JP2023506335A - ベルベリン/ミネラル化コラーゲン複合膜及びその製造方法と応用 - Google Patents
ベルベリン/ミネラル化コラーゲン複合膜及びその製造方法と応用 Download PDFInfo
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- JP2023506335A JP2023506335A JP2021524344A JP2021524344A JP2023506335A JP 2023506335 A JP2023506335 A JP 2023506335A JP 2021524344 A JP2021524344 A JP 2021524344A JP 2021524344 A JP2021524344 A JP 2021524344A JP 2023506335 A JP2023506335 A JP 2023506335A
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- Prior art keywords
- berberine
- mineralized collagen
- membrane
- solution
- composite membrane
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
【解決手段】本発明は、骨修復の技術分野に関し、ベルベリン/ミネラル化コラーゲン複合膜及びその製造方法と応用を提供する。本発明によって提供される複合膜は、ベルベリンナノファイバー膜とベルベリンナノファイバー膜の片側表面に設置されたミネラル化コラーゲン膜を含む。本発明は、生体模倣ミネラル化能力を持っているミネラル化コラーゲンと漢方薬モノマーベルベリンを組み合わせ、得られた二層複合膜は骨形成を促進する効果がよりよく、かつベルベリンの新しい投与剤形を構築して、従来のベルベリン剤形の低い生物学的利用能、頻繁な投与、および大きな副作用等の欠点を解決した。本発明は、エレクトロスピニング法を採用してベルベリンナノファイバー膜を製造し、ミネラル化コラーゲン膜を使用してベルベリンナノファイバーを受容するか、またはベルベリンナノファイバー膜を製造して得られた後、コーティングによってベルベリンナノファイバー膜の表面においてミネラル化コラーゲン膜を製造する。製造方法が簡単で、コストが低く、工業化生産を行いやすい。
【選択図】図4
Description
前記ベルベリンナノファイバー膜には、質量分率において、ポリカプロラクトン20~65%、水溶性化合物18~80%、ベルベリン≦0.1%が含まれ、
前記水溶性化合物には、ポリビニルピロリドン、タンニン、タンパク質、および多糖類のうちの1種類又は複数種類が含まれ、
前記ミネラル化コラーゲン膜には、質量分率において、キトサン15~90%、ミネラル化コラーゲン10~85%が含まれている。
上記の解決手段に記載されたベルベリン/ミネラル化コラーゲン複合膜の製造方法であって、
キトサン、ミネラル化コラーゲン、および氷酢酸溶液を混合し、得られたミネラル化コラーゲン懸濁液を膜にキャストして、ミネラル化コラーゲン膜を得るステップ(1)と、
ポリカプロラクトン、水溶性化合物、ベルベリン、および溶媒を混合して、エレクトロスピニング溶液を得て、前記エレクトロスピニング溶液をエレクトロスピニングし、前記ミネラル化コラーゲン膜によってエレクトロスピニング繊維を受容し、ベルベリン/ミネラル化コラーゲン複合膜を得るステップ(2)と、を含み、
又は、前記ベルベリン/ミネラル化コラーゲン複合膜の製造方法は、
ポリカプロラクトン、水溶性化合物、ベルベリン、および溶媒を混合して、エレクトロスピニング溶液を得て、前記エレクトロスピニング溶液をエレクトロスピニングしてベルベリンナノファイバー膜を得るステップ(i)と、
キトサン、ミネラル化コラーゲン、および氷酢酸溶液を混合し、得られたミネラル化コラーゲン懸濁液を前記ベルベリンナノファイバー膜の表面にコーティングし、乾燥させた後、ベルベリン/ミネラル化コラーゲン複合膜を得るステップ(ii)と、を含むベルベリン/ミネラル化コラーゲン複合膜の製造方法を提供する。
キトサン、ミネラル化コラーゲン、および氷酢酸溶液を混合して、得られたミネラル化コラーゲン懸濁液を膜にキャストして、ミネラル化コラーゲン膜を得るステップ(1)と、
ポリカプロラクトン、水溶性化合物、ベルベリン、および溶媒を混合して、エレクトロスピニング溶液を得て、前記エレクトロスピニング溶液をエレクトロスピニングし、前記ミネラル化コラーゲン膜によってエレクトロスピニング繊維を受容し、ベルベリン/ミネラル化コラーゲン複合膜を得るステップ(2)と、を含む。
ポリカプロラクトン、水溶性化合物、ベルベリン、および溶媒を混合して、エレクトロスピニング溶液を得て、前記エレクトロスピニング溶液をエレクトロスピニングしてベルベリンナノファイバー膜を得るステップ(i)と、
キトサン、ミネラル化コラーゲン、および氷酢酸溶液を混合し、得られたミネラル化コラーゲン懸濁液を前記ベルベリンナノファイバー膜の表面にコーティングし、乾燥させた後、ベルベリン/ミネラル化コラーゲン複合膜を得るステップ(ii)と、を含む。
(1)磁気撹拌条件下で、キトサン(分子量12~16kDa)を1wt%氷酢酸溶液に溶解し、次にミネラル化コラーゲンを添加し、順に超音波及び撹拌を行って、ミネラル化コラーゲン懸濁液を得た。ここでキトサンの質量分率は2%、ミネラル化コラーゲンの質量分率は0.8%であった。
得られたミネラル化コラーゲン懸濁液5mLを直径10cmのプラスチック製時計皿に注ぎ、広げた後、37℃のオーブンで2時間乾燥させ、ミネラル化コラーゲン膜を得て、得られたミネラル化コラーゲン膜中のキトサンの質量分率は71.43%、ミネラル化コラーゲンの質量分率は28.57%であった。
(2)ベルベリンをクロロホルムとメタノールの混合溶媒(クロロホルムとメタノールの体積比は3:1)に溶解してベルベリン溶液を得て、次にポリカプロラクトンをベルベリン溶液に溶解し、ポリカプロラクトン質量分率が10%であるポリカプロラクトン-ベルベリン溶液を得て、ポリビニルピロリドンをベルベリン溶液に溶解して、ポリビニルピロリドンの質量分率が30%であるポリビニルピロリドン-ベルベリン溶液を得て、ポリカプロラクトン溶液-ベルベリンとポリビニルピロリドン-ベルベリン溶液を7:3の体積比で混合し、次にベルベリンを添加して、ベルベリンの濃度が10μmol/Lであるエレクトロスピニング溶液を得た。
(3)注射器を使用してエレクトロスピニング溶液を吸い取り、次に注射器をエレクトロスピニング装置のエミッターに置いて、受容器の表面をミネラル化コラーゲン膜で包み、次に電極を接続してエレクトロスピニングを開始し、スピニングニードルの型番は20G、受容器はアルミホイル紙で包まれた鋼板であり、受容器の面積は20cm×30cm、毎1回のエレクトロスピニング溶液の体積は10mLであった。エレクトロスピニングのパラメータは、液体の流速0.05mm/min、受容距離13cm、正高圧13kVとしてベルベリン/ミネラル化コラーゲン複合膜を得た。ここで、得られたベルベリンナノファイバー膜中のベルベリンの質量分率は0.002%、ポリカプロラクトンの質量分率は43.749%、ポリビニルピロリドンの質量分率は56.249%であった。
エレクトロスピニング溶液中のベルベリンの濃度を5μmol/Lに変更したことを除いて、他の条件は、実施例1と同じであった。
エレクトロスピニング溶液中のベルベリンの濃度を30μmol/Lに変更したことを除いて、他の条件は、実施例1と同じであった。
エレクトロスピニング溶液中のベルベリンの濃度を50μmol/Lに変更したことを除いて、他の条件は、実施例1と同じであった。
ミネラル化コラーゲン懸濁液中のキトサンの質量分率を3%に変更し、ミネラル化コラーゲンの質量分率を0.4%に変更したことを除いて、他の条件は、実施例1と同じであった。
ミネラル化コラーゲン懸濁液中のキトサンの質量分率を6%に変更し、ミネラル化コラーゲンの質量分率を0.2%に変更したことを除いて、他の条件は、実施例1と同じであった。
(1)ミネラル化コラーゲン懸濁液を製造し、製造方法は実施例1と同じであった。
(2)ベルベリンナノファイバー膜をエレクトロスピニング法によって製造し、受容器上にミネラル化コラーゲン膜で包まない以外は、具体的な条件は実施例1と同じであった。
(3)5mLのミネラル化コラーゲン懸濁液を面積が9cm×9cmであるベルベリンナノファイバー膜の表面にスピンコートし、乾燥した後、ベルベリン/ミネラル化コラーゲン複合膜を得た。
エレクトロスピニング溶液の製造時にベルベリンを添加しない以外は、その他の条件は、実施例1と同じであった。得られたベルベリン/ミネラル化コラーゲン複合膜をCF-NFS-0と記した。
エレクトロスピニング溶液中のベルベリンの濃度を1μmol/Lに変更した以外は、その他の条件は、実施例1と同じであった。得られたベルベリン/ミネラル化コラーゲン複合膜をCF-NFS-1と記した。
エレクトロスピニング溶液中のベルベリンの濃度を100μmol/Lに変更した以外は、その他の条件は、実施例1と同じであった。得られたベルベリン/ミネラル化コラーゲン複合膜をCF-NFS-100と記した。
図1は、実施例7で製造したベルベリンナノファイバー膜の走査型電子顕微鏡画像である。左側は5μmのスケールの走査型電子顕微鏡画像であり、右側は1μmのスケールの走査型電子顕微鏡画像である。図1によると、得られたベルベリンエレクトロスピニング膜は均一に分布した3D繊維構造を持ち、各繊維の太さは均一で、ビーディングや接着はなく、直径はほぼ700~800nm程度であることがわかる。
実施例1で製造されたベルベリン/ミネラル化コラーゲン複合膜(Bilayerと表記)、ミネラル化コラーゲン膜(CFと表記)、および実施例7で製造されたベルベリンナノファイバー膜(NFsと表記)の延性、ヤング率および応力-ひずみ曲線について試験を行ったが、その結果を図2~4に示し、図2は、ベルベリン/ミネラル化コラーゲン複合膜、ミネラル化コラーゲン膜およびベルベリンナノファイバー膜の延性試験結果を示すグラフである。図3は、ベルベリン/ミネラル化コラーゲン複合膜、ミネラル化コラーゲン膜およびベルベリンナノファイバー膜のヤング率試験結果を示すグラフである。図4は、ベルベリン/ミネラル化コラーゲン複合膜、ミネラル化コラーゲン膜およびベルベリンナノファイバー膜の応力-ひずみ曲線である。図2~4からわかるように、ベルベリンナノファイバー膜とミネラル化コラーゲン膜を複合した後、得られた複合膜の引張性能は、ベルベリンナノファイバー膜とミネラル化コラーゲン膜の間にある。
骨形成性能試験をMTT実験により実施し、使用した細胞はMC3T3-E1(マウスの胚性骨芽細胞前駆細胞)で、試験手順は次のとおりである。対数増殖期にあるMC3T3-E1細胞を取り、10%ウシ胎児血清で培養した細胞懸濁液を培養プレートに加えて培養し、事前に細胞数を数えてプレートを舗装し、浸出液を調製し、浸出液は、培地1ミリリットルあたりに15mgの薬物を添加することによって調製された。使用した薬物はCF-NFS-0、CF-NFS-1、CF-NFS-10およびCF-NFS-100で、無薬物群(Control)をブランク対照とし、ベルベリン原薬(Berberine)を陽性対照とした。
Claims (13)
- ベルベリン/ミネラル化コラーゲン複合膜であって、ベルベリンナノファイバー膜とベルベリンナノファイバー膜の片側表面に設置されたミネラル化コラーゲン膜を含み、
前記ベルベリンナノファイバー膜には、質量分率において、ポリカプロラクトン20~65%、水溶性化合物18~80%、ベルベリン≦0.1%の成分が含まれ、
前記水溶性化合物には、ポリビニルピロリドン、タンニン、タンパク質、および多糖類のうちの1種類又は複数種類が含まれ、
前記ミネラル化コラーゲン膜には、質量分率において、キトサン15~90%、ミネラル化コラーゲン10~85%の成分が含まれていることを特徴とするベルベリン/ミネラル化コラーゲン複合膜。 - 前記ベルベリンナノファイバー膜における繊維の直径は700~800nmであることを特徴とする請求項1に記載のベルベリン/ミネラル化コラーゲン複合膜。
- 前記ベルベリンナノファイバー膜の厚さは0.1~0.4mm、ミネラル化コラーゲン膜の厚さは0.1~0.4mmであることを特徴とする請求項1に記載のベルベリン/ミネラル化コラーゲン複合膜。
- 前記キトサンの分子量は12~50kDaであることを特徴とする請求項1に記載のベルベリン/ミネラル化コラーゲン複合膜。
- 請求項1~4のいずれか一項に記載のベルベリン/ミネラル化コラーゲン複合膜の製造方法であって、それは、キトサン、ミネラル化コラーゲン、および氷酢酸溶液を混合し、得られたミネラル化コラーゲン懸濁液を膜にキャストして、ミネラル化コラーゲン膜を得るステップ(1)と、
ポリカプロラクトン、水溶性化合物、ベルベリン、および溶媒を混合して、エレクトロスピニング溶液を得て、前記エレクトロスピニング溶液をエレクトロスピニングし、前記ミネラル化コラーゲン膜によってエレクトロスピニング繊維を受容し、ベルベリン/ミネラル化コラーゲン複合膜を得るステップ(2)と、を含み、
又は、前記ベルベリン/ミネラル化コラーゲン複合膜の製造方法は、
ポリカプロラクトン、水溶性化合物、ベルベリン、および溶媒を混合して、エレクトロスピニング溶液を得て、前記エレクトロスピニング溶液をエレクトロスピニングしてベルベリンナノファイバー膜を得るステップ(i)と、
キトサン、ミネラル化コラーゲン、および氷酢酸溶液を混合し、得られたミネラル化コラーゲン懸濁液を前記ベルベリンナノファイバー膜の表面にコーティングし、乾燥させた後にベルベリン/ミネラル化コラーゲン複合膜を得るステップ(ii)と、を含むことを特徴とするベルベリン/ミネラル化コラーゲン複合膜の製造方法。 - 前記ステップ(1)およびステップ(ii)のミネラル化コラーゲン懸濁液中のキトサンの質量分率は0.5~6%であり、ミネラル化コラーゲンの質量分率は0.1~2%であることを特徴とする請求項5に記載の製造方法。
- 前記ステップ(1)で膜にキャストする方法は、前記ミネラル化コラーゲン懸濁液を型に注ぎ、乾燥してミネラル化コラーゲン膜を得る方法であり、前記乾燥温度は25~45℃、時間は2~5時間であることを特徴とする請求項5に記載の製造方法。
- 前記ステップ(2)とステップ(i)における混合するプロセスは、ベルベリンを溶媒に溶解してベルベリン溶液を得て、次に、ポリカプロラクトンおよび水溶性化合物をベルベリン溶液にそれぞれ溶解し、ポリカプロラクトン-ベルベリン溶液および水溶性化合物-ベルベリン溶液を得て、前記ポリカプロラクトン-ベルベリン溶液と水溶性化合物-ベルベリン溶液を混合してエレクトロスピニング溶液を得ることであることを特徴とする請求項5に記載の製造方法。
- 前記ポリカプロラクトン-ベルベリン溶液中のポリカプロラクトンの質量濃度は5~15%、前記水溶性化合物-ベルベリン溶液中の水溶性化合物の質量濃度は10~30%、前記ポリカプロラクトン-ベルベリン溶液と水溶性化合物-ベルベリン溶液の体積比は7:(2~4)、前記エレクトロスピニング溶液中のベルベリンの濃度は5~50μmol/L、前記溶媒はクロロホルムとメタノールの混合溶媒であることを特徴とする請求項8に記載の製造方法。
- 前記混合溶媒中のクロロホルムとメタノールの体積比は(2~4):1であることを特徴とする請求項9に記載の製造方法。
- 前記ステップ(2)およびステップ(i)のエレクトロスピニングのパラメータには、液体の流速が0.01~0.1mm/min、受容距離が10~15cm、正高圧が10~15kVであることが含まれることを特徴とする請求項5に記載の製造方法。
- 請求項1~4のいずれか一項に記載のベルベリン/ミネラル化コラーゲン複合膜、または請求項5~11のいずれか一項に記載の製造方法により製造されたベルベリン/ミネラル化コラーゲン複合膜の骨修復薬の製造への応用。
- 骨形成膜材料として、請求項1~4のいずれか一項に記載のベルベリン/ミネラル化コラーゲン複合膜、または請求項5~11のいずれか一項に記載の製造方法により製造されたベルベリン/ミネラル化コラーゲン複合膜の使用方法であって、前記ベルベリン/ミネラル化コラーゲン複合膜を骨損傷の表面に覆うことを特徴とするベルベリン/ミネラル化コラーゲン複合膜の骨膜形成材料としての使用方法。
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