JP2024030200A - 角膜障害治療剤 - Google Patents
角膜障害治療剤 Download PDFInfo
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- JP2024030200A JP2024030200A JP2022132848A JP2022132848A JP2024030200A JP 2024030200 A JP2024030200 A JP 2024030200A JP 2022132848 A JP2022132848 A JP 2022132848A JP 2022132848 A JP2022132848 A JP 2022132848A JP 2024030200 A JP2024030200 A JP 2024030200A
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- 230000007774 longterm Effects 0.000 description 1
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- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
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- 210000004175 meibomian gland Anatomy 0.000 description 1
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- 235000019271 petrolatum Nutrition 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
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- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 201000006476 shipyard eye Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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Abstract
Description
[1]
特定の分子量又は構成単糖数(例えば、平均分子量が10,000以下)のグリコサミノグリカン及びその類似物質(類似物、誘導体、例えば、グリコサミノグリカンを構成するアミノ糖がグルコサミン及びガラクトサミンを含むものに置換した多糖、グリコサミノグリカンを構成するアミノ糖がグルコサミン及びガラクトサミンのいずれでもないアミノ糖を含む多糖に置換した多糖)から選択された少なくとも1種のグリコサミノグリカン類を含む、角膜障害治療及び/又は予防剤(角膜障害の治療及び/又は予防のための剤又は組成物、以下同じ)。
[2]
グリコサミノグリカン類の平均分子量が8,000以下である、[1]記載の剤。
[3]
グリコサミノグリカン類が、グルコサミン単位を少なくとも含む、[1]又は[2]記載の剤。
[4]
グリコサミノグリカン類を構成する単糖1個あたりの硫酸基の平均個数が0.2個以上である、[1]~[3]のいずれかに記載の剤。
[5]
グリコサミノグリカン類を構成する単糖1個あたりの硫酸基の平均個数が1.1個以上である、[1]~[4]のいずれかに記載の剤。
[6]
グリコサミノグリカン類が、ヘパリン(低分子量ヘパリン)及びへパリノイド(低分子量へパリノイド)から選択された少なくとも1種である、[1]~[5]のいずれかに記載の剤。
[7]
グリコサミノグリカン類の平均分子量が8,000以下、グリコサミノグリカン類を構成する単糖1個あたりの硫酸基の平均個数が1.2個以上であり、グリコサミノグリカン類が、ヘパリン及びへパリノイドから選択された少なくとも1種である、[1]~[6]のいずれかに記載の剤。
[8]
グリコサミノグリカン類が、ダルテパリン、レビパリン、バルナパリン、エノキサパリン、ダナパロイド、ベミパリン、ナドロパリン、セルトパリン、チンザパリン、フォンダパリヌクスおよびこれら化合物の塩から選択された少なくとも1種である、[1]~[7]のいずれかに記載の剤。
[9]
グリコサミノグリカン類が、フォンダパリヌクス及びフォンダパリヌクス塩から選択された少なくとも1種である、[1]~[8]のいずれかに記載の剤。
[10]
点眼液剤、点眼ゲル剤、又は眼軟膏剤である、[1]~[9]のいずれかに記載の剤。
そのため、本発明の剤又は組成物等は、角膜上皮障害の治療用途等に好適に使用しうる。
本発明の剤又は組成物は、眼科用等として好適に使用しうる。
本発明の剤又は組成物は、グリコサミノグリカン及びその類似物質(類似物、誘導体)から選択された少なくとも1種(以下、これらをまとめてグリコサミノグリカン、グリコサミノグリカン類等ということがある)を含む。
なお、硫酸化の程度の上限値は、特に限定されず、例えば、構成する単糖1個あたり(単糖1個あたりの平均値として)、3個、2.5個、2.2個、2個、1.8個、1.7個、1.6個等であってもよい。
グリコサミノグリカン類を構成する単糖の数は、例えば、30以下、好ましくは20以下、さらに好ましくは15以下であってもよい。
本発明の剤又は組成物によれば、前述のように、角膜上皮細胞の遊走、伸展及び/又は増殖等を促進しうる。
HCE-T(不死化ヒト角膜上皮)細胞[ヒト角膜上皮より分離樹立されたもの、理研セルバンク(RIKEN Cell Bank)より入手]を、5%のウシ胎仔血清を含むDMEM/F12培地を用いて、37℃でCO2インキュベーター中にて培養した。
T75フラスコで60~80%コンフルエントに増殖したHCE-T細胞をトリプシン-EDTAで剥離回収し、新たなウシ胎児血清を含むDMEM/F12培地に懸濁した。
各ウェルにcell seeding stopperを装着した96穴のマルチプレートに1ウェルあたり60,000個の細胞をこの細胞懸濁液から播種した。
CO2インキュベーター内で37℃にて一晩培養後、cell stopperを除去し、無血清培地で2回洗浄した。その後、被験物質を添加した無血清培地あるいは無添加コントロールの無血清培地に交換し、28時間培養した。
下記表に、蛍光強度と、この蛍光強度をもとに算出したコントロールに対する蛍光強度(相対蛍光強度)を示した。相対蛍光強度は、無添加群(コントロール)の蛍光強度を100%とし、各被験物添加群の蛍光強度を%で表したものであり、コントロールに対する相対的な細胞遊走の程度を示すものとなる。
そのため、蛍光顕微鏡で撮影した画像から、画像解析によって細胞遊走面積を算出(測定)するとともに、この面積をもとに算出した無添加コントロール群に対する面積(相対遊走面積)を算出した。
相対遊走面積は、無添加コントロール群の細胞遊走面積を100%とし、各被験物添加群の相対的な細胞遊走面積を%で表したものである。
実験1と同じく不死化ヒト角膜上皮細胞のHCE-T細胞を使用し、HCE-T細胞の遊走に対して被験物がどの程度影響するかを調べた。被験物としては、フォンダパリヌクスナトリウム、高分子量ヒアルロン酸ナトリウム(平均分子量887,000)、ヘパラン硫酸ナトリウム(平均分子量23,000)、低分子量ヘパリン(平均分子量5,400)を用いた。これら被験物のうちフォンダパリヌクスナトリウムは前述の通りセレック社より、他のグリコサミノグリカン類はすべて岩井化学薬品株式会社より入手した。被験物の濃度は、それぞれ0.3%(w/v)とした。
Claims (10)
- 平均分子量が10,000以下のグリコサミノグリカン及びその類似物質から選択された少なくとも1種のグリコサミノグリカン類を含む、角膜障害治療及び/又は予防剤。
- グリコサミノグリカン類の平均分子量が8,000以下である、請求項1記載の剤。
- グリコサミノグリカン類が、グルコサミン単位を少なくとも含む、請求項1又は2記載の剤。
- グリコサミノグリカン類を構成する単糖1個あたりの硫酸基の平均個数が0.2個以上である、請求項1又は2記載の剤。
- グリコサミノグリカン類を構成する単糖1個あたりの硫酸基の平均個数が1.1個以上である、請求項1又は2記載の剤。
- グリコサミノグリカン類が、ヘパリン及びへパリノイドから選択された少なくとも1種である、請求項1又は2記載の剤。
- グリコサミノグリカン類の平均分子量が8,000以下、グリコサミノグリカン類を構成する単糖1個あたりの硫酸基の平均個数が1.2個以上であり、グリコサミノグリカン類が、ヘパリン及びへパリノイドから選択された少なくとも1種である、請求項1又は2記載の剤。
- グリコサミノグリカン類が、ダルテパリン、レビパリン、バルナパリン、エノキサパリン、ダナパロイド、ベミパリン、ナドロパリン、セルトパリン、チンザパリン、フォンダパリヌクスおよびこれら化合物の塩から選択された少なくとも1種である、請求項1又は2記載の剤。
- グリコサミノグリカン類が、フォンダパリヌクス及びフォンダパリヌクス塩から選択された少なくとも1種である、請求項1又は2記載の剤。
- 点眼液剤、点眼ゲル剤、又は眼軟膏剤である、請求項1又は2記載の剤。
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