JP2013075892A - Anti-inflammatory and/or antihistaminic agent composition - Google Patents
Anti-inflammatory and/or antihistaminic agent composition Download PDFInfo
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- JP2013075892A JP2013075892A JP2012201092A JP2012201092A JP2013075892A JP 2013075892 A JP2013075892 A JP 2013075892A JP 2012201092 A JP2012201092 A JP 2012201092A JP 2012201092 A JP2012201092 A JP 2012201092A JP 2013075892 A JP2013075892 A JP 2013075892A
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- hydrochloride
- inflammatory
- bromhexine
- fexofenadine
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- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 19
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Abstract
Description
本発明は、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する抗炎症及び/又は抗ヒスタミン剤組成物に関する。 The present invention relates to an anti-inflammatory and / or antihistamine composition comprising fexofenadine hydrochloride and bromhexine hydrochloride.
第二世代の抗ヒスタミン剤であるフェキソフェナジン塩酸塩は、(a)ヒスタミンH1受容体拮抗作用、(b)I型アレルギー反応抑制作用、(c)好酸球、炎症性サイトカイン遊離抑制作用、(d)ケミカルメディエータ遊離抑制作用を有し、本邦では、アレルギー性鼻炎、蕁麻疹、皮膚疾患(湿疹・皮膚炎、皮膚掻痒症、アトピー性皮膚炎)に伴う掻痒の効能・効果が認められている(例えば、非特許文献1参照)。
去痰剤のブロムヘキシン塩酸塩は、(a)漿液性分泌増加作用、(b)酸性糖タンパク溶解・低分子化作用、(c)肺表面活性物質分泌促進作用、(d)線毛運動亢進作用を有し、本邦では、急性気管支炎・慢性気管支炎・塵肺症・手術後の去痰の効能・効果が医療用医薬品として認められている(例えば、非特許文献1参照)。
また、ブロムヘキシン塩酸塩はOTC医薬品では、去痰剤、鎮咳去痰剤、総合感冒薬にも配合されている(例えば、非特許文献2参照)。
Fexofenadine hydrochloride, a second generation antihistamine, has (a) histamine H1 receptor antagonistic action, (b) type I allergic reaction inhibitory action, (c) eosinophil, inflammatory cytokine release inhibitory action, (d ) It has a chemical mediator release inhibitory effect, and it has been confirmed in Japan that it has allergic rhinitis, urticaria, and pruritus associated with skin diseases (eczema / dermatitis, cutaneous pruritus, atopic dermatitis) ( For example, refer nonpatent literature 1).
An expectorant bromhexine hydrochloride has (a) serous secretion increasing action, (b) acidic glycoprotein dissolution / low molecular weight action, (c) lung surface active substance secretion promoting action, (d) ciliary motility enhancing action. In Japan, the efficacy and effects of acute bronchitis, chronic bronchitis, pneumoconiosis, and expectoration after surgery are recognized as ethical drugs (for example, see Non-patent Document 1).
In addition, bromhexine hydrochloride is also included in an expectorant, antitussive expectorant and general cold medicine in OTC pharmaceuticals (see, for example, Non-Patent Document 2).
これまでに、抗ヒスタミン剤とブロムヘキシン又はアンブロキソールを配合したOTC総合感冒薬として以下のものが販売されている。
1)、抗ヒスタミン剤のカルビノキサミン、クレマスチン、クロルフェニラミン、又は、メキタジンと、ブロムヘキシンその他を配合した製品(例えば、非特許文献2参照)。
2)抗ヒスタミン剤のクロルフェニラミンとアンブロキソールその他を配合した製品(例えば、非特許文献2参照)。
さらに、抗ヒスタミン剤とブロムヘキシン又はアンブロキソールの組み合わせとして以下のものが開示されている。
3)抗ヒスタミン剤のエピナスチン、ブロムヘキシンその他を配合した鎮咳剤(特許文献1の実施例2及び4参照)。
4)抗ヒスタミン剤のクロルフェニラミン、ブロムヘキシンその他を配合した製剤(例えば、特許文献2の比較例3及び4参照)。
5)抗ヒスタミン剤のカルビノキサミン、ブロムヘキシンその他を配合した感冒剤(特許文献3の実施例1、3及び5参照)。
6)抗ヒスタミン剤のエピナスチン、アンブロキソールその他を配合した鎮咳剤(特許文献1参照の実施例1及び3)。なお、特許文献1の表1には、鎮咳薬のコデインに、エピナスチンとアンブロキソールを配合すると、風邪による咳嗽症状が著明に改善することが開示されている。
しかし、これまでに、第二世代の抗ヒスタミン剤であるフェキソフェナジンやセチリジンと、ブロムヘキシンの配合を直接記載したものは一切見当たらず、当該配合によって抗炎症作用や抗ヒスタミン作用に如何なる影響をもたらすかを示唆した報告もない。
So far, the following are marketed as OTC general cold medicines containing antihistamines and bromhexine or ambroxol.
1) A product containing the antihistamines carbinoxamine, clemastine, chlorpheniramine, or mequitazine and bromhexine or the like (for example, see Non-Patent Document 2).
2) A product containing the antihistamine chlorpheniramine, ambroxol and others (see Non-Patent Document 2, for example).
Furthermore, the following is disclosed as a combination of an antihistamine and bromhexine or ambroxol.
3) Antitussives containing antihistamines epinastine, bromhexine and others (see Examples 2 and 4 of Patent Document 1).
4) A preparation containing antihistamines chlorpheniramine, bromohexine and others (see, for example, Comparative Examples 3 and 4 in Patent Document 2).
5) A cold medicine containing the antihistamines carbinoxamine, bromhexine and others (see Examples 1, 3 and 5 of Patent Document 3).
6) Antitussive agent containing antinasamine epinastine, ambroxol and others (Examples 1 and 3 of Patent Document 1). In Table 1 of Patent Document 1, it is disclosed that cough symptoms due to a cold are remarkably improved when epinastine and ambroxol are added to codeine, an antitussive agent.
However, until now, there has been no direct description of the combination of fexofenadine and cetirizine, which are second-generation antihistamines, and bromhexine. There are no reports to suggest.
本発明の課題は、優れた抗炎症作用及び/又は抗ヒスタミン作用を有する医薬組成物を提供することである。 An object of the present invention is to provide a pharmaceutical composition having an excellent anti-inflammatory action and / or antihistamine action.
本発明者らは、かかる課題を解決するために多数の薬剤の組み合わせについて鋭意研究を行った結果、抗アレルギー剤として使用されているフェキソフェナジンと、去痰剤のブロムヘキシンとを組み合わせると優れた抗炎症作用が発現することを見出し、本発明を完成させた。 As a result of intensive studies on a combination of a number of drugs in order to solve such problems, the present inventors have found that antibacterial antibacterial agent bromhexine combined with fexofenadine, which is used as an antiallergic agent, has excellent anti The inventors have found that an inflammatory action is expressed and completed the present invention.
すなわち、本発明は下記の(1)〜(4)を提供するものである。
(1)フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する、抗炎症及び/又は抗ヒスタミン剤組成物。
(2)アレルギー性鼻炎又は副鼻腔炎の予防及び/又は治療のための、(1)に記載の抗炎症及び/又は抗ヒスタミン剤組成物。
(3)感冒時の急性鼻炎又は咽頭炎の予防及び/又は治療のための、(1)に記載の抗炎症及び/又は抗ヒスタミン剤組成物。
(4)鎮咳又は去痰のための、(1)に記載の抗炎症及び/又は抗ヒスタミン剤組成物。
That is, the present invention provides the following (1) to (4).
(1) An anti-inflammatory and / or antihistamine composition comprising fexofenadine hydrochloride and bromhexine hydrochloride.
(2) The anti-inflammatory and / or antihistamine composition according to (1) for the prevention and / or treatment of allergic rhinitis or sinusitis.
(3) The anti-inflammatory and / or antihistamine composition according to (1) for the prevention and / or treatment of acute rhinitis or pharyngitis during the cold.
(4) The anti-inflammatory and / or antihistamine composition according to (1) for coughing or expectoration.
本発明の、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する医薬組成物は、優れた抗炎症作用並びに抗アレルギー作用を奏するため有用である。例えば、アレルギー性鼻炎、副鼻腔炎、感冒時における急性鼻炎や咽頭炎等の症状の予防及び/又は治療、さらには鎮咳去痰のための医薬組成物として提供することができる。 The pharmaceutical composition containing fexofenadine hydrochloride and bromhexine hydrochloride of the present invention is useful because it exhibits excellent anti-inflammatory action and anti-allergic action. For example, it can be provided as a pharmaceutical composition for the prevention and / or treatment of symptoms such as allergic rhinitis, sinusitis, acute rhinitis and pharyngitis during the cold, and antitussive expectorant.
本発明の、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩は第16改正日本薬局方に収載されている。 The fexofenadine hydrochloride and bromhexine hydrochloride of the present invention are listed in the 16th revision Japanese Pharmacopoeia.
本発明の組成物の1回投与量における、フェキソフェナジン塩酸塩の含有量は特に制限はないが、10〜120mgの範囲で使用でき、好ましくは30〜60mgである。 The content of fexofenadine hydrochloride in a single dose of the composition of the present invention is not particularly limited, but it can be used in the range of 10 to 120 mg, preferably 30 to 60 mg.
本発明の組成物の1回投与量における、ブロムヘキシン塩酸塩の含有量は特に制限はないが、1〜12mgの範囲で使用でき、好ましくは2〜4mgである。 The content of bromhexine hydrochloride in a single dose of the composition of the present invention is not particularly limited, but can be used in the range of 1 to 12 mg, preferably 2 to 4 mg.
これらの具体的な剤形としては、例えば、錠剤、顆粒剤、散剤(細粒を含む)、カプセル剤、液剤(シロップ剤を含む)等をあげることができ、各剤形に適した添加剤や基材を適宜使用し、日本薬局方等に記載された通常の方法に従い、製造することができる。
上記各剤形において、その剤形に応じ、通常使用される各種添加剤を使用することもできる。例えば、賦形剤、安定化剤、コーティング剤、滑沢剤、吸着剤、結合剤、崩壊剤、界面活性剤、着色剤、pH調節剤及び香料等を適宜使用し、日本薬局方等に記載された通常の方法に従い、製造することができる。
なお、本発明における、フェキソフェナジン塩酸塩、ブロムヘキシン塩酸塩、及び上記添加成分を含有する組成物が錠剤などの固形製剤の場合、該固形製剤は常法に従って製造できるが、上記添加成分が、DADA及び/又はトラネキサム酸との配合禁忌等の課題で、保存安定性等に課題が発生する場合には、適宜、顆粒分け、多層化等により互いに接触しないように製剤化すればよい。ここで、顆粒分け、多層化等の製剤化は公知の方法を用いればよい。また、上記製剤が吸水等により保存安定性や品質に課題が発生する場合には、乾燥剤入り包装、及び/又は、製剤や顆粒の防湿コーティング等により、適宜、対応すればよい。
Specific examples of these dosage forms include tablets, granules, powders (including fine granules), capsules, liquids (including syrups) and the like, and additives suitable for each dosage form. Can be produced according to the usual methods described in the Japanese Pharmacopoeia and the like.
In the above dosage forms, various commonly used additives can be used depending on the dosage form. For example, excipients, stabilizers, coating agents, lubricants, adsorbents, binders, disintegrants, surfactants, colorants, pH regulators and fragrances are used as appropriate, and described in the Japanese Pharmacopoeia, etc. Can be produced according to the usual methods.
In the present invention, when the composition containing fexofenadine hydrochloride, bromohexine hydrochloride, and the above-described additive component is a solid preparation such as a tablet, the solid preparation can be produced according to a conventional method, When problems such as incompatibility with DADA and / or tranexamic acid occur in storage stability and the like, preparations may be made so that they do not come into contact with each other by appropriate granulation or multilayering. Here, a known method may be used for formulation such as granulation and multilayering. In addition, when the above preparation causes problems in storage stability or quality due to water absorption or the like, it can be appropriately handled by packaging with a desiccant and / or moisture-proof coating of the preparation or granules.
本発明の、「感冒時の急性鼻炎又は咽頭炎」とは、感冒罹患時における鼻水、鼻閉、くしゃみ、喉痛を意味する。 The “acute rhinitis or pharyngitis at the time of cold” of the present invention means runny nose, nasal congestion, sneezing, and sore throat at the time of common cold.
以下に、実施例及び試験例を示し、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
(実施例1)錠剤
(1)成分
(表1)
成分 3錠中(mg)
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 4
フェキソフェナジン塩酸塩 40
乳糖 15
ステアリン酸マグネシウム 2
トウモロコシデンプン 30
置換度ヒドロキシプロピルセルロース 適量
――――――――――――――――――――――――――
Example 1 Tablet (1) Ingredient (Table 1)
Ingredients 3 tablets (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Lactose 15
Magnesium stearate 2
Corn starch 30
Degree of substitution hydroxypropylcellulose Suitable amount ――――――――――――――――――――――――――
(2)製法
上記成分及び分量をとり、日局製剤総則「錠剤」の項に準じて錠剤を製造する。
(2) Manufacturing method Take the above ingredients and the amount, and manufacture tablets according to the section of “General Tablets” “Tablet”.
(実施例2)細粒剤
(1)成分
(表2)
成分 1包中(mg)
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 4
フェキソフェナジン塩酸塩 40
乳糖 100
トウモロコシデンプン 500
ステアリン酸マグネシウム 4
低置換度ヒドロキシプロピルセルロース 適量
――――――――――――――――――――――――――
(Example 2) Fine granule (1) component (Table 2)
In 1 pack (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Lactose 100
Corn starch 500
Magnesium stearate 4
Low-substituted hydroxypropylcellulose Suitable amount ――――――――――――――――――――――――――
(2)製法
上記成分及び分量をとり、日局製剤総則「顆粒剤」の項に準じて細粒剤を製造する。
(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”.
(実施例3)カプセル剤
(1)成分
(表3)
成分 3カプセル中(mg)
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 4
フェキソフェナジン塩酸塩 40
乳糖 25
ステアリン酸マグネシウム 3
トウモロコシデンプン 40
ヒドロキシプロピルセルロース 適量
――――――――――――――――――――――――――
Example 3 Capsule (1) Ingredient (Table 3)
In 3 capsules (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Lactose 25
Magnesium stearate 3
Corn starch 40
Hydroxypropylcellulose appropriate amount ――――――――――――――――――――――――――
(2)製法
上記成分及び分量をとり、日局製剤総則「顆粒剤」の項に準じて細粒剤を製造した後、カプセルに充てんして硬カプセル剤を製造する。
(2) Manufacturing method After taking the above components and quantities and preparing a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granules”, it is filled into capsules to produce hard capsules.
(実施例4)シロップ剤
(1)成分
(表4)
成分 10mL中(mg)
――――――――――――――――――――――――――
ブロムヘキシン塩酸塩 4
フェキソフェナジン塩酸塩 40
安息香酸ナトリウム 100
ポリビニルアルコール 20
白糖 900
精製水 残部
――――――――――――――――――――――――――
(Example 4) Syrup (1) component (Table 4)
Ingredients in 10 mL (mg)
――――――――――――――――――――――――――
Bromhexine hydrochloride 4
Fexofenadine hydrochloride 40
Sodium benzoate 100
Polyvinyl alcohol 20
Sucrose 900
Purified water balance ――――――――――――――――――――――――――
(2)製法
上記成分及び分量をとり、日局製剤総則「シロップ剤」の項に準じてシロップ剤を製造した後、褐色ガラス瓶に充てんしてシロップ剤を製造する。
(2) Manufacturing method Take the above ingredients and quantities, and manufacture a syrup according to the Japanese general formulation “Syrup” section, then fill it into a brown glass bottle to manufacture a syrup.
(試験例1)カラゲニン足蹠浮腫法による抗炎症効果試験
(1)被験物質
フェキソフェナジン塩酸塩はサノフィ・アベンティス(株)製のアレグラ(登録商標)錠を、乳鉢を用いて粉砕して使用した。また、セチリジン塩酸塩は東京化成工業(株)製、ブロムヘキシン塩酸塩はLKT Laboratories, Inc.製又は和光純薬工業(株)製、アンブロキソール塩酸塩は和光純薬工業(株)製のものを使用した。
各被験物質は、日本薬局方注射用水を用いて0.5w/v%のメチルセルロース(信越化学工業(株)製)溶液中に、所定量を入れて懸濁して調製し、胃ゾンデを取り付けたポリプロピレン製のディスポーザブル注射筒を用いて強制経口投与した。
(Test Example 1) Anti-inflammatory effect test by carrageenin footpad edema method (1) Test substance Fexofenadine hydrochloride is used by pulverizing Allegra (registered trademark) tablets manufactured by Sanofi-aventis Co., Ltd. using a mortar. did. Cetirizine hydrochloride is manufactured by Tokyo Chemical Industry Co., Ltd., bromohexine hydrochloride is manufactured by LKT Laboratories, Inc. or manufactured by Wako Pure Chemical Industries, Ltd., and ambroxol hydrochloride is manufactured by Wako Pure Chemical Industries, Ltd. It was used.
Each test substance is prepared by suspending a prescribed amount in a 0.5 w / v% methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) solution using Japanese Pharmacopoeia water for injection, and a polypropylene with a stomach tube attached Forcible oral administration was performed using a disposable syringe.
(2)使用動物
Crl:CD雄ラット(日本チャールス・リバー社製)4週齢を購入し、温度23±3℃、湿度55±15%、照明時間6時〜18時、換気回数12回/時(フィルターを通した新鮮空気)に制御された飼育室にて飼育した。なお、入手後5日間の検疫期間、その後、2日以上の馴化期間を設けた。飼料は実験動物用特殊固形飼料(CRF−1、オリエンタル酵母工業社製)および水道水を給水ビンにて自由に摂取させた。
体重推移、一般状態に異常の認められない動物を、馴化終了後に評価での使用動物として群分けに用いた。なお、被験物質投与前18時間以上は絶食とした。
(2) Animals used: Crl: CD male rat (manufactured by Charles River Japan) 4 weeks old, temperature 23 ± 3 ° C., humidity 55 ± 15%, lighting time 6:00 to 18:00, ventilation rate 12 times / Breeding in a breeding room controlled by time (fresh air through filter). In addition, a quarantine period of 5 days after acquisition and then a habituation period of 2 days or more were provided. As the feed, a special solid feed for experimental animals (CRF-1, manufactured by Oriental Yeast Co., Ltd.) and tap water were freely taken in a water supply bottle.
Animals with no abnormalities in weight transition and general condition were used for grouping as animals used for evaluation after habituation. In addition, fasting was performed for 18 hours or more before administration of the test substance.
(3)炎症の惹起
起炎剤として、カラゲニン(逗子化学研究所製)を、1.5w/v%になるように生理食塩液で懸濁して用いた。右側後肢足蹠皮下に27Gマント針を取り付けたポリプロピレン製のディスポーザブル注射筒を用いて、1.5w/v%カラゲニンを0.1mL投与し炎症を惹起させた。
(3) Induction of inflammation Carrageenin (manufactured by Choshi Chemical Laboratories) was used as an inflammatory agent suspended in physiological saline so as to be 1.5 w / v%. Inflammation was induced by administering 0.1 mL of 1.5 w / v% carrageenan using a polypropylene disposable syringe with a 27G cloak needle attached to the right hind footpad.
(4)試験方法
被験薬は、起炎30分前に1回経口投与した。群分け前、起炎後1、2、3、4及び5時間に、マウス・ラット後肢足蹠浮腫容積測定装置(ユニコム製)を用いて、右側後肢足蹠容積を測定した。浮腫率は以下の式により算出して求めた。
(4) Test method The test drug was orally administered once 30 minutes before inflammation. The right hind footpad volume was measured using a mouse / rat hindlimb footpad edema volume measuring device (manufactured by Unicom) before grouping and at 1, 2, 3, 4 and 5 hours after inflammation. The edema rate was calculated by the following formula.
(5)試験結果
予試験によってフェキソフェナジン塩酸塩単剤(FF)、及び、セチリジン塩酸塩単剤(CZ)の抗炎症作用の概略最大無作用量を求め、それらを投与量とした。予試験によるフェキソフェナジン塩酸塩単剤(FF)、及びセチリジン塩酸塩単剤(CZ)の抗炎症作用の最大無作用量は、それぞれ6mg/Kg、及び10mg/Kgであった。
抗炎症作用のない去痰剤の投与量については、上記抗ヒスタミン剤の投与量、ブロムヘキシン及びアンブロキソールの臨床量比を基にして、それぞれ4mg/Kg、及び15mg/Kgとした。
(5) Test results Preliminary tests determined the approximate maximum ineffective amount of anti-inflammatory action of fexofenadine hydrochloride single agent (FF) and cetirizine hydrochloride single agent (CZ), and these were used as doses. The maximum ineffective amount of anti-inflammatory action of fexofenadine hydrochloride single agent (FF) and cetirizine hydrochloride single agent (CZ) by the preliminary test was 6 mg / Kg and 10 mg / Kg, respectively.
The dose of the expectorant without anti-inflammatory action was 4 mg / Kg and 15 mg / Kg, respectively, based on the dose of the antihistamine and the clinical dose ratio of bromhexine and ambroxol.
上記投与量において得られた浮腫率の結果を図1、図2に示した(n=10)。
図1より、フェキソフェナジン塩酸塩及びアンブロキソール塩酸塩を併用(FF+AX)した場合には浮腫が悪化することが判明した。一方、フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を併用(FF+BX)した場合には抗浮腫作用が増強することが判った。
また、時間経過による浮腫率の時間曲線下面積(AUC;area under the time curve)を指標として比較評価した。溶媒を投与した対照群におけるAUCを1とした場合、フェキソフェナジン塩酸塩単剤(FF)では0.99、FF+AXでは1.07、またFF+BXでは0.91であった。
一方、抗ヒスタミン薬のフェキソフェナジン塩酸塩を、同じ、第二世代の抗ヒスタミン剤であるセチリジン塩酸塩(CZ)に置き換え、同様の評価をした結果を図2に示した。図2より、セチリジン塩酸塩及びアンブロキソール塩酸塩を併用(CZ+AX)した場合とセチリジン塩酸塩単剤(CZ)の時間経過による浮腫率の推移は、AUC比としてそれぞれ0.98及び0.95であり、併用群及び単剤群ともに溶媒投与群とほぼ同程度であり、併用によっても浮腫率の抑制効果がほとんど認められなかった。一方、セチリジン塩酸塩及びブロムヘキシン塩酸塩を併用(CZ+BX)した場合にはAUCが1.09に増加し、浮腫が悪化した。
以上の結果より、フェキソフェナジン塩酸塩とブロムヘキシン塩酸塩の併用においてのみ、抗炎症作用の増強が発現することが判明した。
The results of the edema rate obtained at the above dose are shown in FIGS. 1 and 2 (n = 10).
From FIG. 1, it was found that when fexofenadine hydrochloride and ambroxol hydrochloride were used in combination (FF + AX), edema worsened. On the other hand, when fexofenadine hydrochloride and bromhexine hydrochloride were used in combination (FF + BX), it was found that the anti-edema action was enhanced.
In addition, the area under the time curve (AUC) of the edema rate over time was compared and evaluated. When the AUC in the control group to which the solvent was administered was 1, it was 0.99 for fexofenadine hydrochloride (FF), 1.07 for FF + AX, and 0.91 for FF + BX.
On the other hand, FIG. 2 shows the results of a similar evaluation in which the antihistamine drug fexofenadine hydrochloride was replaced with cetirizine hydrochloride (CZ), which is the same second generation antihistamine. From FIG. 2, the change in edema rate over time of cetirizine hydrochloride and ambroxol hydrochloride in combination (CZ + AX) and cetirizine hydrochloride single agent (CZ) is 0.98 and 0.95 as AUC ratios, respectively. Both the combination group and the single agent group were almost the same as those in the solvent administration group, and the combined use showed almost no effect of suppressing the edema rate. On the other hand, when cetirizine hydrochloride and bromhexine hydrochloride were used in combination (CZ + BX), AUC increased to 1.09, and edema worsened.
From the above results, it was found that the enhancement of the anti-inflammatory effect was manifested only in the combined use of fexofenadine hydrochloride and bromhexine hydrochloride.
(試験例2)モルモット摘出回腸のヒスタミンによる収縮試験
(1)被験物質
フェキソフェナジン塩酸塩はアミノケミカル製を使用した。また、セチリジン塩酸塩は東京化成工業(株)製を、ブロムヘキシン塩酸塩は和光純薬工業(株)製又はLKT Laboratories,Inc.製のものを使用した。
各被験物質は、ジメチルスルフォキシド溶液で溶解し、日本薬局方注射用水を用いて希釈し、所定濃度になるように調製した。
(Test Example 2) Contraction test using histamine in the isolated ileum of the guinea pig (1) Test substance Fexofenadine hydrochloride manufactured by Amino Chemical was used. Cetirizine hydrochloride is manufactured by Tokyo Chemical Industry Co., Ltd., and bromohexine hydrochloride is manufactured by Wako Pure Chemical Industries, Ltd. or LKT Laboratories, Inc. The product made from was used.
Each test substance was dissolved in a dimethyl sulfoxide solution, diluted with Japanese Pharmacopoeia water for injection, and prepared to a predetermined concentration.
(2)使用動物
Kwl:Hartley雄モルモット(紀和実験動物研究所社製)3週齢を購入し、温度23±3℃、湿度55±15%、照明時間6時〜18時、換気回数12回/時(フィルターを通した新鮮空気)に制御された飼育室にて飼育した。なお、入手後5日間の検疫期間、その後、2日以上の馴化期間を設けた。飼料は固形飼料(LRC4、オリエンタル酵母工業社製)および水道水を給水ビンにて自由に摂取させた。評価には、体重推移、一般状態に異常が認められない動物を用いた。
(2) Animals used Kwl: Hartley male guinea pig (manufactured by Kiwa Laboratory Animal Research Co., Ltd.) 3 weeks old is purchased, temperature 23 ± 3 ° C., humidity 55 ± 15%, illumination time 6 o'clock to 18 o'clock, ventilation rate 12 times It was reared in a rearing room controlled at / hour (fresh air through a filter). In addition, a quarantine period of 5 days after acquisition and then a habituation period of 2 days or more were provided. As the feed, solid feed (LRC4, manufactured by Oriental Yeast Co., Ltd.) and tap water were freely ingested in a water supply bottle. For the evaluation, animals with no abnormality in weight transition and general condition were used.
(3)標本の作製
該動物を20v/v%イソフルランにて麻酔し、頚動脈を切断して放血死させた後、回腸を摘出後、混合ガス(95%O2+5%CO2)飽和の栄養液(Tyrode液:<組成>NaCl:136.9mmol/L、KCl:2.7mmol/L、CaCl2:1.8mmol/L、MgCl2:1.05mmol/L、NaH2PO4:0.42mmol/L、NaHCO3:11.9mmol/L、Glucose:5.55mmol/L)に浸した。摘出した回腸を切断し、長さ約1cmの標本を作製した。作製した標本は、混合ガスで通気した栄養液が満たされたMagnus管内に、約0.5gの負荷で縦走方向に懸垂させた。
(3) Preparation of specimen The animal was anesthetized with 20v / v% isoflurane, the carotid artery was cut and exsanguinated, the ileum was removed, and mixed gas (95% O 2 + 5% CO 2 ) saturated nutrition Solution (Tyrode solution: <composition> NaCl: 136.9 mmol / L, KCl: 2.7 mmol / L, CaCl2: 1.8 mmol / L, MgCl2: 1.05 mmol / L, NaH2PO4: 0.42 mmol / L, NaHCO3: 11.9 mmol / L, Glucose: 5.55 mmol / L). The excised ileum was cut to prepare a specimen having a length of about 1 cm. The prepared specimen was suspended in the longitudinal direction under a load of about 0.5 g in a Magnus tube filled with a nutrient solution aerated with a mixed gas.
(4)張力の測定
栄養液で満たされたMagnus管内の標本は、懸垂して30分以上平衡化した後、該管内にヒスタミン(終濃度:1×10−6mol/L)を添加して収縮反応を測定する。標本の張力変化は、等張性トランスデューサーとアンプ(日本光電工業製)を介しデータ収集システムで記録した。栄養液で洗浄後、再びヒスタミンを添加して、2回の収縮反応が同程度の場合に限り被験物質の測定に使用することとした。
(4) Measurement of tension The specimen in the Magnus tube filled with nutrient solution was suspended and equilibrated for 30 minutes or more, and then histamine (final concentration: 1 × 10 −6 mol / L) was added to the tube. Measure contractile response. The tension change of the specimen was recorded by a data acquisition system via an isotonic transducer and an amplifier (manufactured by Nihon Kohden Industry). After washing with nutrient solution, histamine was added again, and it was decided to use it for the measurement of the test substance only when the two contraction reactions were similar.
(5)試験方法
静止張力の状態で被験物質を添加し、15分後にヒスタミンを添加して収縮反応に対する被験物質の抑制効果を測定した。抑制率は以下の式により算出して求めた。
(5) Test method The test substance was added in a state of static tension, and histamine was added 15 minutes later to measure the inhibitory effect of the test substance on the contractile reaction. The inhibition rate was calculated by the following formula.
(6)試験結果
フェキソフェナジン塩酸塩単剤(FF)に対する、フェキソフェナジン塩酸塩とブロムヘキシン塩酸塩の併用(FF+BX)における抑制率の比の結果を表5に示した。参考として、表5には、同じ第二世代のセチリジン塩酸塩単剤(CZ)の抑制率に対する、セチリジン塩酸塩とブロムヘキシン塩酸塩の併用(CZ+BX)における抑制率の比を示した。各数値はいずれもn=5の結果の平均値である。
(6) Test result The result of the ratio of the inhibition rate in combined use (FF + BX) of fexofenadine hydrochloride and bromhexine hydrochloride with respect to fexofenadine hydrochloride single agent (FF) was shown in Table 5. For reference, Table 5 shows the ratio of the inhibition rate in the combined use of cetirizine hydrochloride and bromhexine hydrochloride (CZ + BX) with respect to the inhibition rate of the same second-generation cetirizine hydrochloride single agent (CZ). Each numerical value is an average value of the results of n = 5.
(表5)
被験薬(mg/L) 抑制率の比
―――――――――――――――――――――――――――――――
FF(0.02) 1
FF(0.02)+BX(0.016) 1.32
CZ(0.04) 1
CZ(0.04)+BX(0.016) 0.96
―――――――――――――――――――――――――――――――
以上の結果より、フェキソフェナジン塩酸塩(FF)とブロムヘキシン塩酸塩(BX)の併用おいてのみ、抗ヒスタミン作用の増強が発現することが判明した。
(Table 5)
Study drug (mg / L) Ratio of inhibition rate ―――――――――――――――――――――――――――――――
FF (0.02) 1
FF (0.02) + BX (0.016) 1.32
CZ (0.04) 1
CZ (0.04) + BX (0.016) 0.96
―――――――――――――――――――――――――――――――
From the above results, it was found that the antihistaminic activity was enhanced only by the combined use of fexofenadine hydrochloride (FF) and bromohexine hydrochloride (BX).
フェキソフェナジン塩酸塩及びブロムヘキシン塩酸塩を含有する、新たな抗炎症剤及び/又は抗ヒスタミン組成物として利用できる。 It can be used as a new anti-inflammatory agent and / or antihistamine composition containing fexofenadine hydrochloride and bromhexine hydrochloride.
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