JP5854571B2 - Odor control method - Google Patents

Description

 The present invention relates to a method for suppressing the smell of a medicine.

 It is known that some medicines have an unpleasant odor, although there is no problem with the quality of the medicine itself. These drugs are required to be formulated with a reduced odor to improve the compliance of the user.

 In the prior art, for example, a sugar-coated tablet can be used to mask the odor, but the sugar-coated tablet has a drawback that the tablet becomes large and difficult to take. In addition, film-coated tablets coated with a film layer containing hydroxypropylmethylcellulose (Japanese Patent Laid-Open No. 2003-300883) and sodium carboxymethylcellulose (WO 2006/123765 pamphlet) can reduce the odor of prescription. As is known, there are cases in which film-coated preparations are not preferable from the viewpoints of tablet resolution, dissolution and stability. Further, in a pharmaceutical composition containing a specific compound having (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group (hereinafter referred to as “medoxomil group”) in the molecule as an active ingredient, odor reduction There is no known technique for formulating cyclodextrins for this purpose.

JP2003-3000883A International Publication No. 2006/123765 Pamphlet

  The objective of this invention is providing the formulation which can reduce the smell which a chemical | medical agent has even if it does not give a film coat.

  As a result of diligent studies to achieve the above object, the present inventors have surprisingly found that by adding cyclodextrin as an additive, it is possible to reduce odors in the formulation, particularly unpleasant odors. Completed.

That is, the present invention
(1) A pharmaceutical composition comprising a drug having a medoxomil group as an active ingredient and cyclodextrin as an additive,
(2) The pharmaceutical composition according to (1), wherein the drug having a medoxomil group is olmesartan medoxomil;
(3) In (1) or (2), the cyclodextrin is one or more compounds selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and chemically modified cyclodextrin The pharmaceutical composition described,
(4) The pharmaceutical composition according to (1) or (2), wherein the cyclodextrin is one or more compounds selected from β-cyclodextrin and chemically modified β-cyclodextrin,
(5) The pharmaceutical composition according to (1) or (2), wherein the cyclodextrin is β-cyclodextrin,
(6) The pharmaceutical composition according to any one of (1) to (5), wherein the pharmaceutical composition is a solid preparation,
(7) The pharmaceutical composition according to (6), wherein the solid preparation is a powder, fine granules, granules, capsules or tablets,
(8) The pharmaceutical composition according to (6), wherein the solid preparation is a tablet,
(9) The pharmaceutical composition according to (8), wherein the tablet is a film-coated tablet provided with one or more film coats,
(10) The pharmaceutical composition according to any one of (1) to (9), wherein the prescription weight ratio of cyclodextrin is 99: 1 or more of the prescription weight ratio of olmesartan medoxomil and cyclodextrin,
(11) The pharmaceutical composition according to (9), wherein the added cyclodextrin is a film-coated tablet contained as a component in the film coat,
(12) The pharmaceutical composition according to (11), wherein the prescription weight ratio of cyclodextrin is 99: 1 or more of the prescription weight ratio of olmesartan medoxomil and cyclodextrin,
(13) The pharmaceutical composition according to any one of (1) to (12), which further contains one or more of other drugs as an active ingredient,
(14) The pharmaceutical composition according to (13), wherein the other drug is one or more compounds selected from amlodipine (including besylate salt), azelnidipine and hydrochlorothiazide,
(15) The pharmaceutical composition according to any one of (1) to (14) for treating or preventing hypertension,
(16) The pharmaceutical composition according to any one of (1) to (15), wherein generation of odor is reduced,
(17) The pharmaceutical composition according to (16), wherein the odor with reduced occurrence is an unpleasant odor,
(18) A method for reducing odor generation by the pharmaceutical composition according to (1) to (15),
(19) A method for reducing the occurrence of unpleasant odor with the pharmaceutical composition according to (1) to (15),
(20) The method for producing the pharmaceutical composition according to any one of (1) to (15), wherein odor generation is reduced,
(21) The method for producing the pharmaceutical composition according to any one of (1) to (15), wherein unpleasant odor generation is reduced,
(22) Use of cyclodextrin for producing a preparation containing olmesartan medoxomil,
(23) The use of cyclodextrin for the production of a odor-reducing olmesartan medoxomil-containing preparation is provided.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the pharmaceutical composition excellent in the commercial property which does not have an unpleasant odor substantially.

  In the pharmaceutical composition of the present invention, a sufficient odor reducing effect can be obtained only by adding cyclodextrin to a drug having a medoxomil group, for example, olmesartan medoxomil. The cyclodextrin may be chemically modified in addition to α, β, and γ. Examples of the chemically modified cyclodextrin include cyclodextrins such as methylation, acetylation, hydroxypropylation, monochlorotriazination, and sulfobutylation. A plurality of cyclodextrins may be combined. The greater the amount of cyclodextrin added, the greater the effect, but the effect is exhibited even from a relatively small amount. In addition, you may add the additive generally added to a formulation. Even if granulation or slurry preparation is performed with a solvent such as ethanol, the effect is not affected. Even if it is pressure-molded by a tableting machine or the like, the effect is not affected. Cyclodextrin may be uniformly contained in the whole pharmaceutical composition, or may be contained in a part of the pharmaceutical composition. When providing a film coating layer, it may be contained in the film coating layer.

  The lower limit of the cyclodextrin content ratio in the pharmaceutical composition is usually olmesartan medoxomil: cyclodextrin = 99: 1 or more, and even if olmesartan medoxomil: cyclodextrin = 9: 1 or more, olmesartan medoxomil: cyclo Dextrin = 4: 1 or more, or olmesartan medoxomil: cyclodextrin = 2: 1 or more. Preferably, olmesartan medoxomil: cyclodextrin = 1: 1 or more, more preferably olmesartan medoxomil: cyclodextrin = 1: 2 or more, more preferably olmesartan medoxomil: cyclodextrin = 1: 9 or more, The upper limit is not limited from the viewpoint of odor reduction effect, but olmesartan medoxomil: cyclodextrin = 1: 19 or less is preferable from the viewpoint of formulation. In addition, the cyclodextrin content ratio when cyclodextrin is contained as a component in the film coat is usually such that the lower limit is olmesartan medoxomil: cyclodextrin = 999: 1 or more, and olmesartan medoxomil: cyclodextrin = 99: 1 or more. Or, it may be olmesartan medoxomil: cyclodextrin = 19: 1 or more, or olmesartan medoxomil: cyclodextrin = 8: 1 or more. Preferably, olmesartan medoxomil: cyclodextrin = 4: 1 or more, more preferably olmesartan medoxomil: cyclodextrin = 2: 1 or more, more preferably olmesartan medoxomil: cyclodextrin = 1: 1 or more, The upper limit is not limited from the viewpoint of odor reduction effect, but olmesartan medoxomil: cyclodextrin = 1: 2 or less is preferable from the viewpoint of formulation.

  In the present invention, the active ingredient contained in the pharmaceutical composition is not limited by its structure, degree, mechanism, etc., as long as it is a odorous drug. For example, olmesartan medoxomil, 2-amino-5-isobutyl- 4- {2- [5- (N, N′-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole, (5-methyl-2-oxo-1,3-dioxolene-4 -Yl) methyl (5R, 6S) -6-[(R) -1-hydroxyethyl] -2-[(R) -2-tetrahydrofuryl] penem-3-carboxylate, 2-ethoxy-1-{[ 2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl -2-oxo-1,3-dioxol-4-yl) methyl or a salt thereof (hereinafter sometimes referred to as “azirsartan medoxomil”), 2-ethoxy-1-{[2 ′-(5-oxo- 2,5- Hydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4 -Yl) methyl or a salt thereof (hereinafter sometimes referred to as “azirsartan camedoxomyl”), 2-cyclopropyl-1-{[2 ′-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl or its Salt, 2-cyclopropyl-1-{[2 '-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- Examples thereof include benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl or a salt thereof. Preferably olmesartan medoxomil, 2-amino-5-isobutyl-4- {2- [5- (N, N′-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole or (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methyl (5R, 6S) -6-[(R) -1-hydroxyethyl] -2-[(R) -2-tetrahydrofuryl] penem -3-carboxylate, particularly preferably olmesartan medoxomil. Olmesartan medoxomil is used for hypertension or a disease derived from hypertension (more specifically, hypertension, heart disease [angina, myocardial infarction, arrhythmia, heart failure or hypertrophy), kidney disease [diabetic nephropathy. , Glomerulonephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]), and is described in Patent No. 2082519 (US Pat. No. 5,616,599) and the like According to this method, it can be easily manufactured. 2-amino-5-isobutyl-4- {2- [5- (N, N'-bis ((S) -1-ethoxycarbonyl) ethyl) phosphonamido] furanyl} thiazole is a diabetic, hyperglycemic, It is effective for the prevention or treatment of dysfunction, obesity, diabetic complications, etc. (preferably prevention or treatment of diabetes), and can be easily produced according to the method described in International Publication No. 2001/047935 pamphlet etc. it can. In addition, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl (5R, 6S) -6-[(R) -1-hydroxyethyl] -2-[(R) -2- Tetrahydrofuryl] penem-3-carboxylate is a penem compound expected as an antibacterial agent, and can be easily produced according to the method described in International Publication No. 1992/003442 pamphlet or the like. Furthermore, azilsartan medoxomil, azilsartan medoxomil, 2-cyclopropyl-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl- 4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl or a salt thereof and 2-cyclopropyl-1-{[2 '-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (5-methyl- 2-Oxo-1,3-dioxol-4-yl) methyl or a salt thereof is regarded as a promising therapeutic agent for hypertension and the like, and is disclosed in WO 2005/080384 pamphlet or WO 2006/107062 pamphlet. Can be produced by the method disclosed in the above or the like, or a method analogous thereto.

  A compound having a medoxomil group in the molecule, such as olmesartan medoxomil, which is a therapeutic agent for hypertension, is converted to an active substance by gradually cleaving the medoxomil ester to form a low molecular weight 2,3-butanedione (hereinafter “diacetyl”). ”). This diacetyl itself is known as a causative substance of a unique odor, and is considered to be an odor causative substance of a pharmaceutical composition containing a medoxomil group. However, there is no known technique for reducing odor by adding cyclodextrin to a pharmaceutical composition containing a compound having a medoxomil group in the molecule as an active ingredient.

  Moreover, the pharmaceutical composition in this invention may contain the other active ingredient as needed. Examples of the active ingredient include diuretics such as Trichloromethiazide, Hydrochlorothiazide, Benzylhydrochlorothiazide; Azelnidipine, Amlodipine (including besylate salt), Calcita antagonists such as Benidipine, Nitrendipine, Manidipine, Nicardipine, Nifedipine, Cilnidipine, Efonidipine, Barnidipine, Felodipine (Pioglitazone), rosiglitazone (Rosiglitazone), riboglitazone (Rivoglitazone), MCC-555, NN-2344, BMS-298585, AZ-242, LY-519818, TAK-559 insulin resistance improvers; pravastatin ( Pravastatin), simvastatin, atorvas HMG-CoA reductase inhibitors such as tatorine (Atorvastatin), rosuvastatin, cerivastatin, pitavastatin, fluvastatin; ACAT inhibitors such as SMP-797, Pactimibe However, it is not limited to these. The amount of these active ingredients is not particularly limited, and the amount usually used for a preparation may be used.

  The pharmaceutical composition of the present invention further comprises, as necessary, appropriate pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, and the like. Additives can be included.

  “Excipients” used include, for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; Cellulose derivatives; gum arabic; dextran; or organic excipients such as pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; such as calcium hydrogen phosphate An inorganic excipient such as a phosphate; a carbonate such as calcium carbonate; or a sulfate such as calcium sulfate.

  Examples of “lubricants” used include stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bead wax or gay wax; boric acid; adipic acid Sulfate; sodium sulfate; glycol; fumaric acid; sodium stearyl fumarate: sodium benzoate; D, L-leucine; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; anhydrous silicic acid or silicic acid hydrate Or the above starch derivatives.

  Examples of the “binder” used include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or the same compound as the excipient.

  “Disintegrants” used include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or carboxymethyl starch or carboxymethyl starch Mention may be made of starch and cellulose modified chemically such as sodium.

  “Emulsifiers” used include, for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate A cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.

  “Stabilizers” used include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol or cresol Such phenols; thimerosal; dehydroacetic acid; or sorbic acid.

  Examples of the “flavoring agent” used include sweeteners such as sodium saccharin or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon or orange. it can.

  Examples of the “diluent” used include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, and polyvinylpyrrolidone. And magnesium aluminate metasilicate or mixtures thereof.

  The pharmaceutical composition in the present invention is preferably a solid preparation. For example, tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, fine granules, and powders Pills, chewables, lozenges, etc., preferably powders, fine granules, granules, capsules or tablets, more preferably tablets, and even more preferably olmesartan medoxomil and It is a tablet containing cyclodextrin uniformly.

  Examples of the method for producing the preparation in the present invention include The Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman et al .: LEA & FEBIGER 1986, pages 3-99, pages 293-373), Pharmaceutical Dosage Forms: Tablets volume 1 (Second Edition) (Herbert A. Lieberman et al .: MARCEL DEKKER INC. 1989, pages 131-284) .

  The tablet of the present invention is prepared by, for example, granulating, drying and sizing the active ingredient together with excipients, binders, disintegrants, etc. by a method known per se, adding a lubricant etc., mixing and tableting. To obtain tablets. Here, the granulation can be carried out by any of wet granulation, dry granulation, and heat granulation methods. Specifically, a high-speed agitation granulator, a fluidized granulator / dryer, an extrusion It is performed using a granulator, a roller compactor, etc. In addition, after granulation, operations such as drying and sizing may be performed as necessary. A mixture of the active ingredient and excipient, binder, disintegrant, lubricant, etc. can also be compressed directly. The tablet of the present invention may be provided with at least one film coating.

  Coating is performed using, for example, a film coating apparatus, and examples of the film coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like. Can be mentioned.

  As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan and the like may be used in combination. it can.

  Examples of the water-soluble film coating base include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose; polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, Synthetic polymers such as polyvinyl alcohol copolymer; polysaccharides such as pullulan.

  Examples of enteric film coating bases include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic Acrylic acid derivatives such as acid copolymer S; natural products such as shellac.

  Examples of the sustained-release film coating base include cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate / copolymer emulsion, and the like.

  Two or more kinds of the coating bases may be mixed and used at an appropriate ratio. Further, if necessary, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents, preservatives and the like can be contained.

  The pharmaceutical composition of the present invention thus obtained may be administered in the same manner as a normal preparation.

  EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to this.

Example 1
Olmesartan medoxomil and cyclodextrin (α-cyclodextrin (Hayashibara Biochemical Laboratories), β-cyclodextrin (Wako Pure Chemical Industries, Ltd.), γ-cyclodextrin (Wako Pure Chemical Industries, Ltd.), and Hydroxypropyl (HP-) β-cyclodextrin (Rocket Japan Co., Ltd.) was mixed in a mortar at a certain ratio (olmesartan medoxomil / cyclodextrin = 19/1 to 1/19) to obtain 10 g of mixed powder.
About 5 g of the obtained mixed powder was kneaded with an appropriate amount of ethanol to prepare a paste. The paste was dried at 80 ° C. for 1 hour and then sieved (opening: 850 μm) to obtain a processed powder.
The mixed powder and the processed powder were pressurized with φ7.5 mm mortar 10 MPa to obtain tablets (hydraulic pump (RIKEN SEIKI)).

(Comparative Example 1)
Untreated olmesartan medoxomil drug substance (Test Example 1)
In a glass bottle, 100 mg of the untreated olmesartan medoxomil drug substance (Comparative Example 1) or the mixed powder produced in Example 1 as olmesartan medoxomil was placed as an olmesartan medoxomil, which was sealed and stored at 40 ° C. for 30 minutes. Thereafter, the glass bottle was opened, and the odor sensory test was conducted by the six subjects (A to F) according to the following evaluation criteria. The results are shown in Table 1.

(Sensory evaluation criteria (Tables 1 and 2))
<Score><Contents>
0: Does not smell
1: Slightly smell
2: smell
3: It smells pretty

CD: cyclodextrin, OM: olmesartan medoxomil, a: mixed powder, b: processed powder
* Untreated olmesartan medoxomil drug substance

(Test Example 2)
In a glass bottle, 100 mg of the untreated olmesartan medoxomil drug substance (Comparative Example 1) or the powdered powder, processed powder, and tablet produced in Example 1 was added as olmesartan medoxomil as it was, sealed, and stored at 40 ° C. for 30 minutes. Thereafter, the glass bottle was opened, and a sensory test of odor was performed by the six test subjects (A to F) according to the above evaluation criteria. The results are shown in Table 2.

CD: cyclodextrin, OM: olmesartan medoxomil,
a: Mixed powder, b: Processed powder, c: Mixed powder, d: Processed powder
* Untreated olmesartan medoxomil drug substance

(Test Example 3)
500 mg of untreated olmesartan medoxomil drug substance (Comparative Example 1) or the mixed powder prepared in Example 1 as olmesartan medoxomil was placed in a gas chromatography vial (20 mL) and sealed at 40 ° C / 75% RH. Stored for days. Thereafter, the headspace gas was injected into the gas chromatography, and the concentration of the detected gas component (diacetyl) was measured. The results are shown in Table 3. The measurement conditions for gas chromatography are shown below.

[Measurement conditions for gas chromatography]
Apparatus: Gas chromatograph Shimadzu GC-2014 (Shimadzu Corporation)
Detector: Hydrogen flame ionization detector Analytical column: DB-WAX (Agilent Technology Co., Ltd., 0.53 mm id x 30 m, film thickness: 1.00 μm)
Column temperature: 50 ° C
Carrier gas: Helium flow rate: 5.0 mL / min
Inlet temperature: 200 ° C
Detector temperature: 230 ° C
Injection volume: 1.0 mL

ND: Not detected
CD: cyclodextrin, OM: olmesartan medoxomil

(Example 2)
(Example 3)
In the formulation shown in Table 4, tablets were prepared by the following method. Olmesartan medoxomil, β-cyclodextrin (Nippon Shokuhin Kako Co., Ltd.), lactose (Lactochem Co., Ltd.), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), hydroxypropyl cellulose (Nippon Soda Co., Ltd.) After mixing for 5 minutes with a high-speed agitation granulator (VG-10, Paulek Co., Ltd.), an appropriate amount of purified water was added and granulated for 3 minutes. The obtained granulated product was dried with a fluidized bed dryer (FLO-5M, Freund Sangyo Co., Ltd.). This dried product is sized with a comil (Paurec Co., Ltd.) with a screen with an aperture of about 1 mm, added with crystalline cellulose (Asahi Kasei Chemicals Co., Ltd.), magnesium stearate, and V-type mixer (Tokuju Seisakusho) And mixed for 5 minutes. The mixed granules were tableted with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain tablets with a tablet diameter of 8 mm (tablet pressure: 1 ton). The obtained tablets were made into PTP packaging of 10 tablets per sheet (material is unstretched polypropylene, hereinafter referred to as CPP) with a Press Through Package (hereinafter referred to as PTP) packaging machine.

(Comparative Example 2)
In the formulation shown in Table 5, tablets were prepared by the following method. Olmesartan medoxomil, lactose (Lactochem Co., Ltd.), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), hydroxypropyl cellulose (Nippon Soda Co., Ltd.), high-speed agitation granulator (VG-10, Paulec Co., Ltd.) )) After mixing for 5 minutes, an appropriate amount of purified water was added and granulated for 3 minutes. The obtained granulated product was dried with a fluidized bed dryer (FLO-5M, Freund Sangyo Co., Ltd.). This dried product is sized with a comil (Paurec Co., Ltd.) with a screen with an aperture of about 1 mm, added with crystalline cellulose (Asahi Kasei Chemicals Co., Ltd.), magnesium stearate, and V-type mixer (Tokuju Seisakusho) And mixed for 5 minutes. The mixed granules were tableted with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain tablets with a tablet diameter of 8 mm (tablet pressure: 1 ton). The obtained tablets were made into PTP packaging of 10 tablets per sheet (material is CPP) with a PTP packaging machine.

(Test Example 4)
The tablets (PTP packaged products) prepared in Example 2, Example 3 and Comparative Example 2 were stored at 25 ° C./75% RH for 1, 2, 3 months. One tablet of the stored PTP package was cut from the PTP sheet, put into a gas chromatography vial (about 20 mL), and sealed. The tablet was taken out from the PTP sheet using a needle, and the gas accumulated in the PTP pocket was uniformly diffused in the vial. Thereafter, the headspace gas was injected into the gas chromatography, and the concentration of the detected gas component (diacetyl) was measured. The measurement conditions for gas chromatography were the same as in Test Example 3. The results are shown in Table 6.

ND: Not detected
CD: cyclodextrin

(Test Example 5)
The tablets (PTP packaged products) prepared in Example 2, Example 3, and Comparative Example 2 were stored at 40 ° C./75% RH for 1 month. One tablet of the stored PTP package was cut out together with the PTP sheet, put into a gas chromatography vial (about 20 mL), and sealed. The tablet was taken out from the PTP sheet using a needle, and the gas accumulated in the PTP pocket was uniformly diffused in the vial. Thereafter, the headspace gas was injected into the gas chromatography, and the concentration (diacetyl) of the detected gas component was measured. The measurement conditions for gas chromatography were the same as in Test Example 3. The results are shown in Table 7.

ND: Not detected
CD: cyclodextrin

Example 4
(Example 5)
(Example 6)
An unencapsulated tablet was prepared by the formulation and production method of Comparative Example 2 (the cocoon used R の having a tablet diameter of 7.5 mm), and a coating solution containing β-cyclodextrin (Nippon Food Chemical Co., Ltd.) was applied to the coating device ( High coater mini and Freund Sangyo Co., Ltd. were coated with 10 mg or 20 mg as a solid content. The prescription is shown in Table 8. The coating solution is β-cyclodextrin aqueous solution, Opadry OY-S-9607 (Nihon Colorcon Co., Ltd.) consisting of hypromellose, titanium oxide and talc, or OpadryII 85F48011 consisting of polyvinyl alcohol, titanium oxide, talc and macrogol (Japan) Colorcon Co., Ltd.) was suspended and prepared.

(Comparative Example 3)
(Comparative Example 4)
An unencapsulated tablet is produced by the formulation and production method of Comparative Example 2 (杵 uses R 杵 having a tablet diameter of 7.5 mm), and a coating solution containing no β-cyclodextrin is applied to a coating device (HiCoater Mini, Freund Sangyo Co., Ltd.) )), 10 mg or 20 mg was coated as a solid content. The prescription is shown in Table 9. The coating solution is Opadry OY-S-9607 (Nihon Colorcon Co., Ltd.) consisting of hypromellose, titanium oxide and talc or OpadryII 85F48011 (Nihon Colorcon Co., Ltd.) consisting of polyvinyl alcohol, titanium oxide, talc and Macrogol. It was prepared by suspending in purified water.

(Test Example 6)
Three tablets prepared in Examples 4, 5, 6, and Comparative Examples 2, 3, and 4 were placed in a gas chromatography vial (20 mL), sealed, and stored at 40 ° C./75% RH for 3 days. . Thereafter, the headspace gas was injected into the gas chromatography, and the concentration of the detected gas component (diacetyl) was measured. The measurement conditions for gas chromatography were the same as in Test Example 3. The results are shown in Table 10.

ND: Not detected

  According to the present invention, a pharmaceutical composition having substantially no unpleasant odor and excellent merchantability can be obtained.

Claims (22)

The formulation weight ratio of the cyclodextrin is characterized by containing a drug having a medoxomil group as an active ingredient and β -cyclodextrin as an additive. Direct compression tablets (except film-coated tablets and sugar-coated tablets ) that are 19: 1 to 1: 1 (excluding 1: 1 ). The formulation weight ratio of the cyclodextrin is characterized by containing a drug having a medoxomil group as an active ingredient and containing α-cyclodextrin as an additive. Direct compression tablets of 2: 1 or more (excluding film-coated tablets and sugar-coated tablets). The formulation weight ratio of the cyclodextrin is characterized by containing a drug having a medoxomil group as an active ingredient and γ-cyclodextrin as an additive. Direct compression tablets of 2: 1 or more (excluding film-coated tablets and sugar-coated tablets). A drug having a medoxomil group is contained as an active ingredient, and HP-β-cyclodextrin is added as an additive. Direct compression tablets with a weight ratio of 2: 1 or more (excluding film-coated tablets and sugar-coated tablets). The direct compression tablet according to any one of claims 1 to 4 , wherein the drug having a medoxomil group is olmesartan medoxomil. The direct compression tablet according to any one of claims 1 to 5 , further comprising one or more other drugs as an active ingredient. The direct compression tablet according to claim 6 , wherein the other drug is one or more compounds selected from amlodipine (including besylate salt), azelnidipine and hydrochlorothiazide. The direct tableting according to any one of claims 1 to 7 for treating or preventing hypertension. The direct compression tablet according to any one of claims 1 to 8 , wherein generation of odor is reduced. The direct compression tablet according to claim 9 , wherein the odor with reduced occurrence is an unpleasant odor. The method for reducing odor caused by direct compression tablet of claims 1 to 8, wherein. The method for reducing unpleasant odors caused by direct compression tablet of claims 1 to 8, wherein. Method for producing a direct compression tablet was reduced odor generation according to claim 1 to 8. Method for producing a direct compression tablet of claims 1 to 8, wherein the reducing an unpleasant odor generation. Formulation ratio by weight of β- cyclodextrin, olmesartan medoxomil and the cyclodextrin formulation weight ratio 19: 1 to 1: 1 (where 1: 1 except) olmesartan medoxomil-containing direct compression tablet is (however, film-coated tablets and Use of β -cyclodextrin for production (except dragees ). Formulation ratio by weight of β- cyclodextrin, olmesartan medoxomil and the cyclodextrin formulation weight ratio 19: 1 to 1: 1 (where 1: 1 is excluded) odor reduction is olmesartan medoxomil-containing direct compression tablet (However, the film Use of β -cyclodextrin for production (excluding coated tablets and dragees ). α-Cyclodextrin for the production of olmesartan medoxomil-containing direct compression tablets (excluding film-coated tablets and sugar-coated tablets) in which the formulation weight ratio of α-cyclodextrin is 2: 1 or more of the formulation weight ratio of olmesartan medoxomil and cyclodextrin Use of. α for the production of odor-reducing olmesartan medoxomil-containing direct compression tablets (excluding film-coated tablets and sugar-coated tablets) in which the formulation weight ratio of α-cyclodextrin is 2: 1 or more of the formulation weight ratio of olmesartan medoxomil and cyclodextrin -Use of cyclodextrins. γ-Cyclodextrin for the production of olmesartan medoxomil-containing direct compression tablets (excluding film-coated tablets and sugar-coated tablets) in which the formulation weight ratio of γ-cyclodextrin is 2: 1 or more of the formulation weight ratio of olmesartan medoxomil and cyclodextrin Use of. γ for the production of odor-reducing olmesartan medoxomil-containing direct compression tablets (excluding film-coated tablets and sugar-coated tablets) in which the formulation weight ratio of γ-cyclodextrin is 2: 1 or more of the formulation weight ratio of olmesartan medoxomil and cyclodextrin -Use of cyclodextrins. HP-β for production of direct compression tablets containing olmesartan medoxomil (excluding film-coated tablets and sugar-coated tablets) in which the formulation weight ratio of HP-β-cyclodextrin is 2: 1 or more of the formulation weight ratio of olmesartan medoxomil and cyclodextrin Use of β-cyclodextrin. For the production of odor-reducing olmesartan medoxomil-containing direct compression tablets (excluding film-coated tablets and sugar-coated tablets) in which the prescription weight ratio of HP-β-cyclodextrin is 2: 1 or more of the prescription weight ratio of olmesartan medoxomil and cyclodextrin Of HP-β-cyclodextrin.