JP2019069992A - 角結膜障害の治療剤 - Google Patents
角結膜障害の治療剤 Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61P27/02—Ophthalmic agents
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- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation 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
- A61P27/14—Decongestants or antiallergics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Description
本願は特定の実施形態において例えば以下の項目を提供する:
(項目1)
RARγアゴニストを有効成分として含有する角結膜障害の治療剤。
(項目2)
RARγアゴニストが、(E)−4−(2−{3−[(1H−ピラゾール−1−イル)メチル]−5,5,8,8−テトラメチル−5,6,7,8−テトラヒドロナフタレン−2−イル}ビニル)安息香酸、6−[3−(1−アダマンチル)−4−ヒドロキシフェニル]−2−ナフタレン酸、若しくは3−フルオロ−4−[2−ヒドロキシ−2−(5,5,8,8−テトラメチル−5,6,7,8−テトラヒドロナフタレン−2−イル)アセチルアミノ]安息香酸、そのエステル又はその塩である、項目1に記載の治療剤。
(項目3)
角結膜障害が、角膜潰瘍、角膜上皮剥離、角膜炎、ドライアイ、結膜炎、慢性表層角膜炎、角膜糜爛、遷延性角膜障害、点状表層角膜症、角膜上皮欠損、結膜上皮欠損、乾性角結膜炎、上輪部角結膜炎、糸状角結膜炎、感染性角膜炎、非感染性角膜炎、感染性結膜炎、非感染性結膜炎、角膜瘢痕化、結膜瘢痕化からなる群から選択される、項目1又は2に記載の治療剤。
(項目4)
投与形態が点眼投与又は経口投与である、項目1〜3のいずれかに記載の治療剤。
(項目5)
剤型が、点眼剤、眼軟膏、注射剤、錠剤、顆粒剤、細粒剤、散剤又はカプセル剤である、項目1〜4のいずれかに記載の治療剤。
正常ウサギ角膜細胞を用い、Nishidaらの方法(Investigative Ophthalmology & Visual Science 42: 1247−1253(2001))に準じて、3次元コラーゲンゲル分解に対する被験化合物の抑制効果を評価した。
100ml中
RARγアゴニストA 100mg
塩化ナトリウム 800mg
ポリソルベート80 適量
リン酸水素二ナトリウム 適量
リン酸二水素ナトリウム 適量
滅菌精製水 適量
滅菌精製水にRARγアゴニストA及びそれ以外の上記成分を加え、これらを十分に混合して点眼液を調製する。RARγアゴニストA等の添加量を変えることにより、濃度が0.05%(W/V)、0.3%(W/V)、0.5%(W/V)又は1%(W/V)の点眼剤を調製できる。
100g中
RARγアゴニストA 0.3g
流動パラフィン 10.0g
白色ワセリン 適量
均一に溶融した白色ワセリン及び流動パラフィンに、RARγアゴニストAを加え、これらを十分に混合して後に徐々に冷却することで眼軟膏を調製する。RARγアゴニストA等の添加量を変えることにより、濃度が0.05%(W/W)、0.1%(W/W)、0.5%(W/W)又は1%(W/W)の眼軟膏を調製できる。
100mg中
RARγアゴニストA 1mg
乳糖 66.4mg
トウモロコシデンプン 20mg
カルボキシメチルセルロースカルシウム 6mg
ヒドロキシプロピルセルロース 6mg
ステアリン酸マグネシウム 0.6mg
RARγアゴニストA、トウモロコシデンプン及び乳糖を混合機中で混合し、その混合物にカルボキシメチルセルロースカルシウム及びヒドロキシプロピルセルロースを加えて造粒し、得られた顆粒を乾燥後整粒し、その整粒顆粒にステアリン酸マグネシウムを加えて混合し、打錠機で打錠する。また、RARγアゴニストA等の添加量を変えることにより、100mg中の含有量が0.1mg、10mg又は50mgの錠剤を調製できる。
初代結膜下線維芽細胞、初代角膜実質細胞を用い、Nishidaらの方法に準じて、3次元コラーゲンゲル収縮に対する被験化合物の抑制効果を評価した。
初代角膜実質細胞を用い、Nishidaらの方法に準じて、実施例1と同様の方法で3次元コラーゲンゲル分解に対する被験化合物の抑制効果を評価した。
タンパク質分解酵素であるマトリクスメタロプロテアーゼ(MMP)の分泌、発現がタイプIコラーゲンの分解に関与していると考えられている。そこで、RARγアゴニストAによるMMP−1、2、3及び9の発現及び活性化の抑制について調べた。
回収した培養液の上清を、10%ポリアクリルアミドゲルを用いたSDS−PAGEで展開した後、分離したタンパク質をニトロセルロース膜に転写した。次に、ニトロセルロース膜の非特異的部位をブロックし、抗ヒトMMP−1抗体(R&D systems社製)、抗ラビットMMP−3抗体(第一ファインケミカル社製)で4℃、24時間インキュベートし、ECL(登録商標)試薬(GE・ヘルスケア社製)を用いて検出した。
回収した培養液の上清を0.1%のゼラチンを含む10%ポリアクリルアミドゲルを用いたSDS−PAGEで展開した後、2.5%Triton X−100含むTBS溶液で室温にて1時間インキュベートした。インキュベート後のゲルをクマシーブリリアントブルー(和光純薬工業社製)の溶液にて染色し、5%メタノール−7.5%酢酸溶液(ナカライテスク社製)にて脱色した。
日本白色種雄性ウサギ(体重2.5−3.5kg、27匹)に対してケタミン及びキシラジン混合溶液の筋肉内投与により全身麻酔を施した。次に、0.4%塩酸オキシブプロカイン点眼液により局所麻酔を施した。さらに、片眼の角膜実質内に1%LPS(シグマアルドリッチ社製)を30μl注入した。なお、反対眼には注入しなかった。
Claims (1)
- 組成物または治療剤。
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JP2012246373 | 2012-11-08 | ||
JP2012246373 | 2012-11-08 |
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JP2017230426A Division JP6462836B2 (ja) | 2012-11-08 | 2017-11-30 | 角結膜障害の治療剤 |
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JP2019069992A true JP2019069992A (ja) | 2019-05-09 |
JP6744389B2 JP6744389B2 (ja) | 2020-08-19 |
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JP2014545578A Active JP6254529B2 (ja) | 2012-11-08 | 2013-11-07 | 角結膜障害の治療剤 |
JP2017230426A Active JP6462836B2 (ja) | 2012-11-08 | 2017-11-30 | 角結膜障害の治療剤 |
JP2018244364A Active JP6744389B2 (ja) | 2012-11-08 | 2018-12-27 | 角結膜障害の治療剤 |
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JP2014545578A Active JP6254529B2 (ja) | 2012-11-08 | 2013-11-07 | 角結膜障害の治療剤 |
JP2017230426A Active JP6462836B2 (ja) | 2012-11-08 | 2017-11-30 | 角結膜障害の治療剤 |
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Country | Link |
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US (6) | US9492431B2 (ja) |
EP (1) | EP2918290B1 (ja) |
JP (3) | JP6254529B2 (ja) |
KR (1) | KR102173932B1 (ja) |
CN (2) | CN109589324B (ja) |
AU (2) | AU2013342882B2 (ja) |
BR (1) | BR112015010428B1 (ja) |
CA (1) | CA2890424C (ja) |
CL (2) | CL2015001225A1 (ja) |
ES (1) | ES2834111T3 (ja) |
HK (1) | HK1219224A1 (ja) |
MX (2) | MX363111B (ja) |
NZ (1) | NZ708756A (ja) |
RU (1) | RU2659203C2 (ja) |
SG (2) | SG10201704687YA (ja) |
WO (1) | WO2014073209A1 (ja) |
ZA (1) | ZA201504065B (ja) |
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US9492431B2 (en) | 2012-11-08 | 2016-11-15 | Yamaguchi University | Therapeutic agent for keratoconjunctive disorders |
EP2740485B1 (en) * | 2012-12-07 | 2018-10-31 | Brightpulse Holding LTD. | Protein slurp-1 for use in the treatment of ocular diseases |
BR112015029114B1 (pt) | 2013-05-22 | 2020-11-24 | Yamaguchi University | composição |
WO2017210792A1 (en) | 2016-06-08 | 2017-12-14 | Clementia Pharmaceuticals Inc. | Methods for treating heterotopic ossification |
US10980778B2 (en) | 2016-11-16 | 2021-04-20 | Clementia Pharmaceuticals Inc. | Methods for treating multiple osteochondroma (MO) |
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BR112015029114B1 (pt) | 2013-05-22 | 2020-11-24 | Yamaguchi University | composição |
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