JP2021524849A - 瘢痕形成の減少の為の接着斑キナーゼ阻害剤の制御されたヒドロゲル送達 - Google Patents
瘢痕形成の減少の為の接着斑キナーゼ阻害剤の制御されたヒドロゲル送達 Download PDFInfo
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Abstract
Description
本出願は、2018年5月16日に出願された米国仮特許出願第62/672,513号及び2019年5月15日に出願された米国仮特許出願第62/848,515号の利益を主張し、これらの各々の内容全体を、引用する事により本明細書に援用する。
本明細書で挙げられた全ての刊行物及び特許出願の内容全体を、各個別の刊行物又は特許出願が引用により援用されると具体的且つ個別に示された場合と同じ程度で、引用する事により本明細書に援用する。
本発明は、アメリカ国防総省により与えられた助成番号W81XWH−13−2−0052及びW81XWH−13−2−0054、アメリカ国立衛生研究所により与えられた助成番号DE026914、並びに米軍再生医療研究所(AFIRM DoD)により与えられた助成番号WFUHS441011SR01による政府支援によりなされたものである。アメリカ合衆国政府は、本発明に一定の権利を有する。
本開示は、一般に、創傷の治療及び創傷の組織治癒の促進に関する。特に、本明細書には、多孔質足場と、接着斑キナーゼ(FAK)阻害剤とを含む組成物、並びにその様な組成物を作製する方法及び使用する方法が記載されている。
細胞質タンパク質チロシンキナーゼ(PTK2)としても知られる接着斑キナーゼ(FAK)は、細胞外基質成分に付着する細胞間に形成する接着斑に集中する細胞質ゾルタンパク質チロシンキナーゼである(アンドレ等(Andre et al.)(1993年)バイオケミカル・アンド・バイオフィジカル・リサーチ・コミュニケーションズ(Biochem. Biophys. Res. Commun.)第190巻:第140頁〜第147頁を参照)。FAKは、細胞間の接着斑のダイナミクスの関係物として動員され、運動性及び細胞生存に関与する125kDの高度に保存された非受容体型チロシンキナーゼである。FAKは、インテグリンの結合、成長因子の刺激、及び有糸分裂促進性神経ペプチドの作用に応答してリン酸化される。159アミノ酸のカルボキシ末端領域である接着斑標的ドメイン(FAT)は、FAKを接着斑に標的化する役割を担う事が分かっている。接着斑アダプタータンパク質であるパキシリンは、FATドメインと重複するカルボキシ末端ドメインでFAKに結合する。アミノ領域とカルボキシ領域との間には、触媒ドメインがある。このキナーゼドメイン内の活性化ループのリン酸化は、FAKのキナーゼ活性にとって重要である。
本明細書には、治癒の間に組織の瘢痕化の低減を促進する為の組成物が記載されている。上記組成物は、多孔質足場と、有効用量の接着斑キナーゼ(FAK)阻害剤とを含む。FAK阻害剤は制御された薬物放出の為に作製され、足場の細孔内に配置されており、足場は、治療時間の間に制御された速度で組織治癒を促進するのに有効な用量のFAK阻害剤を送達表面に送達する様に構成されている。多孔質足場は、プルラン−ヒドロゲルフィルム等のヒドロゲルフィルムを含み得る。上記組成物は、治療時間の間に組織の瘢痕化を低減させる及び/又は治療時間の間に組織における毛髪成長を促進するのに有効な用量のFAK阻害剤を送達表面に送達する様に構成され得る。上記組成物は、創傷ドレッシング材として構成され得、柔軟であり得る。
接着斑キナーゼ阻害剤の制御送達により、創傷閉鎖の加速と共に瘢痕形成の減少がもたらされる。
生体適合性のFAKI放出ヒドロゲル足場の構築。FAKIであるVS−6062(以前はPF−562271)は、ベラステム社(Verastem, Inc.)(マサチューセッツ州、ニーダム)によって供給された。多孔質プルランコラーゲンヒドロゲルを、以前に記載された様に作製した(ウォン等(Wong et al.),2011c)。FAKIを含むヒドロゲル構築物を、分子インプリンティング(持続放出)又は表面取り込み(迅速放出)のいずれかによって調製した。簡単に説明すると、1gのプルラン(東京化成工業株式会社(TCI)、日本、東京)を、1gのトリメタリン酸三ナトリウム(STMP)(シグマアルドリッチ社(Sigma-Aldrich)、ミズーリ州、セントルイス)及び1gの塩化カリウム(フィッシャー・サイエンティフィック社(Fisher Scientific)、ニューハンプシャー州、ハンプトン)と混合した。該混合物に50mgのラット尾コラーゲンI型、5%(重量/重量)の重量のプルランを含有するコラーゲン溶液(コーニング社(Corning)、ニューヨーク州、コーニング)を添加した。分子インプリンティング(図1A)の為に、該混合物に1mlの5%のジメチルスルホキシド(DMSO)中の10mgのVS−6062(FAKI)を添加した。次いで、水酸化ナトリウム(0.65mlの1Nの溶液)を加え、引き続き、脱イオン水を加えて合計10mlにした。該混合物を均質分布の為に15分間穏やかにボルテックスに掛けた。プルランの架橋により混合物の粘度が上昇したら、該混合物をテフロン(登録商標)シート上に注ぎ、圧縮して2mm厚のフィルムを作製した。フィルムを乾燥させ、洗浄液のpHが7.0になる迄水で洗浄した。この洗浄工程の後に、凡そ50%のFAKIがヒドロゲル中に存在していた。膨潤したヒドロゲルを−80℃で凍結させた後に、凍結乾燥させた。表面取り込み法の為に、最初にブランクのヒドロゲルを作製し、その後にエタノール中に溶解された5mgのFAKIを、乾燥したヒドロゲル上に均一に広げ、引き続き溶剤を蒸発させた。最後に、ヒドロゲルフィルムを水分を含まない容器中で使用する迄4℃で保管した。
動物(マウス):全ての動物処置法は、スタンフォード大学の実験動物管理に関する行政パネル及び米国陸軍医学研究司令部の動物管理使用評価室(Animal Care and Use Review Office)によって承認された。8週齢〜10週齢の野生型の雌C57BL/6Jマウス(ジャクソン研究所(The Jackson Laboratory)、メイン州、バーハーバー)を使用して、公開された方法(ワン等(Wang et al.),2013、ウォン等(Wong et al.),2011b、スルタン等(Sultan et al.),2012)に従って、スプリント装着された全層切除創又は第3度熱傷創のいずれかを作成した。
Claims (43)
- 多孔質足場と、
前記足場の細孔内に配置された接着斑キナーゼ(FAK)阻害剤と、
を含む、組織治癒を促進する組成物であって、前記組成物は、治療時間の間に制御された速度で組織治癒を促進するのに有効な用量のFAK阻害剤を送達する様に構成されている、組成物。 - 前記多孔質足場は、ヒドロゲルフィルムを含む、請求項1に記載の組成物。
- 前記多孔質足場は、プルラン−コラーゲンヒドロゲルを含む、請求項1又は2に記載の組成物。
- 前記FAK阻害剤は、VS−6062(PF−562271)又はPF−562271のベンゼンスルホン酸塩を含む、請求項1〜3のいずれか一項に記載の組成物。
- 前記組成物は、約1μg/cm2〜約500μg/cm2の前記FAK阻害剤を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記組成物は、約40μg/cm2〜約200μg/cm2の前記FAK阻害剤を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記組成物は、前記足場の細孔内に配置された前記FAK阻害剤の持続放出の為に構成されている、請求項1〜6のいずれか一項に記載の組成物。
- 前記組成物は、前記足場の細孔内に配置された前記FAK阻害剤の最大約96時間の期間に亘る持続放出の為に構成されている、請求項7に記載の組成物。
- 前記組成物は、前記多孔質足場の形成の間の前記FAK阻害剤の分子インプリンティングによって作製される、請求項1〜8のいずれか一項に記載の組成物。
- 前記組成物は更に、FAK阻害剤の迅速放出の為に作製されている、請求項1〜8のいずれか一項に記載の組成物。
- 前記組成物は更に、該組成物の送達表面上にFAK阻害剤を含む、請求項10に記載の組成物。
- 前記組成物は更に、該組成物の前記送達表面からのFAK阻害剤の迅速放出の為に構成されている、請求項11に記載の組成物。
- 前記組成物は、該組成物の送達表面からのFAK阻害剤の約24時間以内での迅速放出の為に構成されている、請求項12に記載の組成物。
- 前記組成物は、前記治療時間の間に実質上全ての前記FAK阻害剤を放出する様に作られている、請求項1〜13のいずれか一項に記載の組成物。
- 前記組成物は、前記治療時間の間に約30%の前記FAKI阻害剤から約75%のFAK阻害剤迄を放出する様に作られている、請求項1〜13のいずれか一項に記載の組成物。
- 前記組成物は、1つ以上の層が前記FAK阻害剤の持続放出の為に作製され、1つ以上の層が前記FAK阻害剤の迅速放出の為に作製されている複数の層を含む、請求項1〜15のいずれか一項に記載の組成物。
- 前記組成物は、前記FAK阻害剤の持続放出と前記FAK阻害剤の迅速放出の両方の為に構成された層を含む、請求項1〜15のいずれか一項に記載の組成物。
- 前記組成物は、前記治療時間の間に前記組織の瘢痕化を低減させるのに有効な用量の前記FAK阻害剤を送達する様に構成されている、請求項1〜17のいずれか一項に記載の組成物。
- 前記組成物は、前記治療時間の間に前記組織における毛髪成長を促進するのに有効な用量の前記FAK阻害剤を送達する様に構成されている、請求項1〜18のいずれか一項に記載の組成物。
- 前記組成物は、創傷ドレッシング材として構成されている、請求項1〜19のいずれか一項に記載の組成物。
- 組織治癒を促進する方法であって、
前記組織の表面上に、多孔質足場と、前記足場の細孔内に配置された制御放出の為に作製された接着斑キナーゼ(FAK)阻害剤とを含む組成物を載置する事、及び
前記組織の表面へと、治療時間の間に制御された速度で組織治癒を促進するのに有効な用量の前記FAK阻害剤を送達する事、
を含む、方法。 - 前記多孔質足場は、ヒドロゲルフィルムを含む、請求項21に記載の方法。
- 前記ヒドロゲルは、プルラン−コラーゲンヒドロゲルを含む、請求項22に記載の方法。
- 組織の瘢痕化を低減させる事を更に含む、請求項21〜23のいずれか一項に記載の方法。
- 前記組織における毛髪成長を促進する事を更に含む、請求項21〜24のいずれか一項に記載の方法。
- 前記組成物は、創傷ドレッシング材として構成されている、請求項21〜25のいずれか一項に記載の方法。
- FAK阻害剤は、前記組成物の送達表面上に配置される、請求項21〜26のいずれか一項に記載の方法。
- 前記制御された速度は、迅速放出速度及び持続放出速度を含む、請求項21〜27のいずれか一項に記載の方法。
- 前記送達工程は、載置工程後約24時間以内に前記用量の前記FAK阻害剤を前記組織の表面に送達する事を含む、請求項21〜28のいずれか一項に記載の方法。
- 前記用量の前記FAK阻害剤は、最大約96時間の期間に亘って前記組織表面に送達される、請求項21〜28のいずれか一項に記載の方法。
- 前記組織表面から前記組成物を取り除く事を更に含む、請求項21〜30のいずれか一項に記載の方法。
- 前記載置工程及び前記送達工程を少なくとも3回繰り返す事を更に含む、請求項21〜31のいずれか一項に記載の方法。
- 前記載置工程及び前記送達工程を少なくとも10回繰り返す事を更に含む、請求項21〜31のいずれか一項に記載の方法。
- 前記FAK阻害剤は、VS−6062(PF−562271)又はPF−562271のベンゼンスルホン酸塩である、請求項21〜33のいずれか一項に記載の方法。
- 前記組成物中の約30%の前記FAKI阻害剤から前記組成物中の約75%の前記FAK阻害剤迄を前記組織に送達する事を更に含む、請求項21〜34のいずれか一項に記載の方法。
- 創傷の治療の為の多孔質足場を含む組成物を製造する方法であって、
接着斑キナーゼ(FAK)阻害剤、プルラン、コラーゲン、及びポロゲンを含む混合物を形成する事、並びに
前記ポロゲンを除去する及び/又は前記混合物を脱水する事により、多孔質足場の細孔内に配置された制御された薬物放出の為に作製された接着斑キナーゼ(FAK)阻害剤を有する多孔質足場を含む組成物を作製する事と、
を含む、方法。 - 前記多孔質足場は、ヒドロゲルを含む、請求項36に記載の方法。
- 前記多孔質足場は、プルラン及びコラーゲンヒドロゲルを含む、請求項36又は37に記載の方法。
- 前記組成物の表面上にFAK阻害剤を載置する事を更に含む、請求項36〜38のいずれか一項に記載の方法。
- 前記プルランを架橋する事を更に含む、請求項36〜39のいずれか一項に記載の方法。
- 前記プルランをトリメタリン酸ナトリウム(STMP)及び/又はトリポリリン酸ナトリウム(STPP)で架橋する事を更に含む、請求項36〜40のいずれか一項に記載の方法。
- 前記除去工程の前に前記ポロゲンを結晶化させる事を更に含む、請求項36〜41のいずれか一項に記載の方法。
- 前記組成物は、FAK阻害剤の不均一な分布を含む、請求項36〜42のいずれか一項に記載の方法。
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US201862672513P | 2018-05-16 | 2018-05-16 | |
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US201962848515P | 2019-05-15 | 2019-05-15 | |
US62/848,515 | 2019-05-15 | ||
PCT/US2019/032697 WO2019222520A1 (en) | 2018-05-16 | 2019-05-16 | Controlled hydrogel delivery of focal adhesion kinase inhibitor for decreased scar formation |
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J. INVEST. DERMATOL. (MAY-15 2018) VOL.138, ISSUE 11, P.2452-2460, JPN6023015481, ISSN: 0005045175 * |
TISSUE ENG, PART A (2011) VOL.17, NO.5-6, P.631-644, JPN6023015479, ISSN: 0005045178 * |
WOUND REPAIR REGEN. (2017) VOL.25, ISSUE 4, P.A7(右欄第1演題), JPN6023015480, ISSN: 0005045176 * |
WOUND REPAIR REGEN. (ARP 2018) VOL.26, ISSUE 1, P.A33(P.FS08), JPN6023015482, ISSN: 0005045177 * |
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AU2019269608A1 (en) | 2020-11-26 |
WO2019222520A1 (en) | 2019-11-21 |
EP3793589B1 (en) | 2024-05-01 |
CA3100352A1 (en) | 2019-11-21 |
US20210361833A1 (en) | 2021-11-25 |
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