JP2022500364A - 関節への送達に適した医薬組成物及びその関節痛の治療における使用 - Google Patents
関節への送達に適した医薬組成物及びその関節痛の治療における使用 Download PDFInfo
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Abstract
Description
(a)1種または複数種のリン脂質を含む脂質混合物と、
(b)有効量の治療剤またはその薬学的に許容される塩と、を含む医薬組成物であって、
前記医薬組成物中の前記1種または複数種のリン脂質の総量が、前記医薬組成物1mL(ミリリットル)あたり約20μmоlから約150μmоlである、治療剤の関節への送達に適した医薬組成物が提供される。
(a)1種または複数種のリン脂質からなる脂質混合物と、
(b)有効量の治療剤またはその薬学的に許容される塩と、を含むよう構成されたものであり、
関節注射1回分あたりの前記1種または複数種のリン脂質の総量が約20μmоl〜約150μmоlであり、関節注射1回分あたりのリン脂質の総量が150μmolを超える医薬組成物の有効性と比較して、医薬組成物の有効性が増強される、関節痛治療用の関節注射剤の製造のための医薬組成物の使用が提供される。
以下の用語は、上記及び本開示全体を通して使用されるように、特に明記しない限り、以下の意味を有すると理解されるべきである。
一実施形態において、本開示は、1種または複数種のリン脂質を含む脂質混合物と、有効量の治療剤またはその薬学的に許容される塩とを含む医薬組成物であって、医薬組成物中における1種または複数種のリン脂質の総量が、医薬組成物1mLあたり約20μmоlから約150μmоlである医薬組成物が提供される。
ここで提供される医薬組成物の脂質混合物とは、リン脂質またはリン脂質の混合物を指す。脂質混合物は、医薬組成物に添加される前に、フィルム、ケーキ、顆粒または粉末の形態であってもよいが、これらに限定されない。
治療剤は、ステロイド、インドメタシンなどの非ステロイド性抗炎症薬(NS AID)、疾患修飾性抗リウマチ薬(DMARD)、またはこれらの内の2種以上の組み合わせの他、これらの内の1種または複数種と本明細書に特に記載されていない他の成分または化合物との組み合わせであることができる。DMARDには、メトトレキサート、レフルノミド、スルファサラジン、シクロホスファミド、アザチオプリン、シクロスポリンA、d−ペニシラミン、抗マラリア薬(ヒドロキシクロロキンなど)などの低分子薬剤が含まれる。また、DMARDには生物学的物質も含まれ、例えば、腫瘍壊死因子a(TNF−a)アンタゴニスト(例えば、米国カレッジビルにあるワイス社から商品名エンブレルとして市販されているエタネルセプト、米国イリノイ州アボットパークにあるアボット・ラボラトリーズ社から商品名ヒュミラとして市販されているアダリムマブ)、インターロイキン―1受容体拮抗薬、インターロイキン―6受容体拮抗薬、抗CD20モノクローナル抗体、CTLA−4−Ig、RGDペプチドなどが挙げられる。
医薬組成物は、治療対象疾患に対して適切な期間にわたって、単回または複数回投与され得る。医薬組成物は、利便性を考慮した上で、適切な間隔、例えば、1週間ごと、2週間ごと、6週間ごと、1ヶ月ごと、2ヶ月ごと、3ヶ月またはそれ以上の期間ごと、6ヶ月またはそれ以上の期間ごとに1回の間隔で投与してよく、あるいは疾患(即ち関節痛)の症状と徴候が寛解するまで投与してもよい。
本開示の一態様は、以下の方法の提供に向けたものであり、即ち、対象における関節痛を治療する方法であって、本明細書に記載の医薬組成物の有効量を、関節痛の治療を必要とする対象に投与することを含み、それによって、治療剤によって誘発される副作用が、即時放出または標準的な治療薬製剤の投与後の対象における副作用と比較して低減されること、及び、医薬組成物の治療剤の有効性及び放出速度が、医薬組成物1mLあたり約150μmоl以上のリン脂質を含む医薬組成物の有効性及び放出速度と比較して増大されることとの少なくともいずれかが達成される。一実施形態において、対象者は、変形性関節症、関節リウマチ、急性痛風関節炎、乾癬性関節炎、反応性関節炎、または、エーラス-ダンロス症候群、ヘモクロマトーシス、肝炎、ライム病、シェーグレン病、橋本甲状腺炎、セリアック病、非セリアックグルテン過敏症、炎症性腸疾患、ヘノッホ・ショーンライン紫斑病、再発性熱を伴うD型高免疫グロブリン血症、サルコイドーシス、ウィップル病、TNF受容体関連周期性症候群、多発性血管炎を伴う肉芽腫症、家族性地中海熱、全身性エリテマトーデスに起因する関節炎を患った患者である。
DOPC、DOPG及びコレステロールを含む脂質を67.5:7.5:25のモル%で配合し、フラスコ内で約40℃の99.9%エタノールに溶解して脂質溶液を形成した。脂質の溶解には、卓上型超音波浴処理機を使用した。
本開示による医薬組成物は、実施例1に記載された脂質混合物を、DSP溶液と混合することによって調製されたものである。DSP溶液は、13.2mg/mLのデキサメタゾンリン酸ナトリウム(DSP)(C22H28FNa2O8P、分子量516.41g/L)及び4mg/mLのクエン酸ナトリウムを含むDSP溶液である。これにより調整された医薬組成物は、DSP医薬組成物として以下で用いられ、その1mLあたりのDSP及びリン脂質の含量は、それぞれ約12.0mg/mL及び90μmolであった。
第II相の用量設定臨床環境でインビトロ放出試験を実施した。実施例2の医薬組成物を異なるDSP用量でヒト合成滑液(hsSF)に注入し、各時点でDSPの放出量を測定した。
ヒト合成滑液の組成を表1に示した。簡単に説明すると、ウシ血清アルブミン(BSA)を30mg/mLの濃度になるように0.9%の生理食塩水で溶解した。1%のヒアルロン酸(HA、Mw=1.35×106Da)をBSA溶液に加え、ヒアルロン酸が完全に溶解するように、混合物を室温で2時間、穏やかに撹拌した。この溶液のpHは7.3であった。ヒトの合成滑液には、細菌の増殖を抑制するため0.2%のアジ化ナトリウムを加えた。
DSP医薬組成物のリポソームからのDSPの放出は、異なる時間間隔での封入効率の変化を検出することにより測定した。簡単に言うと、様々な量のDSP医薬組成物を、所定の温度(37℃)の合成滑液に懸濁し、撹拌棒を用いて150rpmで撹拌した(表2)。適切な時間間隔で、懸濁液を回収し、SPEカラムを介して懸濁液を溶出させて遊離DSPを回収し、以下のような手順で封入効率を測定した。
SPEカートリッジを用いてリポソームから遊離DSPを分離した後、採取したサンプルの封入効率の吸光度を測定した。SPEカラムは、1mLのメタノールで湿らせてから更に1mLの蒸留水で湿らせて使用に供された。その後、1mLの生理食塩水でカラムを平衡化してから、回収した懸濁液を充填した。懸濁液を充填した後、SPEカラムを3mLの蒸留水で洗浄し、2mLの溶出緩衝液(2MNH4OAc/MeOH/ACN=2/9/9(v/v)を含む)で遊離DSPを溶出した。遊離DSPを含む溶出画分を、UV-vis分光光度計を用いて240nmでモニターした。封入効率(%)は、[1-(Ifree/12)]×100として計算した。式中、12はサンプル溶液中のDSPの理論値(mg/mL)であり、Ifreeは遊離DSP濃度である。
台湾の台北市にある3箇所の治験地で、12週間にわたる無作為オープンラベル、並行、単回投与の第I/II相治験を実施した。治験デザインの模式図が図2に示されている。本治験は、各治験地で被験者を募集するにあたって、事前に各治験地における治験審査委員会の承認を得た。本治験は、米国CFR21章パート312.20、ヘルシンキ宣言、及びICH(International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use、医薬品規制調和国際会議)の臨床治験ガイドラインに規定された原則に準拠して実施された。治験プロトコルは、ClinicalTrial.gov(NCT02803307)に登録されている。本治験に参加してもらうにあたって、すべての患者から書面によるインフォームドコンセントを得た。
本治験のサンプルサイズは、事前に設定した検定力の想定により決定されたものではない。本治験では、計40名の変形性膝関節症の患者の登録が計画された。すべての統計的評価は両側評価とし、有意水準0.05で評価した。欠損データ(早期中止によるものを含む)はインプットされなかった。連続評価項目(血漿コルチゾールの安全性評価、WOMAC指標、VASスコア)については、観察回数、平均値、中央値、標準偏差、最小値、最大値などの記述統計を、ベースラインからの変化とともに生データに示した。また、連続変数については、治療群の間の差を比較するためにウィルコクソンの順位和検定(Wilcoxon rank sum test)を用いて分析し、ベースラインからの変化を比較するためにウィルコクソンの符号順位検定(Wilcoxon signed-rank test)を用いた。分類別評価項目(IGART、WOMAC及びVASにおいてベースラインから30%または50%以上の減少を達成した患者数)については、回数及びパーセンテージを用いた。群の間の差を比較するために、カイ二乗検定を実施し、データが少ない場合はフィッシャーの正確検定を適用した。すべての統計解析は、SAS(登録商標)ソフトウェア(SAS System for Windows 7、バージョン9.3)を用いて行った。本研究では、安全性の解析には安全性集団を用い、有効性の解析には治療企図(ITT、intent-to-treat)集団とパープロトコル(PP、per-protocol)集団を用いた。安全性集団は、DSP医薬組成物を任意の用量で投与されたすべての被験者と定義した。ITT集団は、DSP医薬組成物を総量で少なくとも1回投与され、ベースライン後に有効性評価を少なくとも1回受けた被験者と定義した。PP集団は、ITT集団の中で、主要なプロトコル逸脱・違反がなかった全ての被験者と定義した。40名の被験者全員が安全性集団とITT集団に含まれた。A群の6名とB群の7名を含む13名の被験者がPP集団に含まれた。主な結論は、PP集団に基づいている。
本研究では、計46名の対象者がスクリーニングされ、そのうち6名はスクリーニング失敗であった。40名が被験者として本研究に登録され、そのうち39名が適格基準を満たした。この他、スクリーニング前の6ヵ月以内に変形性膝関節症と診断された被験者が更に1名登録された。被験者は20名ずつのA群とB群に無作為に分けられ、それぞれ関節内注射1回分につき45μmоlのリン脂質を含む6mgのDSPと、90μmоlのリン脂質を含む12mgのDSPが投与された。被験者の処置の概要を図3に、被験者のデモグラフィック情報を表4に示す。
実施例5.変形性膝関節症患者におけるDSP医薬組成物の有効性の比較分析
実施例6.変形性関節症の動物モデルにおけるDSP医薬組成物中の脂質含有量の効果の評価
Claims (35)
- 治療剤を関節に送達するための医薬組成物であって、
(a)1種または複数種のリン脂質を含む脂質混合物と、
(b)有効量の治療剤またはその薬学的に許容される塩と、を含み、
前記1種または複数種のリン脂質の総量が、前記医薬組成物1mLあたり約20μmоlから約150μmоlである、医薬組成物。 - 前記治療剤がステロイドである、請求項1に記載の医薬組成物。
- 前記治療剤が関節内コルチコステロイドである、請求項1に記載の医薬組成物。
- 前記治療剤が、デキサメタゾンリン酸ナトリウム、デキサメタゾン、ベタメタゾン、ベタメタゾンリン酸ナトリウム、酢酸ベタメタゾン、ジプロピオン酸ベタメタゾン、吉草酸ベタメタゾン、フロ酸モメタゾン、トリアムシノロンアセトニド、トリアムシノロンヘキサセトニド、トリアムシノロンヘキサセトニド、二酢酸トリアムシノロン、コハク酸メチルプレドニゾロンナトリウム、酢酸メチルプレドニゾロン、テブト酸プレドニゾロン、酢酸ヒドロコルチゾン、ジプロピオン酸アルクロメタゾン、ハルシノニド、フルオコルトロン、フルオシノロンアセトニド、またはこれらの組み合わせである、請求項1に記載の医薬組成物。
- 前記ステロイドがデキサメタゾンリン酸ナトリウムである、請求項2に記載の医薬組成物。
- デキサメタゾンリン酸ナトリウムが、医薬組成物1mLあたり約6mg〜約18mgの範囲の量で存在する、請求項5に記載の医薬組成物。
- デキサメタゾンリン酸ナトリウムが、医薬組成物1mLあたり約6mg〜約12mgの範囲の量で存在する、請求項5に記載の医薬組成物。
- デキサメタゾンリン酸ナトリウムが、医薬組成物1mLあたり約12mgの量で存在する、請求項5に記載の医薬組成物。
- 前記脂質混合物が、コレステロールを更に含む、請求項1に記載の医薬組成物。
- 前記脂質混合物が、ジオレオイルホスファチジルコリン(DOPC)及びジオレオイルホスファチジルグリセロール(DOPG)を含む、請求項1に記載の医薬組成物。
- 前記1種または複数種のリン脂質の総量が、医薬組成物1mLあたり約30μmоl〜約140μmоlの範囲である、請求項1〜請求項10のいずれか一項に記載の医薬組成物。
- 前記1種または複数種のリン脂質の総量が、医薬組成物1mlあたり約45μmоl〜約135μmоlの範囲である、請求項1〜請求項10のいずれか一項に記載の医薬組成物。
- 前記1種または複数種のリン脂質の総量が、医薬組成物1mlあたり約50μmоl〜約120μmоlの範囲である、請求項1〜請求項10のいずれか一項に記載の医薬組成物。
- 前記1種または複数種のリン脂質の総量が、医薬組成物1mlあたり約60μmоl〜約110μmоlの範囲である、請求項1〜請求項10のいずれか一項に記載の医薬組成物。
- 前記1種または複数種のリン脂質の総量が、医薬組成物1mlあたり約70μmоl〜約100μmоlである、請求項1〜請求項10のいずれか一項に記載の医薬組成物。
- 関節痛治療用の関節注射剤の製造のための医薬組成物の使用であって、前記医薬組成物は、
(a)1種または複数種のリン脂質からなる脂質混合物と、
(b)有効量の治療剤またはその薬学的に許容される塩と、を含み、
関節注射1回分あたりの前記1種または複数種のリン脂質の総量が約20μmоl〜約150μmоlであり、関節注射1回分あたりの1種または複数種のリン脂質の総量が150μmolを超える医薬組成物の有効性と比較して、医薬組成物の有効性が増強される、関節痛治療用の関節注射剤の製造のための医薬組成物の使用。 - 前記治療剤がステロイドである、請求項16に記載の使用。
- 前記治療剤が関節内コルチコステロイドである、請求項16に記載の使用。
- 前記治療剤が、デキサメタゾンリン酸ナトリウム、デキサメタゾン、ベタメタゾン、ベタメタゾンリン酸ナトリウム、酢酸ベタメタゾン、ジプロピオン酸ベタメタゾン、吉草酸ベタメタゾン、フロ酸モメタゾン、トリアムシノロンアセトニド、トリアムシノロンヘキサセトニド、トリアムシノロンヘキサセトニド、二酢酸トリアムシノロン、コハク酸メチルプレドニゾロンナトリウム、酢酸メチルプレドニゾロン、テブト酸プレドニゾロン、酢酸ヒドロコルチゾン、ジプロピオン酸アルクロメタゾン、ハルシノニド、フルオコルトロン、フルオシノロンアセトニド、またはこれらの組み合わせである、請求項16に記載の使用。
- 前記ステロイドがデキサメタゾンリン酸ナトリウムである、請求項17に記載の使用。
- デキサメタゾンリン酸ナトリウムが、関節注射1回分あたり約6mg〜約18mgの範囲の量で存在する、請求項20に記載の使用。
- デキサメタゾンリン酸ナトリウムが、関節注射1回分あたり約12mgの量で存在する、請求項20に記載の使用。
- 前記脂質混合物が、コレステロールを更に含む、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記脂質混合物が、DOPC及びDOPGを含む、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記1種または複数種のリン脂質の総量が、関節注射1回分あたり約30μmоl〜約140μmоlの範囲である、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記1種または複数種のリン脂質の総量が、関節注射1回分あたり約45μmоl〜約135μmоlの範囲である、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記1種または複数種のリン脂質の総量が、関節注射1回分あたり約50μmоl〜約120μmоlの範囲である、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記1種または複数種のリン脂質の総量が、関節注射1回分あたり約60μmоl〜約110μmоlの範囲である、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記1種または複数種のリン脂質の総量が、関節注射1回分あたり約90μmоlである、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記有効性が、関節痛、圧痛、一過性の朝のこわばり、関節運動時のクレピタス音から選択される少なくとも1つの臨床的徴候の軽減を指す、請求項16〜請求項22のいずれか一項に記載の使用。
- 前記医薬組成物は、関節痛が消失するまで、1週間ごと、2週間ごと、6週間ごと、1ヶ月ごと、2ヶ月ごと、3ヶ月またはそれ以上の期間ごと、6ヶ月またはそれ以上の期間ごとに1回投与される、請求項16〜請求項22のいずれか一項に記載の使用。
- 関節痛の治療を要する対象に、請求項1〜請求項15のいずれか一項に記載の医薬組成物の有効量を関節内に投与することを含む、関節痛を治療する方法
- 前記関節痛が関節炎によるものである、請求項32に記載の方法。
- 前記関節炎が、乾癬、反応性関節炎、または、エーラス-ダンロス症候群、ヘモクロマトーシス、肝炎、ライム病、シェーグレン病、橋本甲状腺炎、セリアック病、非セリアックグルテン過敏症、炎症性腸疾患、ヘノッホ・ショーンライン紫斑病、再発性熱を伴うD型高免疫グロブリン血症、サルコイドーシス、ウィップル病、TNF受容体関連周期性症候群、多発性血管炎を伴う肉芽腫症、家族性地中海熱、全身性エリテマトーデスに起因する関節炎である、請求項33に記載の方法。
- 前記医薬組成物を、関節痛が消失するまで、1週間ごと、2週間ごと、6週間ごと、1ヶ月ごと、2ヶ月ごと、3ヶ月またはそれ以上の期間ごと、6ヶ月またはそれ以上の期間ごとに1回投与する、請求項32に記載の方法。
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