KR20060135853A - Solid pharmaceutical preparation containing dibenz[b,e]oxepine derivative - Google Patents

Abstract

A solid pharmaceutical preparation which contains either a dibenz[b,e]oxepine derivative represented by the following formula (I) [wherein A represents a single bond, -CH=CH-, or (CH2)n- (wherein n is an integer of 1-3); and R 1 and R2 are the same or different and each represents hydrogen or lower alkyl or represents a heterocyclic group in cooperation with the adjacent nitrogen atom] or a pharmaceutically acceptable salt of the derivative and is excellent in storage stability such as light stability. The solid pharmaceutical preparation comprises: a raw pharmaceutical preparation containing a dibenz[b,e]oxepine derivative represented by the following formula (I) or a pharmaceutically acceptable salt of the derivative; and a coating film or capsule containing at least 0.6 parts by weight of a light-shielding agent per 100 parts by weight of the raw pharmaceutical preparation.

Description

Solids containing dibenzo [ｂ, ｅ] oxepin derivatives {SOLID PHARMACEUTICAL PREPARATION CONTAINING DIBENZ [b, e] OXEPINE DERIVATIVE}

TECHNICAL FIELD This invention relates to solid preparations etc. containing a dibenzo [b, e] oxepin derivative.

Solid formulations containing active ingredients such as pharmaceuticals, foods, pesticides and veterinary medicines are required to be stable in the environment in which they are used and in the environment to be preserved. Depending on the active ingredient contained in the solid preparation, it may be unstable with respect to light, and it has been known that the solid preparation provided with the light shielding coating is stabilized with respect to light until now. As the preparation, for example, a cleaning agent containing sertindol, a solid preparation consisting of a film containing titanium oxide as a light shielding agent (see Patent Document 1, etc.), a cleaning agent containing an active ingredient, Tablets consisting of a film containing talc / barium sulfate in place of titanium oxide (see Patent Document 2) and the like have been reported. However, in each of the active ingredients, destabilization may occur due to various factors. Therefore, the formation of a light shielding film on a solid formulation containing an active ingredient that is unstable to light alone is not sufficient to stabilize, or conversely, Destabilization sometimes increases by forming, and it is difficult to predict whether the active ingredient can be formulated stably before producing the solid preparation.

On the other hand, Formula (Ⅰ)

[Formula 1]

[Wherein, A represents a single bond, -CH = CH- or (CH ₂ ) _n- (wherein n represents an integer of 1 to 3), R ¹ and R ² are the same or different and hydrogen Or dialkyl [b, e] oxepin derivatives (hereinafter referred to as compound (I)) represented by lower alkyl or being combined with an adjacent nitrogen atom to form a heterocyclic group]. It is known to have anti-inflammatory action, and is useful for allergic diseases such as nasal allergies and asthma, and skin diseases such as heart margin (see Japanese Patent Application Laid-open No. 63-10784). Or it is known that a stabilized solid formulation can be obtained by adding cellulose derivatives, such as croscarmellose sodium, to the pharmacologically acceptable salt containing formulation (refer patent document 3).

Patent Document 1: International Publication No. 97/39752 Pamphlet

Patent Document 2: Japanese Unexamined Patent Publication No. 2002-212104

Patent Document 3: Japanese Patent Application Laid-Open No. 11-35460

Disclosure of the Invention

Problems to be Solved by the Invention

An object of the present invention is to provide a solid preparation containing compound (I) or a pharmaceutically acceptable salt thereof, and excellent in storage stability such as light stability.

Means to solve the problem

The present invention relates to the following (1) to (15).

(1) Formula (Ⅰ)

[Formula 2]

[Wherein, A represents a single bond, -CH = CH- or (CH ₂ ) _n- (wherein n represents an integer of 1 to 3), R ¹ and R ² are the same or different and hydrogen Or lower alkyl or one of the adjacent nitrogen atoms to form a heterocyclic group], and a preservative containing a dibenzo [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof, Solid preparation containing the film or capsule containing 0.6 weight part or more of light-shielding agents with respect to 100 weight part of cleaning agents.

(2) The solid preparation according to the above (1), wherein the light-shielding agent is at least one substance selected from titanium oxide, yellow iron trioxide, and iron trioxide.

(3) To (1) or (2), wherein the amount of the dibenzo [b, e] oxepin derivative or pharmaceutically acceptable salt thereof contained in the cleaning agent is 0.05 to 5 parts by weight based on 100 parts by weight of the cleaning agent. Solid formulations described.

(4) The solid preparation according to any one of (1) to (3), wherein the cleaning agent is a cleaning agent containing one or more substances selected from sugars, starches, starch derivatives, celluloses, and cellulose derivatives.

(5) The solid preparation according to any one of (1) to (3), wherein the cleaning agent is a cleaning agent containing sugar, cellulose, and a cellulose derivative.

(6) The solid preparation according to the above (4) or (5), wherein the sugar is at least one substance selected from lactose and white sugar.

(7) The agent is an agent comprising a nuclear coating layer containing a nucleus portion and a dibenzo [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof located outside the nucleus portion, and contained in the nuclear coating layer. Solid preparation as described in said (1) or (2) whose quantity of dibenzo [b, e] oxepine derivative or its pharmaceutically acceptable salt is 0.05-5 weight part with respect to 100 weight part of nuclear coating layers.

(8) The cleaning agent is a cleaning agent including a nucleus portion and a nuclear coating layer located outside the nucleus portion, the nucleus portion containing a dibenzo [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof, the nucleus The solid preparation according to the above (1), (2) or (7), wherein the coating layer does not contain a dibenzo [b, e] oxepin derivative and a pharmaceutically acceptable salt thereof.

(9) The solid preparation according to the above (7) or (8), wherein the nuclear coating layer is a nuclear coating layer containing one or more substances selected from sugars, starches, starch derivatives, celluloses and cellulose derivatives.

(10) The solid preparation according to the above (7) or (8), wherein the nuclear coating layer is a nuclear coating layer containing a combination of sugar, starch and / or poorly water-soluble inorganic salt.

(11) The solid preparation according to the above (9) or (10), wherein the sugar is at least one substance selected from lactose and white sugar.

(12) The solid preparation according to any one of (1) to (11), wherein the solid preparation is in the form of fine particles or granules.

(13) The solid preparation according to any one of (1) to (11), wherein the shape of the solid preparation is a tablet or a capsule.

(14) A particulate preparation, multiple unit tablets or dry syrup containing the solid preparation according to (12) above.

(15) Formula (I) having a volume average particle diameter of 5 to 150 µm

[Formula 3]

[Wherein, A represents a single bond, -CH = CH- or (CH ₂ ) _n- (wherein n represents an integer of 1 to 3), R ¹ and R ² are the same or different and hydrogen Or lower alkyl or being combined with an adjacent nitrogen atom to form a heterocyclic group] or a mixture or granulation of a dibenzo [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof and an additive thereof. Solid preparation which can be manufactured by the manufacturing method of the cleaning agent containing a process, and the film | membrane or capsule containing a light-shielding agent.

Effects of the Invention

According to the present invention, there is provided a solid preparation containing the compound (I) or a pharmaceutically acceptable salt thereof and excellent in storage stability such as light stability.

To practice the invention  Best form for

In the definition of each group of the formula (I), as lower alkyl, for example, linear or branched alkyl having 1 to 6 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, hexyl, etc. are mentioned. Examples of the heterocyclic group formed by being combined with an adjacent nitrogen atom include pyrrolidinyl, morpholino, thiomorpholino, N-methylpiperazinyl, pyrazolidinyl, piperidino, piperazinyl, Indolyl, isoindoleyl, etc. are mentioned.

Pharmaceutically acceptable salts of compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Pharmaceutically acceptable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, for example organic acids such as acetate, maleate, fumarate, tartarate, citrate, and the like. And acid salts. Examples of pharmaceutically acceptable metal salts include alkali metal salts such as lithium salts, sodium salts and potassium salts, for example alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and zinc salts. Examples of the pharmaceutically acceptable ammonium salt include salts such as ammonium and tetramethylammonium. Examples of pharmaceutically acceptable organic amine addition salts include, for example, morpholine and piperi. Additive salts, such as dean, are mentioned, As a pharmaceutically acceptable amino acid addition salt, addition salts, such as lysine, glycine, phenylalanine, aspartic acid, glutamic acid, are mentioned, for example.

Compound (I) used in the present invention can be produced by the method disclosed in JP-A-63-10784 or in accordance with it. Among the compounds (I), compounds in which A is CH ₂ and R ¹ and R ² are both CH ₃ are preferable, and as a specific example of compound (I) or a pharmaceutically acceptable salt thereof, Formula (A)

[Formula 4]

And (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid hydrochloride (hereinafter referred to as compound (A)) represented by have.

Moreover, in manufacture of the solid preparation of this invention, the particle diameter of the compound (I) used or its pharmaceutically acceptable salt is 5-150 micrometers by volume average particle diameter as measured by a microscopic method or a sieve classification method. It is preferable that it is, It is more preferable that it is 20-120 micrometers, It is further more preferable that it is 40-100 micrometers.

The solid preparation of the present invention is a solid preparation comprising a preservative containing Compound (I) or a pharmaceutically acceptable salt thereof, and a film or capsule containing a light-shielding agent.

The granulation agent in the solid preparation of this invention means the preparation etc. which can be coated, for example. Although the shape of this cleaning agent is not specifically limited, It is preferable that it is a shape of powder, a granule, a granule, or a tablet. In the present specification, the powder, fine granules, or granule-shaped granules are called granules, and the tablet-shaped granules are called predetermined.

The cleaning agent in the solid preparation of the present invention may contain other active ingredients and / or additives in addition to the compound (I) or a pharmaceutically acceptable salt thereof.

Excipients include, for example, excipients, disintegrants, binders, glidants and the like, and combinations thereof. Preferably, sugars (e.g. lactose, white sugar, maltose, etc.), sugar alcohols (e.g. mannitol, maltitol) , Erythritol, etc.), starch (e.g. corn starch, rice starch, wheat starch, etc.), starch derivatives (e.g. hydroxypropyl starch, carboxymethyl starch sodium, etc.), cellulose (e.g. crystalline cellulose, Powdered cellulose, etc.), cellulose derivatives (e.g. methyl cellulose, carboxypropyl cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), poorly water-soluble Inorganic salts (e.g., talc, hard silicic anhydride, sodium metasilicate, calcium phosphate, etc.) and combinations thereof Can. The additive is more preferably selected from additives having an equilibrium moisture content of preferably 10% or less, more preferably 5% or less. When the additives are used in combination, sugars, starches, starch derivatives, cellulose, cellulose derivatives, and the like (specifically, sugar or starch of sugar, corn starch of starch, hydroxypropyl starch of sodium starch derivative or carboxymethyl starch sodium) , Crystalline cellulose of cellulose, croscarmellose sodium of cellulose derivatives, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose or carboxymethyl cellulose calcium, etc.). It is more preferable to use at least one substance mainly selected from cellulose and the like (specifically, lactose, white sugar, corn starch, crystalline cellulose, etc.), and most preferably sugar (specifically, white sugar, etc.). . When sugar is mainly used, it is preferable to combine with cellulose and a cellulose derivative, and when lactose or white sugar is mainly used, it is more preferable to combine with crystalline cellulose and croscarmellose sodium.

Excipients include, for example, sugars (e.g. lactose, white sugar, maltose, etc.), sugar alcohols (e.g. mannitol, maltitol, erythritol, etc.), starches (e.g. corn starch, rice starch, wheat starch, etc.) , Cellulose (e.g. crystalline cellulose, powdered cellulose, etc.), cellulose derivatives (e.g., croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), poorly water-soluble inorganic salts (e.g. Talc, hard silicic anhydride, sodium metasilicate, calcium phosphate, etc.), and these may be used alone or in combination of two or more thereof. Preferably, sugar, starch, cellulose, cellulose derivative, etc. (Specifically, white sugar or lactose of sugar, corn starch of starch, crystalline cellulose of cellulose, croscarmellose of cellulose derivative, Cerium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, or carboxymethyl cellulose calcium; and the like, and more preferably, sugar, starch, cellulose and the like (specifically, lactose, white sugar, etc.). , Corn starch, crystalline cellulose, and the like.

As disintegrants, for example cellulose (e.g. crystalline cellulose, powdered cellulose, etc.), cellulose derivatives (e.g. croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose calcium, etc.) , α-starch, partially α-starch, etc.), starch derivatives (hydroxypropyl starch, sodium carboxymethyl starch, etc.), crospovidone, bentonite, and the like, may be used alone or in combination of two or more thereof.

As binders for example cellulose derivatives (for example methyl cellulose, carboxymethyl cellulose, carboxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), cellulose (for example crystalline cellulose, etc.), starch (for example (alpha) starch etc.), polyvinyl alcohol, polyvinylpyrrolidone, pullulan, dextrin, gum arabic, gelatin, etc. can be mentioned, You may use these individually or in combination of 2 or more types.

Examples of the lubricant include magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester, polyethylene glycol, and the like, and these may be used alone or in combination of two or more thereof.

The light-shielding agent in the present invention is not particularly limited as long as it is usually used in solid preparations and has a light-shielding effect. For example, titanium oxide, iron oxide, zinc oxide, iron group, carbon black, medicinal carbon, barium sulfate, and edible yellow No. 4 aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, copper chloropin, silicon oxide, etc., Preferably, titanium oxide and iron oxide (specifically, yellow 3 iron dioxide, 3). Iron dioxide, iron sulfate, black iron oxide, and the like), zinc oxide, silicon oxide, and the like, and more preferably, titanium oxide, iron oxide (specifically, yellow triiron dioxide, iron trioxide, etc.); Most preferably, titanium oxide is mentioned. The titanium oxide may be any crystalline form of rutile type and anatase type, and is not particularly limited in terms of its particle diameter. In this invention, you may use together 2 or more types of light-shielding agents, It is preferable to use the 2 or more types of light-shielding agents which differ in color together. Although the combination in the case of using 2 or more types of light-shielding agents in combination is not specifically limited, Preferably, it is titanium oxide, For example, iron oxide, zinc oxide, iron group, carbon black, medicinal carbon, barium sulfate, edible yellow No. 4 Aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, copper chloropin, silicon oxide, and the like, and more preferably, titanium oxide and iron oxide (specifically, yellow 3 iron dioxide). , Iron trioxide, iron sulfate, black iron oxide, and the like), zinc oxide, silicon oxide, and the like, and more preferably titanium oxide and iron oxide (specifically, yellow triiron iron dioxide, triiron iron dioxide, etc.). And combinations thereof.

The film in the solid preparation of this invention is a film which coat | covers the outer side of the said cleaning agent, and means the film formed by coating the coating composition containing the said light-shielding agent to this cleaning agent. This coating composition may contain coating agents, such as a coating base, a plasticizer, and a binder other than the said light-shielding agent, for example, You may mix and use 2 or more types of these coating agents, respectively.

Examples of the coating base include a gas-soluble film coating agent, an enteric film coating agent, a sustained release film coating agent, and the like. As the gasosoluble film coating base, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxy. Cellulose polymers such as ethyl cellulose and methyl hydroxyethyl cellulose, synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E, and polyvinylpyrrolidone, and polysaccharides such as pullulan. As the enteric film coating base, for example, cellulose polymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate cellulose, methacrylic acid copolymer L, methacrylic Acid copolymer LD, methacrylic acid copol Natural products, such as acrylic acid polymers, such as mer S, and shellac, etc. are mentioned, As a sustained-release film coating base, For example, cellulose polymers, such as ethyl cellulose, amino alkyl methacrylate copolymer RS, ethyl methacrylate acrylate Acrylic acid type polymers, such as an acid methyl copolymer, etc. are mentioned.

As a plasticizer, For example, ester, such as triethyl citrate, medium chain fatty acid triglyceride, diethyl phthalate, dibutyl phthalate, triacetin, butyl phthalyl butyl glycolate, and glyceryl caprylic acid ester; Alcohols such as glycerin, propylene glycol, polyethylene glycol, and the like.

Examples of binders and other coating agents include lactose, white sugar, talc, calcium carbonate, gelatin, gum arabic, carnauba wax and the like.

The capsule in the solid preparation of this invention may contain components, such as a capsule base and a plasticizer, in addition to the said light-shielding agent, For example, the component may mix and use 2 or more types, respectively.

Examples of the capsule base include gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, pullulan and agar. Examples of the plasticizer include triethyl citrate and medium chain fatty acid triglycol. Esters such as ceride, diethyl phthalate, dibutyl phthalate, triacetin, butyl phthalyl butyl glycolate, and glyceryl caprylic acid ester; Alcohol, such as glycerin, propylene glycol, polyethylene glycol, etc. are mentioned, As a component contained in the said other said capsule, talc, calcium carbonate, gum arabic, carnauba wax etc. are mentioned, for example.

The solid preparation of the present invention includes, for example, a process for preparing a preservative containing compound (I) or a pharmaceutically acceptable salt thereof, and a coating composition containing a light-shielding agent coated on the preservative to have a coating. It can manufacture by the manufacturing method including the process of manufacturing a solid preparation, or the capsule filling process which fills a preservative with the capsule containing a light-shielding agent, and manufactures a solid preparation.

Hereinafter, the manufacturing method of the solid preparation of this invention is demonstrated in detail for every shape. However, the following manufacturing methods show examples and do not limit the manufacturing method of the solid preparation of this invention.

[Production method of tablet]

In the solid preparation of the present invention, the solid preparation in the form of a tablet is, for example, after compound (I) or a pharmaceutically acceptable salt thereof and an additive is mixed in a powdered state, or after a part of the component is granulated. A process of mixing the remaining components, tableting the obtained mixture to produce a predetermined step, and then coating the coating composition containing the light-shielding agent on the predetermined step to produce a tablet having a coating. can do.

Manufacture of granulated material can be performed by a wet granulation method, a dry granulation method, etc., for example. As a wet granulation method, for example, extrusion granulation method (by screw extrusion granulation apparatus, roll extrusion granulation apparatus etc.), electric granulation method (by rotating drum type granulation apparatus, centrifugal electric granulation apparatus etc.), fluidized bed granulation method (fluid-bed granulation method) Device, electric fluidized bed granulation device, etc.), stirring granulation method (by stirring granulation device and the like), and the like, and more specifically, for example, Compound (I) or a pharmaceutically acceptable salt and additives thereof; And a method of drying the obtained granulated product by adding a solvent or a binder solution to the resulting mixture and granulating the mixture. Examples of the solvent include water, ethanol, isopropyl alcohol, mixed solvents thereof, and the like. Among them, water is preferable, and as the binder solution, for example, water, ethanol, isopropyl alcohol, these Although the binder melt | dissolved the binder etc. are mentioned, The aqueous solution of a binder is optimal. As a dry granulation method, for example, a crushing granulation method in which flakes are manufactured using a commercially available dry granulator, a slug tablet is produced by a tableting machine, and the obtained flakes or slug tablets are crushed by a commercially available crusher or granulator. Etc. can be mentioned. In addition, preferably, each granulated material has a desired particle diameter by appropriately pulverizing and / or sifting.

Predetermined is, for example, a mixture obtained by mixing each component with a mixer or the like, or a mixture obtained by mixing a part of the components into the granulated substance and then mixing the remaining components with a mixer can be produced by compression using a compression tableting machine. The tableting pressure at the time of tableting can be suitably selected from the range of 3-30 kN, for example. The predetermined weight is not particularly limited, but is, for example, 30 to 3000 mg per party.

A tablet having a coating can be prepared by, for example, dissolving and / or dispersing a coating composition containing a light-shielding agent in a solvent (the same meaning as the above solvent) and coating the film as described above. Coating is carried out using, for example, a conventional pan coater, a ventilated coater, a fluidized bed coating device, an electrically fluidized coating device and the like.

[Manufacturing Method of Granules]

In the solid preparation of the present invention, the solid preparation having a granular shape is, for example, only a compound (I) or a pharmaceutically acceptable salt thereof, or a compound (I) or a pharmaceutically acceptable salt thereof and an additive, It can be manufactured by the manufacturing method including the process of manufacturing granules, and then the coating composition containing a light-shielding agent is coated on the granules, and the granule which has a film is manufactured.

The solid preparation whose granules are granular may have any shape such as spherical shape, columnar shape, indefinite shape, and the particle diameter may be any particle diameter that is usually used (for example, volume when measured by microscopy or sieve classification). Average particle diameter, about 0.4 to about 2.0 mm). The small granules can be produced, for example, in the same manner as the production of granulated products in the method for producing tablets.

Granules having a coating can be prepared by, for example, dissolving and / or dispersing a coating composition containing a light-shielding agent in a solvent (the same meaning as the above solvent) and coating the granules. Coating is carried out using, for example, a conventional fan type coater, a ventilated coater, a fluidized bed type coating device, an electrically fluidized coating device, a centrifugal electric coating device, or the like.

[Production method of powder or fine granules]

In the solid preparation of the present invention, the solid preparation in the form of a powder may be any powder as long as it is a general powder, and for example, it is preferable that 5% or less of the total amount do not pass through a 30 (500 µm) sieve.

Among the solid preparations of the present invention, any solid preparation having a shape of fine granules may be any fine granular agent, for example, 5% or less of the total amount does not pass through 30 (500 μm) sieve, and 200 (75 It is preferable that it passes through a sieve 10% or less of whole quantity.

In the solid preparation of the present invention, a solid preparation having a powder or fine granule is produced in the same manner as the method for producing the granules, for example, in each step to be pulverized and / or sifted to obtain a desired particle diameter. It can manufacture.

[Production method of capsule]

Among the solid preparations of the present invention, the solid preparations in the form of capsules can be produced by filling the capsule shell containing the light-shielding agent with the cleaning agent obtained in each of the above-mentioned powder or fine granules, granules, and tablet production methods.

Moreover, as one of the preferable forms of the solid preparation of this invention, the solid preparation which is a cleaning agent containing the nucleus part and the nuclear coating layer located outside the nucleus part is mentioned. The nucleus portion refers to an agent that can be coated, and the nucleus coating layer refers to a coating layer formed by coating compound (I) or a pharmaceutically acceptable salt and / or additive (same meaning as the above additive) in the nucleus portion. The nucleus portion may be composed of a core portion and a core coating layer.

As the nucleus portion, for example, a cleaning agent obtained in each method for producing the tablet, the granules, the powder or the fine granules, commercially available spherical seed particles and the like can be used. The nucleus portion of the core is prepared in the same manner as the dust preparation in the above-described method for producing tablets, granules, powders or fine granules, or commercially available spherical seed particles and the like, and the core coating layer described later. It can be prepared by coating a component of the core layer on the core, and the preferred form of the core layer is also a preferred form of the layer. Spherical seed particles are composed of, for example, refined white sugar, sugar and corn starch mixture, lactose and crystal cellulose mixture, crystalline cellulose and the like, and the particle diameter of the seed particles is measured by microscopy or sieve classification. The volume average particle diameter is generally 180 to 1180 µm.

The nuclear coating layer is prepared by coating compound (I) or a pharmaceutically acceptable salt and / or additive thereof (same meaning as the above additives) in the nucleus part by powder coating method or spray coating method, preferably powder coating method. can do. In the case of coating by powder coating method, compound (I) or a pharmaceutically acceptable salt and / or additive (which means the same as the above additive) is mixed to obtain a powder dispersant, and a solvent (the same as the above solvent) or What is necessary is just to spray a binder solution (same meaning as the said binder solution), and to spread | disperse | distribute the powder dispersing agent, and to laminate | stack and coat in the nucleus part, At this time, for example, a rotary drum type granulator, a centrifugal motorized granulator, a motorized granulator , Electric fluidized bed assembly apparatus, and the like are used.

The additive as the powder dispersant is preferably sugar, starch, starch derivative, cellulose, cellulose derivative or the like (specifically, white sugar or lactose of sugar, corn starch of starch, hydroxypropyl starch or carboxymethyl of starch derivative). Starch sodium, crystalline cellulose of cellulose, croscarmellose sodium of cellulose derivatives, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose or carboxymethyl cellulose calcium), and the like. And one or more substances selected from sugars, starch, cellulose and the like (specifically, lactose, white sugar, corn starch, crystalline cellulose, etc.), and most preferably sugars (specifically, white sugar and the like). have. In the case of using a combination of the additives in the powder spreading agent, sugars, starches, cellulose, cellulose derivatives, and the like (specifically, white sugar or lactose of sugar, corn starch of starch, crystalline cellulose of cellulose, cross-carmelose of cellulose derivative) It is preferable to mainly use one or more substances selected from sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose or calcium carboxymethyl cellulose, and the like, sugar, starch, cellulose (specifically lactose, white sugar, corn). It is more preferable to mainly use one or more substances selected from starch, crystalline cellulose and the like, and most preferably to use sugar (specifically, white sugar or the like). When sugar is mainly used, it is preferable to combine with starch and / or poorly water-soluble inorganic salt, and when lactose or white sugar is mainly used, it is more preferable to combine with corn starch, talc, or light silicic anhydride. The additive in the powder spreading agent is preferably selected from additives having an equilibrium moisture content of preferably 10% or less, more preferably 5% or less, and the particle diameter of the powder spreading agent is microscopic or sieve classification. It is preferable that it is about 100 micrometers or less, as for the volume average particle diameter when measured by "," it is more preferable that it is about 50 micrometers or less, and it is more preferable that it is about 40 micrometers or less. When sugar is mainly used, the particle diameter of the combination with starch and / or the poorly water-soluble inorganic salt and its powder dispersant is preferably about 100 μm or less, more preferably about 50 μm or less, even more preferably It is preferable that it is about 40 micrometers or less from a viewpoint of obtaining this cleaning agent in high yield in manufacture of a cleaning agent.

In the case of coating by the spray coating method, the compound (I) or a pharmaceutically acceptable salt and / or additive thereof is added to a solvent (the same meaning as the solvent) or a binder solution (the same meaning as the binder solution). What is necessary is just to melt | dissolve or suspend and coat by spraying a nucleus part, At this time, the same apparatus used in the manufacturing process of the granule which has a film in the manufacturing method of the said granule is used. The nuclear coating layer is not limited to one layer but may be formed in a plurality of layers. In this case, you may change the kind and / or compounding quantity of the component used for each layer.

The nucleus portion may be any shape, such as spherical, cylindrical, or irregular, but is preferably spherical so that the nucleus coating layer and the coating are easily formed uniformly. In this regard, the compound (I) or a mixture of pharmaceutically acceptable salts and additives thereof is kneaded and combined (by stirring granulation device, etc.), and extrusion granulation (by screw extrusion granulation device, roll extrusion granulation device or the like). The core portion prepared by spherical formulation (by rotating disc-type sizing device, centrifugal motorized granulator, electric fluidized bed granulator, etc.) or spherical seed particles was used as the core, and the core layer component The nucleus portion prepared by coating (containing the active ingredient) or the nucleus portion, which is a spherical seed particle, is more preferable, and the spherical seed particle is used as the core portion, and the core coating component (containing the active ingredient) is used at the core portion. More preferred are the nuclei prepared by coating. It is preferable that it is 180-1180 micrometers, and, as for the particle diameter of the nucleus part by the volume average particle diameter measured by a microscope method or a sieve classification method, it is more preferable that it is 300-650 micrometers.

In the case where the cleaning agent is a cleaning agent including a nucleus part and a nuclear coating layer located outside the nucleus part, the cleaning agent contains a light-shielding agent in the same manner as the cleaning agent in the respective production methods of the tablets, the granules, the powder or the fine granules. Coating with a coating composition or tableting with a tableting powder, if necessary, followed by coating with a coating composition containing a light shielding agent in the same manner as the cleaning agent in the method for producing a tablet; Powder, granules, granules or tablets.

In the film containing the light-shielding agent in the present invention, the amount of the light-shielding agent in the film is 0.6 parts by weight or more with respect to 100 parts by weight of the cleaning agent, but is preferably 0.8 to 50 parts by weight, more preferably 1 to 25 parts by weight. desirable. In addition, when a combination of titanium oxide or titanium oxide and iron oxide (specifically, yellow iron trioxide, iron trioxide, etc.) is used as the light shielding agent, it is 0.6 with respect to 100 parts by weight of titanium oxide or titanium oxide and iron oxide. It is preferable that it is weight part or more, It is more preferable that it is 0.8-50 weight part, It is still more preferable that it is 1-25 weight part.

It is preferable that it is 1-1000 weight part with respect to 100 weight part of cleaning agents, It is more preferable that it is 1.5-100 weight part, It is still more preferable that it is 1.5-50 weight part with respect to the cleaning agent. The concentration of the coating composition at the time of dissolving and / or dispersing the coating composition containing the light-shielding agent for coating on the cleaning agent is preferably 0.1 to 50% by weight, and preferably 0.5 to 20% by weight. More preferred.

It is preferable that the quantity of the compound (I) in the solid preparation of the solid preparation of this invention, or its pharmaceutically acceptable salt is 0.05-5 weight part with respect to 100 weight part of cleaning agents.

When compound (I) or its pharmaceutically acceptable salt is distributed equally in the whole preparation, the quantity of compound (I) or its pharmaceutically acceptable salt in a preparation is 0.05 with respect to 100 weight part of cleaning agents. It is more preferable that it is-5 weight part, and it is still more preferable that it is 0.05-2.5 weight part. In addition, when the cleaning agent is a cleaning agent including a nucleus part and a nuclear coating layer located outside the nucleus part, the amount of Compound (I) or a pharmaceutically acceptable salt thereof in the nuclear coating layer is based on 100 parts by weight of the total components in the nuclear coating layer. 0.05 to 5 parts by weight, containing the remaining compound (I) or a pharmaceutically acceptable salt thereof in the nucleus portion, or containing no compound (I) or its pharmaceutically acceptable salt in the nucleus coating layer, It is more preferable to contain all of compound (I) or a pharmaceutically acceptable salt thereof, and do not contain compound (I) or a pharmaceutically acceptable salt thereof in the nuclear coating layer, and compound (I) or the pharmaceutical thereof in the nucleus part More preferably all of the salts which are acceptable. As described above, the cleaning agent in the solid preparation of the present invention includes a nucleus portion and a nucleus coating layer located outside the nucleus portion, and does not contain an active ingredient in the nucleus coating layer. Although it is preferable to contain, in this case, the fall of the stability of the active ingredient by contact with the component in a film | membrane, air, or humidity outside of a preparation, and moving an active ingredient out of a preparation can be suppressed more.

The amount of each additive contained in the solid preparation of the present invention may be within the range of the general amount of use in the preparation. Moreover, when using a binder as a binder solution, it is preferable that the density | concentration of the binder in a binder solution is generally 0.1-50 weight%, It is more preferable that it is 0.5-20 weight%, The solid preparation of this invention is a binder. In addition to the binder added by spraying the solution, it may contain a binder added in powder.

The amount of the nuclear coating layer (the same as the core coating layer in the case where the nucleus consists of the core portion and the core coating layer) in the cleaning agent in the case where the cleaning agent is the cleaning agent including the nucleus portion and the nuclear coating layer located outside the nucleus portion is the amount of the nucleus. When manufacturing the cleaning agent which has a coating layer by the powder coating method, it is preferable that it is 5-90 weight part with respect to 100 weight part of cleaning agent, It is more preferable that it is 10-75 weight part, It is more preferable that it is 10-50 weight part desirable. When the amount of the nuclear coating layer is 5 parts by weight or more, it is easier to coat the entire nucleus part with a powder dispersant, and when it is 90 parts by weight or less, it is easier to produce a granule having a suitable particle size as a fine grain or granule. On the other hand, when performing by a spray coating method, it is preferable that the quantity of a nuclear coating layer is 0.1-90 weight part with respect to 100 weight part of cleaning agents, It is more preferable that it is 0.5-50 weight part, It is further more preferable that it is 1-30 weight part. Do.

The solid preparation of the present invention may be in any shape as long as it can be administered orally. Among these, the powder, granules, granules, tablets or capsules are preferably in the form, and more preferably in the form of granules or granules. Do. In addition, the solid preparation of the present invention is filled into a capsule, and a granule or dry syrup containing the solid preparation of the present invention is mixed with and / or granulated with the capsule containing the solid preparation of the present invention, or with other additives as necessary. It is good also as a multiple unit tablet containing the solid formulation of this invention.

EMBODIMENT OF THE INVENTION Below, this invention is demonstrated in detail based on an Example, but this invention is not limited to these Examples.

Example  One

Granules A to C shown in Table 1 were produced according to the following procedures.

Microgranules; To 150 g of purified white sugar spherical granules (Nonparel-103, 32-42 mesh, Freund Industries, hereinafter identical) as a nucleus part, using a fluidized bed granulation coating apparatus (Flow coater-Mini, Freund Industries, hereinafter identical), 0.75 g of a compound (A; manufactured by Kyowa Fermentation), 0.375 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd., below) and 75 g of a spray solution of 0.375 g of talc dissolved and dispersed in distilled water were spray-coated. Got.

Granules having a film containing a light-shielding agent; According to the prescription of Table 1, the coating component was dissolved and dispersed in purified water, and the spray liquid of 11.6 weight% of solid content concentration was prepared. The flow coater-Mini was used in 150 g of the granules obtained above, and 5.8 parts by weight (granule A), 11.6 parts by weight (granule B) and 23.2 parts (granule C) of 100 parts by weight of the granules were dried. Granules were obtained by spray coating the respective spray solutions until

Example  2

The granules D-F shown in Table 1 were manufactured in the following procedures.

Microgranules; 900 g of the purified sugar per granule granules as the nucleus part was sprayed with an aqueous hydroxypropyl cellulose solution (5% by weight) using a centrifugal electric granulator (CF-360, CF Granulator 360, manufactured by Freund Industries, hereinafter). By powder coating a mixed powder of 6 g of a compound (A; manufactured by Kyowa fermentation and pulverized to have a volume average particle diameter of approximately 60 µm, the same) and 294 g of a white sugar powder (Nikkyoku refined white sugar, manufactured by Mitsui Sugar, hereinafter identical) Fine granules were obtained.

Granules having a film containing a light-shielding agent; According to the prescription of Table 1, the coating component was dissolved and dispersed in purified water, and the spray liquid of 11.6 weight% of solid content concentration was prepared. Using 800 g of the small granules obtained above, CF-360, the coating layer would be 5.8 parts by weight (granule D), 11.6 parts by weight (granule E) and 23.2 parts (granule F) in a dry state. The granules were obtained by spray-coating each spray liquid until it was.

Comparative example  One

In the same manner as in Example 1, small granules were obtained.

Comparative example  2

In the same manner as in Example 2, small granules were obtained.

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Granule A Granule B Granule C Granule D Granule E Granule F Cattle granules Nonfarel 99.0 99.0 99.0 74.9 74.9 74.9 99.0 74.9 Compound A 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 White sugar - - - 24.5 24.5 24.5 - 24.5 Hydroxypropylcellulose 0.25 0.25 0.25 0.2 0.2 0.2 0.25 0.2 Talc 0.25 0.25 0.25 - - - 0.25 - sub Total 100.0 100.0 100.0 100.1 100.1 100.1 100.0 100.0 Film Hydroxypropylmethylcellulose 2.00 4.00 8.00 2.00 4.00 8.00 - - Lactose 1.10 2.20 4.40 1.10 2.20 4.40 - - Polyethylene glycol 0.40 0.80 1.60 0.40 0.80 1.60 - - Triacetin 0.30 0.60 1.20 0.30 0.60 1.20 - - Titanium oxide 1.16 2.33 4.65 1.16 2.33 4.65 - - Yellow 3 Iron Dioxide (Yellow) 0.03 0.05 0.10 0.03 0.05 0.10 - - 3 iron dioxide (red) 0.01 0.03 0.05 0.01 0.03 0.05 - - Talc 0.80 1.60 3.20 0.80 1.60 3.20 - - sub Total 5.80 11.61 23.20 5.80 11.61 23.20 0.00 0.00 Whole quantity 105.8 111.6 123.2 105.9 111.7 123.3 100.0 100.0

                                                      (Unit: weight ratio)

Test Example  One ( Light stability  exam)

The photostability test was done using each granule obtained from Examples 1-2 and Comparative Examples 1-2, and each granule. The photostability test was carried out by uniformly disposing each granule or each granule on a chalet and irradiating a white fluorescent lamp 5000 Lux light for 10 days (1.2 million Lux · hr) in a thermostat at 25 ° C. and 60% relative humidity. . After the light exposure, sampling was performed and the amount of lead substance produced by Compound (A) was determined by high performance liquid chromatography. Table 2 shows the results of the photostability test.

High Speed Liquid Chromatography Conditions

column ; Inertsil C8 4.6 × 250mm GL Sciences Inc.

Column temperature; Constant temperature around 40 ℃

Mobile phase; 0.05 mol / L phosphate buffer (pH 3.5): acetonitrile = 550 mL: 450 mL + sodium lauryl sulfate 2.3 g

Detection method: ultraviolet absorption photometry (wavelength 299 nm)

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Granule A Granule B Granule C Granule D Granule E Granule F Production amount of lead substance (B) 1.46 0.98 0.40 0.19 0.09 0.04 3.45 0.76

In Table 2, in each granule obtained in Example 1 having a coating containing light-shielding agents (titanium oxide, yellow triiron dioxide and iron trioxide) at 0.6 parts by weight or more with respect to 100 parts by weight of the cleaning agent, Comparative Example 1 without a coating In comparison with the microgranules obtained in, a significant suppression of the cast substance (B) under the exposure to light was observed. Similarly, in each granule obtained in Example 2, remarkable suppression of the flexible substance (B) under light exposure is observed compared with the microgranule obtained in the comparative example 2, and the shaver containing the compound (A) is light-shielded. It has become clear that coating with the coating film containing the agent has a great effect on improving the light stability of the solid preparation containing the compound (A). In addition, the flexible substance (B) is a geometric isomer of the compound (A), is produced by photoisomerization, and does not occur under shading preservation in a solid preparation.

Example  3

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; The granules were obtained by powder-coating a mixed powder of 6 g of Compound (A) and 114 g of white sugar powder while spraying hydroxypropyl cellulose aqueous solution (5% by weight) onto 1080 g of purified white sugar spherical granules as the nucleus part.

Granules having a film containing a light-shielding agent; According to the prescription of Table 3, the coating component was dissolved and dispersed in purified water, and the spray liquid of solid content concentration 11.6 weight% was prepared. The granules were obtained by spraying the spray liquid with respect to 100 weight part of small granules until it became 17.4 weight part in dry conditions using CF-360 for 800 g of small granules obtained above.

Example  4

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; 900 g of the purified white sugar spherical granules as the nucleus part was sprayed with a hydroxypropyl cellulose aqueous solution (5% by weight) using CF-360, while powder coating a mixed powder of 6 g of the compound (A) and 294 g of the white sugar powder was obtained.

Granules having a film containing a light-shielding agent; In the same manner as in Example 3, granules were obtained.

Example  5

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; Microparticles were obtained by powder coating a mixed powder of 6 g of Compound (A) and 594 g of white sugar powder while spraying hydroxypropyl cellulose aqueous solution (5% by weight) onto 600 g of purified white sugar spherical granules as the nucleus part.

Granules having a film containing a light-shielding agent; In the same manner as in Example 3, granules were obtained.

Example  6

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; 6 g of compound (A) and 114 g of white sugar powder were dispersed while spraying an aqueous solution of hydroxypropyl cellulose (5% by weight) using CF-360 to 600 g of purified white sugar granules as a core. The nucleus part containing was obtained. Subsequently, the granules were obtained by powder-coating 480 g of powder per bag, spraying hydroxypropyl cellulose aqueous solution (5 weight%) similarly to this nucleus part.

Granules having a film containing a light-shielding agent; In the same manner as in Example 3, granules were obtained.

Example  7

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; 6 g of compound (A) and 294 g of white sugar powder were dispersed while spraying an aqueous solution of hydroxypropyl cellulose (5% by weight) using CF-360 to 600 g of purified white sugar spherical granules as a core. The nucleus part to contain was obtained. Subsequently, the granules were obtained by powder-coating 300 g of powder per bag, spraying hydroxypropyl cellulose aqueous solution (5 weight%) similarly to this nucleus part.

Granules having a film containing a light-shielding agent; In the same manner as in Example 3, granules were obtained.

Example  8

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; 6 g of Compound (A), 78 g of white sugar powder, corn starch (Starch 1500, manufactured by Caracon), while spraying aqueous solution of hydroxypropyl cellulose (5% by weight) with CF-360 to 600 g of refined white sugar granules as a core The same) 36g of mixed powder was spread | dispersed and the nuclear part containing a compound (A) was obtained. Subsequently, small granules were obtained by powder coating a mixed powder of 336 g of white powder and 144 g of corn starch while spraying the hydroxypropyl cellulose aqueous solution (5% by weight) in the same manner to the nucleus part.

Granules having a film containing a light-shielding agent; In the same manner as in Example 3, granules were obtained.

Example  9

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; 6 g of Compound (A), 113 g of white sugar powder, and hard silicic acid anhydride (Sansia 350, Fuji Silysia) while spraying hydroxypropyl cellulose aqueous solution (5% by weight) onto 600 g of purified white sugar spherical granules as a core using CF-360. Chemical preparation) 1 g of mixed powder was spread | dispersed and the nucleus part containing a compound (A) was obtained. Subsequently, the granules were obtained by powder-coating a mixed powder of 475 g of powder per white powder and 5 g of hard silicic anhydride while spraying the hydroxypropyl cellulose aqueous solution (5% by weight) in the same manner to the nucleus part.

Granules having a film containing a light-shielding agent; In the same manner as in Example 3, granules were obtained.

Example  10

The granules shown in Table 3 were manufactured according to the following procedures.

Microgranules; 6 g of compound (A), 108 g of white sugar powder, and talc (manufactured by Lisbran, Kihara Chemical Chemical Co., Ltd.), while spraying hydroxypropyl cellulose aqueous solution (5% by weight) onto 600 g of refined white sugar spherical granules as a core, using CF-360. The same) 6g of mixed powder was spread | dispersed and the nuclear part containing a compound (A) was obtained. Subsequently, the granules were obtained by powder-coating a mixed powder of 456 g of powder per white powder and 24 g of talc while spraying the hydroxypropyl cellulose aqueous solution (5% by weight) in the same manner to the nucleus part.

Granules having a film containing a light-shielding agent; In the same manner as in Example 3, granules were obtained.

Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Microgranules Nuclear Nonfarel 89.9 74.9 49.9 49.8 49.8 49.6 49.8 49.8 Compound A 0.5 0.5 0.5 0.5 0.5 White sugar 9.5 24.4 6.5 9.4 9.0 Corn starch 3.0 Light anhydrous silicic acid 0.1 Talc 0.5 sub Total 89.9 74.9 49.9 59.8 74.7 59.6 59.8 59.8 Nuclear coating Compound A 0.5 0.5 0.5 White sugar 9.5 24.5 49.4 39.8 24.9 27.8 39.5 37.9 Corn starch 11.9 Light anhydrous silicic acid 0.4 Talc 2.0 sub Total 10.0 25.0 49.9 39.8 24.9 39.7 39.9 39.9 Hydroxypropyl Cellulose (Total in Nucleus and Nuclear Coating Layers) 0.1 0.2 0.2 0.4 0.4 0.7 0.4 0.4 sub Total 100.0 100.1 100.0 100.0 100.0 100.0 100.1 100.1 Film Hydroxypropylmethylcellulose 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Lactose 3.30 3.30 3.30 3.30 3.30 3.30 3.30 3.30 Polyethylene glycol 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.20 Triacetin 0.90 0.90 0.90 0.90 0.90 0.90 0.90 0.90 Titanium oxide 3.49 3.49 3.49 3.49 3.49 3.49 3.49 3.49 Yellow triiron dioxide (yellow) 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 3 iron dioxide (red) 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 Talc 2.40 2.40 2.40 2.40 2.40 2.40 2.40 2.40 sub Total 17.41 17.41 17.41 17.41 17.41 17.41 17.41 17.41 Whole quantity 117.4 117.5 117.4 117.4 117.4 117.4 117.5 117.5

                                                             (Unit: weight ratio)

Test Example  2 ( Light stability  exam)

The photostability test was done using each granule obtained in Examples 3-10. In the light stability test, each granule was uniformly arranged on the chalet, and daylight white light (D65) lamp 1000 Lux light was kept for 50 days (1.2 million Lux · hr) in a thermostat at 25 ° C. and 60% relative humidity. ) To investigate. After the light exposure, sampling was performed and the amount of lead substance produced by Compound (A) was determined by high performance liquid chromatography in the same manner as in Test Example 1. Table 4 shows the results of the light stability test.

Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Production amount of lead substance (B) 0.13 0.09 0.03 0.00 0.00 0.00 0.00 0.00 Total amount of lead material other than B (%) 2.31 1.51 0.60 0.01 0.00 0.33 0.14 0.15

In Table 4, in any of the granules obtained in Examples 3 to 10, it was observed that the production of the flexible substance (B) was significantly suppressed under the light exposure, and it was clear that all were excellent granules.

Example  11

The granules shown in Table 5 were manufactured according to the following procedures.

Microgranules; 23.55 g of Compound (A) and white sugar powder [The above-mentioned sugar was pulverized (sample mill KIIWG-1F,) while spraying hydroxypropyl cellulose aqueous solution (5.9% by weight) onto 2000 g of purified white sugar spheroidal granules as a core, using CF-360. Pulverized using Fuji Powder), and a mixture powder of 368.8 g of light anhydrous silicic acid (Adsorida 101, manufactured by Freind Industries, hereinafter) with a volume average particle diameter of about 30 μm. It spreads and the nuclear part containing a compound (A) was obtained. Subsequently, micronuclear granules were obtained by powder coating a mixed powder of 1587.8 g of white powder and 12.25 g of hard silicic anhydride while spraying the hydroxypropyl cellulose aqueous solution (5.9 wt%) in the same manner to the nucleus part (preparation of the above-mentioned microgranules) Was repeated 3 times.).

The obtained microgranules were classified with a vibrating body 502 CBH (manufactured by Fuji Powder) after drying in a ventilation dryer (VD-1000SJ, Nitto Iwa Kogyo Co., Ltd.). The obtained microgranules were high yield (classification yield 96%).

Granules having a film containing a light-shielding agent; According to the prescription of Table 5, the coating component was dissolved and dispersed in purified water to prepare a spray liquid having a solid content concentration of 11.6% by weight. By using a fluid bed granulation dryer (flow coater FLO-15EX, Freund Industries) for 9300 g of the obtained microgranules, the spray liquid is spray-coated until the coating becomes 17.4 parts by weight with respect to 100 parts by weight of the microgranules granules. Got.

The obtained coated granules were classified using vibrating body 502 CBH (manufactured by Fuji Powder) (355-850 µm, classification yield 96%), and 0.1% by weight of hard silicic anhydride was added to 99.9% by weight of the coated granules and mixed. To obtain a formulation.

Example 11 Microgranules Nuclear Nonfarel 49.9 Compound A 0.6 White sugar 9.2 Light anhydrous silicic acid 0.1 sub Total 9.9 Nuclear coating White sugar 39.6 Light anhydrous silicic acid 0.3 sub Total 39.9 Hydroxypropyl Cellulose (Total in Nucleus and Nuclear Coating Layers) 0.3 sub Total 100.0 Film Hydroxypropylmethylcellulose 6.00 Lactose 3.30 Polyethylene glycol 1.20 Triacetin 0.90 Titanium oxide 3.49 Yellow triiron dioxide (yellow) 0.08 3 iron dioxide (red) 0.04 Talc 2.40 sub Total 17.41 Light anhydrous silicic acid 1.20 Whole quantity 118.6

According to the present invention, there is provided a solid preparation containing the compound (I) or a pharmaceutically acceptable salt thereof and excellent in storage stability such as light stability.

Claims (14)

Formula (Ⅰ) [Formula 5]

[Wherein, A represents a single bond, -CH = CH- or (CH ₂ ) _n- (wherein n represents an integer of 1 to 3), R ¹ and R ² are the same or different and hydrogen Or lower alkyl or one of the adjacent nitrogen atoms to form a heterocyclic group], and a preservative containing a dibenzo [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof, Solid preparation containing the film or capsule containing 0.6 weight part or more of light-shielding agents with respect to 100 weight part of cleaning agents. The method of claim 1, Solid formulation, wherein the light shield is at least one substance selected from titanium oxide, yellow triiron dioxide and triiron dioxide. The method according to claim 1 or 2, The solid preparation which is 0.05-5 weight part with respect to 100 weight part of cleaning agent, in the quantity of the dibenzo [b, e] oxepine derivative or its pharmaceutically acceptable salt contained in a cleaning agent. The method according to any one of claims 1 to 3, The solid preparation is a solid preparation which contains the at least 1 substance chosen from sugar, starch, a starch derivative, cellulose, and a cellulose derivative. The method according to any one of claims 1 to 3, Solid preparation which is a cleaning agent containing sugar, a cellulose, and a cellulose derivative. The method according to claim 4 or 5, Solid preparation, wherein the sugar is at least one substance selected from lactose and white sugar. The method according to claim 1 or 2, The preagent is a preagent comprising a nucleus portion and a nucleus coating layer containing a dibenzo [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof located outside the nucleus portion, the dibenzo [contained in the nucleus coating layer. b, e] Solid preparation which is 0.05-5 weight part with respect to 100 weight part of nuclear coating layers in the quantity of an oxepin derivative or its pharmaceutically acceptable salt. The method according to claim 1, 2 or 7, The cleaning agent is a cleaning agent including a nucleus part and a nuclear coating layer located outside the nucleus part, the nucleus part containing a dibenzo [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof, and the nuclear coating layer is A solid preparation, containing no benzo [b, e] oxepin derivatives and pharmaceutically acceptable salts thereof. The method according to claim 7 or 8, A solid preparation, wherein the nuclear coating layer is a nuclear coating layer containing one or more substances selected from sugars, starches, starch derivatives, celluloses and cellulose derivatives. The method according to claim 7 or 8, The nuclear preparation layer is a solid preparation which is a nuclear coating layer containing a combination of sugar, starch, and / or poorly water-soluble inorganic salt. The method according to claim 9 or 10, Solid preparation, wherein the sugar is at least one substance selected from lactose and white sugar. The method according to any one of claims 1 to 11, Solid preparation, wherein the solid preparation is in the form of fine granules or granules. The method according to any one of claims 1 to 11, Solid formulations, wherein the solid formulation is in the form of a tablet or capsule. A particulate preparation, a multiple unit tablet or a dry syrup containing the solid preparation according to claim 12.