JP5934835B2 - Enteric granules and pharmaceutical compositions - Google Patents

Description

  The present invention relates to enteric granules and pharmaceutical compositions containing the same.

Orally disintegrating tablets are oral preparations that dissolve or disintegrate in the oral cavity immediately after taking.
When the active ingredient is chemically unstable to acids, it is not dissolved in a low pH solution such as gastric juice, but is effective by an enteric film that dissolves in a neutral pH solution such as intestinal fluid. It is common practice to coat and formulate the ingredients.
In WO 2009/069280, in addition to coating the active ingredient with an enteric film, the aqueous solution of the alkaline component in which the chemically unstable active ingredient is dissolved in the alkaline component particles in a fluidized state. A method for improving the storage stability of chemically unstable active ingredients by spraying and granulating is described.
JP-T-2010-526110 describes a tablet that can rapidly release an active ingredient even when the active ingredient is enteric coated.

For enteric fine granules prepared by blending alkaline components to improve the storage stability of active ingredients that are unstable to acids, dissolution test solution simulating the pH of intestinal fluid (dissolution test second solution and near neutral) When the elution test is carried out, the enteric layer dissolves rapidly and gels, and the enteric fine particles agglomerate to hinder the elution of the active ingredient, causing a delay in the elution of the active ingredient. It became clear that In such a preparation, when orally administered, fine particles are aggregated even in the intestinal fluid, and the elution of the active ingredient is expected to be prevented.
There is no known method for suppressing aggregation in an elution test solution simulating the pH of enteric fluid of enteric fine granules prepared by blending an acid-labile active ingredient and an alkaline ingredient.

An object of the present invention is to provide an enteric fine particle capable of suppressing the aggregation of enteric fine particles in intestinal fluid and capable of quickly eluting an active ingredient.
Moreover, this invention makes it a subject to provide the pharmaceutical composition containing the enteric fine particle which suppresses aggregation of enteric fine particles in intestinal fluid, and can elute an active ingredient rapidly.

Means for solving the above-mentioned problems are as follows.
<1> An active ingredient-containing nucleus containing an active ingredient-containing nucleus containing an acid-labile active ingredient and an alkaline component, an intermediate layer covering the active ingredient-containing nucleus, and an enteric layer covering the intermediate layer And at least one selected from the group consisting of intermediate layers, enteric fine granules comprising at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride .
<2 > Enteric fine granules according to <1 >, wherein the salt component contains calcium chloride.
< 3 > The enteric fine granules according to <1> or <2> , wherein the alkaline component contains an alkali having a saturated aqueous solution having a pH of 12 or more at 25 ° C.
< 4 > The enteric fine granules according to any one of <1> to < 3 >, wherein the alkaline component contains sodium hydroxide.
< 5 > The enteric fine granules according to any one of <1> to < 4 >, wherein the acid-labile active ingredient contains a proton pump inhibitor.
< 6 > The enteric fine granules according to any one of <1> to < 5 >, wherein the active ingredient unstable to an acid contains a benzimidazole compound or a salt thereof.
< 7 > The enteric fine granules according to any one of <1> to < 6 >, wherein the active ingredient unstable to an acid contains rabeprazole or rabeprazole sodium.
< 8 > Enteric fine granules according to any one of <1> to < 7 >, wherein the intermediate layer is composed of two or more layers.
<9> the intermediate layer is Ri Do two layers or more of the plurality of layers, alkaline components contained in at least the innermost intermediate layer <1> according to any one of to <8> enteric fine granules .
< 10 > The enteric fine granules according to any one of <1> to < 9 >, wherein the enteric layer contains a (meth) acrylic acid copolymer.
< 11 > At least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer contains at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride, and a sugar or a sugar alcohol < Enteric fine granules according to any one of 1> to < 10 >.
< 12 > At least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer includes at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride, and an inorganic substance having water absorption properties. The enteric fine granules according to any one of <1> to < 10 >.
< 13 > At least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer is at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride , a sugar or a sugar alcohol, and water absorption The enteric fine granules according to any one of <1> to < 10 >, comprising an inorganic substance having a certain amount.
< 14 > A pharmaceutical composition comprising a plurality of enteric fine granules according to any one of <1> to < 13 >.
< 15 > The pharmaceutical composition according to < 14 >, which is an orally disintegrating tablet.

ADVANTAGE OF THE INVENTION According to this invention, the enteric fine particle which can suppress the aggregation of enteric fine particles in intestinal fluid and can elute an active ingredient rapidly can be provided.
Moreover, according to this invention, the pharmaceutical composition containing the enteric fine particle which suppresses aggregation of enteric fine particles in an intestinal fluid and can elute an active ingredient rapidly can be provided.

Hereinafter, the enteric fine granules of the present invention and pharmaceutical compositions containing the same will be described in detail.
In addition, the numerical value range shown using "to" in this specification shows the range which includes the numerical value described before and behind "to" as a minimum value and a maximum value, respectively.
In this specification, the amount of each component in the composition is the sum 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 quantity.
In this specification, the term “process” is not limited to an independent process, and is included in the term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. .
In this specification, the (meth) acrylic acid copolymer means a copolymer containing at least one of acrylic acid and methacrylic acid as a copolymerization component.

≪Enteric fine granules≫
The enteric fine granules of the present invention have an active ingredient-containing nucleus containing an acid-labile active ingredient and an alkaline ingredient, an intermediate layer coated with the active ingredient-containing nucleus, and an enteric layer coated with the intermediate layer. And at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer contains at least one salt component selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts and soluble metal salts. .
The enteric fine granules of the present invention suppress the aggregation of enteric fine granules because the enteric fine granules prepared by blending a chemically unstable active ingredient and an alkaline ingredient contain a salt component. The active ingredient can be eluted quickly. This is presumably because gelation of the enteric membrane is prevented even when the enteric membrane dissolves in the intestinal fluid where the pH value is near neutral.
The enteric fine granules of the present invention may further contain other components or other layers as necessary.

In the present specification, the enteric fine particles mean particles having an average particle diameter of 2 mm or less coated with an enteric layer.
In this specification, the average particle diameter means a volume average particle diameter.
As a measuring method of the average particle diameter, there is a laser diffraction particle size distribution measuring method, and a specific example is a method using a laser diffraction scattering particle size distribution measuring device (product name: LS 13 320, manufactured by Beckman Coulter, Inc.). It is done.

<Active ingredient-containing core>
The active ingredient-containing core contains an acid-unstable active ingredient (hereinafter also simply referred to as “active ingredient”) and an alkaline component.
The acid-labile active ingredient is not particularly limited, and is not limited to antacids, anti-ulcers, antiplatelets, antipsychotics, bronchial asthma, allergic rhinitis, antihypertensives, antidepressants, antihistamines Osteoporosis drugs, diabetes drugs, diuretics, antirheumatic drugs, and the like.
Among them, the proton pump inhibitor is preferable as an active ingredient from the viewpoint that the effect of the present invention can be fully exhibited because it is easily decomposed into an acid, and a benzimidazole compound such as rabeprazole, lansoprazole, omeprazole, pantoprazole or the like. A salt is more preferable, and rabeprazole or rabeprazole sodium which is extremely easily decomposed by an acid is more preferable.
An active ingredient may be used individually by 1 type and can also use 2 or more types together.
50% by mass or more of the active ingredient is preferably rabeprazole or rabeprazole sodium, more preferably 70% by mass or more is rabeprazole or rabeprazole sodium, and most preferably 90% by mass or more is rabeprazole or rabeprazole sodium.

  The content of the active ingredient relative to the total mass of the enteric fine granules can be appropriately determined by taking into consideration the lower limit and upper limit of the daily dose depending on the type of active ingredient. For example, when rabeprazole sodium is used as the active ingredient, the content of the active ingredient is preferably 2% by mass to 16% by mass, and 2.5% by mass with respect to the total mass of the enteric fine granules. It is more preferably ˜12% by mass, and further preferably 3% by mass to 9% by mass.

The alkaline component is not particularly limited as long as the pH of the saturated aqueous solution at 25 ° C. is higher than 7.0. From the viewpoint of the storage stability of the active ingredient unstable to acid in the preparation, the pH of the saturated aqueous solution of the alkaline component at 25 ° C. is preferably 12 or more.
The pH can be measured, for example, with a pH meter (model number: HM-30V, manufactured by Toa DKK Corporation).
The alkali contained in the alkaline component is preferably a saturated aqueous solution having a pH at 25 ° C. of 12 or more.
Examples of the alkali include alkali metals, alkaline earth metals, other metal hydroxides, oxides or carbonates, and organic compounds having an amino group. Specifically, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, sodium bicarbonate, magnesium carbonate, calcium carbonate, magnesium oxide, N-methyl-D-glucamine, trishydroxymethylamino Examples include methane, lysine, arginine, histidine and the like. From the viewpoint of storage stability of the active ingredient, sodium hydroxide, potassium hydroxide, and magnesium oxide are preferable, sodium hydroxide and potassium hydroxide are more preferable, and sodium hydroxide is more preferable.
When the solvent used for the preparation of the active ingredient-containing core is water, it is alkaline in order to prevent decomposition of the active ingredient that may occur during the preparation manufacturing process and to obtain storage stability of the active ingredient after preparation preparation. As the component, those having a saturated aqueous solution having a high pH are preferable. For example, when rabeprazole sodium is used as the active ingredient, it is more preferable to use an alkaline component having a pH of 12 or higher at 25 ° C. of the saturated aqueous solution, and it is more preferable that the alkaline component contains sodium hydroxide.
An alkaline component may be used individually by 1 type, and can also use 2 or more types together.
50% by mass or more of the alkaline component is preferably sodium hydroxide, more preferably 70% by mass or more is sodium hydroxide, and most preferably 90% by mass or more is sodium hydroxide.

  The content of the alkaline component relative to the total mass of the enteric fine granules can be appropriately determined depending on the type of the active ingredient. For example, when rabeprazole sodium is used as the active ingredient, the content of the alkaline component is preferably 0.01% by mass to 10% by mass with respect to the total mass of the enteric fine granules. It is more preferably from 5% by mass to 5% by mass, and further preferably from 0.1% by mass to 3% by mass.

  The mass ratio of the active ingredient contained in the enteric fine granules and the alkaline component is preferably 100: 1 to 1: 100, more preferably 50: 1 to 1:50, 15: 1 More preferably, it is ˜1: 15.

  The active ingredient-containing nucleus may contain other components in addition to the active ingredient and the alkaline component as long as the effects of the present invention are not impaired. When the active ingredient-containing core contains other components, the active ingredient and alkaline component may be mixed with other components, or the surface of the other component may be coated with the active component and alkaline component. It may be a configured. The form to be used can be appropriately determined in consideration of the content of the active ingredient, the daily dose, the particle size, and the like.

Other components include components that can function as excipients that improve moldability and convenience, components that can function as binders that contribute to improved moldability, and function as a disintegrant that promotes disintegration of the preparation. Components that can be used, and components that can function as lubricants and fluidizing agents that contribute to the improvement of manufacturability.
Specific examples of the component that can function as an excipient for improving moldability and convenient administration include sugar, sugar alcohol, crystalline cellulose, and starch. Examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.
Examples of the component that can function as a binder that contributes to improvement of moldability include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.
As a component that can function as a disintegrant that promotes disintegration, a known disintegrant can be used. For example, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, starch Examples include sodium glycolate.
Examples of components that can function as a lubricant or a fluidizing agent that contribute to the improvement of manufacturability include talc and light anhydrous silicic acid.
The content of other components contained in the active ingredient-containing nucleus can be appropriately determined depending on the type of active ingredient. For example, the content of other components can be 99% by mass or less, preferably 10% by mass to 90% by mass, and preferably 50% by mass to 80% by mass with respect to the total mass of the active ingredient and the alkaline component. It is more preferable to make it into the mass%.

  The average particle size of the active ingredient-containing nuclei is preferably 10 μm to 500 μm, more preferably 50 μm to 400 μm, and even more preferably 100 μm to 300 μm.

<Intermediate layer>
The intermediate layer is a layer that covers the active ingredient-containing core and prevents the enteric layer from contacting the active ingredient-containing core. The intermediate layer can include a polymer, for example, a water-soluble polymer, a water-insoluble polymer, an alkaline polymer, and the like. Further, as will be described later, the intermediate layer only needs to be composed of one or more layers, and the intermediate layer may be a multilayer such as two layers or three layers.

The water-soluble polymer contained in the intermediate layer is not particularly limited as long as it is a component that can be dissolved in any of acidic, neutral and alkaline solutions without depending on the pH value of the solution to be contacted. Can be used.
The water-soluble polymer is preferably a water-soluble polymer that does not prevent elution of the coated active ingredient after the enteric layer covering the intermediate layer is dissolved in the intestine.
In the present specification, the water-soluble polymer means a polymer having a solubility in water at 20 ° C. of 10 g / L or more.

Specific examples of the water-soluble polymer include water-soluble cellulose derivatives, water-soluble vinyl polymer derivatives, water-soluble acrylic acid copolymers, polyhydric alcohol polymers, and copolymers thereof. Preferably, a water-soluble cellulose derivative and a water-soluble vinyl polymer derivative are mentioned, More preferably, a water-soluble cellulose derivative is mentioned.
More specifically, examples of the water-soluble cellulose derivative include methyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose. Examples of the water-soluble vinyl polymer derivative include polyvinyl alcohol and polyvinyl pyrrolidone. Examples of the water-soluble acrylic acid copolymer include polymers that contain acrylic acid, acrylic acid ester, methacrylic acid ester, and the like and that can be dissolved in any of acidic, neutral, and alkaline aqueous solutions. Examples of the polyhydric alcohol polymer include macrogol or polyglycerin. Examples of the copolymer of these polymers include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol polyvinyl alcohol graft copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, and the like.
Among these, hydroxypropylmethylcellulose and hydroxypropylcellulose are preferable as the water-soluble polymer from the viewpoints of viscosity and binding properties suitable for fine particle coating.
A commercially available product may be used as the water-soluble polymer. Examples of commercially available products include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (trade name: POVACOAT, manufactured by Daido Kasei Kogyo Co., Ltd.), polyethylene glycol / polyvinyl alcohol graft copolymer (trade name: Kollicoat IR). And a vinyl pyrrolidone / vinyl alcohol copolymer (trade name: Kollicoat VA64, manufactured by BASF).
Any one water-soluble polymer may be used alone, or two or more water-soluble polymers may be used in combination.
The content of the water-soluble polymer contained in the intermediate layer can be appropriately determined in consideration of the type, content, daily dose, particle size, etc. of the active ingredient. For example, the content of the water-soluble polymer can be 100% by mass or less, preferably 15% by mass to 80% by mass, and 30% by mass with respect to the total mass of the film components constituting the intermediate layer. It is more preferable to set it to -60 mass%.

The water-insoluble polymer contained in the intermediate layer is not particularly limited as long as it is a component that does not depend on the pH value of the solution in contact and does not dissolve in any of acidic, neutral and alkaline solutions. Can be used.
The water-insoluble polymer is preferably a polymer that controls the elution of the active ingredient, for example, by slowly releasing the coated active ingredient after the enteric layer covering the intermediate layer is dissolved in the intestine.
In the present specification, the 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 include water-insoluble cellulose ether and water-insoluble acrylic acid copolymer. Examples of the water-insoluble cellulose ether include ethyl cellulose. Examples of the water-insoluble acrylic acid copolymer include ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, and the like.
A commercially available product can also be used as the water-insoluble polymer. Examples of commercially available water-insoluble cellulose ethers include ethylcellulose aqueous dispersions (trade name: Aquacoat ECD, manufactured by FMC). Commercially available water-insoluble acrylic copolymers include ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer (trade name: Eudragit RS, manufactured by Evonik), ethyl acrylate / methyl methacrylate Examples thereof include a polymer dispersion (trade name: Eudragit NE30D, manufactured by Evonik).
As the water-insoluble polymer, any one of the water-insoluble polymers may be used alone, or two or more kinds thereof may be used in combination.
The content of the water-insoluble polymer contained in the intermediate layer can be appropriately determined in consideration of the type, content, daily dose, particle size, etc. of the active ingredient. For example, the content of the water-insoluble polymer can be 100% by mass or less, preferably 15% by mass to 80% by mass, and preferably 30% by mass to 30% by mass with respect to the total mass of the components constituting the intermediate layer. More preferably, it is 60 mass%.

  The alkaline polymer contained in the intermediate layer is not particularly limited as long as the polymer aqueous solution or water suspension exhibits alkalinity, and a known polymer can be used. Specifically, it is a polymer exhibiting a pH of an aqueous solution or suspension of polymer of about 7.5 or more, and preferably a polymer exhibiting 8.5 or more.

Examples of the alkaline polymer include polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, methyl methacrylate / diethylaminoethyl methacrylate copolymer, and the like.
A commercial item can also be used as an alkaline polymer. For example, polyvinyl acetal diethylaminoacetate (trade name: AEA, manufactured by Mitsubishi Chemical Food Co., Ltd.), methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (trade name: Eudragit E100, manufactured by Evonik), methacryl Examples include methyl acid / diethylaminoethyl methacrylate copolymer (trade name: Kollicoat Smartseal 30D, manufactured by BASF).
As the alkaline polymer, any one of the alkaline polymers may be used alone, or two or more may be used in combination.
The content of the alkaline polymer contained in the intermediate layer can be appropriately determined in consideration of the type, content, daily dose, particle size and the like of the active ingredient. For example, the content of the alkaline polymer can be 100% by mass or less, preferably 15% by mass to 80% by mass, and preferably 30% by mass to 30% by mass with respect to the total mass of the film components constituting the intermediate layer. More preferably, it is 60 mass%.

The intermediate layer may contain other components in addition to the polymer as long as the effects of the present invention are not impaired. As other ingredients, components that can function as excipients that improve moldability and convenience, components that can function as binders that contribute to improvement of moldability, and disintegrants that promote the disintegration of formulations A component that can function, a component that can function as a lubricant or a fluidizing agent that contributes to an improvement in manufacturability, and the like, and one component may perform two or more functions.
Specific examples of the component that can function as an excipient for improving moldability and convenient administration include sugar, sugar alcohol, crystalline cellulose, and starch. Examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.
Examples of the component that can function as a binder that contributes to improvement of moldability include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.
A well-known thing can be used as a disintegrating agent. For example, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, starch Examples include sodium glycolate.
Examples of components that can function as a lubricant or a fluidizing agent that contribute to the improvement of manufacturability include talc and light anhydrous silicic acid.

  The form in which the intermediate layer covers the active ingredient-containing nucleus may be in a state where the intermediate layer exists on at least a part of the surface of the active ingredient-containing nucleus. The intermediate layer preferably covers 1/4 or more of the surface of the active ingredient-containing core, and more preferably covers 1/2 or more. Most preferably, the intermediate layer covers the entire surface of the active ingredient-containing core.

The coating amount of the intermediate layer when the active ingredient-containing nuclei are coated with the intermediate layer is not particularly limited as long as the active ingredient-containing nuclei are coated in the intermediate layer. For example, the mass of the intermediate layer used for coating the active ingredient-containing nucleus is 0.01 to 50 times, 0.1 to 5 times, or 0. The amount is 5 times to 1 time.
In forming the intermediate layer, 0.01 times to 50 times, 0.1 times to 5 times, or 0.5 times the amount of the active ingredient-containing core based on the mass. What is necessary is just to melt | dissolve or suspend the component which comprises the intermediate | middle layer of -1 time mass in a pharmacologically acceptable solvent, and to spray on an active ingredient containing nucleus.

As described above, the intermediate layer may be composed of one or more layers, and the intermediate layer may be composed of two or more layers.
By providing a plurality of intermediate layers, it is possible to improve the storage stability of the active ingredient contained in the active ingredient-containing core over time, so that the intermediate layer may be composed of two or more layers. preferable.
In the case of providing an intermediate layer of two or more layers, a plurality of intermediate layer coating liquids having different compositions and the like are divided into a plurality of times for each intermediate layer coating liquid, and the active ingredient-containing core Just spray it. For example, the composition of the intermediate layer coating solution sprayed directly onto the active ingredient-containing core is composed of an alkaline component, a component that can function as a binder, a component that can function as an excipient, a component that can function as a lubricant, and water. Preferably, the composition comprises an alkaline component, a component that can function as a binder, a component that can function as an excipient, a component that can function as a lubricant, and water. preferable.
Moreover, when providing the intermediate layer of two or more layers, it is preferable that an alkaline component is contained in at least the innermost intermediate layer among the intermediate layers.

<Salt component>
The enteric fine granules of the present invention are at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer, and at least selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts and soluble metal salts. Contains one salt component.
By containing the salt component in at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer, the aggregation of enteric fine particles is suppressed and enteric fine granules are compared with the case where no salt component is contained. From this, the active ingredient can be eluted quickly.

Examples of alkali metal salts include lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs) and other alkali metal chlorides, fluorides, bromides, iodides, phosphates, Examples thereof include nitrates, nitrites, sulfates, borates, carbonates, bicarbonates, carboxylates, sulfonates, and the like.
Alkaline earth metal salts include chlorides, fluorides, bromides, iodides, phosphates, nitrates of alkaline earth metals such as magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) Nitrites, sulfates, borates, carbonates, bicarbonates, carboxylates, sulfonates and the like.
Examples of ammonium salts include ammonium chloride, ammonium acetate, and ammonium sulfate.
Soluble metal salts include aluminum (Al), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel, (Ni), copper (Cu ), Zinc (Zn), silver (Ag) and other metal chlorides, fluorides, bromides, iodides, phosphates, nitrates, nitrites, sulfates, borates, carbonates, bicarbonates, carvone And acid salts and sulfonates.
The salt component is at least selected from the group consisting of an alkali metal salt and an alkaline earth metal salt from the viewpoint of inhibiting aggregation between enteric fine granules and from the viewpoint that there are many salts that can be used as pharmaceutical additives. One type is preferable.

  The salt component preferably contains chloride, bromide or iodide, from the viewpoint of inhibiting aggregation between enteric fine granules and from the viewpoint that there are many salts that can be used as a pharmaceutical additive, including chloride. It is more preferable.

  It is preferable that a salt component contains at least 1 sort (s) chosen from the group which consists of calcium chloride, sodium chloride, and potassium chloride from a viewpoint of aggregation suppression of enteric fine granules. Among them, calcium chloride has a high effect of inhibiting aggregation between enteric fine granules, so the amount added to enteric fine granules can be made smaller than other salt components, and the average particle diameter of enteric fine granules It is preferable compared to other salt components in that it is easy to control.

The content of the salt component with respect to the total mass of the enteric fine granules can be appropriately determined in consideration of the type of active ingredient, the content, the daily dose, the particle diameter, the type of salt component, and the like.
When using calcium chloride, the content of calcium chloride with respect to the total mass of the enteric fine granules is preferably 0.05% by mass to 10% by mass, and preferably 0.1% by mass to 8% by mass. Is more preferable, and it is further more preferable that it is 0.5 mass%-5 mass%.
When sodium chloride or potassium chloride is used, the content of sodium chloride or potassium chloride with respect to the total mass of the enteric fine granules is preferably 0.05% by mass to 10% by mass, and 0.1% by mass. % To 8% by mass is more preferable, and 1% to 6% by mass is further preferable.

The salt component may be contained in at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer. Especially, it is preferable that a salt component is contained in an intermediate | middle layer from a viewpoint of the elution rate of the active ingredient from enteric fine granules.
In the enteric fine granules of the present invention, by combining the alkaline component and the salt component, the polymer is insolubilized by the salting out phenomenon by the salt component even after dissolution of the enteric layer, and the dissolution rate of the active ingredient is reduced. There is no reduction.

One of the more preferable embodiments of the enteric fine granules of the present invention is that at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer contains a salt component and a sugar or a sugar alcohol. Thereby, the storage stability of an active ingredient can further improve.
The type of sugar or sugar alcohol is not particularly limited, but is preferably sugar or sugar alcohol having a critical relative humidity of 70% or higher at 37 ° C., and sugar or sugar alcohol having a critical relative humidity of 80% or higher. Is more preferable, and sugar or sugar alcohol having a critical relative humidity of 90% or more is more preferable.
Specific examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like, and lactose is more preferable.
Specific examples of the sugar alcohol include mannitol, sorbitol, xylitol, erythritol, maltitol, lactitol, isomalt, and the like, and mannitol, erythritol, maltitol, or lactitol is more preferable.
Examples of the combination of the salt component and the sugar or sugar alcohol include a combination of calcium chloride and mannitol, a combination of sodium chloride and mannitol, a combination of sodium chloride and lactose.
Calcium chloride has higher hygroscopicity than other salt components, but by combining calcium chloride and mannitol, the storage stability of the active ingredient can be sufficiently maintained even in special environments with high humidity. Therefore, it is preferable.

  The content of sugar or sugar alcohol can be appropriately determined depending on the combination of the salt component and sugar or sugar alcohol. For example, when calcium chloride is used as the salt component and mannitol is used as the sugar or sugar alcohol, the content of mannitol is preferably 10% by mass to 300% by mass with respect to the total mass of calcium chloride. The content is more preferably 25% by mass to 200% by mass, and further preferably 50% by mass to 150% by mass.

As another more preferable aspect of the enteric fine granules of the present invention, at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer contains a salt component and a water-absorbing inorganic substance. Can be mentioned. Thereby, the storage stability of an active ingredient can further improve.
Any inorganic substance having water absorption can be used without particular limitation as long as it can prevent deliquescence when coexisting with a salt exhibiting deliquescence.
Specific examples of the water-absorbing inorganic substance include light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminate metasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, anhydrous calcium hydrogen phosphate, magnesium alumina hydroxide, etc. Is mentioned. Preferably, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminate metasilicate, and anhydrous calcium hydrogen phosphate are used.

Examples of the combination of the salt component and the water-absorbing inorganic material include a combination of calcium chloride and light anhydrous silicic acid, a combination of sodium chloride and hydrous silicon dioxide, a combination of sodium chloride and alumino magnesium metasilicate, and the like.
Calcium chloride is more deliquescent than other salt components, but by combining calcium chloride and light anhydrous silicic acid, the storage stability of the active ingredient is sufficiently maintained even in special environments with high humidity. This is preferable.

The content of the water-absorbing inorganic substance can be appropriately determined depending on the combination of the salt component and the water-absorbing inorganic substance. For example, when calcium chloride is used as the salt component and light anhydrous silicic acid is used as the water-absorbing inorganic substance, the content of light anhydrous silicic acid is 10% by mass to 300% by mass with respect to the total mass of calcium chloride. %, More preferably 25% by mass to 200% by mass, and still more preferably 50% by mass to 150% by mass.
Moreover, as another more preferable aspect of the enteric fine granules of the present invention, at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer comprises a salt component, a sugar or a sugar alcohol, and a water absorption property. And a certain inorganic substance.

<Enteric layer>
The enteric layer is a layer covering the intermediate layer, and preferably contains an enteric coating agent. Moreover, the enteric layer should just be comprised from one or more layers, and multilayers, such as two layers, may be sufficient as an enteric layer.

The enteric coating agent is not particularly limited as long as it is an enteric polymer that is substantially insoluble at an acidic pH but is at least partially soluble at an alkaline pH from a weaker acidic pH. Acidic pH refers to a pH of about 0.5 to about 4.5, preferably a pH of about 1.0 to about 2.0. A weaker acidic pH to alkaline pH represents about 5.0 to 9.0, preferably about 6.0 to about 7.5.
The fact that the enteric coating agent is soluble means that the solubility in a contacting solution at 20 ° C. is 10 g / L or more.

Examples of the enteric coating agent include enteric cellulose derivatives and enteric (meth) acrylic acid copolymers.
Examples of the enteric cellulose derivative include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and the like.
Examples of enteric (meth) acrylic acid copolymers include methacrylic acid copolymers and acrylic acid copolymers. Specifically, methacrylic acid / methyl methacrylate copolymers, methacrylic acid / ethyl acrylate copolymers Examples thereof include a polymer and a methyl acrylate / methyl methacrylate / methacrylic acid copolymer.
Among them, as the enteric film, a (meth) acrylic acid copolymer is preferable from the viewpoint of easy coating of fine particles with a low viscosity even at a high concentration.
Commercially available products can be used as the enteric cellulose derivative and the enteric acrylic acid copolymer. Commercially available enteric cellulose derivatives include hydroxypropyl methylcellulose acetate succinate (trade name: AQOAT, manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl methylcellulose phthalate (trade name: HPMCP, manufactured by Shin-Etsu Chemical Co., Ltd.), Examples thereof include carboxymethyl ethyl cellulose (trade name: CMEC, manufactured by Freund Corporation). Commercially available enteric acrylic copolymers include methacrylic acid / methyl methacrylate copolymers (trade names: Eudragit L100, Eudragit S100, manufactured by Evonik), methacrylic acid / ethyl acrylate copolymers (trade name: Eudragit L100-55, Eudragit L30D55, manufactured by Evonik), methyl acrylate / methyl methacrylate / methacrylic acid copolymer (trade name: Eudragit FS30D, manufactured by Evonik), and the like.
The enteric coating agent may be used alone or in combination of two or more components having different properties or two or more components having different properties depending on the purpose. Good. Moreover, when using combining 2 or more types of components, it can also be used, for example so that it may become the form of a multilayered structure.
The content of the enteric coating agent with respect to the total mass of the enteric fine granules can be appropriately determined in consideration of the type, content, daily dose, particle size, and the like of the active ingredient.

The enteric layer contributes to the improvement of moldability and components that can function as an excipient that makes it easy to take and improve formability, as long as the effects of the present invention are not impaired, in addition to the enteric coating agent. Components that can function as binders, components that can function as lubricants and fluidizing agents that contribute to the improvement of manufacturability, components that can function as plasticizers that improve the plasticity of the film, and pH that adjust the pH of the coating liquid Examples include regulators.
Specific examples of the component that can function as an excipient for improving moldability and convenient administration include sugar, sugar alcohol, crystalline cellulose, and starch.
Examples of the component that can function as a binder that contributes to improvement of moldability include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.
Ingredients that can function as lubricants and fluidizing agents that contribute to the improvement of manufacturability include talc, light anhydrous silicic acid, glyceryl monostearate, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. Can be mentioned.
Examples of the component that can function as a plasticizer for improving the plasticity of the film include triethyl citrate, polyethylene glycol, polyoxyethylene sorbitan monooleate, acetyl triethyl citrate, tributyl citrate, and tributyl acetyl citrate.
Examples of the pH adjuster include citric acid and sodium hydroxide.

  The form in which the enteric layer covers the intermediate layer may be in a state where the enteric layer is present on at least a part of the surface of the intermediate layer. The enteric layer preferably covers 1/4 or more of the surface of the intermediate layer, and more preferably covers 1/2 or more. Most preferably, the enteric layer covers the entire surface of the intermediate layer.

The coating amount of the enteric layer when the intermediate layer is coated with the enteric layer is not particularly limited as long as the intermediate layer is coated with the enteric layer. For example, the mass of the enteric layer used for coating the intermediate layer is preferably 0.1 to 15 times, preferably 1 to 5 times the total mass of the intermediate layer. It is more preferable that the amount is double to 5 times.
Further, when forming the enteric layer, it is 0.1 to 15 times, preferably 1 to 5 times, and preferably 2 times the mass of the intermediate layer on a mass basis. What is necessary is just to melt | dissolve or suspend the component which comprises the enteric layer of the mass more preferable in the quantity-5 times amount in the pharmacologically acceptable solvent, and to spray on an intermediate | middle layer. When the intermediate layer is composed of two or more layers, the layer farthest from the active ingredient-containing nucleus (the layer closest to the enteric layer) is covered with the enteric layer.

The enteric layer may be composed of one or more layers as described above, and the enteric layer may be two layers or the like.
By providing multiple enteric layers, reducing the amount of ingredients that affect the storage stability of active ingredients, etc., providing layers with different flexibility to prevent breakage of fine particles, different solubility Since the elution of the active ingredient can be adjusted by providing a layer, the productivity can be improved, and the like, the enteric layer is preferably two or more layers.
When two or more enteric layers are provided, a plurality of enteric layer coating solutions having different compositions may be sprayed on the intermediate layer in a plurality of times for each enteric layer coating solution.

  The enteric fine granules can contain an active ingredient unstable to acid, an alkaline component, an intermediate layer and an enteric layer, and other pharmacologically acceptable additives for pharmaceutical preparation. Other pharmaceutical additives include binders such as hydroxypropylcellulose and hydroxypropylmethylcellulose, excipients such as mannitol and lactose, lubricants such as talc and glyceryl monostearate, low-substituted hydroxypropylcellulose, partial In addition to disintegrants such as alpha starch, etc., known ingredients are commonly used as pharmaceutical additives generally used in the manufacture of pharmaceuticals such as sweeteners, flavoring agents, fluidizing agents, flavoring agents, and coloring agents. Ingredients known as pharmaceutical additives include components that can function as binders, excipients, lubricants, disintegrants, etc. One component has two or more functions. May be.

The volume average particle diameter of the enteric fine particles is preferably 1 mm or less, more preferably 750 μm or less, and further preferably 500 μm or less.
Moreover, the volume average particle diameter of the enteric fine particles is preferably 50 μm or more, more preferably 150 μm or more, and further preferably 300 μm or more.

Enteric fine granules should be prepared according to known methods such as granulating active ingredient-containing nuclei, coating the granulated active ingredient-containing nuclei with an intermediate layer, and covering the coated intermediate layer with an enteric layer. Can do.
The method of granulating the active ingredient-containing core, the method of coating the granulated active ingredient-containing core with an intermediate layer, the method of coating the coated intermediate layer with an enteric layer, etc. are not particularly limited, and a known method is used. Can be used. For example, fluid bed granulation method, stirring granulation method, spray drying and the like can be mentioned.
Examples of the granulator that can be used in the fluidized bed granulation method include a fluidized bed granulator (product name: FD-MP-01, manufactured by Pou Lec Co., Ltd.), a flow coater (product name: FL-1, Freund). Sangyo Co., Ltd.).

≪Pharmaceutical composition≫
The pharmaceutical composition of the present invention comprises an active ingredient-containing core containing an acid-labile active ingredient and an alkaline ingredient, an intermediate layer coated with the active ingredient-containing core, and an enteric layer coated with the intermediate layer. An intestine containing at least one salt component selected from the group consisting of an alkali metal salt, an alkaline earth metal salt, an ammonium salt and a soluble metal salt in at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer Contains soluble granules.
The pharmaceutical composition of the present invention contains enteric fine granules containing an alkaline component and a salt component, so that even if the enteric membrane dissolves in the intestinal fluid, the enteric membrane is prevented from gelling. Aggregation of soluble fine particles can be suppressed, and active ingredients can be rapidly released from the pharmaceutical composition.
The pharmaceutical composition of the present invention may further contain other components as necessary.
For the acid labile active ingredient, alkaline component, intermediate layer, salt component and enteric layer, the above-mentioned matters for the enteric fine granules are applied as they are.
Pharmaceutical compositions are known as pharmaceutical additives commonly used in the manufacture of pharmaceuticals such as disintegrants, lubricants, excipients, binders, sweeteners, flavoring agents, fluidizing agents, flavoring agents, and coloring agents. May be included.
Examples of the pharmaceutical composition include tablets, capsules, powders, granules, fine granules, dry syrups, etc. Among them, tablets are preferable, and orally disintegrating tablets are particularly preferable.

As the disintegrant, known components can be used as long as they can function as a disintegrant. For example, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, starch Examples include sodium glycolate.
Among these disintegrants, crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose are more preferable from the viewpoint of disintegration.
As the disintegrant, any one disintegrant may be used alone, or two or more kinds may be used in combination.
Although content of a disintegrating agent can be set suitably, it is preferable that it is 0.01 to 5 times amount with respect to the total mass of enteric fine granules, and 0.05 to 1 time amount is preferable. It is more preferable that the amount is 0.1 times to 0.5 times.

As the lubricant, known components can be used as long as they can function as a lubricant. For example, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester and the like can be mentioned.
As the lubricant, any one of the lubricants may be used alone, or two or more may be used in combination.
The content of the lubricant can be appropriately set, but is preferably 0.001 to 0.5 times the total mass of the enteric fine granules, and preferably 0.005 to 0. The amount is more preferably 1 times, and more preferably 0.01 times to 0.05 times.

As the excipient, known ingredients can be used as long as they can function as excipients. Examples include sugar, sugar alcohol, crystalline cellulose, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, and the like.
Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactylol, maltitol, sorbitol, xylitol and the like. Among these sugar alcohols, mannitol and erythritol are preferable from the viewpoint of solubility of the orally disintegrating tablet.
A commercial item can also be used for crystalline cellulose. As a commercially available product, Theolas (manufactured by Asahi Kasei Chemicals Corporation), Pharmacel (manufactured by DFE Pharma) or the like can be used.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, polyvinyl alcohol and the like.
The additive for a formulation may be used individually by 1 type, and may be used in combination of 2 or more type.
The content of the formulation additive can be appropriately determined in consideration of the type, content, daily dose, particle size, and the like of the active ingredient.

  When the pharmaceutical composition is an orally disintegrating tablet, for example, the content of the active ingredient in one orally disintegrating tablet takes into consideration the lower limit and upper limit of the daily dose depending on the type of active ingredient. Can be determined as appropriate. For example, when rabeprazole sodium is used as the active ingredient, it is preferable to contain 10 mg to 20 mg of rabeprazole sodium with respect to one orally disintegrating tablet.

When the pharmaceutical composition is an orally disintegrating tablet, for example, the size and shape of the orally disintegrating tablet are not particularly limited as long as they are pharmaceutically acceptable. In the case of a round tablet, the diameter is 7 mm to 12 mm, the thickness is 3.0 mm to 7.0 mm, preferably 8 mm to 11 mm, the thickness is 3.5 mm to 6.5 mm, etc. : 4 mm to 8 mm, major axis 8 mm to 18 mm, preferably minor axis: 4 mm to 6.5 mm, major axis: 8 mm to 15 mm, etc., thickness 3.0 mm to 7.0 mm, preferably 3.5 mm to 6.5 mm Etc.
In addition, the hardness of the orally disintegrating tablet is not particularly limited. For example, in the case of a circular shape having a tablet diameter of about 8 mm to 11 mm, from the viewpoint of disintegration, transport stability, availability of an automatic packaging machine, etc. It is preferably 20N or more and 100N or less, more preferably 30N or more and 80N or less as measured by a meter. The hardness of the orally disintegrating tablet is measured using a tablet hardness tester Model 8M manufactured by Schleuniger.

In the present specification, the disintegration time is defined as the time during which it was confirmed that a part of the tablet disintegrated in the oral cavity. The disintegration time of the orally disintegrating tablet is preferably less than 30 seconds, and the disintegration time is more preferably less than 20 seconds.
The method for producing the orally disintegrating tablet is not particularly limited, and a known method can be used. For example, enteric fine granules are mixed with pharmaceutical additives such as disintegrants, lubricants, excipients, binders, etc. to obtain a mixture, and the resulting mixture is tableted with a tableting machine. By doing so, an orally disintegrating tablet can be obtained.
The method for mixing the enteric fine granules and the pharmaceutical additive is not particularly limited. For example, it can mix using well-known mixers, such as a V-type mixer (made by Tsutsui Riken Kikai Co., Ltd.) and a fluidized-bed granulator (made by Paulec Co., Ltd.).
Further, the method for tableting the obtained mixture is not particularly limited. For example, tableting can be performed using a known tableting machine such as a rotary tableting machine (product name HT-P18A, manufactured by Hata Iron Works).

  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. Unless otherwise specified, “part” is based on mass.

Example 1
(1) Manufacture of drug substance layer coated fine granules (active ingredient containing core) 600 g of mannitol 150-250 μm spherical spherical granules (Freund Sangyo Co., Ltd .; Non-Parel 108) are produced by a fluidized bed granulator (Powrec Co., Ltd.). MP-01 (SPC)), the supply temperature was adjusted to 60 ° C., the exhaust temperature was adjusted to about 30 ° C., and the liquid speed was 5 g / min.
Spraying was stopped at the time when the prescribed amount of 1500 g of the drug substance was sprayed, and drying was performed for 15 minutes at a supply air temperature of 60 ° C. Sieve through No. 50 round sieve (300 μm) and No. 70 round sieve (212 μm) to obtain drug substance layer coated fine granules.

[Drug substance]
Rabeprazole sodium 320 parts Hydroxypropyl cellulose (type SSL) 96 parts Sodium hydroxide 32 parts Purified water 1552 parts

(2) Production of intermediate layer coating fine particles 700 g of the drug substance layer coating fine particles are charged into a fluidized bed granulator, adjusted to a supply temperature of 60 ° C., an exhaust temperature of about 30 ° C., and a liquid speed of 6 g / min. The intermediate layer 1 coating solution having the following composition was spray coated.
When the specified amount of 1020 g of the intermediate layer 1 coating liquid was sprayed, the spraying was stopped, and the air supply temperature was 60 ° C., and drying was performed for 15 minutes to obtain intermediate layer 1 coated fine granules.
Further, 700 g of the intermediate layer 1 coating fine granules were charged into a fluidized bed granulator, adjusted to an air supply temperature of 60 ° C., an exhaust temperature of about 30 ° C., and a liquid speed of 6 g / min, and prepared in advance as an intermediate layer 2 coating solution having the following composition Was spray coated.
Spraying was stopped at the time when the specified amount of 1694 g of the intermediate layer 2 coating solution was sprayed, and drying was performed for 15 minutes at a supply air temperature of 60 ° C. Sieves were passed through a No. 42 round sieve (355 μm) and a No. 60 round sieve (250 μm) to obtain fine particles coated with an intermediate layer 2.

[Intermediate layer 1 coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 50 parts Talc 20 parts Mannitol 50 parts Sodium hydroxide 12 parts Purified water 868 parts

[Intermediate layer 2 coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts mannitol 10 parts purified water 176 parts

(3) Production of salt-containing layer (intermediate layer 3) coating fine particles 10 g of the intermediate layer 2 coating fine particles are micro fluidized bed granulator (manufactured by Dalton Co., Ltd .; micro fluid bed / granulation / coating device ( With a draft tube), adjusted to an air supply temperature of 60 ° C. and a liquid speed of 0.3 g / min, and spray-coated with a salt-containing coating liquid having the following composition prepared in advance in a specified amount of 31.4 g, and then an air supply temperature of 60 Drying was performed at 0 ° C. for 30 minutes. Sieve through a No. 36 round sieve (425 μm) and a No. 60 round sieve (250 μm) to obtain fine particles containing a salt-containing layer.

[Salt-containing layer coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts sodium chloride 10 parts purified water 176 parts

(4) Manufacture of enteric fine granules 8 g of the above-mentioned salt-containing coating fine granules are charged into a fluidized bed granulator, adjusted to room temperature air supply, liquid speed 0.3 g / min, and prepared in advance with the following composition of enteric Layer 1 coating solution, enteric layer 2 coating solution, and mannitol solution are spray-coated continuously at a predetermined amount of 8.6 g, 45.1 g, and 1.5 g, respectively, and then dried at a supply air temperature of 80 ° C. for 30 minutes. It was. Sieve through No. 30 round sieve (500 μm) and No. 42 round sieve (355 μm) to obtain enteric fine granules including an enteric layer covering the intermediate layer.

[Enteric layer 1 coating solution]
Methacrylic acid copolymer LD (30 w / w% aqueous dispersion) 300 parts ethyl acrylate / methyl methacrylate copolymer dispersion (30 w / w% aqueous dispersion) 33.3 parts Macrogol 6000 10 parts glyceryl monostearate 6 parts polysorbate 80 2.4 parts Citric anhydride 0.025 parts Purified water 428 parts

[Enteric layer 2 coating solution]
Methacrylic acid copolymer LD (30 w / w% aqueous dispersion) 300 parts ethyl acrylate / methyl methacrylate copolymer dispersion (30 w / w% aqueous dispersion)
33.3 parts triethyl citrate 10 parts glyceryl monostearate 6 parts polysorbate 80 2.4 parts anhydrous citric acid 0.025 parts yellow iron sesquioxide 0.1 parts purified water 428 parts

[Mannitol solution]
Mannitol 14 parts Purified water 86 parts

(5) Manufacture of excipient granulated product Mannitol, xylitol, crystalline cellulose, crospovidone and anhydrous calcium hydrogen phosphate mixture (Fuji Chemical Industry Co., Ltd .; Fmelt Type C) 320 g, low substituted hydroxypropyl cellulose (Shin-Etsu Chemical) Industrial Co., Ltd .; L-HPC NBD-022) 50 g, crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .; Theolas KG-802) 50 g was fluidized bed granulator (Paurec Co., Ltd .; MP-01 (FD) The mixture was prepared at a supply temperature of 60 ° C. and a liquid speed of 5 g / min, and granulated by spraying a liquid in which 25 g of mannitol and 5 g of anhydrous citric acid were dissolved in 220 g of purified water. Subsequently, drying was performed for 15 minutes to obtain an excipient granulated product.
(6) Production of orally disintegrating tablets 938 mg of the above granulated excipient, 847 mg of the enteric fine granules and 18 mg of magnesium stearate were sufficiently mixed in a vial to obtain a tableting powder. 361 mg of this tableting powder was weighed out and compressed using a tabletop simple tablet molding machine (Ichibashi Seiki Co., Ltd .; HANDTAB-Jr) at 9 mmφ, 6 kN with a standard R face for 30 seconds, and orally disintegrating tablets (Tablet) was obtained.

  The content of enteric fine granules contained in one orally disintegrating tablet obtained in Example 1 is 168.8 mg. The content of rabeprazole sodium contained in one orally disintegrating tablet is 10 mg, and the content of rabeprazole sodium relative to the total mass of the enteric fine granules is 5.9% by mass. The content of sodium hydroxide in the active ingredient-containing core contained in one orally disintegrating tablet is 1 mg, and the content of sodium hydroxide in the active ingredient-containing core relative to the total mass of the enteric fine granules is 0. 6% by mass. The content of sodium chloride contained in one orally disintegrating tablet is 9.417 mg, and the content of sodium chloride with respect to the total mass of the enteric fine granules is 5.6% by mass.

(Example 2)
Example 1 (3) Orally disintegrating tablets (tablets) were obtained in the same manner as in Example 1 except that potassium chloride was used as the sodium chloride in the production of the salt-containing layer coating fine granules.

(Example 3)
Example 1 (3) Orally disintegrating tablets (tablets) were obtained in the same manner as in Example 1 except that calcium chloride was used as the sodium chloride in the production of the salt-containing layer coating fine granules.

Example 4
Using the intermediate coating fine particles produced in the same manner as in Example 1 (1) and (2), enteric fine granules having an amount of salt of about 1/2 that of Example 1 were prepared as follows. Orally disintegrating tablets (tablets) were prepared by mixing and tableting with the excipient granules prepared in the same manner as in Example 1 (5).

(3) Production of salt-containing layer coated fine granules 10 g of the intermediate layer 2 coated fine granules described in Example 1 (2) were charged into a fluidized bed granulator, and the air supply temperature was 60 ° C and the liquid speed was 0.3 g / min. 15.7 g of a salt-containing coating solution having the following composition prepared in advance was spray coated and dried at a supply air temperature of 60 ° C. for 30 minutes. Sieve through a No. 36 round sieve (425 μm) and a No. 60 round sieve (250 μm) to obtain fine particles containing a salt-containing layer.

[Salt-containing layer coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts sodium chloride 10 parts purified water 176 parts

(4) Manufacture of enteric fine granules 8 g of the above salt-containing coated fine granules are charged into a fluidized bed granulator, prepared at room temperature and a liquid speed of 0.3 g / min, as in Example 1 (4). After spray coating the enteric layer 1 coating solution, enteric layer 2 coating solution, and mannitol solution prepared in advance in the composition of 8.9 g, 47.5 g, and 1.6 g, respectively, in advance, and then adjusting the supply air temperature. Drying was performed at 80 ° C. for 30 minutes. Sieve through No. 30 round sieve (500 μm) and No. 42 round sieve (355 μm) to obtain enteric granules.

(6) Manufacture of orally disintegrating tablets 826 mg of the excipient granulated product described in Example 1 (5), 746 mg of the enteric fine granules and 16 mg of magnesium stearate are thoroughly mixed in a vial to obtain a tableting powder. Obtained. 318 mg of this tableting powder was weighed out and compressed into a buccal tablet (tablet) by compression molding using a tabletop simple tablet molding machine at 9 mmφ and a standard R surface with 6 kN for 30 seconds.

  The content of enteric fine granules contained in one orally disintegrating tablet obtained in Example 4 is 149.6 mg. The content of rabeprazole sodium contained in one orally disintegrating tablet is 10 mg, and the content of rabeprazole sodium relative to the total mass of the enteric fine granules is 6.7% by mass. The content of sodium hydroxide in the active ingredient-containing core contained in one orally disintegrating tablet is 1 mg, and the content of sodium hydroxide in the active ingredient-containing core relative to the total mass of the enteric fine granules is 0. 7% by mass. The content of sodium chloride contained in one orally disintegrating tablet is 4.708 mg, and the content of sodium chloride with respect to the total mass of the enteric fine granules is 3.1% by mass.

(Example 5)
Example 4 (3) Orally disintegrating tablets (tablets) were obtained in the same manner as in Example 1 except that potassium chloride was used as the sodium chloride in the production of the salt-containing layer coating fine granules.

(Example 6)
Example 4 (3) Orally disintegrating tablets (tablets) were obtained in the same manner as in Example 1 except that calcium chloride was used as the sodium chloride in the production of the salt-containing layer coating fine granules.

(Example 7)
Using the intermediate coating fine particles produced in the same manner as in Example 1 (1) and (2), fine particles having an amount of salt of about 1/4 of that in Example 1 were prepared as follows. Orally disintegrating tablets (tablets) were prepared by mixing and tableting with the excipient granules prepared in the same manner as in 1 (5).

(3) Production of salt-containing layer coated fine granules 10 g of the intermediate layer 2 coated fine granules described in Example 1 (2) were charged into a fluidized bed granulator, and the air supply temperature was 60 ° C and the liquid speed was 0.3 g / min. After spray-coating a predetermined amount of 7.9 g of a salt-containing coating solution having the following composition prepared in advance, drying was performed at a supply air temperature of 60 ° C. for 30 minutes. Sieve through a No. 36 round sieve (425 μm) and a No. 60 round sieve (250 μm) to obtain fine particles containing a salt-containing layer.

[Salt-containing layer coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts calcium chloride 10 parts purified water 176 parts

(4) Manufacture of enteric fine granules 8 g of the above salt-containing coated fine granules are charged into a fluidized bed granulator, prepared at room temperature and a liquid speed of 0.3 g / min, as in Example 1 (4). After spray coating the enteric layer 1 coating solution, enteric layer 2 coating solution, and mannitol solution prepared in advance in a predetermined amount of 9.2 g, 48.9 g, and 1.7 g, respectively, Drying was performed at 80 ° C. for 30 minutes. Sieve through No. 30 round sieve (500 μm) and No. 42 round sieve (355 μm) to obtain enteric granules.

(6) Production of orally disintegrating tablet 768 mg of the excipient granulated product described in Example 1 (5), 694 mg of the enteric fine granules and 15 mg of magnesium stearate are thoroughly mixed in a vial to obtain a tableting powder. Obtained. 296 mg of this tableting powder was weighed out, and compressed into a buccal tablet (tablet) by compression molding at 9 kφ and 6 kN for 30 seconds using a standard R-side punch using a tabletop simple tablet molding machine.

  The content of enteric fine granules contained in one orally disintegrating tablet obtained in Example 7 is 139.8 mg. The content of rabeprazole sodium contained in one orally disintegrating tablet is 10 mg, and the content of rabeprazole sodium relative to the total mass of the enteric fine granules is 7.2% by mass. The content of sodium hydroxide in the active ingredient-containing core contained in one orally disintegrating tablet is 1 mg, and the content of sodium hydroxide in the active ingredient-containing core relative to the total mass of the enteric fine granules is 0. 7% by mass. The content of calcium chloride contained in one orally disintegrating tablet is 2.375 mg, and the content of calcium chloride with respect to the total mass of the enteric fine granules is 1.7% by mass.

(Comparative Example 1)
Using the intermediate coating fine particles produced in the same manner as in Example 1 (1) and (2), fine particles to which no salt was added were produced as follows, and the fine particles produced in the same manner as in Example 1 (5) were produced. Orally disintegrating tablets (tablets) were prepared by mixing with tablet granules and tableting.

(4) Production of enteric fine granules 9 g of the salt-free coating fine granules were charged into a minute amount fluidized bed granulator and prepared at room temperature and a liquid speed of 0.3 g / min. Example 1 (4) and After coating the enteric layer 1 coating solution and enteric layer 2 coating solution prepared in advance with the same composition in a predetermined amount of 10.5 g and 56.6 g, respectively, and then spray-coating for 30 minutes at an air supply temperature of 80 ° C. Drying was performed. Sieve through No. 30 round sieve (500 μm) and No. 42 round sieve (355 μm) to obtain enteric granules.

(6) Production of orally disintegrating tablets 10.5 g of a mixture of mannitol, xylitol, crystalline cellulose, crospovidone and anhydrous calcium hydrogen phosphate (Fuji Chemical Industry; Fmelt Type C), erythritol (manufactured by Food Science Co., Ltd.) 8 g, crospovidone (ISP; Polyplastdone XL) 9.5 g and sodium stearyl fumarate (JRS PHARMA; PRUV) 1.9 g were sufficiently mixed in a vial. The mixed powder 696 mg and the enteric fine particles 984 mg were further mixed in a vial to obtain a tableting powder. 280 mg of this tableting powder was weighed out and compressed into a buccal tablet (tablet) by compression molding using a tabletop simple tablet molding machine at 9 mmφ and a standard R surface with 6 kN for 30 seconds.

About the orally disintegrating tablet concerning Example 1- Example 7 and Comparative Example 1, the dissolution test in the Japanese Pharmacopoeia dissolution test 2nd liquid was done.
The dissolution test of the orally disintegrating tablets according to Examples 1 to 7 and Comparative Example 1 was performed by the paddle method using a dissolution tester DT-810 manufactured by JASCO Corporation. The volume of the elution solvent was 900 mL, the temperature was maintained at 37 ± 0.5 ° C., and the paddle speed was 50 rpm. The amount of rabeprazole sodium released from the tablet was measured with a UV spectrophotometer at a wavelength of 290 nm, and the dissolution rate (%) was calculated.
The results (dissolution rate (%)) are shown in Table 1 below.

As is clear from the results in Table 1, the active ingredient was eluted from all the orally disintegrating tablets according to Examples 1 to 7 in the vessel.
In Examples 1 to 7 (excluding Example 3), the elution rate reached approximately 95% or more in 30 minutes, and the active ingredient was released quickly. In these examples, during the dissolution test, each of the enteric fine particles maintained the state of the particles.
On the other hand, Comparative Example 1 shows an elution rate of about 50% at 30 minutes, and the elution rate is less than 75% at 120 minutes. At this time, a lump in which fine particles in the orally disintegrating tablet (tablet) were aggregated was observed at the bottom of the vessel. Elution from fine particles inside this agglomerate is hindered by surrounding enteric fine polymer, so that rapid elution is not performed as in Examples 1 to 7 (except Example 3). it is conceivable that.
Example 3, which has an exceptionally low elution rate of 60 minutes, is an example in which sodium chloride of Example 1 and calcium chloride of the same mass as potassium chloride of Example 2 were added as salt components. In Example 3, aggregation of fine particles was observed, but the state of fine particle aggregation was different from that of Comparative Example 1 in which the salt component was not added, and the entire fine particles were agglomerated in white. Calcium chloride is ranked higher than sodium chloride and potassium chloride in Hofmeister series known as an order of salting-out ability. In Example 3, since the polymer in the enteric fine granules was salted out and insolubilized due to the strong salting out effect of calcium chloride, the enteric fine granules were aggregated. Although the rate is considered to have decreased, the elution rate reached 99% after 120 minutes, which is practically sufficiently superior to the comparative example.

(Example 8)
In the following manner, enteric fine granules obtained by adding mannitol to the salt-containing layer and orally disintegrating tablets were prepared.

(1) Manufacture of fine drug substance layer coated granules 600 g of mannitol spherical spherical granules (manufactured by Freund Sangyo Co., Ltd .; Nonparell 108) are fluidized bed granulator (manufactured by Paulec Co., Ltd .; MP-01 (SPC) )), The supply air temperature is 60 ° C., the supply air flow rate is ^{30 to} 50 m ³ / h, and the liquid speed is adjusted to about 5 g / min. Drying was performed at a temperature of 80 ° C. for 30 minutes. Sieve through No. 50 round sieve (300 μm) and No. 70 round sieve (212 μm) to obtain drug substance layer coating fine granules (active ingredient-containing core).

[Drug substance]
Rabeprazole sodium 240 parts Hydroxypropyl cellulose (type SSL) 72 parts Sodium hydroxide 24 parts Purified water 1264 parts

(2) Production of intermediate layer coating fine particles 600 g of the drug substance layer coating fine particles are charged into a fluidized bed granulator, and the supply air temperature is 60 ° C., the supply air volume is 40 to 50 m ³ / h, and the liquid speed is about 5 g / min. Adjusted and spray-coated intermediate layer 1 coating solution prepared in advance of 874 g, intermediate layer 2 coating solution, 1718 g and salt-containing layer coating solution in order, followed by drying at an air supply temperature of 80 ° C. for 30 minutes. went. Sieve through a No. 36 round sieve (425 μm) and a No. 60 round sieve (250 μm) to obtain fine particles containing a salt-containing layer.

[Intermediate layer 1 coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 50 parts Talc 20 parts Mannitol 50 parts Sodium hydroxide 12 parts Purified water 868 parts

[Intermediate layer 2 coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts mannitol 10 parts purified water 176 parts

[Salt-containing layer coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts calcium chloride 10 parts mannitol 10 parts purified water 166 parts

(3) Production of enteric fine granules 500 g of the salt-containing coating fine granules are charged into a fluidized bed granulator and adjusted at an air supply temperature of 60 ° C., an air supply volume of 50 to 70 m ³ / h, and a liquid speed of 5 to 10 g / min. Then, after pre-prepared and spray-coating a predetermined amount of 677 g, 4599 g, and 488 g of enteric layer 1 coating solution, enteric layer 2 coating solution, and mannitol solution of the following composition prepared in advance, respectively, with the supply temperature of 60 ° C. 60 Drying was performed for 60 minutes, and the supply air temperature was set to 80 ° C. for 60 minutes. Sieve through No. 30 round sieve (500 μm) and No. 42 round sieve (355 μm) to obtain enteric granules.

[Enteric layer 1 coating solution]
Methacrylic acid copolymer LD (30 w / w% aqueous dispersion) 266.7 parts Ethyl acrylate / methyl methacrylate copolymer dispersion (30 w / w% aqueous dispersion)
66.7 parts Macrogol 6000 10 parts glyceryl monostearate 6 parts polysorbate 80 1.5 parts anhydrous citric acid 0.025 parts purified water 422 parts

[Enteric layer 2 coating solution]
Methacrylic acid copolymer LD (30 w / w% aqueous dispersion) 266.7 parts Ethyl acrylate / methyl methacrylate copolymer dispersion (30 w / w% aqueous dispersion)
66.7 parts triethyl citrate 10 parts glyceryl monostearate 6 parts polysorbate 80 1.5 parts anhydrous citric acid 0.025 parts yellow ferric oxide 0.1 parts purified water 237 parts

[Mannitol solution]
Mannitol 14 parts Purified water 86 parts

(4) Manufacture of excipient granulated material Mannitol, xylitol, crystalline cellulose, crospovidone and anhydrous calcium hydrogen phosphate mixture (Fuji Chemical Industry Co., Ltd .; Fmelt Type C) 426.7 g, low substituted hydroxypropyl cellulose 66 .7 g, 66.7 g of crystalline cellulose were charged into a fluidized bed granulator (manufactured by POWREC Co., Ltd .; MP-01 (FD)), supply air temperature 50 ° C., supply air volume 20-30 m ³ / h, liquid speed 5 The mixture was prepared at ˜8 g / min, and granulated by spraying a liquid in which 35 g of mannitol and 7 g of anhydrous citric acid were dissolved in 308 g of purified water. Drying was carried out at an air supply temperature of 80 ° C. for 20 minutes to obtain an excipient granulated product.

(5) Manufacture of orally disintegrating tablets 39.91% by mass of the enteric fine granules, 57.03% by mass of the excipient granulated product, sucralose (manufactured by Sanei FFI Co., Ltd.) 0.51 Mass%, fragrance (Takasago Fragrance Industry Co., Ltd .; Strawberry Micron) 0.10 mass%, magnesium metasilicate aluminate (Fuji Chemical Industry Co., Ltd .; Neusilin UFL2) 2.00 mass%, magnesium stearate (Taipei) Mixing and tableting were carried out at a ratio of 0.45% by mass (manufactured by Chemical Industry Co., Ltd.). After mixing ingredients other than magnesium stearate with a mixer for 30 minutes, magnesium stearate was added and further mixed for 30 minutes to obtain a tableting powder. Using a tableting machine (manufactured by RIVA S.A .; PICCOLA NOVA B-10), the tableting powder is compressed to 540 mg per tablet with 11.0 mmφ, two-step R-side punches, Disintegrating tablets (tablets) were obtained.

  The content of enteric fine granules contained in one orally disintegrating tablet obtained in Example 8 is 216.4 mg. The content of rabeprazole sodium contained in one orally disintegrating tablet is 10 mg, and the content of rabeprazole sodium relative to the total mass of the enteric fine granules is 4.6% by mass. The content of sodium hydroxide in the active ingredient-containing core contained in one orally disintegrating tablet is 1 mg, and the content of sodium hydroxide in the active ingredient-containing core relative to the total mass of the enteric fine granules is 0. 5% by mass. The content of calcium chloride contained in one orally disintegrating tablet is 2.382 mg, and the content of calcium chloride with respect to the total mass of the enteric fine granules is 1.1% by mass.

Example 9
Using the drug substance layer coated fine granules produced in the same manner as in Example 8 (1), enteric fine granules obtained by adding light anhydrous silicic acid to the salt-containing layer and orally disintegrating tablets were produced as follows. .

(2) Production of intermediate layer coating fine particles 600 g of the drug substance layer coating fine particles are charged into a fluidized bed granulator (manufactured by POWREC Co., Ltd .; MP-01 (SPC)), supply air temperature 60 ° C., supply air volume Adjusted at 40 to 50 m ³ / h and a liquid speed of about 5 g / min. After spray coating the intermediate layer 1 coating liquid having the following composition prepared in advance, 874 g and the intermediate layer 2 coating liquid 1718 g in this order, the air supply temperature was set to 80 Drying was carried out at 30 ° C. for 30 minutes. Sieve through a No. 42 round sieve (355 μm) and a No. 60 round sieve (250 μm) to obtain fine particles coated with an intermediate layer.

[Intermediate layer 1 coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 50 parts Talc 20 parts Mannitol 50 parts Sodium hydroxide 12 parts Purified water 868 parts

[Intermediate layer 2 coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts mannitol 10 parts purified water 176 parts

(3) Production of salt-containing layer coating fine particles 600 g of the intermediate layer coating fine particles are charged into a fluidized bed granulator, and the air supply temperature is 50 ° C., the air supply amount is 30 to 40 m ³ / h, and the liquid speed is about 6 g / min. After adjusting and pre-spreading 477 g of a salting-out layer coating solution having the following composition prepared in advance, drying was carried out at an air supply temperature of 80 ° C. for 30 minutes. Sieve through a No. 36 round sieve (425 μm) and a No. 60 round sieve (250 μm) to obtain fine particles containing a salt-containing layer.

[Salt-containing layer coating solution]
Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 10 parts talc 4 parts calcium chloride 10 parts light anhydrous silicic acid 10 parts purified water 166 parts

(4) Production of enteric fine granules 500 g of the salt-containing coating fine granules are charged into a fluidized bed granulator and adjusted at an air supply temperature of 60 ° C., an air supply volume of 50 to 70 m ³ / h, and a liquid speed of 5 to 10 g / min. Then, the enteric layer 1 coating solution, the enteric layer 2 coating solution, and the mannitol solution prepared in advance with the same composition as in Example 1 (4) were spray-coated continuously in predetermined amounts of 677 g, 5113 g, and 509 g, respectively. Drying was performed for 60 minutes while the supply air temperature was 60 ° C., and drying was further performed at a supply air temperature of 80 ° C. for 60 minutes. Sieve through No. 30 round sieve (500 μm) and No. 42 round sieve (355 μm) to obtain enteric granules.

(5) Manufacture of excipient granulated product An excipient granulated product was obtained in the same manner as in Example 8 (4).

(6) Manufacture of orally disintegrating tablets 39.91% by mass of the enteric fine granules, 57.03% by mass of the excipient granulated product, sucralose (manufactured by Sanei FFI Co., Ltd.) 0.51 % By mass, fragrance (manufactured by Takasago International Corporation; Strawberry Micron) 0.10% by mass, magnesium aluminate metasilicate (Fuji Chemical Industry Co., Ltd .; Neusilin UFL2) 2.00% by mass, magnesium stearate (Taihei Chemical) Mixing and tableting were carried out at a ratio of 0.45% by mass (produced by Sangyo Co., Ltd.). After mixing ingredients other than magnesium stearate with a mixer for 30 minutes, magnesium stearate was added and further mixed for 30 minutes to obtain a tableting powder. This tableting powder was tableted with a tableting machine (RIVA SA; PICCOLA NOVA B-10) to give 575 mg per tablet, 11.0 mφ, tableted with a double-sided R-side punch, Disintegrating tablets (tablets) were obtained.

  The content of enteric fine granules contained in one orally disintegrating tablet obtained in Example 9 is 230.8 mg. The content of rabeprazole sodium contained in one orally disintegrating tablet is 10 mg, and the content of rabeprazole sodium relative to the total mass of the enteric fine granules is 4.3% by mass. The content of sodium hydroxide in the active ingredient-containing core contained in one orally disintegrating tablet is 1 mg, and the content of sodium hydroxide in the active ingredient-containing core relative to the total mass of the enteric fine granules is 0. 4% by mass. The content of calcium chloride contained in one orally disintegrating tablet is 2.382 mg, and the content of calcium chloride with respect to the total mass of the enteric fine granules is 1.0% by mass.

When the orally disintegrating tablets according to Example 7, Example 8, and Example 9 were left for 3 days under the severe humidity condition of 25 ° C. and 75% RH, the orally disintegrating tablet according to Example 7 had yellow fine particles. Although it was observed that the color changed from brown to brown, no clear color change was observed in the orally disintegrating tablets according to Example 8 and Example 9, and it was confirmed that the humidity resistance was improved. .
The browning of the orally disintegrating tablet according to Example 7 that occurred under severe humidity conditions is thought to be due to the degradation of the drug substance. In these examples, calcium chloride is used as a salt component, but calcium chloride is highly hygroscopic and has deliquescence. In Example 7, it is considered that due to the hygroscopicity of the salt, the decomposition of the drug substance was promoted and browned. On the other hand, in Example 8, it was considered that the moisture absorption amount of the entire layer was reduced by the coexistence of mannitol having low hygroscopicity in the salt-containing layer. Moreover, in Example 9, it is thought that light anhydrous silicic acid worked to prevent salt deliquescence by absorbing moisture competitively with the salt.

The disclosure of Japanese application 2013-047358 and the disclosure of Japanese application 2013-225760 are incorporated herein by reference in their entirety.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually stated to be incorporated by reference, Incorporated herein by reference.

Claims (15)

An active ingredient-containing nucleus containing an acid-labile active ingredient and an alkaline ingredient, an intermediate layer coated with the active ingredient-containing nucleus, and an enteric layer coated with the intermediate layer, the active ingredient-containing nucleus and the intermediate layer Enteric fine granules containing at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride in at least one selected from the group consisting of The enteric fine granules according to claim 1, wherein the salt component contains calcium chloride. The enteric fine granules according to claim 1 or 2 , wherein the alkaline component contains an alkali having a saturated aqueous solution having a pH of 12 or more at 25 ° C. The enteric fine granules according to any one of claims 1 to 3 , wherein the alkaline component contains sodium hydroxide. The enteric fine granule according to any one of claims 1 to 4 , wherein the active ingredient unstable to an acid contains a proton pump inhibitor. The enteric fine granule according to any one of claims 1 to 5 , wherein the acid-unstable active ingredient comprises a benzimidazole compound or a salt thereof. The enteric fine granule according to any one of claims 1 to 6 , wherein the active ingredient unstable to acid comprises rabeprazole or rabeprazole sodium. The enteric fine granules according to any one of claims 1 to 7 , wherein the intermediate layer comprises a plurality of layers of two layers or more. Ri interlayer Do two layers or more of the plurality of layers, enteric granules according to any one of claims 1 to 8 which contains an alkaline component into at least the innermost intermediate layer. The enteric fine particle according to any one of claims 1 to 9 , wherein the enteric layer contains a (meth) acrylic acid copolymer. The at least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer contains at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride, and a sugar or a sugar alcohol. The enteric fine granules according to claim 10 . 2. At least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer contains at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride, and an inorganic substance having water absorption. The enteric fine granules according to any one of claims 10 to 10 . At least one selected from the group consisting of an active ingredient-containing nucleus and an intermediate layer is at least one salt component selected from the group consisting of calcium chloride, sodium chloride and potassium chloride , a sugar or sugar alcohol, and an inorganic substance having water absorption The enteric fine granules according to any one of claims 1 to 10 , comprising: A pharmaceutical composition comprising a plurality of enteric fine granules according to any one of claims 1 to 13 . The pharmaceutical composition according to claim 14 , which is an orally disintegrating tablet.