JPH08506808A - Use of analgesic S (+) enantiomer in the manufacture of a composition for treating respiratory disorders - Google Patents
Use of analgesic S (+) enantiomer in the manufacture of a composition for treating respiratory disordersInfo
- Publication number
- JPH08506808A JPH08506808A JP6515219A JP51521994A JPH08506808A JP H08506808 A JPH08506808 A JP H08506808A JP 6515219 A JP6515219 A JP 6515219A JP 51521994 A JP51521994 A JP 51521994A JP H08506808 A JPH08506808 A JP H08506808A
- Authority
- JP
- Japan
- Prior art keywords
- composition according
- mixtures
- pharmaceutical composition
- pharmaceutically acceptable
- ibuprofen
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 230000000202 analgesic effect Effects 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title description 4
- 208000023504 respiratory system disease Diseases 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000003172 expectorant agent Substances 0.000 claims abstract description 15
- 229940124584 antitussives Drugs 0.000 claims abstract description 14
- 230000003419 expectorant effect Effects 0.000 claims abstract description 13
- 208000024891 symptom Diseases 0.000 claims abstract description 13
- 239000000850 decongestant Substances 0.000 claims abstract description 12
- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 claims abstract description 12
- 230000000954 anitussive effect Effects 0.000 claims abstract description 10
- 206010022000 influenza Diseases 0.000 claims abstract description 10
- SYTBZMRGLBWNTM-JTQLQIEISA-N (S)-flurbiprofen Chemical compound FC1=CC([C@@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-JTQLQIEISA-N 0.000 claims abstract description 8
- 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 claims abstract 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- -1 Hydrocod Chemical compound 0.000 claims description 10
- 239000003434 antitussive agent Substances 0.000 claims description 8
- 239000000739 antihistaminic agent Substances 0.000 claims description 6
- 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 6
- 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 5
- 229940124581 decongestants Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 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 description 4
- 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 claims description 4
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 4
- 229960001985 dextromethorphan Drugs 0.000 claims description 4
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical group COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 claims description 3
- 230000001387 anti-histamine Effects 0.000 claims description 3
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000725 brompheniramine Drugs 0.000 claims description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 3
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 2
- LZFCSDIBLCSFAK-WLHGVMLRSA-N (e)-but-2-enedioic acid;2-[2-(dimethylamino)ethyl]-4-methyl-2,3-dihydropyrido[3,2-f][1,4]oxazepine-5-thione Chemical compound OC(=O)\C=C\C(O)=O.O1C(CCN(C)C)CN(C)C(=S)C2=CC=CN=C21 LZFCSDIBLCSFAK-WLHGVMLRSA-N 0.000 claims description 2
- JGKJMBOJWVAMIJ-UHFFFAOYSA-N 4-(2-hydroxypropan-2-yl)-1-methylcyclohexan-1-ol;hydrate Chemical compound O.CC(C)(O)C1CCC(C)(O)CC1 JGKJMBOJWVAMIJ-UHFFFAOYSA-N 0.000 claims description 2
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 claims description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 2
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 claims description 2
- ISFHAYSTHMVOJR-UHFFFAOYSA-N Phenindamine Chemical compound C1N(C)CCC(C2=CC=CC=C22)=C1C2C1=CC=CC=C1 ISFHAYSTHMVOJR-UHFFFAOYSA-N 0.000 claims description 2
- 229960004308 acetylcysteine Drugs 0.000 claims description 2
- 229960003792 acrivastine Drugs 0.000 claims description 2
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 claims description 2
- 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 claims description 2
- 229960005174 ambroxol Drugs 0.000 claims description 2
- 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 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 229960001040 ammonium chloride Drugs 0.000 claims description 2
- 229960004574 azelastine Drugs 0.000 claims description 2
- 229960003166 bromazine Drugs 0.000 claims description 2
- NUNIWXHYABYXKF-UHFFFAOYSA-N bromazine Chemical compound C=1C=C(Br)C=CC=1C(OCCN(C)C)C1=CC=CC=C1 NUNIWXHYABYXKF-UHFFFAOYSA-N 0.000 claims description 2
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 claims description 2
- 229960003870 bromhexine Drugs 0.000 claims description 2
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 claims description 2
- 229960000428 carbinoxamine Drugs 0.000 claims 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 claims description 2
- 229960001803 cetirizine Drugs 0.000 claims description 2
- 229960003291 chlorphenamine Drugs 0.000 claims description 2
- 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 claims description 2
- RBNWAMSGVWEHFP-UHFFFAOYSA-N cis-p-Menthan-1,8-diol Natural products CC(C)(O)C1CCC(C)(O)CC1 RBNWAMSGVWEHFP-UHFFFAOYSA-N 0.000 claims description 2
- 229960004126 codeine Drugs 0.000 claims description 2
- 229960001140 cyproheptadine Drugs 0.000 claims description 2
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 claims description 2
- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 claims description 2
- 229960001882 dexchlorpheniramine Drugs 0.000 claims description 2
- 229960000520 diphenhydramine Drugs 0.000 claims description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 2
- 229960005178 doxylamine Drugs 0.000 claims description 2
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 claims description 2
- 229960001971 ebastine Drugs 0.000 claims description 2
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 claims description 2
- 229960002179 ephedrine Drugs 0.000 claims description 2
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 2
- 229960001410 hydromorphone Drugs 0.000 claims description 2
- 229960000991 ketoprofen Drugs 0.000 claims description 2
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- 229960001120 levocabastine Drugs 0.000 claims description 2
- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 claims description 2
- 229960003088 loratadine Drugs 0.000 claims description 2
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 2
- 229960000582 mepyramine Drugs 0.000 claims description 2
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960005042 mequitazine Drugs 0.000 claims description 2
- 229940066491 mucolytics Drugs 0.000 claims description 2
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 claims description 2
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- BAINIUMDFURPJM-UHFFFAOYSA-N oxatomide Chemical compound O=C1NC2=CC=CC=C2N1CCCN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BAINIUMDFURPJM-UHFFFAOYSA-N 0.000 claims description 2
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- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims description 2
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 2
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- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 9
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
(57)【要約】 本発明は、S(+)イブプロフェン、S(+)フルルビプロフェン及びS(+)ケトプロフェン、それらの薬学上許容される塩とそれらの混合物からなる群より選択される、そのR(−)対掌体を実質上含まない鎮痛剤を(a)うっ血除去剤、(b)去痰剤及び(c)鎮咳剤のうち少くとも1種と共に含んだ組成物の安全有効量を投与することにより、感冒、感冒様及び/又はインフルエンザ症状の改善された治療、管理又は緩和を提供する組成物及び方法に関する。 (57) [Summary] The present invention provides R (-) thereof selected from the group consisting of S (+) ibuprofen, S (+) flurbiprofen and S (+) ketoprofen, pharmaceutically acceptable salts thereof and mixtures thereof. By administering a safe and effective amount of a composition containing an analgesic substantially free of antipode together with at least one of (a) a decongestant, (b) an expectorant and (c) an antitussive, , Compositions and methods that provide improved treatment, management or alleviation of cold-like and / or influenza symptoms.
Description
【発明の詳細な説明】 呼吸障害治療用組成物の製造における 鎮痛剤S(+)対掌体の利用 技術分野 本発明は、S(+)イブプロフェン、S(+)フルルビプロフェン(flurbipr ofen)及びS(+)ケトプロフェン、それらの薬学上許容される塩とそれらの混 合物からなる群より選択される、そのR(−)対掌体を実質上含まない鎮痛剤を (a)うっ血除去剤、(b)去痰剤及び(c)鎮咳剤のうち少くとも1種と共に含 んだ組成物の安全有効量を投与することにより、感冒、感冒様及び/又はインフ ルエンザ症状の改善された治療、管理又は緩和を提供する組成物及び方法に関す る。 発明の背景 普通感冒は通常重篤な病気ではないが、高度に流行性で不快な苛立つ苦痛であ る。“普通感冒”という用語は様々な異なる呼吸器ウイルスに起因する軽度の呼 吸器病に適用される。ライノウイルスは普通感冒の主要な既知原因であり、成人 では感冒の約30%に及ぶが、いくつか他のグループのウイルスも重要である。 免疫反応が起き、したがって一部の気道ウイルスによる感染はワクチンで防止で きるが、すべての可能な病原体をカバーする 多型ワクチンの開発は実際的でない。このため、急性の上部呼吸器疾患をコント ロールする問題には複雑なチャレンジを伴い、普通感冒について画一的治癒の長 期間望まれていた発見は非現実的な期待である。 初期症状は軽い倦怠感、咽喉炎及び鼻愁訴だけと最小限である。ライノウイル ス感染の場合には、鼻水、鼻うっ血及びくしゃみの症状が通常病気の初日に始ま り、2又は3日目までに最大重篤度に進行する。鼻症状と一緒に、ヒリヒリ、乾 燥又はチクチクしたのど、しわがれ声及び咳も起きることがある。他の症状には 目の軽い灼熱感、嗅覚及び味覚の喪失、副鼻洞又は耳の圧力又は充満感、頭痛及 び声障害もある。発熱も生じうるが、まれである。インフルエンザ感染は通常、 しばしば突然始まり数日間続いてかなり重篤な発熱;全身痛;疲労及び虚弱;胸 部不快感を含む。 現在、対症治療のみが普通感冒で行える。米国で売薬療法により感冒を治療す る費用は、15億ドル以上の年間費用とみられる。外患クリニックでの治療の直 接費用はほぼ40億ドルとみられる。活動制限による賃金の逸失量に基づいた間 接費用は、実質上もっと高い。 咳、感冒、感冒様及び/又はインフルエンザ症状とそれに伴う不快感、痛み、 発熱及び全身倦怠感の治療について例示される従来の処方物は、通常鎮痛剤(ア スピリン又はアセトアミノフェン)と、1種以上の抗ヒスタミ ン剤、うっ血除去剤、咳抑制剤、鎮咳剤及び去痰剤を含有している。 炎症及び付随する痛みに対抗する上で非ステロイド系抗炎症剤の使用は、容認 されている医療行為である。非ステロイド系は、例えば滑液包炎、関節炎、頭痛 等に伴う痛み及び炎症を軽減するために通常用いられる。薬物の非麻酔系鎮痛ク ラスで最も常用される薬物の中にはアスピリン、アセトアミノフェン、イブプロ フェン及びナプロキセンがある。アスピリン、アセトアミノフェン及びイブプロ フェンは、慣用的な咳/感冒多症状軽減組成物中の痛み軽減及び解熱成分として 今まで含有されてきた。これらの市販製品は通常アスピリン、アセトアミノフェ ン又はイブプロフェンに加えて1種以上の抗ヒスタミン剤、うっ血除去剤、咳抑 制剤、鎮咳剤及び去痰剤を含有している。 イブプロフェン、即ち(±)2‐(p‐イソブチルフェニル)プロピオン酸は、 鎮痛及び解熱活性を有する非ステロイド系抗炎症剤として周知である。イブプロ フェンは一般的に米国で現在処方箋により市販され、しかも 与用に400、600及び800mg錠剤として入手でき 非処方強度(200mg)としてもこの国では最近入手で きるようになった。軽〜中度の痛みの治療には、4〜6時間毎に400mgが、1 日3200mgを超えないで、モ の売薬製品は軽い痛みのときに一般的に勧められており、医者により指示されな いならば、4〜6時間毎に200〜400mgレベルで、1日1200mgを超えな いで経口使用される。 フルルビプロフェン、即ち(±)〔1,1′‐ビフェニル〕‐4‐酢酸,2‐フ ルオロ‐α‐メチルも、鎮痛及び解熱活性を有する非ステロイド系抗炎症剤とし て周知である。フルルビプロフェンは商品名アンセイド(An 投与用に50及び100mg錠剤として入手できる。 ケトプロフェン、即ち(±)2‐(3‐ベンゾイルフェニル)プロピオン酸、 鎮痛及び解熱活性を有するもう1つの周知の非ステロイド系抗炎症剤は、商品名 オルジ 経口投与用に25、50及び75mgカプセルとして入手できる。軽及び中度の痛 みの治療には、6〜8時間毎に25〜50mgが、1日300mgを超えないで、オ ルジス Reference,46th editon,1992,publisher Edward R.Barnhart,Medical Economics Company,Inc.,Oradell,N.J.07649,pp.2351-54,2319-20及び2488-90参照;その 開 示は本明細書に組み込まれる。 それらの化学名から明らかなように、これらの鎮痛剤はラセミ混合物である。 実際にこれまで市販されてきたのは、これら薬剤のラセミ混合物だけである。し かしながら、イブプロフェンの個別S(+)及びR(−)エナンチオマーの研究 がいくつかある。体内において、R(−)エナンチオマーの一部はイブプロフェ ンの薬学上活性な形であるS(+)エナンチオマーに変換される。 イブプロフェンのラセミ混合物とカフェインとの併用は、例えば1984年8 月7日付で発行されたSunshineらの米国特許第4,464,376号明細書で開 示されている。アミン類を含有した咳/感冒医薬組成物の製造における、イブプ ロフェンと、他のそれより新しい非ステロイド系抗炎症剤(即ち、アスピリン、 アセトアミノフェン及びフェナセチンを除く)との使用は、例えば1985年1 1月12日付で発行されたSunshineらの米国特許第4,552,899号明細書 で開示されている。 咳/感冒医薬組成物の製造における、ナプロキセンと、他のそれより新しい非 ステロイド系抗炎症剤(即ち、アスピリン、アセトアミノフェン及びフェナセチ ンを除く)との使用は、例えば1985年11月12日付で発行されたSunshine らの米国特許第4,552,899号明細書で開示されている。上部呼吸器感染 を治療する一部のこれら新しいNSAID単独の使用は、″Therapeutic Utility of Naproxen in Acute Upper Respiratory Infection--Multiclinical Double B1ind Study″(急性上部呼吸器感染におけるナプロキセンの治療有用性 --多臨床二重盲検試験),Kansenshogaku Zasshi,52(5):148-163(1978);″Cl iniCal Evaluation of Sulindac Respiratory Tract Inflammation--Double Blind Comparison With Ibuprofen″ (急性上部気道炎症の治療 ブプロフェンとの二重盲検比較),Kansenshogaku Zasshi,Vol.57,No.3,pp.260 -272(1983) ;″Double Blind Controlled Study of Miroprofen in Acute U pper Respiratory Tract Infections. Comparison With Ibuprofen″(急性上部 気道感染におけるミロプロフェンの二重盲検コントロール試験.イブプロフェン との比較),Kansenshogaku Zasshi,Vol.50,No.5,pp.435-453(1982);″Thera peutic Effects of Fenbufen on the Common Cold.Multiclinic Double-Blind Study″(普通感冒におけるフェンブフェンの治療効果.多臨床二重盲検試験) ,Kansenshogaku Zasshi,Vol.51,No.4,pp.184-196(1977) ;″CliniCal Eval uation of Clinoril Tablets in Acute Respiratory Tract Infections″(急性 気道感染におけるクリノリル錠剤の臨床評価),Kansenshogaku Zasshi,Vol.56, No.12,pp.1186-1195(198 2)において開示されている。 イブプロフェンのS(+)形の使用は、例えば1989年7月25日付で発行 されたSunshineらの米国特許第4,851,444号明細書で、1992年4月 16日付で公開されたGatesらの国際特許第9,205,783号明細書では抗 ヒスタミン剤との併用について開示されている。 本発明者らは、S(+)イブプロフェン、S(+)フルルビプロフェン及びS (+)ケトプロフェン、それらの薬学上許容される塩とそれらの混合物からなる 群より選択される、そのR(−)対掌体を実質上含まない鎮痛剤を(a)うっ血 除去剤、(b)去痰剤及び(c)鎮咳剤のうち少くとも1種と共に含む選択された 組成物が感冒、感冒様及び/又はインフルエンザ症状の改善された治療、管理又 は緩和を提供することを発見した。 したがって、本発明の目的は、治療の必要な哺乳動物生物における咳、感冒、 感冒様及び/又はインフルエンザ症状の治療のために、本発明の組成物をこのよ うな生物に投与することからなる方法を提供することである。 ここにおいてそのような症状とは、鼻感冒、鼻うっ血、洞うっ血、洞痛、上部 呼吸器感染、アレルギー性鼻炎、耳炎、シニティス(sinitis)等をいう。 発明の要旨 本発明は、S(+)イブプロフェン、S(+)フルル ビプロフェン及びS(+)ケトプロフェン、それらの薬学上許容される塩とそれ らの混合物からなる群より選択される、そのR(−)対掌体を実質上含まない鎮 痛剤を(a)うっ血除去剤、(b)去痰剤及び(c)鎮咳剤のうち少くとも1種と 共に含んだ組成物の安全有効量を投与することにより、感冒、感冒様及び/又は インフルエンザ症状の改善された治療、管理又は緩和を提供する組成物及び方法 に関する。 本明細書で用いられるすべてのパーセンテージ及び比率は、他で指摘されない かぎり、重量による。 発明の具体的な説明 本発明は、S(+)イブプロフェン、S(+)フルルビプロフェン及びS(+ )ケトプロフェン、それらの薬学上許容される塩とそれらの混合物からなる群よ り選択される、そのR(−)対掌体を実質上含まない鎮痛剤を(a)うっ血除去 剤、(b)去痰剤及び(c)鎮咳剤のうち少くとも1種と共に含んだ組成物の安全 有効量を投与することにより、感冒、感冒様及び/又はインフルエンザ症状の改 善された治療、管理又は緩和を提供する組成物及び方法に関する。 本発明の鎮痛剤に適用される“S(+)”という用語は、これら薬剤の右旋性 又はS(+)異性体だけでなく、そのあらゆる薬学上許容される鎮痛上有効な塩 も包含した意味である。用語“S(+)”と共に用いられる“R (−)対掌体を実質上含まない”という表現は、S(+)エナンチオマーが望ま しい開始早期化及び高い鎮痛効果を発揮する上でそのR(−)対掌体を実質上含 まないことを意味する。現実的に言えば、これは活性成分が少くとも90重量% のS(+)エナンチオマーと10重量%以下のR(−)エナンチオマーを含有す ることを意味する。好ましくは、S(+)エナンチオマー対R(−)エナンチオ マーの重量比は20:1以上、更に好ましくは97:3以上である。最も好まし くは、S(十)エナンチオマーは99重量%以上であって、R(−)エナンチオ マーを含まず、即ちS対Rの重量比は大体99:1又はそれ以上である。 本発明の組成物で用いられるS(+)イブプロフェンの安全有効量は、通常約 50〜約800mg、好ましくは約50〜約400mg、更に好ましくは約50〜約 200mg、最も好ましくは約50〜約100mgの範囲である。本発明の組成物で 用いられるS(十)フルルビプロフェンの安全有効量は、通常約12.5〜約3 00mg、好ましくは約12.5〜約200mg、更に好ましくは約12.5〜約1 00mg、最も好ましくは約12.5〜約50mgの範囲である。本発明の組成物で 用いられるS(+)ケトプロフェンの安全有効量は、通常約5〜約100mg、好 ましくは約5〜約75mg、更に好ましくは約5〜約50mg、最も好ましくは約5 〜約25mgの範 囲である。 “薬学上許容される塩”という用語は、無機塩基及び有機塩基を含めた薬学上 許容される無毒性塩基から製造される塩に関する。無機塩基から得られる塩には ナトリウム、カリウム、リチウム、アンモニア、カルシウム、マグネシウム、第 一鉄、亜鉛、第一マンガン、アルミニウム、第二鉄、第二マンガン塩等がある。 薬学上許容される有機無毒性塩基から得られる塩には、一級、二級、三級及び四 級アミン類、天然置換アミン類を含めた置換アミン類、環状アミン類と塩基性イ オン交換樹脂、例えばトリエチルアミン、トリプロピルアミン、2‐ジメチルア ミノエタノール、2‐ジエチルアミノエタノール、リジン、アルギニン、ヒスチ ジン、カフェイン、プロカイン、N‐エチルピペリジン、ヒドラバミン、コリン 、ベタイン、エチレンジアミン、グルコサミン、メチルグリカミン、テオブロミ ン、プリン類、ピペラジン、ピペリジン、ポリアミン樹脂等の塩がある。 本発明の組成物は、下記クラス:(a)うっ血除去剤、(b)去痰剤及び(c) 鎮咳剤から選択される少くとも1種の他の薬理活性剤も含有している。本発明の 組成物で有用なうっ血除去剤にはプソイドエフェドリン、フェニルプロパノール アミン、フェニレフリン、エフェドリン、それらの薬学上許容される塩及びそれ らの混合物がある。本発明の組成物で有用な鎮咳剤にはデキストロメトルフ ァン、クロフェジアノール、カルベタペンタン、カラミフェン、ノスカピン、ジ フェンヒドラミン、コデイン、ヒドロコドン、ヒドロモルホン、ホミノベン、そ れらの薬学上許容される塩及びそれらの混合物のようなものがある。本発明の組 成物で有用な去痰剤(粘液溶解剤としても知られる)にはグアヤコール酸グリセ リル、抱水テルピン、塩化アンモニウム、N‐アセチルシステイン、ブロムヘキ シン、アンブロキソール、それらの薬学上許容される塩及びそれらの混合物があ る。これらすべての成分とそれらの許容される投与量範囲は以下で記載されてい る:1988年11月8日付で発行されたSunshineらの米国特許第4,783, 465号、1986年10月28日付で発行されたSunshineらの米国特許第4, 619,934号明細書;これらは参考のため本明細書に組み込まれる。 好ましくは、本発明の医薬組成物は、約200:1〜約1:1、好ましくは約 50:1〜約1:1、最も好ましくは約10:1〜約1:1のS(+)エナンチ オマー:薬理活性剤の比率で、S(+)エナンチオマー及び他の薬理活性剤を含 んでいる。 錠剤、カプセル、顆粒、ロゼンジ及びバルク粉末のような固体形態と、シロッ プ及び懸濁液のような液体形態を含めた様々な経口剤形が使用できる。これらの 経口形態は安全有効量、通常少くとも約5%の活性成分を含有 している。固体経口剤形は、好ましくは約5〜約95%、更に好ましくは約10 〜約95%、最も好ましくは約25〜約95%の活性成分を含有している。液体 経口剤形は、好ましくは約1〜約50%、更に好ましくは約1〜約25%、最も 好ましくは約3〜約10%の活性成分を含有している。 錠剤は、適切な結合剤、滑沢剤、希釈剤、崩壊剤、着色剤、香味剤、保存剤及 び流動誘導剤を含有させて、圧縮、擦り込み錠、腸溶性コート、糖衣化、フィル ムコート又はマルチ圧縮することができる。軟質ゼラチンカプセルも有用である 。 液体経口剤形には、適切な溶媒、保存剤、乳化剤、懸濁剤、希釈剤、甘味剤、 味覚遮断剤、着色剤及び香味剤を含有した、水性及び非水性溶液、エマルジョン 、偽エマルジョン、懸濁液と、非沸騰性顆粒から再調製される溶液及び/又は懸 濁液がある。経口剤形を処方するために用いられる、薬学上許容されるキャリア 及び賦形剤の具体例は、参考のため本明細書に組み込まれる、1975年9月2 日付で発行されたRobertの米国特許第3,903,297号明細書で記載されて いる。固体経口剤形を作るための技術及び組成物は、参考のため本明細書に組み 込まれる、Marshall,″Solid Oral Dosage Forms″,Modern Pharmaceutics,Vol .7(Banker and Rhodes,editors),359-427(1979)で記載されている。錠剤( 圧縮 及び成形)、カプセル(硬質及び軟質ゼラチン)及び丸剤を作るための技術及び 組成物は、参考のため本明細書に組み込まれる、Remington's Pharmaceutical S ciences(Arthur Osol,editor),1553-1593(1980)で記載されている。 液体経口剤形を製造する上で、活性成分は慣用的調剤実務に従い水性ベースで 経口上許容される製剤キャリア中に配合される。“水性ベースで経口上許容され る製剤キャリア”とは、全部又は主要溶媒分が水であるものをいう。典型的キャ リアには単純な水性溶液、シロップ、分散液及び懸濁液と、水中油型のような水 性ベースエマルジョンがある。最も好ましいキャリアは、適切な懸濁剤を含有し た水性ビヒクル中における医薬組成物の懸濁液である。適切な懸濁剤にはアビセ ル(Avicel)RC‐591(FMC市販の微結晶セルロース/カルボキシメチル セルロースナトリウム混合物)、グアーガム等がある。このような懸濁剤は当業 者に周知である。本発明の組成物中における水の量は活性成分の全重量及び容量 と他の任意非活性成分に応じてかなり広範囲にわたるが、最終組成物の重量に基 づく全水分含有率は通常約20〜約75重量/容量%、好ましくは約20〜約4 0%の範囲である。 水自体がキャリア全体を構成してもよいが、典型的液体処方剤では、組成物中 への香油等のような非水溶性成 分の溶解及び配合を助けるために、共溶媒、例えばプロピレングリコール、グリ セリン、ソルビトール溶液等を含有していることが好ましい。したがって、一般 的には、本発明の組成物は、好ましくは約5〜約25容量/容量%、最も好まし くは約10〜約20容量/容量%の共溶媒を含有している。 本発明の組成物は、場合により1種以上の他の公知の治療剤、特に咳/感冒製 剤で常用されるもの、例えばクロルフェニラミン、ブロムフェニラミン、d‐ク ロルフェニラミン、d‐ブロムフェニラミン、トリプロリジン、アザタジン、ド キシルアミン、トリペレナミン、シプロヘプタジン、ヒドロキシジン、クレマス チン、カルビノキサミン、フェニンダミン、ブロモジフェンヒドラミン、ピリラ ミン、それらの薬学上許容される塩のような抗ヒスタミン剤と、アクリバスチン 、AHR‐11325、アステミゾール、アゼラスチン、セチリジン、エバスチ ン、ケトチフェン、ロドキサミド、ロラチジン、レボカバスチン、メキタジン、 オキサトミド、セタスチン、タジフィリン、テメラスチン、テルフェナジン、そ れらの薬学上許容される塩を含めた非鎮静抗ヒスタミン剤を含有していてもよい :これらすべての成分とそれらの許容される投与量範囲は以下で記載されている :1988年11月8日付で発行されたSunshineらの米国特許第4,783,4 65号、1986年10月28日付で発行さ れたSunshineらの米国特許第4,619,934号明細書;これらは参考のため 本明細書に組み込まれる。テルブタリン、アミノフィリン、エピネフリン、イソ プレナリン、メタプロテレノール、ビトテロール、テオフィリン及びアルブテロ ールのような気管支拡張剤と、アセトアミノフェン及びアスピリンのような他の 鎮痛剤も有用である。カフェインが高度に好ましい任意成分である。 薬剤師業界で周知の他の任意成分、例えば嗜好に合う快適な外観の最終製品を 提供するための天然又は人工甘味剤、香味剤、着色剤等と、貯蔵寿命を伸ばして 増すための酸化防止剤、例えばブチル化ヒドロキシアニソール又はブチル化ヒド ロキシトルエン、及び保存剤、例えばメチルもしくはプロピルパラベン又は安息 香酸ナトリウムも、これらの成分について通常知られる量で含有させてよい。 治療方法 投与される医薬組成物の量はその処方内にある活性成分の%に依存しており、 1回分当たりに要求されるうっ血除去剤、咳抑制剤、去痰剤及び/又は抗ヒスタ ミン剤のような任意成分とナフタレン誘導体の量、安定性、放出特性及び他の薬 学的パラメーターの関数である。 通常約1〜約50mg/kg/日、好ましくは約2〜約30mg/kg/日、最も好ましく は約3〜約20mg/kg/日の医薬組成物が本明細書で記載されたように投与される 。この 量は1回で、又は好ましくは複数回(2〜6回)に分けて反復して投与しても、 あるいは治療コースにわたり徐放的に投与してもよい。通常、本発明の医薬組成 物の各個別的投与量は約1〜約25mg/kg、好ましくは約2〜約15mg/kg、最も 好ましくは約3〜約10mg/kgの範囲である。上記より多い投与量も咳、感冒様 、インフルエンザ及びインフルエンザ様症状を軽減する上で有効であるが、有害 な副作用を避ける上ではいかなる薬物に関しても一部の個体で注意が払われねば ならない。 下記例は必須及び任意双方の成分が混合された本発明の態様について示してい る。 例I 経口投与用の硬質ゼラチンカプセル組成物は、下記成分を混合することにより 製造する:成分 量 S(+)イブプロフェン 100mg プソイドエフェドリンHCl 30mg 活性成分を、選択されたカプセルサイズに合った適量のラクトースと共に摩砕 する。 治療の必要なヒトへの上記カプセル1又は2個の投与で、咳、感冒様、インフ ルエンザ及びインフルエンザ様症状の改善された軽減を示す。 例II 経口投与用の硬質ゼラチンカプセル組成物は、下記成 分を混合することにより製造する:成分 量 S(+)フルルビプロフェン 50mg プソイドエフェドリンHCl 30mg アステミゾール 5mg グアヤコール酸グリセリル 100mg 活性成分を、選択されたカプセルサイズに合った適量のラクトースと共に摩砕 する。 治療の必要なヒトへの上記カプセル1又は2個の投与で、咳、感冒様、インフ ルエンザ及びインフルエンザ様症状の改善された軽減を示す。 例III 経口投与用の液体組成物は、下記成分を混合することにより製造する:成分 %W/V S(+)イブプロフェン 1.00 アルコール(95%) 25.000 プソイドエフェドリンHCl 0.30 プロピレングリコール 25.000 クエン酸ナトリウム 2.000 クエン酸 0.250 液体糖(単純シロップ) 25.00 グリセリン 7.000 着色剤 0.008 フレーバー 0.500 精製水 qs 100.000 精製水(最終バッチ容量の約10%)をライトニン(lightnin's)ミキサー装 備のバッチ容器中に注ぐ。クエン酸ナトリウム、クエン酸と、イブプロフェン以 外の活性剤を連続して加え、攪拌しながら溶解させる。次いでグリセリン及び液 体糖を加える。別の容器で、着色剤を精製水(最終バッチ容量の約0.5%)に 加える。次いでこの着色剤溶液を最初のバッチ容器に加える。別の容器で、イブ プロフェンを攪拌しながらアルコールに加える。プロピレングリコール、他の活 性剤及びフレーバーをこのアルコールプレミックスに加え、得られた混合液を均 一になるまで攪拌し、その後最初の容器に加える。残りの精製水を得られた混合 液に加えて、攪拌する。 治療の必要なヒトへの10〜20ml(2〜4さじ)の投与で、咳、感冒様、イ ンフルエンザ及びインフルエンザ様症状の改善された軽減を示す。 例IV 経口投与用の液体組成物は、下記成分を混合することにより製造する:成分 %w/v S(+)イブプロフェン 1.00 マレイン酸クロルフェニラミン 0.02 プソイドエフェドリンHCl 0.30 アルコール(95%) 25.00 プロピレングリコール 25.00 クエン酸ナトリウム 2.00 クエン酸 0.25 液体糖(単純シロップ) 25.00 グリセリン 7.00 着色剤 0.008 フレーバー 0.50 精製水 qs 100.00 精製水(最終バッチ容量の約10%)をライトニンミキサー装備のバッチ容器 中に注ぐ。クエン酸ナトリウム、クエン酸、プソイドエフェドリンHCl及びマ レイン酸クロルフェニラミンを連続して加え、攪拌しながら溶解させる。次いで グリセリン及び液体糖を加える。別の容器で、着色剤を精製水(最終バッチ容量 の約0.5%)に加える。次いでこの着色剤溶液を最初のバッチ容器に加える。 別の容器で、イブプロフェンを攪拌しながらアルコールに加える。プロピレング リコール及びフレーバーをこのアルコールプレミックスに加え、得られた混合 液を均一になるまで攪拌し、その後最初の容器に加える。残りの精製水を得られ た混合液に加えて、攪拌する。 治療の必要なヒトへの10〜20ml(2〜4さじ)の投与で、改善された鎮痛 及び/又は抗炎症効果を示す。 例V 経口投与用の液体組成物は、下記成分を混合することにより製造する:成分 %W/V S(+)イブプロフェン 1.00 プソイドエフェドリンHCl 0.30 マレイン酸クロルフェニラミン 0.02 デキストロメトルファンHBr 0.15 アルコール(95%) 25.00 プロピレングリコール 25.00 クエン酸ナトリウム 2.00 クエン酸 0.25 液体糖(単純シロップ) 25.00 グリセリン 7.00 着色剤 0.008 フレーバー 0.50 精製水 qs 100.00 精製水(最終バッチ容量の約10%)をライトニンミキサー装備のバッチ容器 中に注ぐ。クエン酸ナトリウム、 クエン酸、プソイドエフェドリンHCl及びマレイン酸クロルフェニラミンを連 続して加え、攪拌しながら溶解させる。次いでグリセリン及び液体糖を加える。 別の容器で、着色剤を精製水(最終バッチ容量の約0.5%)に加える。次いで この着色剤溶液を最初のバッチ容器に加える。別の容器で、イブプロフェン及び デキストロメトルファンHBrを攪拌しながらアルコールに連続的に加える。 プロピレングリコール及びフレーバーをこのアルコールプレミックスに加え、 得られた混合液を均一になるまで攪拌し、その後最初の容器に加える。残りの精 製水を得られた混合液に加えて、攪拌する。 治療の必要なヒトへの10〜20ml(2〜4さじ)の投与で、咳、感冒様、 インフルエンザ及びインフルエンザ様症状の改善された軽減を示す。Description: TECHNICAL FIELD The present invention relates to the use of an analgesic S (+) enantiomer in the manufacture of a composition for treating respiratory disorders. The present invention relates to S (+) ibuprofen and S (+) flurbiprofen. ) And S (+) ketoprofen, a pharmaceutically acceptable salt thereof and a mixture thereof and an analgesic agent substantially free of its R (−) enantiomer (a) a decongestant , (B) expectorant and (c) antitussive, at least one of which is administered together with a safe and effective amount of a composition, thereby improving treatment, management or alleviation of cold, cold-like and / or influenza symptoms. And a method of providing the same. BACKGROUND OF THE INVENTION Common cold is not usually a serious illness, but is a highly epidemic and unpleasant irritating affliction. The term "common cold" applies to mild respiratory illness caused by a variety of different respiratory viruses. Rhinoviruses are the common known cause of common colds, accounting for about 30% of common colds in adults, but some other groups of viruses are also important. Although an immune response occurs and thus infection by some respiratory tract viruses can be prevented with vaccines, the development of polymorphic vaccines that cover all possible pathogens is impractical. For this reason, the problem of controlling acute upper respiratory disease is accompanied by complicated challenges, and the long-awaited discovery of uniform healing for common cold is an unrealistic expectation. Initial symptoms are minimal with only mild malaise, sore throat and nasal complaints. In the case of rhinovirus infections, the symptoms of runny nose, nasal congestion and sneezing usually begin on the first day of illness and progress to maximum severity by the second or third day. Tingling, dry or tingling throat, hoarseness and coughing may also occur with nasal symptoms. Other symptoms also include a mild burning sensation in the eyes, loss of smell and taste, sinus or ear pressure or fullness, headaches and voice disorders. Fever can occur but is rare. Influenza infections usually start abruptly and last for several days with fairly severe fever; general pain; fatigue and weakness; chest discomfort. Currently, only symptomatic treatment can be done with common cold. The cost of treating colds with over-the-counter therapies in the United States is estimated to be over $ 1.5 billion annually. The direct cost of treatment at an outpatient clinic is estimated to be approximately $ 4 billion. Indirect costs based on lost wages due to activity restrictions are substantially higher. Conventional formulations exemplified for the treatment of cough, cold, cold-like and / or flu symptoms and associated discomfort, pain, fever and general malaise are usually analgesics (aspirin or acetaminophen) and one It contains the above antihistamines, decongestants, cough suppressants, antitussives and expectorants. The use of non-steroidal anti-inflammatory agents in combating inflammation and associated pain is an accepted medical practice. Non-steroidal systems are commonly used to reduce pain and inflammation associated with, for example, bursitis, arthritis, headaches and the like. Among the most commonly used drugs in the non-narcotic analgesic class of drugs are aspirin, acetaminophen, ibuprofen and naproxen. Aspirin, acetaminophen and ibuprofen have been previously included as pain relief and antipyretic components in conventional cough / cold multi-symptom relief compositions. These commercial products usually contain, in addition to aspirin, acetaminophen or ibuprofen, one or more antihistamines, decongestants, cough suppressants, antitussives and expectorants. Ibuprofen, or (±) 2- (p-isobutylphenyl) propionic acid, is well known as a nonsteroidal anti-inflammatory drug with analgesic and antipyretic activity. Ibuprofen is generally currently marketed by prescription in the United States, and Available as 400, 600 and 800 mg tablets for use Unprescribed strength (200 mg) has recently become available in this country. For the treatment of mild to moderate pain, 400 mg every 4 to 6 hours should not exceed 3200 mg daily. The over-the-counter drug product is generally recommended for mild pain and is used orally at a level of 200-400 mg every 4-6 hours and no more than 1200 mg daily unless instructed by a doctor. Flurbiprofen, ie (±) [1,1′-biphenyl] -4-acetic acid, 2-fluoro-α-methyl, is also well known as a nonsteroidal anti-inflammatory drug with analgesic and antipyretic activity. Flurbiprofen is a trade name of Unsaid (An Available as 50 and 100 mg tablets for administration. Ketoprofen, or (±) 2- (3-benzoylphenyl) propionic acid, another well-known non-steroidal anti-inflammatory drug with analgesic and antipyretic activity is the trade name Ordi Available as 25, 50 and 75 mg capsules for oral administration. For treatment of mild and moderate pain, 25-50 mg every 6-8 hours should not exceed 300 mg daily See Reference, 46th editon, 1992, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, NJ07649, pp. 2351-54, 2319-20 and 2488-90; the disclosures of which are incorporated herein. As is clear from their chemical name, these analgesics are racemic mixtures. In fact, only the racemic mixture of these agents has ever been marketed. However, there are several studies of the individual S (+) and R (-) enantiomers of ibuprofen. In the body, some of the R (−) enantiomers are converted to the pharmaceutically active form of ibuprofen, the S (+) enantiomer. The combination of a racemic mixture of ibuprofen and caffeine is disclosed, for example, in Sunshine et al., U.S. Pat. No. 4,464,376, issued Aug. 7, 1984. The use of ibuprofen with other newer non-steroidal anti-inflammatory agents (ie excluding aspirin, acetaminophen and phenacetin) in the manufacture of a cough / cold pharmaceutical composition containing amines has been described for example in 1985. No. 4,552,899 issued to Sunshine et al. The use of naproxen with other newer non-steroidal anti-inflammatory agents (ie excluding aspirin, acetaminophen and phenacetin) in the manufacture of a cough / cold pharmaceutical composition is described, for example, on November 12, 1985. It is disclosed in U.S. Pat. No. 4,552,899 issued to Sunshine et al. The use of some of these new NSAIDs alone in the treatment of upper respiratory infections has led to the "Therapeutic Utility of Naproxen in Acute Upper Respiratory Infection--Multiclinical Double B1ind Study". Clinical double-blind study), Kansenshogaku Zasshi, 52 (5): 148-163 (1978); "Cl iniCal Evaluation of Sulindac Respiratory Tract Inflammation--Double Blind Comparison With Ibuprofen ″ (Treatment of acute upper airway inflammation Double Blind Controlled Study of Miroprofen in Acute Upper Respiratory Tract Infections. Comparison With Ibuprofen ″ (Kansenshogaku Zasshi, Vol.57, No.3, pp.260 -272 (1983); Double-blind control study of miloprofen in acute upper respiratory tract infection (comparison with ibuprofen), Kansenshogaku Zasshi, Vol.50, No.5, pp.435-453 (1982); "Thera peutic Effects of Fenbufen on the Common Cold .Multiclinic Double-Blind Study ″ (Therapeutic effect of fenbufen for common cold. Multiclinical double-blind study), Kansenshogaku Zasshi, Vol.51, No.4, pp.184-196 (1977) ; “CliniCal Eval uation of Clinoril Tablets in Acute Respiratory Tract Infections ″ (clinical evaluation of clinolyl tablets in acute respiratory tract infection), Kansenshogaku Zasshi, Vol. 56, No. 12, pp. 1186-1195 (1982). The use of the S (+) form of ibuprofen is described, for example, in Sunshine et al., U.S. Pat. No. 4,851,444, issued July 25, 1989, and Gates et al., Published April 16, 1992. International Patent No. 9,205,783 discloses a combination with an antihistamine. The present inventors have selected R (s) selected from the group consisting of S (+) ibuprofen, S (+) flurbiprofen and S (+) ketoprofen, their pharmaceutically acceptable salts and mixtures thereof. -) A selected composition comprising an analgesic substantially free of antipode together with at least one of (a) decongestant, (b) expectorant and (c) antitussive, cold, cold and / or Or found to provide improved treatment, control or alleviation of influenza symptoms. Therefore, an object of the present invention is a method for the treatment of cough, cold, cold-like and / or influenza symptoms in a mammal organism in need thereof, which method comprises administering to the organism a composition of the invention. Is to provide. Here, such symptoms include nasal cold, nasal congestion, sinus congestion, sinus pain, upper respiratory infection, allergic rhinitis, otitis, sinitis, and the like. SUMMARY OF THE INVENTION The present invention is a compound of the formula (R) selected from the group consisting of S (+) ibuprofen, S (+) flurbiprofen and S (+) ketoprofen, their pharmaceutically acceptable salts and mixtures thereof. Administering a safe and effective amount of a composition containing (-) an analgesic substantially free of antipode together with at least one of (a) a decongestant, (b) an expectorant, and (c) an antitussive. Thereby relates to compositions and methods that provide improved treatment, management or alleviation of cold, cold-like and / or influenza symptoms. All percentages and ratios used herein are by weight unless otherwise noted. DETAILED DESCRIPTION OF THE INVENTION The present invention is selected from the group consisting of S (+) ibuprofen, S (+) flurbiprofen and S (+) ketoprofen, their pharmaceutically acceptable salts and mixtures thereof. , A safe and effective amount of a composition containing an analgesic substantially free of its R (-) antipode together with at least one of (a) a decongestant, (b) an expectorant and (c) an antitussive. It relates to compositions and methods which, when administered, provide improved treatment, management or alleviation of cold, cold-like and / or influenza symptoms. The term "S (+)" as applied to the analgesics of the present invention includes not only the dextrorotatory or S (+) isomers of these agents, but also any pharmaceutically acceptable analgesically effective salt thereof. It means that. The expression "substantially free of the R (-) enantiomer" as used in conjunction with the term "S (+)" means that the S (+) enantiomer has the desired early onset and high analgesic effect. -) Means that the antipode is substantially not included. Practically speaking, this means that the active ingredient contains at least 90% by weight of the S (+) enantiomer and up to 10% by weight of the R (-) enantiomer. Preferably, the weight ratio of S (+) enantiomer to R (-) enantiomer is 20: 1 or more, more preferably 97: 3 or more. Most preferably, the S (ten) enantiomer is greater than or equal to 99% by weight and is free of the R (−) enantiomer, ie, the weight ratio of S to R is about 99: 1 or greater. The safe and effective amount of S (+) ibuprofen used in the composition of the present invention is usually about 50 to about 800 mg, preferably about 50 to about 400 mg, more preferably about 50 to about 200 mg, most preferably about 50 to about. It is in the range of 100 mg. The safe and effective amount of S (ten) flurbiprofen used in the composition of the present invention is usually about 12.5 to about 300 mg, preferably about 12.5 to about 200 mg, and more preferably about 12.5 to. It is in the range of about 100 mg, most preferably about 12.5 to about 50 mg. The safe and effective amount of S (+) ketoprofen used in the composition of the present invention is usually about 5 to about 100 mg, preferably about 5 to about 75 mg, more preferably about 5 to about 50 mg, most preferably about 5 to about 5. It is in the range of 25 mg. The term "pharmaceutically acceptable salt" relates to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts obtained from inorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous iron, zinc, ferrous manganese, aluminum, ferric iron and ferric manganese salts. Salts obtained from pharmaceutically acceptable organic non-toxic bases include primary, secondary, tertiary and quaternary amines, substituted amines including naturally substituted amines, cyclic amines and basic ion exchange resins, For example, triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamin, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, There are salts of purines, piperazine, piperidine, polyamine resins and the like. The compositions of the present invention also contain at least one other pharmacologically active agent selected from the following classes: (a) decongestants, (b) expectorants and (c) antitussives. Decongestants useful in the compositions of the present invention include pseudoephedrine, phenylpropanolamine, phenylephrine, ephedrine, pharmaceutically acceptable salts thereof and mixtures thereof. Antitussive agents useful in the compositions of the present invention include dextromethorphan, clofedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, pharmaceutically acceptable salts thereof and mixtures thereof. There is something like this. Expectorants (also known as mucolytics) useful in the compositions of the present invention include glyceryl guaiacol, terpine hydrate, ammonium chloride, N-acetylcysteine, bromhexine, ambroxol, and their pharmaceutically acceptable salts. There are salts and their mixtures. All of these ingredients and their acceptable dosage ranges are set forth below: Sunshine et al., U.S. Pat. No. 4,783,465, issued Nov. 8, 1988, Oct. 28, 1986. U.S. Pat. No. 4,619,934, issued to Sunshine et al .; incorporated herein by reference. Preferably, the pharmaceutical composition of the present invention comprises about 200: 1 to about 1: 1 S (+), preferably about 50: 1 to about 1: 1 and most preferably about 10: 1 to about 1: 1. It contains the S (+) enantiomer and other pharmacologically active agents in a ratio of enantiomer: pharmacologically active agent. Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules, lozenges and bulk powders, as well as liquid forms such as syrups and suspensions. These oral forms contain a safe and effective amount, usually at least about 5% active ingredient. Solid oral dosage forms preferably contain from about 5 to about 95%, more preferably from about 10 to about 95%, and most preferably from about 25 to about 95% active ingredient. Liquid oral dosage forms preferably contain from about 1 to about 50%, more preferably from about 1 to about 25%, and most preferably from about 3 to about 10% active ingredient. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives and glidants and may be compressed, rubbed, enteric coated, sugar coated, film coated or Can be multi-compressed. Soft gelatin capsules are also useful. Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, pseudoemulsions, containing suitable solvents, preservatives, emulsifiers, suspensions, diluents, sweeteners, taste blockers, colorants and flavors. There are suspensions and solutions and / or suspensions that are reconstituted from non-effervescent granules. Specific examples of pharmaceutically acceptable carriers and excipients used to formulate oral dosage forms are incorporated by reference herein in US Pat. Robert, issued Sep. 2, 1975. No. 3,903,297. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms", Modern Pharmaceutics, Vol. 7 (Banker and Rhodes, editors), 359-427 (1979). Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatine) and pills are incorporated herein by reference, Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-. 1593 (1980). In preparing liquid oral dosage forms, the active ingredient is incorporated into an orally acceptable pharmaceutical carrier on an aqueous basis in accordance with conventional pharmaceutical practice. An “orally acceptable pharmaceutical carrier on an aqueous basis” refers to one in which all or the major solvent is water. Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous base emulsions such as oil-in-water. The most preferred carrier is a suspension of the pharmaceutical composition in an aqueous vehicle containing a suitable suspending agent. Suitable suspending agents include Avicel RC-591 (FMC commercially available microcrystalline cellulose / sodium carboxymethyl cellulose mixture), guar gum and the like. Such suspensions are well known to those of ordinary skill in the art. The amount of water in the compositions of the present invention will vary considerably depending on the total weight and volume of active ingredients and other optional non-active ingredients, but the total water content by weight of the final composition is usually from about 20 to about. 75% weight / volume, preferably in the range of about 20 to about 40%. Although water itself may make up the entire carrier, in typical liquid formulations, cosolvents such as propylene glycol, to aid in the dissolution and incorporation of water insoluble ingredients such as perfume oils and the like into the composition, It preferably contains glycerin, a sorbitol solution or the like. Thus, in general, the compositions of the present invention preferably contain from about 5 to about 25% v / v co-solvent, most preferably from about 10 to about 20% v / v. The compositions of the present invention optionally comprise one or more other known therapeutic agents, especially those commonly used in cough / cold formulations, such as chlorpheniramine, brompheniramine, d-chlorpheniramine, d-bromopheneni. Antihistamines such as lamin, triprolidine, azatazine, doxylamine, tripelenamine, cyproheptadine, hydroxyzine, clemastine, carbinoxamine, phenindamine, bromodiphenhydramine, pyrilamine, pharmaceutically acceptable salts thereof, acrivastine, AHR-11325, astemizole, Azelastine, cetirizine, ebastine, ketotifen, rhodoxamide, loratidine, levocabastine, mequitazine, oxatomide, cestatin, tadiphyrin, temerastine, terfenadine, and their pharmaceutically acceptable Non-sedating antihistamines, including salts thereof, may be included: All of these ingredients and their acceptable dosage ranges are set forth below: Sunshine et al., Issued Nov. 8, 1988. U.S. Pat. No. 4,783,465, Sunshine et al., U.S. Pat. No. 4,619,934, issued Oct. 28, 1986; which are incorporated herein by reference. Bronchodilators such as terbutaline, aminophylline, epinephrine, isoprenaline, metaproterenol, bitoterol, theophylline and albuterol, and other analgesics such as acetaminophen and aspirin are also useful. Caffeine is a highly preferred optional ingredient. Other optional ingredients well known in the pharmacist industry, such as natural or artificial sweeteners, flavoring agents, colorants, etc. to provide a palatable and pleasing end product, and antioxidants to extend and increase shelf life. , Butylated hydroxyanisole or butylated hydroxytoluene, and preservatives, such as methyl or propylparaben or sodium benzoate, may also be included in the amounts normally known for these components. Method of Treatment The amount of the pharmaceutical composition administered depends on the percentage of active ingredient in its formulation, such as decongestant, cough suppressant, expectorant and / or antihistamine required per dose. It is a function of the amount of optional ingredients and naphthalene derivative, stability, release profile and other pharmaceutical parameters. Usually about 1 to about 50 mg / kg / day, preferably about 2 to about 30 mg / kg / day, most preferably about 3 to about 20 mg / kg / day of the pharmaceutical composition is administered as described herein. To be done. This amount may be administered once, or may be repeatedly administered in a plurality of times (2 to 6 times), or may be administered slowly over the course of treatment. Generally, each individual dose of the pharmaceutical compositions of this invention will range from about 1 to about 25 mg / kg, preferably from about 2 to about 15 mg / kg, most preferably from about 3 to about 10 mg / kg. Higher doses than above are also effective in alleviating cough, cold-like, flu and flu-like symptoms, but care must be taken by some individuals on any drug to avoid adverse side effects. The following examples illustrate aspects of the invention in which both essential and optional ingredients are mixed. Example I A hard gelatin capsule composition for oral administration is prepared by mixing the following ingredients : Ingredient Amount S (+) ibuprofen 100 mg Pseudoephedrine HCl 30 mg Active ingredient together with appropriate amount of lactose for selected capsule size. Grind. Administration of one or two of the above capsules to a human in need of treatment shows improved relief of cough, cold-like, influenza and flu-like symptoms. Example II A hard gelatin capsule composition for oral administration is prepared by mixing the following ingredients : Ingredient Amount S (+) Flurbiprofen 50 mg Pseudoephedrine HCl 30 mg Astemizole 5 mg Glyceryl guaiacol 100 mg Active ingredient selected Grind with an appropriate amount of lactose matching the capsule size. Administration of one or two of the above capsules to a human in need of treatment shows improved relief of cough, cold-like, influenza and flu-like symptoms. Example III A liquid composition for oral administration is prepared by mixing the following ingredients : Ingredient % W / V S (+) ibuprofen 1.00 Alcohol (95%) 25.000 Pseudoephedrine HCl 0.30 Propylene glycol 25.000 Sodium citrate 2.000 Citric acid 0.250 Liquid sugar (simple syrup) 25.00 Glycerin 7.000 Colorant 0.008 Flavor 0.500 Purified water qs 100.000 Purified water (about 10% of final batch volume) is poured into a batch container equipped with a lightnin's mixer. Sodium citrate, citric acid and an activator other than ibuprofen are continuously added and dissolved with stirring. Then glycerin and liquid sugar are added. In a separate container, add colorant to purified water (about 0.5% of final batch volume). This colorant solution is then added to the first batch container. In a separate container, add ibuprofen to alcohol with stirring. Propylene glycol, other activators and flavors are added to the alcohol premix and the resulting mixture is stirred until uniform and then added to the first container. The remaining purified water is added to the obtained mixed solution and stirred. Administration of 10-20 ml (2-4 scoops) to humans in need of treatment shows improved relief of cough, cold-like, influenza and flu-like symptoms. Example IV A liquid composition for oral administration is prepared by mixing the following ingredients : Ingredient % w / v S (+) ibuprofen 1.00 Chlorpheniramine maleate 0.02 Pseudoephedrine HCl 0.30 Alcohol (95%) 25.00 Propylene glycol 25.00 Sodium citrate 2.00 Citric acid 0.25 Liquid sugar (simple syrup) 25.00 Glycerin 7.00 Colorant 0.008 Flavor 0.50 Purified water qs 100.00 Purified water (about 10% of final batch volume) is poured into a batch container equipped with a Lightnin mixer. Sodium citrate, citric acid, pseudoephedrine HCl and chlorpheniramine maleate are added successively and dissolved with stirring. Then glycerin and liquid sugar are added. In a separate container, add colorant to purified water (about 0.5% of final batch volume). This colorant solution is then added to the first batch container. In a separate container, add ibuprofen to alcohol with stirring. Propylene glycol and flavor are added to the alcohol premix and the resulting mixture is stirred until uniform and then added to the first vessel. The remaining purified water is added to the obtained mixed solution and stirred. Administration of 10-20 ml (2-4 scoops) to humans in need of treatment shows improved analgesic and / or anti-inflammatory effects. Example V A liquid composition for oral administration is prepared by mixing the following ingredients : Ingredient % W / V S (+) ibuprofen 1.00 Pseudoephedrine HCl 0.30 Chlorpheniramine maleate 0.02 Dextromethorphan HBr 0.15 Alcohol (95% ) 25.00 Propylene glycol 25.00 Sodium citrate 2.00 Citric acid 0.25 Liquid sugar (simple syrup) 25.00 Glycerin 7.00 Colorant 0.008 Flavor 0.50 Purified water qs 100.00 Purified water (about 10% of final batch volume) in a batch container equipped with a Lightnin mixer. pour it up. Sodium citrate, citric acid, pseudoephedrine HCl and chlorpheniramine maleate are added successively and dissolved with stirring. Then glycerin and liquid sugar are added. In a separate container, add colorant to purified water (about 0.5% of final batch volume). This colorant solution is then added to the first batch container. In a separate container, ibuprofen and dextromethorphan HBr are continuously added to the alcohol with stirring. Propylene glycol and flavor are added to this alcohol premix, the resulting mixture is stirred until uniform and then added to the first vessel. The remaining purified water is added to the obtained mixed solution and stirred. Administration of 10-20 ml (2-4 scoops) to humans in need of treatment shows improved alleviation of cough, cold-like, influenza and flu-like symptoms.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 シモーヌ,マイケル ジェイムズ アメリカ合衆国オハイオ州、ワイオミン グ、フォレスト、アベニュ、52─────────────────────────────────────────────────── ─── Continued front page (72) Inventor Simone, Michael James Wyoming, Ohio, United States Gu, Forest, Avenue, 52
Claims (1)
Applications Claiming Priority (3)
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US99970192A | 1992-12-21 | 1992-12-21 | |
US07/999,701 | 1992-12-21 | ||
PCT/US1993/012022 WO1994014476A1 (en) | 1992-12-21 | 1993-12-09 | Use of s(+) antipodes of analgesic agents for the manufacture of a composition to treat respiratory disorders |
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JPH08506808A true JPH08506808A (en) | 1996-07-23 |
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JP (1) | JPH08506808A (en) |
CA (1) | CA2151912A1 (en) |
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WO (1) | WO1994014476A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001019638A (en) * | 1999-06-10 | 2001-01-23 | Mcneil Ppc Inc | Fast absorbing liquid composition |
JP2006515299A (en) * | 2002-12-18 | 2006-05-25 | ワイス | Non-steroidal anti-inflammatory, decongestant and antihistamine composition |
JP2009108042A (en) * | 2007-10-10 | 2009-05-21 | Daiichi Sankyo Healthcare Co Ltd | Pharmaceutical composition containing azelastine and ambroxol |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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GB2293099A (en) * | 1994-09-15 | 1996-03-20 | Mailway Packaging Group Ltd | Drug formulation |
GB9523833D0 (en) * | 1995-11-22 | 1996-01-24 | Boots Co Plc | Medical treatment |
AU7916798A (en) * | 1997-05-22 | 1998-12-11 | Boots Company Plc, The | Pharmaceutical compositions of flurbiprofen and burn-masking agent for treating sore throat |
HUP0402299A3 (en) * | 2001-09-04 | 2008-04-28 | Boehringer Ingelheim Int | Anti-influenza drugs containing ambroxol and bromhexine and process for its preparation |
DE10203104A1 (en) * | 2002-01-25 | 2003-08-07 | Boehringer Ingelheim Pharma | Ambroxol for the treatment of chronic pain |
US20050192355A1 (en) * | 2004-02-17 | 2005-09-01 | Wyeth | Compositions of non-steroidal anti-inflammatory drugs and decongestants or anti-histamines |
KR101555457B1 (en) | 2007-07-12 | 2015-09-23 | 지이 헬스케어 에이에스 | Contrast agents |
WO2015163832A1 (en) | 2014-04-25 | 2015-10-29 | Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş. | An ibuprofen and famotidine combined composition having improved stability |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US4552899A (en) * | 1984-04-09 | 1985-11-12 | Analgesic Associates | Cough/cold mixtures comprising non-steroidal anti-inflammatory drugs |
US4999226A (en) * | 1988-06-01 | 1991-03-12 | Merrell Dow Pharmaceuticals Inc. | Pharmaceutical compositions for piperidinoalkanol-ibuprofen combination |
US4990535A (en) * | 1989-05-03 | 1991-02-05 | Schering Corporation | Pharmaceutical composition comprising loratadine, ibuprofen and pseudoephedrine |
JPH06506684A (en) * | 1991-04-01 | 1994-07-28 | メルク エンド カンパニー インコーポレーテッド | Ibuprofen - decongestant formulation |
US5164398A (en) * | 1991-04-01 | 1992-11-17 | Merck & Co., Inc. | Ibuprofen-antitussive combinations |
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1993
- 1993-12-09 WO PCT/US1993/012022 patent/WO1994014476A1/en not_active Application Discontinuation
- 1993-12-09 EP EP94902518A patent/EP0674527A1/en not_active Withdrawn
- 1993-12-09 JP JP6515219A patent/JPH08506808A/en active Pending
- 1993-12-09 CA CA002151912A patent/CA2151912A1/en not_active Abandoned
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1994
- 1994-01-03 MX MX9400040A patent/MX9400040A/en unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001019638A (en) * | 1999-06-10 | 2001-01-23 | Mcneil Ppc Inc | Fast absorbing liquid composition |
JP2006515299A (en) * | 2002-12-18 | 2006-05-25 | ワイス | Non-steroidal anti-inflammatory, decongestant and antihistamine composition |
JP2009108042A (en) * | 2007-10-10 | 2009-05-21 | Daiichi Sankyo Healthcare Co Ltd | Pharmaceutical composition containing azelastine and ambroxol |
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WO1994014476A1 (en) | 1994-07-07 |
EP0674527A1 (en) | 1995-10-04 |
CA2151912A1 (en) | 1994-07-07 |
MX9400040A (en) | 1994-07-29 |
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