TW201340998A - Oral preparation - Google Patents

Abstract

The present invention provides an oral preparation sufficiently masking the unpleasant taste of pioglitazone and a salt thereof, especially a solid preparation. The present invention provides an oral preparation containing pioglitazone or a salt thereof, a sweetener and at least two flavorings, and a method for inhibiting the unpleasant taste of pioglitazon and a salt thereof by using sweetener and at least two flavorings.

Description

Oral preparation

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

Pioglitazone and its salts have an unpleasant taste for people who generally have a taste.

As a preparation for concealing an unpleasant taste such as pioglitazone or a salt thereof, in particular, an unpleasant taste of a pharmaceutical ingredient having a bitter taste, the following preparations are known.

1) A solid preparation containing an alkaline pharmaceutical ingredient having an unpleasant taste, 2) a saccharide, 3) a polyanionic polymer, 4) a flavoring agent, and 5) carboxymethylcellulose (see Patent Document 1).

A solid preparation containing particles in which a core particle containing an excipient is 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).

[Advanced technical literature]

[Patent Literature]

[Patent Document 1] International Publication No. 02/30400

[Patent Document 2] International Publication No. 2007/126136

[Patent Document 3] International Publication No. 2007/136129

In order to improve the compliance of patients, it is expected to develop an oral preparation (especially a solid preparation) which sufficiently hides the unpleasant taste of pioglitazone and its salt. In particular, the orally disintegrating preparation is taken in a short time for disintegration in the oral cavity, and it is considered that the unpleasant taste of pioglitazone and its salt is sufficiently concealed, and it is easier to take it as long as it exhibits a dietary sensation such as food.

The present inventors have found that the formulation of pioglitazone and its salt having an unpleasant taste has found that the unpleasant taste of pioglitazone or a salt thereof can be obtained by using pioglitazone or a salt thereof in combination with a sweetener and at least two kinds of perfumes. A fully concealed oral preparation. According to the findings of the present inventors, it has been confirmed that when one type of fragrance is used, the preparation still has an unpleasant taste after the preparation is disintegrated in the oral cavity, but unexpectedly, if two kinds of fragrances are used, even if the preparation is disintegrated, It is also possible to release the long-lasting unpleasant taste (which can improve the aftertaste in the mouth), thus completing the present invention. That is, the present invention is as follows.

[1] An oral preparation containing the pioglitazone or a salt thereof, a sweetener, and at least two flavors, wherein the sweetener is aspartame (aspartame). [3] The oral preparation according to the above [1] or [2] wherein the two kinds of fragrances are a fragrance for giving a first impression in the oral cavity and a fragrance for improving the aftertaste; [4] as described above [3] The oral preparation according to the above [3], wherein the oral administration agent is a citrus-flavored flavor or a flavor of a fruit-based flavor; [4] The oral preparation according to the above [3], wherein the first impression of the fragrance is a strawberry flavor or a blueberry flavor; [5] The oral preparation according to any one of the above [3], wherein the flavor-improving flavor is a banana flavor flavor, a grape flavor flavor, an apple flavor flavor, The medicinal agent of any one of the above-mentioned [3], [4], [4A], and [4B], wherein the oral agent of any one of the above-mentioned [3], [4], [4A], and [4B], , the improvement The oral medicinal agent of any one of the above-mentioned [3], [4], [4A], and [4B], wherein The scented scented scented scented scented scented scented scented scented scented scented scented scented scented scented scented scented scented scented scented scented Fruity flavor, mint The above-mentioned oral preparation of the above-mentioned [1] or [2], wherein the two kinds of flavors are selected from strawberry flavors, and the flavors of the flavors of the flavors of the flavors of the flavors of the flavors of the flavors of the flavors of the flavors of the present invention. The oral medicinal agent of any one of the above-mentioned [1] to [6], wherein the The medicinal agent is a yoghurt-flavored flavoring agent and a blueberry flavoring agent, wherein the two flavoring agents are yoghurt-flavored flavorings and blueberries. The oral preparation according to any one of the above-mentioned [1], wherein the oral preparation is a tablet; [10] orally as described in the above [9] The oral preparation according to any one of the above-mentioned [1] to [10] wherein the tablet contains about 100 parts by weight of the oral preparation. 0.1 to about 5 parts by weight of the sweetener and a total of about 0.01 to about 1 part by weight of the fragrance; [12] a method for inhibiting the unpleasant taste of pioglitazone or a salt thereof by using a sweetener and at least 2 kinds of perfumes ;[13] a pyr Pioglitazone or a salt thereof of the unpleasant taste by suppressing the production method of the oral preparations, comprising the pioglitazone or a salt thereof, the step of mixing the sweetener and at least two fragrance; and the like.

The oral preparation of the present invention is very easy to take because the unpleasant taste of pioglitazone and its salt is sufficiently concealed, and it is useful as a medicine for taking a highly compliant medicine. Further, the oral preparation of the present invention can be easily produced by combining pioglitazone or a salt thereof, a sweetener, and at least two kinds of perfumes.

Further, when the oral preparation of the present invention is an orally disintegrating solid preparation, the orally disintegrating solid preparation is excellent in concealing the unpleasant taste of pioglitazone or a salt thereof, and has superior oral disintegration It is very useful for patients with dysphagia, elderly patients, or pediatric patients to take compliant medicines. Further, since the oral preparation of the present invention contains at least two types of fragrances, the patient's residual feeling of ingestion can prevent the patient from forgetting to take it and actively contribute to the treatment of the disease.

In the "pioglitazone or a salt thereof" used in the oral preparation of the present invention, the salt of pioglitazone is a pharmacologically acceptable salt, and examples thereof include a salt with an inorganic acid, a salt with an organic acid, and an acidic amine. a salt formed by a base acid or the like.

Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

Preferred examples of the salt with an 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, and benzenesulfonic acid. a salt formed by p-toluenesulfonic acid or the like.

Preferable examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid and the like.

Pioglitazone or a salt thereof is more preferably pioglitazone hydrochloride.

Pioglitazone or a salt thereof may also be diluted with a diluent which is usually used in medical, food, and the like.

The median diameter of pioglitazone or a salt thereof is preferably from 0.5 to 25 μm, more preferably from 1 to 21 μm, still more preferably from 1 to 10 μm. By using these median diameters, an oral agent excellent in dissolution properties of pioglitazone or a salt thereof can be obtained.

Further, the above preferred median diameter is suitable as a raw material for producing the oral preparation of the present invention [including a pulverized product obtained by pulverization in the process of producing a oral preparation, together with a shaped yoke (for example, crystalline cellulose) The pruniglitone or its salt used in the mixed pulverized product obtained by pulverization. That is, the median diameter of pioglitazone or a salt thereof may be changed by the process of preserving the oral preparation of the present invention or the oral preparation after the production, or may be changed by agglutination of pioglitazone or a salt thereof. Further, the pulverization is carried out using a preparation machine such as a mortar, a jet mill, a hammer mill, a mill sieve (P-3; manufactured by Showa Chemical Machinery Co., Ltd.).

In the present specification, the median diameter means a particle diameter of 50% each of the coarse particles and the fine particles in the weight distribution or the number distribution. The median particle size is determined, for example, by a laser refractive particle size distribution measuring device (for example, SYNPATEC HELOS-RODOS particle size distribution measuring device).

The pioglitazone or a salt thereof having the above-mentioned expected median diameter preferably has a degree of dispersion of "the particles of 0.1 μm or less are 10% or less of the total amount and the particles of 1000 μm or more are 10% or less of the total amount".

The content of pioglitazone or its salt in the oral preparation of the present invention is based on oral preparation The dosage form, the amount of administration, and the like are different, and 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, per 100 parts by weight of the solid oral preparation. 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, per 100 parts by weight of the liquid oral preparation.

The "sweetener" used in the oral preparation of the present invention may, for example, arabinose, galactose, xylose, glucose, sorbose, fructose, rhamnose, ribose, heterologous sugar, N-ethinylglucosamine, etc. Monosaccharides; disaccharides such as iso-trehalose, sucrose, trehalose, new trehalose, palatinose, maltose, melibiose, lactulose, lactose; α-cyclodextrin, β-ring Dextrin, isomalto-oligosaccharide (isomaltose, isomaltotriose, panose, etc.), oligo-N-ethyl glucosamine, galactosyl sucrose, galactosyl lactose, galactose Pyranosyl (β 1-3) galactopyranosyl (β 1-4) glucopyranose, galactopyranosyl (β 1-3) glucopyranose, galactopyranosyl (β 1-6) galactopyranosyl (β 1-4) glucopyranose, xylooligosaccharide (xyloose, xylobiose, etc.), gentian oligosaccharide (gentiobiose, gentian three) Sugar, gentiantetraose, etc.), stachyose, dextran oligosaccharide, Aspergillus niger oligosaccharide (black koji saccharide, etc.), palatinose oligosaccharide, palatinose syrup, fucose, fruit Oligosaccharides (cane triose, nytose, etc.), fructofuranosyl nystose Polydextrose, maltosyl β-cyclodextrin, malto-oligosaccharide (maltotriose, tetrasaccharide, pentasaccharide, hexose, heptasaccharide, etc.), raffinose, glucosyl sucrose (Coupling sugar) (trade name)), oligosaccharides such as soybean oligosaccharides, invert sugar, and leech; isomalt, erythritol, xylitol, glycerin, sorbitol, palatinit, maltitol, malt Tetrasaccharide, maltotriitol, mannitol, lactitol, Reduction of isomalto-oligosaccharides, reduction of xylooligosaccharides, reduction of gentian oligosaccharides, reduction of maltose leeches, reduction of maltose and other sugar alcohols; α-glucosyltransferase treatment of stevia, aspartame (trade name), acesulfame Acesulfame potassium, Alitame, licorice extract (glycyrrhizic acid), triammonium glycyrrhizinate, tripotassium glycyrrhizinate, trisodium glycyrrhizinate, diammonium glycyrrhizinate, dipotassium glycyrrhizinate, disodium glycyrrhizinate , Curculin, saccharin, sodium saccharin, cyclohexyl sulfonic acid, sucralose, stevia extract, stevia powder, dulcin, thaumatin (Soma Sweet), Tianling tea extract, naphthalene and raspberry extract, neotame, neohesperidin dihydrochalcone and other high-intensity sweeteners; and honey. These sweeteners may be used alone or in combination of two or more. It is preferably a high-sweetness sweetener such as aspartame (trade name), potassium sulfamate, sucralose, thaumatin, sodium saccharin, dipotassium glycyrrhizinate, and more preferably aspartame ( Product name).

The content of the sweetener in the oral preparation of the present invention varies depending on the kind of the sweetener, etc., and is from about 0.1 to about 5 parts by weight, preferably from about 0.1 to about 1.5 parts by weight, per 100 parts by weight of the solid oral preparation. More preferably, it is about 0.1 to 0.5 parts by weight. It is preferably from about 0.01 to about 100 parts by weight, preferably from about 0.1 to about 70 parts by weight, per 100 parts by weight of the liquid oral preparation.

Further, the amount of the sweetener used in the oral preparation of the present invention is from about 0.1 to about 200 parts by weight, preferably from about 0.1 to about 50 parts by weight, more preferably from about 0.2 to about 100 parts by weight to 100 parts by weight of pioglitazone and its salt. 5 parts by weight.

In a preferred form, the amount of sweetener used in the oral preparation of the present invention It is preferably from about 0.5 to about 40 parts by weight, more preferably from about 0.5 to about 12 parts by weight, most preferably from about 0.5 to about 4 parts by weight, per 100 parts by weight of the pioglitazone and its salt.

The "perfume" used in the oral preparation of the present invention includes all the fragrances contained in the specifications of the pharmaceutical additive and the food additive. Specifically, citrus flavors such as orange (orange extract, orange oil), lemon (lemon oil), lime, grapefruit, citrus, tangerine, etc.; apple, banana, cherry, grape, melon, peach, pineapple ( Pine oil, plum, raspberry, strawberry, blueberry and other fruit flavors; vanilla (vanilla flavor), coffee, cocoa, chocolate and other bean flavors; mint (menthol oil), spearmint (spoon oil) and other mint Spices; peppercorns such as Jamaican pepper, cinnamon (cinnamon powder, cinnamon oil), nutmeg; nutty flavors such as almonds, peanuts, and walnuts; milk flavors such as milk, butter, butter, cheese, and yoghurt; other vegetables , cereals, seaweed and other spices. Further, the perfume used in the present invention may be a composition or a monomer. For example, the monomer may be exemplified by menthol, menthone, vanillin, ethyl vanillin, cinnamic acid, piperonal, d-borneol, maltol, ethyl maltol, camphor, methyl anthranilate, cinnamon Methyl ester, cinnamyl ethanol, methyl N-methylamine anthranilate, methyl β-naphthyl ethyl ketone, limonene, linalool, allyl isothiocyanate, and the like.

Any of water-soluble flavors, oil-soluble flavors, emulsified flavors, and powder flavors can be used for the shape of the fragrance.

The various flavors disclosed above may be used in combination of two or more kinds. Preferably, a combination of a first impression fragrance and a fragrance for improving the aftertaste is provided in the oral cavity.

The "perfume that gives the first impression in the mouth" is a fragrance that is strongly felt in the oral cavity after oral administration, and is also called a top note in the field of perfume. Preferred examples of the flavor include the above-mentioned citrus-flavored flavors, fruit-flavored flavors, and the like. Better flavors for fruit flavors, especially strawberry flavors and blueberry flavors.

"Aroma for improving the aftertaste" is an unpleasant taste in the oral cavity even after about 30 seconds to about 60 seconds after oral administration (the disintegration time in the oral cavity when the ingot is disintegrated in the oral cavity) Spices, also known as the last note in the field of spices. Preferred examples of the flavor include the above-mentioned banana, grape, apple and other fruit flavor flavors, mint flavor flavors, bean flavor flavors, and dairy flavor flavors. Better vanilla flavored spices and yoghurt flavored spices. The vanilla flavored flavor may also be a monomer such as vanillin or ethyl vanillin.

Further preferred examples thereof include two or more kinds of flavors selected from the group consisting of citrus flavors and fruit flavors (preferably strawberry flavors, blueberry flavors, banana flavors, grape flavors, An apple-flavored flavor, a mint-flavored flavor, a bean-flavored flavor, and a milk-flavored flavor, two flavors (preferably two flavors). More preferably, it is a combination of a strawberry-flavored flavor, a blueberry-flavored flavor, a vanilla-flavored flavor, and a yoghurt-flavored flavor. It is preferably a combination of a vanilla flavored spice and a strawberry flavored spice or a yoghurt flavored spice. Fragrant with blueberry flavor Combination of materials. Among the oral preparations of the present invention, at least two kinds of fragrances are preferably a combination of a yoghurt-flavored flavor and a blueberry-flavored flavor.

The content of the fragrance in the oral preparation of the present invention varies depending on the type of the fragrance, etc., and is from about 0.01 to about 1 part by weight, preferably from about 0.01 to about 0.5 part by weight, more preferably about 100 parts by weight to the solid oral preparation. From 0.01 to about 0.1 parts by weight. It is preferably from 0.001 to about 1 part by weight, more preferably from about 0.05 to about 0.5 part by weight, per 100 parts by weight of the liquid oral preparation.

Further, the amount of the fragrance in the oral preparation of the present invention is from about 0.05 to about 10 parts by weight, preferably from about 0.05 to about 1 part by weight, per 100 parts by weight of the pioglitazone and the salt thereof.

In a preferred form, the amount of perfume used in the oral preparation of the present invention is from about 0.08 to about 1 part by weight, preferably from about 0.08 to about 0.5 part by weight, per 100 parts by weight of the pioglitazone and its salt.

The oral preparation of the present invention may contain an additive conventionally used in the field of formulation technology. Examples of the additive include an excipient, a disintegrator, a binder, a lubricant, a colorant, a pH adjuster, a surfactant, a stabilizer, a flavoring agent, a fluidizing agent, a liquid medium, and the like. These additives are used in amounts conventionally used in the art of formulation. Further, these additives may be used in combination of two or more kinds in an appropriate ratio.

The excipients may, for example, be saccharides, crystalline cellulose; corn starch, potato starch, flour starch, rice starch, partially gelatinized starch, alpha-degraded starch Starch such as powder and porous starch; anhydrous calcium phosphate, precipitated calcium carbonate, calcium citrate, powdered cellulose.

Here, examples of the saccharide include granulated sugar, starch sugar, lactose, honey, and sugar alcohol. These saccharides may be used in combination of two or more kinds in an appropriate ratio.

Examples of the granulated sugar include white sugar, glucosyl sucrose [conjugated sugar (trade name)], fructooligosaccharide, and palatinose.

Examples of the starch sugar include glucose, maltose, whitefly, leeches, and fructose.

Examples of the lactose include lactose, heterologous lactose (lactulose), and reduced lactose (lactitol).

Honey can be exemplified by various kinds of honey which are usually eaten.

The sugar alcohol may, for example, be sorbitol, D-mannitol, maltitol, reduced starch saccharide, xylitol, reduced palatinose, erythritol or trehalose.

The sugars are preferably sugar alcohols 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, per 100 parts by weight of the oral preparation.

The above saccharide may also be added as an excipient, and together with the sweetener of the present invention, has the effect of concealing the unpleasant taste of pioglitazone or a salt thereof.

Examples of the crystalline cellulose include, for example, Ceolus KG801, KG802, PH101, PH102, PH301, PH302, PH-F20, RC-A591NF (trade name, manufactured by Asahi Kasei Chemicals Co., Ltd.), and also includes microcrystallization. Cellulose. By using crystalline cellulose, an oral agent having a moderate formulation strength and excellent disintegration in the oral cavity can be obtained.

The content of the crystalline cellulose in the oral preparation is, for example, 0.1 to 50 parts by weight, preferably 0.5 to 40 parts by weight, more preferably 1 to 25 parts by weight, per 100 parts by weight of the oral preparation.

The disintegrant may, for example, be carboxymethylcellulose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone [preferably coleone ( Kollidon) CL, CL-M, CL-F, CL-SF (trade name, manufactured by BASF Japan Co., Ltd.); Polyplasdone XL, XL-10, INF-10 (trade name, ISP) Manufactured by a Japanese company, low-substituted hydroxypropyl cellulose [preferably LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32, LH33 (trade name, Shin-Etsu Chemical Co., Ltd.) ], hydroxypropyl starch. Among them, it is preferably crospovidone, more preferably crotonone CL, CL-F, CL-SF (trade name, manufactured by BASF Japan Co., Ltd.); crospovidone XL (trade name, ISP Japan) (share) company manufacturing). By using crospovidone, an oral agent excellent in oral disintegration properties 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, per 100 parts by weight of the oral preparation.

The binding agent may, for example, be hydroxypropylcellulose [preferably HPC-SSL, SL, L (trade name, manufactured by Nippon Soda Co., Ltd.)], hydroxypropylmethylcellulose, povidone (polyvinylpyrrole) Pyridone), gum arabic powder. Among them, hydroxypropylcellulose is preferred.

The lubricant may, for example, be magnesium stearate, calcium stearate, talc, sucrose fatty acid ester or sodium fumarate. Among them, magnesium stearate is preferred.

Examples of the coloring agent include food yellow No. 5 (sunset yellow, the same as the edible yellow No. 6 in the United States), edible red No. 2, edible blue No. 2, etc., food coloring, edible lake pigment, yellow ferric oxide, and trioxide. Two iron, bismuth trioxide.

The pH adjuster may, for example, be a citrate, a phosphate, a carbonate, a tartrate, a fumarate, an acetate or an amine acid salt.

The surfactant may, for example, be sodium lauryl sulfate, polysorbate 80, polyethylene oxide (160) polypropylene oxide (30) ethylene glycol, polyethylene oxide (196) polypropylene oxide (67). Ethylene glycol, polyethylene oxide hardened castor oil 60.

Examples of the stabilizers include sodium ascorbate, tocopherol, sodium edetate, nicotinic acid amide, cyclodextrin, and alkaline earth metal salts (for example, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, and citric acid). Magnesium, magnesium aluminate), butylated hydroxyanisole.

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

The fluidizing agent may, for example, be light anhydrous citric acid or aqueous cerium oxide. Here, the light anhydrous citric acid may be an aqueous cerium oxide (SiO ₂ .nH ₂ O) (n represents an integer) as a main component, and specific examples thereof include Sylysia 320 (product). Name, manufactured by Fujiya Chemical Co., Ltd., Fumed Silica 200 (trade name, manufactured by Ayase Co., Ltd.).

Examples of the liquid medium include water, ethanol, polyethylene glycol 400, propylene glycol, glycerin, and concentrated glycerin.

When the various additives described above are in a solid form, the particle diameter of the additive is preferably 500 μm or less in order to prevent a rough feeling in the oral cavity.

The dosage form of the oral preparation of the present invention can be exemplified by a solid preparation and a liquid preparation. The solid preparation may, for example, be a tablet, a capsule, a powder, a granule or a buccal tablet. Among them, a tablet is preferred.

The shape of the solid preparation is not particularly limited, and may be any of a circular shape, a capsule shape, a doughnut shape, a long oval shape, and the like.

The solid preparation may be coated with a coating agent, or may be provided with a marking for the identification, a character, and a secant for division.

Here, examples of the coating base include a sugar-based base, a water-soluble film coating base, an enteric film coating base, and a transferable film coating base.

The sugar-based base may be used in combination with one or more kinds selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like.

The water-soluble film coating base may, for example, be hydroxypropylcellulose or hydroxypropyl. Cellulose-based polymer compound such as methyl cellulose, hydroxyethyl cellulose or methyl hydroxyethyl cellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer -E [Eudragit E (trade name)], a synthetic polymer compound such as polyvinylpyrrolidone; a polysaccharide such as polytriglucose or the like.

Examples of the enteric film-coated base include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and phthalic acid fiber. Cellulose-based polymer compound such as phenol; methacrylic acid copolymer-L [Yuraji L (trade name)], methacrylic acid copolymer-LD [Yuraji L-30D55 (trade name)], methacrylic acid An acrylic polymer compound such as copolymer-S [Yuraji S (trade name)]; a natural product such as shellac or the like.

Examples of the retanning film-coating base include a cellulose-based polymer compound such as ethyl cellulose or cellulose acetate; an aminoalkyl methacrylate copolymer-RS [Yuraji RS (trade name)], An acrylic polymer compound such as an ethyl acrylate/methyl methacrylate copolymer suspension [Yuraji NE (trade name)].

The above-mentioned coating base may be used in combination of two or more kinds thereof in an appropriate ratio. Further, a coating additive can also be used at the time of coating.

Examples of the coating additive include opacifiers and/or colorants such as titanium oxide, talc, and ferric oxide; and plasticizers such as polyethylene glycol, triethyl citrate, castor oil, and polysorbate; Organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid, and the like.

The liquid preparation can be exemplified by a liquid preparation, a suspension, a syrup, and the like.

The oral preparation of the present invention can be produced by a method conventionally used in the art of preparation 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 kinds of perfumes with the above various additives, and if necessary, by compression molding.

Here, mixing (including granulation, drying, granulation, etc.) using, for example, a V-type mixer, a drum mixer, a high-speed stirring granulator (FM-VG-10; manufactured by Barrec), a universal machine (manufactured by Handan Iron Works), Flow Granulation Dryer (LAB-1, FD-3S, FD-3SN; manufactured by Barrec), Box Vacuum Dryer (made by Nanmu Machinery Co., Ltd.), Screen Mill (P-3; manufactured by Showa Chemical Machinery Co., Ltd.) and other preparation machinery.

For compression molding, for example, a single-shot tablet machine (manufactured by Kikusui Seisakusho Co., Ltd.), a drum type ingot machine (manufactured by Kikusui Seisakusho Co., Ltd.), an autograph (manufactured by Shimadzu Corporation), and the like are usually used, and the pressure is usually 2 to 35 kN/cm ² . Ingots.

The oral preparation of the present invention is preferably an orally disintegrating solid preparation (preferably an orally disintegrating ingot). Here, the oral disintegration property is a property in which the solid preparation disintegrates in a short period of time (for example, 5 to 90 seconds). The oral disintegration time of the orally disintegrating solid preparation (the time for the saliva of the healthy adult man and the woman's mouth to completely disintegrate the solid preparation) varies depending on the dosage form, size, and the like of the solid preparation, for example, the solid preparation is an ingot In the case of a dose, it is usually from about 5 to 90 seconds, preferably from about 5 to 60 seconds, more preferably from about 5 to 30 seconds.

The orally disintegrating solid preparation is a disease for dysphagia of a medicament It is useful for the prevention and treatment of various diseases in children, elderly people, and children who are easy to take, or which are usually safe for adults.

The hardness of the oral preparation of the present invention (measured by a tablet hardness meter) is preferably from about 15 to 200 N, more preferably from about 15 to 150 N.

Preferred examples of the oral preparation of the present invention include the following preparation (1), preparation (2), preparation (3), and preparation (4).

Formulation (1):

An oral preparation containing pioglitazone or a salt thereof, a sweetener, and at least two kinds of fragrances is an oral preparation containing a coated particle containing a granule of the pioglitazone or a salt thereof.

That is, the preparation (1) is an oral preparation of the present invention, and the pioglitazone or a salt thereof contained in the oral preparation is present in a state of "coating a granule containing pioglitazone or a salt thereof with a granule" The preparation, sweetener and flavor may be contained in any one of the inside or the outside of the coated particle.

Here, the saccharide in the "coated granules containing granules of pioglitazone or a salt thereof" is exemplified using the above saccharides. Among them, lactose is preferred. The content of the saccharide is, for example, 5 to 80 parts by weight, preferably 10 to 50 parts by weight, per 100 parts by weight of the preparation (1).

Regarding the preparation (1), "particles containing pioglitazone or a salt thereof" (abbreviated as "particles of the present invention" in the present specification) can be carried out by using pioglitazone or a salt thereof, a sweetener and at least two kinds of perfumes, if necessary together with the additives. Manufactured by granulation. Further, after granulation, if necessary, drying, granulation, and the like may be performed.

The additive is preferably an excipient (e.g., crystalline cellulose, lactose), a disintegrant (e.g., carboxymethylcellulose calcium), a binder (e.g., hydroxypropylcellulose), a colorant (e.g., yellow ferric oxide). )Wait.

The content of the pioglitazone or a salt thereof in the present invention is preferably from 0.1 to 60 parts by weight, more preferably from 1 to 40 parts by weight, per 100 parts by weight of the particles of the present invention.

The content of the granules of the present invention in the preparation (1) is, for example, 1 to 100 parts by weight, preferably 5 to 90 parts by weight, per 100 parts by weight of the preparation (1).

The "coated particles containing the granules containing the pioglitazone or a salt thereof" (the present invention is simply referred to as "the coated particles of the present invention") contained in the preparation (1) can be obtained by using the particles of the present invention, if necessary The additive is produced by coating with a sugar.

The additive is preferably a binder (for example, hydroxypropylcellulose), a colorant (for example, yellow ferric oxide), or the like.

The coated particles of the present invention are not only the coated particles of the present invention which are coated with the sugars completely (100% of the total surface area of the particles of the present invention), but also the particles of the present invention with a sugar moiety (for example, the total surface area of the particles of the present invention) 30% or more, preferably 50% or more) coated coated particles.

The content of the coated granules of the present invention in the preparation (1) is, for example, 1 to 100 parts by weight, preferably 5 to 90 parts by weight, per 100 parts by weight of the preparation (1).

The preparation (1) can be produced by mixing the coated granules of the present invention, if necessary, with an additive, and if necessary, by compression molding.

The additive is preferably an excipient (for example, crystalline cellulose and mannitol), a disintegrant (such as crospovidone), a lubricant (such as magnesium stearate), a coloring agent (such as yellow ferric oxide). Wait.

The preparation (1) is preferably pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two kinds of perfumes, excipients (preferably crystalline cellulose, lactose). And mannitol), a disintegrant (preferably carboxymethylcellulose calcium and crospovidone), a binder (preferably hydroxypropylcellulose), a saccharide (preferably lactose), and a lubricant ( It is preferably formed of magnesium stearate, and may also contain a solid preparation of a coloring agent (preferably yellow ferric oxide).

Formulation (2):

Including pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two perfumes, excipients (preferably crystalline cellulose and mannitol), disintegrants (preferably crospovidone), a binding agent (preferably hydroxypropylcellulose), a saccharide (preferably lactose), and a lubricant (preferably magnesium stearate), and may also contain coloring A solid preparation of a reagent (preferably yellow ferric oxide).

The preparation (2) is preferably pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two kinds of perfumes, excipients (preferably crystalline cellulose and mannose). a sugar alcohol), a disintegrant (preferably crospovidone), a binder (preferably hydroxypropylcellulose), a saccharide (preferably lactose), and a lubricant (preferably magnesium stearate), A solid preparation (preferably a tablet) obtained by mixing a coloring agent (preferably yellow ferric oxide) and subjecting the obtained mixture to compression molding (preferably, tableting). The colorant can be omitted in the solid preparation.

Formulation (3):

Including pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two kinds of perfumes, excipients (preferably Rudifulra (trade name, BASF Japan ( (manufactured by the company), a mixture of mannitol, crospovidone, vinyl acetate polymer, mannitol, crystalline cellulose, lactose) and a lubricant (preferably magnesium stearate), A solid preparation containing a disintegrant (preferably crospovidone) and/or a colorant (preferably yellow ferric oxide).

The preparation (3) is preferably pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two kinds of perfumes, excipients (preferably Rudifulra) (trade name, manufactured by BASF Japan Co., Ltd.), mannitol, crystalline cellulose, lactose, and a lubricant (preferably magnesium stearate) and a coloring agent (preferably yellow ferric oxide). A solid preparation (preferably a tablet) obtained by compression-molding the obtained mixture. The colorant can be omitted in the solid preparation.

Formulation (4):

An oral preparation containing pioglitazone or a salt thereof, a sweetener, and at least two flavors, which comprises containing pioglitazone or a salt thereof, a saccharide (preferably lactose), a disintegrant (preferably carboxymethylcellulose calcium), and An oral agent for the particles of the binder.

Further, the content of the saccharide (preferably lactose) is, for example, 5 to 80 parts by weight, preferably 10 to 50 parts by weight, per 100 parts by weight of the preparation (4). Further, 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, per 100 parts by weight of the preparation (4).

Formulation (4) may contain a sweetener (for example, aspartame) and at least 2 flavors, and may further contain an excipient, in addition to "particles containing pioglitazone or a salt thereof, a saccharide, a disintegrant, and a binder" (Preferred are Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), a disintegrating agent (preferably crospovidone), and a lubricant (preferably magnesium stearate).

The preparation (4) can be produced, for example, according to the methods described in Examples 3 to 5 to be described later.

The preparation (4) preferably comprises pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), a sweetener (preferably aspartame), at least two flavors, lactose, calcium carboxymethylcellulose, and a binder (Comparative) It is preferably hydroxypropylcellulose), an excipient (preferably Rudifulra (trade name, manufactured by BASF Japan)), a disintegrant (preferably crospovidone), and a lubricant. (preferably magnesium stearate), and may also contain a solid preparation of a colorant (preferably yellow ferric oxide).

In the present specification, the "particles" are obtained by granulating a raw material such as a powder, a lump, a solution or a molten liquid by a wet granulation method, a dry granulation method or a heating granulation method, and have almost uniform shapes and sizes. Particles. The "granules" may, for example, be powders, fine particles and granules, and these preferably have the particle size specified in the fourteenth revision of the Japanese Pharmacopoeia.

That is, in the particle size test of the preparation, the particle size of the powder is preferably "the whole amount passes through the No. 18 (850 μm) sieve, and the residue remaining on the No. 30 (500 μm) sieve is less than 5% of the total amount", and the particle size of the fine particles is preferably the above. In the particle size of the powder, "passing through the No. 200 (75μm) sieve is less than 10% of the total amount, and the particle size is better. In order to pass the No. 10 (1700 μm) sieve, the amount of the sieve remaining on the No. 12 (1400 μm) sieve is less than 5% of the total amount, and the sieve passing through the No. 42 (355 μm) sieve is less than 15% of the total amount.

The average particle diameter of "particles" in the present specification is usually from 44 to 2000 μm, preferably from 75 to 1000 μm. Here, the average particle diameter means a value measured by, for example, a laser refractive particle size distribution measuring apparatus (for example, SYNPATEC HELOS-RODOS particle size distribution measuring apparatus).

The "particles" in the present specification may also change its shape or size in order to obtain a formulation process of the oral preparation of the present invention (for example, a step of compression molding).

In the oral preparation of the present invention, the preparation (3) containing the coated granules is excellent in storage stability, and no change in the quality of the preparation over time (for example, discoloration; change over time in the dissolution of pioglitazone or its salt) is observed. Superior effect, and thus better.

Further, the preparation (3) exerts a superior effect of disintegrating in the oral cavity for a short period of time, and the unpleasant taste of pioglitazone and its salt is sufficiently concealed.

Further, the preparation (3) has excellent manufacturability such as ruthenium/ruthenium which does not adhere to the tableting, and is suitable for production on an industrial scale.

Further, the preparation (3) exhibits superior characteristics of the dissolution behavior of pioglitazone or a salt thereof between the respective preparations (for example, between a plurality of tablets).

In the oral preparation of the present invention, the preparation (4) is more excellent in the dissolution property of pioglitazone or a salt thereof, in addition to the superior effect as the preparation (3).

The oral preparation of the present invention can be administered orally and safely to mammals (e.g., mice, mice, rabbits, cats, dogs, cows, horses, monkeys, humans).

The administration amount of the oral preparation of the present invention varies depending on the subject to be administered, the severity of the disease, and the like, and may be selected within the range of the effective amount of pioglitazone or its salt to be administered. Specifically, for example, an adult (body weight: 60 kg) per person pioglitazone is usually 7.5 to 60 mg/day, preferably 15 to 60 mg/day, and the amount can be administered in two to three divided doses per day.

When the oral preparation of the present invention is an orally disintegrating solid preparation (preferably an orally disintegrating ingot), the solid preparation may be anhydrous or may be administered together with an appropriate amount of water. Further, the solid preparation can also be administered without disintegration in the oral cavity.

The oral preparation of the present invention can be used for diabetes (for example, type 1 diabetes, type 2 diabetes, gestational diabetes), hyperlipidemia (such as hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, high fat after meals) Hemorrhage], impaired glucose tolerance (IGT (Impaired Glucose Tolerance)], diabetic comorbidities [eg neurological disorders, nephropathy, retinopathy, cataracts, macrovascular disorders, osteopenia, diabetic high-impregnation, lethargy, infection Symptoms (eg, respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, dry mouth, decreased hearing, cerebrovascular disorders, peripheral blood disorders, etc., obesity Symptoms, osteoporosis, dyscrasia (eg cancerous dyscrasia, tuberculous dyscrasia, diabetic dyscrasia, blood disease dyscrasia, endocrine disease dyscrasia, infectious dyscrasia or Acquired dyscrasia caused by acquired immunodeficiency syndrome, fatty liver, high blood Pressure, polycystic ovarian syndrome, kidney disease (eg diabetic nephropathy, spheroid nephritis, spheroid sclerosis, renal syndrome, hypertensive sclerosing sclerotherapy, end stage renal disease), muscular dystrophy, myocardial infarction, squint Symptoms, cerebrovascular disorders (eg cerebral infarction, stroke), insulin resistance syndrome, X syndrome, Dysmetabolic syndrome, hyperinsulinemia, hyperinsulinemia, perceptual disorders, tumors (eg leukemia, breast cancer) , prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases [eg Alzheimer's disease, chronic rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, surgery Inflammation after inflammation, swelling of swelling, neuralgia, throat inflammation, cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis], visceral obesity syndrome , atherosclerosis (eg atherosclerosis), multiple sclerosis, sepsis, dryness, Parkinson's disease, atopic Prevention of skin diseases go far. A therapeutic agent; or prevention of two episodes of the above various diseases (for example, prevention of two episodes of cardiovascular events such as myocardial infarction) and inhibition of progression (for example, inhibition of progress from glucose intolerance to diabetes and 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, simply referred to as a combined component). In this case, there is no limitation on the administration period of the components in combination with pioglitazone or a salt thereof, and the administration of the components may be carried out simultaneously or in a time difference. Further, the oral preparation and the concomitant ingredient of the present invention can be administered as a preparation containing two or more kinds of the respective active ingredients, or as a single preparation containing both active ingredients. Give

The amount of the ingredient to be administered can be appropriately selected based on the amount of the clinical use.

Thus, by using the concomitant component, 1) the effect of enhancing the action of the oral or combined component of the present invention (the multiplication effect of the action of the agent), and 2) the effect of reducing the administration amount of the oral or combined component of the present invention (lowering) The effect of the dose of the drug when compared with the single administration), 3) the superior effect of reducing the effect of the secondary action of the oral or combined component of the present invention.

The components for use in the oral preparation of the present invention include, for example, "diabetes therapeutic drugs" (except pioglitazone or a salt thereof), "diabetic complication drugs", "anti-obesity drugs", "hypertension drugs", and "high fats". "Therapeutic drugs for blood", "anti-arteriosclerosis drugs", "antithrombotic drugs", "diuretics", "arthritis treatment drugs", "anti-anxiety drugs", "anti-depression drugs", "psychotic agents", "sleep introduction medicine" and the like. The active ingredients may be low molecular compounds, or may be high molecular proteins, polypeptides, antibodies or vaccines. Further, the active ingredient may be used in combination of two or more kinds in an appropriate ratio.

The above-mentioned "diabetes therapeutic agent" may, for example, be an insulin preparation (for example, an animal insulin preparation extracted from the pancreas of cattle and pigs; a human insulin preparation synthesized by genetic engineering using coliform bacteria, yeast; zinc zinc; fish insulin zinc; Segments or derivatives of insulin (eg INS-1), oral insulin preparations), insulin resistance improving agents (eg rosiglitazone or its salts (preferably maleate), Mehtag Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone, Aleglitazar, Chiglitazar, Lohberg Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, WO2007/013694, WO2007/018314, WO2008/093639 or WO2008/099794), α-glucosidase inhibitors ( For example, Voglibose, Acarbose, Miglitol, Emiglitate, biguanides (such as Metformin, Buformin) or Salt (such as hydrochloride, fumarate, succinate), pancreas A secretion promoting agent (such as a sulfonium urea agent (such as Tolbutamide, Glibenclamide, Gliclazide, Chlorpropamide, Tolazamide) ), Acetohexamide, Glyclopyramide, Glimepiride, Glipizide, Glybuzole, Repaglinide, Nateglinide, Mitiglinide or its calcium salt hydrate, dipeptidyl peptidase IV inhibitor (eg Alogliptin or its salt (preferably benzoate) ), Vildagliptin, sitagliptin, Saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA- 6666, TS-021, KRP-104, 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-di Sideoxy-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile or a salt thereof), a β 3 agonist (eg N-5984), a GPR40 agonist (eg WO2004/041266, WO2004/106276) WO2005/063729, WO2005/063725, WO2005/087710, WO2005/095338, WO2007/ 013689 or a compound described in WO2008/001931), a GLP-1 receptor agonist (eg, GLP-1, GLP-1 MR agent, Liraglutide, Exenatide, AVE-0010, BIM-) 51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131, Albiglutide, auxin agonist (eg Pramlintide), tyramine phosphate Acid phosphatase inhibitors (such as sodium vanadate), sugar stimulating inhibitors (such as glycophosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, FBPase inhibitors), SGLT2 ( Sodium gluconate cotransporter 2) inhibitors (eg dapagliflozin, AVE2268, TS-033, YM543, TA-7284, Reggliflozin, ASP1941), SGLT1 inhibitors , 11 β-hydroxysteroid dehydrogenase inhibitors (eg BVT-3498, INCB-13739), adiponectin or its agonist, IKK inhibitor (eg AS-2868), leptin (Leptin) resistance Sexually improving drugs, Somatostatin receptor activators, glucokinase activators (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 (e.g., PSN821), FGF21, FGF analog, and the like.

The above "diabetic complication therapeutic agent" may, for example, be an aldose reductase inhibitor (for example, Torerestat, Epalrestat, Zopolresrar, Fidaresstat, CT-112, Rennie Ranirestat (AS-3201), Lidorestat, neurotrophic factor and its sputum addition (eg NGF, NT-3, BDNF, WO01/14372) neurotrophin production/secretion promoter (eg 4-(4-Chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), as described in WO2004/039365 Compound), PKC inhibitors (eg Ruboxistaurin mesylate), AGE inhibitors (eg ALT946, N-benzoquinone methylthiazole bromide (ALT766), EXO-226, pyridamine (Pyridorin) ), pyridoxamine, GABA receptor activators (eg Gabapentine, Pregabalin, Serotonin, Noradrenaline Resorbing Inhibitory Drugs (eg Dulosi) Duloxetine), sodium channel inhibitors (eg Lacosamide), reactive oxygen scavengers (eg Thioctic acid), cerebral vasodilators (eg Tiapride, Mexi Mexiletine, Somatostatin receptor activator (eg BIM23190), Apoptosis signal-regulating kinase 1 (ASK-) 1) Inhibiting drugs and the like.

The above "anti-obesity agent" may, for example, be a monoamine reuptake inhibitor (for example, Phentermine, Sibutramine, Mazindol, Fluoxetine, Tesofensine). Tesofensine), serotonin 2C receptor agonist (eg, Lorcaserin, serotonin 6 receptor antagonist, histamine H3 receptor, GABA regulator (eg Topiramate, Neuropeptide Y) Antagonists (eg, Velneperit, Cannabinoids receptor antagonists (eg, Rimonabant, Taranaban), ghrelin (Ghrelin) antagonists, ghrelin receptor antagonists, ghrelin inhibitors, opioid receptor antagonists (eg GSK-1521498), orexin receptor antagonists, melanocortin (Melanocortin) 4 receptor agonist, 11 β-hydroxysteroid dehydrogenase inhibitor (eg AZD-4017), pancreatic lipolytic enzyme inhibitor (eg Orlistat, Cetilistat) , β 3 agonist (eg N-5984), dimercaptoglycerol thiol transferase 1 (DGAT1) inhibitor, acetylated CoA carboxylase (ACC) inhibitor, stearic acid CoA desaturase inhibitor, microparticles Triglyceride transfer protein inhibitor (eg R-256918), sodium gluconate co-transport vector inhibitor (eg JNJ-28431754, repaglin), NF κ inhibitor (eg HE-3286), PPAR agonist (eg GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (eg sodium vanadate, Trodusquemin), GPR119 activators (eg PSN-821), glucokinase activators (eg AZD) -1656), leptin, leptin derivatives (eg, recombinant human leptin (Metreleptin)), CNTF (hairy neurotrophic factor), BDNF (derived from the brain Nutritional factors), cholecystokinin agonists, glucagon-like peptide-1 (GLP-1) preparations (eg, animal GLP-1 preparations extracted from the pancreas of cattle and pigs; using coliforms, yeast, genetic engineering) Synthetic human GLP-1 preparation; segment or derivative of GLP-1 (eg Exenatide, Liraglutide), fragrant gum preparation (eg pramlintide, AC-2307) , a neuropeptide Y agonist (eg, PYY3-36, a derivative of PYY3-36, Obinepitide, TM-30339, TM-30335), an Oxyntomodulin preparation: an FGF21 preparation (eg, Animal FGF21 preparation extracted from the pancreas of cattle and pigs; using coliform, yeast, genetic engineering A human FGF21 preparation; a segment or derivative of FGF21), an ingestion inhibitor (for example, P-57), and the like.

The above "hypertension therapeutic agent" may, for example, be an angiotensin converting enzyme inhibitor (for example, Captopril, Enalapril, Delapril, etc.), angiotensin II antagonist Agents (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, Telmisartan, Irbesartan, Tasosartan, Olmesartan, Olmesartan medoxomil, Azilsartan, Aceh Salicylate (Azilsartan medoxomil, etc.), calcium ion antagonists (such as Manidipine, Nifedipine, Amlodipine, Efonidipine, Nicardipine) , cilnidipine, etc., β-blockers (eg Metoprolol, Atenolol, Propranolol, Carvedilol, frequency Pindolol, etc., Clonidine, and the like.

The above-mentioned "hyperlipidemic therapeutic agent" may, for example, be an HMG-CoA reducing enzyme inhibitor (for example, Pravastatin, Simvastatin, lovastatin, atorvastatin, or atorvastatin). Fluvastatin, Rosuvastatin, pitavastatin or such salts (eg, sodium salts, calcium salts), squalene synthetase inhibitors (eg, as described in WO 97/10224) a compound such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropane) -7-chloro-5-(2,3-dimethoxyphenyl)-2-oxooxy-1,2,3,5-tetrahydro-4,1-benzoxanthene-3 -yl]ethinyl]piperidine-4-acetic acid), Fibrate-based compounds (eg, Bezafibrate, Clofibrate, Simfibrate, Klebebit) (Clinofibrate), anion exchange resin (for example, Cholestyramine, Probucol, niacin-based agents (such as Nicomol, Nicotine pentoxide) , Niaspan), ethyl icosapentate, plant nestol (eg Soysterol, γ-Oryzanol), cholesterol absorption inhibitor (eg Jerky), CETP inhibitors (such as Dalcipeib, Anacetrapib), omega-3 fatty acid preparations (e.g., omega-3-acid ethyl ester 90), and the like.

Examples of the above-mentioned "anti-arteriosclerosis drug" include an acetaminophen coenzyme A cholesterol acetyltransferase (ACAT) inhibitor (for example, K-604) and an LpPLA2 inhibitor (for example, Darapladib, Lirapadi, etc.). ), FLAP inhibitors (eg, AM103, AM803, etc.), 5L0 inhibitors (eg, VIA-2291, etc.), sPLA2 inhibitors (eg, A-002), apoAI mimetic peptides (eg, D4F, etc.), HDL preparations (eg, CSL-111, etc.).

Examples of the above "antithrombotic agent" include heparin (for example, heparin sodium, heparin calcium, Enoxaparin sodium, Dalteparin sodium), Warfarin (e.g., Oxygen potassium), and antithrombin. Drugs (eg Aragatroban, Dabigatran), FXa inhibitors (eg Rivaroxaban, Apixaban, Edoxaban, YM150) WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823 or WO2005/113504 Compounds, thrombolytic drugs (eg, Urokinase, Tisokinase, Alteplase, Nateplase, Monteplase, and indomethacin) (Pamiteplase)), platelet aggregation inhibitor (such as Ticlopidine hydrochloride, Clopidogrel, Prasugrel, E5555, SHC530348, Cilostazol, 20 carbon Ethyl icosapentate, Beraprost sodium, Sarpogrelate hydrochloride, and the like.

Examples of the above-mentioned "diuretic" include xanthine derivatives (for example, sodium salicylate theobromine, calcium salicyl theobromine, etc.), and thiazine-based preparations (for example, thiazide, cyclopentazine, and trichloromethane). , hydrochlorothiazide, hydrofluorothiazide, benzyl hydrochlorothiazide, pentafluorothiazide, poly 5-thiazine, methyl chlorothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamine pterin) (Triamterene), etc., a carbonic acid dehydratase inhibitor (such as etetazolamide), a chlorpheniramine-based preparation (such as chlorthalidone, mefruside, indapa) Indapamide, etc., Azosemide, Isosorbide, Ethacrynic acid, Piretanide, Bumetanide, Furosemide Wait.

The above-mentioned "arthritis therapeutic drug" may, for example, be Ibuprofen or the like.

The above-mentioned "anti-anther drugs" may, for example, be Alprazolam, Etizolam, Oxazolam, and Tandospirone. (Tandospirone), Cloxazolam, Clotiazepam, Clorazepate dipotassium, Chlordiazepoxide, Diazepam, Fludiszepam ), Flutazolam, Flunitrazepam, Prazepam, Bromazepam, Mexazolam, Medazepam, Chlorofluoro Ethyl loflazepate, Lorazepam, etc.

The above-mentioned "anti-depressant" may, for example, be a tricyclic antidepressant (for example, Imipramine, Trimipramine, Clomipramine, Amitriptyline, and A. Nortriptyline, Amoxapine, Lofepramine, Dosulepin, Desipramine, Tetracyclic antidepressants (eg Maprotiline) (Maprotiline), Mianserin (Mianserin), selective serotonin reuptake inhibitors (such as Fluoxetine, Fluvoxamine, Paroxetine, She Qu Sertraline, escitalopram, serotonin/norepinephrine reuptake inhibitors (eg Milnacipran, Duloxetine, Venlafaxine), Trazodone, mirtazapine, Moclobemide, and the like.

Examples of the above-mentioned "psychotic drugs" include stereotyped antipsychotics (e.g., Clocapramine, Chlorpromazine, Phenobarbital, Sultopride, Tiberium). (Tiapride), Thioridazine, Piperperone, Floropipamide, Moperone, Oxypertine, Capitamin ( Carpipramine), Spiperone, Sulpiride, Zotepine, Timiberone, Nemonapride, Haloperidol, and sputum Pimozide), Prochlorperazine, Propericiazine, Bromperidol, Perphenazine, Fluphenazine maleate, Mizoribine ), Levomepromazine, non-type antipsychotics (eg Perospirone, Olanzapine, Quetiapine, Risperidone, Chloronitrogen) Clozapine, Aripiprazole, Ziprasidone, Blondanserin, Lurasidone, and the like.

Examples of the above "sleep-introducing drug" include Rameteon, GABA-based sleep drugs (for example, Brotizolam, Estazolam, Flurazepam, and Nitrodamine). Nitrazepam), Triazolam, Flunitrazepam, Lormetazepam, Rilmazafone, Quatzepam, Zopiclone, Eszro Eszopiclone, Zolpidem, Zaleplon, Indiplon, Gabaculine; non-GABA sleep drugs (eg Eplivanserin) ), Flibanserin, diphenhydramine (Diphenhydramine), Trazodone, Doxepin, and the like.

Among the above-mentioned combined components, a diterpene agent (preferably metformin or a salt thereof (preferably a hydrochloride)), an insulin secretion-promoting drug (preferably a sulfonate-urea agent, a non-sulfonate-urea-based insulin secretion-promoting drug) is preferred. More preferably, it is Glimepiride, Nateglinide, Mitiglinide or its calcium salt hydrate, α-glucosidase inhibitor (preferably voglibide) Voglibose, dipeptidyl peptidase IV inhibitor (preferably Alogliptin or its salt (preferably benzoate), 2-[[6-[(3R)-3-) Amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-di-oxy-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile or a salt thereof (preferably succinate), an HMG-CoA reductase inhibitor (preferably simvastatin, etc.), and a combination of two or more components is preferably a biguanide (preferably) It is a combination of metformin) and an insulin secretion promoting drug (preferably a sulfonium urea agent, more preferably Glimepiride).

The present invention provides a method of using a sweetener and at least two flavors to inhibit the unpleasant taste of pioglitazone or a salt thereof. Here, "sweetener", "perfume" and "pioglitazone or a salt thereof" are exemplified using the above-mentioned oral preparation of the present invention.

The sweetener is used in an amount of from about 0.1 to about 200 parts by weight, preferably from about 0.1 to about 50 parts by weight, more preferably from about 0.2 to about 5 parts by weight, per 100 parts by weight of the pioglitazone and its salt.

In a preferred form, the amount of sweetener used is for pioglitazone and The salt thereof is from about 0.5 to about 40 parts by weight, preferably from about 0.5 to about 12 parts by weight, more preferably from about 0.5 to about 4 parts by weight.

The amount of perfume used is from about 0.05 to about 10 parts by weight, preferably from about 0.05 to about 1 part by weight, per 100 parts by weight of pioglitazone and its salt.

In a preferred form, the perfume is used in an amount of from about 0.08 to about 1 part by weight, preferably from about 0.08 to about 0.5 part by weight, per 100 parts by weight of the pioglitazone and its salt.

According to the above method, for example, "the oral preparation containing pioglitazone or a salt thereof" of the above-described oral preparation of the present invention can remarkably suppress the unpleasant taste of pioglitazone or a salt thereof.

In the present invention, the inhibitory effect of the unpleasant taste of pioglitazone or a salt thereof can be evaluated by, for example, a visual analog scale (VAS) described in Test Example 1 or the like described later. When the VAS evaluation of the total taste (total taste) after the disintegration of the tablet is high, any of the minimum value or the central value (especially the central value) is high, the effect of suppressing the unpleasant taste can be judged. Further, in the VAS evaluation, when the central value is high and the range (distribution) from the minimum value to the maximum value is narrow, it is possible to determine the effect of suppressing the unpleasant taste for all of the subjects.

[Examples]

Hereinafter, the present invention will be described in more detail by way of Reference Examples, Examples, Comparative Examples and Test Examples. However, the present invention is not limited to the examples.

Further, aspartame and stearin used in the following examples and comparative examples Additives such as magnesium sulfate, hydroxypropylcellulose, lactose, carboxymethylcellulose calcium, and crospovidone are used in the Japanese Pharmacopoeia No. 16 revision or pharmaceutical additive specification 2003.

Example 1

Weighed 1.653 g of pioglitazone hydrochloride, 10.71 g of Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 0.063 g of aspartame (manufactured by Ajinomoto Co., Ltd.), and a yoghurt-flavored flavor ( 0.006 g and a blueberry-flavored flavor (manufactured by Takasago Co., Ltd.), 0.006 g, placed in a polyethylene bag (270 mm × 180 mm), and mixed by hand for 50 times. In addition, 0.063 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Example 2

Weighed 1.183 g of pioglitazone hydrochloride, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.) 12.852 g, aspartame (manufactured by Ajinomoto Co., Ltd.) 0.075 g, vanilla flavored spices [vanilla] Aldehyde (manufactured by Merck KGaA)] 0.007 g and a strawberry-flavored flavor (manufactured by Firmenich) 0.007 g, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and added Magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was 0.075 g, and the same vibration was carried out 30 times to obtain a mixed powder. fine 250 mg of the mixed powder obtained by the scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot tableting machine (form; HANDTAB 200, manufactured by Shima Seiki Co., Ltd.).

Comparative example 1

Weighed 1.653 g of pioglitazone hydrochloride, 10.71 g of Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 0.063 g of aspartame (manufactured by Ajinomoto Co., Ltd.), and a flavor of yoghurt flavor ( 0.013 g, manufactured by Ogawa Spice Co., Ltd., placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and added magnesium stearate (Wako Pure Chemical Industries Co., Ltd.) The company made 0.063 g, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Comparative example 2

Weighed 1.653 g of pioglitazone hydrochloride, 10.71 g of Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 0.063 g of aspartame (manufactured by Ajinomoto Co., Ltd.) and a flavor of blueberry flavor (high sand) 0.013 g, manufactured by Perfume Co., Ltd., placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and added magnesium stearate (Wako Pure Chemical Industries Co., Ltd.) Manufactured 0.063 g, the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the precision scale, using a single-shot tableting machine (form; HANDTAB200, manufactured by City Bridge Seiki Co., Ltd.), compression molding (diameter 9 Mm, round ingots approximately 4.3 mm thick).

Comparative example 3

Weighed 1.183 g of pioglitazone hydrochloride, 12.852 g of Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 0.075 g of aspartame (manufactured by Ajinomoto Co., Ltd.), and vanilla flavor as a spice. 0.015 g of the fragrance [vanillin (Merck KGaA)], placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and added magnesium stearate (Wako Pure Chemical Industries ( The company) manufactured by 0.075 g, the same vibration 30 times, to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Comparative example 4

Each of them weighed 1.183 g of pioglitazone hydrochloride, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.) 12.852 g, aspartame (manufactured by Ajinomoto Co., Ltd.) 0.075 g and strawberry flavor (Firmenich) 0.015 g, manufactured by the company, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and added with magnesium stearate (manufactured by Wako Pure Chemical Industries Co., Ltd.) 0.075 g The same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Comparative Example 5

Weighed 1.183 g of pioglitazone hydrochloride and 12.942 g of Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), placed in a polyethylene bag (270 mm × 180 mm), and mixed by hand for 50 times. In addition, 0.075 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Test example 1

This test was conducted after obtaining consent from 8 to 10 healthy adults. The subject contained each tablet in the mouth to disintegrate in the mouth, and after discharging the tablet after 1 minute from the inlet, immediately after the discharge of the tablet, the total taste was based on the visual value of 100 mm. The visual analog scale (VAS) was evaluated. Wash the mouth after the VAS assessment is completed. Each tablet was evaluated for 15 minutes.

As shown in Table 1, the minimum value of the VAS evaluation of the oral preparation of the present invention was high as compared with the comparative example, and the central value was also high. That is, the sweetener and the two flavors are mixed to significantly improve the unpleasant taste of pioglitazone hydrochloride.

Test example 2

The oral disintegration time of the tablet obtained in Example 1 (in a healthy adult, one ingot was contained in the mouth, not crushed, and the disintegration time until disintegration was placed) was 20 seconds (n=8 average value).

Test Example 3

This test was conducted after obtaining consent from 28 healthy adults. The subject contained each tablet in the mouth to disintegrate in the mouth, and after discharging the tablet after 1 minute from the inlet, the taste of the total was based on a visual simulation of 100 mm as the maximum value. The visual analog scale (VAS) was evaluated. Wash the mouth after the VAS assessment is completed. Each tablet was evaluated for 15 minutes.

As shown in Table 2, the minimum value of the VAS evaluation of the oral preparation of the present invention was high as compared with the comparative example, and the central value was also high. That is, the sweetener and the two flavors are mixed to significantly improve the unpleasant taste of pioglitazone hydrochloride.

Test Example 4

The oral disintegration time of the tablet obtained in Example 2 (in a healthy adult, one ingot was contained in the mouth, not crushed, and the disintegration time until disintegration was placed) was 25 seconds (n=28 average value).

Reference example 1

Hydroxypropylcellulose (3900 g) was dissolved in purified water (61.10 L) to prepare a binding solution I. Pioglitazone hydrochloride (19840 g), lactose (45800 g) and calcium carboxymethylcellulose (2160 g) were uniformly mixed in a fluidized bed granulation dryer (WSG-60, manufactured by Leike Co., Ltd.) Binding solution I (30000 g) spray The granulation was carried out by misting, followed by drying to obtain a granulated powder. A part of the obtained granulated powder was pulverized by a crushing granulator (P-7S, manufactured by Showa Chemical Machinery Co., Ltd.) in a 1.5 mm φ punching sieve to obtain a granulated powder I.

Example 3

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( Co., Ltd.) 0.0625 g, yoghurt-flavored flavor (manufactured by Ogawa Spice Co., Ltd.) 0.00625 g and blueberry-flavored flavor (manufactured by Takasago Co., Ltd.) 0.00625 g, placed in a polyethylene bag (270) In the case of mm × 180 mm, the mixture was shaken by hand for 50 times, and 0.0125 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Example 4

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( Co., Ltd.) 0.0625 g, vanilla flavored spice (vanek aldehyde (Merck KGaA)) 0.00625 g and strawberry flavored spice (Firmenich) 0.00625 g, placed in a polyethylene bag (270 mm × 180 mm) , mixing by hand for 50 times, and adding magnesium stearate (manufactured by Wako Pure Chemical Industries Co., Ltd.) 0.0125 g, the same vibration 30 Once, a mixed powder was obtained. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Example 5

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( Co., Ltd.) 0.0625 g, banana-flavored flavor (manufactured by Takasago Co., Ltd.), 0.00625 g, and grape-flavored flavor (manufactured by Ogawa Spice Co., Ltd.) 0.00625 g, placed in a polyethylene bag (270) In the case of mm × 180 mm, the mixture was shaken by hand for 50 times, and 0.0125 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Comparative Example 6

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( (manufactured by the company) 0.00625 g, yoghurt-flavored flavor (manufactured by Ogawa Spice Co., Ltd.) 0.0125 g, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and Then, 0.0125 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. Mixed powder obtained by precision scale 250 mg, a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.) was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm).

Comparative Example 7

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( (manufactured by the company) 0.00625 g, blueberry-flavored flavor (manufactured by Takasago Co., Ltd.) 0.0125 g, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and 0.0125 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Comparative Example 8

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( Co., Ltd.) 0.00625 g, vanilla-flavored flavor [vanillin (manufactured by Merck KGaA)] 0.0125 g, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and mixed Then, 0.0125 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250mg of the mixed powder obtained by the fine scale, compressed and formed by a single-shot ingot machine (form; HANDTAB200, manufactured by Shiqiao Seiki Co., Ltd.) (diameter 9 mm, thickness 4.3 mm) Round ingot).

Comparative Example 9

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( (manufactured by the company) 0.00625 g, strawberry-flavored flavor (manufactured by Firmenich) 0.0125 g, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and added stearic acid Magnesium (manufactured by Wako Pure Chemical Industries, Ltd.) was 0.0125 g, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Comparative Example 10

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( (manufactured by the company) 0.00625 g, banana-flavored flavor (manufactured by Takasago Co., Ltd.) 0.0125 g, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and 0.0125 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Comparative Example 11

The whole powder I obtained in Reference Example 1 was weighed 5.8 g, Rudifulra (trade name, manufactured by BASF Japan Co., Ltd.), 5.9875 g, crospovidone 0.625 g, aspartame (Ajinomoto ( Co., Ltd.) 0.00625 g, grape fruit flavored spice (made by Ogawa Spice Co., Ltd.) 0.0125 g, placed in a polyethylene bag (270 mm × 180 mm), mixed by hand for 50 times, and mixed Then, 0.0125 g of magnesium stearate (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the same vibration was carried out 30 times to obtain a mixed powder. 250 mg of the mixed powder obtained by the weigh scale was compression-molded (a circular ingot having a diameter of 9 mm and a thickness of about 4.3 mm) using a single-shot ingot machine (form; HANDTAB 200, manufactured by City Bridge Seiki Co., Ltd.).

Test Example 5

This test was conducted after obtaining a consent form from 10 healthy adults. The subject contained each tablet in the mouth to disintegrate in the mouth, and after discharging the tablet after 1 minute from the inlet, the taste of the total was based on a visual simulation of 100 mm as the maximum value. The visual analog scale (VAS) was evaluated. Wash the mouth after the VAS assessment is completed. Each tablet was evaluated for 15 minutes.

As shown in Table 3, the minimum and/or central value of the VAS evaluation of the oral preparation of the present invention was high as compared with the comparative example. That is, the sweetener and the two flavors are mixed to significantly improve the unpleasant taste of pioglitazone hydrochloride.

Test Example 6

The oral disintegration time of the tablets obtained in Examples 3, 4, and 5 (in a healthy adult, one tablet was contained in the mouth, not crushed, and the disintegration time until disintegration was placed) was 19.8 seconds. 19.4 seconds, 19.8 seconds (both are the average of n=10).

[Industry use possibility]

The oral preparation of the present invention is very easy to take because the unpleasant taste of pioglitazone and its salt is sufficiently concealed, and it is useful as a medicine for taking a highly compliant medicine. Further, the oral preparation of the present invention can be easily produced by combining pioglitazone or a salt thereof, a sweetener, and at least two kinds of perfumes.

Further, when the oral preparation of the present invention is an orally disintegrating solid preparation, the orally disintegrating solid preparation is excellent in concealing the unpleasant taste of pioglitazone or a salt thereof, and has superior oral disintegration It is very useful for patients with dysphagia, elderly patients, or pediatric patients to take compliant medicines.

This patent application is based on Japanese Patent Application No. 2012-042675 (filed on Feb. 29, 2012), the entire contents of which are incorporated herein by reference.

Claims (13)

An oral preparation comprising pioglitazone or a salt thereof, a sweetener, and at least two flavors. The oral preparation according to claim 1, wherein the sweetener is aspartame. The oral preparation according to claim 1, wherein the two fragrances are a fragrance for giving a first impression in the oral cavity and a fragrance for improving the aftertaste. The oral preparation according to claim 3, wherein the first impression of the fragrance is a citrus flavor or a fruit flavor flavor. The oral preparation according to claim 3, wherein the fragrance for improving the aftertaste is a banana flavor flavor, a grape flavor flavor, an apple flavor flavor, a mint flavor flavor, a bean flavor flavor or milk. A flavored spice. The oral preparation according to claim 1, wherein the two flavors are selected from the group consisting of citrus flavor flavors, fruit flavor flavors, mint flavor flavors, bean flavor flavors, and dairy flavors. 2 kinds of spices of spices. The oral preparation according to claim 1, wherein the two flavors are a vanilla flavor flavor and a strawberry flavor flavor. The oral preparation according to claim 1, wherein the two flavors are a yoghurt-flavored flavor and a blueberry-flavored flavor. The oral preparation according to claim 1, wherein the oral preparation The agent is a tablet. The oral preparation according to claim 9, wherein the tablet is an orally disintegrating ingot. The oral preparation according to claim 1, wherein the adhesive comprises from about 0.1 to about 5 parts by weight of the sweetener and from about 0.01 to about 1 part by weight of the perfume relative to 100 parts by weight of the oral preparation. A method for inhibiting an unpleasant taste of pioglitazone or a salt thereof, which comprises inhibiting an unpleasant taste of pioglitazone or a salt thereof by using a sweetener and at least two kinds of flavors. A method for producing an oral preparation for inhibiting an unpleasant taste of pioglitazone or a salt thereof, comprising the step of mixing pioglitazone or a salt thereof, a sweetener, and at least two kinds of perfumes.