JP5123285B2 - アクリル化ヒアルロン酸 - Google Patents
アクリル化ヒアルロン酸 Download PDFInfo
- Publication number
- JP5123285B2 JP5123285B2 JP2009500563A JP2009500563A JP5123285B2 JP 5123285 B2 JP5123285 B2 JP 5123285B2 JP 2009500563 A JP2009500563 A JP 2009500563A JP 2009500563 A JP2009500563 A JP 2009500563A JP 5123285 B2 JP5123285 B2 JP 5123285B2
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- JP
- Japan
- Prior art keywords
- hyaluronic acid
- process according
- bacillus
- maintained
- acryloyl chloride
- 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.)
- Expired - Fee Related
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- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 109
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- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 106
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- 238000000034 method Methods 0.000 claims abstract description 39
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- 210000002435 tendon Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- A—HUMAN NECESSITIES
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- A61P27/02—Ophthalmic agents
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/246—Intercrosslinking of at least two polymers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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Description
本発明は、アクリル化ヒアルロン酸(HA)を製造するプロセス、その製造物及びそれらの使用に関する。
ヒアルロン酸(HA)は、非硫酸化グリコサミノグリカン類に属する天然及び線状の糖質高分子である。ヒアルロン酸は、ベータ−1,3−N−アセチルグルコサミン及びベータ−1,4−グルクロン酸繰り返し二糖単位から構成され、分子量(MW)が最大6MDaである。HAは、ヒアリン軟骨、滑膜関節滑液、及び真皮と表皮の両方の皮膚組織に存在している。HAは、脊椎動物の結合組織を含む自然組織、ヒトの臍帯、及びニワトリのトサカから抽出することができる。しかしながら、今日では、病原物質を移動させる潜在的なリスクを最小限にし、製造物の均一性、品質及び利用可能性を増加させるために、微生物学的な方法によってHAを調製することが好ましい(米国特許第6,951,743号;WO03/0175902)。
本発明は、アクリル化ヒアルロン酸を製造する方法に関し、該方法は、下記:
(a)ヒアルロン酸を含む、pHが7〜11である水性液体を用意する工程;
(b)アクリルクロリド(acryl chloride)及び塩化メチレン/ジエチルエーテルを含む有機液体を用意する工程;及び
(c)pHが7〜11で維持された状態で、(b)の有機液体と(a)の水性液体とを混合する工程
を含む。
本発明は、アクリル化ヒアルロン酸を製造するプロセスに関し、該プロセスは、下記:a)pHが7〜11で保たれた状態で、ヒアルロン酸を含む水性溶液を用意する工程;b)塩化アクリロイル及び有機溶媒を含む有機溶液を用意する工程;及び、c)pHが7〜11で維持された状態で、(b)の有機液体と(a)の水性液体とを混合する工程を含む。
を有する。
ペルオキシダーゼ(セイヨウワサビ)を酵素触媒として用いて、分子内又は分子間のアクリル官能基の重合/架橋を仲介した。
特定の態様では、酵素は、好熱性酵素である。
特定の態様では、酵素は、中温性酵素である。
a)請求項1のアクリル化ヒアルロン酸製造物;
b)過酸化物源;
c)開始剤;
d)酵素;及び
e)溶媒
を組み合わせることを含む。
特定の態様では、重合/架橋は、不活性雰囲気下でなされる。
高分子量のヒアルロン酸(700,000〜1,000,000ダルトン、50mg)を脱イオン水(25ml)に溶解した。温度を0℃まで下げた。
高分子量のヒアルロン酸(700,000〜1,000,000ダルトン、50mg)は、pH8.0の0.25〜2.0Mリン酸緩衝液(25ml)中に溶解させた。温度を0℃まで下げた。溶液をこのpHで30分間撹拌した。等量の塩化アクリロイル(100〜500μL)及びジクロロメタン(100〜500ml)の混合物は、ヒアルロン酸の混合物に1時間かけて1滴ずつ添加された。塩化アクリロイルの添加が完了後、この溶液をさらに1時間撹拌した。反応の初めから終わりまで、低温(0〜5℃)が維持された。得られた製造物をろ過した。大過剰の冷メタノール(500ml〜1000ml)を用いてろ過物を沈殿させ、エタノールで洗浄した。遠心分離、透析、及び凍結乾燥させた。
高分子量のヒアルロン酸(700,000〜1,000,000ダルトン、50mg)を脱イオン水(25ml)に溶解した。温度を0℃まで下げた。
1H NMR(Varian−300)を用いて、アクリル化ヒアルロン酸(D2O中)の最終の官能性及び純度を測定した。試料は2H2O中にあり、4.79ppmの2HOHピークを基準線として用いた。アクリル化ヒアルロン酸のプロトン−NMRは、別々のアクリルピーク(5.66ppm、1H、及び6.04ppm、2H)を示した。5.66ppmのピークは、二重の二重(11Hz及び2Hz)のようである。カルボニル基に隣接するHXプロトンに結合した二重結合を横切るHAのシスカップリングにより、(11Hz)のカップリング定数が得られる。また、プロトンHMに二重に(geminally)カップルし、2Hzのカップリング定数を得る。HM及びHXプロトン6.04ppmであるようである。17Hz及び13Hzのカップリング定数は、HXからHMの(トランスに)横切る二重結合のカップリング、及びHXからHA(シスに)横切る二重結合のカップリングにより観察される。同様に、HMプロトンは、HXプロトンに対する二重結合を(トランスに)横切ってカップルし、17Hzのカップリング定数が得られる。HM及びHXプロトンは、同領域(6.04ppm)に見られ、低いΔv/J比により、全てのカップリング定数を解析することはできない。修飾の程度は、ヒアルロン酸のN−アセチルプロトン(−NHCOCH3、3H、2.0ppm)に対するアクリレートの相対的な積分から決定した。
Claims (15)
- a)pHが適切なpHで保たれた状態で、ヒアルロン酸を含む水性液体を用意する工程;
b)塩化アクリロイル及び有機溶媒を含む有機液体を用意する工程;及び
c)pHが適切なpHで維持された状態で、(b)の有機液体と(a)の水性液体とを混合する工程
を含むアクリル化ヒアルロン酸製造物を製造する方法。 - 工程c)における混合が撹拌によって達成される、請求項1に記載の方法。
- 工程a)がpH7〜11で維持される、請求項1に記載の方法。
- 工程a)の水性液体がリン酸緩衝液を含む、請求項1に記載の方法。
- リン酸緩衝液が0.1モル濃度〜1モル濃度の量で存在する、請求項4に記載の方法。
- 工程c)がpH7〜11で維持される、請求項1に記載の方法。
- 工程c)が、緩衝剤の使用及び/又は希釈したNaOHの滴状添加によってpH7〜11で維持される、請求項1に記載の方法。
- 工程a)の最中、温度が0℃〜15℃に保たれる、請求項1に記載の方法。
- 工程c)の最中、温度が0℃〜5℃に保たれる、請求項1に記載の方法。
- 工程a)の水性液体のpHが、NaOHを滴状添加することによって調整される、請求項1に記載の方法。
- 工程a)の水性液体のpHが、緩衝剤によって及び/又はNaOHを滴状添加することによって調整される、請求項1に記載の方法。
- 工程c)における塩化アクリロイルの添加が、シリンジポンプの使用によって達成される、請求項1に記載の方法。
- 回収工程をさらに含む、請求項1に記載の方法。
- 回収工程が沈殿工程を含む、請求項13に記載の方法。
- 回収工程が、反応混合物のろ過工程及びろ過物の沈殿工程をさらに含む、請求項13に記載の方法。
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US78258106P | 2006-03-14 | 2006-03-14 | |
US60/782,581 | 2006-03-14 | ||
PCT/US2007/063671 WO2007106738A2 (en) | 2006-03-14 | 2007-03-09 | Acrylated hyaluronic acid |
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JP2009530445A JP2009530445A (ja) | 2009-08-27 |
JP2009530445A5 JP2009530445A5 (ja) | 2010-04-22 |
JP5123285B2 true JP5123285B2 (ja) | 2013-01-23 |
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US (1) | US20090118423A1 (ja) |
EP (1) | EP1999160B1 (ja) |
JP (1) | JP5123285B2 (ja) |
CN (1) | CN101405303B (ja) |
AT (1) | ATE453670T1 (ja) |
AU (1) | AU2007226690B2 (ja) |
BR (1) | BRPI0708776A2 (ja) |
CA (1) | CA2647481A1 (ja) |
DE (1) | DE602007004086D1 (ja) |
DK (1) | DK1999160T3 (ja) |
ES (1) | ES2339181T3 (ja) |
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WO (1) | WO2007106738A2 (ja) |
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KR101100803B1 (ko) * | 2009-04-24 | 2011-12-29 | 서울과학기술대학교 산학협력단 | 리포아마이드가 결합된 고분자화합물과 이의 제조방법 |
JP2014515426A (ja) * | 2011-05-30 | 2014-06-30 | ノボザイムス バイオファーマ デーコー アクティーゼルスカブ | 高分子量ヒアルロン酸の噴霧乾燥 |
JP5714456B2 (ja) * | 2011-09-07 | 2015-05-07 | 株式会社シード | 重合性ヒアルロン酸誘導体、ならびにその重合体を含むヒアルロン酸ヒドロゲルおよびコンタクトレンズ |
US9492484B2 (en) * | 2012-09-27 | 2016-11-15 | The Regents Of The University Of California | Cardiosphere derived cell population and methods of use |
CN104224688B (zh) * | 2013-06-09 | 2017-10-10 | 北京化工大学 | 负载纳米药物的丙烯酸酯化透明质酸水凝胶及其制备方法 |
US10335515B2 (en) | 2013-09-25 | 2019-07-02 | The University Of Kansas | Hydrogel precursors having nanoparticles |
EP2899214A1 (en) * | 2014-01-27 | 2015-07-29 | Basf Se | Ethylenically unsaturated polysaccharides, method for their production and their use |
FR3021537B1 (fr) | 2014-05-28 | 2016-05-27 | Oreal | Procede cosmetique pour attenuer les rides |
FR3021541B1 (fr) * | 2014-05-28 | 2017-10-27 | Oreal | Procede cosmetique pour attenuer les rides |
FR3026298B1 (fr) * | 2014-09-30 | 2017-12-01 | Oreal | Procede cosmetique pour attenuer les rides |
FR3026299B1 (fr) * | 2014-09-30 | 2016-11-25 | Oreal | Procede cosmetique pour attenuer les rides |
FR3026300B1 (fr) * | 2014-09-30 | 2020-01-10 | L'oreal | Procede cosmetique pour attenuer les rides |
CN106967202B (zh) * | 2017-03-06 | 2020-05-22 | 深圳大学 | 纳米凝胶酶及其制备和应用 |
JP2018153296A (ja) * | 2017-03-16 | 2018-10-04 | Jsr株式会社 | 不飽和化合物を含有する組成物 |
WO2018187184A1 (en) * | 2017-04-04 | 2018-10-11 | The Regents Of The University Of California | Injectable therapeutic angiogenic material for brain repair |
KR101974745B1 (ko) * | 2017-10-18 | 2019-09-06 | 서울과학기술대학교 산학협력단 | 그라프트 공중합체와 젤라틴 가교물을 포함하는 히알루론산 하이드로젤 및 이의 제조방법 |
KR101974744B1 (ko) * | 2017-10-12 | 2019-09-06 | 서울과학기술대학교 산학협력단 | 히알루론산 그라프트 공중합체의 가교물을 포함하는 하이드로젤 및 이의 제조방법 |
KR102103180B1 (ko) * | 2017-12-22 | 2020-04-22 | 케이비바이오메드 주식회사 | 히알루론산유도체, 플루란 및 카르복시메틸 셀룰로오스를 포함하는 유착방지용 조성물 및 이의 제조방법 |
CN111359011A (zh) * | 2020-03-31 | 2020-07-03 | 东华大学 | 一种提升酰胺化反应用于制备蛋白质生物墨水的方法 |
CN113943382B (zh) * | 2020-07-16 | 2023-03-10 | 孛朗孚(杭州)生物科技有限公司 | 一种丙烯酸酯类修饰的透明质酸(钠)及其合成方法和应用 |
CN116669781A (zh) * | 2020-12-30 | 2023-08-29 | 康沃特克科技公司 | 用于皮下装置的表面处理***和方法 |
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CA2121129A1 (en) * | 1991-10-29 | 1993-05-13 | Patrick Soon-Shiong | Crosslinkable polysaccharides, polycations and lipids useful for encapsulation and drug release |
US6951743B2 (en) * | 1997-10-31 | 2005-10-04 | University Of Oklahoma Board Of Regents | Hyaluronan synthase genes and expression thereof in bacillus hosts |
US6007833A (en) * | 1998-03-19 | 1999-12-28 | Surmodics, Inc. | Crosslinkable macromers bearing initiator groups |
US6716445B2 (en) * | 1999-04-12 | 2004-04-06 | Cornell Research Foundation, Inc. | Hydrogel entrapping therapeutic agent and stent with coating comprising this |
CA2368617C (en) * | 1999-04-12 | 2010-03-16 | Cornell Research Foundation, Inc. | Hydrogel-forming system with hydrophobic and hydrophilic components |
WO2000078988A1 (en) * | 1999-06-22 | 2000-12-28 | Trustees Of Tufts College | Enzyme-mediated polymerization methods and products |
AU2002258490A1 (en) * | 2001-03-12 | 2003-06-17 | Clemson University | Polysaccharide-based polmerizable hydrogels |
US6673919B2 (en) * | 2001-03-30 | 2004-01-06 | Chisso Cororation | Chemically modified hyaluronic acid or salts thereof, and a process for producing thereof |
JP2005525091A (ja) * | 2001-12-21 | 2005-08-25 | ノボザイムス バイオポリマー アクティーゼルスカブ | 組換え宿主細胞におけるヒアルロナンの生成方法 |
US7311879B2 (en) * | 2003-08-14 | 2007-12-25 | Hodson Steve J | Syringe pump |
US8293890B2 (en) * | 2004-04-30 | 2012-10-23 | Advanced Cardiovascular Systems, Inc. | Hyaluronic acid based copolymers |
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DK1999160T3 (da) | 2010-04-26 |
ATE453670T1 (de) | 2010-01-15 |
JP2009530445A (ja) | 2009-08-27 |
EP1999160A2 (en) | 2008-12-10 |
ES2339181T3 (es) | 2010-05-17 |
US20090118423A1 (en) | 2009-05-07 |
AU2007226690B2 (en) | 2012-04-19 |
DE602007004086D1 (de) | 2010-02-11 |
CA2647481A1 (en) | 2007-09-20 |
WO2007106738A3 (en) | 2008-09-25 |
BRPI0708776A2 (pt) | 2011-06-14 |
CN101405303B (zh) | 2011-11-23 |
AU2007226690A1 (en) | 2007-09-20 |
WO2007106738A2 (en) | 2007-09-20 |
EP1999160B1 (en) | 2009-12-30 |
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