JP2013075892A - Anti-inflammatory and/or antihistaminic agent composition - Google Patents
Anti-inflammatory and/or antihistaminic agent composition Download PDFInfo
- Publication number
- JP2013075892A JP2013075892A JP2012201092A JP2012201092A JP2013075892A JP 2013075892 A JP2013075892 A JP 2013075892A JP 2012201092 A JP2012201092 A JP 2012201092A JP 2012201092 A JP2012201092 A JP 2012201092A JP 2013075892 A JP2013075892 A JP 2013075892A
- Authority
- JP
- Japan
- Prior art keywords
- hydrochloride
- inflammatory
- bromhexine
- fexofenadine
- action
- 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.)
- Granted
Links
- 239000000739 antihistaminic agent Substances 0.000 title claims abstract description 24
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 19
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 229940125715 antihistaminic agent Drugs 0.000 title abstract description 7
- 229940121363 anti-inflammatory agent Drugs 0.000 title abstract description 3
- 239000002260 anti-inflammatory agent Substances 0.000 title abstract description 3
- 229960000354 fexofenadine hydrochloride Drugs 0.000 claims abstract description 45
- RRJFVPUCXDGFJB-UHFFFAOYSA-N Fexofenadine hydrochloride Chemical compound Cl.C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RRJFVPUCXDGFJB-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229960002335 bromhexine hydrochloride Drugs 0.000 claims abstract description 22
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000001387 anti-histamine Effects 0.000 claims abstract description 18
- 239000003172 expectorant agent Substances 0.000 claims abstract description 7
- 230000003419 expectorant effect Effects 0.000 claims abstract description 7
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 16
- 229940124584 antitussives Drugs 0.000 claims description 6
- 201000007100 Pharyngitis Diseases 0.000 claims description 5
- 201000009240 nasopharyngitis Diseases 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 230000000954 anitussive effect Effects 0.000 claims description 4
- 206010039083 rhinitis Diseases 0.000 claims description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- 206010049153 Allergic sinusitis Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 8
- 239000000043 antiallergic agent Substances 0.000 abstract description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 27
- 229960004342 cetirizine hydrochloride Drugs 0.000 description 26
- 238000012360 testing method Methods 0.000 description 20
- 239000000126 substance Substances 0.000 description 16
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 description 14
- 206010030113 Oedema Diseases 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- 229960003870 bromhexine Drugs 0.000 description 8
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 229960005174 ambroxol Drugs 0.000 description 6
- 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 6
- 229940079593 drug Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 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 description 5
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 5
- 229920001525 carrageenan Polymers 0.000 description 5
- 235000010418 carrageenan Nutrition 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 206010052804 Drug tolerance Diseases 0.000 description 3
- 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 3
- 230000009471 action Effects 0.000 description 3
- 208000016150 acute pharyngitis Diseases 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000003434 antitussive agent Substances 0.000 description 3
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 3
- 229960003291 chlorphenamine Drugs 0.000 description 3
- 229940124579 cold medicine Drugs 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229960003449 epinastine Drugs 0.000 description 3
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 3
- 239000004503 fine granule Substances 0.000 description 3
- 230000026781 habituation Effects 0.000 description 3
- 210000003405 ileum Anatomy 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 229960000428 carbinoxamine Drugs 0.000 description 2
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960003592 fexofenadine Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- -1 polypropylene Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 101000957724 Catostomus commersonii Corticoliberin-1 Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241000617482 Kiwa Species 0.000 description 1
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 208000024780 Urticaria Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229940008201 allegra Drugs 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 201000010435 allergic urticaria Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003501 anti-edematous effect Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000009989 contractile response Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229960005042 mequitazine Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 239000004096 non-sedating histamine H1 antagonist Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 206010035653 pneumoconiosis Diseases 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する抗炎症及び／又は抗ヒスタミン剤組成物に関する。 The present invention relates to an anti-inflammatory and / or antihistamine composition comprising fexofenadine hydrochloride and bromhexine hydrochloride.
第二世代の抗ヒスタミン剤であるフェキソフェナジン塩酸塩は、（ａ）ヒスタミンＨ１受容体拮抗作用、（ｂ）Ｉ型アレルギー反応抑制作用、（ｃ）好酸球、炎症性サイトカイン遊離抑制作用、（ｄ）ケミカルメディエータ遊離抑制作用を有し、本邦では、アレルギー性鼻炎、蕁麻疹、皮膚疾患（湿疹・皮膚炎、皮膚掻痒症、アトピー性皮膚炎）に伴う掻痒の効能・効果が認められている（例えば、非特許文献１参照）。
去痰剤のブロムヘキシン塩酸塩は、（ａ）漿液性分泌増加作用、（ｂ）酸性糖タンパク溶解・低分子化作用、（ｃ）肺表面活性物質分泌促進作用、（ｄ）線毛運動亢進作用を有し、本邦では、急性気管支炎・慢性気管支炎・塵肺症・手術後の去痰の効能・効果が医療用医薬品として認められている（例えば、非特許文献１参照）。
また、ブロムヘキシン塩酸塩はＯＴＣ医薬品では、去痰剤、鎮咳去痰剤、総合感冒薬にも配合されている（例えば、非特許文献２参照）。
Fexofenadine hydrochloride, a second generation antihistamine, has (a) histamine H1 receptor antagonistic action, (b) type I allergic reaction inhibitory action, (c) eosinophil, inflammatory cytokine release inhibitory action, (d ) It has a chemical mediator release inhibitory effect, and it has been confirmed in Japan that it has allergic rhinitis, urticaria, and pruritus associated with skin diseases (eczema / dermatitis, cutaneous pruritus, atopic dermatitis) ( For example, refer nonpatent literature 1).
An expectorant bromhexine hydrochloride has (a) serous secretion increasing action, (b) acidic glycoprotein dissolution / low molecular weight action, (c) lung surface active substance secretion promoting action, (d) ciliary motility enhancing action. In Japan, the efficacy and effects of acute bronchitis, chronic bronchitis, pneumoconiosis, and expectoration after surgery are recognized as ethical drugs (for example, see Non-patent Document 1).
In addition, bromhexine hydrochloride is also included in an expectorant, antitussive expectorant and general cold medicine in OTC pharmaceuticals (see, for example, Non-Patent Document 2).
これまでに、抗ヒスタミン剤とブロムヘキシン又はアンブロキソールを配合したOTC総合感冒薬として以下のものが販売されている。
１）、抗ヒスタミン剤のカルビノキサミン、クレマスチン、クロルフェニラミン、又は、メキタジンと、ブロムヘキシンその他を配合した製品（例えば、非特許文献２参照）。
２）抗ヒスタミン剤のクロルフェニラミンとアンブロキソールその他を配合した製品（例えば、非特許文献２参照）。
さらに、抗ヒスタミン剤とブロムヘキシン又はアンブロキソールの組み合わせとして以下のものが開示されている。
３）抗ヒスタミン剤のエピナスチン、ブロムヘキシンその他を配合した鎮咳剤（特許文献１の実施例２及び４参照）。
４）抗ヒスタミン剤のクロルフェニラミン、ブロムヘキシンその他を配合した製剤（例えば、特許文献２の比較例３及び４参照）。
５）抗ヒスタミン剤のカルビノキサミン、ブロムヘキシンその他を配合した感冒剤（特許文献３の実施例１、３及び５参照）。
６）抗ヒスタミン剤のエピナスチン、アンブロキソールその他を配合した鎮咳剤（特許文献１参照の実施例１及び３）。なお、特許文献１の表１には、鎮咳薬のコデインに、エピナスチンとアンブロキソールを配合すると、風邪による咳嗽症状が著明に改善することが開示されている。
しかし、これまでに、第二世代の抗ヒスタミン剤であるフェキソフェナジンやセチリジンと、ブロムヘキシンの配合を直接記載したものは一切見当たらず、当該配合によって抗炎症作用や抗ヒスタミン作用に如何なる影響をもたらすかを示唆した報告もない。
So far, the following are marketed as OTC general cold medicines containing antihistamines and bromhexine or ambroxol.
1) A product containing the antihistamines carbinoxamine, clemastine, chlorpheniramine, or mequitazine and bromhexine or the like (for example, see Non-Patent Document 2).
2) A product containing the antihistamine chlorpheniramine, ambroxol and others (see Non-Patent Document 2, for example).
Furthermore, the following is disclosed as a combination of an antihistamine and bromhexine or ambroxol.
3) Antitussives containing antihistamines epinastine, bromhexine and others (see Examples 2 and 4 of Patent Document 1).
4) A preparation containing antihistamines chlorpheniramine, bromohexine and others (see, for example, Comparative Examples 3 and 4 in Patent Document 2).
5) A cold medicine containing the antihistamines carbinoxamine, bromhexine and others (see Examples 1, 3 and 5 of Patent Document 3).
6) Antitussive agent containing antinasamine epinastine, ambroxol and others (Examples 1 and 3 of Patent Document 1). In Table 1 of Patent Document 1, it is disclosed that cough symptoms due to a cold are remarkably improved when epinastine and ambroxol are added to codeine, an antitussive agent.
However, until now, there has been no direct description of the combination of fexofenadine and cetirizine, which are second-generation antihistamines, and bromhexine. There are no reports to suggest.
本発明の課題は、優れた抗炎症作用及び／又は抗ヒスタミン作用を有する医薬組成物を提供することである。 An object of the present invention is to provide a pharmaceutical composition having an excellent anti-inflammatory action and / or antihistamine action.
本発明者らは、かかる課題を解決するために多数の薬剤の組み合わせについて鋭意研究を行った結果、抗アレルギー剤として使用されているフェキソフェナジンと、去痰剤のブロムヘキシンとを組み合わせると優れた抗炎症作用が発現することを見出し、本発明を完成させた。 As a result of intensive studies on a combination of a number of drugs in order to solve such problems, the present inventors have found that antibacterial antibacterial agent bromhexine combined with fexofenadine, which is used as an antiallergic agent, has excellent anti The inventors have found that an inflammatory action is expressed and completed the present invention.
すなわち、本発明は下記の（１）〜（４）を提供するものである。
（１）フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する、抗炎症及び／又は抗ヒスタミン剤組成物。
（２）アレルギー性鼻炎又は副鼻腔炎の予防及び／又は治療のための、（１）に記載の抗炎症及び／又は抗ヒスタミン剤組成物。
（３）感冒時の急性鼻炎又は咽頭炎の予防及び／又は治療のための、（１）に記載の抗炎症及び／又は抗ヒスタミン剤組成物。
（４）鎮咳又は去痰のための、（１）に記載の抗炎症及び／又は抗ヒスタミン剤組成物。
That is, the present invention provides the following (1) to (4).
(1) An anti-inflammatory and / or antihistamine composition comprising fexofenadine hydrochloride and bromhexine hydrochloride.
(2) The anti-inflammatory and / or antihistamine composition according to (1) for the prevention and / or treatment of allergic rhinitis or sinusitis.
(3) The anti-inflammatory and / or antihistamine composition according to (1) for the prevention and / or treatment of acute rhinitis or pharyngitis during the cold.
(4) The anti-inflammatory and / or antihistamine composition according to (1) for coughing or expectoration.
本発明の、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する医薬組成物は、優れた抗炎症作用並びに抗アレルギー作用を奏するため有用である。例えば、アレルギー性鼻炎、副鼻腔炎、感冒時における急性鼻炎や咽頭炎等の症状の予防及び／又は治療、さらには鎮咳去痰のための医薬組成物として提供することができる。 The pharmaceutical composition containing fexofenadine hydrochloride and bromhexine hydrochloride of the present invention is useful because it exhibits excellent anti-inflammatory action and anti-allergic action. For example, it can be provided as a pharmaceutical composition for the prevention and / or treatment of symptoms such as allergic rhinitis, sinusitis, acute rhinitis and pharyngitis during the cold, and antitussive expectorant.
本発明の、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩は第１６改正日本薬局方に収載されている。 The fexofenadine hydrochloride and bromhexine hydrochloride of the present invention are listed in the 16th revision Japanese Pharmacopoeia.
本発明の組成物の１回投与量における、フェキソフェナジン塩酸塩の含有量は特に制限はないが、１０〜１２０ｍｇの範囲で使用でき、好ましくは３０〜６０ｍｇである。 The content of fexofenadine hydrochloride in a single dose of the composition of the present invention is not particularly limited, but it can be used in the range of 10 to 120 mg, preferably 30 to 60 mg.
本発明の組成物の１回投与量における、ブロムヘキシン塩酸塩の含有量は特に制限はないが、１〜１２ｍｇの範囲で使用でき、好ましくは２〜４ｍｇである。 The content of bromhexine hydrochloride in a single dose of the composition of the present invention is not particularly limited, but can be used in the range of 1 to 12 mg, preferably 2 to 4 mg.
これらの具体的な剤形としては、例えば、錠剤、顆粒剤、散剤（細粒を含む）、カプセル剤、液剤（シロップ剤を含む）等をあげることができ、各剤形に適した添加剤や基材を適宜使用し、日本薬局方等に記載された通常の方法に従い、製造することができる。
上記各剤形において、その剤形に応じ、通常使用される各種添加剤を使用することもできる。例えば、賦形剤、安定化剤、コーティング剤、滑沢剤、吸着剤、結合剤、崩壊剤、界面活性剤、着色剤、ｐＨ調節剤及び香料等を適宜使用し、日本薬局方等に記載された通常の方法に従い、製造することができる。
なお、本発明における、フェキソフェナジン塩酸塩、ブロムヘキシン塩酸塩、及び上記添加成分を含有する組成物が錠剤などの固形製剤の場合、該固形製剤は常法に従って製造できるが、上記添加成分が、ＤＡＤＡ及び／又はトラネキサム酸との配合禁忌等の課題で、保存安定性等に課題が発生する場合には、適宜、顆粒分け、多層化等により互いに接触しないように製剤化すればよい。ここで、顆粒分け、多層化等の製剤化は公知の方法を用いればよい。また、上記製剤が吸水等により保存安定性や品質に課題が発生する場合には、乾燥剤入り包装、及び／又は、製剤や顆粒の防湿コーティング等により、適宜、対応すればよい。
Specific examples of these dosage forms include tablets, granules, powders (including fine granules), capsules, liquids (including syrups) and the like, and additives suitable for each dosage form. Can be produced according to the usual methods described in the Japanese Pharmacopoeia and the like.
In the above dosage forms, various commonly used additives can be used depending on the dosage form. For example, excipients, stabilizers, coating agents, lubricants, adsorbents, binders, disintegrants, surfactants, colorants, pH regulators and fragrances are used as appropriate, and described in the Japanese Pharmacopoeia, etc. Can be produced according to the usual methods.
In the present invention, when the composition containing fexofenadine hydrochloride, bromohexine hydrochloride, and the above-described additive component is a solid preparation such as a tablet, the solid preparation can be produced according to a conventional method, When problems such as incompatibility with DADA and / or tranexamic acid occur in storage stability and the like, preparations may be made so that they do not come into contact with each other by appropriate granulation or multilayering. Here, a known method may be used for formulation such as granulation and multilayering. In addition, when the above preparation causes problems in storage stability or quality due to water absorption or the like, it can be appropriately handled by packaging with a desiccant and / or moisture-proof coating of the preparation or granules.
本発明の、「感冒時の急性鼻炎又は咽頭炎」とは、感冒罹患時における鼻水、鼻閉、くしゃみ、喉痛を意味する。 The “acute rhinitis or pharyngitis at the time of cold” of the present invention means runny nose, nasal congestion, sneezing, and sore throat at the time of common cold.
以下に、実施例及び試験例を示し、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
（実施例１）錠剤
（１）成分
（表１）
成分 ３錠中（ｍｇ）
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 ４
フェキソフェナジン塩酸塩 ４０
乳糖 １５
ステアリン酸マグネシウム ２
トウモロコシデンプン ３０
置換度ヒドロキシプロピルセルロース 適量
――――――――――――――――――――――――――
Example 1 Tablet (1) Ingredient (Table 1)
Ingredients 3 tablets (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Lactose 15
Magnesium stearate 2
Corn starch 30
Degree of substitution hydroxypropylcellulose Suitable amount ――――――――――――――――――――――――――
（２）製法
上記成分及び分量をとり、日局製剤総則「錠剤」の項に準じて錠剤を製造する。
(2) Manufacturing method Take the above ingredients and the amount, and manufacture tablets according to the section of “General Tablets” “Tablet”.
（実施例２）細粒剤
（１）成分
（表２）
成分 １包中（ｍｇ）
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 ４
フェキソフェナジン塩酸塩 ４０
乳糖 １００
トウモロコシデンプン ５００
ステアリン酸マグネシウム ４
低置換度ヒドロキシプロピルセルロース 適量
――――――――――――――――――――――――――
(Example 2) Fine granule (1) component (Table 2)
In 1 pack (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Lactose 100
Corn starch 500
Magnesium stearate 4
Low-substituted hydroxypropylcellulose Suitable amount ――――――――――――――――――――――――――
（２）製法
上記成分及び分量をとり、日局製剤総則「顆粒剤」の項に準じて細粒剤を製造する。
(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”.
（実施例３）カプセル剤
（１）成分
（表３）
成分 ３カプセル中（ｍｇ）
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 ４
フェキソフェナジン塩酸塩 ４０
乳糖 ２５
ステアリン酸マグネシウム ３
トウモロコシデンプン ４０
ヒドロキシプロピルセルロース 適量
――――――――――――――――――――――――――
Example 3 Capsule (1) Ingredient (Table 3)
In 3 capsules (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Lactose 25
Magnesium stearate 3
Corn starch 40
Hydroxypropylcellulose appropriate amount ――――――――――――――――――――――――――
（２）製法
上記成分及び分量をとり、日局製剤総則「顆粒剤」の項に準じて細粒剤を製造した後、カプセルに充てんして硬カプセル剤を製造する。
(2) Manufacturing method After taking the above components and quantities and preparing a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granules”, it is filled into capsules to produce hard capsules.
（実施例４）シロップ剤
（１）成分
（表４）
成分 １０ｍＬ中（ｍｇ）
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 ４
フェキソフェナジン塩酸塩 ４０
安息香酸ナトリウム １００
ポリビニルアルコール ２０
白糖 ９００
精製水 残部
――――――――――――――――――――――――――
(Example 4) Syrup (1) component (Table 4)
Ingredients in 10 mL (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Sodium benzoate 100
Polyvinyl alcohol 20
Sucrose 900
Purified water balance ――――――――――――――――――――――――――
（２）製法
上記成分及び分量をとり、日局製剤総則「シロップ剤」の項に準じてシロップ剤を製造した後、褐色ガラス瓶に充てんしてシロップ剤を製造する。
(2) Manufacturing method Take the above ingredients and quantities, and manufacture a syrup according to the Japanese general formulation “Syrup” section, then fill it into a brown glass bottle to manufacture a syrup.
（試験例１）カラゲニン足蹠浮腫法による抗炎症効果試験
（１）被験物質
フェキソフェナジン塩酸塩はサノフィ・アベンティス（株）製のアレグラ（登録商標）錠を、乳鉢を用いて粉砕して使用した。また、セチリジン塩酸塩は東京化成工業（株）製、ブロムヘキシン塩酸塩はLKT Laboratories, Inc.製又は和光純薬工業（株）製、アンブロキソール塩酸塩は和光純薬工業（株）製のものを使用した。
各被験物質は、日本薬局方注射用水を用いて0.5w/v％のメチルセルロース（信越化学工業（株）製）溶液中に、所定量を入れて懸濁して調製し、胃ゾンデを取り付けたポリプロピレン製のディスポーザブル注射筒を用いて強制経口投与した。
(Test Example 1) Anti-inflammatory effect test by carrageenin footpad edema method (1) Test substance Fexofenadine hydrochloride is used by pulverizing Allegra (registered trademark) tablets manufactured by Sanofi-aventis Co., Ltd. using a mortar. did. Cetirizine hydrochloride is manufactured by Tokyo Chemical Industry Co., Ltd., bromohexine hydrochloride is manufactured by LKT Laboratories, Inc. or manufactured by Wako Pure Chemical Industries, Ltd., and ambroxol hydrochloride is manufactured by Wako Pure Chemical Industries, Ltd. It was used.
Each test substance is prepared by suspending a prescribed amount in a 0.5 w / v% methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) solution using Japanese Pharmacopoeia water for injection, and a polypropylene with a stomach tube attached Forcible oral administration was performed using a disposable syringe.
（２）使用動物
Ｃｒｌ：ＣＤ雄ラット（日本チャールス・リバー社製）４週齢を購入し、温度２３±３℃、湿度５５±１５％、照明時間６時〜１８時、換気回数１２回／時（フィルターを通した新鮮空気）に制御された飼育室にて飼育した。なお、入手後５日間の検疫期間、その後、２日以上の馴化期間を設けた。飼料は実験動物用特殊固形飼料（ＣＲＦ−１、オリエンタル酵母工業社製）および水道水を給水ビンにて自由に摂取させた。
体重推移、一般状態に異常の認められない動物を、馴化終了後に評価での使用動物として群分けに用いた。なお、被験物質投与前１８時間以上は絶食とした。
(2) Animals used: Crl: CD male rat (manufactured by Charles River Japan) 4 weeks old, temperature 23 ± 3 ° C., humidity 55 ± 15%, lighting time 6:00 to 18:00, ventilation rate 12 times / Breeding in a breeding room controlled by time (fresh air through filter). In addition, a quarantine period of 5 days after acquisition and then a habituation period of 2 days or more were provided. As the feed, a special solid feed for experimental animals (CRF-1, manufactured by Oriental Yeast Co., Ltd.) and tap water were freely taken in a water supply bottle.
Animals with no abnormalities in weight transition and general condition were used for grouping as animals used for evaluation after habituation. In addition, fasting was performed for 18 hours or more before administration of the test substance.
（３）炎症の惹起
起炎剤として、カラゲニン（逗子化学研究所製）を、1.5w/v％になるように生理食塩液で懸濁して用いた。右側後肢足蹠皮下に27Gマント針を取り付けたポリプロピレン製のディスポーザブル注射筒を用いて、1.5w/v％カラゲニンを0.1mL投与し炎症を惹起させた。
(3) Induction of inflammation Carrageenin (manufactured by Choshi Chemical Laboratories) was used as an inflammatory agent suspended in physiological saline so as to be 1.5 w / v%. Inflammation was induced by administering 0.1 mL of 1.5 w / v% carrageenan using a polypropylene disposable syringe with a 27G cloak needle attached to the right hind footpad.
（４）試験方法
被験薬は、起炎３０分前に１回経口投与した。群分け前、起炎後１、２、３、４及び５時間に、マウス・ラット後肢足蹠浮腫容積測定装置（ユニコム製）を用いて、右側後肢足蹠容積を測定した。浮腫率は以下の式により算出して求めた。
(4) Test method The test drug was orally administered once 30 minutes before inflammation. The right hind footpad volume was measured using a mouse / rat hindlimb footpad edema volume measuring device (manufactured by Unicom) before grouping and at 1, 2, 3, 4 and 5 hours after inflammation. The edema rate was calculated by the following formula.
（５）試験結果
予試験によってフェキソフェナジン塩酸塩単剤（ＦＦ）、及び、セチリジン塩酸塩単剤（ＣＺ）の抗炎症作用の概略最大無作用量を求め、それらを投与量とした。予試験によるフェキソフェナジン塩酸塩単剤（ＦＦ）、及びセチリジン塩酸塩単剤（ＣＺ）の抗炎症作用の最大無作用量は、それぞれ６ｍｇ／Ｋｇ、及び１０ｍｇ／Ｋｇであった。
抗炎症作用のない去痰剤の投与量については、上記抗ヒスタミン剤の投与量、ブロムヘキシン及びアンブロキソールの臨床量比を基にして、それぞれ４ｍｇ／Ｋｇ、及び１５ｍｇ／Ｋｇとした。
(5) Test results Preliminary tests determined the approximate maximum ineffective amount of anti-inflammatory action of fexofenadine hydrochloride single agent (FF) and cetirizine hydrochloride single agent (CZ), and these were used as doses. The maximum ineffective amount of anti-inflammatory action of fexofenadine hydrochloride single agent (FF) and cetirizine hydrochloride single agent (CZ) by the preliminary test was 6 mg / Kg and 10 mg / Kg, respectively.
The dose of the expectorant without anti-inflammatory action was 4 mg / Kg and 15 mg / Kg, respectively, based on the dose of the antihistamine and the clinical dose ratio of bromhexine and ambroxol.
上記投与量において得られた浮腫率の結果を図１、図２に示した（ｎ＝１０）。
図１より、フェキソフェナジン塩酸塩及びアンブロキソール塩酸塩を併用（ＦＦ＋ＡＸ）した場合には浮腫が悪化することが判明した。一方、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を併用（ＦＦ＋ＢＸ）した場合には抗浮腫作用が増強することが判った。
また、時間経過による浮腫率の時間曲線下面積（ＡＵＣ；area under the time curve）を指標として比較評価した。溶媒を投与した対照群におけるＡＵＣを１とした場合、フェキソフェナジン塩酸塩単剤（ＦＦ）では０．９９、ＦＦ＋ＡＸでは１．０７、またＦＦ＋ＢＸでは０．９１であった。
一方、抗ヒスタミン薬のフェキソフェナジン塩酸塩を、同じ、第二世代の抗ヒスタミン剤であるセチリジン塩酸塩（ＣＺ）に置き換え、同様の評価をした結果を図２に示した。図２より、セチリジン塩酸塩及びアンブロキソール塩酸塩を併用（ＣＺ＋ＡＸ）した場合とセチリジン塩酸塩単剤（ＣＺ）の時間経過による浮腫率の推移は、ＡＵＣ比としてそれぞれ０．９８及び０．９５であり、併用群及び単剤群ともに溶媒投与群とほぼ同程度であり、併用によっても浮腫率の抑制効果がほとんど認められなかった。一方、セチリジン塩酸塩及びブロムヘキシン塩酸塩を併用（ＣＺ＋ＢＸ）した場合にはＡＵＣが１．０９に増加し、浮腫が悪化した。
以上の結果より、フェキソフェナジン塩酸塩とブロムヘキシン塩酸塩の併用においてのみ、抗炎症作用の増強が発現することが判明した。
The results of the edema rate obtained at the above dose are shown in FIGS. 1 and 2 (n = 10).
From FIG. 1, it was found that when fexofenadine hydrochloride and ambroxol hydrochloride were used in combination (FF + AX), edema worsened. On the other hand, when fexofenadine hydrochloride and bromhexine hydrochloride were used in combination (FF + BX), it was found that the anti-edema action was enhanced.
In addition, the area under the time curve (AUC) of the edema rate over time was compared and evaluated. When the AUC in the control group to which the solvent was administered was 1, it was 0.99 for fexofenadine hydrochloride (FF), 1.07 for FF + AX, and 0.91 for FF + BX.
On the other hand, FIG. 2 shows the results of a similar evaluation in which the antihistamine drug fexofenadine hydrochloride was replaced with cetirizine hydrochloride (CZ), which is the same second generation antihistamine. From FIG. 2, the change in edema rate over time of cetirizine hydrochloride and ambroxol hydrochloride in combination (CZ + AX) and cetirizine hydrochloride single agent (CZ) is 0.98 and 0.95 as AUC ratios, respectively. Both the combination group and the single agent group were almost the same as those in the solvent administration group, and the combined use showed almost no effect of suppressing the edema rate. On the other hand, when cetirizine hydrochloride and bromhexine hydrochloride were used in combination (CZ + BX), AUC increased to 1.09, and edema worsened.
From the above results, it was found that the enhancement of the anti-inflammatory effect was manifested only in the combined use of fexofenadine hydrochloride and bromhexine hydrochloride.
（試験例２）モルモット摘出回腸のヒスタミンによる収縮試験
（１）被験物質
フェキソフェナジン塩酸塩はアミノケミカル製を使用した。また、セチリジン塩酸塩は東京化成工業（株）製を、ブロムヘキシン塩酸塩は和光純薬工業（株）製又はＬＫＴ Ｌａｂｏｒａｔｏｒｉｅｓ，Ｉｎｃ．製のものを使用した。
各被験物質は、ジメチルスルフォキシド溶液で溶解し、日本薬局方注射用水を用いて希釈し、所定濃度になるように調製した。
(Test Example 2) Contraction test using histamine in the isolated ileum of the guinea pig (1) Test substance Fexofenadine hydrochloride manufactured by Amino Chemical was used. Cetirizine hydrochloride is manufactured by Tokyo Chemical Industry Co., Ltd., and bromohexine hydrochloride is manufactured by Wako Pure Chemical Industries, Ltd. or LKT Laboratories, Inc. The product made from was used.
Each test substance was dissolved in a dimethyl sulfoxide solution, diluted with Japanese Pharmacopoeia water for injection, and prepared to a predetermined concentration.
（２）使用動物
Ｋｗｌ：Ｈａｒｔｌｅｙ雄モルモット（紀和実験動物研究所社製）３週齢を購入し、温度２３±３℃、湿度５５±１５％、照明時間６時〜１８時、換気回数１２回／時（フィルターを通した新鮮空気）に制御された飼育室にて飼育した。なお、入手後５日間の検疫期間、その後、２日以上の馴化期間を設けた。飼料は固形飼料（ＬＲＣ４、オリエンタル酵母工業社製）および水道水を給水ビンにて自由に摂取させた。評価には、体重推移、一般状態に異常が認められない動物を用いた。
(2) Animals used Kwl: Hartley male guinea pig (manufactured by Kiwa Laboratory Animal Research Co., Ltd.) 3 weeks old is purchased, temperature 23 ± 3 ° C., humidity 55 ± 15%, illumination time 6 o'clock to 18 o'clock, ventilation rate 12 times It was reared in a rearing room controlled at / hour (fresh air through a filter). In addition, a quarantine period of 5 days after acquisition and then a habituation period of 2 days or more were provided. As the feed, solid feed (LRC4, manufactured by Oriental Yeast Co., Ltd.) and tap water were freely ingested in a water supply bottle. For the evaluation, animals with no abnormality in weight transition and general condition were used.
（３）標本の作製
該動物を20v/v%イソフルランにて麻酔し、頚動脈を切断して放血死させた後、回腸を摘出後、混合ガス（95%O２＋5%CO2）飽和の栄養液（Ｔｙｒｏｄｅ液：＜組成＞ＮａＣｌ：１３６．９ｍｍｏｌ／Ｌ、ＫＣｌ：２．７ｍｍｏｌ／Ｌ、ＣａＣｌ２：１．８ｍｍｏｌ／Ｌ、ＭｇＣｌ２：１．０５ｍｍｏｌ／Ｌ、ＮａＨ２ＰＯ４：０．４２ｍｍｏｌ／Ｌ、ＮａＨＣＯ３：１１．９ｍｍｏｌ／Ｌ、Ｇｌｕｃｏｓｅ：５．５５ｍｍｏｌ／Ｌ）に浸した。摘出した回腸を切断し、長さ約１ｃｍの標本を作製した。作製した標本は、混合ガスで通気した栄養液が満たされたMagnus管内に、約0.5gの負荷で縦走方向に懸垂させた。
(3) Preparation of specimen The animal was anesthetized with 20v / v% isoflurane, the carotid artery was cut and exsanguinated, the ileum was removed, and mixed gas (95% O 2 + 5% CO 2 ) saturated nutrition Solution (Tyrode solution: <composition> NaCl: 136.9 mmol / L, KCl: 2.7 mmol / L, CaCl2: 1.8 mmol / L, MgCl2: 1.05 mmol / L, NaH2PO4: 0.42 mmol / L, NaHCO3: 11.9 mmol / L, Glucose: 5.55 mmol / L). The excised ileum was cut to prepare a specimen having a length of about 1 cm. The prepared specimen was suspended in the longitudinal direction under a load of about 0.5 g in a Magnus tube filled with a nutrient solution aerated with a mixed gas.
（４）張力の測定
栄養液で満たされたMagnus管内の標本は、懸垂して３０分以上平衡化した後、該管内にヒスタミン（終濃度：１×１０−６ｍｏｌ／Ｌ）を添加して収縮反応を測定する。標本の張力変化は、等張性トランスデューサーとアンプ（日本光電工業製）を介しデータ収集システムで記録した。栄養液で洗浄後、再びヒスタミンを添加して、２回の収縮反応が同程度の場合に限り被験物質の測定に使用することとした。
(4) Measurement of tension The specimen in the Magnus tube filled with nutrient solution was suspended and equilibrated for 30 minutes or more, and then histamine (final concentration: 1 × 10 −6 mol / L) was added to the tube. Measure contractile response. The tension change of the specimen was recorded by a data acquisition system via an isotonic transducer and an amplifier (manufactured by Nihon Kohden Industry). After washing with nutrient solution, histamine was added again, and it was decided to use it for the measurement of the test substance only when the two contraction reactions were similar.
（５）試験方法
静止張力の状態で被験物質を添加し、15分後にヒスタミンを添加して収縮反応に対する被験物質の抑制効果を測定した。抑制率は以下の式により算出して求めた。
(5) Test method The test substance was added in a state of static tension, and histamine was added 15 minutes later to measure the inhibitory effect of the test substance on the contractile reaction. The inhibition rate was calculated by the following formula.
（６）試験結果
フェキソフェナジン塩酸塩単剤（ＦＦ）に対する、フェキソフェナジン塩酸塩とブロムヘキシン塩酸塩の併用（ＦＦ＋ＢＸ）における抑制率の比の結果を表５に示した。参考として、表５には、同じ第二世代のセチリジン塩酸塩単剤（ＣＺ）の抑制率に対する、セチリジン塩酸塩とブロムヘキシン塩酸塩の併用（ＣＺ＋ＢＸ）における抑制率の比を示した。各数値はいずれもｎ＝５の結果の平均値である。
(6) Test result The result of the ratio of the inhibition rate in combined use (FF + BX) of fexofenadine hydrochloride and bromhexine hydrochloride with respect to fexofenadine hydrochloride single agent (FF) was shown in Table 5. For reference, Table 5 shows the ratio of the inhibition rate in the combined use of cetirizine hydrochloride and bromhexine hydrochloride (CZ + BX) with respect to the inhibition rate of the same second-generation cetirizine hydrochloride single agent (CZ). Each numerical value is an average value of the results of n = 5.
（表５）
被験薬（ｍｇ／Ｌ） 抑制率の比
―――――――――――――――――――――――――――――――
ＦＦ（０．０２） １
ＦＦ（０．０２）＋ＢＸ（０．０１６） １．３２
ＣＺ（０．０４） １
ＣＺ（０．０４）＋ＢＸ（０．０１６） ０．９６
―――――――――――――――――――――――――――――――
以上の結果より、フェキソフェナジン塩酸塩（ＦＦ）とブロムヘキシン塩酸塩（ＢＸ）の併用おいてのみ、抗ヒスタミン作用の増強が発現することが判明した。
(Table 5)
Study drug (mg / L) Ratio of inhibition rate ―――――――――――――――――――――――――――――――
FF (0.02) 1
FF (0.02) + BX (0.016) 1.32
CZ (0.04) 1
CZ (0.04) + BX (0.016) 0.96
―――――――――――――――――――――――――――――――
From the above results, it was found that the antihistaminic activity was enhanced only by the combined use of fexofenadine hydrochloride (FF) and bromohexine hydrochloride (BX).
フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する、新たな抗炎症剤及び／又は抗ヒスタミン組成物として利用できる。 It can be used as a new anti-inflammatory agent and / or antihistamine composition containing fexofenadine hydrochloride and bromhexine hydrochloride.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012201092A JP6178058B2 (en) | 2011-09-14 | 2012-09-13 | Anti-inflammatory and / or antihistamine composition |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011200646 | 2011-09-14 | ||
| JP2011200646 | 2011-09-14 | ||
| JP2012201092A JP6178058B2 (en) | 2011-09-14 | 2012-09-13 | Anti-inflammatory and / or antihistamine composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013075892A true JP2013075892A (en) | 2013-04-25 |
| JP6178058B2 JP6178058B2 (en) | 2017-08-09 |
Family
ID=48479651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012201092A Active JP6178058B2 (en) | 2011-09-14 | 2012-09-13 | Anti-inflammatory and / or antihistamine composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6178058B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017171626A (en) * | 2016-03-25 | 2017-09-28 | 第一三共ヘルスケア株式会社 | Pharmaceutical composition comprising propionic acid-based nonsteroidal antiinflammatory agent |
| JP2021004263A (en) * | 2020-10-16 | 2021-01-14 | 第一三共ヘルスケア株式会社 | Pharmaceutical composition comprising propionic acid-based nonsteroidal antiinflammatory agent |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002255816A (en) * | 2001-03-05 | 2002-09-11 | Taisho Pharmaceut Co Ltd | Composition for treating cold |
| JP2003048834A (en) * | 2001-08-01 | 2003-02-21 | Taisho Pharmaceut Co Ltd | Pharmaceutical composition |
| JP2006008540A (en) * | 2004-06-23 | 2006-01-12 | Noevir Co Ltd | Cold remedy |
| JP2006124831A (en) * | 2004-09-30 | 2006-05-18 | Nichias Corp | Reaction vessel for vapor phase growth, and vapor phase growth method |
| JP2006124381A (en) * | 2004-09-29 | 2006-05-18 | Dai Ichi Seiyaku Co Ltd | Prophylactic and/or therapeutic agent for inflammation |
| JP2007302578A (en) * | 2006-05-09 | 2007-11-22 | Sorm Co Ltd | Combined formulation of general cold drug |
| JP2010111667A (en) * | 2008-10-10 | 2010-05-20 | Daiichi Sankyo Healthcare Co Ltd | Medicinal composition for antitussive action and/or expectoration containing fexofenadine or ebastine |
-
2012
- 2012-09-13 JP JP2012201092A patent/JP6178058B2/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002255816A (en) * | 2001-03-05 | 2002-09-11 | Taisho Pharmaceut Co Ltd | Composition for treating cold |
| JP2003048834A (en) * | 2001-08-01 | 2003-02-21 | Taisho Pharmaceut Co Ltd | Pharmaceutical composition |
| JP2006008540A (en) * | 2004-06-23 | 2006-01-12 | Noevir Co Ltd | Cold remedy |
| JP2006124381A (en) * | 2004-09-29 | 2006-05-18 | Dai Ichi Seiyaku Co Ltd | Prophylactic and/or therapeutic agent for inflammation |
| JP2006124831A (en) * | 2004-09-30 | 2006-05-18 | Nichias Corp | Reaction vessel for vapor phase growth, and vapor phase growth method |
| JP2007302578A (en) * | 2006-05-09 | 2007-11-22 | Sorm Co Ltd | Combined formulation of general cold drug |
| JP2010111667A (en) * | 2008-10-10 | 2010-05-20 | Daiichi Sankyo Healthcare Co Ltd | Medicinal composition for antitussive action and/or expectoration containing fexofenadine or ebastine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017171626A (en) * | 2016-03-25 | 2017-09-28 | 第一三共ヘルスケア株式会社 | Pharmaceutical composition comprising propionic acid-based nonsteroidal antiinflammatory agent |
| JP2021004263A (en) * | 2020-10-16 | 2021-01-14 | 第一三共ヘルスケア株式会社 | Pharmaceutical composition comprising propionic acid-based nonsteroidal antiinflammatory agent |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6178058B2 (en) | 2017-08-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5208473B2 (en) | Pharmaceutical composition containing azelastine and anticholinergic agent | |
| JP2019019132A (en) | Stable pharmaceutical composition | |
| WO2015113200A1 (en) | Hydrochloric tapentadol injection and preparation method thereof | |
| JP6178058B2 (en) | Anti-inflammatory and / or antihistamine composition | |
| JP2006124380A (en) | Medicine composition | |
| JP5815273B2 (en) | Anti-inflammatory composition | |
| JP2008247822A (en) | Analgesic composition | |
| JP2010083871A (en) | Medicinal composition containing anti-adenoviral agent | |
| JP2017171626A (en) | Pharmaceutical composition comprising propionic acid-based nonsteroidal antiinflammatory agent | |
| JP2008115168A (en) | Anti-adenovirus agent | |
| JP5232520B2 (en) | Anti-adenoviral agent containing loxoprofen | |
| JP5094197B2 (en) | Pharmaceutical composition containing antihistamine for suppressing goblet cell hyperplasia | |
| CN104000822A (en) | Compound cold medicinal composition containing bilastine | |
| JP4384435B2 (en) | Sneezing suppression composition | |
| JP4614638B2 (en) | Analgesic composition | |
| JP2017132819A (en) | Pharmaceutical composition containing loxoprofen or salt thereof | |
| JP2011246433A (en) | Loxoprofen-containing pharmaceutical composition | |
| JP6159128B2 (en) | Anti-rotavirus agent | |
| JP4829478B2 (en) | Pharmaceutical composition | |
| JP2008285474A (en) | Medicinal composition containing anti-adenovirus agent | |
| JP6168755B2 (en) | Antihistamine composition | |
| JP2010111667A (en) | Medicinal composition for antitussive action and/or expectoration containing fexofenadine or ebastine | |
| JP2009108042A (en) | Pharmaceutical composition containing azelastine and ambroxol | |
| JP2009007332A (en) | Pharmaceutical composition containing azelastines and ephedorines | |
| WO2021263139A1 (en) | Methods of treating coronavirus infection using hsp90 inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150312 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20151209 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160113 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20160607 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160715 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20160726 |
|
| A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20160902 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170713 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6178058 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |