JPWO2015005345A1 - コアシェル型架橋ヒアルロン酸ゲル粒子、その製造方法及び医用材料 - Google Patents
コアシェル型架橋ヒアルロン酸ゲル粒子、その製造方法及び医用材料 Download PDFInfo
- Publication number
- JPWO2015005345A1 JPWO2015005345A1 JP2015526351A JP2015526351A JPWO2015005345A1 JP WO2015005345 A1 JPWO2015005345 A1 JP WO2015005345A1 JP 2015526351 A JP2015526351 A JP 2015526351A JP 2015526351 A JP2015526351 A JP 2015526351A JP WO2015005345 A1 JPWO2015005345 A1 JP WO2015005345A1
- Authority
- JP
- Japan
- Prior art keywords
- hyaluronic acid
- core
- gel particles
- shell type
- acid gel
- Prior art date
- 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.)
- Granted
Links
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
Description
また、当該ゲル粒子の製造方法及び当該ゲル粒子を含む医用材料を提供することも可能になる。
・・・(1)
(HO−H:3420cm−1のラマン強度、HC−H:2940cm−1のラマン強度)
(ρ:架橋ヒアルロン酸ゲル粒子の密度、ρ0:水系溶媒(緩衝液)の密度)
2Nの硝酸75gを自公転型混練り装置(プライミクス社製)に入れ、−10℃に冷却し、シャーベット状の硝酸凍結物を得た。この硝酸凍結物に、粘度平均分子量220万のヒアルロン酸ナトリウム粉末22.5g(水分含量10%)を投入し、−10℃、100rpmで均一なゴム状になるまで1時間練り混ぜた(ヒアルロン酸ナトリウム20.8質量%)。得られたヒアルロン酸と硝酸の混合物を−20℃に設定した冷凍庫に10日間保存した。その後、5℃の純水1Lにこの混合物を投入し、1時間ごとに2回純水を交換した。その後さらに、5℃、50mMのリン酸緩衝液1Lにこの混合物を投入し、1時間ごとに5回50mMのリン酸緩衝液を交換し、硝酸が完全になくなるまで中和洗浄を行い、自己架橋ヒアルロン酸ゲルを得た。
比較例1で得られた乾燥した自己架橋ヒアルロン酸ゲル粒子(0.1g、500〜355μm)を0.5M塩酸(0.7mL)で、室温(20〜25℃)下、3分間膨潤させた。25%ヘキサデシルトリメチルアンモニウムヒドロキシド/メタノール溶液(1.65mL)と80%グリセリン水溶液(45mL)の混合液を添加し、8分間撹拌後、6M塩酸(0.5mL)を添加し中和した。
80%グリセリン水溶液を80%ジメチルスルホキシド水溶液に変更し、撹拌時間を8分間から3分間に変更した以外は実施例1と同様の方法でコアシェル型架橋ヒアルロン酸ゲル粒子を得た。収率は82%であった。
80%グリセリン水溶液を70%エタノール水溶液に変更し、撹拌時間を8分間から3分間に変更した以外は実施例1と同様の方法でコアシェル型架橋ヒアルロン酸ゲル粒子を得た。収率は61%であった。
0.5M塩酸を0.5M酢酸に変更した以外は、実施例3と同様の方法でコアシェル型架橋ヒアルロン酸ゲル粒子を得た。収率は3%であった。
撹拌時間を8分間から12分間に変更した以外は、実施例1と同様の方法でコアシェル型架橋ヒアルロン酸ゲル粒子を得た。収率は89%であった。
25%ヘキサデシルトリメチルアンモニウムヒドロキシド/メタノール溶液を25%ジメチルジステアリルアンモニウムヒドロキシド/メタノール溶液に変更した以外は、実施例3と同様の方法でコアシェル型架橋ヒアルロン酸ゲル粒子を得た。収率は77%であった。
70%エタノール水溶液を10%エタノール水溶液に変更した以外は、実施例3と同様の方法でコアシェル型架橋ヒアルロン酸ゲル粒子を得た。収率は54%であった。
0.5M塩酸による膨潤を行わなかった以外は、実施例3と同様の方法でコアシェル型架橋ヒアルロン酸ゲル粒子を得た。収率は70%であった。
ヒアルロン酸関節製剤「スベニール」(中外製薬(株)製;粘度平均分子量200万、ヒアルロン酸濃度1w/v%、商品名)を用いた。
実施例1〜6並びに比較例2〜3のコアシェル型架橋ヒアルロン酸ゲル粒子の表面の弾性は、走査型プローブ顕微鏡による表面のプローブ押込み力から分析した。なお、測定条件を以下のとおりとした。
走査型プローブ顕微鏡:SPM−9700型(島津製作所社製、商品名)
プローブ:10μm径の(球形)ガラス質粒子を取り付けたコロイダル型プローブ(CP−CONT−BSG−B、東陽テクニカ社製)
押込み距離:800nm
測定回数:3回
測定温度:23±2℃
実施例1〜6並びに比較例2〜3のコアシェル型架橋ヒアルロン酸ゲル粒子における平衡膨潤倍率は、ヒアルロン酸濃度を指標とした共焦点顕微レーザーラマン分光装置を用いて架橋ヒアルロン酸ゲル粒子の平衡膨潤倍率に相当する計算値として分析した。
共焦点顕微レーザーラマン分光装置:Almega−XR(サーモフィッシャーサイエンティフィック社製、商品名)
レーザ波長:532nm
露光時間:1.0秒
露光回数:8回
測定波数:4232〜116cm−1
測定温度:25±2℃
・・・(3)
(HO−H:3420cm−1のラマン強度、HC−H:2940cm−1のラマン強度)
実施例1〜6並びに比較例2〜3のコアシェル型架橋ヒアルロン酸ゲル粒子、及び比較例1の自己架橋ヒアルロン酸ゲル粒子の生理食塩水懸濁液500μLに対して、メチレンブルー1%水溶液5μLを添加した。室温にて15分以上静置した後、スライドガラス上に70μL採取し、さらにニグロシン1%水溶液1μLを加え、デジタルマイクロスコープ(VHX−500F;キーエンス社製、商品名)を用いて架橋ヒアルロン酸ゲル粒子の顕微鏡画像を撮影した。得られた画像を図1に示す。
実施例1〜6並びに比較例2〜3のコアシェル型架橋ヒアルロン酸ゲル粒子、及び比較例1の自己架橋ヒアルロン酸ゲル粒子について、試験例2と同様に平衡膨潤倍率を算出し、コアとシェルの境界から、シェル表面と外部である生理食塩水の境界までの分析移動距離を、シェルの厚みとして算出した。
実施例1〜6並びに比較例2〜3のコアシェル型架橋ヒアルロン酸ゲル粒子、比較例1の自己架橋ヒアルロン酸ゲル粒子、及び参考例1のヒアルロン酸溶液について、組織親和性を評価するため、ウサギ膝関節内で各試料による局所刺激性により増加する白血球数を指標として分析を行った。
実施例3〜4のコアシェル型架橋ヒアルロン酸ゲル粒子及び参考例1のヒアルロン酸溶液の関節腔内注射が疼痛に及ぼす作用を、ウサギの膝関節半月板部分切除による実験的変形性関節症モデル動物を用いて確認した。
参考文献2:Osteoarthritis and Cartilage,Vol.4,No.2,p.99−110(1996)
参考文献3:関節外科、第15巻、第3号、p.92−98(1996)
参考文献4:薬理と治療、第23巻、p.833−841(1995)
参考文献5:薬理と治療、第33巻、p.303−312(2005)
参考文献6:整形外科基礎科学、第9巻、p.77−79(1982)
参考文献7:整形外科基礎科学、第11巻、p.125−127(1984)
参考文献8:Arthritis & Rheumatism,Vol.48,No.7,p.1923−1929(2003)
Claims (9)
- 中心より表面の平衡膨潤倍率が高く、中心から表面に向けた平衡膨潤倍率の変化曲線に変曲点が存在するコアシェル型架橋ヒアルロン酸ゲル粒子であって、
表面から深さ800nmまでのプローブ押込み力が20nN以下である、コアシェル型架橋ヒアルロン酸ゲル粒子。 - 前記変曲点から前記表面までの平衡膨潤倍率が40以上である、請求項1に記載のコアシェル型架橋ヒアルロン酸ゲル粒子。
- 中心より表面の平衡膨潤倍率が高く、中心から表面に向けた平衡膨潤倍率の変化曲線に変曲点が存在するコアシェル型架橋ヒアルロン酸ゲル粒子であって、
変曲点から表面までの平衡膨潤倍率が65以上である、コアシェル型ヒアルロン酸ゲル粒子。 - 前記変曲点から前記表面までの距離が5μm以上である、請求項1〜3のいずれか一項に記載のコアシェル型架橋ヒアルロン酸ゲル粒子。
- 請求項1〜4のいずれか一項に記載のコアシェル型架橋ヒアルロン酸ゲル粒子を製造する製造方法であって、架橋ヒアルロン酸ゲル粒子と塩基性物質とを接触させることにより、当該ゲル粒子にコアシェル構造を形成させることを含む、製造方法。
- 請求項1〜5のいずれか一項に記載のコアシェル型架橋ヒアルロン酸ゲル粒子を製造する製造方法であって、架橋ヒアルロン酸ゲル粒子の表面に、当該架橋ヒアルロン酸ゲル粒子よりもヒアルロン酸の架橋密度の低い架橋ヒアルロン酸ゲルのシェルを形成させることを含む、製造方法。
- 請求項1〜4のいずれか一項に記載のコアシェル型架橋ヒアルロン酸ゲル粒子を含む医用材料。
- 関節注入剤、薬理活性物質の担体、創傷被覆剤、組織置換型生体組織修復剤、癒着防止剤、止血剤、人工細胞外マトリクス及びダーマルフィラーから選ばれるいずれかである、請求項7に記載の医用材料。
- 関節注入剤である、請求項7又は8に記載の医用材料。
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KR101460815B1 (ko) * | 2006-12-06 | 2014-11-12 | 세이가가쿠 고교 가부시키가이샤 | 관절염 질환 치료의 지속성 효과를 갖는 제약 제제 |
JP2010528039A (ja) * | 2007-05-23 | 2010-08-19 | アラーガン、インコーポレイテッド | 被覆されたヒアルロン酸粒子 |
FR2918377B1 (fr) * | 2007-07-05 | 2010-10-08 | Estelle Piron | Gel co-reticule de polysaccharides |
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IT1395392B1 (it) * | 2009-08-27 | 2012-09-14 | Fidia Farmaceutici | Geli viscoelastici come nuovi filler |
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2014
- 2014-07-08 KR KR1020167002831A patent/KR20160029818A/ko not_active Application Discontinuation
- 2014-07-08 EP EP14822114.6A patent/EP3020733A4/en not_active Withdrawn
- 2014-07-08 WO PCT/JP2014/068195 patent/WO2015005345A1/ja active Application Filing
- 2014-07-08 AU AU2014288252A patent/AU2014288252A1/en not_active Abandoned
- 2014-07-08 CN CN201480039029.9A patent/CN105377899B/zh active Active
- 2014-07-08 CA CA2917715A patent/CA2917715A1/en not_active Abandoned
- 2014-07-08 JP JP2015526351A patent/JP6322192B2/ja active Active
- 2014-07-08 US US14/903,199 patent/US20160143943A1/en not_active Abandoned
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2018
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JP2004181121A (ja) * | 2002-12-06 | 2004-07-02 | Denki Kagaku Kogyo Kk | 軟骨組織再生用注入剤組成物 |
JP2012041512A (ja) * | 2010-08-23 | 2012-03-01 | Denki Kagaku Kogyo Kk | 架橋ヒアルロン酸含有組成物およびその製造方法 |
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WO2015005345A1 (ja) | 2015-01-15 |
KR20160029818A (ko) | 2016-03-15 |
EP3020733A4 (en) | 2017-03-15 |
JP6322192B2 (ja) | 2018-05-09 |
US20180333430A1 (en) | 2018-11-22 |
CN105377899A (zh) | 2016-03-02 |
US20160143943A1 (en) | 2016-05-26 |
CN105377899B (zh) | 2017-12-01 |
EP3020733A1 (en) | 2016-05-18 |
AU2014288252A1 (en) | 2016-02-11 |
CA2917715A1 (en) | 2015-01-15 |
US10806753B2 (en) | 2020-10-20 |
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