JP2021511365A - 5−ヒドロキシトリプトファンのバイオアベイラビリティを高める組成物および方法 - Google Patents
5−ヒドロキシトリプトファンのバイオアベイラビリティを高める組成物および方法 Download PDFInfo
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Abstract
Description
本発明は、NIHによって授与された連邦補助金番号第2R01MH079201−06A1の下で政府支援により成されたものである。政府は、本発明に対して、ある一定の権利を有する。
「5−ヒドロキシトリプトファン」または「5−HTP」は、体内にあるセロトニン(別称、5−ヒドロキシトリプタミン、5−HT)の前駆体である。ヒトの体内では、5−HTPは、食物のトリプトファンから、トリプトファンヒドロキシラーゼ(末梢ではサブタイプ1、たいていのニューロンではサブタイプ2)によって合成される(Jacobsen et al,2016a)。5−HTPは、ベースライン条件下で不飽和である大容量の遍在的に発現される酵素である芳香族アミノ酸デカルボキシラーゼ(AAAD)によって5−HTに迅速に変換される(Bowsher,1986)。したがって、5−HTPは、5−HTの天然中間体であり、かつ律速前駆体である。
カルビドパは、5−HTPの、5−HTへの変換、レボドパの、ドーパミンへの変換、および他の類似した代謝反応を触媒する酵素である芳香族アミノ酸デカルボキシラーゼ(AAAD)を阻害する(Bowsher R.R.,1986)。カルビドパの治療維持用量は、1mg/kg/日を上回る(患者の体重70kgと仮定して)(Merck,2017、Pahwa et al,2014、van Praag,1982)。治療計画では、定常状態で、維持用量のカルビドパの平均血漿レベルは、25ng/ml以上(範囲:25ng/ml〜150ng/ml)である(Verhagen Metman et al,2015、Yeh et al,1989)。
本発明で使用される5−HTPおよび/またはカルビドパは、遊離塩基;塩;コンジュゲート(例えば、アミノ酸コンジュゲート、炭化水素コンジュゲート、脂質コンジュゲート);吸収、分布、代謝および/または排出特性を変化させるコンジュゲート;または吸収、分布、代謝および/または排出特性を変化させる同位体修飾であり得る。参照により本明細書の一部をなす、Tamir et al.に対する米国特許第4,658,038号、Xiang et al.に対する米国特許第7,101,912号、Jacobsen et al.に対する米国特許第8,969,400号を参照されたい。
マウス:成体のマウス、通常の5−HTレベルを有する野生型(WT)マウスおよび脳5−HT合成およびレベルが低減された「5−HTHypo」マウスの両方を使用した(Beaulieu et al,2008)。5−HTHypoマウスは、幾つかのCNS障害、例えば、うつ病および自殺における病原因子であることが知られている脳5−HT欠損の自然論的なモデルである。
5−HTP処置は、血漿5−HTP(図1)、脳5−HT(図2)、および脳5−HIAA(図3)のレベルを上昇させた。同時5−HTP処置を伴わないカルビドパ単独では効果がなかった。5−HTPに加えて投与すると、カルビドパは、多くの状態で、用量依存的に、すべての評価基準に対して5−HTP処置の効果を増強した。血漿5−HTPに対する処置の効果は、WTマウスと5−HTHypoマウスとの間で異ならなかった。5HTHypoマウスが保有する突然変異が、5−HTP吸収および代謝に影響を及ぼさないことから(Beaulieu et al,2008)、このことは予測された。対比して、脳5−HTおよび5−HIAAに対する5HTP+/−カルビドパ処置の効果は、5−HTHypoマウスにおいては、比較的より顕著であった。これは、ベースラインのWTマウスが、高い組織レベルの5−HTをすでに有していたことを部分的に反映し得る。これまでのデータにより、WTマウスにおける5−HTおよび5−HIAAの組織レベルのわずかな上昇が、結果として細胞外空間中の5HT(5−HTExt)の機能的に活性なプールのレベルの実質的な上昇になることが実証されることに留意されたい(Jacobsen et al,2016b)。
Claims (30)
- 5−HTPの投与を必要とするヒト対象において、経腸的に投与された5−HTPのバイオアベイラビリティを高める方法であって、
約0.1mg/kg/日または約0.2mg/kg/日〜約0.5mg/kg/日、約0.6mg/kg/日または約0.8mg/kg/日(あるいは、1日当たり約5mgまたは約10mg〜約35mg、約50mgまたは約60mg)の1日投与量で供給される低用量カルビドパを、前記5−HTPと経腸的に同時投与するステップであって、これにより、前記経腸的に投与された5−HTPの前記バイオアベイラビリティを高める、ステップ
を含む方法。 - 前記5−HTPおよび前記低用量カルビドパが、5−HTP:カルビドパ比100:1〜20:1の1日投与量で投与される、請求項1に記載の方法。
- 前記低用量カルビドパを経腸的に同時投与すると、前記対象が、25ng/ml、20ng/ml、15ng/ml、10ng/ml、5ng/mlまたは2ng/ml未満のカルビドパの血漿レベルを有する、請求項1または2に記載の方法。
- 前記5−HTPおよび前記低用量カルビドパが、1日当たり1回、2回、または3回投与される、請求項1〜3のいずれか1項に記載の方法。
- 前記5−HTPおよび/または前記低用量カルビドパの製剤が、経口即時放出性製剤、経口徐放性製剤、経口腸内ゲル、直腸用坐薬、およびそれらの組合せからなる群から選択される様式で投与される、請求項1〜4のいずれか1項に記載の方法。
- 前記5−HTPおよび前記低用量カルビドパが、前記5−HTPおよび前記低用量カルビドパの徐放性(SR)製剤で、同じ剤形または別個の剤形で供給される、請求項1〜5のいずれか1項に記載の方法。
- 前記SR製剤が胃保持型製剤である、請求項1〜6のいずれか1項に記載の方法。
- 前記5−HTPおよび前記低用量カルビドパが、食事と同時投与される、請求項7に記載の方法。
- 前記対象が、うつ病、社交不安症、パニック障害、全般性不安障害、OCD、衝動制御障害、自殺傾向、境界性パーソナリティー障害、線維筋痛症、運動失調、神経障害(例えば、アルツハイマー病、パーキンソン病)に関連した気分症状、認知症状もしくは行動症状および不穏、脳卒中回復、自閉症、片頭痛、睡眠障害、月経前不快気分、心的外傷後ストレス障害、産後うつ病、またはインターフェロン治療後のうつ病に関する治療を必要とする、請求項1〜8のいずれか1項に記載の方法。
- 前記対象が、気分の異常または衝動制御もしくは攻撃性制御における異常等の精神障害および/または神経障害に関する治療を必要とする、請求項1〜9のいずれか1項に記載の方法。
- 前記対象が、うつ病、不安症、自殺傾向、強迫性障害、またはADHDに関する治療を必要とする、請求項1〜10のいずれか1項に記載の方法。
- 前記対象が、うつ病、大うつ病性障害または治療抵抗性うつ病に関する治療を必要とする、請求項1〜11のいずれか1項に記載の方法。
- 前記5−HTPおよび前記カルビドパを用いた単独療法を含む、請求項1〜12のいずれか1項に記載の方法。
- セロトニンエンハンサーとともに前記5−HTPおよび前記カルビドパを用いた補助療法を含む、請求項1〜13のいずれか1項に記載の方法。
- 前記セロトニンエンハンサーが、セロトニン再取り込み阻害剤、セロトニンノルエピネフリン再取り込み阻害剤、三重再取り込み阻害剤、モノアミンオキシダーゼ阻害剤、三環系抗うつ薬、セロトニン作動薬、アンフェタミン、セロトニン前駆体、セロトニンプロドラッグ、セロトニンの生合成における中間体、およびそれらの薬学的に許容可能な塩からなる群から選択される、請求項14に記載の方法。
- 前記セロトニンエンハンサーが、選択的セロトニン再取り込み阻害剤(SSRI)である、請求項14に記載の方法。
- 前記セロトニンエンハンサーが、シタロプラム、ダポキセチン、エスシタロプラム、フルオキセチン、フルボキサミン、インダルピン、パロキセチン、セルトラリン、ビラゾドン、ボルチオキセチン、ジメリジンおよびそれらの組合せからなる群から選択される、請求項14に記載の方法。
- 前記5−HTPおよび前記低用量カルビドパが、経口的に、同じ剤形または別個の剤形で投与される、請求項1〜17のいずれか1項に記載の方法。
- 前記低用量カルビドパが、約0.1mg/kg/日または約0.2mg/kg/日〜約0.5mg/kg/日(あるいは、1日当たり約5mgまたは約10mg〜約35mg)の1日投与量で供給される、請求項1〜18のいずれか1項に記載の方法。
- 前記5−HTPが、1日当たり約0.1グラム、約0.2グラム、約0.5グラム、または約0.75グラム〜1日当たり約1グラム、約4グラム、または約6グラムの1日投与量で供給される、請求項1〜19のいずれか1項に記載の方法。
- 5−HTPおよび低用量カルビドパを含む経腸投与に適した医薬製剤またはパーツキットであって、前記製剤が、1日1回、2回または3回投与に適している、医薬製剤またはパーツキット。
- 前記低用量カルビドパが、約0.1mg/kg/日または約0.2mg/kg/日〜約0.5mg/kg/日、約0.6mg/kg/日または約0.8mg/kg/日(あるいは、1日当たり約5mgまたは約10mg〜約35mg、約50mgまたは約60mg)の1日投与量で供給される、請求項21に記載の医薬製剤またはパーツキット。
- 前記5−HTPおよび前記低用量カルビドパが、5−HTP:カルビドパの投与量比100:1〜20:1で前記製剤中に供給される、請求項21または請求項22に記載の医薬製剤またはパーツキット。
- 前記製剤が、経口投与または直腸投与に適した固形剤形である、請求項21〜23のいずれか1項に記載の医薬製剤またはパーツキット。
- 前記5−HTPおよび/または前記低用量カルビドパの前記製剤が、1個の錠剤、カプセル、もしくは毎日投薬用の他の製剤、または2個の錠剤、カプセル、もしくは1日2回投薬用の他の製剤(併せると前記1日投与量に達する)である、請求項21〜24のいずれか1項に記載の医薬製剤またはパーツキット。
- 前記5−HTPおよび前記低用量カルビドパの徐放性(SR)製剤を含む、請求項21〜25のいずれか1項に記載の医薬製剤またはパーツキット。
- 前記SR製剤が、胃保持型製剤である、請求項26に記載の方法。
- 前記5−HTPおよび前記低用量カルビドパが、食事と同時投与される、請求項27に記載の方法。
- ヒト対象において5−HTPのバイオアベイラビリティを高める方法における低用量カルビドパの使用であって、前記方法が、前記対象に約0.1mg/kg/日または約0.2mg/kg/日〜約0.5mg/kg/日、約0.6mg/kg/日または約0.8mg/kg/日(あるいは、1日当たり約5mgまたは約10mg〜約35mg、約50mgまたは約60mg)の1日投与量で供給される低用量カルビドパを前記5−HTPと経腸的に同時投与するステップを含むか、それからなるか、または本質的にそれからなり、その結果前記対象において5−HTPの前記バイオアベイラビリティを高める、使用。
- ヒト対象において5−HTPのバイオアベイラビリティを高めるための薬剤を調製する方法における低用量カルビドパの使用であって、前記低用量カルビドパが、経腸投与に関して、約0.1mg/kg/日または約0.2mg/kg/日〜約0.5mg/kg/日、約0.6mg/kg/日または約0.8mg/kg/日(あるいは、1日当たり約5mgまたは約10mg〜約35mg、約50mgまたは約60mg)の1日投与量で供給される、使用。
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