JP2020515533A - マイボーム腺脂質分泌を増加させるための薬剤 - Google Patents
マイボーム腺脂質分泌を増加させるための薬剤 Download PDFInfo
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- JP2020515533A JP2020515533A JP2019550683A JP2019550683A JP2020515533A JP 2020515533 A JP2020515533 A JP 2020515533A JP 2019550683 A JP2019550683 A JP 2019550683A JP 2019550683 A JP2019550683 A JP 2019550683A JP 2020515533 A JP2020515533 A JP 2020515533A
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- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000002955 secretory cell Anatomy 0.000 description 1
- VIDTVPHHDGRGAF-UHFFFAOYSA-N selenium sulfide Chemical compound [Se]=S VIDTVPHHDGRGAF-UHFFFAOYSA-N 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000004489 tear production Effects 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000009723 vascular congestion Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 230000009978 visual deterioration Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
Description
本出願は、2017年3月29日に出願された米国仮特許出願第62/478,501号の利益を主張し、当該文献は参照によってその全体が本明細書中に組み込まれる。
この剤形は、一般的に、皮膚または粘膜への外部適用のためのものである(US FDA Drug Nomenclature Monograph,number C−DRG−00201)。
薬品候補はチオール基を含む化合物であった。陽性対照としての二硫化セレン(CarboxymethylCellulose−CMCで分散したSeS2)。脂腺細胞の分化は、脂質の合成及び蓄積の増加に関連するので、増殖及び分化の評価を、3D脂腺細胞培養(ヒト細胞株−SEBO662)における脂質蓄積の量を計ることにより行った。脂質蓄積を、オイルレッド染色による脂質染色により評価した。
<結果>
図1は、対照に関する3D脂腺細胞の上皮におけるオイルレッドO染色の例示である。図2は、1.0μMのブシラミン関する3D脂腺細胞の上皮におけるオイルレッドO染色の例示である。図3は、0.1μMのブシラミン関する3D脂腺細胞の上皮におけるオイルレッドO染色の例示である。
<定量比較>
二硫化セレン(SeS2)の定量比較は、0.01μM及び0.1μMで、両方の試験濃度にて3D脂腺細胞の上方の領域において、脂質蓄積の統計的に有意な増加を誘導した(それぞれ、対照の282%及び348%)。0.1μM及び1μMで試験されたブシラミンは、3D脂腺細胞の上方の領域において、脂質蓄積の統計的に有意な増加を誘導した(それぞれ対照の172%及び214%)。0.01μMの濃度では、皮脂産生(115%)の有意でない増加が観察された。
<結論>
0.1μM及び1μMの濃度のブシラミンは、3D脂腺細胞モデルにおいて脂質合成に著しい刺激的な効果があった。
実施例2:ブシラミンの角質溶解性の効果の評価
<用量応答と時間的経過の分析>
細胞を、加湿状況下で5%のCO2で37℃で24、48及び72時間、テスト項目の6つの濃度を使用せずまたは使用してインキュベートした。インキュベート期間の終わりに、細胞生存率をMTTアッセイによって測定した。ブランク対照をすべての測定から引いた。結果を図4aに提供する。
<HaCaTターンオーバー(turnover)定量>
テスト項目での処置の際、HaCaT細胞の増殖速度を、BrdUアッセイの使用により検査した。ターンオーバー率の測色評価をELISAリーダによって記録した。結果を図4bに示す。
<ヒト皮膚モデル系におけるエクスビボ評価>
ヒト皮膚臓器培養を整形手術を経験している健康な患者から得た。研究を手術の日から開始した。サンプルの混合物から遊離チオールを分離するために、サンプルを5分間TCA(トリクロロ酢酸)の等しい体積でインキュベートした。その後、チューブを室温で10,000rpmで15minの遠心分離機にかけた。ペレットを評価した。結果は図4cに提供される。
<結論>
インビボ−ブシラミンは角化細胞のターンオーバー率を減少させることにより角質溶解性の効果を示した。
エスクビボ−ブシラミンは、マイボーム腺の閉塞状態を緩和するために、チオール部分を減少させる能力によって角質溶解性の効果を実証し、並びにこのアッセイにおいて有意な効果を示し、遊離チオール部分を無毒な濃度の約6倍増加させた。
実施例3:脂質分泌強化チオール含有剤を含む医薬組成物の製剤。
2.5グラムのブシラミンを、10グラムの流動パラフィン及び87.5グラムの白色の軟性ワセリンと混合させ、均質な混合物を得るまで一定の撹拌により〜60℃に加熱して、これを室温に冷却する。
2.5グラムのブシラミンを、2.5グラムのコレステロール、10グラムの流動パラフィン、及び85グラムのワセリンと混合する。全ての成分が〜80℃で溶け、均質性を得るまで混合物を混合しながら加熱し、その後室温に冷却する。
2.5グラムのブシラミンを、5グラムのスクアレン及び97.5グラムのワセリンと均質性を得るために混合させ、混合物を混合しながら〜60℃に加熱して、これを室温に冷却した。
2.5グラムのブシラミンを、10グラムの鉱油、10グラムのスクワレン、10グラムのカプリン酸/カプリル酸トリグリセリド、10グラムのマイクロクリスタリンワックス、10グラムの硬化植物油、及び3グラムのラノリンと混合し、並びに100グラムになるまでワセリンと混合する。均質性を得るまで、混合物を混合しながら〜80℃−90℃に加熱し、室温に冷却する。
2.5グラムのブシラミンを、3グラムのコレステロール及び10グラムのリン脂質と混合させ、エタノール・アセトンの混合物中で溶解する。混合物を真空下で乾燥し、激しい撹拌、その後高圧の均質化の下で1000mlの食塩水と混合させて、非常に細かいリポソーム分散を産生する。
2.5グラムのブシラミンを、5グラムの硬化植物油及び5グラムの鉱油と混合させ、撹拌しながら〜80℃に加熱し、全ての成分を溶解する。1%のtween80及び2%のリン脂質を含む、80℃に予め加熱された87.5グラムの水溶液を、激しい混合及び高剪断均質化の下で加える。0.8グラムのキサンタンガム(Xantural 3000(登録商標))を、激しい混合の下で加え、混合物を室温に冷却し、固形の脂質分散を得る。
2.5グラムのブシラミンを滅菌注射用蒸留水に溶かし、1.2グラムのキサンタンガム及び0.8グラムの塩化ナトリウムを加え、混合物を撹拌して透明なゲルを得る。
実施例4:マイボーム腺における脂質産生の増加。
実施例5:マイボーム腺からの脂質分泌の増加。
実施例6:MGD患者の処置。
Claims (15)
- マイボーム腺からの脂質分泌を増加させるための方法であって、該方法は、眼科的に許容可能な担体と、マイボーム腺における脂質生成を増加させるか、またはマイボーム腺からの脂質分泌を増加させる、有効な量の少なくとも1つの薬剤とを含む眼科用組成物を、その必要がある患者の眼瞼縁に局所的に投与する工程を含み、前記薬剤はスルフヒドリル基を含む、方法。
- 前記薬剤はブシラミン、またはその薬学的に許容可能な塩である、請求項1に記載の方法。
- 前記薬剤は次のような構造を有する化合物、またはその薬学的に許容可能な塩である、請求項1に記載の方法。
- 前記眼科的に許容可能な担体は、少なくとも1つの眼科的に許容可能な賦形剤を含む、請求項1に記載の方法。
- 患者に角質溶解剤を投与する工程をさらに含む、請求項1に記載の方法。
- 前記角質溶解剤は、過酸化ベンゾイル、コールタール、ジスラノール、サリチル酸、二硫化セレン、アルファヒドロキシ酸、尿素、ホウ酸、レチノイン酸、乳酸、チオグリコール酸ナトリウム、またはアラントイン、からなる群から選択される、請求項5に記載の方法。
- マイボーム腺機能不全の処置のための方法であって、眼科的に許容可能な担体と、治療上有効な量の少なくとも一つの薬剤と、を含む眼科用組成物を、その必要がある患者の眼瞼縁に局所的に投与する工程を含み、前記薬剤はスルフヒドリル基を含む、方法。
- 前記薬剤はブシラミン、またはその薬学的に許容可能な塩である、請求項7に記載の方法。
- 前記薬剤は次のような構造を有する化合物、またはその薬学的に許容可能な塩である、請求項7に記載の方法。
- 前記眼科的に許容可能な担体は、少なくとも1つの眼科的に許容可能な賦形剤を含む、請求項9に記載の方法。
- 患者に角質溶解剤を投与する工程をさらに含む、請求項9に記載の方法。
- 前記角質溶解剤は、過酸化ベンゾイル、コールタール、ジスラノール、サリチル酸、二硫化セレン、アルファヒドロキシ酸、尿素、ホウ酸、レチノイン酸、乳酸、チオグリコール酸ナトリウム、またはアラントイン、からなる群から選択される、請求項11に記載の方法。
- 前記マイボーム腺機能不全は、マイボーム腺の閉塞を特徴とする、請求項9に記載の方法。
- 前記患者の眼瞼縁への薬剤の局所的な投与は、マイボーム腺閉塞が実質的に取り除かれるまで、繰り返される、請求項11に記載の方法。
- 前記患者の眼瞼縁への薬剤の局所的な投与は、マイボーム腺閉塞の形成を防ぐために、定期的に繰り返される、請求項11に記載の方法。
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PCT/IB2018/000415 WO2018178769A1 (en) | 2017-03-29 | 2018-03-28 | Agents for increasing meibomian gland lipid secretion |
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KR102541236B1 (ko) | 2017-03-29 | 2023-06-08 | 아주라 오프탈믹스 엘티디 | 마이봄샘 지질 분비 증가를 위한 작용제 |
CA3136369A1 (en) | 2019-04-18 | 2020-10-22 | Azura Ophthalmics Ltd. | Compounds and methods for the treatment of ocular disorders |
JP2022530322A (ja) | 2019-04-18 | 2022-06-29 | アズーラ オフサルミックス エルティーディー. | 眼障害を処置するための化合物および方法 |
EP4087655A4 (en) | 2020-01-10 | 2024-02-21 | Azura Ophthalmics Ltd | INSTRUCTIONS FOR COMPOSITION AND SENSITIVITY |
US20210308154A1 (en) | 2020-03-24 | 2021-10-07 | Hovione Scientia Limited | Methods and Compositions for Treating Meibomian Gland Dysfunction |
US11459351B1 (en) | 2021-04-05 | 2022-10-04 | Azura Ophthalmics Ltd. | Compounds and methods for the treatment of ocular disorders |
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JP7105244B2 (ja) | 2022-07-22 |
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