JP2006169232A - Treating agent of allergic rhinitis - Google Patents
Treating agent of allergic rhinitis Download PDFInfo
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- JP2006169232A JP2006169232A JP2005323089A JP2005323089A JP2006169232A JP 2006169232 A JP2006169232 A JP 2006169232A JP 2005323089 A JP2005323089 A JP 2005323089A JP 2005323089 A JP2005323089 A JP 2005323089A JP 2006169232 A JP2006169232 A JP 2006169232A
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Abstract
Description
本発明は、アレルギー性鼻炎等のＩ型アレルギー疾患の治療のため、詳しくは即時相反応（くしゃみ・鼻水・鼻づまり）及び遅発相反応（鼻づまり）を抑制する事に加え、鼻炎の慢性化防止に有用なアレルギー性鼻炎治療薬である。 The present invention is for the treatment of type I allergic diseases such as allergic rhinitis. Specifically, in addition to suppressing immediate phase reaction (sneezing, runny nose, nasal congestion) and late phase reaction (nasal congestion), chronic rhinitis It is a therapeutic agent for allergic rhinitis that is useful for preventing oxidization.
アレルギー性鼻炎は、くしゃみ、鼻水、鼻づまり（鼻閉）の３大症状を特徴とするＩ型アレルギー疾患であり、花粉等による抗原惹起直後にくしゃみ、鼻水、鼻づまりを誘発する即時相反応と惹起後４〜２４時間に鼻づまりを誘発する遅発相反応の２相性反応を示すことが知られている。従来、アレルギー性鼻炎の治療には抗ヒスタミン作用を主作用とする抗アレルギー薬が投与されているが、即時相反応におけるくしゃみ、鼻水は強力に抑制するが、鼻づまり症状、特に遅発相反応における鼻づまり症状に対して効果が弱いとされている。遅発相反応における鼻づまり症状に対しては、デキサメタゾンなどのステロイド剤の投与が有効な治療であるが、ステロイド剤には副作用があり、副作用の無い治療薬が望まれている。 Allergic rhinitis is a type I allergic disease characterized by three major symptoms: sneezing, runny nose, and nasal congestion (nasal congestion). Immediate phase reaction and induction that induce sneezing, runny nose and nasal congestion immediately after antigen induction by pollen. It is known to show a biphasic response of late phase reaction that induces nasal congestion 4-24 hours later. Conventionally, allergic rhinitis has been treated with antiallergic drugs that mainly have antihistamine effects, but sneezing and runny nose in the immediate phase reaction are strongly suppressed, but nasal congestion symptoms, particularly late-phase reaction It is said that the effect on nasal congestion is weak. Administration of steroids such as dexamethasone is an effective treatment for nasal congestion symptoms in the late phase reaction, but steroids have side effects, and therapeutic agents without side effects are desired.
また、遅発相反応の発症には、ロイコトリエン（ＬＴｓ）及びトロンボキサン（ＴＸ）が関与することが知られている。ＬＴｓやＴＸ等のケミカルメディエーターは、肥満細胞のみでなく、遅発相反応において局所に浸潤する好酸球により産生されている。従って、遅発相反応における鼻づまり抑制のターゲットとして好酸球浸潤抑制作用のある抗アレルギー薬の開発が望まれている。 In addition, it is known that leukotrienes (LTs) and thromboxane (TX) are involved in the onset of the late phase reaction. Chemical mediators such as LTs and TX are produced not only by mast cells but also by eosinophils that infiltrate locally in the late phase reaction. Therefore, development of an antiallergic drug having an eosinophil infiltration suppressing action is desired as a target for suppressing nasal congestion in the late phase reaction.
ボクソクは、ブナ科のクヌギ又はその他近縁植物の樹皮で、漢方方剤（十味敗毒湯など）の構成生薬であり、化膿性皮膚疾患、急性皮膚疾患、水虫等の皮膚疾患に用いられている。 Bokusoku is a bark of the beech family of beech or other related plants, and is a herbal medicine that is a herbal medicine (such as Tomi-Shito), used for skin diseases such as purulent skin disease, acute skin disease, athlete's foot. ing.
ビンロウジはヤシ科の種子で、漢方方剤（女神散など）の構成生薬であり、健胃・消化・駆虫薬等に用いられている（非特許文献１参照）。 Areca is a seed of the palm family and is a herbal medicine of Chinese herbal medicine (such as Megamisan), and is used for healthy stomach, digestion, anthelmintic and the like (see Non-Patent Document 1).
しかしながら、ボクソク及びビンロウジのアレルギー性鼻炎に対する治療効果、特に鼻づまり症状に対する治療効果及び鼻炎の慢性化を防止する作用は全く知られていない。
本発明は、遅発相反応の発症に関与するロイコトリエン（ＬＴｓ）及びトロンボキサン（ＴＸ）等のケミカルメディエーターにより浸潤する好酸球を抑制することにより、アレルギー性鼻炎に対する治療、特に遅発相反応における鼻づまり症状の抑制に優れた効果を有し、鼻炎の慢性化をも防止する副作用の無いアレルギー性鼻炎治療薬を提供することである。 The present invention treats allergic rhinitis by treating eosinophils infiltrated with chemical mediators such as leukotrienes (LTs) and thromboxane (TX) involved in the onset of late phase reaction, particularly late phase reaction. It is intended to provide a therapeutic agent for allergic rhinitis which has an excellent effect in suppressing nasal congestion and prevents side effects of rhinitis without side effects.
本発明者は、かかる課題を解決するために鋭意研究した結果、ボクソク及びビンロウジが、アレルギー性鼻炎モデルにおける鼻腔内好酸球浸潤反応に対して強力な抑制作用を示し、アレルギー性鼻炎に対する治療、特に遅発相反応における鼻づまり症状の抑制及び鼻炎の慢性化防止に優れた効果を有することを見出し、本発明を完成した。 As a result of diligent research to solve such problems, the present inventor has shown that Boxoku and betel nut show a strong inhibitory action on the nasal eosinophil infiltration reaction in an allergic rhinitis model, treatment for allergic rhinitis, In particular, the inventors have found that the present invention has an excellent effect in suppressing symptoms of nasal congestion in the late phase reaction and preventing chronic rhinitis.
すなわち、本発明は、ボクソク及びビンロウジから選ばれる１種又は２種を配合することを特徴とするアレルギー性鼻炎治療薬である。 That is, the present invention is a therapeutic agent for allergic rhinitis, characterized in that one or two selected from Boxoku and Betel Rowji are blended.
本発明は、特に遅発相反応における鼻づまり症状の抑制に優れた効果を有し、鼻炎の慢性化をも防止する副作用の無いアレルギー性鼻炎治療薬である。 The present invention is a therapeutic agent for allergic rhinitis that has an excellent effect in suppressing symptoms of nasal congestion particularly in late-phase reaction, and has no side effects to prevent chronic rhinitis.
本発明で、ボクソク及びビンロウジの有効量は、経口では原生薬換算量として、成人１日量あたり、0.01〜100g、好適には0.1〜10gがよい。これらの生薬は、実際には、生薬末、生薬エキス等の形で製剤に配合される。 In the present invention, the effective amount of boxoku and betel wax is orally about 0.01 to 100 g, preferably 0.1 to 10 g per day for an adult, as the amount of crude drug equivalent. These herbal medicines are actually blended with pharmaceutical preparations in the form of herbal powders, herbal extracts and the like.
本発明のアレルギー性鼻炎治療薬は、経口又は非経口投与製剤に調整され、経口投与製剤としては、錠剤、丸剤、カプセル剤、顆粒剤、散剤、チュアブル錠などの固形製剤、シロップ剤、ドリンク剤などの液剤であり、慣用的な方法で製造される。固形製剤として調整する場合には、必要に応じて、賦形剤、滑沢剤、崩壊剤等を使用することができる。液剤として調整する場合には、必要に応じて、界面活性剤、溶解補助剤、緩衝剤等を使用することができる。 The therapeutic agent for allergic rhinitis of the present invention is adjusted to a preparation for oral or parenteral administration, and the oral preparation includes solid preparations such as tablets, pills, capsules, granules, powders, chewable tablets, syrups, and drinks. It is a liquid agent such as an agent, and is produced by a conventional method. When preparing as a solid preparation, excipients, lubricants, disintegrants and the like can be used as necessary. When adjusting as a liquid agent, a surfactant, a solubilizing agent, a buffering agent, and the like can be used as necessary.
また、他に保存剤、香料、色素、甘味剤、嬌味剤、清涼化剤等を使用することができる。 In addition, preservatives, fragrances, pigments, sweetening agents, flavoring agents, cooling agents, and the like can be used.
非経口投与製剤としては、粉末剤や液剤に調整し、スプレー剤等で鼻粘膜へ投与される。 As a parenteral preparation, it is prepared into a powder or liquid and administered to the nasal mucosa with a spray or the like.
本発明のアレルギー性鼻炎治療薬は、１日１回又は２〜６回に分けて投与することができる。 The therapeutic agent for allergic rhinitis of the present invention can be administered once a day or divided into 2 to 6 times.
以下に、実施例及び試験例を示し、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to examples and test examples.
ボクソクエキス末1500g、結晶セルロース150g、白糖75g、マンニトール31.5g、ヒドロキシプロピルセルロース300g、低置換度ヒドロキシプロピルセルロース450g、軽質無水ケイ酸45g、メタケイ酸アルミン酸マグネシウム135gを混合し、攪拌造粒機にて精製水で造粒し、流動層乾燥機にて乾燥し、ステアリン酸マグネシウム13.5gを加えて混合し、ロータリー打錠機により１錠300mgの錠剤を得た。 Bokuoku extract powder 1500g, crystalline cellulose 150g, sucrose 75g, mannitol 31.5g, hydroxypropylcellulose 300g, low substituted hydroxypropylcellulose 450g, light anhydrous silicic acid 45g, magnesium metasilicate aluminate 135g, and stirring granulator Granulated with purified water, dried in a fluid bed dryer, 13.5 g of magnesium stearate was added and mixed, and a tablet of 300 mg was obtained with a rotary tableting machine.
ボクソクエキス末1000g、結晶セルロース900g、白糖300g、マンニトール1110g、ヒドロキシプロピルセルロース900g、軽質無水ケイ酸90g、メタケイ酸アルミン酸マグネシウム155gを混合し、流動層造粒乾燥機にて水／エタノール混液（３：７）で造粒、乾燥し、メタケイ酸アルミン酸マグネシウム45gを加えて混合し、１包1.5gの散剤を得た。 Bokuoku extract powder 1000g, crystalline cellulose 900g, sucrose 300g, mannitol 1110g, hydroxypropylcellulose 900g, light anhydrous silicic acid 90g, magnesium metasilicate aluminate 155g, mixed with water / ethanol mixture (3: Granulated and dried in 7), 45 g of magnesium aluminate metasilicate was added and mixed to obtain 1.5 g of powder of 1 packet.
ボクソクエキス末1000g、リン酸水素カルシウム428g、バレイショデンプン360g、結晶セルロース360g、ヒドロキシプロピルセルロース120g、軽質無水ケイ酸36g、ステアリン酸マグネシウム24g、ケイ酸マグネシウム72gを混合し、乾式造粒機にて造粒し、１カプセル400mgのカプセル剤を得た。 Bokuoku extract powder 1000g, calcium hydrogen phosphate 428g, potato starch 360g, crystalline cellulose 360g, hydroxypropylcellulose 120g, light anhydrous silicic acid 36g, magnesium stearate 24g, magnesium silicate 72g and granulated with dry granulator 1 capsule 400 mg capsule was obtained.
ビンロウジエキス末1500g、結晶セルロース200g、白糖30g、マンニトール28g、ヒドロキシプロピルセルロース240g、低置換度ヒドロキシプロピルセルロース240g、軽質無水ケイ酸30g、メタケイ酸アルミン酸マグネシウム120gを混合し、攪拌造粒機にて精製水で造粒し、流動層乾燥機にて乾燥し、ステアリン酸マグネシウム12gを加えて混合し、ロータリー打錠機により１錠400mgの錠剤を得た。 Betel wax extract powder 1500g, crystalline cellulose 200g, sucrose 30g, mannitol 28g, hydroxypropylcellulose 240g, low-substituted hydroxypropylcellulose 240g, light anhydrous silicic acid 30g, magnesium metasilicate aluminate 120g, and stirring granulator The mixture was granulated with purified water, dried with a fluidized bed dryer, 12 g of magnesium stearate was added and mixed, and a 400 mg tablet was obtained with a rotary tableting machine.
ビンロウジエキス末1500g、結晶セルロース400g、白糖300g、マンニトール1110g、ヒドロキシプロピルセルロース900g、軽質無水ケイ酸90g、メタケイ酸アルミン酸マグネシウム155gを混合し、流動層造粒乾燥機にて水／エタノール混液（３：７）で造粒、乾燥し、メタケイ酸アルミン酸マグネシウム45gを加えて混合し、１包1.5gの散剤を得た。 Betel wax extract powder 1500g, crystalline cellulose 400g, sucrose 300g, mannitol 1110g, hydroxypropylcellulose 900g, light anhydrous silicic acid 90g, magnesium metasilicate aluminate 155g, mixed with water / ethanol mixture (3 : 7) Granulated and dried, 45 g of magnesium aluminate metasilicate was added and mixed to obtain 1.5 g of powder of 1 packet.
ビンロウジエキス末1500g、リン酸水素カルシウム128g、バレイショデンプン160g、結晶セルロース360g、ヒドロキシプロピルセルロース120g、軽質無水ケイ酸36g、ステアリン酸マグネシウム24g、ケイ酸マグネシウム72gを混合し、乾式造粒機にて造粒し、１カプセル400mgのカプセル剤を得た。 Betel wax extract powder 1500 g, calcium hydrogen phosphate 128 g, potato starch 160 g, crystalline cellulose 360 g, hydroxypropyl cellulose 120 g, light anhydrous silicic acid 36 g, magnesium stearate 24 g, magnesium silicate 72 g are mixed and granulated with a dry granulator 1 capsule 400 mg capsule was obtained.
試験例：ＯＶＡ惹起マウス鼻腔内好酸球浸潤反応試験
１．動物
BALB/cマウス(雌、5week)を1週間の予備飼育後に実験に供した。
Test example: OVA-induced mouse nasal eosinophil infiltration reaction test animal
BALB / c mice (female, 5weeks) were subjected to experiments after 1 week of pre-breeding.
２．試薬及び被験薬物
試薬として、Ovalbumin (OVA)、硫酸カリウム・アルミニウム、デキサメタゾン、被験薬物は、ボクソクエキス及びビンロウジエキスを使用した。
2. Reagents and Test Drugs Ovalbumin (OVA), potassium sulfate / aluminum, dexamethasone, and test drugs used were Boxox extract and betel wax extract.
３．抗原感作
3-1 Alumの作成
10%硫酸カリウムアルミニウム水溶液（ストック溶液）60.8mLを純水600mLに添加し、pH7.0に調製して水酸化アルミニウム懸濁液を作成した。この懸濁液をリン酸緩衝溶液（PBS）（大日本製薬）を使用し遠心操作(2000rpm, 10min)することで3回洗浄した。洗浄した水酸化アルミニウムの沈殿物をPBSにより最終200mLにメスアップし再懸濁する事でAlum溶液(5mg/ml)を作成した。
3. Antigen sensitization
3-1 Creating Alum
60.8 mL of 10% potassium aluminum sulfate aqueous solution (stock solution) was added to 600 mL of pure water, and adjusted to pH 7.0 to prepare an aluminum hydroxide suspension. This suspension was washed 3 times by using a phosphate buffer solution (PBS) (Dainippon Pharmaceutical Co., Ltd.) and centrifuging (2000 rpm, 10 min). The washed aluminum hydroxide precipitate was made up to a final volume of 200 mL with PBS and resuspended to prepare an Alum solution (5 mg / ml).
3-2 感作
感作はBALB/cマウスにOVA-Alum溶液(OVA 5μg/Alum5mg/mL)を200μL腹腔内投与する事で行った。感作は初回感作(0day)及び追加感作(4,13,27day)の4回行った。
3-2 Sensitization Sensitization was performed by intraperitoneally administering 200 μL of OVA-Alum solution (OVA 5 μg / Alum 5 mg / mL) to BALB / c mice. Sensitization was performed 4 times, first sensitization (0 day) and additional sensitization (4, 13, 27 days).
４．抗原惹起、被験薬物の調整及び投与方法、及び評価
最終感作７日後より隔日に４回、OVA（25μg/ml,20μl）の点鼻惹起を行った。被験薬物として、ボクソクエキス500mg/kg(n=11)、ビンロウジエキス500mg/kg(n=10)を用いた。また、コントロール(n=14)として、0.5%カルボキシメチルセルロース（ＣＭＣ）溶液、比較薬物として、強力な好酸球浸潤抑制作用を有するデキサメタゾン（Ｄｅｘ）を高容量：1mg/kg(n=9)を用いた。各被験薬物は、0.5%ＣＭＣ溶液に溶解又は懸濁し、初回惹起１日前より最終惹起日まで１日１回、経口投与により、マウスに８日間連投した。なお、点鼻惹起当日の投与は、惹起の１時間前に行った。最終惹起６時間後に鼻腔組織を回収し、ホルマリン固定後、定法に従ってLuna染色した。各値は鼻腔組織Level２病理切片当たりの好酸球数をmean±seで示した。有意差検定は、コントロール群と比験薬物投与群間の２群間比較を行った（t-test)。結果を図1に示す。
4). Induction of antigen, preparation and administration of test drug, and evaluation Instillation of OVA (25 μg / ml, 20 μl) was performed four times every other day from 7 days after the final sensitization. As test drugs, Boxoku extract 500 mg / kg (n = 11) and betel nut extract 500 mg / kg (n = 10) were used. In addition, as a control (n = 14), 0.5% carboxymethylcellulose (CMC) solution, and as a comparative drug, dexamethasone (Dex) having a strong eosinophil infiltration inhibitory action, high volume: 1 mg / kg (n = 9) Using. Each test drug was dissolved or suspended in a 0.5% CMC solution and orally administered once a day from the day before the first challenge to the final challenge for 8 days. In addition, administration on the day of instillation was performed 1 hour before the initiation. The nasal cavity tissue was collected 6 hours after the last induction, fixed with formalin, and then stained with Luna according to a conventional method. Each value represents the number of eosinophils per nasal tissue Level 2 pathological section as mean ± se. In the significant difference test, two groups were compared between the control group and the comparative drug administration group (t-test). The results are shown in Figure 1.
５．結果
ボクソク及びビンロウジは、鼻腔内好酸球浸潤反応をコントロールに対して有意に抑制した(t-test)。また、その抑制は、比較薬剤の高用量デキサメタゾン（Ｄｅｘ）には及ばないものの強力であった。
5. Results Bokukoku and betel nut significantly suppressed the nasal eosinophil infiltration reaction compared to the control (t-test). Moreover, the suppression was strong although it did not reach the comparative drug high dose dexamethasone (Dex).
本発明のボクソク及びビンロウジから選ばれる１種又は２種を配合することを特徴とするアレルギー性鼻炎治療薬は、強力な鼻腔内好酸球浸潤抑制作用を有し、アレルギー性鼻炎に対する治療薬として、また特に遅発相反応における鼻づまり症状の抑制及び鼻炎の慢性化防止するアレルギー性鼻炎に対する治療薬として利用できる。 The therapeutic agent for allergic rhinitis, characterized in that it contains one or two selected from the boxoche and areca of the present invention, has a strong inhibitory effect on nasal eosinophil infiltration and is a therapeutic agent for allergic rhinitis In particular, it can be used as a therapeutic agent for allergic rhinitis that suppresses nasal congestion in the late-phase reaction and prevents chronic rhinitis.
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
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| JP2005323089A JP2006169232A (en) | 2004-11-16 | 2005-11-08 | Treating agent of allergic rhinitis |
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| Application Number | Priority Date | Filing Date | Title |
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| JP2004331323 | 2004-11-16 | ||
| JP2005323089A JP2006169232A (en) | 2004-11-16 | 2005-11-08 | Treating agent of allergic rhinitis |
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