JP2020189870A - 関節を治療するための組成物及びキット - Google Patents
関節を治療するための組成物及びキット Download PDFInfo
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- JP2020189870A JP2020189870A JP2020136685A JP2020136685A JP2020189870A JP 2020189870 A JP2020189870 A JP 2020189870A JP 2020136685 A JP2020136685 A JP 2020136685A JP 2020136685 A JP2020136685 A JP 2020136685A JP 2020189870 A JP2020189870 A JP 2020189870A
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- glucosamine
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- chondroitin sulfate
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Abstract
Description
ヒアルロン酸(HA)には様々な処方があり得、ヒアルロン酸(HA)を様々な濃度及び分子量で提供することができる。用語「ヒアルロン酸」、「ヒアルロナン」、「ヒアルロネート」及び「HA」は、本明細書では、ヒアルロン酸、又はヒアルロン酸の塩、例えば、数ある中でもナトリウム、カリウム、マグネシウム及びカルシウム塩を指すために交換可能に用いている。これらの用語は、純粋なヒアルロン酸溶液ばかりでなく、他の微量元素を有するヒアルロン酸、又は他の元素を有する様々な組成でのヒアルロン酸も含むことも意図したものである。用語「ヒアルロン酸」、「ヒアルロナン」及び「HA」は、HAの化学的誘導体、又は高分子誘導体、又は架橋誘導体を包含する。HAに対して行うことがある化学的修飾の例としては、作用物質と、HAの4つの反応性基、すなわちアセトアミド、カルボキシル、ヒドロキシル及び還元末端との任意の反応が挙げられる。本明細書に開示するHAは、(動物組織から単離される)天然製剤、又は(細菌発酵から得られる)合成製剤、又はこれらの組み合わせを含むことを意図したものである。HAを液体形態で、又は適切な濃度を達成するように希釈剤で再構成される固体製剤で、提供することができる。
グルコサミン(C6H13NO5)(「GlcN」)又はその誘導体も、ヒアルロナンの生成に必要な反応物とプロテオグリカンに必要な反応物の両方を供給することにより軟骨及び滑液の重要な成分の合成を増進させるために、前記製剤に含めることができる。GlcNは、4つのヒドロキシル基と1つのアミノ基とを有するアミノ糖であり、グリコシル化タンパク質及び脂質の生化学合成での有名な前駆体である。GlcNは、栄養機能及びエフェクター機能を有する、天然に存在する分子である。本明細書で用いる用語「グルコサミン」は、グルコサミン塩、例えばグルコサミン塩酸塩及びグルコサミン硫酸はもちろん、非塩形態、例えばN−アセチルグルコサミンも含む。一実施形態では、グルコサミン塩酸塩を前記製剤に含める。
軟骨の必須成分であるコンドロイチン硫酸(CS)は、交互にβ(1,3)結合とβ(1,4)結合によって連結されている硫酸化及び/又は非硫酸化D−グルクロン酸(GlcA)残基とN−アセチル−D−ガラクトサミン(GalNAc)残基の交互配列からなる。これらの化合物は、二糖単位の約40〜100回の繰り返しから主としてなる高分子構造を各々が有する。CSを様々な分子量及び濃度で本発明の製剤に使用することができる。CSは、ウシ又は海産物源から単離することができる。コンドロイチン鎖は、100を越える個々の糖を有することができ、それらの糖の各々が様々な位置及び量で硫酸化されていることがある。コンドロイチン−4硫酸、またN−アセチルガラクトサミン(GalNAc)糖の4位炭素の硫酸化物(carbon 4)は、ウシ及びブタの鼻及び気管軟骨中で見つけられる。コンドロイチン−4硫酸は、これらの動物の骨、肉、血液、皮膚、臍帯及び尿中でも見つけられる。コンドロイチン−6硫酸、またGalNAc糖の6位炭素の硫酸化物(carbon 6)は、これらの動物の皮膚、臍帯及び心臓弁から単離されている。コンドロイチン−6硫酸は、コンドロイチン−4硫酸と同じ組成を有するが、物理的特性がわずかに異なる。コンドロイチン硫酸はコラーゲンの結合に関与し、水分の保持にも直接関与する。これらは両方とも、治癒過程を補助する特性である。用語「コンドロイチン硫酸(sulfate)」、「CS」、「コンドロイチン」、「コンドロイチン硫酸(sulfuric acid)」及び「コンスリド」を本明細書では交換可能に用いていること、及びこれらの用語が本明細書を通して化学的誘導体又は異性誘導体又は架橋誘導体も包含することは、当業者には理解されるであろう。
例示的実施形態では、本明細書に開示する組成物及び方法に少なくとも1つの追加成分を加えることができる。本発明の組成物及び方法が、例えばアミノ酸類、タンパク質類、糖類、二糖類、多糖類、脂質類、核酸、緩衝剤、界面活性剤及びこれらの混合物をはじめとする、様々な他の関節治療成分を含むことができることは、当業者には理解されるであろう。他の有用な成分としては、ステロイド、抗炎症剤、非ステロイド性抗炎症剤、鎮痛剤、細胞、抗生物質、抗菌剤、抗炎症剤、増殖因子、増殖因子断片、小分子創傷治癒刺激剤、ホルモン剤、サイトカイン、ペプチド、抗体、酵素、単離細胞、血小板、免疫抑制剤、核酸、細胞タイプ、ウイルス、ウイルス粒子、必須栄養素又はビタミン、及びこれらの組み合わせを挙げることができる。
本発明の組成物及び方法に存在する任意の1つ又はそれ以上の成分を、当技術分野において公知の様々な技術を用いて凍結乾燥することができる。凍結乾燥は、腐敗しやすい材料の保存に概して使用される脱水法であり、その材料を凍結させた後、周囲圧力を低下させ、十分な熱を加えてその材料中の凍結水を固相から気相に直接昇華させることにより機能する。当技術分野において公知の標準的な凍結乾燥技術を用いて、前記成分のいずれか1つ又はそれ以上を凍結乾燥させることができる。例示的実施形態では、グルコサミンとコンドロイチン硫酸を一緒に混合物で凍結乾燥させるか、又は別々に凍結乾燥させる。別の実施形態では、ヒアルロン酸を凍結乾燥させる。別の実施形態では、グルコサミンとコンドロイチン硫酸とヒアルロン酸を一緒に混合物で凍結乾燥させるか、又は別々に凍結乾燥させる。
凍結:15分間で周囲温度から5℃に
100分間5℃で保持する
50分間で−45℃に低下させる
180分間、−45℃で保持する
一次乾燥:圧力を7Pa(50mTorr)に設定する
175分間放置して−15℃にする
2300分間、−15℃で保持する
二次乾燥:圧力を10Pa(75mTorr)に設定する
200分間放置して25℃にする
900分保持する
サイクル終了:約97kPa(約730Torr)になるまで窒素を再充填する
キャップし、圧着させる
HAは、単独で関節の病状の治療に有効であり得るが、本明細書に記載する組成物及び製剤は、関節の病状の治療に対する改善されたアプローチを提供する。
本発明の組成物を、インビボ利用のために、非経口的に注射により又は時間をかけて緩徐灌流により投与することができる。投与は、関節内、静脈内、腹腔内、筋肉内、皮下、腔内又は経皮投与であり得る。
前記方法及び組成物は、継手など関節の障害を治療するためのキットを包含する。さらに別の態様では、キットを開示する。このキットは、ヒアルロン酸(HA)の溶液である第一の構成要素と、ある量のグルコサミン及びコンドロイチン(GlcN/CS)を含む第二の構成要素と、前記第一の構成要素と前記第二の構成要素の混合物を注射するための注射器とを備えることができる。さらに、注射器は、第一の構成要素を収容している第一のチャンバと;第二の構成要素を収容している第二の容器と;第二の構成要素を第一のチャンバに圧入して第一の構成要素と第二の構成要素を混合するように構成されたプランジャとを有することができる。
実施例1:液体/液体製剤
8.7mg/mLのグルコサミン(塩酸塩として)と8.7mg/mLのコンドロイチン硫酸とを含有するGlcN/CNの保存溶液を調製した。関節内注射直前に、おおよそ103uLのこの保存溶液を、15mg/mLのHA濃度を有する400uLのオルトビスク(登録商標)(高分子量ヒアルロン酸)と組み合わせた。三方活弁を使用してこれら2溶液の注射器間混合を行った。得られた溶液は、12mg/mL HA、1.8mg/mL GlcN、及び1.8mg/mL CSを含有した。その溶液を、関節内注射用のより小さい注射器に等分した。注射容量は、ラット研究については約50uLであった。
4mgのGlcN及び4mgのCSを無菌バイアルの中で凍結乾燥させた。注射直前に、2mL又は15mg/mL HAをその凍結粉末バイアルに注入し、完全混合が果たされるまでボルテックスにかけた。得られた溶液は、15mg/mL HA、2mg/mL CS及び2mg/mL GlcNを含有した。その溶液を、関節内注射用のより小さい注射器に等分した。
無菌関節内HA/GlcN/CS製剤をラット内側半月板断裂(MMT)モデルで試験した。このモデルにおける内側半月板の処理は、ヒト変形性関節症によく似ている関節悪化及び体重負荷低減をもたらす。この変性プロセスは数週間にわたって起こり、21日目には有意な変性が顕性になる。
HA/GlcN/CS=12mg/mL/0.18mg/mL/0.18mg/mL(「0.18mg/mL HA/GlcN/CS群/製剤」)
HA/GlcN/CS=12mg/mL/1.8mg/mL/1.8mg/mL(「1.8mg/mL HA/GlcN/CS群/製剤」)
HA/GlcN/CS=12mg/mL/18.0mg/mL/18.0mg/mL(「18.0mg/mL HA/GlcN/CS群/製剤」)
HA/CS=12mg/mL/0.18mg(「0.18mg/mL HA/CS群/製剤」)
HA/CS=12mg/mL/1.8mg(「1.8mg/mL HA/CS群/製剤」)
HA/CS=12mg/mL/18.0mg(「18mg/mL HA/CS群/製剤」)
HA=12mg/mL
したがって、HAの濃度は市販の関節内補充薬に近いレベルで一定に保ったが、グルコサミン及びコンドロイチン硫酸の濃度は変化させた。本考察について、0.18、1.8及び18.0mg/mL表示は、HAと併用でのGlcN及びCSの濃度を指す。これらの製剤に使用したHAは、1.0〜2.9百万ダルトンの分子量範囲指定を有した。
OAが炎症性成分を有することは今では公知であるので、炎症性関節炎を模倣する動物モデルを使用してHA/GlcN/CS製剤を試験した。完全フロイントアジュバント(CFA)は、重度の炎症を誘導するために全身注射又はラットの関節に注射される死菌細胞のエマルジョンを含む。2種類のCFA研究、すなわち、200uL CFA注射を用いて炎症を誘導する第一の研究(CFA#1)、100uLの注射容量を使用する第二の研究(CFA#2)を行った。上で説明した液体/液体製剤方を用いて被験物を調製した。
関節炎のPGPSモデルを使用して、関節の一過性炎症を刺激する。PGPS(ペプチドグリカン多糖類)は、有痛炎症応答を生じさせる結果となる、被験体の関節に直接注射さる連鎖球菌細胞壁製剤である。連続FCA応答とは異なり、PGPSからの炎症性疼痛は一過性であり、概して数日しか続かない。関節へのこの「プライミング」注射後に続いて行う全身性注射は、前に注射を受けた関節において炎症フレアを数日にわたって生じさせる。「再燃」炎症フレアは、何度も繰り返されることがあり、その後の再燃サイクルに伴ってその炎症性疼痛は一般に減少する。或いは、関節を初回再燃後に「再プライミング」して、その後の再燃の際により堅固な炎症応答を生じさせることができる。
HA=15mg/mL
HA/CS=15mg/mL/20mg/mL(「OV/CS 15/20」)
HA/CS=15mg/mL/2mg/mL(「OV/CS 15/2」)
HA/GlcN/CS=15mg/mL/2mg/mL/2mg/mL(「OV/CS/GlcN 15/2/2」)
用量2=用量1[(体重2)**0.75/(体重1)**0.75]
(式中、用量2=ヒト用量、及び用量2=ラット用量)。典型的なラット及びヒト体重は、それぞれ、0.3及び70kgである。例えば、ラットでの1mgの用量をヒト投与に外挿して、相対生長率により次のことが予測される:
用量2=(2mg)*[(70kg)**0.75/(0.3kg)**0.75]=59.7mg
(1) 関節を治療するための組成物であって、
ヒアルロン酸(HA)と、グルコサミンと、コンドロイチン硫酸とを含む注射製剤を含み、前記注射製剤が、約3〜5の範囲のpH、及び約330〜750mOSMの範囲の重量オスモル濃度を有する、組成物。
(2) グルコサミンが、約0.005〜54mg/mLの濃度で存在する、実施態様1に記載の組成物。
(3) コンドロイチン硫酸が、約0.005〜54mg/mLの濃度で存在する、実施態様1に記載の組成物。
(4) HAが、約3.6〜36mg/mLの濃度で存在する、実施態様1に記載の組成物。
(5) グルコサミン及びコンドロイチン硫酸が、約1:1の重量比で存在する、実施態様1に記載の組成物。
(7) グルコサミンが、約18〜20mg/mLの濃度で存在し、
コンドロイチン硫酸が、約18〜20mg/mLの濃度で存在し、
HAが、約12〜17.5mg/mLの濃度で存在し、
前記pHが、約3.5〜4の範囲であり、かつ、
前記重量オスモル濃度が、約600〜650mOSMの範囲である、実施態様1に記載の組成物。
(8) 関節を治療する方法であって、
治療有効量の製剤を対象の関節に注射することを含み、前記製剤が、ヒアルロン酸(HA)とグルコサミンとコンドロイチン硫酸とを含み、3〜5のpH及び330〜750mOSMの重量オスモル濃度を有する、方法。
(9) 注射前約30分未満に前記HAを前記グルコサミンとコンドロイチン硫酸の混合物と組み合わせて前記製剤を形成することをさらに含む、実施態様8に記載の方法。
(10) グルコサミンが、約0.005〜54mg/mLの範囲で前記製剤中に存在する、実施態様8に記載の方法。
(12) HAが、約3.6〜36mg/mLの範囲で前記製剤中に存在する、実施態様8に記載の方法。
(13) グルコサミン及びコンドロイチン硫酸が、約1:1の比で前記製剤中に存在する、実施態様8に記載の方法。
(14) 前記製剤が、トレハロースをさらに含む、実施態様8に記載の方法。
(15) グルコサミンが、約18〜20mg/mLの範囲で前記製剤中に存在し、
コンドロイチン硫酸が、約18〜20mg/mLの範囲で前記製剤中に存在し、
HAが、約12〜17.5mg/mLの範囲で前記製剤中に存在し、
前記pHが、約3.5〜4の範囲であり、かつ、
前記重量オスモル濃度が、約600〜650mOSMの範囲である、実施態様8に記載の方法。
ヒアルロン酸(HA)、並びに、前記HAとは別にグルコサミン及びコンドロイチン硫酸を備えており、前記HAとグルコサミンとコンドロイチン硫酸を組み合わせることにより、約3〜5の範囲のpH及び約330〜750mOSMの範囲の重量オスモル濃度を有する製剤が形成されるものであり、かつ、
前記製剤を関節に注射するための注射器を備えている、キット。
(17) 前記注射器が、
前記HAを収容している第一のチャンバと、
前記グルコサミン及びコンドロイチン硫酸を収容しており、前記第一のチャンバと流体連通している、第二のチャンバと、
前記グルコサミン及びコンドロイチン硫酸を第二の容器から第一の容器に移動させて、前記HAとグルコサミンとコンドロイチン硫酸とを組み合わせ、前記製剤を形成するように構成されたプランジャと
を備えている、実施態様16に記載のキット。
(18) グルコサミンが、約0.005〜54mg/mLの濃度を有する、実施態様16に記載のキット。
(19) コンドロイチン硫酸が、約0.005〜54mg/mLの濃度を有する、実施態様16に記載のキット。
(20) HAが、約3.6〜36mg/mLの濃度を有する、実施態様16に記載のキット。
Claims (15)
- 関節を治療するための組成物であって、
ヒアルロン酸(HA)と、グルコサミンと、コンドロイチン硫酸とを含む注射製剤を含み、前記注射製剤が、約3〜5の範囲のpHを有する、組成物。 - 前記注射製剤が、約330〜750mOSM/kgの範囲の重量オスモル濃度を有する、請求項1に記載の組成物。
- グルコサミンが、約0.005〜54mg/mLの濃度で存在する、請求項1または2に記載の組成物。
- コンドロイチン硫酸が、約0.005〜54mg/mLの濃度で存在する、請求項1〜3のいずれか一項に記載の組成物。
- HAが、約3.6〜36mg/mLの濃度で存在する、請求項1〜4のいずれか一項に記載の組成物。
- グルコサミン及びコンドロイチン硫酸が、約1:1の重量比で存在する、請求項1〜5のいずれか一項に記載の組成物。
- トレハロースをさらに含む、請求項1〜6のいずれか一項に記載の組成物。
- グルコサミンが、約18〜20mg/mLの濃度で存在し、
コンドロイチン硫酸が、約18〜20mg/mLの濃度で存在し、
HAが、約12〜17.5mg/mLの濃度で存在し、
前記pHが、約3.5〜4の範囲であり、かつ、
前記重量オスモル濃度が、約600〜650mOSM/kgの範囲である、請求項2に記載の組成物。 - 溶液の形態である、請求項1〜8のいずれか一項に記載の組成物。
- 関節を治療するためのキットであって、
ヒアルロン酸(HA)、並びに、前記HAとは別にグルコサミン及びコンドロイチン硫酸を備えており、前記HAとグルコサミンとコンドロイチン硫酸を組み合わせることにより、約3〜5の範囲のpHを有する製剤が形成されるものであり、かつ、
前記製剤を関節に注射するための注射器を備えている、キット。 - 形成される前記製剤は、約330〜750mOSM/kgの範囲の重量オスモル濃度を有する、請求項10に記載のキット。
- 前記注射器が、
前記HAを収容している第一のチャンバと、
前記グルコサミン及びコンドロイチン硫酸を収容しており、前記第一のチャンバと流体連通している、第二のチャンバと、
前記グルコサミン及びコンドロイチン硫酸を第二の容器から第一の容器に移動させて、前記HAとグルコサミンとコンドロイチン硫酸とを組み合わせ、前記製剤を形成するように構成されたプランジャと
を備えている、請求項10または11に記載のキット。 - 形成される前記製剤において、グルコサミンが、約0.005〜54mg/mLの濃度を有する、請求項10〜12のいずれか一項に記載のキット。
- 形成される前記製剤において、コンドロイチン硫酸が、約0.005〜54mg/mLの濃度を有する、請求項10〜13のいずれか一項に記載のキット。
- 形成される前記製剤において、HAが、約3.6〜36mg/mLの濃度を有する、請求項10〜14のいずれか一項に記載のキット。
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AU2015275237A1 (en) | 2016-08-04 |
EP3053604A1 (en) | 2016-08-10 |
JP7443443B2 (ja) | 2024-03-05 |
EP3053604B1 (en) | 2018-10-17 |
US10532069B2 (en) | 2020-01-14 |
US20170266221A1 (en) | 2017-09-21 |
AU2015275237B2 (en) | 2020-11-12 |
CA2918048A1 (en) | 2016-07-20 |
CN105796589A (zh) | 2016-07-27 |
BR102016000829A2 (pt) | 2016-08-02 |
US9682099B2 (en) | 2017-06-20 |
JP2022168118A (ja) | 2022-11-04 |
JP2016132669A (ja) | 2016-07-25 |
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