JP2007211006A - Coated solid preparation having elution stability - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a pranlukast hydrate-containing solid preparation having elution stability under storage in a nonpackaged state. <P>SOLUTION: The solid preparation is obtained by coating the original uncoated solid preparation containing a pranlukast hydrate and an excipient with a coating agent comprising one or more polymers selected from acrylate-based polymer and polyvinyl-based polymer and, as desired, a water-soluble substance and/or fat-and-oil. This solid preparation is excellent in moistureproofness, has a coating layer readily disintegrable in the stomach, and has elution stability under storage. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  In the present invention, an uncoated solid preparation containing pranlukast hydrate and an excipient is coated with a coating agent containing one or more selected from acrylate polymers and polyvinyl polymers. It is related with the coating solid formulation which has the elution stability by storage characterized by these.

  Pranlukast hydrate is known as a leukotriene antagonist (see Patent Document 1) and is marketed as a therapeutic agent for bronchial asthma and allergic rhinitis. In addition, pranlukast hydrate has strong adhesion and aggregation properties, and as a method for reducing it, a method of spray-drying pranlukast hydrate together with sugars is known (see Patent Document 2).

  On the other hand, it has been reported that capsules containing pranlukast hydrate become unstable in one week if left unpacked (“Stable tablet / capsule in non-packaging state”). Sexual information "(Revised 3rd edition, published by Pharmaceutical Journal, February 5, 2003, p. 136).

  Under such circumstances, there is a demand for a preparation having elution stability by storage containing pranlukast hydrate, which does not become unstable even when stored in a non-packaging state or a simple packaging state. It was. Until now, the cause of the unstable dissolution of the preparation containing pranlukast hydrate has not been elucidated, but the present inventors have found that the moisture absorption of the preparation is one of the causes. An attempt was made to solve the above problems by coating a formulation containing Lucast Hydrate. However, when the coating is applied until the moisture-proof effect is exhibited by the film coating, the layer becomes thick and the coating layer is difficult to disintegrate in the stomach, so that there is a problem that it does not dissolve quickly.

JP-A-61-050977 Japanese Patent No. 2958863 Information on the stability of tablets and capsules in the unwrapped state (published by Pharmaceutical Journal), February 5, 2003, p. 136

  The object of the present invention is not a solid preparation that is moisture-proof only by a package without any ingenuity in the preparation, has a coating layer that is excellent in moisture resistance and easily disintegrates in the stomach, and is stored in an unwrapped state. It is an object of the present invention to provide a novel coated solid preparation containing pranlukast hydrate having dissolution stability.

  In view of the above problems, as a result of intensive studies, the present inventors surprisingly performed coating with a coating agent comprising one or more selected from acrylate polymers and polyvinyl polymers. The present invention was completed by finding a solid preparation having excellent moisture resistance and having a coating layer that is easily disintegrated in the stomach and having dissolution stability by storage in an unwrapped state.

That is, the present invention includes (1) an uncoated solid preparation containing pranlukast hydrate and an excipient, containing one or more selected from acrylate polymers and polyvinyl polymers, Furthermore, a coated solid preparation having dissolution stability upon storage, characterized by being coated with a coating agent containing a water-soluble substance and / or fats and oils if desired,
(2) The acrylate polymer is aminoalkyl methacrylate copolymer E, the polyvinyl polymer is one or two selected from polyvinyl acetal diethylaminoacetate and polyvinyl alcohol, and the water-soluble substances are water-soluble celluloses and saccharides. The solid preparation according to (1), wherein the fat or oil is one or more selected from stearic acid, magnesium stearate, calcium stearate and carnauba wax,
(3) The solid preparation according to (1), wherein the weight of the coating layer is about 2 to about 12 parts by weight with respect to 100 parts by weight of the uncoated solid preparation,
(4) About 2 to about 9 parts by weight of a total of one or more selected from acrylate polymers and polyvinyl polymers with respect to 100 parts by weight of the uncoated solid preparation, and about 0.1 parts of water-soluble substances. The solid preparation according to the above (1), which is a coating agent comprising 5 to about 8 parts by weight and 0 to about 5 parts by weight of fats and oils,
(5) (1) Oils and fats are not included, the total of one or more selected from acrylate polymers and polyvinyl polymers is about 2 to about 9 parts by weight, and the water-soluble substance is about 0.5 to about A coating agent comprising about 8 parts by weight, or (2) about 2 to about 9 parts by weight of a total of one or more selected from acrylate polymers and polyvinyl polymers, and a water-soluble substance The solid preparation according to (4) above, which is a coating agent comprising about 0.5 to about 8 parts by weight and about 0.5 to about 5 parts by weight of fats and oils,
(6) The solid preparation according to (1), comprising about 50 to about 90 parts by weight of pranlukast hydrate in 100 parts by weight of an uncoated solid preparation,
(7) The solid preparation according to (1) above, containing about 5 to about 80 parts by weight of an excipient with respect to 100 parts by weight of pranlukast hydrate,
(8) The solid preparation according to (1), wherein the excipient is one or two selected from lactose and sucrose.
(9) The solid preparation according to (1), wherein the coated solid preparation is a coated capsule, a coated tablet or a coated granule,
(10) The solid preparation according to (9) above, containing pranlukast hydrate in an amount of about 112.5 mg or about 225 mg per capsule, 1 tablet or 1 capsule, respectively.
(11) The thickness of the coating layer is about 7 to about 42 μm for capsules, about 14 to about 84 μm for tablets, and about 0.3 to about 1.8 μm for granules. The described solid preparation,
(12) The solid according to (1), wherein the difference between the dissolution rate after storage for 1 month under a temperature of 25 ° C. and a relative humidity of 75% in an unwrapped state is within 25%. Formulation,
(13) The solid preparation according to (12), wherein the difference is within 15%,
(14) Capsule having elution stability by storage, filled with the coated granule according to (9),
(15) The capsule according to (14), wherein the capsule is an uncoated capsule,
(16) The capsule is a coated capsule, and 100 parts by weight of the uncoated capsule is (1) one or more selected from acrylate-based polymers and polyvinyl-based polymers without fats and oils A coating agent comprising about 2 to about 9 parts by weight in total and about 0.5 to about 8 parts by weight of a water-soluble substance, or (2) 1 selected from acrylate polymers and polyvinyl polymers Coating with a coating agent comprising from about 2 to about 9 parts by weight of a total of two or more species, from about 0.5 to about 8 parts by weight of a water-soluble substance and from about 0.5 to about 5 parts by weight of fats and oils. The capsule according to (14),
(17) The capsule according to (14), wherein the difference between the dissolution rate after storage for 1 month under a temperature of 25 ° C. and a relative humidity of 75% in an unwrapped state is within 25%. Agent,
(18) The capsule according to (17), wherein the difference is within 15%,
(19) To 100 parts by weight of uncoated solid preparation containing pranlukast hydrate and excipient, (1) 1 selected from acrylate polymer and polyvinyl polymer without oil and fat A coating agent comprising a total of about 3.2 to about 6.4 parts by weight of two or more species and about 0.8 to about 4.8 parts by weight of a water-soluble substance, or (2) an acrylate polymer and polyvinyl A total of about 3.2 to about 6.4 parts by weight of one or more selected from the polymer series, about 0.8 to about 4.8 parts by weight of water-soluble substances, and about 0.5 to about 4.8 parts by weight of fats and oils Elution rate after storage for 1 month at a temperature of 25 ° C. and a relative humidity of 75% in an unwrapped state, and an elution rate before storage, characterized by being coated with a coating agent comprising 4 parts by weight Coating capsules with a difference of 25% or less Ingu tablets or coated granules,
(20) The coated capsule, coated tablet or coated granule according to (19), wherein the difference is within 15%, and (21) pranlukast hydrate per capsule, 1 tablet or 1 capsule, respectively The present invention relates to the coated capsule, coated tablet or coated granule according to (19), which contains about 112.5 mg or about 225 mg.

  In the present invention, “an uncoated solid preparation containing pranlukast hydrate and excipient” means an uncoated powder or granule containing pranlukast hydrate and an excipient , Tablets, capsules, or dissolution / suspension preparations (dry syrups etc.) at the time of use. Preferably, it is a granule, a tablet or a capsule.

  The pranlukast hydrate used in the present invention has the formula (A)

4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran 1/2 hydrate represented by formula (1). The production of pranlukast hydrate can be carried out, for example, according to the description in JP-A-61-050977.

  Examples of the excipient in the present invention include saccharides (eg, glucose, fructose, maltose, lactose, sucrose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol. Corn starch, potato starch, wheat starch, rice starch, etc.), crystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, and calcium silicate. These may be used alone or in combination of two or more. be able to. Lactose or sucrose is preferable, and lactose is more preferable. Further, in the “uncoated solid preparation comprising pranlukast hydrate and excipient”, about 5 to about 80 parts by weight of the excipient is contained with respect to 100 parts by weight of pranlukast hydrate. More preferably, it is about 10 to about 60 parts by weight, and particularly preferably about 20 to about 45 parts by weight.

  The “coated solid preparation” of the present invention is one kind selected from the above-mentioned “uncoated solid preparation containing pranlukast hydrate and excipient” from an acrylate polymer and a polyvinyl polymer. Or a solid preparation formed by coating a coating agent containing two or more kinds, and optionally containing a water-soluble substance and / or fats and oils, specifically, a coated powder, granule, tablet, capsule It means an agent or a dissolution / suspension preparation (dry syrup, etc.). Preferred are coated granules, coated tablets or coated capsules. The coating is carried out using a conventional method such as a coating pan, a fluidized bed granulator, a rolling fluidized bed granulator, a Wurster coating machine, a centrifugal fluidized rolling granulator or the like.

  As the coating agent in the present invention, any of water-based and organic solvent-based coating agents comprising one or more selected from acrylate polymers and polyvinyl polymers can be used. The polymer is used by being dispersed in a solvent, for example, water, an organic solvent (for example, ethanol, acetone, methanol, methylene chloride), or a mixture of two or more selected from them. In the case of a coating agent further comprising a water-soluble substance and / or oil and fat in addition to the polymer, one or more selected from an acrylate polymer and a polyvinyl polymer, and a water-soluble substance or acrylate Water-based and organic solvent-based coating agents containing one or more selected from polymer-based polymers and polyvinyl polymers, water-soluble substances and oils and fats are used. The solvent is preferably the same as described above. In addition, other additives can be added to the present coating agent, and examples thereof include a plasticizer, a colorant, a lubricant, a fluidizing agent, a suspending agent, a brightening agent, and an adhesion preventing agent.

  In the present invention, when the coated solid preparation is a coated granule, an uncoated capsule filled with the coated granule or an uncoated tablet formed by tableting the coated granule is also included. Furthermore, the uncoated capsule or uncoated tablet contains one or more selected from acrylate-based polymers and polyvinyl-based polymers, and further contains water-soluble substances and / or fats and oils as desired. Coating may be performed with a coating agent to form a coated capsule or a coated tablet, respectively. Preferably, it is an uncoated capsule formed by filling a coated granule, and it is also preferable to further coat the uncoated capsule to form a coated capsule.

  In the present invention, examples of the acrylate polymer include aminoalkyl methacrylate copolymer E.

  In the present invention, examples of the polyvinyl polymer include polyvinyl acetal diethylaminoacetate and polyvinyl alcohol. Of these, polyvinyl acetal diethylaminoacetate is preferable.

  In the present invention, examples of the water-soluble substance include one or more selected from water-soluble celluloses and saccharides. The water-soluble celluloses used in the present invention are those in which hydrogen bonds are lost by substituting some of the hydrogen atoms of the hydroxyl groups of cellulose with methyl groups, ethyl groups, propyl groups, hydroxypropyl groups or hydroxyethyl groups. Water-soluble polymer. Examples thereof include hydroxymethyl cellulose, hydroxymethyl ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), and hydroxypropyl methyl cellulose (HPMC). Any of the water-soluble celluloses is preferable, particularly preferably hydroxypropyl methylcellulose, and hydroxypropylmethylcellulose suitably used includes hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, and the like. Specific examples include Metroze 90SH, Metroze 65SH, Metroze 60SH, TC-5 (manufactured by Shin-Etsu Chemical Co., Ltd.), and the like. Examples of TC-5 include TC-5E, TC-5EW, TC-5R, TC-5RW, TC-5MW, and TC-5S.

  Examples of the saccharide in the present invention include glucose, fructose, maltose, lactose, sucrose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch , Wheat starch, and rice starch. Of these, lactose or sucrose is preferable.

  Examples of the fats and oils in the present invention include stearic acid, magnesium stearate, calcium stearate, and carnauba wax. Of these, stearic acid is preferred.

  One or two types selected from acrylate polymers and polyvinyl polymers compared to solid preparations coated with a coating agent comprising only one or two or more types selected from acrylate polymers and polyvinyl polymers As described above, a solid preparation coated with a coating agent further containing a water-soluble substance can be a coated solid preparation having an excellent disintegrating property of the coating layer and an excellent dissolution property. In addition, a solid preparation obtained by coating a coating agent containing one or more selected from acrylate polymers and polyvinyl polymers with a coating agent obtained by adding oils and fats further increases the moisture resistance of the coating layer. It can be a coated solid preparation with improved dissolution stability by storage in a packaged state. In the present invention, a coating agent comprising only one or more selected from acrylate polymers and polyvinyl polymers, one or more selected from acrylate polymers and polyvinyl polymers, and A coating agent comprising a water-soluble substance, or a coating agent comprising one or more selected from an acrylate polymer and a polyvinyl polymer, a water-soluble substance and an oil and fat is preferred.

  The weight part of the coating layer in the coated solid preparation of the present invention is preferably about 2 to about 12 parts by weight, more preferably about 2.4 to about 10 parts by weight, with respect to 100 parts by weight of the uncoated solid preparation. Particularly preferred is about 3.2 to about 8 parts by weight. In addition, the thickness of the coating layer at that time is preferably about 7 to about 42 μm for capsules, about 14 to about 84 μm for tablets, and preferably about 0.3 to about 1.8 μm for granules. . The coating layer having a weight part and thickness of the present invention is excellent in moisture resistance, disintegrating in the stomach, and has dissolution stability upon storage. Moreover, the “coating layer that disintegrates easily in the stomach” in the present invention means a coating layer that disintegrates within 30 minutes from administration.

  The coating agent of the present invention may comprise a total of about 2 to about 9 parts by weight of one or more selected from acrylate polymers and polyvinyl polymers with respect to 100 parts by weight of the uncoated solid preparation. Preferably, it is about 2.4 to about 7.2 parts by weight, particularly preferably about 3.2 to 6.4 parts by weight.

  The coating agent of the present invention preferably contains no water-soluble substance or comprises about 0.5 to about 8 parts by weight, more preferably about 0 to 100 parts by weight of the uncoated solid preparation. 0.8 to about 5.6 parts by weight, particularly preferably about 0.8 to 4.8 parts by weight.

  It is preferable that the coating agent of the present invention does not contain fat or oil, or contains about 0.5 to about 5 parts by weight, more preferably does not contain, relative to 100 parts by weight of the uncoated solid preparation. Or about 0.5 to about 4 parts by weight.

  In the present invention, 100 parts by weight of the uncoated solid preparation contains about 2 to about 9 parts by weight of one or more selected from acrylate polymer and polyvinyl polymer, and contains a water-soluble substance. A coating agent comprising about 0.5 to about 8 parts by weight and 0 to about 5 parts by weight of fats and oils is preferred. More preferably, (1) fat or oil is not included, and the total of one or more selected from acrylate polymers and polyvinyl polymers is about 2 to about 9 parts by weight, and the water-soluble substance is about 0.5 Coating agent comprising about 8 parts by weight, or (2) about 2 to about 9 parts by weight of one or more selected from acrylate polymer and polyvinyl polymer, A coating agent comprising 0.5 to about 8 parts by weight and about 0.5 to about 5 parts by weight of fats and oils.

  In “100 parts by weight of uncoated solid preparation” in the present invention, when the uncoated solid preparation is an uncoated capsule, it means 100 parts by weight of the contents of the uncoated capsule.

  In the present invention, “an uncoated solid preparation containing pranlukast hydrate and excipient” can be produced from a granulated product containing pranlukast hydrate and excipient. In addition to the granulated product, it may contain commonly used additives. For example, excipients, binders, lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, perfumes. , A coloring agent, an antioxidant, a masking agent, an antistatic agent, a fluidizing agent, a wetting agent, and an elution aid can be appropriately blended. Preferably, a lubricant and / or a fluidizing agent is included.

  In the present invention, the “granulated product containing pranlukast hydrate and excipient” may be a granulated product produced by any production method, for example, extrusion granulation method, stirring granulation Method, mixed stirring granulation method, high speed mixing stirring granulation method, fluidized bed granulation method, stirred fluidized bed granulation method, tumbling stirred fluidized bed granulation method, tumbling granulation method, rolling fluidized bed granulation method , Dry (compressed) granulation method, crushing granulation method, spray drying granulation method and the like. The “granulated product containing pranlukast hydrate and an excipient” may contain commonly used additives in addition to the excipient, for example, a binder, a disintegrant, a lubricant. As appropriate, one or two or more selected from among various additives, flavoring agents, flavoring agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, fluidizing agents, wetting agents and dissolution aids. Can be blended. Preferably, a disintegrant is further included. More preferably, it further contains a disintegrant and / or a binder.

The “uncoated solid preparation comprising pranlukast hydrate and excipient” of the present invention includes, for example,
(1) Uncoated solid preparation containing pranlukast hydrate, excipient, fluidizing agent and binder, such as pranlukast hydrate, excipient (lactose, sucrose, etc.) And a fluidizing agent (light anhydrous silicic acid, etc.) into a (high speed) stirring granulator, and an aqueous solution of a binder (hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, etc.) or water and an organic solvent (ethanol etc.) A mixed solution is added, kneaded, granulated by an extrusion granulator, granulated by a spherical granulator, etc., and then dried and produced from a granulated product;
(2) An uncoated solid formulation comprising pranlukast hydrate, excipients, fluidizing agent, and binder, for example, pranlukast hydrate, excipients (lactose, Sucrose, D-mannitol, etc.) and a fluidizing agent (light silicic anhydride, etc.) are mixed and put into a fluidized bed granulator, and an aqueous solution or water of a binder (hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, etc.) It is produced from a granulated product produced by spraying a mixed solution with an organic solvent (ethanol or the like). If desired, a granulated product may be produced by further adding a disintegrant;
(3) An uncoated solid preparation comprising pranlukast hydrate, an excipient and a disintegrant, and optionally a fluidizing agent. For example, this comprises pranlukast hydrate, excipient ( Lactose, sucrose, D-mannitol, etc.), disintegrant (low-substituted hydroxypropylcellulose, etc.), and optionally a fluidizing agent (light silicic anhydride, etc.) are added to the agitation granulator and optionally a binder (hydroxyl) Propyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, etc.) aqueous solution or mixed solution with water and organic solvent (ethanol etc.) was added to produce a wet product, dried with a fluid bed granulator, and sized. It is manufactured from the granulated product. The granulated product is about 0.02 to about 0.30 parts by weight of a disintegrant and about 0.05 to about 0.45 parts by weight of an excipient with respect to 1 part by weight of pranlukast hydrate. Preferably including;
(4) Contains pranlukast hydrate, and one or more excipients (saccharides), and further includes one or more water-soluble polymers and / or one or more surfactants. An uncoated solid preparation containing a spray-dried granulated product. For example, this is a pranlukast hydrate and saccharides (lactose, D-mannitol, sucrose, etc.) and a water-soluble polymer (hydroxypropylmethylcellulose) , Polyvinylpyrrolidone, polyethylene glycol, etc.) and / or surfactant (polysorbate, etc.) are suspended in a suitable solvent (water or a mixture of water and an organic solvent such as alcohol), and the suspension is spray-dried with a spray dryer. Manufactured from the granulated material produced by
(5) Uncoated solid preparation containing pranlukast hydrate, excipient (saccharide) and water-soluble cellulose, such as pranlukast hydrate, saccharide (lactose, mannitol, sucrose, etc. ), Water-soluble celluloses (hydroxypropylmethylcellulose, hydroxypropylcellulose, etc.), and other additives as necessary (excipients, binders, disintegrants, flavoring agents, surfactants, perfumes, lubricants, Colorants, antioxidants, masking agents, antistatic agents, fluidizing agents, wetting agents, flavoring agents, elution aids, etc.) are mixed, or known granulation methods (for example, extrusion granulation method, mixing stirring) Granulation method, high speed mixing and agitation granulation method, fluidized bed granulation method, tumbling agitation fluidized bed granulation method, tumbling granulation method, dry (compression) granulation method, crushing granulation method, spray drying granulation method Etc.) Manufactured from granulated material produced by attaching to It is intended to be. The granulated product preferably contains 0.70 to 0.98 parts by weight of pranlukast hydrate in 1 part by weight of the granulated product, more preferably 0.75 to 0.87 parts by weight. Yes, it is preferably 0.05 to 0.30 parts by weight of saccharide, more preferably 0.10 to 0.25 parts by weight with respect to 1 part by weight of pranlukast hydrate;
(6) An uncoated solid preparation comprising pranlukast hydrate, excipient and water-soluble cellulose, such as pranlukast hydrate, excipient (such as lactose) and water-soluble Cellulose (hydroxypropylcellulose, hydroxypropylcellulose, methylcellulose, etc.) is added to an agitation granulator, an agitated fluidized bed granulator or an agitated rolling fluidized bed granulator, and an aqueous solution of a binder (hydroxypropylcellulose, etc.) is added. Thus, a wet product is produced, dried from a fluidized bed granulator, and then sized and produced from a granulated product. The granulated product preferably contains about 0.1 to 30 parts by weight of water-soluble cellulose to 100 parts by weight of pranlukast hydrate.

In the present invention, the “pranlukast hydrate” includes pranlukast hydrate, pranlukast hydrate-containing solid dispersion, pranlukast hydrate-containing composite particles, or pranlukast hydrate-containing Fine particles or the like can be used. For example, the following are mentioned.
(1) As the pranlukast hydrate, for example, one produced by combining the method described in JP-A-61-050977 and / or a known method is used. The pranlukast hydrate used in the present invention may have any particle size.
(2) Pranlukast hydrate-containing solid dispersion means a solid in which pranlukast hydrate is dispersed in a carrier in a fine crystalline state and / or an amorphous state. The fine crystal is a fine crystal having an average particle diameter of about 0.01 to 1.0 μm. Amorphous means a solid state in which pranlukast hydrate molecules are assembled without forming crystals having a regular spatial arrangement.

The ratio of the fine crystals of pranlukast hydrate to the pranlukast hydrate contained in the solid dispersion containing pranlukast hydrate is preferably about 60 to 100%, more preferably about 70 to 100%. %, More preferably about 80 to 100%. Moreover, what a carrier is 10-1000 weight part with respect to 100 weight part of pranlukast hydrate is preferable, More preferably, it is 25-750 weight part, More preferably, it is 50-500 weight part. The solid dispersion containing pranlukast hydrate is produced, for example, by a solvent method, a melting method, a melt-solvent method, a mixed grinding method, or the like. Among them, the mixed pulverization method is preferable, and examples thereof include a method of treating for about 1 to 18 hours using an apparatus such as a ball mill (for example, a planetary ball mill), a rod mill, or a vibration mill. A preferred treatment time is about 1.5-17 hours, more preferably about 2-16 hours. Examples of the carrier include water-soluble polymers and water-insoluble polymers. Examples of the water-soluble polymer include cellulose derivatives, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, gum arabic, dextrin, gelatin and the like. Examples of the water-insoluble polymer include cross-linked polyvinyl pyrrolidone (for example, crospovidone), aminoalkyl metaalkylate copolymer, polyvinyl chloride, polyethylene, methacrylic acid copolymer (for example, methacrylic acid copolymer L), shellac, and the like. Is mentioned. Among these, cellulose derivatives are preferable, and examples thereof include hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, croscarmellose sodium, cellulose acetate phthalate, and crystalline cellulose. Of these, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate and croscarmellose sodium are preferable, hydroxypropylmethylcellulose and hydroxypropylcellulose are more preferable, and hydroxypropylmethylcellulose is more preferable.
(3) The pranlukast hydrate-containing composite particles have a pranlukast hydrate having an average particle size of 0.01 to 2.0 μm and an average particle size of 0.5 containing a water-soluble excipient. It means composite particles that are ˜50 μm. Composite particles having 2 to 50 parts by weight of a water-soluble excipient with respect to 1 part by weight of pranlukast hydrate are preferred. Examples of water-soluble excipients include sugars or sugar alcohols, specifically glucose, lactose, sucrose, mannitol, xylitol, sorbitol, erythritol, and the like, and water-soluble polysaccharides include starch, dextran, cyclohexane, and the like. Dextrin and the like. The composite particles are prepared, for example, by preparing a spray liquid containing pranlukast hydrate and a spray liquid containing a water-soluble excipient, and applying the spray liquid to a four-fluid nozzle spray dryer (MDL-050, Fujisaki Electric). The liquid is sent separately from the two liquid flow paths, and the spray liquid is thinly stretched on the fluid flow surface by the compressed air from the two gas flow paths, and the strong shock wave generated at the focal point of the edge of the 4-fluid nozzle The fine mist can be produced and then dried. Examples of the solvent used for the spray liquid include water, acetone, alcohol solvents (for example, methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, etc.), ethyl acetate, chloroform, dioxane, cyclohexane, dichloromethane and the like. It is done. Solvents used in spray solutions from different flow paths include water and ethanol, water and acetone, water and methanol, water and methanol / acetone mixtures, ethanol and acetone, ethanol and methanol, methanol and acetone, methanol and acetic acid. Ethyl, methanol and dichloromethane are preferred.
(4) Pranlukast hydrate-containing fine particles mean spherical fine particles having an average particle diameter of 0.1 to 15 μm, comprising pranlukast hydrate and a polymer carrier. The fine particles are preferably 1 to 8 parts by weight of the polymer carrier with respect to 1 part by weight of pranlukast hydrate. Examples of the polymer carrier include water-soluble celluloses (such as hydroxymethylcellulose), synthetic polymers (such as polyvinylpyrrolidone), and light anhydrous silicic acid. The fine particles may be obtained by, for example, dissolving or suspending pranlukast hydrate and a polymer carrier in one or more selected from water and an organic solvent (such as ethanol), and then instantaneously drying the solution or suspension. It can be produced by crushing and drying by the method. In the pulse instantaneous drying method, a solution or suspension of pranlukast hydrate and a polymer carrier is put into a pulse shock wave (ultrasonic wave and hot air) generated by a pulse combustor (High Palcon (manufactured by Partec Co., Ltd.)). This is a method of spraying and instantaneously separating and drying solids and liquids by the shock wave and heat. The fine particles preferably have an average circularity of 0.9 to 1.0.

  In the present invention, “an uncoated capsule filled with a coated granule” or “an uncoated tablet formed by compressing a coated granule” is an additive commonly used in addition to the coated granule. Agents, for example, excipients, binders, lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, One type or two or more types of fluidizing agents, wetting agents, and dissolution aids can be appropriately blended.

  Examples of the binder in the present invention include water-soluble cellulose (hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), povidone, polyvinylpyrrolidone, polyvinyl alcohol, carboxy Examples include sodium methylcellulose, polyethylene glycol, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, and gelatin. These can be used alone or in combination as appropriate.

  Examples of the disintegrant used in the present invention include adipic acid, alginic acid, sodium alginate, pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, hydrous silicon dioxide, licorice powder, kanteng powder, guar gum, cigar Calcium acid, glycerin fatty acid ester, croscarmellose sodium, crospovidone, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose / carmellose sodium, synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, dioctyl sodium sulfo Succinate, sucrose fatty acid ester, magnesium magnesium hydroxide, calcium stearate, polyoxyl 40 stearate, purified white sugar, sesquiolein Sorbitan gelatin, sorbitan fatty acid ester, talc, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, low substituted sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, dextrin, sodium dehydroacetate, corn starch, tragacanth powder, honey, potato Starch, hydroxyethylmethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, partially pregelatinized starch, monosodium fumarate, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxy Propylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) grease , Polysorbate 40, polysorbate 80, polyvinyl acetal diethylaminoacetate, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, D-mannitol, anhydrous citric acid, magnesium metasilicate aluminate, methylcellulose, mono Examples thereof include glyceryl stearate, sodium lauryl sulfate, and calcium dihydrogen phosphate, and these can be used alone or in combination as appropriate. More preferred are low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch or corn starch.

  In the present invention, examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, and polyethylene glycol. Can be used.

  In the present invention, examples of the adhesion preventing agent include talc.

  Examples of the flavoring agent in the present invention include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharine, dipotassium glycyrrhizin, sodium glutamate, 5′-inosinic acid. Examples thereof include sodium and sodium 5′-guanylate, and these can be used alone or in combination as appropriate.

  Examples of the surfactant in the present invention include polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene / polyoxypropylene copolymer, and sodium lauryl sulfate. These may be used alone or in combination of two or more.

  In the present invention, examples of the fragrance include lemon oil, orange oil, menthol, and brackish oil.

  Examples of the colorant in the present invention include titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, yellow sesquioxide.

  Examples of the antioxidant in the present invention include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like.

  In the present invention, examples of the masking agent include titanium oxide.

  In the present invention, examples of the antistatic agent include talc and titanium oxide.

  In the present invention, examples of the fluidizing agent include light anhydrous silicic acid, talc, and hydrous silicon dioxide.

  Examples of the wetting agent in the present invention include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, polyethylene glycol, and hydroxypropyl cellulose (HPC).

  Examples of the dissolution aid in the present invention include dry methacrylic acid copolymer LD, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose phthalate.

  In the present invention, in addition to the above, additives such as those described in publicly known documents such as “Pharmaceutical Additives Dictionary” published by Yakuji Nippo 2005 (edited by the Japan Pharmaceutical Additives Association) may be used.

  In general, formulations with large dissolution rate changes over time of storage and unstable dissolution result in changes in bioavailability after in vivo administration, resulting in insufficient efficacy. Or undesirable side effects.

  In the present invention, “elution stability by storage” means that the dissolution rate of the coated solid preparation after storage for a certain period of time under warmed and / or humidified conditions is delayed or accelerated compared to the dissolution rate of the coated solid preparation before storage. Means that it is hard to happen. For example, the difference between the dissolution rate of the coated solid preparation (i) before storage and the dissolution rate after being subjected to (ii) room temperature storage, (iii) accelerated test, or (iv) severe test in an unwrapped state It is. The difference is calculated, for example, by applying a dissolution test described later. Specifically, in the dissolution test described later, (i) dissolution rate before storage of the coated solid preparation, and (ii) room temperature for 3 years in the unpacked state, (iii) temperature 25 ° C or 40 ° C, relative humidity 75% condition It means that the difference in elution rate after storage for 7 days or 1 month in the lower temperature and humidity chamber or (iv) the temperature chamber at 60 ° C. for 7 days is within 25%. Preferably it is within 20%, more preferably within 15%, and particularly preferably within 10%.

  In the present invention, 100 parts by weight of uncoated solid preparation containing pranlukast hydrate and an excipient is combined with one or more selected from acrylate polymers and polyvinyl polymers. It is characterized by being coated with a coating agent comprising about 3.2 to about 6.4 parts by weight, about 0.8 to about 4.8 parts by weight of a water-soluble substance and 0 to about 4 parts by weight of fats and oils. A coated capsule, coated tablet or coated granule in which the difference between the dissolution rate after storage for 1 month under a temperature of 25 ° C. and a relative humidity of 75% in an unwrapped state is within 25% Agents are preferred. The difference is preferably within 20%, more preferably within 15%, and particularly preferably within 10%. The dissolution test is preferably performed by a dissolution test described later.

  In this case, a coating capsule, a coated tablet or a coated granule containing pranlukast hydrate per capsule, tablet, or about 112.5 mg or about 225 mg per capsule is more preferable.

  In addition, (1) one or more selected from acrylate polymers and polyvinyl polymers, not containing oils and fats, and a total of about 3.2 to about 6.4 parts by weight and a water-soluble substance of about 0.8 A coating agent comprising about 4.8 parts by weight, or (2) one or more selected from acrylate polymers and polyvinyl polymers in a total amount of about 3.2 to about 6.4 parts by weight, water-soluble Particularly preferred is a coating agent comprising about 0.8 to about 4.8 parts by weight of the active substance and about 0.5 to about 4 parts by weight of fats and oils.

  The content of pranlukast hydrate in the coated solid preparation of the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, etc., but should be manufactured so as to obtain the desired effect of the present invention. Is preferred. For example, the dose of pranlukast hydrate per adult is preferably about 25 mg to 2500 mg, more preferably about 112.5 mg to 450 mg. Specifically, about 50 mg, about 70 mg, about 100 mg, about 112.5 mg, about 140 mg, about 200 mg, about 225 mg, about 280 mg or about 450 mg are preferable.

  The amount of pranlukast hydrate contained in the coated solid preparation of the present invention is preferably contained in about 50 to about 90 parts by weight, more preferably about 50 to about 90 parts by weight in 100 parts by weight of the uncoated solid preparation. About 80 parts by weight, particularly preferably about 55 to about 70 parts by weight. The content of pranlukast hydrate contained in the coated solid preparation of the present invention is about 112.5 mg to 450 mg per capsule in one preparation, that is, in one capsule, in one tablet, or in the case of granules. Is preferred, more preferably about 112.5 mg or about 225 mg.

  In order to administer the coated solid preparation of the present invention to children, it is preferably used as a coated powder, granule or dry syrup. The daily dose of pranlukast hydrate per kg body weight of the pediatric patient is preferably about 2 mg to about 10 mg, more preferably about 5 mg to about 8 mg, and even more preferably about 7 mg. In addition, it is preferable to administer pranlukast hydrate from about 50 mg to about 100 mg per day, more preferably about 50 mg or about 100 mg, for pediatric patients weighing 12 kg or more and less than 18 kg. For pediatric patients weighing 18 kg or more and less than 25 kg, it is preferable to administer pranlukast hydrate from about 70 mg to about 140 mg per day, more preferably about 70 mg or about 140 mg. For pediatric patients weighing 25 kg or more and less than 35 kg, it is preferable to administer pranlukast hydrate from about 100 mg to about 200 mg per day, more preferably about 100 mg or about 200 mg. For pediatric patients weighing 35 kg or more and less than 45 kg, it is preferable to administer pranlukast hydrate from about 140 mg to about 280 mg per day, more preferably about 140 mg or about 280 mg.

  Among the solid preparations of the present invention, for example, tablets preferably have a shape and size that do not give a burden to the patient to be taken. For example, a round tablet and a deformed tablet (for example, a caplet tablet) are exemplified. The shape of the tablet is not particularly limited, but is preferably cylindrical and has a curvature surface. Further, the capsule is preferably No. 1, No. 2, No. 3, or No. 4 capsule. For example, No. 2 capsule or No. 3 capsule containing 225 mg of pranlukast hydrate, No. 3 capsule or No. 4 capsule containing 112.5 mg of pranlukast hydrate, etc. It is preferable from the viewpoint of compliance. The capsule skin may be any skin as long as it is usually used, and examples thereof include gelatin, gelatin hydrolyzate, polyethylene glycol-containing gelatin, collagen, starch, agar, pectin, hydroxypropylmethylcellulose, and pullulan. It is done. Particularly preferred is gelatin.

  The solid preparation of the present invention is optionally packaged as desired. The packaging when the solid preparation is a capsule or a tablet may be, for example, non-unit packaging (for example, bulk packaging) that is not individually packaged. Further, when the solid preparation is a capsule, tablet or granule, for example, PTP (Press Through Package) packaging, SP (Strip Package) packaging, stick packaging, sachet packaging (three-side seal, four-side seal), Oblate packaging or aluminum foil packaging may be used, but PTP packaging is particularly preferred for capsules and tablets. Examples of the material include a plastic sheet, an aluminum sheet, and a waterproof sheet. Plastic sheets include polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), vinylidene chloride, polychlorotrifluoroethylene, unstretched polypropylene (CPP or IPP), cyclic polyolefin, polyethylene, unstretched nylon (CNy), two Axial stretched nylon (ONy), biaxially stretched polypropylene (OPP), hard vinyl chloride (VSC), polyethylene terephthalate, polyacrylonitrile copolymer (PAN), polyvinyl alcohol (PVA), polyester (PET), ethylene / vinyl acetate Copolymer (EVA), ionomer (IO), polyamide (PA or Ny), ethylene / vinyl alcohol copolymer (EVOH), polycarbonate (PC), polystyrene (PS) and the like. You may use the composite_body | complex which combined these 2 or more types suitably. Two or more kinds of sheets used as usual packaging materials such as vapor-deposited films on which inorganic substances such as aluminum, silicon oxide, and aluminum oxide are vapor-deposited, paper, aluminum foil, cellophane film, etc. are bonded together in an appropriate combination. May be used.

Further, the solid preparation of the present invention may be subjected to the above PTP packaging, SP packaging, etc., and then secondary packaging of a certain quantity in cans, bottles, bags (carton packaging, shrink packaging, pillow packaging, etc.). Examples of the material for the bag include an aluminum film, a polyethylene film, a high-density polyethylene film, a polyvinylidene chloride film, a high-density polyethylene laminated paper, a polyvinylidene chloride laminate, and cellophane. A pillow package made of an aluminum film is preferable. Further, it may be a bag having a chuck (single chuck, double chuck, etc.). Furthermore, the thing in which the desiccant was put in the secondary package and the humidity in the package was adjusted is also preferable. The desiccant is not particularly limited as long as it is generally used at the time of storage of pharmaceuticals. Examples of the desiccant include aluminum oxide, calcium, calcium chloride, calcium hydride, calcium oxide, calcium sulfate, and sulfuric acid. Copper, lithium aluminum hydride, magnesium, magnesium oxide, magnesium perchlorate, magnesium sulfate, synthetic zeolite (such as molecular sieve), natural zeolite, diphosphorus pentoxide, potassium carbonate, potassium hydroxide, silica gel, silica alumina gel, sodium Sodium hydroxide, sodium sulfate, magnesium aluminate silicate, activated carbon and the like. You may use these in combination of 2 or more type as needed. In addition, examples of the form of the desiccant include granular, film-shaped, plate-shaped and sheet-shaped forms, or granular forms filled in a breathable bag, and the form is not particularly limited. . Preferably, it is formed into a sheet shape.
[Application to pharmaceutical products]
Since the preparation of the present invention contains pranlukast hydrate as an active ingredient, bronchial asthma, allergic rhinitis, sinusitis, chronic obstructive pulmonary disease, Meniere's disease, migraine, cough, exudative otitis media, dysmenorrhea It is useful as a prophylactic and / or therapeutic drug for various diseases such as infectious diseases.
[toxicity]
The coated solid preparation containing pranlukast hydrate provided by the present invention has low toxicity and is sufficiently safe for use as a medicine.

  The uncoated solid preparation containing the pranlukast hydrate and excipient of the present invention contains one or more selected from acrylate-based polymers and polyvinyl-based polymers, and is optionally water-soluble. A solid preparation coated with a coating agent comprising a substance and / or fats and oils is a coated solid preparation having excellent moisture resistance, a coating layer that easily disintegrates in the stomach, and dissolution stability upon storage.

EXAMPLES Hereinafter, although an Example explains this invention in full detail, it is for understanding this invention well and this invention is not limited to these.
Formulation Example 1
Pranlukast hydrate, lactose (excipient; FONTERRA), light anhydrous silicic acid (fluidizing agent; Freund Sangyo Co., Ltd.), high-speed agitation granulator (SPG-2; manufactured by Fuji Powder Co., Ltd.) And 6% aqueous solution of polyvinyl pyrrolidone (binding agent; BASF Takeda Vitamin Co., Ltd.) and polyethylene glycol (binding agent; Nippon Oil & Fats Co., Ltd.). The granules granulated by putting this into an extrusion granulator (MG-55; manufactured by Fuji Powder Co., Ltd.) are sized using a spherical granulator (Q-230T; manufactured by Fuji Powder Co., Ltd.). . This is dried at 70 ° C. for 30 minutes to produce uncoated granules containing pranlukast hydrate.
[Uncoated granules (in 173 mg)]
Pranlukast hydrate 112.5mg
Lactose 30mg
Light anhydrous silicic acid 10.5mg
L-HPC 10mg
Polyvinylpyrrolidone 6mg
Polyethylene glycol 4mg
Formulation Example 2
Pranlukast hydrate, lactose, and light anhydrous silicic acid are mixed in a polyethylene bag and put into a fluidized bed granulator (STREA; manufactured by POWREC). A 6% aqueous solution of polyvinyl pyrrolidone and polyethylene glycol is sprayed and granulated under conditions of an air supply temperature of about 70 ° C. and an exhaust temperature of about 30 ° C. The granulated product is dried at 70 ° C. and sieved using a 1 mm sieve to obtain a granulated product containing pranlukast hydrate.

The Belle container mixer (manufactured by Kotobuki Giken Kogyo Co., Ltd.) is mixed with the granulated product obtained above and magnesium stearate (lubricant; Taihei Chemical Industry Co., Ltd.), and then mixed with a capsule filling machine (LIQFIL F40). No. 3 capsules using Shionogi Qualicaps Co., Ltd.) to produce uncoated capsules containing pranlukast hydrate having the following formulation.
[Uncoated capsule (175 mg in one capsule): 220.4 mg (including capsule weight)]
Pranlukast hydrate 112.5mg
Lactose 30mg
Light anhydrous silicic acid 10.5mg
L-HPC 10mg
Polyvinylpyrrolidone 6mg
Polyethylene glycol 4mg
Magnesium stearate 2mg
Formulation Example 3
Pranlukast hydrate, lactose, and low-substituted hydroxypropylcellulose (L-HPC) are mixed in a stirring granulator (VG25; manufactured by Pauleck Co., Ltd.), and a 6% aqueous solution of polyvinylpyrrolidone and polyethylene glycol is mixed. Add and granulate by stirring granulation method. The granulate is dried at 70 ° C. for 30 minutes and passed through a 32 mesh sieve to obtain a granule containing pranlukast hydrate.

The granulated product obtained above, magnesium stearate and light anhydrous silicic acid are mixed in a Bole container mixer (manufactured by Kotobuki Giken Kogyo Co., Ltd.) and mixed, and a tableting machine (VIRG; Kikusui ( To produce uncoated tablets containing pranlukast hydrate having the following formulation.
[Uncoated tablets (in 1 tablet): 175 mg in total]
Pranlukast hydrate 112.5mg
Lactose 30mg
L-HPC 10mg
Polyvinylpyrrolidone 6mg
Polyethylene glycol 4mg
Magnesium stearate 2mg
Light anhydrous silicic acid 10.5mg
Formulation Example 4 (1)
Hydroxypropyl methylcellulose (3.2 g; water-soluble substance; TC-5E (Shin-Etsu Chemical Co., Ltd.)) was dissolved in water (122 g), and aminoalkyl methacrylate copolymer E (28.8 g; acrylate polymer) was dissolved therein. A solution of Eudragit E100 (DEGUSSA)) in ethanol (486 g) is added and mixed to produce the coating agent (1).

  Prepare uncoated granules (400 g) produced in Formulation Example 1 in a coating machine (NQ125; manufactured by Fuji Powder Co., Ltd.) and spray coating agent (1) under the following conditions to produce coated granules To do.
(Coating conditions)
  Rotor speed: 200rpm
  Air volume: 1.0m³/ Min
  Intake air temperature: Adjust exhaust temperature to 30 ° C
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Aminoalkyl methacrylate copolymer E: 7.2 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Examples 4 (2) -4 (13)
  The uncoated granules (400 g) produced in Formulation Example 1 are coated in the same manner as Formulation Example 4 (1) using the following coating agents (2) to (13) instead of coating agent (1). Thus, the following coated granules are produced.
Formulation Example 4 (2)
  Coating agent (2): Hydroxypropyl methylcellulose (TC-5E; 9.6 g) was dissolved in water (122 g), and an aminoalkyl methacrylate copolymer E (Eudragid E100; 22.4 g) in ethanol (486 g) was added thereto. Add and mix to produce coating agent (2).
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Aminoalkyl methacrylate copolymer E: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
Formulation Example 4 (3)
  Coating agent (3): Hydroxypropyl methylcellulose (TC-5E; 16 g) is dissolved in water (122 g), and a solution of aminoalkyl methacrylate copolymer E (Eudragid E100; 16 g) in ethanol (486 g) is added and mixed. Thus, the coating agent (3) is produced.
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Aminoalkyl methacrylate copolymer E: 4 parts by weight
  Hydroxypropyl methylcellulose: 4 parts by weight
Formulation Example 4 (4)
  Coating agent (4): Hydroxypropyl methylcellulose (TC-5E; 22.4 g) was dissolved in water (122 g), and an aminoalkyl methacrylate copolymer E (Eudragid E100; 9.6 g) in ethanol (486 g) was added thereto. Add and mix to produce coating agent (4).
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Aminoalkyl methacrylate copolymer E: 2.4 parts by weight
  Hydroxypropyl methylcellulose: 5.6 parts by weight
Formulation Example 4 (5)
  Coating agent (5): Lactose (3.2 g; water-soluble substance) is dissolved in water (118 g), and stearic acid (16 g; oil and fat; Nippon Oil & Fat Co., Ltd.) is added and suspended therein. A coating agent (5) is produced by adding a solution of aminoalkyl methacrylate copolymer E (Eudragid E100; 28.8 g; acrylate polymer) in ethanol (474 g) to the suspension and mixing.
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 12 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Aminoalkyl methacrylate copolymer E: 7.2 parts by weight
  Lactose: 0.8 parts by weight
  Stearic acid: 4 parts by weight
Formulation Example 4 (6)
  Coating agent (6): Hydroxypropyl methylcellulose (TC-5E; 3.2 g; water-soluble substance) was dissolved in water (122 g), and polyvinyl acetal diethylaminoacetate (28.8 g; polyvinyl polymer; AEA (Sankyo) Co.)) ethanol (486 g) solution is added and mixed to produce the coating agent (6).
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Polyvinyl acetal diethylaminoacetate: 7.2 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 4 (7)
  Coating (7): Hydroxypropylmethylcellulose (TC-5E; 9.6 g) is dissolved in water (122 g), and a solution of polyvinyl acetal diethylaminoacetate (AEA; 22.4 g) in ethanol (486 g) is added and mixed. Thus, the coating agent (7) is produced.
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Polyvinyl acetal diethylaminoacetate: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
Formulation Example 4 (8)
  Coating agent (8): Hydroxypropyl methylcellulose (TC-5E; 16 g) is dissolved in water (122 g), and a solution of polyvinyl acetal diethylaminoacetate (AEA; 16 g) in ethanol (486 g) is added and mixed to form a coating. An agent (8) is produced.
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Polyvinyl acetal diethylaminoacetate: 4 parts by weight
  Hydroxypropyl methylcellulose: 4 parts by weight
Formulation Example 4 (9)
  Coating agent (9): Hydroxypropyl methylcellulose (TC-5E; 22.4 g) is dissolved in water (122 g), and a solution of polyvinyl acetal diethylaminoacetate (AEA; 9.6 g) in ethanol (486 g) is added and mixed. Thus, the coating agent (9) is produced.
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Polyvinyl acetal diethylaminoacetate: 2.4 parts by weight
  Hydroxypropyl methylcellulose: 5.6 parts by weight
Formulation Example 4 (10)
  Coating agent (10): Lactose (3.2 g; water-soluble substance) is dissolved in water (118 g), and stearic acid (16 g; fat) is added and suspended therein. A solution of polyvinyl acetal diethylaminoacetate (AEA; 28.8 g; polyvinyl polymer) in ethanol (474 g) is added to the suspension and mixed to produce the coating agent (6).
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 12 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Polyvinyl acetal diethylaminoacetate: 7.2 parts by weight
  Lactose: 0.8 parts by weight
  Stearic acid: 4 parts by weight
Formulation Example 4 (11)
  Coating agent (11): Polyvinyl alcohol (22.4 g; polyvinyl polymer; Opadry AMB (COLCON)) and hydroxypropylmethylcellulose (TC-5E; 9.6 g; water-soluble substance) are dissolved in water (453 g). Then, talc (15 g; anti-adhesive agent; MERCK) is added and suspended therein to produce a coating agent (11).
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 11.75 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Polyvinyl acetal diethylaminoacetate: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
  Talc: 3.75 parts by weight
Formulation Example 4 (12)
  Coating agent (12): Hydroxypropyl methylcellulose (TC-5E; 3.2 g) was dissolved in water (90.8 g), and an aminoalkyl methacrylate copolymer E (Eudragid E100; 16 g) in ethanol (340 g) was added thereto. Add and mix to produce coating agent (12).
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 4.8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Aminoalkyl methacrylate copolymer E: 4 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 4 (13)
  Coating agent (13): Hydroxypropyl methylcellulose (TC-5E; 3.2 g) was dissolved in water (100.4 g), and aminoalkyl methacrylate copolymer E (Eudragid E100; 22.4 g) in ethanol (386 g) The solution is added and mixed to produce the coating agent (13).
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated granules: 6.4 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated granules
  Aminoalkyl methacrylate copolymer E: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 5 (1)
  The Boule Container Mixer (manufactured by Kotobuki Giken Kogyo Co., Ltd.) is mixed with the coated granule (432 g) produced in Formulation Example 4 (1) and magnesium stearate, and mixed. The capsule filling machine (LIQFIL F40; Shionogi olicaps ( To produce capsules containing coated granules.
Uncoated capsule containing coated granules (in 1 capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Examples 5 (2) -5 (13)
  By using the coated granules of Formulation Examples 4 (2) to 4 (13) in place of the coated granules of Formulation Example 4 (1), respectively, by operating in the same manner as Formulation Example 5 (1), the following Uncoated capsules containing coated granules are produced.
Formulation Example 5 (2): Uncoated capsule containing the coated granule of Formulation Example 4 (2) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (3): Uncoated capsule containing the coated granule of Formulation Example 4 (3) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (4): Uncoated capsule containing the coated granule of Formulation Example 4 (4) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (5): Uncoated capsule containing the coated granule of Formulation Example 4 (5) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (6): Uncoated capsule containing the coated granule of Formulation Example 4 (6) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (7): Uncoated capsule containing the coated granule of Formulation Example 4 (7) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (8): Uncoated capsule containing the coated granule of Formulation Example 4 (8) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (9): Uncoated capsule containing the coated granule of Formulation Example 4 (9) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (10): Uncoated capsule containing the coated granule of Formulation Example 4 (10) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (11): Uncoated capsule containing the coated granule of Formulation Example 4 (11) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (12): Uncoated capsule containing the coated granule of Formulation Example 4 (12) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 5 (13): Uncoated capsule containing the coated granule of Formulation Example 4 (13) (in one capsule)
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
Formulation Example 6 (1)
  The uncoated capsule (503.7 g) produced in Formulation Example 2 was charged into a coating machine (High Coater Lab; manufactured by Freund Sangyo Co., Ltd.), and the coating agent (1) was sprayed under the following conditions to perform coating. Manufactured capsules.
(Coating conditions)
  Rotor speed: 20rpm
  Air volume: 0.5m³/ Min
  Intake air temperature: Adjust exhaust temperature to 30 ° C
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 12.6mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 7.2 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Examples 6 (2) -6 (13)
  In the same manner as in Formulation Example 6 (1), the coating agents (2) to (13) are used in place of the coating agent (1) in the uncoated capsule (503.7 g) produced in Formulation Example 2. The following coating capsules are produced by coating.
Formulation Example 6 (2): Using coating agent (2).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 9.8 mg
  Hydroxypropyl methylcellulose 4.2mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
Formulation Example 6 (3): Using coating agent (3).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 7.0mg
  Hydroxypropyl methylcellulose 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 4 parts by weight
  Hydroxypropyl methylcellulose: 4 parts by weight
Formulation Example 6 (4): Using coating agent (4).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 4.2mg
  Hydroxypropyl methylcellulose 9.8mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 2.4 parts by weight
  Hydroxypropyl methylcellulose: 5.6 parts by weight
Formulation Example 6 (5): Use coating agent (5).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 12.6mg
  Lactose 1.4mg
  Stearic acid 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 12 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 7.2 parts by weight
  Lactose: 0.8 parts by weight
  Stearic acid: 4 parts by weight
Formulation Example 6 (6): Using coating agent (6).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 12.6mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 7.2 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 6 (7): Using coating agent (7).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 9.8mg
  Hydroxypropyl methylcellulose 4.2mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
Formulation Example 6 (8): Using coating agent (8).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 7.0mg
  Hydroxypropyl methylcellulose 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 4 parts by weight
  Hydroxypropyl methylcellulose: 4 parts by weight
Formulation Example 6 (9): Using coating agent (9).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 4.2mg
  Hydroxypropyl methylcellulose 9.8mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 2.4 parts by weight
  Hydroxypropyl methylcellulose: 5.6 parts by weight
Formulation Example 6 (10): Using coating agent (10).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 12.6mg
  Lactose 1.4mg
  Stearic acid 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 12 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 7.2 parts by weight
  Lactose: 0.8 parts by weight
  Stearic acid: 4 parts by weight
Formulation Example 6 (11): Using coating agent (11).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl alcohol 9.8mg
  Hydroxypropyl methylcellulose 4.2mg
  Talc 6.5mg
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated capsule: 11.75 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl alcohol: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
  Talc: 3.75 parts by weight
Formulation Example 6 (12): Using coating agent (12).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 7.0mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated capsule: 4.8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 4 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 6 (13): Using coating agent (13).
[Coating capsule (in 1 capsule)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 9.8 mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated capsule: 6.4 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 7 (1)
  The uncoated tablet (400 g) produced in Formulation Example 3 is charged into a coating machine (High Coater Lab; manufactured by Freund Sangyo Co., Ltd.) and sprayed with the coating agent (1) under the following conditions to produce a coated tablet. To do.
(Coating conditions)
  Rotor speed: 20rpm
  Air volume: 0.5m³/ Min
  Intake air temperature: Adjust exhaust temperature to 30 ° C
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 12.6mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 7.2 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Examples 7 (2) -7 (13)
  By coating the uncoated tablets (400 g) produced in Formulation Example 3 with the coating agents (2) to (13) in the same manner as Formulation Example 7 (1) instead of the coating agent (1), Of coated tablets.
Formulation Example 7 (2): Using coating agent (2).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 9.8 mg
  Hydroxypropyl methylcellulose 4.2mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
Formulation Example 7 (3): Using coating agent (3).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 7.0mg
  Hydroxypropyl methylcellulose 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 4 parts by weight
  Hydroxypropyl methylcellulose: 4 parts by weight
Formulation Example 7 (4): Using coating agent (4).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 4.2mg
  Hydroxypropyl methylcellulose 9.8mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 2.4 parts by weight
  Hydroxypropyl methylcellulose: 5.6 parts by weight
Formulation Example 7 (5): Use coating agent (5).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 12.6mg
  Lactose 1.4mg
  Stearic acid 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 12 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 7.2 parts by weight
  Lactose: 0.8 parts by weight
  Stearic acid: 4 parts by weight
Formulation Example 7 (6): Using coating agent (6).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 12.6mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 7.2 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 7 (7): Using coating agent (7).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 9.8mg
  Hydroxypropyl methylcellulose 4.2mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
Formulation Example 7 (8): Using coating agent (8).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 7.0mg
  Hydroxypropyl methylcellulose 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 4 parts by weight
  Hydroxypropyl methylcellulose: 4 parts by weight
Formulation Example 7 (9): Using coating agent (9).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 4.2mg
  Hydroxypropyl methylcellulose 9.8mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 2.4 parts by weight
  Hydroxypropyl methylcellulose: 5.6 parts by weight
Formulation Example 7 (10): Using coating agent (10).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl acetal diethylaminoacetate 12.6mg
  Lactose 1.4mg
  Stearic acid 7.0mg
[Parts by weight of coating layer]
-Part by weight of the coating layer with respect to 100 parts by weight of the uncoated capsule: 12 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl acetal diethylaminoacetate: 7.2 parts by weight
  Lactose: 0.8 parts by weight
  Stearic acid: 4 parts by weight
Formulation Example 7 (11): Using coating agent (11).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Polyvinyl alcohol 9.8mg
  Hydroxypropyl methylcellulose 4.2mg
  Magnesium stearate 6.5mg
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated capsule: 11.75 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Polyvinyl alcohol: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 2.4 parts by weight
  Talc: 3.75 parts by weight
Formulation Example 7 (12): Using coating agent (12).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 7.0mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated capsule: 4.8 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 4 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Formulation Example 7 (13): Using coating agent (13).
[Coated tablets (in 1 tablet)]
  Pranlukast hydrate 112.5mg
  Lactose 30mg
  L-HPC 10mg
  Polyvinylpyrrolidone 6mg
  Polyethylene glycol 4mg
  Magnesium stearate 2mg
  Light anhydrous silicic acid 10.5mg
  Aminoalkyl methacrylate copolymer E 9.8 mg
  Hydroxypropyl methylcellulose 1.4mg
[Parts by weight of coating layer]
-Part by weight of coating layer with respect to 100 parts by weight of uncoated capsule: 6.4 parts by weight
・ Parts by weight of each coating composition with respect to 100 parts by weight of uncoated capsules
  Aminoalkyl methacrylate copolymer E: 5.6 parts by weight
  Hydroxypropyl methylcellulose: 0.8 part by weight
Comparative Example 1
  Polyethylene glycol (45.2 g, NOF Corporation) was dissolved in purified water (1027 mL), and lactose (210.8 g; FONTERRA) and pranlukast hydrate (450 g) were added to the suspension. did. This suspension is spray-dried with a spray dryer (air supply (inlet) temperature: 180 ° C., exhaust temperature: 100 to 110 ° C., liquid feed rate: 30 to 40 g / min, atomizer rotational speed: 12000 rpm), and pranlukast A hydrate spray-dried granulate was obtained. Magnesium stearate (14.4 g; Taihei Chemical Industry Co., Ltd.) was added to the spray-dried granulation, mixed and filled into capsules.
Formulation of Comparative Example 1 (in 1 capsule)
  Pranlukast hydrate 112.5mg
  Lactose 52.7mg
  Polyethylene glycol 11.3mg
  Magnesium stearate 3.6mg
Dissolution test 1
  The preparation of the present invention and the preparation prepared in Comparative Example 1 were subjected to a dissolution test using a disintegration tester using a 0.5% polysorbate 80 phosphate buffer (pH 6.8). 45 minutes after the start of the test, a dissolution test solution was collected and filtered to obtain a sample solution. The sample solution was measured by an absorbance method (measurement wavelength: 350 nm), and the elution rate 45 minutes after the start of the test was calculated.
Dissolution test 2
  The preparation of the present invention and the preparation produced in Comparative Example 1 were stored in a thermo-hygrostat at a temperature of 25 ° C. and a relative humidity of 75% without packaging. After storage for 1 month, the dissolution rate was measured in the same manner as the dissolution test 1 described above.

  As a result, the preparation produced in Comparative Example 1 had a dissolution rate of 91.2% 45 minutes after the start of dissolution test 1, that is, the dissolution test before storage, and dissolution test 2; 4%. Thus, the preparation produced in Comparative Example 1 has a low dissolution rate after storage for 1 month under the conditions of a temperature of 25 ° C. and a relative humidity of 75% at 45 minutes after the start of the dissolution test, and the difference from the storage before storage is 50%. Because of the above, the difference in dissolution rate due to storage was very large. On the other hand, the preparation of the present invention is a preparation having a high dissolution rate in dissolution test 1 and dissolution test 2, and having a small difference in dissolution rate before and after storage and having dissolution stability by storage.

  The uncoated solid preparation containing the pranlukast hydrate and excipient of the present invention contains one or more selected from acrylate-based polymers and polyvinyl-based polymers, and is optionally water-soluble. A solid preparation formed by coating with a coating agent containing a substance and / or fats and oils is a preparation having excellent moisture resistance, a coating layer that easily disintegrates in the stomach, and dissolution stability upon storage.

Claims (21)

The uncoated solid preparation containing pranlukast hydrate and an excipient contains one or more selected from acrylate-based polymers and polyvinyl-based polymers, and optionally contains water-soluble substances and / or Alternatively, a coated solid preparation having dissolution stability upon storage, characterized by being coated with a coating agent comprising an oil or fat. The acrylate polymer is aminoalkyl methacrylate copolymer E, the polyvinyl polymer is one or two selected from polyvinyl acetal diethylaminoacetate and polyvinyl alcohol, and the water-soluble substance is selected from water-soluble celluloses and saccharides. The solid preparation according to claim 1, wherein the solid preparation is one or more, and the fat is one or more selected from stearic acid, magnesium stearate, calcium stearate and carnauba wax. The solid preparation according to claim 1, wherein the weight of the coating layer is about 2 to about 12 parts by weight with respect to 100 parts by weight of the uncoated solid preparation. The total of one or more selected from acrylate polymers and polyvinyl polymers is about 2 to about 9 parts by weight and the water-soluble substance is about 0.5 to about 100 parts by weight with respect to 100 parts by weight of the uncoated solid preparation. The solid preparation according to claim 1, which is a coating agent comprising 8 parts by weight and 0 to about 5 parts by weight of fats and oils. (1) Oils and fats are not included, the total of one or more selected from acrylate polymers and polyvinyl polymers is about 2 to about 9 parts by weight, and water-soluble substances are about 0.5 to about 8 parts by weight. Or (2) about 2 to about 9 parts by weight of a total of one or more selected from acrylate polymers and polyvinyl polymers, and about 0. The solid preparation according to claim 4, which is a coating agent comprising 5 to about 8 parts by weight and about 0.5 to about 5 parts by weight of fats and oils. The solid preparation according to claim 1, comprising about 50 to about 90 parts by weight of pranlukast hydrate in 100 parts by weight of the uncoated solid preparation. The solid preparation according to claim 1, comprising about 5 to about 80 parts by weight of an excipient with respect to 100 parts by weight of pranlukast hydrate. The solid preparation according to claim 1, wherein the excipient is one or two selected from lactose and sucrose. The solid preparation according to claim 1, wherein the coated solid preparation is a coated capsule, a coated tablet or a coated granule. The solid preparation according to claim 9, containing pranlukast hydrate in an amount of about 112.5 mg or about 225 mg per capsule, 1 tablet or 1 capsule, respectively. The solid preparation according to claim 9, wherein the thickness of the coating layer is about 7 to about 42 µm for capsules, about 14 to about 84 µm for tablets, and about 0.3 to about 1.8 µm for granules. . 2. The solid preparation according to claim 1, wherein the difference between the dissolution rate after storage for 1 month under a temperature of 25 ° C. and a relative humidity of 75% in an unwrapped state is within 25%. The solid preparation according to claim 12, wherein the difference is within 15%. A capsule that is filled with the coated granule according to claim 9 and has dissolution stability upon storage. The capsule according to claim 14, wherein the capsule is an uncoated capsule. The capsule is a coated capsule, and about 100 parts by weight of the uncoated capsule is (1) one or two or more total selected from acrylate-based polymers and polyvinyl-based polymers without fats and oils. 2 or about 9 parts by weight and a coating agent comprising about 0.5 to about 8 parts by weight of a water-soluble substance, or (2) one or two selected from acrylate polymers and polyvinyl polymers A coating agent comprising about 2 to about 9 parts by weight of the total of the species or more, about 0.5 to about 8 parts by weight of a water-soluble substance, and about 0.5 to about 5 parts by weight of fats and oils. 14. Capsule according to 14. The capsule according to claim 14, wherein the difference between the dissolution rate after storage for 1 month under the conditions of a temperature of 25 ° C and a relative humidity of 75% in an unwrapped state is within 25%. The capsule according to claim 17, wherein the difference is within 15%. 100 parts by weight of uncoated solid preparation containing pranlukast hydrate and excipient (1) one or two selected from (1) oil and fat-free acrylate polymer and polyvinyl polymer A coating agent comprising a total of about 3.2 to about 6.4 parts by weight of at least seeds and about 0.8 to about 4.8 parts by weight of a water-soluble substance, or (2) an acrylate polymer and a polyvinyl polymer A total of about 3.2 to about 6.4 parts by weight of one or more selected from the group consisting of about 0.8 to about 4.8 parts by weight of water-soluble substances and about 0.5 to about 4 parts by weight of fats and oils The difference between the dissolution rate after storage for 1 month at a temperature of 25 ° C. and a relative humidity of 75% in an unwrapped state, and the dissolution rate before storage, characterized by being coated with a coating agent comprising Coating capsules and coatings that are within 25% Agent or coating granules. The coated capsule, coated tablet or coated granule according to claim 19, wherein the difference is within 15%. The coated capsule, coated tablet or coated granule according to claim 19, containing pranlukast hydrate in an amount of about 112.5 mg or about 225 mg per capsule, tablet or capsule, respectively.