TW200800299A - Pharmaceutical composition - Google Patents

Abstract

The present invention provides a solid pharmaceutical composition containing (a) a core containing a compound represented by the formula (I) wherein R1 is an optionally substituted, monocyclic nitrogen-containing heterocyclic group having an optionally deprotonated hydrogen atom, R2 is an optionally esterified carboxyl group, and R3 is an optionally substituted lower alkyl, or a salt thereof or a prodrug thereof, and a substance like fat and oil having a low melting point, (b) a first layer containing a high molecular weight polymer, which coats the core, and (c)a second layer containing pioglitazone hydrochloride, which coats the first layer.

Description

200800299

V IX. Description of the invention: [Technical field to which the invention pertains] The invention of the invention relates to a novel _solid pharmaceutical composition which can be used as, for example, a high standing pressure, a heart gf, a hardening 糖尿病 ^ diabetes, The arthritis is specialized in the treatment of the disease, and the prevention and treatment of diabetes, metabolic syndrome, and the like, and the solid pharmaceutical composition is excellent in medical properties, such as significant inhibition of decomposition of the active ingredient in the preparation. , * [Prior technology]

In recent years, in the field of medical development, the development of a combination of medicinal preparations containing a variety of active ingredients has been actively pursued in an attempt to provide synergistic effects of drug efficacy, reduce side effects, and improve patient convenience. In other words, JP-A-9-67271 describes a combination of a compound having an improved insulin resistance, a compound having α-glucosidase inhibitory activity, a double pulse compound, and the like, which can be used as a diabetes. Prevention or treatment with music. In addition, JP+9-32394〇 describes a combination of a compound having angiotensin> (ang1〇tensin) II antagonistic activity and a compound having improved anti-allergic activity of the prostaglandin, which can be used as a variety of angiotensin-inducing agents. A medicament for the prophylaxis or treatment of a disease; and WO2006/038722, which describes a combination of a specific compound having an angiotensin-antagonizing activity and a pseudo-PPAR r agonist substance, which can be used as a prophylactic or therapeutic agent for metabolic syndrome. As a compound having an angiotensin-antagonizing activity, a benzimidazole-7-carboxylic acid derivative is disclosed in jp--4-364ni, an α-, etc., specifically, a benzoyl group represented by the formula (1) Imidazole derivative 319104 200800299 vf f2~〇-t) CX>-〇-R3 (I) wherein R1 is a monocyclic nitrogen-containing heterocyclic group which may optionally be substituted with a hydrogen atom which may be deprotonated as desired, R2 is a carboxyl group which can be esterified as needed, and a low-carbon alkyl group which can be substituted as needed, and R3 is known to have an extremely strong angiotensin π antagonistic activity and is excellent as an anti-Southern dusting agent. However, although the benzoin-salt derivative represented by the formula (I) is stable to temperature, humidity and light system when it is alone in a solid state, when the compound is prepared as a solid dosage form together with other formulation components, its decomposition accelerates. The degree of quality assurance issues. Thus, JP-A-5-194218 discloses that the decomposition of the benzo-salt derivative of the solid dosage form can be remarkably inhibited by the addition of an oily substance having a low point. Further, JP-A-7-16558 discloses that the decomposition of the benzimidazole derivative in the tablet can significantly inhibit the decomposition thereof by adjusting the density of the general tablet to fall within a specific range. As a compound having an activity of improving insulin resistance, PL 〇 gita tazone hydrochloride is clinically used as an excellent/alpha therapeutic agent for diabetes, and in recent years, it has also been used clinically. A combination of Litazon hydrochloride and metformin. The solid dosage form containing the Pilgita sulphate hydrochloride and its active ingredient and the preparation method thereof are described in Jp_A_2004_l4952i, 319104 7 200800299

V JP A-2004-43478, JP-A-2005-220024, etc. The method comprising the benzimidazole derivative represented by the formula (I) and the piglitazone hydrochloride can effectively treat or prevent not only circulatory diseases such as hyperemia, heart failure, diabetic nephropathy, arteriosclerosis, etc. It can also effectively prevent or treat metabolic diseases such as diabetes and metabolic syndrome, and is highly useful in clinical patients. Therefore, the preparation of a combination drug containing a benzimidazole derivative and pitalita 2 hydrochloride was studied. However, it has been found that the benzopyrene and saliva organisms represented by the formula (I) are not stabilized due to the I force, friction, heat, etc. during the preparation, and coexist with the Pilgitazon hydrochloride in a solid dosage form. Decomposition of various creatures. In order to prevent the physical contact between the citrus sulphate hydrochloride of the formula (1), the granules of the benzo-salt derivative and the granules containing the genitalide hydrochloride are independently prepared. And use $ and other particles to make tablets and capsules. However, it is not possible to fully inhibit benzopyrene, and it can not be used for practical purposes. In addition, since the dissolution rate of the active ingredient from the preparation may affect the administration of the drug, the composition of the preparation needs to be adjusted to optimize the dissolution rate of the active ingredient when the preparation is actually used. Taking the combination drug as an example, since the dissolution rate of the individual active ingredients is particularly required to be optimized, the formulation of the combination music is difficult. For example, as for the composition of the combination drug, a formulation in which a core of the active ingredient is contained in a layer containing another active ingredient is known. In general, the rate of dissolution of the active ingredient contained in the core becomes slow, often hampering the development of the formulation. Thus, the inventors thoroughly conducted research to attempt to obtain a preparation containing the stupid imidazole derivative represented by the formula (1) and the Pilgitazon hydrochloride, and to inhibit the benzo-salt derivative by 319104 8 200800299. Decomposition, in which the dissolution rate of the active ingredient (benzoic olfactory derivative and Piglitazon hydrochloride) can be easily controlled. As a result, the inventors have found that by using a first layer coating containing a high molecular weight polymer to coat a benzo (IV)-containing derivative and a core having a low (four) oleaginous substance, and further using a pitaline-containing hydrochloride The coating of the second layer around it unexpectedly significantly inhibits the decomposition of the benzimidazole derivative, and the dissolution rate of the active ingredient can be easily controlled, resulting in the present invention. [Invention] Thus, the present invention Related to: [1] A solid pharmaceutical composition comprising (a) a compound represented by formula (I) or a salt thereof or a prodrug thereof (hereinafter referred to as "compound (I)"), and a fat having a low melting point Core of the substance R1

Wherein R is a monocyclic nitrogen-containing heterocyclic group which may be optionally substituted with a nitrogen atom which may be deprotonated as needed, R is a carboxyl group which may be esterified as needed, and R3 is a low which may be substituted as needed a carbon alkyl group, (b) a first layer comprising a high molecular weight polymer, which coats the core, and 9 319104 200800299

V 3 has a second layer of Piog Htazone hydrochloride, which coats the first layer (hereinafter referred to as "the pharmaceutical composition of the present invention"); [2] as described above [丨] The composition of the item, wherein the compound represented by the formula (!) or a salt thereof or the bismuth thereof is 2-ethoxy-1-U2, -(5-keto-4, 5-dihydro-1, 2, 4 - oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-t-acid (Compound A); [3] such as the composition of [1], wherein The compound represented by the formula (I) or a salt thereof or a prodrug thereof is 2-ethoxy-bu {[2,-(1H-tetrazol-5-yl)biphenyl-4-yl]indole 1H- Benzopyrene- 7-carboxylic acid oxime-(cyclohexyloxycarbonyloxy)ethyl ester (Compound B); [4] The composition of the item [1], wherein the oily substance having a low melting point [5] The composition according to the above [1], wherein the oily substance having a low melting point is an alkylene oxide polymer having a molecular weight of 1,000 to 1000 {); [6] The composition of the above item [1], wherein the molecular weight of the high molecular weight polymer is from 2,500 to 400,000; [7] the composition of the above item Wherein the high molecular weight polymer is hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl piperidone slightly roar or polyvinyl alcohol or a mixture of these two or more polymers of the like. The solid pharmaceutical composition of the present invention is described in detail below. The solid pharmaceutical composition of the present invention comprises (a) a core comprising a compound (1) and a fatty substance having a low k point, and (b) a first layer comprising a high molecular weight polymer, which coats the core, And (c) a second layer comprising Pilgitazon hydrochloride, which coats the first layer. 319104 10 200800299 w (a) Core The core of the present invention contains a compound (1) and a fatty substance having a point (10). In the above formula (I), R1 is a monocyclic nitrogen-containing heterocyclic group which may be optionally substituted with a hydrogen atom which may be deprotonated as necessary, and a group of earth represented by, for example, tetrazole.

B where i is -0- or -S-, j is > C = 0, > C = S or > S (0) m where m is 〇, 1, or 2 (eg, 4, 5-bin) 5-keto-1,2,4-oxadiazole-3-yl, etc. Specially used as a group which can be protected by the following as needed: low carbon (Cl-4) which can be substituted as needed An alkyl group (for example, anthracenyl, trityl, methoxymethyl, ethoxylated fluorenyl, methoxyphenyloxycarbonyl, ethoxylated oxyalkyl, 1-(cyclohexyl) An oxyhayloxy)ethyl group, a decyloxycarbonyl group 10, etc.), an acid group (for example, a low carbon charcoal (C2-5) succinyl group, a benzoic acid group, etc.). 4, 5-Dihydro-5-keto-1,2, 4-pyrazine diwax-3-yl contains three tautomers of the formula (a, b, and c,):

And the 4,5-dihydro-5-keto-1,2,4-oxadiazol-3-yl group includes all of the aforementioned a, b, and c'. 319104 11 200800299 In the above formula (I), R2 is a carboxyl group which is esterified as necessary, and is, for example, a slow-base or, if necessary, a low-carbon (Cw) alkyl group substituted with a substituent selected from the group consisting of Esterified carboxyl group: hydroxyl group, amine group, halogen, low carbon (C2-0 alkoxy group (e.g., ethoxylated, pentyleneoxy, etc.), low carbon (C4-0 cycloalkaneoxy, ( Low carbon (Cn) alkoxy) prison oxy (eg methoxycarbonyloxy, ethoxycarbonyloxy, etc.), (low carbon (C3_7) cycloalkoxy) carbonyloxy (eg cyclohexyloxy) a carbonyloxy group or the like) and a low carbon (Ci-4) alkoxy group (for example, 1-cyclo(cyclohexyloxycarbonyloxy)ethoxycarbonyl), etc. 3 In the above formula (I), R3 is as needed a lower alkyl group which may be substituted, and R3 is optionally substituted with a lower carbon (Ci5) selected from a substituent selected from a hydroxyl group, an amine group, a halogen atom and a low carbon ((:1-4) alkoxy group). An alkyl group (preferably a low carbon (C2 3) alkyl group) is preferred. Further, it is worthy of the salt formed by the inorganic test to the salt of the compound represented by the formula (I), and it is worth mentioning that it is medically acceptable. Accepted salt, one more Triamcinolone, Μ K L J,. Mentioning are, for example, represented by the formula of (Shu) compound

It is worth mentioning that there are cases of fumaric acid, oxalic acid, tartaric acid, 319104 12 200800299 succinic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, = salt of toluenesulfonic acid or the like. As a preferred example of the test amine salt, it is worth mentioning that there are salts such as arginine, lysine, and auramine; and preferred examples of the acid amine salt, such as a value extractor There are salts formed with aspartic acid and the like. The compound represented by the formula (I) or a salt thereof is a compound which is converted into a compound represented by the formula (1) or a salt thereof by a reaction of an enzyme, a gastric acid or the like under physiological conditions in the body. In other words, it is converted into a compound represented by the formula (I) or a salt thereof by enzymatic oxidation, reduction, hydrolysis or the like; and a compound which is converted into a compound represented by the formula (1) or a salt thereof by hydrolysis or the like by gastric acid or the like. The compound represented by the formula (I) or a salt thereof is exemplified by a compound in which the amine represented by the formula (1) or a salt thereof is deuterated, alkylated, phosphorylated (for example, a compound represented by the formula (I) or The amine group of the salt is decane deuterated, propylamine, pentylaminocarbonyl, (5-methyl-2-keto-oxime, 3-didecene-4-yl) methoxy-transformation a compound such as tetrahydrofuran, 0-methylidyl methylation, p-amyloxy methoxymethylation, and tert-butylation; wherein the hydroxyl group of the compound represented by the formula or its salt is deuterated, The alkylation, the phosphating, or the boration of the compound (for example, the hydroxy group of the compound represented by the formula (I) or a salt thereof is acetylated, palmitized, propionated, pentacene, diterpene, anti- a compound such as butylene dimerization, malonation, dimethylaminomethylcarbonylation or the like; wherein the compound represented by the formula (1) or a salt thereof is esterified or amided with a compound [for example, (I) The carboxyl group of the compound or its salt is esterified, phenyl esterified, methylated, methylated, methylated, methylated, methylated, ethoxylated Esterification of carbonyloxyl, oxime esterification, methylation of (5-methyl-2-keto-1,3-dioxin 13 319104 200800299 decen-4-yl), i-(cyclohexyloxycarbonyl) Alkyl esterification, amidation or the like] and the like. These compounds can be produced from a compound represented by the formula (j) or a salt thereof by a known method. The compound represented by the formula (0) or a salt thereof may be a compound, which is, for example, in the development of pharmaceutical products, No. 7, Molecular Design (M〇lecLQe Design) 163 - 198 pages, Hirokawa Bookstore (Hirokawa) a compound which is converted to a compound represented by the formula (I) or a salt thereof under physiological conditions as described in Shoten) (1990). The δ (I) may be an anhydride or a hydrate. The compound (I) is preferably Crystallized, and has a melting point of, in particular, from 120 to 2001. As for the compound (I), the above-mentioned compound A or compound B is preferred. As the crystal of these compounds, the compound A having a melting point of 1911 is preferably used. A crystal, and preferably a crystal of Compound B having a melting point of 163 ° C. • The chemical substance (1) is 〇· 〇1 Wt% to 50 wt%, preferably 〇· 05 wt% to 4〇Wt% 'More A ratio of from 1 wt% to 30 wt% is contained in the solid pharmaceutical composition of the present invention. As for the oily substance having a low melting point used in the present invention, the use has a melting point of about 2 G ° C to 90 ° c, preferably 2 (TC to 6 G ° C oil = substance). Any substance can be used as long as the substance does not adversely affect the activity of V. In the manufacture of the pharmaceutical composition of the present invention, the rut is in a grease-like substance having 4 points and has a low melting point. The fat-like shellfish can be added to the active ingredient, and as a result, a more stable pharmaceutical composition can be obtained which inhibits the active ingredient, 319104 14 200800299. The oily substance having a low melting point can be water-soluble or water-insoluble. Examples of the oily substance having a water solubility and having a low solubility of 7 include the following epoxy ketones. As for the oily substance having a low (four) used in the present invention, it is worth mentioning that, for example, hydrocarbons, high carbon fatty acids, a high-carbon alcohol, a fatty acid ester of a polyhydric alcohol, a polyol of a polyhydric alcohol, a polymer or a copolymer of an ethylene oxide, and the like; wherein a high-carbon alcohol bond of a fatty acid vinegar or a polyhydric alcohol is preferably used. , ring or copolymer, especially for epoxy-fired polymers.... As far as hydrocarbons are concerned, it is worth mentioning that there are, for example, positives with 17 to 50 carbon atoms, such as Zheng Shiyuan, Zheng Shiba, Zheng Nineteen 垸, 正廿烧,正廿One: n-decane, n-decane, n-decane, n-decane, n-decane, hydrazine: penta-, n-tetradecane, n-pentane, etc. and mixtures thereof (petrol, paraffin , etc.) As for high-carbon fatty acids, it is worth mentioning that, for example, citric acid, strontium, dansolic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, chloric acid, acid and its Mixtures, high-carbon fatty acids recovered from natural oils and fats - as for sterols, it is worth mentioning that, for example, lauryl alcohol, myristyl alcohol, carbon: stearyl alcohol, arachidyl alcohol and mixtures thereof, and two or more alcohols are recovered. Fatty acid vinegar's worthwhile - there are alcohols in a molecule such as ruthenium, or a plurality of hydrazine-based alcohols (for example, alkylene glycol such as ethylene glycol, propylene glycol, propylene glycol, such as polyethylene glycol) Intramolecular dehydration of sorbitol, sorbitol, etc., sorbitol, sorbitol, sorbitol Glycerin, diethanolamine, pentaerythritol, etc.) and fatty acids (eg acetic acid, propionic acid, butyric acid, citric acid, citric acid, eleven carbonic acid, month Lauric acid, thirteen carbonic acid, nutmic acid, fifteen carbonic acid, palmitic acid, heptadecanoic acid, stearic acid, nineteen carbonic acid, undecylenic acid, oleic acid, trans-octadecyl hydrazine + acid, sorbic acid , linoleic acid, linoleic acid, arachidonic acid, hard acid, etc.), especially for the purpose of, for example, a molecular weight of 400 纟 900 sorbitan fatty acid, such as dehydrated pear Sugar alcohol monostearate, sorbitan tristearate, sorbitan monohydrate _, sorbitan sesquioleate, sorbitan monopalmitate s | et al; a polyoxyalkylene sorbitan fatty acid having a molecular weight of i gram to, such as sorbitan polyoxyethylene ethyl distearate, sorbitan polyoxyethylene ethyl ether Sour vinegar, sorbitan polyoxyethylene ethyl palmitate, etc.; polyoxygen keto fatty acid vinegar such as polyoxyethylene sorbitan hexa-stea vinegar, polyoxygen Sorbitan hexaoleate, polyoxyethylene ethyl sorbitol tristearate diol 2, ethyl sorbitol tetralaurate vinegar, etc.; Yamanashi bee ^ organisms such as polyoxyethylene ethyl sorbitol bee soil, oxygen (tetra) lanolin derivatives such as polyoxyethylene ethyl lanolin derivative, such as propylene glycol fatty acid ester with molecular weight from 7 to 0 class. Such as early glyceryl palmitate, monoterpene sulphate, glycerol dilaurate, g g g g, etc., alkylene glycol fatty acid esters such as having a molecular weight of 500 to 1200 Ethylene glycol fatty acid esters 栌 ^ ▲ 里 = two (four), hexadecanoate glycol brewing, stearic acid glycol vinegar, - month "夂 夂 glycol vinegar, dicaramate glycol Brewed, dipalmitic acid Ethylene 319104 16 200800299 \ -f· s 日一(17 烧烧酸) Ethyl alcohol s special purpose, and similar; and has a molecular weight of 550 to 400 聚Castor oil derivatives such as polyoxyxanexene 1 sesame oil derivatives; etc.; polyoxyalkylene 1 fatty acid vinegar having a molecular weight of 1900 to 22 诸如 such as polyoxyethylene ethyl stearate, polyoxyethylene ethyl ether Acid ester, polyoxyethylidene palmitate, polyoxoethyl linolenate, etc.; monoglyceride having a mass of 300 to 600 such as monoacetin, glycerol monopropionate, monostearyl Acid glycerin vinegar, glycerol monooleate, singly succinyl sulphate, mono succinic acid glycerin, etc.; fatty acid with molecular weight 4 〇〇 删 deleted = sucrose vinegar Such as single lauric acid sucrose vinegar, single meat bean diced diced sweet and sour vinegar, monopalmitic acid recommended sweet and sour vinegar, monostearic acid sweet and sour vinegar, trimyristyl acid and vegetable sugar ester, sucrose palmitate, sucrose tristearate Esters, etc., and similar. As for the high-carbon alcohols of polyols, polyols (cited as the alcohol components of the aforementioned fatty acid esters) and high-carbon fatty acid alcohols (for example, alcohols) are often used. , stearyl alcohol, oleyl alcohol, octanol, sterol) formed by vinegar, especially for example, poly-emulsion ethyl higher alcohol such as polyoxyethylene ethyl lauryl scale, • polyoxy-extension ethyl record if Alcohol oxime, polyoxyethylene ethyl stearyl alcohol _, polyoxygen acetonitrile (four), polyoxyethylene ethyl octanol scale, polyoxyethylene ethyl ketone, etc.; poly & propyl polyoxyethylene Base carbon oxime such as polyoxyl propyl polyoxyethylene, its wax chain, polyoxyl propyl polyoxyethyl ether _, polyoxypropylene propylene: ^ ethyl ether _, polyoxygen Propyl polyoxyethylene ethyl phthalate, polyoxypropylene propyl polyoxyethylene ethyl lauryl alcohol _, etc. 10" in "quot; oxygen-fired polymer, preferably using a polymer having a molecular weight of U00 to - (E.g Ethylene glycol 6G_acro⑽% Save As' worth - mentioning are for example ethylene oxide Hyun, glycidoxy 319 104 17 200 800 299

I-based oxide, tetraterpene cough, etc. (preferably epoxy phantom. to two binary, copolymer, etc. preferably use two or more of the foregoing epoxy oximes and have 1,000 to 1 刀 in a knife, Copolymer of bismuth. The oleaginous substance having a low melting point may be used alone or in combination of more than one. The oily waxy substance having a low scent point is preferably GG () 5 to ^ 0.02 wt% to The ratio of 3 〇 wt% and more preferably 〇〇 5 (4) to Η (4) is contained in the pharmaceutical composition of the present invention. The content ratio of the compound (I) to the oleaginous substance having a low melting point (weighted mouth (1) / has a low solubility The above-mentioned core may be of any shape and size as long as it is preferably from about 0.2 to about 10. More preferably from about 0.2 to about 10 Å. The core can be coated by the first layer described below. The core can have any structure, and the = part can be a uniform sentence or a non-uniform sentence. As for the core, preferably (four) ^ Lu Chengyu, compression, etc.) a solid dosage form (for example, a granule or a lozenge wherein a lozenge is preferably used. The core may further contain an additive conventionally used in the field of preparation, and = know the method of manufacture. As for the additive, it is worthwhile - for example, excipients, powders, binders, lubricants, colorants, pH adjusters, surfactants, acidifiers, bridges, slip Such additives can be used in the amount commonly used in the field of preparation. In the excipients, it is worthwhile to mention, for example, starch such as corn house powder, Ma Ling, and wheat (four), rice powder, partially pre-gelatinized Powder killing, 319104 18 200800299 Pre-gelatinized powder, porous temple powder, etc.; sugars or sugar alcohols such as lactose, sugar, glucose, mannitol (for example, _mannitol), mountain half::: fruit such as D- Sorbitol), erythritol (for example, erythritol), water, slanting, crystalline cellulose, smothering carbon _, Shi Xi _ ^ special, ... As for the disintegration agent, the use of, for example, rebel Cellulose, mercapto-killing sodium, cross-methylcellulose::; W-Weilong (ca-), low-substituted propyl fiber / ^ propyl record. The amount of the disintegrating agent is reduced to 30 parts by weight relative to the pharmaceutical composition of the present invention per (10) heavy denier. .5 to 4 parts by weight and more preferably 1 as for the binder. For example, there are, for example, crystalline fibers =): r-propylcellulose, propylmethylcellulose-diethylene: 2: gum arabic powder or the like. The amount of the reducing agent used is 0.5 to 30 parts by weight, based on the weight of the pharmaceutical composition of the present invention, which is equivalent to the parent (10). The main (10) heavy Ζ, = "the preferred example of the agent, worth mentioning - for example, magnesium stearate, calcium talc, sodium sulphate, fatty acid ester sodium.庶搪S曰, anti-butadiene diacid, hard, two, agent, it is worth mentioning that for example, food color such as food yellow k,, " lipstick red 2, food blue 2, etc., food color Material lake color), iron oxide, etc. As for the pH adjuster, only one 4^ 4->> ^ 俚 棱 has citrate, phosphate, carbonate, tartrate, no secret - Ding Kun - S Wen salt, acetate, Amino acid salt and the like. As for the surfactant, it is worth mentioning that there are sodium lauryl sulfate, Polly 319104 19 200800299 ♦ Polysorbate 80, polyoxy-extension ethyl (16 ()) propyl (3 〇) diol and the like. For example, tocopherols, such as tocopherol, ethylenediaminetetraacetic acid tetrasodium salt, nicotinic acid decylamine, cyclodextrin, and the like. As for the deuterium, it is worthwhile to mention, for example, ascorbic acid, ascorbic acid, tartaric acid, malic acid, and the like. As for the car flavor, for example, there are menthol, peppermint oil, lemon oil, and vanilla. As for the π-movement, it is worth mentioning that there are, for example, light acid-free cerium oxide. The f or more of the aforementioned additives may be appropriately ratioed to the mixture. The money = core 2 is usually produced by combining the above-mentioned oily substance having a low melting point σ / ttl, and molding the mixture into a shape. For the case of ^, it can be used in a method commonly used for preparation, such as mixing, making a group; adding and mixing the mussels 3 to the active ingredient (powder addition); or adding a solvent and mixing with it, everyone, (10) 柄 handle L The substance can be mixed by the conventional method, and the above-mentioned mixture can include the mixing of the solution with the active ingredient, and the mixing of the solution and the active ingredient. , granulation, drying (liquid addition), and the like. In addition, a liquid having a low-melting oily substance and a liquid containing the (1) may be separately sprayed on a powder such as an excipient to mix it with: a suitable solvent, for example, may be used. Solvents such as water, dimethyl decylamine, _, ethanol, 319104 20 200800299 propanol, isopropanol, butanol, dichlorodecane, trichloroethane, and the like. After the completion of the mixing, the active ingredient-containing lozenge can be produced by a known compression method. Compression means compression under pressure to obtain the desired form, and the most common compression means ingot or the like. By the addition of the oily substance having a low melting point, the distortion of the crystal of the compound (I) during the kneading, granulation, and compression can be reduced. Further, in the preparation method of the pharmaceutical composition of the present invention, the above various additives may be added in an appropriate step. (b) First layer ® In the present invention, the first layer to be coated with the aforementioned core contains a high molecular weight polymer. The high molecular weight polymer to be used in the first layer of the present invention may be water soluble or fat soluble, preferably a water soluble high molecular weight polymer (e.g., hydroxypropyl decyl cellulose, hydroxypropyl cellulose, polyvinyl ° in any one of pyrrolidone, polyvinyl alcohol, polytriglucose, or the like, or a mixture of two or more thereof). Among them, propyl sulfhydryl cellulose is particularly preferred. The molecular weight of the high molecular weight polymerization # is preferably from 2,500 to 400,000, more preferably from 3,000 to 1,500, and still more preferably from 4,000 to 100,000. As used herein, the molecular weight of the high molecular weight polymer is the weight average molecular weight of the high molecular weight polymer, particularly the weight average molecular weight as measured by gel permeation chromatography (GPC). As for the GPC method, for example, the method described in Kobunshi Ronbunshu, No. 39, part 4, pp. 293-298 (Kato et al.) is used. As for the standard substance and the detailed measurement conditions, the standard rent conditions and conditions suitable for measuring the target high molecular weight polymer can be suitably used. The high molecular weight polymer is 0.01% by weight to 100% by weight, preferably 0.121 319104 200800299 ¥ 忖% to 100 WU, and more preferably 5 n to the first layer. The ratio of up to 10% wt% includes the first layer of i, which can be added to the additive. As for the coating additive, the value of the coating and/or coloring cut such as titanium oxide, k such as light barrier agent ethylene glycol, falling acid: ethyl acid such as lemon sesame oil 'polysorbate vinegar, etc.; There are cellulose, carboxymethyl fiber fine, cross-linked Puwei: Take: through propyl propyl cellulose (such as microcrystalline cellulose) and: U such as the like. \B ~ base ° ° phase, arabium meal powder, etc., and the aforementioned core system according to known methods s, for example, using a film coating device. a 匕 clothes. For coating, it is usually applied in a ratio of "n heavy bruises, preferably rhodium 5 to 2 and cords 1 to 40 per 100 parts by weight of core." U parts by weight when the first layer contains less than 1 part by weight per part by weight, relative to the amount of each (10) baryon, the upper layer is usually tied to the core of the 丨θ, and the ratio is 'and f' Private total C is preferably applied in a ratio of 10 to 80 parts by weight of 50 to 60 parts by weight. The second layer of Xizhongli contains Pilgitazon hydrochloride and covers the first one. 319104 22 200800299 Second layer It may be formed by any method, for example, forming a second coat, compression, or the like to cover the aforementioned first layer. When the second layer is formed by the coating, the 坌_ field is used as the 勹 勹 勹, day 40 — — ▲ may contain a coating agent for use in white slings. For coating additives, for example, a light barrier agent and/or a coloring agent such as oxidized chin, dinning iron, etc.; a plasticizer such as Polyethylene glycol, lemon-like acid triethylene glycol: Moonstone, sorbitan esters, etc.; organic acids such as lemon citrate: 1, poly-acid acid, etc. ; sugars such as lactose, mannose _ bis; ^ acid, low-substituted propyl propyl ketone, and ^ / 'Peng powder such as bismuth, quercetin carboxymethyl cellulose calcium, Jiaosa Villon, etc.; binders such as crystalline cellulose (e.g., microcrystalline cellulose), propyl propyl cellulose, propyl propyl methyl cellulose, polyethylene conjugated gum arabic powder, and the like; and the like. * the core of the compound (1) containing the above-mentioned first layer coating (in comparison with the surface system according to a known method (for example, Jp_A_2〇〇4_43478, 疋月^ 申 fP-A-2005-220024, etc.) a two-layer coating. The coating is used, for example, as a film coating device. The core layer of the first layer coating is usually from 1 to 80 parts by weight, preferably from i to 65, per 100 parts by weight of the first layer of coating. Applying in proportion to parts by weight and more preferably from 5 to 60 parts by weight. When the second layer is formed by dusting, the second layer may further contain a coating additive commonly used in the field of the agent, and may be according to known methods. To make up the additives, such as the additives which can be included in the core as described in the above section (4), etc. Additive. 319304 23 200800299 第二 The second layer is formed to usually be from i to 1000 parts by weight, preferably from 10 to 500 parts by weight, and per 100 parts by weight of the core of the first layer of coating, and Preferably, the ratio is from 25 to 250 parts by weight. Further, the second layer coated formulation may be subjected to further coating (top coating) for improved strength, color, etc. of the coated formulation. For example, the high molecular weight polymer described for the first layer of the high molecular weight polymer, which is referred to as a coating additive which may be contained in the first layer and/or the second layer as a coating additive, etc., according to Know the method shape - Cheng. The weight ratio of the substance (I) to the pitalitazon hydrochloride (Piglitazon hydrochloride/compound (1)) is from about 0001 to about 6,000, preferably about 〇· 〇〇 2 to about 500, more preferably from about 0. 01 to about 1 Torr, and even more preferably from about 0.1 to about 50. The pharmaceutical composition of the present invention is excellent in the design of the formulation because f can be varied by changing the type and/or amount of sugar and/or sugar alcohol, the type and/or amount of the binder, the type and/or amount of the disintegrating agent. Etc., the additive is required to be contained in the second layer containing Pilgitazon hydrochloride; or the medicinal composition can be controlled by the content of the Pilgitazon hydrochloride. The rate of dissolution of the hydrochloride salt. The amount of the Pilgitazon hydrochloride to be contained in the solid pharmaceutical composition of the present invention is 0.1 Wt% to 40% by weight, preferably 0 5 wt% to 3 wt%, and more preferably 1 wt% to 20 wt%. . Because Piglitazon normalized the intracellular insulin signal transduction, the sputum transfer mainly caused insulin resistance, so Pilgitazon reduced the resistance and enhanced the role of insulin, and increased glucose tolerance. For "use", 319104 24 200800299: This pig: Ming: medical use, milk animals (such as people, still, = have to mention such as 姨 素 素 resistance, impaired glucose tolerance: urinary disease 4 Non-insulin dependent (4) urinary disease, the first, 'glycoside resistance-related π> diabetes, u-islet type II sugar, wide-ranging impaired glucose tolerance, associated with diabetes, etc.; various complications such as hyperinsulinemia And associated hypertension, associated with impaired glucose tolerance = fish: high blood syndrome associated with diuresis (eg, type 11 diabetes, etc.); hypertension associated with bismuthemia, and hypertension Associated islet 2 resistance, impaired glucose tolerance associated with two blood pressures, hyperglycemic phase diabetes, hyperinsulinemia associated with hyperglycemia, diabetes/disease UUf lesions, diabetic neuropathy, diabetes Kidney disease = diabetic vision Membrane lesions, diabetic cataracts, macrovascular disease, T-plasmidosis, diabetic hyperosmolar coma, infectious diseases (eg, beer-infected diseases, urinary tract infections, digestive tract infections, skin and soft tissue transmission diseases, Lower extremity infectious diseases, etc., diabetic gangrene, decreased sensation, diabetic cerebrovascular disease, diabetic peripheral blood disease = f disease, two blood pressure, etc., diabetes malignant constitution, etc.; the pharmaceutical composition of the present invention may also Miscellaneous treatment of hypertensive patients with diabetes mellitus. - Because the compound of formula (I) has potent angiotensin π antagonistic activity, the medical composition of the present invention can be used as an angiotensin π receptor. Or in the mammalian body due to the presence of angiotensin u or a factor induced by the presence of angiotensin 11 (eg 319104 25 200800299 human, I Tian, pig, horse, cow, small Diseases developed by vasoconstriction or growth of rats, rats, guinea pigs, dogs, rabbits, etc. (or diseases caused by vasoconstriction or growth) or prevention of organ diseases Or therapeutic agents. As for these diseases, it is worth mentioning such as high blood pressure, abnormal blood pressure, circadian rhythm, heart disease (such as cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, vasodilation, myocardial damage) Lesions, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, rapid heartbeat, heart muscle infarction, etc., cerebrovascular disease (eg asymptomatic cerebrovascular disease, transient cerebral ischemia, stroke, cerebrovascular dementia) , hypertensive brain lesions, cerebral infarction, etc.), cerebral edema, cerebral circulation disorders, cerebrovascular disease recurrence and sequelae (such as neurological symptoms, mental symptoms, subjective symptoms, activities of daily living, etc.), ischemic peripheral circulation disorders , myocardial ischemia, venous insufficiency, cardiac insufficiency after myocardial infarction, kidney disease (eg nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic vascular disease, blood = analysis of complications, Organ dysfunction, including nephropathy caused by radiation injury, etc.), arteriosclerosis including atherosclerosis (such as movement Tumor, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hypertrophy, vascular hypertrophy or occlusion after organ intervention, and organ disorders (eg percutaneous transluminal coronary angioplasty, stent placement, coronary vessels) Microscopic examination, intravascular ultrasound, d〇unce i suppository treatment, etc., blood circulation and restenosis after restoring surgery, restenosis, erythrocytosis, hypertension, post-transplant g disease and Vascular hypertrophy, post-transplant rejection, eye diseases (eg glaucoma, sacral pressure, etc.), thrombosis, multiple organ disorders, endothelial dysfunction, hypertension, ostriches, other cardiovascular diseases [eg deep vein thrombosis, obstructive periphery 319104 26 200800299 t Circulatory disorders, occlusive arteriosclerosis, obstructive thromboangiitis, ischemic cerebral circulation disorders, Raynaud's disease (10) ynaud, s diSease), Berger's disease, etc., metabolic and/or nutritional disorders (eg fat =, high fat = syndrome, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia, etc.), neurodegenerative diseases [eg Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, AIDS brain lesions, etc.], central nervous system and systemic diseases (such as cerebral hemorrhage, cerebral infarction and other diseases and their sequelae and concurrent sinus sputum sputum, also known as spine Injury, cerebral edema, sensory dysfunction, sensory function disorder, autonomic nervous system disorder, autonomic nervous system dysfunction, multiple sclerosis, etc.), dementia, memory loss, disturbance of consciousness, amnesia, anxiety symptoms, nervous symptoms ( Catat〇nic sympt〇m), discomfort mental state, psychopathies (eg depression, epilepsy, alcohol abuse, etc.), inflammatory diseases [eg arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis , periostitis, etc.; inflammation after surgery and injury; swelling and relief; pharyngitis, · cystitis; pneumonia; atopic inflammatory inflammatory bowel disease - such as Crohn's disease (Cr〇hn, s disease), ulcerative colitis, etc. Meningitis; inflammatory eye diseases; inflammatory lung diseases such as pneumonia, silicosis, pulmonary sarcoidosis, tuberculosis, etc., allergic diseases (such as allergic rhinitis, Conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, etc., chronic obstructive pulmonary disease, interstitial pneumonia, pneumocytis carinni pneumonia, collagen disease (eg systemic lupus erythematosus, Scleroderma, polyarteritis, etc.), liver disease (eg hepatitis including chronic hepatitis, cirrhosis, etc.), portal hypertension, digestive disorders (eg gastritis, gastric ulcer, stomach cancer, postoperative gastric disorders, indigestion, food 319104 27 200800299

V-way ulcers, pancreatitis, colon polyps, gallstones, pruritus, esophageal and gastric varices, etc., blood and myocopoietic diseases (eg red blood cells, multiple disease, vascular purpura, autoimmune) Hemolytic anemia, diffuse intravascular coagulation syndrome, multiple myelopathy, etc.), bone disease (eg bone, re-fracture, osteoporosis, osteomalacia, bone batillosis) (Paget, s sease sclerosing myelitis , rheumatoid arthritis, osteoarthritis, etc., which are similar to these == knee and joint dysfunction, etc.), solid _ 'leave: stay (eg malignant melanoma, malignant lymphoma, digestive crying official == (for gastric cancer) , bowel cancer, etc.)

More: endocrine lesions (eg, Edison's disease, Cushing's syndrome 2: cell tumors, primary steroids, etc.), Cui's disease (A) (creutzfeldt_jak〇b disease), urinary and disease (eg Cystitis, photograms of the sacral gland, genital uterine fibroids, 1 case, poisoning, endometriosis, filial piety, filial piety, I disease, sexually transmitted diseases, etc., and environmental factors, lasers! (eg Radiation hazard, ultraviolet light, infrared light or group, pneumonia, asthma, lungs, respiratory diseases (such as colds, sputum, pulmonary thrombosis or pulmonary embolism), and transmission of diseases (such as cell megavirus, fluidity ^Get wood disease, wood disease, rickettsial disease, mother r blood, septic shock, endotoxin, wood disease, maternal (such as septic shock syndrome, etc.), ear "^_ shock, gran Negative septicemia, toxin, taste disorder, dizziness, such as Meniere's syndrome, deafness, dialysis, hypotension, myasthenia 319104 28 200800299 Li Wang body disease such as chronic burnout syndrome, etc. The composition of medicinal herbs can be used as a variety of diseases (such as cerebral blood : The two related diseases, the diseases associated with cardiovascular diseases, the organ diseases associated with diabetes, the intervention of medical treatment for Lv disease, etc.) are related to the crying illnesses, males, and second... At the beginning of the TO S, and/or secondary preventive agent or m-inch', the compound represented by the formula (1) has proteinuria inhibitory activity, and the pharmaceutical composition of the present invention can be used as a renal protective agent. The medical composition can be used for money, when the patient with the anti-resistance of sulphate, (d), sugar, or diabetes or hypertonic acidemia has the aforementioned disease or clinical symptoms. The new standard for the diagnosis of glycocalyx Department J 9 9 9 reported by the Society of Diabetes. According to the report, diabetes is a fasting blood glucose concentration (intravenous plasma glucose) not less than 126 mg / dl, 75 g oral glucose tolerance test (75 ^ 0GTT) The blood glucose level (intravenous plasma glucose concentration) for the last two hours is not less than #00 pg/dl or the random blood glucose concentration (venous plasma glucose concentration) is not less than 200 g/dL. before The condition of the diabetes range, and the condition is not "fasting blood glucose concentration (venous blood polydextrose concentration) less than 110 g / dl or 75 g oral glucose tolerance test (40 GTT) two hours after the blood glucose value (vein "Plasma glucose concentration" is less than 14 mg / dl" (normal type), which is called "marginal type". In addition, 'the diagnostic criteria for diabetes, the new standard is 1997 ADA (American Diabetes Association) and 1998 WH0 According to these reports, diabetes has a fasting blood glucose concentration (intravenous plasma 319104 29 200800299 transglycan concentration) no less than 126 mg / dl, and a two-hour blood glucose level after 75 g oral glucose tolerance test (venous plasma glucose concentration) ) Not less than 200 mg / deciliter. In addition, according to the aforementioned report, the glucose tolerance disorder is a fasting blood glucose concentration (intravenous plasma glucose concentration) of less than 126 mg / deciliter, and the blood glucose level (intravenous plasma glucose concentration) of not less than 140 mg after 75 g oral glucose tolerance test is not less than 140 mg. / liters and less than 200 mg / dl. In addition, according to the ADA report, the fasting blood glucose concentration (intravenous plasma glucose concentration) is not low. • The condition of 110 mg/dl and less than 126 mg/dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the WHO report, in the case of IFG (abnormal fasting glucose), the blood glucose level (intravenous plasma glucose concentration) of less than 140 mg/dl after two hours of 75 g oral glucose tolerance test is called IFG (fasting Impaired Fasting Glycemia) The pharmaceutical composition of the present invention can be used as a diabetes mellitus, marginal type, glucose tolerance disorder, IFG (fasting blood glucose abnormality), and IF G (fasting glycemia) as defined by the aforementioned new diagnostic criteria. An agent or prophylactic or therapeutic agent. Further, the pharmaceutical composition of the present invention can also be used as a therapeutic agent for hypertension in a patient with high blood pressure showing a blood glucose concentration not lower than the aforementioned diagnostic criteria (e.g., a fasting blood glucose concentration of 126 mg/dl). Further, the pharmaceutical composition of the present invention can also be used for preventing edge type, glucose intolerance, IFG (fasting blood glucose abnormality) or IFG (fasting glycemic abnormality) to become diabetes. The pharmaceutical composition of the present invention can be effectively used for heart disease patients with diabetes (such as cardiac hypertrophy, acute heart failure, including congestive heart failure 30 319104 200800299 chronic heart failure, vasodilation disorder, myocardial disease, angina pectoris, myocarditis, Atrial fibrillation, arrhythmia, tachycardia, myocardial infarction, etc.) The cardioprotection of the heart, the progression of cardiac remodeling, and the deterioration of symptoms, or the improvement of the use of drugs, or the reduction of the survival rate. In addition, it can be effectively used to prevent heart disease in diabetic patients (such as cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, vasodilation, myocardial disease, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, heartbeat Overspeed, muscle infarction, and prevention of cerebrovascular diseases (eg asymptomatic cerebrovascular disease, transient ischemic attack, stroke, cerebrovascular dementia, hypertensive brain lesions, cerebral infarction) The attack of et al. The pharmaceutical composition of the present invention can be used as a prophylactic or therapeutic agent for metabolic syndrome. Since metabolic syndrome patients have a very high incidence of cardiovascular disease compared with patients with a single lifestyle-related disease, prevention or treatment of metabolic syndrome is important for the prevention of cardiovascular disease. What is the diagnostic criteria for the syndrome? }1〇 was released in 1999 and released by 2_. According to the criteria of the protocol, in addition to sorghum sputum and (4) sugar tolerance (four) disorders, abnormal obesity, blood lipids HDL cholesterol), high blood pressure in humans b times lower ι: definition and diagnosis of diabetes and its complications: Tile II::: Diabetes, diagnosis and classification, World Health Organization, 曰 Group III, with right ~ Β Yue Chongli adult treatment of cholesterol, high 1: 2: Γ high triglyceride cool, low view diagnosis Metabolic syndrome (the United States ^ - patients are considered to be sturdy and sturdy education: the United States national biliary 319104 31 200800299 sterol education program (NCEP) second report Tubo - Du Fu, Mu, 丨it t ^ σ仃Abstract Adult High Cholesterol Test^(4) Therapeutic Expert Group (Adult Treatment Group (1): 285 Issues of the Second Association Journal, 鸠~2479 pages, _year).” The medical composition of the internal blood plant Sheng=Mingzhi can be used to treat metabolic syndrome. Gaochunshengguang^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Myelitis, gouty arthritis, Membrane inflammation, asthma, allergic disease = vascular sclerosis including arterial brittle sclerosis (aneurysm, coronary cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), digestive tract diseases such as inflammatory bladder diseases (such as Crohn's disease, ulcers) Diabetes complications, diabetic complications (diabetic neurological disorders, diabetic vascular disorders), atopic dermatitis,: sexual resistance, p-hepatic disease, systemic lupus erythematosus, visceral inflammatory disease (renal liver) Somatic immune hemolytic gold deficiency, dryness, neurodegenerative diseases _ (eg Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS brain lesions), φ >& ^ / Middle sacral neurological disorders (such as cerebrovascular diseases such as cerebral hemorrhage and cerebral infarction, head injury, spinal injury, cerebral edema, multiple sclerosis, etc.), meningitis, angina pectoris, myocardial infarction, congestive heart failure, medical treatment Vascular hypertrophy or occlusion and organ disease after coronary artery angioplasty, stent placement, coronary endoscopic ultrasonography, intracoronary thrombosis, etc., after bypass surgery Tube reocclusion or re-consistency 9 diseases, other circulatory diseases (intermittent claudication, obstructive peripheral circulation disorders, obstructive narration green rr. A tt allergic Wang Jinmai hardening, obstructive thrombophlitis , 319104 32 200800299 Ischemic cerebral circulation disorders, Raynaud's disease, Berg's disease), inflammatory eye diseases, inflammatory lung diseases (eg chronic pneumonia, silicosis, pulmonary sarcoidosis, tuberculosis), endometrium Inflammation, toxemia (such as sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome), cachexia (such as cachexia caused by infection, cancerous disease f, acquired immunodeficiency: two groups !, disease, cancer, Edison's disease, Cui's disease, viral infection (such as cell megavirus, epidemic f virus, secret virus, etc.), diffuse intravascular coagulation. . The pharmaceutical composition of the present invention can also be used as an analgesic for preventing or consuming pain in a household. Examples of painful diseases include acute pain caused by inflammation, pain associated with inflammation, various soils of the Soviet Union (4), and 瘊, "- pain associated with heart-burning, postoperative pain (wide incision, pain, postoperative chronic pain) Muscle

Second disease: muscle pain, shoulder stiffness, etc., joint W ^ (gnath gamma thralgia), headache (migraine, tight pain associated with burning, high blood associated with headache), uterine nail heart 0*, angina pectoris, abdominal pain, kidney pain, Yu, hypochondriac pain) 吝 吝 厂 4 4 4 4 4 4 4 ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure ure Menstrual pain), cancer pain, anti: the neuralgia of the two banded sputum, - and the gods. The pharmaceutical composition of the present invention is attenuated, and the compound local pain symptom is effective, such as m and rapid 'k and a variety of patients with reduced pain values and pathology (for example, the eight-chip valve shows excellent pain relief effect), £, diabetes, etc. The complications thereof, etc.) The pharmaceutical composition of the present invention can be used as an analgesic agent associated with chronic inflammation associated with chronic inflammation, 319104 33 200800299; or as an inflammation caused by inflammation; Prophylactic or therapeutic agents: (1) including arteriosclerosis; (2) vascular hypertrophy or organ disease after medical treatment; (3) reocclusion, restenosis after or after bypass surgery, or (8) occlusive arteriosclerosis. a closed-base peripheral painful disease; :: a compound represented by the formula (J) (when the compound represented by the formula (1) is broad or 刖乐乐乐, the dosage system is as in the formula (I-a K . ^ ^ 八, 1) Compounds which are administered orally) The agent 1 for oral administration of adult diabetic patients (weight: 60,000 g, gram) varies depending on the individual, the drug, the target disease, the condition, and the like.曰#曰 Hungary曰 ^ ^ n,^ 5 βΠΛ ^ ^ The mother-day agent is about 0. 1 mg to the summer, and the spoon is 600 gram, preferably about ο 5 vouchers > 1 η山士·克 of the rabbit To about 240 grams, and more preferably, force u to about 100 mg, one or three times. The person only asks for the second knife = the amount of each dose of Tazon hydrochloride is about 至1 to about 6 〇〇 milli" 〇.5 mg to about 240 gram, and more preferably about U 鲁 免, force 100 grams, can be one daily, medicine. Uncle, or two or three times to vote" Ming compounds can be combined with the following agents, such as diabetes / oral therapy, diabetes complications, treatment agent nm 捍 one person wide back Hemorrhagic agent, anti-arterial and hard: Guangnan pressure agent, anti-obesity agent, diuretic, chemotherapeutic agent, free composition can be combined, such as blood vessels (4) ♦;: In addition, the gene therapy of medical pulse blocking of the present invention Wait, or make the next week use. ~A n The regenerative agent for the stem cells of the platform is used in the market. The pharmaceutical composition and the combination drug of the present invention are used. 319104 34 200800299 ¥, the pharmaceutical composition of the present invention and the sputum for the sputum can be separated. Or formulated into a single combination of drugs. When there is no special administration period for the pharmaceutical composition and the combination drug of the separate pharmaceutical dosage form, it may be administered to the individual to be administered at the same time or in a staggered manner. In addition, ★=, Le can contain two or more drugs in an appropriate ratio. The dosage of the combination for oral administration can be appropriately determined according to the criteria used for clinical use of various pharmaceuticals. In addition, the pharmaceutical composition of the present invention and the ratio of administration of the two drugs can be appropriately determined depending on the individual to be administered, the route of administration, the standard, and the disease: the main combination. ～~, As for the therapeutic agent for diabetes, it is worth mentioning that there are, for example, a sulphuric acid preparation such as an animal insulin preparation extracted from the pancreas of cattle or pigs; and genetic engineering using Escherichia coli (E. coli) or yeast synthesis Glucosidase inhibitors (such as Foggis, voglibose, acarbase, miglitol, emiglitate) ), etc., biguanides (such as _^ phenformin, metf〇rmin, buf ormiη, etc.), insulin secretagogues [such as sulfonylureas (such as Tobuta) Tolbutamide, glibenclamide, gliclazide, chi〇rpr〇pamide, tolazamide, atetohaze (acet) 〇 hexam; [de), glyclopyramide, glimepiride, glipizide 'giybuz〇ie, etc.), rapagolina (repagl inide), senagHnjde, nategl inide, Tigri in the body or its J bow salt 35 319104 200800299 ψ hydrate, GLP-1, etc.], powder agonist (such as pramlintide, etc.), filled with acid tyrosine Phosphotyrosine phosphatase inhibitors (such as hunger, etc.), dipeptide peptidase IV inhibitors (such as NVP-DPP-278, PT-100, P32/98, SYR-322, etc.), 10,000 Agonists (eg, CL-316243, SR-5861, A, UL-TG-307, SB-226552, AJ-9677, BMS-1 96085, AZ40140, etc.), glucose stimulating inhibitors (eg, hepatic glucose phosphorylase inhibition) Agent, glucose-6-phosphatase inhibitor, glycoside antagonist %), SGLT (sodium-glucose co-transporter) inhibitor (for example, T-1095, etc.) and the like. As for the therapeutic agent for diabetic complications, it is worth mentioning that, for example, aldose reductase inhibitors (for example, to 1 restat, epalrestat, zenarestat, zobo) Zopolrestat, minalrestat, f idarestat, SNK-860, CT-112, etc., neurotrophic factors (eg NGF, NT-3, BDNF, etc.) , neurotrophic factor accelerating agent, PKC inhibitor (such as LY-333531, etc.), AGE inhibitor (such as ALT946, pimagedine, pyratoxathine, brominated N-benzoquinone) Mercaptothiazole rust (ALT766), EX0-226, etc.), active oxygen scavenger (such as lipoic acid, etc.), cerebral vasodilator (such as tiapride, mexiletine, etc.). As for anti-hyperlipidemic agents, it is worth mentioning that, for example, statin compounds are cholesterol synthesis inhibitors (for example, pravastatin, simvastatin, lo Statins 36 319104 200800299 (lovastatin), At〇rvastatin, flufluvastatin, cerivasutin, ta tastatin Itavastatin) or a salt thereof (e.g., sodium salt, etc.), a squalene human enzyme inhibitor (e.g., TAK-475), a f ibrate compound having a triglyceride-reducing effect (e.g., shellfish) Bezaf ibrate, cl〇f ibrate, simfibrate, clin〇fibrate, etc. As for the anti-arteriosclerosis agent, it is worth mentioning that, for example, 醯Kyethase A cholesterol-based transfer _: (ACAT) inhibitors (such as Melinamide, CS-505, etc.), lipid-rich plaque resolving agents ( For example, compounds such as w〇02^6264, WO 03/059900, and the like). As for antihypertensive agents, it is worth mentioning, for example, angiotensin converting enzyme inhibitors (such as captopril, enalapril, deLapril, etc.), sputum antagonists (for example) Manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc., /3 - blocker (eg metoprolol, atenolol, propranolol, carvedil〇1, pind〇i〇i, etc.), clo Clonidine and the like. As for anti-obesity agents, it is worth mentioning that anti-obesity agents (such as dexfenfluramine, fenfluramine, phentermine, HI) act on the central (cen) Sibutramine, Amphetamine 319104 37 200800299 (amfepramone), dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc., pancreatic lipase inhibition Agents (eg, orlistat, etc.), /3 3 agonists (eg CL-316243, SR-5861 PA, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.) ), appetite suppressant peptides (such as alizarin, CNTF (ciliated neurotrophic factor), etc.), cholecystokinin agonist (such as Lin Titrix, FPL-15849, etc.). As for diuretics, it is worth mentioning that there are, for example, xanthine derivatives (for example, theobromine and sodium salicylate, cocoa and salicylate 4 bows, etc.), thiazide preparations (such as Isaiah) (ethiazide), cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, and jiji keluo clos Benzylhydrochlorothiazide), Pemfluthiazide, polythiazide, methyclothiazide, etc., anti-aldosterone preparations (eg spironolactone, triamterene) ), etc., carbolic anhydride enzyme inhibitors (such as acetazolamide, etc.), chlorhexidine xanthine preparations (such as chittal idone, meifusai: (mefruside), sound Indapamide, etc., azosemide, isosorbide, ethacrynic acid, pitretanide, bumetanide ), Luo Ximai (furosemide) and so on. 319104 38 200800299 As for chemotherapeutic agents, it is worth mentioning, for example, alkylating agents (such as cyclophosphamide, ifosphamide, etc.), metabolic antagonists (such as methotrexate, 5-fluorourine 13 疋), anti-cancer antibiotics (such as mitomycin (JJJ i t (10) y cin), azithromycin (adriamycin), plant-derived anticancer agents (such as Vincent (vincristine) , vindesine (taxol), paclitaxel, cisplatin, carboplatin (carbopla1: in), etoposide (etoposide), etc. It is preferred that those belonging to 5-fluorouracil derivatives, such as furtul〇n and nifufurtul〇n, are preferred. As for immunosuppressive agents, it is worth mentioning that, for example, microbial components or bacteria Ingredients (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides with immunostimulatory activity (eg, lenthinan, schizozuland) (schizophy 1 lan), kristin (krestin, etc.) Cytokines obtained by genetic engineering (such as interferon, interleukin (IL), etc.), community stimulating factors (such as granul〇cyte_c〇l〇ny stimulating factor, erythropoietin, etc.) In addition, several agents, such as an epoxy enzyme inhibitor (such as indomethacin), are preferred in animal models and clinical situations. ), progesterone derivatives (such as megestrol acetate, glucocorticoids (such as dexamethasone, etc.), rice, buckwheat (met〇ci叩 咖 319 319 319104 39 200800299, Tetrahydrocian cantharidin (open literature), fat metabolism improver (such as vermiculite), growth hormone, IGF-, and anti-TNF-α, LIF, IL 6 and Φ can be (4) lure The antibody against the cachexia can also be used in combination with the pharmaceutical composition of the present invention. 斤: When the pharmaceutical composition of the present invention is used in combination with the combination, the amount of each drug can be reduced by considering the opposite effect of the music. The results within the full range can safely prevent the side effects that may be caused by the combination of the agents, and the amount of the combination can be reduced, and as a result, the adverse effects may be effectively prevented by the combined use of the music. Dezhi is used in combination with the pharmaceutical composition of the present invention. The combination is used for 荜, to the best of the Buddha (four) Buddha (four), miscellaneous (such as Libankamai, Gelikra, Klobopa, Torah, 晏 布 佐, etc.). ^ ^ The experimental examples and examples are illustrative of the further details of the present invention, and the experimental examples and examples are not to be considered as limiting. In the formula described in the examples, as a living 柹 ^ ^ ^, ^. θ ^ ^ ^ ^ (listed components. Examples of the present agent and the like 1 hydrochloride salt compound A (5 mg) and Picoli Tower _ y. 59 faint) Lozenge according to the formula shown in the table and the corpse fine two first = cellulose age L '曰 本 #打二(10).)) and Macrol6〇〇〇 (molecular weight: 7_ To 9, 319104 40 200800299 Melting point: 56 to 61 ° C, Sanyo Chemical Industries, Ltd.) Dissolved in pure water to obtain a binder liquid 1. Compound A, lactose (Meggle Japan Co., Ltd.) and corn starch (Nihon Cornstarch Corporation) were uniformly mixed in a fluidized bed granulation dryer, and the mixture was granulated in a dryer. At the same time, the binder liquid 1 is sprayed thereon, and the granules are dried in a fluidized bed granulation dryer to obtain granules. The obtained granules were ground in a powder mill to add microcrystalline cellulose _ (PH101, Asahi Kasei Chemicals

Corporation)), low-substituted hydroxypropyl cellulose (L-HPG-21, Shin-Etswu Chemical Co., Ltd.) and magnesium stearate (Taihei Chemical)

Industrial Co., Ltd.), and mixed in a tumbling mixer to obtain granules for keying. The obtained pellets for ingots were tableted at a weight of 350 mg using a rotary tableting machine and a 9.5 mm diameter punch to obtain a flat ingot containing 5 mg of the compound A per ingot. Hydroxypropyl decyl cellulose 2910 (average molecular group · 19000 'TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Matsumura Sangyo Κ K) are dissolved and suspended in pure water to obtain liquid 1, package The coating liquid 1 was sprayed on the obtained flat ingot in a coating machine to increase the weight of the tablet by 15 mg per ingot to obtain an intermediate layer coated ingot. The company has to coat 'until then Pilgitazon hydrochloride, hydroxypropyl cellulose (average molecular weight: 15,000 to 50,000, Japan Caodas Corporation) and D-mannose soda alcohol (Merck Ltd.) The solution was dissolved and suspended in pure water to obtain a coating liquid 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until a weight gain of 150 mg per 319104 41 200800299 was obtained to obtain an active drug layer coated ingot. Further, hydroxypropyl mercapto cellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrol 6000 (Sanyo Chemical Industries Co., Ltd.) were dissolved in pure water to obtain a hydroxypropylmethylcellulose solution 1; Titanium (Freund Corporation) was dispersed in pure water to obtain a dispersion 1 obtained separately, and the obtained dispersion 1 was added to a hydroxypropyl decyl cellulose solution 1, and the mixture was stirred in a stirrer to obtain a coating liquid 3 . In the coating machine, the coating liquid 3 is sprayed on the obtained active drug layer coated ingot until the weight per tablet is 10 mg, and the tablet having the formula of Table 1 is obtained, and each tablet contains 5 mg of the compound A and 49. 59 mg Pilgitazon hydrochloride. 42 319104 200800299 [Table 1] Compound A Lactose _ Corn Starch Flat Ingot Microcrystalline Cellulose Lowly Substituted Hydroxypropyl Cellulose Magnesium Stearate Middle Layer Hydroxypropyl Methyl Cellulose 2910 Talc Active Drug Layer D- Mannitol light propyl methylcellulose 2 91 total coating of titanium oxide

Macrogol 6000 Additives Propylpropylephrine Pilgitazon Hydrochloride Perfluoropropylcellulose Macrogol 6000

_Comparative Example 1 Containing 5 mg of Compound A in 90 mg of granules & +, the elixirs were prepared according to the formulation shown in Table i. First, propyl cellulose (HPC-L, Japan's Caesar Company) and

Macrogol 6000 (average molecular weight · · 7300 to 9300, melting point · · 56 to 61 C, Sanyo Chemical Industry Co., Ltd.) dissolved in pure water to obtain binder liquid /, compound A, lactose (Mega) and corn house powder ( Japan Corn Palace Powder Co., Ltd. is mixed in a fluidized bed granulation dryer. The mixture is granulated in a dryer 319104 43 200800299 while spraying the binder liquid 1 and then dried in the S machine to obtain 5 mg of the compound. ([Table 2] Additive compounding amount Compound A 5 mg hydroxypropyl cellulose 3 mg Macrogol 6000 3 mg lactose 56 mg corn house powder Γ--------^ 23 mg private sputum amount 90 mg Comparative Example 2 A granule containing 49.59 mg of Pyglicata hydrochloride in 180 mg of granules was prepared according to the formulation shown in Table 3. First, it was dissolved in propyl acetaminophen (HPC-L, Cotai, Japan). Pure water to obtain binder liquid 1, Pilgitazon hydrochloride, lactose (Megaxin company) and half amount of carboxymethyl cellulose calcium (G〇t〇ku Chemical C (10) pany Limited) ) in fluidized bed The mixture is uniformly homogenized in the dryer, and the mixture is granulated in a dryer while spraying the binder liquid 1, and then dried in a fluidized bed granulation dryer to obtain granules. The obtained granules are ground in a powder mill, and the remaining amount of 竣methylcellulose is added. And stearic acid S夂镐 (Taiping Chemical Industry Co., Ltd.). The compound was mixed in a tumbling mixer to obtain 49.59 mg of Pilgitazon hydrochloride in 18 mg of granules. 319104 44 200800299

It is a mixture of the compound A particles of Comparative Example 1 (90 mg) and the Pilgita non-hydrochloride salt particles of Comparative Example 2 (18 mg) to prepare mixed particles. Experimental Example 1 Compound (IV) of Comparative Example 1 (10% by weight), mixed particles of Comparative Example 3 (270 mg) and examples! The obtained key was stored in an open glass bottle under boots/5% relative humidity for one month, and the compound A derived acid was measured [Table 4]'

Xin is the amount of increase in the ketone form of the solution. The results are shown in Table 4. Litazon hydrochloride salt open glass bottle storage as shown in Table 4, compound a granules added a mixture of granules at 40 ° C 75% relative humidity at 319104 45 200800299 for 1 month, from the compound A decomposition derived θ is compared with the mixed particles of Example 3). Apparently, it contains the genus Pygolita (the solid pharmaceutical composition of the present invention shows that _^: together with the compound makes the compound A stable. The increase of the eve eight is less, the example 2. Each = coffee (10) mg) The lozenges of Piglitazon hydrochloride (6.53 pg) were obtained according to the formulation shown in Table 5. First, it is dissolved in pure water by propyl propyl cellulose (HPC_L, 曰本曹打和6_(molecular weight: let _, melting point: Μ to (4), two-year chemical industry company) to obtain the binder liquid, liquid A, lactose ( Meige Japan Company) and Corn House Powder (Japan Corn Palace Powder Company) are uniformly mixed in a fluidized bed granulation dryer, and the mixture is granulated in a dryer while spraying the binder liquid i thereon, and the particles are formed in a fluidized bed. The pellets were dried in a pellet dryer to obtain granules. The obtained granules were ground in a powder mill, and microcrystalline cellulose (PH101, Asahi Kasei Corporation), low-substituted hydroxypropylcellulose (L-HPC-21, Shin-Etsu Chemical Co., Ltd.) and Magnesium stearate (Taiping Chemical Industry Co., Ltd.), and mixed in a tumbling mixer to obtain granules for tableting. The obtained granules for tableting use a rotary tableting machine and a 9.5 mm diameter punch to beat 350 mg. 'Achieved a flat ingot containing 4 〇 mg of compound a per ingot. Dissolved by propyl propyl fluorenyl cellulose 2910 (average molecular weight: 19,000, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Songcun Industry Co., Ltd.) Suspended in pure water to obtain coating liquid 1, the coating liquid 1 is sprayed on the obtained flat ingot in a coating machine until the weight gain of the tablet is increased by 15 mg per ingot, and the middle layer is obtained 46 319104 200800299 layer coating Ingots. Then Pyglytazon hydrochloride, hydroxypropyl ferritic (average molecular weight · 15000 to 50000, Japan Caesar Company) and D-mannitol (Merck) are dissolved and suspended in pure water. The coating liquid 2 is obtained. In the coating machine, the coating liquid 2 is sprayed on the obtained intermediate layer coated ingot until the weight gain of 15 mg per ingot to obtain the active drug layer coated ingot. Methylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogo 1 6 〇〇〇 (Sanyo Chemical Industry Co., Ltd.) are dissolved in pure water to obtain hydroxypropylmethylcellulose solution i; Titanium (Fulunde Company) was dispersed in a dispersion of pure water, and the obtained dispersion 1 was added to a hydroxypropylmethylcellulose solution 1, and the mixture was stirred in a stirrer to obtain a coating liquid 3. In the clothes machine, the coating liquid 3 is misted on the obtained active drug layer coated ingot, Until the weight gain of each ingot is 1〇mg, obtain the tablets of your own side. Each ingot contains 4 g of compound A and the heart of the skin. The 319104 47 200800299 '[Table 5] Additives for compounding See compound A _2 mg lactose corn starch - ____ w / propyl propyl cellulose Macrogol 6000 —~-------- microcrystalline cellulose hydroxypropyl cellulose flat ingot

% Example 3 A tablet containing Compound A (20 mg) and Piglitazone hydrochloride (33.6 oz) per tablet was obtained according to the formulation shown in Table 6. First, hydroxypropylcellulose (HPC-L, Cotai, Japan) and Macrogol 6000 (molecular weight: 7300 to 93 〇〇, melting point: 56 to 61 it, Diyang Chemical Industry Co., Ltd.) dissolved in pure water to obtain a binder liquid 丨. Compound A, lactose (Meg Japan Co., Ltd.) and corn starch (Japan Corn Starch Co., Ltd.) were uniformly mixed in a fluidized bed granulation dryer, and the mixture was made in a dryer 319104 48 200800299 (4) The knot body was healthy on it, (4) (4) The granules are dried in a chemical bed granulator and dried to obtain granules. The obtained granules were ground in a powder mill, and microcrystalline cellulose (PH101, Asahi Kasei Corporation), low-substituted hydroxypropylcellulose (L-HPC-21, Shin-Etsu Chemical Co., Ltd.), and magnesium stearate (Taiping Chemical) were added. Industrial company), and mixed in a tumbling mixer to obtain granules for tableting. The obtained granules for the keystrokes were used to convert the 9.5 mm diameter and 35 mM to the weight of the bar, and the flat ingot containing 2 gram of the compound A per spindle was obtained. Hydroxypropyl methylcellulose 2910 (average molecular weight: 19 〇〇〇, TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Shomura Industrial Co., Ltd.) were dissolved and suspended in pure water to obtain a coating liquid coating solution i. The coating machine was sprayed onto the resulting flat ingot until the tablet weight gain increased by 15 mg per ingot to obtain an intermediate layer coating key. Then Pyglytazon hydrochloride, hydroxypropyl cellulose (average molecular weight 15000 to 50000, Japan Caesar Company) and D-mannitol (Merck) are dissolved and suspended in pure water to obtain a package. Clothing liquid 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained t-layer coated ingot until the weight gain of each of the ingots was 15 Å to obtain the active drug layer coated ingot. Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and MaCrogol 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain a hydroxypropylmethylcellulose solution; oxidized by using a dispersing device Titanium (Brown Lund) was dispersed in a dispersion of pure water, and the obtained dispersion 1 was added to a hydroxypropylmethylcellulose solution 1, and the mixture was stirred with stirring to obtain a coating liquid 3. In the coating machine, the coating liquid 3 is sprayed on the 319104 49 200800299 g, and obtained and 33.06 active drug layer coated ingots, until the weight gain of each ingot is 10 millimeters, the tablet of the formula 6 formula, each ingot Contains 20 mg of compound A mg of Pilgitazon hydrochloride. [Table 6] Additive compounding amount Compound A 20 mg Lactose 169. 2 mg Corn starch 60 mg by propylcellulose 9 mg • Flat! Set Macrogol 6000 5 mg Microcrystalline cellulose 50 mg Low-substituted hydroxypropyl Cellulose Cellulose 35 mg Magnesium Stearate 1.8 mg Intermediate Layer Hydroxypropyl Mercapto Cellulose 2910 13. 5 mg Talc 1. 5 mg Active Drug Layer Petritta Hydrochloride 33·06 mg_D-mannose Alcohol 113. 94 mg hydroxypropylcellulose 3 mg h coating layer hydroxypropyl methylcellulose 2910 7. 5 mg Macrogol 6000 1. 5 mg titanium oxide 1 mg total i 525 mg Example 4 The parent ingot contains Compound A ( The tablets of 40 mg) and Piglitazone hydrochloride (33.06 mg) were obtained according to the formulation shown in Table 7. First, hydroxypropyl cellulose (HPC-L, Japan Caodai company Macrogol 6000 (molecular weight · 7300 to 9300, melting point and .56 to 50 31^104 200800299 Sanyo Chemical Industry Co., Ltd.) dissolved in pure water to obtain a binder liquid i Compound A, lactose (Meg Japan) and corn house powder (Japan Corn Palace Powder Co., Ltd.) were uniformly mixed in a fluidized bed granulation dryer, and the mixture was granulated in a dryer while spraying the binder liquid i thereon. The granules are dried in a fluidized bed granulation dryer to obtain granules. The granules obtained are ground in a powder mill, and microcrystalline cellulose (PH101, Asahi Kasei Co., Ltd.) and low-substituted hydroxypropylcellulose (L-HPC-) are added. 21, Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.) and mixed in a tumbling mixer to obtain granules for tableting. The obtained granules for tableting use a rotary tableting machine and a 9.5 mm diameter The punch was ingots at a weight of 350 mg to obtain a flat ingot containing 40 mg of compound a per serving. Hydroxypropylmethylcellulose 2910 (average molecular weight: 19 〇〇〇, TC-5E, Shin-Etsu Chemical Co., Ltd. And talc (Songcun Industry Co., Ltd.) dissolved and suspended in pure water to obtain coating liquid 1, and the coating liquid was sprayed on the obtained flat ingot in a coating machine until the weight gain of the tablet increased by 15 per spindle. In milligrams, an intermediate coated ingot is obtained. Then, Pyglytazon hydrochloride, hydroxypropyl cellulose (average molecular weight: 15,000 to 50,000, Japan's Caota Corporation) and d-mannitol (Merck) are dissolved and The coating liquid 2 was obtained by suspending in pure water. In the coating machine, the coating liquid 2 was sprayed on the obtained intermediate layer coated ingot until the weight gain of 15 mg per ingot to obtain an active drug layer coated ingot. Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain a propylmethylcellulose solution 1; Oxidizing Chin 319104 51 200800299 (Fulongde Company) Dispersion liquid i obtained by dispersing in pure water, and additionally obtained 8-dispersion liquid 1 added to a propylmethylcellulose solution mixture to obtain a coating liquid 3 In the coating machine, the coating liquid 3 is sprayed on the two active drugs. On the coated tablets, the weight gain of each ingot is 1 〇 mg. · The tablets with the formula of Table 7 contain 40 mg of compound a and 337r 皮 gram pelita sulphate per mirror. [Table 7 ]

Compound A

Corn Palace Powder Hydroxypropyl Fiber i Macrogol 6000 Microcrystalline Cellulose Low-substituted Hydroxyvitamin Magnesium Stearate Flat Ingot

Example 5 A tablet containing Compound A (20 mg) and Piglitazone hydrochloride 319104 52 200800299 (49·59 mg) per bond was obtained according to the formulation shown in Table 8. First, hydroxypropylcellulose (HPC-L, Japan Caesar Co., Ltd.) and Macrogoi 6000 (molecular weight: 73〇〇 to 93〇〇, melting point: 56 to 6i〇c, Eryang Chemical Industry Co., Ltd.) were dissolved in pure water to obtain a bond. Liquid〗. Compound A, lactose (Meg Japan) and corn starch (Japan Corn Starch Co., Ltd.) were uniformly mixed in a fluidized bed granulation dryer, and the mixture was granulated in a dryer while spraying the binder liquid i thereon. The fluidized bed was dried in a dryer to obtain granules. The obtained granules were ground in a powder mill, and microcrystalline cellulose (PH101, Asahi Kasei Co., Ltd.), low-substituted propylcellulose (L-HPC-21, Shin-Etsu Chemical Co., Ltd.), and magnesium stearate were added. Taiping Chemical Industry Co., Ltd., and mixed in a tumbling mixer to obtain granules for tableting. The obtained pellets for ingots were tableted at a weight of 35 mils using a rotary tableting machine and a 9.5 mm diameter punch to obtain a flat ingot containing 20 mg of Compound A per ingot. Hydroxypropyl fluorenylcellulose 2910 (average molecular weight: 19,000, gTC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Shin-mura Industrial Co., Ltd.) were dissolved and suspended in pure water to obtain coating liquid 1, and coating liquid 1 was coated. The machine was sprayed onto the resulting flat ingot until the tablet weight gain increased by 15 mg per ingot to obtain an intermediate layer coated ingot. Then Pyglytazon hydrochloride, propyl propyl cellulose (average molecular weight. 15000 to 50000 'Japan Caesar Company) and D-mannitol (Merck) are dissolved and suspended in pure water to obtain a package. Clothing liquid 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until the weight gain of each of the ingots was 15 Å to obtain the active drug layer coated ingot. 319104 53 200800299 In addition, 'propyl propyl methylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) are dissolved in pure water = dihydroxypropyl methylcellulose solution i; The dispersing device is added to the hydroxypropylmethylcellulose solution by dispersing the oxidized (Fulunde company) dispersion liquid obtained by dispersing the pure water, and the mixture is stirred in a stirrer to obtain a coating liquid. 3. In the coating machine, the coating liquid 3 is sprayed on the obtained active drug layer coated ingot until the weight gain per ingot is 1 g, and the lozenge having the formula of Table 8 is obtained, and each ingot contains 2 g of the compound 1 And 49 59 mg of Pilgitazon hydrochloride. [Table 8]

Intermediate layer Pilgitazon hydrochloride active drug layer D-mannitol magnesium stearate propyl methylcellulose 2 9 1 〇 talc top coating layer total 爹 propyl propyl cellulose hydroxy propyl Base fiber Macrog titanium oxide mg

ΖιΑ mg 525 mg mg mg 319104 54 200800299 实例 Example 6 Lozenges containing compound bismuth (40 mg) and pitalita sulphate (49·59 house gram) per tablet are based on the formula shown in Table 9. obtain. First, hydroxypropyl cellulose (HPC-L, Japan Caesar Co., Ltd.) and MaC, rogol 6000 (molecular weight: 73〇〇 to 93〇〇, 'point; γ6 to 6^, two-year chemical industry company) dissolved in pure water Obtain the binder liquid 1. Compound A, lactose (Meg Japan) and corn starch (Japan Corn Starch Co., Ltd.) are all in the fluidized bed granulation dryer, and the mixture is granulated in the dryer while spraying the binder on it. Drying in a fluidized dryer yields granules. The obtained granules of the bed l were ground in a powder mill, and microcrystalline cellulose (PH101, Asahi Kasei Co., Ltd.), low-substituted hydroxypropylcellulose (L-HPC-21 'Xinyue Chemical Co., Ltd.) and magnesium stearate were added. Taiping Chemical Industry Co., Ltd.' and mixed in a tumbling mixer to obtain granules for tableting. The obtained pellets for ingots were tableted with a rotary tableting machine and a 9.5 mm diameter punch at 35 gram milligrams to obtain a flat ingot containing 4 gram of compound A per spindle. The propyl methacrylate 2910 (average molecular weight: 19000, TC~5E, Shin-Etsu Chemical Co., Ltd.) and talc (Shin-mura Industrial Co., Ltd.) were dissolved and suspended in pure water to obtain a coating liquid 1, and the coating liquid was applied to the package. The machine was sprayed on the obtained flat until the tablet weight gain was increased by 15 mg per ingot to obtain an intermediate layer coated ingot. Then Pyglytazon hydrochloride, hydroxypropyl cellulose (average molecular star · 15000 to 50000 'Japan Caesar Co., Ltd.) and D-mannitol (Merck) are dissolved and suspended in pure water to obtain a coating. Liquid 2. In the coating machine, a package of 319104 55 200800299 is applied to the obtained intermediate layer coated ingots until a weight gain of 1 〇 milligram per ingot to obtain an active drug layer coated ingot. In addition, hydroxypropylmethylcellulose 291 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogo! 6 〇〇〇 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain a propylmethylcellulose solution i; The dispersion 1 obtained by dispersing titanium oxide (Fulunde) in pure water was used, and the dispersion 1 obtained separately was added to the hydroxypropyl f-based cellulose solution 1 using a dispersing device, and the mixture was stirred in a stirred state to obtain a coating. Liquid 3. In the coating machine, the coating liquid 3 is sprayed on the obtained active drug layer coated ingot until the weight gain per ingot is 1 g, and the lozenge having the formula of Table 9 is obtained, and each ingot contains 4 g of the compound. A and 49. 59 亳克皮利塔宗 hydrochloride. 319104 200800299 [Table 9] Chelate A Lactose Corn starch Flat ingot Microcrystalline cellulose Active drug layer Low-substituted propylpropylcellulose Hydroxypropyl-I-Pigrita

Hydroxypropyl cellulose added 齐lj Macrogol 6000

Intermediate layer, propylmethylcellulose 2910

Continuing Test Example 2 Only the tablets obtained in Examples 2 to 5 and the mixed particles of Comparative Example 3 (27 g) were packaged in a waterproof package at 40 ° C under 75% relative humidity (1 month, Compound A was measured). The ketone form of the derivatized acid is shown in Table 1. 'Addition. 3191〇4 57 200800299 [Table 10] The mixed granules of Comparative Example 3 (270 mg) 〃 40 ° C 75% relative humidity &quot ; Example 6 lozenge

Storage conditions The increase in the form of the ketone form is 3.24% ----- 0. 07% Month----- 05% η 0.07% 〇· 07% The tablet of Example 4 is as shown in Table: 〇 As shown, when Pilgitazon hydrochloride was added to Compound A, it was increased by the decomposition of Acacia A when stored at 40 C 75% relative humidity for 1 month (Comparative Example) Mixed Particles of 3^ Conversely 'determine the solid pharmaceutical composition of this statement containing the Pigretitaline hydrochloride phase Compound A. The amount of increase in the ketone form is small to stabilize the compound j. Example 7 uses the same as in Example 6. In the form of a flat spinning agent obtained according to the formula, a tablet containing 49.59 g of piglitazone hydrochloride per tablet was prepared. Hydroxypropyl methylcellulose (average molecular weight: 19 〇〇〇) , Tc-5e, Shin-Etsu Chemical Co., Ltd. and talc (Songcun Industry Co., Ltd.) dissolved and suspended in pure water to obtain coating liquid 1, and the coating liquid 1 was sprayed on the obtained flat ingot in a coating machine until the ingot The weight gain of the agent is increased by 14 gram per key to obtain the intermediate layer coated ingot. Then the Pilgitazon hydrochloride, hydroxypropyl group Vitamins (average molecular weight · 15000 to 50000, Japan Caesar Company), low-substituted hydroxy 319104 58 200800299 propyl cellulose (L-HPC-32, Shin-Etsu Chemical Co., Ltd.) and d-mannitol (default) Co., Ltd. dissolves and suspends in pure water to obtain coating liquid 2. In the coating machine, coating liquid 2 is sprayed on the obtained intermediate layer coated ingot until the weight gain of each tablet is 15 〇 to obtain the active drug In addition, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain hydroxypropylmethylcellulose solution 1; The dispersing device is obtained by dispersing titanium oxide (Fulunde Company) in the dispersion liquid obtained by using pure water, and the obtained sub-government liquid 1 is added to the hydroxypropyl mercapto cellulose solution, and the mixture is stirred in the crucible. The coating liquid 3 was obtained. In the coating machine, the coating liquid 3 was sprayed on the obtained active drug layer coated ingot until the weight gain per tablet was 5 mg, and the tablet having the formulation of Table 11 was obtained, and each ingot contained 49. · 59 mg of Pilgitazon hydrochloride. Now [Table 11]

Ψ~~ Middle layer---. Lozenge active drug layer talc skin Glytazon~—1^4 mg—49?5i^X~ D-mannitol: ~ 67· 41 mg is replaced by low degree Propyl cellulose 30 mg hydroxypropyl fibrin 0 ~ propyl propyl thiol cellulose 2 91 〇 3 _ mg Macrogol 60 〇 ί ~ ^ ~ ~ ' --

319104 59 200800299 Example 8 A flat tablet obtained in the same manner as in Example 6 was used, and according to the formulation of Table 2, a tablet containing 49.59 mg of Pigatitaz Hydrochloride per tablet was produced. Hydroxypropyl fluorenyl group Cellulose (average molecular weight: 19000, TC_5E, Shin-Etsu Chemical Co., Ltd.) and talc (Shin-mura Industrial Co., Ltd.) were dissolved and suspended in pure water to obtain coating liquid 1, and coating liquid 1 was sprayed in a coating machine to obtain a flat On the ingot, until the tablet weight gain is increased by 14 mg per ingot, the middle layer coating is suspected. Then the Pyglytazon hydrochloride, the low-substituted propyl cellulose (L-HPC- 32 'Xinyue Chemical Co., Ltd.), hydroxypropyl cellulose (average molecular weight: 15_ to 5_0, Japan Caesar Company), and erythritol (Nikken Fine Chemieal Gq., Ltd > Dissolve and suspend in pure water to obtain coating liquid 2. In the coating machine towel, the coating liquid 2 is sprayed on the middle of the serving|coating ingots~ until each ingot is increased by 15{Γmg drug layer coating Ingots. In addition, hydroxypropyl fluorenyl cellulose 291 〇 (TC_5E, Xinyuehua, Division) and Macrogol6_ (three Chemical Industry Co., Ltd.) is dissolved in a pure material via a propylmethylcellulose solution i; a dispersing device is used to disperse the oxidized (Brown Lund Company) in pure water, and the obtained one is added to the base. The propylmethylcellulose solution is mixed with the mixture to obtain the coating liquid 3. In the coating machine, the coating liquid 3 is sprayed on the active drug layer to form a difference until the weight gain of each key is 5 mg, which is obtained. Table 12 formula spinner, each containing hunger 59 mg Pigley ^ 319104 60 200800299 sweet [Table 12] flat tablet intermediate layer additive flat tablet active drug layer dosage 3 mg 12 · 6 mg mg 4 9 · _5 9 mg top coating layer

Macrogol 6000 Total 3 · 7 δ mg 〇 __75 mg _ 〇 · 5 mg 519 ^ ΪΤ Example 9 Using the formulation of the flat-made sizing agent obtained in the same manner as in Example 6, the formulation was made to contain 49.59 mg of Pigley per ingot. Lack of '^ 凡 和 曷 合 合 合 合 合 合 盐 0 0 0 0 修 修 修 修 修 修 修 修 修 修 修 羟基 羟基 羟基 修 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基 羟基Dissolved and suspended in pure water to obtain coating liquid 1, and the coating liquid 1 was sprayed on the obtained flat ingot in a coating machine until the weight of the tablet was increased by 14 mg per ingot to obtain an intermediate layer coating key. . Then Pilgitazon hydrochloride, low-substituted propyl cellulose (L-HPC-32 'Xinyue Chemical Co., Ltd.), propyl propyl cellulose (average molecular 1500 rpm) 5 0 0 0 0 'Japan Caesar Company', and sucrose (Ensuiko Sugar Refining Co., Ltd.) were dissolved and suspended in pure water to obtain a coating liquid 2. In a coater, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingots until the weight gain of 15 mg per ingot to obtain an active drug layer coated ingot. Further, hydroxypropyl mercapto cellulose 2910 (TC_5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain a hydroxypropyl methylcellulose solution hydrazine; The company obtained by dispersing the dispersion liquid obtained by the pure water, the dispersion liquid 1 obtained separately was added to the hydroxypropyl methylcellulose solution, and the mixture was stirred and stirred to obtain the coating liquid 3. In the coating machine, the coating liquid 3 was sprayed on the coated tablet of the active drug layer of 'I'm until the weight gain of each tablet was 5 mg, and the tablet having the formula of Table 13 was obtained, and each ingot contained 49 59 mg of peggard Litazon hydrochloride. 13] Flat Lozenge Intermediate Layer Active Drug Layer Top Coating Layer Total Additives Flat Tablets Hydroxylumin 2910 Talc Pelican Hydrochloride Hydroxypropyl ^!^· ~-- Macrogol 6000 Mixing dosage 35 〇毫玉12· 6 mg

49.59 ^ 67.41 3^_mg 3 毫 13775 "iX 〇· 75 mg 519 mg Experimental example for each of the examples 7 'Example 8 and Example 9 _ use ^ 319104 62 200800299 4» Μ hydrochloric acid-potassium chloride buffer ( 9 〇〇 ml, 3rC, PH 2) The dissolving enthalpy of the Pilgitazon hydrochloride was evaluated by the Paddle Method (50 rpm). The results are shown in Table 14. [Table 14] Dissolution rate U) D-mannitol (Example 7) after 30 minutes after 15 minutes after 10 minutes after 20 minutes 86 92 94 96 D-erythritol (Example 8) r——^— —~- 15 35 57 76 'Sucrose (Example 9) 72 81 86 90 As shown in Table 14, the solid pharmaceutical composition of the present invention shows that the dissolution rate of the Pilgitazon hydrochloride can be changed by changing the type of sugar. Experimental Example 4 For the individual tablets obtained in Example 2, Example 4, and Example 6, the use of 〇3^hydrochloric acid-calcium carbonate buffer (900 ml, 37t:, pH2) was evaluated by the paddle method 5, etc. The dissolution properties of Tazon hydrochloride. The results are shown in Table 319104 63 200800299 [Table 15]

Dissolution rate (%) After 30 minutes ^9·59 mg/150 mg (drug concentration in the active drug layer, 33%) 67 89 104 101 100 10 As shown in Table 15, the dissolution rate of the drug can be changed by the preparation The drug concentration is changed. Example 10 Using the flat tablet obtained in Example 6, and according to the formulation of Table 16, a tablet containing 49.59 mg of Pilgitazon hydrochloride per tablet was produced. Base propyl methylcellulose (average molecular weight: 15 〇〇〇 to 5 〇〇〇〇, Japan Caesar Company), sucrose (salt port sugar company) and low-substituted hydroxy/propyl cellulose (L -HPC-32, Shin-Etsu Chemical Co., Ltd. dissolves and suspends in pure X to obtain coating liquid 1, and the coating liquid is sprayed on the obtained flat ingot in a coating machine until the tablet weight gains up to each ingot An increase of 1 mg was obtained to obtain an intermediate layer coated ingot. θ Then Pilgitazon hydrochloride, hydroxypropyl cellulose (average molecular summer · 15000 to 50000, Japan Caesar Company), and D-mannitol (Merck) are dissolved and suspended in pure water to obtain Coating solution 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until a weight gain of 12 gram per ingot was obtained to obtain an active drug layer coated ingot. 319104 64 200800299 In addition, hydroxypropyl decyl cellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) are dissolved in pure water to obtain propyl methacrylate solution 1; The apparatus is further added to the hydroxypropyl decyl cellulose solution 1 by dispersing the titanium oxide (Fulunde Company) in the dispersion 1 obtained by dissolving the pure water, and the mixture is stirred in the donor to obtain a coating liquid. 3. In the coating machine, the coating liquid 3 was sprayed onto the obtained active drug layer coated ingot until the weight gain per tablet was 5 mg, and a tablet having the formulation of Table 16 was obtained, and each ingot contained 49.59 mg of Pigrita. Zong salt _ acid salt. solitary

[Table 16J

Active drug layer 75 mg 49 · 59 mg 67. 41 IX mg 3. 75 mg 丨 · 75 mg 0.5 mg - 575 £ sucrose pitalitazon salt D-mannitol hydroxypropyl cellulose oxime to propyl group Fiber Macrogol 6000 Titanium Oxide Example 11 - Using the flat lozenge obtained in Example 6 and according to the formulation of Table 17, a lozenge containing 49.59 mg of the Pilgita (4) salt per spin was prepared. Hydroxypropyl methylcellulose (average molecular weight: 15,000 to 50,000, 319104 65 200800299 曰本曹打公司), sucrose (saline port refined sugar company) and low-substituted lysylpropyl cellulose (L-HPC-32 , Xinyue Chemical Company) dissolved and suspended in pure water to obtain coating liquid 1, and the coating liquid 1 was sprayed on the obtained flat ingot in a coating machine until the weight gain of the tablet increased by 1 mg per ingot. , obtaining an intermediate layer coated ingot. Then, Pyglytazon hydrochloride, hydroxypropylcellulose (average molecular weight: 15,000 to 50,000, Japan Caesar Co., Ltd.), and D-mannitol (Merck) are dissolved and suspended in pure water to obtain a coating. Liquid 2. In the coating machine, the ® coating liquid 2 is misted on the obtained intermediate layer coated ingot until the weight gain of each of the ingots is 15 宅 to obtain the active drug layer coating key. In addition, hydroxypropyl fluorenylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain hydrazine-methylcellulose solution hydrazine; Titanium oxide (Fulunde Co., Ltd.) was dispersed in a dispersion of pure water, and the obtained dispersion 1 was added to a hydroxypropylmethylcellulose solution, and the mixture was stirred in a stirring apparatus to obtain a coating liquid 3. In the coating machine, the coating liquid 3 is sprayed on the coated active music layer coated ingot until the weight gain of each tablet is 5 mg, and the tablet having the formula of Table 17 is obtained, and each ingot contains 49.59 mg of the skin. Glytazon hydrochloride. 319104 66 200800299 [Table 17] Additives Ingredients Flat Tablets Tablets Tablets 350 mg Intermediate Layer Hydroxypropyl Cellulose 3 mg Lowly Substituted Hydroxypropyl Cellulose 15 mg Sucrose 82 mg Active Drug Layer Peggy Tazon hydrochloride 49. 59 mg D-mannitol 97. 41 mg hydroxypropyl cellulose 3 mg k-sheet coating layer hydroxypropyl fluorenyl cellulose 2910 3. 75 mg Macrogol 6000 0. 75 mg titanium oxide 0.5 mg total 605 mg Experimental Example 5 For individual tablets obtained in Example 10 and Example 11, using a 〇·3 Μ hydrochloric acid-potassium chloride buffer (900 ml, 37 it, ρΗ 2) by paddle method (50 Rpm) Assess the solubility properties of Pilgitazon hydrochloride. The results are shown in Table 18. • Table 18] Pilgitazon hydrochloride / hydroxypropyl cellulose / D-mannitol dissolution rate (%) 10 minutes after 15 minutes, 20 minutes after 30 minutes, 49 · 59 mg / 3 mg / 97 41 mg Example 11 72 88 95 98 49· 50 mg / 3 mg / 67 · 41 mg Example 10 46 70 84 91 As shown in Table 18, the dissolution rate of the drug can be changed by changing the amount of D-mannitol. 67 319104 200800299 Example 12 Using the flat lozenge obtained in Example 6 and according to the formulation of Table 19, a lozenge containing 49. 59 g of Piglitazon hydrochloride per ingot was produced. Hydroxypropyl cellulose (average molecular weight · 15〇〇〇 to 5〇〇〇〇, Japan Caesar Company), sucrose (salt port sugar company) and low-substituted hydroxypropyl cellulose (L-HPC- 32, Xinyue Chemical Company) dissolved and suspended in pure water to know the coating liquid 1, the coating liquid 1 was sprayed on the obtained flat ingot in the coating machine until the weight gain of the tablet increased by 1 per spindle 〇〇胄 ,, get the middle layer coating and then Pyglytazon hydrochloride, hydroxypropyl cellulose (average molecular weight: 15,000 to 50,000, Japan Caesar Company), and mannitol (Merck) dissolved It was suspended in pure water to obtain a coating liquid 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until the weight gain of 15 mg per ingot to obtain an active drug layer coated ingot. Further, hydroxypropylmethylcellulose 29l (Tc-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) are dissolved in pure water to obtain a propylmethylcellulose solution 1; The apparatus was further added to a hydroxypropylmethylcellulose solution by dispersing a dispersion of oxidized chin (Fulunde) in pure water, and the mixture was stirred in a stirrer to obtain a coating liquid 3 . In the coating machine, the coating liquid 3 was sprayed on the obtained active drug layer coated ingot until the weight gain per spin was 5 mg, and the tablet having the formulation of Table 19 was obtained, and each ingot contained 4 9.59 mg. Pilgitazon salt 319104 68 200800299 [Table 19]

Piglitazon hydrochloride active drug layer D-mannitol

H9 mg 94·41 gram

Hydroxypropyl cellulose hydroxypropyl methylcellulose 2910

The specific examples of the β-acid gas = column-U and the individual initiators obtained in Example 12 were used. 0.3 Μ! ====(_ml, 37t, PH2 port 10 to estimate the solvation properties of Picuritazin hydrochloride. ^ 20] 贝 π果頬 is not shown in Table 2. L On Mr ~~~Ξ ~~^ T~ I. ' _______ ^Ising rate (%) in the active drug layer ingot)

As shown in Table 20, the percentage of the leather is less than Φ ^ The rate of release of the product can be changed by changing the content of the active 筚# Yin. Municipal animal husbandry Example 13 319104 69 200800299 A flat preparation obtained in the same manner as in Example 6 was used and a tablet containing 49 59 mg of Pigretatin hydrochloride per spin was prepared according to the formulation of Tables 2 and 22'. Hydroxypropyl fluorenyl cellulose (average molecular weight: 19 〇〇〇, tc_5e, Shin-Etsu Chemical Co., Ltd.) and talc (Shin-mura Co., Ltd.) were dissolved and suspended in pure water to obtain a coating liquid 1 'coating liquid 1 in a package The machine was sprayed on the resulting flat key until the weight gain of the key was increased by 14 mg per ingot to obtain an intermediate layer coating key. (4) Pilgitazon hydrochloride, M-propyl cellulose (average molecular weight: 15,000 to 50,000, Japan Caesar Company), D_# sugar alcohol (Merck) and low-substituted hydroxypropyl fiber The pigment (L_Hpc_32, Shin-Etsu Chemical Co., Ltd.) was dissolved and suspended in pure water to obtain a coating liquid 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until the weight per spin was (10) mg to obtain an active drug layer coated ingot. In addition, thiopropyl methylcellulose 291 (TC_5E, Shin-Etsu Chemical Co., Ltd.) and M〇Cr〇gol6_ (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain lysylpropyl fluorenyl cellulose solution 1; The apparatus was further added to the propyl methacrylate solution mixture by a dispersion obtained by dispersing oxidized chin (brown company) in pure water, and the mixture 1 was stirred to obtain a coating liquid 3. In the coating machine, the coating liquid 3 is sprayed on the coated active music layer coated ingots until the weight gain of each ingot is 5 mg, and the tablets of the formula 2 and 22 and 23 are selected. The bond contains 49.59 mg of Gretazon hydrochloride. 319104 70 200800299 [Table 21] Additives in an amount of flat tablet ingots 350 mg of intermediate layer hydroxypropyl decyl cellulose 2910 12. 6 mg of talc 1. 4 mg of active drug layer Glytazon hydrochloride 49.59 Mg D-mannitol 97.41 mg hydroxypropyl cellulose 3 mg top coating layer) Hydroxypropyl decyl cellulose 2910 3. 75 mg Macrogol 6000 0. 75 mg titanium oxide 0.5 mg total 519 mg [Table 22] Additive dosage: flat ingot flat tableting agent 350 mg middle layer hydroxypropyl methylcellulose 2910 12.6 mg talc 1.4 mg ¥ Tongue drug layer peel Glytazon hydrochloride 49. 59 mg D-mannitol 82 41 mg of low-substituted hydroxypropylcellulose 15 mg hydroxypropylcellulose 3 mg top coating layer hydroxypropyl methylcellulose 2910 3. 75 mg Macrogol 6000 0. 75 mg titanium oxide 0. 5 mg Total 519 mg 71 319104 200800299 [Table 23] Flat ingot _ _^ Additive ΐϊϊ Qi Qi " ^ 晏利土合宗盐酉曼盐无基丙纤维素层Active layer k Coating layer Macrogol β〇〇α ~ Total amount 1 -~~ Dosing amount ^-»>-___ 350 mg---__ 12. 6 mg^~·_ ___1.4 mg---_ ~49· 59 Mg ^ mg ΖΖΓ 30 mg 3 mg ~ ' 3. 75 ^ mg ^ ^ _ — 0. 75 mg ^ ^. ~~ 0 · 5 mg ' 5 Τ 9 mg Experimental Example 7 Individual tablets obtained in Example 13, buffer (10) 0 ml , 3rc, pH will be 3 · Μ hydrochloric acid - potassium chloride Glytazon hydrochloride dissolvability f. Leaf method (5G which) evaluates the skin "Table 24], and the fruit is not shown in Table 24. Dissolution rate (%) 15 minutes after 15 minutes 2 minutes after 30 minutes

The content of the disintegrating agent (low-substituted hydroxypropyl cellulose) in the active drug layer (per ingot) __ - mg i 〇 mg as shown in Table 24, the dissolution of the drug from the mystery 7 mountain 邶 uyv 曰 ^ It is changed by changing the S containing the agent in the active drug layer. 319104 72 200800299 Example 14 Using a flat tablet obtained in the same manner as in Example 6 and according to the formulations of Tables 25, 26 and 27, a lozenge containing 49 59 mg of Pigretatin hydrochloride per spin was prepared. Hydroxypropyl methylcellulose (average molecular weight: 19 〇〇〇, tc_5e, Shin-Etsu Chemical Co., Ltd.) and talc (Shin-mura Industrial Co., Ltd.) were dissolved and suspended in pure water to obtain a coating liquid 1 'coating liquid 1 in a coating The machine sprayed on the obtained flats until the weight gain of the tablets increased by 14 mg per spin, and the middle layer was covered. •, then Pilgitazon hydrochloride, hydroxypropyl cellulose (average molecular weight: 15,000 to 50,000, Japan Caesar), erythritol (Nikkei Precision Chemical Co., Ltd.) and low-substituted hydroxypropyl The base cellulose (L_Hpc_32, Shin-Etsu Chemical Co., Ltd.) was dissolved and suspended in pure water to obtain a coating liquid 2. In the coating machine, the coating liquid 2 was misted on the obtained intermediate layer coated ingot until the weight gain of 150 kg per ingot to obtain an active drug layer coated ingot. Further, hydroxypropyl mercapto cellulose 291 (tc-5E, Shin-Etsu Chemical Co., Ltd.) and MaCrogol 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain a propyl propyl fluorenyl cellulose solution 1; The apparatus is further prepared by dispersing oxygen (Brown Lund) in a dispersion of pure water, and the obtained dispersion 1 is added to a hydroxypropylmethylcellulose solution, and the mixture is stirred in a stirrer to obtain a coating liquid. 3. In the coating machine, the coating liquid 3 is sprayed on the coated tablet of the active drug layer until the weight gain of each tablet is 5 mg, and the tablet having the formulas of Tables 25, 26 and 27 is obtained, and each ingot contains 49.59. MG Pilgitazon hydrochloride. 319104 73 200800299 Gas [Table 25] Additive dosage: Flat ingot flat tableting agent 350 mg Intermediate layer hydroxypropyl methylcellulose 2910 12.6 mg Talc 1.4 mg Active drug layer Pelican hydrochloride 49. 59 mg Low-substituted hydroxypropylcellulose 0 mg erythritol 97. 41 mg hydroxypropylcellulose 3 mg k-coating layer hydroxypropyl fluorenylcellulose 2910 3. 75 mg Macrogol 6000 0. 75 mg Titanium oxide 0. 5 mg total 519 mg [Table 26] Additive preparation 甩 quantity flat ingot flat tableting agent 350 mg intermediate layer hydroxypropyl decyl cellulose 2910 12.6 mg talc 1. 4 mg active drug layer pegli Tazon hydrochloride 49. 59 mg erythritol 82. 41 mg low-substituted hydroxypropyl cellulose 15 mg hydroxypropyl cellulose 3 mg top coating layer hydroxypropyl methylcellulose 2910 3. 75 mg Macrogol 6000 0. 75 mg Oxide 0. 5 mg total 519 mg 74 319104 200800299 [Table 27] Active drug layer ___ Additive tableting agent 291 〇 hydrochloride erythritol 2910

Macrogoi 6Q 〇〇 化 sharpening

For the preparation of ϊ -350 one milligram -12 · 6 ] grams 1.4 mg - 49 · 59 "" gram - 67 · 41 mg 30 mg ~ 1 ~ 3. 75 mg 0. 75 " Ί: gram ~ 0. 5 mg—519~~" i gram test case 8 For the individual tablets delivered in column 14, use buffer (900 ml, ττ Μ salt S夂虱 釺% mmm ^ P 2) by paddle method (50 rpm) to evaluate the lysate of the non-hydrochloride salt of the sputum Γ4 28] The sputum is not shown in Table 28. The disintegration in the drug layer = (lowly substituted hydroxyf-propyl cellulose) Ingots) / 2 minutes after 15 minutes after the clock

As shown in Table 28, the drug dissolution rate, the mountain I... human chelating rate can be changed by changing the content of the active drug layer f; ^ 319104 75 200800299 Example 15 using the same method as in Example 6 In the formulation of the formulation, a lozenge containing 40 mg of Compound 8 and 49 59 Litazon hydrochloride per spin was prepared.良^ Hydroxypropyl fluorenyl cellulose 291〇 (average molecular weight: 19〇〇〇, redundancy-5E, Xinyue Chemical Co., Ltd.) and talc (Songcun Industry Co., Ltd.) and obtained in a pure water to obtain a coating liquid coating solution 1 Sprayed in the coating machine; Γ 平 flat on the ingot, until the ingot language increased by 15 gram per ingot, obtained the middle two stomach f coating key. 3 Then, Pyglytazon hydrochloride, (iv) propyl group (quantity: 15000 to 5_, Japan Caota Corporation) and D-mannitol company were dissolved and suspended in pure water to obtain coating liquid 2. The coating liquid 2 was sprayed onto the obtained intermediate layer bag until the fine weight gain was 225 g, to obtain an active drug layer coated ingot. Hair propyl methacrylate 291G (Tg_5e, Shin-Etsu Co., Ltd.) and egg 1 _ (Sanyo Chemical Industry Co., Ltd.) dissolved in pure water propyl methylcellulose solution 1; using dispersion I through the titanium (Fulunde Company) Dispersion liquid obtained by dispersing in pure water, and the division of the other, the liquid 1 is added to the solution of the propylmethylcellulose, and the mixture is mixed in a solution to obtain the coating liquid 3. In the coating machine, coated on the obtained active drug layer coated ingot, straight / broadcast ... 曰 + 士 j mother red weight gain of 15 mg, 'passed the formula 29 formula of the spinner, each containing 4 〇 Mg of compound a and 49. 59 grams of Pilgitazon hydrochloride. 319104 76 200800299 % [Table 29] mg iML§X 605 mg additive flat ingot intermediate layer active drug layer flat ingot #基纤维素29ΤάPiglitazon hydrochloride D-mannitol hydroxypropyl cellulose_ Cellulose 2910 --------

Macrogol 6000 Titanium Oxide Example 16 Using a flat tablet obtained in the same manner as in Example 5 and according to the formulation of Table 3, a tablet containing 20 mg of Compound A and 49.59 mg of Pigatitaz Hydrochloride per tablet was prepared. ^ propyl propyl fluorenyl cellulose 2910 (average molecular weight: 190 〇〇, • TC-5E, Shin-Etsu Chemical Co., Ltd.) and talc (Shomura Industrial Co., Ltd.) dissolved and suspended in pure water to obtain coating liquid 1, coating The liquid i was sprayed on the obtained flat ingot in a coater until the tablet weight gain was increased by 15 mg per ingot to obtain an intermediate layer coated ingot. Then, Pyglytazon hydrochloride, hydroxypropylcellulose (average molecular weight: 15,000 to 50,000, Japan Caesar Company) and !) a mannitol (Merck) are dissolved and suspended in pure water to obtain a coating. Liquid 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until the weight gain of 225 319 104 77 200800299 ig per ingot to obtain an active drug layer coated ingot. Further, hydroxypropyl mercapto cellulose 291 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain a propylmethylcellulose solution 1; Titanium oxide (Fulunde Co., Ltd.) was dispersed in a dispersion of pure water, and the obtained dispersion 1 was added to a hydroxypropylmethylcellulose solution, and the mixture was stirred in a stirrer to obtain a coating liquid 3. In the coating machine, the coating liquid 3 is sprayed on the coated tablet of the active music layer until the weight gain of each tablet is 15 mg, and the tablet having the formula of Table 30 is obtained, and each tablet contains 2 inches. </ br> </ br> </ br> </ br> </ br> [Table 30]

Example 17 Picalita contains 8 mg of compound hydrazine and 33 - _ of the formula obtained according to the formula shown in Table 31 to obtain 319104 78 200800299 First hydroxypropyl cellulose (HPC-L, Japan Caesar Company), Macrogoi 6_(molecular weight··73〇〇 to 93〇〇, two points; to, Sanyo Chemical Industry Co., Ltd.) and yellow dye No. 5 (Sanrong E. FF j. Company (San-Ei GenF.FI, 1 mouse)) dissolved Get the bond in pure water. Compound B, lactose (Meg Japan) and corn house powder (Japan Erden Powder Co., Ltd.) were uniformly mixed in a fluidized bed granulation dryer, and the mixture was granulated in a dry machine while spraying the bonded hull on it. The granules are dried in an additive bed granulation dryer to obtain granules. /~&quot; The obtained granules are ground in a powder mill, carboxymethylcellulose calcium (Yeku Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.), and mixed in a roll-to-machine to obtain granules for tableting . The obtained granules for tableting were swirled at a weight of 13 〇 with a rotary punching machine and a 7.0 mm diameter punch to obtain a flat ingot containing 8 grams of compound b. , D-mannitol (Merck), and hydroxypropyl cellulose (average molecular weight · 15,000 to 50,000, Japan Caesar Company) dissolved in pure water to obtain a package _ agricultural liquid 1, coating liquid 1 in the package The machine was sprayed on the obtained flat ingot until the weight of the key was increased by 7 mg per ingot to obtain an intermediate layer coated ingot. Then Pyglytazon hydrochloride, D-mannitol (Merck) and hydroxypropyl methylcellulose (average molecular weight··15〇〇〇 to 5〇〇〇〇, Japan's Luka Company) dissolved It was suspended in pure water to obtain a coating liquid 2. In the coating machine, the coating liquid 2 is sprayed onto the obtained intermediate layer coated ingot until the weight per gram is increased by 1 mg to obtain the active drug layer coated ingot. Further, hydroxypropyl f-based cellulose 2910 (TC_5E, Shin-Etsu Chemical Co., Ltd.) and Mocrogo! 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain 319104 200800299 perpropylmethylcellulose solution 1; A dispersion obtained by dispersing titanium oxide (Fulunde), yellow iron oxide (Uni var/Anstead), and iron oxide (BASF Japan) in pure water separately is added to hydroxypropyl hydrazine. Based on the cellulose solution 1, the mixture was stirred with stirring to obtain a coating liquid 3. In the coating machine, the coating liquid 3 is sprayed on the obtained active drug layer coated ingot until the weight gain per tablet is 1 〇 mg, and the tablet having the formula of Table 31 is obtained, and each tablet contains 8 mg of the compound 33 1 〇 克 皮 皮 皮 利 宗 盐 盐 。 。.

319104 200800299 [Table 31] Additive compounding amount Compound B 8 mg Lactose 89.396 mg Corn starch 20 mg Flat tablet hydroxypropyl cellulose 4 mg Macrogol 6000 2. 6 mg Yellow dye No. 5 0. 004 mg Carboxymethyl cellulose calcium 5. 6 mg of stearic acid 0.4 mg &gt; intermediate layer D-mannitol 68.6 mg hydroxypropyl cellulose 1.4 mg active drug layer Pelicane hydrochloride 33. 06 mg D-mannitol 64. 94 mg hydroxypropyl cellulose 2 mg hydroxypropyl methylcellulose 2910 7. 5 mg top coating layer Macrogol 6000 1.5 mg titanium oxide 0.9 mg yellow iron oxide 0. 08 mg iron oxide 0. 02 mg antelope amount -- ---- 310 mg Example 18 Each tablet contains 4 mg of compound b and 33. 10 mg of pitalitapine hydrochloride tablet is obtained according to the formulation shown in Table 32. First, it is dissolved in pure by propyl cellulose (HPC-L, Japan Caesar Co., Ltd.) and M^acrogol 6000 (molecular weight: 73〇〇 to 93〇〇, melting point: 56 to 61〇c, used chemical industry company). Water obtains a binder liquid. Compound

B, lactose (Meg Japan) and jade half eight X ten A j Hanmu wood powder (Japan Corn Starch Company) 319104 81 200800299 Evenly mixed in the fluidized bed granulation dry inorganic, the mixture is granulated in the dryer The binder liquid 1 was sprayed thereon, and the granules were dried in a fluidized bed granulation dryer to obtain granules. The obtained granules were ground in a powder mill with carboxymethyl cellulose calcium (High Toshiki Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.), and mixed in a tumbling mixer to obtain granules for tableting. The obtained granules for tableting were tableted with a rotary tableting machine and a 7,0 mm diameter punch at a weight of 13 〇 mg to obtain a flat tablet containing 4 mg of Compound B per recording. • D-mannitol (Merck), and hydroxypropyl cellulose (average molecular buy · 15,000 to 50000 'Japan Caesar Company) dissolved in pure water to obtain coating liquid 1, coating liquid 1 in the package The machine was sprayed on the obtained flat ingot until the tablet weight gain was increased by 70 mg per ingot to obtain an intermediate layer coated ingot. Then Pilgitazon hydrochloride, D-mannitol (Merck) and hydroxypropyl cellulose (average molecular weight: 15,000 to 5 〇〇〇〇, Japan Caesar Company) were dissolved and suspended in pure water. The coating liquid 2 was obtained. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until the weight gain of 1 mg per ingot to obtain an active drug layer coated ingot. Propylmercapto cellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and MaCr〇g〇i 6000 (Sanyo Chemical Industry Co., Ltd.) were dissolved in pure water to obtain propyl methacrylate solution 1; The dispersion obtained by dispersing oxidized Chin (Fulunde) and yellow iron oxide (Univo/Anshiro) in pure water was added to the hydroxypropylmethylcellulose solution i, and the mixture was stirred in a stirrer. Coating liquid 3. In the coating machine, the coating liquid 3 is sprayed on the obtained active drug layer coated ingot until the weight gain per ingot is 1〇319104 82 200800299 mg, and the tablet having the formula of Table 32 is obtained. Each ingot contains 4 beta and 33·10 mg of Pilgitazon hydrochloride. Compound [Table 32]

Example 19 A reddish tablet containing 8 gram of compound hydrazine and 16 · 5 5 gram of Pigylitazant hydrochloride was obtained according to the formulation shown in Table 33. First hydroxypropyl cellulose (HPC-L, 曰本曹打公司),

Macrogol 6000 (molecular weight: 7300 to 9300, melting point · 56 to 61 ° C, Sanyo Chemical Industry Co., Ltd.) and yellow dye No. 5 (Sanrongyuan ρ·FI) 319104 83 200800299 / combination in pure water; ^ bonding Liquid i. Compound B, lactose (Miguel T.) and corn house powder (Japan Corn Palace Powder Co., Ltd.) were mixed in a fluidized bed granulation machine. The mixture was granulated in a dryer while spraying the binder liquid 1 On top of this, the granules were dried in a fluidized bed granulation dryer to obtain granules. The obtained granules were ground in a powder mill, carboxymethylcellulose calcium (High Toshiki Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.), and mixed in a tumbling mixer to obtain granules for tableting. The obtained granules for tableting were tableted at a weight of 13 g in a spinner using a spin-type tableting machine and a 7·G mm diameter punch to obtain a flat ingot containing 8 mg of the compound B. D-mannitol (Merck), and hydroxypropylcellulose (average molecular weight 15,000 to 5 〇 (10) 〇 'Japan Caesar Co., Ltd.) dissolved in pure water to obtain coating liquid 1, coating liquid 1 in the package The machine was sprayed on the obtained flat ingot until the tablet weight gain was increased by 70 mg per ingot to obtain an intermediate layer coated ingot. Then, Peglidazin hydrochloride, D-mannitol (Merck) and hydroxypropylcellulose (average molecular weight··15000 to 50000, Japan Caesar Co., Ltd.) were dissolved and suspended in pure water to obtain a coating. Liquid 2. In the coating machine, the coating liquid 2 was sprayed onto the obtained intermediate layer coated ingot until the weight gain of each tablet was 5 〇 to obtain the active drug layer coated ingot. Further, hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and Macrogoi 6000 (Sanyo Chemical Industries Co., Ltd.) were dissolved in pure water to obtain a propyl propyl fluorenyl cellulose solution 1; Titanium oxide (Fulongde), and yellow iron oxide (Univo/Anshidai) dispersion obtained by dispersing in pure water separately, added to hydroxypropyl methylcellulose solution, mixed 319104 84 200800299 e In the case of the slinger, the coating liquid is obtained. In the coating machine, the coating liquid 3 is added to the obtained active drug layer coated ingot until the weight gain per ingot is 1 〇, and the tablet having the formula of Table 33 is obtained, and each tablet contains 8 mg of the compound 16 · 55 mg of Pilgitazon hydrochloride. [Table 33] Active drug layer additive compounding amount Compound B 8 mg Lactose 89.396 mg Corn starch 20 mg Rorimyl propylcellulose 4 mg Macrogol 6000 2. 6 mg yellow dye No. 5 0. 004 mg Carboxymethylcellulose calcium 5. 6 mg of magnesium stearate -------------- 0. 4 mg of D-mannitol 68. 6 mg of propylcellulose--;~7:----- _______ 1.4 mg Picuritabine hydrochloride 16. 53 mg D-mannitol ~ ^ 32. 47 mg transpropylcellulose ~ ———______ 1 mg of roricylpropyl thioglycol 291〇 7. 5 mg Macrogol 6000 1. 5 mg Oxide 0. 9 mg yellow iron oxide --------- 0 · 1 mg ----------- 260 mg flat ingot middle layer top Examples of the total amount of the coating layer 20 ages of the mother's cockroach containing 4 mg of the compound hydrazine and 16.55 mg of the genus of the genus Pelican were obtained according to the formulation shown in Table 34. 85 319104 200800299 First, hydroxypropyl cellulose (HPC-L, Japan Caesar Co., Ltd.), Macrogol 6000 (molecular weight: 7300 to 93 〇〇, melting point Γ56 to, Sanyo Chemical Industry Co., Ltd.) was dissolved in pure water to obtain a binder liquid hydrazine. Compound B, lactose (Meg Japan) and corn house powder (Japanese corn house powder) are uniformly mixed in a fluidized bed granulation dryer, and the mixture is sprayed in a dryer while spraying the binder liquid i thereon. The granules are dried in a fluid bed granulation dryer to obtain granules. The obtained granules were ground in a powder mill, carboxymethylcellulose calcium (Goldo Chemical Co., Ltd.) and stearic acid town (Taiping Chemical Industry Co., Ltd.), and mixed in a roll-mixer to obtain granules for tableting. The obtained granules for tableting were used: a rotary tablet machine and a 7.0 mm diameter punch were used to ingot at a weight of 13 〇 mg to obtain a flat ingot containing 4 mg of compound b per spindle. D-mannitol (Merck), and hydroxypropylcellulose (average molecular weight, 15,000 to 50,000, Japan Caesar Co., Ltd.) are dissolved in pure water to obtain coating liquid 1, and coating liquid 1 is coated. The machine sprayed on the obtained flat ingot, and the straight _p] tablet weight gain increased by 7 〇 mg per spindle to obtain an intermediate layer coated ingot. Then Pilgitazon hydrochloride 'D-mannitol (Merck) and hydroxypropyl cellulose (average molecular weight · 15 〇〇〇 to 5 〇〇〇〇, Japan Caesar company trough and suspension The coating liquid 2 was obtained in pure water. In the coating machine, the coating liquid 2 was sprayed on the obtained intermediate layer coated ingot until the weight gain of each tablet was 5 〇 to obtain the active drug layer coated ingot. , hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.) and MaCrogol 6000 (Sanyo Chemical Industry Co., Ltd.) are dissolved in pure water to obtain a propylmethylcellulose solution 1; Titanium 86 319104 200800299 Let I Brown Lund), and yellow iron oxide (Univo/Anshidai) dispersed in pure water 2, the dispersion obtained is added to the hydroxypropyl methylcellulose solution, mixed with a stirrer The coating liquid 3 was obtained by stirring. In a coater, the coating is applied to the obtained active layer coated ingot until the fine weight gain is 10 t to obtain a tablet having a % formulation, each containing 4 mg of compound b·55 mg pegg Litazon hydrochloride. [Table 34]

Example 2 母 The parent bond contains 8 mg of Compound B and 33. 〇 6 mg of Pigylitaban Salt 319104 87 200800299 The acid salt is obtained according to the formulation shown in Table 35. First hydroxypropyl cellulose (HPC-L, 曰本曹打公司), Macrogol 6000 (molecular weight: 73〇〇 to 93〇〇, melting point: 56 to, Eryang Chemical Industry Co., Ltd.) and yellow dye No. 5 (Sanrong) Source F. ρ · I · Company) Dissolved in pure water to obtain a binder liquid 1 . Compound B, lactose (Mega) and corn starch (Japan Corn Starch Co., Ltd.) were uniformly mixed in a fluidized bed granulation dryer, and the mixture was granulated in a dryer while spraying the binder liquid 1 thereon. The granules were obtained by drying in a fluidized bed granulation dryer. The obtained granules were ground in a powder mill, carboxymethylcellulose calcium (High Toshiki Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.), and mixed in a tumbling mixer to obtain granules for tableting. The obtained pellets for ingots were tableted with a rotary bar printer and a 7.0 mm diameter punch at a weight of 13 mg to obtain a flat ingot containing 8 mg of compound b per bond. Propyl propyl thiol cellulose 2910 (average molecular weight: 19 〇〇〇, TC-5E, Xinyue Chemical Co., Ltd.), Macrog〇i β 〇〇〇 (average molecular weight • to mean, melting point: 5 rc to, Sanyo Huacheng Company) and II. (= Industrial Company) are dissolved and suspended in pure water to obtain coating liquid, sprayed on the obtained flat ingot by coating liquid coating machine until the weight gain of the tablet increases to each ingot 5 mg to obtain an intermediate layer coated ingot. Then, 'hydroxypropylmethylcellulose (average molecular weight: 15 〇〇〇 to 50,000, Japan Caesar Co., Ltd.) was dissolved in pure water to obtain hydroxypropyl fluorenyl cellulose Loose 1; using a dispersing device via titanium oxide (Fu Lund Corporation), yellow iron oxide (Univo/Anshidai) and iron oxide (BASF Japan) disperse 319104 88 200800299 1 ;,, characters in f wipe oo or,,,,,, soil methylcellulose Solution &amp;mouth; see half of the stirring to obtain the binder liquid 2 . Pilguli 6 ::: priest) and mannitol (Merck), microcrystalline cellulose (KG, 2, Asahi made two dry:: 喰 喰 斑 社, ν δ, 物The granulation is simultaneously carried out in the dryer: the body of the ::, ..., and then dried in a fluidized bed granulation dryer. • Two: a tr powder grinding machine is ground, and a carboxymethyl fiber phase is added (high rolling mixing: two 1 and = purpose = (Taiping Chemical Industry # company), the mixture in pregnancy visit #^ ί granules for ingots. The obtained pellets for ingots borrowed: τ:: 'Use a 10.° mm diameter punch to use the middle Layer coating ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,晏利 319104 89 200800299

Q

[Table 35] --.~ --^~____ Additives dosage A flat ingot Β —~ —...... 8 mg lactose ~^ ~ 89. 396 mg corn starch ~~ ...... .. 20 mg of hydroxypropylcellulose 4 mg — Macrogol 6000 2. 6 mg of yellow dye No. 5 0.004 mg of methylcellulose 4 bow 5. 6 mg of magnesium stearate~~ 〇. 4 mg 1 middle layer per base Propylmethylcellulose 291 〇 3. 75 mg Macrogol 6000 〇. 75 mg talc ~ ______ 0. 5 mg outer layer 1_ piglitazon hydrochloride 33. 06 mg mannitol 143.54 mg microcrystalline cellulose 52 mg 1. 千千镁化铁0. 1 mg of yellow iron oxide 0. 1 mg of carboxymethyl cellulose calcium 20. 8 mg of magnesium stearate 2. 6 mg total ~----- -1 - ----- 395 mg----- Example 22 Each tablet contains 8 mg of Compound B and 16.53 mg of Pilgitazine Hydrochloride Tablets obtained according to the formulation shown in Table 36. First hydroxypropyl cellulose (HPC-L, 曰本曹打公司), Macrogol 6000 (molecular weight: 7300 to 9300, melting point · 56 to 61 ° C, Sanyo Chemical Industry Co., Ltd.) and yellow dye No. 5 (Sanrong source) F· F· I·Company) 90 319104 200800299 Loose solution to obtain a binder liquid 1 in pure water. Compound B, lactose (Meg) and corn starch (Japan Corn Starch Co., Ltd.) were mixed in a fluidized bed granulation dry and vertical machine, and the mixture was granulated in a dryer while spraying the binder liquid 1 thereto. The granules are dried in a fluidized bed granulation dryer to obtain granules. y The granules are known to be ground in a powder mill, and the methyl cellulose is about (High Toku Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.), and mixed in a tumbling mixing machine to obtain granules for tableting. . The obtained pellets for tableting were tableted with a spinner and a 7. G mm diameter punch at a weight of 13 mg to obtain a flat ingot containing 8 mg of the compound b. Hydroxypropyl methylcellulose 2910 (average molecular weight: 19 〇〇〇, TC - 5E, Shin-Etsu Kita Co., Ltd.), Macr〇g〇1 6 〇〇〇 (average molecular weight · π (10) to let, melting point: 56t: To 6rc, Sanyo Chemical Company) and talc (Songcun Industry Co., Ltd.) dissolved and suspended in pure water to obtain coating liquid, and the coating liquid is sprayed on the flat spinning machine in the coating machine until the tablet is increased. Add up to 5 mg per Miao and obtain a middle layer coated ingot. 9 Then, hydroxypropylmethylcellulose (average molecular weight: I" (10) to 50,000, Japan's Caodai Co., Ltd.) is dissolved in pure water to obtain a binder liquid 2. Glinta sells salt, D-mannitol (Merck Company), microcrystalline cellulose (KG-802, Asahi Kasei Co., Ltd.) and methine cellulose (high-deposited chemical 乂 in a fluidized bed granulation dryer uniformly mixed, the mixture is granulated on the same day = dry to obtain granules. The granules were ground in a powder mill and added with carboxymethylcellulose calcium (high 3191〇4 91 200800299 Women's Library Chemical Company) and magnesium stearate (mixed in Taipinghua and Fengtuan mixer to obtain ingots: f) The mixture is used in the pregnancy ingot tableting machine, using \.. The particles used in the ingots are used as the key, the internal core is keyed, and the 395 mg pregnancy key is obtained. n Tazon hydrochloride has (5) coffee and 16.53 mg of peg. Lee [Table 36]

Example 23 319104 92 200800299 A tablet containing 4 grams of Compound 3 and 16 53 grams of Pyglicata hydrochloride per ingot was obtained according to the formulation shown in the table. First hydroxypropyl cellulose (HPC-L, Japan Caesar Company), and

Macrogol 6000 (molecular weight: 73 至 to 93 〇〇, melting point: % to 6^, used chemical industry company) dissolved in pure water to obtain a binder liquid 1 . Compound B, lactose (Mega) and corn house powder (Japanese corn house powder) ^ are mixed in a fluidized bed granulation dryer, and the mixture is made in a dryer = simultaneously spraying the binder liquid i Above, the granules are dried in a fluidized bed granulation/smelter to obtain granules. The obtained granules were ground in a powder mill, carboxymethylcellulose and (High Toku Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.), and the granules for the ingots were punctured in a tumbling mixer. The obtained pellets for ingots were tableted with a rotary punching machine and a 7. G mm diameter punch at 13 () mg by weight to obtain a flat ingot containing 4 mg of compound β per ingot. Hydroxypropylmethylcellulose 2910 (average molecular weight: 19〇〇〇, /C-5E 'Xinyue Chemical Co., Ltd.), Macr〇g〇1 〇 (average molecular weight · 7 paste to 9300, melting point · 5yc to 6rc, II, Pinghuacheng) and talc (Songcun Industry. 1) Dissolve and suspend Lin water to obtain coating liquid 丨, coating liquid α coating, medium spray on the resulting flat spin, straight _ agent The weight gain is increased by 5 ^: gram per spine to obtain the intermediate layer coated ingot. The chloropropylmethylcellulose (average molecular —,, ▼ v々 j • upper ϋ υ υ υ main Japanese Caodai company) is dissolved in pure water to obtain a binder liquid 2 . Pipa sulphate, mannitol (Merck), microcrystalline 嶋化化化公司) and crosslinked methyl fiber phase (高妥库化学公319104 93 200800299 - '9 Division) in fluidized bed The mixture was uniformly mixed in a pellet dryer, and the mixture was granulated while spraying the binder liquid 2 in a dryer, followed by drying in a fluidized bed granulation dryer to obtain granules. The obtained granules were ground in a powder mill, and carboxymethyl cellulose calcium (Golden Toco Chemical Co., Ltd.) and magnesium stearate (Taiping Chemical Industry Co., Ltd.) were added, and the mixture was mixed in a two-roll mixer to obtain granules for keying. The obtained ingot is used for the pregnant ingot tableting machine, and the 10.0 mm diameter punch is used for the medium;;: Lending: as the internal core ingot, the 395 mg pregnant ingot is obtained. The package is not formulated in two kilograms, and each tablet contains 4 mg of Compound B and μ 53 Gutazon Hydrochloride. B.53 Zucker Pigley 319104 94 200800299 % [Table 37]

(Industrial Applicability) The solid pharmaceutical composition of the present invention can be clinically used as a preventive for metabolic diseases such as burgeoning, heart failure, diabetic nephropathy, arteriosclerosis, sputum, urinary disease, metabolic syndrome, and the like: The case is based on US Provisional Patent Application No. 60/795,179, which is hereby incorporated by reference. All references to patents, special shots, and public notices used in this document are hereby incorporated by reference. 319104 95

Claims (1)

200800299 4 X. Patent application scope: 1 · A solid pharmaceutical composition comprising (a) a compound containing the compound represented by formula (I) or a salt thereof or a prodrug thereof, and a core of a fatty substance having a low scent point R1 • wherein R1 is a monocyclic nitrogen-containing heterocyclic group which may be optionally substituted with a hydrogen atom which may be deprotonated as needed, R is a carboxyl group which may be esterified as needed, and R3 is a low which may be substituted as needed A carbon alkyl group, (b) a first layer comprising a high molecular weight polymer, which coats the core, and a second layer comprising (1) a Pilgita sulphate hydrochloride coating the first layer. 2. The composition of claim 1, wherein the compound represented by the formula (I) or a salt thereof or a prodrug thereof is 2-ethoxy-1-{[2,_(5-keto-4), 5-Dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}_1H_benzimidazole-7-carboxylic acid. 3. The composition of claim </ RTI> wherein the compound represented by the formula (1) or a salt thereof or a prodrug thereof is 2-ethoxy-1-{[2,-(1h-tetrazole-5-) Biphenyl-4-yl]hydrazinb 1H-benzimidazole _7_buffer acid (cyclohexyloxy)oxy)ethyl ester. 319104 96 200800299 * 4. The composition of claim 1, wherein the melting point of the oily substance having a low melting point is 20 ° C to 9 (TC. The female claiming patent consists of one composition, wherein The oily substance having a low melting point is an alkylene oxide polymer having a molecular weight of from 1,000 to 10,000. 6. The composition of the third aspect of the patent application, wherein the molecular weight of the high molecular weight polymer is from 2,500 to 400,000. The composition of the first item, wherein the high molecular weight polymer is a propyl methacrylate, a hydroxypropyl cellulose, a polyvinyl benzopyridone, or a polyvinyl alcohol or two of the polymers Mixture of more or more 319104 97 200800299 V VII. Designated representative figure: None (1) The representative figure of the case is: () Figure (2) The symbolic symbol of the representative figure is simple: ❿8. If there is a chemical formula in this case When revealing the chemical formula that best shows the characteristics of the invention: R1 5 319104