JP7143222B2 - メッシュベースのインサイチュ架橋性組成物 - Google Patents
メッシュベースのインサイチュ架橋性組成物 Download PDFInfo
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- JP7143222B2 JP7143222B2 JP2018558399A JP2018558399A JP7143222B2 JP 7143222 B2 JP7143222 B2 JP 7143222B2 JP 2018558399 A JP2018558399 A JP 2018558399A JP 2018558399 A JP2018558399 A JP 2018558399A JP 7143222 B2 JP7143222 B2 JP 7143222B2
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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Description
図面は次の通りである。
本発明の好ましい実施形態によれば、架橋材料がトランスグルタミナーゼを含み、架橋性タンパク質がゼラチンを含む、メッシュベース組成物が提供される。
本発明の幾つかの実施形態によれば、トランスグルタミナーゼ溶液について、一段階又は複数段階の精製を行い、1つ以上の1)トランスグルタミナーゼ混合物から発酵残留物を除去し;2)トランスグルタミナーゼ溶液中の活性トランスグルタミナーゼの量を濃縮し;3)担体タンパク質又は炭水化物からトランスグルタミナーゼ溶液を更に精製し;4)トランスグルタミナーゼ溶液のエンドトキシンレベルを低下し;及び/又は5)トランスグルタミナーゼ溶液から全ての微生物を除去し、効果的に溶液を滅菌することを実施するが、閉鎖リストに全て制限されるものではない。
任意に上記架橋基質及び架橋材料は、1種類以上の追加材料と混ぜ合わせて、本明細書に記載されているパッチとともに使用するために、本発明の様々な組成物を形成してよい。幾つかの実施形態によれば、接着剤材料は、任意に及び好ましくは(i)ゼラチン;(ii)トランスグルタミナーゼを含む。より好ましくは、ゼラチン及びトランスグルタミナーゼは、組織接着剤、封止剤又は止血剤として有用であるのに十分な量で提供される。
少なくとも幾つかの実施形態によれば、本発明は、一時的な再吸収性抗接着性非付着裏材についてである。医療器具が手袋、外科用器具及び内臓に付着することを防止するために設計される。
幾つかの実施形態によれば、ポリ(エチレンオキシド)(PEO)又はポリオキシエチレン(POE)としても既知のポリエチレングリコール(PEG)は、コポリマーとしてタンパク質/ポリペプチド又は架橋剤溶液に添加され、組成物の1つ以上の特性が改善され、例えば(制限なしに)、組成物の柔軟性を増大させるか又はタンパク質の架橋剤組成物に対する体の免疫応答から保護する。PEGは、300Da~10MDaの分子量の広範囲にわたって利用可能であり、分子量に応じて液体又は低融点固体であってよい。
本発明の幾つかの実施形態によれば、1種類以上の生体適合性界面活性剤が、例えばその溶液の表面張力を低下させるために、架橋性タンパク質又はポリペプチドの溶液に添加される。
本発明の一実施形態では、乾燥架橋剤物質が、架橋性タンパク質又はポリペプチドの凍結乾燥組成物全体に完全に分散された乾燥組成物が形成される。
メッシュベース組成物を作製するために、異なる適切な作製方法を任意に使用してよい。様々な例示的段階が以下に示され、これらは、任意に異なって構成し、再び組み合わせてよい。このような例示的段階のそれぞれは、異なる方法に従って任意に実施してよく、任意にそれぞれを本明細書に記載されている任意のその他の作製方法と組み合わせてよい。その段階は、それらが任意に実施される順序で示される。
任意にメッシュベース組成物はまた、特有の寸法を有するメッシュ器具として記載してよい。このような寸法の非限定的な例は、以下及び図6に示す。
ここで上記の説明とともに、本発明の幾つかの実施形態を非限定的な方法で示す、以下の実施例を参照する。
本明細書に示すように、メッシュベース組成物を特徴とする、構造について様々な例示的実施が可能であり、本発明の範囲内にあると考えられる。
湿ったラテックス手袋に対する様々な基材の粘着性を垂直電気機械試験システム(英国、Instron)を使用して試験した。2種類の裏材、架橋(CL)ゼラチン及びHPMCを使用した。裏材は、非架橋発泡ゼラチン層を覆っていた。ラテックス手袋をしっかりと取り付けたインストロンのヘッドに平らなアタッチメントを接続した。ラテックス手袋をInstronに取り付ける前に0.9%生理食塩水に浸漬した。発泡した接着剤と裏材の試料を、底部の平板に両面テープで接続した。インストロンのヘッドを、0.3~0.9Nの力が達成されるまで、垂直に圧縮した。力を1秒間保持し、伸長荷重を50Nロードセルで測定しながら伸長を実施した。
裏材は、キャストによってフィルムとして作製され、乾燥後、1cm幅の細片に切断され、垂直電気機械試験システム(英国、Instron)のホルダー内に設置された。フィルム長さは5cmだった。裏材を底部と上部のホルダーに設置し、底部のホルダーを固定し、上部のホルダーを50Nのロードセルに接続した。その後、試料の引張り伸びを実施した。伸張速度を0.5mm/sに設定し、引張り応力及びひずみを測定した。
この実施例は、周囲の接着剤マージン部分(図1のA)及びインビボでのその性能に関し、;図4は、ゼラチン-mTG接着剤マトリックスを使用してインビボで腹膜組織に固定された軽量メッシュを示す。この画像は、腹腔鏡下でブタの腹膜に挿入され、適用されたメッシュに基づいた器具を示す。適用されたメッシュのサイズは、接着剤によって取り囲まれ、裏材層(HPMC(k100)+HPMC(k4))及びPlasdoneC17)で構成された結合層によって覆われた外科用メッシュについて、15x15cmであり、メッシュがなく接着剤及び裏材(結合層と接続した)のみを含む周辺部に1cmのマージンを加える。これらのマージンは、器具の中心及び外科手術部位を取り囲む組織とわずかに異なる色を有しており、画像内で視認できる。この植込みでは、メッシュが接着層により組織に十分に接着し、裏材は外科用器具に対する粘着のいずれも防止した。
この実施例は、メッシュベース組成物の作製について非限定的な例示的方法に関する。
d1-器具の底部から外科用メッシュまでの接着剤の厚み
d2-外科用メッシュから結合層までの接着剤の厚み
d3-外科用メッシュの厚み
d4-裏材の厚み
d5-結合層の厚み
pH値の低下によるメッシュ作製プロセスの「湿った」部分全体にわたるmTG酵素の阻害は、ゼラチン溶液の早すぎる架橋を防止するのに役立つ。
ゼラチン溶液の作製-9%w/w、(pH3.8の例):
12285gの精製水を40~45℃に予熱した。円錐状のオーバーヘッドスターラーで攪拌しながら、1350gのゼラチンを容器に徐々に添加した。
加圧ガスを用いた物理的通気
図8は、通気及び混合システムの概略図を示し、通気のためにゲル化溶液を入れるホッパーを特徴としている。通気は混合ヘッドで生じ、続いて温度制御されたチューブを通って移動する。mTG溶液の注入後、静的混合が生じる。次に材料は、フローマニホールドを通って流出する。
ゼラチン溶液の作製-9%w/w水、pH=3.8、15kg;12285gの精製水40~45℃に予熱した。円錐状のオーバーヘッドスターラーで攪拌しながら、1350gのゼラチンを容器に徐々に添加した。ゼラチンが完全に溶解した後、1365gの酢酸を、5分間攪拌しながら、容器に添加した。pHは3.8±0.5となるようにpHメーターで試験した。
56.5gの濃縮精製mTG溶液(885U/ml)を943.5gの20mMクエン酸ナトリウム溶液と混合し、希釈mTG溶液(50U/ml)を得た。
図9は、実施例7に記載されているプロセスによって作製されたゼラチン-mTG乾燥発泡品における断面のSEM画像を示す。
方法:
275ブルームのゼラチン粒子(米国、Gelita)をDW中にて50℃で1時間混合することによって、水中における様々な濃度のゼラチン溶液を作製した。
6x7cm(WxL)のサイズに切断したコラーゲンシートを、水和させ、次に36~37℃に加熱するまで、0.9%生理食塩水に浸漬した。試料を、メッシュベース組成物品全体を5x7cm(WxL)の試験片に切断し、試験機で把持するために7cmのうち2cをテープで覆うことによって作製した。メッシュベース組成物の試料を予熱したコラーゲンシートに適用して、37℃のインキュベーターで4分硬化させた。
少なくとも幾つかの実施形態によれば、ゼラチン発泡体に関する特定の外科用メッシュの配置によって、組織の埋め込みに関するものを含む、望ましい特性が増大し得る。単一の仮説によって制限されるものではないが、驚くべきことに本発明者らは、発泡コーティング内のメッシュの位置が、組織への製品適用の初期段階でプロテーゼに対する組織応答の程度を低減し得ることを見いだした。
以下の実施例では、予備硬化された裏材層上に接着層が直接適用され、接着層が乾燥するときにそれらを一緒に結合するので、結合層は使用されなかった。
図11Aは、LM-147品の断面のSEM画像を示し、メッシュは、発泡体の中央に埋め込まれる。図11Bは、LM-149品の断面のSEM画像を示し、外科用メッシュは、底部(表面)に位置する。図12Aは、LM-147品における底部表面のSEM画像を示し、外科用メッシュは、発泡体によって完全に覆われているので見えない。図12Bは、LM-149品における底部表面のSEM画像を示し、外科用メッシュは、表面に位置し、完全に覆われていない。図13Aは、組織のシミュレーション基材としてコラーゲン上に固定した(コラーゲンは最下層)後のLM-149のSEM画像を示す。図13Bは、組織のシミュレーション基材としてコラーゲン上に固定(コラーゲンは最上層)した後のLM-147のSEM画像を示す。
発泡体の多孔質ゼラチン構造は、組織が迅速に外科用メッシュへ融合するために重要であると想定されていた。これは、発泡体の高い有効表面積が、体内の酵素分解の可能性を高め、架橋ゼラチンの迅速な分解(数日以内)を可能にするためである。架橋ゼラチンが分解すると、新しい組織の浸潤及び増殖のための空間を作り、外科用メッシュ繊維を封入し、それをしっかりと定位置に固定する。一方、面積当たりの発泡体の荷重を増加させることによって、植込み後数日において主な耐荷重性の固定要素である、架橋ゼラチンゲルマトリックスの強度に寄与できる。したがって、迅速な組織の融合とゲルマトリックスの初期固定強度の最適条件が求められた。
注-以下の実施例では、予備硬化された裏材層上に接着層が直接適用され、接着層が乾燥するときにそれらを一緒に結合するので、結合層は使用されなかった。
表11は、左の縦列(2000ミクロン)がより深く、右の縦列(1400ミクロン)がより浅い、異なる発泡体の深さを適用した結果を示す。
製品は、水で活性化した接着剤コーティング内に埋め込まれた外科用メッシュを含有する。仮出願に記載されているように、製品はまた、製品がその裏側(すなわち、外科医がその製品を利用するときの手袋、外科用器具等)に付着するのを防止する裏材層もまた含有する。
HPMC裏材(GF-199):
溶液:1%HPMCK100(Ashland)、0.3%PEG400(Aldrich)、オートクレーブを実施
溶液:1%ゼラチン225タイプA(Gelita)を0.2μmのフィルターを通してろ過した。
溶液:5%ゼラチン(Gelita)、2.1%PEG400(Merck)+5u精製mTG酵素(TP1701)/gゼラチン(溶液中の合計)
0.9%生理食塩水溶液に24時間浸漬後のコラーゲンに対する固定強度を2種類のモデルに対して試験した。:LM-274(架橋ゼラチンに基づく裏材層)及びLM-216(HPMCに基づく裏材層)。結果を以下のように表12に示す。
ゼラチン/アルギン酸塩溶液の作製
300gの精製水を約40℃まで加熱した。8.35gゼラチン粉末(Gelita、タイプAゼラチン、ブルーム275)を加熱された水に添加し、均一になるまでマグネチックスターラーで混合した。
50U/mlの濃度の精製mTG酵素原液を80U/gゼラチンの比率で酸性化ゼラチン-アルギン酸塩溶液に添加した。溶液を1分間完全に混合した。
LifeMeshを5x7cm(WxL)の試料に切断し、2cmの長さをテープで覆い、試験機で試料を把持できる部分を作製した。コラーゲンシートを6x7cm(WxL)の試験片に切断し、生理食塩水で浸したガーゼで覆って、36~37℃に予熱した。LifeMesh試料をコラーゲンに適用し、37℃のインキュベーター内で4分硬化させた。硬化後、試料を0.9%生理食塩水/0.9%生理食塩水含有カルシウム源(CaCl2)に浸漬した。試料を37℃で24時間維持し、次にモデル3433Instron万能試験機を使用して重ねせん断で試験した。
それぞれの総固体含量が2%w/w、総重量が300gである、ゼラチン(Gelita、タイプAゼラチン、ブルーム275)と低MWのキトサン(Aldrich cat#448869)の3種類の混合物を作製(表13を参照)した。
Claims (24)
- メッシュ及びコーティングを含む、メッシュベースの組成物であって、前記コーティングが、1種類以上の架橋性のタンパク質又はポリペプチド及び1種類以上の架橋材料を含み、前記メッシュの少なくとも一部が、前記コーティングでコーティングされており、それにより形成されるコーティングされたメッシュの組成物は、自己接着性であり、追加の固定を必要とせず、適用時の組織癒着を最小限に抑えることができ、前記コーティングは、前記コーティングの平面方向の総面積が前記メッシュの総面積よりも大きくなるように、前記メッシュを超えて広がる、メッシュベースの組成物。
- 前記メッシュが複合メッシュを含み、前記架橋性のタンパク質又はポリペプチド及び前記1種類以上の架橋材料の発泡組成物を含む、請求項1に記載の組成物。
- 前記架橋性のタンパク質又はポリペプチドが、ゼラチンを含む、請求項1または2に記載の組成物。
- 前記1種類以上の架橋材料が、トランスグルタミナーゼを含む、請求項1~3のいずれか1項に記載の組成物。
- 前記メッシュのみが、埋め込み1ヶ月後に残っている、請求項1~4のいずれか1項に記載の組成物。
- メッシュ及びコーティングを含む、メッシュベースの組成物であって、前記コーティングが、1種類以上の架橋性のタンパク質又はポリペプチド及び1種類以上の架橋材料を含み、前記メッシュの少なくとも一部が前記コーティングでコーティングされており、それにより形成されるコーティングされたメッシュの組成物は、自己接着性であり、前記コーティングが、前記架橋性のタンパク質又はポリペプチド及び前記1種類以上の架橋材料の発泡組成物を含み、前記コーティングは、前記コーティングの平面方向の総面積が前記メッシュの総面積よりも大きくなるように、前記メッシュを超えて広がる、メッシュベースの組成物。
- メッシュ及びコーティングを含む、メッシュベースの組成物であって、前記コーティングが、1種類以上の架橋性のタンパク質又はポリペプチド及び前記1種類以上の架橋性のタンパク質又はポリペプチドを架橋できる酵素を含み、前記メッシュの少なくとも一部が、前記コーティングでコーティングされており、それにより形成されるコーティングされたメッシュの組成物は、自己接着性であり、前記コーティングが、前記架橋性のタンパク質又はポリペプチド及び前記酵素の発泡組成物を含み、ただし、前記タンパク質又はポリペプチドは、フィブリンでもフィブリノゲンでもなく、前記酵素が、トランスグルタミナーゼ又はマルチ-銅オキシダーゼのうちの1つ以上を含み、前記コーティングは、前記コーティングの平面方向の総面積が前記メッシュの総面積よりも大きくなるように、前記メッシュを超えて広がる、メッシュベースの組成物。
- 前記タンパク質がゼラチンを含み、前記発泡組成物が、1~100mg/cm3の密度範囲内の密度を有する、請求項2、6および7のいずれか1項に記載の組成物。
- 前記ゼラチンが、ゼラチン溶液を発泡させることによって作製され、発泡前の前記ゼラチン溶液の濃度が、0.1%~30%w/wの間である、請求項3または8に記載の組成物。
- 発泡前の前記ゼラチン溶液の濃度が、5%~15%w/wの間である、請求項9に記載の組成物。
- 発泡したゼラチンが、乾燥発泡ゼラチン又は凍結乾燥発泡ゼラチンを含む、請求項8~10のいずれか1項に記載の組成物。
- 前記発泡組成物が、ガスで発泡する、請求項2および6~11のいずれか1項に記載の組成物。
- 前記メッシュが外科用メッシュを含む、請求項1~12のいずれか1項に記載の組成物。
- 前記外科用メッシュがヘルニア用メッシュを含む、請求項13に記載の組成物。
- 前記1種類以上の架橋材料がトランスグルタミナーゼを含み、前記トランスグルタミナーゼの活性レベルが、ゼラチン1gあたり約1~約500Uである、請求項1~3および6~14のいずれか1項に記載の組成物。
- 前記活性レベルが、ゼラチン1gあたり約5~約120Uである、請求項15に記載の組成物。
- 前記1種類以上の架橋材料がトランスグルタミナーゼを含み、前記1種類以上の架橋性のタンパク質又はポリペプチドがゼラチンを含み、ゼラチン対トランスグルタミナーゼの重量比が約50:1~約5000:1の範囲である、請求項1、2、6および7のいずれか1項に記載の組成物。
- 前記トランスグルタミナーゼが、微生物のトランスグルタミナーゼを含む、請求項4、7および15~17のいずれか1項に記載の組成物。
- 前記メッシュベースの組成物が、再吸収性材料を含む裏材層を特徴とする、請求項1~18のいずれか1項に記載の組成物。
- 前記メッシュが非分解性である、請求項1~19のいずれか1項に記載の組成物。
- 請求項1~20のいずれか1項に記載の組成物を調製するための方法であって、非接着性裏材を適用すること、前記架橋性のタンパク質のための多孔質構造を作製すること、前記架橋性のタンパク質と前記酵素および/または架橋材料を混合すること、架橋性のタンパク質と酵素および/または架橋材料の前記混合物を前記非接着性裏材に適用すること、ならびに前記メッシュを架橋性のタンパク質と酵素および/または架橋材料の混合物に対して配置することを含む、方法。
- 前記架橋性のタンパク質がゼラチンを含み、
前記架橋性のタンパク質のための多孔質構造を作製することが、ゼラチン溶液のガス発泡を含む、請求項21に記載の方法。 - 前記架橋性のタンパク質がゼラチンを含み、前記架橋性のタンパク質のための多孔質構造を作製することが、エマルション凍結乾燥、溶媒キャスト/粒子浸出、超臨界ガスを用いた高圧プロセス、ガス発泡/粒子浸出、熱誘起相分離法、電界紡糸及び/又はラピッドプロトタイピングのうちの1つ以上を含む、請求項21に記載の方法。
- 前記架橋性のタンパク質のための多孔質構造を作製することが、-20℃での凍結乾燥により実施される、請求項23に記載の方法。
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JP7216735B2 (ja) * | 2018-09-03 | 2023-02-01 | 富士フイルム株式会社 | ゲル形成キット、ゲルおよびゲルの製造方法 |
JP7332125B2 (ja) * | 2018-10-05 | 2023-08-23 | 青葉化成株式会社 | 粘弾性を有する天然高分子化合物組成物の製造方法 |
JP2021115287A (ja) * | 2020-01-28 | 2021-08-10 | 青葉化成株式会社 | 液状医療材料 |
JP2021115285A (ja) * | 2020-01-28 | 2021-08-10 | 青葉化成株式会社 | 液状高分子化合物組成物 |
US11826028B2 (en) | 2020-06-10 | 2023-11-28 | Ethicon, Inc. | Two component sealing systems including synthetic matrices and biosynthetic adhesives for sealing resected surfaces of organs to control bleeding, fluid leaks and air leaks |
EP4029457A1 (en) | 2021-01-18 | 2022-07-20 | Tissium | Applicator, kit and method for applying an adhesive composition on a support, such as a tissue repair support |
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