JP2007302578A - Combined formulation of general cold drug - Google Patents
Combined formulation of general cold drug Download PDFInfo
- Publication number
- JP2007302578A JP2007302578A JP2006130327A JP2006130327A JP2007302578A JP 2007302578 A JP2007302578 A JP 2007302578A JP 2006130327 A JP2006130327 A JP 2006130327A JP 2006130327 A JP2006130327 A JP 2006130327A JP 2007302578 A JP2007302578 A JP 2007302578A
- Authority
- JP
- Japan
- Prior art keywords
- antihistamine
- cold medicine
- combination preparation
- pharmaceutically acceptable
- cold
- 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
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- 229940079593 drug Drugs 0.000 title claims abstract description 42
- 239000000203 mixture Substances 0.000 title description 10
- 238000009472 formulation Methods 0.000 title description 7
- 239000000739 antihistaminic agent Substances 0.000 claims abstract description 131
- 230000000147 hypnotic effect Effects 0.000 claims abstract description 90
- 230000001387 anti-histamine Effects 0.000 claims description 93
- 229940124579 cold medicine Drugs 0.000 claims description 90
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- 238000002360 preparation method Methods 0.000 claims description 68
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 52
- 239000003826 tablet Substances 0.000 claims description 49
- 229940125715 antihistaminic agent Drugs 0.000 claims description 37
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- 150000003839 salts Chemical class 0.000 claims description 30
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- 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 8
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- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 claims description 8
- 239000003907 antipyretic analgesic agent Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
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- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 claims description 6
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 6
- FMCGSUUBYTWNDP-UHFFFAOYSA-N N-Methylephedrine Natural products CN(C)C(C)C(O)C1=CC=CC=C1 FMCGSUUBYTWNDP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000890 drug combination Substances 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
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- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims description 6
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- 229940124630 bronchodilator Drugs 0.000 claims description 5
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- 239000006188 syrup Substances 0.000 claims description 5
- 235000020357 syrup Nutrition 0.000 claims description 5
- FLNXBVJLPJNOSI-UHFFFAOYSA-N 1-[2-[(4-chlorophenyl)-phenylmethoxy]ethyl]piperidine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)OCCN1CCCCC1 FLNXBVJLPJNOSI-UHFFFAOYSA-N 0.000 claims description 4
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- 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
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- 239000004615 ingredient Substances 0.000 claims description 4
- 229960004934 mebhydrolin Drugs 0.000 claims description 4
- FQQIIPAOSKSOJM-UHFFFAOYSA-N mebhydrolin Chemical compound C1N(C)CCC2=C1C1=CC=CC=C1N2CC1=CC=CC=C1 FQQIIPAOSKSOJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- PXWLVJLKJGVOKE-UHFFFAOYSA-N propyphenazone Chemical compound O=C1C(C(C)C)=C(C)N(C)N1C1=CC=CC=C1 PXWLVJLKJGVOKE-UHFFFAOYSA-N 0.000 claims description 4
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- CFJMRBQWBDQYMK-UHFFFAOYSA-N 1-phenyl-1-cyclopentanecarboxylic acid 2-[2-(diethylamino)ethoxy]ethyl ester Chemical compound C=1C=CC=CC=1C1(C(=O)OCCOCCN(CC)CC)CCCC1 CFJMRBQWBDQYMK-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
Description
本発明は、感冒の治療方針に従い、及び治療をしながらのＱＯＬ（Quality of Life）の向上を目的とした総合感冒薬組み合わせ製剤に関する。 The present invention relates to a general cold medicine combination preparation for the purpose of improving the quality of life (QOL) according to the treatment policy of the common cold and during treatment.
インフルエンザなどの重篤な感染症を除く一般かぜ症候群は、くしゃみ、鼻水、咳、痰、発熱、頭痛などの多岐にわたる愁訴を呈する。感冒治療において、感染症候群の治療とともに、該症候群の治癒及び改善並びにＱＯＬの向上の両面からこの愁訴改善に対する治療が重要な位置を占めている。また、一般かぜ症候群では、罹患初期に愁訴を軽減することが安静・安眠、食欲増進又は精神的苦痛の軽減などの治癒能力を向上する上で重要である。この意味で、一般かぜ症候群に対する対症療法薬として、または重篤化及び慢性化の予防を推進するための一般用医薬品として、総合感冒製剤が汎用されている。 Common cold syndromes, excluding serious infections such as influenza, present a wide range of complaints including sneezing, runny nose, cough, sputum, fever, and headache. In the treatment of the common cold, the treatment for the improvement of complaints occupies an important position in terms of both the cure and improvement of the syndrome and the improvement of QOL, as well as the treatment of the infectious syndrome. In general cold syndrome, reducing complaints in the early stages of illness is important for improving healing ability such as rest / sleep, increased appetite, or reduced mental distress. In this sense, a general cold preparation is widely used as a symptomatic treatment for common cold syndrome or as an over-the-counter drug for promoting prevention of serious and chronic symptoms.
しかし、罹患者の多くは、総合感冒製剤を服用しながら、日常の生活を営む。その際、昼間では業務又は学勉集中、自動車の運転、精密・危険業務への従事等を避け得ないし、さらに夜間では愁訴からの安静・安眠が治療効果を上げるためには必要である。総合感冒製剤においてもこれらを満足する、よりＱＯＬ向上の治療方針が現代では必要となりつつある。 However, many affected individuals live their daily lives while taking a general cold product. At that time, it is inevitable to concentrate on work or study, car driving, precision / dangerous work in the daytime, and rest and sleep from complaints are necessary to improve the therapeutic effect at night. In the present day, a treatment policy for improving QOL that satisfies these requirements is also needed in the general cold preparation.
一方、総合感冒薬は厚生労働省により配合剤に関するガイドラインが既に設定されている。これを応用して、ＱＯＬの向上を目的とし、市販では中枢興奮薬であるカフェインが朝及び昼用に配合処方され、一方夜間用に配合処方されていない総合感冒組み合わせ製剤が既に上市されている。しかし、カフェインの処方の有無だけでは抗ヒスタミン剤からもたらされる昼間の就業又は活動中の催眠の副作用は回避できないし、交通又は業務上の事故に対するリスクも軽減できない。また、かぜ罹患時では、愁訴による夜間の安静・安眠又は睡眠導入の障害、熟眠度の低下が、罹患期間の延長又は罹患の悪化を招くため、抗ヒスタミン剤の催眠作用が有効である。 On the other hand, guidelines for combination drugs have already been set by the Ministry of Health, Labor and Welfare. Applying this, caffeine, which is a central stimulant, is formulated in the morning and noon for the purpose of improving QOL. On the other hand, a general cold combination product that has not been formulated for night is already on the market. Yes. However, the side effects of hypnosis during work or activities during the day caused by antihistamines cannot be avoided only by the presence or absence of caffeine prescription, and the risk for traffic or work accidents cannot be reduced. Moreover, when cold is afflicted, resting / sleeping at night or disturbance of sleep induction due to complaints and a decrease in the degree of deep sleep cause prolongation of the affected period or worsening of the affected condition, and thus the hypnotic action of the antihistamine is effective.
従来の総合感冒薬は、解熱鎮痛成分、抗ヒスタミン成分、鎮咳成分、去痰成分又は気管支拡張成分等を含有し、同じ処方のものを例えば１日３回又は１日２回服用することになっており、かぜ罹患時特有の上述の状況を考慮していない。従来の総合感冒薬の多くは、くしゃみ、鼻水を抑制する成分として抗ヒスタミン剤が処方されているが、その副作用として眠気、催眠作用が問題となっている。これらの理由から、上述の夜間用の配合処方では、中枢興奮薬であるカフェインを含有していない。 Conventional general cold medicine contains antipyretic analgesic component, antihistamine component, antitussive component, expectorant component, bronchodilator component, etc., and the same prescription is to be taken, for example, three times a day or twice a day. And does not take into account the above-mentioned situation peculiar to cold cases. Many of the conventional general cold medicines are prescribed antihistamines as an ingredient to suppress sneezing and runny nose, but as a side effect thereof, drowsiness and hypnotic action are problematic. For these reasons, the above-mentioned formula for night use does not contain caffeine, which is a central stimulant.
カフェインが朝用及び／又は昼用に配合処方され、一方夜用及び／又は就寝前用に配合処方されていない総合感冒組み合わせ製剤では、朝、昼間においてカフェインが中枢神経興奮の作用を引き立て、かつ就寝前においてカフェインが配合処方から外されていることから、カフェインによる中枢興奮作用を除去する点では合理的である。しかし、抗ヒスタミン剤の催眠作用を抑制、除去する、又は就寝・安静作用を積極的に利用する点では消極的である。従って、抗ヒスタミン剤の催眠作用の発現を有効に利用し、さらにカフェインの作用を際だたせ、総合感冒薬の有用性をＱＯＬの観点から向上する新規の組み合わせ製剤が望まれている。 Caffeine is formulated in the morning and / or daytime, while in the common cold combination product that is not formulated at night and / or before going to bed, caffeine enhances CNS excitability in the morning and daytime. In addition, since caffeine is excluded from the prescription before going to bed, it is rational in terms of removing the central excitatory effect of caffeine. However, it is reluctant to suppress or eliminate the hypnotic action of antihistamines or to actively use the sleeping / resting action. Therefore, there is a demand for a novel combination preparation that effectively utilizes the expression of hypnotic action of an antihistamine, further highlights the action of caffeine, and improves the usefulness of comprehensive cold medicine from the viewpoint of QOL.
抗ヒスタミン剤は、血管、平滑筋などに存在するＨ１受容体との結合において、ヒスタミンと拮抗する薬剤である。抗ヒスタミン剤は、皮膚疾患に伴うそう痒、蕁麻疹、アレルギー性鼻炎、くしゃみ、鼻水に対して効能・効果を示す。抗ヒスタミン剤は、総合感冒薬において、感冒症候群のくしゃみ、鼻水、鼻づまりへの対症療法薬として処方される。 Antihistamines are drugs that antagonize histamine in binding to H1 receptors present in blood vessels, smooth muscles and the like. Antihistamines are effective for pruritus, urticaria, allergic rhinitis, sneezing and runny nose associated with skin diseases. Antihistamines are prescribed in general cold medicine as a symptomatic treatment for cold syndrome sneezing, runny nose and nasal congestion.
抗ヒスタミン剤は、その構造から、エタノールアミン骨格（ジフェンヒドラミン、ジフェニルピラリン、カルビノキサミン、クレマスチン等）、プロピルアミン骨格（クロルフェニラミン、トリプロリジン等）、フェノチアジン骨格（プロメタジン、アリメマジン、メキタジン等）、ピペリジン骨格（シプロヘプタジン等）等に分類され、その種類は多い。 Antihistamines have an ethanolamine skeleton (diphenhydramine, diphenylpyralin, carbinoxamine, clemastine, etc.), a propylamine skeleton (chlorpheniramine, triprolidine, etc.), a phenothiazine skeleton (promethazine, alimemazine, mequitazine, etc.), a piperidine skeleton (cyproheptadine). Etc.), and there are many types.
また、抗ヒスタミン剤は、従来から副作用としての催眠作用が問題視されており、その点からの改良が進められてきた。１９８０年代に、催眠作用の少ないとされる第二世代抗ヒスタミン剤が開発され、従来の抗ヒスタミン剤（第一世代抗ヒスタミン剤）と区別される。第二世代抗ヒスタミン剤の代表的な例として、メキタジン（日本国において１９８２年承認）が挙げられる。このように、抗ヒスタミン剤の催眠作用の観点から第一世代、第二世代という分類が存在する。 Further, antihistamines have conventionally been regarded as a problem of hypnotic action as a side effect, and improvements have been made from that point. In the 1980s, a second-generation antihistamine that is considered to have less hypnotic action was developed and distinguished from conventional antihistamines (first-generation antihistamines). A typical example of the second generation antihistamine is mequitazine (approved in Japan in 1982). Thus, there are classifications of the first generation and the second generation from the viewpoint of the hypnotic action of antihistamines.
別の分類として、各種抗ヒスタミン剤の催眠作用の発現割合には多少が存在することが知られている[非特許文献１、２]。催眠作用の発現割合の多少は、以前は拮抗するＨ１受容体のサブタイプが薬剤間で異なるためと考えられていた。しかし、現在では、近年の研究により脳内への移行率の差によるものと考えられている[非特許文献３]。本発明は、抗ヒスタミン剤の薬剤間の催眠作用の発現割合の多少を、総合感冒薬組み合わせ製剤の処方に当たり考慮し、感冒の治療方針に従い、及び治療をしながらのＱＯＬの向上に積極的に利用することを特徴とする。 As another classification, it is known that there are some hypnotic effects of various antihistamines [Non-patent Documents 1 and 2]. The degree of hypnotic action was previously thought to be due to differences in antagonizing H1 receptor subtype among drugs. However, at present, it is considered that this is due to the difference in the rate of transfer into the brain according to recent studies [Non-Patent Document 3]. The present invention takes into account the degree of hypnotic action between antihistamines in the formulation of a general cold drug combination preparation, and actively uses it to improve QOL according to the cold treatment policy and during treatment. It is characterized by that.
抗ヒスタミン剤の催眠作用を利用した技術として、以下が知られている。 The following is known as a technique using the hypnotic action of an antihistamine.
特許文献１は、抗ヒスタミン剤を鎮静性抗ヒスタミン剤と非鎮静性抗ヒスタミン剤とに分類し、その組み合わせた組成物を開示し、非鎮静性抗ヒスタミン剤を遅延放出とし、１日１回投与を目的とするが、抗ヒスタミン剤の催眠作用の発現割合に着目した組み合わせ製剤を開示しない。 Patent document 1 classifies antihistamines into sedative antihistamines and non-sedative antihistamines, and discloses a combined composition thereof. The non-sedative antihistamines are intended to be administered once a day with delayed release. No combination preparation focusing on the hypnotic action ratio is disclosed.
特許文献２は、生体リズムに基づき処方が異なる２種類以上の製剤のキットを開示する。特許文献２では眠気を催す成分として抗ヒスタミン剤が挙げられているが、各種抗ヒスタミン剤の催眠作用発現割合に着目していない。さらに、特許文献２は昼夜の生体リズムに基づいた製剤の処方を目的としているが、かぜ罹患時特有の症状を考慮していない。 Patent Document 2 discloses a kit of two or more kinds of preparations having different prescriptions based on biological rhythm. Patent Document 2 mentions an antihistamine as a component that causes drowsiness, but does not focus on the hypnotic action expression ratio of various antihistamines. Furthermore, although patent document 2 aims at prescription of the formulation based on the biological rhythm of day and night, it does not consider the symptom peculiar at the time of a cold.
抗ヒスタミン剤の催眠作用を主作用とした製剤はすでに存在し、一般医薬品として市販されている。ドリエル（製造販売元；エスエス製薬株式会社）は抗ヒスタミン剤である塩酸ジフェンヒドラミンを主成分とした睡眠改善薬である。塩酸ジフェンヒドラミンは抗ヒスタミン作用のほかに、強い催眠作用を示すことが知られている[非特許文献４]。塩酸ジフェンヒドラミンの催眠作用については、Rickels K.が臨床試験を実施しており、就眠前の服用が各睡眠パラメーターを有意に改善することを報告している[非特許文献５]。 There are already preparations mainly based on the hypnotic action of antihistamines and are marketed as general pharmaceuticals. Doriel (manufacturer and distributor; SS Pharmaceutical Co., Ltd.) is a sleep-improving drug based on diphenhydramine hydrochloride, which is an antihistamine. It is known that diphenhydramine hydrochloride exhibits a strong hypnotic action in addition to the antihistamine action [Non-Patent Document 4]. Regarding the hypnotic action of diphenhydramine hydrochloride, Rickels K. has conducted clinical trials and reported that taking before sleep significantly improves each sleep parameter [Non-Patent Document 5].
このように、抗ヒスタミン剤の催眠作用を製剤へ利用した例は上記の通り存在するが、抗ヒスタミン剤間の発現割合の多少に着目し、それを組み合わせ製剤への処方に適用した例はこれまでに存在しない。 As described above, there are examples of using the hypnotic action of antihistamines in the preparation as described above. However, there has been no example of applying it to the formulation of a combined preparation by paying attention to the expression ratio between antihistamines. .
本発明者らは、抗ヒスタミン剤の副作用である催眠作用に着目し、その発現割合の多少を利用し、異なる抗ヒスタミン剤を処方した総合感冒薬組み合わせ製剤とすることで、感冒の治療方針に従い、及び治療をしながらのＱＯＬの向上を目的とした総合感冒薬組み合わせ製剤を提供することができることを見出し、本発明を完成させるに至った。すなわち、本発明は、抗ヒスタミン剤の催眠作用の発現割合の多少により、異なる抗ヒスタミン剤を処方した総合感冒薬２種を含む総合感冒薬組み合わせ製剤である。 The present inventors paid attention to the hypnotic action that is a side effect of antihistamines, and made use of some of their expression ratios to make a combined cold medicine combination formulation that prescribed different antihistamines. However, the present inventors have found that it is possible to provide a general cold medicine combination preparation for the purpose of improving QOL, and have completed the present invention. That is, the present invention is a combined cold medicine combination preparation comprising two kinds of common cold drugs formulated with different antihistamines depending on the degree of hypnotic action of the antihistamine.
本発明によれば、従来の総合感冒薬に比べて、感冒の治療方針に従い、及び治療をしながらのＱＯＬをより向上することができる。 According to the present invention, it is possible to further improve the QOL according to the treatment policy of the common cold and during the treatment as compared with the conventional general cold medicine.
抗ヒスタミン剤
抗ヒスタミン剤とは、血管、平滑筋などに存在するＨ１受容体との結合において、ヒスタミンと拮抗する作用、すなわち抗ヒスタミン作用を有する薬理学的に許容可能な化合物をいう。さらに、広義には、ヒスタミンを含むケミカルメディエーターの遊離抑制、及び拮抗作用、すなわち、抗アレルギー作用を有する薬理学的に許容可能な化合物を含めてよい。
Antihistamine An antihistamine refers to a pharmacologically acceptable compound having an action that antagonizes histamine in binding to H1 receptors existing in blood vessels, smooth muscles, etc., that is, an antihistamine action. Furthermore, in a broad sense, a pharmacologically acceptable compound having inhibition of release of chemical mediators including histamine and antagonism, that is, antiallergic activity may be included.
抗ヒスタミン剤として、ジフェニルピラリン、メブヒドロリン、メキタジン、ｄｌ−クロルフェニラミン、トリプロリジン、トンジルアミン、メトジラジン、カルビノキサミン、アリメマジン、クレマスチン、プロメタジン、ケトチフェン、イソチペンジル、ｄ−クロルフェニラミン、ジフェンヒドラミン、トリペレナミン、シプロヘプタジン、ジフェテロール、ホモクロルシクリジン若しくはフェネタジン、又はそれらの製薬学的に許容しうる塩を挙げることができるが、これらに限定されない。 Examples of antihistamines include diphenylpyralin, mebuhydroline, mequitazine, dl-chlorpheniramine, triprolidine, tondilamine, methodirazine, carbinoxamine, alimemazine, clemastine, promethazine, ketotifen, istipendil, d-chlorpheniramine, diphenhydramine, propereptadiamine, propereptamine Examples include, but are not limited to, chlorcyclidine or phenetadine, or a pharmaceutically acceptable salt thereof.
製薬学的に許容しうる塩として、塩酸、サリチル酸、ジフェニルスルホン酸、酒石酸、タンニン酸、テオクル酸、ナパジシル酸、メチレン二サリチル酸、マレイン酸、リン酸、又はフマル酸を挙げることができるが、これらに限定されない。 Examples of pharmaceutically acceptable salts include hydrochloric acid, salicylic acid, diphenylsulfonic acid, tartaric acid, tannic acid, teocric acid, napadisylic acid, methylene disalicylic acid, maleic acid, phosphoric acid, or fumaric acid. It is not limited to.
フマル酸クレマスチン、メキタジンはスイッチＯＴＣ薬であり、それぞれ１９８７年、１９９３年に感冒薬（一般用医薬品）への配合が承認された。フマル酸クレマスチン、メキタジンは薬理学的研究により、抗ヒスタミン作用が持続的である特徴がある［非特許文献６、７］。また、メキタジンは催眠作用が少なく、抗アレルギー作用も有する抗ヒスタミン剤である[非特許文献７]。 Clemastine fumarate and mequitazine are switch OTC drugs, which were approved for use in common cold drugs (over-the-counter drugs) in 1987 and 1993, respectively. Clemastine fumarate and mequitazine are characterized by persistent antihistaminic activity by pharmacological studies [Non-patent Documents 6 and 7]. In addition, mequitazine is an antihistamine that has little hypnotic action and also has antiallergic action [Non-patent Document 7].
本発明で云う抗ヒスタミン剤は、抗アレルギー薬に分類されているが抗ヒスタミン作用も有する薬剤も含む。アレルギー疾患治療に用いられる薬剤には、抗アレルギー作用に加え抗ヒスタミン作用を有する薬剤も多い。その例として、アゼラスチン、エバスチン、エピナスチン、エメダスチン、オキサトミド、オロパタジン、ケトチフェン、セチリジン、フェキソフェナジン、ベポタスチン若しくはロラタジン、又はそれらの製薬学的に許容しうる塩を挙げることができるが、これらに限定されない。これら薬剤は、主としてアレルギー治療剤として使用されるが、その薬理作用に抗ヒスタミン作用を有する。この抗ヒスタミン作用を期待して、本発明の総合感冒薬に抗ヒスタミン剤として処方してよい。さらに、これらのアレルギー治療剤は副作用として眠気も報告されており、その催眠作用を期待して本発明に使用してもよい。フマル酸ケトチフェンは２００５年に点鼻薬（一般医薬品）への配合が承認されたスイッチＯＴＣ薬である。 The antihistamines referred to in the present invention include drugs that are classified as antiallergic agents but also have antihistaminic activity. Many drugs used for treating allergic diseases have an antihistaminic action in addition to an antiallergic action. Examples include, but are not limited to, azelastine, ebastine, epinastine, emedastine, oxatomide, olopatadine, ketotifen, cetirizine, fexofenadine, bepotastine or loratadine, or a pharmaceutically acceptable salt thereof. . These drugs are mainly used as a therapeutic agent for allergies, but have an antihistaminic action in their pharmacological action. In anticipation of this antihistamine action, the general cold medicine of the present invention may be formulated as an antihistamine. Furthermore, these allergy therapeutic agents have also been reported to cause drowsiness as a side effect, and may be used in the present invention in anticipation of their hypnotic action. Ketotifen fumarate is a switch OTC drug that was approved for inclusion in nasal sprays (general drugs) in 2005.
総合感冒薬
本発明の「総合感冒薬」とは、かぜ薬製造（輸入）承認基準に基づき、かぜ症候群に用いるために調整された内服用の薬剤であって、漢方処方に基づく製剤及び生薬のみよりなる製剤を除いたものをいう。従って、鼻かぜ、感冒時の頭痛、かぜの咳等、かぜに関する効能又は効果を謳う薬剤であって、抗ヒスタミン剤を配合したものは本発明の総合感冒薬に該当する。
Comprehensive cold medicine “Comprehensive cold medicine” of the present invention is a drug for internal use adjusted for use in cold syndrome based on the cold drug manufacturing (import) approval standards, and only preparations and crude drugs based on Kampo prescriptions Refers to the product excluding the preparation. Therefore, a drug that has an effect or an effect related to cold, such as a nasal cold, a headache at the time of cold, a cough of cold, and the like, which contains an antihistamine, corresponds to the general cold drug of the present invention.
本発明の総合感冒薬は、抗ヒスタミン剤の他に、好ましくは解熱鎮痛成分、鎮咳成分、去痰成分、気管支拡張成分、消炎酵素成分、鎮咳去痰成分、解熱鎮痛・抗炎症成分、副交感神経遮断成分又は交感神経興奮成分のいずれか１以上をさらに含む。 In addition to antihistamines, the general cold medicine of the present invention is preferably antipyretic analgesic component, antitussive component, expectorant component, bronchodilator component, antiphlogistic enzyme component, antitussive expectorant component, antipyretic analgesic / antiinflammatory component, parasympathetic nerve blocking component or sympathetic It further includes any one or more of neural excitatory components.
解熱鎮痛成分として、アスピリン、アセトアミノフェン、エテンザミド、サザピリン、サリチルアミド、ラクチルフェネチジン、イソプロピルアンチピリン、イブプロフェン、又はそれらの製薬学的に許容しうる塩を挙げることができるが、これらに限定されない。 Examples of antipyretic analgesics include, but are not limited to, aspirin, acetaminophen, etenzamide, sazapyrine, salicylamide, lactylphenetidine, isopropylantipyrine, ibuprofen, or a pharmaceutically acceptable salt thereof.
鎮咳成分として、アロクラミド、クロペラスチン、ペンタトキシベリン（カルベタペンタン）、チペピジン、ジブナート、デキストロメトルファン、コデイン、ジヒドロコデイン、ノスカピン、メチルエフェドリン、ジメモルファン又はそれらの製薬学的に許容しうる塩を挙げることができるが、これらに限定されない。 As an antitussive component, mention may be made of aloclamide, cloperastine, pentaoxyberine (carbetapentane), tipepidine, dibutate, dextromethorphan, codeine, dihydrocodeine, noscapine, methylephedrine, dimemorphan or a pharmaceutically acceptable salt thereof. Although it can, it is not limited to these.
去痰成分として、チペピジン、メチルエフェドリン、グアヤコールスルホン酸、グアイフェネシン又はそれらの製薬学的に許容しうる塩を挙げることができるが、これらに限定されない。 Examples of the expectorant component include, but are not limited to, tipepidine, methylephedrine, guaiacol sulfonic acid, guaifenesin, or a pharmaceutically acceptable salt thereof.
気管支拡張成分として、メチルエフェドリン又はそれらの製薬学的に許容しうる塩を挙げることができるが、これらに限定されない。 The bronchodilator component can include, but is not limited to, methylephedrine or a pharmaceutically acceptable salt thereof.
本発明の総合感冒薬は、消炎酵素成分として例えばリゾチーム、セラペプターゼ、セミアルカリプロティナーゼ、ブロメライン又はそれらの製薬学的に許容しうる塩、鎮咳去痰成分として例えばクレゾールスルホン酸、ブロメライン、ブロムヘキシン、セミアルカリプロティナーゼ、カルボシステイン、エプラジノン、セラペプターゼ、トラネキサム酸、ジメモルファン、エチルシステイン又はそれらの製薬学的に許容しうる塩、解熱鎮痛・抗炎症成分として例えばトラネキサム酸、副交感神経遮断成分として例えばベラドンナ総アルカロイド、交感神経興奮成分としてフェニルプロパノールアミン又はそれらの製薬学的に許容しうる塩のいずれか１以上をさらに含んでよい。 The common cold medicine of the present invention is, for example, lysozyme, serrapeptase, semi-alkaline proteinase, bromelain or a pharmaceutically acceptable salt thereof as an anti-inflammatory enzyme component, for example, cresolsulfonic acid, bromelain, bromhexine, semi-alkaline proteinase as an antitussive expectorant component , Carbocysteine, eprazinone, serrapeptase, tranexamic acid, dimemorphan, ethylcysteine or a pharmaceutically acceptable salt thereof, antipyretic analgesic / anti-inflammatory component such as tranexamic acid, parasympathetic nerve blocking component such as belladonna total alkaloid, sympathetic nerve It may further comprise any one or more of phenylpropanolamine or a pharmaceutically acceptable salt thereof as an excitatory component.
本発明の総合感冒薬に、カフェイン類をさらに配合してもよい。カフェイン類としては、無水カフェイン、カフェイン又はそれらの製薬学的に許容しうる塩を挙げることができるが、これらに限定されない。カフェイン類は抗ヒスタミン剤の催眠作用を抑制、除去する目的で配合してもよいし、カフェイン類の中枢興奮作用を目的とし配合してもよい。従って、カフェイン類は、好ましくは朝用及び／又は昼用の総合感冒薬に処方される。一方、カフェイン類は安静、安眠を目的として、または抗ヒスタミン剤の催眠作用を十分に発揮させる目的で配合しなくてもよく、好ましくは夜用及び／又は就寝前用の総合感冒薬に処方されない。 You may further mix | blend caffeine with the comprehensive cold medicine of this invention. Examples of caffeine include, but are not limited to, anhydrous caffeine, caffeine, or a pharmaceutically acceptable salt thereof. Caffeine may be added for the purpose of suppressing or removing the hypnotic action of the antihistamine, or may be added for the purpose of central excitatory action of caffeine. Therefore, caffeine is preferably prescribed for morning and / or daytime common cold drugs. On the other hand, caffeine does not have to be formulated for the purpose of resting and sleeping, or for the purpose of fully exerting the hypnotic action of the antihistamine, and is preferably not prescribed as a general cold medicine for night use and / or before going to bed.
本発明の総合感冒薬剤形として、錠剤、カプセル剤、丸剤、顆粒剤、細粒剤、散剤（粉末剤）、チュアブル剤、シロップ剤（内用液剤）、ドライシロップ剤、トローチ剤、液剤、カプレット剤、ゼリー剤、徐放剤、又は速溶剤を挙げることができるが、これらに限定されない。 As the common cold pharmaceutical form of the present invention, tablets, capsules, pills, granules, fine granules, powders (powder), chewables, syrups (liquid for internal use), dry syrups, troches, liquids, caplets May include, but are not limited to, agents, jelly agents, sustained release agents, or fast solvents.
総合感冒薬組み合わせ製剤
本発明の「総合感冒薬組み合わせ製剤」とは、医薬品製造指針に基づき、配合成分を分ち、それぞれを組み合わせた一個の医薬品のことをいう。通常一個の医薬品は一つの製剤とすることが原則であって、二つ以上の製剤を組み合せて一個の医薬品とすることは適当と認められず、承認されない。しかし、配合成分を分ち、それぞれを組み合せて一個の医薬品とすることが必要であり、かつその組み合わせが合理的である場合について、例外的にこの種の剤型、すなわち組み合わせ製剤が認められている。組み合わせ製剤の例として、上述したカフェインの処方の有無の総合感冒薬を組み合わせた製剤以外に、ヘリコバクター・ピロリ除菌用組み合わせ製剤がある。胃潰瘍又は十二指腸潰瘍におけるヘリコバクター・ピロリの除菌には、ランソプラゾール、アモキシシリン及びクラリスロマイシンの３剤併用が臨床の場で実施されてきたが、３剤併用の除菌療法においては、不完全な除菌による耐性菌出現、副作用の増加等の問題につながるおそれがあり、定められた用法・用量を遵守する必要性があった。そこで、用法・用量の遵守をより確実にするために、３製剤の１日服用分を１シートにまとめた組み合わせ製剤が承認されている（製品名 ランサップ400、ランサップ800、武田薬品工業株式会社）。
Comprehensive cold medicine combination preparation The “comprehensive cold medicine combination preparation” of the present invention refers to a single medicine in which the ingredients are separated and combined based on the pharmaceutical production guidelines. In general, one pharmaceutical product is in principle a single formulation, and combining two or more formulations into a single pharmaceutical product is not considered appropriate and is not approved. However, in cases where it is necessary to divide the ingredients and combine them into a single drug and the combination is reasonable, this type of dosage form, that is, a combination product is exceptionally permitted. Yes. As an example of a combination preparation, there is a combination preparation for Helicobacter pylori eradication in addition to the preparation combined with the above-mentioned common cold medicine with or without caffeine prescription. For the eradication of Helicobacter pylori in gastric ulcer or duodenal ulcer, a combination of lansoprazole, amoxicillin and clarithromycin has been practiced in the clinical setting, but incomplete eradication therapy with a combination of three agents is incomplete eradication. There is a possibility that it may lead to problems such as emergence of resistant bacteria due to bacteria and increased side effects, and it is necessary to observe the prescribed dosage and administration. Therefore, in order to ensure adherence to dosage and administration, a combined preparation that combines the daily doses of the three preparations into one sheet has been approved (Product names Lansup 400, Lansup 800, Takeda Pharmaceutical Co., Ltd.) .
本発明の総合感冒薬組み合わせ製剤とは、例えば、異なる抗ヒスタミン剤を夫々処方した総合感冒薬を一日服用量分、又は数日服用量分としてまとめ組み合わせた製剤、すなわち第１の抗ヒスタミン剤を処方した第１の総合感冒薬と、該第１の抗ヒスタミン剤と催眠作用の発現割合が異なる第２の抗ヒスタミン剤を処方した第２の総合感冒薬とを含む総合感冒薬組み合わせ製剤をいう。さらに好ましくは、第２の抗ヒスタミン剤の催眠作用の発現割合が、第１の抗ヒスタミン剤の催眠作用の発現割合よりも多く、このように催眠作用の発現割合が異なる抗ヒスタミン剤の催眠作用を積極的に利用する。さらに効果的にする目的で、第１の総合感冒薬がカフェイン類を含み、第２の総合感冒薬がカフェイン類を含まないような総合感冒薬組み合わせ製剤でもよい。本発明の総合感冒薬組み合わせ製剤において、第１の総合感冒薬が朝用及び／又は昼用であり、第２の総合感冒薬が夜用及び／又は就寝前用である。 The common cold medicine combination preparation of the present invention is, for example, a preparation in which different common antihistamines are preliminarily combined and combined as a daily dose or several days, that is, a first antihistamine prescription. A general cold drug combination preparation comprising 1 general cold drug and a second general cold drug formulated with a second antihistamine having a different hypnotic effect from the first antihistamine. More preferably, the hypnotic effect of the second antihistamine is higher than the hypnotic effect of the first antihistamine, and thus the hypnotic effect of the antihistamine having a different hypnotic effect is actively used. . For the purpose of making it more effective, it may be a general cold medicine combination preparation in which the first general cold medicine contains caffeine and the second general cold medicine does not contain caffeine. In the general cold medicine combination preparation of the present invention, the first general cold medicine is for morning and / or noon, and the second general cold medicine is for night and / or before going to bed.
総合感冒薬組み合わせ製剤の包装形態として、総合感冒薬の形態に対応させるようにした包装体であれば特に限定されないが、例えば薬剤が錠剤である場合、該錠剤を入れるアルミ又はＰＴＰシートであり、顆粒剤である場合、該顆粒剤を入れる小袋である。これらアルミ又はＰＴＰシート、小袋はさらにピロー包装されて、外箱にいれられうる。本発明の一実施態様として、経口投与に適用される総合感冒薬組み合わせ製剤であって、一日分である一包装単位中に、経口投与するように決められた第１の総合感冒薬と第２の総合感冒薬を含み、それらはその包装単位中に空間的に分離され、個々に取り出すことができるように納められており、第１の総合感冒薬は第１の抗ヒスタミン剤を含み、第２の総合感冒薬は第２の抗ヒスタミン剤を含み、第２の抗ヒスタミン剤の催眠作用の発現割合が第１の抗ヒスタミン剤の催眠作用の発現割合よりも多い、総合感冒薬組み合わせ製剤が提供される。 The packaging form of the general cold medicine combination preparation is not particularly limited as long as it is a package adapted to the form of the general cold medicine, for example, when the drug is a tablet, it is an aluminum or PTP sheet containing the tablet, When it is a granule, it is a sachet that contains the granule. These aluminum or PTP sheets and sachets can be further pillow-wrapped and placed in an outer box. In one embodiment of the present invention, there is provided a combination product of a common cold drug applied to oral administration, wherein the first common cold drug and the first common cold drug are determined to be administered orally in a single package unit. Two general cold medicines, which are spatially separated in the packaging unit and stored so that they can be removed individually, the first general cold medicine contains a first antihistamine, The general cold medicine comprises a second antihistamine, and a total cold medicine combination preparation is provided in which the hypnotic action rate of the second antihistamine is greater than the hypnotic action rate of the first antihistamine.
催眠作用の発現割合が異なる
本発明において「催眠作用の発現割合が異なる」ことは、例えば以下の（１）、（２）の方法により求められる。
In the present invention in which the expression rate of hypnotic action is different, “the expression ratio of hypnotic action is different” is determined by the following methods (1) and (2), for example.
（１）文献調査による催眠作用の発現割合比較
抗ヒスタミン剤の催眠作用の発現について、抗ヒスタミン剤を投与した文献、例えば臨床文献、医学文献を調査し、催眠作用の発現割合を算出する。臨床文献、医学文献の他に、抗ヒスタミン剤又は抗ヒスタミン剤が含まれる医薬品の臨床試験、使用成績調査、市販後調査等の結果を用いることができる。催眠作用の発現割合は、各抗ヒスタミン剤又は抗ヒスタミン剤含有製剤の投与を行った投与例数の合計（Ａ）、催眠作用又は眠気が発現した例数の合計（Ｂ）を集計し、催眠作用又は眠気が発現した例数の合計（Ｂ）／投与例数の合計（Ａ）×１００により算出する。そして、算出された催眠作用の発現割合が各抗ヒスタミン剤間で異なることを、「催眠作用の発現割合が異なる」という。
(1) Comparison of expression ratio of hypnotic action by literature survey Regarding the expression of hypnotic action of antihistamine, literatures administered with antihistamine, such as clinical literature and medical literature, are investigated, and the expression ratio of hypnotic action is calculated. In addition to the clinical literature and medical literature, the results of clinical tests, use-results surveys, post-marketing surveys, etc. of antihistamines or pharmaceuticals containing antihistamines can be used. The expression rate of hypnotic action is the sum of the number of administration cases where each antihistamine or antihistamine-containing preparation was administered (A), and the total number of cases where hypnosis or sleepiness occurred (B). Calculated by the sum of the number of cases expressed (B) / the total number of administration cases (A) × 100. And, the fact that the calculated expression rate of hypnotic action differs among the antihistamines is referred to as “the expression ratio of hypnotic action is different”.
上記算出方法に従い、抗ヒスタミン剤として、塩酸イソチペンジル、塩酸ジフェニルピラリン、塩酸ジフェンヒドラミン、塩酸トリプロリジン、トリペレナミン、塩酸トンジルアミン、塩酸メトジラジン、マレイン酸カルビノキサミン、アリメマジン、ナバジシル酸メブヒドロリン、プロメタジン、ｄ−マレイン酸クロルフェニラミン、ｄｌ−マレイン酸クロルフェニラミン、フマル酸クレマスチン、メキタジン、塩酸シプロヘプタジン、フマル酸ケトチフェンの計１７種について催眠作用の発現割合を算出した。その結果を下記表１に示す。 In accordance with the above calculation method, as an antihistamine, isothipenzil hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, methodirazine hydrochloride, carbinoxamine maleate, alimemazine, mebhydroline nabadisylate, promethazine, chlorpheniramine d-malate, The expression rate of hypnotic action was calculated for a total of 17 kinds of dl-chlorpheniramine maleate, clemastine fumarate, mequitazine, cyproheptadine hydrochloride, and ketotifen fumarate. The results are shown in Table 1 below.
上記結果から、抗ヒスタミン剤の催眠作用の発現割合は抗ヒスタミン剤間で異なり、２．９％〜２５．８％と幅があることが示された。
本発明の総合感冒薬組み合わせ製剤に処方する抗ヒスタミン剤の例として、第２の抗ヒスタミン剤の催眠作用の発現割合が、第１の抗ヒスタミン剤の催眠作用の発現割合より少なくとも５％以上、好ましくは１０％以上、より好ましくは１５％以上、さらに好ましくは２０％以上、さらにより好ましくは２０％以上大きい。
下記表２−１〜２−１２に、第１の抗ヒスタミン剤を基準にした場合の、第２の抗ヒスタミン剤の組み合わせを示す。
From the above results, it was shown that the rate of hypnotic action of antihistamines varies among antihistamines and varies from 2.9% to 25.8%.
As an example of an antihistamine prescribed in the combined cold medicine combination preparation of the present invention, the hypnotic action expression rate of the second antihistamine is at least 5%, preferably 10% or more than the hypnotic action expression ratio of the first antihistamine. More preferably, it is 15% or more, more preferably 20% or more, and still more preferably 20% or more.
Tables 2-1 to 2-12 below show combinations of the second antihistamines based on the first antihistamine.
さらに、抗ヒスタミン剤の催眠作用の発現割合を（ａ）０％より上〜５％未満、（ｂ）５％以上〜１０％未満、（ｃ）１０％以上〜１５％未満、（ｄ）１５％以上〜２０％未満、（ｅ）２０％以上の５区分に分類し（下記表３を参照）、各区分に属する抗ヒスタミン剤の組み合わせから、第１の抗ヒスタミン剤、第２の抗ヒスタミン剤を夫々選ぶことができる。 Furthermore, the expression rate of the hypnotic action of the antihistamine is (a) above 0% to less than 5%, (b) from 5% to less than 10%, (c) from 10% to less than 15%, (d) 15% or more It is classified into 5 categories of less than -20% and (e) 20% or more (see Table 3 below), and the first antihistamine and the second antihistamine can be selected from combinations of antihistamines belonging to each category.
第１の抗ヒスタミン剤が区分（ａ）、第２の抗ヒスタミン剤が区分（ｂ）〜（ｅ）から選ばれる場合、第１の抗ヒスタミン剤は、ジフェニルピラリン、メブヒドロリン、メキタジン及びそれらの製薬学的に許容しうる塩からなる群より選ばれ、及び第２の抗ヒスタミン剤は、ｄｌ−クロルフェニラミン、トリプロリジン、トンジルアミン、メトジラジン、カルビノキサミン、アリメマジン、クレマスチン、プロメタジン、ケトチフェン、イソチペンジル、ｄ−クロルフェニラミン、ジフェンヒドラミン、トリペレナミン、シプロヘプタジン及びそれらの製薬学的に許容しうる塩からなる群より選ばれる。 When the first antihistamine is selected from category (a) and the second antihistamine is selected from categories (b) to (e), the first antihistamine is diphenylpyralin, mebhydroline, mequitazine and their pharmaceutically acceptable substances. The second antihistamine selected from the group consisting of salts is dl-chlorpheniramine, triprolidine, tondilamine, methodirazine, carbinoxamine, alimemazine, clemastine, promethazine, ketotifen, istipendil, d-chlorpheniramine, diphenhydramine, tripelenamine, It is selected from the group consisting of cyproheptadine and their pharmaceutically acceptable salts.
第１の抗ヒスタミン剤が区分（ｂ）、第２の抗ヒスタミン剤が区分（ｃ）〜（ｅ）から選ばれる場合、第１の抗ヒスタミン剤は、ｄｌ−クロルフェニラミン、トリプロリジン、トンジルアミン及びそれらの製薬学的に許容しうる塩からなる群より選ばれ、及び第２の抗ヒスタミン剤は、メトジラジン、カルビノキサミン、アリメマジン、クレマスチン、プロメタジン、ケトチフェン、イソチペンジル、ｄ−クロルフェニラミン、ジフェンヒドラミン、トリペレナミン、シプロヘプタジン及びそれらの製薬学的に許容しうる塩からなる群より選ばれる。 When the first antihistamine is selected from category (b) and the second antihistamine is selected from categories (c) to (e), the first antihistamine is dl-chlorpheniramine, triprolidine, tonsilamine and their pharmaceuticals. And a second antihistamine is methodirazine, carbinoxamine, alimemazine, clemastine, promethazine, ketotifen, isothipentyl, d-chlorpheniramine, diphenhydramine, tripelenamine, cyproheptadine and their pharmaceuticals Selected from the group consisting of acceptable salts.
第１の抗ヒスタミン剤が区分（ｃ）、第２の抗ヒスタミン剤が区分（ｄ）〜（ｅ）から選ばれる場合、第１の抗ヒスタミン剤は、メトジラジン、カルビノキサミン、アリメマジン、クレマスチン及びそれらの製薬学的に許容しうる塩からなる群より選ばれ、及び第２の抗ヒスタミン剤は、プロメタジン、ケトチフェン、イソチペンジル、ｄ−クロルフェニラミン、ジフェンヒドラミン、トリペレナミン、シプロヘプタジン及びそれらの製薬学的に許容しうる塩からなる群より選ばれる。 When the first antihistamine is selected from category (c) and the second antihistamine is selected from categories (d) to (e), the first antihistamine is methodirazine, carbinoxamine, alimemazine, clemastine and their pharmaceutically acceptable drugs. And the second antihistamine is selected from the group consisting of promethazine, ketotifen, isotipenzil, d-chlorpheniramine, diphenhydramine, tripelenamine, cyproheptadine and their pharmaceutically acceptable salts. .
第１の抗ヒスタミン剤が区分（ｃ）、第２の抗ヒスタミン剤が区分（ｄ）〜（ｅ）から選ばれる場合、第１の抗ヒスタミン剤は、プロメタジン、ケトチフェン、イソチペンジル、ｄ−クロルフェニラミン及びそれらの製薬学的に許容しうる塩からなる群より選ばれ、及び第２の抗ヒスタミン剤は、ジフェンヒドラミン、トリペレナミン、シプロヘプタジン及びそれらの製薬学的に許容しうる塩からなる群より選ばれる。 When the first antihistamine is selected from the category (c) and the second antihistamine is selected from the categories (d) to (e), the first antihistamine is promethazine, ketotifen, isotipezil, d-chlorpheniramine and their pharmaceutical preparations And the second antihistamine is selected from the group consisting of diphenhydramine, tripelenamine, cyproheptadine and their pharmaceutically acceptable salts.
（２）臨床試験による催眠作用の発現割合比較
非特許文献１３では、アレルギー患者群に５種類の抗ヒスタミン剤（トリペレナミン、ジフェンヒドラミン、クロルフェニラミン、ヒドロキシジン、トリメプラジン）を夫々投与し、催眠作用の発現割合が調査された。抗ヒスタミン剤の催眠作用の各発現割合は、それぞれ以下の通りである：トリペレンアミン ２５％、ジフェンヒドラミン ２３％、クロルフェニラミン １４％、ヒドロキシジン １９％、トリメプラジン １１％。
このように、「催眠作用の発現割合が異なる」ことは、所定の方法により抗ヒスタミン剤の催眠作用の発現割合を測定することによって判断してもよい。
(2) Comparison of expression rate of hypnotic action by clinical trials In Non-patent Document 13, five types of antihistamines (triperenamine, diphenhydramine, chlorpheniramine, hydroxyzine, trimeprazine) were administered to allergic patients, respectively, and the expression ratio of hypnotic action Was investigated. Each expression ratio of the hypnotic action of the antihistamine is as follows: tripelenamine 25%, diphenhydramine 23%, chlorpheniramine 14%, hydroxyzine 19%, trimeprazine 11%.
Thus, “difference in the rate of hypnotic action” may be determined by measuring the rate of hypnotic action of the antihistamine by a predetermined method.
また、抗アレルギー剤に分類されているが抗ヒスタミン作用も有する薬剤についても、上記と同様に、所定の方法により抗ヒスタミン剤の催眠作用の発現割合を測定することによって判断してもよい。
非特許文献７５では、全国の薬局薬剤師を介した抗アレルギー剤４成分６品目（エバスチン５ｍｇ・１０ｍｇ、フェキソフェナジン６０ｍｇ、セチリジン５ｍｇ・１０ｍｇ、ロラタジン１０ｍｇ）の催眠作用の発現割合の調査がされた。これら抗アレルギー剤４成分は抗ヒスタミン作用も有する。各抗アレルギー剤の眠気発現率は、それぞれ以下の通りである：エバスチン５ｍｇ １２．２％、エバスチン１０ｍｇ １４．３％、フェキソフェナジン ８．９％、セチリジン５ｍｇ １６．３％、セチリジン１０ｍｇ １９．０％、ロラタジン ９．３％。なお、エバスチンとセチリジンについて、催眠作用の発現割合に用量依存的に若干の差が見られる。しかし、非特許文献３では、抗ヒスタミン剤（ｄ-マレイン酸クロルフェニラミン）の脳内Ｈ１受容体占拠率をＰＥＴを用いて測定した場合、受容体占拠率が３０％を超えると眠気の発生率が飽和化し、従って受容体占拠率に用量依存性が見られるが、眠気の発生率に用量依存性は見られない旨が記載されている。従って、エバスチン、セチリジンについて催眠作用の発現割合に用量依存的に若干の差が見られるが、催眠作用の発現割合に大きな影響を与えるものではない。
In addition, a drug classified as an antiallergic agent but also having an antihistamine action may be determined by measuring the expression rate of the hypnotic action of the antihistamine drug by a predetermined method, as described above.
In Non-Patent Document 75, the rate of hypnotic action of anti-allergic agent 4 components 6 items (ebastine 5mg · 10mg, fexofenadine 60mg, cetirizine 5mg · 10mg, loratadine 10mg) was investigated through pharmacists in Japan . These four antiallergic agents also have an antihistaminic action. The incidence of sleepiness of each antiallergic agent is as follows: Ebastine 5 mg 12.2%, Ebastine 10 mg 14.3%, Fexofenadine 8.9%, Cetirizine 5 mg 16.3%, Cetirizine 10 mg 19. 0%, loratadine 9.3%. In addition, about ebastine and cetirizine, a slight difference is seen by the dose-dependent expression rate of a hypnotic action. However, in Non-Patent Document 3, when the brain H1 receptor occupancy rate of an antihistamine (d-chlorpheniramine maleate) is measured using PET, if the receptor occupancy rate exceeds 30%, the incidence of sleepiness is increased. It is stated that it is saturated and therefore dose-dependent in receptor occupancy, but not dose-dependent in the incidence of sleepiness. Therefore, although there are some dose-dependent differences in the expression rate of hypnotic action between ebastine and cetirizine, it does not significantly affect the expression rate of hypnotic action.
このように、「催眠作用の発現割合が異なる」ことは、所定の方法により抗アレルギー剤（抗ヒスタミン作用も有する）の催眠作用の発現割合を測定することによって判断してもよい。 Thus, “difference in the rate of hypnotic action” may be determined by measuring the rate of hypnotic action of an antiallergic agent (also having an antihistamine effect) by a predetermined method.
実施例
以下、本発明を詳細に説明するために実施例を記載するが、本発明はこれら実施例によって何ら限定されるものではない。
Examples Hereinafter, examples will be described to describe the present invention in detail, but the present invention is not limited to these examples.
催眠作用の発現割合の異なる塩酸ジフェニルピラリン、ｄ−マレイン酸クロルフェニラミンを夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−１] 朝、昼として２回服用 ４錠 ４錠中
イブプロフェン ３００ ｍｇ
塩酸ジフェニルピラリン ２．６ ｍｇ
塩酸ブロムヘキシン ８ ｍｇ
塩化リゾチーム ４０ ｍｇ
臭化水素酸デキストロメトルファン ３２ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
無水カフェイン ５０ ｍｇ
[総合感冒薬−２] 夜１回服用 ２錠 ２錠中
イブプロフェン １５０ ｍｇ
ｄ−マレイン酸クロルフェニラミン １．１５ ｍｇ
塩酸ブロムヘキシン ４ ｍｇ
塩化リゾチーム ２０ ｍｇ
臭化水素酸デキストロメトルファン １６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
The following two types of common cold medicines (tablets) each formulated with diphenylpyralin hydrochloride and d-chlorpheniramine maleate with different expression rates of hypnotic action were prepared as combined preparations (PTP packaging).
[General cold medicine-1] Taken twice in the morning and noon 4 tablets 4 tablets 4 tablets ibuprofen 300 mg
Diphenylpyraline hydrochloride 2.6 mg
Bromohexine hydrochloride 8 mg
Lysozyme chloride 40 mg
Dextromethorphan hydrobromide 32 mg
dl-methylephedrine hydrochloride 40 mg
Anhydrous caffeine 50 mg
[General cold drug-2] Taken once a night 2 tablets 2 tablets Ibuprofen 150 mg
d-Chlorpheniramine maleate 1.15 mg
Bromohexine hydrochloride 4 mg
Lysozyme chloride 20 mg
Dextromethorphan hydrobromide 16 mg
dl-methylephedrine hydrochloride 20 mg
催眠作用の発現割合の異なるメキタジン、ｄ−マレイン酸クロルフェニラミンを夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−３] 朝、昼として２回服用 ６錠 ６錠中
イブプロフェン ３００ ｍｇ
メキタジン ２．６６ ｍｇ
リン酸ジヒドロコデイン １６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
無水カフェイン ５０ ｍｇ
ヘスペリジン ６０ ｍｇ
[総合感冒薬−４] 夜１回服用 ３錠 ３錠中
イブプロフェン １５０ ｍｇ
ｄ−マレイン酸クロルフェニラミン １．１６ ｍｇ
リン酸ジヒドロコデイン ８ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
ヘスペリジン ３０ ｍｇ
The following two types of common cold medicines (tablets) each formulated with mequitazine and d-chlorpheniramine maleate with different expression rates of hypnotic action were prepared and used as combined preparations (PTP packaging).
[General cold medicine-3] Take twice a day in the morning and noon 6 tablets 6 tablets 6 tablets ibuprofen 300 mg
Mequitazine 2.66 mg
Dihydrocodeine phosphate 16 mg
dl-methylephedrine hydrochloride 40 mg
Anhydrous caffeine 50 mg
Hesperidin 60 mg
[General cold drug-4] Taken once a night 3 tablets 3 tablets 3 tablets ibuprofen 150 mg
d-chlorpheniramine maleate 1.16 mg
Dihydrocodeine phosphate 8 mg
dl-methylephedrine hydrochloride 20 mg
Hesperidin 30 mg
催眠作用の発現割合の異なるｄｌ−マレイン酸クロルフェニラミン、マレイン酸カルビノキサミンを夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−５] 朝、昼として２回服用 ６錠 ６錠中
アセトアミノフェン ６００ ｍｇ
ｄｌ−マレイン酸クロルフェニラミ ５ ｍｇ
リン酸ジヒドロコデイン １６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
塩酸ブロムヘキシン ８ ｍｇ
無水カフェイン ５０ ｍｇ
硝酸チアミン １６ ｍｇ
ビタミンＢ２ ８ ｍｇ
[総合感冒薬−６] 夜１回服用 ３錠 ３錠中
アセトアミノフェン ３００ ｍｇ
マレイン酸カルビノキサミン ２．５ ｍｇ
リン酸ジヒドロコデイン ８ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
塩酸ブロムヘキシン ４ ｍｇ
硝酸チアミン ８ ｍｇ
ビタミンＢ２ ４ ｍｇ
先述した調査（１）の結果に基づき、ｄｌマレイン酸クロルフェニラミン、マレイン酸クロルフェニラミンは両者とも催眠作用発現割合の多い群に分類されるが、マレイン酸クロルフェニラミンの催眠作用の発現割合（１１．８％）は、ｄｌマレイン酸クロルフェニラミンの眠気作用の発現割合（６．１％）よりも、５．７％多い。
The following two types of general cold medicines (tablets) each formulated with dl-chlorpheniramine maleate and carbinoxamine maleate with different expression rates of hypnotic action were prepared as combined preparations (PTP packaging).
[General cold medicine-5] Take twice a day in the morning and noon 6 tablets 6 tablets Acetaminophen 600 mg
dl-chlorphenirami maleate 5 mg
Dihydrocodeine phosphate 16 mg
dl-methylephedrine hydrochloride 40 mg
Bromohexine hydrochloride 8 mg
Anhydrous caffeine 50 mg
Thiamine nitrate 16 mg
Vitamin B2 8 mg
[General cold medicine -6] Take once a night 3 tablets 3 tablets Acetaminophen 300 mg
Carbinoxamine maleate 2.5 mg
Dihydrocodeine phosphate 8 mg
dl-methylephedrine hydrochloride 20 mg
Bromohexine hydrochloride 4 mg
Thiamine nitrate 8 mg
Vitamin B2 4 mg
Based on the results of the survey (1) described above, dl chlorpheniramine maleate and chlorpheniramine maleate are both classified into groups with a high hypnotic effect, but the rate of hypnotic action of chlorpheniramine maleate (11.8%) is 5.7% higher than the expression rate (6.1%) of the sleepiness effect of dl chlorpheniramine maleate.
催眠作用の発現割合の異なる塩酸トリプロリジン、塩酸トリペレナミンを夫々処方した以下の２種の総合感冒薬（カプセル剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−７] 朝、昼として２回服用 ４カプセル ４カプセル中
アセトアミノフェン １８０ ｍｇ
エテンザミド ７００ ｍｇ
塩酸トリプロリジン ２．６６ ｍｇ
臭化水素酸デキストロメトルファン ３２ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
無水カフェイン ５０ ｍｇ
アスコルビン酸ナトリウム ３３３ ｍｇ
[総合感冒薬−８] 夜１回服用 ２カプセル ２カプセル中
アセトアミノフェン ９０ ｍｇ
エテンザミド ３５０ ｍｇ
塩酸トリペレナミン ３３ ｍｇ
臭化水素酸デキストロメトルファン １６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
アスコルビン酸ナトリウム １６７ ｍｇ
先述した調査（１）の結果に基づき、塩酸トリプロリジン、塩酸トリペレナミンは両者とも催眠作用発現割合の多い群に分類されるが、塩酸トリペレナミンの催眠作用の発現割合（２５．１％）は、塩酸トリプロリジンの催眠作用の発現割合（８．６％）よりも、１６．５％多い。
The following two types of common cold medicines (capsules) formulated with triprolidine hydrochloride and tripelenamine hydrochloride with different expression rates of hypnotic action were prepared as combined preparations (PTP packaging).
[General cold medicine-7] Taken twice in the morning and noon 4 capsules 4 capsules Acetaminophen 180 mg
Ethenzamid 700 mg
Triprolidine hydrochloride 2.66 mg
Dextromethorphan hydrobromide 32 mg
dl-methylephedrine hydrochloride 40 mg
Anhydrous caffeine 50 mg
Sodium ascorbate 333 mg
[General cold drug-8] Taken once a night 2 capsules 2 capsules Acetaminophen 90 mg
Ethenzamid 350 mg
Tripelenamine hydrochloride 33 mg
Dextromethorphan hydrobromide 16 mg
dl-methylephedrine hydrochloride 20 mg
Sodium ascorbate 167 mg
Based on the results of the survey (1) described above, triprolidine hydrochloride and tripelenamine hydrochloride are both classified into groups with a high hypnotic effect, but the expression rate (25.1%) of tripelenamine hydrochloride is It is 16.5% more than the expression rate (8.6%) of the hypnotic action of triprolidine.
催眠作用の発現割合の異なるナパジシル酸メブヒドロリン、ｄ−マレイン酸クロルフェニラミンを夫々処方した以下の２種の総合感冒薬（カプセル剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−９] 朝、昼として２回服用 ４カプセル ４カプセル中
アセトアミノフェン ２６０ ｍｇ
トラネキサム酸 ２８０ ｍｇ
エテンザミド ５６７ ｍｇ
ナパジシル酸メブヒドロリン １００ ｍｇ
ヒベンズ酸チペピジン ５０ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
無水カフェイン ５０ ｍｇ
[総合感冒薬−１０] 夜１回服用 ２カプセル ２カプセル中
アセトアミノフェン １３０ ｍｇ
トラネキサム酸 １４０ ｍｇ
エテンザミド ２８３ ｍｇ
ｄ−マレイン酸クロルフェニラミン １．１６ ｍｇ
ヒベンズ酸チペピジン ２５ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
The following two types of common cold medicines (capsules) formulated with mebhydroline napadisylate and d-chlorpheniramine maleate, which have different expression rates of hypnotic action, were prepared and used as combined preparations (PTP packaging).
[General cold drug-9] Taken twice in the morning and noon 4 capsules 4 capsules Acetaminophen 260 mg
Tranexamic acid 280 mg
Ethenzamid 567 mg
Mebuhydroline napadisylate 100 mg
Tipepidine hibenzate 50 mg
dl-methylephedrine hydrochloride 40 mg
Anhydrous caffeine 50 mg
[General cold medicine -10] Take once a night 2 capsules 2 capsules Acetaminophen 130 mg
Tranexamic acid 140 mg
Ethenzamid 283 mg
d-chlorpheniramine maleate 1.16 mg
Tipepidine hibenzate 25 mg
dl-methylephedrine hydrochloride 20 mg
催眠作用の発現割合の異なる塩酸ジフェニルピラリン、塩酸ジフェンヒドラミンを夫々処方した以下の２種の総合感冒薬（カプセル剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−１１] 朝、昼として２回服用 ４カプセル ４カプセル中
アセトアミノフェン ３００ ｍｇ
エテンザミド ５００ ｍｇ
塩酸ジフェニルピラリン ２．６６ ｍｇ
リン酸ジヒドロコデイン １６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
グアヤコールスルホン酸カリウム １００ ｍｇ
無水カフェイン ５０ ｍｇ
[総合感冒薬−１２] 夜１回服用 ２カプセル ２カプセル中
アセトアミノフェン １５０ ｍｇ
エテンザミド ２５０ ｍｇ
塩酸ジフェンヒドラミン ２５ ｍｇ
リン酸ジヒドロコデイン ８ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
グアヤコールスルホン酸カリウム ５０ ｍｇ
The following two types of common cold medicines (capsules) formulated with diphenylpyraline hydrochloride and diphenhydramine hydrochloride with different expression rates of hypnotic action were prepared and used as combined preparations (PTP packaging).
[General cold drug-11] Taken twice in the morning and noon 4 capsules 4 capsules Acetaminophen 300 mg
Ethenzamid 500 mg
Diphenylpyraline hydrochloride 2.66 mg
Dihydrocodeine phosphate 16 mg
dl-methylephedrine hydrochloride 40 mg
Potassium guaiacol sulfonate 100 mg
Anhydrous caffeine 50 mg
[General cold drug-12] Taken once a night 2 capsules 2 capsules Acetaminophen 150 mg
Ethenzamid 250 mg
Diphenhydramine hydrochloride 25 mg
Dihydrocodeine phosphate 8 mg
dl-methylephedrine hydrochloride 20 mg
Potassium guaiacol sulfonate 50 mg
催眠作用の発現割合の異なる塩酸ジフェニルピラリン、塩酸トンジルアミンを夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−１３] 朝１回服用 ３錠 ３錠中
アセトアミノフェン ４５０ ｍｇ
塩酸ジフェニルピラリン ２ ｍｇ
リン酸ジヒドロコデイン １２ ｍｇ
ｄｌ−塩酸メチルエフェドリン ３０ ｍｇ
無水カフェイン ５０ ｍｇ
ビタミンＣ ５０ ｍｇ
[総合感冒薬−１４] 夜１回服用 ３錠 ３錠中
アセトアミノフェン ４５０ ｍｇ
塩酸トンジルアミン ２５ ｍｇ
リン酸ジヒドロコデイン １２ ｍｇ
ｄｌ−塩酸メチルエフェドリン ３０ ｍｇ
ビタミンＣ ５０ ｍｇ
The following two types of common cold drugs (tablets) formulated with diphenylpyraline hydrochloride and tonsilamine hydrochloride with different expression rates of hypnotic action were prepared as combined preparations (PTP packaging).
[General cold medicine -13] Acetaminophen 450 mg taken in the morning 3 tablets 3 tablets
Diphenylpyraline hydrochloride 2 mg
Dihydrocodeine phosphate 12 mg
dl-Methylephedrine hydrochloride 30 mg
Anhydrous caffeine 50 mg
Vitamin C 50 mg
[General cold drug-14] Taken once a night 3 tablets 3 tablets Acetaminophen 450 mg
Tonsilamine hydrochloride 25 mg
Dihydrocodeine phosphate 12 mg
dl-Methylephedrine hydrochloride 30 mg
Vitamin C 50 mg
催眠作用の発現割合の異なるナパジシル酸メブヒドロリン、フマル酸クレマスチンを夫々処方した以下の２種の総合感冒薬（散剤）を作製し、組み合わせ製剤（小袋）とした。
[総合感冒薬−１５] 朝、昼として２回服用 ２包 ２包中
イソプロピルアンチピリン ２００ ｍｇ
アセトアミノフェン ３００ ｍｇ
ナパジジル酸メブヒドロリン １００ ｍｇ
フェンジゾ酸クロペラスチン ５６ ｍｇ
ノスカピン ３６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
セミアルカリプロティナーゼ ２０ ｍｇ
無水カフェイン ５０ ｍｇ
硝酸チアミン １６ ｍｇ
リボフラビン ８ ｍｇ
ニンジン乾燥エキス ６７ ｍｇ
[総合感冒薬−１６] 夜１回服用 １包 １包中
イソプロピルアンチピリン １００ ｍｇ
アセトアミノフェン １５０ ｍｇ
フマル酸クレマスチン ０．４４ ｍｇ
フェンジゾ酸クロペラスチン ２８ ｍｇ
ノスカピン １２ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
セミアルカリプロティナーゼ １０ ｍｇ
硝酸チアミン ８ ｍｇ
リボフラビン ４ ｍｇ
ニンジン乾燥エキス ３３ ｍｇ
The following two types of general cold medicine (powder), each formulated with mebhydroline napadisylate and clemastine fumarate with different expression rates of hypnotic action, were prepared as combined preparations (sachets).
[General cold medicine -15] Take twice a day in the morning and noon 2 capsules 2 capsules Isopropylantipyrine 200 mg
Acetaminophen 300 mg
Mebhydroline napadidylate 100 mg
Fendizoic acid cloperastine 56 mg
Noscapine 36 mg
dl-methylephedrine hydrochloride 40 mg
Semi-alkaline proteinase 20 mg
Anhydrous caffeine 50 mg
Thiamine nitrate 16 mg
Riboflavin 8 mg
Carrot dry extract 67 mg
[General cold medicine-16] Take once a night 1 packet 1 package Isopropylantipyrine 100 mg
Acetaminophen 150 mg
Cremastine fumarate 0.44 mg
Fendizoic acid cloperastine 28 mg
Noscapine 12 mg
dl-methylephedrine hydrochloride 20 mg
Semi-alkaline proteinase 10 mg
Thiamine nitrate 8 mg
Riboflavin 4 mg
Carrot dry extract 33 mg
催眠作用の発現割合の異なる塩酸トンジルアミン、プロメタジンメチレン二サリチル酸塩を夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−１７] 朝、昼として２回服用 ６錠 ６錠中
アセトアミノフェン ６００ ｍｇ
塩酸トンジルアミン ３３．３ ｍｇ
リン酸ジメモルファン ２０ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
セミアルカリプロティナーゼ １０ ｍｇ
無水カフェイン ５０ ｍｇ
アスコルビン酸 １６６ ｍｇ
[総合感冒薬−１８] 夜１回服用 ３錠 ３錠中
アセトアミノフェン ３００ ｍｇ
プロメタジンメチレン二サリチル酸塩 １３．３ ｍｇ
リン酸ジメモルファン １０ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
セミアルカリプロティナーゼ ５ ｍｇ
アスコルビン酸 ８４ ｍｇ
The following two types of common cold medicines (tablets) formulated with tonsilamine hydrochloride and promethazine methylene disalicylate with different expression rates of hypnotic action were prepared as combined preparations (PTP packaging).
[General cold drug-17] Taken twice in the morning and noon 6 tablets 6 tablets Acetaminophen 600 mg
Tonsilamine hydrochloride 33.3 mg
Dimemorphan phosphate 20 mg
dl-methylephedrine hydrochloride 40 mg
Semi-alkaline proteinase 10 mg
Anhydrous caffeine 50 mg
Ascorbic acid 166 mg
[General cold drug-18] Taken once a night 3 tablets 3 tablets Acetaminophen 300 mg
Promethazine methylene disalicylate 13.3 mg
Dimemorphan phosphate 10 mg
dl-methylephedrine hydrochloride 20 mg
Semi-alkaline proteinase 5 mg
Ascorbic acid 84 mg
催眠作用の発現割合の異なる塩酸メトジラジン、塩酸イソチペンジルを夫々処方した以下の２種の総合感冒薬（カプセル剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−１９] 朝、昼として２回服用 ４カプセル ４カプセル中
アセトアミノフェン ４８０ ｍｇ
塩酸メトジラジン ５．３ ｍｇ
ノスカピン ２０ ｍｇ
無水カフェイン ５０ ｍｇ
合成ケイ酸アルミニウム ４００ ｍｇ
葛根湯乾燥エキス ５５６ ｍｇ
[総合感冒薬−２０] 夜１回服用 ２カプセル ２カプセル中
アセトアミノフェン ２４０ ｍｇ
塩酸メトジラジン ２．３ ｍｇ
ノスカピン １０ ｍｇ
合成ケイ酸アルミニウム ２００ ｍｇ
葛根湯乾燥エキス ２７８ ｍｇ
The following two types of common cold medicines (capsules) formulated with methodirazin hydrochloride and isothipenzil hydrochloride with different expression rates of hypnotic action were prepared and used as combined preparations (PTP packaging).
[General cold drug-19] Taken twice in the morning and noon 4 capsules 4 capsules Acetaminophen 480 mg
Metodirazine hydrochloride 5.3 mg
Noscapine 20 mg
Anhydrous caffeine 50 mg
Synthetic aluminum silicate 400 mg
Kakkonto dried extract 556 mg
[General cold medicine-20] Taken once a night 2 capsules 2 capsules Acetaminophen 240 mg
Metodirazine hydrochloride 2.3 mg
Noscapine 10 mg
Synthetic aluminum silicate 200 mg
Kakkonto dry extract 278 mg
催眠作用の発現割合の異なるマレイン酸カルビノキサミン、塩酸ジフェンヒドラミンを夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−２１] 朝、昼として２回服用 ４錠 ４錠中
アセトアミノフェン ６００ ｍｇ
マレイン酸カルビノキサミン ５ ｍｇ
リン酸ジヒドロコデイン １６ ｍｇ
ノスカピン ２４ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
グアヤコールスルホン酸カリウム １６０ ｍｇ
無水カフェイン ５０ ｍｇ
塩化リゾチーム ４０ ｍｇ
[総合感冒薬−２２] 夜１回服用 ２錠 ２錠中
アセトアミノフェン ３００ ｍｇ
塩酸ジフェンヒドラミン ２５ ｍｇ
リン酸ジヒドロコデイン ８ ｍｇ
ノスカピン １２ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
グアヤコールスルホン酸カリウム ８０ ｍｇ
塩化リゾチーム ２０ ｍｇ
The following two types of general cold medicines (tablets) formulated with carbinoxamine maleate and diphenhydramine hydrochloride with different expression rates of hypnotic action were prepared as combined preparations (PTP packaging).
[General cold medicine-21] Taken twice a day in the morning and noon 4 tablets Acetaminophen 600 mg in 4 tablets
Carbinoxamine maleate 5 mg
Dihydrocodeine phosphate 16 mg
Noscapine 24 mg
dl-methylephedrine hydrochloride 40 mg
Potassium guaiacol sulfonate 160 mg
Anhydrous caffeine 50 mg
Lysozyme chloride 40 mg
[General cold medicine-22] Taken once a night 2 tablets 2 tablets Acetaminophen 300 mg
Diphenhydramine hydrochloride 25 mg
Dihydrocodeine phosphate 8 mg
Noscapine 12 mg
dl-methylephedrine hydrochloride 20 mg
Potassium guaiacol sulfonate 80 mg
Lysozyme chloride 20 mg
催眠作用の発現割合の異なるプロメタジンメチレン二サリチル酸塩、塩酸ジフェンヒドラミンを夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−２３] 朝、昼として２回服用 ６錠 ６錠中
イブプロフェン ３００ ｍｇ
プロメタジンメチレン二サリチル酸塩 ２６．６ ｍｇ
リン酸ジヒドロコデイン １６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
無水カフェイン ５０ ｍｇ
硝酸チアミン（ビタミンＢ１） １６ ｍｇ
アスコルビン酸（ビタミンＣ） ２００ ｍｇ
[総合感冒薬−２４] 夜１回服用 ３錠 ３錠中
イブプロフェン １５０ ｍｇ
塩酸ジフェンヒドラミン ２５ ｍｇ
リン酸ジヒドロコデイン ８ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
硝酸チアミン（ビタミンＢ１） ８ ｍｇ
アスコルビン酸（ビタミンＣ） １００ ｍｇ
The following two types of general cold medicines (tablets) formulated with promethazine methylene disalicylate and diphenhydramine hydrochloride with different expression rates of hypnotic action were prepared and used as combined preparations (PTP packaging).
[General cold drug-23] Take twice a day in the morning and noon 6 tablets 6 tablets Of ibuprofen 300 mg
Promethazine methylene disalicylate 26.6 mg
Dihydrocodeine phosphate 16 mg
dl-methylephedrine hydrochloride 40 mg
Anhydrous caffeine 50 mg
Thiamine nitrate (vitamin B1) 16 mg
Ascorbic acid (vitamin C) 200 mg
[General cold medicine -24] Take once a night 3 tablets 3 tablets 3 tablets ibuprofen 150 mg
Diphenhydramine hydrochloride 25 mg
Dihydrocodeine phosphate 8 mg
dl-methylephedrine hydrochloride 20 mg
Thiamine nitrate (vitamin B1) 8 mg
Ascorbic acid (vitamin C) 100 mg
催眠作用の発現割合の異なる塩酸ジフェニルピラリン、塩酸ジフェンヒドラミンを夫々処方した以下の２種の総合感冒薬（錠剤）を作製し、組み合わせ製剤（ＰＴＰ包装）とした。
[総合感冒薬−２５] 朝、昼として２回服用 ４錠 ４錠中
イブプロフェン ３００ ｍｇ
塩酸ジフェニルピラリン ２．６ ｍｇ
塩酸ブロムヘキシン ８ ｍｇ
塩化リゾチーム ４０ ｍｇ
臭化水素酸デキストロメトルファン ３２ ｍｇ
ｄｌ−塩酸メチルエフェドリン ４０ ｍｇ
無水カフェイン ５０ ｍｇ
[総合感冒薬−２６] 夜１回服用 ２錠 ２錠中
イブプロフェン １５０ ｍｇ
塩酸ジフェンヒドラミン ２５ ｍｇ
塩酸ブロムヘキシン ４ ｍｇ
塩化リゾチーム ２０ ｍｇ
臭化水素酸デキストロメトルファン １６ ｍｇ
ｄｌ−塩酸メチルエフェドリン ２０ ｍｇ
The following two types of common cold medicines (tablets) formulated with diphenylpyraline hydrochloride and diphenhydramine hydrochloride with different expression rates of hypnotic action were prepared and used as combined preparations (PTP packaging).
[Comprehensive cold medicine-25] Taken twice in the morning and noon 4 tablets 4 tablets Of ibuprofen 300 mg
Diphenylpyraline hydrochloride 2.6 mg
Bromohexine hydrochloride 8 mg
Lysozyme chloride 40 mg
Dextromethorphan hydrobromide 32 mg
dl-methylephedrine hydrochloride 40 mg
Anhydrous caffeine 50 mg
[General cold medicine -26] Take once a night 2 tablets 2 tablets Ibuprofen 150 mg
Diphenhydramine hydrochloride 25 mg
Bromohexine hydrochloride 4 mg
Lysozyme chloride 20 mg
Dextromethorphan hydrobromide 16 mg
dl-methylephedrine hydrochloride 20 mg
実施例１〜１３の総合感冒薬組み合わせ製剤を服用した被験者（夫々の総合感冒薬組み合わせ製剤について男３名、女３名、年齢２３〜２９、健康状態；感冒初期）は、第一の総合感冒薬（朝又は昼用の総合感冒薬）について、催眠作用の少ない抗ヒスタミン剤により眠気を感じることなく又は少なく愁訴が抑えられた、との結果が得られた。一方、第２の総合感冒薬（夜用の総合感冒薬）について、催眠作用の多い抗ヒスタミン剤により夕方から就寝前の愁訴からの安静が得られ、愁訴による睡眠導入障害、熟眠度の低下を抑制し、安眠を得ることができた、との結果が得られた。従って、第一の総合感冒薬により、催眠作用による仕事、学業への支障を最小限に抑えることができ、また、第２の総合感冒薬により、夜間に十分な睡眠が得られたことにより、翌日の朝、昼に眠気を感じることなく又は少なくなる効果も得られた。このように、第一の総合感冒薬と第２の総合感冒薬を朝又は昼、及び、夜又は就寝前という状況に応じ使い分けることにより、感冒治療をしながらのＱＯＬの向上が得られ、安静・安眠によりかぜ症候群からの早い回復をした。 The subjects who took the general cold medicine combination preparations of Examples 1 to 13 (three males, three females, ages 23 to 29, health condition; early cold) for each common cold medicine combination preparation, As for the medicine (the common cold medicine for morning or noon), the results showed that complaints were suppressed without feeling drowsiness or with an antihistamine with little hypnotic action. On the other hand, the second general cold medicine (night-time common cold medicine) has a resting from complaints before going to bed from the evening by antihistamines with a lot of hypnotic action, and suppresses sleep induction disorder due to complaints and decrease in deep sleep. I was able to get a good night's sleep. Therefore, the first general cold medicine can minimize the troubles to work and academic work due to hypnotic action, and the second general cold medicine has obtained sufficient sleep at night, There was also an effect that the next day morning, no sleepiness was felt at noon or less. In this way, by using the first common cold medicine and the second common cold medicine according to the situation of morning or noon and at night or before going to bed, an improvement in QOL can be obtained while treating colds.・ We recovered quickly from cold syndrome by sleeping well.
以上のように、本発明の総合感冒薬組み合わせ製剤は、従来の総合感冒薬に比べて、感冒の治療方針に従い安静・安眠が得られやすく、及び治療をしながらのＱＯＬの向上を計ることが出来る利点がある。 As described above, the general cold medicine combination preparation of the present invention is more likely to provide rest and sleep according to the treatment policy of the common cold than conventional general cold medicines, and can improve QOL while being treated. There are advantages that can be made.
Claims (21)
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| JP2011132226A (en) * | 2009-11-27 | 2011-07-07 | Kowa Co | Loxoprofen-containing medicinal composition and medicinal preparation containing the composition |
| JP2013075892A (en) * | 2011-09-14 | 2013-04-25 | Daiichi Sankyo Healthcare Co Ltd | Anti-inflammatory and / or antihistamine composition |
| WO2016130094A1 (en) * | 2015-02-10 | 2016-08-18 | PHARMACTlVE ILAÇ SANAYI VE TlCARET A.Ş. | A pharmaceutical composition containing ibuprofen, pseudoephedrine and vitamin c |
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| US10751331B2 (en) | 2009-10-26 | 2020-08-25 | Sephoris Pharmaceuticals, Llc | Treatment of sunburn using analgesics and antihistamines |
| EP2853262B1 (en) * | 2009-10-26 | 2016-11-30 | Sephoris Pharmaceuticals, LLC | Treatment of sunburn using analgesics and antihistamines |
| US9895360B2 (en) | 2009-10-26 | 2018-02-20 | Sephoris Pharmaceuticals, Llc | Treatment of sunburn using analgesics and antihistamines |
| JP2015157866A (en) * | 2009-11-27 | 2015-09-03 | 興和株式会社 | Loxoprofen-containing composition |
| JP2011132226A (en) * | 2009-11-27 | 2011-07-07 | Kowa Co | Loxoprofen-containing medicinal composition and medicinal preparation containing the composition |
| JP2013075892A (en) * | 2011-09-14 | 2013-04-25 | Daiichi Sankyo Healthcare Co Ltd | Anti-inflammatory and / or antihistamine composition |
| WO2016130094A1 (en) * | 2015-02-10 | 2016-08-18 | PHARMACTlVE ILAÇ SANAYI VE TlCARET A.Ş. | A pharmaceutical composition containing ibuprofen, pseudoephedrine and vitamin c |
| JP2019214562A (en) * | 2018-06-08 | 2019-12-19 | シオノギヘルスケア株式会社 | Solid composition having improved light stability |
| JP7285040B2 (en) | 2018-06-08 | 2023-06-01 | シオノギヘルスケア株式会社 | Solid composition with improved photostability |
| JP2021075528A (en) * | 2019-11-07 | 2021-05-20 | 武田コンシューマーヘルスケア株式会社 | Pharmaceutical composition |
| JP7673337B2 (en) | 2019-11-07 | 2025-05-09 | アリナミン製薬株式会社 | Pharmaceutical Compositions |
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| US12138243B2 (en) | 2021-12-31 | 2024-11-12 | Crescenta Biosciences | Antiviral use of FABP4 modulating compounds |
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