JP2015172093A - Pharmaceutical composition containing loxoprofen or salt thereof - Google Patents
Pharmaceutical composition containing loxoprofen or salt thereof Download PDFInfo
- Publication number
- JP2015172093A JP2015172093A JP2015136059A JP2015136059A JP2015172093A JP 2015172093 A JP2015172093 A JP 2015172093A JP 2015136059 A JP2015136059 A JP 2015136059A JP 2015136059 A JP2015136059 A JP 2015136059A JP 2015172093 A JP2015172093 A JP 2015172093A
- Authority
- JP
- Japan
- Prior art keywords
- salt
- loxoprofen
- pharmaceutical composition
- hydrochloride
- taken
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 204
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 title claims abstract description 128
- 229960002373 loxoprofen Drugs 0.000 title claims abstract description 126
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 81
- 239000000739 antihistaminic agent Substances 0.000 claims abstract description 79
- 230000001387 anti-histamine Effects 0.000 claims abstract description 74
- 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 abstract description 73
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims abstract description 42
- 229960003291 chlorphenamine Drugs 0.000 claims abstract description 26
- 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 abstract description 26
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims abstract description 24
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- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims abstract description 4
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- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 13
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- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 9
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- LPRLDRXGWKXRMQ-UHFFFAOYSA-N diphenylpyraline hydrochloride Chemical compound [Cl-].C1C[NH+](C)CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 LPRLDRXGWKXRMQ-UHFFFAOYSA-N 0.000 description 8
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- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 6
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本発明は、ロキソプロフェン又はその塩を含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof.
ロキソプロフェン又はその塩は、非ステロイド性消炎鎮痛剤(NSAID)の一種であり、関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩腕症候群、歯痛、急性上気道炎、手術後・外傷後・抜歯後等の消炎・鎮痛・解熱に有効なものとして知られている(非特許文献1)。 Loxoprofen or its salt is a kind of non-steroidal anti-inflammatory analgesic (NSAID), rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, neck-shoulder arm syndrome, toothache, acute upper respiratory tract inflammation, after surgery It is known as effective for anti-inflammatory, analgesic and antipyretic after trauma and tooth extraction (Non-patent Document 1).
一方、抗ヒスタミン剤としては、アゼラスチン塩酸塩、アリメマジン酒石酸塩、イソチペンジル塩酸塩、イプロヘプチン塩酸塩、エバスチン、エピナスチン塩酸塩、エメダスチンフマル酸塩、オキサトミド、オロパタジン塩酸塩、カルビノキサミンジフェニルジスルホン酸塩、カルビノキサミンマレイン酸塩、クレマスチンフマル酸塩、クロルフェニラミンマレイン酸塩、ケトチフェンフマル酸塩、ジフェテロール塩酸塩、ジフェテロールリン酸塩、ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩、ジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩、ジフェンヒドラミンタンニン酸塩、シプロヘプタジン塩酸塩水和物、セチリジン塩酸塩、トリプロリジン塩酸塩、トリペレナミン塩酸塩、トンジルアミン塩酸塩、フェキソフェナジン、フェネタジン塩酸塩、プロメタジン塩酸塩、プロメタジンメチレン二サリチル酸塩、ベポタスチンベシル酸塩、ホモクロルシクリジン塩酸塩、メキタジン、メトジラジン塩酸塩、メブヒドロリンナパジシル酸塩、ロラタジン等が知られ、これらは抗ヒスタミン作用に基づく抗アレルギー薬や抗ヒスタミン成分として、総合感冒薬や鼻炎用内服薬等に用いられている薬物である(非特許文献2)。
また、エフェドリン類は、交感神経興奮作用に基づく気管支拡張作用により、鎮咳効果をもたらすことが知られている。このため、鎮咳成分として、総合感冒薬、鎮咳去痰薬に配合され、また、血管収縮作用による鼻づまりの緩和を目的として鼻炎用内服薬等に配合される薬物である(非特許文献3及び4)。
On the other hand, antihistamines include azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine diphenyldisulfonate, carbibi Noxamine maleate, clemastine fumarate, chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocluic acid salt, diphenhydramine hydrochloride, Diphenhydramine salicylate, diphenhydramine tannate, cyproheptadine hydrochloride hydrate, cetirizine hydrochloride, triprolyzine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, Exophenazine, phenetadine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besylate, homochlorcyclidine hydrochloride, mequitazine, methodirazine hydrochloride, mebhydrolinapadisilate, loratadine, etc. These are known drugs that are used in general cold medicines, oral rhinitis drugs, etc. as antiallergic drugs and antihistamine components based on antihistamine action (Non-patent Document 2).
In addition, ephedrines are known to have an antitussive effect by bronchodilating action based on sympathomimetic action. For this reason, it is a drug compounded in general cold medicine and antitussive expectorant as an antitussive component, and in a rhinitis drug for the purpose of alleviating nasal congestion due to vasoconstriction (Non-patent Documents 3 and 4).
ロキソプロフェン又はその塩は、その優れた薬理作用から、様々な薬物と組合わせることが検討されている。当該組み合わせにより得られる作用としては、例えば、カフェイン、エテンザミドやアセトアミノフェンと組合わせることによる消炎・鎮痛・解熱効果の増強作用(特許文献1)、ブロムヘキシン塩酸塩やアンブロキソール塩酸塩と組合わせることによる咳嗽症状に対する効果の増強作用(特許文献2)及び杯細胞過形成抑制作用(特許文献3)等が知られている。 Loxoprofen or a salt thereof has been studied for combining with various drugs because of its excellent pharmacological action. The action obtained by the combination includes, for example, an action of enhancing anti-inflammatory, analgesic and antipyretic effects by combining with caffeine, ethenamide and acetaminophen (Patent Document 1), and a combination with bromhexine hydrochloride and ambroxol hydrochloride. A potentiating effect on cough symptoms by combining them (Patent Document 2) and an inhibitory effect on goblet cell hyperplasia (Patent Document 3) are known.
そして、ロキソプロフェン又はその塩と抗ヒスタミン剤の2成分の組合わせ、及びロキソプロフェン又はその塩とエフェドリン類の2成分の組合わせも既に知られている。
ロキソプロフェン又はその塩と抗ヒスタミン剤の2成分の組合わせによる作用については、具体的には、ロキソプロフェンと、エピナスチン塩酸塩、カルビノキサミンマレイン酸塩、クロルフェニラミンマレイン酸塩、ケトチフェンフマル酸塩やメキタジンとを組合わせることによる鼻閉症状の改善作用(特許文献4)、ロキソプロフェンと、アゼラスチン塩酸塩やメキタジンとを組み合わせることによる杯細胞過形成抑制作用(特許文献5)、ロキソプロフェンと、カルビノキサミンマレイン酸塩やクロルフェニラミンマレイン酸塩とを組合わせることによる鎮痛作用の増強作用、ロキソプロフェンと、カルビノキサミンマレイン酸塩とを組合わせることによる抗炎症作用及び解熱作用の増強作用、ロキソプロフェンと、クレマスチンフマル酸塩やクロルフェニラミンマレイン酸塩とを組合わせることによる抗ヒスタミン作用の増強作用(特許文献6)が知られている。
また、ロキソプロフェン又はその塩とエフェドリン類の2成分の組合わせによる作用については、具体的には、ロキソプロフェンとdl−メチルエフェドリン塩酸塩とを組合わせることによる抗炎症作用及び解熱作用の増強作用(特許文献6)、ロキソプロフェンとプソイドエフェドリンとを組合わせることによる抗くしゃみ作用の増強作用(特許文献7)、ロキソプロフェンとメチルエフェドリン塩酸塩とを組合わせることによる気道杯細胞過形成抑制作用(特許文献8)が知られている。
A combination of two components of loxoprofen or a salt thereof and an antihistamine, and a combination of two components of loxoprofen or a salt thereof and ephedrine are already known.
Regarding the action of the combination of loxoprofen or a salt thereof and an antihistamine, specifically, with loxoprofen, epinastine hydrochloride, carbinoxamine maleate, chlorpheniramine maleate, ketotifen fumarate and mequitazine For improving nasal obstruction symptoms (PTL 4), combination of loxoprofen with azelastine hydrochloride and mequitazine (PTL 5), loxoprofen and carbinoxamine maleic acid Increased analgesic effect by combining salt and chlorpheniramine maleate, anti-inflammatory and antipyretic effect by combining loxoprofen and carbinoxamine maleate, loxoprofen and clemastine fuma Potentiation of antihistaminic action by combining the salt and chlorpheniramine maleate (Patent Document 6) are known.
In addition, as for the action of the combination of loxoprofen or a salt thereof and ephedrines, specifically, the anti-inflammatory action and antipyretic action enhancing action by combining loxoprofen and dl-methylephedrine hydrochloride (patent) Literature 6), anti-sneezing action enhancement effect by combining loxoprofen and pseudoephedrine (Patent Document 7), airway goblet cell hyperplasia inhibitory action by combining loxoprofen and methylephedrine hydrochloride (Patent Document 8) Are known.
しかしながら、ロキソプロフェン又はその塩、抗ヒスタミン剤、及びエフェドリン類を含有する医薬組成物については全く知られていない。 However, there is no known pharmaceutical composition containing loxoprofen or a salt thereof, an antihistamine, and ephedrines.
本発明の課題は、優れた薬理作用を有する医薬組成物の提供にある。 The subject of this invention is providing the pharmaceutical composition which has the outstanding pharmacological action.
そこで、本発明者は、鋭意検討したところ、ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類の3成分の組み合わせが、格別に優れた鎮痛作用や解熱作用等の薬理作用を示し、医薬として有用であることを見出した。 Therefore, the present inventor has intensively studied, and that the combination of loxoprofen or a salt thereof, an antihistamine and ephedrines has a particularly excellent pharmacological action such as analgesic action and antipyretic action, and is useful as a medicine. I found.
すなわち、本発明は、ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する医薬組成物を提供するものである。 That is, the present invention provides a pharmaceutical composition containing loxoprofen or a salt thereof, an antihistamine, and ephedrines.
ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類の3成分を併用すると、優れた鎮痛作用及び/又は解熱作用が奏される。従って、本発明によれば、優れた薬理作用を有する医薬組成物を提供することができる。
また、抗ヒスタミン剤及び/又はエフェドリン類は、ロキソプロフェン又はその塩に起因する消化管障害に対して抑制作用を有する。
従って、本発明によれば、優れた薬理作用を有し、ロキソプロフェン又はその塩に起因する消化管障害が抑制された安全性に優れる医薬組成物を提供することができる。
When three components of loxoprofen or a salt thereof, an antihistamine and ephedrines are used in combination, an excellent analgesic action and / or antipyretic action is exhibited. Therefore, according to the present invention, a pharmaceutical composition having an excellent pharmacological action can be provided.
In addition, antihistamines and / or ephedrines have an inhibitory action against gastrointestinal disorders caused by loxoprofen or a salt thereof.
Therefore, according to the present invention, it is possible to provide a pharmaceutical composition having excellent pharmacological action and excellent safety in which gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed.
本発明の医薬組成物は、ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する。まず、ロキソプロフェン又はその塩について説明する。
本発明の医薬組成物に用いられる「ロキソプロフェン又はその塩」には、ロキソプロフェンのみならず、ロキソプロフェンの薬学上許容される塩、さらにはロキソプロフェンやその薬学上許容される塩と水やアルコール等との溶媒和物が含まれる。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。本発明において、ロキソプロフェン又はその塩としては、ロキソプロフェンナトリウム水和物(化学名:Monosodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate dihydrate)が好ましい。
The pharmaceutical composition of the present invention contains loxoprofen or a salt thereof, an antihistamine, and ephedrines. First, loxoprofen or a salt thereof will be described.
“Loxoprofen or a salt thereof” used in the pharmaceutical composition of the present invention includes not only loxoprofen, but also a pharmaceutically acceptable salt of loxoprofen, and further, loxoprofen or a pharmaceutically acceptable salt thereof and water, alcohol, etc. Solvates are included. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).
本発明の医薬組成物におけるロキソプロフェン又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、1日あたり、ロキソプロフェンナトリウム無水物換算で10〜300mg、より好適には30〜240mg、特に好適には60〜180mg服用できる量を含有せしめることができる。本発明においては、ロキソプロフェン又はその塩を医薬組成物全質量に対して、ロキソプロフェン無水物換算で0.4〜50質量%含有するのが好ましく、0.8〜25質量%含有するのがより好ましく、1.2〜20質量%含有するのがさらに好ましく、1.6〜15質量%含有するのがさらに好ましく、2.0〜12質量%含有するのが特に好ましい。 The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 10 to 300 mg, more preferably 30 to 240 mg, particularly preferably 60 to 180 mg in terms of loxoprofen sodium anhydride can be contained per day. In the present invention, loxoprofen or a salt thereof is preferably contained in an amount of 0.4 to 50% by mass, more preferably 0.8 to 25% by mass in terms of anhydrous loxoprofen, relative to the total mass of the pharmaceutical composition. 1.2 to 20% by mass is more preferable, 1.6 to 15% by mass is more preferable, and 2.0 to 12% by mass is particularly preferable.
次に、本発明で用いる抗ヒスタミン剤について、詳細に説明する。
本発明の医薬組成物に用いられる「抗ヒスタミン剤」としては、ヒスタミンH1受容体拮抗作用を有するものであれば特に限定されるものではなく、具体的には例えば、アゼラスチン、アリメマジン、イソチペンジル、イプロヘプチン、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、カルビノキサミン、クレマスチン、クロルフェニラミン、ケトチフェン、ジフェテロール、ジフェニルピラリン、ジフェンヒドラミン、シプロヘプタジン、セチリジン、トリプロリジン、トリペレナミン、トンジルアミン、フェキソフェナジン、フェネタジン、プロメタジン、ベポタスチン、ホモクロルシクリジン、メキタジン、メトジラジン、メブヒドロリン及びロラタジン並びにこれらの塩からなる群より選ばれる1種以上が挙げられる。なお、塩としては、無機酸や有機酸、無機塩基や有機塩基等との塩が挙げられ、例えば、塩酸塩、酒石酸塩、マレイン酸塩、フマル酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、サリチル酸塩、タンニン酸塩、ベシル酸塩、ナパジシル酸塩、リン酸塩等が挙げられる。また、抗ヒスタミン剤の化学構造中、不斉炭素が存する場合は、種々の光学異性体を有するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。さらに、抗ヒスタミン剤は溶媒和物の状態にあってもよく、上記各種化合物やその塩と水やアルコール等との溶媒和物も「抗ヒスタミン剤」に含まれる(従って、「各種化合物又はその塩」には、当該化合物やその塩の溶媒和物も包含される。)。
上述の抗ヒスタミン剤は、公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。
Next, the antihistamine used in the present invention will be described in detail.
The “antihistamine” used in the pharmaceutical composition of the present invention is not particularly limited as long as it has a histamine H 1 receptor antagonistic action, and specifically includes, for example, azelastine, alimemazine, isotipezil, iproheptin, Ebastine, epinastine, emedastine, oxatomide, olopatadine, carbinoxamine, clemastine, chlorpheniramine, ketotifen, dipheterol, diphenylpyraline, diphenhydramine, cyproheptadine, cetirizine, triprolidine, tripelenamine, tondylamine, fexofenadine, pronetoporazine, At least one selected from the group consisting of cyclidine, mequitazine, methodirazine, mebuhydroline, loratadine and salts thereof; It is below. Examples of the salt include salts with inorganic acids, organic acids, inorganic bases, organic bases, etc., for example, hydrochloride, tartrate, maleate, fumarate, diphenyldisulfonate, teocrate, Examples include salicylate, tannate, besylate, napadisylate, phosphate, and the like. In the chemical structure of the antihistamine, when an asymmetric carbon exists, it has various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. It may be a mixture of isomers. Further, the antihistamine may be in the form of a solvate, and solvates of the above-mentioned various compounds and salts thereof with water, alcohol, etc. are also included in the “antihistamine” (therefore, “various compounds or salts thereof” And solvates of the compounds and salts thereof).
The above-mentioned antihistamine is a known compound and can be produced by a known method, or a commercially available product can be used.
本発明に用いられる抗ヒスタミン剤としては、アゼラスチン塩酸塩等のアゼラスチン又はその塩;アリメマジン酒石酸塩等のアリメマジン又はその塩;イソチペンジル塩酸塩等のイソチペンジル又はその塩;イプロヘプチン塩酸塩等のイプロへプチン又はその塩;エバスチン又はその塩;エピナスチン塩酸塩等のエピナスチン又はその塩;エメダスチンフマル酸塩等のエメダスチン又はその塩;オキサトミド又はその塩;オロパタジン塩酸塩等のオロパタジン又はその塩;カルビノキサミンジフェニルジスルホン酸塩、カルビノキサミンマレイン酸塩等のカルビノキサミン又はその塩;クレマスチンフマル酸塩等のクレマスチン又はその塩;d−クロルフェニラミンマレイン酸塩、dl−クロルフェニラミンマレイン酸塩等のクロルフェニラミン又はその塩;ケトチフェンフマル酸塩等のケトチフェン又はその塩;ジフェテロール塩酸塩、ジフェテロールリン酸塩等のジフェテロール又はその塩;ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩等のジフェニルピラリン又はその塩;ジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩、ジフェンヒドラミンタンニン酸塩等のジフェンヒドラミン又はその塩;シプロヘプタジン塩酸塩水和物等のシプロヘプタジン又はその塩;セチリジン塩酸塩等のセチリジン又はその塩;トリプロリジン塩酸塩等のトリプロリジン又はその塩;トリペレナミン塩酸塩等のトリペレナミン又はその塩;トンジルアミン塩酸塩等のトンジルアミン又はその塩;フェキソフェナジン又はその塩;フェネタジン塩酸塩等のフェネタジン又はその塩;プロメタジン塩酸塩、プロメタジンメチレン二サリチル酸塩等のプロメタジン又はその塩;ベポタスチンベシル酸塩等のベポタスチン又はその塩;ホモクロルシクリジン塩酸塩等のホモクロルシクリジン又はその塩;メキタジン又はその塩;メトジラジン塩酸塩等のメトジラジン又はその塩;メブヒドロリンナパジシル酸塩等のメブヒドロリン又はその塩;ロラタジン又はその塩等が好ましい。 Examples of the antihistamine used in the present invention include azelastine such as azelastine hydrochloride or a salt thereof; alimemazine such as alimemazine tartrate or a salt thereof; istipendil or a salt thereof such as istipendil hydrochloride; iproheptin such as iproheptin hydrochloride or a salt thereof Evastin or a salt thereof; Epinastine or a salt thereof such as epinastine hydrochloride; Emedastine or a salt thereof such as emedastine fumarate; Oxatamide or a salt thereof; Olopatadine such as olopatadine hydrochloride or a salt thereof; Carbinoxamine diphenyldisulfonic acid Salt, carbinoxamine such as carbinoxamine maleate or the salt thereof; clemastine such as clemastine fumarate or the salt thereof; chlorphenilla such as d-chlorpheniramine maleate, dl-chlorpheniramine maleate Ketotifen such as ketotifen fumarate or salt thereof; Dipheterol such as difeterol hydrochloride or difeterol phosphate or salt thereof; Diphenylpyraline such as diphenylpyraline hydrochloride or diphenylpyraline theoclurate or the like Salt; diphenhydramine such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate or the salt thereof; cyproheptazine or salt thereof such as cyproheptadine hydrochloride hydrate; cetirizine such as cetirizine hydrochloride or salt thereof; Lysine or salt thereof; tripelenamine or salt thereof such as tripelenamine hydrochloride; tonsilamine or salt thereof such as tonsilamine hydrochloride; fexofenadine or salt thereof; phenetadine such as phenetadine hydrochloride Or a salt thereof; promethazine such as promethazine hydrochloride or promethazine methylene disalicylate or a salt thereof; bepotastine or a salt thereof such as bepotastine besylate; a homochlorcyclidine such as a homochlorcyclidine hydrochloride or a salt thereof; mequitazine Or a salt thereof; methodirazine such as methodirazine hydrochloride or a salt thereof; mebhydroline such as mebhydroline napadisilate or a salt thereof; loratadine or a salt thereof is preferable.
本発明の医薬組成物における抗ヒスタミン剤の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、1日あたり、抗ヒスタミン剤を0.01〜400mg、より好適には0.03〜300mg、特に好適には0.1〜200mg服用できる量を含有せしめることができる。なお、抗ヒスタミン剤として具体的な成分を用いる場合における好適な含有量を以下に例示するが、本発明は何らこれに限定されるものではない。 The content of the antihistamine in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 0.01 to 400 mg, more preferably 0.03 to 300 mg, and particularly preferably 0.1 to 200 mg of an antihistamine can be contained per day. In addition, although suitable content in the case of using a specific component as an antihistamine is illustrated below, this invention is not limited to this at all.
本発明の医薬組成物において、抗ヒスタミン剤としてアゼラスチン又はその塩を用いる場合、その含有量は、1日あたり、0.03〜10mg服用できる量が好ましく、0.1〜5mg服用できる量がより好ましく、0.3〜2.5mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてアリメマジン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜20mg服用できる量が好ましく、0.3〜15mg服用できる量がより好ましく、1〜10mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてイソチペンジル又はその塩を用いる場合、その含有量は、1日あたり、0.1〜30mg服用できる量が好ましく、0.3〜15mg服用できる量がより好ましく、1〜7.5mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてイプロヘプチン又はその塩を用いる場合、その含有量は、1日あたり、5〜400mg服用できる量が好ましく、10〜300mg服用できる量がより好ましく、15〜200mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when azelastine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken 0.03 to 10 mg, more preferably an amount that can be taken 0.1 to 5 mg, The amount that can be taken 0.3 to 2.5 mg is more preferable.
In the pharmaceutical composition of the present invention, when using alimemazine or a salt thereof as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 20 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 10 mg is more preferable.
In the pharmaceutical composition of the present invention, when isothipentil or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 30 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 7.5 mg is more preferable.
In the pharmaceutical composition of the present invention, when iproheptin or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 5 to 400 mg per day, more preferably an amount that can be taken from 10 to 300 mg, and 15 to 200 mg taken. The amount that can be produced is more preferred.
本発明の医薬組成物において、抗ヒスタミン剤としてエバスチン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜50mg服用できる量が好ましく、0.5〜30mg服用できる量がより好ましく、1〜20mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてエピナスチン又はその塩を用いる場合、その含有量は、1日あたり、0.3〜50mg服用できる量が好ましく、1〜35mg服用できる量がより好ましく、2.5〜25mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてエメダスチン又はその塩を用いる場合、その含有量は、1日あたり、0.01〜10mg服用できる量が好ましく、0.03〜7.5mg服用できる量がより好ましく、0.1〜5mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてオキサトミド又はその塩を用いる場合、その含有量は、1日あたり、0.3〜200mg服用できる量が好ましく、1〜100mg服用できる量がより好ましく、6〜60mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when ebastine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 50 mg, more preferably an amount that can be taken from 0.5 to 30 mg, The amount that can be taken 1-20 mg is more preferred.
In the pharmaceutical composition of the present invention, when epinastine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken 0.3 to 50 mg, more preferably 1 to 35 mg. The amount that can be taken 5 to 25 mg is more preferable.
In the pharmaceutical composition of the present invention, when emedastine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 0.01 to 10 mg per day, and more preferably from 0.03 to 7.5 mg. The amount that can be taken 0.1 to 5 mg is more preferable.
In the pharmaceutical composition of the present invention, when oxatomide or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken 0.3 to 200 mg per day, more preferably an amount that can be taken 1 to 100 mg, 6 to The amount that can be taken 60 mg is more preferable.
本発明の医薬組成物において、抗ヒスタミン剤としてオロパタジン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜30mg服用できる量が好ましく、0.3〜15mg服用できる量がより好ましく、1〜10mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてカルビノキサミン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜60mg服用できる量が好ましく、0.5〜30mg服用できる量がより好ましく、1〜16mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてクレマスチン又はその塩を用いる場合、その含有量は、1日あたり、クレマスチンのフリー体換算で、0.01〜5mg服用できる量が好ましく、0.05〜3mg服用できる量がより好ましく、0.1〜2mg服用できる量がさらに好ましい。なお、クレマスチンフマル酸塩1.34mgはクレマスチンのフリー体として1mgに相当するものである。
本発明の医薬組成物において、抗ヒスタミン剤としてクロルフェニラミン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜20mg服用できる量が好ましく、0.6〜12mg服用できる量がより好ましい。なお、クロルフェニラミン又はその塩として、d−クロルフェニラミンマレイン酸塩を用いる場合、1日あたり、0.1〜15mg服用できる量が好ましく、0.6〜6mg服用できる量がより好ましく、1〜5mg服用できる量がさらに好ましい。dl−クロルフェニラミンマレイン酸塩を用いる場合は、1日あたり、0.5〜20mg服用できる量が好ましく、1〜12mg服用できる量がより好ましく、2〜10mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when olopatadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 30 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 10 mg is more preferable.
In the pharmaceutical composition of the present invention, when carbinoxamine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 60 mg, more preferably an amount that can be taken from 0.5 to 30 mg, The amount that can be taken 1 to 16 mg is more preferable.
In the pharmaceutical composition of the present invention, when clemastine or a salt thereof is used as the antihistamine, the content thereof is preferably an amount that can be taken in an amount of 0.01 to 5 mg per day in terms of free form of clemastine, 0.05 to 3 mg. The amount that can be taken is more preferred, and the amount that can be taken 0.1 to 2 mg is more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
In the pharmaceutical composition of the present invention, when chlorpheniramine or a salt thereof is used as an antihistamine, its content is preferably 0.1 to 20 mg per day, more preferably 0.6 to 12 mg. preferable. In addition, when using d-chlorpheniramine maleate as chlorpheniramine or its salt, the quantity which can be taken | dosed 0.1-15 mg per day is preferable, and the quantity which can be taken | dosed 0.6-6 mg is more preferable, 1 An amount that can be taken by -5 mg is more preferred. When dl-chlorpheniramine maleate is used, the amount that can be taken from 0.5 to 20 mg per day is preferred, the amount that can be taken from 1 to 12 mg is more preferred, and the amount that can be taken from 2 to 10 mg is even more preferred.
本発明の医薬組成物において、抗ヒスタミン剤としてケトチフェン又はその塩を用いる場合、その含有量は、1日あたり、0.05〜10mg服用できる量が好ましく、0.1〜5mg服用できる量がより好ましく、0.3〜3mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてジフェテロール又はその塩を用いる場合、その含有量は、1日あたり、1〜300mg服用できる量が好ましく、5〜150mg服用できる量がより好ましく、10〜100mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてジフェニルピラリン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜13.5mg服用できる量が好ましく、1〜4.5mg服用できる量がより好ましい。なお、ジフェニルピラリン又はその塩として、ジフェニルピラリン塩酸塩を用いる場合、1日あたり、0.1〜12mg服用できる量が好ましく、1〜4mg服用できる量がより好ましい。ジフェニルピラリンテオクル酸塩を用いる場合、1日あたり、0.1〜13.5mg服用できる量が好ましく、1〜4.5mg服用できる量がより好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてジフェンヒドラミン又はその塩を用いる場合、その含有量は、1日あたり、1〜300mg服用できる量が好ましく、5〜200mg服用できる量がより好ましく、15〜150mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when ketotifen or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken 0.05 to 10 mg, more preferably an amount that can be taken 0.1 to 5 mg, The amount that can be taken 0.3 to 3 mg is more preferable.
In the pharmaceutical composition of the present invention, when dipheterol or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 1 to 300 mg per day, more preferably an amount that can be taken from 5 to 150 mg, and taken from 10 to 100 mg. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when diphenylpyrine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 0.1 to 13.5 mg per day, and an amount that can be taken from 1 to 4.5 mg. More preferred. In addition, when using a diphenyl pyraline hydrochloride as diphenyl pyraline or its salt, the quantity which can be taken | dosed 0.1-12 mg per day is preferable, and the quantity which can be taken | dosed 1-4 mg is more preferable. When using diphenylpyraline theocuroate, the amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
In the pharmaceutical composition of the present invention, when diphenhydramine or a salt thereof is used as an antihistamine, the content thereof is preferably 1 to 300 mg per day, more preferably 5 to 200 mg, more preferably 15 to 150 mg. The amount that can be produced is more preferred.
本発明の医薬組成物において、抗ヒスタミン剤としてシプロヘプタジン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜32mg服用できる量が好ましく、0.3〜20mg服用できる量がより好ましく、1〜15mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてセチリジン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜50mg服用できる量が好ましく、0.3〜30mg服用できる量がより好ましく、1〜20mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてトリプロリジン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜20mg服用できる量が好ましく、0.3〜15mg服用できる量がより好ましく、1〜10mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてトリペレナミン又はその塩を用いる場合、その含有量は、1日あたり、1〜400mg服用できる量が好ましく、3〜200mg服用できる量がより好ましく、10〜100mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when cyproheptadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 32 mg, more preferably an amount that can be taken from 0.3 to 20 mg, The amount that can be taken 1 to 15 mg is more preferable.
In the pharmaceutical composition of the present invention, when cetirizine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 50 mg, more preferably an amount that can be taken from 0.3 to 30 mg, The amount that can be taken 1-20 mg is more preferred.
In the pharmaceutical composition of the present invention, when triprolidine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 20 mg, more preferably an amount that can be taken from 0.3 to 15 mg per day. The amount that can be taken 1 to 10 mg is more preferable.
In the pharmaceutical composition of the present invention, when tripelamine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 1 to 400 mg per day, more preferably an amount that can be taken from 3 to 200 mg, and taken from 10 to 100 mg. The amount that can be produced is more preferred.
本発明の医薬組成物において、抗ヒスタミン剤としてトンジルアミン又はその塩を用いる場合、その含有量は、1日あたり、1〜300mg服用できる量が好ましく、3〜150mg服用できる量がより好ましく、10〜75mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてフェキソフェナジン又はその塩を用いる場合、その含有量は、1日あたり、0.3〜200mg服用できる量が好ましく、1〜100mg服用できる量がより好ましく、6〜60mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてフェネタジン又はその塩を用いる場合、その含有量は、1日あたり、1〜300mg服用できる量が好ましく、3〜150mg服用できる量がより好ましく、10〜75mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてプロメタジン又はその塩を用いる場合、その含有量は、1日あたり、0.5〜200mg服用できる量が好ましく、1〜100mg服用できる量がより好ましく、5〜75mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when tongylamine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 1 to 300 mg per day, more preferably an amount that can be taken from 3 to 150 mg, and taken from 10 to 75 mg. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when fexofenadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.3 to 200 mg per day, more preferably an amount that can be taken from 1 to 100 mg, The amount that can be taken 6 to 60 mg is more preferable.
In the pharmaceutical composition of the present invention, when phenetazine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 1 to 300 mg per day, more preferably an amount that can be taken from 3 to 150 mg, and 10 to 75 mg taken. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when promethazine or a salt thereof is used as the antihistamine, the content thereof is preferably an amount that can be taken from 0.5 to 200 mg per day, more preferably an amount that can be taken from 1 to 100 mg, The amount that can be taken 75 mg is more preferable.
本発明の医薬組成物において、抗ヒスタミン剤としてベポタスチン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜40mg服用できる量が好ましく、0.5〜30mg服用できる量がより好ましく、2〜20mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてホモクロルシクリジン又はその塩を用いる場合、その含有量は、1日あたり、0.3〜180mg服用できる量が好ましく、1〜90mg服用できる量がより好ましく、3〜60mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてメキタジン又はその塩を用いる場合、その含有量は、1日あたり、0.05〜20mg服用できる量が好ましく、0.1〜12mg服用できる量がより好ましく、0.6〜6mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてメトジラジン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜40mg服用できる量が好ましく、0.3〜20mg服用できる量がより好ましく、1〜10mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when bepotastine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 40 mg, more preferably an amount that can be taken from 0.5 to 30 mg, The amount that can be taken 2 to 20 mg is more preferable.
In the pharmaceutical composition of the present invention, when homochlorocyclidine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 0.3 to 180 mg per day, and more preferably an amount that can be taken from 1 to 90 mg. The amount that can be taken 3 to 60 mg is more preferable.
In the pharmaceutical composition of the present invention, when mequitazine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken 0.05 to 20 mg per day, more preferably an amount that can be taken 0.1 to 12 mg, The amount that can be taken 0.6 to 6 mg is more preferable.
In the pharmaceutical composition of the present invention, when methodirazine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 40 mg, more preferably an amount that can be taken from 0.3 to 20 mg, The amount that can be taken 1 to 10 mg is more preferable.
本発明の医薬組成物において、抗ヒスタミン剤としてメブヒドロリン又はその塩を用いる場合、その含有量は、1日あたり、1〜450mg服用できる量が好ましく、5〜300mg服用できる量がより好ましく、15〜200mg服用できる量がさらに好ましい。
本発明の医薬組成物において、抗ヒスタミン剤としてロラタジン又はその塩を用いる場合、その含有量は、1日あたり、0.1〜30mg服用できる量が好ましく、0.3〜15mg服用できる量がより好ましく、1〜10mg服用できる量がさらに好ましい。
In the pharmaceutical composition of the present invention, when mebhydroline or a salt thereof is used as an antihistamine, its content is preferably 1 to 450 mg per day, more preferably 5 to 300 mg, more preferably 15 to 200 mg. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when loratadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 30 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 10 mg is more preferable.
上述のような抗ヒスタミン剤の中でも、鎮痛作用、解熱作用及び/又は消化管障害の抑制作用の観点から、クロルフェニラミン又はその塩、クレマスチン又はその塩、カルビノキサミン又はその塩、ジフェニルピラリン又はその塩、メキタジン又はその塩が好ましく、鎮痛作用及び/又は解熱作用の観点から、クロルフェニラミン又はその塩、クレマスチン又はその塩がより好ましい。この中でも、解熱作用の観点から、クロルフェニラミン又はその塩が特に好ましい。 Among the antihistamines as described above, chlorpheniramine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, diphenylpyraline or a salt thereof, mequitazine from the viewpoint of an analgesic action, an antipyretic action and / or a gastrointestinal disorder inhibiting action. Or a salt thereof is preferable, and chlorpheniramine or a salt thereof, clemastine or a salt thereof is more preferable from the viewpoint of analgesic action and / or antipyretic action. Among these, chlorpheniramine or a salt thereof is particularly preferable from the viewpoint of antipyretic action.
本発明において、クロルフェニラミン又はその塩には、クロルフェニラミンそのもののほか、クロルフェニラミンの薬学上許容される塩も含まれる。クロルフェニラミンには不斉炭素が存するため、光学異性体を有するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。これらのうち、本発明においては、d−体、dl−体が好ましい。当該クロルフェニラミン又はその塩の好適な具体例としては例えば、クロルフェニラミン、クロルフェニラミンマレイン酸塩、d−クロルフェニラミンマレイン酸塩、dl−クロルフェニラミンマレイン酸塩等が挙げられ、これらを単独で、又は2種以上を組合わせて用いることができる。本発明においては、d−クロルフェニラミンマレイン酸塩、dl−クロルフェニラミンマレイン酸塩がより好ましく、d−クロルフェニラミンマレイン酸塩が特に好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, chlorpheniramine or a salt thereof includes not only chlorpheniramine itself but also a pharmaceutically acceptable salt of chlorpheniramine. Since chlorpheniramine has an asymmetric carbon, it has an optical isomer, but in the present invention, any optical isomer may be included, which may be a single optical isomer or a mixture of various optical isomers. . Among these, in the present invention, d-form and dl-form are preferable. Preferable specific examples of the chlorpheniramine or a salt thereof include, for example, chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, etc. Can be used alone or in combination of two or more. In the present invention, d-chlorpheniramine maleate and dl-chlorpheniramine maleate are more preferable, and d-chlorpheniramine maleate is particularly preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.
本発明の医薬組成物におけるクロルフェニラミン又はその塩の含有量は特に限定されず、上述した1日あたりの服用量に応じて適宜検討して決定すればよいが、クロルフェニラミン又はその塩を医薬組成物全質量に対して0.004〜1.5質量%含有するのが好ましく、0.02〜0.8質量%含有するのがより好ましく、0.04〜0.7質量%含有するのが特に好ましい。 The content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. It is preferable to contain 0.004-1.5 mass% with respect to the pharmaceutical composition total mass, it is more preferable to contain 0.02-0.8 mass%, and 0.04-0.7 mass% is contained. Is particularly preferred.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びクロルフェニラミン又はその塩の含有比は特に限定されず、上述した各成分の1日あたりの服用量に応じて、適宜検討して決定すればよいが、ロキソプロフェン又はその塩を、ロキソプロフェンナトリウム無水物換算で1質量部に対し、クロルフェニラミン又はその塩を0.0001〜25質量部含有するものが好ましく、0.0001〜8質量部含有するものがより好ましく、0.0001〜3質量部含有するものがさらに好ましい。このうち、クロルフェニラミン又はその塩を0.0001〜1.5質量部含有するものが好ましく、0.0005〜0.7質量部含有するものがより好ましい。 The content ratio of loxoprofen or a salt thereof, and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and is determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof contains 0.0001 to 25 parts by mass of chlorpheniramine or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0001 to 8 parts by mass. What contains is more preferable, and what contains 0.0001-3 mass parts is further more preferable. Among these, what contains 0.0001-1.5 mass parts of chlorpheniramine or its salt is preferable, and what contains 0.0005-0.7 mass parts is more preferable.
本発明において、クレマスチン又はその塩には、クレマスチンそのもののほか、クレマスチンの薬学上許容される塩も含まれる。クレマスチン又はその塩の具体例としては例えば、クレマスチン、クレマスチンフマル酸塩等が挙げられ、本発明においては、クレマスチンフマル酸塩が好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, clemastine or a salt thereof includes not only clemastine itself but also a pharmaceutically acceptable salt of clemastine. Specific examples of clemastine or a salt thereof include, for example, clemastine, clemastine fumarate, etc. In the present invention, clemastine fumarate is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
本発明の医薬組成物におけるクレマスチン又はその塩の含有量は特に限定されず、上述した1日あたりの服用量に応じて適宜検討して決定すればよいが、クレマスチン又はその塩を医薬組成物全質量に対してクレマスチンのフリー体換算で0.008〜0.4質量%含有するのが好ましく、0.01〜0.2質量%含有するのがより好ましく、0.015〜0.15質量%含有するのが特に好ましい。なお、クレマスチンフマル酸塩1.34mgはクレマスチンのフリー体として1mgに相当するものである。 The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose, but clemastine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.008-0.4 mass% in conversion of the free body of clemastine with respect to mass, It is more preferable to contain 0.01-0.2 mass%, 0.015-0.15 mass% It is particularly preferable to contain it. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩とクレマスチン又はその塩の含有比は特に限定されず、上述した各成分の1日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、クレマスチン又はその塩をクレマスチンのフリー体換算で0.0006〜0.5質量部含有するものが好ましく、0.0012〜0.1質量部含有するものがより好ましく、0.002〜0.03質量部含有するものがさらに好ましい。 The content ratio of loxoprofen or a salt thereof and clemastine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably contained in an amount of 0.0006 to 0.5 parts by mass of clemastine or a salt thereof in terms of a free form of clemastine relative to 1 part by mass in terms of anhydrous loxoprofen sodium. What contains 1 mass part is more preferable, and what contains 0.002-0.03 mass part is further more preferable.
本発明において、カルビノキサミン又はその塩には、カルビノキサミンそのもののほか、カルビノキサミンの薬学上許容される塩も含まれる。カルビノキサミン又はその塩の具体例としては例えば、カルビノキサミン、カルビノキサミンマレイン酸塩、カルビノキサミンジフェニルジスルホン酸塩等が挙げられ、本発明においては、カルビノキサミンマレイン酸塩がより好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, carbinoxamine or a salt thereof includes not only carbinoxamine itself but also a pharmaceutically acceptable salt of carbinoxamine. Specific examples of carbinoxamine or a salt thereof include carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate, and the like, and carbinoxamine maleate is more preferable in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.
本発明の医薬組成物におけるカルビノキサミン又はその塩の含有量は特に限定されず、上述した1日あたりの服用量に応じて適宜検討して決定すればよいが、カルビノキサミン又はその塩を医薬組成物全質量に対して0.004〜4質量%含有するのが好ましく、0.02〜2質量%含有するのがより好ましく、0.04〜1質量%含有するのが特に好ましい。 The content of carbinoxamine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. Carbinoxamine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.004-4 mass% with respect to mass, It is more preferable to contain 0.02-2 mass%, It is especially preferable to contain 0.04-1 mass%.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びカルビノキサミン又はその塩の含有比は特に限定されず、上述した各成分の1日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、カルビノキサミン又はその塩を0.0003〜6質量部含有するものが好ましく、0.002〜1質量部含有するものがより好ましく、0.005〜0.5質量部含有するものがさらに好ましく、0.005〜0.3質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and carbinoxamine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, with respect to 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium, one containing 0.0003 to 6 parts by mass of carbinoxamine or a salt thereof is preferable, and one containing 0.002 to 1 parts by mass is more preferable. More preferably, 0.005 to 0.5 parts by mass is contained, and 0.005 to 0.3 parts by mass is particularly preferred.
本発明において、ジフェニルピラリン又はその塩には、ジフェニルピラリンそのもののほか、ジフェニルピラリンの薬学上許容される塩も含まれる。ジフェニルピラリン又はその塩の具体例としては例えば、ジフェニルピラリン、ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩等が挙げられ、本発明においては、ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩が好ましく、ジフェニルピラリン塩酸塩が特に好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, diphenylpyralin or a salt thereof includes not only diphenylpyralin itself but also a pharmaceutically acceptable salt of diphenylpyralin. Specific examples of diphenylpyraline or a salt thereof include, for example, diphenylpyraline, diphenylpyraline hydrochloride, diphenylpyraline theocuroate and the like. In the present invention, diphenylpyraline hydrochloride and diphenylpyraline theocuroate are preferable, Diphenylpyraline hydrochloride is particularly preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
本発明の医薬組成物におけるジフェニルピラリン又はその塩の含有量は特に限定されず、上述した1日あたりの服用量に応じて適宜検討して決定すればよいが、ジフェニルピラリン又はその塩を医薬組成物全質量に対して0.004〜1質量%含有するのが好ましく、0.004〜0.5質量%含有するのがより好ましく、0.04〜0.3質量%含有するのがさらに好ましく、0.06〜0.25質量%含有するのが特に好ましい。 The content of diphenylpyralin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the above-mentioned daily dose. The content is preferably 0.004 to 1% by mass, more preferably 0.004 to 0.5% by mass, and still more preferably 0.04 to 0.3% by mass based on the total mass of the product. 0.06 to 0.25% by mass is particularly preferable.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びジフェニルピラリン又はその塩の含有比は特に限定されず、上述した各成分の1日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、ジフェニルピラリン又はその塩を0.0001〜3質量部含有するものが好ましく、0.0005〜2.5質量部含有するものがより好ましく、0.001〜1質量部含有するものがさらに好ましく、0.001〜0.3質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and diphenylpyraline or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. Although it is good, what contains 0.0001-3 mass parts of diphenyl pyralin or its salt is preferable with respect to 1 mass part of loxoprofen or its salt in conversion of loxoprofen sodium anhydride, 0.0005-2.5 mass part is contained. More preferable are those containing 0.001 to 1 parts by mass, and particularly preferable are those containing 0.001 to 0.3 parts by mass.
本発明において、メキタジン又はその塩には、メキタジンそのもののほか、メキタジンの薬学上許容される塩も含まれる。メキタジン又はその塩の具体例としては例えば、メキタジン等が挙げられる。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 In the present invention, mequitazine or a salt thereof includes not only mequitazine itself but also a pharmaceutically acceptable salt of mequitazine. Specific examples of mequitazine or a salt thereof include mequitazine and the like. These are known compounds, and can be produced by known methods, or commercially available products can be used.
本発明の医薬組成物におけるメキタジン又はその塩の含有量は特に限定されず、上述した1日あたりの服用量に応じて適宜検討して決定すればよいが、メキタジン又はその塩を医薬組成物全質量に対して0.004〜1質量%含有するのが好ましく、0.008〜0.5質量%含有するのがより好ましく、0.04〜0.3質量%含有するのが特に好ましい。 The content of mequitazine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined and determined according to the above-mentioned daily dose. Mequitazine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.004-1 mass% with respect to mass, It is more preferable to contain 0.008-0.5 mass%, It is especially preferable to contain 0.04-0.3 mass%.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びメキタジン又はその塩の含有比は特に限定されず、上述した各成分の1日あたりの服用量に応じて適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、メキタジン又はその塩を0.0001〜3質量部含有するものが好ましく、0.0005〜2.5質量部含有するものがより好ましく、0.001〜0.3質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and mequitazine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, those containing 0.0001 to 3 parts by mass of mequitazine or a salt thereof are preferred, and those containing 0.0005 to 2.5 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium. More preferably, one containing 0.001 to 0.3 parts by mass is particularly preferable.
次に、本発明で用いるエフェドリン類について説明する。
本発明の医薬組成物に用いられる「エフェドリン類」とは、エフェドリン及びエフェドリンの誘導体並びにそれらの塩からなる群より選ばれる1種以上を意味する。ここで、エフェドリンの誘導体としては、ノルエフェドリン(フェニルプロパノールアミン)、メチルエフェドリン等が挙げられる。また、塩としては、薬学上許容される無機酸や有機酸の塩が挙げられ、好適な具体例としては、塩酸塩、硫酸塩、サッカリン塩が挙げられる。また、エフェドリンには2つの不斉炭素が存するため、種々の光学異性体が存するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。本発明においては、l−体、dl−体が好ましい。
Next, ephedrines used in the present invention will be described.
The “ephedrines” used in the pharmaceutical composition of the present invention means one or more selected from the group consisting of ephedrine, ephedrine derivatives, and salts thereof. Here, examples of derivatives of ephedrine include norephedrine (phenylpropanolamine) and methylephedrine. Examples of the salt include salts of pharmaceutically acceptable inorganic acids and organic acids, and preferred specific examples include hydrochloride, sulfate, and saccharin salt. In addition, since ephedrine has two asymmetric carbons, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of In the present invention, l-form and dl-form are preferable.
本発明におけるエフェドリン類の好適な具体例としては例えば、l−メチルエフェドリン塩酸塩、dl−メチルエフェドリン塩酸塩、l−メチルエフェドリンサッカリン塩、dl−メチルエフェドリンサッカリン塩、プソイドエフェドリン塩酸塩、プソイドエフェドリン硫酸塩等が挙げられ、これらを単独で、又は2種以上を組合わせて用いることができる。なお、エフェドリンとプソイドエフェドリンは互いにエナンチオマーの関係にあるものである。本発明においては、dl−メチルエフェドリン塩酸塩が好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 Preferable specific examples of ephedrines in the present invention include, for example, 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, pseudoephedrine sulfate, etc. These can be used alone or in combination of two or more. Ephedrine and pseudoephedrine are in an enantiomeric relationship with each other. In the present invention, dl-methylephedrine hydrochloride is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.
また、本発明において「エフェドリン類」としては、これらを成分として含有するマオウ(麻黄)も用いることができる。
マオウは、第十五改正日本薬局方に掲載されているとおり、Ephedra sinica Stapf、Ephedra intermedia Schrenk et C. A. Meyer又はEphedra equisetina Bunge (Ephedraceae) の地上茎を意味する。マオウは必要に応じてその形態を調節することができ、小片、小塊に切断若しくは破砕、又は粉末に粉砕することができる。例えば、マオウの粉末は「マオウ末」という。
また、マオウは、第十五改正日本薬局方 製剤総則等に記載の公知の方法に基づき、適当な大きさとした後に、適当な浸出剤を加えて浸出した液や浸出液を濃縮した液、すなわち「エキス」や「チンキ」等としてもよい。浸出剤としては、メタノール、エタノール及びn−ブタノール等の低級一価アルコール;エチレングリコール、プロピレングリコール、1,3−ブチレングリコール及びグリセリン等の低級多価アルコール;ジエチルエーテル等のエーテル類;アセトン及びエチルメチルケトン等のケトン類;酢酸エチルエステル等のエステル類;ジクロロメタン及びクロロホルム等のハロゲノアルカン類;ベンゼン及びトルエン等の芳香族炭化水素;及び水等が挙げられる。これらは各々単独で用いてもよいし、2種以上を混合して用いてもよい。さらにエキスは乾燥することもできる。
In the present invention, “ephedrines” can also be used mah (mao) containing these as ingredients.
Maou means the ground stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et CA Meyer or Ephedra equisetina Bunge (Ephedraceae), as published in the 15th Amendment Japanese Pharmacopoeia. Maow can be adjusted in shape as needed, and can be cut or crushed into small pieces, lumps, or ground into powder. For example, Maow powder is called “Maow powder”.
In addition, Maou is a liquid obtained by adding an appropriate leaching agent and concentrating the leaching liquid after being appropriately sized based on a known method described in the 15th revision of the Japanese Pharmacopoeia General Rules for Preparations, etc. It may be “extract” or “tinced”. Examples of leaching agents include lower monohydric alcohols such as methanol, ethanol and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and glycerine; ethers such as diethyl ether; acetone and ethyl Ketones such as methyl ketone; esters such as ethyl acetate; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; and water. These may be used alone or in combination of two or more. Furthermore, the extract can be dried.
本発明において、エフェドリン類としてマオウを用いる場合、マオウ末、マオウ流エキス、マオウ軟エキス、マオウ乾燥エキス、マオウエキス等が好ましく、これらを単独で、又は2種以上を組合わせて用いることができる。さらに、マオウを用いる場合は、マオウを含む漢方処方である、カッコントウ(葛根湯)、ショウセイリュウトウ(小青竜湯)、マオウトウ(麻黄湯)等を用いることもできる。これらは、公知の方法により製造してもよいし、市販品を用いてもよい。 In the present invention, when maou is used as the ephedrines, maou powder, mao stream extract, mao soft extract, mao dry extract, mao extract and the like are preferred, and these can be used alone or in combination of two or more. Furthermore, when using maou, Chinese herbal prescriptions including maou, kakonto (Kakkonto), shosei ryoutou (Sho Seiryuto), maoutou (maoyuto), etc. can also be used. These may be produced by known methods, or commercially available products may be used.
本発明の医薬組成物におけるエフェドリン類の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて、適宜検討して決定すればよい。例えば、1日あたり、エフェドリン類を5〜500mg、より好適には10〜360mg、特に好適には20〜240mg服用できる量を含有せしめることができる。
なお、エフェドリン類の一部又は全ては、上述のマオウに代替することができる。エフェドリン類としてマオウを用いる場合は、例えば、1日あたり、マオウを0.1〜25g(原生薬換算量)、より好適には0.25〜10g(原生薬換算量)、特に好適には0.4〜4g(原生薬換算量)服用できる量を含有せしめることができる。
本発明においては、エフェドリン類を医薬組成物全質量に対して0.1〜40質量%含有するのが好ましく、0.5〜20質量%含有するのがより好ましく、1〜10質量%含有するのが特に好ましい。また、エフェドリン類としてマオウを用いる場合は、マオウを医薬組成物全質量に対して1〜98質量%含有するのが好ましく、2〜50質量%含有するのがより好ましく、4〜20質量%含有するのが特に好ましい。
The content of ephedrines in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, the amount of ephedrine that can be taken per day is 5 to 500 mg, more preferably 10 to 360 mg, and particularly preferably 20 to 240 mg.
In addition, a part or all of ephedrines can be substituted for the above-mentioned maou. When using maou as ephedrines, for example, 0.1 to 25 g (powder equivalent) of maou per day, more preferably 0.25 to 10 g (powder equivalent), particularly preferably 0 .4 to 4 g (concentration in bulk drug substance) can be included.
In this invention, it is preferable to contain 0.1-40 mass% of ephedrine with respect to pharmaceutical composition total mass, It is more preferable to contain 0.5-20 mass%, It contains 1-10 mass%. Is particularly preferred. Moreover, when using maou as ephedrine, it is preferable to contain 1 to 98 mass% of maou with respect to the total mass of the pharmaceutical composition, more preferably 2 to 50 mass%, and more preferably 4 to 20 mass%. It is particularly preferable to do this.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びエフェドリン類の含有比は特に限定されず、上述した各成分の1日あたりの服用量に応じて、適宜検討して決定すればよいが、ロキソプロフェン又はその塩を、ロキソプロフェンナトリウム無水物換算で1質量部に対し、エフェドリン類を0.015〜50質量部含有するものが好ましく、0.05〜12質量部含有するものがより好ましく、0.1〜6質量部含有するものがさらに好ましく、0.1〜4質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and ephedrine contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably 0.015 to 50 parts by mass of ephedrines, more preferably 0.05 to 12 parts by mass based on 1 part by mass of loxoprofen sodium anhydride. Those containing 1 to 6 parts by mass are more preferable, and those containing 0.1 to 4 parts by mass are particularly preferable.
本発明の医薬組成物は、例えば、第十五改正日本薬局方 製剤総則等に記載の公知の方法により製造することができる。また、剤形は特に限定されるものではなく、固形状、半固形状、液状のいずれの形状であってもよく、その利用目的等に応じて医薬品において通常利用される形状とすることができる。具体的には例えば、錠剤(チュアブル錠、発泡錠、口腔内崩壊錠などを含む)、トローチ剤、ドロップ剤、硬カプセル剤、軟カプセル剤、顆粒剤、細粒剤、散剤、丸剤、ドライシロップ剤、坐剤、パップ剤、プラスター剤などの固形製剤;舐剤、チューインガム剤、ゼリー剤、ゼリー状ドロップ剤、ホイップ剤、軟膏剤、クリーム剤、フォーム剤、インへラー剤、ナザールジェル剤などの半固形製剤;シロップ剤、ドリンク剤、懸濁剤、酒精剤、液剤、点眼剤、エアゾール剤、噴霧剤、スプレー剤などの液状製剤などの、第十五改正日本薬局方 製剤総則等に記載の剤形とすることができる。
本発明においては、服用の簡便性や薬物服用量の管理等の点で、ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類の3成分を含む固形製剤であるのが好ましく、錠剤、カプセル剤、丸剤、顆粒剤、散剤及び細粒剤からなる群より選ばれる固形製剤であるのがより好ましく、錠剤又はカプセル剤であるのが特に好ましい。
The pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations. The dosage form is not particularly limited, and may be any of solid, semi-solid, and liquid shapes, and can be a shape that is usually used in pharmaceuticals depending on the purpose of use. . Specifically, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), troches, drops, hard capsules, soft capsules, granules, fine granules, powders, pills, dry syrup Solid preparations such as suppositories, suppositories, poultices, plasters; lozenges, chewing gums, jelly agents, jelly drops, whipped agents, ointments, creams, foams, inhalers, nazar gels, etc. Semi-solid preparations; syrups, drinks, suspensions, spirits, liquids, eye drops, aerosols, sprays, sprays, and other liquid preparations, etc. It can be made into a dosage form.
In the present invention, it is preferably a solid preparation containing three components of loxoprofen or a salt thereof, an antihistamine and an ephedrine, from the viewpoint of ease of administration and management of drug dose, and the like. Tablets, capsules, pills, A solid preparation selected from the group consisting of granules, powders and fine granules is more preferable, and tablets or capsules are particularly preferable.
本発明の医薬組成物の服用経路としては、経口及び経直腸や経膣等の非経口が挙げられ、経口投与が好ましい。また、本発明の医薬組成物は、例えば、1日につき1〜4回程度に分けて、食前、食間、食後、就寝前等に服用することができる。 Examples of the route of taking the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal administration, and oral administration is preferred. The pharmaceutical composition of the present invention can be taken, for example, before meals, between meals, after meals, before going to bed, etc., divided into about 1 to 4 times per day.
本発明の医薬組成物には、医薬成分として、ロキソプロフェン又はその塩、抗ヒスタミン剤とエフェドリン類以外の薬物、例えば、解熱鎮痛剤、鎮咳剤、ノスカピン類、気管支拡張剤、去痰剤、催眠鎮静剤、ビタミン類、抗炎症剤、胃粘膜保護剤、抗コリン剤、生薬類、漢方処方、カフェイン類、キサンチン系成分等からなる群より選ばれる1種又は2種以上を含んでいてもよい。 In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof, an antihistamine and an ephedrine, such as an antipyretic analgesic, an antitussive, a noscapine, a bronchodilator, an expectorant, a hypnotic sedative, a vitamin 1 type, or 2 or more types chosen from the group which consists of an anti-inflammatory agent, a gastric mucosa protective agent, an anticholinergic agent, a herbal medicine, a Chinese medicine prescription, caffeine, a xanthine type component, etc. may be included.
解熱鎮痛剤としては、例えば、アスピリン、アスピリンアルミニウム、アセトアミノフェン、イソプロピルアンチピリン、イブプロフェン、エテンザミド、サザピリン、サリチルアミド、サリチル酸ナトリウム、チアラミド塩酸塩、ラクチルフェネチジン等が挙げられる。 Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine, and the like.
鎮咳剤としては、例えば、アロクラミド塩酸塩、エプラジノン塩酸塩、カルベタペンタンクエン酸塩、クロペラスチン塩酸塩、クロペラスチンフェンジゾ酸塩、コデインリン酸塩、ジヒドロコデインリン酸塩、ジブナートナトリウム、ジメモルファンリン酸塩、デキストロメトルファン臭化水素酸塩、デキストロメトルファン・フェノールフタリン塩、チペピジンクエン酸塩、チペピジンヒベンズ酸塩等が挙げられる。 Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate, dibutarate sodium, dimemorphan Examples thereof include phosphate, dextromethorphan hydrobromide, dextromethorphan / phenol phthaline salt, tipepidine citrate, and tipepidine hibenzate.
ノスカピン類としては、例えば、ノスカピン塩酸塩、ノスカピン等が挙げられる。
気管支拡張剤としては、例えば、トリメトキノール塩酸塩、フェニレフリン塩酸塩、メトキシフェナミン塩酸塩等が挙げられる。
Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of the bronchodilator include trimethquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.
去痰剤としては、例えば、アンブロキソール塩酸塩、アンモニア・ウイキョウ精、エチルシステイン塩酸塩、塩化アンモニウム、カルボシステイン、グアイフェネシン、グアヤコールスルホン酸カリウム、クレゾールスルホン酸カリウム、ブロムヘキシン塩酸塩、メチルシステイン塩酸塩、l−メントール、リゾチーム塩酸塩等が挙げられる。 As an expectorant, for example, ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine hydrochloride, Examples thereof include l-menthol and lysozyme hydrochloride.
催眠鎮静剤としては、例えば、アリルイソプロピルアセチル尿素やブロムワレリル尿素等が挙げられる。
ビタミン類としては、例えば、ビタミンB1、ビタミンB2、ビタミンB5、ビタミンB6、ビタミンB12、ビタミンC、ヘスペリジン及びその誘導体並びにそれらの塩類等(例えば、チアミン、チアミン塩化物塩酸塩、チアミン硝化物、ジセチアミン塩酸塩、セトチアミン塩酸塩、フルスルチアミン、フルスルチアミン塩酸塩、オクトチアミン、シコチアミン、チアミンジスルフィド、ビスイブチアミン、ビスベンチアミン、プロスルチアミン、ベンフォチアミン、リボフラビン、リボフラビンリン酸エステル、リボフラビン酪酸エステル、リン酸リボフラビンナトリウム、パンテノール、パンテチン、パントテン酸カルシウム、パントテン酸ナトリウム、ピリドキシン塩酸塩、ピリドキサールリン酸エステル、シアノコバラミン、メコバラミン、アスコルビン酸、アスコルビン酸ナトリウム、アスコルビン酸カルシウム、ヘスペリジン等)が挙げられる。
Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.
Examples of vitamins include vitamin B 1 , vitamin B 2 , vitamin B 5 , vitamin B 6 , vitamin B 12 , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, sodium riboflavin phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecoba Lamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).
抗炎症剤としては、例えば、グリチルリチン酸及びその誘導体並びにそれらの塩類(例えば、グリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム等)、セアプローゼ、セミアルカリプロティナーゼ、セラペプターゼ、トラネキサム酸、プロクターゼ、プロナーゼ、ブロメライン等が挙げられる。 Examples of the anti-inflammatory agent include glycyrrhizic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain and the like. Can be mentioned.
胃粘膜保護剤としては、例えば、アミノ酢酸、アルジオキサ、ケイ酸マグネシウム、ゲファルナート、合成ケイ酸アルミニウム、合成ヒドロタルサイト、酸化マグネシウム、ジヒドロキシアルミニウム・アミノ酢酸塩(アルミニウムグリシネート)、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸水素ナトリウムの共沈生成物、水酸化アルミニウム・炭酸カルシウム・炭酸マグネシウムの共沈生成物、水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物、スクラルファート、セトラキサート塩酸塩、ソファルコン、炭酸マグネシウム、テプレノン、銅クロロフィリンカリウム、銅クロロフィリンナトリウム、メタケイ酸アルミン酸マグネシウム、メチルメチオニンスルホニウムクロリド等が挙げられる。 Examples of the gastric mucosa protective agent include aminoacetic acid, aldioxa, magnesium silicate, gefarnate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product , Sucralfate, cetraxate hydrochloride, sofalcone, magnesium carbonate, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, magnesium metasilicate aluminate, methylmethionine sulfate Niumukurorido, and the like.
抗コリン薬としては、例えば、オキシフェンサイクリミン塩酸塩、ジサイクロミン塩酸塩、メチキセン塩酸塩、スコポラミン臭化水素酸塩、ダツラエキス、チペピジウム臭化物、メチルアトロピン臭化物、メチルアニソトロピン臭化物、メチルスコポラミン臭化物、メチル−l−ヒヨスチアミン臭化物、メチルベナクチジウム臭化物、ピレンゼピン塩酸塩、ブチルスコポラミン臭化物、ベラドンナアルカロイド、ベラドンナエキス、ベラドンナ総アルカロイド、ヨウ化イソプロパミド、ヨウ化ジフェニルピペリジノメチルジオキソラン、ロートエキス、ロート根、ロート根総アルカロイドクエン酸塩等が挙げられる。 Anticholinergic agents include, for example, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipidium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl- 1-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide iodide, diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel Examples include root total alkaloid citrate.
生薬類としては、例えば、アカメガシワ(赤芽柏)、アセンヤク(阿仙薬)、インヨウカク(淫羊霍)、ウイキョウ(茴香)、ウコン(鬱金)、エンゴサク(延胡索)、エンメイソウ(延命草)、オウゴン(黄岑)、オウセイ(黄精)、オウバク(黄柏)、オウヒ(桜皮)、オウレン(黄連)、オンジ(遠志)、ガジュツ(我朮)、カノコソウ(鹿子草)、カミツレ、カロニン(か楼仁)、カンゾウ(甘草)、キキョウ(桔梗)、キョウニン(杏仁)、クコシ(枸杞子)、クコヨウ(枸杞葉)、ケイガイ(荊芥)、ケイヒ(桂皮)、ケツメイシ(決明子)、ゲンチアナ、ゲンノショウコ(現証拠)、コウブシ(香附子)、ゴオウ(牛黄)、ゴミシ(五味子)、サイシン(細辛)、サンショウ(山椒)、シオン(紫苑)、ジコッピ(地骨皮)、シャクヤク(芍薬)、ジャコウ(麝香)、シャジン(沙参)、シャゼンシ(車前子)、シャゼンソウ(車前草)、獣胆(ユウタン(熊胆)を含む)、ショウキョウ(生姜)、ジリュウ(地竜)、シンイ(辛夷)、セキサン(石蒜)、セネガ、センキュウ(川きゅう)、ゼンコ(前胡)、センブリ(千振)、ソウジュツ(蒼朮)、ソウハクヒ(桑白皮)、ソヨウ(蘇葉)、タイサン(大蒜)、チクセツニンジン(竹節人参)、チョウジ(丁子)、チンピ (陳皮)、トウキ(当帰)、トコン(吐根)、ナンテンジツ(南天実)、ニンジン(人参)、バイモ(貝母)、バクモンドウ(麦門冬)、ハッカ(薄荷)、ハンゲ(半夏)、バンコウカ(番紅花)、ハンピ(反鼻)、ビャクシ(白し)、ビャクジュツ(白朮)、ブクリョウ(茯苓)、ボタンピ(牡丹皮)、ボレイ(牡蠣)、ロクジョウ(鹿茸)等の生薬及びこれらの抽出物(エキス、チンキ、乾燥エキス等)等が挙げられる。 Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Owaku (yellow twilight), Spruce (cherry bark), Auren (yellow ream), Onji (distant), Gajutsu (weather), valerian (deer grass), chamomile, caronin (karojin), Licorice, licorice, bellflowers, kokushi (coconut), cucumber (cucumber leaves), keigai (cocoon), keihi (cinnamon), ketsumeishi (actual child), gentian, gennoshouko (current evidence), Koubushi (Kosuke), Gooh (Gyuhuang), Goshi (Gomiko), Saishin (Spicy), Salamander (Sambu), Zion (Purple), Zykopi (Peel), Peonies (Glue), Ji Jakkou, Shajin, Shazenshi (car forerunner), Shazenso (car forerunner), Beast gall (including yutan (gum gal)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu Carrot (Takebushi Ginseng), Clove (Chiko), Chimp (Chan), Toki (Toki), Tokon (Nanten), Carrot (Ginseng), Baimo (Shell), Bacmond (Wheat) Gate winter), mint (light load), Hange (semi-summer), bankouka (banka), hampi (anti-nose), juniper (white bean), juniper (white moth), bukkuri (茯苓), button pi (peony skin), volley (Oysters), Rokujo (deer) etc. These extracts (extract, tincture, dry extract, etc.) and the like.
漢方処方としては、例えば、ケイシトウ(桂枝湯)、コウソサン(香蘇散)、サイコケイシトウ(柴胡桂枝湯)、ショウサイコトウ(小柴胡湯)、バクモンドウトウ(麦門冬湯)、ハンゲコウボクトウ(半夏厚朴湯)等が挙げられる。 Examples of Kampo prescriptions include Keishito (Katsura-yu), Kousosan (Kousosan), Psycho-keito (Shibako), Bakumondou (Bakumontoyu), Hange Examples include Kokubokuto (half-summer Koboku-yu).
カフェイン類としては、例えば、カフェイン、無水カフェイン、安息香酸ナトリウムカフェイン、クエン酸カフェイン等が挙げられる。 Examples of caffeine include caffeine, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate.
キサンチン系成分としては、例えば、アミノフィリン、ジプロフィリン、テオフィリン、プロキシフィリン等が挙げられる。 Examples of the xanthine component include aminophylline, diprofylline, theophylline, proxyphylline and the like.
なお、本発明の医薬組成物としては、以下の(a)〜(e)以外のものが好ましい。 In addition, as a pharmaceutical composition of this invention, things other than the following (a)-(e) are preferable.
(a)ロキソプロフェンナトリウム2水和物 60mg(無水物として換算)、マレイン酸カルビノキサミン 4mg、dl−塩酸メチルエフェドリン 20mg、セラペプターゼ 10mg、ステアリン酸マグネシウム 7mg、結晶セルロース 60mg、デンプン 176mg、乳糖 13mgを含有するハードカプセル剤;
(b)ロキソプロフェンナトリウム2水和物 60mg(無水物として換算)、マレイン酸カルビノキサミン 4mg、dl−塩酸メチルエフェドリン 20mg、セラペプターゼ 10mg、ステアリン酸マグネシウム 7mg、結晶セルロース 60mg、デンプン 176mg、乳糖 13mgを含有する錠剤;
(c)ロキソプロフェンナトリウム2水和物 60mg(無水物として換算)、マレイン酸カルビノキサミン 4mg、dl−塩酸メチルエフェドリン 20mg、セラペプターゼ 10mg、β−シクロデキストリン 254mg、アスパルテーム 30mg、クエン酸 965mg、炭酸水素ナトリウム 813mg、乳糖 194mg、ステアリン酸マグネシウム 50mgを含有する発泡錠;
(d)ロキソプロフェンナトリウム2水和物 60mg(無水物として換算)、マレイン酸カルビノキサミン 4mg、dl−塩酸メチルエフェドリン 20mg、セラペプターゼ 10mg、β−シクロデキストリン 300mg、アスパルテーム 30mg、マンニトール 262mg、ステアリン酸マグネシウム 14mgを含有する速溶錠及びチュアブル錠;
(e)下記の各成分を混合した後、混合粉体を打錠して製される1錠重量230mgの錠剤:ロキソプロフェンナトリウム 90g、d−マレイン酸クロルフェニラミン 6g、塩酸プソイドエフェドリン 200g、テオフィリン 450g、グアイフェネシン 200g、乳糖 400g、微結晶セルロース 375g、ステアリン酸マグネシウム 20g、硬化ヒマシ油 19g
(A) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg, lactose 13 mg Agent;
(B) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg, lactose 13 mg ;
(C) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 254 mg, aspartame 30 mg, citric acid 965 mg, sodium bicarbonate 813 mg, Effervescent tablets containing 194 mg of lactose and 50 mg of magnesium stearate;
(D) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 300 mg, aspartame 30 mg, mannitol 262 mg, magnesium stearate 14 mg Fast dissolving tablets and chewable tablets;
(E) A tablet having a weight of 230 mg produced by tableting the mixed powder after mixing the following components: 90 g of loxoprofen sodium, 6 g of chlorpheniramine d-maleate, 200 g of pseudoephedrine hydrochloride, 450 g of theophylline, Guaifenesin 200g, lactose 400g, microcrystalline cellulose 375g, magnesium stearate 20g, hydrogenated castor oil 19g
本発明の医薬組成物は、下記試験例1及び2に示すとおり、特に優れた解熱作用及び/又は鎮痛作用を有することから、発熱及び痛みを伴う種々の疾患・症状に対し有効であることが明らかである。従って、本発明の医薬組成物としては、ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する解熱及び/又は鎮痛用組成物が好ましく、より具体的には、頭痛、歯痛、抜歯後の疼痛、咽頭痛、耳痛、関節痛、神経痛、腰痛、筋肉痛、肩こり痛、打撲痛、骨折痛、ねんざ痛、月経痛(生理痛)及び外傷痛から選ばれる1種以上の痛みの鎮痛;のどの痛み、頭痛、関節の痛み及び筋肉の痛みから選ばれる1種以上の症状の緩和(なお、当該「のどの痛み」としては、かぜの諸症状としてののどの痛み及び急性鼻炎、アレルギー性鼻炎又は副鼻腔炎による諸症状としてののどの痛みを含む。また、「頭痛」、「関節の痛み」及び「筋肉の痛み」としては、かぜの諸症状としてのこれらの症状を含む。);悪感、発熱時の解熱;及び/又は悪感、発熱の症状の緩和(なお、当該「悪感」および「発熱」としては、かぜの諸症状としてのこれらの症状を含む。)に用いられる医薬として好適に利用できる。
また、本発明の医薬組成物の好適な具体例としては、下記組成物(A)〜(D)からなる群より選ばれる1種以上:
Since the pharmaceutical composition of the present invention has particularly excellent antipyretic action and / or analgesic action as shown in Test Examples 1 and 2 below, it is effective for various diseases and symptoms accompanied by fever and pain. it is obvious. Therefore, the pharmaceutical composition of the present invention is preferably an antipyretic and / or analgesic composition containing loxoprofen or a salt thereof, an antihistamine and ephedrines, and more specifically, headache, toothache, pain after extraction, pharynx One or more pain relief selected from pain, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain) and trauma pain Alleviation of one or more symptoms selected from pain, headache, joint pain and muscle pain (note that the “throat pain” includes sore throat and acute rhinitis, allergic rhinitis Including throat pain as symptoms of sinusitis, and “headache”, “joint pain” and “muscle pain” include these symptoms as cold symptoms)); Antipyretic at the time of fever And / or Akkan, alleviation of the symptoms of fever (As the said "Akkan" and "heating" includes. These symptoms as symptoms of a cold) can be suitably used as a medicament for use in.
Moreover, as a suitable specific example of the pharmaceutical composition of this invention, 1 or more types chosen from the group which consists of the following composition (A)-(D):
(A)ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する、頭痛、歯痛、抜歯後の疼痛、咽頭痛、耳痛、関節痛、神経痛、腰痛、筋肉痛、肩こり痛、打撲痛、骨折痛、ねんざ痛、月経痛(生理痛)及び外傷痛から選ばれる1種以上の痛みの鎮痛用組成物、
(B)ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する、のどの痛み、頭痛、関節の痛み及び筋肉の痛みから選ばれる1種以上の緩和(かぜの諸症状としてののどの痛み、頭痛、関節の痛み及び筋肉の痛みから選ばれる1種以上の症状の緩和を含む)用組成物、
(C)ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する、のどの痛みの緩和(急性鼻炎、アレルギー性鼻炎又は副鼻腔炎による諸症状としてののどの痛みの緩和を含む)用組成物、並びに
(D)ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する、悪寒及び/又は発熱時の解熱(かぜの諸症状としての悪寒及び/又は発熱の緩和を含む)用組成物が挙げられ、上記組成物(B)及び(D)が好ましく、上記組成物(B)が特に好ましい。
(A) containing loxoprofen or a salt thereof, an antihistamine and ephedrine, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, One or more pain relieving compositions selected from pain, menstrual pain, and traumatic pain,
(B) one or more relief selected from loxoprofen or a salt thereof, an antihistamine, and ephedrines from sore throat, headache, joint pain and muscle pain (sore throat as a symptom of cold, headache, Including a relief of one or more symptoms selected from joint pain and muscle pain),
(C) a composition for relief of sore throat (including relief of sore throat as symptoms due to acute rhinitis, allergic rhinitis or sinusitis), comprising loxoprofen or a salt thereof, an antihistamine and ephedrines, and (D) A composition for antipyretic (including mitigation of chills and / or fever as cold symptoms) containing loxoprofen or a salt thereof, an antihistamine, and ephedrines, including the above-mentioned composition The products (B) and (D) are preferable, and the composition (B) is particularly preferable.
さらに、ロキソプロフェンはNSAIDの1種であり、副作用として消化管障害(胃粘膜刺激、潰瘍形成等)が問題となるが、下記試験例3に具体的に開示されているとおり、抗ヒスタミン剤及びエフェドリン類が、当該ロキソプロフェンに起因する消化管障害に対し抑制作用を有することが見出された。
従って、ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する本発明の医薬組成物は、ロキソプロフェン又はその塩に起因する消化管障害が抑制されるため安全性に優れるという有利な効果を有する。
また、従来、ロキソプロフェンを含有する医薬においては投与禁忌とされている消化性潰瘍の罹患者や、慎重投与とされている消化性潰瘍の既往歴のある患者であっても安全に服用することができ、ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類を含有する本発明の医薬組成物は、消化性潰瘍の罹患者及び/又は消化性潰瘍の既往歴のある者に投与するための医薬組成物としても好適に利用できる。
さらに、本発明によれば、抗ヒスタミン剤及び/又はエフェドリン類を有効成分として含有する、アルミノプロフェン、アンピロキシカム、アンフェナク、イブプロフェン、インドメタシン、エトドラク、エピリゾール、オキサプロジン、ケトプロフェン、ザルトプロフェン、ジクロフェナク、スリンダク、セレコキシブ、チアプロフェン酸、チアラミド、テノキシカム、トルフェナム酸、ナブメトン、ナプロキセン、ピロキシカム、プラノプロフェン、フルフェナム酸、フルルビプロフェン、プログルメタシン、メフェナム酸、メロキシカム、モフェゾラク、ロキソプロフェン及びロルノキシカム並びにこれらの塩等の非ステロイド性消炎鎮痛剤(好適にはロキソプロフェン又はその塩)に起因する消化管障害(例えば、NSAID潰瘍)の軽減又は抑制剤を提供できる。
Furthermore, loxoprofen is a kind of NSAID, and as a side effect, gastrointestinal disorders (gastric mucosal irritation, ulceration, etc.) are problematic, but as specifically disclosed in Test Example 3 below, antihistamines and ephedrines are It was found to have an inhibitory action on gastrointestinal disorders caused by the loxoprofen.
Therefore, the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, an antihistamine, and ephedrines has an advantageous effect of being excellent in safety because gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed.
In addition, patients with peptic ulcers that have been conventionally contraindicated for drugs containing loxoprofen and patients with a history of peptic ulcers that have been carefully administered can be safely taken. The pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, an antihistamine and ephedrines can also be used as a pharmaceutical composition for administration to a patient with peptic ulcer and / or a person with a history of peptic ulcer. It can be suitably used.
Furthermore, according to the present invention, an aluminoprofen, ampiroxicam, ampenac, ibuprofen, indomethacin, etodolac, epilysole, oxaprozin, ketoprofen, saltoprofen, diclofenac, sulindac, celecoxib, containing an antihistamine and / or ephedrine as an active ingredient Non-steroids such as thiaprofenic acid, thiaramide, tenoxicam, tolfenamic acid, nabumetone, naproxen, piroxicam, pranoprofen, flufenamic acid, flurbiprofen, progouritacin, mefenamic acid, meloxicam, mofezolac, loxoprofen and lornoxicam and their salts Gastrointestinal disorders (for example, NSAID ulcers) caused by persistent anti-inflammatory analgesics (preferably loxoprofen or a salt thereof) It can provide relief or inhibitor.
以下に実施例等を挙げて本発明を詳細に説明するが、本発明はこれら実施例等に何ら限定されるものではない。
[試験例1]鎮痛試験
試験例1−1 ロキソプロフェン又はその塩、クロルフェニラミン又はその塩及びエフェドリン類の3成分の組合わせによる鎮痛作用の検討
5〜6週齢のWistar系雄性ラット(体重99.3〜112.0g)の右後肢足の疼痛閾値を測定し、「炎症惹起前疼痛閾値」とした。
炎症惹起前疼痛閾値の測定後、右後肢足蹠に20%酵母液を100μL皮下投与して炎症を惹起した。炎症惹起3時間後に疼痛閾値を測定し、「薬物投与前疼痛閾値」とした。
薬物投与前疼痛閾値の測定直後に被験薬物を経口投与し、当該薬物投与の3時間後を測定ポイントとして疼痛閾値を測定し、「薬物投与後疼痛閾値」とした。
得られた疼痛閾値から、以下の式に従い、疼痛改善率を算出した。
Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
[Test Example 1] Analgesic Test Test Example 1-1 Examination of analgesic action by combining three components of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof and ephedrine 5-6 weeks old Wistar male rats (weight 99) .3 to 112.0 g) of the right hind leg pain threshold was measured and designated as “the pain threshold before inflammation”.
After measurement of the pain threshold before inducing inflammation, 100 μL of 20% yeast solution was subcutaneously administered to the right hind footpad to induce inflammation. The pain threshold was measured 3 hours after the onset of inflammation and was defined as “pain threshold before drug administration”.
Immediately after the measurement of the pain threshold before drug administration, the test drug was orally administered, and the pain threshold was measured at 3 hours after the drug administration as a measurement point, which was designated as “pain threshold after drug administration”.
The pain improvement rate was calculated from the obtained pain threshold according to the following formula.
疼痛改善率(%)=(薬物投与後疼痛閾値−薬物投与前疼痛閾値)/(炎症惹起前疼痛閾値−薬物投与前疼痛閾値)×100 Pain improvement rate (%) = (pain threshold after drug administration−pain threshold before drug administration) / (pain threshold before inflammation induction−pain threshold before drug administration) × 100
なお、疼痛閾値は、ランダルセリット式鎮痛効果測定装置(MK−201D:室町機械(株)製)を用いて測定した。 In addition, the pain threshold value was measured using the Randall Cerit type analgesic effect measuring apparatus (MK-201D: Muromachi Kikai Co., Ltd. product).
被験薬物は、それぞれ以下の群構成に従い投与した。
1:ロキソプロフェンナトリウム水和物 単独投与群(以下、「LX単独」と表記する。)
ロキソプロフェンナトリウム水和物を0.1mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
2:d−クロルフェニラミンマレイン酸塩 単独投与群(以下、「CM単独」と表記する。)
d−クロルフェニラミンマレイン酸塩を1mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
3:dl−メチルエフェドリン塩酸塩 単独投与群(以下、「ME単独」と表記する。)
dl−メチルエフェドリン塩酸塩を0.3g/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
Each test drug was administered according to the following group composition.
1: Loxoprofen sodium hydrate alone administration group (hereinafter referred to as “LX alone”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
2: d-chlorpheniramine maleate single administration group (hereinafter referred to as “CM alone”)
d-Chlorpheniramine maleate was administered at a dose of 1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: dl-methylephedrine hydrochloride alone administration group (hereinafter referred to as “ME alone”)
dl-Methylephedrine hydrochloride was administered at a dose of 0.3 g / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
4:ロキソプロフェンナトリウム水和物とd−クロルフェニラミンマレイン酸塩の2成分併用投与群(以下、「LX+CM」と表記する。)
ロキソプロフェンナトリウム水和物を0.1mg/kg体重の用量で、d−クロルフェニラミンマレイン酸塩を1mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて同時に投与した。
5:ロキソプロフェンナトリウム水和物とdl−メチルエフェドリン塩酸塩の2成分併用投与群(以下、「LX+ME」と表記する。)
ロキソプロフェンナトリウム水和物を0.1mg/kg体重の用量で、dl−メチルエフェドリン塩酸塩を0.3g/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて同時に投与した。
6:ロキソプロフェンナトリウム水和物、d−クロルフェニラミンマレイン酸塩及びdl−メチルエフェドリン塩酸塩の3成分併用投与群(以下、「LX+CM+ME」と表記する。)
ロキソプロフェンナトリウム水和物を0.1mg/kg体重の用量で、d−クロルフェニラミンマレイン酸塩を1mg/kg体重の用量で、dl−メチルエフェドリン塩酸塩を0.3g/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて同時に投与した。
4: Two-component combination administration group of loxoprofen sodium hydrate and d-chlorpheniramine maleate (hereinafter referred to as “LX + CM”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight and d-chlorpheniramine maleate was dissolved at a dose of 1 mg / kg body weight in 0.5% methylcellulose solution or administered simultaneously.
5: Loxoprofen sodium hydrate and dl-methylephedrine hydrochloride combined administration group (hereinafter referred to as “LX + ME”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution simultaneously at a dose of 0.1 mg / kg body weight and dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight.
6: Loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride combined administration group (hereinafter referred to as “LX + CM + ME”)
Loxoprofen sodium hydrate at a dose of 0.1 mg / kg body weight, d-chlorpheniramine maleate at a dose of 1 mg / kg body weight, dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight, It was dissolved or suspended in a 0.5% methylcellulose solution and administered simultaneously.
なお、被験薬物投与群それぞれ各群につき、4匹のラットを使用した。
結果を表1に示す。なお、疼痛改善率は、各群当たりの平均値±標準誤差で表示した。
Four rats were used for each test drug administration group.
The results are shown in Table 1. The pain improvement rate was expressed as an average value ± standard error per group.
表1に示す試験結果より、ロキソプロフェンナトリウム水和物、d−クロルフェニラミンマレイン酸塩及びdl−メチルエフェドリン塩酸塩の3成分の組み合わせ(第6群)は、優れた鎮痛作用を有することが明らかとなった。
特に、その疼痛改善率(約70%)は、鎮痛作用の増強作用が知られるロキソプロフェンナトリウム水和物とd−クロルフェニラミンマレイン酸塩の2成分の組み合わせの疼痛改善率(第4群:約0%)、抗炎症作用の増強作用が知られるロキソプロフェンナトリウム水和物とdl−メチルエフェドリン塩酸塩の2成分の組み合わせの疼痛改善率(第5群:約11%)と比較しても格段に大きく、当該2成分の組み合わせからも予想できないほど格別に優れたものであった。
From the test results shown in Table 1, it is clear that the combination of loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride (group 6) has an excellent analgesic action. It became.
In particular, the pain improvement rate (about 70%) is the pain improvement rate of the combination of the two components of loxoprofen sodium hydrate and d-chlorpheniramine maleate, which is known to enhance the analgesic action (Group 4: 0%), the pain improvement rate of the combination of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride, which is known to enhance the anti-inflammatory action (group 5: about 11%). It was large and exceptionally excellent even as expected from the combination of the two components.
以上の試験結果から、ロキソプロフェン又はその塩、抗ヒスタミン剤であるクロルフェニラミン又はその塩及びエフェドリン類の3成分の組合わせは、組合わせに係る各成分単独、ロキソプロフェン又はその塩とクロルフェニラミン又はその塩の2成分の組合わせ、及びロキソプロフェン又はその塩とエフェドリン類の2成分の組合わせからは予想できない格別に優れた鎮痛作用を奏することが明らかとなった。 From the above test results, the combination of three components of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof and ephedrine as an antihistamine is each component alone, loxoprofen or a salt thereof and chlorpheniramine or a salt thereof. The combination of these two components, and the combination of loxoprofen or a salt thereof and the two components of ephedrine, it was clarified that there was an exceptionally excellent analgesic action that could not be expected.
試験例1−2 ロキソプロフェン又はその塩、クレマスチン又はその塩及びエフェドリン類の3成分の組合わせによる鎮痛作用の検討
被験薬物を以下の群構成に従い投与したほかは試験例1−1と同様の方法により鎮痛試験を行なった。
1:ロキソプロフェンナトリウム水和物 単独投与群(以下、「LX単独」と表記する。)
ロキソプロフェンナトリウム水和物を0.1mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
2:クレマスチンフマル酸塩 単独投与群(以下、「CF単独」と表記する。)
クレマスチンフマル酸塩を3mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
3:dl−メチルエフェドリン塩酸塩 単独投与群(以下、「ME単独」と表記する。)
dl−メチルエフェドリン塩酸塩を0.3g/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
Test Example 1-2 Examination of analgesic action by combining three components of loxoprofen or a salt thereof, clemastine or a salt thereof and ephedrine According to the same method as in Test Example 1-1 except that the test drug was administered according to the following group constitution An analgesic test was performed.
1: Loxoprofen sodium hydrate alone administration group (hereinafter referred to as “LX alone”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
2: Cremastine fumarate single administration group (hereinafter referred to as “CF alone”)
Cremastine fumarate was administered at a dose of 3 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: dl-methylephedrine hydrochloride alone administration group (hereinafter referred to as “ME alone”)
dl-Methylephedrine hydrochloride was administered at a dose of 0.3 g / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
4:ロキソプロフェンナトリウム水和物とdl−メチルエフェドリン塩酸塩の2成分併用投与群(以下、「LX+ME」と表記する。)
ロキソプロフェンナトリウム水和物を0.1mg/kg体重の用量で、dl−メチルエフェドリン塩酸塩を0.3g/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて同時に投与した。
5:ロキソプロフェンナトリウム水和物、クレマスチンフマル酸塩及びdl−メチルエフェドリン塩酸塩の3成分併用投与群(以下、「LX+CF+ME」と表記する。)
ロキソプロフェンナトリウム水和物を0.1mg/kg体重の用量で、クレマスチンフマル酸塩を3mg/kg体重の用量で、dl−メチルエフェドリン塩酸塩を0.3g/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて同時に投与した。
結果を表2に示す。なお、疼痛改善率は、各群当たりの平均値±標準誤差で表示した。
4: Two-component combination administration group of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride (hereinafter referred to as “LX + ME”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution simultaneously at a dose of 0.1 mg / kg body weight and dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight.
5: Three-component combination administration group of loxoprofen sodium hydrate, clemastine fumarate and dl-methylephedrine hydrochloride (hereinafter referred to as “LX + CF + ME”)
Loxoprofen sodium hydrate at a dose of 0.1 mg / kg body weight, clemastine fumarate at a dose of 3 mg / kg body weight, dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight, 0.5% It was dissolved or suspended in a methylcellulose solution and administered simultaneously.
The results are shown in Table 2. The pain improvement rate was expressed as an average value ± standard error per group.
表2に示す試験結果より、ロキソプロフェンナトリウム水和物、クレマスチンフマル酸塩及びdl−メチルエフェドリン塩酸塩の3成分の組み合わせ(第5群)は、優れた鎮痛作用を有することが明らかとなった。
特に、その疼痛改善率(50%強)は、抗炎症作用の増強作用が知られるロキソプロフェンナトリウム水和物とdl−メチルエフェドリン塩酸塩の2成分の組み合わせの疼痛改善率(第4群:約11%)と比較しても格段に大きく、当該2成分の組み合わせからも予測できないほど格別に優れたものであった。
From the test results shown in Table 2, it was revealed that the combination of the three components of loxoprofen sodium hydrate, clemastine fumarate and dl-methylephedrine hydrochloride (group 5) has an excellent analgesic action.
In particular, the pain improvement rate (over 50%) is the pain improvement rate of a combination of two components of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride, which is known to have an anti-inflammatory action enhancement effect (Group 4: approximately 11). %), Which was much larger than the combination of the two components.
以上の試験結果から、ロキソプロフェン又はその塩、抗ヒスタミン剤であるクレマスチン又はその塩及びエフェドリン類の3成分の組合わせは、組合わせに係る各成分単独、及びロキソプロフェン又はその塩とエフェドリン類の2成分の組合わせからは予測できない格別に優れた鎮痛作用を奏することが明らかとなった。 From the above test results, the combination of loxoprofen or a salt thereof, clemastine which is an antihistamine or a salt thereof and ephedrines is a combination of each component alone, or a combination of loxoprofen or a salt thereof and ephedrines. It became clear from the combination that it has an exceptionally excellent analgesic effect that cannot be predicted.
さらに、試験例1−1及び1−2の試験結果から、ロキソプロフェン又はその塩、クロルフェニラミン又はその塩やクレマスチン又はその塩を含む抗ヒスタミン剤、及びエフェドリン類の3成分を組合わせることにより、格別に優れた鎮痛作用を奏することが明らかとなった。 Furthermore, from the test results of Test Example 1-1 and 1-2, by combining three components of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof, an antihistamine containing clemastine or a salt thereof, and ephedrines, It became clear that there was an excellent analgesic action.
[試験例2]解熱試験
8週齢のWistar系雄性ラット(体重202.0〜251.4g)を用い、被験薬物投与群、及び溶媒投与群それぞれ1群当り4〜7匹として試験を実施した。
微小精密温度計(BAT−12、Physitemp社製)を直腸に4.5cm挿入し、ラットの直腸温を測定して、これを平常時体温とした。次いで、粉砕したビール酵母(エビオス錠、アサヒフードアンドヘルスケア)を生理食塩液に懸濁し20%濃度としたものを、ラット背部皮下に10mL/kg体重の用量で投与した。
ラットを酵母投与後絶食(水は自由摂取とした。)し、投与約16時間後、直腸温を測定し、これを発熱時体温とした。発熱量(発熱時体温−平常時体温)が1℃以上の個体を、平均発熱量がほぼ等しくなるように群分けした。
[Test Example 2] Antipyretic Test An 8-week-old Wistar male rat (body weight 202.0 to 251.4 g) was used, and the test was conducted as 4 to 7 animals per test drug administration group and solvent administration group, respectively. .
A micro precision thermometer (BAT-12, manufactured by Physitemp) was inserted into the rectum 4.5 cm, and the rectal temperature of the rat was measured. Next, crushed brewer's yeast (Ebios tablets, Asahi Food and Health Care) suspended in physiological saline to a concentration of 20% was administered subcutaneously at the back of the rat at a dose of 10 mL / kg body weight.
Rats were fasted after yeast administration (water was ad libitum), and about 16 hours after administration, rectal temperature was measured, and this was taken as body temperature during fever. Individuals with a calorific value (body temperature during fever-normal body temperature) of 1 ° C. or higher were grouped so that the average calorific value was approximately equal.
上記群分けを行なった直後に被験薬物又は溶媒(0.5%メチルセルロース溶液:以下、「0.5%MC」と表記する。)を経口投与し、その1時間後に直腸温を測定し、被験薬物投与群の発熱量(被験薬物投与後の体温−平常時体温)及び溶媒投与群の発熱量(溶媒投与後の体温−平常時体温)を算出して、以下の数式に基づき、発熱抑制率(%)を算出した。 Immediately after the above grouping, the test drug or solvent (0.5% methylcellulose solution: hereinafter referred to as “0.5% MC”) was orally administered, and after 1 hour, rectal temperature was measured, and the test was performed. Calculate the calorific value of the drug administration group (body temperature after administration of the test drug-normal body temperature) and the calorific value of the solvent administration group (body temperature after administration of the solvent-normal body temperature). (%) Was calculated.
発熱抑制率(%)=(溶媒投与群の発熱量の平均値−被験薬物投与群の発熱量の平均値)/溶媒投与群の発熱量の平均値×100 Fever suppression rate (%) = (average value of calorific value of solvent administration group−average value of calorific value of test drug administration group) / average value of calorific value of solvent administration group × 100
被験薬物は、それぞれ以下の群構成に従い投与した。
1:ロキソプロフェンナトリウム水和物 単独投与群(以下、「LX単独」と表記する。)
ロキソプロフェンナトリウム水和物を、1mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
2:d−クロルフェニラミンマレイン酸塩 単独投与群(以下、「CM単独」と表記する。)
d−クロルフェニラミンマレイン酸塩を3.5mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
3:dl−メチルエフェドリン塩酸塩 単独投与群(以下、「ME単独」と表記する。)
dl−メチルエフェドリン塩酸塩を6mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて投与した。
4:ロキソプロフェンナトリウム水和物、d−クロルフェニラミンマレイン酸塩及びdl−メチルエフェドリン塩酸塩の3成分併用投与群(以下、「LX+CM+ME」と表記する。)
ロキソプロフェンナトリウム水和物を1mg/kg体重の用量で、d−クロルフェニラミンマレイン酸塩を3.5mg/kg体重の用量で、dl−メチルエフェドリン塩酸塩を6mg/kg体重の用量で、0.5%メチルセルロース溶液に溶解又は懸濁させて同時に投与した。
結果を表3に示す。
Each test drug was administered according to the following group composition.
1: Loxoprofen sodium hydrate alone administration group (hereinafter referred to as “LX alone”)
Loxoprofen sodium hydrate was administered at a dose of 1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
2: d-chlorpheniramine maleate single administration group (hereinafter referred to as “CM alone”)
d-Chlorpheniramine maleate was administered at a dose of 3.5 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: dl-methylephedrine hydrochloride alone administration group (hereinafter referred to as “ME alone”)
dl-Methylephedrine hydrochloride was administered at a dose of 6 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
4: Loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride combined administration group (hereinafter referred to as “LX + CM + ME”)
Loxoprofen sodium hydrate at a dose of 1 mg / kg body weight, d-chlorpheniramine maleate at a dose of 3.5 mg / kg body weight, and dl-methylephedrine hydrochloride at a dose of 6 mg / kg body weight. It was dissolved or suspended in a 5% methylcellulose solution and administered simultaneously.
The results are shown in Table 3.
表3に示す試験結果より、ロキソプロフェンナトリウム水和物(第1群)は発熱抑制、すなわち解熱作用を示した(発熱抑制率:約50%)。一方、d−クロルフェニラミンマレイン酸塩(第2群)及びdl−メチルエフェドリン塩酸塩(第3群)はいずれもほとんど解熱作用を示さなかった(発熱抑制率:それぞれ約8%及び約3%)。
ところが、ロキソプロフェンナトリウム水和物、d−クロルフェニラミンマレイン酸塩及びdl−メチルエフェドリン塩酸塩の3成分の組み合わせ(第4群)は、特に第1群と比較しても優れた解熱作用を示した(発熱抑制率:約80%)。
From the test results shown in Table 3, loxoprofen sodium hydrate (Group 1) showed an exothermic inhibition, that is, an antipyretic action (exothermic inhibition rate: about 50%). On the other hand, both d-chlorpheniramine maleate (group 2) and dl-methylephedrine hydrochloride (group 3) showed almost no antipyretic action (fever suppression rate: about 8% and about 3%, respectively) ).
However, the combination of the three components of loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride (group 4) shows an excellent antipyretic effect even when compared with the group 1 in particular. (Fever suppression rate: about 80%).
以上の試験結果から、ロキソプロフェン又はその塩、クロルフェニラミン又はその塩を含む抗ヒスタミン剤、及びエフェドリン類の3成分を組合わせることにより、優れた解熱作用を奏することが明らかとなった。 From the above test results, it has been clarified that an excellent antipyretic effect can be obtained by combining three components of loxoprofen or a salt thereof, an antihistamine containing chlorpheniramine or a salt thereof, and ephedrines.
[試験例3]ロキソプロフェン誘発消化管障害抑制試験
試験例3−1 エフェドリン類による、ロキソプロフェン誘発消化管障害の抑制作用の検討
8週齢のWistar系雄性ラットを用い、被験薬物投与群、及び溶媒投与群(対照群)それぞれ1群当り6匹として試験を実施した。ラットは、試験開始の16時間以上前より絶食とした。水の摂取は試験開始前1時間までは自由摂取とし、以後絶水とした。
被験薬物として、dl−メチルエフェドリン塩酸塩(以下、「ME」と表記する。)を0.5%メチルセルロース溶液に溶解又は懸濁し、所定量(20、60、180mg/5mL/kg体重)経口投与した。また、溶媒投与群には0.5%メチルセルロース溶液のみ(以下、「0.5%MC」と表記する。)をそれぞれ同容量(5mL/kg)経口投与した。
被験薬物又は溶媒の投与1時間後に、ロキソプロフェンナトリウム水和物120mg/2mL生理食塩水/kg体重を経口投与し、胃粘膜障害を誘発した。ロキソプロフェンナトリウム水和物の投与5時間後、ラットを頚椎脱臼により安楽死させ、噴門部を結紮し胃を摘出した。幽門部から胃内に1%ホルマリン溶液10mLを注入し、幽門部を結紮後、胃全体を同ホルマリン溶液中に約20分間浸漬して軽度に固定した。
Test Example 3 Loxoprofen-Induced Gastrointestinal Disorder Inhibition Test Test Example 3-1 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibition Effect by Ephedrines Using Tested Drug Administration Group and Solvent Administration Using 8-week-old Wistar Male Rats Each group (control group) was tested as 6 animals per group. Rats were fasted at least 16 hours before the start of the study. Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, dl-methylephedrine hydrochloride (hereinafter referred to as “ME”) is dissolved or suspended in a 0.5% methylcellulose solution and given orally (20, 60, 180 mg / 5 mL / kg body weight). did. Further, only 0.5% methylcellulose solution (hereinafter referred to as “0.5% MC”) was orally administered to the solvent administration group in the same volume (5 mL / kg).
One hour after administration of the test drug or solvent, loxoprofen sodium hydrate 120 mg / 2 mL physiological saline / kg body weight was orally administered to induce gastric mucosal damage. Five hours after administration of loxoprofen sodium hydrate, the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.
胃粘膜障害の程度の評価は、胃を大弯に沿って切開した後、実体顕微鏡下にて腺胃部に発生した個々の損傷(びらん)の長さ(mm)を測定することにより行い、ラット1匹当たりの損傷の総和を潰瘍指数とし、被験薬物投与群、及び溶媒投与群それぞれ各群につき、潰瘍指数(平均値±標準誤差)を算出した。また、以下の式に従い、溶媒投与群の潰瘍指数の平均値を100%とした場合における被験薬物による潰瘍抑制率(%)を算出した。 Evaluation of the degree of gastric mucosal damage is performed by measuring the length (mm) of individual damage (erosion) occurring in the glandular stomach portion under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was taken as the ulcer index, and the ulcer index (average value ± standard error) was calculated for each group administered with the test drug and the solvent administration group. Further, according to the following formula, the ulcer suppression rate (%) by the test drug was calculated when the average value of the ulcer index of the solvent administration group was 100%.
潰瘍抑制率(%)=(溶媒投与群における潰瘍指数の平均値−被験薬物投与群における潰瘍指数の平均値)/溶媒投与群における潰瘍指数の平均値×100 Ulcer inhibition rate (%) = (average value of ulcer index in solvent administration group−average value of ulcer index in test drug administration group) / average value of ulcer index in solvent administration group × 100
結果を表4に示す。なお、潰瘍指数は各群当りの平均値±標準誤差で表示した。 The results are shown in Table 4. The ulcer index was expressed as an average value ± standard error for each group.
表4から明らかなように、dl−メチルエフェドリン塩酸塩が用量依存的にロキソプロフェンナトリウム水和物に起因する胃粘膜障害を抑制した。
以上の試験結果から、エフェドリン類が、ロキソプロフェン又はその塩に起因する消化管障害に対し抑制作用を有することが明らかとなった。また、エフェドリン類は、ロキソプロフェンと同様に消化管障害を引き起こす他のNSAIDに対しても、同様の抑制作用を有するものと考えられた。
As is apparent from Table 4, dl-methylephedrine hydrochloride suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.
From the above test results, it has been clarified that ephedrines have an inhibitory effect on gastrointestinal disorders caused by loxoprofen or a salt thereof. In addition, ephedrines were considered to have the same inhibitory action against other NSAIDs that cause gastrointestinal disorders as well as loxoprofen.
試験例3−2 クロルフェニラミン又はその塩による、ロキソプロフェン誘発消化管障害の抑制作用の検討
被験薬物としてd−クロルフェニラミンマレイン酸塩(以下、「CM」と表記する。)を0.5%メチルセルロース溶液に溶解又は懸濁し、所定量(5、40mg/5mL/kg体重)を経口投与することにより、試験例3−1と同様に試験を実施した。結果を表5に示す。なお、潰瘍指数は各群当たりの平均値±標準誤差で表示した。
Test Example 3-2 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Chlorpheniramine or its Salt 0.5% of d-chlorpheniramine maleate (hereinafter referred to as “CM”) as a test drug The test was carried out in the same manner as in Test Example 3-1, by dissolving or suspending in a methylcellulose solution and orally administering a predetermined amount (5, 40 mg / 5 mL / kg body weight). The results are shown in Table 5. The ulcer index was expressed as an average value ± standard error per group.
表5から明らかなように、抗ヒスタミン剤であるd−クロルフェニラミンマレイン酸塩が用量依存的にロキソプロフェンナトリウム水和物に起因する胃粘膜障害を抑制した。 As is apparent from Table 5, d-chlorpheniramine maleate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.
試験例3−3 クレマスチン又はその塩による、ロキソプロフェン誘発消化管障害の抑制作用の検討
被験薬物としてクレマスチンフマル酸塩(以下、「CF」と表記する。)を0.5%メチルセルロース溶液に溶解又は懸濁し、所定量(1mg/5mL/kg体重)を経口投与することにより、試験例3−1と同様に試験を実施した。結果を表6に示す。なお、潰瘍指数は各群当たりの平均値±標準誤差で表示した。
Test Example 3-3 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibition Effect of Clemastine or its Salt As a test drug, clemastine fumarate (hereinafter referred to as “CF”) is dissolved or suspended in a 0.5% methylcellulose solution. The test was carried out in the same manner as in Test Example 3-1, by turbidity and oral administration of a predetermined amount (1 mg / 5 mL / kg body weight). The results are shown in Table 6. The ulcer index was expressed as an average value ± standard error per group.
表6から明らかなように、抗ヒスタミン剤であるクレマスチンフマル酸塩がロキソプロフェンナトリウム水和物に起因する胃粘膜障害を抑制した。 As is apparent from Table 6, clemastine fumarate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate.
試験例3−4 カルビノキサミン又はその塩による、ロキソプロフェン誘発消化管障害の抑制作用の検討
被験薬物としてカルビノキサミンマレイン酸塩(以下、「CAM」と表記する。)を0.5%メチルセルロース溶液に溶解又は懸濁し、所定量(0.75、75mg/5mL/kg体重)を経口投与することにより、試験例3−1と同様に試験を実施した。結果を表7に示す。なお、潰瘍指数は各群当たりの平均値±標準誤差で表示した。
Test Example 3-4 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibition Effect by Carbinoxamine or its Salt Carbinoxamine maleate (hereinafter referred to as “CAM”) as a test drug is dissolved in a 0.5% methylcellulose solution. Alternatively, the test was carried out in the same manner as in Test Example 3-1, by suspending and orally administering a predetermined amount (0.75, 75 mg / 5 mL / kg body weight). The results are shown in Table 7. The ulcer index was expressed as an average value ± standard error per group.
表7から明らかなように、抗ヒスタミン剤であるカルビノキサミンマレイン酸塩が用量依存的にロキソプロフェンナトリウム水和物に起因する胃粘膜障害を抑制した。 As is apparent from Table 7, carbinoxamine maleate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.
試験例3−5 ジフェニルピラリン又はその塩による、ロキソプロフェン誘発消化管障害の抑制作用の検討
被験薬物としてジフェニルピラリン塩酸塩(以下、「PP」と表記する。)を0.5%メチルセルロース溶液に溶解又は懸濁し、所定量(3、10mg/5mL/kg体重)を経口投与することにより、試験例3−1と同様に試験を実施した。結果を表8に示す。なお、潰瘍指数は各群当たりの平均値±標準誤差で表示した。
Test Example 3-5 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Diphenylpyraline or its Salt Dissolve diphenylpyraline hydrochloride (hereinafter referred to as “PP”) as a test drug in a 0.5% methylcellulose solution or The test was carried out in the same manner as in Test Example 3-1, by suspending and orally administering a predetermined amount (3, 10 mg / 5 mL / kg body weight). The results are shown in Table 8. The ulcer index was expressed as an average value ± standard error per group.
表8から明らかなように、抗ヒスタミン剤であるジフェニルピラリン塩酸塩が用量依存的にロキソプロフェンナトリウム水和物に起因する胃粘膜障害を抑制した。 As is apparent from Table 8, diphenylpyraline hydrochloride, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.
試験例3−6 メキタジン又はその塩による、ロキソプロフェン誘発消化管障害の抑制作用の検討
被験薬物としてメキタジン(以下、「MQ」と表記する。)を0.5%メチルセルロース溶液に溶解又は懸濁し、所定量(1、3、10mg/5mL/kg体重)を経口投与することにより、試験例3−1と同様に試験を実施した。結果を表9に示す。なお、潰瘍指数は各群当たりの平均値±標準誤差で表示した。
Test Example 3-6 Examination of Loxoprofen-induced Gastrointestinal Disorder Inhibitory Effect by Mequitazine or its Salt Mequitazine (hereinafter referred to as “MQ”) as a test drug was dissolved or suspended in a 0.5% methylcellulose solution, The test was carried out in the same manner as in Test Example 3-1, by orally administering a fixed amount (1, 3, 10 mg / 5 mL / kg body weight). The results are shown in Table 9. The ulcer index was expressed as an average value ± standard error per group.
表9から明らかなように、抗ヒスタミン剤であるメキタジンが用量依存的にロキソプロフェンナトリウム水和物に起因する胃粘膜障害を抑制した。 As is apparent from Table 9, mequitazine, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.
試験例3−2〜3−6の試験結果から、クロルフェニラミン又はその塩、クレマスチン又はその塩、カルビノキサミン又はその塩、ジフェニルピラリン又はその塩、メキタジン又はその塩を含む抗ヒスタミン剤が、ロキソプロフェン又はその塩に起因する消化管障害に対し抑制作用を有することが明らかとなった。また、抗ヒスタミン剤は、ロキソプロフェンと同様に消化管障害を引き起こす他のNSAIDに対しても、同様の抑制作用を有するものと考えられた。 From the test results of Test Examples 3-2 to 3-6, an antihistamine containing chlorpheniramine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, diphenylpyraline or a salt thereof, mequitazine or a salt thereof is loxoprofen or a salt thereof. It was clarified that it has an inhibitory effect on gastrointestinal disorders caused by. Moreover, it was thought that an antihistamine has the same inhibitory effect also with respect to other NSAIDs that cause gastrointestinal dysfunction in the same manner as loxoprofen.
[実施例1]
9錠(1日量)中に以下の成分を含有する錠剤を、第十五改正日本薬局方 製剤総則の「錠剤」の項に準じて、常法により製造した。
ロキソプロフェンナトリウム水和物(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物) 204.3mg
d−クロルフェニラミンマレイン酸塩(金剛化学製:商品名 D−マレイン酸クロルフェニラミン) 3.5mg
dl−メチルエフェドリン塩酸塩(アルプス薬品工業製:商品名 日本薬局方 dl−塩酸メチルエフェドリン末) 60mg
ヒドロキシプロピルセルロース 72.9mg
カルメロースカルシウム 243mg
結晶セルロース 1822mg
ステアリン酸マグネシウム 24.3mg
[Example 1]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
d-Chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd., trade name: D-chlorpheniramine maleate) 3.5 mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1822mg
Magnesium stearate 24.3mg
かぜに伴う諸症状(のどの痛み、悪寒、発熱、頭痛、関節の痛み及び筋肉の痛み)を訴えている成人男性(43歳)に、同意のうえ実施例1の錠剤を1回3錠 1日3回毎食後の用法で2日間投薬した。投薬後、上記諸症状に関しヒアリングしたところ、いずれの症状についても緩和された旨の回答が得られた。 For adult male (43 years old) complaining of cold-related symptoms (sore pain, chills, fever, headache, joint pain and muscle pain) The dosage was taken 3 times a day for 2 days after use. After the medication, interviews were conducted regarding the above symptoms, and an answer that all symptoms were alleviated was obtained.
[実施例2]
6錠(1日量)中に以下の成分を含有する錠剤を、第十五改正日本薬局方 製剤総則の「錠剤」の項に準じて、常法により製造した。
ロキソプロフェンナトリウム水和物(大和薬品工業製:商品名 日本薬局方 ロキソプロフェンナトリウム水和物) 204.3mg
クレマスチンフマル酸塩(ダイト製:商品名 クレマスチンフマル酸塩) 1.34mg
dl−メチルエフェドリン塩酸塩(アルプス薬品工業製:商品名 日本薬局方 dl−塩酸メチルエフェドリン末) 60mg
トラネキサム酸 750mg
ブロムヘキシン塩酸塩 12mg
ジヒドロコデインリン酸塩 24mg
チアミン硝化物(ビタミンB1硝酸塩) 25mg
リボフラビン(ビタミンB2) 12mg
トレハロース 600mg
結晶セルロース 467.36mg
マクロゴール6000 60mg
クロスカルメロースナトリウム 80mg
ポリビニルアルコール 1mg
軽質無水ケイ酸 24mg
硬化油 65mg
ステアリン酸マグネシウム 44mg
[Example 2]
Tablets containing the following components in 6 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 60mg
Tranexamic acid 750mg
Bromhexine hydrochloride 12mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 12mg
Trehalose 600mg
Crystalline cellulose 467.36mg
Macrogol 6000 60mg
Croscarmellose sodium 80mg
Polyvinyl alcohol 1mg
Light anhydrous silicic acid 24mg
Hardened oil 65mg
Magnesium stearate 44mg
ロキソプロフェン又はその塩、抗ヒスタミン剤及びエフェドリン類の3成分を併用すると、優れた鎮痛作用及び/又は解熱作用を奏する。また、抗ヒスタミン剤及び/又はエフェドリン類は、ロキソプロフェン又はその塩に起因する消化管障害に対し抑制作用を有する。従って、本発明によれば、優れた薬理効果を示し、ロキソプロフェン又はその塩に起因する消化管障害が抑制された安全性に優れる医薬組成物を提供することができ、医薬品産業において好適に利用できる。 Combined use of loxoprofen or a salt thereof, an antihistamine, and ephedrines provides excellent analgesic and / or antipyretic effects. In addition, antihistamines and / or ephedrines have an inhibitory action on gastrointestinal disorders caused by loxoprofen or a salt thereof. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition that exhibits excellent pharmacological effects and is excellent in safety in which gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed, and can be suitably used in the pharmaceutical industry. .
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JP2006515299A (en) * | 2002-12-18 | 2006-05-25 | ワイス | Non-steroidal anti-inflammatory, decongestant and antihistamine composition |
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JP2011225527A (en) | 2011-11-10 |
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