JPWO2013129436A1 - Oral - Google Patents

Abstract

Provided are oral preparations, in particular solid preparations, in which the unpleasant taste of pioglitazone and its salts is sufficiently masked. An oral preparation containing pioglitazone or a salt thereof, a sweetener and at least two flavors, and a method for suppressing the unpleasant taste of pioglitazone or a salt thereof by using the sweetener and at least two flavors.

Description

  The present invention relates to an oral preparation containing pioglitazone or a salt thereof, a sweetener, and at least two flavors and having an unpleasant taste of pioglitazone or a salt thereof suppressed.

(Background of the Invention)
Pioglitazone and its salts have an unpleasant taste for those with a normal taste.
The following preparations are known as preparations in which the unpleasant taste of pharmaceutical ingredients having a bitter taste, such as pioglitazone and salts thereof, are concealed.
1) A basic pharmaceutical ingredient having an unpleasant taste, 2) a saccharide, 3) a polyanionic polymer, 4) a corrigent, and 5) a solid preparation containing carboxymethylcellulose (see Patent Document 1).
A solid preparation containing granules in which core particles composed of an excipient are coated with pioglitazone or a salt thereof and an acid-soluble polymer (see Patent Document 2).
An oral preparation containing pioglitazone or a salt thereof and an alkali metal chloride (see Patent Document 3).

International Publication No. 02/30400 Pamphlet International Publication No. 2007/126136 Pamphlet International Publication No. 2007/136129 Pamphlet

  In order to increase patient compliance, development of oral preparations (especially solid preparations) in which the unpleasant taste of pioglitazone and its salts is sufficiently masked is desired. In particular, since orally disintegrating preparations are disintegrated in the oral cavity in a short period of time and taken, the unpleasant taste of pioglitazone and its salts is sufficiently concealed, and if the food and drink feels like food It is considered easy to take.

  The inventors of the present invention have studied the formulation of pioglitazone having an unpleasant taste and a salt thereof. As a result, pioglitazone or a salt thereof is used in combination with a sweetener and at least two flavors. It has been found that an oral preparation is obtained in which the unpleasant taste of salt is sufficiently masked. According to the knowledge of the present inventors, there is a subject who feels an unpleasant taste after the preparation is disintegrated in the oral cavity with one kind of fragrance, but surprisingly after the preparation is disintegrated by using two kinds of fragrances. However, it has been demonstrated that long and unpleasant taste can be eliminated (aftertaste can be improved), and the present invention has been completed. That is, the present invention is as follows.

[1] An oral preparation containing pioglitazone or a salt thereof, a sweetener and at least two flavors;
[2] The agent according to [1], wherein the sweetener is aspartame;
[3] The agent according to [1] or [2], wherein the two fragrances are a fragrance that gives a first impression in the oral cavity and a fragrance that improves aftertaste;
[4] The agent according to [3] above, wherein the fragrance giving a first impression is a citrus-flavored flavor or a fruit-flavored flavor.
[4A] The agent according to [3] above, wherein the flavor imparting the first impression is a fruit flavor flavor;
[4B] The agent according to [3] above, wherein the flavor imparting the first impression is a strawberry flavor or a blueberry flavor;
[5] The above-mentioned [3], wherein the flavor improving the aftertaste is a banana flavored flavor, a grape flavored flavor, an apple flavored flavor, a mint flavored flavor, a bins flavored flavor or a milk flavored flavor. [4], the agent according to any one of [4A] and [4B];
[5A] The agent according to any one of [3], [4], [4A] and [4B], wherein the flavor improving the aftertaste is a flavor of a bins flavor or a flavor of a milk flavor;
[5B] The agent according to any one of [3], [4], [4A] and [4B], wherein the flavor improving the aftertaste is a vanilla flavored flavor or a yogurt flavored flavor;
[6] The two flavors are two flavors selected from a citrus flavor flavor, a fruit flavor flavor, a mint flavor flavor, a bins flavor flavor, and a milk flavor flavor. And the agent according to the above [1] or [2];
[6A] The above-mentioned [1] or [2], wherein the two flavors are two flavors selected from a strawberry flavor, a blueberry flavor, a vanilla flavor, and a yogurt flavor Agent;
[7] The agent according to any one of [1] to [6], wherein the two kinds of flavors are a vanilla-flavored flavor and a strawberry-flavored flavor;
[8] The agent according to any one of [1] to [6], wherein the two kinds of flavors are a yogurt flavored flavor and a blueberry flavored flavor;
[9] The agent according to any one of [1] to [8], which is a tablet;
[10] The agent according to [9], wherein the tablet is an orally disintegrating tablet;
[11] The above [1] to [10] containing about 0.1 to about 5 parts by weight of a sweetener and a total of about 0.01 to about 1 part by weight of a flavor per 100 parts by weight of the oral preparation. The agent according to any one of
[12] A method for suppressing an unpleasant taste of pioglitazone or a salt thereof by using a sweetener and at least two flavors;
[13] A method for producing an oral preparation that suppresses the unpleasant taste of pioglitazone or a salt thereof, comprising a step of mixing pioglitazone or a salt thereof with a sweetener and at least two flavors;
Etc.

Since the unpleasant taste of pioglitazone and its salts is sufficiently concealed and is very easy to take, the oral preparation of the present invention is useful as a pharmaceutical with high patient compliance. Moreover, the oral preparation of the present invention can be easily produced by combining pioglitazone or a salt thereof, a sweetener and at least two flavors.
Further, when the oral preparation of the present invention is an intraoral rapidly disintegrating solid preparation, the intraoral rapidly disintegrating solid preparation is sufficiently concealed by the unpleasant taste of pioglitazone or a salt thereof, and has an excellent oral cavity Because of its disintegrating property, it is extremely useful as a pharmaceutical with high compliance for patients such as patients who have difficulty in swallowing drugs, elderly people, and pediatric patients. In addition, since the oral preparation of the present invention contains at least two kinds of fragrances, it leaves a memorable impression to the patient, so that the patient can prevent forgetting to drink and can positively tackle the disease.

(Detailed description of the invention)
In the “pioglitazone or a salt thereof” used in the oral preparation of the present invention, the pioglitazone salt may be a pharmacologically acceptable salt, such as a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, or the like. Is mentioned.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
Pioglitazone or a salt thereof is particularly preferably pioglitazone hydrochloride.
Pioglitazone or a salt thereof may be diluted with a diluent or the like generally used in the medical or food fields.
The median diameter of pioglitazone or a salt thereof is preferably 0.5 to 25 μm, more preferably 1 to 21 μm, particularly preferably 1 to 10 μm. By adopting such a median diameter, an oral preparation excellent in the dissolution property of pioglitazone or a salt thereof can be obtained.
In addition, the above-mentioned preferable median diameter is pulverized together with the raw material for producing the oral preparation of the present invention [pulverized product obtained by pulverizing in the process of producing the oral preparation, excipient (eg, crystalline cellulose). To the pioglitazone or a salt thereof used as a mixed pulverized product obtained by That is, the median diameter of pioglitazone or a salt thereof may be changed by aggregation of pioglitazone or a salt thereof in the process of producing the oral preparation of the present invention or in the process of preserving the oral preparation after production. In addition, grinding | pulverization is performed using formulation machines, such as a mortar, a jet mill, a hammer mill, and a screen mill (P-3; Showa Chemical Machinery Co., Ltd.), for example.
In this specification, the median diameter means a particle diameter that divides coarse particles and fine particles into 50% by weight in the weight distribution or number distribution. The median diameter is measured by, for example, a laser diffraction type particle size distribution measuring device (eg, SYNPATEC HELOS-RODOS particle size distribution measuring device).
Regarding the pioglitazone having a desired median diameter or a salt thereof, the degree of dispersion is preferably “particles of 0.1 μm or less are 10% or less of the total amount and particles of 1000 μm or more are 10% or less of the total amount”.
The content of pioglitazone or a salt thereof in the oral preparation of the present invention varies depending on the dosage form, dosage, etc. of the oral preparation, but when the oral preparation is a solid preparation, it is usually 0. 01 to 60 parts by weight, preferably 0.01 to 40 parts by weight. In the case of a liquid preparation, it is usually 0.01 to 30 parts by weight, preferably 0.01 to 20 parts by weight with respect to 100 parts by weight of the liquid oral preparation.

  Examples of the “sweetener” used in the oral preparation of the present invention include arabinose, galactose, xylose, glucose, sorbose, fructose, rhamnose, ribose, isomerized sugar, monosaccharides such as N-acetylglucosamine; isotrehalose, sucrose, trehalulose , Neotrehalulose, palatinose, maltose, melibiose, lactulose, lactose and other disaccharides; α-cyclodextrin, β-cyclodextrin, isomaligoligosaccharides (isomaltose, isomaltotriose, panose, etc.), oligo-N-acetylglucosamine , Galactosyl sucrose, galactosyl lactose, galactopyranosyl (β1-3) galactopyranosyl (β1-4) glucopyranose, galactopyranosyl (β1-3) glucopyranose Galactopyranosyl (β1-6) galactopyranosyl (β1-4) glucopyranose, xylo-oligosaccharide (xylotriose, xylobiose, etc.), gentio-oligosaccharide (gentiobiose, gentiotriose, gentiotetraose, etc.), stachyose, Theande oligo, nigerooligosaccharide (such as nigerose), palatinose oligosaccharide, palatinose syrup, fucose, fructooligosaccharide (such as kestose, nystose), fructofuranosyl nystose, polydextrose, maltosyl β-cyclodextrin, malto-oligosaccharide (maltotriose, tetraose , Pentaose, hexaose, heptaose, etc.), raffinose, glycosyl sucrose (coupling sugar (trade name)), soy oligosaccharide, invert sugar, chickenpox, etc. Oligosaccharides: isomaltitol, erythritol, xylitol, glycerol, sorbitol, palatinit, maltitol, maltoteitol, maltotriitol, mannitol, lactitol, reduced isomaltoligosaccharide, reduced xylooligosaccharide, reduced gentiooligosaccharide, reduced maltose starch syrup, Sugar alcohol such as reduced starch syrup; α-glucosyltransferase-treated stevia, aspartame (trade name), acesulfame potassium, aritem, licorice extract (glycyrrhizin), triammonium glycyrrhizinate, tripotassium glycyrrhizinate, trisodium glycyrrhizinate, diglycyrrhizinate Ammonium, dipotassium glycyrrhizinate, disodium glycyrrhizinate, curculin, saccharin, sodium saccharin, Illustrate high-intensity sweeteners such as ramates, sucralose, stevia extract, stevia powder, dulcin, thaumatin (thaumatin), tenryo tea extract, neiseria berry extract, neotame, neohesperidin dihydrochalcone; and honey Can do. These sweeteners can be used alone or in any combination of two or more. Preferred are high-intensity sweeteners such as aspartame (trade name), acesulfame potassium, sucralose, thaumatin, sodium saccharin, dipotassium glycyrrhizinate, and aspartame (trade name) is more preferred.

The content of the sweetener in the oral preparation of the present invention varies depending on the type of sweetener, etc., but is about 0.1 to about 5 parts by weight, preferably about 0.1 to about 100 parts by weight of the solid oral preparation. About 1.5 parts by weight, more preferably about 0.1 to 0.5 parts by weight. The amount is about 0.01 to about 100 parts by weight, preferably about 0.1 to about 70 parts by weight, based on 100 parts by weight of the liquid oral preparation.
In the oral preparation of the present invention, the amount of the sweetener used is about 0.1 to about 200 parts by weight, preferably about 0.1 to about 50 parts by weight, and more preferably about 0.1 to about 50 parts by weight with respect to 100 parts by weight of pioglitazone and a salt thereof. Preferably it is about 0.2 to about 5 parts by weight.
In another preferred embodiment, the amount of the sweetener used in the oral preparation of the present invention is preferably about 0.5 to about 40 parts by weight, preferably about 0.5 to about 40 parts by weight per 100 parts by weight of pioglitazone and a salt thereof. 12 parts by weight is more preferred, and about 0.5 to about 4 parts by weight is even more preferred.

Examples of the “fragrance” used in the oral preparation of the present invention include all the flavors listed in the pharmaceutical additive standard and the food additive official standard. Specifically, citrus flavors such as orange (orange extract, orange oil), lemon (lemon oil), lime, grapefruit, mandarin, tangerine; apple, banana, cherry, grape, melon, peach, pineapple (pine oil) , Plums, raspberries, strawberries, blueberries and other fruit flavors; vanilla (vanilla flavor), coffee, cocoa, chocolate and other bins flavors; peppermint (peppermint essence), spearmint (spearmint oil) and other mint flavors; allspice , Spices such as cinnamon (powder, cinnamon oil) and nutmeg; nuts such as almonds, peanuts and walnuts; milks such as milk, cream, butter, cheese and yogurt; Vegetables, grains, can be exemplified various flavors such as seaweed. The fragrance used in the present invention may be a composition or a simple substance. For example, menthols, menthone, vanillin, ethyl vanillin, cinnamic acid, piperonal, d-borneol, maltol, ethyl maltol, camphor, methyl anthranilate, methyl cinnamate, cinnamic alcohol, methyl N-methylanthranilate, methyl β-naphthyl ketone, limonene, linalool, allyl isothiocyanate and the like can be exemplified.
As the shape of the fragrance, any of water-soluble fragrance, oil-soluble fragrance, emulsified fragrance, powdered fragrance and the like can be used.

The various fragrances listed above are used in combination of two or more. A preferred combination is a fragrance that gives a first impression in the oral cavity and a fragrance that improves the aftertaste.
“A fragrance that gives a first impression in the oral cavity” means a fragrance that is strongly felt in the oral cavity immediately after oral administration, and is also referred to as a so-called top note in the field of fragrances. Suitable fragrances include the citrus flavors and fruit flavors described above. More preferred are fruit flavored fragrances, especially strawberry flavored and blueberry flavored fragrances.
The “perfume that improves aftertaste” is a perfume that does not cause an unpleasant taste in the oral cavity even after about 30 seconds to about 60 seconds after oral administration (in the case of an orally disintegrating tablet, time to disintegrate in the oral cavity). It is also called the so-called last note in the field of fragrances. Suitable fragrances include the fruit-flavored fragrances such as banana, grape, and apple, the mint-flavored fragrances, the bins-flavored fragrances, and the milk-flavored fragrances. More preferred are a vanilla-flavored flavor and a yogurt-flavored flavor. The vanilla-flavored fragrance may be a simple substance such as vanillin or ethyl vanillin.

  Another preferred combination is a citrus flavor, a fruit flavor (preferably a strawberry flavor, a blueberry flavor, a banana flavor, a grape flavor, an apple flavor), a mint flavor Examples include flavors, flavors of bins flavor, and two or more flavors (preferably two flavors) selected from flavors of milk flavor. More preferably, there are two flavors selected from a strawberry flavor, a blueberry flavor, a vanilla flavor and a yogurt flavor, and more preferably a combination of a vanilla flavor and a strawberry flavor. Alternatively, a combination of a yogurt-flavored flavor and a blueberry-flavored flavor. As the at least two kinds of fragrances in the oral preparation of the present invention, a combination of a yogurt-flavored flavor and a blueberry-flavored flavor is particularly preferable.

The content of the fragrance in the oral preparation of the present invention varies depending on the kind of the fragrance, but is about 0.01 to about 1 part by weight, preferably about 0.01 to about 0, per 100 parts by weight of the solid oral preparation. 0.5 parts by weight, more preferably about 0.01 to about 0.1 parts by weight. The amount is about 0.001 to about 1 part by weight, preferably about 0.05 to about 0.5 part by weight, based on 100 parts by weight of the liquid oral preparation.
In the oral preparation of the present invention, the fragrance is used in an amount of about 0.05 to about 10 parts by weight, preferably about 0.05 to about 1 part by weight per 100 parts by weight of pioglitazone and a salt thereof.
In another preferred embodiment, the amount of the flavor used in the oral preparation of the present invention is preferably from about 0.08 to about 1 part by weight, preferably from about 0.08 to about 0, per 100 parts by weight of pioglitazone and a salt thereof. More preferably, 5 parts by weight.

  The oral preparation of the present invention may contain additives commonly used in the pharmaceutical technical field. Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a colorant, a pH adjuster, a surfactant, a stabilizer, a corrigent, a fluidizing agent, and a liquid medium. These additives are used in amounts conventionally used in the technical field of pharmaceutical preparations. Moreover, you may use these additives, mixing 2 or more types in a suitable ratio.

Examples of the excipient include sugars, crystalline cellulose; corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch and the like; anhydrous calcium phosphate, precipitated calcium carbonate, silicic acid Examples include calcium and powdered cellulose.
Here, examples of the saccharide include sugar, starch sugar, lactose, honey, and sugar alcohol. Two or more of these saccharides may be mixed and used at an appropriate ratio.
Examples of the sugar include sucrose, glycosyl sucrose [coupling sugar (trade name)], fructooligosaccharide, and palatinose.
Examples of starch sugar include glucose, maltose, powdered koji, starch syrup, and fructose.
Examples of lactose include lactose, isomerized lactose (lactulose), and reduced lactose (lactitol).
Examples of honey include various honeys that are generally used for food.
Examples of the sugar alcohol include sorbitol, D-mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, and trehalose.
The saccharides are preferably sugar alcohol and lactose, more preferably D-mannitol and lactose.
The content of the saccharide in the oral preparation is, for example, 10 to 90 parts by weight, preferably 40 to 85 parts by weight with respect to 100 parts by weight of the oral preparation.
The saccharide is added as an excipient, and may have an action of concealing the unpleasant taste of pioglitazone or a salt thereof together with the sweetener in the present invention.
Examples of the crystalline cellulose include Theorus KG801, KG802, PH101, PH102, PH301, PH302, PH-F20, RC-A591NF (trade name, Asahi Kasei Chemicals Corporation), and include what is called microcrystalline cellulose. It is. By using crystalline cellulose, an oral preparation having an appropriate formulation strength and excellent in rapid oral disintegration can be obtained.
The content of crystalline cellulose in the oral preparation is, for example, 0.1 to 50 parts by weight, preferably 0.5 to 40 parts by weight, and particularly preferably 1 to 25 parts by weight with respect to 100 parts by weight of the oral preparation.

Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium (carmellose calcium), carboxymethyl starch sodium, croscarmellose sodium, crospovidone [preferably, Kollidon CL, CL-M, CL-F, CL-SF (commodity) Name, BASF Japan Ltd.); polyplastidone XL, XL-10, INF-10 (trade name, ISP Japan Ltd.)], low-substituted hydroxypropylcellulose [preferably LH11, LH21, LH31, LH22, LH32 , LH20, LH30, LH32, LH33 (trade name, Shin-Etsu Chemical Co., Ltd.)], and hydroxypropyl starch. Among them, crospovidone is preferable, and Kollidon CL, CL-F, CL-SF (trade name, BASF Japan Ltd.); Polyplastidone XL (trade name, ISP Japan Ltd.) is more preferred. By using crospovidone, an oral preparation excellent in rapid oral disintegration property can be obtained.
The content of the disintegrant in the oral preparation is, for example, 0.5 to 25 parts by weight, preferably 1 to 15 parts by weight with respect to 100 parts by weight of the oral preparation.

  Examples of the binder include hydroxypropylcellulose [preferably HPC-SSL, SL, L (trade name, Nippon Soda Co., Ltd.)], hydroxypropylmethylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder. Of these, hydroxypropylcellulose is preferable.

  Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate. Of these, magnesium stearate is preferable.

  Examples of the colorant include edible dyes such as edible yellow No. 5 (same as sunset yellow and edible yellow No. 6 in the United States), edible red No. 2 and edible blue No. 2, edible lake dyes, yellow ferric oxide, sesquioxide. Examples include iron and black iron sesquioxide.

  Examples of the pH adjuster include citrate, phosphate, carbonate, tartrate, fumarate, acetate, and amino acid salt.

  Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene hydrogenated castor oil 60. Can be mentioned.

  Examples of stabilizers include sodium ascorbate, tocopherol, tetrasodium edetate, nicotinamide, cyclodextrins; alkaline earth metal salts (eg, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, silicic acid) Magnesium, magnesium aluminate) and butylhydroxyanisole.

  Examples of the corrigent include ascorbic acid, (anhydrous) citric acid, citric acid hydrate, tartaric acid, and malic acid.

Examples of the fluidizing agent include light anhydrous silicic acid and hydrous silicon dioxide. Here, the light anhydrous silicic acid only needs to contain hydrous silicon dioxide (SiO ₂ .nH ₂ O) (n represents an integer) as a main component. As a specific example thereof, for example, Silicia 320 (trade name, Fuji Silysia Chemical Co., Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.), and the like.
Examples of the liquid medium include water, ethanol, macrogol 400, propylene glycol, glycerin, concentrated glycerin and the like.
When the various additives described above are solid, the particle diameter of the additive is preferably 500 μm or less, which is less likely to cause roughness in the oral cavity.

Examples of the dosage form of the oral preparation of the present invention include solid preparations and liquid preparations. Examples of solid preparations include tablets, capsules, powders, granules, and lozenges. Of these, tablets are preferred.
The shape of the solid preparation is not particularly limited, and may be any of round shape, caplet shape, donut shape, oblong shape and the like.
The solid preparation may be coated with a coating agent, and may be provided with a mark for identification, characters, and a dividing line for division.
Here, examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like.
As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)] And synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name)] And acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)] and methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
Sustained release film coating bases include, for example, cellulose polymers such as ethyl cellulose and cellulose acetate; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymer such as liquid [Eudragit NE (trade name)].
Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use a coating additive in the case of coating.
Examples of the coating additive include light-shielding agents and / or colorants such as titanium oxide, talc, and iron sesquioxide; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, and polysorbates; citric acid, tartaric acid, malic acid And organic acids such as ascorbic acid.
Examples of liquid preparations include solutions, suspensions, syrups and the like.

The oral preparation of the present invention can be produced by a conventional method in the pharmaceutical technical field using the various additives described above.
Specifically, the oral preparation of the present invention can be produced by mixing pioglitazone or a salt thereof, a sweetener, and at least two flavors together with the above-mentioned various additives and, if necessary, compression molding. .
Here, mixing (including granulation, drying, sizing, etc.) can be performed by, for example, a V-type mixer, a tumbler mixer, a high-speed agitation granulator (FM-VG-10; Paulek), a universal kneader ( Hata Iron Works), fluidized granulator / dryer (LAB-1, FD-3S, FD-3SN; Paulek), box-type vacuum dryer (Kashiki Machine), screen mill (P-3; Showa Chemical Machinery Works) It is performed using a formulation machine such as.
The compression molding is performed by, for example, tableting using a single tablet machine (Kikusui Seisakusho), rotary tableting machine (Kikusui Seisakusho), Autograph (Shimadzu Corporation), etc., usually at a pressure of ^{2 to} 35 kN / cm ^2. Is called.

The oral preparation of the present invention is preferably an intraoral rapidly disintegrating solid preparation (preferably an orally disintegrating tablet). Here, the intraoral quick disintegrating property means the property that the solid preparation disintegrates within a short time (for example, 5 to 90 seconds) in the oral cavity. The oral disintegration time of the rapidly disintegrating solid preparation in the oral cavity (the time until the solid preparation is completely disintegrated by the saliva in the oral cavity of healthy adult boys and girls) varies depending on the dosage form and size of the solid preparation. For example, when the solid preparation is a tablet, it is usually 5 to 90 seconds, preferably 5 to 60 seconds, and more preferably about 5 to 30 seconds.
The intraoral rapidly disintegrating solid preparation is useful for the prevention and treatment of various diseases as an easy-to-use preparation for patients, elderly people, and children who have difficulty in swallowing drugs, and as a safe preparation for emergencies of general adults. It is.
The hardness (measured by a tablet hardness meter) of the oral preparation of the present invention is preferably 15 to 200 N, more preferably about 15 to 150 N.

Preferable specific examples of the oral preparation of the present invention include the following preparation (1), preparation (2), preparation (3) and preparation (4).
Formulation (1):
An agent comprising an oral preparation containing pioglitazone or a salt thereof, a sweetener and at least two flavors, wherein the pioglitazone or a salt thereof is coated with a saccharide.
That is, in the preparation (1), among the oral preparations of the present invention, pioglitazone or a salt thereof contained in the oral preparation is present in a state of “coated granules in which grains containing pioglitazone or a salt thereof are coated with sugar”. It is a formulation, and sweeteners and flavors may be contained either inside or outside the coated particles.
Here, as the saccharide in the “coated particle obtained by coating a particle containing pioglitazone or a salt thereof with a saccharide”, those exemplified as the saccharide may be used. Of these, lactose is preferable. The content of the saccharide is, for example, 5 to 80 parts by weight, preferably 10 to 50 parts by weight with respect to 100 parts by weight of the preparation (1).

Regarding the preparation (1), “a granule containing pioglitazone or a salt thereof” (sometimes abbreviated as “a granule of the present invention” in the present specification) includes pioglitazone or a salt thereof, a sweetener, and at least two flavors. Can be produced by granulation with additives as required. In addition, after granulation, operations such as drying and sizing may be performed as necessary.
The additive is preferably an excipient (eg, crystalline cellulose, lactose), a disintegrant (eg, carboxymethylcellulose calcium), a binder (eg, hydroxypropylcellulose), a colorant (eg, yellow ferric oxide), etc. It is.
The content of pioglitazone or a salt thereof in the grain of the present invention is preferably 0.1 to 60 parts by weight, and more preferably 1 to 40 parts by weight with respect to 100 parts by weight of the grain of the present invention.
The content of the granule of the present invention in the preparation (1) is, for example, 1 to 100 parts by weight, preferably 5 to 90 parts by weight with respect to 100 parts by weight of the preparation (1).

“Coated granules in which granules containing pioglitazone or a salt thereof are coated with saccharides” (sometimes abbreviated as “coated grains of the present invention”) included in the preparation (1) are particles of the present invention. Can be produced by coating with sugars together with additives as necessary.
The additive is preferably a binder (eg, hydroxypropylcellulose), a colorant (eg, yellow iron sesquioxide) and the like.
The coated particles of the present invention are not only coated particles in which the particles of the present invention are completely coated with saccharides (100% of the total surface area of the particles of the present invention), but also the particles of the present invention are partially (for example, Also included are coated grains that are coated 30% or more, preferably 50% or more of the total surface area of the grains of the present invention.
The content of the coated particles of the present invention in the preparation (1) is, for example, 1 to 100 parts by weight, preferably 5 to 90 parts by weight with respect to 100 parts by weight of the preparation (1).

The preparation (1) can be produced by mixing the coated particles of the present invention with additives as necessary, and further compression-molding as necessary.
The additives are preferably excipients (eg, crystalline cellulose and mannitol), disintegrants (eg, crospovidone), lubricants (eg, magnesium stearate), colorants (eg, yellow ferric oxide), etc. It is.
The preparation (1) preferably comprises pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), sweetener (preferably aspartame), at least two flavors, excipients (preferably crystalline cellulose, lactose and mannitol), disintegrant ( Preferably it consists of carboxymethylcellulose calcium and crospovidone), a binder (preferably hydroxypropylcellulose), a saccharide (preferably lactose) and a lubricant (preferably magnesium stearate), and a colorant (preferably yellow ferric oxide) ) Is a solid preparation that may contain.

Formulation (2):
Pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), sweetener (preferably aspartame), at least two flavors, excipients (preferably crystalline cellulose and mannitol), disintegrant (preferably crospovidone), binder (preferably Is a solid preparation comprising a hydroxypropyl cellulose), a saccharide (preferably lactose) and a lubricant (preferably magnesium stearate), and may further contain a colorant (preferably yellow ferric oxide).
The preparation (2) preferably comprises pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two flavors, excipients (preferably crystalline cellulose and mannitol), a disintegrant (preferably Obtained by mixing crospovidone), binder (preferably hydroxypropylcellulose), sugar (preferably lactose) and lubricant (preferably magnesium stearate), and further colorant (preferably yellow ferric oxide). It is a solid preparation (preferably a tablet) obtained by compression molding (preferably tableting) the mixture. In the solid preparation, the colorant may be omitted.
Formulation (3):
Pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), sweetener (preferably aspartame), at least two flavors, excipient (preferably Rudiflash (trade name, BASF Japan Ltd. Mannitol, crospovidone, vinyl acetate polymer) A mixture of mannitol, crystalline cellulose, lactose) and a lubricant (preferably magnesium stearate), and further contains a disintegrant (preferably crospovidone) and / or a colorant (preferably yellow ferric oxide). It is a solid preparation that may be released.
The preparation (3) is preferably pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two flavors, and an excipient (preferably Rudiflash (trade name, BASF Japan Ltd.). , Mannitol, crystalline cellulose, lactose) and a lubricant (preferably magnesium stearate), and further a colorant (preferably yellow ferric oxide), and compression molding (preferably tableting) the resulting mixture. The resulting solid preparation (preferably a tablet). In the solid preparation, the colorant may be omitted.

Formulation (4):
An oral preparation containing pioglitazone or a salt thereof, a sweetener and at least two flavors, and containing pioglitazone or a salt thereof, a saccharide (preferably lactose), a disintegrant (preferably carboxymethylcellulose calcium) and a binder An agent that contains grains.
In addition, the content of saccharide (preferably lactose) is, for example, 5 to 80 parts by weight, preferably 10 to 50 parts by weight with respect to 100 parts by weight of the preparation (4). Moreover, the content of the disintegrant (preferably, carboxymethylcellulose calcium) is, for example, 0.5 to 25 parts by weight, preferably 1 to 15 parts by weight with respect to 100 parts by weight of the preparation (4).

The preparation (4) contains a sweetener (preferably aspartame) and at least two flavors in addition to “a granule containing pioglitazone or a salt thereof, a saccharide, a disintegrant and a binder”, and further includes an excipient ( Preferably, Rudyflash (trade name, BASF Japan Ltd.)), a disintegrant (preferably crospovidone) and a lubricant (preferably magnesium stearate) can be contained.
The preparation (4) can be produced, for example, according to the method described in Examples 3 to 5 described later.
The preparation (4) preferably comprises pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two flavors, lactose, carboxymethylcellulose calcium, a binder (preferably hydroxypropylcellulose), an additive. Forming agent (preferably Rudiflash (trade name, BASF Japan Ltd.)), disintegrant (preferably crospovidone) and lubricant (preferably magnesium stearate), and further colorant (preferably yellow ferric oxide) ) Is a solid preparation that may contain.

In the present specification, “grain” means a substantially uniform material obtained by granulating raw materials such as powder, lump, solution or molten liquid by a wet granulation method, a dry granulation method or a heating granulation method. Means grains with shape and size. Examples of the “grains” include powders, fine granules and granules, and these preferably have a grain size defined in the Japanese Pharmacopoeia 14th revision.
That is, in the particle size test of the preparation, the particle size of the powder is preferably “5% or less of the total amount passing through the No. 18 (850 μm) sieve and remaining on the No. 30 (500 μm) sieve”. The particle size is preferably 10% or less of the total amount passing through the No. 200 (75 μm) sieve among the particle sizes of the powders, and the granule particle size preferably passes through the entire No. 10 (1700 μm) sieve No. 12 (1400 μm) sieve remains 5% or less of the total amount, and No. 42 (355 μm) sieve passes 15% or less of the total amount.
In the present specification, the average particle diameter of “grains” is usually 44 to 2000 μm, preferably 75 to 1000 μm. Here, an average particle diameter shows the value measured, for example with a laser diffraction type particle size distribution measuring apparatus (for example, SYNPATEC HELOS-RODOS particle size distribution measuring apparatus).
The “grain” in the present specification may be changed in its shape and size in the process of formulation for obtaining the oral preparation of the present invention (eg, compression molding process).

Among the oral preparations of the present invention, the preparation (3) containing coated particles is excellent in storage stability, and changes in the preparation quality over time (eg, discoloration; changes over time in the dissolution of pioglitazone or a salt thereof) are not observed. It is preferable because it has an excellent effect.
In addition, the preparation (3) has an excellent effect that it disintegrates in the oral cavity in a short time and the unpleasant taste of pioglitazone and its salt is sufficiently masked.
Furthermore, the preparation (3) is suitable for production on an industrial scale because it has excellent manufacturability such as no adhesion to the punch and die during tableting.
Furthermore, the preparation (3) exhibits an excellent characteristic that variation in dissolution behavior of pioglitazone or a salt thereof is small between the preparations (for example, between a plurality of tablets).
Among the oral preparations of the present invention, the preparation (4) is particularly preferable because it exhibits the same excellent effects as the preparation (3) and is excellent in the dissolution property of pioglitazone or a salt thereof.

The oral preparation of the present invention can be safely administered orally to mammals (eg, mouse, rat, rabbit, cat, dog, cow, horse, monkey, human).
The dose of the oral preparation of the present invention varies depending on the administration subject, the severity of the disease, etc., but may be selected from the range in which the dose of pioglitazone or a salt thereof is an effective amount. Specifically, for example, per adult (body weight 60 kg), pioglitazone is usually 7.5 to 60 mg / day, preferably 15 to 60 mg / day, and this amount is divided into 2 to 3 times a day. It may be administered.
When the oral preparation of the present invention is an orally disintegrating solid preparation (preferably an orally disintegrating tablet), the solid preparation can be taken without water or with an appropriate amount of water. The solid preparation can also be taken without being disintegrated in the oral cavity.

  The oral preparation of the present invention has diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes), hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia). ), Impaired glucose tolerance [IGT (Impaired Glucose Tolerance)], diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection ( E.g. respiratory infection, urinary tract infection, gastrointestinal infection, skin soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder, etc.], Obesity, osteoporosis, cachexia (eg, cancer cachex, tuberculosis cachex, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia or acquired immunodeficiency syndrome) Cachexia), fatty liver, high blood pressure, Polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy, end-stage renal disease), muscular dystrophy, myocardial infarction, angina, cerebrovascular disorder (Eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, dysmetabolic syndrome, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin) Cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory disease [eg, Alzheimer's disease, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, post-traumatic inflammation, swelling relief, neuralgia Pharyngopharyngitis, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis Preventive and therapeutic agents for diseases such as visceral obesity syndrome, arteriosclerosis (eg, atherosclerosis), multiple sclerosis, sepsis, psoriasis, Parkinson's disease, atopic dermatitis; or 2 of the above-mentioned various diseases It is useful for secondary prevention (eg, secondary prevention of cardiovascular events such as myocardial infarction) and progression inhibition (eg, inhibition of progression from impaired glucose tolerance to diabetes, inhibition of progression of arteriosclerosis in diabetic patients).

The oral preparation of the present invention can be used in combination with an active ingredient other than pioglitazone or a salt thereof (hereinafter sometimes abbreviated as a combination ingredient). In this case, the administration time of pioglitazone or a salt thereof and the concomitant component is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference. Furthermore, the oral preparation and the combination component of the present invention may be administered as two or more preparations containing the respective active ingredients, or may be administered as a single preparation containing both active ingredients. Good.
The dosage of the concomitant component can be appropriately selected based on the clinically used dose.
Thus, by using the combination component, 1) the effect of enhancing the action of the oral preparation or combination component of the present invention (synergistic effect of the drug action), 2) the effect of reducing the dose of the oral preparation or combination component of the present invention (Reduction effect of drug dosage when compared with single administration) 3) Excellent effects such as a reduction effect of the secondary action of the oral preparation or combination component of the present invention can be obtained.
Examples of the concomitant component in the oral preparation of the present invention include, for example, “diabetes therapeutic drug” (excluding pioglitazone or a salt thereof), “diabetic complication drug”, “anti-obesity drug”, “hypertension drug”, “hyperlipidemia” , “Antisclerosis”, “Antithrombotic”, “Diuretic”, “Arthritis”, “Anxiolytic”, “Antidepressant”, “Psychiatry”, “Sleep” Introducing drugs "and the like. These active ingredients may be low molecular weight compounds, high molecular proteins, polypeptides, antibodies, or vaccines. Two or more active ingredients may be mixed and used at an appropriate ratio.

Examples of the “diabetes therapeutic agent” include, for example, insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc An insulin fragment or derivative (eg, INS-1), an oral insulin preparation), an insulin sensitizer (eg, rosiglitazone or a salt thereof (preferably maleate), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, WO2007 / 013694, compounds described in WO2007 / 018314, WO2008 / 093639 or WO2008 / 099794), α-glucosidase inhibitors Examples, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)), insulin secretagogues (eg, sulfonylurea (eg, sulfonylurea) , Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate), dipeptidyl peptidase IV inhibitor (eg, Alogliptin or a salt thereof (preferably benzoate), vildagliptin, Sitagliptin, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, P HX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, 2-[[6-[(3R) -3-Amino-1-piperidinyl] -3,4-dihydro-3- Methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof), β3 agonist (eg, N-5984), GPR40 agonist (eg, WO2004 / 041266, WO2004 / 106276 , WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 or WO2008 / 001931), GLP-1 receptor agonist (eg, GLP-1, GLP-1MR agent, liraglutide (Liraglutide) ), exenatide (exenatide), AVE-0010, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH 2, CJC-1131, Albiglutide), amylin agonists (e.g., pramlintide), phosphotyrosine phosphatase inhibitors Agents (eg, sodium vanadate), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists) FBPase inhibitor), SGLT2 (sodium-glucose cotransporter 2) inhibitor (eg, Depagliflozin, AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitor, 11β-hydroxysteroid dehydrogenase inhibitor (eg, , BVT-3498, INCB-13739), adiponectin or agonist thereof, IKK inhibitor (eg, AS-2868), leptin resistance ameliorating agent, somatostatin receptor agonist, glucokinase activator (eg, Piragliatin, AZD1656) , AZD6370, TTP-355, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 or WO2008 / 156757), GIP (Glucose-dependent insulinotropic peptide), GPR119 agonist (eg, PSN821) ), FGF21, FGF analog and the like.
Examples of the above-mentioned “diabetic complication therapeutic agent” include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its Increaser (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl)- 5- [3- (2-methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N -Phenacylthiazolium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor agonists (eg, gabapentin, pregabalin), serotonin noradrenaline Reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiaprid, mexiletine), somatostatin receptor agonists (eg, , BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitor and the like.
Examples of the above “anti-obesity agents” include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, Berneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban), ghrelin antagonist, ghrelin receptor antagonist, ghrelin acyl Synthase inhibitors, opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (Eg, orlistat, cetilistat), β3 agonist (eg, N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitor, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibitor, microsomal triglyceride transfer protein inhibitor (eg, R-256918), Na -Glucose co-transport carrier inhibitors (eg, JNJ-28431754, remogliflozin), NFκ inhibitors (eg, HE-3286), PPAR agonists (eg, GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (eg, vanadine) Sodium phosphate, Trodusquemin), GPR119 agonist (eg, PSN-821), glucokinase activator (eg, AZD-1656), leptin, leptin derivatives (eg, metreleptin), CNTF (ciliary neurotrophic) Factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonist, glucagon-like peptide-1 (GLP-1) preparation (eg, extracted from bovine and porcine pancreas) Animal GLP-1 preparation; human GLP-1 preparation genetically engineered using E. coli and yeast; GLP-1 fragment or derivative (eg, exenatide, liraglutide)), amylin preparation (eg, pramlintide, AC-2307), neuropeptide Y agonists (eg, PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparation: FGF21 preparation (eg, extracted from bovine, porcine pancreas) Animal FGF21 preparations; human FGF21 preparations synthesized by genetic engineering using Escherichia coli and yeast; FGF21 fragments or derivatives), antifeedants (eg, P-57), and the like.
Examples of the above-mentioned “hypertensive agent” include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan , Irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine, etc.), β-blockers (eg, metoprolol, atenolol, protelol, protelol) Carvedilol, pindolol, etc.), clonidine and the like.
Examples of the “hyperlipidemic agent” include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, calcium salt) )), Squalene synthase inhibitors (eg, compounds described in WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5 -(2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds ( Eg, bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol) , Niaspan), ethyl icosapentate, plant sterols (eg, soysterol, gamma-oryzanol), cholesterol absorption inhibitors (eg, zetia), CETP inhibitors (eg, dalcetrapib) ), Anacetrapib), omega-3 fatty acid preparations (eg, omega-3-acid ethyl esters 90), and the like.
Examples of the above-mentioned “anti-arteriosclerotic agents” include acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitors (eg, K-604), LpPLA2 inhibitors (eg, dalapradiv, rilapradib etc.), FLAP inhibitors (eg, AM103, AM803, etc.), 5LO inhibitors (eg, VIA-2291), sPLA2 inhibitors (eg, A-002), apoAI mimetic peptides (eg, D4F), HDL preparations (eg, CSL-111) Etc.
Examples of the “antithrombotic agent” include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, , Argatroban (aragatroban), dabigatran, FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 Or compounds described in WO2005 / 113504), thrombolytic drugs (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor (Eg, ticlopidine hydrochloride, clopidogrel, plus Barrel, E5555, SHC530348, cilostazol (cilostazol), ethyl icosapentate, beraprost sodium (beraprost sodium), and the like sarpogrelate hydrochloride (sarpogrelate hydrochloride)) is.
Examples of the “diuretic” include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide). , Penfluthiazide, poly-5thiazide, meticlotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside) And azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
Examples of the “arthritis therapeutic agent” include ibuprofen and the like.
Examples of the above-mentioned `` anti-anxiety drugs '' include alprazolam, etizolam, oxazolam, tandospirone, cloxazolam, clothiazepam, chlorazepate dipotassium, chlordiazepoxide, diazepam, fludiazepam, flutazolam, flutopazepam, prazepam, bromazepam, zepamazolam, And lorazepam.
Examples of the “antidepressant” include tricyclic antidepressants (eg, imipramine, trimipramine, clomipramine, amitriptyline, nortriptyline, amoxapine, lofepramine, dosrepin, desipramine), tetracyclic antidepressants (eg, maprotiline, Mianserin, seriprine), selective serotonin uptake inhibitors (eg, fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram), serotonin and noradrenaline uptake inhibitors (eg, milnacipran, duloxetine, venlafaxine), trazodone, mirtazapine , Moclobecdo and the like.
Examples of the above-mentioned “mental nerve agent” include, for example, typical antipsychotic drugs (eg, clocapramine, chlorpromazine, phenobarbital, sultopride, thioprid, thioridazine, fluropamide, mosapramine, moperon, oxypertin, carpipramine, spiperone, sulpiride, zotepine, timiperone, Nemonapride, haloperidol, pimozide, prochlorperazine, propericazine, bromperidol, perphenazine, fluphenazine maleate, mizoribine, levomepromazine), atypical antipsychotics (eg, perospirone, olanzapine, quetiapine, risperidone, clozapine, Aripiprazole, ziprasidone, blonanserin, lurasidone) and the like.
Examples of the “sleep inducer” include, for example, ramelteon, GABA hypnotic (eg, brotizolam, estazolam, flurazepam, nitrazepam, triazolam, flunitrazepam, lormetazepam, rilmazafone, quazepam, zopiclone, eszopicone, zolpidem, zolepidin, Non-GABA hypnotics (eg, eprivaserin, purvanserin, diphenhydramine, trazodone, doxepin) and the like.

  Among the above combination components, biguanides (preferably metformin or a salt thereof (preferably hydrochloride)), insulin secretagogues (preferably sulfonylureas, non-sulfonylurea insulin secretagogues, more preferably glimepiride, nateglinide, mitiglinide Or a calcium salt hydrate thereof), an α-glucosidase inhibitor (preferably voglibose), a dipeptidyl peptidase IV inhibitor (preferably alogliptin or a salt thereof (preferably benzoate), 2-[[6- [(3R) -3-Amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof (preferably Are succinate)), HMG-CoA reductase inhibitors (preferably simvastatin) and the like. Further, as a combination in the case of using two or more kinds of combination components, a combination of a biguanide agent (preferably metformin) and an insulin secretagogue (preferably sulfonylurea agent, more preferably glimepiride) is preferable.

The present invention provides a method of suppressing the unpleasant taste of pioglitazone or a salt thereof by using a sweetener and at least two flavors. Here, as the “sweetener”, “fragrance” and “pioglitazone or a salt thereof”, those exemplified in the oral preparation of the present invention described above can be used.
The amount of the sweetener used is about 0.1 to about 200 parts by weight, preferably about 0.1 to about 50 parts by weight, more preferably about 0.2 to about 5 parts, per 100 parts by weight of pioglitazone and a salt thereof. Parts by weight.
In another preferred embodiment, the amount of sweetener used is about 0.5 to about 40 parts by weight, preferably about 0.5 to about 12 parts by weight, more preferably about 100 parts by weight of pioglitazone and its salts. 0.5 to about 4 parts by weight.
The amount of the fragrance used is about 0.05 to about 10 parts by weight, preferably about 0.05 to about 1 part by weight, per 100 parts by weight of pioglitazone and a salt thereof.
In another preferred embodiment, the amount of the fragrance used is about 0.08 to about 1 part by weight, preferably about 0.08 to about 0.5 part by weight, per 100 parts by weight of pioglitazone and a salt thereof.
By the above-mentioned method, for example, in the above-mentioned “oral preparation containing pioglitazone or a salt thereof” such as the oral preparation of the present invention, the unpleasant taste of pioglitazone or a salt thereof can be remarkably suppressed.

  In the present invention, the effect of suppressing unpleasant taste of pioglitazone or a salt thereof can be evaluated by, for example, visual analog scale (VAS) described in Test Example 1 described later. In the VAS evaluation of the overall taste after tablet disintegration (overall taste), if either the minimum value or the median value (especially the median value) is high, it should be judged that an unpleasant taste suppression effect has been obtained. Can do. In addition, in the VAS evaluation, when the median is high and the range (distribution) between the minimum and maximum values is narrow, it is determined that an unpleasant taste suppression effect is universally obtained for the entire subject. Can do.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto.
In addition, aspartame, magnesium stearate, hydroxypropylcellulose, lactose, carmellose calcium, crospovidone and the like used in the following examples and comparative examples are Japanese Pharmacopoeia 16th revision or pharmaceutical additive standard 2003 compliant products Was used.

Example 1
1.653 g of pioglitazone hydrochloride, 10.71 g of Rudy Flash (trade name, BASF Japan Ltd.), 0.063 g of aspartame (Ajinomoto Co., Inc.), 0.006 g of yogurt-flavored flavor (Ogawa Fragrance Co., Ltd.) ) Weigh each 0.006g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, and add 0.063 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.). Shake 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Example 2
Pioglitazone hydrochloride (1.983 g), Rudy Flash (trade name, BASF Japan Ltd.) 12.852 g, Aspartame (Ajinomoto Co., Inc.) 0.075 g, Vanilla-flavored flavor [Vanillin (Merck KGaA)] 0.007 g and Strawberry-flavored flavor (Firmenich) ) Weigh each 0.007g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, and add 0.075 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.). Shake 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 1
Weigh each 1.653 g of pioglitazone hydrochloride, 10.71 g of Rudyflash (trade name, BASF Japan Ltd.), 0.063 g of aspartame (Ajinomoto Co., Inc.) and 0.013 g of yogurt-flavored flavor (Ogawa Fragrance Co., Ltd.). 270 mm × 180 mm) and mixed while shaking 50 times by hand. Further, 0.063 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.) was added, and the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 2
Weigh each 1.653 g of pioglitazone hydrochloride, 10.71 g of Rudyflash (trade name, BASF Japan Ltd.), 0.063 g of aspartame (Ajinomoto Co., Inc.) and 0.013 g of blueberry flavored fragrance (Takasago Fragrance Co., Ltd.). 270 mm × 180 mm) and mixed while shaking 50 times by hand. Further, 0.063 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.) was added, and the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 3
Weigh 1.983 g of pioglitazone hydrochloride, Rudyflash (trade name, BASF Japan Ltd.) 12.852 g, 0.075 g of aspartame (Ajinomoto Co., Inc.) and 0.015 g of vanilla-flavored fragrance [Vanillin (Merck KGaA)] Put in a plastic bag (270 mm x 180 mm) and mix by shaking 50 times by hand, then add 0.075 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.) and shake 30 times in the same manner to obtain a mixed powder. . 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 4
Weigh 1.983 g of pioglitazone hydrochloride, 12.852 g of Rudyflash (trade name, BASF Japan Ltd.), 0.075 g of aspartame (Ajinomoto Co., Inc.) and 0.015 g of strawberry flavor (Firmenich), respectively, and weigh polyethylene bags (270 mm × 180 mm) and mixed while shaking 50 times by hand, 0.075 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.) was further added, and the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 5
Pioglitazone hydrochloride (1.983 g) and Rudyflash (trade name, BASF Japan Ltd.) (12.942 g) are weighed, placed in a polyethylene bag (270 mm x 180 mm), mixed by shaking 50 times by hand, and then magnesium stearate. (Wako Pure Chemical Industries, Ltd.) 0.075 g was added, and the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Test example 1
This study was conducted after obtaining written consent from 8 to 10 healthy adults. Subjects included each tablet in their mouth, disintegrated in the mouth, spit out the disintegrated tablet 1 minute after putting it in the mouth, and immediately after that, by visual analog scale (VAS) with a maximum value of 100 mm for overall taste evaluated. After completion of the VAS evaluation, the oral cavity was washed. Evaluation of each tablet was spaced 15 minutes apart.

  As shown in Table 1, in the oral preparation of the present invention, the minimum value of VAS evaluation was higher than that of the comparative example, and the median was also higher. That is, the unpleasant taste of pioglitazone hydrochloride was remarkably improved by mixing the sweetener and the two flavors.

Test example 2
As a result of measuring the disintegration time in the oral cavity of the tablets obtained in Example 1 (in healthy adults, one tablet was included in the mouth, left to disintegrate without chewing and disintegrated), 20 seconds (n = Average value of 8).

Test example 3
This study was conducted after obtaining written consent from 28 healthy adults. Subjects included each tablet in their mouth, disintegrated in the mouth, spit out the disintegrated tablet 1 minute after putting it in the mouth, and immediately after that, by visual analog scale (VAS) with a maximum value of 100 mm for overall taste evaluated. After completion of the VAS evaluation, the oral cavity was washed. Evaluation of each tablet was spaced 15 minutes apart.

  As shown in Table 2, in the oral preparation of the present invention, the minimum value of VAS evaluation was higher than that of the comparative example, and the median was also higher. That is, the unpleasant taste of pioglitazone hydrochloride was remarkably improved by mixing the sweetener and the two flavors.

Test example 4
As a result of measuring the disintegration time in the oral cavity of the tablet obtained in Example 2 (in a healthy adult, 1 tablet is included in the mouth, left to disintegrate without chewing and disintegrates), 25 seconds (n = Average value of 28).

Reference example 1
Hydroxypropyl cellulose (3900 g) was dissolved in purified water (61.10 L) to prepare a binding solution I. After mixing pioglitazone hydrochloride (19840 g), lactose (45800 g) and carmellose calcium (2160 g) uniformly in a fluidized bed granulator / dryer (WSG-60, Pauleck Co., Ltd.), the binding liquid I (30000 g) is sprayed. The mixture was granulated and then dried to obtain a granulated powder. Part of the obtained granulated powder was pulverized with a 1.5 mmφ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.

Example 3
Size adjusted powder I obtained in Reference Example I 5.8 g, Rudy Flash (trade name, BASF Japan Co., Ltd.) 5.9875 g, Crospovidone 0.625 g, Aspartame (Ajinomoto Co., Inc.) 0.0625 g, Yogurt flavored fragrance (Ogawa Fragrance Stock Company) 0.00625g and Blueberry flavored fragrance (Takasago Fragrance Co., Ltd.) 0.00625g were weighed, placed in a polyethylene bag (270 mm x 180 mm), mixed by shaking 50 times, and then magnesium stearate ( Wako Pure Chemical Industries, Ltd.) was added (0.0125 g), and the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Example 4
5.8 g of the sized powder I obtained in Reference Example 1, 5.9875 g of Rudy Flash (trade name, BASF Japan Ltd.), 0.625 g of crospovidone, 0.0625 g of Aspartame (Ajinomoto Co., Inc.), a vanilla-flavored fragrance [Merck KGaA)] 0.00625g and Strawberry flavored fragrance (Firmenich) 0.00625g were weighed, put in a polyethylene bag (270 mm x 180 mm) and mixed by shaking 50 times by hand, and then magnesium stearate ( Wako Pure Chemical Industries, Ltd.) was added (0.0125 g), and the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Example 5
The sized powder I obtained in Reference Example 1 5.8 g, Rudy Flash (trade name, BASF Japan Ltd.) 5.9875 g, Crospovidone 0.625 g, Aspartame (Ajinomoto Co., Inc.) 0.0625 g, Banana flavored fragrance (Takasago Incense Stock) Company) 0.00625g and Grapefruit flavored fragrance (Ogawa Fragrance Co., Ltd.) 0.00625g each weighed, placed in a polyethylene bag (270 mm x 180 mm), shaken 50 times by hand, and mixed with magnesium stearate ( Wako Pure Chemical Industries, Ltd.) was added (0.0125 g), and the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 6
The sized powder I obtained in Reference Example I 5.8 g, Rudy Flash (trade name, BASF Japan Ltd.) 5.9875 g, Crospovidone 0.625 g, Aspartame (Ajinomoto Co.) 0.00625 g, Yogurt flavored fragrance (Ogawa Fragrance Stock Company) Weigh each 0.0125g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, and add 0.0125 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.). The mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 7
The sized powder I5.8g obtained in Reference Example 1, Rudy Flash (trade name, BASF Japan Ltd.) 5.9875g, Crospovidone 0.625g, Aspartame (Ajinomoto Co.) 0.00625g, Blueberry flavored fragrance (Takasago flavor stock Company) Weigh each 0.0125g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, and add 0.0125 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.). The mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 8
5.8 g of the sized powder I obtained in Reference Example 1, 5.9875 g of Rudyflash (trade name, BASF Japan Ltd.), 0.625 g of crospovidone, 0.00625 g of Aspartame (Ajinomoto Co., Inc.), a vanilla-flavored fragrance [Merck KGaA))] Weigh each 0.0125g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, and then add 0.0125 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.) Similarly, the mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 9
The sized powder I obtained in Reference Example 1 5.8 g, Rudy Flash (trade name, BASF Japan Ltd.) 5.9875 g, Crospovidone 0.625 g, Aspartame (Ajinomoto Co.) 0.00625 g, Strawberry flavor (Firmenich) Weigh each 0.0125g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, add 0.0125 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.), and add 30 By shaking, a mixed powder was obtained. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 10
The sized powder I obtained in Reference Example 1 5.8 g, Rudy Flash (trade name, BASF Japan Ltd.) 5.9875 g, Crospovidone 0.625 g, Aspartame (Ajinomoto Co.) 0.00625 g, Banana flavored fragrance (Takasago Fragrance Stock Company) Weigh each 0.0125g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, and add 0.0125 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.). The mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 11
The sized powder I obtained in Reference Example I 5.8 g, Rudy Flash (trade name, BASF Japan Ltd.) 5.9875 g, Crospovidone 0.625 g, Aspartame (Ajinomoto Co.) 0.00625 g, Grapefruit-flavored flavor (Ogawa flavor stock) Company) Weigh each 0.0125g, put it in a polyethylene bag (270 mm x 180 mm), mix by shaking 50 times by hand, and add 0.0125 g of magnesium stearate (Wako Pure Chemical Industries, Ltd.). The mixture was shaken 30 times to obtain a mixed powder. 250 mg of the obtained mixed powder was precisely weighed and compression molded using a single tableting machine (type: HANDTAB200, Ichihashi Seiki Co., Ltd.) (round tablet having a diameter of 9 mm and a thickness of about 4.3 mm).

Test Example 5
This study was conducted after obtaining written consent from 10 healthy adults. Subjects included each tablet in their mouth, disintegrated in the mouth, spit out the disintegrated tablet 1 minute after putting it in the mouth, and immediately after that, by visual analog scale (VAS) with a maximum value of 100 mm for overall taste evaluated. After completion of the VAS evaluation, the oral cavity was washed. Evaluation of each tablet was spaced 15 minutes apart.

  As shown in Table 3, in the oral preparation of the present invention, the minimum value and / or median value of VAS evaluation was higher than that of the comparative example. That is, the unpleasant taste of pioglitazone hydrochloride was remarkably improved by mixing the sweetener and the two flavors.

Test Example 6
As a result of measuring the disintegration time in the oral cavity of the tablets obtained in Examples 3, 4, and 5 (in healthy adults, 1 tablet was included in the mouth, left to disintegrate without chewing, and the time until disintegration), 19.8 Seconds, 19.4 seconds, and 19.8 seconds (all are average values of n = 10).

Since the unpleasant taste of pioglitazone and its salts is sufficiently concealed and is very easy to take, the oral preparation of the present invention is useful as a pharmaceutical with high patient compliance. Moreover, the oral preparation of the present invention can be easily produced by combining pioglitazone or a salt thereof, a sweetener and at least two flavors.
Further, when the oral preparation of the present invention is an intraoral rapidly disintegrating solid preparation, the intraoral rapidly disintegrating solid preparation is sufficiently concealed by the unpleasant taste of pioglitazone or a salt thereof, and has an excellent oral cavity Because of its disintegrating property, it is extremely useful as a pharmaceutical with high compliance for patients such as patients who have difficulty in swallowing drugs, elderly people, and pediatric patients.

  This application is based on a patent application No. 2012-042675 filed in Japan (filing date: February 29, 2012), the contents of which are incorporated in full herein.

Claims (13)

  An oral preparation containing pioglitazone or a salt thereof, a sweetener and at least two flavors.   The agent according to claim 1, wherein the sweetener is aspartame.   The agent of Claim 1 whose 2 types of fragrance | flavors are the fragrance | flavor which improves the aftertaste and the fragrance | flavor which give a first impression in the oral cavity.   The agent of Claim 3 whose fragrance | flavor which gives a 1st impression is a fragrance | flavor of citrus flavor or a fruit flavor.   The agent according to claim 3, wherein the flavor improving the aftertaste is a banana flavored flavor, a grape flavored flavor, an apple flavored flavor, a mint flavored flavor, a bins flavored flavor or a milk flavored flavor.   The two kinds of fragrances are two kinds of fragrances selected from citrus flavors, fruit flavors, mint flavors, bins flavors, and milk flavors. 1. The agent according to 1.   The agent according to claim 1, wherein the two fragrances are a vanilla-flavored fragrance and a strawberry-flavored fragrance.   The agent according to claim 1, wherein the two flavors are a yogurt-flavored flavor and a blueberry-flavored flavor.   The agent according to claim 1, which is a tablet.   The agent according to claim 9, wherein the tablet is an orally disintegrating tablet.   The agent according to claim 1, comprising about 0.1 to about 5 parts by weight of a sweetener and a total of about 0.01 to about 1 part by weight of a fragrance per 100 parts by weight of the oral preparation.   A method for suppressing an unpleasant taste of pioglitazone or a salt thereof by using a sweetener and at least two flavors.   A method for producing an oral preparation that suppresses an unpleasant taste of pioglitazone or a salt thereof, comprising a step of mixing pioglitazone or a salt thereof with a sweetener and at least two flavors.