JP2007211005A - Composition for solid preparation and solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a composition for a solid preparation, which contains a pranlukast hydrate produced by using a fluidized bed granulation method having high convenience and a solid preparation containing the composition for solid preparation. <P>SOLUTION: The composition for solid preparation comprising pranlukast hydrate, a fluidizing agent, a binder, an excipient and optionally a disintegrator is produced by a fluidized bed granulation method. A pranlukast hydrate having high cohesive aggregation is used by a fluidized bed granulation method by the combination of the optimum average particle diameter of the pranlukast hydrate with the optimum amount of the fluidizing agent. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a solid preparation composition containing pranlukast hydrate and a fluidizing agent and produced by a fluidized bed granulation method, and a solid preparation produced using the solid preparation composition.

  Pranlukast hydrate is known as a leukotriene antagonist (see Patent Document 1), and a capsule (trade name: ONON (registered trademark) capsule) or dry syrup containing pranlukast hydrate as an active ingredient (Trade name: ONON (registered trademark) dry syrup) is on the market. The solid preparation containing pranlukast hydrate is a very useful preparation as a therapeutic agent for bronchial asthma and allergic rhinitis. However, since pranlukast hydrate has very strong adhesion and cohesiveness, it is difficult to produce a solid preparation suitable for administration by a usual method, and a special formulation method is required. For example, as a method for reducing the adhesion aggregation property, a method of spray-drying pranlukast hydrate together with saccharides is known (see Patent Document 2).

  On the other hand, the fluidized bed granulation method is a highly convenient method in which powder mixing, granulation and drying, and even coating can be performed with one apparatus. Furthermore, the composition granulated by the fluidized bed granulation method has an advantage that fluidity and compression moldability are good. However, since it is necessary to blow into the granulator and fluidize the preparation raw material, this method is not suitable when the preparation raw material contains a compound having high adhesion and cohesiveness.

  In addition to the fluidized bed granulation method, granulation methods such as stirring granulation are known. For example, a preparation produced by stirring granulation with a hydrogel-forming substance blended with pranlukast hydrate has been reported. ing. However, when a hydrogel-forming substance is blended with pranlukast hydrate and granulated using the fluidized bed granulation method, adhesion cohesion and fluidity cannot be improved. It is described that it is not suitable as a method for producing a Japanese-containing preparation (see Patent Document 3).

  In addition, it is reported that the solubility and fluidity of poorly soluble drugs can be improved by granulating a mixture of poorly water-soluble drugs and fluidizing agents using water or water-containing alcoholic solutions of water-soluble polymers. However, there is no description regarding pranlukast hydrate (see Patent Document 4).

JP-A-61-050977 Japanese Patent No. 2958863 JP-A-2005-187406 JP 2005-82503 A

  An object of the present invention is to contain a composition for solid preparations containing pranlukast hydrate that can be produced using a fluidized bed granulation method with high convenience, and the composition for solid preparations. It is to provide a solid formulation.

  As a result of intensive studies, the present inventors have improved the adhesion and cohesion during granulation by mixing pranlukast hydrate with a fluidizing agent and performing fluidized bed granulation, and pranlukast hydration. It discovered that the composition for product-containing solid preparations could be manufactured. If the particle size of pranlukast hydrate is too small, adhesion and cohesion occur, and if it is too large, dissolution of the drug is delayed. In addition, if the amount of the fluidizing agent is too small, there is no adhesion suppressing effect. If the amount is too large, the adhesion and cohesiveness during granulation is improved, but the content becomes too light and it becomes difficult to control the flow in the apparatus. . Furthermore, the fluidity of the obtained granulated product becomes poor, and it is difficult to handle at the time of tableting and capsule filling after granulation. The inventors of the present invention have found that the optimal particle size of pranlukast hydrate and the optimal amount of fluidizing agent for producing a composition for pranlukast hydrate-containing solid preparations by the fluidized bed granulation method I found. Surprisingly, the solid preparation composition and the solid preparation of the present invention have stable dissolution, and in particular, a solid preparation produced using a solid preparation composition having a water content of about 1 to 3% or less. Found that the storage stability was also excellent. Based on the above, the present inventors have completed the present invention by finding a composition for solid preparations and solid preparations that have improved adhesion and aggregation properties during the fluidized bed granulation method and have stable dissolution properties.

The present invention
1. A composition for solid preparation containing pranlukast hydrate, a fluidizing agent, a binder and an excipient, and further containing a disintegrating agent,
2. The fluidizing agent is at least one selected from light silicic anhydride and hydrous silicon dioxide, the binder is at least one selected from hydroxypropylcellulose and hydroxypropylmethylcellulose, and the excipients are lactose, sucrose and D- 2. The composition for solid preparation according to 1 above, which is at least one selected from mannitol;
3. 2. The solid preparation according to 1 above, comprising about 2 to 30 parts by weight of a fluidizing agent, about 1 to 50 parts by weight of a binder, and about 20 to 150 parts by weight of an excipient with respect to 100 parts by weight of pranlukast hydrate. Composition,
4). 2. The composition for solid preparation according to 1, wherein the average particle size of pranlukast hydrate is about 1 to 40 μm,
5). 2. The composition for solid preparation according to 1, wherein the average particle size is about 50 to 500 μm,
6). 2. The composition for solid preparation according to 1 above, wherein the water content is about 1 to 3%;
7). 2. The composition for solid preparation according to the above 1, characterized by granulating a pranlukast hydrate, a fluidizing agent, a binder and an excipient, and optionally a disintegrant by a fluidized bed granulation method,
8). A solid preparation comprising the composition for solid preparation according to 1 above,
9. 9. The solid preparation according to the above 8, which is a capsule, tablet, powder or granule,
10. 10. The solid preparation according to 9 above, which is a capsule or tablet containing about 112.5 mg or about 225 mg of pranlukast hydrate per preparation,
11.1 Powders or granules with a daily dose of pranlukast hydrate of 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 The solid preparation according to 9 above,
12 Pranlukast hydrate having an average particle size of about 1 to 40 μm, a fluidizing agent, a binder and an excipient, and optionally a disintegrant granulated by a fluidized bed granulation method. A capsule containing a composition for solid preparation having a water content of about 1 to 3%, which is 50 to 500 μm,
13. Pranlukast hydrate having an average particle size of about 1 to 40 μm, a fluidizing agent, a binder and an excipient, and optionally a disintegrant granulated by a fluidized bed granulation method. A tablet comprising a composition for solid preparations having a water content of about 1 to 3%, which is 50 to 500 μm;
14 Pranlukast hydrate, fluidizing agent and excipient, and if necessary, add disintegrant and mix, spray liquid with binder dissolved in solvent, and supply temperature at fluid bed granulator 2. The method for producing a composition for solid preparation according to claim 1, wherein granulation is performed under conditions of 70 ° C. and an exhaust temperature of about 30 ° C., and after granulation, drying is performed at an air supply temperature of about 70 ° C.

  In the present invention, the composition for solid preparation represents a granulated product for producing a solid preparation, for example, powder, granule and the like. Examples of solid preparations include capsules, tablets, powders or granules. In addition, tablets, powders or granules may be used as dry syrups.

  The composition for solid preparation or the solid preparation of the present invention contains pranlukast hydrate, a fluidizing agent, a binder and an excipient, but may further contain a disintegrant and / or other additives. Good.

  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 the formula: The production of pranlukast hydrate can be carried out, for example, according to the method described in JP-A 61-050977.

  Examples of the fluidizing agent used in the present invention include light anhydrous silicic acid, talc, hydrous silicon dioxide, and the like. Preferred is light anhydrous silicic acid or hydrous silicon dioxide.

  Examples of the excipient used in the present invention include saccharides, crystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, and the like. Preferably, saccharides are used. Examples of the saccharide include glucose, fructose, maltose, lactose, sucrose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch, wheat Examples include starch and rice starch. Lactose, sucrose or D-mannitol is preferred.

  Examples of the binder used in the present invention include water-soluble celluloses, povidone, polyvinylpyrrolidone, polyethylene glycol (PEG), polyvinyl alcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, and arabic. Examples thereof include rubber powder and gelatin. Water-soluble celluloses are water-soluble polymers in which hydrogen bonds are lost by substituting part of the hydrogen atoms of the hydroxyl group of cellulose with methyl, ethyl, propyl, hydroxypropyl or hydroxyethyl groups. It is. Examples include hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and the like. One or more of these can be appropriately blended and used. The binder preferably includes water-soluble celluloses or polyethylene glycol, and more preferably hydroxypropylcellulose and hydroxypropylmethylcellulose.

  Examples of the disintegrant used in the present invention include adipic acid, alginic acid, sodium alginate, pregelatinized starch, carboxymethyl starch sodium, carmellose, carmellose calcium, carmellose sodium, hydrous silicon dioxide, licorice powder, kangten powder, guar gum , Calcium citrate, 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, dioctylso Dium sulfosuccinate, sucrose fatty acid ester, magnesium hydroxide alumina, calcium stearate, polyoxyl 40 stearate, purified white sugar, sesquiole Sorbitan gelatin acid, sorbitan fatty acid ester, talc, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, low substituted sodium carboxymethyl starch, low substituted hydroxypropylcellulose, dextrin, sodium dehydroacetate, corn starch, tragacanth powder, honey Potato starch, hydroxyethyl methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, partially pregelatinized starch, monosodium fumarate, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) Polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) Recall, polysorbate 40, polysorbate 80, polyvinyl acetal diethylaminoacetate, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, D-mannitol, anhydrous citric acid, magnesium metasilicate aluminate, methylcellulose, monostearin Examples thereof include glycerin acid, sodium lauryl sulfate, calcium dihydrogen phosphate, and the like. Preferably, carmellose, carmellose calcium, carmellose sodium, corn starch, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, or low-substituted hydroxypropylcellulose. More preferred is low-substituted hydroxypropylcellulose.

  Methods for producing the composition for solid preparation of the present invention are known, for example, pranlukast hydrate, fluidizing agent, binder, excipient, disintegrant as required, and other additions as required The agent can be produced by granulating by a fluidized bed granulation method and performing drying, sizing, classification, etc. as necessary. The binder may be mixed with other raw materials in advance, or as a liquid in which the binder is dissolved in a solvent (for example, water or ethanol, or a mixed solvent thereof) (hereinafter abbreviated as a binding liquid). You may add by spraying at the time of granulation. For example, pranlukast hydrate, a fluidizing agent and an excipient, and if necessary, a disintegrating agent is added and mixed, and a binding solution is sprayed, and a supply air temperature is about 70 ° C. in a fluid bed granulator. Granulation is carried out under conditions of a temperature of about 30 ° C., and after granulation, the composition is dried at an air supply temperature of about 70 ° C. to obtain the composition for solid preparation of the present invention. In order to perform fluidized bed granulation using pranlukast hydrate with high adhesion and cohesion, use pranlukast hydrate with an optimal average particle size and add an optimal amount of fluidizing agent. It is important to.

  In order to perform the fluidized bed granulation method, for example, it is preferable to use pranlukast hydrate having an average particle diameter of about 1 to 40 μm. More preferably, it is about 1-15 micrometers, Most preferably, it is about 2-15 micrometers. When pranlukast hydrate having an average particle size of less than the optimum range is used, it causes adhesion cohesion and is not suitable for fluidized bed granulation. When pranlukast hydrate having an average particle size larger than the optimum range is used, dissolution delay occurs in the produced solid preparation.

Pranlukast hydrate having an average particle size of about 1 to 40 μm can be easily produced by those skilled in the art by combining known methods such as the method described in JP-A No. 61-050977. it can. For example, pranlukast hydrate having an average particle size of about 39.2 μm can be obtained by the following method;
Ethanol (6.67 L) and water (12 L) were added to pranlukast hydrate (1500 g), and the mixture was stirred at an internal temperature of 20 to 30 ° C. for about 5 minutes. Thereafter, sodium hydrogen carbonate (314.4 g) was added, and the temperature was raised to an internal temperature of about 65 ° C. to dissolve pranlukast hydrate. While stirring the obtained solution, acetic acid (402.6 g) was added, and the mixture was stirred at an internal temperature of about 65 ° C. for about 1 hour. The obtained crystallization liquid was filtered with a centrifuge and washed twice with ethanol (10 L). Ethanol (18 L) was added to the obtained crystals, and the mixture was stirred at an internal temperature of 20 to 30 ° C. for about 1 hour. The crystallization liquid was filtered with a centrifugal separator, and the obtained crystals were dried with a vacuum dryer at a drying temperature of 40 ° C. for 12 hours or more. After drying, a glass petri dish containing water was placed in the dryer, and the container was sealed under reduced pressure. A moisture absorption operation was performed at room temperature until the moisture content of the crystals reached 1.5 to 2.0%.

  Pranlukast hydrate produced by the method described in JP-A-61-050977 or the above method may be used as it is, or pulverized by a known method such as a hammer mill, a ball mill or a jet mill. It can also be adjusted to a desired average particle size.

  In the present invention, the average particle diameter of pranlukast hydrate means the average particle diameter of the primary particles (weight-based average diameter), and for example, a generally used laser diffraction type particle size distribution measuring apparatus (for example, SALD-2100 (Shimadzu Corporation)).

  In the present invention, as a method for measuring the particle size of granules, powders, etc., for example, there is a screening method, which can be obtained by a method of measuring the particle size distribution of granules using an appropriately sized sieve.

  In order to perform fluidized bed granulation, about 2 to 30 parts by weight, more preferably about 4 to 30 parts by weight, and particularly preferably about 4 to 20 parts by weight per 100 parts by weight of pranlukast hydrate. Part of the fluidizing agent is preferably added. If the amount of the fluidizing agent is less than the optimum range, the adhesion and aggregation properties are not improved.If a fluidizing agent exceeding the optimum range is used, the adhesion and aggregation properties during granulation are improved, but the content is It becomes too light and it becomes difficult to control the flow in the apparatus. Furthermore, the fluidity of the obtained granulated product becomes poor, and it is difficult to handle at the time of tableting and capsule filling after granulation.

  In order to perform fluidized bed granulation appropriately, it is preferable to use a combination of the average particle diameter of pranlukast hydrate in the above range and the amount of fluidizing agent in the above range.

  The amount of pranlukast hydrate in 1 part by weight of the composition for solid preparations of the present invention is preferably about 0.50 to 0.98 parts by weight, more preferably about 0.55 to 0.90 parts by weight, particularly preferably. Is about 0.60 to 0.80 parts by weight.

  In the solid preparation composition or solid preparation of the present invention, the weight ratio of the excipient to 100 parts by weight of pranlukast hydrate is preferably about 20 to 150 parts by weight, more preferably about 20 to 100 parts by weight. Parts, particularly preferably about 20 to 60 parts by weight.

  In the composition for solid preparation or the solid preparation of the present invention, the weight ratio of the binder to 100 parts by weight of pranlukast hydrate is preferably about 1 to 50 parts by weight, more preferably about 1 to 30 parts by weight. is there.

  In the composition for solid preparation or the solid preparation of the present invention, the weight ratio of the disintegrant to 100 parts by weight of pranlukast hydrate is preferably about 1 to 50 parts by weight, more preferably about 2 to 30 parts by weight. It is.

  The composition for solid preparation of the present invention further contains an additive (formulation base) generally used in producing a solid preparation, in addition to the fluidizing agent, excipient, binder or disintegrant. For example, one or more lubricants, flavoring agents, flavoring agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents, elution aids, etc. Can be used.

  Examples of the corrigent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharine, dipotassium glycyrrhizin, sodium glutamate, 5′-sodium inosinate, 5 '-Sodium guanylate and the like can be mentioned. Examples of the surfactant include polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil 60 etc. are mentioned. As a fragrance | flavor, lemon oil, orange oil, menthol, brackish oil etc. are mentioned, for example. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the concealing agent include titanium oxide. Examples of the antistatic agent include talc and titanium oxide. Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like. Examples of the dissolution aid include dry methacrylic acid copolymer LD, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and the like.

  The average particle diameter of the composition for solid preparations of the present invention obtained by the above method is about 50 to 500 μm, preferably about 100 to 300 μm, which is optimal for preparation molding.

  The solid preparation of the present invention, for example, a capsule, a tablet, a powder or a granule can be produced using the composition for solid preparation obtained by the above method. Furthermore, it can be used as a dissolution / suspension preparation (for example, a dry syrup preparation) at the time of taking a tablet, powder or granule as a solution or suspension at the time of taking. For example, the solid formulation composition obtained by the above method may be used as it is, or may be mixed with other additives such as a disintegrant and a lubricant, if necessary, to form a powder or a granule. Moreover, it is good also as a tablet or a capsule by mixing the composition for solid preparations with other additives, such as a disintegrating agent and a lubricant, as needed, and tableting or capsule-filling by a well-known method. The material for the capsule filled with the composition for solid preparation of the present invention may be any material as long as it is usually used, and examples thereof include gelatin, gelatin blended with polyethylene glycol, hydroxypropyl methylcellulose, and pullulan. . The size of the capsule is not particularly limited, but No. 1, No. 2, No. 3, or No. 4 capsule is preferable. In particular, No. 3 capsule or No. 4 capsule is preferable from the viewpoint of patient compliance. Moreover, a tablet may be coat | covered using the film coating base which is accept | permitted pharmacologically as needed and does not prevent the effect of this invention. Furthermore, the powder, granule or tablet obtained by the above method can be used as a dry syrup as it is, and if desired, a commonly used bitterness improving agent (flavoring agent) is added and suspended in water at the time of use. It can also be used as a dry syrup that can be taken.

  Other additives that may be added in the process of producing a solid preparation from the composition for solid preparation include, for example, an excipient, a disintegrant, a binder, a fluidizing agent, a corrigent, a surfactant, a fragrance, A lubricant, a colorant, an antioxidant, a masking agent, an antistatic agent, a wetting agent, a flavoring agent, an elution auxiliary agent, and the like may be used, and one or more selected from these may be appropriately blended and used. Excipients, disintegrants, binders, fluidizing agents, flavoring agents, surfactants, fragrances, lubricants, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents, flavoring agents, dissolution aids As mentioned above, those mentioned above can be mentioned.

  The content of pranlukast hydrate in the solid preparation of the present invention varies depending on age, weight, symptom, therapeutic effect, administration method, treatment time, dosage form, etc., but it is prepared so as to obtain the desired effect of the present invention. It is preferable to do. The dose of pranlukast hydrate per day for an adult is preferably about 25 to 2500 mg, more preferably about 112.5 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. For example, when the solid preparation is a capsule or a tablet, the content of pranlukast hydrate is preferably about 112.5 mg or about 225 mg per preparation, and more preferably about 112.5 mg.

  In order to administer the solid preparation of the present invention to children, it is preferably used as a 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.

  After the solid preparation of the present invention is produced as described above, it is optionally packed as desired. Such packaging may be, for example, non-unit packaging that is not individually packaged (for example, bulk packaging). For example, hermetically sealed packaging such as so-called heat-sealing packaging that seals pharmaceuticals with a heat-adhesive film. Is preferred. The hermetic packaging is not particularly limited as long as it has hermetic properties, but preferably has a property that can prevent the inflow and outflow of gas such as water vapor. Examples of the material for such hermetic packaging include aluminum film, high-density polyethylene film, polyvinylidene chloride film, high-density polyethylene laminated paper, polyvinylidene chloride laminated paper, polyethylene, and cellophane. Examples of the sealed packaging include cans, bottles, bags (for example, car toner packaging, shrink packaging, pillow packaging), heat sealing packaging, and the like. Furthermore, when the form of sealed packaging is a bag, it may be a bag having a chuck (for example, a single chuck or a double chuck). The sealed packaging in the present invention includes, for example, packaging using a pharmacopoeia-defined “airtight container” or “sealed container”.

  The heat seal packaging includes PTP (Press Through Pack) packaging, SP (Stripe Package) packaging, and the like. Among solid preparations, PTP packaging is preferable for packaging of tablets or capsules, and SP packaging is preferable for packaging of powders or granules.

  Plastic sheets used as materials for PTP packaging include polyvinyl chloride, polyvinylidene chloride (PVDC), vinylidene chloride, polychlorotrifluoroethylene, unstretched polypropylene (CPP or IPP), cyclic polyolefin, polyethylene, unstretched nylon ( CNy), biaxially oriented nylon (ONy), biaxially oriented polypropylene (OPP), hard vinyl chloride, polyethylene terephthalate, polyacrylonitrile copolymer (PAN), polyvinyl alcohol (PVA), polyester (PET), ethylene / acetic acid Examples include vinyl copolymer (EVA), ionomer (IO), polyamide (PA or Ny), ethylene / vinyl alcohol copolymer (EVOH), polycarbonate (PC), polystyrene (PS), and the like. These plastic sheets may use composites in which two or more kinds are appropriately combined.

The plastic sheet is not particularly limited as long as it has a moisture permeability (water vapor permeability) of about 0.5 to 5.0 g / m ² · 24 hr. , Composites combining hard vinyl chloride and polyvinylidene chloride, unstretched polypropylene and the like, and hard vinyl chloride is preferred. Here, the moisture permeability means the amount of water vapor that passes through a film-like substance of a unit area in a certain time under the conditions of a predetermined temperature and humidity, and the measurement can be performed by a known method. For example, it is generally performed according to a method known as a method for measuring moisture permeability of a packaging material such as a plastic sheet or a sheet, among others, a moisture sensor method (Lyssy method) (JIS K7129), a cup method (JIS Z0208), etc. preferable.

  In the present invention, when a plastic sheet is used as a package, it is used as a normal packaging material such as a vapor-deposited film, paper, aluminum foil, cellophane film, etc., on which an inorganic substance such as aluminum, silicon oxide, or aluminum oxide is vapor-deposited. Two or more kinds of those obtained may be appropriately combined and bonded together for the purpose of protecting the contents. Examples of the method for bonding the plastic sheet and the above-described film include dry lamination, extrusion coating / lamination, wet lamination, hot melt lamination, coextrusion lamination, non-solvent lamination, thermal lamination, and the like.

  PTP packaging is preferably used in combination with aluminum packaging. Furthermore, the tablets or capsules of the present invention may be subjected to PTP packaging or SP packaging and then secondary packaging (so-called pillow packaging) with a certain amount of polyethylene or aluminum foil.

  The internal humidity in which the tablet or capsule of the present invention is secondarily packaged can be controlled by a desiccant or a humectant.

  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 (eg, 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 types as needed. In addition to these, the desiccant in the present invention includes a water-absorbing agent containing a high molecular polymer as a constituent component. Such a water-absorbing agent is not particularly limited. For example, vinyl acetate- (meth) acrylic acid ester copolymer, vinyl acetate-maleic anhydride copolymer, isobutylene-maleic anhydride copolymer, acrylic acid- Examples include methacrylic acid copolymers, polyvinyl alcohol, polyethylene oxide, polypropylene oxide, polyvinyl pyrrolidone, sulfonated polystyrene, polyvinyl pyridine, polyacrylamide, and polymethacrylamide.

  Examples of the desiccant used in the present invention include granules, films, plates and sheets, or granules filled in a breathable bag. There is no particular limitation. Preferably, it is formed into a sheet shape. In the case of forming into a sheet form, a desiccant is blended with a suitable support, for example, plastic for molding, and the desiccant is kneaded into the plastic to form into a sheet form. Examples of the desiccant formed into a sheet include an ID sheet (ID Co., Ltd .; calcium chloride), high sheet dry (Marutani Kako Co., Ltd .; silica gel), and high dry pack (Marutani Kako Co., Ltd .; silica gel). .

  The desiccant used in the present invention is preferably a desiccant having a moisture absorption rate of about 20 to 35% at a temperature of 25 ° C. and a relative humidity of 50%. For example, silica gel, silica alumina gel, calcium chloride, pentoxide Diphosphorus, synthetic zeolite, natural zeolite and the like are preferred. More preferably, calcium chloride etc. are mentioned, More preferably, calcium chloride shape | molded in the sheet form, for example, ID sheet etc., are mentioned.

  In the present invention, the humectant means a substance having water absorption and moisture absorption functions and a function capable of maintaining a constant humidity, that is, an equilibrium humidity. Examples of such a humectant include hydrated ethylene glycol-containing sheets, dry keep (registered trademark; Sasaki Chemical Co., Ltd.), and the like.

  The water content of the solid preparation composition of the present invention is preferably about 1 to 3%, more preferably about 1 to 2.5%. A solid preparation produced using a composition for solid preparation having a water content of about 1 to 3% has a disintegration delay during storage, a dissolution delay, abnormalities (for example, capsules or tablets cracked, chipped, etc.), Deliquesce can be suppressed.

  In the present invention, the water content means the amount of water contained in the solid pharmaceutical composition, that is, the water content. The water content of the composition for solid preparation can be measured by a known method. For example, it can be performed according to a method known in the art for measuring the moisture content of pharmaceuticals, in particular, according to the moisture measurement method listed in the Japanese Pharmacopoeia, in particular, the moisture measurement method (Karl Fischer method) listed in the 14th revision Japanese Pharmacopoeia.

  In the present invention, the disintegration delay is, as will be apparent to those skilled in the art, in order for a drug (particularly a solid preparation for internal use) to be rapidly absorbed from the digestive tract wall, the preparation disintegrates and is subdivided into small particles. Since it is believed that elution of the active ingredient is ensured by increasing the surface area, it means that the dissolution rate of the drug is delayed by extending the disintegration time of the drug.

  In the present invention, the degree of disintegration delay is determined by subjecting a solid preparation containing the composition for solid preparation of the present invention to a disintegration test after being stored for an arbitrary period of time inside and outside the drug package, and comparing with an initial value. This can be confirmed. The disintegration test can be performed by a known method. For example, methods commonly known as disintegration test methods for internal solid preparations such as tablets and capsules, especially disintegration test methods listed in the Japanese Pharmacopoeia, especially disintegration test methods listed in the 14th revised Japanese Pharmacopoeia Etc.

  In the present invention, the elution delay is, as will be apparent to those skilled in the art, because the elution rate of a drug (particularly a solid preparation for internal use) defines the bioavailability of the drug. The delay in the dissolution rate of the active ingredient means that the bioavailability after in vivo administration is changed, and it is considered that there is a possibility that the medicinal effect will be insufficient or that there will be side effects.

  In the present invention, the degree of dissolution delay is determined by subjecting the solid preparation containing the composition for solid preparation of the present invention to an elution test after storing it for an arbitrary period inside and outside the drug package, and comparing it with the initial value. This can be confirmed. The dissolution test can be performed by a known method. For example, methods generally known as dissolution test methods for internal solid preparations such as tablets and capsules, especially dissolution test methods listed in the Japanese Pharmacopoeia, especially dissolution test methods listed in the 14th revised Japanese Pharmacopoeia For example, it can be performed according to the first method (rotating basket method), the second method (paddle method), the third method (flow-through cell method), or the like.

The conditions of storage for confirming the degree of elution delay are not particularly limited, but may be, for example, room temperature as is usually performed by those skilled in the art, and are generally referred to as accelerated tests or severe tests. It may be a high temperature and / or high humidity condition. By making the conditions of high temperature and / or high humidity, the result of long-term storage at room temperature can be obtained in a shorter period of time.
[Application to pharmaceutical products]
Since the preparation of the present invention contains pranlukast hydrate as an active ingredient, respiratory diseases such as bronchial asthma, allergic rhinitis, sinusitis, COPD (chronic obstructive pulmonary disease), Meniere's disease, migraine, It is useful as a preventive and / or therapeutic agent for various diseases such as cough, exudative otitis media, and dysmenorrhea.
[toxicity]
The preparation containing pranlukast hydrate provided by the present invention has low toxicity and is sufficiently safe for use as a medicine.

  Although the composition for solid preparations of the present invention contains pranlukast hydrate having high adhesion and aggregation properties, it can be produced by a fluid bed granulation method with high convenience.

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.
Comparative Example 1
Pranlukast hydrate (225 g) having an average particle size of 2.9 μm and lactose (80 g, NZMP Ltd.) were mixed in a polyethylene bag and charged into a fluidized bed granulator (STREA: Powrec Co., Ltd.). However, it did not flow in the apparatus.
Comparative Example 2
Pranlukast hydrate (225 g) having an average particle size of 2.9 μm, lactose (80 g, NZMP Ltd.) and light anhydrous silicic acid (1 g, Adsolider: Freund Sangyo Co., Ltd.) were mixed in a polyethylene bag, Although it put into the fluidized bed granulator (STREA: Pauleck Co., Ltd.), it did not flow in an apparatus.
Comparative Example 3
Pranlukast hydrate (225 g) having an average particle size of 2.9 μm, lactose (80 g, NZMP Ltd.) and light anhydrous silicic acid (4 g, Adsolider: Freund Sangyo Co., Ltd.) were mixed in a polyethylene bag, Although it put into the fluidized bed granulator (STREA: Pauleck Co., Ltd.), it did not flow in an apparatus.
Example 1
Pranlukast hydrate (225 g) having an average particle size of 2.9 μm, lactose (80 g, NZMP Ltd.) and light anhydrous silicic acid (10 g, Adsolider: Freund Sangyo Co., Ltd.) were mixed in a polyethylene bag, It was put into a fluidized bed granulator (STREA: Paulek Co., Ltd.) and confirmed to flow in the apparatus. A 7% hydroxypropylmethylcellulose (180 g, TC-5: Shin-Etsu Chemical Co., Ltd.) aqueous solution is sprayed and granulated under conditions of an air supply temperature of 70 ° C. and an exhaust temperature of about 30 ° C. After granulation, the air supply temperature of 70 Dry at ℃. The dried product is sieved using a 1 mm sieve to obtain a composition for solid preparation.
Example 2
Pranlukast hydrate (202.5 g) having an average particle diameter of 2.9 μm, lactose (72 g, NZMP Ltd.) and light anhydrous silicic acid (36 g, Adsolider: Freund Sangyo Co., Ltd.) are mixed in a polyethylene bag. Then, it was put into a fluidized bed granulator (STREA: Paulec Co., Ltd.) and confirmed to flow in the apparatus. 7% hydroxypropylmethylcellulose (177.4 g, TC-5: Shin-Etsu Chemical Co., Ltd.) aqueous solution is sprayed and granulated under conditions of an air supply temperature of 70 ° C and an exhaust temperature of about 30 ° C. Dry at a temperature of 70 ° C. The dried product is sieved using a 1 mm sieve to obtain a composition for solid preparation.
Comparative Example 4
Pranlukast hydrate (180 g) having an average particle size of 2.9 μm, lactose (64 g, NZMP Ltd.) and light anhydrous silicic acid (64 g, Adsolider: Freund Sangyo Co., Ltd.) were mixed in a polyethylene bag, It was put into a fluidized bed granulator (STREA: Paulek Co., Ltd.) and confirmed to flow in the apparatus. A 7% hydroxypropylmethylcellulose (176 g, TC-5: Shin-Etsu Chemical Co., Ltd.) aqueous solution is sprayed and granulated under conditions of an air supply temperature of 70 ° C. and an exhaust temperature of about 30 ° C. After granulation, the air supply temperature of 70 Dry at ℃. The dried product is sieved using a 1 mm sieve to obtain a composition for solid preparation.
Comparative Example 5
Pranlukast hydrate (225 g) having an average particle size of 0.9 μm, lactose (80 g, NZMP Ltd.) and light anhydrous silicic acid (10 g, Adsolider: Freund Sangyo Co., Ltd.) are mixed in a polyethylene bag, Although it put into the fluidized bed granulator (STREA: Pauleck Co., Ltd.), it did not flow in an apparatus.
Example 3
Pranlukast hydrate (225 g) having an average particle size of 9.2 μm, lactose (80 g, NZMP Ltd.) and light silicic acid anhydride (10 g, Adsolider: Freund Sangyo Co., Ltd.) were mixed in a polyethylene bag, It was put into a fluidized bed granulator (STREA: Paulek Co., Ltd.) and confirmed to flow in the apparatus. A 7% hydroxypropylmethylcellulose (180 g, TC-5: Shin-Etsu Chemical Co., Ltd.) aqueous solution is sprayed and granulated under conditions of an air supply temperature of 70 ° C. and an exhaust temperature of about 30 ° C. After granulation, the air supply temperature of 70 Dry at ℃. The dried product is sieved using a 1 mm sieve to obtain a composition for solid preparation.
Example 4
Pranlukast hydrate (225 g) having an average particle diameter of 39.2 μm, lactose (80 g, NZMP Ltd.) and light anhydrous silicic acid (10 g, Adsolider: Freund Sangyo Co., Ltd.) were mixed in a polyethylene bag, It was put into a fluidized bed granulator (STREA: Paulek Co., Ltd.) and confirmed to flow in the apparatus. A 7% hydroxypropylmethylcellulose (180 g, TC-5: Shin-Etsu Chemical Co., Ltd.) aqueous solution is sprayed and granulated under conditions of an air supply temperature of 70 ° C. and an exhaust temperature of about 30 ° C. After granulation, the air supply temperature of 70 Dry at ℃. The dried product is sieved using a 1 mm sieve to obtain a composition for solid preparation.
Experiment 1 Effect of fluidizing agent on fluidity during granulation According to the prescriptions of Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Example 1 and Example 2, the raw material, ie, pranlukast hydration Depending on the product, excipient, and formulation, a fluidizing agent was mixed, and the fluidity during granulation was evaluated. Furthermore, regarding the fluidized formulation, a binder is added and granulated to evaluate the adhesion in the fluidized bed apparatus and the physical properties of the obtained composition for solid preparation. Evaluation methods for fluidity, adhesion and physical property evaluation are shown below.
<Evaluation method>
1. Fluidity Before the granulation, the fluidity of the contents in the fluidized bed granulator was visually observed. “◎” indicates that the suspension state has been maintained without problems, “○” indicates that the flow state is poor but the suspension state continues, “△” indicates that the suspension state is partially suspended, and “△” indicates that the suspension state does not flow. Was designated as “×”.
2. Adhesiveness in fluidized bed apparatus Visual observation is performed on the adhesiveness of the contents in the apparatus during the flow or after completion of flow and granulation. “○” indicates that there was no adhesion, “△” indicates that there was a small amount of adhesion, and “×” indicates that there was a large amount of adhesion in a layered manner.
3. Evaluation of physical properties of the composition for solid preparations For granulated formulations, those that are considered to have fluidity suitable for tableting are designated as “appropriate”, and those that are considered insufficient in fluidity are designated as “unsuitable”. . In addition, when 112.5 mg of pranlukast hydrate is filled in one capsule, “○” indicates that the No. 3 capsule can be filled, and “x” indicates that it cannot.

  The evaluation results are shown in Table 1.

  Comparative Example 1 containing no fluidizing agent and a comparative example in which the amount of fluidizing agent is less than 2 parts by weight with respect to 100 parts by weight of pranlukast hydrate. In the formulations of Example 2 and Comparative Example 3, the raw material did not flow in the fluidized bed apparatus. In the formulation of Comparative Example 4 containing a large amount of fluidizing agent, although granulation was possible, the composition for solid preparation was bulky and the fluidity was insufficient, so that it could be filled into No. 3 capsules. There wasn't.

  As a result of producing a composition for solid preparation according to the formulation of Example 1 and Example 2 having good fluidity and evaluating physical properties, the composition for solid preparation produced in Example 1 or Example 2 was obtained. Had good fluidity and could be filled into No. 3 capsules.

From the above results, a solid formulation composition containing about 2 to 30 parts by weight of a fluidizing agent with respect to 100 parts by weight of pranlukast hydrate can be produced by a fluidized bed granulation method. It has been shown that it can be used appropriately to produce a formulation.
Experiment 2 Influence of particle size of pranlukast hydrate on fluidity during granulation Comparative Example 5, Example 1, Example 3 and Example 4 using pranlukast hydrate having different average particle sizes According to the formulation, raw materials, ie, pranlukast hydrate, excipient, and a fluidizing agent depending on the formulation were mixed, and the fluidity during granulation was evaluated. Furthermore, regarding the fluidized formulation, a binder is added and granulated, and the adhesion in the fluidized bed apparatus and the physical properties of the obtained solid pharmaceutical composition are evaluated by the same method as in Experiment 1.

  The evaluation results are shown in Table 2.

  In Comparative Example 5 using pranlukast hydrate having an average particle size of 0.9 μm, the fluidity was insufficient and fluidized bed granulation was impossible. On the other hand, the composition for solid preparations produced using pranlukast hydrate having an average particle diameter of 1 μm or more has good fluidity and can be filled into No. 3 capsules. Therefore, it was suggested that the fluidized bed granulation method can be performed by using pranlukast hydrate having an average particle diameter of 1 μm or more.

  Although the composition for solid preparations of the present invention contains pranlukast hydrate having high adhesion and aggregation properties, it can be produced by a fluid bed granulation method with high convenience. Moreover, the solid formulation manufactured using this composition for solid formulations has a good and stable dissolution of the active ingredient and is useful as a pharmaceutical product.

Claims (14)

A composition for solid preparation containing pranlukast hydrate, a fluidizing agent, a binder and an excipient, and further may contain a disintegrating agent. The fluidizing agent is at least one selected from light silicic anhydride and hydrous silicon dioxide, the binder is at least one selected from hydroxypropylcellulose and hydroxypropylmethylcellulose, and the excipients are lactose, sucrose and D- The composition for solid preparation according to claim 1, which is one or more selected from mannitol. The solid according to claim 1, comprising about 2 to 30 parts by weight of a fluidizing agent, about 1 to 50 parts by weight of a binder, and about 20 to 150 parts by weight of an excipient based on 100 parts by weight of pranlukast hydrate. Formulation composition. The composition for solid preparation according to claim 1, wherein the average particle size of pranlukast hydrate is about 1 to 40 µm. The composition for solid preparation according to claim 1, wherein the average particle size is about 50 to 500 µm. The composition for solid preparation according to claim 1, wherein the water content is about 1 to 3%. 2. The composition for solid preparation according to claim 1, wherein the pranlukast hydrate, the fluidizing agent, the binder and the excipient, and further a disintegrant as required are granulated by a fluidized bed granulation method. A solid preparation comprising the composition for solid preparation according to claim 1. The solid preparation according to claim 8, which is a capsule, tablet, powder or granule. The solid preparation according to claim 9, which is a capsule or a tablet containing about 112.5 mg or about 225 mg of pranlukast hydrate per preparation. A powder or granule having a daily dosage of pranlukast hydrate of 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 Item 10. A solid preparation according to Item 9. Pranlukast hydrate having an average particle size of about 1 to 40 μm, a fluidizing agent, a binder and an excipient, and optionally a disintegrant granulated by a fluidized bed granulation method. A capsule containing a composition for solid preparations having a moisture content of about 1 to 3%, which is 50 to 500 μm. Pranlukast hydrate having an average particle size of about 1 to 40 μm, a fluidizing agent, a binder and an excipient, and optionally a disintegrant granulated by a fluidized bed granulation method. A tablet comprising a composition for solid preparations having a moisture content of about 1 to 3% and a size of 50 to 500 μm. Pranlukast hydrate, fluidizing agent and excipient, and if necessary, add disintegrant and mix, spray liquid with binder dissolved in solvent, and supply temperature at fluid bed granulator 2. The method for producing a composition for solid preparation according to claim 1, wherein granulation is performed under conditions of 70 ° C. and an exhaust temperature of about 30 ° C., and after granulation, drying is performed at an air supply temperature of about 70 ° C.