JP2008120684A - Antiallergic drug - Google Patents

Antiallergic drug Download PDF

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JP2008120684A
JP2008120684A JP2005062642A JP2005062642A JP2008120684A JP 2008120684 A JP2008120684 A JP 2008120684A JP 2005062642 A JP2005062642 A JP 2005062642A JP 2005062642 A JP2005062642 A JP 2005062642A JP 2008120684 A JP2008120684 A JP 2008120684A
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fexofenadine
fxd
glycoprotein
liver
test substance
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Teruko Imai
輝子 今井
Shinichi Ninomiya
真一 二宮
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Daiichi Pure Chemicals Co Ltd
Kumamoto University NUC
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Daiichi Pure Chemicals Co Ltd
Kumamoto University NUC
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Priority to JP2005062642A priority Critical patent/JP2008120684A/en
Priority to PCT/JP2006/304352 priority patent/WO2006095723A1/en
Publication of JP2008120684A publication Critical patent/JP2008120684A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antiallergic drug having excellent bioavailability and persistence, and effective by once oral dose a day. <P>SOLUTION: The antiallergic drug contains fexofenadine alkyl ester or a salt thereof, and is used by orally administering 30-60 mg dose of the fexofenadine alkyl ester or the salt thereof as a dose per day per adult by once a day. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は、１日１回の経口投与で有効な抗アレルギー薬に関する。   The present invention relates to an antiallergic agent effective by oral administration once a day.

フェキソフェナジンは、化学名（±）−４−［１−ヒドロキシ−４−［４−（ヒドロキシジフェニルメチル）−１−ピペリジニル］ブチル］−α，α−ジメチルベンゼン酢酸であり、主作用としてヒスタミンＨ１受容体拮抗作用を有し、さらに炎症性サイトカイン産生抑制作用、好酸球遊走抑制作用、ケミカルメディエータ遊離抑制作用などを有する抗アレルギー薬として広く使用されている（特許文献１及び２）。   Fexofenadine is the chemical name (±) -4- [1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butyl] -α, α-dimethylbenzeneacetic acid, which has histamine as the main action. It is widely used as an antiallergic agent having an H1 receptor antagonistic action and further having an inflammatory cytokine production inhibitory action, an eosinophil migration inhibitory action, a chemical mediator release inhibitory action, etc. (Patent Documents 1 and 2).

しかしながら、フェキソフェナジン類は、その物理化学的特性のために、膜透過性が悪く、さらに腸管上皮のｐ−糖蛋白質逆輸送系の標的となることから、経口投与した場合に十分なバイオアベイラビリティーが得られないという問題がある。そして、その解決策として、フェキソフェナジン類にｐ−糖蛋白質抑制物質を併用することが提案されている（特許文献２）
特開昭５５−１４１４６９号公報 特表２００１−５１５０４１号公報 However, fexofenadines have poor membrane permeability due to their physicochemical properties and are also targets of the p-glycoprotein reverse transport system of the intestinal epithelium. Therefore, sufficient bioavailability when administered orally. There is a problem that can not be obtained. As a solution, it has been proposed to use a p-glycoprotein inhibitor together with fexofenadine (Patent Document 2).
JP-A-55-141469 Special table 2001-515041 gazette

フェキソフェナジンにｐ−糖蛋白質抑制物質を併用した場合、腸管上皮における透過性が向上する可能性はあるものの、この効果はフェキソフェナジンとｐ−糖蛋白質抑制物質が消化管内で同時に局在して始めて発揮できるものである。一方、消化管内での薬物の移動や溶解性をコントロールすることは非常に困難であり、食物との相互作用も考えられるため、フェキソフェナジンとｐ−糖蛋白質抑制物質とを併用する投与方法では、フェキソフェナジンの一定した血中濃度を得ることは難しい。また、フェキソフェナジンに加えてｐ−糖蛋白質抑制物質を投与することは、新たな薬物相互作用、投与量の増大等などの問題が生じる。
従って、本発明の目的は、一成分で優れたバイオアベイラビリティーと持続性とを満たし、１日１回の経口投与で有効な抗アレルギー薬を提供することにある。 When p-glycoprotein inhibitor is used in combination with fexofenadine, permeability in the intestinal epithelium may be improved, but this effect is due to the simultaneous localization of fexofenadine and p-glycoprotein inhibitor in the digestive tract. Can only be demonstrated. On the other hand, since it is very difficult to control the movement and solubility of drugs in the gastrointestinal tract and interaction with food is also considered, in the administration method using fexofenadine and a p-glycoprotein inhibitor in combination, It is difficult to obtain a constant blood concentration of fexofenadine. Moreover, administration of a p-glycoprotein inhibitor in addition to fexofenadine causes problems such as new drug interaction and increased dosage.
Accordingly, an object of the present invention is to provide an antiallergic drug which satisfies a superior bioavailability and durability with one component and is effective by oral administration once a day.

そこで本発明者は、フェキソフェナジン誘導体のｐ−糖蛋白質発現細胞における膜透過性及びエステラーゼによる作用について検討してきた結果、全く意外にもフェキソフェナジンアルキルエステルは、フェキソフェナジンやフェキソフェナジンヒドロキシアルキルエステルとはこれらの作用が相違し、ｐ−糖蛋白質発現細胞における膜透過性が良好で、かつ小腸エステラーゼによる加水分解を受けずに、エステル体として吸収された後に肝臓エステラーゼによって活性体であるフェキソフェナジンに変化することから、優れたバイオアベイラビリティーと持続性を有し、１日１回の経口投与で十分有効であることを見出し、抗アレルギー薬に関する本発明を完成した。
さらに本発明者らは、上記検討で使用した試験を方法を利用すれば、エステル型プロドラッグの体内での動態を予測できることを見出し、エステル型プロドラッグの体内での動態を予測する方法に関する本発明を完成した。 Therefore, the present inventors have investigated the membrane permeability and the action of esterase in p-glycoprotein-expressing cells of fexofenadine derivatives. As a result, fexofenadine alkyl ester is surprisingly fexofenadine or fexofenadine hydroxy. These functions are different from those of alkyl esters, have good membrane permeability in p-glycoprotein-expressing cells, and are activated by liver esterase after being absorbed as an ester without being hydrolyzed by small intestinal esterase. Since it was changed to fexofenadine, it was found that it had excellent bioavailability and durability and was sufficiently effective by oral administration once a day, and completed the present invention relating to an antiallergic drug.
Furthermore, the present inventors have found that the dynamics in the body of the ester-type prodrug can be predicted by using the method used in the examination described above, and the present invention relates to a method for predicting the dynamics of the ester-type prodrug in the body. Completed the invention.

すなわち、本発明は、フェキソフェナジンアルキルエステル又はその塩を含有する抗アレルギー薬であって、フェキソフェナジンアルキルエステル又はその塩を成人あたり１日投与量として３０〜６０mgの用量を１日１回経口投与するための抗アレルギー薬を提供するものである。
また、本発明は、エステル型プロドラッグの体内での動態を予測する方法であって、以下の２つの工程含むものである。
（１）被検物質を小腸由来分画あるいは肝臓由来分画とインキュベートし、被検物質の臓器特異的な加水分解を評価する工程、
（２）被検物質のｐ−糖蛋白質非発現細胞あるいはｐ−糖蛋白質発現細胞を固着させた多孔性膜での透過性を評価する工程。 That is, the present invention relates to an antiallergic drug containing fexofenadine alkyl ester or a salt thereof, and a dose of 30 to 60 mg once a day with fexofenadine alkyl ester or a salt thereof as a daily dose per adult. An antiallergic drug for oral administration is provided.
The present invention is also a method for predicting the kinetics of an ester prodrug in the body, and includes the following two steps.
(1) Incubating a test substance with a fraction derived from the small intestine or a fraction derived from the liver, and evaluating an organ-specific hydrolysis of the test substance,
(2) A step of evaluating the permeability of the test substance through a porous membrane to which p-glycoprotein non-expressing cells or p-glycoprotein expressing cells are fixed.

本発明の抗アレルギー薬は、細胞膜透過性が高く、薬物排出蛋白質であるｐ−糖蛋白質の作用を受けないことから腸管上皮の透過性が良好であり、かつ小腸エステラーゼの作用により加水分解されずに、エステル体として肝臓に移行し、肝臓エステラーゼによって、活性本体であるフェキソフェナジンを生じることから、経口投与によるバイオアベイラビリティーが優れているとともに持続性に優れ、少ない投与量の１日１回経口投与で有効である。
また、本発明のエステル型プロドラッグの体内での動態を予測する方法は、従来見落とされていた有用な薬物を見出すことができ、また、新規物質のスクリーニングの際に有用である。 The antiallergic agent of the present invention has high cell membrane permeability and is not affected by the action of p-glycoprotein, which is a drug efflux protein, and therefore has good permeability of the intestinal epithelium and is not hydrolyzed by the action of small intestinal esterase. Furthermore, since it is transferred to the liver as an ester and the active ester fexofenadine is produced by liver esterase, it is excellent in bioavailability by oral administration and excellent in sustainability, once a day at a small dose. Effective with oral administration.
In addition, the method for predicting the kinetics of the ester-type prodrug of the present invention in the body can find a useful drug that has been conventionally overlooked, and is useful for screening a novel substance.

本発明の抗アレルギー薬は、フェキソフェナジンアルキルエステル又はその塩を含有するものである。フェキソフェナジンアルキルエステルは、下記式（１）   The antiallergic agent of the present invention contains fexofenadine alkyl ester or a salt thereof. The fexofenadine alkyl ester has the following formula (1)

（式中、Ｒ1はアルキル基を示す）
で表される化合物である。Ｒ1のアルキル基としては、炭素数１〜１２の直鎖又は分岐鎖のアルキル基が好ましく、炭素数１〜６の直鎖又は分岐鎖のアルキル基がより好ましい。当該アルキル基の具体例としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基等が挙げられ、このうちエチル基が特に好ましい。 (Wherein R 1 represents an alkyl group)
It is a compound represented by these. As the alkyl group for R 1 , a linear or branched alkyl group having 1 to 12 carbon atoms is preferable, and a linear or branched alkyl group having 1 to 6 carbon atoms is more preferable. Specific examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, and the like. Of these, an ethyl group is particularly preferred.

フェキソフェナジンアルキルエステルの塩としては、薬学的に許容される塩、例えば塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩等の無機酸塩、酢酸塩、プロピオン酸塩、乳酸塩、マロン酸塩、コハク酸塩、酒石酸塩等の有機酸塩が挙げられる。また、フェキソフェナジンアルキルエステル又はその塩には、水和物に代表される溶媒和物も含まれる。   Examples of the salt of fexofenadine alkyl ester include pharmaceutically acceptable salts, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, propionate, lactate, Examples include organic acid salts such as malonate, succinate, and tartrate. The fexofenadine alkyl ester or a salt thereof includes a solvate typified by a hydrate.

フェキソフェナジンアルキルエステル又はその塩は、前記特許文献１記載の方法に従って製造することができる。   The fexofenadine alkyl ester or a salt thereof can be produced according to the method described in Patent Document 1.

フェキソフェナジンアルキルエステルは、前記特許文献１及び２中に記載されている。しかし、これらの文献中において、抗ヒスタミン作用等の薬理作用が示されているのはフェキソフェナジンのみであり、フェキソフェナジンアルキルエステルの薬理作用や体内動態などについては何ら記載されていない。後記実施例に示すように、フェキソフェナジンは膜透過性が悪い上に、ｐ−糖蛋白質によって排出されてしまうことから、腸管上皮の透過性が低いことは明らかである。一方、フェキソフェナジンヒドロキシアルキルエステルは、膜透過性は良いもののｐ−糖蛋白質により排出されてしまい、さらに、吸収されたとしても、小腸および肝臓エステラーゼのいずれによっても加水分解されないために、生体内で作用本体であるフェキソフェナジンに変換されにくい。これに対し、フェキソフェナジンアルキルエステルは、細胞膜透過性が良く、加えて、ｐ−糖蛋白質により排出されないため、腸管上皮の透過性が高い。また、フェキソフェナジンアルキルエステルは、ヒト小腸エステラーゼによって分解されずに、肝臓に移行した後、肝臓エステラーゼによって、フェキソフェナジンを生じることから、体内に吸収後に抗アレルギー作用を発揮する。そして、その効果は持続的である。   Fexofenadine alkyl esters are described in Patent Documents 1 and 2. However, in these documents, only fexofenadine has shown pharmacological action such as antihistamine action and does not describe any pharmacological action or pharmacokinetics of fexofenadine alkyl ester. As shown in Examples below, fexofenadine has poor membrane permeability and is excreted by p-glycoprotein, so it is clear that the permeability of the intestinal epithelium is low. On the other hand, although fexofenadine hydroxyalkyl ester has good membrane permeability, it is excreted by p-glycoprotein, and even if absorbed, it is not hydrolyzed by any of the small intestine and liver esterase. It is difficult to be converted into fexofenadine, which is the main body of action. In contrast, fexofenadine alkyl ester has good cell membrane permeability and, in addition, is not excreted by p-glycoprotein, and therefore has high permeability of the intestinal epithelium. In addition, fexofenadine alkyl ester is not decomposed by human small intestine esterase and moves to the liver, and then produces fexofenadine by liver esterase, and thus exhibits an antiallergic action after absorption in the body. And the effect is lasting.

本発明の抗アレルギー薬は、前記した特性を有しているため、所望の血中濃度を得ることが容易であり、症状等にあわせて適宜、投与量をコントロールすることが可能である。
従って、本発明の抗アレルギー薬は、フェキソフェナジンアルキルエステル又はその塩を成人あたり１日投与量として３０〜６０mgの用量を１日１回経口投与すればよい。なお、現在、商業的に入手可能なフェキソフェナジンの製剤は、塩酸塩として６０ｍｇを含有する錠剤として供給されている。推奨されている用量は１回６０ｍｇを１日２回である（ＰＨＹＳＩＣＩＡＮ’Ｓ ＤＥＳＫ ＲＥＦＥＲＥＮＣＥ，第５２版、１９９８年、第１２３８〜１２４４ページ，Ｍｅｄｉｃａｌ Ｅｃｏｎｏｍｉｃｓ Ｄａｔｅ， Ｍｅｄｉｃａｌ Ｅｃｏｎｏｍｉｃｓ Ｃｏｍｐａｎｙ Ｉｎｃ．の部，Ｍｏｎｔｖａｌｅ，Ｎｅｗ Ｊｅｒｓｅｙ）。 Since the antiallergic agent of the present invention has the above-mentioned properties, it is easy to obtain a desired blood concentration, and the dosage can be appropriately controlled according to symptoms and the like.
Therefore, the antiallergic agent of the present invention may be orally administered once a day at a dose of 30 to 60 mg with a daily dosage of fexofenadine alkyl ester or a salt thereof per adult. Currently, a commercially available formulation of fexofenadine is supplied as a tablet containing 60 mg of hydrochloride. The recommended dose is 60 mg once a day (PHYSICIAN'S DESK REFERENCE, 52nd edition, 1998, pages 1238-1244, Medical Economics Company Inc, part of Medical Economics Inc., Le, Mon. New Jersey).

本発明の抗アレルギー薬は、経口投与された後体内、主に肝臓でフェキソフェナジンアルキルエステルがフェキソフェナジンに変換されるので、フェキソフェナジンとしての高い血中濃度が長時間維持される。従って、フェキソフェナジンの薬理作用すなわち、ヒスタミンＨ１受容体拮抗作用、炎症性サイトカイン産生抑制作用、好酸球遊走抑制作用、ケミカルメディエータ遊離抑制作用等が生じる。このように、本発明の抗アレルギー薬は、アレルギー性鼻炎、じんましん、湿疹、皮膚炎、皮膚そう痒症、アトピー性皮膚炎、喘息等に有用である。   Since the anti-allergic agent of the present invention is orally administered, fexofenadine alkyl ester is converted into fexofenadine in the body, mainly in the liver, so that a high blood concentration as fexofenadine is maintained for a long time. Therefore, the pharmacological action of fexofenadine, that is, histamine H1 receptor antagonistic action, inflammatory cytokine production inhibitory action, eosinophil migration inhibitory action, chemical mediator release inhibitory action, and the like occur. Thus, the antiallergic agent of the present invention is useful for allergic rhinitis, urticaria, eczema, dermatitis, cutaneous pruritus, atopic dermatitis, asthma and the like.

本発明の抗アレルギー薬は、フェキソフェナジンアルキルエステル又はその塩を経口投与できる形態であればよく、例えば錠剤、顆粒剤、細粒剤、粉末剤、丸剤、カプセル剤、シロップ剤等の製剤にすることができる。これらの製剤を製造するにあたっては、薬学的に許容される担体を用いることができ、当該担体としてはセルロース誘導体、トラガカントガム、ゼラチン、ポリビニルピロリドン（ＰＶＰ）、ポビドン等の結合剤；デンプン、乳糖、ショ糖等の賦形剤；界面活性剤；アルギン酸、コーンスターチ、炭酸水素ナトリウム、炭酸水素カルシウム等の崩壊剤；ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸亜鉛等の滑沢剤、二酸化ケイ素、タルク、甘味剤、香料等が挙げられる。   The antiallergic agent of the present invention may be in any form that allows oral administration of fexofenadine alkyl ester or a salt thereof. For example, preparations such as tablets, granules, fine granules, powders, pills, capsules, syrups, etc. Can be. In producing these preparations, a pharmaceutically acceptable carrier can be used, and the carrier includes a binder such as cellulose derivative, gum tragacanth, gelatin, polyvinylpyrrolidone (PVP), povidone; starch, lactose, starch Excipients such as sugar; surfactants; disintegrants such as alginic acid, corn starch, sodium bicarbonate, calcium bicarbonate; lubricants such as magnesium stearate, calcium stearate, zinc stearate, silicon dioxide, talc, sweetener And fragrances.

また、本発明のエステル型プロドラッグの体内での動態を予測する方法は、以下２つの工程含むものである。
（１）被検物質を小腸由来分画あるいは肝臓由来分画とインキュベートし、被検物質の臓器特異的な加水分解を評価する工程、
（２）被検物質のｐ−糖蛋白質非発現細胞あるいはｐ−糖蛋白質発現細胞を固着させた多孔性膜での透過性を評価する工程。 The method for predicting the kinetics of the ester-type prodrug of the present invention in the body includes the following two steps.
(1) Incubating a test substance with a fraction derived from the small intestine or a fraction derived from the liver, and evaluating an organ-specific hydrolysis of the test substance,
(2) A step of evaluating the permeability of the test substance through a porous membrane to which p-glycoprotein non-expressing cells or p-glycoprotein expressing cells are fixed.

小腸由来分画あるいは肝臓由来分画としては、ミクロソームまたはＳ９分画を使用することができる。被検物質とこれらの分画をインキュベートすることにより、被検物質の臓器特異的な加水分解、特に臓器特異的なエステラーゼによる加水分解を評価できる。インキュベーション後の被検物質の残存量及び／又は、加水分解により被検物質が変換され生成した物質の生成量を測定することで、加水分解を評価することができる。   As a fraction derived from the small intestine or a fraction derived from the liver, a microsome or an S9 fraction can be used. By incubating the test substance and these fractions, it is possible to evaluate the organ-specific hydrolysis of the test substance, particularly the hydrolysis by the organ-specific esterase. Hydrolysis can be evaluated by measuring the remaining amount of the test substance after incubation and / or the amount of the substance produced by conversion of the test substance by hydrolysis.

ｐ−糖蛋白質非発現細胞としてはブタ腎臓由来培養細胞ＬＬＣ−ＰＫ１などを、ｐ−糖蛋白質発現細胞としては、ＬＬＣ−ＧＡ５−ＣＯＬ３００細胞を使用できる。これらはいずれも市販されており、推奨されている培養方法により培養することができる。   Porcine kidney-derived cultured cells LLC-PK1 and the like can be used as p-glycoprotein non-expressing cells, and LLC-GA5-COL300 cells can be used as p-glycoprotein expressing cells. These are all commercially available and can be cultured by a recommended culture method.

各細胞を多孔性膜へ固着させる方法は公知の方法が使用できる。被検物質を頂側膜側、あるいは基底側膜側に適用し、多孔性膜を透過した被検物質の量を測定することで透過性は評価することができる。   As a method for fixing each cell to the porous membrane, a known method can be used. The permeability can be evaluated by applying the test substance to the top membrane side or the basal membrane side and measuring the amount of the test substance that has permeated the porous membrane.

次に実施例を挙げて本発明を更に詳細に説明するが、本発明は何らこれら実施例に限定されるものではない。   EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these Examples at all.

実施例１ ヒト小腸および肝臓ミクロソームにおけるフェキソフェナジン誘導体の加水分解
（１）方法
ａ）フェキソフェナジンエステル誘導体の臓器ミクロソームにおける反応
フェキソフェナジン誘導体とヒト小腸あるいは肝臓ミクロソーム（いずれもＧＥＮＴＥＳＴ社）とをインキュベーションし、臓器特異的なフェキソフェナジン誘導体の加水分解を確認した。フェキソフェナジン誘導体として、フェキソフェナジンエチルエステル（Ｅ−ＦＸＤ）（分子量：５２９．７、ＨＢＳＳ緩衝液（ｐＨ７．４）とオクタノールでの分配係数：５．４５）、フェキソフェナジン−２−ヒドロキシエチルエステル（２ＨＥ−ＦＸＤ）（分子量：５４６．７、ＨＢＳＳ緩衝液（ｐＨ７．４）とオクタノールでの分配係数：３．５６）を使用した。ＨＢＳＳ緩衝液の組成は以下である。９．８ｇ／Ｌ ＨＢＳＳ（Ｈａｎｋｓ’ ｂａｌａｎｃｅｄ ｓａｌｔ ｓｏｌｕｔｉｏｎ、ＳＩＧＭＡ社）、０．３７ｇ／Ｌ ＮａＨＣＯ3、３．５ｇ／Ｌ Ｄ−グルコース、２．６１ｇ／Ｌ ＨＥＰＥＳ、５Ｎ ＮａＯＨ １．２ｍＬ／Ｌ）Ｅ−ＦＸＤ（１〜３０μｍｏｌ／Ｌ）あるいは２ＨＥ−ＦＸＤ（５０μｍｏｌ／Ｌ）を、ヒト小腸ミクロソーム（１００μｇ蛋白／ｍＬ）あるいは肝臓ミクロソーム（４０μｇ／ｍＬ）を、Ｅ−ＦＸＤの場合は３７℃、１５分間、２ＨＥ−ＦＸＤの場合は３７℃、１時間、５０ｍｍｏｌ／Ｌ ＨＥＰＥＳ緩衝液（ｐＨ７．４）中でインキュベーションした後、それぞれＨＰＬＣ用移動相の有機溶媒を添加して、酵素反応を停止させた（濃度はすべて終濃度を記載）。反応液は４℃、３０００ｒｐｍで５分間遠心し、上清を下記の条件で、ＨＰＬＣで定量分析した。
ｂ）ＨＰＬＣ分析
ＵＶ検出器（ＪＡＳＣＯ、ＵＶ−２０７５Ｐｌｕｓ）、ポンプ（ＪＡＳＣＯ、ＰＵ−９８０）、データ処理装置（ＳＨＩＭＡＤＺＵ、ＣＨＲＯＭＡＴＯＰＡＣ Ｃ−Ｒ４Ａ）、オートサンプラー（ＪＡＳＣＯ、ＡＳ−９５０）を装備したＨＰＬＣ装置を用いて、以下の条件で定量した。移動相ＡではＦＸＤとＥ−ＦＸＤの保持時間はそれぞれ６．１分と１９分であり、移動相ＢではＦＸＤと２ＨＥ−ＦＸＤの保持時間がそれぞれ２３分と２７分であった。
カラム；Ｗａｋｏｓｕｌ−II ５Ｃ１８ Ｎｏ．０７１０７（５μｍ、１５０×４．６ｍ
ｍ ｉ．ｄ．）。カラム温度；４０℃。
移動相Ａ（Ｅ−ＦＸＤ分析用）；アセトニトリル：メタノール：１２ｍｍoｌ／Ｌ 酢酸アンモニウム（ｐＨ４）＝３９：１０：５１（ｖ／ｖ／ｖ）。
移動相Ｂ（２ＨＥ−ＦＸＤ分析用）；アセトニトリル：メタノール：１２ｍｍｏｌ／Ｌ 酢酸アンモニウム（ｐＨ４）＝２２：１５：６３（ｖ／ｖ／ｖ）。
流速；１ｍＬ／ｍｉｎ。検出；ＵＶ２１８ｎｍ。注入量；１００μＬ。 Example 1 Hydrolysis of fexofenadine derivative in human small intestine and liver microsome (1) Method a) Reaction of fexofenadine ester derivative in organ microsome Fexofenadine derivative and human small intestine or liver microsome (both from GENTEST) Incubation was performed to confirm the hydrolysis of the organ-specific fexofenadine derivative. As fexofenadine derivatives, fexofenadine ethyl ester (E-FXD) (molecular weight: 529.7, partition coefficient in HBSS buffer (pH 7.4) and octanol: 5.45), fexofenadine-2-hydroxy Ethyl ester (2HE-FXD) (molecular weight: 546.7, HBSS buffer (pH 7.4) and octanol partition coefficient: 3.56) was used. The composition of the HBSS buffer is as follows. 9.8 g / L HBSS (Hanks' balanced salt solution, SIGMA), 0.37 g / L NaHCO 3 , 3.5 g / L D-glucose, 2.61 g / L HEPES, 5 N NaOH 1.2 mL / L) E -FXD (1-30 μmol / L) or 2HE-FXD (50 μmol / L), human small intestine microsomes (100 μg protein / mL) or liver microsomes (40 μg / mL), E-FXD at 37 ° C. for 15 minutes In the case of 2HE-FXD, after incubation in 50 mmol / L HEPES buffer (pH 7.4) at 37 ° C. for 1 hour, the organic reaction of the mobile phase for HPLC was added to stop the enzyme reaction ( All concentrations are final concentrations). The reaction solution was centrifuged at 3000 rpm for 5 minutes at 4 ° C., and the supernatant was quantitatively analyzed by HPLC under the following conditions.
b) HPLC analysis HPLC apparatus equipped with a UV detector (JASCO, UV-2075 Plus), pump (JASCO, PU-980), data processing device (SHIMADZU, CHROMAPAC C-R4A), autosampler (JASCO, AS-950) Was quantified under the following conditions. In mobile phase A, the retention times of FXD and E-FXD were 6.1 minutes and 19 minutes, respectively, and in mobile phase B, the retention times of FXD and 2HE-FXD were 23 minutes and 27 minutes, respectively.
Column; Wakosul-II 5C18 No. 07107 (5 μm, 150 × 4.6 m
mi. d. ). Column temperature: 40 ° C.
Mobile phase A (for E-FXD analysis); acetonitrile: methanol: 12 mmol / L ammonium acetate (pH 4) = 39: 10: 51 (v / v / v).
Mobile phase B (for 2HE-FXD analysis); acetonitrile: methanol: 12 mmol / L ammonium acetate (pH 4) = 22: 15: 63 (v / v / v).
Flow rate: 1 mL / min. Detection; UV 218 nm. Injection volume: 100 μL.

（２）結果
２ＨＥ−ＦＸＤは、ヒト小腸および肝臓ミクロソームのどちらにおいても加水分解されなかった。一方、Ｅ−ＦＸＤは小腸ミクロソームでは加水分解されず、肝臓ミクロソームで加水分解された（表１）。１〜３０μｍｏｌ／ＬのＥ−ＦＸＤ存在下の肝臓ミクローソームの加水分解活性は、Ｅ−ＦＸＤの濃度に依存的であり直線的に増大した（図１）。ＦＸＤの溶解度のため、基質濃度を最大３０μｍｏｌ／Ｌに設定したが、この濃度範囲の活性値からＬｉｎｅｗｅａｖｅｒ−Ｂｕｒｋ ｐｌｏｔによりＫｍ値、Ｖｍａｘを求めたところ、Ｋｍ値は約１００μｍｏｌ／Ｌ、Ｖｍａｘは１２ｎｍｏｌ／ｍｉｎ／ｍｇ蛋白質であった。Ｋｍ値は、ＦＸＤの1回の投与量６０ｍｇから考えると、肝臓での代謝飽和を起こすような値ではないと考えられた。また肝クリアランスの面から考えると、固有クリアランス（ＣＬｉｎｔ＝Ｖｍａｘ／Ｋｍ）は０．１２ｍＬ／ｍｉｎ／ｍｇ蛋白質であった。膜透過性の高いＥ−ＦＸＤは肝臓への移行性も良く、肝臓に積極的に取込まれた後に、肝臓で代謝されて活性体のＦＸＤとして全身循環に移行するものと考えられた。以上の結果より、２ＨＥ−ＦＸＤは小腸および肝臓において加水分解されないため、プロドラッグとしては適していない一方、Ｅ−ＦＸＤは小腸では加水分解されにくく肝臓で加水分解されるため、吸収増大を目的としたプロドラッグとして好適であることがわかった。 (2) Results 2HE-FXD was not hydrolyzed in either human small intestine or liver microsomes. On the other hand, E-FXD was not hydrolyzed in small intestine microsomes but hydrolyzed in liver microsomes (Table 1). The hydrolytic activity of liver microsomes in the presence of 1-30 μmol / L E-FXD was dependent on the concentration of E-FXD and increased linearly (FIG. 1). Due to the solubility of FXD, the substrate concentration was set to a maximum of 30 μmol / L. When the Km value and Vmax were determined from the Lineweaver-Burk plot from the activity value in this concentration range, the Km value was about 100 μmol / L, and Vmax was 12 nmol. / Min / mg protein. The Km value was considered not to cause metabolic saturation in the liver, considering a single dose of 60 mg of FXD. In terms of liver clearance, the intrinsic clearance (CLint = Vmax / Km) was 0.12 mL / min / mg protein. E-FXD with high membrane permeability has good transferability to the liver, and after being actively taken into the liver, it is considered that it is metabolized in the liver and transferred to the systemic circulation as active FXD. From the above results, 2HE-FXD is not suitable as a prodrug because it is not hydrolyzed in the small intestine and liver, whereas E-FXD is hardly hydrolyzed in the small intestine and hydrolyzed in the liver. It was found to be suitable as a prodrug.

実施例２ ＦＸＤ、ＦＸＤ誘導体のＬＬＣ−ＰＫ１細胞、ＬＬＣ−ＧＡ５−ＣＯＬ３００細胞単層膜を介した透過実験
（１）方法
ブタ腎臓由来培養細胞ＬＬＣ−ＰＫ１（大日本製薬）及び、ｐ−糖蛋白質を発現させたＬＬＣ−ＧＡ５−ＣＯＬ３００（理化学研究所）をポリカーボネート膜フィルター（３μｍ孔、６ｗｅｌｌ、ＴＲＡＮＳＷＥＬＬ３４１４、Ｃｏｓｔａｒ社）の上部に、それぞれ４×１０5 細胞／ｃｍ2、５×１０5細胞／ｃｍ2の細胞懸濁液を播種した。フィルター上部に１．５ｍＬ、下部に２．６ｍＬの培地を満たし、３７℃、９５％空気、５％ＣＯ2存在下で３日間培養し、培地の交換は毎日行った。透過実験の６時間前にすべての細胞の培地をコルヒチンを含まない１９９培地（日水製薬）に置き換えた。acceptor側（頂側膜（apical）側：ＡＰ側１．５ｍＬ、基底側膜（basolateral）側：ＢＬ側２．６ｍＬ）には１９９培地を、donor側には１９９培地に溶解させた薬物（ＦＸＤ、ＦＸＤ誘導体；２ＨＥ−ＦＸＤとＥ−ＦＸＤ）溶液を添加し、３７℃でインキュベーションした。経時的にacceptor側からは１００μＬ、donor側からは２０μＬサンプリングし、acceptor側にはＨＢＳＳを１００μＬ添加し、acceptor側の容量が変わらないようにした。透過終了後、細胞を１９９培地で２回洗い、スパーテルで細胞を剥ぎ取った後、２００μＬのメタノールでｔｒａｎｓｗｅｌｌを洗うように細胞を採取し、この操作を２回繰り返した。採取したメタノール溶液を超音波処理（２０秒×３回、氷冷）し、遠心後、上清を濃縮乾固した。donor側のサンプルには８０μＬの１９９培地を添加し、すべての透過溶液のサンプルには実施例１のＨＰＬＣ移動層の有機溶媒を１００μＬ添加後、ボルテックスをかけ、遠心した上清を実施例１に順じてＨＰＬＣにて定量した。タンパク質量は、牛血清アルブミン（ＳＩＧＭＡ社）を標準タンパク質としてＣＢＢ法（Ｂｒａｄｆｏｒｄ法）に準じて求めた。
みかけの透過係数（Ｐａｐｐ）は時間に対する累積透過量をプロットし、その初期直線の傾き（ｄＱ／ｄｔ）から次式に従って求めた。
Ｐａｐｐ＝ｄＱ／ｄｔ／Ａ／Ｃ0
Ｐａｐｐ（ｃｍ／ｓｅｃ）：ａｐｐａｒｅｎｔ ｐｅｒｍｅａｂｉｌｉｔｙ ｃｏｅｆｆｉｃｉｅｎｔｓ
ｄＱ／ｄｔ（μｍｏｌ／ｓｅｃ）：ｉｎｉｔｉａｌ ｔｒａｎｓｐｏｒｔ ｒａｔｅ
Ａ（ｃｍ2）：ｓｕｒｆａｃｅ ａｒｅａｓ ｏｆ ｍｏｎｏｌａｙｅｒ
Ｃ0（μｍｏｌ／ｍＬ）：ｉｎｉｔｉａｌ ｃｏｎｃｎ． ｉｎ ｔｈｅ ｄｏｎｏｒ ｃｈａｍｂｅｒ Example 2 Permeation experiment of FXD and FXD derivative through LLC-PK1 cell, LLC-GA5-COL300 cell monolayer membrane (1) Method Porcine kidney-derived cultured cell LLC-PK1 (Dainippon Pharmaceutical) and p-glycoprotein LLC-GA5-COL300 (RIKEN), on which the protein is expressed, is 4 × 10 5 cells / cm 2 and 5 × 10 5 cells / cm on the top of a polycarbonate membrane filter (3 μm pore, 6 well, TRANSWELL 3414, Costar), respectively. Two cell suspensions were seeded. The upper part of the filter was filled with 1.5 mL of the medium, and the lower part was filled with 2.6 mL of the medium. The medium was cultured at 37 ° C. in the presence of 95% air and 5% CO 2 for 3 days, and the medium was changed every day. The medium of all cells was replaced with 199 medium (Nissui Pharmaceutical) without colchicine 6 hours before the permeation experiment. Drug (FXD) dissolved in 199 medium on the acceptor side (apical side: AP side 1.5 mL, basolateral side: BL side 2.6 mL) and donor side 199 medium , FXD derivative; 2HE-FXD and E-FXD) solution was added and incubated at 37 ° C. Over time, 100 μL was sampled from the acceptor side and 20 μL was sampled from the donor side, and 100 μL of HBSS was added to the acceptor side so that the capacity on the acceptor side did not change. After completion of permeation, the cells were washed twice with 199 medium, peeled off with a spatula, and then collected to wash the transwell with 200 μL of methanol. This operation was repeated twice. The collected methanol solution was sonicated (20 seconds × 3 times, ice-cooled), centrifuged, and the supernatant was concentrated to dryness. 80 μL of 199 medium is added to the donor-side sample, and 100 μL of the organic solvent in the HPLC moving layer of Example 1 is added to all the permeated solution samples, and then vortexed and the centrifuged supernatant is added to Example 1. The amount was sequentially determined by HPLC. The amount of protein was determined according to the CBB method (Bradford method) using bovine serum albumin (SIGMA) as a standard protein.
The apparent transmission coefficient (Papp) was obtained by plotting the cumulative transmission amount against time and calculating the initial transmission line slope (dQ / dt) according to the following equation.
Papp = dQ / dt / A / C0
Papp (cm / sec): apparent permeability coefficients
dQ / dt (μmol / sec): initial transport rate
A (cm 2 ): surface area of monolayer
C0 (μmol / mL): initial conc. in the donor chamber

（２）結果
表２に両細胞単層膜における透過実験を行った結果を示す。ＡＰ→ＢＬとＢＬ→ＡＰのＰａｐｐを比較すると、ＦＸＤでは、ＬＬＣ−ＧＡ５−ＣＯＬ３００細胞のＬＬＣ−ＰＫ１細胞に対するＰａｐｐ比が３．６倍であり、ｐ−糖蛋白質の基質として輸送されているものと考えられた。一方、２ＨＥ−ＦＸＤに関してはＡＰ→ＢＬのＰａｐｐがＬＬＣ−ＧＡ５−ＣＯＬ３００細胞でＬＬＣ−ＰＫ１細胞の約３分の１に減少し、ＢＬ→ＡＰでは約２．９倍と増大したため、ＬＬＣ−ＧＡ５−ＣＯＬ３００細胞におけるＰａｐｐ比が８．９倍とＦＸＤよりも大きな値を示した。したがって２ＨＥ−ＦＸＤはＦＸＤよりもｐ−糖蛋白質の基質として認識されやすいものと考えられた。Ｅ−ＦＸＤは、Ｐａｐｐ比がＬＬＣ−ＰＫ１細胞で１．１倍、ＬＬＣ−ＧＡ５−ＣＯＬ３００細胞で１．５倍であったことから、ｐ−糖蛋白質による輸送活性は低いことが示された。また、ＦＸＤのＰａｐｐは他の３つの化合物に比べて非常に小さく、ＦＸＤの膜透過性が低いことが明らかであった。さらに、これに対し、ＦＸＤ誘導体のＰａｐｐは、ＬＬＣ−ＰＫ１細胞におけるＦＸＤの１０から２５倍大きい値であった。 (2) Results Table 2 shows the results of permeation experiments on both cell monolayers. Comparing the AP → BL and BL → AP Papp, the FXD has a Papp ratio of 3.6 times that of LLC-GA5-COL300 cells to LLC-PK1 cells and is transported as a substrate for p-glycoprotein It was considered. On the other hand, with regard to 2HE-FXD, the AP → BL Pappa decreased to about one third of that of LLC-PK1 cells in LLC-GA5-COL300 cells, and increased to about 2.9 times in BL → AP. -The PAPP ratio in COL300 cells was 8.9 times larger than FXD. Therefore, 2HE-FXD was considered to be more easily recognized as a p-glycoprotein substrate than FXD. Since E-FXD had a Papp ratio of 1.1 times in LLC-PK1 cells and 1.5 times in LLC-GA5-COL300 cells, it was shown that transport activity by p-glycoprotein was low. Further, the FXD Papp was very small compared to the other three compounds, and it was clear that FXD membrane permeability was low. In contrast, the FXD derivative Papp was 10 to 25 times greater than FXD in LLC-PK1 cells.

表２から明らかなように、ＦＸＤは、膜透過性が極めて低い上に、Ｐａｐｐ比がＬＬＣ−ＰＫ１細胞に比べてＬＬＣ−ＧＡ５−ＣＯＬ３００細胞で大きく、ｐ−糖蛋白質の基質になると考えられた。エステル体の２ＨＥ−ＦＸＤはＰａｐｐ比がＬＬＣ−ＧＡ５−ＣＯＬ３００細胞で約９倍となりＦＸＤよりもｐ−糖蛋白質の基質になりやすい結果を得た。一方、Ｅ−ＦＸＤはフェキソフェナジン２ＨＥ−ＦＸＤとは異なり、両細胞におけるＰａｐｐ比には有意な差が認められず、p−糖蛋白質の基質として認識され難いものと思われた。
また、本発明方法によれば、エステル型プロドラッグの体内動態、特に小腸及び肝臓における加水分解及びｐ−糖蛋白質輸送系の標的になるか否かが評価できる。 As is clear from Table 2, FXD has a very low membrane permeability, and the Papp ratio is larger in LLC-GA5-COL300 cells than in LLC-PK1 cells, and is considered to be a substrate for p-glycoprotein. . The ester form of 2HE-FXD had a Papp ratio of about 9 times in LLC-GA5-COL300 cells, and was more likely to be a substrate for p-glycoprotein than FXD. On the other hand, E-FXD, unlike fexofenadine 2HE-FXD, did not show a significant difference in the Papp ratio in both cells, and was thought to be difficult to recognize as a substrate for p-glycoprotein.
Further, according to the method of the present invention, it is possible to evaluate the pharmacokinetics of an ester-type prodrug, particularly whether it becomes a target for hydrolysis and p-glycoprotein transport system in the small intestine and liver.

Ｅ−ＦＸＤに対する肝臓ミクロソームの加水分解活性を示す図である。It is a figure which shows the hydrolysis activity of the liver microsome with respect to E-FXD.

Claims (5)

フェキソフェナジンアルキルエステル又はその塩を含有する抗アレルギー薬であって、フェキソフェナジンアルキルエステル又はその塩を成人あたり１日投与量として３０〜６０mgの用量を１日１回経口投与するための抗アレルギー薬。   An antiallergic agent containing fexofenadine alkyl ester or a salt thereof, wherein 30 to 60 mg is orally administered once a day as a daily dose of fexofenadine alkyl ester or a salt thereof per adult Allergic drugs. 下記２つの工程を行うことを特徴とするエステル型プロドラッグの体内での動態を予測する方法。
（１）被検物質を小腸由来分画あるいは肝臓由来分画とインキュベートし、被検物質の臓器特異的な加水分解を評価する工程、
（２）被検物質のｐ−糖蛋白質非発現細胞あるいはｐ−糖蛋白質発現細胞を固着させた多孔性膜での透過性を評価する工程。 A method for predicting the in vivo kinetics of an ester-type prodrug characterized by performing the following two steps.
(1) Incubating a test substance with a fraction derived from the small intestine or a fraction derived from the liver, and evaluating an organ-specific hydrolysis of the test substance,
(2) A step of evaluating the permeability of the test substance through a porous membrane to which p-glycoprotein non-expressing cells or p-glycoprotein expressing cells are fixed. 小腸由来分画あるいは肝臓由来分画が、ミクロソームまたはＳ９分画から選ばれるものである、請求項２に記載の方法。   The method according to claim 2, wherein the fraction derived from the small intestine or the fraction derived from the liver is selected from microsomes or S9 fractions. 加水分解を評価する工程が、エステラーゼによる加水分解を評価するものである、請求項２又は３に記載の方法。   The method according to claim 2 or 3, wherein the step of evaluating hydrolysis evaluates hydrolysis by esterase. 透過性を評価する工程が、ｐ−糖蛋白質の基質であるか否かを評価するものである、請求項２又は３に記載の方法。   The method according to claim 2 or 3, wherein the step of evaluating permeability evaluates whether or not the substrate is a p-glycoprotein substrate.
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