JP2022500405A - 阻害の方法 - Google Patents
阻害の方法 Download PDFInfo
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- JP2022500405A JP2022500405A JP2021513845A JP2021513845A JP2022500405A JP 2022500405 A JP2022500405 A JP 2022500405A JP 2021513845 A JP2021513845 A JP 2021513845A JP 2021513845 A JP2021513845 A JP 2021513845A JP 2022500405 A JP2022500405 A JP 2022500405A
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- Prior art keywords
- dopamine
- acid
- composition
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- pharmaceutically acceptable
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- 230000005764 inhibitory process Effects 0.000 title description 5
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- 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
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- 239000008159 sesame oil Substances 0.000 description 1
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- 229940001474 sodium thiosulfate Drugs 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 238000007619 statistical method Methods 0.000 description 1
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- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
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Abstract
Description
本出願は、2018年9月13日に出願した「阻害の方法」と題されたオーストラリア仮出願第2018903445号に優先権を主張し、その全ての内容がこれによって参照によって本明細書に組み込まれる。
特に断りがない限り、本明細書で用いられる技術的及び科学的用語は、本発明に属する当該技術分野の当業者により一般的に理解されているものと同じ意味を有する。本明細書に記載されるものと同様又は同等の任意の方法及び材料を本発明の実行又は試験において用いることができ、好ましい方法及び材料を記載する。本発明の目的のための、次の用語は以下に定義される。
次の略語は本出願を通じて使用される:
D=重水素
本発明は、ドパミン[2−(3,4−ジヒドロキシフェニル)エチルアミン]又は重水素化したドパミン誘導体又はそのアナログが眼組織に浸透することができ、そして網膜を含む、後眼部の構造に影響を与えうる発見に部分的に基づいている。従って、本発明は、ドパミン又は重水素化したドパミン又は重水素化したドパミンの誘導体を含む組成物が局所的に投与されることができ、対象、特に減少したドパミン濃度、例えば近眼、糖尿病性網膜症に関連した視覚障害、又はパーキンソン病に関連した視覚障害を含む後眼部における視覚障害の発生又は進行を阻害することを考え出した。
R1、R2、R3、R4、R5、R6、R7、R8、R10及びR11がH及びDより互いに独立して選択され;
R9はH、D及びC(O)OR12より選択され;
R12はH及びDより選択され;かつ
ここで少なくとも一つのR1〜R12がDである。
本発明の組成物は、対象における、視覚障害、特に眼内の減少したドパミン濃度を含む視覚障害、例えば糖尿病性網膜症又はパーキンソン病、又は近眼に関係した視覚障害の進行又は発生を阻害するために有用である。従って、本発明の組成物は対象の視覚障害の進行又は発生を阻害する方法において用いられうる。また、本発明の組成物は本明細書に記載される使用のための薬剤の製造において用いられうる。
150mMストック溶液を作製するために、(Sigma−Aldrich Co.LLCから商用利用可能な、ドパミン塩酸塩の形態において)28.4mgのドパミンを1×PBS(pH約5.5)中に0.1%アスコルビン酸を含む溶液1mLに溶解した。そのストック溶液をさらに1×PBS中に0.1%アスコルビン酸を含む溶液の適当量に希釈し、0.15mM(0.0028重量%)、1.5mM(0.028重量%)及び15mM(0.28重量%)溶液を作製した。
30羽の白い雄鶏を以下に定義される6つの治療群(1群あたりn=5)にランダムに割り当て4日間治療した。
・左目に半透明のディフューザーを装着して、形態覚遮断近視(FDM)を誘導したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例1に従って調製した1.5mM(0.028%)のドパミン溶液を硝子体内に注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例1に従って調製した1.5mM(0.028%)のドパミン溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例1に従って調製した15mM(0.28%)のドパミン溶液を硝子体内に注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例1に従って調製した15mM(0.28%)のドパミン溶液を局所投与したヒヨコ;
・同齢の未処理のコントロール群。
本結果を図1に示す。硝子体内注射を介するドパミン溶液の投与は、形態覚遮断近視(FDM;9.12±0.05mm)(ANOVA,F(3,23)=6.934,p=0.002;図1)に関連した軸の伸長を阻害した。調査したドパミン濃度(1.5mM及び15mM)の両方は、ディフューザーのみで処理した対応においてみられたものと比較して形態覚遮断近視に関係した軸の伸長を著しく阻害した(1.5mM:8.82±0.04mm、78%保護、p<0.05;15mM:8.82±0.11mm、78%保護、p<0.05)。さらに、両方のドパミン濃度で処理した眼の軸長は、同齢の未処理のヒヨコと統計的に差異はなかった(8.74±0.04mm、両方の濃度についてp=1,000)。全ての条件にわたり、前房深度(ANOVA,F(3,23)=0.348,p=0.791)又はレンズの厚さ(ANOVA,F(3,23)=6.112,p=0.003)における差異はなかった。
70羽の白い雄鶏を以下に定義される14処理群の一つにランダムに割り当て、そして4日間処理した。
・左目に半透明のディフューザーを装着して、FDMを誘導したヒヨコ;
・同齢の未処理のコントロール群;
・左目に半透明のディフューザーを装着して、1日1回実施例1に従って調製した0.15mM(0.0028%)のドパミン溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回0.25mM(0.018%)のアトロピン溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例1に従って調製した0.15mM(0.0028%)のドパミン及び0.25mM(0.018%)のアトロピン溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回17mM(0.72%)のピレンゼピン溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回0.15mM(0.0028%)のドパミン及び17mM(0.72%)のピレンゼピン溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回18.6mM(0.29%)のTPMPA溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例1に従って調製した0.15mM(0.0028%)のドパミン及び18.6mM(0.29%)のTPMPA溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例1に従って調製した1.5mM(0.028%)のドパミン溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回50mM(3.5%)のアトロピン溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例1に従って調製した1.5mM(0.028%)のドパミン及び50mM(3.5%)アトロピン溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回18.6mM(0.29%)のTPMPA溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例1に従って調製した1.5mM(0.028%)のドパミン及び18.6mM(0.29%)のTPMPA溶液を局所投与したヒヨコ。
本結果を図2及び3に示す。ムスカリン性アセチルコリン受容体拮抗薬のアトロピン;M1ムスカリン性アセチルコリン受容体拮抗薬のピレンゼピン;及びGABAc受容体拮抗薬のTPMPA;単体又は硝子体内注射によるドパミン(0.15mM)との組み合わせのいずれかの投与は、形態覚遮断近視に関連した超過した軸の伸長を阻害した(ANOVA,F(8,53)=7.894,p<0.000;図2)。重要なことに、ドパミンと任意の3つの化合物とを組み合わせることは、形態覚遮断近視がこれらの化合物が単体で投与される場合と比較して阻害される程度において小さいが有意な改善を誘発した(ドパミン及びアトロピン:8.76±0.02mm,p<0.000;ドパミン及びピレンゼピン:8.76±0.03mm、p<0.000;ドパミン及びTPMPA:8.60±0.07mm、p<0.000)。試験した全ての条件にわたり、前房深度(ANOVA,F(8,53)=0.426,p=0.900)又はレンズの厚さ(ANOVA,F(8,53)=1.349,p=0.241)において有意な差異はなかった。代わりに、ディフューザー装着及び試験化合物の硝子体内注射に関連して、軸長における変化は硝子体眼房深度内の変化を示した(ANOVA,F(8,53)=7.561,p=0.000)。
150mMのストック溶液を作製するために、(Sigma−Aldrich Co.LLCより商用利用可能な、ドパミン−1,1,2,2−d4塩酸塩の形態において)29mgドパミン−1,1,2,2−d4を1×PBS中に0.1%アスコルビン酸を含む溶液1mLに溶解した(pH約5.5)。そのストック溶液をさらに1×PBS中に0.1%アスコルビン酸を含む溶液の適当量において希釈し、0.15mM(0.0029重量%)、1.5mM(0.029重量%)及び15mM(0.29重量%)溶液を作製した。
30羽の白い雄鶏を以下に定義される(1群あたりn=5の)6つの処理群の一つにランダムに割り当て、そして4日間処理した。
・左目に半透明のディフューザーを装着して、FDMを誘導したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例4に従って調製した15mM(0.29%)のドパミン−1,1,2,2−d4溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例4に従って調製した1.5mM(0.029%)のドパミン−1,1,2,2−d4溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例4に従って調製した15mM(0.29%)のドパミン−1,1,2,2−d4溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例4に従って調製した1.5mM(0.029%)のドパミン−1,1,2,2−d4溶液を局所投与したヒヨコ;
・同齢の未処理のコントロール群;
本結果を図4に示す。ドパミン−1,1,2,2−d4溶液の硝子体内投与は、形態覚遮断近視に関連した軸の成長を著しく阻害した(ANOVA,F(3,22)=13.562,p<0.000;図4)。図4に見られうるように、試験したドパミン−1,1,2,2−d4溶液の両方の濃度(1.5mM及び15mM)は、ディフューザーのみの処理した動物に見られる軸の伸長と比較して、同様の水準の保護を実証した(1.5mM:8.77±0.11mm、92%保護、p<0.001;15mM:8.72±0.06mm、103%保護、p<0.001)。ドパミン−1,1,2,2−d4の両方の濃度で、ディフューザー処理した眼の眼軸長はそれらの同齢の未処理の一方と差異はなかった(1.5mM p=0.686,15mM p=0.707)。試験した全ての条件にわたり、前房深度(ANOVA,F(3,24)=0.646,p=0.594)及びレンズの厚さ(ANOVA,F(3,24)=1.627,p=0.213)の両方に有意差は無かった。代わりに、ディフューザー装着及びドパミンの硝子体内注射に関連した眼軸長の変化は、硝子体眼房深度における変化を示した(ANOVA,F(3,24)=9.592,p<0.000)。
60羽の白い雄鶏を以下に定義される(1群当たりn=5の)12処理群の一つにランダムに割り当て、そして4日間処理した。
・左目に半透明のディフューザーを装着して、FDMを誘導したヒヨコ;
・同齢の未処理のコントロール群;
・左目に半透明のディフューザーを装着して、1日1回実施例4に従って調製した0.15mM(0.0029%)のドパミン−1,1,2,2−d4溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回0.25mM(0.018%)のアトロピン溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例4に従って調製した0.15mM(0.0029%)のドパミン−1,1,2,2−d4及び0.25mM(0.018%)のアトロピン溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回18.6mM(0.29%)のTPMPA溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日1回実施例4に従って調製した0.15mM(0.0029%)のドパミン−1,1,2,2−d4及び18.6mM(0.29%)のTPMPA溶液を硝子体内注射したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例4に従って調製した1.5mM(0.029%)のドパミン−1,1,2,2−d4溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回50mM(3.5%)のアトロピン溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例4に従って調製した1.5mM(0.029%)のドパミン−1,1,2,2−d4及び50mM(3.5%)アトロピン溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回18.6mM(0.29%)のTPMPA溶液を局所投与したヒヨコ;
・左目に半透明のディフューザーを装着して、1日2回実施例4に従って調製した1.5mM(0.029%)のドパミン−1,1,2,2−d4及び18.6mM(0.29%)のTPMPA溶液を局所投与したヒヨコ。
本結果を図5及び6において示した。硝子体内注射を介したアトロピン若しくはTPMPAのいずれかとの組み合わせたドパミン−1,1,2,2−d4の投与は、又は硝子体内注射を介したこれらの化合物単体の各投与は、形態覚遮断近視に関連した過剰な軸の伸長を有意に阻害した(ANOVA,F(6,44)=16.918,p<0.000;図5)。重要なことに、ドパミン−1,1,2,2−d4とTPMPAとの組み合わせは、これらの化合物が単体で投与される場合と比較して、形態覚遮断近視が阻害される程度に小さいが有意な改善を誘発した(ドパミン−1,1,2,2−d4及びTPMPA;8.61±0.05mm、p=0.014)。ドパミン−1,1,2,2−d4とアトロピンとの組み合わせは、形態覚遮断近視が阻害される程度に小さいが有意でない改善をもたらした(ドパミン−1,1,2,2−d4及びアトロピン:8.73±0.07mm,p=0.068)。全ての条件にわたり、前房深度(ANOVA,F(6,44)=0.508,p=0.809)又はレンズの厚さ(ANOVA,F(6,44)=0.626,p=0.708)における差異はなかった。代わりに、ディフューザー装着及び試験化合物の硝子体内注射に関連した、眼軸長の変化は硝子体眼房深度における変化を示した(ANOVA,F(6,44)=12.758,p<0.000)。
Claims (56)
- 対象における視覚障害の発生又は進行を阻害するための方法であって、前記対象の眼にドパミン又はその医薬的に許容可能な塩を含む組成物を局所的に投与することを含む方法。
- 前記組成物がさらに水性担体を含む、請求項1に記載の方法。
- 前記水性担体が、生理食塩水、水、水性緩衝剤、水及び混和性溶媒含む水性溶液、並びにそれらの組み合わせからなる群から選択される、請求項2に記載の方法。
- 前記組成物がさらに抗酸化剤を含む、請求項1〜3のいずれか一項に記載の方法。
- 前記抗酸化剤が、アスコルビン酸、フェノール酸、ソルビン酸、亜硫酸水素ナトリウム、二亜硫酸ナトリウム、アセチルシステイン、チオ硫酸ナトリウム、エチレンジアミン四酢酸、亜硝酸ナトリウム、ステアリン酸アスコルビル、パルミチン酸アスコルビル、α−チオグリセロール、エリソルビン酸、塩酸システイン、クエン酸、トコフェロール、又はビタミンE、酢酸トコフェロール、ジブチルヒドロキシトルエン、大豆レチシン、チオグリコール酸ナトリウム、ブチルヒドロキシアニソール、没食子酸プロピル、尿酸、メラトニン、チオ尿素、並びにそれらの医薬的に許容可能な塩及びそれらの組み合わせからなる群より選択される。
- 前記視覚障害が、近眼、糖尿病性網膜症と関連した視覚障害、及びパーキンソン病と関連した視覚障害からなる群より選択される、請求項1〜5のいずれか一項に記載の方法。
- 前記視覚障害が近眼である、請求項6に記載の方法。
- ドパミン受容体作動薬を同時に、別々に、又は連続して投与することをさらに含む、請求項1〜7のいずれか一項に記載の方法。
- 前記ドパミン受容体作動薬がレボドパ、キンピロール、アポモルフィン、ロピニロール、プラミペキソール、デクスプラミペキソール、ピリベジル、ロチゴチン、ブロモクリプチン、リスリド、カベルゴリン、2−アミノ−6,7−ジヒドロキシ−1,2,3,4−テトラリン、ペルゴリド、Calidopa、ジヒドレキシジン、doxathrine、プロピルノルアポモルフィン、キナゴリド、ロキシンドール、スマニロール、フェノルドパム、エルゴコルニン、1−フェニル−2,3,4,5−テトラヒドロ−(1H)−3−ベンザゼピン−7,8−ジオール、2−(N−フェネチル−N−プロピル)アミノ−5−ヒドロキシテトラリン、ジヒドロエルゴタミン、(1R,3S)−1−(アミノメチル)−3−フェニル−3,4−ジヒドロ−1H−イソクロメン−5,6−ジオール、カルモキシロール、フェノルドパム、並びにそれらの医薬的に許容可能な塩及びそれらの組み合わせからなる群より選択される、請求項8に記載の方法。
- GABA受容体拮抗薬を同時に、別々に、又は連続して投与することをさらに含む、請求項1〜9のいずれか一項に記載の方法。
- 前記GABA受容体作動薬がビククリン、フルマゼニル、ガバジン、フェニレンテトラゾール(phenylenetetrazol)、(1,2,5,6−テトラヒドロピリジン−4−イル)メチルホスフィン酸、(3−アミノプロピル)(シクロヘキシルメチル)ホスフィン酸、並びにそれらの医薬的に許容可能な塩及びそれらの組み合わせからなる群より選択される、請求項10に記載の方法。
- ムスカリン性アセチルコリン受容体拮抗薬を同時に、別々に、又は連続して投与することをさらに含む、請求項1〜11のいずれか一項に記載の方法。
- 前記ムスカリン性アセチルコリン受容体拮抗薬がアトロピン、ピレンゼピン、ヒンバシン、ヒヨスチン、シクロペントラート、イプラトロピウム、オキシトロピウム、トロピカミド、オキシブチニン、トルテロジン、ジフェンヒドラミン、ジシクロベリン、フラボキサート、チオトロピウム、トリヘキシフェニジル、ソリフェナシン、ダリフェナシン、ベンザトロピン、メベベリン、プロシクリジン、アクリジニウム、並びにそれらの医薬的に許容可能な塩及びそれらの混合物からなる群より選択される、請求項12のいずれか一項に記載の方法。
- 前記組成物がドパミン又はその医薬的に許容可能な塩の角膜上皮を通じる浸透のために製剤化される、請求項1〜13のいずれか一項に記載の方法。
- 前記組成物のpHが4から8の範囲内である、請求項1〜14のいずれか一項に記載の方法。
- 前記組成物のpHが5.0から7.0の範囲内である、請求項15に記載の方法。
- 前記組成物のpHが5.5から6.5の範囲内である、請求項16に記載の方法。
- 対象における視覚障害の発生又は進行を阻害するための方法であって、前記対象の眼に、重水素化したドパミン若しくは重水素化したドパミン誘導体、又はそれらの医薬的に許容可能な塩を含む、組成物を局所投与することを含む方法。
- 前記組成物が重水素化したドパミン又はその医薬的に許容可能な塩を含む、請求項18に記載の方法。
- 前記重水素化したドパミンがドパミン−1,1,2,2−d4[2−(3,4−ジヒドロキシフェニル)エチル−1,1,2,2,d4−アミン];2−(3,4−ジヒドロキシフェニル)エチル−1−ジュウテロ−アミン;2−(3,4−ジヒドロキシフェニル)エチル−2,2−ジジュウテロ−アミン:又はそれらの医薬的に許容可能な塩である、請求項19に記載の方法。
- 前記重水素化したドパミンがドパミン−1,1,2,2−d4塩酸塩である、請求項20に記載の方法。
- 前記組成物が重水素化したドパミン誘導体を含む、請求項18に記載の方法。
- 前記組成物が重水素化したレボドパ又はその医薬的に許容可能な塩を含む、請求項22に記載の方法。
- 前記組重水素化したレボドパが、2−アミノ−2−ジュウテロ−3−(3,4−ジヒドロフェニル)プロピオン酸;2−アミノ−2,3−ジジュウテロ−3−(3,4−ジヒドロキシフェニル)プロピオン酸;2−アミノ−2,3,3−トリジュウテロ−3−(3,4−ジヒドロキシフェニル)プロピオン酸;2−アミノ−3,3−ジジュウテロ−3−(3,4−ジヒドロキシフェニル)プロピオン酸;2−アミノ−3,3−ジジュウテロ−3−(3,4−ジジュウテロキシフェニル)プロピオン酸;2−アミノ−2−ジュウテロ−3−(2,3,6−トリジュウテロ−4,5−ジヒドロキシフェニル)プロピオン酸;2−アミノ−2,3−ジジュウテロ−3−(2,3,6−トリジュウテロ−4,5−ジヒドロキシフェニル)プロピオン酸);2−アミノ−2,3,3−トリジュウテロ−3−(2,3,6−トリジュウテロ−4,5−ジヒドロキシフェニル)プロピオン酸;2−アミノ−2,3,3−トリジュウテロ−3−(2,3,6−トリジュウテロ−4,5−ジジュウテロキシフェニル)プロピオン酸;又はそれらの医薬的に許容可能な塩からなる群より選択される、請求項23に記載の方法。
- 前記重水素化したレボドパが、2−アミノ−2,3,3−トリジュウテロ−3−(3,4−ジヒドロキシフェニル)プロピオン酸又はその医薬的な許容可能な塩である、請求項24に記載の方法。
- R6、R7、R8及びR9がDである、請求項26に記載の方法。
- R1、R2、R3、R4、R5、R10及びR11がHである、請求項26又は27に記載の方法。
- R9がC(O)OR12である、請求項26に記載の方法。
- R12がHである、請求項29に記載の方法。
- R6及びR7がDである、請求項29又は30に記載の方法。
- R8がDである、請求項31に記載の方法。
- R1及びR2がDである、請求項31に記載の方法。
- R3、R4及びR5がDである、請求項32又は33に記載の方法。
- R8がDである、請求項26に記載の方法。
- R6がDである、請求項35の記載の方法。
- R3、R4、及びR5がDである、請求項35又は36の記載の方法。
- 前記組成物がさらに水性担体を含む、請求項18〜37のいずれか一項に記載の方法。
- 前記水性担体が、生理食塩水、水、水性緩衝剤、水及び混和性溶媒を含む水性溶液、及びそれらの組み合わせからなる群より選択される、請求項38に記載の方法。
- 前記組成物がさらに抗酸化剤を含む、請求項18〜39のいずれか一項に記載の方法。
- 前記抗酸化物が、アスコルビン酸、フェノール酸、ソルビン酸、亜硫酸水素ナトリウム、二亜硫酸ナトリウム、アセチルシステイン、チオ硫酸ナトリウム、エチレンジアミン四酢酸、亜硝酸ナトリウム、ステアリン酸アスコルビル、パルミテート、α−チオグリセロール、エリソルビン酸塩、塩酸システイン、クエン酸、トコフェロール、又はビタミンE、酢酸トコフェロール、ジブチルヒドロキシトルエン、大豆レチシン、チオグリコール酸ナトリウム、ブチルヒドロキシアニソール、没食子酸プロピル、尿酸、メラトニン、チオ尿素、並びにそれらの医薬的に許容可能な塩及びそれらの組み合わせからなる群より選択される、請求項40に記載の方法。
- 前記視覚障害が、近眼、糖尿病性網膜症と関連した視覚障害、及びパーキンソン病と関連した視覚障害からなる群より選択される、請求項18〜41のいずれか一項に記載の方法。
- 前記視覚障害が近眼である、請求項42に記載の方法。
- ドパミン受容体作動薬を同時に、別々に、又は連続して投与することを含む、請求項18〜43のいずれか一項に記載の方法。
- 前記ドパミン受容体作動薬がレボドパ、キンピロール、アポモルフィン、ロピニロール、プラミペキソール、デスクプラミペキソール、ピリベジル、ロチゴチン、ブロモクリプチン、リスリド、カベルゴリン、2−アミノ−6,7−ジヒドロキシ−1,2,3,4−テトラリン、ペルゴリド、Calidopa、ジヒドレキシジン、doxathrine、プロピルノルアポモルフィン、キナゴリド、ロキシンドール、スマニロール、フェノルドパム、エルゴコルニン、1−フェニル−2,3,4,5−テトラヒドロ−(1H)−3−ベンザゼピン−7,8−ジオール、2−(N−フェネチル−N−プロピル)アミノ−5−ヒドロキシテトラリン、ジヒドロエルゴタミン、(1R,3S)−1−(アミノメチル)−3−フェニル−3,4−ジヒドロ−1H−イソクロメン−5,6−ジオール、カルモキシロール、フェノルドパム、並びにそれらの医薬的に許容可能な塩及びそれらの組み合わせからなる群より選択される、請求項44に記載の方法。
- GABA受容体拮抗薬を同時に、別々に、又は連続して投与することを含む、請求項18〜45のいずれか一項に記載の方法。
- 前記GABA受容体拮抗薬がビククリン、フルマゼニル、ガバジン、フェニレンテトラゾール(phenylenetetrazol)、(1,2,5,6−テトラヒドロピリジン−4−イル)メチルホスフィン酸、(3−アミノプロピル)(シクロヘキシルメチル)ホスフィン酸、並びにそれらの医薬的に許容可能な塩及びそれらの組み合わせからなる群より選択される、請求項46に記載の方法。
- 前記ムスカリン性アセチルコリン受容体拮抗薬を同時に、別々に、又は連続して投与することをさらに含む、請求項18〜47のいずれか一項に記載の方法。
- 前記ムスカリン性アセチルコリン受容体拮抗薬がアトロピン、ピレンゼピン、ヒンバシン、ヒヨスチン、シクロペントラート、イプラトロピウム、オキシトロピウム、トロピカミド、オキシブチニン、トルテロジン、ジフェンヒドラミン、ジシクロベリン、フラボキサート、チオトロピウム、トリヘキシフェニジル、ソリフェナシン、ダリフェナシン、ベンザトロピン、メベベリン、プロシクリジン、アクリジニウム、並びにそれらの医薬的に許容可能な塩及びそれらの組み合わせからなる群より選択される、請求項48に記載の方法。
- 前記組成物が前記対象の眼に局所的に投与される、請求項18〜49のいずれか一項に記載の方法。
- 前記組成物が、重水素化したドパミン又は重水素化したドパミン誘導体、又はそれらの医薬的に許容可能な塩の角膜上皮を通じる浸透のために製剤化される、請求項50に記載の方法。
- 前記組成物が前記対象の眼内に注射される、請求項18〜49のいずれか一項に記載の方法。
- 前記組成物が硝子体内の注射を介して投与される、請求項52に記載の方法。
- 前記組成物のpHが4から8の範囲内である、請求項18〜53のいずれか一項に記載の方法。
- 前記組成物のpHが5.0から7.0の範囲内である、請求項54に記載の方法。
- 前記組成物のpHが5.5から6.5の範囲内である、請求項55に記載の方法。
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US10155948B2 (en) * | 2016-05-12 | 2018-12-18 | Kangwon National University University-Industry Cooperation Foundation and | Pharmaceutical composition for preventing or treating diabetic complications and screening method for preventive or therapeutic agent for diabetic complications |
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2019
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US20160009705A1 (en) * | 2014-06-24 | 2016-01-14 | Sydnexis, Inc. | Ophthalmic composition |
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KR20210061355A (ko) | 2021-05-27 |
JP7457391B2 (ja) | 2024-03-28 |
AU2019338938B2 (en) | 2023-01-19 |
EP3849533A1 (en) | 2021-07-21 |
CA3111589A1 (en) | 2020-03-19 |
US20220047529A1 (en) | 2022-02-17 |
AU2019338938A1 (en) | 2021-03-18 |
CN112770734A (zh) | 2021-05-07 |
WO2020051648A1 (en) | 2020-03-19 |
SG11202101817UA (en) | 2021-03-30 |
CA3111589C (en) | 2023-12-19 |
EP3849533A4 (en) | 2022-06-22 |
TW202023533A (zh) | 2020-07-01 |
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