JP6886402B2 - 生分解性インジェクタブルゲル - Google Patents
生分解性インジェクタブルゲル Download PDFInfo
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- JP6886402B2 JP6886402B2 JP2017536444A JP2017536444A JP6886402B2 JP 6886402 B2 JP6886402 B2 JP 6886402B2 JP 2017536444 A JP2017536444 A JP 2017536444A JP 2017536444 A JP2017536444 A JP 2017536444A JP 6886402 B2 JP6886402 B2 JP 6886402B2
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Description
[1]ポリエチレングリコール−ポリ(D,L−ラクチド)−ポリエチレングリコール骨格を有する、トリブロック共重合体、
[2]式I:
(式中、
nは、重合度を表し、好ましくは、10〜1000の範囲であり、
mは、重合度を表し、好ましくは、1〜100の範囲である)
で示される繰り返し単位を含む、請求項1に記載のトリブロック共重合体、
[3]上記[1]又は[2]に記載のトリブロック共重合体、キトサン、自己組織化ペプチドを含む、生分解性インジェクタブルゲル、
[4]自己組織化ペプチドが、(RADA)4である、[3]に記載の生分解性インジェクタブルゲル、
[5]下記:
(式中、
nは、重合度を表し10〜1000の範囲である)
をD,L−ラクチドと反応させ、
(式中、
mは、重合度を表し1〜100の範囲である)
を得る工程、
得られた
を
と反応させ
を得る工程、
得られた
を脱保護し、
を得る工程、
得られた
を炭酸ジ(N−スクシンイミジル)と反応させ
を得る工程
を含む、ポリエチレングリコール−ポリ(D,L−ラクチド)−ポリエチレングリコール骨格を有する、トリブロック共重合体の製造方法、
[6]上記[1]のトリブロック共重合体を含む、架橋剤。
以下、実施例により本発明を詳細に説明するが、本発明はこれら実施例によって限定されるものではない。なお、以下の例で用いた薬品は、とくに断りの無い場合は市販品をそのまま用いた。以下の例において、各実施例で得られた重合体の分子量分布の測定は以下のようにして行った。
ピーク分子量が既知の標準ポリスチレンを用い、該標準ポリスチレンで校正したゲル浸透クロマトグラフィー(GPC)(東ソー社製「TOSO HLC−8320GPC」、カラム構成:TSKguardcolumn SuperMP(HZ)−M, TSKgel SuperMultiporeHZ−M 4本直列)を使用して、重合体の数平均分子量(Mn)及び重量平均分子量(Mw)を測定した。(溶媒:THF、温度:40℃、流量:0.35mL/min)。
上記の方法で求めた重量平均分子量(Mw)と数平均分子量(Mn)の値を用い、その比(Mw/Mn)として求めた。
ポリマーの構造解析については、NMR測定装置(Bruker製、400MHz)を用い、1H−NMR測定及び13C−NMR測定を行った。なお、ケミカルシフトはCDCl3(1H:7.26ppm、13C:77.1ppm)を基準とした。
キトサン/PEG 2.0/1.0wt% 300μLゲルの作製
PBS(150mM,pH7.4)を用いて調製した6.0wt%キトサン100μLにPBS 150μLを添加した。そこにPBS(150mM,pH7.4)を用いて調製した6.0wt%両末端NHS−PEG 50μLを添加した。
PBS(150mM,pH7.4)を用いて調製した6.0wt%キトサン100μLにPBS(300mM,pH7.4)75μLを添加した。そこにPBS(150mM,pH7.4)を用いて調製した6.0wt%両末端NHS−PEG50μLを添加した後、1.0wt%RADA16水溶液75μLを素早く添加した。
・実験操作
溶液のゲル化を、20分間静置させた後、tilting test により評価した。各々のゲル化挙動を観察した後、ゲル化相図を作成した。目的とする濃度のキトサン/PEG−PLA−PEGゲルは、キトサン,PEG−PLA−PEG,PBSの混合比を適宜変化させることで作製した。すべてのゲルにおいて、イオン濃度の異なるPBSを適宜用いることで、最終PBS濃度が150mMとなるように調整した。ゲル化相図を図5に示す。
体積300μLのゲルを、直径15mmのディスク型に成形した。PBS(150mM,pH7.4)中で24時間膨潤させた(4℃)後、装置台座にセットした。パラレルプレートを、0.5Nの荷重が掛かるようにゲルに接近させた。周波数測定において、せん断応力ひずみは1%(=γ)とし、発振周波数を0.1−100Hzの範囲で測定した(図7)。双方において、貯蔵弾性率(G’)は損失弾性率(G”)よりも高く、典型的なゲル物性を確認した。
ゲル化挙動を、ゲルの典型的作製法と同様の手法でレオメーター台座上に体積210μLのゲル前駆体溶液を調製した後、即座に粘弾性測定を開始することで評価した。測定周波数は1Hzとし、測定荷重は1Paで行った。なお、RADAのゲル化は、PBS(200mM,pH7.4)157.5μLに対して1.0wt%RADA16水溶液52.5μLを添加することで観察した(図8)。
体積300μLのゲルを、直径15mmのディスク型に成形した。PBS(150mM,pH7.4)中で24時間膨潤させた(4℃)後、装置台座にセットした。
測定周波数を1Hzに固定した後、各ゲルサンプルに1Paから3000Paまでの圧力を印加することで力学強度を測定した。損失弾性率G”が貯蔵弾性率G’を上回る点をゲルの破断点と定義し、応力−ひずみ曲線を作成した。得られた応力−ひずみ曲線の初期の傾きを直線近似することで、ヤング率を算出した(図10)。
体積300μLのゲルを作製し、PBS(150mM,pH7.4)中で48時間膨潤させた(4℃)後、膨潤後のゲルの重量を測定した。各サンプルを24時間凍結乾燥させた後、ゲルの重量を再度測定した。以下の式を用いて、膨潤度Q0を算出した(図11)。
Q0=(Ws−Wd)/Wd
Ws:膨潤ゲルの重量、Wd:乾燥ゲルの重量
分解試験を、以下:
・酸加速分解試験(酢酸、室温条件下)
・実験操作
について行った。
体積300μLのゲルをそれぞれ作製し、1mLのPBS(150mM,pH7.4)中で48時間膨潤させた(4℃)。ゲルを膨潤させた後、PBSを取り除き、CH3COOHを1mL加え、室温条件下で静置した。所定時間経過後、サンプルを、PBSを用いて3回洗浄し、ゲルの膨潤重量を測定した。各サンプルを24時間凍結乾燥させた後、ゲルの乾燥重量を測定した。以下の式を用いて、膨潤度Q、重量損失を算出した。溶液は1日毎に取り換えた(図12)。
Q=(Ws−Wd)/Wd
WS:膨潤ゲルの重量、Wd:乾燥ゲルの重量
重量損失(%)=(Wd0−Wd)/Wd0×100
Wd0:初期乾燥重量(day0)
体積300μLのゲルをそれぞれ作製し、1mLのPBS(150mM,pH7.4)中で48時間膨潤させた(4℃)。ゲルを膨潤させた後、PBSを取り除き、新たなPBSを1mL加え、37℃条件下で静置した。所定時間経過後、サンプルをPBSを用いて3回洗浄し、ゲルの膨潤重量を測定した。各サンプルを24時間凍結乾燥させた後、ゲルの乾燥重量を測定した。以下の式を用いて、膨潤度Q、重量損失を算出した。溶液は3日毎に取り換えた(図13)。
Q=(Ws−Wd)/Wd
WS:膨潤ゲルの重量、Wd:乾燥ゲルの重量
重量損失(%)=(Wd0−Wd)/Wd0×100
Wd0:初期乾燥重量(day0)
体積90μLの各サンプルをそれぞれ作製し、光路長0.1mmの石英セルに塗布した。測定条件は以下のとおりである。
測定波長:300−205nm
データ間隔:0.5nm
走査速度:200nm/min
積算回数:3回
レスポンス:2.0s
バンド幅:1.0nm
測定温度:20℃
(1)20分間のUV滅菌処理を施したキトサン(カルボキシメチルキトサン、甲陽ケミカル)を用い、4wt%キトサン溶液(150mM PBS)を調製した。
(2)予めインキュベーター(37℃、5%CO2)で培養したサブコンフルのウシ由来軟骨細胞(P1)をトリプシン処理により基板から剥がし、遠心後(1,500rpm,5分間)、上澄みを除去した。
(3)DMEM培地を10mL加え、細胞数を測定した。
(4)遠心(1,500rpm,5分間)し、上澄み除去後、4wt%キトサン溶液を用いて、細胞懸濁液を作製した。
(5)1.5mLサンプリングチューブに細胞懸濁液を25μL加えた。
(6)20分間のUV処理を施したNHS−PEG−PLA−PEG−NHSを用いて、4wt%PEG溶液(300mMPBS中)を別途調製した。
(7)上記の(5)に(6)の4wt%PEG溶液を12.5μL加え、ピペッティングを行った後すぐに、1.0wt%RADA16溶液を12.5μL加え混ぜ合わせた。なお、キトサン/PEG−PLA−PEG=2.0/1.0wt%を足場とする場合には、RADA16溶液の代わりに同体積の150mM PBSを添加した。
(8)10分間ゲル化させた後、ゲル上部にDMEM(10%FBS,2%pen−strep)を500μL加え、インキュベーター(37℃,5%CO2)内で培養した。2−3日毎に培地サンプルを回収し、フレッシュなDMEMを500μL添加した。回収した培地サンプルは−80℃で保存した。
1.キトサン/PEG5k=2.0/1.0wt%
2.キトサン/PEG−PLA−PEG=2.0/1.0wt%
3.キトサン/PEG5k/RADA16=2.0/1.0/0.25wt%
4.キトサン/PEG−PLA−PEG/RADA16=2.0/1.0/0.25wt%
細胞数:5.0×105細胞
細胞密度:1.0×107細胞/ml
ゲル体積:50μL
培地量:500μL
分解挙動評価(細胞存在下)
上記と同様の方法で、体積300μLのキトサン/PEG 5k ゲル及びキトサン/PEG−PLA−PEGゲルをそれぞれ作製し、DMEMを1mL加え、37℃、5%CO2条件下で静置した。所定時間経過後、サンプルをPBSを用いて3回洗浄し、各サンプルを24時間凍結乾燥させ、ゲルの乾燥重量を測定した。以下の式を用いて、重量損失を算出した。培地は2,3日毎に取り換えた。
重量損失(%)=(Wd0−Wd)/Wd0×100
Wd0:初期乾燥重量(day0)
細胞数:3.0×106細胞
細胞密度:1.0×107細胞/ml
ゲル体積:300μL
培地量:1000μL
(1)サンプルの培地を交換する際に、DMEMを450μL加え、5mg/mL MTT試薬を50μL加えた。
(2)24時間、インキュベーション(37℃,5%CO2)した。
(3)上澄みを除去し、ゲルを崩し、MTT抽出用試薬(2−プロパノール:1M HCl=24:1vol%)を500μL加え、37℃で24時間振とうした。
(4)遠心(1,500rpm,5分間)後、96ウェルプレートに上澄みを100μL/ウェル加え、570nmにおける吸光度を測定した(図16)。
(1)DMMB 4mgをエタノール1.25mLに溶解させ、ギ酸0.75mL,1.0M NaOH溶液6.4mLを添加し、計250mLになるまでMilli Q水でメスアップすることにより、DMMB溶液を調製した。
(2)96ウェルプレートにDMMB溶液を125μL/ウェル加えた。
(3)検量線用コンドロイチン硫酸溶液(PBS中),サンプル(2倍希釈培地、ゲル融解液)を20μL/ウェル加え、よくピペッティングした。
(4)570nmにおける吸光度を測定した(図17〜19)。
Claims (3)
- 請求項1記載のトリブロック共重合体を含む架橋剤であって、トリブロック共重合体が、スクシンイミド−ポリエチレングリコール−ポリ(D,L−ラクチド)−ポリエチレングリコール−スクシンイミドである、架橋剤。
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JPH09157368A (ja) * | 1995-12-01 | 1997-06-17 | Kanebo Ltd | ポリ乳酸−ポリエチレングリコール−ポリ乳酸三元ブロック共重合体の精製方法 |
US6162241A (en) * | 1997-08-06 | 2000-12-19 | Focal, Inc. | Hemostatic tissue sealants |
KR20010022708A (ko) * | 1997-08-08 | 2001-03-26 | 프레드한 아룬디프 에스 | 약물 수송에 이용할 수 있는 생분해가능한 주사용 블록공중합체 겔 |
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CA2490007C (en) | 2002-07-19 | 2011-05-24 | Omeros Corporation | Biodegradable triblock copolymers, synthesis methods therefor, and hydrogels and biomaterials made there from |
JP4686970B2 (ja) | 2002-10-29 | 2011-05-25 | 東レ株式会社 | 血管塞栓材料 |
US20050112170A1 (en) * | 2003-11-20 | 2005-05-26 | Hossainy Syed F. | Coatings for implantable devices comprising polymers of lactic acid and methods for fabricating the same |
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JP2010010327A (ja) | 2008-06-26 | 2010-01-14 | Nisshinbo Holdings Inc | 太陽電池モジュールの検査装置および検査方法 |
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CN103384702B (zh) * | 2011-02-24 | 2015-02-18 | 东丽株式会社 | 聚乳酸系膜 |
KR101368775B1 (ko) * | 2012-03-30 | 2014-02-28 | 에스케이씨 주식회사 | 고분자량의 폴리알킬렌글리콜과 락티드의 블록 공중합 폴리락티드 |
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SE537633C2 (sv) * | 2012-09-18 | 2015-08-25 | Corticalis As | Hydrogelbelagd titandioxidscaffold och metod för att framställa denna scaffold |
US9707322B2 (en) | 2012-12-21 | 2017-07-18 | University Of Connecticut | Gradient porous scaffolds |
JPWO2014133027A1 (ja) * | 2013-02-26 | 2017-02-02 | 株式会社スリー・ディー・マトリックス | ハイドロゲル |
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