JP2005508908A - 経皮投与用の生物学的前駆体 - Google Patents
経皮投与用の生物学的前駆体 Download PDFInfo
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- JP2005508908A JP2005508908A JP2003528800A JP2003528800A JP2005508908A JP 2005508908 A JP2005508908 A JP 2005508908A JP 2003528800 A JP2003528800 A JP 2003528800A JP 2003528800 A JP2003528800 A JP 2003528800A JP 2005508908 A JP2005508908 A JP 2005508908A
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Classifications
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
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Abstract
Description
−レチノールをそのパルミチン酸とのエステルから放出する。
−保湿剤、またはより具体的には皮膚の発汗を制御する剤、例えば、糖類 (グルコース、ソルビトールまたはヒアルロン酸) 以外に、グリセロールおよびα−ヒドロキシ酸、さらにはその極性部分により保湿する、植物由来のセラミド類。ヒドロキシ酸の中でも、L-アスコルビン酸は特に適した剤であるが、その理由は、この主要な特性に加えて、他の効果、即ち、抗酸化効果や、さらに3個のプロα鎖に対するmRNAコーディングレベルの特異的な増大によってコラーゲン合成 (従って、弾力線維の合成) を刺激する能力、も持ち合わせているからである。さらに、アスコルビン酸は、プロコラーゲンからコラーゲンの生成を行う酵素を活性化する [S.R. Pinel et al., Arch. Dermatol. (1987), 123, 1684-1687];
M.P. Mora et al., Chem. Phys. Lipids (1999), 101, 255-265 J.R. Trevithick et al., Biochem. Mol. Biol. Int. (1999), 47, 509-511
A1 およびA2 は、互いに独立して、皮膚科学または美容学に使用可能な分子から誘導された基を意味し、そしてXおよびYは、互いに独立して、水素原子、ヒドロキシル基または (C1〜C20)アルキル基を意味し、そして
nは0〜10の整数を意味する。
本発明の別の具体的態様において、A1 およびA2 は、互いに独立してアスコルビル、コレカルシフェリル、レチニルまたはトコフェリル基を意味する。
本発明に係るさらに一層有利な1態様では、一般式(I) で示される化合物が、トコフェリルレチニルスクシネート、トコフェリルコレカルシフェリルスクシネート、およびトコフェリルアスコルビルスクシネートよりなる群から選ばれる。
本発明によると、この組成物を皮膚に適用 (塗布) した時に、この複合体がエステラーゼ型の酵素加水分解をを受けて、有効成分の放出を生じ、この有効成分が遅延して放出されるので、皮膚の各種の層における蓄積が全く起こらない。
この組成物は、水中油型 (O/W) または油中水型 (W/O) エマルジョンの形態でよい。組成物はまた、球状体、例えば、リポソーム、ナノカプセルまたはナノスフィア (ナノ球) の形態でもよい。
製造方法の特に有利な1態様では、一般式(II)
A1−H (II)
(式中、A1 は上記の通りの意味) で示される化合物を、一般式(III)
A2−H (V)
で示される化合物と反応させて、一般式(I) で示される化合物を得るあ
本発明に係る方法の別の有利な態様においては、一般式(II)で示される化合物を、一般式(III) で示される化合物の活性化形態、例えば、無水コハク酸、と反応させる。
−最も反応性の高いヒドロキシル官能性を中和することによる有効成分の安定化 (ビタミンD、EまたはA) 。表皮の生きている層のエステラーゼ活性の大きさと、角質層におけるその実質的な不存在のために [U.K. Jain et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater. (1995), 22, 702-703]、有効成分の安定化形態となる前駆体は、酸化ストレス (UVおよびオゾン) に最も曝される部分に対応する角質層を通る遅い移行を通して保存される [G. Valacchi et al., FEBS Letters (2000), 446, 165-168];
−抑制された速度での放出 (皮膚生理学の非常に精密な調節を考慮して) および貯槽の効果。
実施例1: O-(4-オキソ-4-{[2,5,7,8-テトラメチル-2-(4,8,12-トリメチルトリデシル)-3,4-ジヒドロ-2H-クロメン-6-イル] オキシ}ブタノイル) レチノール、即ち、トコフェリルレチニルスクシネート (CV-105)
1H NMR (CDCl3, 250 MHz): 2.87 (dt, 4H, H-(Cac succ) 2J=21, 3J=6.6); 2.58 (t, 4H, H-(C4, C3), 3J=6); 2.08, 2.01, 1.97 (3s, 9H, CH3-(C5), CH3-(C7), CH3-(C8)), 1.61-1 (ブロード多重線, 24H, CH3-(C1) + 9 x CH2, 3 x CH トコフェロール), 0.88, 0.84 (2s, 12H, 4 x CH3 トコフェロール) 。
MS (CI, NH3) : 548 ([MNH4]+, 100); 531 ([MH]+, 11.3); 530 ([M]+, 3.4)。
C33H54O5に対する元素分析:計算値 C 74.67, H 10.25; 実測値 C 74.85, H 10.26。
1.2: トコフェリルレチニルスクシネート (CV-105)
実施例2:トコフェリルコレカルシフェリルスクシネート (CV-125)
Rf (EtOAc/PE 2:8): 0.91; (EtOAc/PE 5:95): 0.32。
MS (CI, NH3) : 914 ([MNH4]+, 100); 897 ([MH]+, 2.86); 896 ([M]+, 2.71) 。
実施例3:トコフェリルアスコルビルスクシネート (CV-106)
3.1: 保護ビタミンC (CV-100)
結合はビタミンCのC3ではなく主にC2で起きているようである。具体的には、NMR データが既報のC2エステル [Cabral J., J. Org. Chem. (1988), 53, 5742-50] の方と、より一致している。
外観:白色フォーム状粉末
Rf (EtOAc/CH2Cl2/MeOH 1:8:1): 0.38; (EtOAc/CH2Cl2/MeOH 1:8:2): 0.48 。
MS (CI, NH3) : 746 ([MNH4]+, 96); 728 ([M]+, 2.6); 612 (6.7); CV-104 の[MNH4]+ 548 (20.3); 423 (16); CV-100 の[MNH4]+ 234 (59)。
実施例4:酵素加水分解
4.1: 方法
ジメチルスルホキシド (DMSO) 中の1mM溶液 150μl を、15 ml の血清単独中のHaCaT ケラチン生成細胞系 (75 cm2) を入れた皿に加える。細胞を37℃のインキュベータに24時間入れる。培地を酢酸エチル15 ml で抽出する。次に有機相を単離し、蒸発させる。
結果を次の表にまとめて示す。
Claims (13)
- 皮膚科学または美容学に使用可能な分子が抗炎症、抗菌、抗生物またはビタミン活性を有することを特徴とする、請求項1に記載の生物学的前駆体。
- A1 およびA2 が、互いに独立してアスコルビル、コレカルシフェリル、レチニルまたはトコフェリル基を意味する、請求項1および2のいずれかに記載の生物学的前駆体。
- A1 がトコフェリル基を意味し、そしてA2 がレチニル、コレカルシフェリルおよびアスコルビル基よりなる群から選ばれる基を意味することを特徴とする請求項3に記載の生物学的前駆体。
- トコフェリルレチニルスクシネート、トコフェリルコレカルシフェリルスクシネート、およびトコフェリルアスコルビルスクシネートよりなる群から選ばれることを特徴とする、請求項1〜4のいずれか1項に記載の生物学的前駆体。
- 経皮投与に適した賦形剤と組合わせて請求項1〜6のいずれか1項に記載の少なくとも1種の生物学的前駆体を含有することを特徴とする薬剤組成物。
- 組成物の全重量に対して 0.001〜10重量%、好ましくは0.01〜0.1 重量%の生物学的前駆体を含有することを特徴とする、請求項7に記載の薬剤組成物。
- 水中油型 (O/W) または油中水型 (W/O) エマルジョンの形態であることを特徴とする、請求項7および8のいずれかに記載の薬剤組成物。
- 球状体の形態であることを特徴とする、請求項7および8のいずれかに記載の薬剤組成物。
- 組成物の全重量に対して油相の割合が5〜80重量%、好ましくは5〜50重量%であることを特徴とする、請求項9に記載の薬剤組成物。
- 許容される美容学的または皮膚科学的添加剤をさらに含有することを特徴とする、請求項7〜11のいずれか1項に記載の薬剤組成物。
- 一般式(II)
A1−H (II)
(式中、A1 は請求項1に記載した通りの意味) で示される化合物を、一般式(III)
A2−H (V)
で示される化合物と反応させて、一般式(I) で示される化合物を得ることを特徴とする、請求項1〜5のいずれか1項に記載の生物学的前駆体を製造する方法。
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FR0111982A FR2829762B1 (fr) | 2001-09-17 | 2001-09-17 | Bioprecurseurs destines a une application percutanee |
FR0111982 | 2001-09-17 | ||
PCT/FR2002/003148 WO2003024952A1 (fr) | 2001-09-17 | 2002-09-16 | Bioprecurseurs destines a une application percutanee |
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EP (1) | EP1427717B1 (ja) |
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DE (1) | DE60216296T2 (ja) |
ES (1) | ES2275923T3 (ja) |
FR (1) | FR2829762B1 (ja) |
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US9550744B2 (en) * | 2013-09-25 | 2017-01-24 | University Of Florida Research Foundation, Inc. | Vitamin C prodrugs and uses thereof |
KR102644587B1 (ko) * | 2015-12-24 | 2024-03-07 | (주)아모레퍼시픽 | 유사 세라마이드 화합물 및 그 제조방법 |
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US2407726A (en) * | 1941-08-07 | 1946-09-17 | Univ Minnesota | Methods of preparing chemical products |
US2680749A (en) * | 1951-12-01 | 1954-06-08 | Eastman Kodak Co | Water-soluble tocopherol derivatives |
FR2608045B1 (fr) * | 1986-12-12 | 1990-03-02 | Chauvin Laboratoires | Utilisation d'inhibiteurs de xanthine- oxydase, de piegeurs de radicaux libres oxygenes et de chelateurs du fer pour la fabrication d'une composition pharmaceutique destinee au traitement du glaucome et compositions pharmaceutiques destinees au traitement du glaucome |
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FR2791679B1 (fr) * | 1999-03-31 | 2003-04-11 | Fabre Pierre Dermo Cosmetique | Bioprecurseurs aptes a liberer un derive retinoique par mise a profit de l'activite enzymatique de la surface cutanee et compositions pharmaceutiques et/ou cosmetiques |
US6045826A (en) * | 1999-04-02 | 2000-04-04 | National Research Council Of Canada | Water-soluble compositions of bioactive lipophilic compounds |
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EP1427717B1 (fr) | 2006-11-22 |
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EP1427717A1 (fr) | 2004-06-16 |
CA2460783A1 (fr) | 2003-03-27 |
US7084172B2 (en) | 2006-08-01 |
PT1427717E (pt) | 2007-02-28 |
FR2829762B1 (fr) | 2004-02-13 |
DE60216296T2 (de) | 2007-06-21 |
FR2829762A1 (fr) | 2003-03-21 |
DE60216296D1 (de) | 2007-01-04 |
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