JP3899522B2 - Formulation containing pranlukast hydrate with reduced bitterness - Google Patents

Description

  The present invention relates to a granule containing pranlukast hydrate as an active ingredient and a preparation containing the granule.

Pranlukast hydrate is known as a leukotriene (LT) receptor antagonist (see Patent Document 1) and is widely used as a therapeutic agent for bronchial asthma and allergic rhinitis. In addition to capsules for adults, pranlukast hydrate is provided in dry syrup formulations for children with bronchial asthma. Advantages of the dry syrup preparation include that it can be easily taken even in children who are difficult to swallow by dissolving or suspending in water.
On the other hand, the operation of dissolving or suspending in water at the time of use is cumbersome. In particular, since this drug is intended for children, the burden on patients or their guardians increases in the absence of water and containers, and compliance May decrease. In addition, there is a problem that the bitterness derived from the drug (pranlukast hydrate) tends to remain in the oral cavity when taken without being suspended.

Therefore, there is a demand for a preparation with further improved compliance, and in recent years, various studies have been vigorously conducted to improve the above problems.
For example, a method of adding xylit (see Patent Document 2) is known as a method for improving the problems when taking a drug having a bitter taste as a dry syrup preparation. However, xylit does not have a bitter taste improving effect on all drugs and is not universally usable.
In addition, the intraoral quick disintegrating tablet that rapidly disintegrates in the oral cavity is easy to take even without water, and its single dose is accurate, so various reports have been made on its constitution and production method.
However, when pranlukast hydrate having a bitter taste is used as a rapidly disintegrating tablet in the oral cavity, the pharmaceutical component having a bitter taste is exposed to the oral cavity as the preparation immediately disintegrates in the oral cavity. In addition, at this time, since it is taken without water, it feels bitter for a longer time than a normal oral tablet, which is a demerit of an intraoral quick-disintegrating tablet characterized by being easy to take.

For example, as a means of concealing the bitter component, the pharmaceutical component having a bitter taste blended in the chewable preparation is coated with a polymer such as ethyl cellulose or Eudragit, and the pharmaceutical component is directly exposed even if the tablet disintegrates in the oral cavity. There has been proposed a method (see Patent Document 3) for preventing such a situation. However, the coating requires equipment and long work, which may be expensive.
On the other hand, the following are known as pharmaceutical compositions containing pranlukast hydrate. For example, pranlukast hydrate has adhesion and cohesiveness, and therefore, when the drug substance of the present compound is tableted as it is, it adheres to the tableting machine (sticking) and is not necessarily preferable from the viewpoint of mass production. There is no. As a method for reducing adhesion, a method of spray-drying pranlukast hydrate together with sugars is known, but there is no description regarding reduction of the bitterness of pranlukast hydrate (see Patent Document 4).
Also, Patent Document 5 describes a novel composition for solid preparation containing pranlukast hydrate that can be made into a small-sized preparation with improved compliance, but the bitterness of pranlukast hydrate There is no description regarding the reduction of.
JP-A-61-050977 JP-A-6-157712 Japanese translation of PCT publication No. 6-502194 Japanese Patent No. 2958863 JP 2006-008676 A

  An object of the present invention is to provide a preparation that can reduce the bitter taste of pranlukast hydrate and can be easily taken with almost no bitter taste.

  As a result of intensive studies to solve the above problems, the present inventors have focused on the fact that the average particle size of pranlukast hydrate is related to the bitter taste of pranlukast hydrate. As a result, pranlukast hydrate having a small average particle size is bitter to the general idea that bitterness increases because the surface area increases because the number of particles itself increases when the average particle size is small. As a result of finding an inverse correlation that it may have a reducing effect, and finding that a granule containing pranlukast hydrate gives good disintegration when having a specific bulk density, Based on this knowledge, we found that it is possible to increase the proportion of pranlukast hydrate and reduce the proportion of saccharides by reducing the bitterness, thereby providing a high-content formulation of pranlukast hydrate. The present invention has been completed.

That is, this invention relates to the granule containing a pranlukast hydrate, saccharides, and a water-soluble polymer, and the formulation containing this granule.
More specifically, the present invention provides [1] granule with reduced bitterness comprising pranlukast hydrate, saccharide and a water-soluble polymer, characterized by the following (i) to (iii): Granules having
(I) containing about 5 to about 55% by weight of pranlukast hydrate based on 100% by weight of granules;
(Ii) the average particle size of pranlukast hydrate is about 1 to about 40 μm, and (iii) the bulk density of the granules is about 0.35 to about 0.70 g / cm ³ .
[2] The granule according to the above item [1], wherein the saccharide is one or more selected from mannitol, sucrose, lactose, erythritol, xylitol, sorbitol, maltitol and trehalose,
[3] The granule according to [1] above, further containing a taste-masking agent,
[4] The granule according to [3] above, wherein the corrigent is at least one selected from aspartame and yogurt flavor,
[5] The granule according to [1] above, wherein the water-soluble polymer is at least one selected from hydroxypropylcellulose and hydroxypropylmethylcellulose;
[6] The granule according to [1] above, wherein the average particle size of pranlukast hydrate is about 1 to about 15 μm,
[7] The granule according to the above item [1], containing 100 to 5% by weight of granule and about 5 to about 25% by weight of pranlukast hydrate,
[8] The granule according to [1] above, wherein the granule has an average particle size of about 50 to about 600 μm,
[9] The granule according to [8] above, wherein the average particle size of the granule is about 300 to about 550 μm,
[10] The granule according to [1] above, wherein the bulk density of the granule is about 0.35 to about 0.67 g / cm ³ .
[11] The granule according to [1] above, wherein the score value by human bitterness sensory test is 0 to 2.00,
[12] The granule according to [1] above, which is a dry syrup,

[13] A dry syrup comprising pranlukast hydrate, a saccharide, and a water-soluble polymer, wherein the dry syrup is 100% by weight, and pranlukast hydrate is contained in an amount of about 5 to about 25% by weight, The average particle size of pranlukast hydrate is about 1 to about 15 μm, the bulk density of dry syrup is about 0.35 to about 0.67 g / cm ³ , and the average particle size of dry syrup is about 50 to about A dry syrup with reduced bitterness, characterized in that the score value according to the human bitter taste sensory test is 0 to 2.00, 600 μm,
[14] The dry syrup according to [13] above, wherein the daily dose of dry syrup is about 0.2 to about 9.0 g;

[15] A preparation comprising the granule according to [1] above,
[16] The preparation of the above-mentioned [15], which is an intraoral rapidly disintegrating tablet,
[17] The preparation of the above-mentioned [16], wherein the disintegration time in the human oral cavity is about 5 to about 80 seconds,
[18] The preparation according to [16] above, which contains about 50 to about 125 mg of pranlukast hydrate in one tablet,
[19] The preparation of the above-mentioned [16], wherein the score value by human bitterness sensory test is 0 to 2.00,

[20] A tablet comprising granule containing pranlukast hydrate, saccharide and water-soluble polymer and other additives, wherein the tablet is 100% by weight and pranlukast hydrate is about 5%. About 55% by weight, the average particle size of pranlukast hydrate is about 1 to about 15 μm, the score value by human bitterness sensory test is 0 to 2.00, and the disintegration time in the human oral cavity is An orally rapidly disintegrating tablet with reduced bitterness, characterized by containing about 50 to about 125 mg of pranlukast hydrate in about 5 to about 80 seconds and 1 tablet; and

[21] In a preparation comprising granule containing pranlukast hydrate, saccharide and water-soluble polymer, pranlukast hydrate having an average particle size of about 1 to about 40 μm is used, and the bulk density of the granule is adjusted. Pranlukast, characterized by having a pranlukast hydrate content of about 0.35 to about 0.70 g / cm ³ and about 100% by weight of the preparation, about 5 to about 55% by weight. The present invention relates to a method for reducing the bitterness of a strike hydrate.

  According to the present invention, it is possible to provide a granule containing pranlukast hydrate and a formulation containing the granule with reduced bitterness of pranlukast hydrate.

で示される４−オキソ−８−［４−（４−フェニルブトキシ）ベンゾイルアミノ］−２−（テトラゾール−５−イル）−４Ｈ−１−ベンゾピラン・半水和物である。プランルカスト水和物の製造は、例えば、上記特許文献１記載の方法に準じて行なうことができる。
本発明において、「プランルカスト水和物、糖類および水溶性高分子を含有してなる、苦味が低減された顆粒」（以下、「顆粒」と略記する場合がある。）における糖類としては、例えば、糖、糖アルコール等が挙げられ、これらから選択される１種を用いることができ、または２種以上を適宜組み合わせて用いることができる。糖としては、例えば、単糖類（ブドウ糖（グルコース）、果糖（フルクトース）、ガラクトース、マンノース等）、少糖類（乳糖（ラクトース）、麦芽糖（マルトース）、ショ糖（スクロース）、白糖（精製白糖を含む。）、セロビオース、トレハロース等）が挙げられる。糖アルコールとしては、例えば、マンニトール、ソルビトール、マルチトール、エリスリトール、キシリトール等が挙げられる。 Hereinafter, the granule of the present invention and the preparation containing the granule will be described.
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 hemihydrate represented by the formula: The production of pranlukast hydrate can be performed, for example, according to the method described in Patent Document 1.
In the present invention, the saccharide in “a granule containing pranlukast hydrate, a saccharide and a water-soluble polymer with reduced bitterness” (hereinafter sometimes abbreviated as “granule”). For example, sugar, sugar alcohol, etc. are mentioned, 1 type selected from these can be used, or 2 or more types can be used in combination as appropriate. Examples of the sugar include monosaccharides (glucose (glucose), fructose, galactose, mannose, etc.), oligosaccharides (lactose (lactose), maltose (maltose), sucrose (sucrose), and white sugar (purified white sugar). .), Cellobiose, trehalose and the like. Examples of the sugar alcohol include mannitol, sorbitol, maltitol, erythritol, xylitol and the like.

  Of these saccharides, mannitol, sucrose, lactose, erythritol, xylitol, sorbitol, maltitol and trehalose are preferable, and sucrose or mannitol is more preferable. As mannitol, D-mannitol is more preferable. As the sucrose, purified sucrose is preferable. In addition, as saccharides, those having excellent moldability and disintegration, non-hygroscopicity, high melting point, good stability, no active ingredients incompatible, refreshing It is also preferable that there is.

  The ratio of the saccharide used in the granule of the present invention is preferably about 40 to about 90% by weight, more preferably about 40 to about 85% by weight, based on 100% by weight of the granule. Further, the ratio of the saccharide when the formulation (eg, tablet) containing the granules is 100% by weight is preferably about 40 to about 90% by weight, more preferably about 40 to about 85% by weight. More preferably about 40 to about 75% by weight.

Examples of the water-soluble polymer in the granule of the present invention include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, sodium carboxymethylcellulose, cellulose acetate phthalate, gum arabic, Examples include agar, gelatin, sodium alginate, polyvinyl pyrrolidone, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, macrogol, and the like. One or more selected from these can be used in appropriate combination. .
Of these water-soluble polymers, hydroxypropylmethylcellulose, hydroxypropylcellulose and the like are preferable, and any of them can be obtained as a commercial product. Examples of hydroxypropylmethylcellulose (HPMC) include TC-5E, TC-5EW, TC-5MW, TC-5R, TC-5RW, TC-RG, and TC-5S manufactured by Shin-Etsu Chemical Co., Ltd. Among these, TC-5EW and TC-5RW are preferable. Examples of hydroxypropyl cellulose (HPC) include HPC-SSL, HPC-SL, HPC-L, HPC-M, and HPC-H manufactured by Nippon Soda Co., Ltd. Among these, HPC-L is preferable. . These can be obtained as commercial products.

“Pranlukast hydrate, granules containing saccharides and water-soluble polymer” further includes other additives (formulation bases) commonly used in the production of granule preparations. May be.
In the present invention, the “preparation containing granules” refers to a preparation containing the granules of the present invention and other additives (preparation base) as necessary (hereinafter sometimes abbreviated as the present preparation). Is). Although it does not specifically limit as a formulation form, For example, a tablet, a capsule, etc. are mentioned.

The granule of the present invention and a preparation containing the granule (the preparation of the present invention) can be produced according to a known method. For example, pranlukast hydrate, saccharides, water-soluble polymer and other additives as necessary are mixed, or known granulation methods (for example, extrusion granulation method, mixed stirring granulation method, high speed Mixed stirring granulation method, fluidized bed granulation method, tumbling stirring fluidized bed granulation method, tumbling granulation method, dry (compression) granulation method, crushing granulation method, spray drying granulation method, etc.) Granules can be produced by drying, sizing, and classifying the granulated product as necessary. In addition, other additives may be added to the granules thus obtained as necessary, and capsule filling or using a known tableting machine (for example, a rotary tableting machine or a single tableting machine). Capsules and tablets can be produced by tableting. 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.
The spray drying (spray drying) granulation method is obvious to those skilled in the art, but the liquid mixture is made into small droplets (atomization), and the spray drying granulator, fluidized bed drying granulator, rolling fluidized bed Widely represents a granulation method including a step of quickly removing a solvent from a mixture in a spray drying apparatus such as a granulator or a tablet coating machine. In the case of using a powder containing two or more kinds of saccharides, a powder obtained by spray-drying the two or more kinds of saccharides in advance as a mixed solution may be used, or a powder that is individually spray-dried and then mixed may be used. Good. In any of the production methods, it is also possible to perform compression molding after applying a lubricant in advance to the die of a tableting machine without mixing a lubricant or the like at the time of compression molding.

Examples of the other additives include excipients, binders, lubricants, disintegrating agents, flavoring agents, surfactants, coloring agents, antioxidants, masking agents, antistatic agents, fluidizing agents, and wetting agents. Agents, elution aids, flavoring agents, essential oils, dispersion aids, foaming agents and the like. One selected from these can be used, or two or more can be used in appropriate combination. These additives can be obtained as commercial products.
Examples of the excipient include sugars (eg, glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, etc.), starch ( Corn starch, potato starch, wheat starch, rice starch, etc.), lactose colloidal silica, crystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like. Examples of the crystalline cellulose include what is called microcrystalline cellulose. For example, various grades commercially available from Asahi Kasei Kogyo Co., Ltd., Theolas (registered trademark, hereinafter the same) KG802, Theolas PH101, Theolas PH102, Theolas PH301. , Theolas PH302, Theolas PH-F20JP, Theolas RC-A591NF (crystalline cellulose / carmellose sodium) and the like. Both are preferred, but more preferred is Theolas PH301. The excipient (for example, crystalline cellulose) should be contained in an amount of about 0.5 to about 30% by weight, preferably about 1 to about 20% by weight, with the preparation of the present invention (for example, tablet) as 100% by weight. Is preferred. In particular, it is preferable to add about 5 to about 15% by weight.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin and the like. Can be mentioned.
Examples of the disintegrant include starch, corn starch, potato starch, sodium carboxymethyl starch, partially pregelatinized starch, carboxymethylcellulose calcium (calcium fibrin glycolate), carboxymethylcellulose, and crospovidone (for example, products manufactured by BASF Japan Ltd.). Name Kollidon CL), low substituted hydroxypropyl cellulose, crystalline cellulose, L-hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, hydroxypropyl starch, etc., corn starch, crospovidone and low substituted hydroxy More preferred is propylcellulose.
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, phospholipid, glycerin fatty acid ester Sorbitan fatty acid ester, polyoxyethylene fatty acid ester, glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, light anhydrous silicic acid, hydrous silicon dioxide and the like.
Examples of the colorant include titanium oxide, edible red No. 3, edible red No. 102, edible yellow No. 5, edible yellow No. 4 aluminum lake, edible blue No. 1, edible blue No. 2, iron sesquioxide, yellow sesquioxide. , Riboflavin, caramel 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 fluidizing agent include light anhydrous silicic acid (for example, trade name Adsolider 101 manufactured by Freund Sangyo Co., Ltd.), talc, hydrous silicon dioxide, and the like.
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, cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, arginine, lysine, and tris. Examples include aminomethane, polyethylene glycol, propylene glycol, glutamic acid, and aspartic acid.

  Examples of the flavoring agent (bitter taste improving agent) include sweeteners (saccharin or a salt thereof (sodium salt), aspartame, stevia extract, glycyrrhizic acid or a salt thereof (dipotassium salt, disodium salt, trisodium salt, diammonium salt). Monoammonium salt), sucralose, thaumatin, acesulfame potassium, sucrose, D-sorbitol, xylitol, thaumatin (thaumatin), sodium 5'-inosinate, etc. Fruit flavor, strawberry flavor, chocolate flavor, lemon, lemon lime, orange, orange essence, orange extract, mint, l-menthol, 1-camphor, etc., acidulant (citric acid, anhydrous citric acid, tartar , Malic acid, sodium citrate, succinic acid, fumaric acid, glutamic acid or a salt thereof (sodium salt), ascorbic acid, sodium 5'-guanylate, etc.) and the like. Examples of the stevia extract include these sugar transfer products in addition to natural stevia extract. For example, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, α- And glucosyl stevioside. Sucralose is 4,1 ', 6'-trideoxy-4,1', 6'-trichloro-galactosucrose obtained by sucrose halogenation with a sweetener derived from sucrose. Aspartame is preferred as a sweetener, yogurt flavor as a flavor, and anhydrous citric acid as an acidulant.

  The amount of sweetener and flavor used in the preparation of the present invention is preferably about 0.01 to about 5% by weight, and about 0.05 to about 1% by weight, with the preparation of the present invention being 100% by weight. More preferred.

Examples of essential oils include mint oil, eucalyptus oil, cinnamon oil, fennel oil, clove oil, orange oil, lemon oil, lime oil, pine oil, rose oil and the like, preferably mint oil, eucalyptus oil, cinnamon oil, etc. Oil, fennel oil, clove oil and the like.
Examples of the dispersion aid include glucose, fructose, maltose, trehalose, mannitol, xylitol, erythritol, phosphate, citrate, silicate, glycine, glutamic acid, arginine and the like.
Examples of the foaming agent include sodium hydrogen carbonate, sodium carbonate, calcium carbonate, calcium hydrogen carbonate and the like.

In the present invention, both “a granule containing pranlukast hydrate, saccharide and water-soluble polymer” and “a preparation containing granules” are preferred.
As a preparation form in “a preparation containing granules”, a tablet is preferable, and an intraoral rapidly disintegrating tablet is more preferable.
In the present invention, the intraoral quick-disintegrating tablet is also simply called a quick-disintegrating tablet, and is a tablet that disintegrates rapidly when combined with saliva. Oral quick disintegrating tablets include so-called chewable tablets.
Tableting of the tablet in the preparation of the present invention is performed in consideration of moldability and disintegration property in the oral cavity. For example, when a 9 mm diameter punch is used, the tableting may be performed at about 2.5 to about 15 kN. Preferably, it is about 3.0 to about 12.0 kN.

In addition, “granules containing pranlukast hydrate, saccharide and water-soluble polymer” can be taken as granules, powders, and dry syrups.
In the case of a granule or powder, it may be taken with water as it is, or it may be taken after dissolving or suspending in water.
According to the 14th revision Japanese Pharmacopoeia, dry syrup means a preparation to be taken after being dissolved or suspended at the time of use, but it may be taken with water as needed.

  The granule of the present invention can be suspended or dissolved in water and used as a liquid (for example, oral syrup). When preparing a liquid agent, one or more additives can be appropriately used as necessary. For example, a solubilizer (polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polyvinylpyrrolidone, macrogol, etc.), thickener (Polyhydric alcohol (glycerin, macrogol, etc.), cellulose (methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, etc.), hydrophilic polymer (polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, Hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), sodium alginate, chondroit Sulfuric acid, cyclodextrin, etc.), suspending agents (surfactants (stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, polyoxyethylene hardened castor Oil, polysorbate, etc.), saccharides (sorbitol, mannitol, sucrose, etc.), celluloses (methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, etc.), isotonic agents (glucose, D-sorbitol, sodium chloride, glycerin, D -Mannitol, potassium chloride, concentrated glycerin, propylene glycol, sucrose, etc.), buffer (phosphate (sodium hydrogen phosphate, sodium dihydrogen phosphate, etc.), boric acid, borax, acetate (sodium acetate) Um, etc.), carbonates (sodium carbonate, calcium carbonate, potassium carbonate, etc.), citric acid, additives L- sodium glutamate and the like) and the like can be combined as appropriate. The granule dosage form of the present invention is preferably a granule or a dry syrup, more preferably a dry syrup.

  The granule of the present invention or the preparation of the present invention may optionally contain one or more coating agents (for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose, ethyl acrylate / methyl methacrylate copolymer, etc. ). In addition, preservatives commonly used as needed (for example, paraoxybenzoates (methyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), parabens (methylparaben, ethylparaben, propylparaben, butylparaben) ), Reverse soaps (benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, etc.), alcohol derivatives (chlorobutanol, benzyl alcohol, phenethyl alcohol, etc.), organic acids and salts thereof (sodium dehydroacetate, Sorbic acid, sodium sorbate, etc.), phenols (parachloromethoxyphenol, parachlorometacresol, etc.), antioxidants (eg sulfites, ascorbic acid, citric acid, sodium edetate) ) Can also be added additives such as. Further, for example, the raw powder of pranlukast hydrate is used as it is, or a suitable coating agent (representing the same as described above), a plasticizer (for example, polyethylene glycol, triethyl citrate, etc.), etc. The pranlukast hydrate thus coated can be mixed with a binder (eg, hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), etc., and formulated into a conventional method for use.

The average particle size of pranlukast hydrate used in the present invention is preferably about 1 to about 40 μm from the effect of reducing bitterness. More preferably, it is about 1 to about 15 μm, and particularly preferably about 1 to about 10 μm.
Pranlukast hydrate having an average particle size of about 1 to about 40 μm can be easily obtained by those skilled in the art by appropriately combining known methods (for example, the method described in JP-A No. 61-050977). Can be manufactured. 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) are added to pranlukast hydrate (1500 g), and the mixture is stirred at an internal temperature of about 20 to about 30 ° C. for about 5 minutes. Thereafter, sodium hydrogen carbonate (314.4 g) is added and the temperature is raised to about 65 ° C. to dissolve pranlukast hydrate. While stirring the resulting solution, acetic acid (402.6 g) is added and stirred at an internal temperature of about 65 ° C. for about 1 hour. The resulting crystallization solution is filtered with a centrifuge and washed twice with ethanol (10 L). Ethanol (18 L) is added to the resulting crystals and stirred at an internal temperature of about 20-30 ° C. for about 1 hour. The crystallization liquid is filtered with a centrifuge, and the resulting crystals are 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 is placed in the dryer, and the container is sealed under reduced pressure. A moisture absorption operation is performed at room temperature until the moisture content of the crystals reaches 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). For example, a generally used laser diffraction particle size distribution measuring apparatus. (For example, SALD-2100 (Shimadzu Corporation)).

The average particle size of the granule of the present invention or the granule contained in the preparation of the present invention is preferably in the range of about 50 to about 600 μm. When the average particle size of the granules contained in the preparation of the present invention (for example, intraoral rapidly disintegrating tablet) is large, it may cause a feeling of roughness in the oral cavity, and if it is small, bitterness may remain in the oral cavity for a long time. Therefore, the thickness is preferably about 50 to about 150 μm, more preferably about 50 to about 100 μm. In addition, when a pediatric patient takes the granule of the present invention, if it is too small, it may be a cause of thinning. Therefore, the more preferable average particle size of the granule of the present invention is about 300 to about 550 μm, Preferably, it is about 350 to about 500 μm.
Moreover, as a measuring method of the average particle diameter of the granule of this invention, there exists a sifting method, for example, It can obtain | require by the method of measuring the particle size distribution of a granule using the sieve of an appropriate size.
Moreover, the disintegration property and bitterness score in the human oral cavity are affected by the bulk density of the granules, and it is effective to define the bulk density range. That is, the bulk density of the granule of the present invention is preferably about 0.35 to about 0.70 g / cm ³ , more preferably about 0.35 to about 0.67 g / cm ³ . The bulk density of the granules contained in the preparation of the present invention is preferably about 0.35 to about 0.70 g / cm ³ , more preferably about 0.35 to about 0.65 g / cm ³ . More preferably, it is about 0.35 to about 0.55 g / cm ³ .
In the present invention, “bulk density of granules” means a value (loose bulk density) obtained by dividing “granule mass” by “volume when granules are put in a container”, for example, a sample of about 30 g. Measure accurately by placing the sample in a dry graduated cylinder without compaction, reading to the smallest unit of the scale, and dividing the weight of the powder by the final bulk volume of the powder to obtain the bulk density. Can do.

  In the preparation of the present invention (for example, a rapidly disintegrating tablet in the oral cavity), the feeling of dosing can be improved and the bitterness can be reduced by defining the disintegration time in the human oral cavity. Preferably, the preparation has a disintegration time in the human oral cavity of about 5 to about 80 seconds, more preferably a preparation having a disintegration time in the human oral cavity of about 5 to about 70 seconds, and more preferably in the human oral cavity. The preparation has a disintegration time of about 5 to about 40 seconds.

  Moreover, as a method for measuring the disintegration property (disintegration time) of the preparation of the present invention, for example, a disintegration test according to the method described in the Japanese Pharmacopoeia 14th Amendment is also preferable. In this disintegration test, for example, the preferable disintegration time in the disintegration test when the test solution is water is about 5 to about 60 seconds, more preferably about 5 to about 50 seconds, and still more preferably about 5 To about 45 seconds, particularly preferably about 5 to about 30 seconds.

Further, like the disintegration time, the bitterness score is also suitable for expressing the effect of the present invention. That is, if the bitterness score in the bitterness sensory test 1 described later is in the range of 0 to 2.00, it can be said that the present invention has reduced bitterness. More preferably, the preparation of the present invention has a bitterness score of 0 to 1.00.
Also in the bitterness score in the bitter taste sensory test 2 described later, if it is in the range of 0 to 2.00, it can be said that the bitterness is reduced. Preferably, the bitterness score is 0 to 1.50. Preferably, it is a granule having a bitterness score of 0 to 1.45.

  According to the present invention, a high content granule or preparation of pranlukast hydrate can be provided. Specifically, the content of pranlukast hydrate is preferably about 5 to 55% by weight, more preferably about 5 to about 45% by weight when the granule of the present invention is 100% by weight. More preferably about 5 to about 35% by weight, particularly preferably about 5 to about 25% by weight. In addition, when the preparation of the present invention (for example, tablet) is 100% by weight, it is preferably about 5 to about 55% by weight, more preferably about 5 to about 45% by weight, and further preferably about 5 to about 55% by weight. 40% by weight, particularly preferably about 5 to 35% by weight.

When the form of the preparation of the present invention is a tablet, the content of pranlukast hydrate in one tablet is preferably about 30 to about 225 mg, more preferably about 35 to about 150 mg, and further preferably about 40 to about 112.5 mg.
A dry syrup form is preferred for administering the granules of the invention to children. 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. is there. 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.
The daily dose when the granule of the present invention is used as a dry syrup is preferably about 0.09 to about 9.00 g, more preferably about 0.11 to 9.00 g, and still more preferably It is about 0.14 g to about 9.00 g, and particularly preferably about 0.20 to about 9.00 g. The content of pranlukast hydrate contained in the dry syrup is preferably not more than about 450 mg.

[Application to pharmaceutical products]
Pranlukast hydrate is used for various diseases such as bronchial asthma, allergic rhinitis, sinusitis, COPD (chronic obstructive pulmonary disease), Meniere syndrome, migraine, cough, exudative otitis media, dysmenorrhea, etc. It is useful as a preventive and / or therapeutic agent.
To use pranlukast hydrate for the above purposes, it is usually administered systemically or locally, in oral or parenteral form. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of about 112.5 to about 450 mg of pranlukast hydrate per adult. Orally once to several times a day.
In addition, for children, pranlukast hydrate is usually orally administered at a daily dose of about 5 to about 10 mg / kg.
Of course, as described above, since the administration method and dosage vary depending on various conditions, it is not limited to the above, and administration methods other than the above can be used, and an amount smaller than the above dosage may be sufficient. However, administration may be necessary beyond the range.
In addition, the size of the preparation of the present invention is not particularly limited, and may be of a size that does not exceed the range of common sense, for example, a size that can be put in the mouth in an intraoral rapidly disintegrating tablet. It is determined in consideration of the amount of the product. Also, the shape is not particularly limited, and may be, for example, a general round tablet or a deformed tablet (for example, a caplet tablet, a perforated tablet, etc.).

[toxicity]
The granule of the present invention and the preparation of the present invention have low toxicity and are sufficiently safe for use as a medicine.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely in detail, this invention is not limited to these.

Example 1
A suspension of yogurt flavor (trade name: yogurt oil (manufactured by San-Ei Gen FFI Co., Ltd.); 2.4 g) in absolute ethanol (9.6 g) is suspended in purified water (345.2 g). It became cloudy and a binding solution was obtained. Pranlukast hydrate (400 g) having an average particle size of 2.9 μm, hydroxypropylmethylcellulose (trade name: TC-) in a container of a stirring granulator (VG-10 type vertical granulator: manufactured by Paulek Co., Ltd.) 5 RW (manufactured by Shin-Etsu Chemical Co., Ltd.); 48 g), mannitol (manufactured by Merck & Co., 1524.8 g), aspartame (manufactured by Ajinomoto Co., Inc., 4.8 g) and crospovidone (trade name: Kollidon CL (BASF) 120 g) was added, and after mixing for 1 minute, the previously obtained binding solution was added to obtain a wet product of pranlukast hydrate (blade rotation speed: 400 rpm, chopper rotation speed: 2000 rpm). , Liquid feeding speed: 20-30 g / min). This was sized with a 1.40 mm sieve and dried using a fluidized bed granulator (WSG-5: manufactured by Pauleck Co., Ltd.) (air supply temperature: 85 ° C.). The dried product is sized again (screen diameter: 1.397 mm and 0.813 mm) with a sizing machine (QUADRO COMIL: manufactured by Pauleck Co., Ltd.), and further sieved with a 1 mm sieve. Granules (about 1900 g) containing pranlukast hydrate were obtained. This granule has an average particle diameter of 163.0 μm and a bulk density of 0.650 g / cm ³ (bulk density is a value obtained by dividing the mass when approximately 30 g of granules are put into a 100 mL measuring cylinder by volume. The same applies hereinafter.) To this granule (262.5 g), anhydrous citric acid (manufactured by Komatsuya Chemical Co., Ltd., 1.5 g), microcrystalline cellulose (trade name: Theolas PH301 (manufactured by Asahi Kasei Chemicals Corporation); 32.4 g) , Magnesium stearate (made by Taihei Chemical Sangyo Co., Ltd., 2.4 g) and light anhydrous silicic acid (trade name: AdSolider 101 (manufactured by Freund Sangyo Co., Ltd.); 1.2 g) were added to mix the bags. A tableting powder was obtained. The tableting powder was tableted at 4.9 kN using a 9.5 mm diameter punch with a tableting machine (Virgo: manufactured by Kikusui Seisakusho Co., Ltd.). A tablet having the composition shown below was obtained. The tablet hardness of the obtained tablets was 29.5 N, and the tablet thickness was 4.35 mm. In addition, disintegration time in a disintegration test conducted in accordance with the method described in the Japanese Pharmacopoeia No. 14 Revision using water as a test solution (hereinafter referred to as “pharmacological disintegration time” in distinction from disintegration time in the human oral cavity). Was 35 seconds. The tablet hardness was measured with a tablet continuous measuring machine (WHT-2E: manufactured by PHARMA TEST).

Example 2
The amount of purified water was changed from 345.2 g to 401.0 g by using pranlukast hydrate having an average particle size of 9.2 μm instead of pranlukast hydrate having an average particle size of 2.9 μm. Except for the above, the same operation as that shown in Example 1 was performed, and granules containing pranlukast hydrate (average particle size: 268.1 μm, bulk density: 0.544 g / cm ³ ) and tableting Got the end. The tableting powder was tableted at 4.5 kN using the same tableting machine and scissors as in Example 1 to obtain tablets having the composition shown in Table 2 below per tablet. The tablet hardness of the obtained tablets was 29.7 N, the tablet thickness was 4.50 mm, and the pharmacopoeia disintegration time was 33 seconds.

Example 3
The amount of purified water was changed from 345.2 g to 421.0 g by using pranlukast hydrate having an average particle diameter of 39.2 μm instead of pranlukast hydrate having an average particle diameter of 2.9 μm. Except for the above, the same operation as that shown in Example 1 was carried out to prepare granules containing pranlukast hydrate (average particle size: 254.5 μm, bulk density: 0.599 g / cm ³ ) and tableting Got the end. The tableting powder was tableted at 4.3 kN using the same tableting machine and scissors as in Example 1 to obtain tablets having the composition shown in Table 3 below per tablet. The tablet hardness of the obtained tablets was 29.6 N, the tablet thickness was 4.46 mm, and the pharmacopeia disintegration time was 24 seconds.

Example 4
The amount of purified water was changed from 345.2 g to 355.2 g, and the screen diameter for sizing with a granulator was changed from 1.397 mm and 0.813 mm to 1.397 mm and 0.457 mm. Except that, granule (average particle size: 163.0 μm, bulk density: 0.605 g / cm ³ ) containing pranlukast hydrate by the same operation as that shown in Example 1 and A powder for tableting was obtained. The tableting powder was tableted at 4.7 kN using the same tableting machine and scissors as in Example 1 to obtain tablets having the composition shown in Table 4 below per tablet. The tablet hardness of the obtained tablet was 29.9 N, the tablet thickness was 4.47 mm, and the pharmacopoeia disintegration time was 26 seconds.

Example 5
A suspension of absolute ethanol (9.6 g) in yogurt flavor (trade name: yogurt oil (manufactured by Saneigen FFI Co., Ltd.); 2.4 g) is suspended in purified water (200.0 g). It became cloudy and used as a binding solution. A stirrer granulator (VG-10 vertical granulator: manufactured by Paulec Co., Ltd.), pranlukast hydrate (particle diameter: 2.9 μm; 400 g), hydroxypropyl methylcellulose (TC-5RW (Shin-Etsu Chemical Co., Ltd.)) 48 g), purified sucrose (produced by Hiranoya Co., Ltd., 1553.6 g) and crospovidone (trade name: Kollidon CL (manufactured by BASF Japan); 120 g) for 1 minute, and then the binding solution is mixed. In addition, a wet product of pranlukast hydrate was obtained (blade rotation speed: 400 rpm, chopper rotation speed: 2000 rpm, liquid feeding speed: 20 to 30 g / min). This was sized with a 1.40 mm sieve and dried with a fluidized bed granulator (WSG-5: manufactured by Paulek Co., Ltd.). The dried product is again sized (screen diameter: 1.397 mm) with a sizing machine (Quadrocomil: manufactured by POWREC Co., Ltd.), further sieved with a 1 mm sieve, and about 1900 g of granules (average) Particle size: 271.9 μm, bulk density: 0.695 g / cm ³ ). To this granule (265.5 g), microcrystalline cellulose (trade name: Theolas PH301 (manufactured by Asahi Kasei Chemicals Corporation); 30.9 g), magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd., 2.4 g) After adding light anhydrous silicic acid (trade name: Adsolider 101 (Freund Sangyo Co., Ltd.); 1.2 g), bag mixing was performed to obtain a tableting powder. The tableting powder was tableted with a tableting machine (Burgo: manufactured by Kikusui Seisakusho Co., Ltd.) using a 9.5 mm diameter punch at 6.1 kN and shown in Table 5 below per tablet. A tablet consisting of the composition was produced. The tablet hardness of the obtained tablet was 31.0 N, the tablet thickness was 4.18 mm, and the pharmacopoeia disintegration time was 455 seconds.

Example 6
Hydroxypropyl methylcellulose (trade name: TC-5EW (manufactured by Shin-Etsu Chemical Co., Ltd.); 1.2 g) was dissolved in purified water (990 mL), mannitol (manufactured by Merck, 785.2 g) and pranlukast Hydrate (200 g; average particle size 2.9 μm) was added and suspended. After stirring and defoaming overnight at low speed, aspartame (Ajinomoto Co., Inc., 2.4 g) was added, and yogurt flavor (trade name: Yogurt Oil (manufactured by Saneigen FFI Co., Ltd.)): 1 0.2 g) of absolute ethanol (4.8 g) suspension was added. This was spray-dried with a spray-drying granulator (L-8 type spray dryer: manufactured by Okawahara Chemical Co., Ltd.) to obtain a spray-dried product containing pranlukast hydrate. This was sieved with a 500 μm sieve to obtain about 800 g of granules (average particle size: 83.0 μm, bulk density: 0.490 g / cm ³ ). To this granule (247.5 g), anhydrous citric acid (1.5 g), crospovidone (trade name: Kollidon CL (manufactured by BASF Japan); 15 g), microcrystalline cellulose (trade name: Theolas PH301 (Asahi Kasei Chemicals ( 31.5 g) and magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd., 4.5 g) were added to obtain a tableting powder. The tableting powder was tableted with a tableting machine (Burgo: manufactured by Kikusui Seisakusho Co., Ltd.) using a 9.5 mm diameter punch at 4.9 kN, and the composition shown in Table 6 below per tablet was used. A tablet consisting of The tablet hardness of the obtained tablet was 31.0 N, the tablet thickness was 4.52 mm, and the pharmacopeia disintegration time was 21 seconds.

Example 7
The same procedure as described in Example 6 was performed except that the amount of mannitol was changed from 785.2 g to 705.2 g and the amount of pranlukast hydrate was changed from 200 g to 280 g. Thus, granules containing pranlukast hydrate (average particle size: 89.4 μm, bulk density: 0.412 g / cm ³ ) and tableting powder were obtained. The tableting powder was tableted at 3.9 kN using the same tableting machine and scissors as in Example 1 to obtain tablets having the composition shown in Table 7 below per tablet. The tablet hardness of the obtained tablet was 30.2 N, the tablet thickness was 4.65 mm, and the pharmacopoeia disintegration time was 35 seconds.

Example 8
The same procedure as described in Example 6 was performed except that the amount of mannitol was changed from 785.2 g to 585.2 g and the amount of pranlukast hydrate was changed from 200 g to 400 g. Thus, granules containing pranlukast hydrate (average particle size: 81.1 μm, bulk density: 0.390 g / cm ³ ) and powder for tableting were obtained. The tableting powder was tableted at 3.2 kN using the same tableting machine and scissors as in Example 1 to obtain tablets having the composition shown in Table 8 below per tablet. The tablet hardness of the obtained tablet was 31.0 N, the tablet thickness was 4.76 mm, and the pharmacopeia disintegration time was 40 seconds.

Example 9
Pranlukast hydrate (60.0 g) having an average particle size of 2.9 μm, mannitol (Merck, 209) in a container of a stirring granulator (VG-01 type vertical granulator: manufactured by Pauleck Co., Ltd.) .3 g), corn starch (manufactured by Nissho Chemical Co., Ltd., 21.0 g), hydroxypropylcellulose (trade name: HPC-L (manufactured by Nippon Soda Co., Ltd.); 9.0 g) and aspartame (Ajinomoto) Co., Ltd., 0.7 g) was added, and after mixing for 1 minute, purified water (53 g) was added to the mixture to obtain a wet product of pranlukast hydrate (blade rotation speed: 500 rpm, chopper rotation speed: 2500 rpm). This wet product was dried using a fluidized bed granulator (STREA: manufactured by POWREC Co., Ltd.) at an intake air temperature of 80 ° C. until the exhaust temperature reached 45 ° C. The dried product was collected by a sieving method to collect a fraction of 300 μm to 710 μm to obtain granules containing pranlukast hydrate (average particle size: 453.9 μm, bulk density: 0.550 g / cm ³ ). Table 9 below shows the composition per 250 mg of granules.

Example 10
Except that pranlukast hydrate with an average particle size of 9.2 μm was used instead of pranlukast hydrate with an average particle size of 2.9 μm, and the amount of purified water was changed from 53 g to 55 g. The same operation as shown in Example 9 was performed to obtain granules containing pranlukast hydrate (average particle size: 430.2 μm, bulk density: 0.541 g / cm ³ ). Table 10 below shows the composition per 250 mg of granules.

Example 11
Except that pranlukast hydrate with an average particle size of 38.4 μm was used instead of pranlukast hydrate with an average particle size of 2.9 μm, and the amount of purified water was changed from 53 g to 60 g. The same operation as shown in Example 9 was performed to obtain granules (average particle size: 531.8 μm, bulk density: 0.577 g / cm ³ ) containing pranlukast hydrate. Table 11 below shows the composition per 250 mg of granules.

Example 12
Pranlukast hydrate was prepared in the same manner as in Example 9 except that purified sucrose was used instead of mannitol and ethanol (53 g) was used instead of purified water (53 g). (Average particle diameter: 465.5 μm, bulk density: 0.652 g / cm ³ ). Table 12 below shows the composition per 250 mg of granules.

Example 13
The amount of purified water was changed from 53 g to 50 g, and except that lactose (manufactured by Lactose New Zealand) was used instead of mannitol, the same operation as shown in Example 9 was performed, and pranlukast water Granules (average particle size: 465.5 μm, bulk density: 0.652 g / cm ³ ) containing a Japanese product were obtained. Table 13 below shows the composition per 250 mg of granules.

Bitter taste sensory test 1
A sensory test was performed using the tablet of the present invention.
14 males and females aged 25 to 45 years old contained 1 tablet prepared in Examples 1 to 8 without any water in the oral cavity, and the tablet was rubbed with the tongue and upper jaw. The time until complete disintegration (disintegration time (second) in the human oral cavity) was measured, and the bitterness at that time was evaluated. The evaluation standard (score) of bitterness is as follows.
0: Feel no bitterness 1: Can perceive bitterness 2: Feel bitterness slightly 3: Feel bitterness 4: Feel bitterness strongly

In Table 14 and Table 15 below, the average particle size (μm), bitterness score (relative value), disintegration time (disintegration time in the human oral cavity (seconds)) of each tablet drug (pranlukast hydrate), The average particle diameter (μm) of the granules contained in the tablet and the bulk density (g / cm ³ ) of the granules are shown.

From the above test results, the present inventors have obtained the following findings.
1. Preferred range of average particle diameter of drug From Table 14, when the preparations of Examples 1, 2 and 3 subjected to stirring granulation are compared, the preparation of Example 1 having an average drug particle diameter of 2.9 μm is 1. 64. The formulation of Example 3 showing the lowest bitterness score of 64, the bitterness score of the formulation of Example 2 having an average drug particle size of 9.2 μm and 1.93 μm, and the average particle size of the drug being 39.2 μm The bitterness score of 2.07 was 2.07, and the lower the average particle size of the drug, the lower the bitterness score. From this, the average particle size of the drug capable of improving bitterness is preferably about 1 to about 40 μm, more preferably about 1 to about 15 μm, and further preferably about 1 to about 10 μm.
2. Preferred range of tablet disintegration time (disintegration time in human oral cavity) From Tables 14 and 15, comparing the preparations of Examples 1, 5 and 6, those having a short disintegration time are excellent in the bitterness improving effect. Therefore, the disintegration time for improving the bitter taste of pranlukast hydrate is preferably about 5 to about 80 seconds, more preferably about 5 to about 70 seconds, and further preferably about 5 to about 40 seconds. It is.
3. Additive Optimization From Table 14, when comparing the preparations of Examples 5 and 6, mannitol was used instead of purified sucrose, and bitterness was improved by using aspartame as a flavoring agent. Because it is shortened, both mannitol and purified sucrose are suitable as sugars, but mannitol is more preferred, and aspartame (sweetener) is more preferred as a corrigent. It is also preferable to use yogurt flavor as a fragrance.

4). Preferred range of average particle diameter of granules From Tables 14 and 15, in the preparations of Examples 1 and 5 having a large average particle diameter of granules, the bitterness score appears relatively high, and the disintegration time becomes longer. On the other hand, since the bitterness score is low and the disintegration time is shortened in the preparations of Examples 6 to 8 in which the average particle size of the granules is small, it is preferable that the average particle size of the granules contained in the tablet is small. From this, in view of the improvement time of disintegration time and bitterness, the average particle size of the granules contained in the preparation of the present invention is preferably about 50 to about 150 μm, more preferably about 50 to about 100 μm.
5. Preferred range of the bulk density of the granules From Table 15, the preparations of Examples 6, 7 and 8 in which the bulk densities of the granules are 0.490, 0.412 and 0.390 g / cm ³ respectively The disintegration times of are 23 seconds, 26 seconds and 31 seconds, showing good disintegration properties. Moreover, it turns out that the formulation of Examples 1-5 has disintegration property next to the formulation of Examples 6-8. From these, in terms of disintegration properties, bulk density of the granules contained in the present preparation is preferably from 0.35 to 0.70 g / cm ^3, more preferably 0.35 to 0.55 g / cm ³ It is.
6). Preferred range of drug content From Table 15, when comparing the preparations of Example 6, Example 7 and Example 8 in which the drug content was varied, any preparation of 50 mg, 70 mg and 100 mg in a total weight of 300 mg However, a high content formulation with a low bitterness score and reduced bitterness can be provided. From this, the drug content in the preparation of the present invention is preferably about 5 to about 55% by weight, more preferably about 5 to about 45% by weight, still more preferably about 5 to about 40% by weight, and particularly preferably About 5 to about 35% by weight.

Bitter taste sensory test 2
A sensory test was performed using the granules of the present invention.
After 16 males and females aged 25-45 years old contained 250 mg of the granules produced in Examples 9-13 without water in the oral cavity and rubbed the granules with the tongue and upper jaw for 30 seconds. The bitterness when swallowing was evaluated. The evaluation standard (score) of bitterness is as follows.
0: Feel no bitterness 1: Can perceive bitterness 2: Feel bitterness slightly 3: Feel bitterness 4: Feel bitterness strongly

Table 16 below shows the average particle size (μm), bitterness score (relative value), disintegration time (disintegration time in the human oral cavity (seconds)), and average of granules of each granule (pranlukast hydrate) The particle diameter (μm) and the bulk density (g / cm ³ ) of the granules are shown.

From the above test results, the present inventors have obtained the following findings.
From Table 16, when the preparations of Examples 9, 10 and 11 are compared, the preparation of Example 9 in which the average particle size of the drug is 2.9 μm is 1. The formulation of Example 11 showing the lowest bitterness score of 13, the bitterness score of the formulation of Example 10 having an average drug particle size of 9.2 μm of 1.19 and the average particle size of drug being 38.4 μm The bitterness score of 1.50 was 1.50, and the lower the drug average particle size, the lower the bitterness score. From this, the average particle size of the drug capable of improving bitterness is preferably about 1 to about 40 μm, more preferably about 1 to about 15 μm, and further preferably about 1 to about 10 μm.
Moreover, when the preparations of Examples 9, 12 and 13 are compared, the saccharides contained are mannitol, purified sucrose and lactose, respectively. Since any preparation has an effect of improving bitterness, any saccharide contained in the granule of the present invention is preferred, but more preferably, purified sucrose and mannitol.

Since the granule of the present invention or the preparation of the present invention (for example, intraoral rapidly disintegrating tablet) reduces the bitter taste of pranlukast hydrate, it can provide a preparation with improved compliance.

Claims (4)

A granule containing pranlukast hydrate, a saccharide and a water-soluble polymer, comprising 100% by weight of the granule and 5 to 25% by weight of pranlukast hydrate, The average particle diameter is 1 to 15 μm, the bulk density of the granules is 0.35 to 0.67 g / cm ³ , the average particle diameter of the granules is 50 to 600 μm, and the saccharide is selected from mannitol, sucrose and lactose A granule with reduced bitterness, which is one or more and the water-soluble polymer is one or more selected from hydroxypropylcellulose and hydroxypropylmethylcellulose. The granule according to claim 1, which has a score value of 0 to 2.00 according to the following human bitterness sensory test.
[Human bitterness sensory test]
250 mg of granules are contained in the mouth without containing water, and the bitterness when swallowed after rubbing the granules with the tongue and upper jaw for 30 seconds is evaluated according to the following evaluation criteria (score) of bitterness.
0: Feel no bitterness
1: Can perceive bitterness
2: Feel bitterness slightly
3: Feel bitter
4: Strong bitterness Furthermore, the granule of Claim 1 containing 1 or more types chosen from a corrigent and an excipient | filler. The granule according to any one of claims 1 to 3, which is a granule or a dry syrup.