JP2017513821A - 関節障害の処置のために使用される生分解性ポリエステルアミド - Google Patents
関節障害の処置のために使用される生分解性ポリエステルアミド Download PDFInfo
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Abstract
Description
(式中、
− mは、0.01〜0.99の間で変動し;pは、0.99〜0.01の間で変動し;かつqは、0.99〜0.01の間で変動し;
− nは、5〜100の間で変動し、
− R1は、(C2〜C20)アルキレンおよびそれらの組み合わせからなる群から独立して選択され;
− それぞれ単一主鎖単位mまたはpの中にあるR3およびR4は、水素、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C6〜C10)アリール(C1〜C6)アルキル、−(CH2)SH、−(CH2)2S(CH3)、−CH2OH、−CH(OH)CH3、−(CH2)4NH3+、−CH2COOH、−CH2−CO−NH2、−CH2CH2−CO−NH2、−CH2CH2COOH、CH3−CH2−CH(CH3)−、(CH3)2−CH−CH2−、H2N−(CH2)4−、フェニル−CH2−、−CH=CH−CH3、HO−p−フェニル−CH2−、(CH3)2−CH−、フェニル−NH−、NH2−(CH2)3−CH2−またはNH2−CH=N−CH=C−CH2−からなる群から独立して選択され、
− R5は、(C2〜C20)アルキレン、(C2〜C20)アルケニレンからなる群から選択され、
− R6は、構造式(II)
の1,4:3,6−ジアンヒドロヘキシトールの二環式断片から選択され;
− R7は、水素、(C6〜C10)アリール、(C1〜C6)アルキルまたは保護基(例えば、ベンジル)であり;
− R8は、独立して、(C1〜C20)アルキレンである)
を含む、ランダムコポリマーである。
− PGE−2濃度を自然な状態(コントロール−実験)で産生されるレベルと比較する。
− TnF−αの存在は、軟骨細胞からのPGE−2の産生を、300%に増加させる(実験コントロール+)。
− 空粒子の存在は、コントロール+実験と比較して、軟骨細胞からのPGE−2の産生に影響を与えない。
− 0.1μMのTAAが軟骨細胞によるPGE−2の産生を停止させる。これは、トリアムシノロンアセトニドが炎症を軽減することを示している。
− TAA配合微粒子と共にインキュベートされる軟骨細胞は、PGE−2を産生しない。この条件は、ヒト軟骨細胞の炎症をTnF−αにより刺激される場合でさえも制限する活性薬剤を、微粒子が放出することを明らかにする。
− PEA−III−Bzポリマーを、以下の実施例で使用する。PEA−III−Bzのより詳細な説明は、ポリ−8−[(L−Leu−DAS)0.45(L−Leu−6)0.3−[L−Lys(Bz)]0.25である。構造を式IIIに示す。割合は、スキーム1に示される合成における各モノマーの全体的な割合を示す。
− PEA−I−Bzポリマーが、PEA−III−Bz微粒子との比較のために微粒子中で使用される。PEA−I−Bzポリエステルアミドの構造を、以下の式(IV)に示す。
(式中、mは、0.1〜0.9の間で変動し;pは、0.9〜0.1の間で変動し;nは、50〜150の間で変動し;
− 各R1は、独立して、(C1〜C20)アルキレンであり;各R2は、独立して、水素、または(C6〜C10)アリール(C1〜C6)アルキル(例えば、ベンジル)であり、
− 各R3は、独立して、水素、(C1〜C6)アルキル、(C2〜C6)アルケニル、C2〜C6)アルキニル、または(C6〜C10)アリール(C1〜C6)アルキルであり;そして各R4は、独立して、(C2〜C20)アルキレンである。)
トリエチルアミン(30.9mL、0.222モル、2.2当量)およびN,N−ジメチルホルムアミド(53.07mL、0.689モル)を、室温でオーバーヘッドスターラーを備えた窒素フラッシュした500mL丸底フラスコ中のジ−OSu−セバシナート(sebacinate)(39.940g、0.1008モル、1.0当量)、L−ロイシン(6)−2TosOH(20.823g、0.0302モル、0.30当量)、L−ロイシン−(DAS)−2TosOH(32.503g、0.0453モル、0.45当量)およびL−リジン(Bz)−2TosOH(14.628g、0.0252モル、0.25当量)の混合物に添加した。結果として生じた混合物を、反応を進行させるために60℃に加熱し、THF中でのGPC分析によりモニタリングした。36時間後に安定した分子量を得、次いで、トリエチルアミン(1.76mL、0.0126モル)およびN,N−ジメチルホルムアミド(4.54mL、0.0590モル)と一緒に少しばかりのL−ロイシン(6)−2TosOH(4.338g、0.0063モル)を添加して、重合反応を停止させた。混合物をさらに24時間加熱し、その後、その粘稠溶液をN,N−ジメチルホルムアミド(407.85g、5.301モル)でさらに希釈し、室温まで冷却させた。室温で無水酢酸(1.89mL、0.0199モル)を添加して、ポリマーのアミノ官能性末端基をアシル化した。混合物を室温で24時間撹拌した。スキーム1に、全体的な反応を示す。
薬物としてTAAを含む薬物配合微小球をこの調査で使用する。対照として、拡散駆動放出を、細胞培養培地中で行った。予想放出曲線は、仮説に基づく図3Aに酷似することが予想される。
[実施例1]
[TAA配合PEA−III−Bz微粒子の製造]
300mgのPEA−III−Bzをジクロロメタンに溶解させた。75mgのTAAを溶液に添加し、超音波によりホモジナイズした。この懸濁液を、ultra−Turrax(登録商標)を用いて、高剪断下で、1重量%のポリ(ビニルアルコール)を含有する20mlの冷水に添加した。安定した懸濁液が得られた後に、1重量%のポリ(ビニルアルコール)を含有する100mlの水中で、粒子を12時間硬化させた。水および界面活性剤の過剰分を、水洗および遠心分離により除去した。最後に粒子を凍結させ、真空下で乾燥させた。微粒子の写真を図1に示す。微粒子の粒度分布を図2に示す。
[TAA配合PEA−III−Bz微粒子の存在下での軟骨細胞の培養]
3人のヒトドナーからのOA軟骨細胞を、膝関節全置換から採取し、培養した。細胞を、トランスウェル中で、5μgの実施例1で作製した微粒子と共にインキュベートした。3日置きに、細胞および培地を収集し、トランスウェルを、新たにプレートされた同じドナーからのOA軟骨細胞を含むウェルに移した。インキュベーションの時間の間に細胞によって産生されたPGE−2(プロスタグランジン−E2)の量を、ELISAにより測定した。全実験期間は28日であった。
1.コントロール実験;粒子なし。
2.陽性コントロール。TNF−αによって刺激された軟骨細胞。粒子なし。
3.TNF−αによって刺激された軟骨細胞。5μgの空PEA−III−Bz粒子と共にインキュベートした。
4.TNF−αによって刺激された軟骨細胞。20重量%のトリアムシノロンアセトニドが配合された5μgのPEA−III−Bz粒子と共にインキュベートした。
5.TNF−αによって刺激された軟骨細胞。0.1μMの一定濃度のトリアムシノロンアセトニドと共にインキュベートした。
結果を図3に示す。
[PEA−III−Bzフィルムからのフルオレセインの累積放出]
原理証明調査を、フィルムからゆっくりと放出される色素としてフルオレセインを用いて実施した。
101.3mgのフルオレセインおよび999.3mgのPEA−III−Bzを、19mlのエタノールに溶解させた。この溶液を、オービタルシェーカー上での穏やかな撹拌下で一晩溶解させておいた。
2つの放出系を、共に三重反復試験にて開始した。各時間点で溶液を新しくした。結果を図4および図5に示す。
系1は、全期間にわたってPBS緩衝液中で放出した(拡散駆動放出)。系2におけるフルオレセインの放出を、4つの異なる相に分割した。
[実施例1で説明したとおりのPEA−III−Bz微粒子の製造]
[PEA−I微粒子の製造]
300mgのPEA−I−Bzを、ジクロロメタンに溶解させた。この懸濁液を、ultra−Turrax(登録商標)を用いて高剪断下で、1重量%のポリ(ビニルアルコール)を含有する20mlの冷水に添加した。安定した懸濁液が得られた後に、1重量%のポリ(ビニルアルコール)を含有する100mlの水中で、粒子を12時間硬化させた。水および界面活性剤の過剰分を、水洗および遠心分離によって除去した。最後に粒子を凍結させ、真空下で乾燥させた。
30mgのPEA−III−Bz微小球およびPEA−I−Bz微小球を、0.5mlの水で懸濁させ、20℃で120rpmにて振盪機にかけた。微粒子の大きさおよび凝集を、10分間および400分間の水への浸漬後に、両方の種類の粒子について、粒度分布測定(光散乱技術を使用)および目視評価(光学顕微鏡技術)によってモニタリングした。
粒度分布は、D10、D50、D90およびSPANにより定義される。図6〜9に見られ得るように、D10は累積分布の10%のところの粒子直径の値に相当し、D50は累積分布の50%のところの粒子直径の値に相当し、D90は累積分布の90%のところの粒子直径の値に相当する。
Claims (19)
- 関節障害の処置における使用のための、二環式1,4:3,6−ジアンヒドロヘキシトールのジオールを少なくとも含む生分解性ポリエステルアミドコポリマーを含んだ注射用サイズの物品を含む処方物。
- 前記ポリエステルアミドコポリマーが、二塩基酸、二環式1,4:3,6−ジアンヒドロヘキシトールと異なるジオール、および少なくとも2種の異なるアミノ酸をさらに含む、請求項1に記載の処方物。
- 前記ポリエステルアミドコポリマーが、構造式(I)
(式中、
− mは、0.01〜0.99の間で変動し;pは、0.99〜0.01の間で変動し;かつqは、0.99〜0.01の間で変動し;
− nは、5〜100の間で変動し、
− R1は、(C2〜C20)アルキレン、(C2〜C20)アルケニレンおよびそれらの組み合わせからなる群から独立して選択され;
− それぞれ単一主鎖単位mまたはpの中にあるR3およびR4は、水素、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C6〜C10)アリール(C1〜C6)アルキル、−(CH2)SH、−(CH2)2S(CH3)、−CH2OH、−CH(OH)CH3、−(CH2)4NH3+、−CH2COOH、−(CH2)COOH、−CH2−CO−NH2、−CH2CH2−CO−NH2、−CH2CH2COOH、CH3−CH2−CH(CH3)−、−(CH3)2−CH−CH2−、H2N−(CH2)4−、フェニル−CH2−、−CH=CH−CH3、HO−p−フェニル−CH2−、(CH3)2−CH−、フェニル−NH−、NH2−(CH2)3−CH2−またはNH2−CH=N−CH=C−CH2−からなる群から独立して選択され、
− R5は、(C2〜C20)アルキレン、(C2〜C20)アルケニレンからなる群から選択され、
− R6は、構造式(II)
の1,4:3,6−ジアンヒドロヘキシトールの二環式断片から選択され;
− R7は、水素、(C6〜C10)アリール、(C1〜C6)アルキルまたは保護基(例えば、ベンジル)であり;
− R8は、独立して、(C1〜C20)アルキレンまたは(C2〜C20)アルケニルである)
を含む、請求項1または2に記載の処方物。 - 前記式(I)のポリエステルアミドコポリマーが、R1が−(CH2)8−であり;前記主鎖単位mおよびpの中のR3およびR4がロイシンであり、−R5が−(CH2)6−であり、R6が構造式(II)の1,4:3,6−ジアンヒドロヘキシトールの二環式断片であり;R7がベンジル基であり、かつR8が−(CH2)4−である、m+p+q=1、q=0.25、p=0.45を含む、請求項3に記載の処方物。
- 抗炎症薬、局所麻酔薬およびオピオイドの群から選択される鎮痛薬をさらに含むか、または疾患緩和用抗リウマチ薬を含む、請求項1〜4のいずれか一項に記載の処方物。
- 前記鎮痛薬が、NSAID COX−2阻害剤から選択される、請求項5に記載の処方物。
- 前記鎮痛薬が、コルチコステロイドである、請求項5に記載の処方物。
- 前記コルチコステロイドが、トリアムシノロンアセトニドから選択される、請求項7に記載の処方物。
- 前記物品が、微粒子、繊維、管または棒の群から選択される、請求項1に記載の処方物。
- 前記物品が、微粒子である、請求項1〜9のいずれか一項に記載の処方物。
- 前記微粒子の大きさが、0.1〜1000マイクロメートルの間で変動する、請求項9または10に記載の処方物。
- 関節炎の処置における使用のための、請求項1〜11のいずれか一項に記載の処方物。
- 変形性関節症の処置における使用のための、請求項12に記載の処方物。
- 膝、股関節部、脊椎または肩の変形性関節症の処置における使用のための、請求項13に記載の処方物。
- 前記処方物が、1年に1回または2回の注射で投与される、関節障害の処置における使用のための請求項1〜11のいずれか一項に記載の処方物。
- ヒトまたは獣医学的患者における疼痛または炎症を処置する方法であって、治療有効量の請求項1〜11のいずれか一項に記載の処方物を前記患者に投与することを含む方法。
- ヒトまたは獣医学的患者における慢性炎症性疾患と関係する進行性構造的組織損傷を緩慢化する、阻止するまたは逆転させる方法であって、治療有効量の請求項1〜11のいずれか一項に記載の処方物を前記患者に投与することを含む方法。
- 請求項1〜11に記載の処方物が、1年に1回または2回の注射で投与される、請求項16または17に記載の方法。
- 前記ヒトまたは獣医学的患者が、変形性関節症、関節リウマチ、乾癬性関節炎、自己免疫性関節炎、化膿性関節炎または滑膜炎に罹っている、請求項16または17に記載の方法。
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PCT/EP2015/054785 WO2015154924A1 (en) | 2014-04-08 | 2015-03-06 | Biodegradable polyesteramide used for the treatment of arthritic disorders |
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JP2021529798A (ja) * | 2018-07-03 | 2021-11-04 | ブルーベリー セラピューティクス リミテッド | 組成物及び治療方法 |
JP2022068212A (ja) * | 2016-03-24 | 2022-05-09 | ロケート・バイオ・リミテッド | 足場材料、方法および使用 |
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USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
WO2023148105A1 (en) * | 2022-02-01 | 2023-08-10 | Dsm Ip Assets B.V. | Degradable particles comprising high levels of rapamycin |
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JP2021529798A (ja) * | 2018-07-03 | 2021-11-04 | ブルーベリー セラピューティクス リミテッド | 組成物及び治療方法 |
JP7476164B2 (ja) | 2018-07-03 | 2024-04-30 | ブルーベリー セラピューティクス リミテッド | 組成物及び治療方法 |
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WO2015154924A1 (en) | 2015-10-15 |
CN111514108B (zh) | 2022-11-29 |
CA2943322A1 (en) | 2015-10-15 |
US20170119813A1 (en) | 2017-05-04 |
CN106132399A (zh) | 2016-11-16 |
JP6460540B2 (ja) | 2019-01-30 |
EP3129073A1 (en) | 2017-02-15 |
CN106132399B (zh) | 2020-05-12 |
US20220202851A1 (en) | 2022-06-30 |
CN111514108A (zh) | 2020-08-11 |
EP3129073B1 (en) | 2018-10-31 |
CA2943322C (en) | 2023-09-19 |
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