JP2021532121A - 眼を治療するための組成物及び方法 - Google Patents
眼を治療するための組成物及び方法 Download PDFInfo
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- JP2021532121A JP2021532121A JP2021503746A JP2021503746A JP2021532121A JP 2021532121 A JP2021532121 A JP 2021532121A JP 2021503746 A JP2021503746 A JP 2021503746A JP 2021503746 A JP2021503746 A JP 2021503746A JP 2021532121 A JP2021532121 A JP 2021532121A
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Abstract
Description
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)眼科的に許容可能な担体と、を含む、組成物に関する。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、安全かつ有効な量の透過促進剤と、
iii)任意選択的に、眼科的に許容可能な担体と、を含む、方法に関する。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)1種若しくは2種以上の粘滑薬又は無痛化剤と、
iii)任意選択的に、安全かつ有効な量の透過促進剤と、
iv)任意選択的に、眼科的に許容可能な担体と、を含む、方法に関する。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、安全かつ有効な量の透過促進剤と、
iii)任意選択的に、眼科的に許容可能な担体と、を含む、方法に関する。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、安全かつ有効な量の透過促進剤と、
iii)任意選択的に、眼科的に許容可能な担体と、を含む、方法に関する。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、安全かつ有効な量の透過促進剤と、
iii)任意選択的に、眼科的に許容可能な担体と、を含む、方法に関する。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法に関する。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、安全かつ有効な量の透過促進剤と、
iii)任意選択的に、眼科的に許容可能な担体と、を含む、方法に関する。
上皮は、
・化学物質及び水に対するバリアを提供し、
・微生物に対するバリアを提供し、
・眼の屈折力に寄与する涙液膜−角膜境界面の内側部分としての滑らかな光学面を提供し、
・重要な免疫学的機能を行うランゲルハンス細胞を収容する。
・角膜形状の維持を助ける。
・角膜に機械的強度を提供し、
・角膜の透明性を提供し、
・屈折レンズとして機能する。
・内皮細胞の休止層として機能する。
・角膜実質から水を除去することによって角膜の透明度を維持する。
・涙液のMUC5AC濃度
涙液試料中の分泌されたムチンMUC5ACの濃度を、酵素結合イムノアッセイ(E90756Hu;USCN Life Science)によって定量化した。(Maker AV,Katabi N,Gonen M,et al.のPancreatic cyst fluid and serum mucin levels predict dysplasia in intraductal papillary mucinous neoplasms of the pancreas.Ann Surg Oncol.2011;18(1):199−206を参照)全試料を、製造業者の取扱説明書に従って分析した。吸光度を450nmで測定し、キット中の標準溶液を組換えヒトMUC5ACとした。タンパク質アッセイ試薬キット(BCAタンパク質アッセイキット;Pierce)を使用して、涙液試料中のタンパク質濃度を求めた。MUC5AC濃度を、涙液タンパク質含量に対して正規化し、涙液総タンパク質(ミリグラム)当たりのMUC5ACタンパク質(ナノグラム)として表した。
本発明は、角膜からかつ/又は角膜内でのムチンの産生/放出/送達/排出を誘導、促進、及び/又は改善する1種若しくは2種以上の化合物及び/又は抽出物を含む。
−5〜300g/Lの固形分含量、
−4〜9のpH、
−2〜170g/Lのタンパク質含量、及び
−1〜100g/Lの範囲の糖含量
−次いで、バイオマスをボールミルで粉砕する。次いで、粉砕された材料を、1リットル当たり50グラムの濃度で水に再懸濁させた後、基本培地で30℃で6時間、酵素加水分解する。
−加水分解後、産生物を遠心分離し、滅菌前に濾過する。
−異なるサイズのフィルタ上で連続的に濾過することにより、固形物の総重量に対して少なくとも30%のマンナンを含有する加水分解物が得られ、かつ/又は特定の重量平均分子量のタンパク質が得られる。(得られた加水分解物は淡黄色の透明な液体水溶液の形態である。)
1.ピキア・アノマーラ抽出物A:
I.ピキア・アノマーラ抽出物Aの抽出:
ピキア・アノマーラ抽出物Aの調製は、以下の工程を含む。
−成長に適合した環境における酵母ピキア・アノマーラの培養、
−バイオマスを回収するための遠心分離、
−バイオマスの可溶化、
−塩基性pHでの酵素加水分解、
−可溶性相と不溶性相との分離、
−熱処理
−濾過、及び
−滅菌濾過。
II.ピキア・アノマーラ抽出物Aの特性評価:
上記のピキア・アノマーラ抽出物Aは、以下を特徴とする。
− −48〜84g/Lの固形分含量、
− −4〜9のpH、
− −19〜48g/Lのタンパク質含量、及び
− −10〜42g/Lの総糖含量。
2.ピキア・アノマーラ抽出物B
I.ピキア・アノマーラ抽出物Bの抽出:
ピキア・アノマーラ抽出物Bの調製は、以下の工程を含む。
−成長に適合した環境における酵母ピキア・アノマーラの培養、
−バイオマスを回収するための遠心分離、
−バイオマスの可溶化、
−酸pHでの酵素加水分解、
−可溶性相と不溶性相との分離、
−熱処理
−濾過、及び
−滅菌濾過。
II.ピキア・アノマーラ抽出物Bの特性評価:
上記のピキア・アノマーラ抽出物Bは、以下を特徴とする。
− −58〜95g/Lの固形分含量、
− −4〜9のpH、
− −23〜54g/Lのタンパク質含量、及び
− −12〜32g/Lの総糖含量。
3.ピキア・アノマーラ抽出物C
I.ピキア・アノマーラ抽出物Cの抽出:
ピキア・アノマーラ抽出物Cの調製は、以下の工程を含む。
−成長に適合した環境における酵母ピキア・アノマーラの培養、
−バイオマスを回収するための遠心分離、
−バイオマスの可溶化、
−基本培地での連続的な酵素加水分解、
−可溶性相と不溶性相との分離、
−熱処理
−濾過、及び
−滅菌濾過。
II.ピキア・アノマーラ抽出物Cの特性評価:
上記のピキア・アノマーラ抽出物Cは、以下を特徴とする。
− −91〜195g/Lの固形分含量、
− −4〜9のpH、
− −36〜111g/Lのタンパク質含量、及び
− −18〜65g/Lの総糖含量。
4.ピキア・アノマーラ抽出物D
I.ピキア・アノマーラ抽出物Dの抽出:
ピキア・アノマーラ抽出物Dの調製は、以下の工程を含む。
−成長に適合した環境における酵母ピキア・アノマーラの培養、
−バイオマスを回収するための遠心分離、
−バイオマスの可溶化、
−酸pHで少なくとも2つの酵素と同時に加水分解、
−可溶性相と不溶性相との分離、
−熱処理
−濾過、及び
−滅菌濾過。
II.ピキア・アノマーラ抽出物Dの特性評価:
上記のピキア・アノマーラ抽出物Dは、以下を特徴とする。
− −5〜53g/Lの固形分含量、
− −4〜9のpH、
− −2〜30g/Lのタンパク質含量、及び
− −1〜18g/Lの総糖含量。
5.ピキア・アノマーラ抽出物E
I.ピキア・アノマーラ抽出物Eの抽出:
ピキア・アノマーラ抽出物Eの調製は、以下の工程を含む。
−成長に適合した環境における酵母ピキア・アノマーラの培養、
−バイオマスを回収するための遠心分離、
−ヒドログリコール性環境におけるバイオマスの可溶化、
−酸pHで少なくとも2つの酵素と同時に加水分解、
−可溶性相と不溶性相との分離、
−熱処理
−濾過、及び
−滅菌濾過。
II.ピキア・アノマーラ抽出物Eの特性評価:
上記のピキア・アノマーラ抽出物Eは、以下を特徴とする。
− −172〜300g/Lの固形分含量、
− −4〜9のpH、
− −69〜170g/Lのタンパク質含量、及び
− −34〜100g/Lの総糖含量。
特定の実施形態では、本発明の組成物は、任意選択的に、透過促進剤を含む。
本発明の組成物はまた、水性、水中油型エマルション、又は油中水型エマルションキャリアも含む。担体は、眼科的に許容可能である。有用な水中油型担体及び水−油担体は、米国特許公開第20030165545(A1)号並びに米国特許第9480645号、同第8828412号及び同第8496976号に見出すことができ、これらの特許文献の各々は、その全体が参照により本明細書に組み込まれる。
(実施例1)
タイトジャンクション構造(すなわち、組織への化学的浸透を通常阻害するこれらの表面構造[例えば、膜又は薄膜バリア])によって潜在的に引き起こされる妨害を低減するために、ヒト上角膜3D組織におけるムチン分泌の誘導は、角膜組織の底部細胞層(すなわち、組織への化学的浸透を阻害するタイトジャンクション構造を有しない細胞層)を増殖培地中に浸漬するように、角膜組織をピキア・アノマーラ発酵抽出物(ヒアルロジン)を含有する増殖培地(すなわち、「処置」培地)と接触させることによって観察された。角膜組織の底部細胞層をピキア・アノマーラ発酵抽出物を含有する増殖培地と接触させることによって、抽出物は、任意のタイトジャンクション構造又は他の表面バリアを最初に通過する必要なく直接接触し、内側角膜組織内へと上方に移動することができ、角膜組織細胞へのピキア・アノマーラの改善された生物学的利用能をもたらす。
0.39mg/mL、0.78mg/mL、1.56mg/mL、及び1.95mg/mLの濃度のピキア・アノマーラ発酵抽出物(ヒアルロジン)を含有するように処置した増殖培地中のヒトの上角膜3D組織は、ヒト上角膜3D組織におけるMUC4遺伝子発現の増加を示した。*、p<0.05。
PBS中の1.95mg/mL、7.8mg/mL、19.5mg/mL及び39mg/mLの濃度のピキア・アノマーラ抽出物を有する組成物は、角膜組織細胞に局所適用されたときに、ヒトの上角膜3D組織におけるムチン−1分泌の増加を示した。*、p<0.05。
表1は、従来の混合技術を使用して、その構成成分を以下に記載されるように組み込むことができる、(配合物4A及び4Bに示すような)そのような配合物の構成成分を例示する。
1.1500mLビーカーに、800グラムの精製水USPを添加する。
2.上記に、10gのポリソルベート80及び50gのポリソルベート20を添加する。両者が十分混合及び溶解するまで、溶液を混合する。
3.上記に、20.0gのキウイ抽出物を添加する。キウイ抽出物が溶解するまで溶液を混合する。
4.溶液を0.45マイクロメートルのフィルタを通して濾過し、1500mLビーカーに戻す。
5.工程4の溶液に、2.0グラムのヒアルロン酸ナトリウムを添加する。溶液を混合して、ヒアルロン酸ナトリウムを完全に溶解させる。
6.次に、以下の成分を順次添加し、次のものを添加する前に各々を溶解させる:2.5グラムのポリエチレングリコール400、6.0グラムのホウ酸、0.05グラムのホウ酸ナトリウム、1.0グラムの塩化カリウム、0.06グラムの塩化カルシウム二水和物、0.06グラムの塩化マグネシウム、及び0.0015グラムのポリクオタニウム42(水溶液)。
7.混合を継続しながら、0.14グラムの亜塩素酸ナトリウム二水和物を添加し、かつ混合して溶解させる。
8.処方物の張度を求め、塩化ナトリウムで280mOsm/Kgに調整する。
9.1N水酸化ナトリウム及び/又は1N塩酸を用いて、処方物のpHを7.2のpHに調整する。
10.精製水USPを用いて溶液を1000.0グラムにし、かつ10分間混合して完全に均一にする。
11.0.22マイクロメートルのフィルタを用いて溶液を濾過する。
1.1500mLビーカーに、800グラムの精製水USPを添加する。
2.上記に、20gのポリソルベート10及び100gのポリソルベート20を添加する。両者が十分混合及び溶解するまで、溶液を混合する。
3.上記に、50gのキウイ抽出物を添加する。キウイ抽出物が溶解するまで溶液を混合する。
4.溶液を0.45マイクロメートルのフィルタを通して濾過し、1500mLビーカーに戻す。
5.工程4の溶液に、1.5グラムのヒアルロン酸ナトリウムを添加する。溶液を混合して、ヒアルロン酸ナトリウムを完全に溶解させる。
6.次に、以下の成分を順次添加し、次のものを添加する前に各々を溶解させる:6.0グラムのホウ酸、0.05グラムのホウ酸ナトリウム、1.0グラムの塩化カリウム、0.06グラムの塩化カルシウム二水和物、0.06グラムの塩化マグネシウム、及び0.0015グラムのポリクオタニウム42(水溶液)。
7.混合を続けながら、0.14グラムの塩化ナトリウム二水和物を添加し、かつ混合して溶解させる。
8.処方物の張度を求め、塩化ナトリウムで280mOsm/Kgに調整する。
9.1N水酸化ナトリウム及び/又は1N塩酸を用いて、処方物のpHを7.2のpHに調整する。
10.精製水USPを用いて溶液を1000.0グラムにし、かつ10分間混合して完全に均一にする。
11.0.22マイクロメートルのフィルタを用いて溶液を濾過する。
表2は、従来の混合技術を使用して以下に記載されるように成分を組み込むことができる、本発明の製剤(製剤5A及び5Bに示すような)の成分を示す。
1.1500mLビーカーに、800グラムの精製水USPを添加する。
2.上記に、10gのポリソルベート80及び30gのポリソルベート20を添加する。両者が十分混合及び溶解するまで、溶液を混合する。
3.上記に、10.0gのキウイ抽出物を添加する。キウイ抽出物が溶解するまで溶液を混合する。
4.溶液を0.45マイクロメートルのフィルタを通して濾過し、1500mLビーカーに戻す。
5.上記に、1.98gのヒプロメロースE3 Premiumを添加する。ヒプロメロースE3 Premiumが溶解するまで溶液を混合する。
6.次に次の成分を順次添加し、次のものを添加する前に各々を溶解させる:2.50グラムのグリセリン、4.0グラムのホウ酸、0.22グラムのホウ酸ナトリウム、0.27グラムのリン酸二ナトリウム、4.00グラムのクエン酸ナトリウム二水和物、1グラムの塩化カリウム、0.57グラムの乳酸ナトリウム(50%水溶液)、0.13グラムの塩化マグネシウム、0.036グラムのグルコース、0.0002グラムのグリシン、0.0001グラムのアスコルビン酸、0.10グラムのエデト酸二ナトリウム、0.030グラムのポリクオタニウム−42(33%水溶液)、及び0.14グラムの亜塩素酸ナトリウム。
7.溶液の張度を求め、かつ塩化ナトリウムで280mOsmに調整する。
8.溶液のpHを測定し、かつ1N水酸化ナトリウム及び/又は1N塩酸で7.2に調整する。
9.溶液を精製水で1,000.00グラムの体積にし、かつ10分間混合する。
10.0.22マイクロメートルのフィルタを用いて溶液を濾過する。
1.1500mLビーカーに、800グラムの精製水USPを添加する。
2.上記に、10gのポリソルベート80及び50gのポリソルベート20を添加する。両者が十分混合及び溶解するまで、溶液を混合する。
3.上記に、20.0gのキウイ抽出物を添加する。キウイ抽出物が溶解するまで溶液を混合する。
4.溶液を0.45マイクロメートルのフィルタを通して濾過し、1500mLビーカーに戻す。
5.上記に、1.98gのヒプロメロースE3 Premiumを添加する。ヒプロメロースE3 Premiumが溶解するまで溶液を混合する。
6.次に次の成分を順次添加し、次のものを添加する前に各々を溶解させる:2.50グラムのグリセリン、4.0グラムのホウ酸、0.22グラムのホウ酸ナトリウム、0.27グラムのリン酸二ナトリウム、4.00グラムのクエン酸ナトリウム二水和物、1グラムの塩化カリウム、0.57グラムの乳酸ナトリウム(50%水溶液)、0.13グラムの塩化マグネシウム、0.036グラムのグルコース、0.0002グラムのグリシン、0.0001グラムのアスコルビン酸、0.05グラムのエデト酸二ナトリウム、0.015グラムのポリクオタニウム−42(33%水溶液)、及び0.14グラムの亜塩素酸ナトリウム。
7.溶液の張度を求め、かつ塩化ナトリウムで280mOsmに調整する。
8.溶液のpHを測定し、かつ1N水酸化ナトリウム及び/又は1N塩酸で7.2に調整する。
9.溶液を精製水で1,000.00グラムの体積にし、かつ10分間混合する。
10.0.22マイクロメートルのフィルタを用いて溶液を濾過する。
1.眼を治療するための組成物であって、
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)眼科的に許容可能な担体と、を含む、組成物。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
(1) 眼を治療するための組成物であって、
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)眼科的に許容可能な担体と、を含む、組成物。
(2) 前記ピキア属が、ピキア・アノマーラ、ピキア・ギリエルモンディ、ピキア・ノルベジェンシス、ピキア・オーメリ、及びこれらの混合物から選択される、実施態様1に記載の組成物。
(3) 前記ピキア属が、ピキア・アノマーラである、実施態様2に記載の組成物。
(4) 前記ピキア属の前記1種若しくは2種以上の抽出物又は抽出物源が、前記組成物全体の約0.001重量%〜約100重量%の濃度で存在する、実施態様1に記載の組成物。
(5) 前記ピキア属の前記1種若しくは2種以上の抽出物又は抽出物源が、前記組成物全体の約0.005重量%〜約95重量%の濃度で存在する、実施態様1に記載の組成物。
(7) 透過促進剤を含む、実施態様1に記載の組成物。
(8) 前記透過促進剤が、前記組成物全体の約0.01%(w/v)〜約20%(w/v)の濃度で存在する、実施態様7に記載の組成物。
(9) 前記透過促進剤が、前記組成物全体の約0.1%(w/v)〜10%(w/v)の濃度で存在する、実施態様8に記載の組成物。
(10) 前記透過促進剤が、前記組成物全体の約0.25%(w/v)〜5%(w/v)の濃度で存在する、実施態様9に記載の組成物。
(12) 前記ピキア属の抽出物が、約180〜約800,000Daの重量平均分子量を有するオリゴ糖及び多糖類を含む、実施態様1に記載の組成物。
(13) 前記ピキア属の抽出物が、DP1〜DP4444の平均重合度を有するオリゴ糖及び多糖類を含む、実施態様1に記載の組成物。
(14) 組成物を投与する工程を含む、角膜からかつ/又は角膜内でムチンを産生/放出/送達/排出するための方法であって、前記組成物が、
iii)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
iv)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
(15) 前記ピキア属が、ピキア・アノマーラ、ピキア・ギリエルモンディ、ピキア・ノルベジェンシス、ピキア・オーメリ、及びこれらの混合物から選択される、実施態様14に記載の方法。
(17) 組成物を投与する工程を含む、涙中のMU5ACの濃度をタンパク質1ミリグラム当たり8ナノグラム以上15ナノグラムの範囲内に維持するための方法であって、前記組成物が、
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
(18) 眼、患者に組成物を局所投与する工程を含む、角膜からかつ/又は角膜内でのムチンの減少した又は低レベルの産生/放出/送達/排出を有する患者を治療するための方法であって、前記組成物が、
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
(19) 組成物を投与する工程を含む、患者の眼の中かつ/又は眼の上の創傷の治癒を促進するか又は治癒速度を増加させるための方法であって、前記組成物が、
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
(20) 組成物を投与する工程を含む、患者の涙における抗菌特性を改善するための方法であって、前記組成物が、
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)任意選択的に、眼科的に許容可能な担体と、を含む、方法。
Claims (13)
- 眼を治療するための組成物であって、
i)ピキア属の1種若しくは2種以上の抽出物又は抽出物源と、
ii)眼科的に許容可能な担体と、を含む、組成物。 - 前記ピキア属が、ピキア・アノマーラ、ピキア・ギリエルモンディ、ピキア・ノルベジェンシス、ピキア・オーメリ、及びこれらの混合物から選択される、請求項1に記載の組成物。
- 前記ピキア属が、ピキア・アノマーラである、請求項2に記載の組成物。
- 前記ピキア属の前記1種若しくは2種以上の抽出物又は抽出物源が、前記組成物全体の約0.001重量%〜約100重量%の濃度で存在する、請求項1に記載の組成物。
- 前記ピキア属の前記1種若しくは2種以上の抽出物又は抽出物源が、前記組成物全体の約0.005重量%〜約95重量%の濃度で存在する、請求項1に記載の組成物。
- 前記ピキア属の前記1種若しくは2種以上の抽出物又は抽出物源が、前記組成物全体の約0.01重量%〜約90重量%の濃度で存在する、請求項1に記載の組成物。
- 透過促進剤を含む、請求項1に記載の組成物。
- 前記透過促進剤が、前記組成物全体の約0.01%(w/v)〜約20%(w/v)の濃度で存在する、請求項7に記載の組成物。
- 前記透過促進剤が、前記組成物全体の約0.1%(w/v)〜10%(w/v)の濃度で存在する、請求項8に記載の組成物。
- 前記透過促進剤が、前記組成物全体の約0.25%(w/v)〜5%(w/v)の濃度で存在する、請求項9に記載の組成物。
- 前記透過促進剤が、ポリオキシエチレン、脂肪酸のポリオキシエチレンエーテル、モノオレイン酸ソルビタン、モノラウリン酸ソルビタン、モノラウリン酸ポリオキシエチレン、モノラウリン酸ポリオキシエチレンソルビタン、フシジン酸及びその誘導体、EDTA、EDTA二ナトリウム、コール酸、デオキシコール酸、グリココール酸、グリコデオキシコール酸、タウロコール酸、タウロデオキシコール酸、コール酸ナトリウム、グリココール酸ナトリウム、グリココール酸塩、デオキシコール酸ナトリウム、タウロコール酸ナトリウム、グリコデオキシコール酸ナトリウム、タウロデオキシコール酸ナトリウム、ケノデオキシコール酸、ウルソデオキシコール酸、サポニン、グリチルリチン酸、グリチルリチン酸アンモニウム、デカメトニウム、臭化デカメトニウム、及び臭化ドデシルトリメチルアンモニウム、又は上記のうちのいずれかの混合物から選択される、請求項7に記載の組成物。
- 前記ピキア属の抽出物が、約180〜約800,000Daの重量平均分子量を有するオリゴ糖及び多糖類を含む、請求項1に記載の組成物。
- 前記ピキア属の抽出物が、DP1〜DP4444の平均重合度を有するオリゴ糖及び多糖類を含む、請求項1に記載の組成物。
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CA3106898A1 (en) | 2020-01-30 |
AU2019311849B2 (en) | 2023-06-08 |
CN112654359A (zh) | 2021-04-13 |
US20220378858A1 (en) | 2022-12-01 |
KR20210038600A (ko) | 2021-04-07 |
EP3829610A1 (en) | 2021-06-09 |
BR112021000634A2 (pt) | 2021-04-06 |
US11878042B2 (en) | 2024-01-23 |
AU2019311849A1 (en) | 2021-01-21 |
ZA202101360B (en) | 2022-07-27 |
JP2024109914A (ja) | 2024-08-14 |
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