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JP2013032408A - Orally dissolution type or mandibulate type rhinitis treatment solid internal pharmaceutical formulation

Publication number

JP2013032408A

JP2013032408A JP2012256294A JP2012256294A JP2013032408A JP 2013032408 A JP2013032408 A JP 2013032408A JP 2012256294 A JP2012256294 A JP 2012256294A JP 2012256294 A JP2012256294 A JP 2012256294A JP 2013032408 A JP2013032408 A JP 2013032408A

Authority

JP

Japan

Prior art keywords

hydrochloride

rhinitis

diphenhydramine

nasal

drug

Prior art date

2012-11-22

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Pending

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• 239000000391 magnesium silicate Substances 0.000 description 1
• 229910052919 magnesium silicate Inorganic materials 0.000 description 1
• 235000019792 magnesium silicate Nutrition 0.000 description 1
• AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
• ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 description 1
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

PROBLEM TO BE SOLVED: To provide a stable and effective rhinitis medication combining immediate effectivity and long acting property.SOLUTION: There is provided an orally dissolution type or mandibulate type rhinitis treatment solid internal pharmaceutical formulation containing a rhinitis medication.

本発明は即効性と持続性を有する口中溶解型又は咀嚼型の鼻炎症状治療用固形内服医薬組成物に関する。   The present invention relates to a solid oral pharmaceutical composition for treating nasal inflammation in the mouth which has immediate effect and persistence and which is dissolved in the mouth or chewable.

鼻の入口（鼻孔）は小さいが、その奥に粘膜で覆われた大きい空間（鼻腔）があり、鼻腔はさらに奥の方で咽頭とつながっている。鼻炎はこの鼻腔の粘膜に何らかの原因で炎症が起こった状態であり、主な原因として、アレルギー、ウイルスや細菌による感染症を挙げることができる。
近年、花粉症やハウスダストによるアレルギー性鼻炎に悩む患者は増加の一途にある。また、ウイルス等によるインフルエンザや感冒等、いわゆる「かぜ」の諸症状の一つとしての鼻炎症状を示す患者は絶えることがない。通常、慢性的な鼻炎症状を示す原因の代表はアレルギーであるが、「かぜ」の治療が中途半端な場合には鼻炎が治らず慢性鼻炎に移行する例もある。また、「かぜ」の患者ではウイルス感染等により鼻の自浄作用が低下するためにブドウ球菌、溶連菌等の常在性細菌によって鼻炎が悪化する場合がある。
このように原因は様々であるが、鼻炎に共通する具体的症状として、鼻汁、鼻閉、くしゃみ、鼻腔の痒み、涙目、のどの痛み等がある。鼻閉症状は鼻の粘膜が腫れて鼻腔が狭くなることによるものであり、呼吸困難や頭重感等を伴うことがある。また、鼻汁分泌は、それ自身、不快感をもたらすが、頻繁に鼻を噛むことにより鼻腔の炎症を誘発する恐れがある。涙目は、涙の分泌が促進されることによって引き起こされる症状である。 Although the entrance to the nose (nasal passage) is small, there is a large space (nasal cavity) covered with mucous membranes in the back, and the nasal cavity is further connected to the pharynx at the back. Rhinitis is a condition in which inflammation occurs in the mucous membrane of the nasal cavity for some reason, and the main causes include allergies, infections caused by viruses and bacteria.
In recent years, an increasing number of patients suffer from allergic rhinitis caused by hay fever and house dust. In addition, patients who show nasal inflammation as one of the symptoms of so-called “cold” such as influenza due to viruses and colds, etc. are invariable. The typical cause of chronic rhinitis is usually allergy, but if treatment of “cold” is halfway, rhinitis may not be cured and there may be cases where chronic rhinitis is transferred. In the case of “cold” patients, rhinitis may be exacerbated by resident bacteria such as staphylococci and streptococci, because the nasal self-cleaning action decreases due to viral infection and the like.
There are various causes, but specific symptoms common to rhinitis include nasal discharge, nasal congestion, sneezing, itching of the nasal cavity, tear eyes, and sore throat. Nasal obstruction symptoms are caused by swelling of the nasal mucosa and narrowing of the nasal cavity, which may be accompanied by difficulty breathing and head feeling. In addition, nasal discharge itself causes discomfort, but can frequently cause inflammation of the nasal cavity by biting the nose. The lacrimal eye is a symptom caused by the promotion of tear secretion.

多くの鼻炎患者が上記の不快な症状を複数、繰り返して、又は慢性的に発現している。そのような状態が長期間にわたって持続すると、患者の生活の質（ＱＯＬ）が低下し、日常生活に支障をきたすことになる。これら鼻炎症状、特に鼻閉及び鼻汁の増加は耐え難い不快感を与えることから、鼻炎患者は即効性のある有効な治療を強く求める傾向がある。そのため、総合的鼻炎症状の緩和に留まらず、鼻汁分泌抑制や鼻閉改善効果の増強された即効性と持続性に優れた医薬製剤の開発が強く望まれていた。
従来、鼻炎症状に対する薬物治療は、主として抗ヒスタミン薬、交感神経興奮薬（血管収縮薬）、副交感神経遮断薬、抗炎症剤、消炎酵素等の薬物を経口内服剤、もしくは点鼻剤として投与することによって行われている。 Many rhinitis patients develop the above-mentioned unpleasant symptoms more than once, repeatedly or chronically. If such a state persists for a long period of time, the quality of life (QOL) of the patient will be reduced, which will interfere with daily life. Because these nasal inflammation symptoms, particularly increased nasal congestion and nasal discharge, can be intolerable and uncomfortable, rhinitis patients have a strong tendency to seek immediate and effective treatment. For this reason, there has been a strong demand for the development of a pharmaceutical preparation excellent in immediate effect and sustainability that is not limited to alleviating the symptoms of nasal inflammation but also has enhanced nasal secretion suppression and nasal closure improvement effects.
Conventionally, pharmacological treatment for nasal inflammation is mainly administered as an antihistamine, sympathomimetic drug (vasoconstrictor), parasympatholytic agent, anti-inflammatory agent, anti-inflammatory enzyme, etc. Is done by that.

点鼻剤は、鼻孔から鼻腔へ薬物を噴霧又は滴下して直接粘膜に到達させるために、鼻閉に対する即効性は期待できる。しかし、鼻汁過多の場合には、鼻腔の生理機能により鼻腔から鼻孔に向かって鼻汁が押出されるために、薬物を鼻腔に効果的に到達できない場合がある。また、効果の持続性や、鼻汁、頭重、涙目の緩和という点では十分な効果を示さない。一方、経口内服剤は、効果の持続性や、鼻閉、鼻汁、頭重、のどの痛み、涙目の治療という点では有用であるが、即効性を期待することはできない。より優れた即効性の内服固形剤として、鼻炎用ソフトカプセル剤が提供されているが、この製剤も服用後速やかに胃に到達するため、鼻腔への直接作用がなく、即時に効果を示すことはできない。また、一般に内服固形剤は、消化管を経て吸収され、局所に作用するものであることから、効果の発現が食事内容の影響を受けて変動し、確実な効果を期待できないばかりか、投与した薬物のごく一部が目的の部位(鼻腔)に到達し、効果を発揮するにすぎず、薬物の有効利用という点でも問題がある。
従って、投与した薬物が迅速に炎症部位に到達して作用すると同時に、その作用が確実に持続し、生物学的利用率が高く、薬物の効果を最大限に引き出すことができる医薬組成物の開発が望まれていた。 Since the nasal drops are sprayed or dripped from the nostril into the nasal cavity to reach the mucosa directly, immediate effects on nasal congestion can be expected. However, in the case of excessive nasal discharge, the nasal discharge is pushed from the nasal cavity toward the nostril due to the physiological function of the nasal cavity, so that the drug may not effectively reach the nasal cavity. In addition, it does not show sufficient effects in terms of the persistence of effects and the relief of nasal discharge, head weight and tears. On the other hand, oral preparations are useful in terms of sustained effects, treatment of nasal congestion, nasal discharge, head weight, sore throat, and tears, but cannot be expected to be effective immediately. Soft capsules for rhinitis have been provided as a more immediate solid agent for immediate use, but since this preparation also reaches the stomach quickly after taking it, there is no direct action on the nasal cavity and it is effective immediately Can not. In general, oral solids are absorbed through the gastrointestinal tract and act locally, so the effects of the drug fluctuate under the influence of the meal content, and a reliable effect cannot be expected. Only a small part of the drug reaches the target site (nasal cavity) and exhibits its effect, and there is a problem in terms of effective use of the drug.
Therefore, the development of a pharmaceutical composition that allows the administered drug to quickly reach the site of inflammation and at the same time ensure that the action lasts, has high bioavailability, and maximizes the effect of the drug. Was desired.

本発明者らは、鼻炎症状の治療に即効性と確実な持続性とを示す、有効な鼻炎治療用の固形内服医薬組成物を提供することを目的として鋭意、研究を重ねた結果、同量の有効成分を作用させる場合に、口中溶解型又は咀嚼型の形態にすると、効果の即効性、持続性のみならず高い生物学的利用率をも達成できることを見出し、本発明を完成するに至った。
すなわち、本発明は鼻炎治療薬を含有する口中溶解型又は咀嚼型の鼻炎治療用固形医薬組成物を提供するものである。 The inventors of the present invention have intensively and intensively studied for the purpose of providing an effective solid oral pharmaceutical composition for the treatment of rhinitis, which exhibits an immediate effect and a reliable persistence in the treatment of nasal inflammation. When the active ingredient of the present invention is allowed to act, it has been found that if it is in the mouth-dissolving or chewing form, not only the immediate effect and sustainability of the effect can be achieved, but also a high bioavailability can be achieved. It was.
That is, the present invention provides a solid pharmaceutical composition for treating rhinitis which is dissolved in the mouth or contains mastication type rhinitis.

従って、本発明は以下を提供する。
（１）鼻炎治療薬を含有する口中溶解型又は咀嚼型の鼻炎治療用固形内服医薬組成物。
（２）鼻炎治療薬が副交感神経遮断薬、抗ヒスタミン薬、交感神経興奮薬、抗アレルギー薬、抗炎症薬及び消炎酵素から選択される１又はそれ以上の医薬である項目（１）記載の医薬組成物。
（３）副交感神経遮断薬がダツラエキス、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ロートエキス及びヨウ化イソプロパミドから選択されるものである項目（２）記載の医薬組成物。
（４）副交感神経遮断薬がベラドンナアルカロイド、ベラドンナ総アルカロイド及びヨウ化イソプロパミドから選択されるものである項目（３）記載の医薬組成物。
（５）抗ヒスタミン薬が、塩酸イソチペンジル、塩酸イプロヘプチン、塩酸ジフェテロール、塩酸ジフェニルピラリン、塩酸ジフェンヒドラミン、ジフェンヒドラミン、塩酸トリプロリジン、塩酸トリペレナミン、塩酸トンジルアミン、塩酸プロメタジン、塩酸メトジラジン、サリチル酸ジフェンヒドラミン、ジフェニルジスルホン酸カルビノキサミン、酒石酸アリメマジン、タンニン酸ジフェンヒドラミン、テオクル酸ジフェニルピラリン、マレイン酸カルビノキサミン、マレイン酸クロルフェニラミン（ｄ体、ｄｌ体）、メチレンジサリチル酸プロメタジンから選択されるものである項目（２）記載の医薬組成物。
（６）抗ヒスタミン薬が塩酸イソチペンジル、塩酸イプロヘプチン、塩酸ジフェンヒドラミン、ジフェンヒドラミン、酒石酸アリメマジン、タンニン酸ジフェンヒドラミン及びマレイン酸クロルフェニラミン（ｄ体、ｄｌ体）、又はそれらの塩から選択されるものである項目（５）記載の医薬組成物。
（７）交感神経興奮薬が塩酸フェニルプロパノールアミン、塩酸フェニレフリン、塩酸メチルエフェドリン、塩酸メトキシフェナミン、エピネフリン、塩酸エフェドリン、ノルエピネフリン、硝酸ナファゾリン、ジャイロメタゾリン、ミドドリン、メトキサミン及び塩酸テトラヒドロゾリン、又はそれらの塩から選択されるものである項目（２）記載の医薬組成物。
（８）交感神経興奮薬等が塩酸フェニルプロパノールアミン、塩酸フェニレフリン、塩酸メチルエフェドリン及び塩酸メトキシフェナミン、又はそれらの塩から選択されるものである項目（７）記載の医薬組成物。
（９）抗アレルギー薬がアステミゾール、塩酸シプロヘプタジン、テルフェナジン、イブジラスト、オキサトミド、アンレキサノクス、トラニラスト、ケトチフェン、アゼラスチン、クロモグリク酸ナトリウム、レピリナスト、エメダスチン、メキタジン、オザグレル、タザノラスト、ペミロラスト、フマル酸クレマスチン、アリメマジン、エピナスチン及びスプラタスト、又はそれらの塩から選択されるものである項目（２）記載の医薬組成物。
（１０）抗アレルギー薬がアステミゾール、塩酸シプロヘプタジン、アンレキサノクス、フマル酸ケトチフェン、塩酸アゼラスチン、クロモグリク酸ナトリウム、メキタジン、フマル酸クレマスチン及びアリメマジン、塩酸エピナスチン、トラニラスト、フマル酸エメダスチン、オキサトミド、ペミロラストカリウム又はそれらの塩から選択されるものである項目（９）記載の医薬組成物。
（１１）抗炎症薬がグリチルリチン酸及びその塩、カンゾウ及びトラネキサム酸から選択されるものである項目（２）記載の医薬組成物。
（１２）消炎酵素が塩化リゾチーム、ブロメライン、α−キモトリプシン、セミアルカリプロティナーゼ（セアプローゼＳ−ＡＰ）、プロテナーゼ、セラチオペプチダーゼ（セラペプチダーゼ）、ストレプトキナーゼ及びストレプドルナーゼから選択されるものである項目（２）記載の医薬組成物。
（１３）消炎酵素が、セミアルカリプロティナーゼ、塩化リゾチーム、ブロメライン及びセラチオペプチダーゼ（セラペプチダーゼ）から選択されるものである項目（１２）記載の医薬組成物。
（１４）さらにメントール、カンフル又はシネロールをも含有する項目（１）又は（２）記載の医薬組成物。
（１５）さらにカフェインをも含有する項目（１）、（２）、（１４）のいずれかに記載の医薬組成物。
（１６）口中咀嚼型製剤である項目（１）〜（１５）のいずれかに記載の医薬組成物。 Accordingly, the present invention provides the following.
(1) A solid oral pharmaceutical composition for treating rhinitis in the mouth, containing a therapeutic agent for rhinitis.
(2) The medicament according to item (1), wherein the rhinitis therapeutic agent is one or more medicaments selected from parasympatholytic agents, antihistamines, sympathomimetics, antiallergic agents, antiinflammatory agents and anti-inflammatory enzymes. Composition.
(3) The pharmaceutical composition according to item (2), wherein the parasympathetic nerve blocker is selected from datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, funnel extract, and iodopropamide.
(4) The pharmaceutical composition according to item (3), wherein the parasympathetic nerve blocker is selected from belladonna alkaloids, belladonna total alkaloids, and isopropamide iodide.
(5) Antihistamines are isothipenzil hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, triprolidine hydrochloride, tripelenamine hydrochloride, tonsilamine hydrochloride, promethazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, The pharmaceutical composition according to item (2), which is selected from alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, carbinoxamine maleate, chlorpheniramine maleate (d form, dl form), and promethazine methylene disalicylate.
(6) An item wherein the antihistamine is selected from isothipentyl hydrochloride, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, alimemazine tartrate, diphenhydramine tannate and chlorpheniramine maleate (d-form, dl-form), or salts thereof (5) The pharmaceutical composition as described.
(7) The sympathomimetic drug is phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, methoxyphenamine hydrochloride, epinephrine, ephedrine hydrochloride, norepinephrine, naphazoline nitrate, gyrometazoline, middolin, methoxamine and tetrahydrozoline hydrochloride, or salts thereof The pharmaceutical composition according to item (2), which is selected from:
(8) The pharmaceutical composition according to item (7), wherein the sympathomimetic drug or the like is selected from phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride and methoxyphenamine hydrochloride, or salts thereof.
(9) Antiallergic drugs include astemizole, cyproheptadine hydrochloride, terfenadine, ibudilast, oxatomide, amlexanox, tranilast, ketotifen, azelastine, cromoglycate sodium, repirinast, emedastine, mequitazine, ozagrel, tazanolast, pemilomastin, fumarine The pharmaceutical composition according to item (2), which is selected from suplatast or a salt thereof.
(10) Antiallergic drugs are astemizole, cyproheptadine hydrochloride, amlexanox, ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate, mequitazine, clemastine fumarate and alimemazine, epinastine hydrochloride, tranilast, emedastine fumarate, oxatomide, pemirolast potassium The pharmaceutical composition according to item (9), which is selected from the salts of
(11) The pharmaceutical composition according to item (2), wherein the anti-inflammatory drug is selected from glycyrrhizic acid and salts thereof, licorice and tranexamic acid.
(12) An item in which the anti-inflammatory enzyme is selected from lysozyme chloride, bromelain, α-chymotrypsin, semi-alkaline proteinase (Seaprose S-AP), proteinase, serratopeptidase (serapeptidase), streptokinase and strepdornase ( 2) The pharmaceutical composition described.
(13) The pharmaceutical composition according to item (12), wherein the anti-inflammatory enzyme is selected from semi-alkaline proteinase, lysozyme chloride, bromelain and serratopeptidase (serapeptidase).
(14) The pharmaceutical composition according to item (1) or (2), which further contains menthol, camphor or cinerol.
(15) The pharmaceutical composition according to any one of items (1), (2), and (14), which further contains caffeine.
(16) The pharmaceutical composition according to any one of items (1) to (15), which is a chewable preparation in the mouth.

本発明の口中溶解型又は咀嚼型鼻炎治療用医薬組成物とは、口腔内で唾液の存在下、瞬時又は漸次溶解させて服用する製剤、又は咀嚼、粉砕して唾液と混合することにより一部又は全部を溶解させてから服用する製剤であり、アレルギーや、インフルエンザ、感冒等の風邪に伴う鼻炎症状の治療に用いる医薬組成物を意味する。
後述の試験例に示すように、本発明の口中溶解型又は咀嚼型の医薬組成物は、同量の鼻炎治療薬を口中で溶解又は咀嚼することなく内服錠剤として服用した場合に比較して、予想外に優れた治療効果を奏する。このように、本発明により鼻炎治療効果の増強が達成されたことで、鼻閉、鼻汁、頭重、涙目、のどの痛みを含むすべての鼻炎症状を、投与直後から長時間にわたって効果的に解消することができる。
この優れた効果は、鼻炎が口腔に密接した部位における症状であり、口中で本発明の医薬組成物を溶解及び／又は咀嚼する過程で唾液と混和されることにより、薬物の溶出が促進されてその一部が、咽頭側から鼻腔内の局所に直接作用し即効性を発揮すること、唾液との混合物として吸収されやすい状態で吸収部位に到達し、安定性を保って消化管から吸収され高い効果を発揮することができること等に関連する。 The pharmaceutical composition for treating mouth-dissolving or masticating rhinitis of the present invention is a preparation prepared by instant or gradual dissolution in the oral cavity in the presence of saliva, or partly by chewing, pulverizing and mixing with saliva. Or, it is a preparation that is taken after all is dissolved, and means a pharmaceutical composition that is used to treat allergic symptoms, nasal inflammation associated with colds such as influenza and colds.
As shown in the test examples described later, the mouth-dissolving or chewing type pharmaceutical composition of the present invention is compared with the case where the same amount of rhinitis therapeutic agent is taken as an internal tablet without dissolving or chewing in the mouth, Unexpectedly excellent therapeutic effect. As described above, the enhancement of rhinitis treatment effect is achieved by the present invention, so that all symptoms of nasal inflammation including nasal congestion, nasal discharge, headache, tears, and sore throat can be effectively eliminated for a long time immediately after administration. can do.
This excellent effect is a symptom at a site where rhinitis is in close contact with the oral cavity, and the dissolution of the drug is promoted by being mixed with saliva in the process of dissolving and / or chewing the pharmaceutical composition of the present invention in the mouth. A part of it acts directly on the nasal cavity from the pharynx side to exert immediate effect, reaches the absorption site in a state of being easily absorbed as a mixture with saliva, and is highly absorbed by the digestive tract while maintaining stability It relates to being able to exert the effect.

本発明の医薬組成物には、口中で溶解させ又は咀嚼することに適しない薬物を除き、任意の既知の鼻炎治療薬を含有させることができる。
そのような鼻炎治療薬として、副交感神経遮断薬、抗ヒスタミン薬、交感神経興奮薬、抗アレルギー薬、抗炎症薬及び消炎酵素を挙げることができ、本発明の医薬組成物を調製する際には、それらから選択される薬物を１又は複数用いる。複数の薬物を用いる場合、それらの薬物は同じ種類（作用によって分類した場合）であってもよく、異なる種類であってもよい。通常、鼻炎患者は、鼻閉、鼻汁、頭重、涙目等の複数の症状を呈することが多いので、総合的に優れた治療効果を得るために、本発明組成物には２種以上の薬物を併用することが好ましい。 The pharmaceutical composition of the present invention may contain any known rhinitis therapeutic agent except for drugs that are not suitable for being dissolved or chewed in the mouth.
Examples of such rhinitis therapeutic agents include parasympatholytic agents, antihistamines, sympathomimetics, antiallergic agents, anti-inflammatory agents and anti-inflammatory enzymes, and when preparing the pharmaceutical composition of the present invention One or more drugs selected from them are used. When a plurality of drugs are used, the drugs may be the same type (when classified by action) or different types. In general, rhinitis patients often exhibit multiple symptoms such as nasal congestion, nasal discharge, head weight, and tears. Therefore, in order to obtain a comprehensive therapeutic effect, the composition of the present invention contains two or more drugs. It is preferable to use together.

本発明に用いられる副交感神経遮断薬は、抗アセチルコリン作用を遮断することに基づく粘液分泌抑制効果、鼻汁抑制効果を有する薬物であり、鼻汁抑制に有用である。例えば、ダツラエキス、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ロートエキス、ヨウ化イソプロパミド等が例示され、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ロートエキス、ヨウ化イソプロパミドが好ましく、ベラドンナアルカロイド、ベラドンナ総アルカロイド、ヨウ化イソプロパミドがより好ましい。これらは単独又は２種以上を併せて用いることができる。副交感神経遮断薬には、唾液分泌の抑制による口渇の副作用があるが、口中で溶解又は咀嚼することにより、内服投与の場合よりも投与量当たりの効果が高くなり、即効性と高い生物学的利用率が確保されるので、結果的に副作用の発現を回避することができる。   The parasympathetic nerve blocker used in the present invention is a drug having a mucus secretion inhibitory effect and a nasal discharge inhibitory effect based on blocking the antiacetylcholine action, and is useful for nasal discharge suppression. For example, datsura extract, belladonna alkaloid, belladonna total alkaloid, belladonna extract, funnel extract, iodoisopropamide, etc. More preferred is isopropamide iodide. These can be used alone or in combination of two or more. Parasympathetic blockade has the side effects of dry mouth due to suppression of salivary secretion, but by dissolving or chewing in the mouth, the effect per dose is higher than in the case of oral administration, and immediate action and high biology As a result, the occurrence of side effects can be avoided.

副交感神経遮断薬は、通常、成人に対して、１日あたり有効成分の量として、通常、０.０１〜１００ｍｇを投与することができ、例えばベラドンナアルカロイドの場合には、０.０１〜１mg、ロートエキス、ベラドンナエキス、ダツラエキスでは１〜１００mg、ヨウ化イソプロパミドであれば０.１〜１０mgを１日１回ないし数回に分けて経口投与することができる。本発明組成物の場合、投与量当たりの効果が高められるので投与量を減少することができる。従って、ベラドンナアルカロイドの場合には、０.１〜０.６mg、ロートエキス、ベラドンナエキス、ダツラエキスでは１０〜６０mg、ヨウ化イソプロパミドであれば１〜８mgの範囲であっても有効であり、口渇等の副作用を避ける意味で、この範囲が好ましい。しかし、投与量は、患者の年齢、体重、病状に応じて適宜増減することができ、上記範囲に限定されない。   The parasympatholytic agent can usually be administered to an adult in an amount of 0.01 to 100 mg as an active ingredient per day. For example, in the case of belladonna alkaloids, 0.01 to 1 mg, In the case of funnel extract, belladonna extract, and duck extract, 1-100 mg can be administered orally in the case of isopropamide iodide, 0.1-10 mg once a day or several times a day. In the case of the composition of the present invention, since the effect per dose is enhanced, the dose can be reduced. Accordingly, in the case of belladonna alkaloids, 0.1 to 0.6 mg, 10-60 mg for funnel extract, belladonna extract, and duck extract, and 1-8 mg for isopropamide iodide are effective. This range is preferable in order to avoid side effects. However, the dose can be appropriately increased or decreased according to the patient's age, weight, and medical condition, and is not limited to the above range.

抗ヒスタミン薬はヒスタミンの作用をブロックする薬物であって、例えば、塩酸イソチペンジル、塩酸イプロヘプチン、塩酸ジフェテロール、塩酸ジフェニルピラリン、塩酸ジフェンヒドラミン、ジフェンヒドラミン、塩酸トリプロリジン、塩酸トリペレナミン、塩酸トンジルアミン、塩酸プロメタジン、塩酸メトジラジン、サリチル酸ジフェンヒドラミン、ジフェニルジスルホン酸カルビノキサミン、酒石酸アリメマジン、タンニン酸ジフェンヒドラミン、テオクル酸ジフェニルピラリン、マレイン酸カルビノキサミン、マレイン酸クロルフェニラミン（ｄ体、ｄｌ体）、メチレンジサリチル酸プロメタジン又はそれらの塩類等が挙げられ、単独又は２種以上を併用することができる。塩類としては、塩酸塩、マレイン酸塩、酒石酸塩、サリチル酸塩、タンニン酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、メチレンジサリチル酸塩等がある。好ましい抗ヒスタミン薬は塩酸イソチペンジル、塩酸イプロヘプチン、塩酸ジフェンヒドラミン、ジフェンヒドラミン、酒石酸アリメマジン、タンニン酸ジフェンヒドラミン及びマレイン酸クロルフェニラミン（ｄ体、ｄｌ体）、又はそれらの塩類である。抗ヒスタミン薬は、通常、成人に対し、１日量にして、１〜２００ｍｇ、好ましくは１〜１００mg投与するが、適量は薬物によって異なる。例えば、塩酸ジフェンヒドラミンであれば、１〜１００mg、マレイン酸クロルフェニラミン（ｄｌ体）であれば、１〜１０mgが適量であり、薬物により適宜使用することができる。   Antihistamines are drugs that block the action of histamine and are, for example, isothipentyl hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, triprolidine hydrochloride, tripelamine amine hydrochloride, tonsilamine hydrochloride, promethazine hydrochloride, methodiazine hydrochloride , Diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, carbinoxamine maleate, chlorpheniramine maleate (d-form, dl-form), promethazine methylenedisalicylate or salts thereof These can be used alone or in combination of two or more. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyl disulfonate, theocrate, methylene disalicylate, and the like. Preferred antihistamines are istipendil hydrochloride, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, alimemazine tartrate, diphenhydramine tannate and chlorpheniramine maleate (d form, dl form), or salts thereof. The antihistamine is usually administered to adults at a daily dose of 1 to 200 mg, preferably 1 to 100 mg, but the appropriate amount varies depending on the drug. For example, in the case of diphenhydramine hydrochloride, 1 to 100 mg is appropriate, and in the case of chlorpheniramine maleate (dl form), 1 to 10 mg is an appropriate amount and can be appropriately used depending on the drug.

抗アレルギー薬として、アステミゾール、塩酸シクロヘプタジン、テルフェナジン、イブジラスト、オキサトミド、アンレキサノクス、トラニラスト、ケトチフェン、アゼラスチン、クロモグリク酸ナトリウム、レピリナスト、エメダスチン、メキタジン、オザグレル、タザノラスト、ペミロラスト、フマル酸クレマスチン、アリメマジン、エピナスチン、スプラタスト等又はそれらの塩類等が挙げられ、単独又は２種以上を併用することができる。塩類としては、塩酸塩、マレイン酸塩、酒石酸塩、サリチル酸塩、タンニン酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、メチレンジサリチル酸塩、硝酸塩、フマル酸塩等がある。好ましい抗アレルギー薬は、アステミゾール、塩酸シクロヘプタジン、アンレキサノクス、フマル酸ケトチフェン、塩酸アゼラスチン、クロモグリク酸ナトリウム、メキタジン、フマル酸クレマスチン、塩酸エピナスチン、トラニラスト、フマル酸エメダスチン、オキサトミド、ペミロラストカリウム及びアリメマジン、又はそれらの塩類である。抗アレルギー薬は、通常、成人に対し、１日量にして、０.０１〜３００mg投与するが、適量は薬物によって異なり、通常用いられる範囲で適宜使用することができる。例えば、アステミゾールは２.５〜５ｍｇ、フマル酸ケトチフェンは0.２〜５ｍｇ、塩酸エピナスチンは２〜３０ｍｇ、メキタジンは0.５〜１５ｍｇ、酒石酸アリメマジンは２〜１５ｍｇである。   Antiallergic drugs include astemizole, cycloheptadine hydrochloride, terfenadine, ibudilast, oxatomide, amlexanox, tranilast, ketotifen, azelastine, sodium cromoglycate, repirinast, emedastine, mequitazine, ozagrel, tazanolast, pemirolastine, fumaricine, fumaricine, fumaricine, Examples thereof include suplatast and the like and salts thereof, and can be used alone or in combination of two or more. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyldisulfonate, theocrate, methylenedisalicylate, nitrate, and fumarate. Preferred antiallergic agents are astemizole, cycloheptadine hydrochloride, amlexanox, ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate, mequitazine, clemastine fumarate, epinastine hydrochloride, tranilast, emedastine fumarate, oxatomide, pemirolast potassium and alimemazine, Or a salt thereof. Antiallergic drugs are usually administered to adults in an amount of 0.01 to 300 mg per day, but the appropriate amount varies depending on the drug and can be used as appropriate within the usual range. For example, astemizole is 2.5-5 mg, ketotifen fumarate is 0.2-5 mg, epinastine hydrochloride is 2-30 mg, mequitazine is 0.5-15 mg, and alimemazine tartrate is 2-15 mg.

交感神経興奮薬（血管収縮薬）として、塩酸フェニルプロパノールアミン、塩酸フェニレフリン、塩酸メチルエフェドリン、塩酸メトキシフェナミン、エピネフリン、塩酸エフェドリン、ノルエピネフリン、硝酸ナファゾリン、ジャイロメタゾリン、ミドドリン、メトキサミン、塩酸テトラヒドロゾリン等の薬物又はそれらの塩類等が挙げられ、単独又は２種以上を併用することができる。塩類としては、塩酸塩、マレイン酸塩、酒石酸塩、サリチル酸塩、タンニン酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、メチレンジサリチル酸、硝酸塩等がある。塩類としては、塩酸塩、マレイン酸塩、酒石酸塩、サリチル酸塩、タンニン酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、メチレンジサリチル酸、硝酸塩等がある。好ましい交感神経興奮薬（血管収縮薬）は、塩酸フェニルプロパノールアミン、塩酸フェニレフリン及び塩酸メトキシフェナミン、塩酸メチルエフェドリン又はそれらの塩類である。交感神経興奮薬（血管収縮薬）は通常、成人に対する１日量として、１〜３００ｍｇ、好ましくは１〜１５０ｍｇを投与するが、適量は薬物によって異なり、例えば、塩酸フェニルプロパノールアミンであれば、１〜１２０ｍｇ、塩酸フェニレフリンであれば、１〜４０ｍｇ、塩酸メチルエフェドリンであれば１〜１２５ｍｇ、塩酸メトキシフェナミンであれば、１〜１７５ｍｇを投与するが、症状等により適宜増減できる。   Sympathomimetic drugs (vasoconstrictors) such as phenylpropanolamine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, methoxyphenamine hydrochloride, epinephrine hydrochloride, ephedrine, norepinephrine, naphazoline nitrate, gyrometazoline, middolin, methoxamine, tetrahydrozoline hydrochloride, etc. Drugs or salts thereof may be mentioned, and these may be used alone or in combination of two or more. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyl disulfonate, theocrate, methylene disalicylic acid, nitrate, and the like. Examples of the salts include hydrochloride, maleate, tartrate, salicylate, tannate, diphenyl disulfonate, theocrate, methylene disalicylic acid, nitrate, and the like. Preferred sympathomimetics (vasoconstrictors) are phenylpropanolamine hydrochloride, phenylephrine hydrochloride and methoxyphenamine hydrochloride, methylephedrine hydrochloride or salts thereof. A sympathomimetic drug (vasoconstrictor) is usually administered in an amount of 1 to 300 mg, preferably 1 to 150 mg as a daily dose for an adult. The appropriate amount varies depending on the drug, for example, phenylpropanolamine hydrochloride is 1 -120 mg, 1 to 40 mg for phenylephrine hydrochloride, 1 to 125 mg for methylephedrine hydrochloride, and 1 to 175 mg for methoxyphenamine hydrochloride, which can be appropriately increased or decreased depending on symptoms.

消炎酵素として、塩化リゾチーム、ブロメライン、α−キモトリプシン、セミアルカリプロティナーゼ（セアプローゼＳ−ＡＰ）、プロテナーゼ、セラチオペプチダーゼ（セラペプチダーゼ）、ストレプトキナーゼ、ストレプドルナーゼ等を挙げることができる。好ましい消炎酵素は、セミアルカリプロティナーゼ、塩化リゾチーム、ブロメライン及びセラチオペプチダーゼ（セラペプチダーゼ）である。消炎酵素は、通常、成人に対し、１日量にして、１.０〜２００mg、好ましくは１〜１００ｍｇ投与するが、適量は薬物によって異なり、通常用いられる範囲で適宜使用することができる。例えば、塩化リゾチームであれば、１〜１００ｍｇの範囲が適当である。   Examples of the anti-inflammatory enzyme include lysozyme chloride, bromelain, α-chymotrypsin, semi-alkaline proteinase (Ceaprose S-AP), proteinase, serratopeptidase (serapeptidase), streptokinase, strepdornase and the like. Preferred anti-inflammatory enzymes are semi-alkaline proteinase, lysozyme chloride, bromelain and serratopeptidase (serapeptidase). The anti-inflammatory enzyme is usually administered to adults at a daily dose of 1.0 to 200 mg, preferably 1 to 100 mg, but the appropriate amount varies depending on the drug and can be appropriately used within the usual range. For example, in the case of lysozyme chloride, a range of 1 to 100 mg is appropriate.

抗炎症薬は、グリチルリチン酸、グリチルリチン酸ジカリウム、グリチルリチン酸モノアンモニウム、グリチルリチン酸ジアンモニウム等のグリチルリチン酸及びその塩類の他、カンゾウ、トラネキサム酸等が挙げられ、これらは単独でも併用することもできる。抗炎症薬は、通常、成人に対し、１日量にして、グリチルリチン酸の量として０.１〜３００mg投与するが、適量は薬物によって異なり、通常用いられる範囲で適宜使用することができる。   Anti-inflammatory agents include glycyrrhizic acid such as glycyrrhizic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate and diammonium glycyrrhizinate and salts thereof, licorice, tranexamic acid and the like, and these can be used alone or in combination. The anti-inflammatory drug is usually administered to an adult in a daily dose of 0.1 to 300 mg as the amount of glycyrrhizic acid, but the appropriate amount varies depending on the drug, and can be used as appropriate within the usual range.

本発明の医薬組成物に、鼻炎治療薬に加えて中枢神経興奮薬を配合すると、鼻炎による頭重に対する効果が一層高まるほか、ある種の鼻炎治療薬の副作用である眠気に対して有効であり、総合的な治療効果の向上に寄与することから、好ましい場合もある。
中枢神経刺激薬としては、カフェイン類が例示され、具体的には無水カフェイン、カフェイン、安息香酸ナトリウムカフェイン等が挙げられる。投与量は、成人に対し１日量にして１２〜３００mgが好ましい。より好ましくは、１００〜２００mgである。 When the central nervous system stimulant is added to the pharmaceutical composition of the present invention in addition to the rhinitis therapeutic agent, the effect on head weight due to rhinitis is further enhanced, and it is effective against sleepiness that is a side effect of certain rhinitis therapeutic agents, It may be preferable because it contributes to the improvement of the overall therapeutic effect.
Examples of the central nervous stimulant include caffeine, and specific examples include anhydrous caffeine, caffeine, sodium benzoate caffeine and the like. The dosage is preferably 12 to 300 mg per day for adults. More preferably, it is 100-200 mg.

本発明の組成物にはさらにメントール、シネロール、カンフルを共に用いることができる。後述の試験例に示されているように、メントールを含有すると、コンプライアンスの向上に加えて即効性が更に顕著に増強がされるため、好ましい。メントールは、メントールとして使用しても、ハッカ油、スペアミント油やペパーミント油、ミント油といったメントールを含有する精油として使用しても良い。メントールの投与量は、通常、成人に対し、1日量で０.００１〜４０mgの範囲である。組成物中のメントールの好ましい濃度は０.１〜２.２５重量％であり、この範囲であれば、苦味を伴うことなくすっきりした清涼感を与え、患者のコンプライアンスの向上に有効である、この範囲を超えると、メントールの刺激が逆に不快感となりうる。
メントールは文献（第１３改正日本薬局方、Ｄ１０５０〜１０５８）に記載されているものであって、市販のものを使用することも可能である。天然精油由来及び合成品のいずれであってもよい。本発明組成物に用いる場合、メントールはｌ体、ｄｌ体のいずれでもよい。シネロール、カンフルはともに日本薬局方に記載されているものであって、市販のものを使用することも可能である。シネロールはユーカリ油に多く含まれ、シネロールとして使用してもユーカリ油として使用しても良い。カンフルはカンフル油に多く含まれ、カンフルとして使用してもカンフル油として使用しても良い。また、口中で溶解及び／又は咀嚼する剤形である本発明の組成物は、口中での滞留時間が長く味覚芽に薬物が直接接触するために、味覚・臭覚への影響も考慮することが好ましい。そのような観点から、メントール、カンフル、シネロールを含有する精油や、フルーツフレーバーを共に用いると、患者のコンプライアンス（服薬遵守）の向上に役立つ。これは、特に苦味のある薬物を用いる場合に、それをマスキングすることが可能となるので好ましい。 Menthol, cinerol, and camphor can be used together in the composition of the present invention. As shown in the test examples described later, the inclusion of menthol is preferable because the immediate effect is further remarkably enhanced in addition to the improvement of compliance. Menthol may be used as menthol or as an essential oil containing menthol such as peppermint oil, spearmint oil, peppermint oil and mint oil. The dose of menthol is usually in the range of 0.001 to 40 mg per day for an adult. The preferred concentration of menthol in the composition is 0.1 to 2.25% by weight, and if it is in this range, it provides a refreshing refreshment without bitterness and is effective in improving patient compliance. Beyond the range, menthol stimulation can be uncomfortable.
Menthol is described in the literature (13th revised Japanese Pharmacopoeia, D1050 to 1058), and commercially available products can also be used. Either natural essential oil-derived or synthetic products may be used. When used in the composition of the present invention, menthol may be either l-form or dl-form. Cinerol and camphor are both described in the Japanese Pharmacopoeia, and commercially available products can also be used. Cinerol is abundant in eucalyptus oil, and may be used as cinerol or eucalyptus oil. A lot of camphor is contained in camphor oil, and it may be used as camphor or as camphor oil. In addition, the composition of the present invention, which is a dosage form that dissolves and / or chews in the mouth, has a long residence time in the mouth, and the drug directly contacts the taste buds. preferable. From such a point of view, the use of essential oils containing menthol, camphor, and cinerol and fruit flavors together helps improve patient compliance. This is preferable because a drug having a bitter taste can be masked.

本発明の組成物には、本発明の目的に従って任意の薬効成分を配合することができ、上記の薬物に限定されない。
また、鼻炎症状治療効果を損なわない限り、当該技術分野で通常用いられている他の物質（医薬品又は医薬部外品）を添加してもよい。そのような物質として、ビタミン薬、生薬、鎮咳薬、去痰薬、喀痰溶解薬、解熱鎮痛薬、制酸薬等がある。
風邪薬用の成分を共に配合すると、風邪に伴う鼻炎症状の治療に有用である。 In the composition of the present invention, any medicinal component can be blended according to the object of the present invention, and is not limited to the above-mentioned drugs.
Moreover, as long as the effect of treating nasal inflammation is not impaired, other substances (pharmaceuticals or quasi-drugs) commonly used in the art may be added. Such substances include vitamins, herbal medicines, antitussives, expectorants, sputum solubilizers, antipyretic analgesics, antacids and the like.
When combined with ingredients for cold medicines, it is useful for treating nasal inflammation associated with colds.

上記の他の成分は、それぞれ、通常用いられている投与量の範囲内で配合される。生薬としては、ケイガイ、サイシン、ショウキョウ、シンイ、ゼンコ、ビャクシ等、鎮咳薬としては、リン酸コデイン、デキストロメトロファン類等、去痰薬としてはグアイフェネシン、グアヤコールスルホン酸カリウム等、喀痰溶解薬としては塩化リゾチーム、システイン類等、解熱鎮痛薬としてはアセトアミノフェン、エテンザミド、アスピリン等、制酸薬としてはケイ酸マグネシウム、酸化マグネシウム、水酸化マグネシウム等が挙げられる。   Each of the other components described above is blended within the dose range usually used. Herbal medicines include mussels, saicin, ginger, shini, zenko, peony, etc., antitussives such as codeine phosphate, dextrometrophans, etc., expectorants as guaifenesin, potassium guaiacol sulfonate, etc. Includes lysozyme chloride, cysteine, etc., antipyretic analgesics such as acetaminophen, etenzaamide, aspirin and the like, and antacids include magnesium silicate, magnesium oxide, magnesium hydroxide and the like.

本発明の医薬組成物は、口中で溶解又は咀嚼することにより服用する形態であれば、剤形は任意であり、錠剤（素錠、糖衣錠）、キャンディー（飴）、グミ剤、ヌガー剤等が例示される。形や大きさは口中にて服用することに不都合がない範囲で適宜選択される。
錠剤は、粉末状の薬物と製薬上許容される賦形剤とを混合して圧縮成形することにより、また、キャンディー（飴）、グミ剤、ヌガー剤等は、製菓の分野で既知の方法で調製することができる。
例えば、錠剤は、当該技術分野で既知の押しだし造粒法、粉砕造粒法、乾式圧密造粒法、流動層造粒法、転動造粒法、高速攪拌造粒法、湿式打錠法、直接打錠法等を、目的に応じて適宜組み合わせて製造すればよい。
本発明の実施に好ましい剤形は、錠剤であり、特に口中で咀嚼することにより服用する形態である咀嚼型の錠剤である。 The pharmaceutical composition of the present invention may have any dosage form as long as it is in a form that can be taken by dissolving or chewing in the mouth, such as tablets (plain tablets, sugar-coated tablets), candy (candy), gummi, nougat, etc. Illustrated. The shape and size are appropriately selected as long as there is no inconvenience for taking in the mouth.
Tablets are prepared by mixing powdered drugs and pharmaceutically acceptable excipients and compression-molding. Also, candy (gummy), gummi, nougat, etc. can be prepared by methods known in the confectionery field. Can be prepared.
For example, the tablet may be an extrusion granulation method, a pulverization granulation method, a dry compaction granulation method, a fluidized bed granulation method, a rolling granulation method, a high-speed stirring granulation method, a wet tableting method known in the art. What is necessary is just to manufacture combining a direct tableting method etc. suitably according to the objective.
A preferable dosage form for practicing the present invention is a tablet, and in particular, a chewable tablet which is a form to be taken by chewing in the mouth.

本発明製剤には、本発明の効果に影響を与えない限り、一般的に医薬品添加剤として使用されている任意の成分を添加することができる。そのような添加剤として、トウモロコシデンプン、バレイショデンプン、白糖、タルク、カオリン、硫酸カルシウム、炭酸カルシウム、結晶セルロース等の賦形剤、ステアリン酸マグネシウム、ステアリン酸カルシウム等の滑沢剤、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシメチルセルロース等の崩壊剤、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ゼラチン、セルロース高分子、アクリル酸系高分子、メチルセルロース、アラビアゴム、ポリビニルアルコール等の結合剤、その他の甘味剤、着香剤、着色剤、矯味剤、吸着剤、防腐剤、湿潤剤、帯電防止剤等が挙げられる。
また、本発明の組成物は、目的に応じて薬物放出を制御することにより、薬理効果の発現を制御し、より持続性のある製剤とすることもできる。 Any component that is generally used as a pharmaceutical additive can be added to the preparation of the present invention as long as the effect of the present invention is not affected. Such additives include corn starch, potato starch, sucrose, talc, kaolin, calcium sulfate, calcium carbonate, excipients such as crystalline cellulose, lubricants such as magnesium stearate and calcium stearate, carboxymethylcellulose calcium, low Degrading agents such as hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, cellulose polymers, acrylic polymers, binders such as methylcellulose, gum arabic, and polyvinyl alcohol, other sweeteners, wearing Examples include flavoring agents, coloring agents, flavoring agents, adsorbents, preservatives, wetting agents, and antistatic agents.
In addition, the composition of the present invention can control the expression of a pharmacological effect by controlling the release of a drug according to the purpose, and can be a more durable preparation.

以下に実施例を挙げて本発明をさらに詳しく説明する。
実施例１ 錠剤

日本薬局方 製剤総則「錠剤」に準じて、錠剤を製した。具体的には、ｄ−マレイン酸クロルフェニラミンからマンニットまでの成分をとり、湿式造粒法により、顆粒（A）を調製する。他方、メントールとアビセルを混合して、メントール倍散（B）を調製する。次に、顆粒（A）、メントール倍散（B）、及びステアリン酸マグネシウムを混合して、打錠用顆粒とし、これを重量４００ｍｇ／錠ととして、打錠機で錠剤を製した。   According to the Japanese Pharmacopoeia General Rules for Tablets “Tablets”, tablets were produced. Specifically, the components from d-chlorpheniramine maleate to mannitol are taken, and granules (A) are prepared by a wet granulation method. On the other hand, menthol doubling (B) is prepared by mixing menthol and Avicel. Next, the granule (A), menthol trituration (B), and magnesium stearate were mixed to prepare a tableting tablet, and the tablet was made with a tableting machine with a weight of 400 mg / tablet.

実施例２ 錠剤

実施例１と同様に、塩酸ジフェンヒドラミンからキシリットまでの成分を用いて顆粒（A）を調製し、他方、アビセルからペパーミントオイルまでの成分を混合して、メントール倍散（B）を調製し、１錠３００ｍｇの錠剤を製した。   As in Example 1, granules (A) were prepared using ingredients from diphenhydramine hydrochloride to xylit, while ingredients from Avicel to peppermint oil were mixed to prepare menthol trituration (B). A 300 mg tablet was produced.

実施例３ 錠剤

実施例１と同様に、サリチル酸ジフェンヒドラミンからマンニットまでの成分を用いて顆粒（A）を調製し、他方、アビセルからミントオイル又はハッカ油までの成分を混合して、メントール倍散（B）を調製し、１錠４００ｍｇの錠剤を製した。   As in Example 1, granules (A) were prepared using ingredients from diphenhydramine salicylate to mannitol, while ingredients from Avicel to mint oil or mint oil were mixed to give menthol trituration (B). 1 tablet of 400 mg was prepared.

実施例４ 錠剤

実施例１と同様に、フマル酸クレマスチンからソルビットまでの成分を用いて顆粒（A）を調製し、他方、Ｌ−ＨＰＣとメントールから、メントール倍散（B）を調製し、１錠２５０ｍｇの錠剤を製した。   As in Example 1, granules (A) were prepared using ingredients from clemastine fumarate to sorbite, while menthol trituration (B) was prepared from L-HPC and menthol, and one tablet of 250 mg Made.

実施例５ 錠剤

実施例１と同様に、メキタジンからマンニットまでの成分を用いて顆粒（A）を調製し、他方、アビセルからミントオイル又はハッカ油までの成分を混合して、メントール倍散（B）を調製し、１錠５００ｍｇの錠剤を製した。   As in Example 1, granules (A) were prepared using ingredients from mequitazine to mannitol, while ingredients from Avicel to mint oil or mint oil were mixed to prepare menthol trituration (B). One tablet of 500 mg was made.

実施例６ 錠剤

実施例１と同様に、フマル酸ケトチフェンからソルビットまでの成分を用いて顆粒（Ａ）を調製し、他方、Ｌ−ＨＰＣとメントールからメントール倍散（B）を調製し、１錠２５０ｍｇの錠剤を製した。
実施例７ キャンディ
塩酸フェニレフリン ２５．０部
塩化リゾチーム ６０．０
砂糖 ２２０２．５
水飴 ２１００．０
クエン酸 ９．０
メントール ９．０
レモンオイル ４．５
水 ９０．０
４５００．０
上記の成分を混合し、常法通り、１個当たり１.５ｇ（用量：1日3個）のキャンディを製した。 As in Example 1, granules (A) were prepared using components from ketotifen fumarate to sorbit, while menthol trituration (B) was prepared from L-HPC and menthol. Made.
Example 7 Candy Phenylephrine hydrochloride 25.0 parts Lysozyme chloride 60.0
Sugar 2202.5
Minamata 2100.0
Citric acid 9.0
Menthol 9.0
Lemon oil 4.5
Water 90.0
4500.0
The above ingredients were mixed, and 1.5 g (dose: 3 per day) of candy was produced as usual.

実施例８ ヌガー
ｄ−マレイン酸クロルフェニラミン ６.０ 部
塩酸フェニルプロパノールアミン ９０.０
カフェイン ６０.０
砂糖 ２６７７.２
水飴 ２１００.０
膨張ゼラチン（５０％ゼラチン） ３９０.０
植物性油脂 ５４.０
色素 ５.４
メントール １２.０
グレープフルーツエッセンス ５.４
５４００.０
上記の成分を混合し、常法通り、１個当たり１.８ｇ（用量：1日3個）のヌガーを製した。 Example 8 Nougat
d-Chlorpheniramine maleate 6.0 parts Phenylpropanolamine hydrochloride 90.0
Caffeine 60.0
Sugar 2677.2
Minamata 210.0
Expanded gelatin (50% gelatin) 390.0
Vegetable oil 54.0
Dye 5.4
Menthol 12.0
Grapefruit essence 5.4
540.0
The above ingredients were mixed and 1.8 g (dosage: 3 per day) of nougat was produced per unit as usual.

実施例９ グミ
塩酸ジフェンヒドラミン ５０.０部
塩酸フェニルプロパノールアミン ９０.０
カフェイン ６０.０
粉末ゼラチン（１８０ブルーム） ４３０.５
砂糖 １２００.０
水飴 １２００.０
メントール １５.０
レモンオイル ４.５
熱湯 １４５０.０
４５００.０
上記の成分を混合し、常法通り、１個当たり１.５ｇ（用量：1日3個）のグミを製した。 Example 9 Gummy diphenhydramine hydrochloride 50.0 parts Phenylpropanolamine hydrochloride 90.0
Caffeine 60.0
Powdered gelatin (180 bloom) 430.5
Sugar 120.0
Minamata 120.0
Menthol 15.0
Lemon oil 4.5
Hot water 1450.0
450.0
The above ingredients were mixed, and 1.5 g (dose: 3 per day) of gummy per one was produced as usual.

実施例１０ ガム
ｄ−マレイン酸クロルフェニラミン ６.０ 部
ベラゾンナ総アルカロイド ０.４
カフェイン ６０.０
ガムベース ２１００.０
砂糖 ４６５６.８
ブドウ糖 ９００.０
コーンシロップ １２００.０
グリセリン ５５.８
メントール １２.０
ペパーミントオイル ９.０
９０００.０
上記の成分を混合し、常法通り、１枚当たり３.０ｇ（用量：1日3枚）のガムを製した。 Example 10 Gum d-Chlorpheniramine maleate 6.0 parts Verazonna total alkaloid 0.4
Caffeine 60.0
Gum base 210.0
Sugar 4656.8
Glucose 90.0
Corn syrup 120.0
Glycerin 55.8
Menthol 12.0
Peppermint oil 9.0
90.0
The above ingredients were mixed, and 3.0 g (dose: 3 sheets per day) of gum was produced as usual.

試験例１ 溶出試験
実施例１のチュアブル錠と市販の鼻炎用内服剤を用い、日本薬局方の一般試験法である溶出試験法（パドル法）に従って試験を行った。試験溶液として、精製水を用い、試験溶液500ml中、37℃で、パドルの回転数100rpmとして行った。実施例１のチュアブル錠は、口中で約５から１５回かみ砕いた後、試料として試験溶液に添加した。試験開始後、経時的に溶出液を採取し、チュアブル錠に配合されているマレイン酸クロルフェニラミンを指標成分として薬物溶出量を測定した。
対照として、有効成分としてマレイン酸クロルフェニラミンを含有する市販の硬カプセル剤（市販品１）、錠剤（糖衣錠）（市販品２）、顆粒剤（市販品３）、及び軟カプセル剤（市販品４）を用い、これらは咀嚼せずに試験した。マレイン酸クロルフェニラミンは常法のＨＰＬＣ法にて測定した。結果を表７に示す。 Test Example 1 Dissolution Test Using the chewable tablet of Example 1 and a commercially available internal medicine for rhinitis, a test was conducted according to the dissolution test method (paddle method) which is a general test method of the Japanese Pharmacopoeia. Purified water was used as a test solution in a 500 ml test solution at 37 ° C. and a paddle rotation speed of 100 rpm. The chewable tablet of Example 1 was chewed about 5 to 15 times in the mouth and then added to the test solution as a sample. After starting the test, the eluate was collected over time, and the drug elution amount was measured using chlorpheniramine maleate blended in the chewable tablet as an indicator component.
As controls, commercially available hard capsules (commercial product 1), tablets (sugar-coated tablets) (commercial product 2), granules (commercial product 3), and soft capsules (commercial product) containing chlorpheniramine maleate as an active ingredient These were tested without chewing using 4). Chlorpheniramine maleate was measured by a conventional HPLC method. The results are shown in Table 7.

表７及び８から、実施例１のチュアブル錠からの薬物の溶出は極めて迅速であり、短時間で完全に溶出する（ほぼ１００％）ことが分かる。その溶出速度は表面積の大きい顆粒剤(市販品３）よりも優れている。また、表８から、実施例１のチュアブル錠からの溶出はｐＨの影響を全く受けないことが分かる。
咀嚼による表面積の増大によって薬物の溶出が促進されると考えられるが、市販品３の顆粒剤と比較すると、胃内（ｐＨ＝１.２）、口内（ｐＨ＝６.８）のいずれの条件下でも、本発明組成物の方が優れた薬物溶出効果を示している。これは、本発明組成物における溶出促進が、単に咀嚼による表面積の増大のみに起因するものでないことを示唆している。
薬物放出速度とその変動は、消化管内での薬物吸収の速度、吸収量と密接に関連しており、薬物治療の効果の発現に大きい影響を及ぼすことが知られている。上記の試験結果は、本発明の製剤が従来の製剤に比較して優れた溶出速度を示すものであることを明らかにし、本発明製剤が即効性であると同時に生物学的利用率が高く、確実に持続して高い効果を発揮しうる有用な製剤であることを証明するものである。 From Tables 7 and 8, it can be seen that the dissolution of the drug from the chewable tablet of Example 1 is very rapid and completely dissolves in a short time (almost 100%). The dissolution rate is superior to that of a granule having a large surface area (commercial product 3). Moreover, it can be seen from Table 8 that the dissolution from the chewable tablet of Example 1 is not affected by the pH at all.
It is thought that the elution of the drug is promoted by the increase of the surface area by chewing, but when compared with the granule of the commercial product 3, any condition in the stomach (pH = 1.2) or in the mouth (pH = 6.8) Even below, the composition of the present invention shows a better drug elution effect. This suggests that the dissolution enhancement in the composition of the present invention is not simply due to an increase in surface area due to chewing.
It is known that the drug release rate and its variation are closely related to the rate and amount of drug absorption in the gastrointestinal tract, and have a great influence on the manifestation of the effect of drug treatment. The above test results reveal that the preparation of the present invention exhibits an excellent dissolution rate as compared with the conventional preparation, and the preparation of the present invention has an immediate effect and a high bioavailability, It proves that it is a useful preparation that can reliably and sustainably exhibit high effects.

試験例２ 有効性試験

本発明の錠剤Ａ−１、Ａ−２、及びＢを、非咀嚼、非溶解型の錠剤Ｃと比較すると、１０分後の改善率が有意に高く、４時間後の改善率においても優れており、即効性と持続性の両方を兼ね備えていることが分かる。また、これら本発明の製剤Ａ−１，Ａ−２及びＢを、メントール以外の薬物を含有しない錠剤Ｅ（咀嚼して服用）と比較すると、１０分後、４時間後のいずれにおいても、メントール単独の組成物よりもはるかに有効であることが分かる。一方、非咀嚼、非溶解型の錠剤Ｃ及びＤはメントールの有無に関係無く、改善率が低い。
また、メントールを含有する咀嚼型（Ａ−１）及び溶解型（Ａ−２）の製剤をメントールを含有しない咀嚼型（Ｂ）製剤と比較すると、前２者は後者よりも即効性が極めて高いことが分かる（表１０参照）。これは、咀嚼型又は溶解型製剤にメントールを含有させると、即効性が顕著に増強されることを示している。
以上の結果から、本発明の溶解型又は咀嚼型製剤は、通常の嚥下型の錠剤に比較して鼻炎症状に対して即効性であり、かつ持続的な効果を有することが明らかである。投与から４時間後においても、対応する錠剤に比較して高い効果を示すことから、本発明の組成物は、高い即効性と高い生物学的利用率を兼ね備えた、治療効果が増強された優れた製剤であるといえる。これらの優れた作用の原因として以下の点が考察される。
１.口中で唾液と混和されるために、薬物溶解が促進される。
２.即座に吸収され、かつ吸収量が高まる。
３.顎の運動により鼻腔の血行が促進される。
４.咽頭部からの鼻腔直接作用がある。 When the tablets A-1, A-2, and B of the present invention are compared with the non-chewable, non-dissolving tablet C, the improvement rate after 10 minutes is significantly high, and the improvement rate after 4 hours is also excellent. It turns out that it has both immediate effect and sustainability. Further, when these preparations A-1, A-2 and B of the present invention were compared with tablet E (masticated and taken) containing no drug other than menthol, menthol was observed after 10 minutes and after 4 hours. It can be seen that it is much more effective than the single composition. On the other hand, non-chewable and non-dissolvable tablets C and D have a low improvement rate regardless of the presence or absence of menthol.
In addition, comparing the chewable type (A-1) and dissolved type (A-2) preparations containing menthol with the chewable type (B) preparations containing no menthol, the former two have a higher immediate effect than the latter. (See Table 10). This indicates that when menthol is included in the chewable or dissolved preparation, the immediate effect is remarkably enhanced.
From the above results, it is clear that the dissolution type or chewing type preparation of the present invention has an immediate effect on the symptoms of nasal inflammation and a sustained effect as compared with a normal swallow type tablet. Even after 4 hours from administration, the composition of the present invention exhibits a high effect as compared with the corresponding tablet. Therefore, the composition of the present invention has a high immediate effect and a high bioavailability, and has an excellent therapeutic effect. It can be said that it is a preparation. The following points are considered as causes of these excellent actions.
1. Because it is mixed with saliva in the mouth, drug dissolution is promoted.
2. Immediate absorption and increased absorption.
3. Jaw movement promotes nasal circulation.
4. Direct action on the nasal cavity from the pharynx.

本発明の医薬組成物は、口中で長時間保持され唾液と混合されるために、鼻粘膜に咽頭部から直接作用することができるので、鼻汁過多を含むあらゆるタイプの鼻炎症状に対して即効性を示す。この即効性は鼻閉にとどまらず、鼻汁や頭重、のどの痛みなどの鼻炎の諸症状の緩和に有効である。同時に、消化管からも吸収され、確実に持続的な効果を発揮することができ、同量の活性成分を含有する通常の内服用錠剤に比較して十分に高い生物学的利用率を達成できる。その結果、薬物の有効利用が可能となり投与量の減少等を通して、患者の負担を軽減すると共に、生活の質を向上させることができる。   Since the pharmaceutical composition of the present invention is retained in the mouth for a long time and mixed with saliva, it can act directly on the nasal mucosa from the pharynx, so that it is immediately effective against all types of nasal inflammation including nasal discharge. Indicates. This immediate effect is not limited to nasal congestion, but is effective in alleviating symptoms of rhinitis such as nasal discharge, head weight, and sore throat. At the same time, it can be absorbed from the gastrointestinal tract, ensuring a lasting effect, and achieving a sufficiently high bioavailability compared to ordinary oral tablets containing the same amount of active ingredient. . As a result, the drug can be effectively used, and the burden on the patient can be reduced and the quality of life can be improved through the reduction of the dose.

鼻炎治療薬を含有する、口中溶解型又は咀嚼型の鼻炎治療用固形内服医薬組成物［但し、鼻炎治療薬として、（Ａ）ベラドンナアルカロイド、ベラドンナ総アルカロイド、ベラドンナエキス、ダツラエキス、及びロートエキスからなる群より選択される少なくとも１種と、（Ｂ）マレイン酸クロルフェニラミン、塩酸イソチペンジル、塩酸イプロヘプチン、塩酸ジフェテロール、塩酸ジフェニルピラリン、塩酸ジフェンヒドラミン、ジフェンヒドラミン、塩酸トリプロリジン、塩酸トリペレナミン、塩酸トンジルアミン、塩酸プロメタジン、塩酸メトジラジン、サリチル酸ジフェンヒドラミン、ジフェニルジスルホン酸カルビノキサミン、酒石酸アリメマジン、タンニン酸ジフェンヒドラミン、テオクル酸ジフェニルピラリン、マレイン酸カルビノキサミン、メチレンジサリチル酸プロメタジン、アステミゾール、塩酸シクロヘプタジン、テルフェナジン、オキサトミド、ケトチフェン、アゼラスチン、エメダスチン、メキタジン、フマル酸クレマスチン、アリメマジン、及びエピナスチンからなる群より選択される少なくとも１種とを含有する場合を除く］。   Mouth-dissolved or chewable solid oral pharmaceutical composition for treating rhinitis containing rhinitis therapeutic agent [However, as rhinitis therapeutic agent, it consists of (A) belladonna alkaloid, belladonna total alkaloid, belladonna extract, datsura extract, and funnel extract At least one selected from the group, and (B) chlorpheniramine maleate, istipendil hydrochloride, iproheptin hydrochloride, dipheterol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, triprolidine hydrochloride, tripelenamine hydrochloride, tonsilamine hydrochloride, promethazine hydrochloride, Methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teolate, potassium maleate A case of containing at least one selected from the group consisting of vinoxamine, promethazine methylenedisalicylate, astemizole, cycloheptazine hydrochloride, terfenadine, oxatomide, ketotifen, azelastine, emedastine, mequitazine, clemastine fumarate, alimemazine, and epinastine except].

• 2012
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