JP2023071617A - solid composition - Google Patents
solid composition Download PDFInfo
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- JP2023071617A JP2023071617A JP2022177767A JP2022177767A JP2023071617A JP 2023071617 A JP2023071617 A JP 2023071617A JP 2022177767 A JP2022177767 A JP 2022177767A JP 2022177767 A JP2022177767 A JP 2022177767A JP 2023071617 A JP2023071617 A JP 2023071617A
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- Prior art keywords
- salt
- solid composition
- methoxyphenamine
- dextromethorphan
- tranexamic acid
- 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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- 239000008247 solid mixture Substances 0.000 title claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- OEHAYUOVELTAPG-UHFFFAOYSA-N methoxyphenamine Chemical compound CNC(C)CC1=CC=CC=C1OC OEHAYUOVELTAPG-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960005405 methoxyphenamine Drugs 0.000 claims abstract description 27
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims abstract description 25
- 229960001985 dextromethorphan Drugs 0.000 claims abstract description 25
- 229960000401 tranexamic acid Drugs 0.000 claims abstract description 19
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims abstract description 19
- 239000008187 granular material Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 230000008961 swelling Effects 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 3
- FGSJNNQVSUVTPW-UHFFFAOYSA-N methoxyphenamine hydrochloride Chemical group Cl.CNC(C)CC1=CC=CC=C1OC FGSJNNQVSUVTPW-UHFFFAOYSA-N 0.000 claims description 3
- 229960000659 methoxyphenamine hydrochloride Drugs 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 9
- 239000003826 tablet Substances 0.000 description 19
- 238000003860 storage Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- -1 organic acid salts Chemical class 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 3
- 229940124584 antitussives Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000820 nonprescription drug Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 239000003434 antitussive agent Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940001468 citrate Drugs 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 229940001447 lactate Drugs 0.000 description 2
- 239000000314 lubricant Substances 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
- 229940049920 malate Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-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
- 239000000654 additive Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory 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
- 239000002221 antipyretic Substances 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical class CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002552 dosage form Substances 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
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940071117 starch glycolate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000011782 vitamin Substances 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
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、メトキシフェナミン又はその塩を含有する固形組成物に関する。 The present invention relates to solid compositions containing methoxyphenamine or salts 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、特に咳の発作を抑制すること（鎮咳）は、患者の負担が軽減されるため大変重要である。
メトキシフェナミンは交感神経興奮作用に基づく気管支拡張作用を有する医薬品であり、総合感冒薬の鎮咳成分として配合されている（非特許文献１）。
今までに、メトキシフェナミン塩酸塩とトラネキサム酸を配合した固形組成物が知られている（特許文献１）。しかしながら、保存安定性に問題を生じるか否かについては、開示されていない。また、メトキシフェナミン又はその塩及びデキストロメトルファン又はその塩を含有する固形組成物については今までに報告されておらず、当然のことながらこれらを含有する固形組成物において、製剤の膨張が生じるか否かについて報告されていない。
In the field of over-the-counter drugs (OTC), it is important in drug development how to effectively remove various symptoms of colds. Among cold syndromes, suppressing coughing attacks (antitussives) is very important because it reduces the burden on patients.
Methoxyphenamine is a drug having a bronchodilatory action based on sympathomimetic action, and is blended as an antitussive ingredient in common cold medicines (Non-Patent Document 1).
A solid composition containing methoxyphenamine hydrochloride and tranexamic acid has been known so far (Patent Document 1). However, there is no disclosure as to whether or not there is a problem with storage stability. Moreover, solid compositions containing methoxyphenamine or a salt thereof and dextromethorphan or a salt thereof have not been reported so far, and it is a matter of course that swelling of the formulation occurs in solid compositions containing these. It is not reported whether or not
本発明者らは、メトキシフェナミン又はその塩及びデキストロメトルファン又はその塩を含有する固形組成物を製造したところ、固形組成物が膨張するという知見を得た。また、メトキシフェナミン又はその塩と、トラネキサム酸を含有する固形組成物を製造したところ、固形組成物が膨張するという知見を得た。 The present inventors produced a solid composition containing methoxyphenamine or its salt and dextromethorphan or its salt and found that the solid composition swelled. Moreover, when a solid composition containing methoxyphenamine or a salt thereof and tranexamic acid was produced, it was found that the solid composition swelled.
しかしながら、意外なことに、メトキシフェナミン又はその塩、トラネキサム酸、及びデキストロメトルファン又はその塩を組み合わせると、固形組成物の膨張が抑制されることを見出した。 However, it was unexpectedly found that the combination of methoxyphenamine or its salt, tranexamic acid, and dextromethorphan or its salt inhibits swelling of the solid composition.
すなわち、本発明は
（１）（ａ）メトキシフェナミン又はその塩、（ｂ）デキストロメトルファン又はその塩、及び（ｃ）トラネキサム酸を含有することを特徴とする固形組成物、
（２）（ａ）メトキシフェナミンの塩がメトキシフェナミン塩酸塩である（１）に記載の固形組成物、
（３）（ｂ）デキストロメトルファンの塩がデキストロメトルファン臭化水素酸塩水和物である（１）～（２）のいずれかに記載の固形組成物、
（４）錠剤、散剤、細粒剤、顆粒剤、丸剤、又はカプセル剤である（１）～（３）のいずれかに記載の固形組成物、
（５）（ｃ）トラネキサム酸を配合することによって、（ａ）メトキシフェナミン又はその塩及び（ｂ）デキストロメトルファン又はその塩を含有する固形組成物の膨張を抑制する方法、
（６）（ｂ）デキストロメトルファン又はその塩を配合することによって、（ａ）メトキシフェナミン又はその塩及び（ｃ）トラネキサム酸を含有する固形組成物の膨張を抑制する方法、
である。
That is, the present invention provides (1) a solid composition comprising (a) methoxyphenamine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) tranexamic acid,
(2) (a) The solid composition according to (1), wherein the salt of methoxyphenamine is methoxyphenamine hydrochloride;
(3) (b) The solid composition according to any one of (1) to (2), wherein the salt of dextromethorphan is dextromethorphan hydrobromide hydrate;
(4) The solid composition according to any one of (1) to (3), which is a tablet, powder, fine granules, granules, pills, or capsules;
(5) A method of suppressing swelling of a solid composition containing (a) methoxyphenamine or a salt thereof and (b) dextromethorphan or a salt thereof by incorporating (c) tranexamic acid;
(6) A method of suppressing swelling of a solid composition containing (a) methoxyphenamine or a salt thereof and (c) tranexamic acid by incorporating (b) dextromethorphan or a salt thereof;
is.
本発明により、膨張が抑制された固形組成物の提供が可能となった。 INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a solid composition in which expansion is suppressed.
本発明に用いられるメトキシフェナミン又はその塩は、化学式Ｃ１１Ｈ１７ＮＯで示される化合物又はその塩であり、これらのうちの一種を単独で用いても二種以上を組み合わせて用いてもよい。このようなメトキシフェナミン又はその塩としては、公知の方法により製造できるほか、市販のものを用いることができる。また、メトキシフェナミン又はその塩は医薬的に許容されるものであれば特に限定されないが、前記塩とは、例えば、塩酸塩、臭化水素酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくは塩酸塩である。本発明の固形組成物中におけるメトキシフェナミン又はその塩の含有量（メトキシフェナミン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常０．１～７０質量％、好ましくは１～５０質量％、より好ましくは５～２０質量％である。 Methoxyphenamine or a salt thereof used in the present invention is a compound represented by the chemical formula C 11 H 17 NO or a salt thereof, and one of them may be used alone or two or more of them may be used in combination. . Such methoxyphenamine or a salt thereof can be produced by a known method, or commercially available products can be used. In addition, methoxyphenamine or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. And organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. Hydrochloride is particularly preferred. The content of methoxyphenamine or a salt thereof in the solid composition of the present invention (when two or more of methoxyphenamine or salts thereof are contained, the total content thereof; the same shall apply hereinafter) indicates the efficacy of the composition. Although it is not particularly limited as long as the amount shows, it is usually 0.1 to 70% by mass, preferably 1 to 50% by mass, more preferably 5 to 20% by mass.
本発明に用いられるデキストロメトルファン又はその塩は、化学式Ｃ１８Ｈ２５ＮＯで示される化合物又はその塩であり、これらのうちの一種を単独で用いても二種以上を組み合わせて用いてもよい。このようなデキストロメトルファン又はその塩としては、公知の方法により製造できるほか、市販のものを用いることができる。また、デキストロメトルファン又はその塩は医薬的に許容されるものであれば特に限定されないが、前記塩とは、例えば、塩酸塩、臭化水素酸塩、フェノールフタリン酸塩、リン酸塩等の無機酸の塩、及び酢酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、炭酸塩等の有機酸塩等が挙げられ、特に好ましくは臭化水素酸塩又はフェノールフタリン酸塩である。本発明の固形組成物中におけるデキストロメトルファン又はその塩の含有量（デキストロメトルファン又はその塩のうちの２種以上が含有される場合にはそれらの合計含有量、以下同じ）は、その薬効を示す量であれば特に限定されないが、通常０．１～５０質量％、好ましくは０．５～３０質量％、より好ましくは１～１０質量％である。 Dextromethorphan or a salt thereof used in the present invention is a compound represented by the chemical formula C 18 H 25 NO or a salt thereof, and one of them may be used alone or two or more of them may be used in combination. . Such dextromethorphan or a salt thereof can be produced by a known method, or commercially available products can be used. Dextromethorphan or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. Examples of the salt include hydrochloride, hydrobromide, phenolphthalate, phosphate, and the like. and organic acids such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. salts, etc., and particularly preferably hydrobromide or phenolphthalate. The content of dextromethorphan or a salt thereof in the solid composition of the present invention (when two or more of dextromethorphan or salts thereof are contained, the total content thereof; the same shall apply hereinafter) Although it is not particularly limited as long as it is an amount showing
本発明に用いられるトラネキサム酸は、化学式Ｃ８Ｈ１５ＮＯ２で示される化合物である．このようなトラネキサム酸としては、公知の方法により製造できるほか、市販のものを用いることができる。本発明の固形組成物中におけるトラネキサム酸の含有量は、その薬効を示す量であれば特に限定されないが、通常１～８０質量％、好ましくは５～７０質量％、より好ましくは２０～６５質量％である。 Tranexamic acid used in the present invention is a compound represented by the chemical formula C 8 H 15 NO 2 . Such tranexamic acid can be produced by known methods, and commercially available products can also be used. The content of tranexamic acid in the solid composition of the present invention is not particularly limited as long as it is an amount exhibiting its efficacy, but is usually 1 to 80% by mass, preferably 5 to 70% by mass, more preferably 20 to 65% by mass. %.
（ａ）メトキシフェナミン又はその塩と（ｂ）デキストロメトルファン又はその塩の配合比は、（ｂ）デキストロメトルファン又はその塩１質量部に対し、（ａ）メトキシフェナミン又はその塩が０．００１～２０質量部、好ましくは０.０５～１５質量部、さらに好ましくは１～１０質量部である。 The blending ratio of (a) methoxyphenamine or its salt and (b) dextromethorphan or its salt is such that (a) methoxyphenamine or its salt is 0 per 1 part by mass of (b) dextromethorphan or its salt. 0.001 to 20 parts by mass, preferably 0.05 to 15 parts by mass, more preferably 1 to 10 parts by mass.
（ｂ）デキストロメトルファン又はその塩と（ｃ）トラネキサム酸の配合比は、（ｂ）デキストロメトルファン又はそれらの塩１質量部に対し、（ｃ）トラネキサム酸が、特に限定されないが、０．００１～４０質量部、好ましくは０．０１～３５質量部、さらに好ましくは１～３０質量部である。 The blending ratio of (b) dextromethorphan or a salt thereof and (c) tranexamic acid is, although not particularly limited, 1 part by mass of (b) dextromethorphan or a salt thereof and (c) tranexamic acid. 001 to 40 parts by mass, preferably 0.01 to 35 parts by mass, more preferably 1 to 30 parts by mass.
（ａ）メトキシフェナミン又はその塩と（ｃ）トラネキサム酸の配合比は、（ａ）メトキシフェナミン又はその塩１質量部に対し、（ｃ）トラネキサム酸が、特に限定されないが、０．０１～３０質量部、好ましくは０．１～２０質量部、さらに好ましくは１～１０質量部である。 The blending ratio of (a) methoxyphenamine or its salt and (c) tranexamic acid is, although not particularly limited, 0.01 of (c) tranexamic acid per 1 part by mass of (a) methoxyphenamine or its salt. to 30 parts by mass, preferably 0.1 to 20 parts by mass, more preferably 1 to 10 parts by mass.
本発明の固形組成物中には本発明の効果を損なわない質的、量的範囲で、通常用いられる他の有効成分、賦形剤、崩壊剤、結合剤、流動化剤、滑沢剤、清涼化剤、着色剤、矯味剤、矯臭剤、香料、コーティング剤などを配合することができる。本発明の固形組成物に配合できる他の有効成分としては、例えば、解熱鎮痛剤、抗ヒスタミン剤、鎮咳剤、ノスカピン類、気管支拡張剤、去痰剤、催眠鎮静剤、ビタミン類、抗炎症剤、胃粘膜保護剤、生薬類、漢方処方、カフェイン類等があげられ、これらからなる群より選ばれる１種又は２種以上を含有しても良い。 In the solid composition of the present invention, other commonly used active ingredients, excipients, disintegrants, binders, fluidizing agents, lubricants, Cooling agents, coloring agents, flavoring agents, flavoring agents, perfumes, coating agents and the like can be added. Other active ingredients that can be incorporated into the solid composition of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics, vitamins, anti-inflammatory agents, and gastric mucosa protectants. medicines, herbal medicines, herbal medicines, caffeines, etc., and may contain one or more selected from the group consisting of these.
本発明の固形組成物に配合できる賦形剤としては、例えば、乳糖、デンプン類、結晶セルロース、ショ糖、糖アルコール等が挙げられ、崩壊剤としては、低置換度ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、クロスポビドン、カルメロース、カルメロースナトリウム、カルメロースカルシウム、アルファー化デンプン等が挙げられ、結合剤としては、ヒドロキシプロピルセルロース、ヒプロメロース、ゼラチン、アルファー化デンプン、ポリビニルピロリドン、プルラン等が挙げられ、流動化剤としては、軽質無水ケイ酸、含水二酸化ケイ素等が挙げられ、滑沢剤としては、ショ糖脂肪酸エステル、硬化油、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム等が挙げられ、清涼化剤としては、メントール、ハッカ油、ユーカリ油等が挙げられる。 Examples of excipients that can be incorporated into the solid composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, etc. Disintegrants include low-substituted hydroxypropyl cellulose and starch glycolate. sodium, crospovidone, carmellose, carmellose sodium, carmellose calcium, pregelatinized starch, etc., and binders include hydroxypropyl cellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc.; Examples of the agent include light anhydrous silicic acid, hydrous silicon dioxide, and the like. Examples of the lubricant include sucrose fatty acid ester, hydrogenated oil, stearic acid, magnesium stearate, calcium stearate, and the like. include menthol, peppermint oil, eucalyptus oil, and the like.
本発明の固形組成物は、常法により製造することができ、その方法は特に限定されるものではない。
例えば、（ａ）メトキシフェナミン又はその塩（以下、（ａ）成分ともいう）、（ｂ）デキストロメトルファン又はそれらの塩（以下、（ｂ）成分ともいう）、（ｃ）トラネキサム酸を単に混合するだけでも良く、混合後に造粒しても良く、得られた造粒物を被覆してもよい。また、（ａ）成分、（ｂ）成分又は（ｃ）成分は必ずしも同一の造粒物に含まれている必要はない。 例えば、（ａ）成分と（ｃ）成分を含有する造粒物を製造後に、（ｂ）成分を混合する、あるいは、（ａ）成分と（ｂ）成分を含有する造粒物を製造後に、（ｃ）成分を混合する、あるいは、（ａ）成分と（ｃ）成分を含有する造粒物と、（ｂ）成分と（ｃ）成分を含有する造粒物を製造後、２つの造粒物を混合する、等である。
The solid composition of the present invention can be produced by a conventional method, and the method is not particularly limited.
For example, (a) methoxyphenamine or a salt thereof (hereinafter also referred to as component (a)), (b) dextromethorphan or a salt thereof (hereinafter also referred to as component (b)), (c) tranexamic acid is simply The mixture may be simply mixed, granulated after mixing, or the obtained granules may be coated. In addition, component (a), component (b) or component (c) does not necessarily have to be contained in the same granules. For example, after producing granules containing components (a) and (c), component (b) is mixed, or after producing granules containing components (a) and (b), After mixing component (c) or producing granules containing components (a) and (c) and granules containing components (b) and (c), two granules mixing things, etc.
本願発明において、（ａ）成分と（ｂ）成分を別々に造粒しても固形組成物の膨張が発生し、（ｃ）成分がこれらと同一の造粒物に含まなくても膨張は抑制される。また、（ａ）成分と（ｃ）成分を別々に造粒しても固形組成物の膨張が発生し、（ｂ）成分がこれらと同一の造粒物に含まなくても膨張は抑制される。 In the present invention, the expansion of the solid composition occurs even if the components (a) and (b) are separately granulated, and the expansion is suppressed even if the component (c) is not included in the same granules. be done. Further, even if the components (a) and (c) are separately granulated, the solid composition expands, and the expansion is suppressed even if the component (b) is not included in the same granules. .
造粒方法も特に限定されず、湿式造粒法、乾式造粒法又は溶融造粒法などにより製造できるが、好ましくは湿式造粒法である。湿式造粒法には、例えば撹拌造粒法、流動層造粒法、練合造粒法、押し出し造粒法、転動流動造粒法が挙げられる。また得られた造粒物に適宜上記有効成分や賦形剤などの慣用の製剤添加剤を配合してもよい。また、このようにして得た混合物を打錠して錠剤とすることもできる。錠剤を製造する場合は、直接打錠法により製造してもよい。 The granulation method is also not particularly limited, and can be produced by a wet granulation method, a dry granulation method, a melt granulation method, or the like, but the wet granulation method is preferred. Wet granulation methods include, for example, stirring granulation, fluid bed granulation, kneading granulation, extrusion granulation, and rolling fluidized granulation. In addition, the obtained granules may optionally be blended with conventional formulation additives such as the above active ingredients and excipients. Alternatively, the mixture thus obtained can be compressed into tablets. When producing tablets, they may be produced by a direct compression method.
本発明の固形組成物は、通常、日本薬局方の製剤通則に規定されている剤形であれば特に限定されないが、好ましくは錠剤、散剤、細粒剤、顆粒剤、丸剤、カプセル剤である。日本薬局方の製剤通則に規定されている錠剤には、口腔内崩壊錠、チュアブル錠、発泡錠、分散錠及び溶解錠、フィルムコーティング錠、糖衣錠、有核錠、積層錠などが含まれる。また、錠剤に割線や識別性向上のためのマーク、刻印を設けることができる。さらに、本製剤の錠剤は、丸錠であってもよいし、異型錠であってもよい。 The solid composition of the present invention is generally not particularly limited as long as it is in the dosage form prescribed in the Japanese Pharmacopoeia General Rules for Pharmaceutical Preparation, but preferably tablets, powders, fine granules, granules, pills and capsules. be. Tablets defined in the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets, film-coated tablets, sugar-coated tablets, dry-coated tablets, laminated tablets, and the like. In addition, the tablet can be provided with a score line, a mark for improving identification, or an engraving. Furthermore, the tablet of this preparation may be a round tablet or an irregularly shaped tablet.
以下に実施例及び比較例を挙げ、本発明をより詳しく説明するが、本発明はこれら実施例等に限定されるものではない。 EXAMPLES The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.
（比較例１～３、実施例１～３）
表１及び２に示す処方に従い各成分を量り取った後に混合、打錠し、固形組成物を得た。
(Comparative Examples 1-3, Examples 1-3)
Each component was weighed according to the formulations shown in Tables 1 and 2, mixed and tableted to obtain a solid composition.
（試験例１）
比較例１～３、実施例１～３の固形組成物を４０℃７５％ＲＨ条件下で１２時間保存した。保存後の固形組成物について、保存開始時の錠厚に対するそれぞれ組成物の錠厚変化率を以下の式にて算出した。結果を表１及び２に示した。
錠厚変化率（％）
＝４０℃７５％ＲＨ－１２時間で保存後の錠厚（ｍｍ）÷ 保存開始時の錠厚（ｍｍ）×１００
(Test example 1)
The solid compositions of Comparative Examples 1-3 and Examples 1-3 were stored under conditions of 40° C. and 75% RH for 12 hours. Regarding the solid composition after storage, the tablet thickness change rate of each composition relative to the tablet thickness at the start of storage was calculated by the following formula. The results are shown in Tables 1 and 2.
Tablet thickness change rate (%)
= Tablet thickness after storage at 40°C, 75% RH - 12 hours (mm) ÷ Tablet thickness at the start of storage (mm) x 100
表１に示すように、実施例１及び２では、比較例１及び２と比較して４０℃７５％ＲＨ-１２時間保存後の錠厚変化率が低値を示した。 As shown in Table 1, in Examples 1 and 2, compared with Comparative Examples 1 and 2, the tablet thickness change rate after storage at 40°C, 75% RH for 12 hours showed a lower value.
表２に示すように、実施例３では、比較例３と比較して４０℃７５％ＲＨ-１２時間保存後の錠厚変化率が低値を示した。 As shown in Table 2, in Example 3, compared with Comparative Example 3, the change in tablet thickness after storage at 40°C, 75% RH for 12 hours showed a lower value.
本発明により、膨張を抑制し、保存安定性に優れた固形組成物の提供が可能となった。 INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a solid composition that suppresses expansion and has excellent storage stability.
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