JP2022009901A - マグネシウム含有オキシトシン製剤および使用の方法 - Google Patents
マグネシウム含有オキシトシン製剤および使用の方法 Download PDFInfo
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- JP2022009901A JP2022009901A JP2021179295A JP2021179295A JP2022009901A JP 2022009901 A JP2022009901 A JP 2022009901A JP 2021179295 A JP2021179295 A JP 2021179295A JP 2021179295 A JP2021179295 A JP 2021179295A JP 2022009901 A JP2022009901 A JP 2022009901A
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- Prior art keywords
- magnesium
- oxytocin
- pain
- oxytocin peptide
- peptide
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Abstract
【解決手段】頭蓋顔面粘膜投与(例えば、鼻腔内投与)を介して疼痛を処置するための方法、ならびに、オキシトシンペプチドおよびマグネシウム塩を含む組成物が提供される。本明細書中に記載される方法およびマグネシウム含有オキシトシンペプチド製剤は、オキシトシン単独と比べてより速い、より強いおよびより長く持続する鎮痛効果を提供する。
【選択図】なし
Description
本出願は、2015年1月7日に出願された米国仮特許出願番号第62/100,862号に基づく優先権を主張しており、この仮特許出願の開示は、その全体が参考として本明細書中に援用される。
本発明は、オキシトシンペプチドおよびマグネシウム塩を含む組成物に関する。オキシトシンペプチドとマグネシウム塩との同時投与を含む、疼痛(例えば、片頭痛)を処置するための方法も開示される。
オキシトシンは、哺乳動物の視床下部の室傍核および視索上核で主に産生される天然に存在する9アミノ酸の神経ペプチドである。オキシトシンは、分散した神経路を介して中枢神経系に放出され、下垂体後葉を介して末梢循環に放出される。合成オキシトシン(Pitocin(登録商標))の筋肉内注射または点滴静注は、子宮収縮を生じさせるかまたは改善して経腟分娩を促すために、および分娩後出血を管理するために、現在、米国において承認されている。鼻腔内オキシトシン(Syntocinon(登録商標))は、射乳を刺激して母乳栄養を促すために1960年から1997年まで米国において承認されていた。Syntocinon(登録商標)という鼻腔用スプレーは、製造者の要請で米国市場から撤退したが、鼻腔内オキシトシンは、今でもスイス、ポルトガルまたはブラジルなどの米国国外の国で販売されている。最近、鼻腔内投与による頭痛などの疼痛の処置におけるオキシトシンペプチドの使用が実証された。WO2007/025249A2およびWO2007/025286A2を参照のこと(これらの開示は、参照により本明細書中に援用される)。
オキシトシンは、三叉神経痛および片頭痛などの、三叉神経に関連する疼痛、特に慢性疼痛を低減させると示されている。ヒトでの臨床試験から、片頭痛の処置における鼻腔内オキシトシンの有効性が実証された。しかしながら、これらの治験は、経鼻オキシトシンによって引き起こされる痛覚消失までの潜時がおよそ2時間であり、投与の約4時間後まで最大鎮痛効果が顕われなかったことを示した。したがって、より速く鎮痛効果を発揮することができるオキシトシンペプチド製剤が必要とされている。
頭蓋顔面粘膜投与(例えば、鼻腔内投与)を介して疼痛を処置するための方法ならびにオキシトシンペプチドおよびマグネシウム塩を含む組成物が提供される。本明細書中に記載される方法およびマグネシウム含有オキシトシンペプチド製剤は、オキシトシン単独と比べてより速い、より強いおよびより長く持続する鎮痛効果を提供する。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
疼痛の処置を必要とする被験体に有効用量のオキシトシンペプチドおよびマグネシウム塩を投与する工程を含む、疼痛を処置するための方法であって、ここで、該オキシトシンペプチドと該マグネシウム塩との同時投与は、相乗的な痛覚消失をもたらす、方法。
(項目2)
前記オキシトシンペプチドが、前記マグネシウム塩と同時に投与される、項目1に記載の方法。
(項目3)
前記オキシトシンペプチドが、前記マグネシウム塩の投与の前または後に投与される、項目1に記載の方法。
(項目4)
前記オキシトシンペプチドが、頭蓋顔面粘膜投与を介して投与される、項目1~3のいずれか1項に記載の方法。
(項目5)
前記オキシトシンペプチドが、鼻腔内投与を介して投与される、項目4に記載の方法。
(項目6)
前記オキシトシンペプチドおよび前記マグネシウム塩が、鼻腔内投与を介して投与される、項目5に記載の方法。
(項目7)
前記マグネシウム塩が、塩化マグネシウムを含む、項目1~6のいずれか1項に記載の方法。
(項目8)
前記マグネシウム塩が、クエン酸マグネシウムを含む、項目1~7のいずれか1項に記載の方法。
(項目9)
前記オキシトシンペプチドの有効用量が、約0.5μg~約2000μgである、項目8に記載の方法。
(項目10)
前記マグネシウム塩の有効用量が、約50μg~約68mgのマグネシウムを提供する、項目8に記載の方法。
(項目11)
前記オキシトシンペプチドおよび前記マグネシウム塩の有効用量が、約1.1%~約1.6%(w/v)のマグネシウムを含む水溶液において投与される約15μg~約120μgの該オキシトシンペプチドを含む、項目8に記載の方法。
(項目12)
前記オキシトシンペプチドおよび前記マグネシウム塩の有効用量が、約1.36%のマグネシウムを含む水溶液において投与される約66μgの該オキシトシンペプチドを含む、項目8に記載の方法。
(項目13)
前記疼痛が、慢性疼痛である、項目1~12のいずれか1項に記載の方法。
(項目14)
前記疼痛が、急性疼痛である、項目1~12のいずれか1項に記載の方法。
(項目15)
前記疼痛が、偶発性疼痛である、項目1~12のいずれか1項に記載の方法。
(項目16)
前記疼痛が、頭痛または顔面痛である、項目1~12のいずれか1項に記載の方法。
(項目17)
前記疼痛が、三叉神経関連の疼痛である、項目1~12のいずれか1項に記載の方法。
(項目18)
前記疼痛が、片頭痛である、項目1~12のいずれか1項に記載の方法。
(項目19)
前記疼痛が、頸部痛、肩部痛または上肢痛である、項目1~12のいずれか1項に記載の方法。
(項目20)
前記疼痛が、頸神経関連の疼痛である、項目1~12のいずれか1項に記載の方法。
(項目21)
前記オキシトシンペプチドが、ヒトオキシトシン(配列番号1)である、項目1~20のいずれか1項に記載の方法。
(項目22)
オキシトシンペプチドおよびマグネシウム塩を含む組成物であって、該オキシトシンペプチドおよび該マグネシウム塩は、疼痛の処置において使用されたとき相乗的な痛覚消失をもたらす量で存在する、組成物。
(項目23)
前記オキシトシンペプチドが、ヒトオキシトシン(配列番号1)である、項目22に記載の組成物。
(項目24)
前記マグネシウム塩が、クエン酸マグネシウムおよび/または塩化マグネシウムを含む、項目22または23に記載の組成物。
(項目25)
前記マグネシウム塩が、塩化マグネシウムおよびクエン酸マグネシウムを含む、項目24に記載の組成物。
(項目26)
前記組成物が、約0.01mg/mL~約16mg/mLの前記オキシトシンペプチドを含む液体製剤である、項目22~25のいずれか1項に記載の組成物。
(項目27)
前記液体製剤が、約0.15mg/mL~約1.5mg/mLの前記オキシトシンペプチドを含む、項目26に記載の組成物。
(項目28)
前記組成物が、約3mg/mL~約30mg/mLのマグネシウムを提供する量で前記マグネシウム塩を含む液体製剤である、項目22~27のいずれか1項に記載の組成物。
(項目29)
前記液体製剤が、約11mg/mL~約15mg/mLのマグネシウムを含む、項目28に記載の組成物。
(項目30)
1つまたはそれを超える賦形剤、ビヒクル、乳化剤、安定剤、保存剤、粘膜接着剤、抗菌剤、緩衝剤および/または他の添加物をさらに含む、項目22~29のいずれか1項に記載の組成物。
(項目31)
前記組成物が、約4.5のpHを有する、項目22~29のいずれか1項に記載の組成物。
(項目32)
前記組成物が、経鼻投与に適している、項目22~31のいずれか1項に記載の組成物。
(項目33)
さらに鼻腔内投与用のデバイスを含む、項目32に記載の組成物。
(項目34)
鼻腔内投与用の前記デバイスが、鼻腔用ポンプ装置である、項目33に記載の組成物。
(項目35)
前記鼻腔用ポンプ装置が、ポンプアクチュエータに取り付けられた貯蔵ボトルを備える、項目34に記載の組成物。
(項目36)
前記ポンプアクチュエータが、約50μLという特定体積を送達するように計量する、項目35に記載の組成物。
(項目37)
前記鼻腔用ポンプ装置が、エアロゾライザに取り付けられた貯蔵ボトルを備える、項目34に記載の組成物。
(項目38)
前記鼻腔用ポンプ装置が、以下:
(i)逆流を防止するためのフィルター、
(ii)無金属流路、および
(iii)ガンマ線に対して安定なプラスチック材料
のうちの1つ以上を備える、項目34~37のいずれか1項に記載の組成物。
(項目39)
疼痛の処置を必要とする被験体に有効用量の項目22~32のいずれか1項に記載の組成物および薬学的に許容され得るキャリアを投与する工程を含む、疼痛を処置するための方法。
(項目40)
項目22~38のいずれか1項に記載の組成物および包装材を含む、キット。
(項目41)
項目39に記載の方法に従って前記組成物を投与するための指示書をさらに含む、項目40に記載のキット。
本発明は、とりわけ、オキシトシンペプチドおよびマグネシウム塩を含む組成物ならびにそのマグネシウム含有オキシトシンペプチド製剤の頭蓋顔面投与(例えば、鼻腔内投与)によって疼痛を処置するための方法を提供する。
本明細書中で使用されるとき、別段特定されない限り、用語「処置」または「疼痛を処置する」とは、目的の作用物質を被験体に投与することを指し、ここで、その作用物質は、疼痛を軽減するか、またはその被験体が処置される原因である有痛性の病態を予防する。
オキシトシンは、単離および配列決定された最初のペプチドホルモンの1つであった。天然のオキシトシンは、1位と6位の間にジスルフィド架橋を形成する2つのシステイン残基を有する9アミノ酸の環状ペプチドホルモンである。ヒトオキシトシンのアミノ酸配列は、Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly(配列番号1)である。
1つの態様において、本発明は、マグネシウム含有オキシトシンペプチド製剤および疼痛の処置におけるその使用を提供する。
[%Mg2+(w/v)]=(24.3/214.4)*[%クエン酸Mg(w/v)]=0.113*[%クエン酸Mg(w/v)]
mM Mg2+=411.5*[%Mg2+(w/v)]=46.6*[%クエン酸Mg(w/v)]
mg/mL Mg2+=10*[%Mg2+(w/v)]=0.0243*[mM Mg2+]=1.13*[%クエン酸Mg(w/v)]
マグネシウム含有オキシトシンペプチド製剤または組成物は、頭蓋顔面粘膜投与(例えば、経鼻、頬側、舌下または眼球投与)に適合し得る。いくつかの実施形態において、組成物はさらに粘膜送達用のデバイスを構成し得る。いくつかの実施形態において、組成物は、頬側および/または舌下の粘膜送達に適合しており、その組成物はさらに、頬側および/または舌下の粘膜投与用のデバイス(例えば、単位用量容器、ポンプスプレー、滴注器、スクイーズボトル、保存剤非含有エアレススプレー、ネブライザー、用量吸入器(dose inhalers)および加圧式用量吸入器)を構成し得る。いくつかの実施形態において、組成物は、眼球送達に適合しており、その組成物はさらに、結膜投与用のデバイス(例えば、滴注器またはスクイーズボトル)を構成し得る。いくつかの実施形態において、組成物は、鼻腔内投与に適合しており、その組成物はさらに、鼻腔内投与用のデバイス(例えば、滴注器、ポンプスプレー、スクイーズボトル、保存剤非含有エアレススプレーまたは鼻腔用ポンプ装置、例えば、エアロゾライザに取り付けられた貯蔵ボトルを備える鼻腔用ポンプ装置)を構成し得る。
1つの態様において、本発明は、疼痛の処置を必要とする被験体に有効用量のオキシトシンペプチドおよびマグネシウム塩を投与する工程を含む、疼痛を処置するための方法を提供し、ここで、そのオキシトシンペプチドとマグネシウム塩との同時投与は、相乗的な痛覚消失をもたらす。いくつかの実施形態において、オキシトシンペプチドおよびマグネシウム塩は、個別に投与される等価な用量のオキシトシンペプチドおよびマグネシウム塩の痛覚消失または鎮痛効果の合計を超える全体的な痛覚消失または鎮痛効果をもたらす用量で投与される。いくつかの実施形態において、オキシトシンペプチドとマグネシウム塩との同時投与は、個別に投与される等価な用量のオキシトシンペプチドおよびマグネシウム塩による有痛性の刺激(異痛症および/または痛覚過敏)に対する疼痛の強度または感度の低下の合計を超える、被験体が経験する有痛性の刺激(異痛症および/または痛覚過敏)に対する疼痛の強度または感度の低下をもたらす。いくつかの実施形態において、オキシトシンペプチドとマグネシウム塩との同時投与は、個別に投与される等価な用量のオキシトシンペプチドおよびマグネシウム塩による疼痛頻度の低下の合計を超える、被験体が経験する疼痛の頻度の低下をもたらす。いくつかの実施形態において、オキシトシンペプチドとマグネシウム塩との同時投与は、個別に投与される等価な用量の任意の鎮痛剤よりも速い痛覚消失または鎮痛効果の発生をもたらす。いくつかの実施形態において、オキシトシンペプチドとマグネシウム塩との同時投与は、個別に投与される等価な用量の任意の鎮痛剤よりも長く持続する痛覚消失または鎮痛効果をもたらす。
本明細書中に記載される方法のいずれかを行うためのキットが本明細書中に提供される。疼痛の処置および/または予防において使用するためのキットが提供される。いくつかの実施形態において、そのキットは、好適な包装材に入った、オキシトシンペプチドおよびマグネシウム塩(ここで、そのオキシトシンペプチドおよびマグネシウム塩は、疼痛の処置において使用されたとき相乗的な痛覚消失をもたらす量で存在する)および頭蓋顔面粘膜投与(例えば、鼻腔内投与)用のデバイスを含む。キットは、プロテアーゼ阻害剤および/または少なくとも1つの吸収促進剤をさらに含み得る。他のキットは、本明細書中に記載される方法のいずれか1つを行うためにユーザーおよび/または医療提供者に情報を提供する指示書をさらに含み得る。
予め剪毛したラットの頬に投光ランプからの熱を集中させ、6.5~8.5秒の潜時の引っ込め反応が得られるように強度を変動させた。そのような潜時を達成するために適用される強度を各動物について記録した。安定した/許容され得るベースライン値が得られたら、各ラットに対する平均潜時を算出した。全ラットについてベースラインの頬引っ込め潜時を測定した後、Freyが開発した方法(Thorneら、Neuroscience.,127:481-496(2004))に従って、通常の生理食塩水、15%塩化マグネシウム水溶液または1%乳酸マグネシウム水溶液のいずれかの単回経鼻投与を各ラットに行った。簡潔には、ラット(ウレタン麻酔下)を、背側の頸部の下に挿入されたロールパッド(2×2ガーゼ)を用いて背臥位にし、頭部を支持面に向かって伸ばした。薬物溶液を鼻腔内に維持するためおよび鼻咽頭から垂れ落ちるのを最小限にするために、投与手順全体にわたって、頸部の上面を水平に維持した。それぞれの薬物溶液の6μLの液滴を小型ピペットの先端から落とし、ラットの左側の外鼻孔に逆の外鼻孔を塞ぎながら与えた。各外鼻孔に交互に1滴を2分ごとに投与した(したがって要するに同じ外鼻孔への用量の間に4分の間隔)。各鼻孔には4滴を投与し、合計で48μL(各6μLの8滴)という合計体積になる。送達する物質に関して実験者の盲検を維持するために、薬物溶液をコード化した。次いで、放射熱刺激に対する左頬引っ込め潜時を次の3時間にわたって計測した。経鼻投与前ならびに処置の1、2および3時間後に引っ込め潜時を計測した。
4つの濃度のうちの1つの二塩基性クエン酸マグネシウム(1:1Mg/クエン酸)をラットに適用し、顔面の侵害性熱刺激への反応に対するこれらの適用の効果を上に記載したように評価した。上に記載した方法に従って、各ラットに対して、3、6、10または12%クエン酸マグネシウム水溶液の単回経鼻投与を行った(6匹のラット/群)。次いで、放射熱刺激に対する左頬引っ込め潜時をその後の300分間にわたって計測した。経鼻投与前ならびに処置の15、30、45、60、120、180、240および300分後に引っ込め潜時を計測した。
緩衝食塩水中の3つの用量のうちの1つのオキシトシンをラットに適用し、顔面の侵害性熱刺激への反応に対するこれらの適用の効果を上に記載したように評価した。上に記載した方法に従って、各ラットに対して、1、4または8μgのオキシトシンを含む水溶液の単回経鼻投与を行った(6匹のラット/群)。次いで、放射熱刺激に対する左頬引っ込め潜時をその後の300分間にわたって計測した。経鼻投与前ならびに処置の15、30、45、60、120、180、240および300分後に引っ込め潜時を計測した。
実施例4A-クエン酸マグネシウム/オキシトシン併用
3つの濃度のうちの1つのクエン酸マグネシウムと3つの用量のうちの1つのオキシトシンとの組み合わせを含む水溶液をラットに経鼻的に適用し、引っ込め反応潜時の変化を上記のように計測した。上に記載した方法に従って、各ラットに対して、3、6または12%クエン酸マグネシウムを含む水溶液中の1、4または8μgのオキシトシンの単回経鼻投与を行った。次いで、放射熱刺激に対する左頬引っ込め潜時をその後の300分間にわたって計測した。経鼻投与前ならびに処置の15、30、45、60、120、180、240および300分後に引っ込め潜時を計測した。
硫酸マグネシウムとオキシトシンとの組み合わせを含む水溶液をラットに経鼻的に適用し、引っ込め反応潜時の変化を上記のように計測した。上に記載した方法に従って、各ラットに対して、20%硫酸マグネシウム七水和物(MgSO4・7H2O,MW246.5)を含む水溶液中の8μgのオキシトシンの単回経鼻投与を行った。次いで、放射熱刺激に対する左頬引っ込め潜時をその後の300分間にわたって計測した。経鼻投与前ならびに処置の15、30、45、60、120、180、240および300分後に引っ込め潜時を計測した。
実施例5A
高張性であり、pH4.5を目標とする薬物製品製剤は、オキシトシンUSP(150IU/mL);塩化マグネシウムUSP(六水和物または無水塩として);クエン酸USP(無水物または一水和物の形態として);水酸化ナトリウムNF;および滅菌注射用水USPからなる。量的組成を表1に提供する。すべての成分が、対応するモノグラフの公定書(USP/NF)の要件を満たす。
等張性であり、pH4.5を目標とする、薬物製品製剤は、オキシトシンUSP(150IU/mL);クエン酸マグネシウム、塩化ナトリウムUSP;酢酸ナトリウム三水和物USP;氷酢酸USP;および滅菌注射用水USPからなる。量的組成を表2に提供する。pH4.5またはpH4.5付近における最適な製剤安定性に基づいて4.5という目標pHが選択される(Haweら、Pharmaceut.Res.26:1679-1688(2009))。すべての成分が、対応するモノグラフの公定書(USP/NF)の要件を満たす。
実施例6A
高頻度の片頭痛を有する一部の患者を、米国の南カリフォルニアの大病院のクリニックにおいて頭痛の専門家が調べた。その専門家は、それらの患者にA、BおよびCと記された3種の鼻腔用スプレーを与えて、家に持ち帰らせた。それらの患者は、その後片頭痛を3回経験したとき毎回それらのバイアルのうちの1つを使用し、そのスプレーの結果として経験した疼痛緩和の程度を評価した。それらの3つのバイアルは、12%溶液中の48ミリグラムのクエン酸マグネシウム佐剤(バイアルA)、66マイクログラムのオキシトシン(バイアルB)または12%溶液中の48mgのクエン酸マグネシウム佐剤+66マイクログラムのオキシトシン(バイアルC)を送達するのに十分な液体を含んでいた。患者は、バイアルAからは疼痛緩和に関して恩恵を報告せず、バイアルBからはいくらかの恩恵を報告し、バイアルCからはかなり強い疼痛緩和を報告した。これらの結果から、頭蓋顔面痛の緩和におけるオキシトシンとマグネシウム含有佐剤との相乗効果が実証する。
前兆有りまたは無しの片頭痛に苦しむ90人のヒト患者を無作為化二重盲検並行研究に登録する。各被験体は、90日間参加する。ステージ1は、患者が頭痛の発生および標準的な薬剤の摂取を記録する28日間のベースライン(スクリーニング)を含む。ステージ2は、患者が頭痛を起こしたとき経鼻オキシトシン/クエン酸マグネシウム製剤を摂取する56日間である。60人の患者を有効群(オキシトシン/マグネシウム製剤)に割り当て、30人をプラセボ群に割り当てる。
慢性緊張型頭痛を有する患者は、頭部、頸部および肩部に激しい疼痛を有すると記録した。その患者は、30単位の用量のために7.5IU/スプレーのオキシトシンを4スプレー摂取し、その時点において頭痛は無くなったが、頸部痛および肩部痛は残っていた。その患者は、薬の摂取を続け、最終的には、さらに8~10スプレー、すなわち合計60~75IUを摂取し、その時点において、頸部痛および肩部痛は、弱まり、止んだ。したがって、頸部痛および肩部痛に作用するためには、同じ患者において頭痛を阻害するために必要な用量よりも高用量が必要であった。
頸神経関連の炎症性疼痛に対する経鼻的に投与されたオキシトシンの鎮痛効果が、ラット足炎症モデルにおいて評価された(Martinら、Pain 1999,82:199-205)。3つの用量(48マイクロリットル中の193、385または768マイクログラム)のうちの1つのオキシトシンを経鼻的に投与し、次の3時間にわたって一定間隔で、炎症領域(前足)の機械的刺激の後に、グラムを単位とする引っ込め力閾値を測定し、ビヒクル(リン酸緩衝食塩水)で処置されたラットのそれと比較した。フロイント完全アジュバントをラットの左前足に注射して、その足に強い炎症ならびに引っ込め反応(機械的異痛症)を誘発するのに必要な力の実質的な減少をもたらした。結果を図8に示す。最低用量のオキシトシンは、疼痛閾値の上昇に効果的でなかったのに対して、より高い2つの用量は、炎症に起因する機械的異痛症の統計学的に有意な部分的回復をもたらした。これらの結果は、頸神経に関連する疼痛に対して鎮痛性である経鼻オキシトシンと一致する。
最近、交通事故に遭った20歳の女性患者は、重度の頸部痛に苦しんでいた。その患者を実施例5Aのマグネシウム含有オキシトシン製剤で処置した。その頸部痛を11点の疼痛ランク付け数値スケールで計測した。その患者に、自身の疼痛に、内在的な知覚に対する数値を割り当てるように依頼した。「1」が、閾値レベルの疼痛、すなわちかろうじて有痛性であり、「10」が、患者が想像し得る最もひどい疼痛である(このスケールにおけるゼロは、疼痛が無いことを意味する)。60IUのオキシトシン(400μLの製剤に含まれる)を、1スプレーあたり100μLの4スプレーで患者の鼻に適用したとき、その患者の頸部痛は、11点の疼痛ランク付け数値スケールにおいて、「9」というランク付けから「4」というランク付けに低下した。その患者の疼痛緩和は、処置の10分以内に生じた。
本発明は、以下の実施形態によってさらに説明される。それらの実施形態の各々の特徴は、必要に応じて、および差し支えなければ、他の実施形態のいずれかと組み合わせ可能である。
(i)逆流を防止するためのフィルター、
(ii)無金属流路、および
(iii)ガンマ線に対して安定なプラスチック材料
のうちの1つ以上を備える。
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