Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

• the present invention relates to an oral preparation containing pioglitazone or a salt thereof, a sweetener, and at least two kinds of flavors and having an unpleasant taste of pioglitazone or a salt thereof suppressed.
• 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.
• 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).
• the inventors of the present invention have studied the formulation of pioglitazone having an unpleasant taste and a salt thereof.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• a salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• 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 ⁇ m, more preferably 1 to 21 ⁇ m, particularly preferably 1 to 10 ⁇ m.
• an oral preparation excellent in the dissolution property of pioglitazone or a salt thereof can be obtained.
• the above-mentioned preferable median diameter is pulverized together with raw materials for producing the oral preparation of the present invention [pulverized product obtained by pulverization in the course of producing the oral preparation, excipient (eg, crystalline cellulose).
• the pulverization is carried out using a formulation machine such as a mortar, jet mill, hammer mill, screen mill (P-3; Showa Chemical Machinery Co., Ltd.).
• 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 particle size distribution analyzer (eg, SYNPATEC HELOS-RODOS particle size distribution analyzer).
• the degree of dispersion is preferably “particles of 0.1 ⁇ m or less are 10% or less of the total amount, and particles of 1000 ⁇ m 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.
• the “sweetener” used in the oral preparation of the present invention includes monosaccharides such as arabinose, galactose, xylose, glucose, sorbose, fructose, rhamnose, ribose, isomerized sugar, N-acetylglucosamine; isotrehalose, sucrose, trehalulose , Neotrehalulose, palatinose, maltose, melibiose, lactulose, lactose, and other disaccharides; ⁇ -cyclodextrin, ⁇ -cyclodextrin, isomaly oligosaccharides (isomaltose, isomaltotriose, panose, etc.), oligo-N-acetylglucosamine , Galactosyl sucrose, galactosyl lactose, galactopyranosyl ( ⁇ 1-3) galactopyranosyl ( ⁇ 1-4) glucopyranose,
• Oligosaccharides isomalitol, 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; ⁇ -glucosyltransferase-treated stevia, aspartame (trade name), acesulfame potassium, aritem, licorice extract (glycyrrhizin), triammonium glycyrrhizinate, tripotassium glycyrrhizinate, trisodium glycyrrhizinate, glycyrrhizic acid Diammonium, dipot
• sweeteners can be used alone or in any combination of two or more.
• 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 with respect to 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.
• 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 with respect to 100 parts by weight of pioglitazone and a salt thereof. More preferred is 12 parts by weight, and even more preferred is about 0.5 to about 4 parts by weight.
• citrus flavors such as orange (orange extract, orange oil), lemon (lemon oil), lime, grapefruit, mandarin, tangerine
• the fragrance used in the present invention may be a composition or a simple substance.
• menthol menthone, vanillin, ethyl vanillin, cinnamic acid, piperonal, d-borneol, maltol, ethyl maltol, camphor, methyl anthranilate, methyl cinnamate, cinnamic alcohol, methyl N-methylanthranilate, methyl ⁇ -naphthyl ketone, limonene, linalool, allyl isothiocyanate and the like can be exemplified.
• shape of the fragrance any of water-soluble fragrance, oil-soluble fragrance, emulsified fragrance, powdered fragrance and the like can be used.
• 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.
• fragrance 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
• flavors 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.
• 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, relative to 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 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.
• 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 conventionally used in the field of pharmaceutical technology.
• 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.
• excipient examples 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.
• 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.
• sugar include sucrose, glycosyl sucrose [coupling sugar (trade name)], fructooligosaccharide, and palatinose.
• starch sugar examples include glucose, maltose, powdered koji, starch syrup, and fructose.
• lactose examples include lactose, isomerized lactose (lactulose), and reduced lactose (lactitol).
• honey examples include various honeys that are generally used for food.
• sugar alcohol examples include sorbitol, D-mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, and trehalose.
• the sugars are preferably sugar alcohols and lactose, more preferably D-mannitol and lactose.
• the saccharide content 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.
• the crystalline cellulose include Theola KG801, KG802, PH101, PH102, PH301, PH302, PH-F20, RC-A591NF (trade name, Asahi Kasei Chemicals Corporation), and also 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, particularly preferably 1 to 25 parts by weight with respect to 100 parts by weight of the oral preparation.
• disintegrant examples include carboxymethylcellulose, carboxymethylcellulose calcium (carmellose calcium), carboxymethyl starch sodium, croscarmellose sodium, crospovidone [preferably, Kollidon CL, CL-M, CL-F, CL-SF (commercial product) Name, BASF Japan Ltd.); Polyplastidone XL, XL-10, INF-10 (trade name, ISP Japan Ltd.)], low substituted hydroxypropyl cellulose [preferably LH11, LH21, LH31, LH22, LH32 , LH20, LH30, LH32, LH33 (trade name, Shin-Etsu Chemical Co., Ltd.)], and hydroxypropyl starch.
• 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.
• 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.
• binder examples 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.
• the lubricant examples include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate. Of these, magnesium stearate is preferable.
• colorant examples 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.
• pH adjuster examples include citrate, phosphate, carbonate, tartrate, fumarate, acetate, and amino acid salt.
• surfactant examples 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.
• 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.
• corrigent examples include ascorbic acid, (anhydrous) citric acid, citric acid hydrate, tartaric acid, and malic acid.
• the fluidizing agent examples include light anhydrous silicic acid and hydrous silicon dioxide.
• 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.
• siO 2 .nH 2 O hydrous silicon dioxide
• the liquid medium examples include water, ethanol, macrogol 400, propylene glycol, glycerin, concentrated glycerin and the like.
• the particle diameter of the additive is preferably 500 ⁇ m 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.
• 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.
• 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.
• 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.
• 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.
• cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
• methacrylic acid copolymer L (Eudragit L (trade name)]
• acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)] and methacrylic
• 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)].
• 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.
• the coating additive examples 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.
• plasticizers such as polyethylene glycol, triethyl citrate, castor oil, and polysorbates
• citric acid tartaric acid, malic acid
• organic acids such as ascorbic acid.
• 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. .
• the mixing can be performed by, for example, a V-type mixer, a tumbler mixer, a high-speed stirring 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.
• a V-type mixer a tumbler mixer
• a high-speed stirring 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
• the compression molding is performed, for example, by using a single tablet machine (Kikusui Seisakusho), a rotary tableting machine (Kikusui Seisakusho), an autograph (Shimadzu Seisakusho), etc., and usually tableting 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).
• 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, 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 about 15 to 200 N, more preferably about 15 to 150 N.
• composition (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.
• 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).
• a granule containing pioglitazone or a salt thereof includes pioglitazone or a salt thereof, a sweetener, and at least two flavors.
• 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, 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 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, based on 100 parts by weight of the preparation (1).
• Coated granules in which granules containing pioglitazone or a salt thereof are coated with saccharides are particles of the present invention.
• the additive is preferably a binder (eg, hydroxypropylcellulose), a colorant (eg, yellow iron sesquioxide) and the like.
• 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.
• pioglitazone or a salt thereof preferably pioglitazone hydrochloride
• sweetener preferably aspartame
• at least two flavors preferably crystalline cellulose, lactose and mannitol
• disintegrant Preferably it consists of carboxymethylcellulose calcium and crospovidone
• a binder preferably hydroxypropylcellulose
• 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).
• sweetener preferably aspartame
• excipients preferably crystalline cellulose and mannitol
• disintegrant preferably crospovidone
• binder preferably Is a solid preparation comprising a hydroxypropyl cellulose
• saccharide preferably lactose
• a lubricant preferably magnesium stearate
• 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)
• sweetener preferably aspartame
• excipient preferably Rudiflash (trade name, BASF Japan Ltd. Mannitol, crospovidone, vinyl acetate polymer
• 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.
• 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).
• the content of the disintegrant preferably carboxymethylcellulose calcium
• 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.
• a sweetener preferably aspartame
• carboxymethylcellulose calcium preferably hydroxypropylcellulose
• a binder preferably hydroxypropylcellulose
• Forming agent preferably Rudiflash (trade name, BASF Japan Ltd.)
• disintegrant preferably crospovidone
• lubricant preferably magnesium stearate
• further colorant preferably yellow ferric oxide
• “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 ⁇ m) sieve and remaining on the No. 30 (500 ⁇ m) sieve”.
• the particle size is preferably 10% or less of the total amount passing through the No. 200 (75 ⁇ m) sieve among the particle sizes of the powders, and the granule particle size preferably passes through the entire No. 10 (1700 ⁇ m) sieve No. 12 (1400 ⁇ m) sieve remains 5% or less of the total amount, and No. 42 (355 ⁇ m) sieve passes 15% or less of the total amount.
• the average particle diameter of “grains” is usually 44 to 2000 ⁇ m, preferably 75 to 1000 ⁇ m.
• the average particle diameter indicates a value measured by, for example, a laser diffraction particle size distribution measuring device (eg, SYNPATEC HELOS-RODOS particle size distribution measuring device).
• 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).
• 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.
• 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.
• 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.
• 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).
• 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.
• 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). ), Glucose intolerance [IGT (Impaired Glucose Tolerance)], diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection ( E.g.
• cachexia eg, cancer cachex, tuberculosis cachex, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia or acquired immunodeficiency syndrome) Cachexia
• fatty liver high blood
• Polycystic ovary syndrome kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy, end-stage renal disease), muscular dystrophy, myocardial infarction, angina, cerebrovascular Disorders (eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, dysmetabolic syndrome, hyperinsulinemia, sensory impairment in hyperinsulinemia, tumors (eg, leukemia,
• 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).
• 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.
• 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.
• 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.
• 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), ⁇ -glucosidase inhibitors Examples, voglibose, acarbose, miglitol, e
• diabetic complication therapeutic agent examples 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 .
• 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, 11 ⁇ -hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (Eg, orlistat, cetilistat), ⁇ 3 agonist (e
• FGF21 preparation eg, extracted from bovine, porcine pancreas
• Animal FGF21 preparations eg, bovine, porcine pancreas
• human FGF21 preparations synthesized by genetic engineering using Escherichia coli and yeast
• FGF21 fragments or derivatives antifeedants (eg, P-57), and the like.
• hypotensive agent examples 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.), ⁇ -blockers (eg, metoprolol, atenolol, protelol, protelol) Carvedilol, pindolol, pindo
• hypolipidemic agent examples 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, cholest
• anti-arteriosclerotic agents examples 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.
• ACAT acylcoenzyme A cholesterol acyltransferase
• 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
• antithrombotic agent examples 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,reteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor (Eg, ticlopidine hydrochloride, clopidogrel, plus Barrel, E5555, SHC530, he
• diuretic examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium theoylbromide salicylate), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide).
• xanthine derivatives eg, sodium salicylate theobromine, calcium theoylbromide salicylate
• thiazide preparations eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide.
• Penfluthiazide poly-5thiazide, methiclotiazide, etc.
• anti-aldosterone preparations eg, spironolactone, triamterene, etc.
• carbonic anhydrase inhibitors eg, acetazolamide, etc.
• chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside
• azosemide isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
• 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.
• antidepressant examples 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.
• tricyclic antidepressants eg, imipramine, trimipramine, clomipramine, amitriptyline, nortriptyline, amoxapine, lofepramine, dosrepin, des
• mental nerve agent examples 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.
• typical antipsychotic drugs eg
• 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.
• GABA hypnotic eg, brotizolam, estazolam, flurazepam, nitrazepam, triazolam, flunitrazepam, lormetazepam, rilmazafone, quazepam, zopiclone, eszopicone, zolpidem,
• biguanides preferably metformin or a salt thereof (preferably hydrochloride)
• insulin secretagogues preferably sulfonylurea, non-sulfonylurea insulin secretagogues, more preferably glimepiride, nateglinide, mitiglinide Or a calcium salt hydrate thereof
• an ⁇ -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
• 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.
• a sweetener 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.
• the amount of the 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 a salt thereof. 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.
• the amount of the flavor used is about 0.08 to about 1 part by weight, preferably about 0.08 to about 0.5 part by weight, based on 100 parts by weight of pioglitazone and a salt thereof.
• the effect of suppressing the 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.
• VAS visual analog scale
• 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 if the median is high and the range (distribution) between the minimum and maximum values is narrow, it should be judged that an unpleasant taste suppression effect is universally obtained for the entire subject. Can do.
• 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).
• 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.
• VAS visual analog scale
• 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 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.
• VAS visual analog scale
• 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.
• Reference example 1 Hydroxypropyl cellulose (3900 g) was dissolved in purified water (61.10 L) to prepare a binding solution I.
• Pioglitazone hydrochloride (19840 g), lactose (45800 g) and carmellose calcium (2160 g) are uniformly mixed in a fluidized bed granulator / dryer (WSG-60, Paulek Co., Ltd.), and then 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 mm ⁇ punching screen using a power mill grinder (P-7S, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder I.
• P-7S Showa Chemical Machinery Co., Ltd.
• 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.
• VAS visual analog scale
• the minimum value and / or median value of the 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.
• 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.

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• 2013
  • 2013-02-27 WO PCT/JP2013/055043 patent/WO2013129436A1/fr not_active Ceased
  • 2013-02-27 TW TW102106865A patent/TW201340998A/zh unknown
  • 2013-02-27 JP JP2014502272A patent/JPWO2013129436A1/ja active Pending

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