KR100957731B1 - Pranlukast hydrate-containing preparation having relieved bitterness - Google Patents

Abstract

In providing granules containing franlukast hydrate and preparations containing the granules (fast buccal tablets in the mouth), bitter taste can be reduced by reducing the average particle diameter of franlukast hydrate, The effect of the present invention can be enhanced by defining the average particle diameter and bulk density of the granules containing lucast hydrate, so that the granules containing the franlukast hydrate of the present invention and the tablets containing the granules have a reduced bitter taste. In addition, it can be provided as a formulation having excellent dosage properties by rapidly disintegrating, and can also be provided as a high-content formulation in which saccharides are increased while a saccharide is increased.

Description

PRANLUKAST HYDRATE-CONTAINING PREPARATION HAVING RELIEVED BITTERNESS}

The present invention relates to granules comprising franlukast hydrate as an active ingredient and a formulation containing the granules.

Franlukast hydrate is known as a leukotriene (LT) receptor antagonist (see Patent Document 1), and is widely used as a therapeutic agent for bronchial asthma or allergic rhinitis. In addition to adult capsules, franlukast hydrates are provided with dry syrup formulations for pediatric bronchial asthma patients. As an advantage of the dry syrup preparation, it is possible to easily take children, which are difficult to swallow, by dissolving or suspending it in water.

On the other hand, the operation of dissolving or suspending in water is complicated, if necessary, especially for children, so the burden on patients or their caregivers is increased in the absence of water and containers, and the dose compliance may be reduced. There is concern. Moreover, when taken without suspending, there exists a problem that the bitterness derived from drug (franlukast hydrate) is easy to remain in an oral cavity.

Therefore, a formulation with improved dosage compliance is desired, and in recent years, various studies have been actively conducted to improve the above problems.

For example, a method of adding xylitol (see Patent Document 2) is known as a method of improving the problem when taking a drug having a bitter taste as a dry syrup preparation. However, xylitol does not have a bitter taste improvement effect on all drugs and is not universally available.

In addition, in the oral disintegrating tablet rapidly disintegrating in the oral cavity, it is easy to take even without water, and since a single dose is accurate, various reports have been made on the structure and manufacturing method thereof.

However, in the case where the franlukast hydrate having a bitter taste is a fast disintegrating tablet in the oral cavity, the drug component having a bitter taste is exposed to the oral cavity by disintegrating the preparation immediately in the oral cavity. In addition, at this time, since it is taken without water, it feels bitter than a normal oral tablet for a long time, and it has become a demerit of fast disintegrating tablet in oral cavity characterized by being easy to take.

For example, as a means for concealing the bitter component, the drug component having a bitter taste blended in the chewable formulation is coated with a polymer such as ethyl cellulose, Eudragit, and the like, even if the tablet disintegrates in the oral cavity. A method of preventing direct exposure (see Patent Document 3) has been proposed. However, there is a fear that the coating requires a facility and a long time of operation, resulting in high cost.

On the other hand, the following are known as a formulation composition containing franlukast hydrate. For example, since lancastast hydrate has adhesion cohesion, when the original medicine of this compound is compressed as it is, it adheres to a tableting machine (sticking) and is not necessarily preferable in terms of mass production. As a method of reducing adhesiveness, a method of spray-drying franlukast hydrate together with sugars is known, but there is no description regarding the reduction of bitter taste of franlukast hydrate (see Patent Document 4).

In addition, Patent Document 5 also describes a novel solid formulation composition containing franlukast hydrate, which is capable of compact formulation with improved dose compliance, but there is no description regarding the reduction of bitter taste of franlukast hydrate.

Patent Document 1: European Patent Application Publication No. 0173516

Patent Document 2: Japanese Patent Application Laid-open No. Hei 6-157312 (No foreign correspondence)

Patent Document 3: International Publication No. 93/01805 Pamphlet

Patent Document 4: International Publication No. 96/41628 Pamphlet

Patent Document 5: Japanese Laid-Open Patent Publication No. 2006-008676 (no foreign correspondence)

Disclosure of Invention

Problems to be Solved by the Invention

An object of this invention is to reduce the bitter taste of franlukast hydrate, and to provide the formulation which can be taken easily, without feeling most bitter taste.

Means to solve the problem

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, the inventors noticed that the average particle diameter of franlukast hydrate is related to the bitter taste of franlukast hydrate. As a result, if the average particle diameter is small, the surface area is increased in that the number of particles themselves increases, so that, in the general idea that the bitter taste is increased, franlukast hydrate having a small average particle diameter may have a bitter taste reducing effect. As a result of reversing the correlation and finding that the granules containing franlukast hydrate have good disintegration properties when they have a specific bulk density, further studies have been conducted to reduce the bitter taste of the franlukast hydrate. It was found out that the ratio of saccharides can be reduced while increasing the ratio, thereby providing a high content formulation of franlukast hydrate, and thus the present invention has been completed based on such knowledge.

That is, the present invention relates to granules containing franlukast hydrate, sugars and water-soluble polymers, and to formulations containing the granules.

More specifically, the present invention

[1] granules having the following characteristics (i) to (iii), wherein the granules containing franlukast hydrate, sugars and water-soluble polymers have reduced bitter taste;

(i) 100% by weight of the granules, containing about 5% to about 55% by weight of franlukast hydrate,

(Ii) the average particle diameter of the franlukast hydrate is about 1 to about 40 mu m, and

(Iii) the bulk density of the granules is from about 0.35 to about 0.70 g / cm 3,

[2] The granule according to the above [1], wherein the sugar is at least one selected from mannitol, sucrose, lactose, erythritol, xylitol, sorbitol, maltitol and trehalose;

[3] the granules according to the above [1], further comprising a copper,

[4] the granule according to the above [3], wherein the copper is at least one selected from aspartame and yogurt flavor;

[5] The granule according to the preceding item [1], wherein the water-soluble polymer is at least one selected from hydroxypropyl cellulose and hydroxypropyl methyl cellulose;

[6] the granule according to the preceding item [1], wherein the average particle diameter of the franlukast hydrate is about 1 to about 15 µm;

[7] The granules according to the above [1], wherein the granules are 100% by weight and contain about 5 to about 25% by weight of franlukast hydrate.

[8] the granule according to the preceding item [1], wherein the granule average particle diameter is about 50 to about 600 µm;

[9] the granule according to the preceding item [8], wherein the granule average particle diameter is about 300 to about 550 µm;

[10] The granules according to the above [1], wherein the bulk density of the granules is about 0.35 to about 0.67 g / cm 3.

[11] The granule according to the item [1], wherein the score value of the human bitterness sensory test is 0 to 2.00;

[12] the granules according to the above [1], which are dry syrup,

[13] A dry syrup comprising franlukast hydrate, sugars, and a water-soluble polymer, the dry syrup being 100% by weight, containing about 5% to about 25% by weight of franlukast hydrate, and the average of franlukast hydrate. The particle diameter is about 1 to about 15 µm, the bulk density of the dry syrup is about 0.35 to about 0.67 g / cm 3, and the average particle diameter of the dry syrup is about 50 to about 600 µm, and scores by human bitterness sensory test Dry syrup with reduced bitterness, characterized in that the value is 0 to 2.00,

[14] The dry syrup according to the above [13], wherein the dosage of the dry syrup per day is about 0.2 to about 9.0 g.

[15] A formulation comprising the granule according to the above [1],

[16] The agent according to the above [15], which is an intraoral fast tablet.

[17] The agent according to the above [16], wherein the disintegration time in the human oral cavity is about 5 to about 80 seconds;

[18] The agent according to the above [16], wherein the tablet contains about 50 mg to about 125 mg of franlukast hydrate.

[19] The formulation as described in the preceding item [16], wherein the score value of the human bitterness sensory test is 0 to 2.00;

[20] A tablet comprising granules containing franlukast hydrate, sugars and water-soluble polymers, and other additives, the tablet being 100% by weight, containing about 5 to about 55% by weight of franlukast hydrate, The average particle diameter of the hydrate is about 1 to about 15 µm, the score value according to the human bitterness sensory test is 0 to 2.00, the disintegration time in the human oral cavity is about 5 to about 80 seconds, and one tablet Fast bore tablets in the oral cavity of reduced bitterness, characterized by containing about 50 mg to about 125 mg of franlukast hydrate.

[21] A formulation consisting of granules containing franlukast hydrate, a saccharide, and a water-soluble polymer, wherein the bulk density of the granules is from about 0.35 to about 40 using a franlukast hydrate having an average particle diameter of about 1 to about 40 µm. It relates to a method for reducing the bitter taste of franlukast hydrate, wherein the content of franlukast hydrate is set at 0.70 g / cm 3, and the content of franlukast hydrate when the formulation is 100 wt% is about 5 to about 55 wt%.

Effects of the Invention

According to this invention, the granules containing franlukast hydrate and the formulation containing the granules which reduced the bitter taste of franlukast hydrate can be provided.

To practice the invention  Best form for

EMBODIMENT OF THE INVENTION Hereinafter, the granule of this invention and the formulation containing this granule are demonstrated.

Franlukast hydrate used in the present invention is formula (A)

[Formula 1]

4-oxy-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate represented by. The production of franlukast hydrate can be carried out according to the method described in Patent Document 1, for example.

In the present invention, as a saccharide in "granule with reduced bitterness, which contains franlukast hydrate, a saccharide and a water-soluble polymer" (hereinafter, abbreviated as "granule"), for example, The sugar, sugar alcohol, etc. can be mentioned, One type selected from these can be used, or 2 or more types can be used in combination suitably. As the sugar, for example, sucrose (glucose (glucose), fructose (fructose), galactose, mannose, etc.), small sugars (lactose (lactose), maltose (maltose), sucrose (sucrose), sucrose (tablet) And sucrose, trehalose, and the like). As a sugar alcohol, mannitol, sorbitol, maltitol, erythritol, xylitol, etc. are mentioned, for example.

Among these sugars, mannitol, sucrose, lactose, erythritol, xylitol, sorbitol, maltitol and trehalose are preferable, more preferably sucrose or mannitol. As mannitol, D-mannitol is more preferable. As sucrose, purified sucrose is preferable. The sugars are preferably those having excellent moldability and disintegrability, being non-hygroscopic, having a high melting point, having good stability, having no compounding contraindications for the active ingredient, and having refreshing properties.

As a ratio of the saccharide used for the granules of this invention, 100 weight% of granules are preferable, and about 40 to about 90 weight% are preferable, More preferably, it is about 40 to about 85 weight%. In addition, about 40 to about 90 weight% is preferable as a saccharide ratio when the formulation (for example, a tablet) which contains the granule is 100 weight%, More preferably, it is about 40 to about 85 weight %, More preferably about 40 to about 75% by weight.

As the water-soluble polymer in the granule of the present invention, for example, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate saxate, carboxymethyl cellulose Sodium, cellulose acetate, gum arabic, agar, gelatin, sodium alginate, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, macrogol and the like. And 1 or more types selected from these can be used in combination suitably.

Among these water-soluble polymers, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and the like are preferable, and all can be obtained as commercial products. As hydroxypropyl methyl cellulose (HPMC), TC-5E, TC-5EW, TC-5MW, TC-5R, TC-5RW, TC-RG, TC-5S etc. made by Shin-Etsu Chemical Co., Ltd. are mentioned, for example. Can be mentioned. Especially, TC-5EW, TC-5RW, etc. are preferable. Examples of hydroxypropyl cellulose (HPC) include HPC-SSL, HPC-SL, HPC-L, HPC-M, HPC-H, etc., manufactured by Nippon Soda Co., Ltd., among which HPC-L is preferred. Do. These can be obtained as a commercial item.

"Granules containing franlukast hydrate, sugars and water-soluble polymers" may further include other additives (formulation bases) generally used when producing granule formulations.

In this invention, "the formulation which contains a granule" means the formulation (Hereafter abbreviated as the formulation of this invention) containing the granule of this invention and another additive (formulation base) as needed. Although it does not specifically limit as a form of formulation, For example, a tablet, a capsule, etc. are mentioned.

The granules of the present invention and preparations containing the granules (preparation of the present invention) can be produced according to a known method. For example, franlukast hydrates, sugars, water soluble polymers and other additives as needed, or known granulation methods (e.g., extrusion granulation, mixed stirring granulation, high speed mixing stirring granulation, fluidized bed granulation, electric stirring fluidized bed) Granules can be produced by drying, sizing, classifying and the like of the granulated product obtained by the granulation method, the rolling granulation method, the dry (compression) granulation method, the crush granulation method, the spray drying granulation method and the like as necessary. Moreover, a capsule or a tablet can be manufactured by adding another additive as needed to a granule obtained in this way, and capsule-filling or tableting using a well-known tablet machine (for example, a rotary tablet machine or a single tablet machine). have. In addition, the tablet may be coated using a film coating base that is pharmaceutically acceptable if necessary and does not interfere with the effects of the present invention.

The spray drying (spray dry) granulation method is clear to those skilled in the art, but the liquid mixture may be dropped into small droplets (atomized), and the solvent may be rapidly removed from the mixture in a spray drying apparatus such as a spray drying granulator, a fluidized bed dry granulator, an electric fluidized bed granulator, a tablet coating machine, and the like. The granulation method including the process of removing is shown widely. When using the powder containing 2 or more types of saccharides, the powder spray-dried using the 2 or more types of saccharides as a mixed liquid previously may be used, and what mixed after spray-drying an individual may be used. Moreover, also in any manufacturing method, at the time of compression shaping | molding, compression molding can also be carried out after apply | coating a lubricant to the base of a tableting machine, without mixing a lubricant or the like.

Such other additives include, for example, excipients, binders, lubricants, disintegrants, odorants, surfactants, colorants, antioxidants, masking agents, antistatic agents, glidants, humectants, elution aids, tinting agents, essential oils, dispersions. An adjuvant, a foaming agent, etc. can be mentioned, One type selected from these can be used, or 2 or more types can be used in combination suitably. These additives can be obtained as a commercial item.

Excipients include, for example, sugars (e.g., glucose, fructose, maltose, lactose, isomerized lactose, reducing lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, paratinose, trehalose, sorbitol, etc.), Starch (corn starch, potato starch, wheat starch, rice starch, etc.), lactose colloidal silica, crystalline cellulose, silicic anhydride, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like. As said crystalline cellulose, what is called a microcrystalline cellulose is included, For example, various grades, the Zeoras (registered trademark. Or less) are marketed by Asahi Kasei Kogyo Co., Ltd. KG802, Theoras PH101, Theoras PH102, These include the Zeorath PH301, the Zeorath PH302, the Zeorath PH-F20JP, and the Zeorath RC-A591NF (crystalline cellulose, sodium carmellose). Although all are preferable, More preferably, it is the thios PH301. The excipient (e.g., crystalline cellulose) may be contained in an amount of about 0.5 to about 30% by weight, preferably about 1 to about 20% by weight, based on 100% by weight of the formulation (e.g., tablet) of the present invention. desirable. In particular, it is preferable to mix | blend about 5 to about 15 weight%.

As the binder, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, polyvinylpyrrolidone, methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose sodium, partially α starch, α starch, sodium alginate , Pullulan, gum arabic, gelatin and the like.

Examples of disintegrating agents include starch, corn starch, potato starch, sodium carboxymethyl starch, partially α-starch, calcium carboxymethyl cellulose (calcium cellulose glycolate), carboxymethyl cellulose, crospovidone (e.g. BASF Japan Co., Ltd. product name Collidone CL), low-substituted hydroxypropyl cellulose, crystalline cellulose, L-hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, hydroxypropyl starch, etc. And corn starch, crospovidone and low-substituted hydroxypropyl cellulose.

As surfactant, For example, polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene polyoxy Propylene copolymer, sodium lauryl sulfate, phospholipid, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, glycol fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester, and the like. .

Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, hard silicic anhydride, hydrous silicon dioxide, and the like.

As a coloring agent, for example, 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 trioxide, yellow trioxide, Riboflavin, caramel, etc. are mentioned.

As antioxidant, sodium ascorbate, L-cysteine, sodium sulfite, vitamin E etc. are mentioned, for example.

As a concealment agent, titanium oxide etc. are mentioned, for example.

As an antistatic agent, talc, titanium oxide, etc. are mentioned, for example.

Examples of the fluidizing agent include hard silicic anhydride (for example, trade name Adsorida 101 manufactured by Freund Industries, Inc.), talc, hydrous silicon dioxide, and the like.

Examples of the humectant include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like.

As an elution adjuvant, For example, cyclodextrins, such as a dry methacrylic acid copolymer LD, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, (alpha)-cyclodextrin, (beta) -cyclodextrin, (gamma)-cyclodextrin, etc. And arginine, lysine, trisaminomethane, polyethylene glycol, propylene glycol, glutamic acid and aspartic acid.

Examples of copulating agents (bitter improvers) include sweeteners (saccharin or salts thereof (sodium salts), aspartame, stevia extract, glycyrrhizin acid or salts thereof (2 potassium salts, 2 sodium salts, 3 sodium salts, 2 ammonium salts, mono) Ammonium salt), sucralose, somartin, acesulfame potassium, sucrose, D-sorbitol, xylitol, somartin (tomatin), 5'-inosinate, etc.), fragrance (persimmon powder, caramel, yogurt flavor, vanilla flavor, fruit Flavor, Strawberry Flavor, Chocolate Flavor, Lemon, Lemon Lime, Orange, Orange Essence, Orange Extract, Mint, 1-Menthol, 1-Camper, etc., Acidulants (citric acid, citric anhydride, tartaric acid, malic acid, sodium citrate, succinic acid, Fumaric acid, glutamic acid or its salt (sodium salt), ascorbic acid, 5'-sodium guanylate, etc.) etc. are mentioned. Examples of the stevia extract include sugar transfer materials thereof in addition to the natural stevia extract. For example, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, and rebaudio Side E, (alpha)-glucosyl stevioside, etc. are mentioned. Sucralose is a sweetener derived from sucrose and is 4,1 ', 6'-trideoxy-4,1', 6'-trichloro-galacto sucrose obtained by halogenation of sucrose. Aspartame is preferred as a sweetener, yogurt flavor as a flavor, and citric acid anhydride as an acidulant.

As a compounding quantity of the sweetener and a fragrance | flavor used for the formulation of this invention, about 0.01 to about 5 weight% is preferable, respectively, making the formulation of this invention 100 weight%, respectively, More preferably, about 0.05 to about 1 weight% Do.

Essential oils include, for example, peppermint oil, eucalyptus oil, cinnamon oil, fennel oil, cloves oil, orange oil, lemon oil, lime oil, pine oil, rose oil, and the like, and preferably peppermint oil, eucalyptus oil, cinnamon oil, fennel oil, Clove oil.

Examples of the dispersing aid include glucose, fructose, maltose, trehalose, mannitol, xylitol, erythritol, phosphate, citrate, silicate, glycine, glutamic acid and arginine.

As a blowing agent, sodium hydrogencarbonate, sodium carbonate, calcium carbonate, calcium hydrogencarbonate, etc. are mentioned, for example.

In this invention, any of "the granule which contains a franlukast hydrate, a saccharide, and a water-soluble polymer", and "the formulation which contains a granule" are preferable.

As a formulation form in "the formulation which contains a granule," a tablet is preferable, and also an intraoral fast tablet is more preferable.

In the present invention, the fast disintegrating tablet in the oral cavity is simply referred to as fast disintegrating tablet and is a tablet which is rapidly disintegrated by compounding with saliva. In the oral cavity, a so-called chewable tablet is included.

Tableting in the formulation of the present invention is carried out in consideration of moldability and disintegration in the oral cavity, but, for example, when using a nominal ball with a diameter of 9 mm, tableting is preferably performed at about 2.5 to about 15 kN. More preferably, it is about 3.0 to about 12.0 kN.

Moreover, "the granule containing a franlukast hydrate, a saccharide, and a water-soluble polymer" can take itself as a granule, a powder, and a dry syrup.

In the case of granules or powders, they may be taken together with water as they are, or may be taken after being dissolved or suspended in water.

According to the 14th revised Japanese pharmacy room, dry syrup means the preparation which melt | dissolves or suspends when needed, but you may take with water as needed.

The granules of the present invention may be suspended or dissolved in water and provided as a liquid (for example, an oral syrup). When using it as a liquid, 1 type, or 2 or more types of additives can be used suitably as needed. Dissolution aids (polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polyvinylpyrrolidone, macrogol, etc.), thickeners (multivalent Alcohols (glycerine, macrogol, etc.), celluloses (methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, etc.), hydrophilic polymers (polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, methyl Cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), sodium alginate, chondroitin sulfate, cyclodextrin, etc., suspending agents (surfactants (stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, Lecithin, Benzalkonium Chloride, Benzetonium Chloride, Mono Glycerine terarate, polyoxyethylene hardened castor oil, polysorbate, etc.), sugars (sorbitol, mannitol, sucrose, etc.), celluloses (methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, 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 (acetic acid Additives such as sodium), carbonates (sodium carbonate, calcium carbonate, potassium carbonate, etc.), citric acid, sodium L-glutamate, etc.) can be used in appropriate combination. The dosage form of the granules of the present invention is preferably granules or dry syrup, more preferably dry syrup.

In addition, the granules of the present invention or the formulation of the present invention may be one or more coating agents (for example, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, ethyl acrylate). Or methyl methacrylate copolymer). Moreover, preservatives (for example, paraoxybenzoic acid esters (methyl paraoxybenzoate, propyl paraoxybenzoic acid, butyl paraoxybenzoate, etc.) commonly used as needed, parabens (methyl paraben, ethyl paraben, propyl paraben, butyl paraben) Etc.), reverse soaps (benzalkonium chloride, benzetonium chloride, chlorhexidine gluconate, cetylpyridinium chloride), alcohol derivatives (chlorobutanol, benzyl alcohol, phenethyl alcohol, etc.), organic acids and salts thereof (sodium dehydroacetic acid) Additives such as sorbic acid, sodium sorbate, etc.), phenols (such as parachloromethoxyphenol, parachloromethcresol, etc.), and antioxidants (for example, sulfite, ascorbic acid, citric acid, sodium edetate, etc.) It can also be added. For example, the original leucast hydrate powder is coated as it is, or coated using a coating agent (same as above), a plasticizer (for example, polyethylene glycol, triethyl citrate, etc.) suitable for granulated granules and the like. It can also be mixed and used with a binder (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.), etc., to franlukast hydrate.

As an average particle diameter of the franlukast hydrate used in this invention, about 1 to about 40 micrometers is preferable from the effect which reduces bitter taste. More preferably, it is about 1-about 15 micrometers, Especially preferably, it is about 1-about 10 micrometers.

Franlukast hydrates having an average particle diameter of about 1 to about 40 µm are readily available to those skilled in the art by appropriately combining known methods (for example, the method described in JP-A-61-050977) and the like. It can manufacture. For example, franlukast hydrate having an average particle diameter of about 39.2 µm can be obtained by the following method;

Ethanol (6.67L) and water (12L) are added to the franlukast hydrate (1500 g), and the mixture is stirred at about 20 to about 30 ° C for about 5 minutes. Thereafter, sodium bicarbonate (314.4 g) is added and the temperature is raised to about 65 deg. C to dissolve the franlukast hydrate. Acetic acid (402.6 g) is added while stirring the obtained solution, and it stirred at internal temperature about 65 degreeC for about 1 hour. The obtained crystallized liquid is filtered in a centrifuge and washed twice with ethanol (10 L). Ethanol (18L) is added to the obtained crystal and stirred for about 1 hour at about 20-30 degreeC of internal temperature. The crystals obtained by filtering the crystallized solution in a centrifugal separator are dried at a drying temperature of 40 ° C. for 12 hours or more with a vacuum dryer. After drying, the glass share containing water is put in a dryer, it is made into the closed state under reduced pressure, and a moisture absorption operation is performed at room temperature until the water content of a crystal | crystallization becomes 1.5 to 2.0%.

The lanukast hydrate produced by the method described in JP-A-61-050977 or the method described above may be used as it is, or by grinding with a known method, for example, a hammer mill, a ball mill, a jet mill, or the like, and desired desired particles. It can also adjust with a diameter.

In addition, in this invention, the average particle diameter of franlukast hydrate means the average particle diameter (weight-based average diameter) of the primary particle, For example, the laser diffraction type particle size distribution measuring apparatus generally used (For example, SALD-2100 (Shimadzu Corporation)) can be calculated | required.

As a granule of this invention or the granule average particle diameter contained in the formulation of this invention, it is preferable to exist in the range of about 50 micrometers-about 600 micrometers. When the average particle diameter of the granules contained in the formulation of the present invention (for example, fast-acting tablets in the oral cavity) is large, it causes a feeling of gritty feeling in the oral cavity. , About 50 to about 150 μm is preferred, and more preferably about 50 to about 100 μm. In addition, when a pediatric patient takes the granules of the present invention, it can be considered that too small causes the neck to dry, and as a more preferable average particle diameter of the granules of the present invention, it is about 300 to about 550 μm. More preferably about 350 to about 500 µm.

Moreover, as a granule average particle diameter measuring method of this invention, there exists a classification method, for example, It can obtain | require by the method of measuring the particle size distribution of granules using the sieve of a suitable size.

In addition, the bulk density of the granules affects the collapsability and bitterness score in the human mouth, and it is effective to define the bulk density range. That is, the bulk density of the granules 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. In addition, the bulk density of the granules included in the formulation 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, still more preferably about 0.35 to about 0.55 g / cm 3.

In addition, in this invention, "bulk density of a granule" means the value (loose bulk density) which divided "granular mass" by "volume when a granule is put into a container", For example, about 30g of samples The measurement is carried out precisely, placed in a dry measuring cylinder so as not to be consolidated, the reading is carried out to the minimum unit of the scale, and the weight of the powder is divided by the final bulk volume of the powder.

In the formulation of the present invention (for example, fast-acting tablets in the oral cavity), it is possible to improve the feeling of taking and reduce the bitter taste by the definition of the disintegration time in the human mouth. Preferably, the formulation has a disintegration time in the oral cavity of a person of about 5 to about 80 seconds, more preferably the formulation has a disintegration time in the oral cavity of a person of about 5 to about 70 seconds, still more preferably It is a formulation whose disintegration time in oral cavity is about 5 to about 40 second.

Moreover, as a method of measuring the disintegration | disintegration time (decay time) of the formulation of this invention, the disintegration test based on the method of the 14th revision of the Japanese pharmacy room is also preferable. In this disintegration test, for example, the preferable disintegration time by the disintegration test when the test solution is water is about 5 to about 60 seconds, more preferably about 5 to about 50 seconds, more preferably About 5 to about 45 seconds, particularly preferably about 5 to about 30 seconds.

Moreover, the bitterness score is also preferable to show the effect of this invention similarly to collapse time. That is, in the bitterness score in bitterness sensory test (1) mentioned later, when it exists in the range of 0-2.00, it can be said that this invention formulation with bitterness was reduced. More preferably, it is the formulation of this invention whose bitterness score is 0-1.00.

Also in the bitterness score in the bitterness sensory test (2) which will be mentioned later, if it exists in the range of 0-2.00, it can be said to be granules with reduced bitterness, Preferably it is granules whose bitterness score is 0-1.50, More preferably, Is granule whose bitterness score is 0-1.45.

According to the present invention, high content granules or formulations of franlukast hydrate can be provided. Specifically, the content of franlukast hydrate is preferably about 5 to 55% by weight, more preferably about 5 to about 45% by weight, even more preferably, when the granule of the present invention is 100% by weight. It is preferably about 5 to about 35% by weight, particularly preferably about 5 to about 25% by weight. Moreover, when the formulation (for example, tablet) of this invention is 100 weight%, Preferably it is about 5 to about 55 weight%, More preferably, it is about 5 to about 45 weight%, More preferably, about It is 5 to about 40 weight%, Especially preferably, it is about 5 to 35 weight%.

When the form of the preparation of the present invention is a tablet, the content of franlukast hydrate in one tablet is preferably about 30 to about 225 mg, more preferably about 35 to about 150 mg, still more preferably about 40 It is about 112.5 mg.

When the granules of the present invention are administered to children, the form of dry syrup is preferred. As a dosage of franlukast hydrate per kilogram of body weight of a pediatric patient, about 2 mg-about 10 mg are preferable, More preferably, it is about 5 mg-about 8 mg, More preferably, it is about 7 mg. Moreover, it is preferable to administer about 50 mg-about 100 mg per day of franlukast hydrate to the pediatric patient whose weight is 12 kg or more and less than 18 kg, More preferably, it is about 50 mg or about 100 mg. For pediatric patients with a body weight of 18 kg or more and less than 25 kg, it is preferable to administer about 70 mg to about 140 mg per day of franlukast hydrate, 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 about 100 mg to about 200 mg per day of franlukast hydrate, 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 about 140 mg to about 280 mg per day of franlukast hydrate, more preferably about 140 mg or about 280 mg.

The daily dosage in the case of using the granules of the present invention as a dry syrup is preferably about 0.09 to about 9.00 g, more preferably about 0.11 to 9.00 g, still more preferably about 0.14 g to about 9.00 g g, particularly preferably about 0.20 to about 9.00 g. In addition, it is preferable that the content of franlukast hydrate contained in dry syrup does not exceed about 450 mg.

[Application to Drugs]

Franlukast hydrate prevents and / or prevents various diseases such as bronchial asthma, allergic rhinitis, sinusitis, COPD (chronic obstructive pulmonary disease), Ménière's syndrome, migraine, seawater, true otitis media and dysmenorrhea Or as a therapeutic drug.

To use lanlukast hydrate for this purpose, it is usually administered orally or parenterally, either systemically or locally. The dosage varies depending on age, weight, symptoms, therapeutic effect, method of administration, treatment time, etc., but usually once per adult, Francuca hydrate is once to several times in the range of about 112.5 to about 450 mg. It is administered orally.

In addition, children are usually orally administered franlukast hydrate in the range of about 5 to about 10 mg / kg.

Of course, as mentioned above, since the administration method and dosage are fluctuate | varied by various conditions, it is not limited to the above, The administration method of that excepting the above can also be used, In addition, the amount smaller than the said dosage may be sufficient, and also the range It may be necessary to administer in excess of.

In addition, the size of the preparation of the present invention is not particularly limited, and the size of the preparation of the present invention should not exceed the range of common sense. do. In addition, the shape is not particularly limited, and may be, for example, a general circular tablet or a release tablet (for example, caplet tablets, perforated tablets, etc.).

[toxicity]

The toxicity of the granules of the invention and the formulations of the invention is low and safe enough for use as a medicament.

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

Example  One

Anhydrous ethanol (9.6 g) suspension of yoghurt flavor (brand name: yoghurt oil (manufactured by SAN AG F. Eye Co., Ltd.); 2.4 g) was suspended in purified water (345.2 g) to obtain a binding solution. Into a vessel of a stirred granulator (VG-10 type Vatical Granulator: manufactured by Faurek Co., Ltd.), lanukast hydrate (400 g) having an average particle diameter of 2.9 µm, and hydroxypropylmethylcellulose (trade name: TC-5RW (Shin-Etsu) Chemicals Co., Ltd. make; 48 g), mannitol (Merck Co., Ltd., 1524.8 g), aspartame (manufactured by Ajinomoto Co., Ltd., 4.8 g) and crospovidone (trade name: Collidone CL (manufactured by BASF Japan); 120 g) After mixing for 1 minute, the binder solution obtained first was added to obtain a wet product of franlukast hydrate (blade rotational speed: 400rpm, chopper rotational speed: 2000rpm, liquid feeding rate: 20-30g / min). It was squeezed and dried using a fluidized bed granulator (WSG-5 manufactured by Faurek Co., Ltd.) (air supply temperature: 85 ° C.). The dried product was again prepared by a sizing machine (QUADRO COMIL: manufactured by Faurek Co., Ltd.). ) Screen size (1.397 mm and 0.813 mm) The granules containing franlukast hydrate (about 1900 g) were obtained by sieving in a 1 mm sieve, The granule average particle diameter was 163.0 µm, and the bulk density was 0.650 g / cm 3 (The bulk density was about 30 g in a 100 ml volumetric cylinder. The mass when the granules were added was divided by the volume and is the same below.The granules (262.5 g) were citric anhydride (manufactured by Komatsuya Chemical Co., Ltd., 1.5 g) and microcrystalline cellulose (trade name: Seoras). PH301 (manufactured by Asahi Kasei Chemicals Co., Ltd.); 32.4 g), magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd., 2.4 g) and hard silicic anhydride (trade name: Adsorida 101 (manufactured by Freind Industries Co., Ltd.) ); 1.2 g) was added and mixed largely to obtain a tableting powder, which was prepared using a tableting machine (VIRGO: manufactured by Kikusui Co., Ltd.) at 4.9 kN in diameter. A vote of 1 political party or less The tablet which consists of a composition shown by 1 was obtained. The tablet hardness of the obtained tablet was 29.5N and the tablet thickness was 4.35 mm. In addition, the disintegration time (hereinafter referred to as `` pharmaceutical defense disintegration time '' as distinguished from the disintegration time in the oral cavity of a person) was 35 seconds in the disintegration test conducted in accordance with the method described in the JP-14 rev. In addition, the measurement of tablet hardness was performed with the tablet continuous measuring device (WHT-2E: product made by PHARMA TEST).

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Mannitol Aspartame Collidone CL Yogurt Flavor TC-5RW 50.0 190.6 0.6 15.0 0.3 6.0 Tableting additive Anhydrous citric acid seolas PH301 magnesium stearate adsorbate -101 1.5 32.4 2.4 1.2 Sum 300.0

Example  2

An operation similar to the operation shown in Example 1 was carried out except for using franlukast hydrate having an average particle diameter of 9.2 µm and changing the amount of purified water from 345.2 g to 401.0 g instead of franlukast hydrate having an average particle diameter of 2.9 µm. To obtain granules (average particle diameter: 268.1 µm, bulk density: 0.544 g / cm 3) containing franlukast hydrate and tableting powder. This tableting powder was compressed into tablets at 4.5 kN using the same tableting machine and pickle as in Example 1 to obtain a tablet having a composition shown in Table 2 below. The tablet hardness of the obtained tablet was 29.7 N, the tablet thickness was 4.50 mm, and the drugstore disintegration time was 33 seconds.

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Mannitol Aspartame Collidone CL Yogurt Flavor TC-5RW 50.0 190.6 0.6 15.0 0.3 6.0 Tableting additive Anhydrous citric acid seolas PH301 magnesium stearate adsorbate -101 1.5 32.4 2.4 1.2 Sum 300.0

Example  3

The same operation as in Example 1 was carried out except for using franlukast hydrate having an average particle diameter of 39.2 μm instead of franlukast hydrate having an average particle diameter of 2.9 μm and changing the amount of purified water from 345.2 g to 421.0 g. The granules (average particle diameter: 254.5 micrometers, bulk density: 0.599 g / cm <3>) containing franlukast hydrate and the tableting powder were obtained. This tableting powder was compressed into tablets at 4.3 kN using the same tableting machine and pickle as in Example 1 to obtain a tablet having a composition shown in Table 3 below. The tablet hardness of the obtained tablet was 29.6 N, the tablet thickness was 4.46 mm, and the drugstore disintegration time was 24 seconds.

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Mannitol Aspartame Collidone CL Yogurt Flavor TC-5RW 50.0 190.6 0.6 15.0 0.3 6.0 Tableting additive Anhydrous citric acid seolas PH301 magnesium stearate adsorbate -101 1.5 32.4 2.4 1.2 Sum 300.0

Example  4

The same operation as in Example 1 was carried out except that the amount of purified water was changed from 345.2 g to 355.2 g, and the screen diameter was changed from 1.397 mm and 0.813 mm to 1.397 mm and 0.457 mm in the sizing by Granules containing franlukast hydrate (average particle diameter: 163.0 mu m, bulk density: 0.605 g / cm 3) and tableting powder were obtained. This tableting powder was compressed into tablets at 4.7 kN using the same tableting machine and pickle as in Example 1 to obtain a tablet having a composition shown in Table 4 below. The tablet hardness of the obtained tablet was 29.9 N, the tablet thickness was 4.47 mm, and the drugstore disintegration time was 26 seconds.

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Mannitol Aspartame Collidone CL Yogurt Flavor TC-5RW 50.0 190.6 0.6 15.0 0.3 6.0 Tableting additive Anhydrous citric acid seolas PH301 magnesium stearate adsorbate -101 1.5 32.4 2.4 1.2 Sum 300.0

Example  5

Anhydrous ethanol (9.6 g) suspension of yoghurt flavor (brand name: yoghurt oil (made by SAN AG F. Eye Co., Ltd.); 2.4 g) was suspended in purified water (200.0 g) to obtain a binding solution. Frangiast hydrate (particle diameter: 2.9 µm; 400 g) and hydroxypropylmethylcellulose (TC-5RW (manufactured by Shin-Etsu Chemical Co., Ltd.) in a stirring granulator (VG-10 type granular granulator: manufactured by Faurek Co., Ltd.) ); 48 g), refined white sugar (Hiranoya Co., Ltd., 1553.6 g) and crospovidone (trade name: Collidone CL (BASF Japan); 120 g), followed by mixing for 1 minute The wet product of lucast hydrate was obtained (blade rotation speed 400 rpm, chopper rotation speed: 2000 rpm, liquid feeding speed: 20-30 g / min). This was sieved with a sieve of 1.40 mm and dried in a fluidized bed granulator (WSG-5 manufactured by Faurek Co., Ltd.). The dried product was further subjected to sizing (screen diameter: 1.397 mm) in a sizing machine (Quadrocomil: Paurek Co., Ltd.), and further sieved through a 1 mm sieve to about 1900 g of granules (average particle diameter: 271.9 μm, bulk). Density: 0.695 g / cm 3). To this granule (265.5 g), microcrystalline cellulose (trade name: Seoras PH301 (manufactured by Asahi Chemical Chemicals Co., Ltd.); 30.9 g), magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd., 2.4 g) and hard silicic acid After adding (brand name: Adsorida 101 (manufactured by Freund Industries Co., Ltd.); 1.2 g), the mixture was mixed in a pack to obtain a tableting powder. This tableting powder was tableted at 6.1 kN using a tableting machine (Bago: Kikkusui Co., Ltd. make) using a 9.5 mm diameter fine ball, and the tablet which consists of a composition shown in Table 5 of one party or less was manufactured. The tablet hardness of the obtained tablet was 31.0 N, the tablet thickness was 4.18 mm, and the drugstore disintegration time was 455 seconds.

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Purified White Sugar Collidone CL Yogurt Flavor TC-5RW 50.0 194.2 15.0 0.3 6.0 Tableting additive Seoras PH301 magnesium stearate adsorbate -101 30.9 2.4 1.2 Sum 300.0

Example  6

Hydroxypropylmethylcellulose (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 franlukast hydrate (200 g; The average particle diameter of 2.9 mu m) was added and suspended. After stirring and degassing at low speed overnight, aspartame (manufactured by Ajinomoto Co., Ltd., 2.4 g) was added, and furthermore, yogurt flavor (brand name: yogurt oil (manufactured by San-Eigen F-I Co., Ltd.); 1.2 g) Anhydrous ethanol (4.8 g) suspension was added. This was spray-dried by the spray-drying granulator (L-8 type | mold spray dryer: product of Okawara Kakoki Co., Ltd.), and the spray-drying product containing franlukast hydrate was obtained. This was filtered through a 500 μm sieve to obtain about 800 g of granules (average particle diameter: 83.0 μm, bulk density: 0.490 g / cm 3). Citric acid anhydride (1.5 g), crospovidone (brand name: collidone CL (made by BASF Japan); 15 g), microcrystalline cellulose (brand name: Seolas PH301 (made by Asahi Kasei Chemicals Co., Ltd.)) to this granule (247.5 g); 31.5 g) and magnesium stearate (4.5 g of Taihei Chemical Co., Ltd.) were added to obtain a tableting powder. The tableting powder was tableted at 4.9 kN using a tableting machine (Bago; manufactured by Kikusui Co., Ltd.) at a diameter of 9.5 mm, thereby obtaining a tablet having a composition shown in Table 6 below. The tablet hardness of the obtained tablet was 31.0 N, the tablet thickness was 4.52 mm, and the drugstore disintegration time was 21 seconds.

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Mannitol Aspartame Yogurt Flavor TC-5EW 50.0 196.3 0.6 0.3 0.3 Tableting additive Anhydrous Collidon Citrate CL Seoras PH301 Magnesium Stearate 1.5 15.0 31.5 4.5 Sum 300.0

Example  7

Granules containing franlukast hydrate (average) were subjected to the same operation as described in Example 6, except that the amount of mannitol was changed from 785.2 g to 705.2 g, and the amount of franlukast hydrate was changed from 200 g to 280 g. Particle diameter: 89.4 µm, bulk density: 0.412 g / cm 3) and tableting powder. This tableting powder was compressed into tablets at 3.9 kN using the same tableting machine and pickle as in Example 1 to obtain a tablet having a composition shown in Table 7 below. The tablet hardness of the obtained tablet was 30.2 N, the tablet thickness was 4.65 mm, and the drugstore disintegration time was 35 seconds.

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Mannitol Aspartame Yogurt Flavor TC-5EW 70.0 176.3 0.6 0.3 0.3 Tableting additive Anhydrous Collidon Citrate CL Seoras PH301 Magnesium Stearate 1.5 15.0 31.5 4.5 Sum 300.0

Example  8

Granules containing franlukast hydrate were prepared in the same manner as described in Example 6, except that the amount of mannitol was changed from 785.2 g to 585.2 g, and the amount of franlukast hydrate was changed from 200 g to 400 g. A particle diameter: 81.1 µm, a bulk density: 0.390 g / cm 3) and a tableting powder were obtained. This tableting powder was compressed into tablets at 3.2 kN using the same tableting machine and pickle as in Example 1 to obtain a tablet having a composition shown in Table 8 below. The tablet hardness of the obtained tablet was 31.0 N, the tablet thickness was 4.76 mm, and the drugstore disintegration time was 40 seconds.

Furtherance Amount (mg) Ingredients of granules Franlukast Carb Mannitol Aspartame Yogurt Flavor TC-5EW 100.0 146.3 0.6 0.3 0.3 Tableting additive Anhydrous Collidon Citrate CL Seoras PH301 Magnesium Stearate 1.5 15.0 31.5 4.5 Sum 300.0

Example  9

Into a container of a stirred granulator (VG-01 type granular granulator: manufactured by Faurek Co., Ltd.), franlukast hydrate (60.0 g), mannitol (manufactured by Merck, 209.3 g), and corn starch having an average particle diameter of 2.9 µm. (21.0 g of Nichiden Chemical Co., Ltd.), hydroxypropyl cellulose (trade name: HPC-L (manufactured by Nippon Soda Co., Ltd.); 9.0 g) and aspartame (manufactured by Ajinomoto Co., Ltd., 0.7 g) After mixing for 1 minute, purified water (53 g) was added to the mixture to obtain a wet product of franlukast hydrate (blade rotation speed: 500 rpm, chopper rotation speed: 2500 rpm). The wet product was dried at an intake temperature of 80 ° C. until the exhaust temperature became 45 ° C. using a fluidized bed granulator (STREA: manufactured by Faurek Co., Ltd.). Fractions of 300 µm to 710 µm were collected by the classification method to obtain granules containing franlukast hydrate (average particle diameter: 453.9 µm, bulk density: 0.550 g / cm 3). Table 9 below shows the composition per 250 mg of granules.

Composition of granules Amount (mg) Franlukast Carb Mannitol Corn Starch HPC-L Aspartame 50.0 174.4 18.0 8.0 0.6 Sum 250.0

Example  10

In the same manner as in Example 9, the same procedure as in Example 9 was carried out except for using franlukast hydrate having an average particle diameter of 9.2 탆 instead of franlukast hydrate having an average particle diameter of 2.9 µm and changing the amount of purified water from 53 g to 55 g. Granules containing franlukast hydrate (average particle diameter: 430.2 µm, bulk density: 0.541 g / cm 3) were obtained. The composition of sugar per 250 mg of granules is shown in Table 10 below.

Composition of granules Amount (mg) Franlukast Carb Mannitol Corn Starch HPC-L Aspartame 50.0 174.4 18.0 8.0 0.6 Sum 250.0

Example  11

The same procedure as in Example 9 was carried out except for using franlukast hydrate having an average particle diameter of 38.4 µm and changing the amount of purified water from 53 g to 60 g instead of franlukast hydrate having an average particle diameter of 2.9 µm. And granules containing franlukast hydrate (average particle diameter: 531.8 µm, bulk density: 0.577 g / cm 3) were obtained. The composition of 250 mg of granules is shown in Table 11 below.

Composition of granules Amount (mg) Franlukast Carb Mannitol Corn Starch HPC-L Aspartame 50.0 174.4 18.0 8.0 0.6 Sum 250.0

Example  12

Granules containing franlukast hydrate (average particle diameter: 465.5 μm) by the same operation as described in Example 9, except that purified white sugar was used instead of mannitol and ethanol (53 g) was used instead of purified water (53 g). And bulk density: 0.652 g / cm 3). Table 12 below shows the composition per 250 mg of granules.

Composition of granules Amount (mg) Franlukast Carb Purified White Sugar Corn Starch HPC-L Aspartame 50.0 174.4 18.0 8.0 0.6 Sum 250.0

Example  13

Granules containing franlukast hydrate (average particle diameter) in the same manner as in Example 9, except that the amount of purified water was changed from 53 g to 50 g, and lactose (manufactured by Lactose New Zealand) was used instead of mannitol. : 465.5 μm, bulk density: 0.652 g / cm 3). The composition of 250 mg of granules is shown in Table 13 below.

Composition of granules Amount (mg) Franlukast Carb Lactose Corn Starch HPC-L Aspartame 50.0 174.4 18.0 8.0 0.6 Sum 250.0

Bitter sensory test 1

Sensory tests were carried out using the tablets of the present invention.

To 14 men and women aged 25 to 45 years old, tablets prepared in Examples 1 to 8 were put in a state without containing water in the oral cavity, and the tablets were completely collapsed by rubbing the tablets with the tongue and upper jaw. The time until (disintegration time (seconds) in a human mouth) was measured, and the bitterness at that time was evaluated. Evaluation criteria (score) of bitterness are as follows.

0: do not feel bitter taste at all

1: Perceived bitter taste

2: feeling a bit bitter

3: Feel the bitter taste

4: strong feeling of bitterness

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

Prescription number Example 1 Example 2 Example 3 Example 4 Example 5 Average particle diameter of drug 2.9 9.2 39.2 2.9 2.9 Bitterness score 1.64 1.93 2.07 1.93 2.00 Decay time 65 60 61 66 76 Average Particle Diameter of Granules 268.1 199.7 254.5 163.0 271.9 Bulk density 0.650 0.544 0.599 0.605 0.695

Prescription number Example 6 Example 7 Example 8 Average particle diameter of drug 2.9 2.9 2.9 Bitterness score 0.3 0.64 0.86 Decay time 23 26 31 Average Particle Diameter of Granules 83.0 89.4 81.1 Bulk density 0.490 0.412 0.390

From the test results, the present inventors obtained the following findings.

1. Average particle diameter of the drug of  Desirable range

Comparing the formulations of Examples 1, 2 and 3 subjected to stirring granulation from Table 14, the formulation of Example 1 having an average particle diameter of drug of 2.9 μm exhibited the lowest bitterness score of 1.64, and the average particle diameter of drug was The bitterness score of the formulation of Example 2 having 9.2 μm was 1.93, and the bitterness score of the formulation of Example 3 having an average particle diameter of 39.2 μm was 2.07, and the smaller the mean particle diameter of the drug was, the lower the bitter taste score was. From this, about 1 to about 40 micrometers is preferable, as for the average particle diameter of the drug which can improve a bitter taste, More preferably, it is about 1 to about 15 micrometers, More preferably, it is about 1 to about 10 micrometers.

2. Preferred range of disintegration time of tablets (disintegration time in human mouth)

Comparing the formulations of Examples 1, 5, and 6 from Table 14 and Table 15, the shorter tablet disintegration time was superior in the bitter taste improving effect, and the disintegration time for improving the bitter taste of franlukast hydrate was about 5 to About 80 seconds are preferable, More preferably, it is about 5 to about 70 seconds, More preferably, it is about 5 to about 40 seconds.

3. Optimization of Additives

Comparing the formulations of Examples 5 and 6 from Table 14, both mannitol and purified sucrose were found to have improved bitter taste and shortened disintegration time by using mannitol instead of purified sucrose and using aspartame as a copper. Although preferable as a saccharide, mannitol is more preferable, and aspartame (sweetening agent) is more preferable as a copper. Moreover, it is also preferable to use a yoghurt flavor as a fragrance.

4. Granule Average Particle Diameter of  Desirable range

From Tables 14 and 15, in the formulations of Examples 1 and 5 having a large granule average particle diameter, the bitterness score is relatively high, and the disintegration time is long. On the other hand, in the formulation of Examples 6-8 with a small granule average particle diameter, since the bitterness score is low and a disintegration time becomes short, it is preferable that the granule average particle diameter contained in a tablet is small. From this point of view, considering the degree of improvement of disintegration time and bitter taste, the average particle diameter of the granules included in the formulation of the present invention is preferably about 50 to about 150 µm, more preferably about 50 to about 100 µm.

5. Preferred Range of Bulk Density of Granules

From Table 15, the formulations of Examples 6, 7 and 8, with the bulk densities of the granules of 0.490, 0.412 and 0.390 g / cm 3, respectively, show good disintegration with oral disintegration times of 23 seconds, 26 seconds and 31 seconds. . Moreover, it turned out that the formulation of Examples 1-5 is disintegratable after the formulation of Examples 6-8. From these, 0.35-0.70 g / cm <3> is preferable and, as for the bulk density of the granules contained in the formulation of this invention, More preferably, it is 0.35-0.55 g / cm <3>.

6. Preferred range of drug content

Comparing the formulations of Examples 6, 7 and 8 in which the drug content was varied from Table 15, the bitterness score was lower in all formulations among 50 mg, 70 mg and 100 mg in the total weight of 300 mg, and the bitter taste was Reduced high content formulations can be provided. From this, the drug content in the formulation 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, Preferably from about 5 to about 35% by weight.

Bitter sensory test 2

Sensory tests were carried out using the granules of the invention.

16 males and females of 25 to 45 years of age, 250 mg of granules prepared in Examples 9 to 13 were put in a state without containing water in the oral cavity, and when swallowed after rubbing the granules with the tongue and upper jaw for 30 seconds. The bitter taste of was evaluated. Evaluation criteria (score) of bitterness are as follows.

0: do not feel bitter taste at all

1: Perceived bitter taste

2: feeling a bit bitter

3: Feel the bitter taste

4: strong feeling of bitterness

Table 16 below shows the average particle diameter (μm), bitterness score (relative value), disintegration time (disintegration time in human mouth (seconds), and granule average particle of drug (franlukast hydrate) of each granule. Diameter (μm) and bulk density (g / cm 3) of the granules.

Prescription number Example 9 Example 10 Example 11 Example 12 Example 13 Average particle diameter of drug 2.9 9.2 38.4 2.9 2.9 Bitterness score 1.13 1.19 1.50 1.00 1.50 Average Particle Diameter of Granules 453.9 430.2 531.8 465.5 449.8 Bulk density 0.550 0.541 0.577 0.652 0.545

From the test results, the present inventors obtained the following findings.

Comparing the formulations of Examples 9, 10, and 11 from Table 16, the formulation of Example 9 having an average particle diameter of drug of 2.9 µm had the lowest bitterness score of 1.13, similar to the knowledge obtained in the Bitter Taste Sensory Test 1 above. The bitterness score of the formulation of Example 10 having a mean particle diameter of the drug of 9.2 μm is 1.19, and the mean particle diameter of the drug of the formulation of Example 11 having a mean particle diameter of 38.4 μm of 1.50 is small. The lower bitterness score was shown. From this, about 1 to about 40 micrometers is preferable, as for the average particle diameter of the drug which can improve a bitter taste, More preferably, it is about 1 to about 15 micrometers, More preferably, it is about 1 to about 10 micrometers.

When the formulations of Examples 9, 12, and 13 were compared, the saccharides included were mannitol, purified white sugar, and lactose, respectively. Since all the preparations are recognized for their bitterness improving action, all of the sugars contained in the granules of the present invention are preferable, but more preferably, refined white sugar and mannitol.

The granules of the present invention or the preparations of the present invention (for example, fast-acting tablets in the oral cavity) can provide a preparation having improved dosage compliance because the bitter taste of franlukast hydrate is reduced.

Claims (25)

delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete Granules containing franlukast hydrate, sugars, and water-soluble polymers, the granules being 100% by weight, containing 5-25% by weight of franlukast hydrate, and the average particle diameter of the franlukast hydrate being 1-15 占 퐉. 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, the saccharide is at least one selected from mannitol, white sugar and lactose, and the water-soluble polymer is hydroxypropyl cellulose and hydroxy. Granules with reduced bitterness, which is at least one selected from propylmethylcellulose.        The method of claim 22,        Granules having a score value of 0 to 2.00 by the bitter sensory test of the following persons: [Bitter taste sensory test of people]       250 mg of granules are placed in the oral cavity without water, and the bitter taste when swallowed after rubbing the granules with the tongue and upper jaw for 30 seconds is evaluated by the following criteria for evaluation of bitter taste (score): 0: do not feel bitter taste at all 1: Perceived bitter taste 2: feeling a bit bitter 3: Feel the bitter taste        4: Strong feeling of bitterness. The method of claim 22, Further, granules containing at least one member selected from mating agents and excipients. The method according to any one of claims 22 to 24, Granules that are granules or dry syrups.