JP5878761B2 - 皮膚、粘膜、および/または頭皮の治療および/またはケアに用いられるペプチド、ならびに、美容または医薬組成物におけるその使用 - Google Patents
皮膚、粘膜、および/または頭皮の治療および/またはケアに用いられるペプチド、ならびに、美容または医薬組成物におけるその使用 Download PDFInfo
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- 239000000779 smoke Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940079833 sodium oleanolate Drugs 0.000 description 1
- DUAZSEDLBBRXQJ-ANQQBNRBSA-M sodium;(1s,2r,4as,6ar,6as,6br,8ar,10s,12ar,14bs)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1h-picene-4a-carboxylate Chemical compound [Na+].C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C([O-])=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C DUAZSEDLBBRXQJ-ANQQBNRBSA-M 0.000 description 1
- QNELTPKHJFMSNK-RLFONNADSA-M sodium;(4as,6ar,6as,6br,8ar,10s,12ar,14bs)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylate Chemical compound [Na+].C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C([O-])=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C QNELTPKHJFMSNK-RLFONNADSA-M 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 229950006451 sorbitan laurate Drugs 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 235000020712 soy bean extract Nutrition 0.000 description 1
- 235000003687 soy isoflavones Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000019710 soybean protein Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
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- 238000011191 terminal modification Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000008354 tissue degradation Effects 0.000 description 1
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- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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Description
‐ 平坦で蒼白色の瘢痕:身体の自然治癒プロセスの結果として形成される。
‐ 沈み込んだ瘢痕:筋肉などのより深い構造と結合した皮膚によって形成されるか、または内部組織における脂肪の喪失によって形成される。このような瘢痕は、皮膚内へ陥凹しており、通常は損傷の結果である。
‐ 肥厚性瘢痕:治癒プロセスの過程で、身体が過剰のコラーゲンを産生する場合に見られる。このような瘢痕は皮膚表面にわたって盛り上がり、不規則に組織化されたコラーゲンを含有する。
‐ ケロイド瘢痕:治癒プロセスの過程において、不均衡なコラーゲン産生の結果として形成される。このような瘢痕は、皮膚表面にわたって盛り上がるだけではなく、元の創傷の境界を越えて拡大し、いつまでも成長し続ける場合がある。
‐ 挫瘡瘢痕:挫瘡患部の皮膚に形成される。この瘢痕は沈み込むかまたはケロイドになる場合がある。水痘に罹患したことのある人が同様の瘢痕を持つ場合がある。
‐ 伸展した瘢痕:治癒プロセスの過程において、治癒する創傷の周囲の皮膚が張力下に置かれる場合に発生する。この瘢痕は、最初は正常に見えるが、数週間または数ヶ月間の期間にわたって幅広く細くなり得る。これは創傷が関節に近く、動作の間に伸展されることによって起こり得るか、または一般的な健康不良もしくは栄養不良によって治癒が不十分であることに起因し得る。
‐ ストレッチマーク:例えば妊娠中または青年期の急成長の過程で、皮膚が急速に伸展される際に発生する。
本発明を理解しやすくするために、本発明に関して用いられるいくつかの用語および表現の意味を示す。
本発明の化合物は、一般式(I)
R1−Wp−Xn−AA1−AA2−AA3−AA4−Ym−R2 (I)
これらの立体異性体、その混合物、および/またはこれらの美容的もしくは薬理学的に許容される塩、で定められ、アミノ酸AA1、AA2、またはAA4のうちの少なくとも1つがコードされないものであることを特徴とし、および:
AA1は、−Arg−、−Phg−、および−Nle−から成る群より選択されるか、または結合であり;
AA2は、−Ala−、−Phg−、−Cit−、および−Nle−から成る群より選択され;
AA3は、−Trp−、−Val−、および−Tyr−から成る群より選択され;
AA4は、−Phg−および−Gly−から成る群より選択され;
W、X、およびYは、独立して、コードされる、またはコードされないアミノ酸から成る群より選択され;
p、n、およびmは、0から1までの範囲であり;
R1は、H、置換もしくは無置換の非環式脂肪族基、置換もしくは無置換のアリシクリル、置換もしくは無置換のヘテロシクリル、置換もしくは無置換のヘテロアリールアルキル、置換もしくは無置換のアリール、置換もしくは無置換のアラルキル、およびR5−CO−から成る群より選択され;
R2は、−NR3R4、−OR3、および−SR3から成る群より選択され;
ここで、R3およびR4は、独立して、H、置換もしくは無置換の非環式脂肪族基、置換もしくは無置換のアリシクリル、置換もしくは無置換のヘテロシクリル、置換もしくは無置換のヘテロアリールアルキル、置換もしくは無置換のアリール、および置換もしくは無置換のアラルキルから成る群より選択され;
ここで、R5は、H、置換もしくは無置換の非環式脂肪族基、置換もしくは無置換のアリシクリル、、置換もしくは無置換のアリール、置換もしくは無置換のアラルキル、置換もしくは無置換のヘテロシクリル、および置換もしくは無置換のヘテロアリールアルキルから成る群より選択され;
ただし、AA1が結合である場合、AA2は−Phg−であり、AA3は、−Trp−である。
Ac−Arg−Phg−Val−Gly−OH;
Ac−Arg−Phg−Val−Gly−NH2、
Ac−Arg−Phg−Val−Phg−OH、
Ac−Arg−Phg−Val−Phg−NH2、
Ac−Arg−Phg−Trp−Phg−OH、
Ac−Arg−Phg−Trp−Phg−NH2、
Ac−Nle−Phg−Trp−Phg−OH、
Ac−Nle−Phg−Trp−Phg−NH2、
Ac−Phg−Phg−Trp−Phg−OH、
Ac−Phg−Phg−Trp−Phg−NH2、
Ac−Phg−Phg−Val−Phg−OH、
Ac−Phg−Phg−Val−Phg−NH2、
Ac−Phg−Phg−Val−Gly−OH、
Ac−Phg−Phg−Val−Gly−NH2、
Ac−Nle−Phg−Val−Phg−OH、
Ac−Nle−Phg−Val−Phg−NH2、
Ac−Phg−Phg−Tyr−Phg−OH、
Ac−Phg−Phg−Tyr−Phg−NH2、
Ac−Nle−Phg−Tyr−Phg−OH、
Ac−Nle−Phg−Tyr−Phg−NH2、
Ac−Arg−Phg−Tyr−Phg−OH、
Ac−Arg−Phg−Tyr−Phg−NH2、
Ac−Nle−Ala−Trp−Phg−OH、
Ac−Nle−Ala−Trp−Phg−NH2、
Ac−Nle−Ala−Tyr−Phg−OH、
Ac−Nle−Ala−Tyr−Phg−NH2、
Ac−Nle−Phg−Tyr−Gly−OH、
Ac−Nle−Phg−Tyr−Gly−NH2、
Palm−Phg−Cit−Trp−Phg−OH、
Palm−Phg−Nle−Trp−Phg−NH2、
H−Arg−Cit−Val−Phg−OH、
H−Arg−Nle−Val−Phg−OH、
Ac−Arg−Nle−Val−Gly−OH、
Ac−Arg−Nle−Val−Gly−NH2、
Ac−Phg−Trp−Phg−OH、
Ac−Phg−Trp−Phg−NH2、
Palm−Arg−Phg−Val−Phg−NH2、
Palm−Arg−Phg−Trp−Phg−NH2、
Ac−Arg−Phg−Trp−Phg−NH−(CH2)15−CH3、
H−Arg−Phg−Val−Gly−NH2
Ac−Phg−Phg−Trp−Phg−OH、
Ac−Phg−Phg−Trp−Gly−OH、
Ac−Nle−Phg−Val−Gly−OH、
Ac−Nle−Phg−Trp−Gly−OH、
Ac−Gly−Phg−Phg−Trp−Phg−Gly−OH、
Ac−Ala−Gly−Nle−Phg−Trp−Phg−OH、
Ac−Gly−Gly−Arg−Phg−Trp−Phg−Gly−OH、
Ac−Arg−Phg−Tyr−Phg−Ile−OH、
Ac−Leu−Nle−Phg−Tyr−Phg−Gly−NH2、
Ac−Ser−Phe−Arg−Phg−Val−Phg−Phg−OH、および、
Ac−Phg−Phg−Arg−Phg−Val−Gly−Phg−OH;
これらの立体異性体、その混合物、ならびに/またはこれらの美容的もしくは薬理学的に許容される塩、
から成る群より選択される。
本発明のペプチド、それらの立体異性体、その混合物、および/またはそれらの美容的もしくは薬理学的に許容される塩の合成は、例えば、固相ペプチド合成の方法(Stewart J.M.and Young J.D.(1984)“Solid Phase Peptide Synthesis,2nd edition”Pierce Chemical Company,Rockford,Illinois;Bodanzsky M.and Bodanzsky A.(1984)“The practice of Peptide Synthesis”Springer Verlag,New York,Lloyd Williams P.,Albericio F.and Giralt E.(1997)“Chemical Approaches to the Synthesis of Peptides and Proteins”CRC,Boca Raton,FL,USA)、溶液中での合成の方法、固相合成および溶液合成の方法の組み合わせ、または酵素合成の方法(Kullmann W.(1980)“Proteases as catalysts for enzymic syntheses of opioid peptides”J.Biol.Chem.255:8234‐8238)など、先行技術において公知の従来の方法に従って実施することができる。ペプチドは、所望される配列を産生させる目的で遺伝子操作されたものであっても、されていないものであっても、細菌株の発酵によって得ることもでき、または、動物もしくは植物由来、好ましくは植物由来のタンパク質の制御された加水分解により少なくとも所望される配列を含有するペプチド断片を遊離させることによって得ることもできる。
‐ N末端が遊離であり、C末端が保護されているかまたは固相支持体に結合しているアミノ酸上へ、N末端が保護され、C末端が遊離であるアミノ酸をカップリングする工程;
‐ N末端の保護基を除去する工程;
‐ カップリングおよびN末端保護基の除去の一連の操作を繰り返して、所望されるペプチド配列を得る工程;
‐ C末端の保護基の除去、または固相支持体からの開裂を行う工程、
を含む。
本発明のペプチドは、皮膚、粘膜、および/または頭皮におけるエラスターゼ活性の阻害および/またはコラーゲン合成の刺激のために、哺乳類、好ましくはヒトの身体の作用部位とこのペプチドとを接触させる任意の手段により、それを含有する組成物の形態で、投与することができる。
本発明の別の局面は、皮膚、粘膜、および/または頭皮の治療および/またはケアのための美容または医薬組成物の作製における、一般式(I)のペプチド、その立体異性体、その混合物、および/またはその美容的もしくは薬理学的に許容される塩の少なくとも1つの使用に関する。
試薬および溶媒はすべて合成グレードであり、追加の処理を行うことなく使用される。
アミノ酸に用いられる略語は、Eur.J.Biochem.(1984)138:9‐37およびJ.Biol.Chem.(1989)264:633‐673において指定される、IUPAC‐IUBの生化学命名委員会(Commission on Biochemical Nomenclature)の規則に従う。
合成プロセスはすべて多孔性ポリエチレンのディスクを取り付けたポリプロピレンシリンジまたは多孔性プレートを取り付けたPyrex(登録商標)反応器で行う。溶媒および可溶性試薬は、吸引によって取り出す。Fmoc基の除去は、ピペリジン‐DMFで行う(2:8、v/v)(1×1分、1×5分、5mL/g 樹脂)(Lloyd Williams P.,Albericio F.and Giralt E.(1997)“Chemical Approaches to the Synthesis of Peptides and Proteins”CRC,Boca Raton,FL,USA)。脱保護、カップリング、および再度の脱保護の工程間の洗浄は、各回に10mL 溶媒/g 樹脂のDMF(3×1分間)を用いて行った。カップリング反応は、3mL 溶媒/g 樹脂で行った。カップリングの制御は、ニンヒドリン試験で行う(Kaiser E.,Colescott R.L.,Bossing C.D.and Cook P.I.(1970)Color test for detection of free terminal amino groups in the solid phase synthesis of peptides,”Anal.Biochem.34:595 598)。合成反応および洗浄はすべて室温で行った。
Fmoc−Xn−AA1−AA2−AA3−AA4−Ym−O−2‐ClTrt−Rの合成、ここで、AA4は−L‐Phg−、−D‐Phg−、または−Gly−、AA3は−L‐Trp−、−L‐Tyr−、または−L‐Val−;AA2は−L‐Ala−、−L‐Cit−、−L‐Nle−、−L‐Phg−、または−D‐Phg−;AA1は−L‐Arg−、−L‐Phg−、−D‐Phg−、または−L‐Nle−;ならびに、nおよびmは0である。
3.29gのFmoc−L‐Phg−OH、3.29gのFmoc−D‐Phg−OH、または2.61gのFmoc−Gly−OH(8.8mmol;1当量)を55mlのDCMに溶解し、これに1.3mlのDIEA(7.6mmol;0.86当量)を添加したものを、乾燥2‐クロロトリチル樹脂(5.5g;8.8mmol)にカップリングさせた。この懸濁液を5分間攪拌し、その後、2.5mLのDIEAを添加した(14.6mmol;1.66当量)。この混合物を40分間反応させた。4.4mLのMeOHで処理することで、残留塩素基を封止した。
Fmoc−Xn−AA1−AA2−AA3−AA4−Ym−AM−MBHA−Rの合成、ここで、AA4は−L‐Phg−、−D‐Phg−、または−Gly−;AA3は−L‐Trp−、−L‐Tyr−、または−L‐Val−;AA2は−L‐Ala−、−L‐Cit−、−L‐Nle−、−L‐Phg−、または−D‐Phg−;AA1は−L‐Arg−、−L‐Phg−、−D‐Phg−、または−L‐Nle−;ならびに、nおよびmは0である。
0.73mmol/g(5mmol)のローディングである6.85gのFmoc−AM−MBHA樹脂を、Fmoc基を除去する目的で、記載した一般的なプロトコルに従ってピペリジン‐DMFで処理した。この脱保護した樹脂上への9.33gのFmoc−L‐Phg−OH、9.33gのFmoc−D‐Phg−OH、または7.43gのFmoc−Gly−OH(25mmol;5当量)の組み込みを、DIPCDI(3.85mL、25mmol;5当量)およびHOBt(3.85g、25mmol;5当量)、ならびに溶媒としてDMFを用いて1時間行った。
Fmoc N末端保護基除去のための一般手順
実施例1および2で得られたペプチジル樹脂のFmoc N末端基を、全般的な方法で述べたようにして脱保護した(20%ピペリジン、1×5分間+1×20分間)。ペプチジル樹脂をDMF(5×1分間)、DCM(4×1分間)、ジエチルエーテル(4×1分間)で洗浄し、真空乾燥させた。
実施例3で得られたペプチジル樹脂上へR1パルミトイル基を導入するための手順
DMF(1mL)中に予め溶解させた2.56gのパルミチン酸(10mmol;10当量)を、1.53gのHOBt(10mmol;10当量)および1.54mLのDIPCDI(10mmol;10当量)の存在下にて、実施例3で得られたペプチジル樹脂の1mmolへ添加した。これを15時間反応させ、その後、樹脂をTHF(5×1分間)、DCM(5×1分間)、DMF(5×1分間)、MeOH(5×1分間)、DMF(5×1分間)、THF(5×1分間)、DMF(5×1分間)、DCM(4×1分間)、エーテル(3×1分間)で洗浄し、真空乾燥させた。
実施例3で得られたペプチジル樹脂上へアセチル基R1を導入するための手順
実施例3で得られたペプチジル樹脂の1mmolを、25当量のDIEAの存在下、溶媒として5mLのDMFを用い、25当量の無水酢酸で処理した。これを30分間反応させ、その後、ペプチジル樹脂をDMF(5×1分間)、DCM(4×1分間)、ジエチルエーテル(4×1分間)で洗浄し、真空乾燥させた。
実施例3、4、および5で得られたペプチジル樹脂の開裂手順
実施例3、4、および5で得られた乾燥ペプチジル樹脂200mgを、室温にて攪拌しながら2時間、5mLのTFA‐TIS‐H2O(90:5:5)で処理した。ろ液を50mLの冷ジエチルエーテルへ取り、多孔性ポリエチレンディスクを取り付けたポリプロピレンシリンジを通してろ過し、50mLのジエチルエーテルで5回洗浄した。最終的な析出物を真空乾燥させた。
ポリマー支持体の開裂手順およびR2置換アミンによる誘導体化:Ac−Xn−AA1−AA2−AA3−AA4−Ym−NH−(CH2)15−CH3の合成、ここで、AA4は−L‐Phg−、−D‐Phg−、または−Gly−;AA3は−L‐Trp−、−L‐Tyr−、または−L‐Val−;AA2は−L‐Ala−、−L‐Cit−、−L‐Nle−、−L‐Phg−、または−D‐Phg−;AA1は−L‐Arg−、−L‐Phg−、−D‐Phg−、または−L‐Nle−;ならびに、nおよびmは0である。
予めKOHの存在下にて真空乾燥しておいた実施例5のペプチジル樹脂、Ac−Xn−AA1−AA2−AA3−AA4−Ym−O−2‐ClTrt−Rの150mgを、DCM中の3%TFA溶液の3mLで5分間処理することにより、側鎖が完全に保護されたペプチド、Ac−Xn−AA1−AA2−AA3−AA4−Ym−OHが得られた。ろ液を50mLの冷ジエチルエーテルへ取り、この処理を3回繰り返した。エーテル性溶液を室温にて真空蒸発乾固させ、析出物をH2O中の50%MeCNへ溶解し、凍結乾燥した。得られた粗生成物の10mgをフラスコ中に秤量し、3当量のヘキサデシルアミンおよび25mLの無水DMFを添加した。2当量のDIPCDIを添加し、マグネティックスターラーで攪拌しながら47℃で反応させた。反応は、出発物質の消滅をHPLCでモニタリングし、24〜48時間後に完了した。溶媒を蒸発乾固させ、DCMで2回共蒸発させた。得られた残渣(側鎖が完全に保護されたAc−Xn−AA1−AA2−AA3−AA4−Ym−NH−(CH2)15−CH3)を25mLのDCM‐TFA‐アニソール混合物(49:49:2)中に再懸濁させ、室温にて30分間反応させた。これを250mLの冷ジエチルエーテルへ添加し、溶媒を減圧下で蒸発させ、さらにエーテルによる共蒸発を追加で2回行った。残渣をH2O中の50%MeCNの混合物へ溶解し、凍結乾燥させた。
エラスターゼ阻害アッセイ
ペプチドを、0.5%DMSOの存在下にて水に再懸濁させた。このアッセイは、EnzChek(登録商標)Elastase Assay Kit(モレキュラープローブズ(Molecular Probes))を用い、96ウェルブラックマイクロプレート上で実施した。この目的のために、ペプチドを0.1mMにて1時間、0.4ユニット/mLのエラスターゼと共に室温で穏やかに攪拌しながら予めインキュベートし、その後、結合基質を、最終濃度25μg/mLでフルオレセイン(DQ(商標)Elastin)へ添加し、反応物を、遮光下にて攪拌しながら、室温で2時間インキュベートした。蛍光が阻害された基質は、エラスターゼによって消化されて蛍光断片を放出し、これを、励起に対しては485nmフィルターを、発光に対しては530nmフィルターを用いたFLUOstar galaxy reader(BMGラボテクノロジーズ(BMG LabTechnologies))で、蛍光によりモニタリングする。
ヒトエラスターゼ阻害アッセイ
ヒト好中球エラスターゼを、50mM 酢酸ナトリウム、200mm NaCl、pH5.5のバッファー中にて5μg/mLで再構成した。0.2μg/mlのプロテアーゼを、ペプチドと共に最終濃度0.05〜2mMにて、96ウェルブラックマイクロプレート中、室温で1時間、予めインキュベートした。予備インキュベーションの後、25μg/mLの基質(MeOSuc−Ala−Ala−Pro−Valアミノメチルクマリン)をウェルへ添加し、このサンプルを遮光下、室温にて2時間インキュベートした。基質の消化によって放出された蛍光を、自動マルチプレート蛍光リーダーを用い、励起370nm、読み取り460nmで測定した。
Palm−L‐Nle−Phg−L‐Tyr−Phg−NH2を含有する美容組成物の作製
Ac−L‐Arg−Phg−L‐Val−Phg−OHを含有するリポソームの作製
ジパルミトイルホスファチジルコリン(DPPC)を秤量し、クロロホルムに溶解した。溶媒を、リン脂質の薄層が得られるまで減圧留去し、この層を、ペプチドの水溶液での処理を55℃で行うことによって所望の濃度まで水和し(Phenonip(登録商標)含有)、MLVリポソームを得た。ULVリポソームは、MLVリポソームの超音波浴への浸漬を、55℃にて、5分間隔で2分間のサイクルを8回行うことで得た。ULVリポソームのサイズは、高圧で押出しシステムを通過させることで低下させた。
Ac−Phg−Phg−L‐Trp−Phg−OHを含有するフェイシャルクリームの組成
Ac−L‐Arg−Phg−L‐Val−Phg−OHを含有するリポソームゲルの形態の組成物の作製
実施例11のリポソームを保存料(EDTA、イミダゾリジニル尿素、およびPhenonip(登録商標))と共にゆるやかに攪拌しながら水に分散させた。Hispagel(登録商標)200を添加し[INCI:水、グリセリン、グリセリルポリアクリレート]、均質混合物が得られるまでゆるやかに攪拌した。
Ac−L‐Arg−Phg−L‐Trp−Phg−OHを含有するマイクロエマルジョンの組成
Ac−L‐Arg−Phg−L‐Trp−Phg−OHを含有するボディジェルの組成
Ac−L‐Arg−Phg−L‐Trp−Phg−NH−(CH2)15−CH3を含有するヘアローションの組成
Ac−L‐Arg−Phg−L‐Trp−Phg−OHを含有する混合ミセルの組成物の作製
サンプル全体に適する容器中にフェーズAの成分を秤量し、約30℃まで僅かに加温して保存料のいくつかの溶解を補助した。次に、フェーズBの成分を添加し、穏やかに攪拌しながら均質化した。
実施例15の組成物による皮膚弾性の上昇への効果
本発明の実施例15の組成物の効果を評価するために、ボランティアの被験者20人の大腿部に、1日2回のローションの適用を2ヶ月間行った。
実施例15の組成物に対応するプラセボ組成物による皮膚弾性の上昇への効果
本発明の実施例15の組成物に対応するプラセボ組成物の効果を評価するために、ボランティアの被験者20人の一群に対して、大腿部への1日2回のローションの適用を2ヶ月間行った。
コラーゲン合成刺激アッセイ
ヒト皮膚線維芽細胞を、線維芽細胞のための特定の成長因子を添加したM106培地中にてコンフルーエントまで成長させた。次に、これをストリプシン処理し(strypsinized)、24ウェルプレートに、5×104細胞/ウェルで播種した。37℃、5%CO2雰囲気中での24時間のインキュベーションの後、15μg/mlのペプチドの段階希釈と共に、またはネガティブコントロールとしての媒体と共に、新しい培地を添加した。細胞をさらに48時間インキュベートし、その後、培地を回収した。
Claims (14)
- 一般式(I)
R1−AA1−AA2−AA3−AA4−R2 (I)
のペプチドであって、アミノ酸AA1、AA2、およびAA4のうちの少なくとも1つが非コードアミノ酸であることを特徴とし、ここで:
AA1は、−Arg−、−Phg−、および−Nle−から成る群より選択されるか、または結合であり;
AA2は、−Phg−から成る群より選択され;
AA3は、−Trp−および−Val−から成る群より選択され;
AA4は、−Phg−および−Gly−から成る群より選択され;
R1は、HおよびR5−COから成る群より選択され;
R2は、−NR3R4 および−OR 3 から成る群より選択され;
ここで、R3 は、Hであり、R4は、Hおよび無置換C 1 −C 24 アルキルから成る群より選択され;
ここで、R5は、Hおよび無置換C 1 −C 24 アルキルから成る群より選択され;
ただし、AA1が結合である場合、AA2は−Phg−であり、AA3は−Trp−であり、AA 4 は−Phg−である、
ペプチド、その立体異性体、その混合物、および/またはその美容的もしくは薬理学的に許容される塩。 - R1は、H、アセチル、ラウロイル、ミリストイル、またはパルミトイルから成る群より選択され、AA1は、−L‐Arg−、または−L‐Nle−、または結合であり、AA2は、−L‐Phg−または−D‐Phg−であり、AA3は、−L‐Trp−であり、AA4は、−L‐Phg−または−D‐Phg−であり、およびR2は、−NR3R4または−OR3であり、ここで、R3 は、Hであり、R4は、H、メチル、エチル、ヘキシル、ドデシル、およびヘキサデシルから選択されることを特徴とする、請求項1に記載のペプチド。
- R1は、H、アセチル、ラウロイル、ミリストイル、またはパルミトイルから成る群より選択され、AA1は、−L‐Arg−であり、AA2は、−L‐Phg−または−D‐Phg−であり、AA3は、−L‐Val−であり、AA4は、−L‐Phg−または−D‐Phg−、または−L‐Gly−であり、およびR2は、−NR3R4または−OR3であり、ここで、R3 は、Hであり、R4は、H、メチル、エチル、ヘキシル、ドデシル、およびヘキサデシルから選択されることを特徴とする、請求項1に記載のペプチド。
- R1は、H、アセチル、ラウロイル、ミリストイル、またはパルミトイルから成る群より選択され、AA1は、−L‐Phg−または−D‐Phg−であり、AA2は、−L‐Phg−または−D‐Phg−であり、AA3は、−L‐Trp−であり、AA4は、−L‐Phg−または−D‐Phg−であり、およびR2は、−NR3R4または−OR3であり、ここで、R3 は、Hであり、R4は、H、メチル、エチル、ヘキシル、ドデシル、およびヘキサデシルから選択されることを特徴とする、請求項1に記載のペプチド。
- 皮膚、粘膜、および/または頭皮の治療および/またはケアのための、請求項1から4のいずれか一項に記載の一般式(I)のペプチド、その立体異性体、その混合物、および/またはその美容的もしくは薬理学的に許容される塩。
- エラスターゼ活性に起因する、皮膚、粘膜、および/または頭皮の状態、障害、および/または疾患の治療、予防、および/またはケアのための、請求項5に記載のペプチド。
- 一般式(I)のペプチド、その立体異性体、その混合物、および/またはその美容的もしくは薬理学的に許容される塩であって、コラーゲン合成の刺激のための、請求項1から4のいずれか一項に記載のペプチド。
- 前記治療、予防、および/またはケアは、老化および/または光老化の徴候を低減、遅延、および/もしくは予防し、ならびに/または皮膚弾性を高め、ならびに/または顔のシワを低減または除去するものである、請求項5に記載のペプチド。
- 美容的または薬理学的効果量の、請求項1から4のいずれか一項に記載の一般式(I)のペプチド、その立体異性体、その混合物、および/またはその美容的もしくは薬理学的に許容される塩の少なくとも1つ、ならびに賦形剤または美容的もしくは薬理学的に許容される補助剤の少なくとも1つを含有する、美容または医薬組成物。
- 前記一般式(I)のペプチド、その立体異性体、その混合物、および/またはその美容的もしくは薬理学的に許容される塩は、リポソーム、混合リポソーム、オレオソーム、ニオソーム、ミリカプセル、マイクロカプセル、ナノカプセル、スポンジ、シクロデキストリン、小胞、ミセル、界面活性剤の混合ミセル、界面活性剤‐リン脂質混合ミセル、ミリスフェア、マイクロスフェア、ナノスフェア、リポスフェア、マイクロエマルジョン、ナノエマルジョン、小粒子、ミリ粒子、マイクロ粒子、ナノ粒子、および固体脂質ナノ粒子から成る群より選択される、美容的もしくは薬理学的に許容される送達システムまたは徐放システムに組み込まれるか、または、タルク、ベントナイト、シリカ、デンプン、もしくはマルトデキストリンから成る群より選択される美容的もしくは薬理学的に許容される固体有機ポリマーまたは固体無機基材に吸着されることを特徴とする、請求項9に記載の組成物。
- 前記組成物は、クリーム、多相エマルジョン、無水組成物、水性分散液、オイル、ミルク、バルサム、フォーム、ローション、ジェル、クリームジェル、水性アルコール溶液、水性グリコール溶液(hydroglycolic solutions)、ヒドロゲル、リニメント、血清(sera)、石鹸、シャンプー、コンディショナー、血清(serums)、軟膏、ムース、ポマード、粉末、バー型(bars)、ペンシル型(pencils)、スプレー、エアロゾル、カプセル、ゼラチンカプセル、錠剤、糖衣錠、顆粒、チューイングガム、溶液、懸濁液、エマルジョン、シロップ、多糖フィルム、ゼリー、およびゼラチンから成る群より選択される製剤であることを特徴とする、請求項9または10に記載の組成物。
- 前記組成物は、コンシーラー、メークアップファンデーション、メークアップリムーバルローション、メークアップリムーバルミルク、アイシャドー、口紅、リップグロス、リッププロテクター、およびパウダーから成る群より選択される製品であることを特徴とする、請求項9から11のいずれか一項に記載の組成物。
- 前記一般式(I)のペプチド、その立体異性体、その混合物、および/またはその美容的もしくは薬理学的に許容される塩は、布、不織布、または医療用デバイスに組み込まれることを特徴とする、請求項9から11のいずれか一項に記載の組成物。
- 前記組成物は、エラスターゼ阻害剤、マトリックスメタロプロテアーゼ阻害剤、メラニン合成の刺激または阻害剤、美白または脱色剤、着色促進剤(propigmenting agents)、セルフタンニング剤、老化防止剤、NO‐シンターゼの阻害剤、5α‐レダクターゼの阻害剤、リジル‐および/またはプロリルヒドロキシラーゼの阻害剤、酸化防止剤、遊離ラジカル捕捉剤および/または抗大気汚染剤、反応性カルボニル種捕捉剤、抗糖化剤、抗ヒスタミン剤、制吐剤、抗ウィルス剤、抗寄生虫剤、乳化剤、皮膚軟化剤、有機溶媒、液体噴霧剤、皮膚調整剤、湿潤剤、水分を保持する物質、アルファヒドロキシ酸、ベータヒドロキシ酸、保湿剤、表皮加水分解酵素、ビタミン、顔料または着色剤、色素、ゲル化ポリマー、増粘剤、界面活性剤、軟化剤、シワ防止剤、目の下のクマを低減または治療できる剤、剥離剤、抗菌剤、抗真菌剤、静真菌剤、殺菌剤、静菌剤、真皮もしくは表皮の高分子合成を刺激する剤および/またはそれらの分解を阻害もしくは予防する能力を持つ剤、コラーゲン合成を刺激する剤、エラスチン合成を刺激する剤、デコリン合成を刺激する剤、ラミニン合成を刺激する剤、デフェンシン合成を刺激する剤、シャペロン合成を刺激する剤、アクアポリン合成を刺激する剤、ヒアルロン酸合成を刺激する剤、脂質および角質層成分の合成を刺激する剤、セラミドの合成を刺激する剤、コラーゲン分解を阻害する剤、エラスチン分解を阻害する剤、線維芽細胞増殖を刺激する剤、ケラチノサイト増殖を刺激する剤、脂肪細胞増殖を刺激する剤、メラノサイト増殖を刺激する剤、ケラチノサイト分化を刺激する剤、脂肪細胞分化を刺激する剤、アセチルコリンエステラーゼを阻害する剤、皮膚弛緩剤、グリコサミノグリカン合成を刺激する剤、抗過角化症剤、面皰分解剤(comedolytic agents)、抗乾癬剤、DNA修復剤、DNA保護剤、抗掻痒剤、敏感肌の治療および/またはケアのための剤、固化剤(firming agents)、抗ストレッチマーク剤、結合剤、皮脂産生を制御する剤、脂肪分解剤または脂肪分解を刺激する剤、抗セルライト剤、抗発汗剤、治癒を刺激する剤、治癒共補助剤(coadjuvant healing agents)、再上皮化を刺激する剤、再上皮化共補助剤(coadjuvant reepithelialization agents)、サイトカイン成長因子、沈静剤、抗炎症剤、麻酔剤、毛細血管循環および/または微小循環に作用する剤、血管新生を刺激する剤、血管透過性を阻害する剤、静脈強壮剤(venotonic agents)、細胞代謝に作用する剤、真皮‐表皮接合を改善する剤、発毛を誘発する剤、発毛阻害もしくは抑制剤、保存料、芳香物質、キレート剤、植物抽出物、エッセンシャルオイル、海産抽出物、生物発酵プロセスから得られる剤、無機塩、細胞抽出物、ならびに日焼け止め、紫外線Aおよび/もしくはBに対して作用する有機または無機の光防護剤、またはこれらの混合物から成る群より選択される、美容的もしくは薬理学的効果量の少なくとも1つの補助剤をさらに含むことを特徴とする、請求項9から13のいずれか一項に記載の組成物。
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WO2024092334A1 (pt) * | 2022-10-31 | 2024-05-10 | Chemyunion Ltda | Compostos, composições cosméticas, dermocosméticas, cosmecêuticas ou farmacêutica para o relaxamento da musculatura, incluindo a musculatura esquelética da face, para ação cosmética antienvelhecimento, para redução e/ou suavização de linhas de expressão e rugas e/ou para ação antitranspirante, usos e métodos |
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JP2012519656A (ja) | 2012-08-30 |
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MX2011008616A (es) | 2011-09-09 |
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AU2010213094B2 (en) | 2014-07-24 |
HK1162540A1 (en) | 2012-08-31 |
CA2751436A1 (en) | 2010-08-19 |
EP2408801A1 (en) | 2012-01-25 |
KR101810695B1 (ko) | 2017-12-19 |
CN102317307A (zh) | 2012-01-11 |
ES2349972A1 (es) | 2011-01-13 |
KR20110125247A (ko) | 2011-11-18 |
ES2349972B1 (es) | 2011-11-24 |
IL214462A0 (en) | 2011-09-27 |
CN102317307B (zh) | 2015-04-08 |
AU2010213094A1 (en) | 2011-08-18 |
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