JP2013537887A - ドライアイの治療用医薬組成物 - Google Patents
ドライアイの治療用医薬組成物 Download PDFInfo
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- JP2013537887A JP2013537887A JP2013527651A JP2013527651A JP2013537887A JP 2013537887 A JP2013537887 A JP 2013537887A JP 2013527651 A JP2013527651 A JP 2013527651A JP 2013527651 A JP2013527651 A JP 2013527651A JP 2013537887 A JP2013537887 A JP 2013537887A
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- trpm8
- methyl
- ethyl
- isopropyl
- agonist
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Abstract
Description
このように、本発明は、眼球乾燥症、膣乾燥及び口腔灼熱症候群から選択される疾患の治療用又は予防用医薬品を製造するためのTRPM8アゴニスト又はそれらの組み合わせの使用に関する。
本発明で用いるTRPM8アゴニストは、TRPM8アゴニスト抗体、又はTRPM8受容体、より具体的にはTRPM8受容体の細胞外ドメインに特異的に結合してその活性化を誘導することができるTRPM8アゴニスト抗体の断片とすることができる。アゴニスト抗体は、ヒトTRPM8受容体又は相同なTRPM8受容体のオーソログに特異的に結合して活性化することができる。
- S.Duebel著「治療用抗体のハンドブック(Handbook of Therapeutic Antibodies)」、出版社:Wiley−VCH、2007年、Vol:Ia III (ISBN978―3527314539);
- G.Subramanian編「抗体:第1巻:産生及び精製(Antibodies: Volume 1: Production and Purification)」、出版社:Springer、第1版、2004 年(ISBN 978―0306482458);
- G.Subramanian編「抗体:第2巻:新規な技術及び治療的使用(Antibodies:Volume 2:Novel Technologies and Therapeutic Use)」、出版社:Springer、第1版、2004年 (ISBN978―0306483158);
- J.Sambrook及びD.W.Russel編「分子クローニング:実験室マニュアル(Molecular Cloning:a Laboratory manual)」、出版社:Cold Spring Harbor Laboratory Press、第3版、2001年(ISBN978―0879695774)。
本発明において、TRPM8アゴニストは、TRPM8受容体の構成的に活性な変異体又はそれらの機能的に等価な変異体も包含する。
当業者により理解されるように、TRPM8アゴニストを、眼球乾燥症、膣乾燥及び口腔灼熱症候群の治療に有用な他の薬物と組み合わせて用いることができる。従って、別の態様では、本発明は、少なくとも1種のTRPM8アゴニストと、眼球乾燥症、膣乾燥及び口腔灼熱症候群から選択される1つ以上の疾患の治療に有用な少なくとも1種の薬物と、必要に応じ、医薬として許容されるビヒクルと、を含む組成物に関する。
別の態様では、本発明は、流涙症の治療用又は予防用医薬品を製造するためのTRPM8アンタゴニスト又はそれらの組み合わせの使用に関する。
特定の実施形態では、例えば、(その活性を阻害することを目的として)TRPM8をコードする核酸の転写及び/又は翻訳の阻害といった、TRPM8をコードする遺伝子の発現の阻害に特異的なアンチセンスオリゴヌクレオチドを用いる。アンチセンスオリゴヌクレオチドは、通常の塩基相補性によるか、又は、例えば、二本鎖DNAに結合する場合は、二重らせんの主溝における特異的相互作用を介して、その潜在的標的に結合することができる。本発明での使用のため、アンチセンスオリゴヌクレオチドを含む構築物を、例えば、細胞内で転写された場合に、TRPM8をコードする細胞mRNAの一部分に少なくとも相補性であるRNAを生成する発現プラスミドとして分布させることができる。あるいは、アンチセンス構築物が、生体外で形成され、細胞内に配置された場合に、標的核酸のmRNA及び/又はゲノム配列とハイブリダイズすることによって遺伝子発現の阻害を引き起こす、オリゴヌクレオチドのプローブである。これらオリゴヌクレオチドプローブは、好ましくは、内因性ヌクレアーゼ、例えば、エキソヌクレアーゼ及び/又はエンドヌクレアーゼに抵抗性であり、従って、生体内で安定な、修飾オリゴヌクレオチドである。アンチセンスオリゴヌクレオチド用の例示的な核酸分子としては、ホスホロアミデート、ホスホチオネート及びメチルホスホネートのDNA類似体が挙げられる(例えば、米国特許第5176966号、米国特許第5264564号及び米国特許第5256775号を参照のこと)。加えて、アンチセンス療法で有用なオリゴマーを構築するための一般的な手法の概説については、例えば、Van der Krolら著、BioTechniques 6:958−976、1988年及びSteinら著、Cancer Res 48:2659−2668、1988年を参照されたい。
別の特定の実施形態では、特異的なDNA酵素を用いてTRPM8をコードする遺伝子の発現を阻害する。DNA酵素は、アンチセンスオリゴヌクレオチド技術とリボザイム技術の両方のメカニズム特徴の幾つかを含有する。DNA酵素を、アンチセンスオリゴヌクレオチドと同様に、特定の核酸配列(本事例では、TRPM8をコードする配列)の標的配列を認識するように設計する;しかしながら、リボザイムと同様に、DNA酵素は、触媒的であり、標的核酸を特異的に切断する。
別の特定の実施形態では、標的mRNAの転写産物を触媒的に切断して、活性を阻害することが意図されるTRPM8をコードするmRNAの翻訳を妨げるように設計された、特異的なリボザイムを用いる。リボザイムは、特異的なRNA切断[概説のため、Rossi著、1994年、Current Biology 4: 469−471を参照のこと]を触媒することができるRNA酵素分子である。リボザイム分子の配列は、好ましくは、標的mRNAに相補的な1個又は2個以上の配列と、mRNA切断に関与する周知の配列又は機能的に等価な配列[例えば、米国特許第5093246号を参照のこと]とを含む。
別の特定の実施形態では、TRPM8をコードする配列に特異的なマイクロRNAを用いる。知られているように、マイクロRNA(miRNA)は、21〜25ヌクレオチドの長さの一本鎖RNAであり、RNA干渉経路を用いた複数過程によって、他の遺伝子の発現を調節する能力を有する。
別の特定の実施形態では、活性を阻害することを意図されるTRPM8をコードする配列に特異的な小型干渉RNA(siRNA)のような干渉RNA(iRNA)を用いる。
- ヌクレオチド間の結合が、ホスホロチオエート結合のような、天然に存在するものと異なるsiRNA;
- フルオロフォアのような、機能性試薬を有するRNA鎖のコンジュゲート;
- 2’位のヒドロキシルの異なる官能基での修飾により、RNA鎖の末端における、特に3’末端における修飾;
- 2’−O−メチルリボース又は2’−O−フルオロリボースといった、2’位におけるO−アルキル化残基のような、修飾した糖を有するヌクレオチド;
- ハロゲン塩基(例えば、5−ブロモウラシル及び5−ヨードウラシル)、アルキル化塩基(例えば、7−メチルグアノシン)のような、修飾した塩基を有するヌクレオチド。
別の特定の実施形態では、TRPM8阻害剤ペプチドを用いて、このタンパク質がそのいずれかの機能、特に、ナトリウムイオン及びカルシウムイオンのチャネル通過を果たすのを妨げる。
別の特定の実施形態では、TRPM8阻害剤抗体を用いて、このタンパク質がそのいずれかの機能、特に、ナトリウムイオン及びカルシウムイオンのチャネル通過を果たすのを妨げる。従って、TRPM8「阻害剤」抗体は、ここで用いるように、TRPM8に特異的に結合してナトリウムイオン及びカルシウムイオンのチャネル通過を阻害することができる抗体を指す。前記抗体は、当業者に既知のいずれかの方法を用いて調製することができる。TRPM8に結合する能力を有する抗体を同定すれば、阻害剤の同定のためのアッセイを用いて、このタンパク質の活性を阻害することができる抗体を選択できるであろう[例えば、Metz Sら著、2008年、J.Biol.Chem. 283:5985−5995を参照のこと]。
別の特定の実施形態では、TRPM8と接触するときにこのタンパク質の活性を減少させる化合物を用いる。実例としては、これら化合物に限定しないが、BCTC、CTPC、チオ−BCTC、SB−452533、SKF96365、エコナゾール、クロトリマゾール、ACA、AMTB、カプサゼピン、フェナントロリン、MAD1d及びMAD2e等の表3(化合物8〜20)に示す化合物が挙げられる。
別の態様では、本発明は、少なくとも1種のTRPM8アンタゴニストと流涙症の治療に有用な少なくとも1種の薬物と、必要に応じ、医薬として許容されるビヒクルと、を含む組成物(これ以降は、本発明の第二組成物)に関する。
Claims (20)
- 眼球乾燥症、膣乾燥及び口腔灼熱症候群から選択される疾患の治療用又は予防用医薬品を製造するためのTRPM8アゴニスト又はその組み合わせの使用。
- 前記疾患が眼球乾燥症である、請求項1に記載の使用。
- 前記アゴニストがTRPM8活性化により冷感受性線維による涙液分泌の刺激を増加させる、請求項2に記載の使用。
- 前記TRPM8アゴニストが表1に記載されたアゴニストから選択される、請求項1〜3のいずれか1項に記載の使用。
- 前記TRPM8アゴニストがWS−5(エチル3−(p−メンタン−3−カルボキサミド))、CPS369、CPS368、CPS125、フレスコラートMGA−2異性体、クーリングエージェント10、(−)−イソプレゴール(クールアクトP(登録商標))、比率約62:38の(+)−シス及び(−)−トランスp−メンタン−3,8−ジオール(クールアクト38D(登録商標))、(−)−クベボール、ハセガワ製冷却化合物、IFF製新GRAS冷却物質、イシリン、5−メチル−4−(1−ピロリジニル)−3−[2H]−フラノン、4,5−ジメチル−3−(1−ピロリジニル)−2[5H]−フラノン、4−メチル−3−(1−ピロリジニル)−2[5H]−フラノン、N−エチル−p−メンタン−3−カルボキサミド、WS−11(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸(2−ヒドロキシ−1,1−ジメチル−エチル酸)−アミド)、WS−12(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸(4−メトキシフェニル)−アミド)、WS−14(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸tert−ブチルアミド)、WS−23(2−イソプロピル−N−2,3−トリメチルブチルアミド)、WS−30(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸エステル2,3−ジヒドロキシ−プロピル)、WS−148(1−(ジ−sec−ブチル−ホスフィノイル)−へプタン)、メントール、ゲラニオール、リナロール、ユーカリプトール、ヒドロキシル−シトロネラール、PMD−38(p−メンタン−3,8−ジオール)、TRPM8特異的アゴニスト抗体、及び構成的に活性なTRPM8変異体から選択される、請求項4に記載の使用。
- 少なくとも1種のTRPM8アゴニストと、眼球乾燥症、膣乾燥及び口腔灼熱症候群から選択される1又は2以上の疾患の治療に有用な少なくとも1種の薬物と、必要に応じ、医薬として許容されるビヒクルと、を含む組成物。
- 眼球乾燥症、膣乾燥及び口腔灼熱症候群から選択される1又は2以上の疾患の治療用医薬品を製造するための請求項6に記載の組成物の使用。
- 前記TRPM8アゴニストが表1に示すTRPM8アゴニストから選択される、請求項6又は7に記載の組成物又は使用。
- 前記TRPM8アゴニストがTRPM8アゴニスト及び/又はメントール若しくはその誘導体でないアゴニストから選択される、請求項6に記載の組成物又は請求項7若しくは8に記載の使用。
- 前記TRPM8アゴニストがWS−5(エチル3−(p−メンタン−3−カルボキサミド))、CPS369、CPS368、CPS125、フレスコラートMGA−2異性体、クーリングエージェント10、(−)−イソプレゴール(クールアクトP(登録商標))、比率約62:38の(+)−シス及び(−)−トランスp−メンタン−3,8−ジオール(クールアクト38D(登録商標))、(−)−クベボール、ハセガワ製冷却化合物、IFF製新GRAS冷却物質、イシリン、5−メチル−4−(1−ピロリジニル)−3−[2H]−フラノン、4,5−ジメチル−3−(1−ピロリジニル)−2[5H]−フラノン、4−メチル−3−(1−ピロリジニル)−2[5H]−フラノン、N−エチル−p−メンタン−3−カルボキサミド、WS−11(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸(2−ヒドロキシ−1,1−ジメチル−エチル酸)−アミド)、WS−12(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸(4−メトキシフェニル)−アミド)、WS−14(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸tert−ブチルアミド)、WS−23(2−イソプロピル−N−2,3−トリメチルブチルアミド)、WS−30(2−イソプロピル−5−メチル−シクロヘキサンカルボン酸エステル2,3−ジヒドロキシ−プロピル)、WS−148(1−(ジ−sec−ブチル−ホスフィノイル)−へプタン)、メントール、ゲラニオール、リナロール、ユーカリプトール、ヒドロキシル−シトロネラール、PMD−38(p−メンタン−3,8−ジオール)、TRPM8に特異的なアゴニスト抗体、及び構成的に活性なTRPM8変異体から選択される、請求項9に記載の使用又は組成物。
- 流涙症の治療用医薬品を製造するためのTRPM8アンタゴニストの使用。
- 前記流涙症が、グレーブス−バセドウ病、角膜腫瘍、アッカーマン症候群、アレルギー(動物、花粉等)、細菌性結膜炎、眼瞼炎、顔面神経麻痺、外反症、又は鼻涙管若しくは涙嚢の障害から選択される疾患と関連する、請求項11に記載の使用。
- 前記アンタゴニストがTRPM8不活性化によって冷感受性線維による涙液分泌の刺激を低減する、請求項11又は12に記載の使用。
- 前記TRPM8アンタゴニストが表3に示すTRPM8アンタゴニストから選択される、請求項11〜13のいずれか1項に記載の使用。
- 前記TRPM8アンタゴニストが、TRPM8をコードする遺伝子の配列に特異的なアンチセンスオリゴヌクレオチド、TRPM8配列に特異的なDNA酵素、TRPM8をコードする遺伝子に特異的なマイクロRNA、TRPM8をコードする遺伝子の配列に特異的なリボザイム、TRPM8をコードする遺伝子の配列に特異的な干渉RNA、TRPM8に特異的に結合してその活性を阻害する能力を有するペプチド、TRPM8に特異的に結合してこのチャネルの活性を阻害する能力を有する抗体、BCTC(N−(4−tert−ブチル−フェニル)−4−(3−クロロピリジン−2−イル)テトラヒドロピラジン−1(2H)−カルボキサミド)、CTPC((2R)−4−(3−クロロ−2−ピリジニル)−2−メチル−N−[4−(トリフルオロメチル)フェニル]−1−ピペラジン−カルボキサミド)、チオ−BCTC(N-(4−tert−ブチル−フェニル)−4−(3−クロロピリジン−2−イル)テトラヒドロピラジン−1(2H)−(チオ)カルボキサミド)、SB−452533(N−(2−ブロモフェニル)−N’−(2−[エチル(3−メチルフェニル)アミノ]エチル)ウレア)、SKF96365(1−[2−(4−メトキシフェニル)−2−[3−(4−メトキシフェニル)プロポキシ]エチル−1H−イミダゾール)、エコナゾール(1−[2−[(4−クロロフェニル)メトキシ]−2−(2,4−ジクロロフェニル)エチル]−1H−イミダゾール)、クロトリマゾール(1−[(2−クロロフェニル)ジフェニルメチル]−1H−イミダゾール)、ACA(N−(p−アミルシンナモイル)アントラニル酸)、AMTB(N−(3−アミノプロピル)−2−{[(3−メチルフェニル)メチル]オキシ}−N−(2−チエニルメチル)−ベンズアミド)、カプサゼピン(N−[2−(4−クロロフェニル)エチル]−1,3,4,5−テトラヒドロ−7,8−ジヒドロキシ−2H−2−ベンズアゼピン−2−カルボチオアミド)、フェナントロリン、MAD1d(N−[(1R,2S,5R)−2−イソプロピル−5−メチルシクロヘキシル]ビフェニル−4−カルボキサミド)、MAD2e(4−tert−ブチルフェニル(1R,2S,5R)−2−イソプロピル−5−メチルシクロヘキシルカルバメート)からなる群より選択される、請求項14に記載の使用。
- 少なくとも1種のTRPM8アンタゴニストと、流涙症の治療に有用な少なくとも1種の薬物と、必要に応じ、医薬として許容されるビヒクルと、を含む組成物。
- 流涙症の治療用医薬品を製造するための請求項16に記載の組成物の使用。
- 前記流涙症が、グレーブス−バセドウ病、角膜腫瘍、アッカーマン症候群、アレルギー(動物、花粉等)、細菌性結膜炎、眼瞼炎、顔面神経麻痺、外反症、又は鼻涙管若しくは涙嚢の障害から選択される疾患と関連する、請求項17に記載の使用。
- 前記TRPM8アンタゴニストが表3に示すTRPM8アンタゴニストから選択される、請求項16に記載の組成物又は請求項17若しくは18に記載の使用。
- 前記TRPM8アンタゴニストが、TRPM8をコードする遺伝子の配列に特異的なアンチセンスオリゴヌクレオチド、TRPM8配列に特異的なDNA酵素、TRPM8をコードする遺伝子に特異的なマイクロRNA、TRPM8をコードする遺伝子の配列に特異的なリボザイム、TRPM8をコードする遺伝子の配列に特異的な干渉RNA、TRPM8に特異的に結合してその活性を阻害する能力を有するペプチド、TRPM8に特異的に結合してこのチャネルの活性を阻害する能力を有する抗体、BCTC(N−(4−tert−ブチル−フェニル)−4−(3−クロロピリジン−2−イル)テトラヒドロピラジン−1(2H)−カルボキサミド)、CTPC((2R)−4−(3−クロロ−2−ピリジニル)−2−メチル−N−[4−(トリフルオロメチル)フェニル]−1−ピペラジン−カルボキサミド)、チオ−BCTC(N-(4−tert−ブチル−フェニル)−4−(3−クロロピリジン−2−イル)テトラヒドロピラジン−1(2H)−(チオ)カルボキサミド)、SB−452533(N−(2−ブロモフェニル)−N’−(2−[エチル(3−メチルフェニル)アミノ]エチル)ウレア)、SKF96365(1−[2−(4−メトキシフェニル)−2−[3−(4−メトキシフェニル)プロポキシ]エチル−1H−イミダゾール)、エコナゾール(1−[2−[(4−クロロフェニル)メトキシ]−2−(2,4−ジクロロフェニル)エチル]−1H−イミダゾール)、クロトリマゾール(1−[(2−クロロフェニル)ジフェニルメチル]−1H−イミダゾール)、ACA(N−(p−アミルシンナモイル)アントラニル酸)、AMTB(N−(3−アミノプロピル)−2−{[(3−メチルフェニル)メチル]オキシ}−N−(2−チエニルメチル)−ベンズアミド)、カプサゼピン(N−[2−(4−クロロフェニル)エチル]−1,3,4,5−テトラヒドロ−7,8−ジヒドロキシ−2H−2−ベンズアゼピン−2−カルボチオアミド)、フェナントロリン、MAD1d(N−[(1R,2S,5R)−2−イソプロピル−5−メチルシクロヘキシル]ビフェニル−4−カルボキサミド)、MAD2e(4−tert−ブチルフェニル(1R,2S,5R)−2−イソプロピル−5−メチルシクロヘキシルカルバメート)からなる群より選択される、請求項19に記載の組成物又は使用。
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WO2015108136A1 (ja) * | 2014-01-17 | 2015-07-23 | キッセイ薬品工業株式会社 | α-置換グリシンアミド誘導体 |
JP2016535742A (ja) * | 2013-10-22 | 2016-11-17 | エドワード タク ウェイWEI, Edward Tak | 感覚的不快感の治療向け局所薬としてのジ−イソプロピル−アルカン(dapa)化合物 |
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JP2018158933A (ja) * | 2018-06-06 | 2018-10-11 | エドワード タク ウェイWEI, Edward Tak | 感覚的不快感の治療向け局所薬としてのジ−イソプロピル−アルカン(dapa)化合物 |
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JP2016535742A (ja) * | 2013-10-22 | 2016-11-17 | エドワード タク ウェイWEI, Edward Tak | 感覚的不快感の治療向け局所薬としてのジ−イソプロピル−アルカン(dapa)化合物 |
WO2015108136A1 (ja) * | 2014-01-17 | 2015-07-23 | キッセイ薬品工業株式会社 | α-置換グリシンアミド誘導体 |
JPWO2015108136A1 (ja) * | 2014-01-17 | 2017-03-23 | キッセイ薬品工業株式会社 | α−置換グリシンアミド誘導体 |
JP2018501194A (ja) * | 2014-10-31 | 2018-01-18 | アヴェント インコーポレイテッド | 膀胱収縮の抑制に関連する用途のための方法および装置 |
JP2018158933A (ja) * | 2018-06-06 | 2018-10-11 | エドワード タク ウェイWEI, Edward Tak | 感覚的不快感の治療向け局所薬としてのジ−イソプロピル−アルカン(dapa)化合物 |
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WO2012032209A2 (es) | 2012-03-15 |
ES2377785B2 (es) | 2012-09-26 |
EP4268814A2 (en) | 2023-11-01 |
JP2024069452A (ja) | 2024-05-21 |
EP2614860A4 (en) | 2014-01-29 |
EP4268814A3 (en) | 2024-01-24 |
US20170071875A1 (en) | 2017-03-16 |
US9433679B2 (en) | 2016-09-06 |
US20150313854A1 (en) | 2015-11-05 |
JP2017036298A (ja) | 2017-02-16 |
JP2021107422A (ja) | 2021-07-29 |
US10028920B2 (en) | 2018-07-24 |
JP2019131621A (ja) | 2019-08-08 |
ES2377785A1 (es) | 2012-04-02 |
EP2614860A2 (en) | 2013-07-17 |
US9095609B2 (en) | 2015-08-04 |
US20170049728A1 (en) | 2017-02-23 |
US20130245231A1 (en) | 2013-09-19 |
WO2012032209A3 (es) | 2012-07-12 |
US9901549B2 (en) | 2018-02-27 |
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