JP2013529598A - 部分的および完全硫酸化ヒアルロナンの用途 - Google Patents
部分的および完全硫酸化ヒアルロナンの用途 Download PDFInfo
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- JP2013529598A JP2013529598A JP2013514324A JP2013514324A JP2013529598A JP 2013529598 A JP2013529598 A JP 2013529598A JP 2013514324 A JP2013514324 A JP 2013514324A JP 2013514324 A JP2013514324 A JP 2013514324A JP 2013529598 A JP2013529598 A JP 2013529598A
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- hyaluronan
- fully sulfated
- sulfated hyaluronan
- inflammatory
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Abstract
【選択図】図1
Description
本出願は、2010年6月8日に出願された米国仮特許出願第61/352,550号および2011年3月23日に出願された米国非仮出願第13/069,860号に基づき優先権を主張するものである。これらの出願の教示内容全体は参照によって本明細書に組み込まれるものとする。
被験対象に炎症を誘発するLL−37量を実験動物に投与すること、
工程(a)の前および/または工程(a)の後に、化合物を動物に投与すること、および
LL−37は同量投与されるが、化合物は投与されない対照動物と、この動物の炎症量を比較すること
を含む。
a.塩基処理LMW HA
HA(2g、67kDa)を100mLのビーカー中のNaOH(40%w/v)20mLに溶解し、その混合物を室温で2時間撹拌して、鎖切断を誘導することによりHAを部分的に解重合させた。得られた粘稠液を、イソプロパノール100mLを含む400mLのビーカーに移し、室温で24時間撹拌した。得られた溶液を自然落下で濾過(濾紙)し、粗生成物を集め、蒸留水250mLに溶解し、pHを7.0に調整した。水浴を4回交換しながら24時間、この溶液を蒸留水に対して透析し、次いで凍結乾燥して塩基処理HA1.2gを得た。この生成物のサイズは、HPLC<GPCまたは電気泳動により決定することができ、通常5kDa〜20kDaの範囲に入る。
LMW HAのトリブチルアミン(TBA)塩を得るために、TBA0.2mLを蒸留水20mL中の塩基処理HA(0.2g)に加えた。この混合物を激しく撹拌し、凍結乾燥した。得られた塩(LMW HA−TBA)をN,N−ジメチルホルムアミド(DMF)20mLに溶解し、それにピリジン−三酸化イオウ複合体(0.325g)を必要な過剰量(6mol/HA中の総水酸基の当量、二糖当たり4)加えた。40℃で3時間の後、水20mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール30mLを加えて、粗物質を沈殿させた。硫酸化粗生成物を濾過により集めて、蒸留水(30mL)に溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析し、凍結乾燥した。生成物の収率は61%(0.22g)であった。1H NMRにより、置換度は約0.5〜1であった。元素分析により、イオウ含量は4.13%であった。平均分子量はGPCにより6,100であると測定され、多分散性は2.3であった。
HAのトリブチルアミン(TBA)塩を得るために、TBA0.2mLを蒸留水20mL中の塩基処理HA(0.2g)に加えた。この混合物を激しく撹拌し、凍結乾燥した。得られた塩(LMW HA−TBA)をN,N−ジメチルホルムアミド(DMF)20mLに溶解し、それにピリジン−三酸化イオウ複合体(11.0g)を必要な過剰量(16mol/HA中の利用可能な水酸基の当量)加えた。40℃で3時間の後、水20mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール30mLを加えて、粗生成物を沈殿させた。硫酸化生成物を濾過により集めて、蒸留水(30mL)に溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析して、凍結乾燥し、生成物0.26g(収率60%)を得た。1H NMRにより生成物を特徴づけしたところ、約3.5の近似置換度が得られた。元素分析により、イオウ含量は13.22%であった。平均分子量はGPCにより5,900であると測定され、多分散性は2.2であった。
a.完全O−硫酸化低分子量HA(F−OSHA(1)−10,000)
HAのトリブチルアミン(TBA)塩を得るために、TBA0.2mLを、蒸留水20mL中のHA(0.2g、約10,000Da、1.3MDaのHAから分解されたもの)に加えた。この混合物を激しく混合し、凍結乾燥した。得られた塩(HA−TBA)をN,N−ジメチルホルムアミド(DMF)20mLに溶解し、それにピリジン−三酸化イオウ複合体(0.325g)を必要な過剰量(6mol/HA中の利用可能な水酸基の当量)加えた。40℃で3時間の後、水20mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール30mLを加えて、粗物質を沈殿させた。硫酸化生成物を濾過により集めて、蒸留水(30mL)に溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析して、凍結乾燥し、生成物0.19g(収率58%)を得た。元素分析により、イオウ含量は12.62%であり、これは3.0〜3.5の硫酸化を示す。分子量は3,000Da未満であり、これにより硫酸化および後処理の間の酸解重合が示唆された。
HAのトリブチルアミン(TBA)塩を得るために、TBA0.2mLを蒸留水20mL中の酸修飾された10,000MW HA(0.2g)に加えた。この混合物を激しく混合し、凍結乾燥した。得られた塩(HA−TBA)をDMF20mLに溶解し、それにピリジン−三酸化イオウ複合体(1.1g)を必要な過剰量(16mol/HA中の利用可能な水酸基の当量)加えた。40℃で3時間の後、水20mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール30mLを加えて、粗物質を沈殿させた。硫酸化生成物を濾過により集めて、蒸留水(30mL)に溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析して、凍結乾燥し、生成物0.23g(収率62%)を得た。1H NMRにより生成物を特徴づけしたところ、3.0〜3.5の置換度が得られた。元素分析により、イオウ含量は12.10%であった。分子量は3,000Da未満であった。
Kewpie Hyalo-Oligo HA(200mg、0.5mmole、8.4kDa)をDMF10mLに溶解した。TBA(1当量 0.5mmole、0.12mL)を撹拌しながら加え、さらに10分間撹拌した。ピリジン−三酸化イオウ複合体(24当量 12mmole、1.916g)を必要な過剰量(6mol/HA中の利用可能な水酸基の当量)加えた。40℃で3時間撹拌した後、水15mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール25mLを加えて、粗物質を沈殿させた。硫酸化生成物を濾過により集めて、蒸留水25mLに溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析して、凍結乾燥し、生成物0.175g(収率51%)を得た。1H NMRにより生成物を特徴づけしたところ、3.5を超える置換度が得られた。平均分子量はGPCにより6,800であると測定され、多分散性は1.88であった。
11kDaに分解されたNovozymes HA(200mg、0.5mmole)をDMF10mLに溶解した。TBA(1当量 0.5mmole、0.12mL)を撹拌しながら加え、混合物をさらに10分間撹拌した。次いで、ピリジン−三酸化イオウ複合体(24当量 12mmole、1.916g)を必要な過剰量(6mol/HA中の利用可能な水酸基の当量)加えた。40℃で3時間撹拌した後、水15mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール25mLを加えて、粗物質を沈殿させた。硫酸化生成物を濾過により集めて、蒸留水25mLに溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析して、凍結乾燥し、生成物0.194g(収率57%)を得た。1H NMRにより生成物を特徴づけしたところ、約3.0〜3.5の置換度が得られた。平均分子量はGPCにより8,100Daであると測定され、多分散性は2.00であった。
11kDaに分解されたNovozymes HA(400mg、1.0mmole)をDMF25mLに溶解した。TBA(1当量 1.0mmole、0.24mL)を撹拌しながら加え、さらに10分間撹拌した。ピリジン−三酸化イオウ複合体(12当量 12mmole、1.908g)を必要な過剰量(3mol/HA中の利用可能な水酸基の当量)加えた。40℃で3時間撹拌した後、水30mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール50mLを加えて、粗物質を沈殿させ、次いで濾過して集めた。得られた部分的O−硫酸化粗HAを、蒸留水40mLに溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析して、凍結乾燥し、生成物0.386g(収率56%)を得た。1H NMRにより生成物を特徴づけしたところ、2.0の置換度が得られた。平均分子量はGPCにより9,500Daであると測定され、多分散性は1.77であった。
11kDaに分解されたNovozymes HA(200mg、0.5mmole)をDMF10mLに溶解した。TBA(1当量 0.5mmole、0.12mL)を撹拌しながら加え、混合物をさらに10分間撹拌した。DMF−三酸化イオウ複合体(24当量 12mmole、1.836g)を必要な過剰量(6mol/HA中の利用可能な水酸基の当量)加えた。30℃で3時間撹拌した後、水15mLを加えて反応を停止し、無水酢酸ナトリウムで飽和した冷エタノール25mLを加えて、粗物質を沈殿させ、次いで濾過して集めた。得られた完全O−硫酸化粗HAを、蒸留水25mLに溶解し、100mM NaCl溶液(溶液を6回交換)および水(水を2回交換)に対して2日間、1日に4回溶液を交換しながら透析して、凍結乾燥し、生成物0.057g(収率17%)を得た。1H NMRにより生成物を特徴づけしたところ、約3.0〜3.5の置換度が得られた。平均分子量はGPCにより1,900Daであると測定され、多分散性は2.48であった。
a.ヒト白血球エラスターゼ(HLE)の阻害測定
白血球エラスターゼに対する硫酸化HAの阻害効果を検討するために、7.5μg/ml HLE100μlを、0.001〜100μg/mLの濃度範囲の硫酸化HA100μlと共にインキュベートした。この混合物にHLE基質suc-Ala-Ala-Val-pNA(1.5mM)を50μl加えた後、25℃で10分間インキュベートした。活性なHLEは基質を切断し、発色性のpNAを生成する。pNAは、動力学的読み取りを使用して、405nmの吸光度変化を測定することにより追跡した。Vmax(吸光速度)対硫酸化HA濃度に関し、4パラメーターのロジスティックス非線形回帰式を使用して、IC50値を得た(表1)。
CML−BSAとRAGEとの複合体の阻害測定は、ポリ塩化ビニルプレートを5μg/ml CML−BSA100μlでコーティングすることにより準備した。別に、PBST−0.1%BSA中の1μg/mlRAGE−Fcキメラ溶液を、0.0005μg/ml〜100μg/mlの濃度範囲に連続希釈した硫酸化低分子量ヒアルロナンおよびHAオリゴ糖の等量と4℃で一晩インキュベートした。翌日、RAGE−硫酸化HA混合物50μlを各リガンドコーティングウェルにそれぞれ移し、37℃で1時間インキュベートした。次いで、ウェルをPBSTで4回洗浄した。結合したRAGEを検出するために、0.5μg/ml抗RAGE抗体50μlを各ウェルに加えた。プレートを室温で1時間インキュベートし、ウェルをPBSTでさらに4回洗浄した。HRP結合二次抗体(ウェル当たり50μl)を加え、ウェルを室温で1時間インキュベートし、次いでPBSTで4回洗浄した。比色定量反応をTMB100μlの添加により開始し、1N HCl50μlの添加で終了した。吸光度450nmを硫酸化HA濃度に対してプロットし、4パラメーターのロジスティックス非線形回帰式を使用して、IC50値を得た(表2)。
ピリジン−三酸化イオウ複合体を使用して調製した硫酸化HA試料のピリジニウム含量を、UV吸収によって分析した。1−ブチルピリジニウムブロマイド(Sigma, St. Louis, MO)を使用して標準曲線を作成し、UV測定が標準曲線の範囲内に入る必要があるので、硫酸化HA試料を2〜0.025mg/mlに希釈した。標準物質および試料に対して、石英セルにおける255nmの吸光度を記録した。標準曲線から、各試料に対して重量パーセントピリジニウム値を計算し、表3に示す。FOSHA-Kewpie-Pyr.SO3のピリジニウム付加物はまた、13C NMR分光法により特徴づけられ、公表データ(Hintze V, Moeller S, Schnabelrauch M, Beirbaum S, Viola M, Worch H, Scharnweber D. "Modifications of Hyaluronan Influence the Interaction with Human Bone Morphogenetic Protein-4 (hBMP-4)" Biomacromolecules 10:3290-3297, 2009)と比較された。13C NMRデータを表4に示す。最後に、図5に、FOSHA-Kewpie-Pyr.SO3の1H NMRスペクトルを示す。このスペクトルにはピリジニウム付加物のピリジニウムプロトンを表わす8.00ppmと9.10ppmとの間の3つのピークが示される。
a.マウス膀胱炎症モデル
マウス膀胱は、LL−37(カテリシジンペプチド)を含む種々の催炎物質に感受性があり、膀胱炎を含む炎症性疾患の潜在的な治療薬を試験するための優れた動物モデルとして寄与してきた。硫酸化HAの抗炎症作用を検討するために、FOSHA誘導体の保護効果をマウス膀胱炎モデルで測定した。最初に、C57/BL6成熟雌マウスを麻酔し、尿道を通してカテーテルを膀胱に挿入した。0.9%滅菌生理食塩水を注入および排出して膀胱を洗浄した。次いで、膀胱に、生理食塩水、10mg/ml FOSHA(Kewpie)、または10mg/ml FOSHA(Novozymes)のいずれかを150μL、1時間、前注入した。膀胱を空にしてから、320μM LL−37を150μLさらに1時間注入した。動物はすべて、合併症を伴わずに完全に回復した。手順完了の24時間後に、膀胱を取り出し、撮影し、MPO分析のために凍結した。
催炎物質に対する主要な細胞応答は、種々の免疫細胞を標的部位に動員する、損傷細胞からの種々のサイトカインの分泌である。MPOは多核白血球において大量に発現されるペルオキシダーゼ酵素であるが、多核白血球が炎症の初期段階に炎症部位に動員される主たる細胞であるため、MPOは炎症の程度を定量的に測定する優れたマーカーになる。マウス膀胱炎モデルにおける完全硫酸化HAの抗炎症作用を分析するために、硫酸化HAで前処置された膀胱における、MPOの発現量を測定し、未処置膀胱および生理食塩水対照における、MPOの発現量と比較した。膀胱を秤量し、ホモジナイズした。ホモジナイズした試料を5,000rpmで遠心分離して、組織デブリから可溶性画分を分離し、組織ホモジネート中のMPO濃度(ng/mg組織)を、マウスMPO ELISAキット(HK210, Hycult biotech, The Netherlands)を使用して測定し、生理食塩水注入対照(炎症のない正常な膀胱)とのパーセント差として表現した。結果を図2に示す。
インビトロ試験の結果から、RAGEアンタゴニスト活性に関して硫酸化度の重要性が実証される(表2)。部分的硫酸化(6%未満のイオウ)では、かなり弱い効力のRAGEアンタゴニストが生じる。MWが2,000Da未満の硫酸化HA化合物も、インビトロ測定で効力の低下を示した。1%w/wを上回るピリジニウム付加物を有するものを含む完全硫酸化HA化合物は、マウス膀胱炎症モデルにおける炎症を低減する良好なインビボ効果を示した。
Claims (39)
- 被験対象の炎症を低減または予防するための方法であって、前記被験対象に部分的もしくは完全硫酸化ヒアルロナンまたはその薬学的に許容可能な塩もしくはエステルを有効量投与することを含む方法。
- 前記N−アセチルグルコサミン残基の少なくとも1つの一級C−6水酸基プロトンが、硫酸基で置換されている、請求項1に記載の方法。
- ヒアルロナンの前記N−アセチルグルコサミン残基の一級C−6水酸基プロトンの少なくとも1%が、硫酸基で置換されている、請求項1に記載の方法。
- ヒアルロナンの前記N−アセチルグルコサミン残基の一級C−6水酸基プロトンの1%〜100%が、硫酸基で置換されている、請求項1に記載の方法。
- ウロン酸残基の少なくとも1つのC−2水酸基プロトンもしくはC−3水酸基プロトンまたはN−アセチルグルコサミン残基の少なくとも1つのC−4水酸基プロトンが、硫酸基で置換されている、請求項1〜4のいずれか一項に記載の方法。
- ウロン酸残基の少なくとも1つのC−2水酸基プロトンおよびC−3水酸基プロトンならびにN−アセチルグルコサミン残基の少なくとも1つのC−4水酸基プロトンが、硫酸基で置換されている、請求項1〜4のいずれか一項に記載の方法。
- 前記化合物が、二糖単位当たり0.1〜4.0の硫酸化度を有する、請求項1に記載の方法。
- 前記部分的または完全硫酸化ヒアルロナンが、10kDa未満の平均分子サイズを有する、請求項1に記載の方法。
- 前記部分的または完全硫酸化ヒアルロナンが、0.5kDa〜10kDaの平均分子サイズを有する、請求項1に記載の方法。
- 前記ヒアルロナンが、動物源に由来しない、請求項1に記載の方法。
- 前記薬学的に許容可能なエステルが、プロドラッグである、請求項1に記載の方法。
- 前記部分的もしくは完全硫酸化ヒアルロナンまたはその薬学的に許容可能な塩もしくはエステルが、医薬組成物として投与される、請求項1に記載の方法。
- 前記組成物が、カプセル剤、錠剤、チューインガム、ロゼンジ剤、散剤、または飲料を含む、請求項12に記載の方法。
- 前記組成物が、静脈内、筋肉内、皮下、関節内、眼、膣、直腸、鼻腔内、摂取により、口腔粘膜に局所的にもしくは直接適用して、歯肉、または歯周ポケットに投与される、請求項12に記載の方法。
- 前記組成物が、抗炎症薬、解熱薬、抗炎症用途のステロイド性および非ステロイド性薬物、ホルモン、増殖因子、避妊薬、抗ウイルス薬、抗菌薬、抗真菌薬、鎮痛薬、催眠薬、鎮静薬、トランキライザ、抗痙攣薬、筋弛緩薬、局所麻酔薬、鎮痙薬、抗潰瘍薬、ペプチドアゴニスト、交感神経作動薬、心血管作動薬、抗腫瘍薬、またはオリゴヌクレオチドをさらに含む、請求項12に記載の方法。
- 前記薬学的に許容可能な塩が、有機塩、金属塩、またはそれらの組合せを含む、請求項1に記載の方法。
- 前記薬学的に許容可能な塩が、NH4 +、Na+、Li+、K+、Ca+2、Mg+2、Fe+2、Fe+3、Cu+2、Al+3、Zn+2、2−トリメチルエタノールアンモニウム陽イオン(コリン)、またはイソプロピルアミンの四級塩、トリメチルアミン、ジエチルアミン、トリエチルアミン、トリプロピルアミン、エタノールアミン、2−ジメチルアミノエタノール、2−ジエチルアミノエタノール、リジン、アルギニン、およびヒスチジンからなる群から選択される塩を含む、請求項1に記載の方法。
- 前記部分的または完全硫酸化ヒアルロナンが、ヒアルロナンをピリジン−三酸化イオウと反応させることにより生成し、かつ前記部分的または完全硫酸化ヒアルロナンが、ピリジニウム付加物を含む、請求項1に記載の方法。
- 前記ピリジニウム付加物を含む前記部分的または完全硫酸化ヒアルロナンが、10kDa以下の分子量を有する、請求項18に記載の方法。
- 前記炎症が、癌、多発性硬化症、骨関節炎、慢性関節リウマチ、アルツハイマー型ベータアミロイドペプチド、歯周疾患、歯肉炎、インプラント周囲炎、糖尿病性腎症、炎症性腸疾患、喘息、鼻炎、副鼻腔炎、慢性閉塞性肺疾患、急性肺障害、嚢胞性繊維症、鎌状赤血球貧血、心血管の炎症性疾患、肺の炎症性疾患、眼の炎症性疾患、大脳の炎症性疾患、または腸管の炎症性疾患により発症する、請求項1〜19のいずれか一項に記載の方法。
- 眼科的症状、尿生殖器症状、呼吸器系症状、心血管症状、胃腸疾患、リウマチ性および免疫学的疾患、腎疾患、退行性骨関節症、歯牙もしくは口腔疾患、または神経系疾患を治療または予防するための、部分的または完全硫酸化ヒアルロナンの使用。
- 歯科外科、歯周外科、および口腔外科における部分的または完全硫酸化ヒアルロナンの使用。
- 皮膚疾患を治療または予防するための方法であって、前記皮膚の表面上に部分的または完全硫酸化ヒアルロナンを有効量適用することを含む方法。
- 前記皮膚疾患が、酒さ、アトピー性皮膚炎(湿疹)、アレルギー性接触皮膚炎、乾癬、疱疹状皮膚炎、座瘡、糖尿病性皮膚潰瘍および他の糖尿病性損傷、熱傷、日焼け、瘢痕化の予防、光線性角化症、昆虫刺傷からの炎症、漆かぶれ、放射線誘発皮膚炎/熱傷、間質性膀胱炎、光線性皮膚老化、または脂漏性皮膚炎を含む、請求項23に記載の方法。
- 部分的もしくは完全硫酸化ヒアルロナンまたはその薬学的に許容可能な塩もしくはエステルを有効量含む口腔ケア製品。
- 前記製品が、ゲル、ペースト、リンス、または部分的または完全硫酸化ヒアルロナンのコーティングを含む器具を含む、請求項25に記載の製品。
- 前記器具が、フロス、歯周囲ブラシ、または歯肉消息子である、請求項26に記載の製品。
- 眼疾患を治療または予防するための方法であって、前記眼に部分的または完全硫酸化ヒアルロナンを有効量投与することを含む方法。
- 前記眼疾患が、加齢黄斑変性症、糖尿病性網膜症、眼球乾燥症候群、結膜炎、虹彩炎、ブドウ膜炎、アレルギー性結膜炎、または角膜の炎症および瘢痕化を含む、請求項28に記載の方法。
- 前記化合物が、眼内または眼表面に投与される、請求項28に記載の方法。
- 被験対象の泌尿器科的炎症を治療または予防するための方法であって、前記被験対象に部分的もしくは完全硫酸化ヒアルロナンまたはその薬学的に許容可能な塩もしくはエステルを有効量投与することを含む方法。
- 前記泌尿器科的炎症が、膀胱、尿道、尿路上皮裏層、腎臓、前立腺、膣、子宮、またはそれらの任意の組合せの炎症を含む、請求項31に記載の方法。
- 前記組成物が、静脈内、筋肉内、皮下、摂取により、または口腔粘膜に投与される、請求項31に記載の方法。
- 前記組成物が口腔粘膜に投与され、前記口腔粘膜投与が、頬貫通、舌下腺、経口、膣、鼻腔内、直腸、または膀胱内注入による、請求項31に記載の方法。
- P−セレクチンおよび/またはL−セレクチンの活性を低減または阻害するための、部分的または完全硫酸化ヒアルロナンの使用。
- 種々のリガンドの1つによるRAGEの活性化を低減または阻害するための、部分的または完全硫酸化ヒアルロナンの使用。
- 前記リガンドが、AGE生成物、HMGB1、またはS100ファミリーリガンドである、請求項36に記載の使用。
- ヒト白血球エラスターゼの活性を低減または阻害するための、部分的または完全硫酸化ヒアルロナンの使用。
- カチオン性ポリペプチドの活性を低減または阻害するための、部分的または完全硫酸化ヒアルロナンの使用。
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JP2016084351A (ja) * | 2010-06-08 | 2016-05-19 | ユニバーシティ・オブ・ユタ・リサーチ・ファウンデイション | 部分的および完全硫酸化ヒアルロナンの用途 |
JP2021519281A (ja) * | 2018-03-26 | 2021-08-10 | サンテン エスエーエス | 眼病態の処置のための多糖類 |
Also Published As
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CA2838493C (en) | 2019-05-28 |
EP2579715B1 (en) | 2018-07-25 |
JP2016084351A (ja) | 2016-05-19 |
US8343942B2 (en) | 2013-01-01 |
CA2838493A1 (en) | 2011-12-15 |
WO2011156445A1 (en) | 2011-12-15 |
JP6230909B2 (ja) | 2017-11-15 |
JP6334506B2 (ja) | 2018-05-30 |
EP2579715A4 (en) | 2013-08-07 |
US20120021968A1 (en) | 2012-01-26 |
EP2579715A1 (en) | 2013-04-17 |
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