JP2013224331A - 副作用プロファイルを最小限にしながら片頭痛の迅速な緩和を可能にするdheの治療上の投与方法 - Google Patents
副作用プロファイルを最小限にしながら片頭痛の迅速な緩和を可能にするdheの治療上の投与方法 Download PDFInfo
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- JP2013224331A JP2013224331A JP2013162032A JP2013162032A JP2013224331A JP 2013224331 A JP2013224331 A JP 2013224331A JP 2013162032 A JP2013162032 A JP 2013162032A JP 2013162032 A JP2013162032 A JP 2013162032A JP 2013224331 A JP2013224331 A JP 2013224331A
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Abstract
【解決手段】DHEにより片頭痛を速やかに処置する方法であって、ピーク血漿濃度(Cmax)を下げ、ピークをやや遅延させて、ドーパミン作動性受容体およびアドレナリン作動性受容体の活性化を抑えるようにしながら、片頭痛の症状の速やかな消散を可能にする時間枠内でセロトニン受容体に対して十分に活発な結合が得られ、片頭痛の症状が緩和することを含む、方法を開示する。この方法に好適な吸入器装置も開示する。本発明の方法を実施するキットも開示する。
【選択図】なし
Description
片頭痛の診断では、3項目の片頭痛診断(ID Migraine)臨床判断ルールが策定されている。(非特許文献2)。片頭痛は一次性頭痛の一種で、一部の人では周期的に繰り返される。片頭痛は、悪心、嘔吐または光過敏などの症状を伴うため、他の頭痛とは異なる。ほとんどの人の場合、頭の片側だけに拍動痛を感じる。片頭痛は、「前兆を伴う」片頭痛か、「前兆を伴わない」片頭痛かのいずれかに分類される。前兆は一群の神経学的症状であり、通常、警告のサインになる視覚障害である。前兆が現れた患者は一般に、頭痛(headache pain)が始まる少し前に鮮やかな閃光または点滅する閃光が見える。しかしながら、片頭痛の人のほとんどは、そうした警告のサインを発しない。
32:21 23(1992);非特許文献4;およびBeckerら、Headache 36:144 148(1996))。しかしながら、その投与には、悪心、嘔吐、胸部圧迫感などの好ましからぬ副作用プロファイルが伴ううえ、その使用に関連して血圧不安定および動脈収縮などの心血管系への影響が報告されている。
例えば、本発明は以下の項目を提供する。
(項目1)
副作用を最小限にとどめながらDHEまたはその塩、水和物、多形、プロドラッグ、イオン対および代謝産物により個体の片頭痛を速やかに処置する方法であって、
片頭痛の症状の緩和が得られる十分な速度で一定量のDHE製剤を該個体に投与することを含み、
DHE投与の量および速度は副作用の有意な軽減の原因となる、
方法。
(項目2)
DHE投与の量および速度は、DHEがセロトニン受容体に対してアゴニストとして働き片頭痛の症状が緩和されるような、DHEの循環血漿濃度レベルを生じるのに十分であり、
さらに、DHEの該循環血漿濃度レベルは、アドレナリン作動性受容体またはドーパミン作動性受容体または動脈収縮筋(arterial constrictor)セロトニン受容体に対して活発に結合して副作用を引き起こすのに必要なレベル未満にとどまる、項目1に記載の方法。
(項目3)
前記副作用は、悪心、嘔吐、血管痙攣、感覚異常、高血圧、眩暈、不安症、呼吸困難、頭痛、潮紅、下痢、発疹、発汗増加、心弁膜症、胸膜および後腹膜線維症、有害な心血管作用、血圧不安定ならびに動脈収縮からなる群から選択される、項目1に記載の方法。
(項目4)
前記副作用は、悪心および嘔吐からなる群から選択される、項目1に記載の方法。
(項目5)
前記循環血漿濃度レベルのDHEは、ドーパミン作動性受容体の50%未満に活発に結合する、項目2に記載の方法。
(項目6)
前記ドーパミン作動性受容体は、D 1 およびD 2 からなる群から選択される、項目5に記載の方法。
(項目7)
前記副作用は、悪心および嘔吐からなる群から選択される、項目5に記載の方法。
(項目8)
前記循環血漿濃度レベルのDHEは、ドーパミン作動性受容体の20%未満に活発に結合する、項目2に記載の方法。
(項目9)
前記ドーパミン作動性受容体は、D 1 およびD 2 からなる群から選択される、項目8に記載の方法。
(項目10)
前記副作用は、悪心および嘔吐からなる群から選択される、項目8に記載の方法。
(項目11)
前記循環血漿濃度レベルのDHEは、5−HT 3 受容体の20%未満に活発に結合する、項目2に記載の方法。
(項目12)
前記副作用は悪心である、項目11に記載の方法。
(項目13)
前記循環血漿濃度レベルのDHEは、動脈収縮筋セロトニン受容体の20%未満に活発に結合する、項目2に記載の方法。
(項目14)
前記動脈収縮筋セロトニン受容体は、5−HT 2A 受容体である、項目13に記載の方法。
(項目15)
前記動脈収縮筋セロトニン受容体は、5−HT 2B 受容体である、項目13に記載の方法。
(項目16)
前記副作用は、血管収縮状態および心血管系状態からなる群から選択される、項目13に記載の方法。
(項目17)
前記循環血漿濃度レベルのDHEは、アドレナリン作動性受容体の60%未満に活発に結合する、項目2に記載の方法。
(項目18)
前記循環血漿濃度レベルのDHEは、アドレナリン作動性受容体の20%未満に活発に結合する、項目17に記載の方法。
(項目19)
前記副作用は、血管収縮状態、血圧上昇状態および心血管系状態からなる群から選択される、項目17に記載の方法。
(項目20)
前記循環血漿濃度レベルのDHEは、片頭痛の症状の緩和が得られる十分なレベルで5−HT 1A 、5、−HT 1B および5−HT 1D からなる群から選択されるセロトニン受容体に活発に結合する、項目2に記載の方法。
(項目21)
前記DHEは、ピーク血漿濃度(C max )がヒトの循環血漿中15,000pg/ml未満の濃度であり、かつ投与後に該ピーク血漿濃度に達する時間(T max )が投与後30分未満であるような速度で投与される、項目1に記載の方法。
(項目22)
DHEの前記C max が循環血漿中10,000pg/mL未満である、項目21に記載の方法。
(項目23)
DHEの前記C max が循環血漿中7,500pg/mL未満である、項目21に記載の方法。
(項目24)
前記DHEは、循環血漿中のDHEのT max が20分未満であるような速度で投与される、項目21に記載の方法。
(項目25)
前記DHEは、DHEのピーク血漿濃度(C max )が、直接的な静脈内送達により投与されるDHEのC max から少なくとも10分の1に低減するような速度で投与される、項目1に記載の方法。
(項目26)
前記DHEは、DHEのピーク血漿濃度(C max )が、直接的な静脈内送達により投与されるDHEのT max よりも少なくとも1分遅延するような速度で投与される、項目1に記載の方法。
(項目27)
前記C max レベルおよびT max レベルが得られるDHEの前記投与により、疼痛、悪心、音恐怖および光恐怖からなる群から選択される片頭痛症候群の少なくとも一部が緩和し、該緩和は30分以内に得られ、さらに薬剤によって誘発される悪心、心血管系副作用または他の有害作用が軽減される、項目24に記載の方法。
(項目28)
片頭痛症候群の前記緩和は、DHEの投与時に「0」を超える片頭痛症状についてのIHSスコアが投与30分後、60分後、90分後または120分後に≦1のスコアに低下することで測定される、項目1に記載の方法。
(項目29)
2.0mg未満のDHEまたはその塩、水和物、多形 プロドラッグ、イオン対および代謝産物の単位用量が投与される、項目1に記載の方法。
(項目30)
2.0mg未満のDHEまたはその塩、水和物、多形 プロドラッグ、イオン対および代謝産物の単位用量が投与され、送達された薬剤の体循環中の該薬剤の濃度対時間の曲線の面積(AUC)が匹敵する静脈内(IV)送達用量の75%以内である、項目14に記載の方法。
(項目31)
前記投与の結果、DHEの一次活性代謝産物におけるピーク血漿濃度がC max で1,000pg/ml未満となる、項目1に記載の方法。
(項目32)
DHEの前記一次活性代謝産物は、8−ヒドロキシ−ジヒドロエルゴタミンである、項目31に記載の方法。
(項目33)
前記一次代謝産物のC max が循環血漿中500pg/mL未満である、項目31に記載の方法。
(項目34)
前記一次代謝産物のC max が循環血漿中200pg/mL未満である、項目31に記載の方法。
(項目35)
前記一次代謝産物のT max が循環血漿中90分未満である、項目31に記載の方法。
(項目36)
DHEまたはその塩、水和物、多形、プロドラッグ、イオン対および代謝産物を含む製剤であって、項目1に記載の方法による投与に好適な製剤。
(項目37)
片頭痛の症状が緩和されるように、セロトニン受容体に対するアゴニストとして有効なDHEの循環血漿濃度レベルを生じるのに十分な量での前記DHE製剤の投与は、該循環血漿濃度レベルのDHEが、副作用を引き起こすレベルでアドレナリン作動性受容体またはドーパミン作動性受容体または動脈収縮筋セロトニン受容体に結合することを引き起こさない、項目36に記載の製剤。
(項目38)
前記DHE製剤は、静脈内投与、動脈内投与、腹腔内投与、肺内投与、経口投与、舌下投与、口腔投与、鼻腔内投与、経口吸入投与、膀胱内投与、筋肉内投与、気管内投与、皮下投与、イオン導入投与および経皮投与からなる群から選択される様式で投与される、項目1に記載の方法。
(項目39)
前記DHE製剤は、エアロゾル、乾燥粉末吸入器、ネブライザー、気化器または加圧式定量吸入器(pMDI)を含む肺吸入により投与される、項目38に記載の方法。
(項目40)
前記DHE製剤は、呼吸作動型定量吸入器により投与される、項目38に記載の方法。
(項目41)
前記DHE製剤は、静脈内投与、動脈内投与、腹腔内投与、肺内投与、経口投与、舌下投与、口腔投与、鼻腔内投与、経口吸入投与、膀胱内投与、筋肉内投与、気管内投与、皮下投与、イオン導入投与および経皮投与からなる群から選択される様式で投与され、
さらに、前記DHEは、ピーク血漿濃度(C max )がヒトの循環血漿中10,000pg/ml未満の濃度であり、かつ投与後に該ピーク血漿濃度に達する時間(T max )が投与後30分未満であるような速度で投与される、項目1に記載の方法。
(項目42)
前記DHE製剤は、エアロゾル、乾燥粉末吸入器、ネブライザー、気化器または加圧式定量吸入器(pMDI)を含む肺吸入により投与される、項目41に記載の方法。
(項目43)
前記DHE製剤は、呼吸作動型定量吸入器により投与される、項目42に記載の方法。
(項目44)
前記DHE製剤は、前記個体に制吐薬を投与せずに投与される、項目43に記載の方法。
(項目45)
前記DHE製剤は、呼吸作動型定量吸入器により個体に投与され、
前記DHEは、ピーク血漿濃度(C max )がヒトの循環血漿中10,000pg/ml未満の濃度であり、投与後に該ピーク血漿濃度に達する時間(T max )が投与後20分未満であるような速度で投与され、
さらに、該DHE製剤は、制吐薬を該個体に投与せずに投与される、項目1に記載の方法。
(項目46)
単位用量のDHEまたはその塩、水和物、多形、プロドラッグ、イオン対および代謝産物を含むキットであって、該単位用量は、ヒト個体に投与される場合、DHE投与の量および速度が副作用を引き起こさない条件下で片頭痛の症状の緩和を得るのに十分である、キット
(項目47)
吸入器装置をさらに含む、項目46に記載のキット。
(項目48)
ネブライザーをさらに含む、項目46に記載のキット。
(項目49)
加圧式定量吸入器をさらに含む、項目46に記載のキット。
(項目50)
1つまたは複数の単位用量のDHE製剤を含む吸入器装置であって、各単位用量は、ピーク血漿濃度(C max )がヒトの循環血漿中10,000pg/ml未満の濃度であり、かつ投与後に該ピーク血漿濃度に達する時間(T max )が投与後30分未満であるような速度で投与される、吸入器装置。
(項目51)
前記DHE製剤は密封容器で提供される、項目50に記載の吸入器装置。
(項目52)
化合物を用いて個体の疾患または状態を速やかに処置するための方法であって、
ここで、該化合物は(a)1種または複数種の第1の受容体に結合し、該第1の受容体への該化合物の結合は該疾患または状態を緩和し、かつ(b)1種または複数種の第2の受容体に結合し、該第2の受容体への該化合物の結合は副作用を引き起こし、
該方法は、
化合物が該第1の受容体に対してアゴニストとして働き、該疾患または状態の緩和を提供するように、該化合物の循環血漿濃度レベルを生じるのに十分な速度で一定量の該化合物を該個体に投与することを含み、
該化合物の該循環血漿濃度レベルは、該第2の受容体に対する結合が副作用を引き起こすのに必要なレベル未満にとどまる、
方法。
ジヒドロエルゴタミン(DHE)は、1946以来片頭痛の処置に使用されている半合成麦角アルカロイドである。DHEは、生理的分子との構造類似性があるため、生体アミン受容体、特にセロトニン(5−HT)サブタイプ、アドレナリン(αおよびβ)サブタイプおよびドーパミン(D)サブタイプ)に対する作用を介した様々な薬理作用を持っている(表1)。
静脈内DHEの有効性および安全性を証明するため、成人を対象とした多く研究が行われてきた。重度の片頭痛を処置するためDHEの反復静脈内投与を用いてDHEを静脈内投与する現在の方法は、Raskinにより紹介された。(Raskin NH.Repetitive intravenous dihydroergotamine as therapy for intractable migraine.Neurology 1986;36:995−997)。本明細書において「直接的な静脈内送達」という場合、Raskin(Neurology 36:995−997(1986))に記載された手順に従ってDHEを直接IV投与することを指すと解釈する。
本明細書に記載の組成物については、たとえば、静脈内、動脈内、腹腔内、肺内、経口、吸入、膀胱内、筋肉内、気管内、皮下、眼内、髄膜内、経粘膜および経皮など、様々な経路により個体(ヒトなど)に投与できる。本発明の一実施形態では、以下に限定されるものではないが、経口、筋肉内、経皮、静脈内、吸入器または他の経気道送達系および同種のものなど許容可能な任意の経路により、本発明の化合物のナノ粒子(薬剤と一緒に製剤化されたタンパク質ナノ粒子または炭水化物ナノ粒子など)を投与してもよい。
本発明は、疼痛、悪心、音恐怖および光恐怖という片頭痛症候群の4つの主な症状を効果的かつ迅速に緩和する十分な投薬プロファイルが得られると同時に副作用を最小限にとどめるか消失させる、DHEの投与方法を教示する。発明者らが行った臨床試験では、予想外の現象が観察された。DHEを前述の要領で投与すると、意外にもピーク血漿濃度の著しい「急上昇」が回避され、悪心、胸部圧迫感または疼痛、血圧変動、嘔吐の副作用が最小限にとどまるか、あるいは、完全に消失しても、なお片頭痛の症状の迅速な緩和が得られた。
0=症状なし
1=軽度の症状(通常の日常生活を妨げない)
2=中等度の症状(通常の生活が一部制限される)
3=重度(通常の日常生活を送ることができなくなる)
の各段階でスコア評価する
頭痛(headache pain)の強度は、4段階の重症度スケール(0=疼痛なし、1=軽度、2=中等度、3=重度)で測定する。頭痛の改善(当初の強度よりも1段階下がる)までの平均経過時間、軽度の頭痛までの平均経過時間および頭痛なしまでの平均経過時間を測定する。効果的な片頭痛治療であれば、1.5〜2時間後には頭痛症状が軽度または頭痛なしに軽減されるであろう。
0=障害なし
1=やや障害がある
2=中等度の障害がある
3=重度または完全な障害がある
の4段階で測定する。
0=著しく改善
1=かなり改善
2=やや改善
3=変化なし
4=やや悪化
5=かなり悪化
6=著しく悪化
作用機序
実施例2および3に詳細に記載したCmax濃度で結合する受容体の調査から、有害作用プロファイルで観察される相違の根拠が得られた。理論に束縛されるものではないが、ドーパミン作動性受容体およびアドレナリン作動性受容体結合を最小限に抑えるようにCmax濃度を調節し、それにより副作用を回避しながら、片頭痛の症状の処置に効果があるセロトニン受容体への十分な結合を達成することで、副作用を起こさずにDHEで片頭痛を処置する方法を実現できると考えられる。
receptor agonists in the rat brain.British Journal of Pharmacology 2003;139:424−434)。
鎮痛の達成に必要なDHEの薬物動態プロファイル。
Cmax濃度における受容体結合
IV投与されたDHE(1mg)と吸入されたDHEとを比較した、臨床研究の示差的有害作用プロファイルを報告した(表2)。IV投薬後に有害作用の頻度が増大することが明白となった。ジヒドロエルゴタミンメシラート(DHE)の(1)静脈内注射と(2)吸入との間で薬理学的に生じる有害作用の相違を調べるため、臨床研究において吸入投薬および静脈内(IV)投薬後に報告されたCmaxレベルに一致する濃度に基づき、ジヒドロエルゴタミンメシラートの生体アミン受容体(セロトニン(5−HT)、アドレナリン、ドーパミン作動性)結合をインビトロで判定した。
ピーク血漿濃度に相当する濃度でのDHEによるセロトニン受容体、アドレナリン作動性受容体およびドーパミン作動性受容体への結合
放射性リガンド受容体結合アッセイを行うと、DHEが複数の受容体部位で広範囲な薬理作用を示すことが明確に明らかになる。(図3〜図5)。IVのCmaxに相当する濃度ではDHEは大部分の受容体に対して顕著な結合が認められるのに対し、吸入の結合では、各用量で異なるプロファイルが得られる。IVでない方法を用いて投与すると、ほとんどの場合、結合が減少する。
5−HT1Bサブタイプ受容体のアゴニストは、片頭痛および関連する症状の処置に有用であることが知られている。5−HT2B受容体は、片頭痛の発症において引き金の役割を果たしていることが知られている。図5は、高濃度対照(5μm)、IVのCmax(77.6nM)、4回の吸入のCmax(6.25nM)および非常に低濃度(0.25nM)における5−HT1Bおよび5−HT2B受容体の選択的アゴニズムを示す。5−HT1Bのアゴニズムはすべての濃度において維持され、効力が高いこと示されるのに対し、経口吸入のDHEでは5−HT2B受容体のアゴニズムは存在しない。
TEMPO(商標)吸入器を用いたDHE製剤の経肺投与
吸入送達用のDHE粒子の製造に大きな利点がある超臨界流体プロセスを用いてDHE粉末を作製し、単一のステップで所望の大きさの呼吸性粒子を製造する。(国際公開第2005/025506A2号を参照されたい。)処理後のDHE原薬の特徴は、超臨界流体処理した結晶の表面が極めて滑らかで表面エネルギーが小さく、したがって、噴射剤を用いた系で効果的に分散する傾向があることである。DHEのかなりの割合が確実に肺に沈着するように、微結晶の制御粒度を選択した。
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2015
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WO2005025506A2 (en) * | 2003-09-10 | 2005-03-24 | Map Pharmaceuticals, Inc. | Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation |
JP2010518095A (ja) * | 2007-02-11 | 2010-05-27 | マップ ファーマシューティカルズ, インコーポレイテッド | 副作用プロファイルを最小限にしながら片頭痛の迅速な緩和を可能にするdheの治療上の投与方法 |
Non-Patent Citations (2)
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JPN6013015076; SILBERSTEIN,S.D. et al: Headache Vol.43, No.2, 2003, p.144-66 * |
JPN6014031183; Journal of Chromatography Vol.768, 2002, pp.267-275 * |
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