WO2010018777A1 - Odor-controlling method - Google Patents
Odor-controlling method Download PDFInfo
- Publication number
- WO2010018777A1 WO2010018777A1 PCT/JP2009/063922 JP2009063922W WO2010018777A1 WO 2010018777 A1 WO2010018777 A1 WO 2010018777A1 JP 2009063922 W JP2009063922 W JP 2009063922W WO 2010018777 A1 WO2010018777 A1 WO 2010018777A1
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- WO
- WIPO (PCT)
- Prior art keywords
- cyclodextrin
- pharmaceutical composition
- composition according
- odor
- olmesartan medoxomil
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to a method for suppressing the smell of drugs.
- 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”
- medoxomil group a specific compound having (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group
- An object of the present invention is to provide a preparation capable of reducing the odor of a drug without applying a film coat.
- 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 ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -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 ⁇ -cyclodextrin and chemically modified ⁇ -cyclodextrin, (5) The pharmaceutical composition according to (1) or (2), wherein the cyclodextrin is ⁇ -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 any
- 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 ⁇ , ⁇ , and ⁇ .
- Examples of the chemically modified cyclodextrin include cyclodextrins such as methylation, acetylation, hydroxypropylation, monochlorotriazination, and sulfobutylation.
- a plurality of cyclodextrins may be combined.
- 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 active ingredient contained in the pharmaceutical composition is not limited by its structure, degree, mechanism, etc., as long as it is a odorous drug.
- 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-carbox
- 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.
- (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.
- 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
- a compound having a medoxomil group in its molecule such as olmesartan medoxomil, which is a therapeutic agent for hypertension, is converted to an active substance by gradually cleaving the medoxomil ester, whereby a low molecular 2,3-butanedione (hereinafter referred to as “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.
- the pharmaceutical composition in the present invention may contain other active ingredients as necessary.
- 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 (A
- 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, ⁇ -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.
- lubricants 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 silicate hydrate Or the above starch derivatives.
- binder examples 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.
- Emsifiers 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.
- 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
- 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.
- sweeteners such as sodium saccharin or aspartame
- acidifiers such as citric acid, malic acid or tartaric acid
- 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.
- tablets including sublingual tablets and orally disintegrating tablets
- capsules including soft capsules and microcapsules
- granules fine granules
- powders Pills chewables, lozenges, etc.
- powders fine granules, granules, capsules or tablets, more preferably tablets, and even more preferably olmesartan medoxomil and It is a tablet containing cyclodextrin uniformly.
- the preparation method of the present invention includes The Theory and Practice and Pharmacy (Third Edition) (Leon and Lachman and others: LEA and FEBIGER, 1986, pages 3-99 and pages 293-373), Pharmaceutical and Dosage and Forms: Tablets and volumes. (Second Edition) (Herbert A.Lieberman et al .: MARCEL DEKKER INC. 1989, pp. 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.
- 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.
- 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.
- 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.
- water-soluble film coating base examples include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, Synthetic polymers such as polyvinyl alcohol copolymer; polysaccharides such as pullulan.
- cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose
- polysaccharides such as pullulan.
- 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.
- sustained-release film coating bases 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 of the above 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.
- 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 conducted according to the above evaluation criteria by 6 subjects (A to F). The results are shown in Table 2.
- 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.
- Example 2 Example 3
- Example 3 Tablets were prepared by the following method. Olmesartan medoxomil, ⁇ -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.
- VG-10 high-speed agitation granulator
- 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.
- 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.).
- 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.
- 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.
- 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.
- 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 ⁇ having a tablet diameter of 7.5 mm), and a coating solution containing ⁇ -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 ⁇ -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 ( ⁇ uses R ⁇ having a tablet diameter of 7.5 mm), and a coating solution containing no ⁇ -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. (Table 10) Diacetyl concentration (ng / mL) ND: Not detected
- a pharmaceutical composition having substantially no unpleasant odor and excellent merchantability can be obtained.
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Abstract
Provided is a preparation by which the odor of a medicinal agent can be reduced without coating with a film. A medicinal composition containing a compound having a medoxomil group as a medicinal component which further contains cyclodextrin as an additive.
Description
本発明は、薬剤のにおい抑制方法に関する。
The present invention relates to a method for suppressing the smell of drugs.
医薬品の中には、薬剤の品質自体に全く問題がないものの、不快な臭いを有する薬剤があることが知られている。これら薬剤は、服用者のコンプライアンス向上のため、臭いを低減した製剤とすることが求められる。
It is known that some pharmaceutical products have an unpleasant odor, although there is no problem with the quality of the drug itself. These drugs are required to be formulated with a reduced odor to improve the compliance of the user.
従来技術では、例えば糖衣錠とし、臭いをマスキングすることは可能であったが、糖衣錠では錠剤が大型化し服用しにくくなる欠点があった。また、ヒドロキシプロピルメチルセルロース（特開２００３－３００８８３号公報）やカルボキシメチルセルロースナトリウム(国際公開第２００６／１２３７６５号パンフレット）を配合したフィルム層でコーティングされたフィルムコート錠が、処方の臭いを低減することは知られているが、フィルムコート製剤は錠剤の分割性、溶出性、安定性の観点で好ましくないケースが存在する。また、分子内に（５－メチル－２－オキソー１，３ジオキソレン－４－イル）メチル基（以下、「メドキソミル基」という）を有する特定の化合物を有効成分とする医薬組成物において、臭い低減のためにシクロデキストリンを配合する技術は知られていない。
In the prior art, for example, sugar-coated tablets could be used to mask the odor, but sugar-coated tablets had the disadvantage that the tablets were 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 the formulation. 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.
本発明の目的は、フィルムコートを施さなくても薬剤の有する臭いを低減できる製剤を提供することにある。
目的 An object of the present invention is to provide a preparation capable of reducing the odor of a drug without applying a film coat.
本発明者らは前記目的を達成するために鋭意検討の結果、驚くべきことに、シクロデキストリンを添加剤として配合することにより、処方中の臭い、特に不快臭を低減できることを見出し、本発明を完成させた。
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.
すなわち、本発明は、
（１）メドキソミル基を有する薬物を有効成分として含有し、シクロデキストリンを添加剤として含有することを特徴とする医薬組成物、
（２）メドキソミル基を有する薬物が、オルメサルタンメドキソミルである（１）に記載の医薬組成物、
（３）シクロデキストリンが、α-シクロデキストリン、β-シクロデキストリン、γ-シクロデキストリン及び化学修飾されたシクロデキストリンから選択される化合物の１種又は２種以上である（１）又は（２）に記載の医薬組成物、
（４）シクロデキストリンが、β-シクロデキストリン及び化学修飾されたβ-シクロデキストリンから選択される化合物の１種又は２種以上である（１）又は（２）に記載の医薬組成物、
（５）シクロデキストリンが、β-シクロデキストリンである（１）又は（２）に記載の医薬組成物、
（６）医薬組成物が、固形製剤である（１）乃至（５）のいずれかに記載の医薬組成物、
（７）固形製剤が、散剤、細粒剤、顆粒剤、カプセル剤又は錠剤である（６）に記載の医薬組成物、
（８）固形製剤が、錠剤である（６）に記載の医薬組成物、
（９）錠剤が、１種又は２種以上のフィルムコートの設けられたフィルムコート錠である（８）に記載の医薬組成物、
（１０）シクロデキストリンの処方重量比が、オルメサルタンメドキソミルとシクロデキストリンの処方重量比９９：１以上である（１）乃至（９）いずれかに記載の医薬組成物、
（１１）添加されるシクロデキストリンが、フィルムコート中成分として含有されるフィルムコート錠である（９）に記載の医薬組成物、
（１２）シクロデキストリンの処方重量比が、オルメサルタンメドキソミルとシクロデキストリンの処方重量比９９：１以上である（１１）に記載の医薬組成物、
（１３）有効成分として他薬剤の１種又は２種以上をさらに含有する（１）乃至（１２）のいずれかに記載の医薬組成物、
（１４）他薬剤がアムロジピン(ベシレート塩を含む)、アゼルニジピン及びヒドロクロロチアジドから選択される化合物の１種又は２種以上である（１３）に記載の医薬組成物、
（１５）高血圧症治療又は予防のための（１）乃至（１４）のいずれかに記載の医薬組成物、
（１６）臭いの発生が低減された（１）乃至（１５）のいずれかに記載の医薬組成物、
（１７）発生が低減された臭いが不快な臭いである（１６）に記載の医薬組成物、
（１８）（１）乃至（１５）に記載の医薬組成物による臭い発生の低減方法、
（１９）（１）乃至（１５）に記載の医薬組成物による不快臭発生の低減方法、
（２０）臭い発生を低減化した（１）乃至（１５）に記載の医薬組成物の製造方法、
（２１）不快臭発生を低減化した（１）乃至（１５）に記載の医薬組成物の製造方法、
（２２）オルメサルタンメドキソミル含有製剤製造のためのシクロデキストリンの使用、
（２３）臭い低減化オルメサルタンメドキソミル含有製剤製造のためのシクロデキストリンの使用等を提供するものである。 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.
（１）メドキソミル基を有する薬物を有効成分として含有し、シクロデキストリンを添加剤として含有することを特徴とする医薬組成物、
（２）メドキソミル基を有する薬物が、オルメサルタンメドキソミルである（１）に記載の医薬組成物、
（３）シクロデキストリンが、α-シクロデキストリン、β-シクロデキストリン、γ-シクロデキストリン及び化学修飾されたシクロデキストリンから選択される化合物の１種又は２種以上である（１）又は（２）に記載の医薬組成物、
（４）シクロデキストリンが、β-シクロデキストリン及び化学修飾されたβ-シクロデキストリンから選択される化合物の１種又は２種以上である（１）又は（２）に記載の医薬組成物、
（５）シクロデキストリンが、β-シクロデキストリンである（１）又は（２）に記載の医薬組成物、
（６）医薬組成物が、固形製剤である（１）乃至（５）のいずれかに記載の医薬組成物、
（７）固形製剤が、散剤、細粒剤、顆粒剤、カプセル剤又は錠剤である（６）に記載の医薬組成物、
（８）固形製剤が、錠剤である（６）に記載の医薬組成物、
（９）錠剤が、１種又は２種以上のフィルムコートの設けられたフィルムコート錠である（８）に記載の医薬組成物、
（１０）シクロデキストリンの処方重量比が、オルメサルタンメドキソミルとシクロデキストリンの処方重量比９９：１以上である（１）乃至（９）いずれかに記載の医薬組成物、
（１１）添加されるシクロデキストリンが、フィルムコート中成分として含有されるフィルムコート錠である（９）に記載の医薬組成物、
（１２）シクロデキストリンの処方重量比が、オルメサルタンメドキソミルとシクロデキストリンの処方重量比９９：１以上である（１１）に記載の医薬組成物、
（１３）有効成分として他薬剤の１種又は２種以上をさらに含有する（１）乃至（１２）のいずれかに記載の医薬組成物、
（１４）他薬剤がアムロジピン(ベシレート塩を含む)、アゼルニジピン及びヒドロクロロチアジドから選択される化合物の１種又は２種以上である（１３）に記載の医薬組成物、
（１５）高血圧症治療又は予防のための（１）乃至（１４）のいずれかに記載の医薬組成物、
（１６）臭いの発生が低減された（１）乃至（１５）のいずれかに記載の医薬組成物、
（１７）発生が低減された臭いが不快な臭いである（１６）に記載の医薬組成物、
（１８）（１）乃至（１５）に記載の医薬組成物による臭い発生の低減方法、
（１９）（１）乃至（１５）に記載の医薬組成物による不快臭発生の低減方法、
（２０）臭い発生を低減化した（１）乃至（１５）に記載の医薬組成物の製造方法、
（２１）不快臭発生を低減化した（１）乃至（１５）に記載の医薬組成物の製造方法、
（２２）オルメサルタンメドキソミル含有製剤製造のためのシクロデキストリンの使用、
（２３）臭い低減化オルメサルタンメドキソミル含有製剤製造のためのシクロデキストリンの使用等を提供するものである。 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.
本発明によれば、実質的に不快臭のない、商品性に優れた医薬組成物を提供することが可能となる。
れ ば According to the present invention, it is possible to provide a pharmaceutical composition having substantially no unpleasant odor and excellent in commercial properties.
本発明における医薬組成物においては、メドキソミル基を有する薬物、例えば、オルメサルタンメドキソミルにシクロデキストリンを配合するだけで十分なにおい低減効果を得られる。シクロデキストリンはα、β、γに加え、化学修飾されたものでも構わない。化学修飾されたシクロデキストリンとしては、例えば、メチル化、アセチル化、ヒドロキシプロピル化、モノクロロトリアジノ化、スルフォブチル化のようなシクロデキストリンを挙げることができる。また複数のシクロデキストリンを組み合わせても構わない。シクロデキストリンの添加量が多いほどその効果は大きいが、比較的少量からでも効果を発揮する。その他、一般に製剤に添加される添加剤を加えても構わない。エタノール等の溶媒で造粒やスラーリー調製をしてもその効果に影響はない。また打錠機等により加圧成型してもその効果に影響はない。シクロデキストリンは、医薬組成物全体に均一に含まれていてもよく、医薬組成物の一部に含まれていてもよい。フィルムコーティング層を設ける場合には、フィルムコーティング層中に含まれていてもよい。
In the pharmaceutical composition according to 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.
医薬組成物中のシクロデキストリン含有比は、通常、下限は、オルメサルタンメドキソミル：シクロデキストリン＝９９：１以上であればよく、オルメサルタンメドキソミル：シクロデキストリン＝９：１以上であっても、オルメサルタンメドキソミル：シクロデキストリン＝４：１以上であっても、オルメサルタンメドキソミル：シクロデキストリン＝２：１以上であってもよい。好ましくは、オルメサルタンメドキソミル：シクロデキストリン＝１：１以上であり、より好ましくは、オルメサルタンメドキソミル：シクロデキストリン＝１：２以上であり、さらに好ましくは、オルメサルタンメドキソミル：シクロデキストリン＝１：９以上であり、上限は、におい低減効果の観点からは制限はないが、製剤化の観点からオルメサルタンメドキソミル：シクロデキストリン＝１：１９以下が好ましい。また、フィルムコート中成分としてシクロデキストリン含有される場合のシクロデキストリン含有比は、通常、下限は、オルメサルタンメドキソミル：シクロデキストリン＝９９９：１以上であればよく、オルメサルタンメドキソミル：シクロデキストリン＝９９：１以上であっても、オルメサルタンメドキソミル：シクロデキストリン＝１９：１以上であっても、オルメサルタンメドキソミル：シクロデキストリン＝８：１以上であってもよい。好ましくは、オルメサルタンメドキソミル：シクロデキストリン＝４：１以上であり、より好ましくは、オルメサルタンメドキソミル：シクロデキストリン＝２：１以上であり、さらに好ましくは、オルメサルタンメドキソミル：シクロデキストリン＝１：１以上であり、上限は、におい低減効果の観点からは制限はないが、製剤化の観点からオルメサルタンメドキソミル：シクロデキストリン＝１：２以下が好ましい。
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 usually has a lower limit of 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.
本発明において、医薬組成物に含まれる有効成分としては、臭いを有する薬物であればその構造、程度、機構等により限定されるものではなく、例えば、オルメサルタンメドキソミル、2-アミノ-5-イソブチル-4-{2-[5-(N,N'-ビス((S)-1-エトキシカルボニル)エチル)ホスホンアミド]フラニル}チアゾール、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル）メチル （5Ｒ，6Ｓ）-6-[（Ｒ）-1-ヒドロキシエチル]-2-[（Ｒ）-2-テトラヒドロフリル]ペネム-3-カルボキシレート、2-エトキシ-1-｛[2'-(5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル｝-1H-ベンズイミダゾール-7-カルボン酸(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル又はその塩(以下、「アジルサルタンメドキソミル」と称する場合がある)、2-エトキシ-1-｛[2'-(5-オキソ-2,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル｝-1H-ベンズイミダゾール-7-カルボン酸(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル又はその塩(以下、「アジルサルタンカメドキソミル」と称する場合がある)、2-シクロプロピル-1-｛[2'-(5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル｝-1H-ベンズイミダゾール-7-カルボン酸(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル又はその塩、2-シクロプロピル-1-｛[2'-(5-オキソ-2,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル｝-1H-ベンズイミダゾール-7-カルボン酸(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル又はその塩等を挙げることができる。好適にはオルメサルタンメドキソミル、2-アミノ-5-イソブチル-4-{2-[5-(N,N'-ビス((S)-1-エトキシカルボニル)エチル)ホスホンアミド]フラニル}チアゾールまたは(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル）メチル （5Ｒ，6Ｓ）-6-[（Ｒ）-1-ヒドロキシエチル]-2-[（Ｒ）-2-テトラヒドロフリル]ペネム-3-カルボキシレートであり、特に好適にはオルメサルタンメドキソミルである。尚、オルメサルタンメドキソミルは、高血圧症又は高血圧症に由来する疾患（より具体的には、高血圧症、心臓疾患［狭心症、心筋梗塞、不整脈、心不全若しくは心肥大］、腎臓疾患［糖尿病性腎症、糸球体腎炎若しくは腎硬化症］又は脳血管性疾患［脳梗塞若しくは脳出血］）の予防又は治療に有効であり、特許第２０８２５１９号公報（米国特許第５，６１６，５９９号公報）等に記載の方法に従い、容易に製造することができる。2-アミノ-5-イソブチル-4-{2-[5-(N,N'-ビス((S)-1-エトキシカルボニル)エチル)ホスホンアミド]フラニル}チアゾールは、糖尿病、高血糖症、耐糖能不全、肥満症、糖尿病合併症等の予防又は治療に有効であり（好適には糖尿病の予防又は治療）、国際公開第２００１／０４７９３５号パンフレット等に記載の方法に従い、容易に製造することができる。また、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル）メチル（5Ｒ，6Ｓ）-6-[（Ｒ）-1-ヒドロキシエチル]-2-[（Ｒ）-2-テトラヒドロフリル]ペネム-3-カルボキシレートは、抗菌剤として期待されているペネム化合物であり、国際公開第１９９２／００３４４２号パンフレット等に記載の方法に従い、容易に製造することができる。さらに、アジルサルタンメドキソミル、アジルサルタンカメドキソミル、2-シクロプロピル-1-｛[2'-(5-オキソ-4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル｝-1H-ベンズイミダゾール-7-カルボン酸(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル又はその塩ならびに2-シクロプロピル-1-｛[2'-(5-オキソ-2,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル｝-1H-ベンズイミダゾール-7-カルボン酸(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メチル又はその塩は、高血圧症などの治療薬として有望視されており、国際公開第２００５／０８０３８４号パンフレットもしくは国際公開第２００６／１０７０６２号パンフレット等に開示された方法又はそれに準じた方法などによって製造することができる。
なお、分子内にメドキソミル基を有する化合物、例えば高血圧症治療薬であるオルメサルタンメドキソミルは、メドキソミルエステルが徐々に切断され活性本体に変化することにより、低分子の２、３－ブタンジオン（以下、「ジアセチル」という）を発生する化合物である。このジアセチル自体は特異な臭気の原因物質として知られており、メドキソミル基を含有する医薬組成物の臭い原因物質であると考えられている。しかしながら、分子内にメドキソミル基を有する化合物を有効成分とする医薬組成物処方中にシクロデキストリンを加えることにより、臭い低減を図る技術は知られていない。 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-di Dro-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 its molecule, such as olmesartan medoxomil, which is a therapeutic agent for hypertension, is converted to an active substance by gradually cleaving the medoxomil ester, whereby a low molecular 2,3-butanedione (hereinafter referred to as “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.
なお、分子内にメドキソミル基を有する化合物、例えば高血圧症治療薬であるオルメサルタンメドキソミルは、メドキソミルエステルが徐々に切断され活性本体に変化することにより、低分子の２、３－ブタンジオン（以下、「ジアセチル」という）を発生する化合物である。このジアセチル自体は特異な臭気の原因物質として知られており、メドキソミル基を含有する医薬組成物の臭い原因物質であると考えられている。しかしながら、分子内にメドキソミル基を有する化合物を有効成分とする医薬組成物処方中にシクロデキストリンを加えることにより、臭い低減を図る技術は知られていない。 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-di Dro-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 its molecule, such as olmesartan medoxomil, which is a therapeutic agent for hypertension, is converted to an active substance by gradually cleaving the medoxomil ester, whereby a low molecular 2,3-butanedione (hereinafter referred to as “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.
また、本発明における医薬組成物は、必要に応じてその他の有効成分を含有していてもよい。該有効成分としては、例えば、トリクロルメチアジド(Trichloromethiazide)、ヒドロクロロチアジド（Hydrochlorothiazide)、ベンジルヒドロクロロチアジド（Benzylhydrochlorothiazide)、のような利尿剤；アゼルニジピン(Azelnidipine)、アムロジピン(Amlodipine)(ベシレート塩を含む)、ベニジピン(Benidipine)、ニトレンジピン(Nitrendipine)、マニジピン(Manidipine)、ニカルジピン(Nicardipine)、ニフェジピン(Nifedipine)、シルニジピン(Cilnidipine)、エホニジピン(Efonidipine)、バルニジピン(Barnidipine)、フェロジピン(Felodipine)のようなカルシウム拮抗剤；ピオグリタゾン(Pioglitazone)、ロジグリタゾン(Rosiglitazone)、リボグリタゾン(Rivoglitazone)、MCC-555、NN-2344、BMS-298585、AZ-242、LY-519818、TAK-559のようなインスリン抵抗性改善剤；プラバスタチン(Pravastatin)、シンバスタチン(Simvastatin)、アトルバスタチン(Atorvastatin)、ロスバスタチン(Rosuvastatin)、セリバスタチン(Cerivastatin)、ピタバスタチン(Pitavastatin)、フルバスタチン(Fluvastatin)のようなHMG-CoA還元酵素阻害剤；SMP-797、パクチミベ（Pactimibe）のようなACAT阻害剤などを挙げることができるが、これらに限定されるものではない。これらの有効成分の量は、特に限定されるものではなく、通常製剤に用いられる量を用いればよい。
In addition, the pharmaceutical composition in the present invention may contain other active ingredients as necessary. 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.
本発明の医薬組成物は、さらに必要に応じて、適宜の薬理学的に許容される賦形剤、滑沢剤、結合剤、崩壊剤、乳化剤、安定剤、矯味矯臭剤、希釈剤等の添加剤を含むことができる。
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.
使用される「賦形剤」としては、例えば、乳糖、白糖、葡萄糖、マンニトール若しくはソルビトールのような糖誘導体；トウモロコシデンプン、バレイショデンプン、α－澱粉若しくはデキストリンのような澱粉誘導体；結晶セルロースのようなセルロース誘導体；アラビアゴム；デキストラン；又はプルランのような有機系賦形剤；或いは、軽質無水珪酸、合成珪酸アルミニウム、珪酸カルシウム若しくはメタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体；リン酸水素カルシウムのような燐酸塩；炭酸カルシウムのような炭酸塩；又は、硫酸カルシウムのような硫酸塩等の無機系賦形剤を挙げることができる。
“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.
使用される「滑沢剤」としては、例えば、ステアリン酸；ステアリン酸カルシウム若しくはステアリン酸マグネシウムのようなステアリン酸金属塩；タルク；コロイドシリカ；ビーズワックス若しくはゲイ蝋のようなワックス類；硼酸；アジピン酸；硫酸ナトリウムのような硫酸塩；グリコール；フマル酸；フマル酸ステアリルナトリウム：安息香酸ナトリウム；Ｄ，Ｌ－ロイシン；ラウリル硫酸ナトリウム若しくはラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸若しくは珪酸水和物のような珪酸類；又は、上記澱粉誘導体を挙げることができる。
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 silicate hydrate Or the above starch derivatives.
使用される「結合剤」としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール、又は、前記賦形剤と同様の化合物を挙げることができる。
Examples of the “binder” to be used include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or the same compound as the excipient.
使用される「崩壊剤」としては、例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体；架橋ポリビニルピロリドン；又は、カルボキシメチルスターチ若しくはカルボキシメチルスターチナトリウムのような化学修飾されたデンプン・セルロース類を挙げることができる。
“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.
使用される「乳化剤」としては、例えば、ベントナイト若しくはビーガムのようなコロイド性粘土；水酸化マグネシウム若しくは水酸化アルミニウムのような金属水酸化物；ラウリル硫酸ナトリウム若しくはステアリン酸カルシウムのような陰イオン界面活性剤；塩化ベンザルコニウムのような陽イオン界面活性剤；又は、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル若しくはショ糖脂肪酸エステルのような非イオン界面活性剤を挙げることができる。
“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.
使用される「安定剤」としては、例えば、メチルパラベン若しくはプロピルパラベンのようなパラヒドロキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール若しくはクレゾールのようなフェノール類；チメロサール；デヒドロ酢酸；又は、ソルビン酸を挙げることができる。
“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.
使用される「矯味矯臭剤」としては、例えば、サッカリンナトリウム若しくはアスパルテームのような甘味料；クエン酸、リンゴ酸若しくは酒石酸のような酸味料；又は、メントール、レモン若しくはオレンジのような香料を挙げることができる。
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.
使用される「希釈剤」としては、例えば、ラクトース、マンニトール、グルコース、スクロース、硫酸カルシウム、リン酸カルシウム、ヒドロキシプロピルセルロース、微結晶性セルロース、水、エタノール、ポリエチレングリコール、プロピレングリコール、グリセロール、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム又はこれらの混合物を挙げることができる。
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.
本発明における医薬組成物は固形製剤であることが好ましく、例えば、錠剤（舌下錠、口腔内崩壊錠を含む）、カプセル剤（ソフトカプセル、マイクロカプセルを含む）、顆粒剤、細粒剤、散剤、丸剤、チュワブル剤、トローチ剤等を挙げることができ、好適には散剤、細粒剤、顆粒剤、カプセル剤又は錠剤であり、より好適には錠剤であり、さらに好適にはオルメサルタンメドキソミル及びシクロデキストリンが均一に配合された錠剤である。
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.
本発明における製剤の製造方法としては、The Theory and Practice of Industrial Pharmacy （Third Edition）（Leon Lachman 他：LEA & FEBIGER 1986、3-99ページ、293-373ページ）や、Pharmaceutical Dosage Forms:Tablets volume 1（Second Edition）（Herbert A.Lieberman他：MARCEL DEKKER INC. 1989、131-284ページ）のような刊行物に記載されている一般的な方法を用いて製造すればよく、特別な制限は設けない。
The preparation method of the present invention includes The Theory and Practice and Pharmacy (Third Edition) (Leon and Lachman and others: LEA and FEBIGER, 1986, pages 3-99 and pages 293-373), Pharmaceutical and Dosage and Forms: Tablets and volumes. (Second Edition) (Herbert A.Lieberman et al .: MARCEL DEKKER INC. 1989, pp. 131-284) .
本発明の錠剤は、例えば、それ自体公知の方法で主薬を賦形剤、結合剤、崩壊剤等とともに造粒、乾燥、整粒し、滑沢剤等を加えて混合し、製錠することにより錠剤を得る。ここで、造粒は、湿式造粒法、乾式造粒法あるいは加熱造粒法のいずれの方法によっても行うことができ、具体的には、高速攪拌造粒機、流動造粒乾燥機、押し出し造粒機、ローラーコンパクターなどを用いて行われる。また、造粒の後、必要により乾燥、整粒などの操作を行ってもよい。主薬と賦形剤、結合剤、崩壊剤、滑沢剤等の混合物を直接打錠することもできる。また、本発明の錠剤には少なくとも１層のフィルムコーティングを設けてもよい。
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.
コーティングは、例えば、フィルムコーティング装置を用いて行われ、フィルムコーティング基剤としては、例えば、糖衣基剤、水溶性フィルムコーティング基剤、腸溶性フィルムコーティング基剤、徐放性フィルムコーティング基剤などが挙げられる。
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.
糖衣基剤としては、白糖が用いられ、さらに、タルク、沈降炭酸カルシウム、リン酸カルシウム、硫酸カルシウム、ゼラチン、アラビアゴム、ポリビニルピロリドン、プルラン、などから選ばれる１種または２種以上を組み合わせて用いることもできる。
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.
水溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウムなどのセルロース誘導体；ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタクリレートコポリマー、ポリビニルピロリドン、ポリビニルアルコール、ポリビニルアルコールコポリマーなどの合成高分子；プルランなどの多糖類などが挙げられる。
Examples of the water-soluble film coating base include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone, polyvinyl alcohol, Synthetic polymers such as polyvinyl alcohol copolymer; polysaccharides such as pullulan.
腸溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロースなどのセルロース誘導体；メタアクリル酸コポリマーL、メタアクリル酸コポリマーLD、メタアクリル酸コポリマーSなどのアクリル酸誘導体；セラックなどの天然物などが挙げられる。
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.
徐放性フィルムコーティング基剤としては、例えば、エチルセルロースなどのセルロース誘導体；アミノアルキルメタクリレートコポリマーRS、アクリル酸エチル・メタクリル酸メチル・共重合体乳濁液などのアクリル酸誘導体などが挙げられる。
Examples of sustained-release film coating bases 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.
上記コーティング基剤は、その２種以上を適宜の割合で混合して用いてもよい。また、さらに必要に応じて、適宜の薬理学的に許容される可塑剤、賦形剤、滑沢剤、隠蔽剤、着色剤、防腐剤等の添加剤を含むことができる。
Two or more of the above 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.
かくして得られる本発明の医薬組成物は、通常の製剤と同様に投与すれば良い。
The pharmaceutical composition of the present invention thus obtained may be administered in the same manner as a normal preparation.
以下、実施例等により本発明をさらに詳細に説明するが、本発明はこれに限定されるものでない。
（実施例1）
オルメサルタンメドキソミルとシクロデキストリン（α-シクロデキストリン（（株）林原生物化学研究所）、β-シクロデキストリン（和光純薬工業（株））、γ-シクロデキストリン（和光純薬工業（株））、及びヒドロキシプロピル（HP-）β-シクロデキストリン（ロケットジャパン（株）））をある比率（オルメサルタンメドキソミル/シクロデキストリン＝19/1～1/19）において乳鉢混合し、10gの混合末を得た。 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.
（実施例1）
オルメサルタンメドキソミルとシクロデキストリン（α-シクロデキストリン（（株）林原生物化学研究所）、β-シクロデキストリン（和光純薬工業（株））、γ-シクロデキストリン（和光純薬工業（株））、及びヒドロキシプロピル（HP-）β-シクロデキストリン（ロケットジャパン（株）））をある比率（オルメサルタンメドキソミル/シクロデキストリン＝19/1～1/19）において乳鉢混合し、10gの混合末を得た。 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.
得られた混合末の内、約5gを適当量のエタノールを用いて混練し、ペーストを調製した。本ペーストを80℃で1時間乾燥後篩過（目開き：850 μm）し、処理末を得た。
ペ ー ス ト 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.
混合末、処理末をΦ7.5mmの臼杵10MPaで加圧し錠剤を得た（油圧ポンプ（理研精器））。
（比較例１）
無処理オルメサルタンメドキソミル原薬
（試験例１）
ガラス瓶に、無処理オルメサルタンメドキソミル原薬（比較例１）または実施例１で製造した、混合末、処理末をオルメサルタンメドキソミルとして100 mg入れ、密栓後、40℃で30分保存した。この後、ガラス瓶を開栓して、被験者6人(Ａ～Ｆ)により下記評価基準で臭いの官能試験を実施した。結果を表1に示す。 The mixed powder and the processed powder were pressurized with a 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 a sensory test of odor was performed by the six subjects (A to F) according to the following evaluation criteria. The results are shown in Table 1.
（比較例１）
無処理オルメサルタンメドキソミル原薬
（試験例１）
ガラス瓶に、無処理オルメサルタンメドキソミル原薬（比較例１）または実施例１で製造した、混合末、処理末をオルメサルタンメドキソミルとして100 mg入れ、密栓後、40℃で30分保存した。この後、ガラス瓶を開栓して、被験者6人(Ａ～Ｆ)により下記評価基準で臭いの官能試験を実施した。結果を表1に示す。 The mixed powder and the processed powder were pressurized with a 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 a sensory test of odor was performed by the six subjects (A to F) according to the following evaluation criteria. The results are shown in Table 1.
（官能評価基準（表1、2とも））
＜評点＞ ＜内容＞
0 ： 臭わない
1 ： やや臭う
2 ： 臭う
3 ： かなり臭う
(Sensory evaluation criteria (both Table 1 and 2))
<Score><Contents>
0: Does not smell 1: Smells somewhat 2: Smells 3: Smells quite
＜評点＞ ＜内容＞
0 ： 臭わない
1 ： やや臭う
2 ： 臭う
3 ： かなり臭う
(Sensory evaluation criteria (both Table 1 and 2))
<Score><Contents>
0: Does not smell 1: Smells somewhat 2: Smells 3: Smells quite
（表1）混合末、処理末の臭い評価
CD：シクロデキストリン、OM：オルメサルタンメドキソミル、a：混合末、b：処理末
*無処理オルメサルタンメドキソミル原薬 (Table 1) Odor evaluation of mixed powder and processed powder
CD: cyclodextrin, OM: olmesartan medoxomil, a: mixed powder, b: processed powder
* Untreated olmesartan medoxomil drug substance
*無処理オルメサルタンメドキソミル原薬 (Table 1) Odor evaluation of mixed powder and processed powder
* Untreated olmesartan medoxomil drug substance
（試験例2）
ガラス瓶に、無処理オルメサルタンメドキソミル原薬（比較例１）または実施例１で製造した、混合末、処理末、錠剤をオルメサルタンメドキソミルとして100 mg入れ、密栓後、40℃で30分保存した。この後、ガラス瓶を開栓して、被験者6人(Ａ～Ｆ)により前記評価基準で臭いの官能試験を実施した。結果を表2に示す。 (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 conducted according to the above evaluation criteria by 6 subjects (A to F). The results are shown in Table 2.
ガラス瓶に、無処理オルメサルタンメドキソミル原薬（比較例１）または実施例１で製造した、混合末、処理末、錠剤をオルメサルタンメドキソミルとして100 mg入れ、密栓後、40℃で30分保存した。この後、ガラス瓶を開栓して、被験者6人(Ａ～Ｆ)により前記評価基準で臭いの官能試験を実施した。結果を表2に示す。 (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 conducted according to the above evaluation criteria by 6 subjects (A to F). The results are shown in Table 2.
（表2）混合末、処理末、錠剤の臭い評価
CD：シクロデキストリン、OM：オルメサルタンメドキソミル、
a：混合末、b：処理末、c：混合末錠、d：処理末錠
*無処理オルメサルタンメドキソミル原薬 (Table 2) Odor evaluation of mixed powder, processed powder, and tablets
CD: cyclodextrin, OM: olmesartan medoxomil,
a: Mixed powder, b: Processed powder, c: Mixed powder, d: Processed powder
* Untreated olmesartan medoxomil drug substance
a：混合末、b：処理末、c：混合末錠、d：処理末錠
*無処理オルメサルタンメドキソミル原薬 (Table 2) Odor evaluation of mixed powder, processed powder, and tablets
a: Mixed powder, b: Processed powder, c: Mixed powder, d: Processed powder
* Untreated olmesartan medoxomil drug substance
（試験例3）
ガスクロマトグラフィー用のバイアル（20 mL）に、無処理オルメサルタンメドキソミル原薬（比較例１）または実施例1で調製した混合末をオルメサルタンメドキソミルとして500 mg入れ、密栓後40℃/75%RHで4日間保存した。その後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、検出されるガス成分（ジアセチル）の濃度を測定した。結果を表3に示す。なお、ガスクロマトグラフィーの測定条件を下に示す。
〔ガスクロマトグラフィーの測定条件〕
装置：ガスクロマトグラフ 島津GC-2014（（株）島津製作所）
検出器：水素炎イオン化検出器
分析カラム：DB-WAX（アジレントテクノロジー（株）、0.53 mm i.d. ×30 m、膜厚:1.00 μm）
カラム温度：50℃
キャリヤーガス：ヘリウム
流量：5.0 mL/min
注入口温度：200℃
検出器温度：230℃
注入量：1.0 mL (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
ガスクロマトグラフィー用のバイアル（20 mL）に、無処理オルメサルタンメドキソミル原薬（比較例１）または実施例1で調製した混合末をオルメサルタンメドキソミルとして500 mg入れ、密栓後40℃/75%RHで4日間保存した。その後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、検出されるガス成分（ジアセチル）の濃度を測定した。結果を表3に示す。なお、ガスクロマトグラフィーの測定条件を下に示す。
〔ガスクロマトグラフィーの測定条件〕
装置：ガスクロマトグラフ 島津GC-2014（（株）島津製作所）
検出器：水素炎イオン化検出器
分析カラム：DB-WAX（アジレントテクノロジー（株）、0.53 mm i.d. ×30 m、膜厚:1.00 μm）
カラム温度：50℃
キャリヤーガス：ヘリウム
流量：5.0 mL/min
注入口温度：200℃
検出器温度：230℃
注入量：1.0 mL (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
（表3） ジアセチル濃度 （ng/mL）
ND：検出されない
CD：シクロデキストリン、OM：オルメサルタンメドキソミル (Table 3) Diacetyl concentration (ng / mL)
ND: Not detected
CD: cyclodextrin, OM: olmesartan medoxomil
CD：シクロデキストリン、OM：オルメサルタンメドキソミル (Table 3) Diacetyl concentration (ng / mL)
CD: cyclodextrin, OM: olmesartan medoxomil
（実施例2）
（実施例3）
表4に示す処方において、以下の方法にて錠剤を作成した。オルメサルタンメドキソミル、β-シクロデキストリン（日本食品化工（株））、乳糖（ラクトケム（株））、低置換度ヒドロキシプロピルセルロース（信越化学工業（株））、ヒドロキシプロピルセルロース（日本曹達（株））を高速撹拌造粒機（VG-10、パウレック（株））で5分混合後、精製水を適量添加し3分造粒した。得られた造粒物を流動層乾燥機（FLO-5M、フロイント産業（株））で乾燥させた。この乾燥品を目開き約1 mmのスクリーンを付けたコーミル（パウレック（株））で整粒し、結晶セルロース（旭化成ケミカルズ（株））、ステアリン酸マグネシウムを添加し、V型混合機（徳寿製作所（株））で5分間混合した。混合顆粒をロータリー式打錠機（菊水製作所（株））で打錠して錠径8 mmの錠剤を得た（打錠圧：1ton）。得られた錠剤をPress Through Package（以下PTP）包装機にて10錠1シートのPTP包装（材質は無延伸ポリプロピレン、以下CPP）とした。 (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.
（実施例3）
表4に示す処方において、以下の方法にて錠剤を作成した。オルメサルタンメドキソミル、β-シクロデキストリン（日本食品化工（株））、乳糖（ラクトケム（株））、低置換度ヒドロキシプロピルセルロース（信越化学工業（株））、ヒドロキシプロピルセルロース（日本曹達（株））を高速撹拌造粒機（VG-10、パウレック（株））で5分混合後、精製水を適量添加し3分造粒した。得られた造粒物を流動層乾燥機（FLO-5M、フロイント産業（株））で乾燥させた。この乾燥品を目開き約1 mmのスクリーンを付けたコーミル（パウレック（株））で整粒し、結晶セルロース（旭化成ケミカルズ（株））、ステアリン酸マグネシウムを添加し、V型混合機（徳寿製作所（株））で5分間混合した。混合顆粒をロータリー式打錠機（菊水製作所（株））で打錠して錠径8 mmの錠剤を得た（打錠圧：1ton）。得られた錠剤をPress Through Package（以下PTP）包装機にて10錠1シートのPTP包装（材質は無延伸ポリプロピレン、以下CPP）とした。 (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.
(表4) 実施例２および実施例３処方 （mg/錠）
(Table 4) Example 2 and Example 3 formulations (mg / tablet)
（比較例２）
表5に示す処方において、以下の方法にて錠剤を作成した。オルメサルタンメドキソミル、乳糖（ラクトケム（株））、低置換度ヒドロキシプロピルセルロース（信越化学工業（株））、ヒドロキシプロピルセルロース（日本曹達（株））を高速撹拌造粒機（VG-10、パウレック（株））で5分混合後、精製水を適量添加し3分造粒した。得られた造粒物を流動層乾燥機（FLO-5M、フロイント産業（株））で乾燥させた。この乾燥品を目開き約1 mmのスクリーンを付けたコーミル（パウレック（株））で整粒し、結晶セルロース（旭化成ケミカルズ（株））、ステアリン酸マグネシウムを添加し、V型混合機（徳寿製作所（株））で5分間混合した。混合顆粒をロータリー式打錠機（菊水製作所（株））で打錠して錠径8 mmの錠剤を得た（打錠圧：1ton）。得られた錠剤をPTP包装機にて10錠1シートのPTP包装（材質はCPP）とした。 (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.
表5に示す処方において、以下の方法にて錠剤を作成した。オルメサルタンメドキソミル、乳糖（ラクトケム（株））、低置換度ヒドロキシプロピルセルロース（信越化学工業（株））、ヒドロキシプロピルセルロース（日本曹達（株））を高速撹拌造粒機（VG-10、パウレック（株））で5分混合後、精製水を適量添加し3分造粒した。得られた造粒物を流動層乾燥機（FLO-5M、フロイント産業（株））で乾燥させた。この乾燥品を目開き約1 mmのスクリーンを付けたコーミル（パウレック（株））で整粒し、結晶セルロース（旭化成ケミカルズ（株））、ステアリン酸マグネシウムを添加し、V型混合機（徳寿製作所（株））で5分間混合した。混合顆粒をロータリー式打錠機（菊水製作所（株））で打錠して錠径8 mmの錠剤を得た（打錠圧：1ton）。得られた錠剤をPTP包装機にて10錠1シートのPTP包装（材質はCPP）とした。 (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.
（表5）比較例２処方 （mg/錠）
(Table 5) Prescription for Comparative Example 2 (mg / tablet)
（試験例4）
実施例２、実施例３および比較例２で調製した錠剤（PTP包装品）を25℃/75%RHで1, 2, 3箇月保存した。保存したPTP包装品1錠分をPTPシートから切り取り、ガスクロマトグラフィーのバイアル（約20 mL）に入れ、密栓した。ニードルを用いて錠剤をPTPシートから取り出し、PTPポケット内に溜まったガスをバイアル内で均一に拡散させた。その後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、検出されるガス成分（ジアセチル）の濃度を測定した。ガスクロマトグラフィーの測定条件は試験例3と同一とした。結果を表6に示す。 (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.
実施例２、実施例３および比較例２で調製した錠剤（PTP包装品）を25℃/75%RHで1, 2, 3箇月保存した。保存したPTP包装品1錠分をPTPシートから切り取り、ガスクロマトグラフィーのバイアル（約20 mL）に入れ、密栓した。ニードルを用いて錠剤をPTPシートから取り出し、PTPポケット内に溜まったガスをバイアル内で均一に拡散させた。その後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、検出されるガス成分（ジアセチル）の濃度を測定した。ガスクロマトグラフィーの測定条件は試験例3と同一とした。結果を表6に示す。 (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.
（表6）ジアセチル濃度（25℃/75%RH） （ng/mL）
ND：検出されない
CD：シクロデキストリン (Table 6) Diacetyl concentration (25 ℃ / 75% RH) (ng / mL)
ND: Not detected
CD: cyclodextrin
CD：シクロデキストリン (Table 6) Diacetyl concentration (25 ℃ / 75% RH) (ng / mL)
CD: cyclodextrin
（試験例5）
実施例２、実施例３および比較例２で調製した錠剤（PTP包装品）を40℃/75%RHで1箇月保存した。保存したPTP包装品1錠分をPTPシートごと切り取り、ガスクロマトグラフィーのバイアル（約20 mL）に入れ、密栓した。ニードルを用いて錠剤をPTPシートから取り出し、PTPポケット内に溜まったガスをバイアル内で均一に拡散させた。その後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、検出されるガス成分の濃度（ジアセチル）を測定した。ガスクロマトグラフィーの測定条件は試験例3と同一とした。結果を表7に示す。 (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.
実施例２、実施例３および比較例２で調製した錠剤（PTP包装品）を40℃/75%RHで1箇月保存した。保存したPTP包装品1錠分をPTPシートごと切り取り、ガスクロマトグラフィーのバイアル（約20 mL）に入れ、密栓した。ニードルを用いて錠剤をPTPシートから取り出し、PTPポケット内に溜まったガスをバイアル内で均一に拡散させた。その後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、検出されるガス成分の濃度（ジアセチル）を測定した。ガスクロマトグラフィーの測定条件は試験例3と同一とした。結果を表7に示す。 (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.
（表7）ジアセチル濃度（40℃/75%RH）（ng/mL）
ND：検出されない
CD：シクロデキストリン (Table 7) Diacetyl concentration (40 ℃ / 75% RH) (ng / mL)
ND: Not detected
CD: cyclodextrin
CD：シクロデキストリン (Table 7) Diacetyl concentration (40 ℃ / 75% RH) (ng / mL)
CD: cyclodextrin
（実施例４）
（実施例５）
（実施例６）
比較例２の処方、製法にて未包被錠を製し（杵は錠径7.5 mmのR杵使用）、β-シクロデキストリン（日本食品化工（株））を含有するコーティング液をコーティング装置（ハイコーターミニ、フロイント産業（株））にて、固形分として10 mgもしくは20 mgコーティングした。処方を表8に示す。なお、コーティング液はβ-シクロデキストリン水溶液に、ヒプロメロース、酸化チタン、タルクから成るOpadry OY-S-9607（日本カラコン（株））またはポリビニルアルコール、酸化チタン、タルク、マクロゴールから成るOpadryII 85F48011（日本カラコン（株））を懸濁させ調製した。 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.
（実施例５）
（実施例６）
比較例２の処方、製法にて未包被錠を製し（杵は錠径7.5 mmのR杵使用）、β-シクロデキストリン（日本食品化工（株））を含有するコーティング液をコーティング装置（ハイコーターミニ、フロイント産業（株））にて、固形分として10 mgもしくは20 mgコーティングした。処方を表8に示す。なお、コーティング液はβ-シクロデキストリン水溶液に、ヒプロメロース、酸化チタン、タルクから成るOpadry OY-S-9607（日本カラコン（株））またはポリビニルアルコール、酸化チタン、タルク、マクロゴールから成るOpadryII 85F48011（日本カラコン（株））を懸濁させ調製した。 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.
（表８）実施例４、実施例５および実施例６処方 （mg/錠）
(Table 8) Formulas of Example 4, Example 5 and Example 6 (mg / tablet)
（比較例３）
（比較例４）
比較例２の処方、製法にて未包被錠を製し（杵は錠径7.5 mmのR杵使用）、β-シクロデキストリンを含まないコーティング液をコーティング装置（ハイコーターミニ、フロイント産業（株））にて、固形分として10 mgまたは20 mgコーティングした。処方を表9に示す。なお、コーティング液は、ヒプロメロース、酸化チタン、タルクから成るOpadry OY-S-9607（日本カラコン（株））またはポリビニルアルコール、酸化チタン、タルク、マクロゴールから成るOpadryII 85F48011（日本カラコン（株））を精製水に懸濁させ調製した。
(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.
（表９）比較例３および比較例４処方 （mg/錠）
(Table 9) Formulation of Comparative Example 3 and Comparative Example 4 (mg / tablet)
（試験例6）
ガスクロマトグラフィー用のバイアル（20 mL）に、実施例４、５、６、比較例２、３、４で製した錠剤を各3錠入れ、密栓後40℃/75%RHで3日間保存した。その後、ヘッドスペースガスをガスクロマトグラフィーにインジェクションし、検出されるガス成分（ジアセチル）の濃度を測定した。ガスクロマトグラフィーの測定条件は試験例3と同一とした。結果を表10に示す。
（表１０）ジアセチル濃度 （ng/mL）
(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.
(Table 10) Diacetyl concentration (ng / mL)
本発明によれば、実質的に不快臭のない、商品性に優れた医薬組成物が得られる。
According to the present invention, a pharmaceutical composition having substantially no unpleasant odor and excellent merchantability can be obtained.
According to the present invention, a pharmaceutical composition having substantially no unpleasant odor and excellent merchantability can be obtained.
Claims (23)
- メドキソミル基を有する薬物を有効成分として含有し、シクロデキストリンを添加剤として含有することを特徴とする医薬組成物。 A pharmaceutical composition comprising a drug having medoxomil group as an active ingredient and cyclodextrin as an additive.
- メドキソミル基を有する薬物が、オルメサルタンメドキソミルである請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the drug having 有 す る medoxomil group is olmesartan medoxomil.
- シクロデキストリンが、α-シクロデキストリン、β-シクロデキストリン、γ-シクロデキストリン及び化学修飾されたシクロデキストリンから選択される化合物の１種又は２種以上である請求項１又は２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the cyclodextrin is one or more compounds selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and chemically modified cyclodextrin. .
- シクロデキストリンが、β-シクロデキストリン及び化学修飾されたβ-シクロデキストリンから選択される化合物の１種又は２種以上である請求項１又は２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the cyclodextrin is one or more compounds selected from β-cyclodextrin and chemically modified β-cyclodextrin.
- シクロデキストリンが、β-シクロデキストリンである請求項１又は２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the cyclodextrin is β-cyclodextrin.
- 医薬組成物が、固形製剤である請求項１乃至５いずれかに記載の医薬組成物。 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is a solid preparation.
- 固形製剤が、散剤、細粒剤、顆粒剤、カプセル剤又は錠剤である請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, wherein the solid preparation is a powder, fine granules, granules, capsules or tablets.
- 固形製剤が、錠剤である請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, wherein the solid preparation is a tablet.
- 錠剤が、１種又は２種以上のフィルムコートの設けられたフィルムコート錠である請求項８に記載の医薬組成物。 The pharmaceutical composition according to claim 8, wherein the tablet is a film-coated tablet provided with one or more film coats.
- シクロデキストリンの処方重量比が、オルメサルタンメドキソミルとシクロデキストリンの処方重量比９９：１以上である請求項１乃至９いずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, wherein the prescription weight ratio of デ キ ス ト リ ン cyclodextrin is 99: 1 or more of the prescription weight ratio of olmesartan medoxomil and cyclodextrin.
- 添加されるシクロデキストリンが、フィルムコート中成分として含有されるフィルムコート錠である請求項９に記載の医薬組成物。 The pharmaceutical composition according to claim 9, wherein the cyclodextrin added is a film-coated tablet contained as a component in the film coat.
- シクロデキストリンの処方重量比が、オルメサルタンメドキソミルとシクロデキストリンの処方重量比９９：１以上である請求項１１に記載の医薬組成物。 12. The pharmaceutical composition according to claim 11, wherein the formulation weight ratio of cyclodextrin is 99: 1 or more of the formulation weight ratio of olmesartan medoxomil and cyclodextrin.
- 有効成分として他薬剤の１種又は２種以上をさらに含有する請求項１乃至１２いずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 12, further comprising one or more other drugs as active ingredients.
- 他薬剤がアムロジピン(ベシレート塩を含む)、アゼルニジピン及びヒドロクロロチアジドから選択される化合物の１種又は２種以上である請求項１３に記載の医薬組成物。 14. The pharmaceutical composition according to claim 13, wherein the other drug is one or more of compounds selected from amlodipine (including besylate salt), azelnidipine and hydrochlorothiazide.
- 高血圧症治療又は予防のための請求項１乃至１４のいずれかに記載の医薬組成物。 15. A pharmaceutical composition according to any one of claims 1 to 14 for treating or preventing hypertension.
- 臭いの発生が低減された請求項１乃至１５いずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 15, wherein the occurrence of odor is reduced.
- 発生が低減された臭いが不快な臭いである請求項１６に記載の医薬組成物。 The pharmaceutical composition according to claim 16, wherein the odor with reduced wrinkle generation is an unpleasant odor.
- 請求項１乃至１５記載の医薬組成物による臭い発生の低減方法。 A method for reducing odor generation by the pharmaceutical composition according to claim 1.
- 請求項１乃至１５記載の医薬組成物による不快臭発生の低減方法。 A method for reducing the occurrence of unpleasant odor with the pharmaceutical composition according to claim 1.
- 臭い発生を低減化した請求項１乃至１５記載の医薬組成物の製造方法。 The method for producing a pharmaceutical composition according to any one of claims 1 to 15, wherein the generation of odor is reduced.
- 不快臭発生を低減化した請求項１乃至１５記載の医薬組成物の製造方法。 The method for producing a pharmaceutical composition according to claim 1, wherein generation of unpleasant odor is reduced.
- オルメサルタンメドキソミル含有製剤製造のためのシクロデキストリンの使用。 Use of cyclodextrin for the preparation of olmesartan medoxomil-containing preparations.
- 臭い低減化オルメサルタンメドキソミル含有製剤製造のためのシクロデキストリンの使用。
Use of cyclodextrin for the preparation of a odor-reducing olmesartan medoxomil-containing preparation.
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| JP2010524712A JP5688799B2 (en) | 2008-08-11 | 2009-08-06 | Odor control method |
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| PCT/JP2009/063922 WO2010018777A1 (en) | 2008-08-11 | 2009-08-06 | Odor-controlling method |
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| JP (2) | JP5688799B2 (en) |
| TW (1) | TW201010699A (en) |
| WO (1) | WO2010018777A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014188728A1 (en) * | 2013-05-24 | 2014-11-27 | 持田製薬株式会社 | Film-coating composition |
| JP2014224099A (en) * | 2013-04-15 | 2014-12-04 | 株式会社三和化学研究所 | Olmesartan medoxomil-containing pharmaceutical composition |
| JP2015061828A (en) * | 2013-08-23 | 2015-04-02 | 第一三共株式会社 | Intraorally disintegrable tablet and method for producing the same |
| JP2016044170A (en) * | 2014-08-27 | 2016-04-04 | 日本ケミファ株式会社 | Olmesartan prodrug formulation |
| JP2016135755A (en) * | 2015-01-15 | 2016-07-28 | 大原薬品工業株式会社 | Film coating formulation containing prodrug having medoxomil group |
| JP2017001999A (en) * | 2015-06-12 | 2017-01-05 | 富士フイルム株式会社 | Manufacturing method of medicine-containing particles, medicine-containing particles, pharmaceutical composition, and orally disintegrating tablet |
| WO2017164208A1 (en) * | 2016-03-24 | 2017-09-28 | 第一三共株式会社 | Medicine for treating renal disease |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20240031121A (en) * | 2022-08-31 | 2024-03-07 | (주)셀트리온 | Double Odor Masking Pharmaceutical Composition |
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| JPH01197432A (en) * | 1988-01-29 | 1989-08-09 | Takeda Chem Ind Ltd | Solution for forming sugar layers, sugar layer and formation thereof |
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| JPWO2014188728A1 (en) * | 2013-05-24 | 2017-02-23 | 持田製薬株式会社 | Film coating composition |
| JP2015061828A (en) * | 2013-08-23 | 2015-04-02 | 第一三共株式会社 | Intraorally disintegrable tablet and method for producing the same |
| JP2016044170A (en) * | 2014-08-27 | 2016-04-04 | 日本ケミファ株式会社 | Olmesartan prodrug formulation |
| JP2016135755A (en) * | 2015-01-15 | 2016-07-28 | 大原薬品工業株式会社 | Film coating formulation containing prodrug having medoxomil group |
| JP2017001999A (en) * | 2015-06-12 | 2017-01-05 | 富士フイルム株式会社 | Manufacturing method of medicine-containing particles, medicine-containing particles, pharmaceutical composition, and orally disintegrating tablet |
| WO2017164208A1 (en) * | 2016-03-24 | 2017-09-28 | 第一三共株式会社 | Medicine for treating renal disease |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5854571B2 (en) | 2016-02-09 |
| JP5688799B2 (en) | 2015-03-25 |
| JP2015017136A (en) | 2015-01-29 |
| JPWO2010018777A1 (en) | 2012-01-26 |
| TW201010699A (en) | 2010-03-16 |
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