and is pharmacologically acceptable, and a known excipient can be used. The excipient may be an organic excipient or an inorganic excipient. Examples of the organic excipient include mannitol, sorbitol, erythritol, lactose, purified sucrose, crystalline cellulose, ethyl cellulose and the like. Examples of the inorganic excipient include magnesium aluminate metasilicate, magnesium oxide, magnesium carbonate, magnesium phosphate, calcium silicate, anhydrous calcium phosphate, and the like. As an excipient | filler, 1 type may be used independently and 2 or more types may be used together.

  The disintegrant is not particularly limited as long as it is a component that can function as a disintegrant and is pharmacologically acceptable, and a known disintegrant can be used. For example, as a disintegrating agent, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarboxymethylcellulose, crospovidone, low-substituted hydroxypropylcellulose, crystalline cellulose And hydroxypropyl starch. As a disintegrating agent, 1 type may be used independently and 2 or more types may be used together.

  The lubricant is not particularly limited as long as it is a component that can function as a lubricant and is pharmacologically acceptable, and a known lubricant can be used. For example, examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, glyceryl monostearate, talc, and light anhydrous silicic acid. As the lubricant, one type may be used alone, or two or more types may be used in combination.

  The binder is not particularly limited as long as it is a component that can function as a binder and is a pharmacologically acceptable component, and a known binder can be used. For example, examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxyvinyl polymer, sodium carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, gum arabic, gelatin, pregelatinized starch, and pullulan. As a binder, 1 type may be used independently and 2 or more types may be used together.

  The fluidizing agent is not particularly limited as long as it is a component that can function as a fluidizing agent and is pharmacologically acceptable, and a known fluidizing agent can be used. For example, examples of the fluidizing agent include talc and light anhydrous silicic acid. As a fluidizing agent, 1 type may be used independently and 2 or more types may be used together.

  Examples of sweeteners include aspartame, thaumatin, sucralose, acesulfame potassium, stevia and the like.

As an additive for formulation, 1 type may be used independently and 2 or more types may be used together.
The content of the additive for formulation in the formed component contained on the outside with respect to the fine granules is appropriately set in consideration of the content ratio of fine granules in the orally disintegrating tablet, the average particle diameter of fine granules, etc. be able to.

  Moreover, the active ingredient other than olmesartan medoxomil may be contained outside the fine granules. Examples of other active ingredients include antihypertensive agents, antidiabetic agents, antihyperlipidemic agents, and hyperuricemia agents described in the section on active ingredient-containing nuclei.

[Properties of orally disintegrating tablets]
The orally disintegrating tablet of the present invention preferably contains 5 mg to 80 mg of olmesartan medoxomil per one orally disintegrating tablet.

The shape of the orally disintegrating tablet of the present invention is not particularly limited as long as it is pharmaceutically acceptable. The shape of the orally disintegrating tablet of the present invention may be, for example, a round tablet or a deformed tablet, and may be appropriately set in consideration of medication compliance.
The size of the orally disintegrating tablet of the present invention is not particularly limited as long as it is pharmaceutically acceptable. In general, in view of the fact that orally disintegrating tablets are often used for patients who have difficulty in swallowing, it is preferable that the size of the orally disintegrating tablet of the present invention is as small as possible in consideration of medicinal effects.

The orally disintegrating tablet of the present invention preferably has an oral disintegration time of less than 40 seconds and more preferably less than 30 seconds from the viewpoint of medication compliance.
In the present specification, “orally disintegrating time” means an orally disintegrating tablet measuring device (product name: tricope tester, Okada Seiko Co., Ltd.), and purified water at 37 ° C. with respect to the orally disintegrating tablet. Although it refers to the disintegration time of a tablet measured when it is dropped at 6 mL / min, it is not limited thereto.

  From the viewpoint of drug effectiveness, the orally disintegrating tablet of the present invention is a Japanese Pharmacopoeia dissolution test (paddle method: paddle rotation speed 50 rpm, dissolution test solution: assuming dissolution of the drug in the small intestine that is the absorption site of the drug: The elution rate after 30 minutes in the Japanese Pharmacopoeia dissolution test second solution) is preferably 55% or more, and more preferably 80% or more.

[Method for producing orally disintegrating tablets]
The manufacturing method of the orally disintegrating tablet of this invention is not specifically limited, A well-known method can be used. The orally disintegrating tablet of the present invention can be obtained, for example, by mixing fine granules and a formed component, tableting the obtained mixed powder, and drying.
The method for mixing the fine particles and the forming component is not particularly limited. As a method of mixing the fine particles and the forming component, for example, mixing is performed using a known mixer such as a V-type mixer (Tsutsui Riken Kikai Co., Ltd.), a fluidized bed granulator (Paurec Co., Ltd.) or the like. The method of doing is mentioned.
Conditions such as the time required for mixing can be appropriately adjusted depending on the type of fine particles and the portion to be formed.
The method for tableting the mixed powder of fine granules and forming ingredients is not particularly limited. The temperature at the time of tableting is not particularly limited, and can be set as appropriate.
Examples of the method for tableting the mixed powder of fine granules and forming ingredients include, for example, a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.), a high-speed rotary tableting machine (product). Name: A method of tableting using a tableting machine such as AQUARIUS G, Kikusui Seisakusho Co., Ltd.
The method for drying the tableted product obtained by tableting the mixed powder is not particularly limited. Examples of the method for drying the tableted product obtained by tableting the mixed powder include a method of drying by vacuum drying, fluidized bed drying or the like.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist thereof.

[Examples 1 to 12]
As a core particle, 700 g of Nonparel (registered trademark) -108 (trade name, D-mannitol, spherical particles having a particle diameter of 150 μm to 250 μm, Freund Sangyo Co., Ltd.) is used as a rolling fluidized bed granulator (trade name: FD-MP). -01, Pauleck Co., Ltd.). The rotor rotation speed was adjusted to 400 rpm and the supply air temperature was adjusted to 70 ° C. to 80 ° C., respectively, and 395.4 g of an undercoat layer spray liquid having the following composition prepared in advance was sprayed into the rolling fluidized bed granulator. After spraying, the supply air temperature was adjusted to 80 ° C. and drying was performed for 10 minutes. The obtained granulated product is sieved with a No. 50 round sieve (300 μm) and a No. 100 round sieve (150 μm), whereby the surface of the core particles is coated with an undercoat layer (hereinafter referred to as “ Undercoat layer-coated fine granules (1) ”) were obtained.

[Undercoat layer spray]
・ Hydroxypropylmethylcellulose 10 mass% aqueous solution
50 parts by mass, 1 part by mass of talc, 49 parts by mass of purified water

  350 g of the obtained undercoat layer-coated fine granules (1) and 80.01 g of olmesartan medoxomil were charged into a tumbling fluidized bed granulator (trade name: FD-MP-01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 500 rpm and the supply air temperature was adjusted to 60 ° C. to 70 ° C., respectively, and 350 g of a spray liquid for the drug substance layer (1) prepared in advance was sprayed into the rolling fluidized bed granulator. Next, the spraying is interrupted, and after adding 80.01 g of olmesartan medoxomil into the rolling fluidized bed granulator, spraying 350 g of the drug substance layer (1) spray liquid into the rolling fluidized bed granulator 2 Repeated times. Next, spraying was interrupted and 80.01 g of olmesartan medoxomil was added to the rolling fluidized bed granulator, and then 321.5 g of the drug substance (1) spray solution was sprayed into the rolling fluidized bed granulator ( A total of 1371.5 g of spray solution for drug substance layer (1) is sprayed). Thereafter, the supply air temperature was adjusted to 80 ° C., and drying was performed for 15 minutes. The obtained granulated product is sieved with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the undercoat layer-coated fine granules (1) is the drug substance layer (1). The drug substance-containing nucleus (1) coated with (1) was obtained.

[Spray liquid for drug substance layer (1)]
・ Hydroxypropylcellulose 10 mass% aqueous solution
45.0 parts by mass, talc 1.5 parts by mass, purified water 53.5 parts by mass

  700 g of the obtained drug substance-containing nucleus (1) was charged into a tumbling fluidized bed granulator (trade name: FD-MP-01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 500 rpm, the supply air temperature was adjusted to 40 ° C. to 60 ° C., and 950.6 g of the spray liquid for barrier layer (1) prepared in advance was sprayed into the rolling fluidized bed granulator. . After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. The surface of the drug substance-containing core (1) is covered with the barrier layer (1) by sieving the resulting granulated product with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm). Fine particles (hereinafter referred to as “barrier layer-coated fine particles (1)”).

[Spray liquid for barrier layer (1)]
・ Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer 10 mass% aqueous solution (POVACOAT (registered trademark, Daido Kasei Kogyo Co., Ltd.))
30 parts by mass of 10% by weight aqueous solution of hydroxypropylmethylcellulose
10 parts by mass, 4 parts by mass of talc, 1.6 parts by mass of triacetin, 54.4 parts by mass of purified water

  700 g of the obtained barrier layer-coated fine granules (1) were charged into a rolling fluidized bed granulator (trade name: FD-MP-01, Powrec Co., Ltd.). Then, the rotor rotation speed is adjusted to 500 rpm, the supply air temperature is adjusted to 60 ° C. to 80 ° C., and 482.5 g of the spray solution for the elution accelerating layer (1) prepared in advance is sprayed into the rolling fluidized bed granulator. did. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. By sieving the obtained granulated product with a round sieve of No. 40 (425 μm) and a round sieve of No. 150 (100 μm), the surface of the barrier layer-coated fine granules (1) is an elution promoting layer (1). Coated fine particles (hereinafter referred to as “elution promoting layer-coated fine particles (1)”) were obtained.

[Spray liquid for dissolution promoting layer (1)]
・ Hydroxypropylmethylcellulose 10 mass% aqueous solution
40.0 parts by mass / sucrose fatty acid ester 4.0 parts by mass (Surf Hope (registered trademark) SE PHARMA J-1801 (trade name, Mitsubishi Chemical Foods))
・ Talc 1.6 parts by mass ・ Purified water 54.4 parts by mass

  700 g of the obtained elution accelerating layer-coated fine granules (1) were charged into a rolling fluidized bed granulator (trade name: FD-MP-01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 500 rpm and the supply air temperature was adjusted to 35 ° C. to 55 ° C., respectively, and 604.9 g of the spray liquid for the water-insoluble polymer layer (1) having the following composition prepared in advance was placed in the rolling fluidized bed granulator. The surface of the elution promoting layer-coated fine granules (1) was coated with the water-insoluble polymer layer (1) by spraying.

[Spray liquid for water-insoluble polymer layer (1)]
-90.7 parts by mass of ethyl cellulose 30% by mass aqueous dispersion (trade name: Aquacoat (registered trademark) ECD, FMC)
-Triacetin 6.8 parts by mass-Purified water 507.4 parts by mass

  Subsequently, the rotor rotation speed was adjusted to 500 rpm and the supply air temperature was adjusted to 35 ° C. to 50 ° C., respectively, and 236.9 g of an overcoat layer spray solution having the following composition prepared in advance was sprayed into the rolling fluidized bed granulator.

[Spray liquid for overcoat layer]
・ D-mannitol 14 parts by mass ・ Purified water 86 parts by mass

  Thereafter, the rotation of the rotor was stopped, the product temperature was adjusted to around 60 ° C., and the flow was continued for 2 hours, whereby the polymer contained in the particles was cured and dried. By sieving the obtained granulated product with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), the surface of the elution accelerating layer-coated fine granules (1) becomes a water-insoluble polymer layer (1 ) And fine granules coated with an overcoat layer.

The obtained fine granules and the formed component were mixed with the compositions shown in Tables 1 and 2 to obtain tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).
In addition, the numerical value of each component in Table 1 and Table 2 shows content (mg) in one orally disintegrating tablet.

[Comparative Example 1]
Barrier layer-coated fine granules (1) were obtained by the same production method as in Example 1.
The obtained barrier layer-coated fine granules (1) and the formed component were mixed in the composition shown in Table 2 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Comparative Example 2]
The drug substance-containing nucleus (1) was obtained by the same production method as in Example 1.
700 g of the obtained drug substance-containing nucleus (1) was charged into a tumbling fluidized bed granulator (trade name: FD-MP-01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 500 rpm, the supply air temperature was adjusted to 40 ° C. to 60 ° C., and 950.6 g of the spray liquid for barrier layer (2) having the following composition prepared in advance was sprayed into the rolling fluidized bed granulator. . After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. The surface of the drug substance-containing core (1) is covered with the barrier layer (2) by sieving the obtained granulated product with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm). Fine particles (hereinafter referred to as “barrier layer-coated fine particles (2)”).

[Spray liquid for barrier layer (2)]
・ Hydroxypropylmethylcellulose 10 mass% aqueous solution
40.0 parts by mass, talc 4.0 parts by mass, triacetin 1.6 parts by mass, purified water 54.4 parts by mass

The obtained barrier layer-coated fine granules (2) and the formed component were mixed in the composition shown in Table 2 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Evaluation]
(Evaluation 1: Dissolution test)
About the orally disintegrating tablet of Examples 1-12 and Comparative Examples 1-2, the dissolution test was done according to the dissolution test as described in the 16th revision Japanese Pharmacopoeia second supplement "olmesartan medoxomil tablet". The dissolution test was carried out by the paddle method (paddle rotation speed: 50 rpm) using a dissolution tester DT-810 manufactured by JASCO Corporation. The Japanese Pharmacopoeia dissolution test second solution (volume: 900 mL) was used as the dissolution test solution, and the temperature was maintained at 37 ± 0.5 ° C. after heating and degassing at 50 ° C. for 2 hours or more.
The amount of olmesartan medoxomil released from the tablet at a test time of 30 minutes was measured at a wavelength of 257 nm using an ultraviolet spectrophotometer, and the dissolution rate (%) was calculated.

(Evaluation 2: Measurement of diacetyl area using gas chromatography)
The orally disintegrating tablets of Examples 1 to 12 and Comparative Examples 1 to 2 were put in 14 glass bottles and sealed. Each glass bottle was stored at 40 ° C. for 1 week. The gas in the head space of the glass bottle after storage was extracted, and the area of the peak attributed to diacetyl (diacetyl area) was measured using gas chromatography.
Measurement equipment and measurement conditions are as follows.

<Measurement equipment and measurement conditions>
Gas chromatography system: 7890A (Agilent Technology Co., Ltd.)
Headspace sampler: 7697A (Agilent Technology Co., Ltd.)
Detector: Hydrogen flame ionization detector Analytical column: DB-WAX (Agilent Technology Co., Ltd.)
Injection volume: 1.0 mL
Flow rate: 5.0 mL / min Column temperature: 50 ° C

(Evaluation 3: Sensory evaluation of odor)
The glass bottle after storage used for the measurement of the diacetyl area was opened, and the odor in the bottle was evaluated at a five-level level of 0-4. Evaluation was performed by five panelists, the evaluation results were averaged, and the value rounded to the first decimal place was taken as the odor score.
The evaluation criteria are as follows. Levels 0, 1, and 2 are practically acceptable levels.
In addition, the numerical value in the parenthesis written together with the evaluation standard is a range of the diacetyl area in gas chromatography in which the correlation with the evaluation standard for sensory evaluation was confirmed.

<Evaluation criteria>
0 Odorless (less than 2)
1 Smell that can be finally detected (2 or more and less than 5)
2 Smell enough to tell what odor is (5 or more and less than 10)
3 Easily perceived odor (10 to less than 15)
4 Strong unpleasant odor (more than 15)

(Evaluation 4: Disintegration test)
Using an orally disintegrating tablet measuring device (product name: Tricorp Tester, Okada Seiko Co., Ltd.), purified water at 37 ° C. was added to 6 mL / mL with respect to the orally disintegrating tablets of Examples 1-12 and Comparative Examples 1-2. The time (disintegration time) until the tablet disintegrates when dropped in minutes was measured.

(Evaluation 5: Sensory evaluation of bitterness)
The orally disintegrating tablets of Examples 1 to 12 and Comparative Examples 1 to 2 were included in the mouth for 30 seconds. After the tablets were disintegrated, they were discharged from the mouth, and the taste was evaluated at 6 levels of 0 to 5. Evaluation was performed by five panelists, the evaluation results were averaged, and the value rounded to the first decimal place was taken as the bitterness score.
The evaluation criteria are as follows.

<Evaluation criteria>
0 Taste 1 Slightly perceivable taste 2 Slight bitterness 3 Easily perceivable bitterness 4 Strong bitterness 5 Strong bitterness

  The results of evaluations 1 to 5 are shown in Tables 1 and 2. In Tables 1 and 2, a left-pointing arrow in the content of each component means that the numerical value is the same as that on the left. Moreover, the blank in the content of each component means that the component is not included. Further, “ND” in the evaluation of the diacetyl area means that a peak attributed to diacetyl could not be detected.

As shown in Table 1 and Table 2, the orally disintegrating tablets of Examples 1 to 12 were able to reduce the odor and bitterness derived from olmesartan medoxomil. Moreover, the orally disintegrating tablets of Examples 1 to 12 had a disintegration time of less than 30 seconds and good disintegration properties.
In particular, the orally disintegrating tablets of Examples 2 to 6 and 12 containing at least one selected from a magnesium salt and an aluminum salt in the formed component contained on the outside of the fine granules are the oral cavity of Example 1. The odor derived from olmesartan medoxomil was reduced compared to the internally disintegrating tablet.
In addition, Examples 7 to 7 containing at least one selected from calcium silicate, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, and cross carboxymethyl cellulose sodium in the forming component contained outside the fine granules In the orally disintegrating tablet of 12, the bitter taste derived from olmesartan medoxomil was reduced as compared with the orally disintegrating tablet of Example 1.

On the other hand, as shown in Table 2, it has a barrier layer containing at least one selected from polyvinyl alcohol and vinyl alcohol copolymers, and contains fine particles not having a water-insoluble polymer layer. The orally disintegrating tablet had a significantly delayed disintegration time as compared with the orally disintegrating tablets of Examples 1 to 12, and was inferior in disintegrating property. Moreover, the orally disintegrating tablet of Comparative Example 1 could not reduce the bitterness derived from olmesartan medoxomil.
In addition, the barrier layer does not have a barrier layer containing at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer, and the oral disintegration of Comparative Example 2 contains fine particles not having a water-insoluble polymer layer Although the tablet was good in disintegration, the odor and bitterness derived from olmesartan medoxomil could not be reduced.

[Example 13]
As a core particle, 1100 g of Nonparel (registered trademark) -108 (trade name, D-mannitol, spherical particles having a particle size of 150 μm to 250 μm, Freund Sangyo Co., Ltd.) was used as a rolling fluidized bed granulator (trade name: FD-MP). -01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 400 rpm and the supply air temperature was adjusted to 70 ° C. to 80 ° C., respectively, and 1699.9 g of the above-described spray solution for undercoat layer prepared in advance was sprayed into the rolling fluidized bed granulator. After spraying, the supply air temperature was adjusted to 80 ° C. and drying was performed for 10 minutes. The obtained granulated product is sieved with a No. 50 round sieve (300 μm) and a No. 100 round sieve (150 μm), whereby the surface of the core particles is coated with an undercoat layer (hereinafter referred to as “ Undercoat layer-coated fine granules (2) ”) were obtained.

  350 g of the obtained undercoat layer-coated fine granules (2) and 80.1 g of olmesartan medoxomil were charged into a tumbling fluidized bed granulator (trade name: FD-MP-01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 500 rpm and the supply air temperature was adjusted to 60 ° C. to 70 ° C., respectively, and 500 g of the spray liquid for drug substance layer (2) prepared in advance was sprayed into the rolling fluidized bed granulator. Next, the spraying is interrupted, and after adding 80.1 g of olmesartan medoxomil into the rolling fluidized bed granulator, spraying 500 g of the drug substance layer (2) spray liquid into the rolling fluidized bed granulator 2 Repeated times. Next, spraying was interrupted, and 80.1 g of olmesartan medoxomil was added into the rolling fluidized bed granulator, and then 561.2 g of the spray liquid for the drug substance layer (2) was sprayed into the rolling fluidized bed granulator ( A total of 2061.2 g of spray solution for drug substance layer (2) is sprayed). Thereafter, the supply air temperature was adjusted to 80 ° C., and drying was performed for 15 minutes. The obtained granulated material is sieved with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the undercoat layer-coated fine granules (2) is the drug substance layer (2). The drug substance-containing nucleus (2) coated with (1) was obtained.

[Spray solution for drug substance layer (2)]
・ Hydroxypropylcellulose 10 mass% aqueous solution
30 parts by mass, 1 part by mass of talc, 69 parts by mass of purified water

  500 g of the obtained drug substance-containing core (2) was charged into a tumbling fluidized bed granulator (trade name: FD-MP-01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 500 rpm and the supply air temperature was adjusted to 40 ° C. to 60 ° C., respectively, and 1441 g of the barrier layer (3) spray liquid prepared in advance was sprayed into the rolling fluidized bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. The obtained granulated material is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the drug substance-containing core (2) is covered with the barrier layer (3). Fine particles (hereinafter referred to as “barrier layer-coated fine particles (3)”).

[Spray liquid for barrier layer (3)]
・ Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer 10 mass% aqueous solution (POVACOAT (registered trademark, Daido Kasei Kogyo Co., Ltd.))
40.0 parts by mass, talc 4.0 parts by mass, triethyl citrate 1.6 parts by mass, purified water 54.4 parts by mass

  10 g of the obtained barrier layer-coated fine granules (3) were charged into a micro fluidized bed granulator (Dalton Co., Ltd.). Then, the supply air temperature was adjusted to around 35 ° C. to 55 ° C., and 17.57 g of the previously prepared spray solution for the elution accelerating layer (1) was sprayed into the micro fluidized bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. By sieving the obtained granulated product with a round sieve of No. 40 (425 μm) and a round sieve of No. 150 (100 μm), the surface of the barrier layer-coated fine granules (3) is an elution promoting layer (1). Coated fine particles (hereinafter referred to as “elution promoting layer-coated fine particles (2)”) were obtained.

  10 g of the obtained elution accelerating layer-coated fine granules (2) was charged into a small amount fluidized bed granulator (Dalton Co., Ltd.). And an elution acceleration | stimulation layer is adjusted by spraying 7g spray liquid for water-insoluble polymer layers (2) of the following composition prepared in advance in the micro fluidized bed granulator by adjusting supply temperature to 35 to 55 degreeC vicinity. The surface of the coated fine granules (2) was coated with a water-insoluble polymer layer (2).

[Spray liquid for water-insoluble polymer layer (2)]
-Ethylcellulose 30% by weight aqueous dispersion 0.25 part by mass (trade name: Aquacoat (registered trademark) ECD, FMC)
Macrogol 6000 0.03 parts by mass Talc 0.06 parts by mass Triethyl citrate 0.04 parts by mass Purified water 6.62 parts by mass

  Subsequently, the air supply temperature was adjusted to around 55 ° C. to 65 ° C., and 3.9 g of the above-mentioned spray solution for overcoat layer prepared in advance was sprayed into the microfluidized bed granulator.

  Thereafter, the particles were dried by adjusting the supply air temperature to around 60 ° C. and continuing the flow for 30 minutes. The obtained granulated material is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the elution accelerating layer-coated fine granules (2) has a water-insoluble polymer layer (2 ) And fine granules coated with an overcoat layer. The obtained fine particles were put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles.

The obtained fine granules and the formed component were mixed in the composition shown in Table 3 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).
In addition, the numerical value of each component in Table 3 indicates the content (mg) in one orally disintegrating tablet.

[Example 14]
Barrier layer-coated fine granules (3) were obtained by the same production method as in Example 13.
10 g of the obtained barrier layer-coated fine granules (3) were charged into a micro fluidized bed granulator (Dalton Co., Ltd.). And supply air temperature was adjusted to 35 to 55 degreeC vicinity, and the spray liquid 177.57g for the elution acceleration | stimulation layer (3) of the following composition prepared previously was sprayed in the minute amount granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. By sieving the obtained granulated product with a round sieve of No. 30 (600 μm) and a round sieve of No. 150 (100 μm), the surface of the barrier layer coated fine granules (3) is an elution promoting layer (2). Coated fine particles (hereinafter referred to as “elution promoting layer-coated fine particles (3)”) were obtained.

[Spray liquid for elution promoting layer (2)]
・ Hydroxypropylmethylcellulose 10 mass% aqueous solution
40.0 parts by mass sucrose fatty acid ester 2.7 parts by mass (Surf Hope (registered trademark) SE PHARMA J-1801 (trade name, Mitsubishi Chemical Foods))
-D-mannitol 1.3 mass parts-Talc 1.6 mass parts-Purified water 54.4 mass parts

  10 g of the obtained elution accelerating layer-coated fine granules (3) was charged into a micro fluidized bed granulator (Dalton Co., Ltd.). Then, the elution accelerating layer coating is carried out by adjusting the air supply temperature to around 35 ° C. to 55 ° C. and spraying 7 g of the previously prepared spray solution for the water-insoluble polymer layer (2) in a micro fluidized bed granulator. The surface of the fine particles (3) was covered with a water-insoluble polymer layer (2).

  Subsequently, the air supply temperature was adjusted to around 55 ° C. to 65 ° C., and 3.9 g of the above-mentioned spray solution for overcoat layer prepared in advance was sprayed into the microfluidized bed granulator.

  Thereafter, the particles were dried by adjusting the supply air temperature to around 60 ° C. and continuing the flow for 30 minutes. The obtained granulated material is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the elution accelerating layer-coated fine granules (3) has a water-insoluble polymer layer (2 ) And fine granules coated with an overcoat layer. The obtained fine particles were put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles.

The obtained fine granules and the formed component were mixed in the composition shown in Table 3 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Example 15]
Barrier layer-coated fine granules (3) were obtained by the same production method as in Example 13.
10 g of the obtained barrier layer-coated fine granules (3) were charged into a micro fluidized bed granulator (Dalton Co., Ltd.). And supply air temperature was adjusted to 35 to 55 degreeC vicinity, and the spray liquid 177.57g for the elution acceleration | stimulation layer (4) of the following composition prepared previously was sprayed in the micro fluidized bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. By sieving the obtained granulated product with a round sieve of No. 30 (600 μm) and a round sieve of No. 150 (100 μm), the surface of the barrier layer coated fine granules (3) is an elution promoting layer (3). Coated fine particles (hereinafter referred to as “elution promoting layer-coated fine particles (4)”) were obtained.

[Spray liquid for elution promoting layer (3)]
・ Hydroxypropylmethylcellulose 10 mass% aqueous solution
40.0 parts by mass-Sucrose fatty acid ester 1.3 parts by mass (Surf Hope (registered trademark) SE PHARMA J-1801 (trade name, Mitsubishi Chemical Foods Co., Ltd.))
-D-mannitol 2.7 mass parts-Talc 1.6 mass parts-Purified water 54.4 mass parts

  10 g of the obtained elution accelerating layer-coated fine granules (4) was charged into a minute amount fluidized bed granulator (Dalton Co., Ltd.). Then, the elution accelerating layer coating is carried out by adjusting the air supply temperature to around 35 ° C. to 55 ° C. and spraying 7 g of the previously prepared spray solution for the water-insoluble polymer layer (2) in a micro fluidized bed granulator. The surface of the fine particles (4) was covered with a water-insoluble polymer layer (2).

  Subsequently, the air supply temperature was adjusted to around 55 ° C. to 65 ° C., and 3.9 g of the above-mentioned spray solution for overcoat layer prepared in advance was sprayed into the microfluidized bed granulator.

  Thereafter, the particles were dried by adjusting the supply air temperature to around 60 ° C. and continuing the flow for 30 minutes. The obtained granulated product is sieved with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the elution accelerating layer-coated fine granules (4) has a water-insoluble polymer layer (2 ) And fine granules coated with an overcoat layer. The obtained fine particles were put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles.

The obtained fine granules and the formed component were mixed in the composition shown in Table 3 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Example 16]
Barrier layer-coated fine granules (3) were obtained by the same production method as in Example 13.
10 g of the obtained barrier layer-coated fine granules (3) were charged into a micro fluidized bed granulator (Dalton Co., Ltd.). And supply air temperature was adjusted to 35 to 55 degreeC vicinity, and the spray liquid 177.57g for the elution acceleration | stimulation layer (4) of the following composition prepared previously was sprayed in the micro fluidized bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. By sieving the obtained granulated product with a round sieve of No. 40 (425 μm) and a round sieve of No. 150 (100 μm), the surface of the barrier layer coated fine granules (3) is an elution promoting layer (4) Coated fine particles (hereinafter referred to as “elution promoting layer-coated fine particles (5)”) were obtained.

[Elution promotion layer (4) spray solution]
・ Hydroxypropylmethylcellulose 10 mass% aqueous solution
40.0 parts by mass, meglumine 4.0 parts by mass, talc 1.6 parts by mass, purified water 54.4 parts by mass

  10 g of the obtained elution accelerating layer-coated fine granules (5) was charged into a small amount fluidized bed granulator (Dalton Co., Ltd.). Then, the elution accelerating layer coating is carried out by adjusting the air supply temperature to around 35 ° C. to 55 ° C. and spraying 7 g of the previously prepared spray solution for the water-insoluble polymer layer (2) in a micro fluidized bed granulator. The surface of the fine particles (5) was covered with a water-insoluble polymer layer (2).

  Subsequently, the air supply temperature was adjusted to around 55 ° C. to 65 ° C., and 3.9 g of the above-mentioned spray solution for overcoat layer prepared in advance was sprayed into the microfluidized bed granulator.

  Thereafter, the particles were dried by adjusting the supply air temperature to around 60 ° C. and continuing the flow for 30 minutes. The obtained granulated material is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the elution accelerating layer-coated fine granules (5) has a water-insoluble polymer layer (2 ) And fine granules coated with an overcoat layer. The obtained fine particles were put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles.

The obtained fine granules and the formed component were mixed in the composition shown in Table 3 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Example 17]
Barrier layer-coated fine granules (3) were obtained by the same production method as in Example 13.
10 g of the obtained barrier layer-coated fine granules (3) were charged into a micro fluidized bed granulator (Dalton Co., Ltd.). And supply air temperature was adjusted to 35 to 55 degreeC vicinity, and the spray liquid 177.57g for the elution acceleration | stimulation layer (5) of the following composition prepared previously was sprayed in the micro fluid bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. By sieving the obtained granulated product with a round sieve of No. 40 (425 μm) and a round sieve of No. 150 (100 μm), the surface of the barrier layer-coated fine granules (3) is an elution promoting layer (5). Coated fine particles (hereinafter referred to as “elution promoting layer-coated fine particles (6)”) were obtained.

[Elution promotion layer (5) spray solution]
・ Hydroxypropylmethylcellulose 10 mass% aqueous solution
40.0 parts by mass, synthetic hydrotalcite 4.0 parts by mass, talc 1.6 parts by mass, purified water 54.4 parts by mass

  10 g of the obtained elution accelerating layer-coated fine granules (6) was charged into a minute amount fluidized bed granulator (Dalton Co., Ltd.). Then, the elution accelerating layer coating is carried out by adjusting the air supply temperature to around 35 ° C. to 55 ° C. and spraying 7 g of the previously prepared spray solution for the water-insoluble polymer layer (2) in a micro fluidized bed granulator. The surface of the fine particles (6) was covered with a water-insoluble polymer layer (2).

  Subsequently, the air supply temperature was adjusted to around 55 ° C. to 65 ° C., and 3.9 g of the above-mentioned spray solution for overcoat layer prepared in advance was sprayed into the microfluidized bed granulator.

  Thereafter, the particles were dried by adjusting the supply air temperature to around 60 ° C. and continuing the flow for 30 minutes. The obtained granulated material is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the elution accelerating layer-coated fine granules (6) has a water-insoluble polymer layer (2 ) And fine particles coated with the overcoat layer (2). The obtained fine particles were put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles.

The obtained fine granules and the formed component were mixed in the composition shown in Table 3 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Example 18]
Barrier layer-coated fine granules (3) were obtained by the same production method as in Example 13.
12 g of the obtained barrier layer-coated fine granules (3) were charged into a micro fluidized bed granulator (Dalton Co., Ltd.). Then, the air supply temperature is adjusted to around 35 ° C. to 55 ° C., and a 10 g spray solution for the water-insoluble polymer layer (3) having the following composition prepared in advance is sprayed into the micro fluidized bed granulator to cover the barrier layer. The surface of the fine particles (3) was covered with a water-insoluble polymer layer (3).

[Spray liquid for water-insoluble polymer layer (3)]
-0.22 parts by mass of 30% by weight ethylcellulose aqueous dispersion (trade name: Aquacoat (registered trademark) ECD, FMC)
Macrogol 6000 0.03 parts by mass Talc 0.06 parts by mass Triethyl citrate 0.04 parts by mass Purified water 9.65 parts by mass

  Subsequently, the supply air temperature was adjusted to around 55 ° C. to 65 ° C., and 4.1 g of the above-mentioned spray solution for overcoat layer prepared in advance was sprayed into a micro fluidized bed granulator.

  Thereafter, the particles were dried by adjusting the supply air temperature to around 60 ° C. and continuing the flow for 30 minutes. The obtained granulated material is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the barrier layer-coated fine granules (3) has a water-insoluble polymer layer (3). And fine granules coated with an overcoat layer were obtained. The obtained fine particles were put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles.

The obtained fine granules and the formed component were mixed in the composition shown in Table 3 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Example 19]
The drug substance-containing nucleus (2) was obtained by the same production method as in Example 13.
10 g of the obtained drug substance-containing core (2) was charged into a small amount fluidized bed granulator (Dalton Co., Ltd.). Then, the air supply temperature was adjusted to 60 ° C., and 46.1 g of the spray liquid for the barrier layer (4) having the following composition prepared in advance was sprayed into the fine fluid bed granulator. After spraying, the supply air temperature was adjusted to 60 ° C. and drying was performed for 30 minutes. The obtained granulated material is sieved with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the drug substance-containing core (2) is covered with the barrier layer (4). Fine particles (hereinafter referred to as “barrier layer-coated fine particles (4)”) were obtained.

[Spray liquid for barrier layer (4)]
・ Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer 10 mass% aqueous solution (POVACOAT (registered trademark, Daido Kasei Kogyo Co., Ltd.))
17.5 parts by mass, 10% by weight aqueous solution of hydroxypropylmethylcellulose
7.6 parts by mass, talc 2.6 parts by mass, triethyl citrate 1.0 part by mass, purified water 71.3 parts by mass

  10 g of the obtained barrier layer-coated fine granules (4) were charged into a micro fluidized bed granulator (Dalton Co., Ltd.). Then, the air supply temperature is adjusted to around 35 ° C. to 55 ° C., and 8.3 g of the spray liquid for the water-insoluble polymer layer (4) having the following composition prepared in advance is sprayed into the microfluidized fluidized bed granulator. The surface of the layer-coated fine granules (4) was coated with a water-insoluble polymer layer (4).

[Spray liquid for water-insoluble polymer layer (4)]
-Ethylcellulose 30% by weight aqueous dispersion 0.19 parts by mass (trade name: Aquacoat (registered trademark) ECD, FMC)
Macrogol 6000 0.02 parts by mass Talc 0.05 parts by mass Triethyl citrate 0.03 parts by mass Purified water 8.02 parts by mass

  Subsequently, the supply air temperature was adjusted to around 55 ° C. to 65 ° C., and 3.5 g of the above-mentioned spray solution for overcoat layer prepared in advance was sprayed into the micro fluidized bed granulator.

  Thereafter, the particles were dried by adjusting the supply air temperature to around 60 ° C. and continuing the flow for 30 minutes. The obtained granulated product is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the barrier layer-coated fine granules (4) is a water-insoluble polymer layer (4). And fine granules coated with an overcoat layer were obtained. The obtained fine particles were put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles.

The obtained fine granules and the formed component were mixed in the composition shown in Table 3 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Evaluation]
The orally disintegrating tablets of Examples 13 to 19 were evaluated by the same method as in Evaluation 1 above.
The results are shown in Table 3. In Table 3, a left-pointing arrow in the content of each component means that the numerical value is the same as that on the left. Moreover, the blank in the content of each component means that the component is not included.

As shown in Table 3, the orally disintegrating tablets of Examples 13 to 17 containing fine granules having an elution promoting layer are finer than the orally disintegrating tablets of Example 18 in which the fine granules do not have an elution promoting layer. Was excellent in dissolution of olmesartan medoxomil from
The orally disintegrating tablet of Example 19 containing hydroxypropylmethylcellulose in the barrier layer was excellent in the dissolution property of olmesartan medoxomil from the fine particles, even though the fine particles did not have the dissolution promoting layer.

[Example 20]
Non-parel (registered trademark) -108 (trade name, D-mannitol, spherical particles having a particle diameter of 75 μm to 150 μm, Freund Sangyo Co., Ltd.) 500 g and Olmesartan Medoxomil 178.058 g as core particles and a rolling fluidized bed granulator (Product name: FD-MP-01, Pauleck Co., Ltd.). Then, the rotor rotation speed was adjusted to 500 rpm and the supply air temperature was adjusted to 60 to 70 ° C., respectively, and 2782.1 g of the previously prepared spray liquid for drug substance layer (2) was sprayed into the rolling fluidized bed granulator. Thereafter, the supply air temperature was adjusted to 80 ° C. and drying was performed for 15 minutes. The obtained granulated material is sieved with a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the core particle is contained in the drug substance layer (2). The nucleus (3) was obtained.

  The obtained drug substance-containing core (3) (460 g) was charged into a rolling fluidized bed granulator (trade name: FD-MP-01, Pauleck Co., Ltd.). The rotor rotation speed was adjusted to 500 rpm and the supply air temperature was adjusted to 40 ° C. to 60 ° C., respectively, and 1097.2 g of the barrier layer (3) spray liquid prepared in advance was sprayed into the rolling fluidized bed granulator. After the completion of spraying, 460 g of the obtained granulated material was extracted, and 1058.6 g of the barrier layer (3) spray liquid was further sprayed into the rolling fluidized bed granulator. After spraying, the air supply temperature was adjusted to 80 ° C. and drying was performed for 30 minutes. The surface of the drug substance-containing core (3) is covered with the barrier layer (3) by sieving the resulting granulated product with a round sieve (355 μm) of No. 42 and a round sieve of No. 150 (100 μm). (Hereinafter referred to as “barrier layer-coated fine particles (5)”).

  12 g of the obtained barrier layer-coated fine granules (5) were charged into a small amount fluidized bed granulator (Dalton Co., Ltd.). Then, the air supply temperature is adjusted to around 35 ° C. to 55 ° C., and 10.5 g of the spray liquid for the water-insoluble polymer layer (5) having the following composition prepared in advance is sprayed into the microfluidized fluidized bed granulator to obtain a barrier. The surface of the layer-coated fine granules (5) was coated with a water-insoluble polymer layer (5).

[Spray liquid for water-insoluble polymer layer (5)]
・ Ethylcellulose 30% by weight aqueous dispersion 18.5 parts by mass (trade name: Aquacoat (registered trademark) ECD, FMC)
-0.7 parts by mass of triethyl citrate-12.1 parts by mass of purified water

  Subsequently, the air supply temperature was adjusted to around 80 ° C., and 9.9 g of the above-described overcoat layer spray solution prepared in advance was sprayed into the micro fluidized bed granulator.

  Thereafter, the particles were dried by continuing to flow for 30 minutes while maintaining the supply air temperature at around 80 ° C. The obtained granulated material was put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles. The obtained granulated product is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the barrier layer-coated fine granules (5) has a water-insoluble polymer layer (5). And fine granules coated with an overcoat layer were obtained.

The obtained fine granules and the formed component were mixed in the composition shown in Table 4 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).
In addition, the numerical value of each component in Table 4 shows content (mg) in one orally disintegrating tablet.

[Comparative Example 3]
Barrier layer-coated fine granules (5) were obtained by the same production method as in Example 20.
12 g of the obtained barrier layer-coated fine granules (5) were charged into a small amount fluidized bed granulator (Dalton Co., Ltd.). Then, the air supply temperature is adjusted to around 40 ° C., and 22.2 g of the spray liquid for water-insoluble polymer layer (6) having the following composition prepared in advance is sprayed into the microfluidized fluidized bed granulator so as to cover the barrier layer. The surface of the grain (5) was covered with a water-insoluble polymer layer (6).

[Spray liquid for water-insoluble polymer layer (6)]
Aminoalkyl methacrylate copolymer RS 12.5 parts by mass (trade name: Eudragit (registered trademark) RS30D, 30% by mass aqueous dispersion, Evonik)
-Sodium carboxymethyl cellulose 8.4 parts by mass-Polysorbate 80 0.8 parts by mass-Light anhydrous silicic acid 0.8 parts by mass-Purified water 44.2 parts by mass

  Subsequently, the air supply temperature was adjusted to around 80 ° C., and 9.9 g of the above-described overcoat layer spray solution prepared in advance was sprayed into the micro fluidized bed granulator.

  Thereafter, the particles were dried by continuing to flow for 30 minutes while maintaining the supply air temperature at around 80 ° C. The obtained granulated material was put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles. The obtained granulated product is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the barrier layer-coated fine granules (5) has a water-insoluble polymer layer (6). And fine granules coated with an overcoat layer were obtained.

The obtained fine granules and the formed component were mixed in the composition shown in Table 4 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Comparative Example 4]
Barrier layer-coated fine granules (5) were obtained by the same production method as in Example 20.
12 g of the obtained barrier layer-coated fine granules (5) were charged into a small amount fluidized bed granulator (Dalton Co., Ltd.). Then, the air supply temperature is adjusted to around 40 ° C., and 16.8 g of the spray liquid for the water-insoluble polymer layer (7) having the following composition prepared in advance is sprayed into the microfluidized fluidized bed granulator so as to cover the barrier layer. The surface of the grain (5) was covered with a water-insoluble polymer layer (7).

[Spray liquid for water-insoluble polymer layer (7)]
Aminoalkyl methacrylate copolymer E 100 parts by mass (trade name: Eudragit (registered trademark) EPO, Evonik)
-Sodium lauryl sulfate 10 parts by mass-Stearic acid 15 parts by mass-Monostearate glycerin 5 parts by mass-Polysorbate 80 2 parts by mass-Purified water 868 parts by mass

  Subsequently, the air supply temperature was adjusted to around 80 ° C., and 9.9 g of the above-described overcoat layer spray solution prepared in advance was sprayed into the micro fluidized bed granulator.

  Thereafter, the particles were dried by continuing to flow for 30 minutes while maintaining the supply air temperature at around 80 ° C. The obtained granulated material was put into a glass bottle containing silica gel and allowed to stand in a thermostatic bath at 60 ° C. for 2 hours to cure the polymer contained in the particles. The obtained granulated product is passed through a No. 40 round sieve (425 μm) and a No. 150 round sieve (100 μm), so that the surface of the barrier layer-coated fine granules (5) has a water-insoluble polymer layer (7). And fine granules coated with an overcoat layer were obtained.

The obtained fine granules and the formed component were mixed in the composition shown in Table 4 to obtain a tableting powder (mixed powder).
A specified amount of the obtained tableting powder (mixed powder) was weighed, and using a rotary tableting machine (product name: HT-AP-SS, Hata Iron Works Co., Ltd.) Was used and compression molded at a rotation speed of 20 rpm and a tableting pressure of about 10 kN to obtain an orally disintegrating tablet (tablet).

[Evaluation]
About the orally disintegrating tablet of Example 20 and Comparative Examples 3-4, it evaluated by the same method as said evaluation 2-5.
The results are shown in Table 4. In Table 4, the left-pointing arrow in the content of each component means that the numerical value is the same as that on the left. Moreover, the blank in the content of each component means that the component is not included.

As shown in Table 4, the orally disintegrating tablet of Example 20 was able to reduce the odor and bitterness derived from olmesartan medoxomil.
On the other hand, the orally disintegrating tablets of Comparative Examples 3 to 4 in which the water-insoluble polymer contained in the water-insoluble polymer layer has an amino group could not reduce the odor derived from olmesartan medoxomil.

Claims (12)

A barrier layer containing mainly olmesartan medoxomil-containing drug substance-containing nuclei and containing at least one selected from polyvinyl alcohol and vinyl alcohol copolymers in order from the drug substance-containing nuclei side, and water having no amino group Fine granules having a water-insoluble polymer layer comprising an insoluble polymer;
An external formation for fine grains;
Orally disintegrating tablets.   The formed component contained outside with respect to the fine granules contains at least one selected from calcium silicate, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, and cross carboxymethyl cellulose sodium. Orally disintegrating tablets.   The orally disintegrating tablet according to claim 1 or 2, comprising at least one selected from magnesium salts and aluminum salts.   The orally disintegrating tablet according to claim 3, wherein the formed component contained on the outside of the fine granules contains at least one selected from a magnesium salt and an aluminum salt.   The fine particles have an elution promoting layer containing at least one selected from a surfactant and a basic substance between the barrier layer and the water-insoluble polymer layer. Orally disintegrating tablets.   The oral disintegration according to any one of claims 1 to 5, wherein at least one selected from polyvinyl alcohol and a vinyl alcohol copolymer is a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. Tablets.   The orally disintegrating tablet according to any one of claims 1 to 6, wherein the water-insoluble polymer having no amino group is ethyl cellulose.   The at least one selected from magnesium salts and aluminum salts is at least one selected from magnesium oxide, magnesium hydroxide, magnesium carbonate, synthetic hydrotalcite, and aluminum hydroxide. Orally disintegrating tablets.   The orally disintegrating tablet according to claim 5, wherein the surfactant is a sucrose fatty acid ester.   The orally disintegrating tablet according to claim 5 or 9, wherein the basic substance is at least one selected from synthetic hydrotalcite and meglumine.   The orally disintegrating tablet according to any one of claims 1 to 10, wherein the barrier layer further comprises hydroxypropylmethylcellulose.   The orally-disintegrating tablet according to any one of claims 1 to 11, wherein the drug substance-containing core has a core particle as a center and a drug substance layer containing olmesartan medoxomil on the outside of the core particle.