JP4899304B2 - Solid preparation for internal use containing ambroxol hydrochloride - Google Patents
Solid preparation for internal use containing ambroxol hydrochloride Download PDFInfo
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- JP4899304B2 JP4899304B2 JP2004304212A JP2004304212A JP4899304B2 JP 4899304 B2 JP4899304 B2 JP 4899304B2 JP 2004304212 A JP2004304212 A JP 2004304212A JP 2004304212 A JP2004304212 A JP 2004304212A JP 4899304 B2 JP4899304 B2 JP 4899304B2
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- ambroxol hydrochloride
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- ascorbic acid
- solid preparation
- internal use
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- 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 description 48
- 229960000985 ambroxol hydrochloride Drugs 0.000 title claims description 48
- 238000002360 preparation method Methods 0.000 title claims description 33
- 239000007787 solid Substances 0.000 title claims description 24
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 54
- 235000010323 ascorbic acid Nutrition 0.000 claims description 26
- 239000011668 ascorbic acid Substances 0.000 claims description 26
- 229960005070 ascorbic acid Drugs 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 21
- 229960003495 thiamine Drugs 0.000 claims description 16
- 239000008187 granular material Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 claims description 7
- 235000010376 calcium ascorbate Nutrition 0.000 claims description 4
- 239000011692 calcium ascorbate Substances 0.000 claims description 4
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 claims description 4
- 230000000087 stabilizing effect Effects 0.000 claims description 4
- CKHJPWQVLKHBIH-ZDSKVHJSSA-N sulbutiamine Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(/C)=C(/CCOC(=O)C(C)C)SS\C(CCOC(=O)C(C)C)=C(\C)N(C=O)CC1=CN=C(C)N=C1N CKHJPWQVLKHBIH-ZDSKVHJSSA-N 0.000 claims description 4
- 229940047036 calcium ascorbate Drugs 0.000 claims description 3
- 229960003211 sulbutiamine Drugs 0.000 claims description 3
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 2
- 235000019157 thiamine Nutrition 0.000 claims description 2
- 239000011721 thiamine Substances 0.000 claims description 2
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 claims description 2
- 229960004860 thiamine mononitrate Drugs 0.000 claims 1
- 235000019191 thiamine mononitrate Nutrition 0.000 claims 1
- 239000011748 thiamine mononitrate Substances 0.000 claims 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 15
- 229930003451 Vitamin B1 Natural products 0.000 description 14
- 235000010374 vitamin B1 Nutrition 0.000 description 14
- 239000011691 vitamin B1 Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 11
- 238000005469 granulation Methods 0.000 description 10
- 230000003179 granulation Effects 0.000 description 10
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 230000003419 expectorant effect Effects 0.000 description 7
- 229940124579 cold medicine Drugs 0.000 description 6
- 229960000920 dihydrocodeine Drugs 0.000 description 6
- 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 6
- 238000009472 formulation Methods 0.000 description 6
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 5
- 235000012239 silicon dioxide Nutrition 0.000 description 5
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 4
- 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 4
- 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 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 4
- 229960001948 caffeine Drugs 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 4
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- 229940079593 drug Drugs 0.000 description 4
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- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 4
- 229960004708 noscapine Drugs 0.000 description 4
- 229960005489 paracetamol Drugs 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 235000019192 riboflavin Nutrition 0.000 description 4
- 229960002477 riboflavin Drugs 0.000 description 4
- 239000002151 riboflavin Substances 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
- 235000013343 vitamin Nutrition 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- 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 3
- 239000000654 additive Substances 0.000 description 3
- 239000002269 analeptic agent Substances 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 229940125715 antihistaminic agent Drugs 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 239000002221 antipyretic Substances 0.000 description 3
- 239000003434 antitussive agent Substances 0.000 description 3
- 229940124584 antitussives Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 229940124630 bronchodilator Drugs 0.000 description 2
- 239000000168 bronchodilator agent Substances 0.000 description 2
- 229960000456 carbinoxamine maleate Drugs 0.000 description 2
- 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 2
- 238000013329 compounding Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- 230000000510 mucolytic effect Effects 0.000 description 2
- 239000000820 nonprescription drug Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 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
- 239000004260 Potassium ascorbate Substances 0.000 description 1
- 229930003268 Vitamin C Natural products 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
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 229960005174 ambroxol Drugs 0.000 description 1
- 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 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940076638 ascorbic acid and calcium Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
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- 238000010348 incorporation Methods 0.000 description 1
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- 239000000314 lubricant Substances 0.000 description 1
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- 229940074358 magnesium ascorbate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AIOKQVJVNPDJKA-ZZMNMWMASA-L magnesium;(2r)-2-[(1s)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2h-furan-3-olate Chemical compound [Mg+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] AIOKQVJVNPDJKA-ZZMNMWMASA-L 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
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- 239000006187 pill Substances 0.000 description 1
- 235000019275 potassium ascorbate Nutrition 0.000 description 1
- 229940017794 potassium ascorbate Drugs 0.000 description 1
- CONVKSGEGAVTMB-RXSVEWSESA-M potassium-L-ascorbate Chemical compound [K+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] CONVKSGEGAVTMB-RXSVEWSESA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
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- 230000028327 secretion Effects 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 150000003544 thiamines Chemical class 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Description
本発明は、安定化された塩酸アンブロキソール含有内服用固形製剤に関する。 The present invention relates to a solid preparation for internal use containing stabilized ambroxol hydrochloride.
一般用医薬品（ＯＴＣ）の分野においては、如何に効果的に風邪の諸症状を除去等するかが薬剤開発において重要である。風邪症候群のうち、特に痰の喀出（去痰）を図ることは、患者の負担が軽減されるため大変重要である。 In the field of over-the-counter medicines (OTC), how to effectively eliminate symptoms of cold etc. is important in drug development. Of the cold syndromes, in particular, it is very important to eliminate sputum because it reduces the burden on the patient.
塩酸アンブロキソールは、気道粘膜潤滑作用及び粘液溶解作用を有し、優れた去痰作用を有する化合物として広く知られている薬物である。従来、塩酸アンブロキソールの去痰作用を増強させるとして、粘液分泌促進作用を有する生薬と組み合わせて痰の喀出（去痰）を容易にすることが知られている（特許文献１）。また、塩酸アンブロキソールにシャゼンソウとノスカピンを配合すると、それぞれ単独または２種類の成分の場合と比較して去痰効果が向上することが知られている（特許文献２）。また、ビタミンＣ類と組み合わせることで、塩酸アンブロキソールの粘液溶解効果を高め、去痰効果が増強されることが知られている（特許文献３）
かぜ薬に汎用される解熱鎮痛剤、抗ヒスタミン剤、鎮咳剤、中枢興奮剤およびビタミン剤などとともに、去痰剤として塩酸アンブロキソールを配合し、さらに内服用固形製剤に汎用される添加剤を配合して製剤を製造したところ、塩酸アンブロキソールの含量が経時的に低下するという驚くべき知見を得た。さらに研究を進めた結果、意外にも塩酸アンブロキソールは、ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上の薬剤と配合禁忌であることを見出した。 Formulated with antipyretic analgesics, antihistamines, antitussives, central stimulants and vitamins commonly used for cold medicines, ambroxol hydrochloride as an expectorant, and additives commonly used for solid preparations for internal use As a result, a surprising finding that the content of ambroxol hydrochloride decreases with time was obtained. As a result of further research, it was surprisingly found that ambroxol hydrochloride is contraindicated with one or more drugs selected from the group consisting of vitamin B1 and ascorbic acid or a salt thereof.
本発明の目的は、塩酸アンブロキソールの経時的分解が顕著に抑制され、製品価値の高い内服用固形製剤及びその製造方法を提供することにある。本発明のさらに他の目的は、塩酸アンブロキソールとビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上を配合するにも拘わらず、塩酸アンブロキソールが安定化された内服用固形製剤およびその製造方法を提供することにある。本発明のさらに他の目的は、塩酸アンブロキソールとビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上の薬剤とを効率よく安定化できる安定化方法を提供することにある。本発明のさらに他の目的は、塩酸アンブロキソールの配合された総合感冒薬などのかぜ薬製剤として、有用な内服用固形製剤およびその製造方法を提供することにある。 An object of the present invention is to provide a solid preparation for internal use having a high product value, in which decomposition of ambroxol hydrochloride with time is remarkably suppressed, and a method for producing the same. Yet another object of the present invention is that ambroxol hydrochloride is stabilized despite the incorporation of ambroxol hydrochloride and one or more selected from the group consisting of vitamin B1 and ascorbic acid or a salt thereof. The object is to provide a solid preparation for internal use and a method for producing the same. Still another object of the present invention is to provide a stabilization method capable of efficiently stabilizing ambroxol hydrochloride and one or more drugs selected from the group consisting of vitamin B1s and ascorbic acid or a salt thereof. is there. Still another object of the present invention is to provide a solid preparation for internal use that is useful as a cold medicine preparation such as a common cold medicine containing ambroxol hydrochloride and a method for producing the same.
今までに塩酸アンブロキソールとビタミンＢ１類及びアスコルビン酸またはその塩からなる群より選択される１種以上を配合した内服用固形製剤において、充分実用性のある安定化された製剤について報告された例はない。 So far, a stable preparation with sufficient practicality has been reported in a solid preparation for internal use containing at least one selected from the group consisting of ambroxol hydrochloride, vitamin B1 and ascorbic acid or a salt thereof. There is no example.
本発明者らは、上記目的を達成するために塩酸アンブロキソールを配合した内服用固形製剤の安定化を図るべく安定化手段を種々試み検討を行ったところ、（Ａ）塩酸アンブロキソールと（Ｂ）ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上の少なくとも一方を造粒物とすると、塩酸アンブロキソールの安定化が著しく図れ、安定性の高い製剤が得られることを見出した。 In order to achieve the above object, the present inventors have conducted various trials on stabilizing means in order to stabilize a solid preparation for internal use containing ambroxol hydrochloride. As a result, (A) ambroxol hydrochloride and (B) When at least one selected from the group consisting of vitamin B1 and ascorbic acid or a salt thereof is used as a granulated product, ambroxol hydrochloride can be remarkably stabilized, and a highly stable preparation can be obtained. I found out that
すなわち、本発明は（１）（Ａ）塩酸アンブロキソール及び（Ｂ）ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上を含有し、（Ａ）と（Ｂ）の少なくとも一方が造粒物であることを特徴とする内服用固形製剤、（２）（Ａ）塩酸アンブロキソール及び（Ｂ）ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上を含有し、塩酸アンブロキソールを安定化する方法、（３）（Ａ）塩酸アンブロキソールと、（Ｂ）ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上を含有し、塩酸アンブロキソールを安定化させるために（Ａ）と（Ｂ）の少なくとも一方を造粒して製造することを特徴とする、内服用固形製剤の製造方法を提供するものである。 That is, the present invention comprises (1) (A) ambroxol hydrochloride and (B) one or more selected from the group consisting of vitamin B1 and ascorbic acid or a salt thereof, and (A) and (B) A solid preparation for internal use, wherein at least one is a granulated product, (2) one selected from the group consisting of (A) ambroxol hydrochloride and (B) vitamin B1 and ascorbic acid or a salt thereof A method of stabilizing ambroxol hydrochloride, comprising (1) at least one selected from the group consisting of (A) ambroxol hydrochloride and (B) vitamin B1 and ascorbic acid or a salt thereof A method for producing a solid preparation for internal use, comprising granulating at least one of (A) and (B) in order to contain and stabilize ambroxol hydrochloride A.
本発明の製剤中における塩酸アンブロキソールの効果は、ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上の成分と直接接触しないという理由、またこれら成分の分解物などにより影響を受けることがないために生じると推定される。このような知見は今までに報告された例はない。 The effect of ambroxol hydrochloride in the preparation of the present invention is due to the reason that it does not come into direct contact with one or more components selected from the group consisting of vitamin B1s and ascorbic acid or a salt thereof, and decomposition products of these components. It is presumed that it occurs because it is not affected. No such findings have been reported so far.
本発明は、塩酸アンブロキソールは、ビタミンＢ１類およびアスコルビン酸またはその塩からなる群と直接接触しない限り、塩酸アンブロキソールを安定化できる。特に、（Ａ）と（Ｂ）の少なくとも一方を造粒物とすることで、両者の直接的な接触を効果的に防ぐことができる。すなわち、塩酸アンブロキソールと、ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上の少なくとも一方を造粒して製造することで、塩酸アンブロキソールを安定化する。 The present invention can stabilize ambroxol hydrochloride as long as it is not in direct contact with the group consisting of vitamin B1 and ascorbic acid or a salt thereof. In particular, by making at least one of (A) and (B) a granulated product, direct contact between them can be effectively prevented. That is, ambroxol hydrochloride is stabilized by granulating and producing at least one selected from the group consisting of vitamin B1 and ascorbic acid or a salt thereof.
本発明の内服用固形製剤中における塩酸アンブロキソールの配合量は、その薬効を示す量であれば特に限定されるものではないが、通常０．５〜１０重量％、好ましくは１．０〜３．０重量％配合するのが好ましい。 The compounding amount of ambroxol hydrochloride in the solid preparation for internal use of the present invention is not particularly limited as long as it shows the medicinal effect, but is usually 0.5 to 10% by weight, preferably 1.0 to It is preferable to blend 3.0% by weight.
また（Ａ）には、塩酸アンブロキソールの他に、アセトアミノフェン、イブプロフェン等の解熱鎮痛剤、リン酸ジヒドロコデイン等の鎮咳剤、マレイン酸クロルフェニラミン、マレイン酸カルビノキサミン等の抗ヒスタミン剤、dl-塩酸メチルエフェドリン等の気管支拡張剤、無水カフェイン等の中枢興奮剤などの有効成分、賦形剤、崩壊剤、結合剤を配合しうる。これらは、通常内服用固形製剤に用いられる有効量を配合すればよい。 In addition to (A), in addition to ambroxol hydrochloride, antipyretic analgesics such as acetaminophen and ibuprofen, antitussives such as dihydrocodeine phosphate, antihistamines such as chlorpheniramine maleate and carbinoxamine maleate, dl-methyl hydrochloride Active ingredients such as bronchodilators such as ephedrine and central stimulants such as anhydrous caffeine, excipients, disintegrants, and binders can be blended. What is necessary is just to mix | blend the effective amount normally used for the solid formulation for internal use.
本発明で用いるビタミンＢ１類としてはチアミン、塩酸チアミン、硝酸チアミン、ビスイブチアミンなどのビタミンＢ1誘導体などが挙げられるが、硝酸チアミン、ビスイブチアミンが好ましい。本発明の内服用固形製剤中におけるビタミンＢ１類の配合量は、通常０．５〜２．０重量％、特に０．６〜０．９重量％配合するのが好ましい。また、塩酸アンブロキソールとビタミンＢ１類の配合比（重量比）は、１：０．０１〜３０、特に１：１．２〜３．０の配合比が、塩酸アンブロキソールの安定性の面で好ましい。 Examples of vitamin B1 used in the present invention include vitamin B1 derivatives such as thiamine, thiamine hydrochloride, thiamine nitrate, and bisibutiamine, and thiamine nitrate and bisibutiamine are preferable. The amount of vitamin B1 compounded in the solid preparation for internal use of the present invention is usually 0.5 to 2.0% by weight, particularly preferably 0.6 to 0.9% by weight. Moreover, the mixing ratio (weight ratio) of ambroxol hydrochloride and vitamin B1 is 1: 0.01 to 30, particularly 1: 1.2 to 3.0, which is the stability of ambroxol hydrochloride. In terms of surface.
また、本発明で用いるアスコルビン酸またはその塩としては、アスコルビン酸、アスコルビン酸カルシウム、アスコルビン酸ナトリウム、アスコルビン酸カリウム、アスコルビン酸マグネシウム等が挙げられるが、特にアスコルビン酸とアスコルビン酸カルシウムが好ましい。本発明の内服用固形製剤のアスコルビン酸またはその塩の配合量は、通常５．０〜４０重量、特に１３〜１７重量％配合するのがよい。また、塩酸アンブロキソールとアスコルビン酸またはその塩の配合比は、１：０．１〜３０、特に１：０．３〜１．０の配合比が、塩酸アンブロキソールの安定性の面で好ましい。 Examples of ascorbic acid or a salt thereof used in the present invention include ascorbic acid, calcium ascorbate, sodium ascorbate, potassium ascorbate, and magnesium ascorbate, and ascorbic acid and calcium ascorbate are particularly preferable. The compounding amount of ascorbic acid or a salt thereof in the solid preparation for internal use of the present invention is usually 5.0 to 40% by weight, particularly 13 to 17% by weight. The mixing ratio of ambroxol hydrochloride and ascorbic acid or a salt thereof is 1: 0.1 to 30, particularly 1: 0.3 to 1.0 in terms of the stability of ambroxol hydrochloride. preferable.
また（Ｂ）には、ビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上の成分の他に、アセトアミノフェン、イブプロフェン等の解熱鎮痛剤、リン酸ジヒドロコデイン、ノスカピン等の鎮咳剤、マレイン酸クロルフェニラミン、マレイン酸カルビノキサミン等の抗ヒスタミン剤、dl-塩酸メチルエフェドリン等の気管支拡張剤、無水カフェイン等の中枢興奮剤などの有効成分、賦形剤、崩壊剤、結合剤を配合しうる。これらは、通常内服用固形製剤に用いられる有効量を配合すればよい。 In addition to (B), in addition to one or more components selected from the group consisting of vitamin B1 and ascorbic acid or a salt thereof, antipyretic analgesics such as acetaminophen and ibuprofen, dihydrocodeine phosphate, noscapine and the like Contains active ingredients such as antitussives, antihistamines such as chlorpheniramine maleate and carbinoxamine maleate, bronchodilators such as dl-methylephedrine hydrochloride, and central stimulants such as anhydrous caffeine, excipients, disintegrants and binders Yes. What is necessary is just to mix | blend the effective amount normally used for the solid formulation for internal use.
ここで、（Ａ）または（Ｂ）を造粒物とする方法であればその造粒方法は限定されず、その剤形に応じて、任意の慣用の方法、例えば攪拌造粒、流動層造粒、押し出し造粒、転動流動造粒、乾式造粒などの方法を採用すればよい。これらは一般的な製剤機器を用いて製剤化を行うことができる。具体的には、例えば（Ａ）及び（Ｂ）をそれぞれ別々に混合・粉砕し造粒を行った後、（Ａ）と（Ｂ）を混合して製造する。また、（Ａ）のみ造粒する場合は、（Ａ）を混合・粉砕し、造粒を行った後、（Ｂ）を添加して製造する。また（Ｂ）のみ造粒する場合は、（Ｂ）を混合・粉砕し、造粒を行った後、（Ａ）を添加して製造する。 Here, the granulation method is not limited as long as (A) or (B) is a granulated product, and any conventional method such as stirring granulation or fluidized bed granulation is used depending on the dosage form. Methods such as granulation, extrusion granulation, rolling fluid granulation, and dry granulation may be employed. These can be formulated using common formulation equipment. Specifically, for example, (A) and (B) are separately mixed and pulverized and granulated, and then (A) and (B) are mixed and manufactured. Moreover, when granulating only (A), after mixing and grind | pulverizing (A) and performing granulation, (B) is added and manufactured. When only (B) is granulated, (B) is mixed and pulverized, granulated, and then (A) is added for production.
上記のように造粒した後、造粒物を被覆しても良い。また、その造粒物に適宜有効成分や賦形剤などの慣用の製剤添加剤を配合し、混合物を打錠すれば錠剤を得ることができる。造粒物を用いて市販の積層錠剤機により２層の錠剤としてもよい。製剤の剤形は、これらに限定されず、散剤、細粒剤、顆粒剤、丸剤、錠剤（フィルムコーティング錠、積層錠を含む）、カプセル剤等の剤形を包含する。それぞれ必要に応じて有効成分、賦形剤、結合剤、崩壊剤、フィルムコーティング剤、滑沢剤、抗酸化剤、香料、および着色剤等の慣用の製剤添加剤を適当量配合しても良い。 After granulation as described above, the granulated product may be coated. Also, tablets can be obtained by blending the granulated product with conventional formulation additives such as active ingredients and excipients as appropriate, and tableting the mixture. It is good also as a tablet of two layers by a commercially available laminated tablet machine using a granulated material. The dosage form of the preparation is not limited to these, and includes dosage forms such as powders, fine granules, granules, pills, tablets (including film-coated tablets and laminated tablets), and capsules. If necessary, an appropriate amount of conventional formulation additives such as active ingredients, excipients, binders, disintegrants, film coating agents, lubricants, antioxidants, fragrances, and coloring agents may be blended. .
本発明の内服用固形製剤は、その剤形に応じて、通常の内服用固形製剤と同様に投与することができる。その投与量は、製剤の用途等によって異なるが、例えばかぜ薬製剤の場合、１日３回の投与で、一般的に成人（体重５０ｋｇとして）においては、一日につき塩酸アンブロキソールの投与量が約１０ｍｇ〜５０ｍｇ、好ましくは約３０〜５０ｍｇとなることを基準とする。 The solid preparation for internal use of the present invention can be administered in the same manner as a solid preparation for internal use depending on the dosage form. The dosage varies depending on the use of the preparation. For example, in the case of a cold medicine preparation, it is administered 3 times a day. Generally, in adults (with a body weight of 50 kg), the dosage of ambroxol hydrochloride per day Is about 10 to 50 mg, preferably about 30 to 50 mg.
本発明により、塩酸アンブロキソールの経時的分解が顕著に抑制され、製品価値の高い内服用固形製剤が得られる。 According to the present invention, degradation over time of ambroxol hydrochloride is remarkably suppressed, and a solid preparation for internal use having a high product value can be obtained.
以下に比較例及び実施例を挙げ、本発明をより詳しく説明する。 Hereinafter, the present invention will be described in more detail with reference to comparative examples and examples.
＜試験例１＞
表１に示す各成分および分量を秤量、混合し得られた物理混合物を蓋付ガラス瓶に入れて６５℃で２週間保存後、塩酸アンブロキソールの安定性をＨＰＬＣ法により評価した。結果を表２に示す。サンプル１、２、３および４は塩酸アンブロキソール含量に３％以上の低下が認められた。特に２、３、４は、塩酸アンブロキソール含量に10％以上の低下が認められた。特に３、４で顕著であり、その中でも４は約３０％もの著しい低下が認められた。この結果から、アンブロキソールはビタミンＢ１類、アスコルビン酸またはその塩と配合禁忌であることが分かった。
<Test Example 1>
Each component and amount shown in Table 1 were weighed and mixed, and the resulting physical mixture was placed in a glass bottle with a lid and stored at 65 ° C. for 2 weeks. Then, the stability of ambroxol hydrochloride was evaluated by HPLC. The results are shown in Table 2. Samples 1, 2, 3 and 4 showed a decrease of 3% or more in the content of ambroxol hydrochloride. In particular, 2, 3 and 4 showed a decrease of 10% or more in the content of ambroxol hydrochloride. In particular, 3 and 4 were remarkable, and among them, 4 was significantly reduced by about 30%. From this result, it was found that ambroxol is incompatible with vitamin B1s, ascorbic acid or a salt thereof.
以下に、実施例、比較例を挙げて本発明をより詳細に説明するが、本発明はこれらの実施例等により限定されるものではない。
実施例１
（処方）
（Ａ）
塩酸アンブロキソール 45ｇ
リン酸ジヒドロコデイン 10ｇ
dl-塩酸メチルエフェドリン 60ｇ
無水カフェイン 75ｇ
マレイン酸クロルフェニラミン 7.5ｇ
リボフラビン 4ｇ
アスパルテーム 90ｇ
ヒドロキシプロピルセルロース 144ｇ
マンニトール 745ｇ
結晶セルロース 150ｇ
軽質無水ケイ酸 12ｇ
（Ｂ）
リン酸ジヒドロコデイン 14ｇ
アセトアミノフェン 900ｇ
ノスカピン 48ｇ
硝酸チアミン 24ｇ
リボフラビン 5ｇ
バレイショデンプン 300ｇ
ヒドロキシプロピルセルロース 174ｇ
マンニトール 106.5ｇ
結晶セルロース 141ｇ
軽質無水ケイ酸 9ｇ
（Ａ）、（Ｂ）の各成分および分量を秤量し均一に混合した後、得られた各々の混合粉末を湿式攪拌造粒法により造粒し、造粒物Ａおよび造粒物Ｂを得た。得られた２種の造粒物とアスコルビン酸500ｇ、リボフラビン3ｇ、メタケイ酸アルミン酸マグネシウム30ｇおよび香料3ｇを混合した。この混合物を分包して１包重量1200ｍｇの散剤を得た。
Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples and the like.
Example 1
(Prescription)
(A)
Ambroxol hydrochloride 45g
Dihydrocodeine phosphate 10g
dl-methylephedrine hydrochloride 60g
Anhydrous caffeine 75g
Chlorpheniramine maleate 7.5g
Riboflavin 4g
Aspartame 90g
Hydroxypropylcellulose 144g
Mannitol 745g
150g of crystalline cellulose
Light anhydrous silicic acid 12g
(B)
14g dihydrocodeine phosphate
Acetaminophen 900g
Noscapine 48g
24g thiamine nitrate
Riboflavin 5g
Potato starch 300g
Hydroxypropylcellulose 174g
Mannitol 106.5g
141g of crystalline cellulose
Light anhydrous silicic acid 9g
After each component and amount of (A) and (B) are weighed and mixed uniformly, each of the obtained mixed powders is granulated by a wet stirring granulation method to obtain a granulated product A and a granulated product B. It was. The two types of granules obtained were mixed with 500 g of ascorbic acid, 3 g of riboflavin, 30 g of magnesium aluminate metasilicate and 3 g of fragrance. The mixture was packaged to obtain a powder having a package weight of 1200 mg.
実施例２
（処方）
（Ａ）
塩酸アンブロキソール 45ｇ
リン酸ジヒドロコデイン 7ｇ
dl-塩酸メチルエフェドリン 60ｇ
マレイン酸クロルフェニラミン 7.5ｇ
リボフラビン 12ｇ
ヒドロキシプロピルセルロース 40ｇ
低置換度ヒドロキシプロピルセルロース 120ｇ
結晶セルロース 250ｇ
軽質無水ケイ酸 5ｇ
（Ｂ）
リン酸ジヒドロコデイン 17ｇ
アセトアミノフェン 900ｇ
ノスカピン 48ｇ
硝酸チアミン 24ｇ
ヒドロキシプロピルセルロース 110ｇ
低置換度ヒドロキシプロピルセルロース 170ｇ
結晶セルロース 302.5ｇ
軽質無水ケイ酸 10ｇ
（Ａ）、（Ｂ）の各成分および分量を秤量し均一に混合した後、得られた各々の混合粉末を湿式攪拌造粒法により造粒し、造粒物Ａおよび造粒物Ｂを得た。得られた２種の造粒物と無水カフェイン75ｇ、直打用アスコルビン酸515ｇ、クロスカルメロースナトリウム90ｇ、軽質無水ケイ酸27ｇ、ステアリン酸マグネシウム適量および硬化油適量を混合した。この混合物を打錠して１錠重量320ｍｇの錠剤を得た。
Example 2
(Prescription)
(A)
Ambroxol hydrochloride 45g
Dihydrocodeine phosphate 7g
dl-methylephedrine hydrochloride 60g
Chlorpheniramine maleate 7.5g
Riboflavin 12g
Hydroxypropylcellulose 40g
Low substituted hydroxypropylcellulose 120g
Crystalline cellulose 250g
Light anhydrous silicic acid 5g
(B)
17g dihydrocodeine phosphate
Acetaminophen 900g
Noscapine 48g
24g thiamine nitrate
110g hydroxypropylcellulose
Low substituted hydroxypropylcellulose 170g
Crystalline cellulose 302.5g
Light anhydrous silicic acid 10g
After each component and amount of (A) and (B) are weighed and mixed uniformly, each of the obtained mixed powders is granulated by a wet stirring granulation method to obtain a granulated product A and a granulated product B. It was. The obtained two types of granules were mixed with 75 g of anhydrous caffeine, 515 g of ascorbic acid for direct hitting, 90 g of croscarmellose sodium, 27 g of light anhydrous silicic acid, an appropriate amount of magnesium stearate and an appropriate amount of hardened oil. This mixture was tableted to obtain tablets each having a weight of 320 mg.
実施例３
実施例１においてアスコルビン酸をアスコルビン酸カルシウムに置き換えた処方で、実施例１に準拠し、１包重量1200ｍｇの散剤を得た。
Example 3
According to the formulation in which ascorbic acid was replaced with calcium ascorbate in Example 1, a powder with a single package weight of 1200 mg was obtained in accordance with Example 1.
比較例２
実施例１において、ＡおよびＢの成分を混合・造粒して１顆粒とし、実施例１に準拠し、１包重量1200ｍｇの散剤を得た。
Comparative Example 2
In Example 1, the components A and B were mixed and granulated to form one granule. According to Example 1, a powder with a one-pack weight of 1200 mg was obtained.
比較例３
実施例３において、ＡおよびＢの成分を混合・造粒して１顆粒とし、実施例１に準拠し、１包重量1200ｍｇの散剤を得た。
Comparative Example 3
In Example 3, the ingredients of A and B were mixed and granulated to form one granule, and according to Example 1, a powder with a package weight of 1200 mg was obtained.
試験例２
実施例１、２および比較例２で製造した製剤を全て瓶に充填、密栓し、65℃で１週間保存後、塩酸アンブロキソールの安定性をＨＰＬＣ法により評価した。
Test example 2
The preparations prepared in Examples 1 and 2 and Comparative Example 2 were all filled in bottles, sealed, and stored at 65 ° C. for 1 week, and then the stability of ambroxol hydrochloride was evaluated by HPLC.
去痰剤の配合された総合感冒薬などのかぜ薬製剤として、有用な内服用固形製剤およびその製造方法を提供することにある。より詳細には、去痰剤である塩酸アンブロキソールとかぜの諸症状に効果のあるビタミンＢ１類およびアスコルビン酸またはその塩からなる群より選択される１種以上を含有する、塩酸アンブロキソールの安定化された内服用固形製剤を提供する。 An object of the present invention is to provide a solid preparation for internal use useful as a cold medicine preparation such as a general cold medicine containing an expectorant and a method for producing the same. More specifically, ambroxol hydrochloride containing ambroxol hydrochloride as an expectorant and one or more selected from the group consisting of vitamin B1 effective in various symptoms of cold and ascorbic acid or a salt thereof A stabilized solid preparation for internal use is provided.
Claims (5)
（Ｂ）硝酸チアミン、ビスイブチアミン、およびアスコルビン酸またはその塩からなる群より選択される１種以上を含有し、
（Ａ）成分及び（Ｂ）成分が別々の造粒物であるか、又は、（Ａ）成分及び（Ｂ）成分の一方の成分のみが造粒物であって、かつもう一方の成分が該造粒物内に含まれていないことを特徴とする内服用固形製剤。 Containing (A) ambroxol hydrochloride and (B) one or more selected from the group consisting of thiamine nitrate, bisibuthiamine, and ascorbic acid or a salt thereof;
(A) and component (B) or component are separate granules, or, (A) and component (B) only one component of the component a granulated product, and the other component is the A solid preparation for internal use, which is not contained in a granulated product .
（Ｂ）硝酸チアミン、ビスイブチアミン、およびアスコルビン酸またはその塩からなる群より選択される１種以上を含有し、（Ａ）成分及び（Ｂ）成分が別々の造粒物であるか、又は、（Ａ）成分及び（Ｂ）成分の一方の成分のみが造粒物であって、かつもう一方の成分が該造粒物内に含まれていないことを特徴とする塩酸アンブロキソールを安定化する方法。 Containing (A) ambroxol hydrochloride and (B) one or more selected from the group consisting of thiamine nitrate, bisibutiamine, and ascorbic acid or a salt thereof, wherein (A) component and (B) component are separate It is a granulated product, or only one of the components (A) and (B) is a granulated product, and the other component is not contained in the granulated product method of stabilizing the ambroxol hydrochloride to be.
（Ｂ）硝酸チアミン、ビスイブチアミン、およびアスコルビン酸またはその塩からなる群より選択される１種以上を含有し、塩酸アンブロキソールを安定化させるために、（Ａ）成分及び（Ｂ）成分を別々に造粒するか、又は、（Ａ）成分及び（Ｂ）成分の一方の成分のみを造粒した後にもう一方の成分を添加して製造することを特徴とする、内服用固形製剤の製造方法。 (A) ambroxol hydrochloride;
(B) thiamine mononitrate, contain one or more selected from the group consisting of bis Eve thiamine, and ascorbic acid or a salt thereof, in order to stabilize the ambroxol hydrochloride, (A) component and the (B) component Of a solid preparation for internal use, characterized by being granulated separately, or by granulating only one of the components (A) and (B) and then adding the other component Production method.
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