JP2007055924A - Solid preparation containing ibuprofen and ambroxol hydrochloride - Google Patents
Solid preparation containing ibuprofen and ambroxol hydrochloride Download PDFInfo
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- JP2007055924A JP2007055924A JP2005242081A JP2005242081A JP2007055924A JP 2007055924 A JP2007055924 A JP 2007055924A JP 2005242081 A JP2005242081 A JP 2005242081A JP 2005242081 A JP2005242081 A JP 2005242081A JP 2007055924 A JP2007055924 A JP 2007055924A
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- JP
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- Prior art keywords
- ibuprofen
- ambroxol hydrochloride
- preparation
- coating
- solid preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 64
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960000985 ambroxol hydrochloride Drugs 0.000 title claims abstract description 46
- 239000007787 solid Substances 0.000 title claims abstract description 29
- 238000000576 coating method Methods 0.000 claims abstract description 35
- 239000011248 coating agent Substances 0.000 claims abstract description 30
- 239000007771 core particle Substances 0.000 claims abstract description 28
- 239000011247 coating layer Substances 0.000 claims abstract description 20
- 239000000454 talc Substances 0.000 claims abstract description 15
- 229910052623 talc Inorganic materials 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 11
- 238000004220 aggregation Methods 0.000 abstract description 7
- 230000002776 aggregation Effects 0.000 abstract description 7
- 238000000354 decomposition reaction Methods 0.000 abstract description 5
- 239000008187 granular material Substances 0.000 description 37
- 238000000034 method Methods 0.000 description 23
- 238000004519 manufacturing process Methods 0.000 description 20
- 229940079593 drug Drugs 0.000 description 18
- 239000003814 drug Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000005469 granulation Methods 0.000 description 13
- 230000003179 granulation Effects 0.000 description 13
- 238000002156 mixing Methods 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229920003169 water-soluble polymer Polymers 0.000 description 8
- 239000000654 additive Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000001754 anti-pyretic effect Effects 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- 239000002221 antipyretic Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 3
- 235000019596 Masking bitterness Nutrition 0.000 description 3
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- 229960005174 ambroxol Drugs 0.000 description 3
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
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- 238000013329 compounding Methods 0.000 description 3
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- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- -1 acetal diethylaminoacetate Chemical class 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001886 ciliary effect Effects 0.000 description 2
- 229940124579 cold medicine Drugs 0.000 description 2
- 229960000920 dihydrocodeine Drugs 0.000 description 2
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000000622 irritating effect Effects 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229960002477 riboflavin Drugs 0.000 description 2
- 235000019192 riboflavin Nutrition 0.000 description 2
- 239000002151 riboflavin Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
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- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
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- 235000010323 ascorbic acid Nutrition 0.000 description 1
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- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- GVNWHCVWDRNXAZ-BTJKTKAUSA-N carbinoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 GVNWHCVWDRNXAZ-BTJKTKAUSA-N 0.000 description 1
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- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
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- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
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- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
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- 241000411851 herbal medicine Species 0.000 description 1
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- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
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- 239000003580 lung surfactant Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
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- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
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- 208000004296 neuralgia Diseases 0.000 description 1
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、イブプロフェンと塩酸アンブロキソールとを含有する固形製剤に関する。 The present invention relates to a solid preparation containing ibuprofen and ambroxol hydrochloride.
イブプロフェンは抗炎症、鎮痛、解熱等の作用を有する解熱消炎鎮痛剤、塩酸アンブロキソールは肺表面活性物質の分泌促進作用、気道液の分泌促進作用及び線毛運動亢進作用により喀痰喀出を促進する気道潤滑去痰剤であって、共に感冒薬として常用されている成分である。そして、例えば、特開２００１−１８１２０６号公報（特許文献１）には、粘液溶解薬及びビタミンＣ類を配合することを特徴とする固形剤が開示されており、明細書中においてイブプロフェンと塩酸アンブロキソールとを共に配合した固形剤が記載されている。 Ibuprofen is an antipyretic and anti-inflammatory analgesic with anti-inflammatory, analgesic and antipyretic effects, and ambroxol hydrochloride promotes exudation by promoting the secretion of pulmonary surfactants, promoting airway fluid secretion and promoting ciliary movement Airway lubrication expectorant, both commonly used as cold medicines. For example, Japanese Patent Application Laid-Open No. 2001-181206 (Patent Document 1) discloses a solid preparation characterized by containing a mucolytic agent and vitamin C. In the specification, ibuprofen and ambrohydrochloride are disclosed. A solid agent formulated with xol is described.
一方、刺激性のある苦味を有する薬物については服用性の向上の観点から、例えば、特開２０００−２７３０３７号公報（特許文献２）には、苦味又は刺激性を有する解熱及び／又は鎮痛薬を含有するチュアブル錠であって、苦味又は刺激性を有する薬物１００重量部に対して、１重量部以上の水不溶性化合物及び被覆剤を含有する解熱・鎮痛チュアブル錠が開示されている。また、特開２００３−１０４８９２号公報（特許文献３）には、芯粒子の表面にイトラコナゾール、親水性のポリマー及び凝集防止剤の被膜層を形成してなるイトラコナゾール経口用固形製剤において、前記芯粒子が直径約５００μｍ（３０メッシュ）以下のものであることを特徴とするイトラコナゾール経口用固形製剤が開示されており、明細書中においてコーティング工程時に固形製剤が凝集するという問題を解決する目的で、コーティング液にステアリン酸マグネシウム等の凝集防止剤を加えたものを使用することが記載されている。
本発明者が、イブプロフェンと塩酸アンブロキソールとを共に含有する固形製剤を調製したところ、塩酸アンブロキソールの安定性が著しく低下することがわかった。また、イブプロフェンと塩酸アンブロキソールを別々に配合した顆粒を調製し、イブプロフェンの苦味をマスキングするためにイブプロフェン含有顆粒にステアリン酸マグネシウムを含有するコーティング液を用いてフィルムコートし、塩酸アンブロキソール含有顆粒と混合したところ、直接混合して製剤化した場合とほとんど変わらずに塩酸アンブロキソールの経時的安定性が著しく低下することがわかった。 When the present inventor prepared a solid preparation containing both ibuprofen and ambroxol hydrochloride, it was found that the stability of ambroxol hydrochloride significantly decreased. In addition, granules containing ibuprofen and ambroxol hydrochloride were prepared separately. In order to mask the bitter taste of ibuprofen, the ibuprofen-containing granules were film-coated with a coating solution containing magnesium stearate and contained ambroxol hydrochloride. When mixed with granules, it was found that the stability over time of ambroxol hydrochloride was markedly reduced, almost unchanged from the case of direct mixing.
本発明は、イブプロフェンと塩酸アンブロキソールとを含有する固形製剤において、イブプロフェン含有製剤のコーティング中に凝集が起こらず作業性に優れ、且つ塩酸アンブロキソールの経時的分解が十分に抑制されて安定な固形製剤を提供することを目的とする。 In the solid preparation containing ibuprofen and ambroxol hydrochloride, the present invention is excellent in workability without aggregation during the coating of the ibuprofen-containing preparation, and stable over time because the decomposition of ambroxol hydrochloride is sufficiently suppressed. An object of the present invention is to provide a solid preparation.
本発明者は、上記目的を達成すべく鋭意研究を重ねた結果、イブプロフェンを含有する核粒子をタルクを含有するコーティング液を用いてフィルムコーティングしてイブプロフェン含有製剤を得た後に、イブプロフェン含有製剤と塩酸アンブロキソール含有製剤とを混合することによりコーティング工程時の凝集がなく作業性に優れ、しかも驚くべきことに塩酸アンブロキソールの経時的分解が十分に抑制されて安定な固形製剤が得られることを見い出し、本発明を完成するに至った。 As a result of intensive studies to achieve the above object, the present inventor obtained an ibuprofen-containing preparation after film-coating the core particles containing ibuprofen with a coating solution containing talc, Mixing with an ambroxol hydrochloride-containing preparation is excellent in workability without aggregation during the coating process, and surprisingly, the decomposition of ambroxol hydrochloride over time is sufficiently suppressed, and a stable solid preparation is obtained. As a result, the present invention has been completed.
すなわち、本発明の固形製剤は、イブプロフェンを含有する核粒子と、タルク及びコーティング基剤を含有し且つ前記核粒子を覆うコーティング層とを備えるイブプロフェン含有製剤、並びに、
塩酸アンブロキソール含有製剤、
を含有することを特徴とするものである。
That is, the solid preparation of the present invention comprises an ibuprofen-containing preparation comprising core particles containing ibuprofen, a coating layer containing talc and a coating base and covering the core particles, and
A formulation containing ambroxol hydrochloride,
It is characterized by containing.
また、本発明の固形製剤においては、前記イブプロフェン含有製剤及び前記塩酸アンブロキソール含有製剤が造粒物であることが好ましい。 In the solid preparation of the present invention, the ibuprofen-containing preparation and the ambroxol hydrochloride-containing preparation are preferably granulated products.
本発明によれば、イブプロフェンと塩酸アンブロキソールとを含有する固形製剤において、イブプロフェン含有製剤のコーティング中に凝集が起こらず作業性に優れ、且つ塩酸アンブロキソールの経時的分解が十分に抑制されて安定な固形製剤を提供することが可能となる。 According to the present invention, in a solid preparation containing ibuprofen and ambroxol hydrochloride, aggregation does not occur during the coating of the ibuprofen-containing preparation and the workability is excellent, and the decomposition of ambroxol hydrochloride with time is sufficiently suppressed. And stable solid preparations can be provided.
以下、本発明をその好適な実施形態に即して詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to preferred embodiments thereof.
本発明の固形製剤は、（i）イブプロフェンを含有する核粒子と、タルク及びコーティング基剤を含有し且つ前記核粒子を覆うコーティング層とを備えるイブプロフェン含有製剤、並びに、（ii）塩酸アンブロキソール含有製剤を含有するものである。そして、本発明にかかるイブプロフェン含有製剤は、イブプロフェンを含有する核粒子を備える。本発明にかかるイブプロフェンとは、フェニルプロピオン酸系の解熱消炎鎮痛剤であり、医療用医薬品として慢性関節リウマチ、関節痛及び神経痛に対して用いられているほか、一般用医薬品では解熱鎮痛薬やかぜ薬として用いられているものをいい、イブプロフェンの他にイブプロフェンの製薬学的に許容される塩の形態であってもよい。 The solid preparation of the present invention includes (i) a core particle containing ibuprofen, a ibuprofen-containing preparation comprising a coating layer containing talc and a coating base and covering the core particle, and (ii) ambroxol hydrochloride It contains a formulation containing. And the ibuprofen containing formulation concerning this invention is equipped with the core particle containing ibuprofen. The ibuprofen according to the present invention is a phenylpropionic acid antipyretic and analgesic and is used as a medical drug for rheumatoid arthritis, joint pain and neuralgia. It refers to what is used as a drug, and may be in the form of a pharmaceutically acceptable salt of ibuprofen in addition to ibuprofen.
このようなイブプロフェンを含有する核粒子は、イブプロフェン以外の添加成分を含んでいてもよく、例えば、添加剤、水溶性高分子、その他の有効成分を含んでいてもよい。このような添加剤としては、特に限定されないが、結晶セルロース、軽質無水ケイ酸、カルボキシメチルスターチナトリウム、クロスカルメロース、含水二酸化ケイ素、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、ヒドロキシプロピルスターチ、アメ粉、粉糖、エリスリトール、キシリトール、ソルビトール、マルチトール、ラクチトール等を挙げることができる。また、このような水溶性高分子としては、特に限定されないが、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、ポリビニルアルコール、澱粉等を挙げることができる。さらに、その他の有効成分としては、イブプロフェンとの間に配禁性を有さないものであればよく、特に限定されないが、リボフラビン、リン酸ジヒドロコデイン、マレイン酸カルビノキサミン、ｄｌ−塩酸メチルエフェドリン、アスコルビン酸、マレイン酸クロルフェニラミン等を挙げることができる。 Such core particles containing ibuprofen may contain an additive component other than ibuprofen, and may contain, for example, an additive, a water-soluble polymer, and other active ingredients. Examples of such additives include, but are not limited to, crystalline cellulose, light anhydrous silicic acid, sodium carboxymethyl starch, croscarmellose, hydrous silicon dioxide, low-substituted hydroxypropyl cellulose, croscarmellose sodium, hydroxypropyl starch, Examples thereof include candy powder, powdered sugar, erythritol, xylitol, sorbitol, maltitol, and lactitol. Such water-soluble polymers are not particularly limited, and examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and starch. Furthermore, other active ingredients are not particularly limited as long as they have no binding property with ibuprofen, and are not particularly limited, but riboflavin, dihydrocodeine phosphate, carbinoxamine maleate, dl-methylephedrine hydrochloride, ascorbic acid And chlorpheniramine maleate.
また、本発明にかかるイブプロフェンの配合量は、前記イブプロフェン含有製剤の全体質量に対して２０〜５０質量％の範囲であることが好ましい。なお、本発明で使用するイブプロフェンの配合量は、効果の点から成人１日あたり１５０〜６００ｍｇの投与量となる範囲の量に相当することが好ましい。 Moreover, it is preferable that the compounding quantity of the ibuprofen concerning this invention is the range of 20-50 mass% with respect to the whole mass of the said ibuprofen containing formulation. In addition, it is preferable that the compounding quantity of the ibuprofen used by this invention corresponds to the quantity of the range used as the dosage of 150-600 mg per day for an adult from the point of an effect.
さらに、イブプロフェンを含有する核粒子は造粒物であることが好ましい。そして、このような造粒物は、例えば、イブプロフェンを添加成分と混合し、前記水溶性高分子を溶媒（水、エタノール又はエタノール及び水の混合物）に溶解した溶液を用いて造粒することにより得られる。また、このように造粒する方法としては、一般的な造粒法でよく、特に限定されないが、例えば、攪拌造粒法、流動層造粒法、転動流動造粒法、練合造粒法、押し出し造粒法、乾式造粒法、噴霧造粒法が挙げられる。さらに、イブプロフェンを含有する核粒子の平均粒径は特に制限されないが、７５〜４００μｍの範囲であることが好ましい。 Furthermore, the core particle containing ibuprofen is preferably a granulated product. And such a granulated material is obtained by, for example, granulating using a solution in which ibuprofen is mixed with an additive component and the water-soluble polymer is dissolved in a solvent (water, ethanol or a mixture of ethanol and water). can get. In addition, the granulation method may be a general granulation method and is not particularly limited. For example, the stirring granulation method, fluidized bed granulation method, rolling fluid granulation method, kneading granulation Method, extrusion granulation method, dry granulation method and spray granulation method. Furthermore, the average particle size of the core particles containing ibuprofen is not particularly limited, but is preferably in the range of 75 to 400 μm.
本発明にかかるイブプロフェン含有製剤は、前記イブプロフェンを含有する核粒子が、タルク及びコーティング基剤を含有するコーティング層によって覆われている。本発明にかかるタルクとは、マグネシウムの含水ケイ酸塩鉱物を医療用に微粉化したものをいう。 In the ibuprofen-containing preparation according to the present invention, the core particles containing ibuprofen are covered with a coating layer containing talc and a coating base. The talc according to the present invention is obtained by pulverizing magnesium hydrous silicate mineral for medical use.
このようなタルクの配合量は、凝集抑制と製剤の大きさの観点から、前記イブプロフェン含有製剤の全体質量に対して２〜６質量％の範囲であることが好ましい。 The blending amount of such talc is preferably in the range of 2 to 6% by mass with respect to the total mass of the ibuprofen-containing preparation from the viewpoint of aggregation suppression and the size of the preparation.
また、本発明にかかるコーティング基剤としては、通常各種固形製剤のコーティング基剤として使用されるものであればよく、特に限定されないが、例えば、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、ポリビニルピロリドン、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、セルロースアセテートトリメリテート、セルロースアセテートフタレート、アミノアルキルメタアクリレートコポリマー、アクリル酸コポリマー、メタクリル酸コポリマー、ポリビニルアセタールジエチルアミノアセテートを挙げることができる。これらのコーティング基剤の中でも、苦味マスキング、薬物の安定性、薬物の溶出性等の観点から、エチルセルロースが好ましい。さらに、本発明にかかるコーティング基剤の配合量は、苦味マスキング、薬物の安定性、薬物の溶出性等の観点から、前記イブプロフェン含有製剤の全体質量に対して１〜１５質量％の範囲であることが好ましい。 The coating base according to the present invention is not particularly limited as long as it is usually used as a coating base for various solid preparations. For example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl Mention may be made of pyrrolidone, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate trimellitate, cellulose acetate phthalate, aminoalkyl methacrylate copolymer, acrylic acid copolymer, methacrylic acid copolymer, polyvinyl acetal diethylaminoacetate. it can. Among these coating bases, ethylcellulose is preferable from the viewpoints of bitterness masking, drug stability, drug elution, and the like. Furthermore, the blending amount of the coating base according to the present invention is in the range of 1 to 15% by mass with respect to the total mass of the ibuprofen-containing preparation from the viewpoints of bitterness masking, drug stability, drug elution and the like. It is preferable.
本発明にかかるコーティング層は、前記タルク及び前記コーティング基剤を含有し且つ前記核粒子を覆う層である。このようなコーティング層の前記イブプロフェン含有製剤全体に対する割合としては、苦味マスキング、薬物の安定性、薬物の溶出性等の観点から、前記イブプロフェン含有製剤の全体質量に対して５〜２０質量％の範囲であることが好ましい。また、このようなコーティング層における前記タルクと前記コーティング基剤との割合としては、質量比で２：８〜５：５（タルク：コーティング基剤）の範囲であることが好ましく、４：６（タルク：コーティング基剤）程度であることが特に好ましい。さらに、このようなコーティング層と前記核粒子との割合としては、質量比で０．５：９．５〜４：６（コーティング層：核粒子）の範囲であることが好ましい。 The coating layer concerning this invention is a layer which contains the said talc and the said coating base, and covers the said core particle. The ratio of such a coating layer to the whole ibuprofen-containing preparation is in the range of 5 to 20% by mass with respect to the total mass of the ibuprofen-containing preparation from the viewpoints of bitterness masking, drug stability, drug dissolution, etc. It is preferable that Moreover, as a ratio of the said talc and the said coating base in such a coating layer, it is preferable that it is the range of 2: 8-5: 5 (talc: coating base) by mass ratio, 4: 6 ( It is particularly preferable that the amount is about talc: coating base). Furthermore, the ratio of the coating layer to the core particles is preferably in the range of 0.5: 9.5 to 4: 6 (coating layer: core particles) in terms of mass ratio.
また、前記核粒子を前記コーティング層でコーティングする方法としては、一般的な方法を用いることができ、例えば、パンコーティング法、流動コーティング法、転動コーティング法、流動転動コーティング法が挙げられる。さらに、このような方法に用いられるコーティング液は、前記コーティング基剤と、前記タルクと、溶媒（好ましくは、エタノール又はエタノール及び水の混合物）とを混合することにより得られる。そして、このようなコーティング液の固形分濃度としては、このようなコーティング液の全体質量に対して５〜１５質量％の範囲であることが好ましい。 In addition, as a method of coating the core particles with the coating layer, a general method can be used, and examples thereof include a pan coating method, a fluid coating method, a rolling coating method, and a fluid rolling coating method. Furthermore, the coating liquid used in such a method is obtained by mixing the coating base, the talc, and a solvent (preferably ethanol or a mixture of ethanol and water). And as solid content concentration of such a coating liquid, it is preferable that it is the range of 5-15 mass% with respect to the whole mass of such a coating liquid.
本発明の固形製剤は、前述のイブプロフェン含有製剤と共に塩酸アンブロキソール含有製剤を含有する。本発明にかかる塩酸アンブロキソールとは、肺表面活性物質分泌促進作用、気道液分泌促進作用及び線毛運動動更亢進作用により気道壁を潤滑にして喀痰喀出を促進する気道潤滑去痰剤であり、錠剤、内用液剤、シロップ剤等の剤型として広く用いられているものをいい、アンブロキソールの塩酸塩の他にアンブロキソールの製薬学的に許容される塩の形態であってもよい。 The solid preparation of the present invention contains an ambroxol hydrochloride-containing preparation together with the aforementioned ibuprofen-containing preparation. Ambroxol hydrochloride according to the present invention is an airway lubricating expectorant that lubricates the airway wall and promotes exudation by pulmonary surface active substance secretion promoting action, airway fluid secretion promoting action and ciliary movement enhancement action. Refers to those widely used as dosage forms such as tablets, liquids for internal use, syrups, etc. In addition to the hydrochloride salt of ambroxol, it may be in the form of a pharmaceutically acceptable salt of ambroxol Good.
本発明にかかる塩酸アンブロキソール含有製剤は、塩酸アンブロキソール以外の成分を含んでいてもよく、例えば、添加剤、水溶性高分子、その他の有効成分を含んでいてもよい。このような添加剤及び水溶性高分子としては、前述したイブプロフェンを含有する核粒子における添加剤及び水溶性高分子と同様のものが挙げられる。また、その他の有効成分としては、塩酸アンブロキソールとの間に配禁性を有さないものであればよく、特に限定されないが、リボフラビン、カフェイン−無水、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン等を挙げることができる。さらに、本発明にかかる塩酸アンブロキソールの配合量としては、前記塩酸アンブロキソール含有製剤の全体質量に対して１〜１０質量％の範囲であることが好ましい。なお、本発明で使用する塩酸アンブロキソールの配合量は、効果の点から成人１日あたり３０〜６０ｍｇの投与量となる範囲の量に相当することが好ましい。 The ambroxol hydrochloride-containing preparation according to the present invention may contain components other than ambroxol hydrochloride, and may contain, for example, additives, water-soluble polymers, and other active ingredients. Examples of such additives and water-soluble polymers include those similar to the additives and water-soluble polymers in the aforementioned core particles containing ibuprofen. Other active ingredients are not particularly limited as long as they have no binding property with ambroxol hydrochloride, and are not particularly limited, but include riboflavin, caffeine-anhydrous, dihydrocodeine phosphate, dl-methyl hydrochloride Examples include ephedrine. Furthermore, the amount of ambroxol hydrochloride according to the present invention is preferably in the range of 1 to 10% by mass relative to the total mass of the ambroxol hydrochloride-containing preparation. In addition, it is preferable that the compounding quantity of the ambroxol hydrochloride used by this invention corresponds to the quantity of the range used as the dosage of 30-60 mg per day for an adult from the point of an effect.
また、塩酸アンブロキソール含有製剤は造粒物であることが好ましい。そして、このような造粒物は塩酸アンブロキソールと前記水溶性高分子以外の添加成分と混合し、前記水溶性高分子を溶媒（水、エタノール又はエタノール及び水の混合物）に溶解した溶液を用いて造粒することにより得られる。また、このように造粒する方法としては、前述したイブプロフェンを含有する核粒子における造粒する方法と同様の方法が挙げられる。さらに、このような塩酸アンブロキソール含有製剤の平均粒径は特に制限されないが、７５〜４００μｍの範囲であることが好ましい。 The preparation containing ambroxol hydrochloride is preferably a granulated product. Such a granulated product is mixed with ambroxol hydrochloride and an additional component other than the water-soluble polymer, and a solution obtained by dissolving the water-soluble polymer in a solvent (water, ethanol or a mixture of ethanol and water) is obtained. It is obtained by using and granulating. Examples of the granulation method include the same method as the granulation method for the core particles containing ibuprofen described above. Furthermore, the average particle diameter of such an ambroxol hydrochloride-containing preparation is not particularly limited, but is preferably in the range of 75 to 400 μm.
本発明の固形製剤は、前記イブプロフェン含有製剤と前記塩酸アンブロキソール含有製剤とを混合した後に、例えば、混合された製剤を打錠する方法等の常法により調製することができる。また、このような固形製剤の投与形態としては、特に限定されないが、例えば、顆粒剤、散剤、丸剤、錠剤、カプセル剤を挙げることができる。 The solid preparation of the present invention can be prepared by a conventional method such as a method of tableting the mixed preparation after mixing the ibuprofen-containing preparation and the ambroxol hydrochloride-containing preparation. In addition, the administration form of such a solid preparation is not particularly limited, and examples thereof include granules, powders, pills, tablets, and capsules.
また、本発明においてはイブプロフェン含有製剤及び塩酸アンブロキソール含有製剤以外に、適応症に応じてその他の有効成分含有製剤を混合することができる。このような有効成分含有製剤としては、特に限定されないが、例えば、非ステロイド抗炎症薬、消炎酵素薬、気管支拡張薬、中枢神経興奮薬、鎮咳薬、抗ヒスタミン薬又は抗アレルギー薬、抗コリン薬、他のビタミン類、制酸薬、生薬を含有する製剤を挙げることができる。これらは単独で又は２種以上を混合して用いることができ、例えば医薬品製造指針に収載されている風邪薬基準等に準拠して配合することができる。 In the present invention, in addition to the ibuprofen-containing preparation and the ambroxol hydrochloride-containing preparation, other active ingredient-containing preparations can be mixed depending on the indication. Such active ingredient-containing preparations are not particularly limited, but include, for example, non-steroidal anti-inflammatory drugs, anti-inflammatory enzymes, bronchodilators, central nervous stimulants, antitussives, antihistamines or antiallergic drugs, anticholinergic drugs And preparations containing other vitamins, antacids and herbal medicines. These can be used alone or in admixture of two or more. For example, they can be blended according to the cold medicine standards listed in the pharmaceutical production guidelines.
さらに、本発明においては前述した成分以外に、補助成分として服用時の不快感を軽減するために、メタケイ酸アルミン酸マグネシウム、香料、甘味剤（例えば、ステビア抽出精製物）等を混合することができる。 Further, in the present invention, in addition to the components described above, magnesium aluminate metasilicate, a fragrance, a sweetener (for example, stevia extract purified product), etc. may be mixed as an auxiliary component in order to reduce discomfort during taking. it can.
以下、実施例及び比較例に基づいて本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example.
（製造例１）イブプロフェンを含有する核粒子の製造
表１に記載した処方（Ａ顆粒／核粒子）に従って諸成分を配合して得られた配合物を転動流動層造粒機（パウレック社製）に仕込み、転動流動層造粒法にてイブプロフェン含有核粒子を造粒した。得られたイブプロフェン含有核粒子の平均粒径は３００μｍであった。
(Production Example 1) Production of core particles containing ibuprofen A composition obtained by blending various components according to the formulation (A granule / core particle) described in Table 1 is used as a rolling fluidized bed granulator (manufactured by POWREC). The ibuprofen-containing core particles were granulated by a rolling fluidized bed granulation method. The average particle diameter of the obtained ibuprofen-containing core particles was 300 μm.
（製造例２）イブプロフェン含有顆粒（コーティング層にタルク含有）の製造
先ず、表１に記載した実施例１に関する処方（Ａ顆粒／コーティング層）に従って諸成分を配合して得られた配合物を仕込み、さらに、エタノール１１３１ｇ及び水８５８ｇと混合してコーティング液を調製した。次いで、得られたコーティング液をドラフトチューブ付噴流層（パウレック社製）を用いて、製造例１で得られたイブプロフェン含有核粒子に塗布することによりイブプロフェン含有顆粒１を調製した。なお、イブプロフェン含有顆粒１を調製する際に凝集は起こらず、作業性に問題はなかった。
(Production Example 2) Production of ibuprofen-containing granules (containing talc in the coating layer) First, a compound obtained by blending various components according to the formulation (A granule / coating layer) relating to Example 1 described in Table 1 was charged. Further, it was mixed with 1131 g of ethanol and 858 g of water to prepare a coating solution. Subsequently, the ibuprofen containing granule 1 was prepared by apply | coating the obtained coating liquid to the ibuprofen containing core particle obtained by manufacture example 1 using the spouted bed with a draft tube (made by Paulek). In addition, when preparing the ibuprofen containing granule 1, aggregation did not occur and there was no problem in workability.
（製造例３）イブプロフェン含有顆粒（コーティング層にステアリン酸マグネシウム含有）の製造
先ず、表１に記載した比較例２に関する処方（Ａ顆粒／コーティング層）に従って諸成分を配合して得られた配合物を仕込み、さらに、エタノール８６４ｇ及び水７２９ｇと混合してコーティング液を調製した。次いで、得られたコーティング液をドラフトチューブ付噴流層（パウレック社製）を用いて、製造例１で得られたイブプロフェン含有核粒子に塗布することによりイブプロフェン含有顆粒２を調製した。なお、イブプロフェン含有顆粒２を調製する際に凝集は起こらず、作業性に問題はなかった。
(Production Example 3) Production of ibuprofen-containing granules (magnesium stearate contained in the coating layer) First, a composition obtained by blending various components according to the formulation (A granule / coating layer) relating to Comparative Example 2 described in Table 1 Was further mixed with 864 g of ethanol and 729 g of water to prepare a coating solution. Subsequently, the ibuprofen containing granule 2 was prepared by apply | coating the obtained coating liquid to the ibuprofen containing core particle obtained by manufacture example 1 using the spouted bed with a draft tube (made by Paulek). In addition, when preparing the ibuprofen containing granule 2, aggregation did not occur and there was no problem in workability.
（製造例４）塩酸アンブロキソール含有顆粒の製造
表１に記載した処方（Ｂ顆粒）に従って諸成分を配合して得られた配合物を高速撹拌造粒機（パウレック社製）に仕込み、高速撹拌造粒法にて塩酸アンブロキソール含有顆粒を調製した。
(Production Example 4) Production of Ambroxol Hydrochloride-Containing Granules A compound obtained by blending various components in accordance with the formulation (B granule) described in Table 1 was charged into a high-speed agitation granulator (manufactured by POWREC). Granules containing ambroxol hydrochloride were prepared by the stirring granulation method.
（製造例５）その他の有効成分含有顆粒の製造
表１に記載した処方（Ｃ顆粒）に従って諸成分を配合して得られた配合物を高速撹拌造粒機（パウレック社製）に仕込み、高速撹拌造粒法にてその他の有効成分含有顆粒を調製した。
(Production Example 5) Production of Other Active Ingredient-Containing Granules A blend obtained by blending various components in accordance with the formulation (C granules) described in Table 1 was charged into a high-speed agitation granulator (manufactured by POWREC). Granules containing other active ingredients were prepared by the stirring granulation method.
（実施例１）
製造例２で得られたイブプロフェン含有顆粒１と、製造例４で得られた塩酸アンブロキソール含有顆粒と、製造例５で得られたその他の有効成分含有顆粒とを混合し、さらに、メタケイ酸アルミン酸マグネシウム３２．５ｇ及び香料３．９ｇと混合して顆粒剤を得た。
Example 1
The ibuprofen-containing granule 1 obtained in Production Example 2, the ambroxol hydrochloride-containing granule obtained in Production Example 4 and the other active ingredient-containing granule obtained in Production Example 5 are mixed, and further, metasilicate Granules were obtained by mixing with 32.5 g of magnesium aluminate and 3.9 g of fragrance.
（比較例１）
製造例２で得られたイブプロフェン含有顆粒１に代えて、製造例１で得られたイブプロフェン含有核粒子をコーティング層を形成させずにそのまま用いた以外は実施例１と同様にして顆粒剤を得た。
(Comparative Example 1)
Instead of the ibuprofen-containing granules 1 obtained in Production Example 2, granules were obtained in the same manner as in Example 1 except that the ibuprofen-containing core particles obtained in Production Example 1 were used as they were without forming a coating layer. It was.
（比較例２）
製造例２で得られたイブプロフェン含有顆粒１に代えて、製造例３で得られたイブプロフェン含有顆粒２を用いた以外は実施例１と同様にして顆粒剤を得た。
(Comparative Example 2)
A granule was obtained in the same manner as in Example 1 except that the ibuprofen-containing granule 2 obtained in Production Example 3 was used in place of the ibuprofen-containing granule 1 obtained in Production Example 2.
＜経時的安定性の評価＞
実施例１及び比較例１〜２で得られた各顆粒剤について、塩酸アンブロキソールの経時的安定性を以下の方法で評価した。得られた結果を表２に示す。
<Evaluation of stability over time>
About each granule obtained in Example 1 and Comparative Examples 1-2, the temporal stability of ambroxol hydrochloride was evaluated by the following method. The obtained results are shown in Table 2.
（i）塩酸アンブロキソールの経時的安定性の評価方法
先ず、実施例１及び比較例１〜２で得られた顆粒剤を透明ビンに７ｇずつ充填、密栓し、５℃及び６５℃で１週間保存してサンプルを作製した。次に、サンプル中のイブプロフェン及び塩酸アンブロキソールの量を高速液体クロマトグラフ法（ＨＰＬＣ法）により測定し、それらの結果に基いて各薬物の残存率を求めた。そして、６５℃で１週間保存したサンプル中の薬物の残存率の５℃で１週間保存したサンプル中の薬物の残存率に対する百分率（６５℃−１週薬物残存率／５℃−１週薬物残存率）が９０％以上の場合には、薬物の経時的安定性が「十分」と判定し、それ以外の場合には、薬物の経時的安定性が「不十分」と判定した。
(I) Method for evaluating the temporal stability of ambroxol hydrochloride First, 7 g each of the granules obtained in Example 1 and Comparative Examples 1 and 2 were filled in a transparent bottle, sealed, and sealed at 5 ° C. and 65 ° C. Samples were prepared after weekly storage. Next, the amounts of ibuprofen and ambroxol hydrochloride in the sample were measured by high performance liquid chromatography (HPLC method), and the residual ratio of each drug was determined based on the results. Then, the percentage of the drug remaining rate in the sample stored at 65 ° C. for 1 week to the drug remaining rate in the sample stored at 5 ° C. for 1 week (65 ° C.-1 week drug remaining rate / 5 ° C.-1 week drug remaining rate) When the ratio was 90% or higher, the drug's stability over time was determined to be “sufficient”, and in other cases, the drug's stability over time was determined to be “insufficient”.
（ii）塩酸アンブロキソールの経時的安定性の評価結果
表２に記載した結果からも明らかなように、塩酸アンブロキソールと配禁性を有するイブプロフェンを別顆粒とした３顆粒法による製剤設計において、イブプロフェン含有顆粒がコーティング層を有さない顆粒剤（比較例１）、イブプロフェン含有顆粒のコーティング層にステアリン酸マグネシウム及びメタケイ酸アルミン酸マグネシウムを含有する顆粒剤（比較例２）は塩酸アンブロキソールの経時的安定性が「不十分」であったが、イブプロフェン含有顆粒のコーティング層にタルクを含有する顆粒剤（実施例１）は塩酸アンブロキソールの経時的安定性が「十分」となることが確認された。
(Ii) Evaluation results of stability over time of ambroxol hydrochloride As is clear from the results shown in Table 2, the formulation design by the 3-granule method using ambroxol hydrochloride and ibuprofen having incontinence as separate granules In which the ibuprofen-containing granules have no coating layer (Comparative Example 1), and the ibuprofen-containing granules have a coating layer containing magnesium stearate and magnesium aluminate metasilicate (Comparative Example 2) The stability over time of the sole was “insufficient”, but the granule containing talc in the coating layer of the ibuprofen-containing granule (Example 1) had sufficient stability over time of ambroxol hydrochloride. It was confirmed.
以上説明したように、本発明によれば、イブプロフェンと塩酸アンブロキソールとを含有する固形製剤において、イブプロフェン含有製剤のコーティング中に凝集が起こらず作業性に優れ、且つ塩酸アンブロキソールの経時的分解が十分に抑制されて安定な固形製剤を提供することが可能となる。 As described above, according to the present invention, in the solid preparation containing ibuprofen and ambroxol hydrochloride, the coagulation does not occur in the coating of the ibuprofen-containing preparation and the workability is excellent. It is possible to provide a stable solid preparation in which decomposition is sufficiently suppressed.
したがって、本発明の固形製剤は、イブプロフェンと塩酸アンブロキソールとを含有する固形製剤において、製剤中の塩酸アンブロキソールを安定化させる技術として非常に有用である。
Therefore, the solid preparation of the present invention is very useful as a technique for stabilizing ambroxol hydrochloride in a preparation in a solid preparation containing ibuprofen and ambroxol hydrochloride.
Claims (2)
塩酸アンブロキソール含有製剤、
を含有することを特徴とする固形製剤。 An ibuprofen-containing preparation comprising a core particle containing ibuprofen, and a coating layer containing talc and a coating base and covering the core particle, and
A formulation containing ambroxol hydrochloride,
A solid preparation characterized by containing.
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| JP2011116733A (en) * | 2009-04-28 | 2011-06-16 | Kowa Co | Loxoprofen-containing pharmaceutical preparation |
| JP2011132210A (en) * | 2009-04-28 | 2011-07-07 | Kowa Co | Loxoprofen-containing medicinal preparation |
| WO2011093498A1 (en) * | 2010-01-29 | 2011-08-04 | 興和株式会社 | Loxoprofen-containing pharmaceutical composition |
| JP2012046484A (en) * | 2010-06-30 | 2012-03-08 | Kowa Co | Loxoprofen-containing pharmaceutical composition |
| JP2017043546A (en) * | 2015-08-24 | 2017-03-02 | エスエス製薬株式会社 | Pharmaceutical composition for common cold |
| WO2017115745A1 (en) * | 2015-12-28 | 2017-07-06 | エスエス製薬株式会社 | Compacted pharmaceutical preparation |
| JP6260736B1 (en) * | 2016-12-20 | 2018-01-17 | 大正製薬株式会社 | Solid preparation |
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| JPH10259130A (en) * | 1997-01-17 | 1998-09-29 | Taisho Pharmaceut Co Ltd | Pharmaceutical preparation for oral administration |
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| JPH023608A (en) * | 1988-06-22 | 1990-01-09 | Taisho Pharmaceut Co Ltd | Slowly releasing ibuprofen preparation |
| WO1996033704A1 (en) * | 1995-04-26 | 1996-10-31 | Taisho Pharmaceutical Co., Ltd. | Preparation for oral administration |
| JPH10101581A (en) * | 1996-09-26 | 1998-04-21 | Taisho Pharmaceut Co Ltd | Stabilized preparation of bromhexine hydrochloride and its stabilizing method |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2011116733A (en) * | 2009-04-28 | 2011-06-16 | Kowa Co | Loxoprofen-containing pharmaceutical preparation |
| JP2011132210A (en) * | 2009-04-28 | 2011-07-07 | Kowa Co | Loxoprofen-containing medicinal preparation |
| WO2011093498A1 (en) * | 2010-01-29 | 2011-08-04 | 興和株式会社 | Loxoprofen-containing pharmaceutical composition |
| JP4787912B2 (en) * | 2010-01-29 | 2011-10-05 | 興和株式会社 | Loxoprofen-containing pharmaceutical composition |
| JP2012046484A (en) * | 2010-06-30 | 2012-03-08 | Kowa Co | Loxoprofen-containing pharmaceutical composition |
| JP2017043546A (en) * | 2015-08-24 | 2017-03-02 | エスエス製薬株式会社 | Pharmaceutical composition for common cold |
| WO2017115745A1 (en) * | 2015-12-28 | 2017-07-06 | エスエス製薬株式会社 | Compacted pharmaceutical preparation |
| JPWO2017115745A1 (en) * | 2015-12-28 | 2018-10-18 | エスエス製薬株式会社 | Compression molding |
| JP6260736B1 (en) * | 2016-12-20 | 2018-01-17 | 大正製薬株式会社 | Solid preparation |
| JP2018100259A (en) * | 2016-12-20 | 2018-06-28 | 大正製薬株式会社 | Solid preparation |
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