JP2008150297A - Solid preparation - Google Patents
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- JP2008150297A JP2008150297A JP2006337082A JP2006337082A JP2008150297A JP 2008150297 A JP2008150297 A JP 2008150297A JP 2006337082 A JP2006337082 A JP 2006337082A JP 2006337082 A JP2006337082 A JP 2006337082A JP 2008150297 A JP2008150297 A JP 2008150297A
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- ascorbic acid
- ambroxol hydrochloride
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000007787 solid Substances 0.000 title claims abstract description 21
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 58
- 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 claims abstract description 31
- 229960000985 ambroxol hydrochloride Drugs 0.000 claims abstract description 31
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 28
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 28
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 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
- 229940047036 calcium ascorbate Drugs 0.000 claims description 3
- 238000005469 granulation Methods 0.000 abstract description 10
- 230000003179 granulation Effects 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 10
- 238000000354 decomposition reaction Methods 0.000 abstract 1
- 238000007789 sealing Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 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 6
- 239000003826 tablet Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000003419 expectorant effect Effects 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 3
- 239000004480 active ingredient Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229960000920 dihydrocodeine Drugs 0.000 description 3
- 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 3
- 238000009472 formulation Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002151 riboflavin Substances 0.000 description 3
- 235000019192 riboflavin Nutrition 0.000 description 3
- 229960002477 riboflavin Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 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 2
- 239000000654 additive Substances 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
- 239000011230 binding agent Substances 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 2
- 229940124579 cold medicine Drugs 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003172 expectorant agent Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000000510 mucolytic effect Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000000820 nonprescription drug Substances 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 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 description 2
- 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 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 239000004260 Potassium ascorbate Substances 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 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 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229940076638 ascorbic acid and calcium Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960000456 carbinoxamine maleate Drugs 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
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 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
- 239000008298 dragée Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007908 dry granulation Methods 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
- 235000013305 food Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229940074358 magnesium ascorbate Drugs 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
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 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
- 230000001737 promoting effect Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 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
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Abstract
Description
本発明は、塩酸アンブロキソールとアスコルビン酸又はその塩を含有する内服用固形製剤に関する。 The present invention relates to a solid preparation for internal use containing ambroxol hydrochloride and ascorbic acid or a salt thereof.
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）。 Ambroxol hydrochloride is a drug widely known as a compound having an airway mucosal lubricating action and a mucolytic action and an excellent expectorant action. Conventionally, it has been known that, in order to enhance the expectorant action of ambroxol hydrochloride, facilitation of expectoration (descancy) is facilitated in combination with a crude drug having a mucus secretion promoting action (Patent Document 1). In addition, it is known that adding shazensou and noscapine to ambroxol hydrochloride improves the expectorant effect as compared with the case of using one or two kinds of components, respectively (Patent Document 2). Moreover, it is known that the combination with vitamin C enhances the mucolytic effect of ambroxol hydrochloride and enhances the expectorant effect (Patent Document 3).
さらに配合禁忌である塩酸アンブロキソールとアスコルビン酸を別顆粒にすることにより塩酸アンブロキソールの安定化をはかる技術も知られている（特許文献４）。 Furthermore, a technique for stabilizing ambroxol hydrochloride by making ambroxol hydrochloride and ascorbic acid, which are contraindicated, into separate granules is also known (Patent Document 4).
なお、従来配合禁忌関係にある成分の安定性を確保するために窒素雰囲気下保存するという知見は知られていない。 In addition, the knowledge that it preserve | saves in nitrogen atmosphere in order to ensure the stability of the component in a conventional combination contraindication relation is not known.
配合禁忌である塩酸アンブロキソールとアスコルビン酸またはその塩を同時配合するために、従来知られている別顆粒法は工数が多くなることから作業効率の点で満足できるものではなかった。 In order to simultaneously blend incombination ambroxol hydrochloride and ascorbic acid or a salt thereof, which is a contraindication, the conventionally known separate granule method is not satisfactory in terms of work efficiency because of the increased number of steps.
本発明の目的は、塩酸アンブロキソールとアスコルビン酸を同時配合した際の経時的分解が顕著に抑制され、さらに製造する際の作業効率に優れた固形製剤の提供を目的とする。 An object of the present invention is to provide a solid preparation that is remarkably suppressed in degradation over time when ambroxol hydrochloride and ascorbic acid are blended at the same time, and further excellent in work efficiency in production.
本発明者らは課題を解決するために種々検討した結果、塩酸アンブロキソール及びアスコルビン酸またはその塩を含有した製剤を、容器中の空気を窒素で置換した容器に封入することにより、配合禁忌の塩酸アンブロキソール及びアスコルビン酸またはその塩を同一顆粒中に配合して造粒しても両成分とも安定性が確保できることを見出し本発明を完成した。 As a result of various investigations to solve the problems, the present inventors have found that a preparation containing ambroxol hydrochloride and ascorbic acid or a salt thereof is contained in a container in which the air in the container is replaced with nitrogen, and thus contraindicated. As a result, it was found that the stability of both components can be ensured by blending and granulating ambroxol hydrochloride and ascorbic acid or a salt thereof in the same granule.
すなわち本発明は
（１）塩酸アンブロキソール及びアスコルビン酸またはその塩を含有した製剤を、容器中の空気を窒素で置換した容器に封入したことを特徴とする固形製剤、
（２）アスコルビン酸またはその塩が、アスコルビン酸またはアスコルビン酸カルシウムである（１）記載の固形製剤、
（３）製剤中の塩酸アンブロキソールの配合量が０．２〜３．０質量％である（１）記載の内服固形製剤、
（４）塩酸アンブロキソール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種以上を含有する製剤を、窒素置換した容器に封入することを特徴とする塩酸アンブロキソール及びアスコルビン酸又はその塩の両方を安定に保存する方法、
（５）塩酸アンブロキソール及びアスコルビン酸又はその塩を安定化させるために、容器中の空気を窒素置換することを特徴とする固形製剤の製造方法、
である。
That is, the present invention is (1) a solid preparation characterized in that a preparation containing ambroxol hydrochloride and ascorbic acid or a salt thereof is enclosed in a container in which air in the container is replaced with nitrogen,
(2) The solid preparation according to (1), wherein the ascorbic acid or a salt thereof is ascorbic acid or calcium ascorbate,
(3) The internal solid preparation according to (1), wherein the amount of ambroxol hydrochloride in the preparation is 0.2 to 3.0% by mass,
(4) Ambroxol hydrochloride and ascorbic acid, or a composition thereof, characterized by enclosing a preparation containing at least one selected from the group consisting of ambroxol hydrochloride and ascorbic acid or a salt thereof in a container purged with nitrogen A method to store both salt stably,
(5) In order to stabilize ambroxol hydrochloride and ascorbic acid or a salt thereof, a method for producing a solid preparation characterized by substituting the air in the container with nitrogen,
It is.
本発明により、塩酸アンブロキソールとアスコルビン酸又はその塩が接触する製法で製造した製剤であっても、両成分とも経時的分解が顕著に抑制されることがわかった。 According to the present invention, it was found that degradation over time is remarkably suppressed in both components even in a preparation produced by a process in which ambroxol hydrochloride and ascorbic acid or a salt thereof are in contact with each other.
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０．２〜３．０重量％、好ましくは１．０〜２．５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 0.2 to 3.0% by weight, preferably 1. It is preferable to add 0 to 2.5% by weight.
また薬物として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、硝酸チアミン、リボフラビンなどのビタミン剤などの有効成分、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量を配合すればよい。 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, and bronchials such as dl-methylephedrine hydrochloride Active ingredients such as extenders, central stimulants such as anhydrous caffeine, vitamins such as thiamine nitrate and riboflavin, excipients, disintegrants and binders may be incorporated. What is necessary is just to mix | blend the quantity normally used for the solid formulation for internal use.
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２．５〜４０重量、特に１３〜１７重量％配合するのがよい。 Ascorbic acid or a salt thereof used in the present invention includes ascorbic acid, calcium ascorbate, sodium ascorbate, potassium ascorbate, magnesium ascorbate and the like, 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 2.5 to 40% by weight, particularly 13 to 17% by weight.
本発明では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一般的な方法で製剤化を行うことができる。 In the present invention, the granulation method is not limited, and depending on the dosage form, any conventional method such as stirring granulation, fluidized bed granulation, extrusion granulation, rolling fluid granulation, dry granulation, etc. Should be adopted. These can be formulated by a general method using a general pharmaceutical device.
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層以上の多層錠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、糖衣錠、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 a multilayer tablet of two or more layers using a granulation thing with a commercially available laminated tablet machine. 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, dragees, laminated tablets), capsules and the like. 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. .
このようにして得られた固形製剤は、外気との遮断が可能な容器中を窒素置換し充填することにより本発明の固形製剤を得ることができる。 The solid preparation of the present invention can be obtained by filling the solid preparation obtained in this way with nitrogen replacement in a container capable of blocking from the outside air.
ここで、容器としては、アルミラミネート分包容器、瓶、缶、ＰＴＰ、カプセルなどの一般の医薬品に用いられる容器が使用できる。 Here, as a container, the container used for common pharmaceuticals, such as an aluminum laminate packaging container, a bottle, a can, PTP, a capsule, can be used.
本発明で窒素充填は通常食品などに使用される一般的な装置を使用することができ、また製剤封入時に窒素雰囲気下のグローブボックスなどで封入することによっても製造することができる。 In the present invention, nitrogen filling can be carried out by using a general apparatus usually used for foods or the like, and can also be produced by enclosing in a glove box or the like in a nitrogen atmosphere when encapsulating the preparation.
本発明で窒素置換とは窒素が大部分の雰囲気において酸素濃度が１０％以下程度、好ましくは３％以下程度まで減少している状態であり、一部にヘリウム、アルゴンなどの不活性ガスを含む窒素で充填することも可能である。 In the present invention, nitrogen substitution is a state in which the oxygen concentration is reduced to about 10% or less, preferably about 3% or less in an atmosphere in which most nitrogen is contained, and partially contains an inert gas such as helium or argon. It is also possible to fill with nitrogen.
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.
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。
実施例
以下、実施例、比較例及び試験例を挙げて、本発明を更に詳細に説明する。
比較例１（別顆粒法）
[Ａ]
塩酸アンブロキソール ４５ｇ
リン酸ジヒドロコデイン ９ｇ
dl-塩酸メチルエフェドリン ６０ｇ
無水カフェイン ７５ｇ
リボフラビン ４ｇ
ヒドロキシプロピルセルロース １０２ｇ
マンニトール ５５６ｇ
結晶セルロース １０２ｇ
軽質無水ケイ酸 １０ｇ
[Ｂ]
リン酸ジヒドロコデイン １５ｇ
マレイン酸クロルフェニラミン ７．５ｇ
アスコルビン酸 ５００ｇ
硝酸チアミン ２４ｇ
リボフラビン ４ｇ
バレイショデンプン ５００ｇ
低置換度ヒドロキシプロピルセルロース ７２ｇ
マンニトール ３１４ｇ
ヒドロキシプロピルセルロース ６０ｇ
軽質無水ケイ酸 ３０ｇ
Ａ、Ｂ各成分をそれぞれ撹拌造粒法で造粒し、造粒物Ａおよび造粒物Ｂを得た。得られた２種の造粒物とメタケイ酸アルミン酸マグネシウム１８ｇを混合し、分包して散剤を得た。
Hereinafter, the present invention will be described in more detail with reference to comparative examples and examples.
Examples Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples.
Comparative Example 1 (another granule method)
[A]
Ambroxol hydrochloride 45g
9g dihydrocodeine phosphate
dl-methylephedrine hydrochloride 60g
Anhydrous caffeine 75g
Riboflavin 4g
102g hydroxypropylcellulose
Mannitol 556g
Crystalline cellulose 102g
Light anhydrous silicic acid 10g
[B]
15g dihydrocodeine phosphate
Chlorpheniramine maleate 7.5g
Ascorbic acid 500g
24g thiamine nitrate
Riboflavin 4g
Potato starch 500g
Low substituted hydroxypropylcellulose 72g
Mannitol 314g
Hydroxypropylcellulose 60g
Light anhydrous silicic acid 30g
The A and B components were each granulated by a stirring granulation method to obtain a granulated product A and a granulated product B. The two types of granules obtained and 18 g of magnesium aluminate metasilicate were mixed and packaged to obtain a powder.
実施例１
比較例１で製造した散剤を窒素充填したグローブボックス内で分包内に封入し、窒素パージ（酸素濃度１％）した。
Example 1
The powder produced in Comparative Example 1 was sealed in a sachet in a glove box filled with nitrogen and purged with nitrogen (oxygen concentration 1%).
比較例２
比較例１のＡ、Ｂ全成分を混合し、撹拌造粒法で造粒して造粒物を得た。得られた造粒物にメタケイ酸アルミン酸マグネシウム１８ｇを混合し、分包して散剤を得た。
Comparative Example 2
All components A and B of Comparative Example 1 were mixed and granulated by a stirring granulation method to obtain a granulated product. The obtained granulated product was mixed with 18 g of magnesium aluminate metasilicate and packaged to obtain a powder.
実施例２
比較例２で製造した散剤を窒素充填したグローブボックス内で分包内に封入し、窒素パージ（酸素濃度１％）した。
Example 2
The powder produced in Comparative Example 2 was sealed in a sachet in a glove box filled with nitrogen and purged with nitrogen (oxygen concentration 1%).
試験例１
実施例１、２および比較例１、２で製造した製剤を４０℃−３箇月間保存し、塩酸アンブロキソールおよびアスコルビン酸の安定性をＨＰＬＣ法により評価した。数値は全て対直後％である。
Test example 1
The preparations produced in Examples 1 and 2 and Comparative Examples 1 and 2 were stored at 40 ° C. for 3 months, and the stability of ambroxol hydrochloride and ascorbic acid was evaluated by HPLC. All figures are% immediately after.
本発明により塩酸アンブロキソールとアスコルビン酸を１顆粒でも同時配合することが可能になったので、医薬品の感冒薬として利用可能である。 According to the present invention, ambroxol hydrochloride and ascorbic acid can be blended at the same time even in one granule, so that it can be used as a cold medicine for pharmaceuticals.
Claims (5)
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103864628A (en) * | 2014-02-28 | 2014-06-18 | 悦康药业集团有限公司 | Ambroxol hydrochloride compound and orally disintegrating tablet |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864628A (en) * | 2014-02-28 | 2014-06-18 | 悦康药业集团有限公司 | Ambroxol hydrochloride compound and orally disintegrating tablet |
| CN103864628B (en) * | 2014-02-28 | 2015-09-23 | 悦康药业集团有限公司 | Ambroxol hydrochloride compound and orally disintegrating tablet |
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