CZ309857B6 - Hexapeptide, compositions comprising this hexapeptide, and topical use thereof - Google Patents
Hexapeptide, compositions comprising this hexapeptide, and topical use thereof Download PDFInfo
- Publication number
- CZ309857B6 CZ309857B6 CZ2022-141A CZ2022141A CZ309857B6 CZ 309857 B6 CZ309857 B6 CZ 309857B6 CZ 2022141 A CZ2022141 A CZ 2022141A CZ 309857 B6 CZ309857 B6 CZ 309857B6
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- CZ
- Czechia
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- fwahkk
- hexapeptide
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- acne
- extract
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- 239000000203 mixture Substances 0.000 title claims abstract description 49
- 230000000699 topical effect Effects 0.000 title claims abstract description 30
- 125000002811 oleoyl 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])=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])[H] 0.000 claims abstract description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 3
- 125000004057 biotinyl group Chemical group [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 claims abstract description 3
- 210000004899 c-terminal region Anatomy 0.000 claims abstract description 3
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- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 claims abstract description 3
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- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims abstract description 3
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 15
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Abstract
Description
Hexapeptid, kompozice zahrnující tento hexapeptid a jejich topické použitíHexapeptide, compositions comprising this hexapeptide, and topical use thereof
Oblast technikyField of technology
Stávající vynález se týká uměle navrženého peptidu o sekvenci X-Phe-Trp-Ala-His-Lys-Lys-Z, jeho derivátů nebo komplexů s ionty kovů, topické kompozice, která je zahrnuje a jejich topického použití. Týká se zejména použití peptidů pro ošetření pokožky lidí nebo zvířat pro kosmetické nebo dermo-farmaceutické účely.The present invention relates to an engineered peptide of the sequence X-Phe-Trp-Ala-His-Lys-Lys-Z, its derivatives or complexes with metal ions, a topical composition comprising them and their topical use. It relates in particular to the use of peptides for treating the skin of humans or animals for cosmetic or dermo-pharmaceutical purposes.
Dosavadní stav technikyCurrent state of the art
Acne vulgarisAcne vulgaris
Acne vulgaris (dále akné) je velmi běžné chronické kožní onemocnění pilosebaceousní jednotky s hlubokým negativním psychosociálním dopadem na kvalitu života pacientů. Ačkoli ovlivňuje jedince všech věků, objevuje se obvykle během adolescence a často přetrvává do dospělosti (Yentzer a kol. 2010).Acne vulgaris (hereafter acne) is a very common chronic skin disease of the pilosebaceous unit with a profound negative psychosocial impact on patients' quality of life. Although it affects individuals of all ages, it usually appears during adolescence and often persists into adulthood (Yentzer et al. 2010).
Patogeneze acne vulgaris je multifaktorová se čtyřmi hlavními událostmi: hyperseborrhea, epiteliální hyperproliferace a hyperkeratinizace, kolonizace Cutibacterium acnes a zánět.The pathogenesis of acne vulgaris is multifactorial with four major events: hyperseborrhea, epithelial hyperproliferation and hyperkeratinization, Cutibacterium acnes colonization, and inflammation.
HyperseborrheaHyperseborrhea
Zvýšená produkce kožního mazu je považována za jednu z klíčových událostí patogeneze akné. V regulaci produkce kožního mazu kůží jsou zahrnuty různé sloučeniny signálních drah, z nichž šest hormonů hraje klíčovou roli. Mezi nejvýznamnějšími stimulátory produkce kožního mazu jsou androgeny, jejichž upregulace je často spojená s vývojem akné (da Cunha, Fonseca, a Machado 2013). V kožních buňkách je testosteron, nejběžnější androgen, rychle redukován na 5α-dihydrotestosteron (DHT) 5α-reduktázou, typem I (Fritsch, Orfanos, a Zouboulis 2001). Jak testosteron, tak DHT se vážou na androgenní receptory (AR), avšak DHT je 5 až 10 krát účinnější AR agonista a je považován za hlavní androgenní hormon ve vlasových folikulech (Anderson a Liao 1968).Increased sebum production is considered one of the key events in the pathogenesis of acne. Different signaling pathway compounds are involved in the regulation of sebum production by the skin, of which six hormones play a key role. Among the most important stimulators of sebum production are androgens, the upregulation of which is often associated with the development of acne (da Cunha, Fonseca, and Machado 2013). In skin cells, testosterone, the most common androgen, is rapidly reduced to 5α-dihydrotestosterone (DHT) by 5α-reductase, type I (Fritsch, Orfanos, and Zouboulis 2001). Both testosterone and DHT bind to androgen receptors (ARs), but DHT is a 5- to 10-fold more potent AR agonist and is considered the major androgen hormone in hair follicles (Anderson and Liao 1968).
Epiteliální hyperproliferace a hyperkeratinizaceEpithelial hyperproliferation and hyperkeratinization
Další typickou událostí v patogenezi akné je hyperproliferace folikulárních keratinocytů a jejich abnormální diferenciace (Thiboutot 2000). Druhá zmíněná je spojená se zvýšenou kohezivitou korneocytů, která vede k jejich nefunkční desquamaci (Thiboutot 2000). Nahromaděná hmota keratinizovaných korneocytů společně s kožním mazem částečně brání folikulům, což vede k jejich protažení a vytvoření vhodných podmínek pro růst C. acnes (Thiboutot 2000).Another typical event in the pathogenesis of acne is the hyperproliferation of follicular keratinocytes and their abnormal differentiation (Thiboutot 2000). The latter is associated with increased cohesiveness of corneocytes, which leads to their non-functional desquamation (Thiboutot 2000). The accumulated mass of keratinized corneocytes together with the sebum partially obstructs the follicles, which leads to their stretching and the creation of suitable conditions for the growth of C. acnes (Thiboutot 2000).
Existuje několik hypotéz vysvětlujících příčinu hyperproliferace keratinocytů a změněnou diferenciaci u akné. Bylo ukázáno, že androgeny, kromě stimulace produkce kožního mazu, indukují výše zmíněné procesy a také produkci pro-zánětlivého interleukinu IL- 1α (Kumtornrut a kol. 2019; Guy a Kealey 1998). Další možný spouštěč hyperkeratinizace je nízká koncentrace esenciální mastné kyseliny, linolenové kyseliny, která je snížena v pokožce postižené akné kvůli jejímu naředění vysokým množstvím kožního mazu (Downing a kol. 1986).There are several hypotheses explaining the cause of keratinocyte hyperproliferation and altered differentiation in acne. Androgens, in addition to stimulating sebum production, have been shown to induce the aforementioned processes as well as the production of the pro-inflammatory interleukin IL-1α (Kumtornrut et al. 2019; Guy and Kealey 1998). Another possible trigger for hyperkeratinization is a low concentration of the essential fatty acid, linolenic acid, which is reduced in acne-affected skin due to its dilution by high levels of sebum (Downing et al. 1986).
Cutibacterium acnesCutibacterium acnes
C. acnes je bakterie žijící na a v lidské pokožce jako část normálního lidského kožního mikrobiomu. Sídlí především hluboko v mazových folikulech v kontaktu s keratinocyty.C. acnes is a bacterium living on and in human skin as part of the normal human skin microbiome. It resides mainly deep in sebaceous follicles in contact with keratinocytes.
- 1 CZ 309857 B6- 1 CZ 309857 B6
Je potvrzeno, že C. acnes hraje významnou roli v patogenezi akné (McLaughlin a kol. 2019). Zdá se, že pro vývoj akné není tak důležité celkové množství C. acnes jako přítomnost určitých kmenů C. acnes (Dréno a kol. 2018). Bylo ukázáno, že tyto kmeny spojené s akné jsou více virulentní a produkují velké množství různých prozánětlivých faktorů (Dréno a kol. 2018).C. acnes is confirmed to play a significant role in the pathogenesis of acne (McLaughlin et al. 2019). It seems that the total amount of C. acnes is not as important for the development of acne as the presence of certain strains of C. acnes (Dréno et al. 2018). These strains associated with acne have been shown to be more virulent and produce a large number of different pro-inflammatory factors (Dréno et al. 2018).
ZánětInflammation
Zánět je považován za klíčovou část v patogenezi akné. V minulosti byl zánět považován za druhotnou událost indukovanou kolonizací C. acnes. V současné době se předpokládá, že zánětlivé procesy jsou zahrnuty ve všech stádiích vývoje akné a akné je nyní považována za opravdu zánětlivé onemocnění (Tanghetti 2013).Inflammation is considered a key part in the pathogenesis of acne. In the past, inflammation was considered a secondary event induced by C. acnes colonization. Inflammatory processes are now believed to be involved in all stages of acne development, and acne is now considered a truly inflammatory disease (Tanghetti 2013).
Léčba aknéAcne treatment
Protože akné je multifaktorové onemocnění, je doporučen přístup kombinované terapie. Typicky je vybrána kombinace povrchového retinoidu (tretinoin, isotretinoin, adapalen, tazaroten, retinol, retinaldehyd atd.) a antimikrobiální látky (např. benzoyl peroxid) jako léčba první linie (Moradi Tuchayi a kol. 2015). Hormonální, antiandrogenní terapie (orální antikoncepce, spironolakton) je často dávána ženám pro snížení produkce kožního mazu. Povrchová a orální antibiotika (erytromycin, klindamycin, doxycyklin, minocyklin a sarecyklin) jsou používána v léčbě mírné až těžké akné obvykle v kombinaci s benzoyl peroxidem nebo retinoidy. Z dalších používaných povrchových látek proti akné může být zmíněna salicylová kyselina, azelaiková kyselina, zinek, síra, niacinamid, glykolová kyselina a antimikrobiální peptidy (Liu a kol. 2020).Because acne is a multifactorial disease, a combination therapy approach is recommended. A combination of a topical retinoid (tretinoin, isotretinoin, adapalene, tazarotene, retinol, retinaldehyde, etc.) and an antimicrobial agent (eg, benzoyl peroxide) is typically chosen as first-line treatment (Moradi Tuchayi et al. 2015). Hormonal, antiandrogen therapy (oral contraceptives, spironolactone) is often given to women to reduce sebum production. Topical and oral antibiotics (erythromycin, clindamycin, doxycycline, minocycline, and sarecycline) are used to treat mild to severe acne, usually in combination with benzoyl peroxide or retinoids. Other anti-acne surfactants used include salicylic acid, azelaic acid, zinc, sulfur, niacinamide, glycolic acid, and antimicrobial peptides (Liu et al. 2020).
Zinek v léčbě aknéZinc in the treatment of acne
Hladina zinku u pacientů s akné je často významně nižší a bylo ukázáno, že její doplnění (ústně nebo topicky) zlepšuje akné (Yee a kol. 2020). Ačkoli jeho přesný mechanismus působení není zcela pochopen, současná znalost navrhuje četné mechanismy včetně protizánětlivých, antioxidačních účinků, inhibice proliferace C. acnes a inhibice 5n-reduktázy, což vede ke snížené produkci kožního mazu in vivo (Abendrot a Kalinowska-Lis 2018; Cervantes a kol. 2018).Zinc levels in acne patients are often significantly lower, and zinc supplementation (orally or topically) has been shown to improve acne (Yee et al. 2020). Although its exact mechanism of action is not fully understood, current knowledge suggests multiple mechanisms including anti-inflammatory, antioxidant effects, inhibition of C. acnes proliferation and inhibition of 5n-reductase, leading to reduced sebum production in vivo (Abendrot and Kalinowska-Lis 2018; Cervantes and col. 2018).
Peptidy a léčba aknéPeptides and acne treatment
Další slibnou skupinou sloučenin v léčbě akné jsou peptidy vykazující antimikrobiální (AMP) (Ma a kol. 2021; Melo, Dugourd a Castanho 2006; Zhang a kol. 2013), protizánětlivé (Zhang a kol. 2013) a další vlastnosti jako jsou antioxidační účinky (Mills a kol. 2016). Bylo ukázáno, že některé látky odvozené od přírodních látek nebo čistě syntetické, navržené AMP mají slibné účinky proti akné:Another promising group of compounds in the treatment of acne are peptides showing antimicrobial (AMP) (Ma et al. 2021; Melo, Dugourd, and Castanho 2006; Zhang et al. 2013), anti-inflammatory (Zhang et al. 2013) and other properties such as antioxidant effects (Mills et al. 2016). Some naturally derived or purely synthetic substances designed by AMPs have been shown to have promising anti-acne effects:
• Omiganan pentahydrochlorid odvozený od hovězího AMP indolicidinu (Melo, Dugourd, a Castanho 2006; Rubinchik a kol. 2009) • GDP-20 (peptidy odvozené od granulysin) (Lim a kol. 2015; Ma a kol. 2021;• Omiganan pentahydrochloride derived from the bovine AMP indolicidin (Melo, Dugourd, and Castanho 2006; Rubinchik et al. 2009) • GDP-20 (peptides derived from granulysin) (Lim et al. 2015; Ma et al. 2021;
McInturff, Modlin, a Kim 2005) • Peptid LZ1 (VKRWKKWWRKWKKWV-NH2) (Zhang a kol. 2013) • AMP z kůže žab ([D4k]ascaphin-8, [G4K]XT-7, [T5k]temporin-Dra, brevinin-2GU a B2RP-Era (Popovic a kol. 2012) • Peptidy (Br-p) izolované z kořene lopuchu (Arctium lappa L.) (Miazga-Karska, Michalak a Ginalska 2020)McInturff, Modlin, and Kim 2005) • Peptide LZ1 (VKRWKKWWRKWKKWV-NH2) (Zhang et al. 2013) • AMPs from frog skin ([D4k]ascaphin-8, [G4K]XT-7, [T5k]temporin-Dra, brevinin-2GU and B2RP-Era (Popovic et al. 2012) • Peptides (Br-p) isolated from burdock root (Arctium lappa L.) (Miazga-Karska, Michalak and Ginalska 2020)
- 2 CZ 309857 B6 • Temporin-1Dra a moronecidin (Wu, Zhang a Zhou 2020) • Bombininu podobný peptid 7 (BLP-7) z Bombina orientalis (Wu a kol. 2020) • Cathelicidin-BF byl purifikován z hadích jedů z Bungarus fasciatus (Wang a kol. 2011) • Head-to-tail cyklizovaný bakteriocin AS-48 (Cebrián a kol. 2018) • CEN1HC-Br izolovaný ze zelené mořské okurky (Han a kol. 2018) • AMP C12-50 (Nair a kol. 2017) • α-helikální kationický peptid, P5 (Sunhyo Ryu a kol. 2015) • Helicobacter pylori - odvozený syntetický antimikrobiální peptid HPA3NT3 (S. Ryu a kol. 2014) • Syntetický epinecidin-1(22-42) peptid byl odvozen z pozic 22-42 Epinephelus coioides epinecidin-1 (Pan a kol. 2009) • Enterococcus faecalis-odvozený AMP SL-5 (Kang a kol. 2009) • Bacteriocinu podobná inhibitorní látka (BLIS-podobná látka) produkovaná Streptococcus salivarius (Bowe a kol. 2006) • Syntetický, navržený AMP (Woodburn, Jaynes a Clemens 2020)- 2 CZ 309857 B6 • Temporin-1Dra and moronecidin (Wu, Zhang and Zhou 2020) • Bombinin-like peptide 7 (BLP-7) from Bombina orientalis (Wu et al. 2020) • Cathelicidin-BF was purified from snake venoms from Bungarus fasciatus (Wang et al. 2011) • Head-to-tail cyclized bacteriocin AS-48 (Cebrián et al. 2018) • CEN1HC-Br isolated from green sea cucumber (Han et al. 2018) • AMP C12-50 (Nair et al. al. 2017) • α-helical cationic peptide, P5 (Sunhyo Ryu et al. 2015) • Helicobacter pylori - derived synthetic antimicrobial peptide HPA3NT3 (S. Ryu et al. 2014) • Synthetic epinecidin-1(22-42) peptide was derived from positions 22-42 of Epinephelus coioides epinecidin-1 (Pan et al. 2009) • Enterococcus faecalis-derived AMP SL-5 (Kang et al. 2009) • Bacteriocin-like inhibitory substance (BLIS-like substance) produced by Streptococcus salivarius (Bowe et al. 2006) • Synthetic, designed by AMP (Woodburn, Jaynes, and Clemens 2020)
Příklady patentů popisujících použití peptidů v léčbě akné:Examples of patents describing the use of peptides in the treatment of acne:
• WO 2021175186 A1 Použití malé molekuly krátkého peptidu v přípravku produktu pro ošetření akné (LQLWQAEER, odvozený od bFGF, 100 μg/ml, inhibuje růst sebocytů, snižuje produkci kožního mazu) • CN 111253469 A Self-assembly krátký řetězec peptid a aplikace krátkého řetězce peptidu při léčbě akné (FFLQLQAEER) • CN 107698662 A Peptidová kombinace pro ošetření akné (WKIKIDSEAE a• WO 2021175186 A1 Use of a small molecule short peptide in the formulation of an acne treatment product (LQLWQAEER, derived from bFGF, 100 μg/ml, inhibits sebocyte growth, reduces sebum production) • CN 111253469 A Self-assembly short chain peptide and application of short chain peptide in the treatment of acne (FFLQLQAEER) • CN 107698662 A Peptide combination for the treatment of acne (WKIKIDSEAE and
PNMIYSKDY) • CN 112979762 A Cyklický peptid PIZ a jeho aplikace (EYPYKHSGYYHRAV) • KR 20200101767 A Peptid s antimikrobiální aktivitou a kompozice pro antimikrobiální zahrnující totéž (KTTKS) • WO 03015809 A2 Antimikrobiální kationické peptidy a jejich formulace • WO 2005025598 A1 antibakteriální lék pro propionibakterium acnes • EP 1853620 A2 Antimikrobiální hexapeptidyPNMIYSKDY) • CN 112979762 A Cyclic peptide PIZ and its application (EYPYKHSGYYHRAV) • KR 20200101767 A Peptide with antimicrobial activity and composition for antimicrobial comprising the same (KTTKS) • WO 03015809 A2 Antimicrobial cationic peptides and their formulation • WO 2005025598 A1 Antibacterial drug for Propionibacterium acnes • EP 1853620 A2 Antimicrobial hexapeptides
Avšak neexistuje patent ani publikace popisující jakýkoli peptid o aminokyselinové sekvenci podle stávajícího vynálezu, který je klíčový pro fyzikálně-chemické vlastnosti peptidu a také pro jeho biologickou aktivitu.However, there is no patent or publication describing any peptide of the amino acid sequence of the present invention, which is key to the physicochemical properties of the peptide as well as its biological activity.
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Mnoho výše zmíněných možností ošetření má negativní vedlejší účinky. Retinoidy zejména, ale také zinek nebo salicylová kyselina, běžně způsobují vysušení kůže, loupání, svědění, zčervenání a citlivost na slunce (Thielitz a Gollnick 2008; Cervantes a kol. 2018; Arif 2015). Znepokojující je zejména známý teratogenní účinek retinoidů pozorovaný po orálním použití (Thielitz a Gollnick 2008). Ačkoli se ukázalo, že povrchové použití retinoidů nezvyšovalo riziko poškození při narození, nejsou preventivně doporučeny pro těhotné ženy (Panchaud a kol. 2012). Použití antibiotik jako další běžný přístup při terapii akné je spojeno s vysokým rizikem selekce rezistentních bakteriálních kmenů (Walsh, Efthimiou a Dréno 2016). Proto nemohou být použita jako monoterapie a jsou doporučena pouze pro krátkodobé použití (Walsh, Efthimiou a Dréno 2016).Many of the treatment options mentioned above have negative side effects. Retinoids in particular, but also zinc or salicylic acid, commonly cause skin dryness, peeling, itching, redness, and sun sensitivity (Thielitz and Gollnick 2008; Cervantes et al. 2018; Arif 2015). Of particular concern is the known teratogenic effect of retinoids observed after oral use (Thielitz and Gollnick 2008). Although topical retinoids have not been shown to increase the risk of birth defects, they are not recommended for pregnant women as a precaution (Panchaud et al. 2012). The use of antibiotics as another common approach in acne therapy is associated with a high risk of selection of resistant bacterial strains (Walsh, Efthimiou and Dréno 2016). Therefore, they cannot be used as monotherapy and are only recommended for short-term use (Walsh, Efthimiou and Dréno 2016).
Ze všech těchto důvodů existuje stále potřeba pro nové, účinnější, komplexní a bezpečnější ošetření akné.For all these reasons, there is still a need for new, more effective, comprehensive and safer acne treatments.
Podstata vynálezuThe essence of the invention
Překvapivě byly zjištěny nové aktivity hexapeptidu Phe-Trp-Ala-His-Lys-Lys na buňky pokožky a zlepšení stavu pokožky.Surprisingly, novel activities of the hexapeptide Phe-Trp-Ala-His-Lys-Lys on skin cells and improvement of skin condition were found.
Předmět vynálezu se týká hexapeptidu jako zlepšovače buněk pokožky s obecným vzorcem IThe subject of the invention relates to a hexapeptide as a skin cell improver with the general formula I
X-Phe-Trp-Ala-His-Lys-Lys-Z (I) kde:X-Phe-Trp-Ala-His-Lys-Lys-Z (I) where:
X je -NHX1 skupina fenylalaninu na N-terminálním konci hexapeptidu, kdeX is a -NHX 1 phenylalanine group at the N-terminal end of the hexapeptide, where
X1 je vybrané ze skupiny zahrnující H, acetyl, oktanoyl, dekanoyl, lauryl, myristoyl, palmitoyl, stearoyl, elaidoyl, oleoyl, biotinoyl nebo lipoyl. S výhodou X1 je H.X 1 is selected from the group consisting of H, acetyl, octanoyl, decanoyl, lauryl, myristoyl, palmitoyl, stearoyl, elaidoyl, oleoyl, biotinoyl or lipoyl. Preferably X 1 is H.
Z je COZ1 skupina lyzinu na C-terminálním konci hexapeptidu, kde Z1 je vybrané ze skupiny zahrnující OH, OCH3, OCH2CH3 nebo NH2. S výhodou Z1 je OH.Z is a COZ 1 lysine group at the C-terminal end of the hexapeptide, where Z 1 is selected from the group consisting of OH, OCH 3 , OCH 2 CH 3 or NH 2 . Preferably, Z 1 is OH.
Hexapeptid podle stávajícího vynálezu zlepšuje buňky pokožky tak, že může být aplikován topicky na kůži a může se také nazývat topický hexapeptid.The hexapeptide of the present invention improves skin cells so that it can be applied topically to the skin and can also be called a topical hexapeptide.
Hexapeptid obecného vzorce I podle stávajícího vynálezu je s výhodou ve formě komplexu s iontem kovu vybraným ze skupiny zahrnující iont zinku, ion mědi, ion manganu nebo ion hořčíku. Ion kovu je vázán koordinačně kovalentní vaznou v komplexu. S výhodou je iontem kovu zinečnatý ion (Zn2+) a komplex je schematicky uveden níže jako Zn-FWAHKK komplex nebo jednoduše jako Zn-FWAHKK.The hexapeptide of general formula I according to the present invention is preferably in the form of a complex with a metal ion selected from the group comprising a zinc ion, a copper ion, a manganese ion or a magnesium ion. The metal ion is bound by a coordinative covalent bond in the complex. Preferably, the metal ion is zinc ion (Zn 2+ ) and the complex is shown schematically below as the Zn-FWAHKK complex or simply as Zn-FWAHKK.
Hexapeptid obecného vzorce I podle stávajícího vynálezu může být opticky čistý nebo složený z L- nebo D-izomerů nebo jejich směsi. L-izomery, což jsou ty nacházející se v přírodě, jsou výhodné.The hexapeptide of general formula I according to the present invention can be optically pure or composed of L- or D-isomers or their mixture. The L-isomers, which are those found in nature, are preferred.
Hexapeptid podle stávajícího vynálezu může být ve formě solí, zejména solí kyseliny chlorovodíkové, kyseliny mravenčí nebo kyseliny octové nebo jakékoli soli běžně používané v kosmetice.The hexapeptide according to the present invention can be in the form of salts, especially salts of hydrochloric acid, formic acid or acetic acid, or any salt commonly used in cosmetics.
Další provedení podle stávajícího vynálezu je topická kompozice zahrnující alespoň jeden hexapeptid obecného vzorce I, jak je uvedeno výše.Another embodiment according to the present invention is a topical composition comprising at least one hexapeptide of general formula I as mentioned above.
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Podle výhodného provedení topické kompozice podle stávajícího vynálezu je koncentrace hexapeptidu obecného vzorce I, jak je uvedeno výše, v rozsahu 0,0001 až 0,135 % (hmotn./hmotn.), s výhodou v rozsahu 0,001 až 0,05 % (hmotn./hmotn.), výhodněji od 0,001 do 0,0135 % (hmotn./hmotn.). Množství hexapeptidu závisí na účelu kompozice a požadovaném konečném efektu.According to a preferred embodiment of the topical composition according to the present invention, the concentration of the hexapeptide of general formula I, as mentioned above, is in the range of 0.0001 to 0.135% (w/w), preferably in the range of 0.001 to 0.05% (w/w wt.), more preferably from 0.001 to 0.0135% (wt/wt). The amount of hexapeptide depends on the purpose of the composition and the desired final effect.
Stávající vynález také zahrnuje topickou kompozici, která obsahuje alespoň jeden hexapeptid podle stávajícího vynálezu ve formě pro topickou kožní aplikaci, která může být vybraná ze skupiny zahrnující krém, sérum, bezvodý gel, pastu, disperzi vezikulů, prášek, nanovlákna, makro-, mikro- nebo nanočástice nebo makro-, mikro- nebo nano-sféry, které mohou být adsorbovány na organických polymerních prášcích, mastcích, bentonitech a dalších anorganických nebo organických podpůrných materiálech.The present invention also includes a topical composition that contains at least one hexapeptide according to the present invention in a form for topical skin application, which can be selected from the group consisting of cream, serum, anhydrous gel, paste, vesicle dispersion, powder, nanofibers, macro-, micro- or nanoparticles or macro-, micro- or nano-spheres that can be adsorbed on organic polymer powders, talcs, bentonites and other inorganic or organic support materials.
Tato topická kompozice podle stávajícího vynálezu je ve formě krému vybraného ze skupiny zahrnující emulzi voda-v-oleji nebo olej-ve-vodě, mikro- nebo nano-emulzi.This topical composition according to the present invention is in the form of a cream selected from the group comprising a water-in-oil or oil-in-water emulsion, micro- or nano-emulsion.
Tato topická kompozice podle stávajícího vynálezu je ve formě séra vybraného ze skupiny zahrnující sterilní nebo nesterilní vodný nebo vodno-alkoholový roztok nebo gel.This topical composition according to the present invention is in the form of a serum selected from the group comprising a sterile or non-sterile aqueous or aqueous-alcohol solution or gel.
Podle dalšího výhodného provedení je topická kompozice podle stávajícího vynálezu ve formě vybrané ze skupiny zahrnující krém nebo sérum.According to another preferred embodiment, the topical composition according to the present invention is in a form selected from the group comprising a cream or a serum.
V případě, že je topická kompozice podle stávajícího vynálezu ve formě krému, je koncentrace hexapeptidu obecného vzorce I, jak je uvedeno výše, v rozsahu 0,0001 až 0,135 % (hmotn./hmotn.), s výhodou 0,001 % až 0,0135 % (hmotn./hmotn.).In the case that the topical composition of the present invention is in the form of a cream, the concentration of the hexapeptide of the general formula I as mentioned above is in the range of 0.0001 to 0.135% (w/w), preferably 0.001% to 0.0135 % (w/w).
S výhodou kompozice ve formě krému dále zahrnuje alespoň jednu kosmetickou nebo dermofarmaceutickou pomocnou látku vybranou ze skupiny zahrnující olej, vosk, máslo, emulgátor, pomocnou aktivní složku nebo konzervant.Advantageously, the composition in the form of a cream further comprises at least one cosmetic or dermopharmaceutical excipient selected from the group comprising oil, wax, butter, emulsifier, auxiliary active ingredient or preservative.
S výhodou je množství oleje, vosku, másla nebo jejich směsi v kompozici podle stávajícího vynálezu v rozsahu 20 až 55 % (hmotn./hmotn.), s výhodou 20 až 40 % (hmotn./hmotn.), výhodněji 20 až 30 % (hmotn./hmotn.). S výhodou je množství emulgátoru v kompozici podle stávajícího vynálezu v rozsahu od 1 do 20 % (hmotn./hmotn.), s výhodou 2 až 15 % (hmotn./hmotn.), výhodněji 2 až 10 % (hmotn./hmotn.). S výhodou je množství další aktivní složky v kompozici podle stávajícího vynálezu v rozsahu od 0,001 do 20 % (hmotn./hmotn.), s výhodou 0,001 až 10 % (hmotn./hmotn.), výhodněji 0,001 až 5 % (hmotn./hmotn.). S výhodou je množství konzervantu v kompozici podle stávajícího vynálezu v rozsahu od 0,1 do 2,5 % (hmotn./hmotn.), s výhodou 0,1 až 1,5 % (hmotn./hmotn.), výhodněji 0,8 až 1,2 % (hmotn./hmotn.).Preferably, the amount of oil, wax, butter or their mixture in the composition according to the present invention is in the range of 20 to 55% (wt/wt), preferably 20 to 40% (wt/wt), more preferably 20 to 30% (wt/wt). Preferably, the amount of emulsifier in the composition according to the present invention is in the range from 1 to 20% (w/w), preferably 2 to 15% (w/w), more preferably 2 to 10% (w/w). ). Preferably, the amount of the additional active ingredient in the composition according to the present invention is in the range from 0.001 to 20% (wt/wt), preferably 0.001 to 10% (wt/wt), more preferably 0.001 to 5% (wt/wt wt.). Preferably, the amount of preservative in the composition according to the present invention is in the range from 0.1 to 2.5% (wt/wt), preferably 0.1 to 1.5% (wt/wt), more preferably 0, 8 to 1.2% (w/w).
S výhodou je olej vybraný ze skupiny zahrnující arganový, kokosový, avokádový, mandlový, sezamový, olivový, slunečnicový, konopný, jojobový, makadamový, z pšeničných klíčků, marulový, mokřadkový, rýžový, makový, šípkový, meruňkový, ricinový olej, kaprylový/kaprový triglycerid; máslo je vybráno ze skupiny zahrnující kakaové máslo, bambucké máslo, ilipové máslo, kokum máslo, murumurové máslo, mangové máslo, kupuakové máslo, avokádové máslo; a vosk je vybraný ze skupiny zahrnující lanolin, včelí vosk, karnauba, kandelilový vosk a vazelínu.Preferably, the oil is selected from the group including argan, coconut, avocado, almond, sesame, olive, sunflower, hemp, jojoba, macadamia, wheat germ, marula, safflower, rice, poppy, rosehip, apricot, castor oil, caprylic/carp oil triglyceride; the butter is selected from the group consisting of cocoa butter, shea butter, ilip butter, kokum butter, murumuru butter, mango butter, kupuak butter, avocado butter; and the wax is selected from the group consisting of lanolin, beeswax, carnauba, candelilla wax and petroleum jelly.
S výhodou je emulgátor vybraný ze skupiny zahrnující glyceryl stearát, glyceryl kaprylát, behenyl alkohol, glyceryl behenát, cetearyl glukosid, methyl glukózu, sekvistearát, glyceryl stearát citrát, polyglyceryl-3 stearát, cetearyl olivát, lecitin, stearyl alkohol, sorbitan oleát, polysorbát, stearovou kyselinu, cetyl alkohol a cetearyl alkohol, akrylát sodný, akryloyldimethyl taurát sodný kopolymer, izohexadekan, polysorbát 80 nebo jejich směs.Advantageously, the emulsifier is selected from the group comprising glyceryl stearate, glyceryl caprylate, behenyl alcohol, glyceryl behenate, cetearyl glucoside, methyl glucose, sestearate, glyceryl stearate citrate, polyglyceryl-3 stearate, cetearyl olivate, lecithin, stearyl alcohol, sorbitan oleate, polysorbate, stearic acid, cetyl alcohol and cetearyl alcohol, sodium acrylate, sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 or a mixture thereof.
- 5 CZ 309857 B6- 5 CZ 309857 B6
Topická kompozice podle stávajícího vynálezu ve formě krému obsahujícího alespoň jeden hexapeptid podle stávajícího vynálezu může být také kombinována s dalšími pomocnými aktivními složkami, které mohou mít synergický nebo aditivní účinek pro zvýšení nebo rozšíření požadované aktivity popsané v tomto vynálezu. Tato další aktivní složka je vybrána ze skupiny obsahující následující látky: proti akné, proti stárnutí, proti vráskám, zesvětlující, bělicí, proti skvrnám, pigmentující, hydratační, zvlhčující, zvlhčovací, zeštíhlující, odlupovací, proti zčervenání, protizánětlivé, antioxidanty, vychytávače radikálů, proti glykaci, zvětšující objem, restrukturalizační, omlazující, regenerační, proti karbonylaci, dermo-relaxační, zlepšující stratum corneum, dermo-epidermální spojení, pevnost, elasticitu, kolagenové boostery, oční kontury (tmavé kruhy a podoční vaky), podporující prokrvení atd.A topical composition according to the present invention in the form of a cream containing at least one hexapeptide according to the present invention may also be combined with other auxiliary active ingredients that may have a synergistic or additive effect to increase or extend the desired activity described in the present invention. This additional active ingredient is selected from the group containing the following: anti-acne, anti-aging, anti-wrinkle, lightening, whitening, anti-blemish, pigmenting, hydrating, moisturizing, moisturizing, slimming, exfoliating, anti-redness, anti-inflammatory, antioxidant, radical scavenger, anti-glycation, increasing volume, restructuring, rejuvenating, regenerating, anti-carbonylation, dermo-relaxing, improving the stratum corneum, dermo-epidermal connection, firmness, elasticity, collagen boosters, eye contours (dark circles and bags under the eyes), promoting blood circulation, etc.
Výše uvedené další aktivní složky mohou být syntetické nebo získané z rostlin, bakterií, hub, buněčných kultur nebo jejich produkty.The other active ingredients mentioned above can be synthetic or obtained from plants, bacteria, fungi, cell cultures or their products.
S výhodou je další aktivní složka vybraná ze skupiny zahrnující vitamíny A, D, E, K, C, Bskupina, koenzym Q10, alantoin, bisabolol, bakuchiol, resveratrol, kyselinu mléčnou, aminokyseliny, benzoylperoxid, síru, azelaovou kyselinu, peptidy s výhodou acetyl hexapeptid-8, palmitoyl tripeptid-1, palmitoyl tetrapeptid-7, tripeptid-1 mědi, hexapeptid-1, palmitoyl pentapeptid-4, peptidy saccharomyces a proteiny, s výhodou rýže, sóji, quinoa nebo pšeničný protein; polysacharidy s výhodou hyaluronovou kyselinu nebo její farmaceuticky a kosmeticky přijatelnou sůl nebo derivát s výhodou oleoyl hyaluronát sodný, retinoyl hyaluronát sodný, hyaluronát krospolymer-3 sodný; karboxymethyl glukan, schizofylan, glukomanan; pantenol; močovinu; glycerin; rostlinné extrakty, s výhodou extrakt z aloe vera, heřmánkový extrakt, acai extrakt, extrakt ze zeleného čaje, extrakt z řas, ovesný extrakt, konopný extrakt, brusinkový extrakt; extrakty, fermenty, lyzáty nebo filtráty z bakterií s výhodou z Lactobacillus spp., Thalassospira spp., Bifidobacterium spp., Halobacterium spp., nebo z hub s výhodou ze Saccharomyces spp., Agaricus subrufencens, Choiromyces maendrformis, Cordyceps sinensis, Ganoderma lucidum, Grfola frondosa, Hypsizygus ulmarium, Inonotus obliquus, Lentinula edodes, Polyporus spp., Trametes versicolor, Tremella fucformis, Tuber spp., Schizophyllum commune.Advantageously, another active ingredient is selected from the group comprising vitamins A, D, E, K, C, Bgroup, coenzyme Q10, allantoin, bisabolol, bakuchiol, resveratrol, lactic acid, amino acids, benzoyl peroxide, sulfur, azelaic acid, peptides, preferably acetyl hexapeptide-8, palmitoyl tripeptide-1, palmitoyl tetrapeptide-7, copper tripeptide-1, hexapeptide-1, palmitoyl pentapeptide-4, saccharomyces peptides and proteins, preferably rice, soy, quinoa or wheat protein; polysaccharides, preferably hyaluronic acid or its pharmaceutically and cosmetically acceptable salt or derivative, preferably sodium oleoyl hyaluronate, sodium retinoyl hyaluronate, crosspolymer-3 sodium hyaluronate; carboxymethyl glucan, schizophyllan, glucomannan; panthenol; urea; glycerine; plant extracts, preferably aloe vera extract, chamomile extract, acai extract, green tea extract, algae extract, oat extract, hemp extract, cranberry extract; extracts, ferments, lysates or filtrates from bacteria, preferably from Lactobacillus spp., Thalassospira spp., Bifidobacterium spp., Halobacterium spp., or from fungi, preferably from Saccharomyces spp., Agaricus subrufencens, Choiromyces maendrformis, Cordyceps sinensis, Ganoderma lucidum, Grfola frondosa, Hypsizygus ulmarium, Inonotus obliquus, Lentinula edodes, Polyporus spp., Trametes versicolor, Tremella fucformis, Tuber spp., Schizophyllum commune.
S výhodou je konzervant vybraný ze skupiny zahrnující aromatické kyseliny a jejich deriváty s výhodou benzoovou kyselinu, benzoát sodný, kyselinu salicylovou, kyselinu dehydrooctovou, sorbát draselný, parabeny; alkoholy s výhodou ethanol, isopropanol, benzylalkohol, fenoxyethanol, fenethyl alkohol; imidazolové deriváty s výhodou hydantoin, imidazolidinyl močovinu; kationické povrchově aktivní látky, s výhodou benzalkonium chlorid.Preferably, the preservative is selected from the group including aromatic acids and their derivatives, preferably benzoic acid, sodium benzoate, salicylic acid, dehydroacetic acid, potassium sorbate, parabens; alcohols preferably ethanol, isopropanol, benzyl alcohol, phenoxyethanol, phenethyl alcohol; imidazole derivatives preferably hydantoin, imidazolidinyl urea; cationic surfactants, preferably benzalkonium chloride.
Pokud je topická kompozice podle stávajícího vynálezu ve formě séra, koncentrace hexapeptidu obecného vzorce I, jak je uvedeno výše, je v rozsahu 0,001 až 0,135 % (hmotn./hmotn.), s výhodou 0,001 % až 0,0135 % (hmotn./hmotn.).When the topical composition of the present invention is in the form of a serum, the concentration of the hexapeptide of general formula I as mentioned above is in the range of 0.001 to 0.135% (wt/wt), preferably 0.001% to 0.0135% (wt/wt wt.).
S výhodou kompozice ve formě séra dále zahrnuje alespoň jednu kosmetickou nebo dermofarmaceutickou pomocnou složku vybranou ze skupiny zahrnující zahušťovadlo, pomocnou aktivní složku a konzervant, jak je definováno výše.Advantageously, the composition in the form of a serum further comprises at least one cosmetic or dermopharmaceutical auxiliary ingredient selected from the group comprising a thickener, an auxiliary active ingredient and a preservative as defined above.
S výhodou je množství zahušťovadla v kompozici podle stávajícího vynálezu v rozsahu 0,1 % až 20 % (hmotn./hmotn.), s výhodou 0,1 % až 5 % (hmotn./hmotn.), výhodněji 0,2 až 0,5 % (hmotn./hmotn.). S výhodou je množství pomocné aktivní složky v kompozici podle stávajícího vynálezu v rozsahu 0,001 až 20 % (hmotn./hmotn.), s výhodou 0,001 až 10 % (hmotn./hmotn.), výhodněji 0,001 až 5 % (hmotn./hmotn.). S výhodou je množství konzervantu v kompozici podle stávajícího vynálezu v rozsahu 0,1 až 2,5 % (hmotn./hmotn.), s výhodou 0,1 až 1,5 % (hmotn./hmotn.), výhodněji 0,8 až 1,2 % (hmotn./hmotn.).Preferably, the amount of thickener in the composition according to the present invention is in the range of 0.1% to 20% (w/w), preferably 0.1% to 5% (w/w), more preferably 0.2 to 0 .5% (w/w). Preferably, the amount of auxiliary active ingredient in the composition according to the present invention is in the range of 0.001 to 20% (wt/wt), preferably 0.001 to 10% (wt/wt), more preferably 0.001 to 5% (wt/wt .). Preferably, the amount of preservative in the composition according to the present invention is in the range of 0.1 to 2.5% (wt/wt), preferably 0.1 to 1.5% (wt/wt), more preferably 0.8 up to 1.2% (w/w).
S výhodou je zahušťovadlo vybráno ze skupiny zahrnující xanthamovou gumu, sklerotiovou gumu, guarovou gumu, celulózovou gumu, karbomer, hydroxyethylcelulózu, kořenový extraktPreferably, the thickener is selected from the group consisting of xantham gum, sclerotia gum, guar gum, cellulose gum, carbomer, hydroxyethyl cellulose, root extract
- 6 CZ 309857 B6 z Amorphophallus konjac, karagenan, pululan, lecitin, lysolecitin, akrylát sodný, akryloyldimethyltaurát sodný kopolymer, izohexadekan, polysorbát 80 nebo jejich směsi.- 6 CZ 309857 B6 from Amorphophallus konjac, carrageenan, pullulan, lecithin, lysolecithin, sodium acrylate, sodium acryloyldimethyltaurate copolymer, isohexadecane, polysorbate 80 or their mixtures.
Topická kompozice podle stávajícího vynálezu obsahující alespoň jeden hexapeptid podle stávajícího vynálezu může být také kombinována s dalšími aktivními složkami, které mohou mít synergický nebo aditivní účinek pro zvýšení rozsahu požadované aktivity popsané ve vynálezu. Pomocná aktivní složka je vybraná ze skupiny zahrnující následující látky: proti akné, proti stárnutí, proti vráskám, zesvětlující, bělicí, proti skvrnám, pigmentující, hydratační, zvlhčující, zvlhčovací, zeštíhlující, odlupující, proti zčervenání, protizánětlivé, antioxidanty, vychytávače radikálů, proti glykaci, zvětšující objem, restrukturalizační, omlazující, regenerující, proti karbonylaci, dermo-relaxační, zlepšující stratum corneum, dermo-epidermální spojení, pevnost, elasticitu, kolagenové boostery, oční kontury (tmavé kruhy a podoční vaky), zlepšující cirkulaci krve atd.A topical composition according to the present invention containing at least one hexapeptide according to the present invention may also be combined with other active ingredients that may have a synergistic or additive effect to increase the scope of the desired activity described in the invention. The auxiliary active ingredient is selected from the group including the following substances: anti-acne, anti-aging, anti-wrinkle, lightening, whitening, anti-blemish, pigmenting, hydrating, moisturizing, moisturizing, slimming, exfoliating, anti-redness, anti-inflammatory, antioxidants, radical scavengers, anti glycation, increasing volume, restructuring, rejuvenating, regenerating, anti-carbonylation, dermo-relaxing, improving the stratum corneum, dermo-epidermal connection, firmness, elasticity, collagen boosters, eye contours (dark circles and bags under the eyes), improving blood circulation, etc.
Výše zmíněné pomocné aktivní složky mohou být syntetické nebo získané z rostlin, bakterií, hub, buněčných kultur nebo jejich produkty.The auxiliary active ingredients mentioned above can be synthetic or obtained from plants, bacteria, fungi, cell cultures or their products.
S výhodou je pomocná aktivní složka vybraná ze skupiny zahrnující vitamín C a skupinu vitamínů B; aminokyseliny, peptidy s výhodou acetyl hexapeptid-8, palmitoyl tripeptid-1, měďnatý tripeptid-1, peptidy Saccharomyces, hexapeptid-1, a proteiny s výhodou rýžový protein, sójový protein, quinoa nebo pšeničný protein; další polysacharidy s výhodou hyaluronovou kyselinu nebo její farmaceuticky a kosmeticky přijatelnou sůl nebo derivát s výhodou oleoyl hyaluronát sodný, retinoyl hyaluronát sodný, hyaluronát krospolymer-3 sodný; karboxymethyl glukan, schizophyllan, glukomanan, pantenol, močovinu, glycerin; rostlinné extrakty, s výhodou extrakt z aloe vera, heřmánkový extrakt, acai extrakt, extrakt ze zeleného čaje, extrakt z řas, ovesný extrakt, konopný extrakt, brusinkový extrakt; extrakty, fermenty, lyzáty nebo filtráty z bakterií, s výhodou z Lactobacillus spp., Thalassospira spp., Bifidobacterium spp., Halobacterium spp., nebo hub s výhodou z Saccharomyces spp., Agaricus subrufescens, Choiromyces maendrformis, Cordyceps sinensis, Ganoderma lucidum, Grfola. frondosa, Hypsizygus ulmarium, Inonotus obliquus, Lentinula edodes, Polyporus spp., Trametes versicolor, Tremella fucformis, Tuber spp., Schizophyllum commune.Advantageously, the auxiliary active ingredient is selected from the group comprising vitamin C and the group of B vitamins; amino acids, peptides preferably acetyl hexapeptide-8, palmitoyl tripeptide-1, copper tripeptide-1, Saccharomyces peptides, hexapeptide-1, and proteins preferably rice protein, soy protein, quinoa or wheat protein; other polysaccharides, preferably hyaluronic acid or its pharmaceutically and cosmetically acceptable salt or derivative, preferably sodium oleoyl hyaluronate, sodium retinoyl hyaluronate, crospolymer-3 sodium hyaluronate; carboxymethyl glucan, schizophyllan, glucomannan, panthenol, urea, glycerin; plant extracts, preferably aloe vera extract, chamomile extract, acai extract, green tea extract, algae extract, oat extract, hemp extract, cranberry extract; extracts, ferments, lysates or filtrates from bacteria, preferably from Lactobacillus spp., Thalassospira spp., Bifidobacterium spp., Halobacterium spp., or mushrooms, preferably from Saccharomyces spp., Agaricus subrufescens, Choiromyces maendrformis, Cordyceps sinensis, Ganoderma lucidum, Grfola. frondosa, Hypsizygus ulmarium, Inonotus obliquus, Lentinula edodes, Polyporus spp., Trametes versicolor, Tremella fucformis, Tuber spp., Schizophyllum commune.
S výhodou je konzervant vybraný ze skupiny zahrnující aromatické kyseliny a jejich deriváty s výhodou kyselinu benzoovou, benzoát sodný, kyselinu salicylovou, kyselinu dehydrooctovou; sorbát draselný, parabeny; alkoholy s výhodou ethanol, isopropanol, benzylalkohol, fenoxyethanol, fenethylalkohol; imidazolové deriváty s výhodou hydantoin, imidazolidinyl močovinu; kationické povrchově aktivní látky s výhodou benzalkonium chlorid.Preferably, the preservative is selected from the group comprising aromatic acids and their derivatives, preferably benzoic acid, sodium benzoate, salicylic acid, dehydroacetic acid; potassium sorbate, parabens; alcohols preferably ethanol, isopropanol, benzyl alcohol, phenoxyethanol, phenethyl alcohol; imidazole derivatives preferably hydantoin, imidazolidinyl urea; cationic surfactants, preferably benzalkonium chloride.
Všechna % uvedena níže, jsou (hmotn./hmotn.%) pokud nebude uvedeno jinak, a vztahují se k celkové hmotnosti kompozice, pokud se % týká topické kompozice podle stávajícího vynálezu.All % given below are (wt/wt%) unless otherwise stated and refer to the total weight of the composition when the % refers to the topical composition of the present invention.
Obecně odpovídá množství vody v kompozici podle stávajícího vynálezu ve formě krému nebo séra množství vody přidané do 100 % (hmotn./hmotn.) kompozice.In general, the amount of water in the composition of the present invention in the form of a cream or serum corresponds to the amount of water added to 100% (w/w) of the composition.
Kosmeticky a farmaceuticky přijatelné soli hyaluronové kyseliny mají být takové, které jsou tvořené z kyselin, které tvoří netoxické kyselé anionty vybrané ze skupiny zahrnující sodík, draslík, vápník, hořčík, zinek.Cosmetically and pharmaceutically acceptable salts of hyaluronic acid should be those formed from acids that form non-toxic acidic anions selected from the group including sodium, potassium, calcium, magnesium, zinc.
Nový je hexapeptid obecného vzorce I podle stávajícího vynálezu a jeho použití nebo použití kosmetických nebo dermo-farmaceutických topických kompozic podle stávajícího vynálezu obsahujících uvedený hexapeptid pro zlepšení mastného a k akné náchylného stavu pokožky a vzhledu. Konkrétněji hexapeptid podle stávajícího vynálezu inhibuje epidermální keratinizaci, snižuje produkci kožního mazu inhibicí klíčového enzymu 5n-reduktázy, má protizánětlivou aktivitu tím, že inhibuje prozánětlivé interleukiny, má antimikrobiální účinek ke CutibacteriumNew is the hexapeptide of general formula I according to the present invention and its use or the use of cosmetic or dermo-pharmaceutical topical compositions according to the present invention containing said hexapeptide for improving oily and acne-prone skin condition and appearance. More specifically, the hexapeptide of the present invention inhibits epidermal keratinization, reduces sebum production by inhibiting the key enzyme 5n-reductase, has anti-inflammatory activity by inhibiting pro-inflammatory interleukins, has an antimicrobial effect on Cutibacterium
- 7 CZ 309857 B6 acnes a snižuje počet lézí akné in vivo. Dále má uvedený hexapeptid podle stávajícího vynálezu také účinek proti stárnutí stimulací kolagenové syntézy a snížením vrásek in vivo.- 7 CZ 309857 B6 acnes and reduces the number of acne lesions in vivo. Furthermore, said hexapeptide according to the present invention also has an anti-aging effect by stimulating collagen synthesis and reducing wrinkles in vivo.
Uvedený hexapeptid topické kompozice podle stávajícího vynálezu je určen pro mastnou a k akné náchylnou pokožku a také pro normální kůži.Said hexapeptide of the topical composition according to the present invention is intended for oily and acne-prone skin as well as for normal skin.
Podle dalšího výhodného provedení hexapeptid podle obecného vzorce I podle stávajícího vynálezu a topická kompozice podle stávajícího vynálezu jsou určené pro použití při léčbě pokožky. S výhodou pro použití při lékařském ošetření kožní nemoci vybrané ze skupiny zahrnující akné, atopickou dermatitidu, psoriázu, nemoc odlupování kůže, ichtyózu. Nebo s výhodou pro použití pro kosmetické ošetření kůže.According to another preferred embodiment, the hexapeptide according to the general formula I according to the present invention and the topical composition according to the present invention are intended for use in the treatment of the skin. Preferably for use in the medical treatment of skin diseases selected from the group including acne, atopic dermatitis, psoriasis, skin peeling disease, ichthyosis. Or preferably for use for cosmetic skin treatment.
Objasnění výkresůClarification of drawings
Obr. 1 Hexapeptid FWAHKK tvoří komplex se zinkem. Spektrofotometrické stanovení schopnosti zinku tvořit komplex s FWAHKK hexapeptidem použitím dithizonu jako volného zinkového indikátoru.Giant. 1 Hexapeptide FWAHKK forms a complex with zinc. Spectrophotometric determination of the ability of zinc to form a complex with FWAHKK hexapeptide using dithizone as a free zinc indicator.
Obr. 2. Zinek proniká do buněk účinněji, když je v Zn-FWAHKK komplexu. HaCaT keratinocyty byly inkubovány se Zn-FWAHKK nebo ZnSO4*7H2O (Zn) s odpovídající koncentrací 3 h. Intracelulární zinek byl vizualizován použitím fluorescenční mikroskopie.Giant. 2. Zinc penetrates cells more efficiently when it is in the Zn-FWAHKK complex. HaCaT keratinocytes were incubated with Zn-FWAHKK or ZnSO4*7H2O (Zn) at the appropriate concentration for 3 h. Intracellular zinc was visualized using fluorescence microscopy.
Obr. 3. Hexapeptid FWAHKK zvyšuje buněčnou viabilitu a zabraňuje cytotoxickému účinku zinku v Zn-FWAHKK komplexu. NIH-3T3 fibroblasty byly inkubovány s FWAHKK, ZnFWAHKK nebo ZnSO4*7H2O (Zn) při odpovídajících koncentracích 48 h. Buněčná viabilita byla stanovena MTT postupem. * p<0,05; ** p<0,01; *** p<0,001 v porovnání s kontrolou, pokud není uvedeno jinak.Giant. 3. Hexapeptide FWAHKK increases cell viability and prevents the cytotoxic effect of zinc in the Zn-FWAHKK complex. NIH-3T3 fibroblasts were incubated with FWAHKK, ZnFWAHKK or ZnSO4*7H2O (Zn) at the corresponding concentrations for 48 h. Cell viability was determined by the MTT method. *p<0.05; ** p<0.01; *** p<0.001 compared to control unless otherwise stated.
Obr. 4. Hexapeptid FWAHKK a ZnSO4*7H2O snížil expresi genu 5n-reduktázy v porovnání s retinolem. Zn-FWAHKK komplex byl dokonce účinnější než jeho jednotlivé složky. HaCaT keratinocyty byly ošetřeny FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) a retinolem 72 h. Relativní genová exprese 5n-reduktázy (gen SRD5A1) byla stanovena pomocí qRT-PCR. *p<0,05; ** p<0,01; *** p<0,001 v porovnání s příslušnými kontrolami.Giant. 4. Hexapeptide FWAHKK and ZnSO4*7H2O decreased 5n-reductase gene expression compared to retinol. The Zn-FWAHKK complex was even more effective than its individual components. HaCaT keratinocytes were treated with FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) and retinol for 72 h. Relative gene expression of 5n-reductase (SRD5A1 gene) was determined by qRT-PCR. *p<0.05; ** p<0.01; *** p<0.001 compared to respective controls.
Obr. 5. Hexapeptidy FWAHKK a Zn-FWAHKK významně snížily UVB-indukovanou expresi genu IL1A vzhledem k zinku nebo retinolu. HaCaT keratinocyty byly ozářeny 10 mJ/cm2 UVB a ošetřeny FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) a retinolem 24 h. Relativní genová exprese IL-Ια (gen IL1A) byla stanovena qRT-PCR. *** p<0,001 v porovnání s příslušnými UVB kontrolami.Giant. 5. Hexapeptides FWAHKK and Zn-FWAHKK significantly reduced UVB-induced IL1A gene expression relative to zinc or retinol. HaCaT keratinocytes were irradiated with 10 mJ/cm 2 UVB and treated with FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) and retinol for 24 h. The relative gene expression of IL-Ια (IL1A gene) was determined by qRT-PCR. *** p<0.001 compared to respective UVB controls.
Obr. 6. Hexapeptidy FWAHKK a Zn-FWAHKK snížily expresi genů spojených s keratinocytovou diferenciací podobně jako retinol, když zinek neměl žádný takový účinek. HaCaT keratinocyty byly ošetřeny FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) a retinolem 72 h. Relativní genová exprese 5n-reduktázy (gen SRD5A1) byla stanovena qRT-PCR * p<0,05; ** p<0,01; *** p<0,001 v porovnání s příslušnými kontrolami.Giant. 6. Hexapeptides FWAHKK and Zn-FWAHKK reduced the expression of genes associated with keratinocyte differentiation similar to retinol, while zinc had no such effect. HaCaT keratinocytes were treated with FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) and retinol for 72 h. The relative gene expression of 5n-reductase (SRD5A1 gene) was determined by qRT-PCR * p<0.05; ** p<0.01; *** p<0.001 compared to respective controls.
Obr. 7. Hexapeptidy FWAHKK a Zn-FWAHKK významně snížily UVB-indukovanou genovou expresi IL6 a IL8 v porovnání se zinkem nebo retinolem. HaCaT keratinocyty byly ozářeny 10 mJ/cm2 UVB a ošetřeny FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) a retinolem 24 h. Relativní genová exprese pro-zánětlivých interleukinů Il-6 a IL-8 (geny IL6 a IL8) byla stanovena qRT-PCR. * p<0,05; ** p<0,01; *** p<0,001 v porovnání s příslušnými UVB kontrolami.Giant. 7. Hexapeptides FWAHKK and Zn-FWAHKK significantly reduced UVB-induced gene expression of IL6 and IL8 compared to zinc or retinol. HaCaT keratinocytes were irradiated with 10 mJ/cm 2 UVB and treated with FWAHKK, Zn-FWAHKK, ZnSO4*7H2O (Zn) and retinol for 24 h. The relative gene expression of pro-inflammatory interleukins IL-6 and IL-8 (IL6 and IL8 genes) was determined by qRT-PCR. *p<0.05; ** p<0.01; *** p<0.001 compared to respective UVB controls.
- 8 CZ 309857 B6- 8 CZ 309857 B6
Obr. 8. Hexapeptid FWAHKK a zinek měly antimikrobiální aktivitu proti C. acnes rostoucích v suspenzi. Zn-FWAHKK měl vyšší aktivitu než jednotlivé složky. C. acnes rostoucí v suspenzi byly kultivovány s FWAHKK, Zn-FWAHKK and ZnSO4*7H2O (Zn) 72 h. Potom bylo změřeno OD590. * p<0,05; ** p<0,01; *** p<0,001 v porovnání s kontrolou, pokud není uvedeno jinak.Giant. 8. Hexapeptide FWAHKK and zinc had antimicrobial activity against C. acnes growing in suspension. Zn-FWAHKK had higher activity than the individual components. C. acnes growing in suspension were cultured with FWAHKK, Zn-FWAHKK and ZnSO4*7H2O (Zn) for 72 h. Then OD590 was measured. *p<0.05; ** p<0.01; *** p<0.001 compared to control unless otherwise stated.
Obr. 9. Hexapeptidy FWAHKK a Zn-FWAHKK stimulovaly kolagen 1 genovou expresi v porovnání se zinkem nebo retinolem. HaCaT keratinocyty byly ošetřeny FAWHKK, ZnFWAHKK, ZnSO4*7H2O (Zn), a retinolem 72 h. Relativní genová exprese 5a-reduktázy (gen SRD5A1) byla stanovena qRT-PCR. * p<0,05; ** p<0,01; *** p<0,001 v porovnání s příslušnými kontrolami.Giant. 9. Hexapeptides FWAHKK and Zn-FWAHKK stimulated collagen 1 gene expression compared to zinc or retinol. HaCaT keratinocytes were treated with FAWHKK, ZnFWAHKK, ZnSO4*7H2O (Zn), and retinol for 72 h. Relative gene expression of 5α-reductase (SRD5A1 gene) was determined by qRT-PCR. *p<0.05; ** p<0.01; *** p<0.001 compared to respective controls.
Obr. 10. Zn-FWAHKK komplex měl aktivitu proti akné a proti stárnutí a je účinnější než retinol. In vivo studie na 40 dobrovolnících s pokožkou náchylnou k akné, kteří si aplikovali dvě emulze s 13,5 pg/ml Zn-FWAHKK a placebem (30 subjektů) nebo 0,2% retinol a placebo (10 subjektů) na dvou polovinách obličeje v daném pořadí jednou denně 6 týdnů. Počet lézí akné (A) byl stanoven obrazovou analýzou celoobličejových obrázků získaných VisiaCR. Hloubka vrásek vraních stop (B) byla stanovena 3D fotoaparátem. * p<0,05; ** p<0,01, *** p<0,001 v porovnání s placebem.Giant. 10. The Zn-FWAHKK complex had anti-acne and anti-aging activity and is more effective than retinol. In vivo study of 40 volunteers with acne-prone skin who applied two emulsions with 13.5 pg/ml Zn-FWAHKK and placebo (30 subjects) or 0.2% retinol and placebo (10 subjects) on two halves of the face in given order once a day for 6 weeks. The number of acne lesions (A) was determined by image analysis of full-face images acquired by VisiaCR. The depth of crow's feet wrinkles (B) was determined by a 3D camera. *p<0.05; ** p<0.01, *** p<0.001 compared to placebo.
Příklady uskutečnění vynálezuExamples of implementation of the invention
Příklad 1. Příprava FWAHKK, Zn-FWAHKK, acetyl-FWAHKK a palmitoyl-FWAHKK peptiduExample 1. Preparation of FWAHKK, Zn-FWAHKK, acetyl-FWAHKK and palmitoyl-FWAHKK peptide
Nejdříve byl syntetizován FWAHKK peptid standardní syntézou peptidů na pevné fázi použitím Fmoc/tBu strategie na Wangově resinu (Amblard a kol. 2006).First, the FWAHKK peptide was synthesized by standard solid-phase peptide synthesis using the Fmoc/tBu strategy on Wang resin (Amblard et al. 2006).
Připojení první aminokyseliny na Wangův resin (Sunresin, Čína) bylo provedeno stříkačkovým reaktorem v dimethylformamidu (DMF) použitím diisopropylkarbodiimidu (DIC) a OxymaPure® (Iris Biotech, Německo) v 3 molárním nadbytku (meq) Fmoc-Lys(Boc)-OH přes noc. Po spojení byly zbytkové hydroxylové skupiny na resinu překryty roztokem acetanhydrid/pyridin (1/1, obj./obj.).Attachment of the first amino acid to Wang resin (Sunresin, China) was performed by syringe reactor in dimethylformamide (DMF) using diisopropylcarbodiimide (DIC) and OxymaPure® (Iris Biotech, Germany) in 3 molar excess (meq) of Fmoc-Lys(Boc)-OH via night. After coupling, the residual hydroxyl groups on the resin were covered with a solution of acetic anhydride/pyridine (1/1, v/v).
FWAHKK peptid byl syntetizován v 0,1 mmol škále použitím CEM Liberty Blue automatizovaného mikrovlnného peptidového syntetizéru (CEM, USA) na Wangově resinu nasyceném první Fmoc-AA. Fmoc deprotekce byly provedeny 20% pyridinem v DMF. Slučovací reakce byly provedeny použitím 5 ekvivalentů Fmoc-AA/DIC/Oxyma Pure® v DMF.The FWAHKK peptide was synthesized on a 0.1 mmol scale using a CEM Liberty Blue automated microwave peptide synthesizer (CEM, USA) on Wang resin saturated with first Fmoc-AA. Fmoc deprotections were performed with 20% pyridine in DMF. Coupling reactions were performed using 5 equivalents of Fmoc-AA/DIC/Oxyma Pure ® in DMF.
Pro přípravu acetyl-FWAHKK a palmitoyl-FWAHKK byl N-konec syntetizovaného peptidu FWAHKK na resinu acetylován nebo palmitoylován použitím 2 meq acetandhydridu nebo palmitoylanhydridu/pyridinu (1/1, obj./obj.) v DMF 30 min při teplotě místnosti.To prepare acetyl-FWAHKK and palmitoyl-FWAHKK, the N-terminus of the synthesized FWAHKK peptide was acetylated or palmitoylated on the resin using 2 meq of acetaldehyde or palmitoyl anhydride/pyridine (1/1, v/v) in DMF for 30 min at room temperature.
Štěpení peptidů (FWAHKK, acetyl-FWAHKK nebo palmitoyl-FWAHKK) z resinu bylo provedeno 30 min zvýšením teploty (38 °C) použitím CEM Razor® robustního peptidového štěpícího systému (CEM, USA) se směsí trifluoroctová kyselina/anisol/thioanisol/H2O/dichlormethan (85/2,5/2,5/5/5). Peptidy byly potom vysráženy ve studeném diethyletheru.Cleavage of peptides (FWAHKK, acetyl-FWAHKK or palmitoyl-FWAHKK) from the resin was performed by raising the temperature (38 °C) for 30 min using a CEM Razor® robust peptide cleavage system (CEM, USA) with a mixture of trifluoroacetic acid/anisole/thioanisole/H2O/ dichloromethane (85/2.5/2.5/5/5). The peptides were then precipitated in cold diethyl ether.
Surové FWAHKK a acetyl-FWAHKK peptidy byly rozpuštěny v 50% acetonitrilu, surový palmitoyl-FWAHKK byl rozpuštěn ve 100% acetonitrilu. Potom byly purifikovány na Shimadzu preparativní HPLC (série Prominence). XBridge OBD Prep Column Reversed-Phase 5 pm Sférický Hybrid, 50 mm x 50 mm byla použita pro rozdělení s průtokem 30 ml/min. Mobilní fáze byla A 0,1% HCOOH ve vodě a B acetonitril. Čistota peptidů byla ověřena PDA a MS detektorem. Purifikované peptidy byly potom lyofilizovány.Crude FWAHKK and acetyl-FWAHKK peptides were dissolved in 50% acetonitrile, crude palmitoyl-FWAHKK was dissolved in 100% acetonitrile. They were then purified on Shimadzu preparative HPLC (Prominence series). XBridge OBD Prep Column Reversed-Phase 5 pm Spherical Hybrid, 50 mm x 50 mm was used for separation at a flow rate of 30 ml/min. The mobile phase was A 0.1% HCOOH in water and B acetonitrile. The purity of the peptides was verified by PDA and MS detector. The purified peptides were then lyophilized.
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Pro přípravu FWAHKK hexapeptidu v komplexu se zinkem (Zn-FWAHKK) byl připraven vodný roztok 10% FWAHKK hexapeptidu a 3,52% ZnSO4*7H2O (síran zinečnatý, heptahydrát, Lachner, Česká republika) odpovídající molárnímu poměru 1:1, mícháno přes noc při teplotě místnosti a potom byl roztok lyofilizován.For the preparation of FWAHKK hexapeptide in complex with zinc (Zn-FWAHKK), an aqueous solution of 10% FWAHKK hexapeptide and 3.52% ZnSO4*7H2O (zinc sulfate, heptahydrate, Lachner, Czech Republic) corresponding to a molar ratio of 1:1 was prepared, stirred overnight at room temperature and then the solution was lyophilized.
Příklad 2. Schopnost FWAHKK peptidu tvořit komplex se zinkemExample 2. Ability of the FWAHKK peptide to form a complex with zinc
Schopnost FWAHKK peptidu tvořit komplex se zinkem byla vyhodnocena, jak bylo popsáno dříve s menšími modifikacemi (Catapano a kol., 2018). Stručně, 20 pl roztoku FWAHKK (0 až 600 μΜ (0 až 490 pg/ml; 0 až 0,049 hmotn./hmotn.%) připraveno, jak je popsáno v Příkladu 1) a 60 μΜ (17,3 pg/ml; 0,00173%) ZnSO4*7H2O v 15 mM HEPES, pH 6,8 byl smíchán s 20 pl 250 μΜ dithizonu v DMSO a 80 pl 15 mM HEPES, pH 6,8. Dithizon byl použit jako indikátor volného zinku. Po 30 min inkubace při teplotě místnosti (RT) byla změřena absorbance při 520 nm a byla spočítána procenta zinku v komplexu s FWAHKK peptidem.The ability of the FWAHKK peptide to form a complex with zinc was evaluated as previously described with minor modifications (Catapano et al., 2018). Briefly, 20 µl of FWAHKK solution (0 to 600 μΜ (0 to 490 pg/ml; 0 to 0.049 w/w%) prepared as described in Example 1) and 60 μΜ (17.3 pg/ml; 0 .00173%) ZnSO4*7H2O in 15 mM HEPES, pH 6.8 was mixed with 20 μl of 250 μΜ dithizone in DMSO and 80 μl of 15 mM HEPES, pH 6.8. Dithizone was used as an indicator of free zinc. After 30 min of incubation at room temperature (RT), the absorbance at 520 nm was measured and the percentage of zinc complexed with the FWAHKK peptide was calculated.
Výsledky (obr. 1) potvrdily schopnost peptidu FWAHKK tvořit komplex se zinkem. V komplexu Zn-FWAHKK připraveném, jak je popsáno v příkladu 1, ve kterém je molární poměr FWAHKK a zinku 1:1, je přibližně 50 % zinku v komplexu s hexapeptidem.The results (Fig. 1) confirmed the ability of the FWAHKK peptide to complex with zinc. In the Zn-FWAHKK complex prepared as described in Example 1, in which the molar ratio of FWAHKK to zinc is 1:1, approximately 50% of the zinc is complexed with the hexapeptide.
Příklad 3. Zvýšená penetrace zinku v komplexu Zn-FWAHKK do buněkExample 3. Increased penetration of zinc in the Zn-FWAHKK complex into cells
HaCaT keratinocyty (CLS sbírka, Německo) byly kultivovány v Dubelccově modifikovaném Eaglově médiu (DMEM) doplněném 10% fetálním bovinním sérem, 0,2 mg/ml glutaminu, 100 U/ml penicilinu a 0,1 mg/ml streptomycinu (vše Sigma-Aldrich, USA) při 37 °C v humidifikované atmosféře s 5% CO2.HaCaT keratinocytes (CLS collection, Germany) were cultured in Dubelc's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 0.2 mg/ml glutamine, 100 U/ml penicillin, and 0.1 mg/ml streptomycin (all Sigma-Aldrich). Aldrich, USA) at 37 °C in a humidified atmosphere with 5% CO2.
Buňky nasazené ve vhodné hustotě na 96-jamkové destičky byly ošetřeny 1352 pg/ml (0,1352 %) Zn-FWAHKK komplexem (připraveno, jak je popsáno v příkladu 1) nebo ZnSO4*7H2O s odpovídající koncentrací (352 pg/ml (0,0352 %)) 3 h. Potom byly buňky promyty buněčným kultivačním médiem a inkubovány s 1 pM FluoZinTM-3 AM (Invitrogen, USA), buněčným permeačním činidlem, fluorogenním Zn2+ - selektivním indikátorem, a 20 pM Hoechst (Abcam, UK), fluorescenční DNA barvou v buněčném kultivačním médiu 30 min při 37 °C ve tmě. Potom byly buňky opláchnuty fosfátovým fyziologickým roztokem (PBS). Fluorescence byla pozorována použitím Eclipse 50i fluorescenčního mikroskopu vybaveného DS-Fi1 kamerou (oboje Nikon, Japonsko). Výsledky (obr. 2) ukázaly, že penetrace zinku do kožních buněk byla účinnější, když byl ion v komplexu Zn-FWAHKK.Cells seeded at the appropriate density in 96-well plates were treated with 1352 pg/ml (0.1352%) Zn-FWAHKK complex (prepared as described in Example 1) or ZnSO4*7H2O at the corresponding concentration (352 pg/ml (0 .0352 %)) for 3 h. Then the cells were washed with cell culture medium and incubated with 1 pM FluoZin TM -3 AM (Invitrogen, USA), a cell permeation agent, a fluorogenic Zn 2+ -selective indicator, and 20 pM Hoechst (Abcam, UK), fluorescent DNA dye in cell culture medium for 30 min at 37 °C in the dark. The cells were then rinsed with phosphate-buffered saline (PBS). Fluorescence was observed using an Eclipse 50i fluorescence microscope equipped with a DS-Fi1 camera (both Nikon, Japan). The results (Fig. 2) showed that zinc penetration into skin cells was more efficient when the ion was in the Zn-FWAHKK complex.
Příklad 4. FWAHKK zvyšuje buněčnou viabilitu a brání cytotoxickému účinku zinku v komplexu Zn-FWAHKKExample 4. FWAHKK increases cell viability and prevents the cytotoxic effect of zinc in the Zn-FWAHKK complex
NIH-3T3 myší embryonální fibroblasty (ATCC sbírka, USA) byly kultivovány stejným způsobem jako HaCaT keratinocyty, jak je popsáno v Příkladu 3. Buňky nasazené ve vhodné hustotě na 96-jamkové destičky byly ošetřeny FWAHKK (2,5 až 80 pg/ml (0,00025 až 0,008%)), Zn-FWAHKK (3,4 až 108 pg/ml (0,00034 až 0,0108%)) (oboje připraveno, jak je popsáno v Příkladu 1) a ZnSO4*7H2O (0,9 až 28,2 pg/ml (0,00009 až 0,00282%)) 48 h. Potom byla buněčná viabilita stanovena postupem MTT (Riss a kol., 2016). Stručně, buňky byly inkubovány s 0,5 mg/ml MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-difenyl-tetrazolium bromid) v buněčném kultivačním médiu 2,5 h při 37 °C. Po odstranění MTT byla provedena lyze buněk a rozpuštění formazanu inkubací buněk se solubilizačním roztokem (45% isopropanol, 45% DMSO, 10% Triton-X, 0,3 M HCl) 30 min při RT, třepání. Absorbance byla potom měřena při 570 nm spektrofotometrem (EnVision® 2105 Multimode Destičkový Reader, Perkin, Elmer, USA). T-test byl použit pro statistické vyhodnocení výsledků.NIH-3T3 mouse embryonic fibroblasts (ATCC collection, USA) were cultured in the same manner as HaCaT keratinocytes as described in Example 3. Cells seeded at an appropriate density in 96-well plates were treated with FWAHKK (2.5 to 80 pg/ml ( 0.00025 to 0.008%)), Zn-FWAHKK (3.4 to 108 pg/ml (0.00034 to 0.0108%)) (both prepared as described in Example 1), and ZnSO4*7H2O (0. 9 to 28.2 pg/ml (0.00009 to 0.00282%)) 48 h. Then cell viability was determined by the MTT method (Riss et al., 2016). Briefly, cells were incubated with 0.5 mg/ml MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) in cell culture medium for 2.5 h at 37°C. After MTT removal, cell lysis and formazan dissolution was performed by incubating cells with solubilization solution (45% isopropanol, 45% DMSO, 10% Triton-X, 0.3 M HCl) for 30 min at RT, shaking. The absorbance was then measured at 570 nm with a spectrophotometer (EnVision® 2105 Multimode Plate Reader, Perkin, Elmer, USA). T-test was used for statistical evaluation of the results.
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Výsledky (obr. 3) ukázaly, že ZnSO4*7H2O v koncentracích od 10,6 μg/ml významně snížily buněčnou viabilitu. Na druhou stranu, FWAHKK peptid zvýšil buněčnou viabilitu a tvorba ZnFWAHKK komplexu zabránila cytotoxickému účinku zinku.The results (Fig. 3) showed that ZnSO4*7H2O in concentrations from 10.6 μg/ml significantly reduced cell viability. On the other hand, the FWAHKK peptide increased cell viability and the formation of the ZnFWAHKK complex prevented the cytotoxic effect of zinc.
Příklad 5. Inhibice 5a-reduktázové genové exprese FWAHKK a Zn-FWAHKKExample 5. Inhibition of 5α-reductase gene expression of FWAHKK and Zn-FWAHKK
HaCaT keratinocyty (CLS sbírka, Německo) byly kultivovány, jak je popsáno v příkladu 3. Buňky nasazené ve vhodné hustotě do 6-jamkových destiček byly ošetřeny FWAHKK (1 μg/ml (0,0001%) a 10 μg/ml (0,001%)), Zn-FWAHKK (1,35 μg/ml (0,000135%) a 13,5 μg/ml (0,00135%)) (oboje připraveno, jak je popsáno v příkladu 1), ZnSO4*7H2O (Zn, 0,35 μg/ml (0,000035%) a 3,5 μg/ml (0,00035%)), a 10 μΜ retinolem (v DMSO, finální koncentrace DMSO byla 0,1%) 72 h. Kontrolní buňky byly neošetřeny nebo ošetřeny 0,1% DMSO v případě retinolové kontroly.HaCaT keratinocytes (CLS collection, Germany) were cultured as described in Example 3. Cells seeded at an appropriate density in 6-well plates were treated with FWAHKK (1 μg/ml (0.0001%) and 10 μg/ml (0.001% )), Zn-FWAHKK (1.35 μg/ml (0.000135%) and 13.5 μg/ml (0.00135%)) (both prepared as described in Example 1), ZnSO4*7H2O (Zn , 0.35 μg/ml (0.000035%) and 3.5 μg/ml (0.00035%)), and 10 μΜ retinol (in DMSO, final concentration of DMSO was 0.1%) for 72 h. Control cells were untreated or treated with 0.1% DMSO in case of retinol control.
Potom byla exprese genu 5a-reduktázy (gen SRD5A1) stanovena kvantitativně, real-time, PCR s reverzní transkripcí (qRT-PCR), jak následuje. Celková RNA byla izolována z buněk metodou kyselé extrakce guanidin thiokyanát-fenol použitím TRI Reagentu (Sigma Aldrich, USA) podle instrukcí poskytnutých dodavatelem. Reverzní transkripce byla provedena použitím Velkokapacitního kitu cDNA reverzní transkripce (Thermo Fisher Scientific, MA, USA) v GenePro termálním cykleru (Bioer Technology, Čína) podle instrukcí výrobce. Následná qPCR byla provedena specifickou TaqMan genovou expresní metodou pro SRD5A1 (qHsaCEP0052536, BioRad, CA, USA), a RPL13A (Hs04194366_g1, Thermo Fisher Scientific, MA, USA) jako referenčním genem; a TaqMan Fast Advanced Master mix (všechny Thermo Fisher Scientific, MA, USA) podle doporučení dodavatele v Jednokrokovém real-time PCR cykleru (Thermo Fisher Scientific, MA, USA). Data byla analyzována použitím 2-ΔΔα metody. Data byla normalizována na negativní kontroly nebo v případě retinolu na DMSO kontroly. Ttest byl použit pro statistické vyhodnocení dat.Then, the expression of the 5α-reductase gene (SRD5A1 gene) was quantitatively determined by real-time reverse transcription PCR (qRT-PCR) as follows. Total RNA was isolated from cells by the guanidine thiocyanate-phenol acid extraction method using TRI Reagent (Sigma Aldrich, USA) according to the instructions provided by the supplier. Reverse transcription was performed using the Large Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific, MA, USA) in a GenePro thermal cycler (Bioer Technology, China) according to the manufacturer's instructions. Subsequent qPCR was performed by a specific TaqMan gene expression method for SRD5A1 (qHsaCEP0052536, BioRad, CA, USA), and RPL13A (Hs04194366_g1, Thermo Fisher Scientific, MA, USA) as a reference gene; and TaqMan Fast Advanced Master mix (all Thermo Fisher Scientific, MA, USA) as recommended by the supplier in a One-Step Real-time PCR cycler (Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2 -ΔΔα method. Data were normalized to negative controls or, in the case of retinol, to DMSO controls. The ttest was used for statistical evaluation of the data.
5a-reduktáza je klíčový enzym zahrnutý v androgenně indukované produkci kožního mazu. Tento enzym konvertuje testosteron, nejběžnější androgen, na DHT, který je několikrát účinnější při stimulaci produkce kožního mazu. Výsledky (Obr. 4) ukázaly, že hexapeptid FWAHKK, ZnFWAHKK a také ZnSO4*7H2O významně snížily expresi genu 5a-reduktázy (gen SRD5A1). Komplex Zn-FWAHKK byl účinnější než jeho jednotlivé složky s odpovídajícími koncentracemi. Na druhou stranu, retinol neměl žádný významný účinek na genovou expresi 5αreduktázy.5α-reductase is a key enzyme involved in androgen-induced sebum production. This enzyme converts testosterone, the most common androgen, to DHT, which is several times more effective at stimulating sebum production. The results (Fig. 4) showed that the hexapeptide FWAHKK, ZnFWAHKK and also ZnSO4*7H2O significantly decreased the expression of the 5a-reductase gene (SRD5A1 gene). The Zn-FWAHKK complex was more effective than its individual components at the corresponding concentrations. On the other hand, retinol had no significant effect on 5αreductase gene expression.
Příklad 6. Inhibice IL-1 α genové exprese FWAHKK a Zn-FWAHKKExample 6. IL-1α inhibition of FWAHKK and Zn-FWAHKK gene expression
HaCaT keratinocyty (CLS sbírka, Německo) byly kultivovány, jak je popsáno v příkladu 3. Buňky nasazené ve vhodné hustotě na 6-jamkové destičky byly promyty v PBS a ozářeny 10 mJ/cm2 UVB použitím 300 W xenonové obloukové lampy (Oriel Arc Lamp Housing, Newport, CA, USA) a 300±10 nm optickým filtrem (Newport, CA, USA). Potom byly ošetřeny FWAHKK (1μg/ml (0,0001%) a 10 μg/ml (0,001%)), Zn-FWAHKK (1,35 μg/ml (0,0001%) a 13,5 μg/ml (0,001%)) (oboje připraveno, jak je popsáno v Příkladu 1), ZnSO4*7 H2O (Zn; 0,35 μg/ml (0,000035%) a 3,5 μg/ml (0,00035%)) a 10 μM retinolu (v DMSO, finální koncentrace DMSO byla 0,1%) 24 h. Kontrolní buňky byly neošetřeny nebo ošetřeny 0,1% DMSO v případě retinolové kontroly.HaCaT keratinocytes (CLS collection, Germany) were cultured as described in Example 3. Cells seeded at the appropriate density in 6-well plates were washed in PBS and irradiated with 10 mJ/cm 2 UVB using a 300 W xenon arc lamp (Oriel Arc Lamp Housing, Newport, CA, USA) and a 300±10 nm optical filter (Newport, CA, USA). They were then treated with FWAHKK (1μg/ml (0.0001%) and 10μg/ml (0.001%), Zn-FWAHKK (1.35μg/ml (0.0001%) and 13.5μg/ml (0.001 %)) (both prepared as described in Example 1), ZnSO4*7 H2O (Zn; 0.35 μg/ml (0.000035%) and 3.5 μg/ml (0.00035%)) and 10 μM retinol (in DMSO, final DMSO concentration was 0.1%) 24 h. Control cells were untreated or treated with 0.1% DMSO in case of retinol control.
IL1A genová exprese byla stanovena real-time qRT-PCR, jak je popsáno v příkladu 5, použitím specifické TaqMan genové expresní metody pro IL1A (qHsaCIP0030471, BioRad, CA, USA), a RPL13A (Hs04194366_g1, Thermo Fisher Scientific, MA, USA) jako referenčního genu. Data byla analyzována použitím metody 2-ΔΔCt. Data byla normalizována na UVB neošetřené kontroly nebo v případě retinolu na UVB DMSO kontroly. T-test byl použit pro statistické vyhodnocení výsledků.IL1A gene expression was determined by real-time qRT-PCR as described in Example 5, using a specific TaqMan gene expression method for IL1A (qHsaCIP0030471, BioRad, CA, USA), and RPL13A (Hs04194366_g1, Thermo Fisher Scientific, MA, USA) as a reference gene. Data were analyzed using the 2 -ΔΔCt method. Data were normalized to UVB untreated controls or, in the case of retinol, to UVB DMSO controls. T-test was used for statistical evaluation of the results.
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IL-1 α je prozánětlivý interleukin stimulující hyperkeratinizaci folikulárních keratinocytů (Guy a Kealey 1998) v časných fázích patogeneze akné. V našich experimentech jsme indukovali IL-1α genovou expresi v HaCaT keratinocytech použitím UVB ozáření (obr. 5). Potom jsme pozorovali významnou inhibici UVB-indukované IL1A genové exprese po FWAHKKa Zn-FWAHKK ošetření, zatímco zinek a retinol neukázaly žádný účinek (obr. 5).IL-1α is a pro-inflammatory interleukin stimulating hyperkeratinization of follicular keratinocytes (Guy and Kealey 1998) in the early stages of acne pathogenesis. In our experiments, we induced IL-1α gene expression in HaCaT keratinocytes using UVB irradiation (Fig. 5). Then, we observed a significant inhibition of UVB-induced IL1A gene expression after FWAHKKa Zn-FWAHKK treatment, while zinc and retinol showed no effect (Fig. 5).
Příklad 7. Inhibice diferenciace keratinocytů FWAHKK a Zn-FWAHKKExample 7. Inhibition of keratinocyte differentiation by FWAHKK and Zn-FWAHKK
HaCaT keratinocyty (CLS sbírka, Německo) byly kultivovány, jak je popsáno v příkladu 3. Buňky nasazené ve vhodné hustotě na 6-jamkové destičky byly ošetřeny FWAHKK (1 μg/ml (0,0001 %) a 10 μg/ml (0,001 %)), Zn-FWAHKK (1.35 μg/ml (0,000135 %) a 13,5 μg/ml (0,00135 %)) (oboje připraveno, jak je popsáno v příkladu 1), ZnSO4*7H2O (Zn; 0.35 μg/ml (0,000035 %) a 3.5 μg/ml (0,00035 %)) a 10 μΜ retinolu (v DMSO, finální koncentrace DMSO byla 0,1 %) pro 72 h.HaCaT keratinocytes (CLS collection, Germany) were cultured as described in Example 3. Cells seeded at an appropriate density in 6-well plates were treated with FWAHKK (1 μg/ml (0.0001%) and 10 μg/ml (0.001%) )), Zn-FWAHKK (1.35 μg/ml (0.000135%) and 13.5 μg/ml (0.00135%)) (both prepared as described in Example 1), ZnSO4*7H2O (Zn; 0.35 μg/ml (0.000035%) and 3.5 μg/ml (0.00035%)) and 10 μΜ retinol (in DMSO, final DMSO concentration was 0.1%) for 72 h.
Exprese vybraných genů zahrnutých v diferenciaci keratinocytů byla stanovena real-time qRTPCR, jak je popsáno v příkladu 5, použitím specifické TaqMan genové expresní metody pro FLG (Hs00856927_g1), OCLN (Hs00170162_m1), LCE2C (Hs02390636_s1), SPRR2E (qHsaCEP0055677, BioRad, CA, USA), KRT10 (Hs01043114_g1) a RPL13A (Hs04194366_g1) jako referenčního genu (všechny mimo SPRR2E Thermo Fisher Scientific, MA, USA). Data byla analyzována použitím metody 2-AACt. Data byla normalizována na neošetřené kontroly nebo v případě retinolu na DMSO kontroly. T-test byl použit pro statistické vyhodnocení výsledků.Expression of selected genes involved in keratinocyte differentiation was determined by real-time qRTPCR as described in Example 5 using the specific TaqMan gene expression method for FLG (Hs00856927_g1), OCLN (Hs00170162_m1), LCE2C (Hs02390636_s1), SPRR2E (qHsaCEP0055677, BioRad, CA , USA), KRT10 (Hs01043114_g1) and RPL13A (Hs04194366_g1) as a reference gene (all except SPRR2E Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2 -AACt method. Data were normalized to untreated controls or, in the case of retinol, to DMSO controls. T-test was used for statistical evaluation of the results.
Ukázalo se, že hexapeptid FWAHKK a také Zn-FWAHKK downregulují geny spojené s diferenciací keratinocytů stejným způsobem jako 10 μΜ retinol, zatímco zinek při odpovídajících koncentracích neměl žádný takový účinek (obr. 6).Hexapeptide FWAHKK as well as Zn-FWAHKK were shown to downregulate genes associated with keratinocyte differentiation in the same manner as 10 μΜ retinol, whereas zinc at the corresponding concentrations had no such effect (Fig. 6).
Příklad 8. Protizánětlivý účinek FWAHKK a Zn-FWAHKKExample 8. Anti-inflammatory effect of FWAHKK and Zn-FWAHKK
HaCaT keratinocyty (CLS sbírka, Německo) byly kultivovány, jak je popsáno v příkladu 3. Buňky nasazené ve vhodné hustotě do 6-jamkových destiček byly promyty v PBS a ozářeny 10 mJ/cm2 UVB použitím 300 W xenonové obloukové lampy (Oriel Arc Lamp Housing, Newport, CA, USA) a 300 ±10 nm optickým filtrem (Newport, CA, USA). Potom byly ošetřeny FWAHKK (1 μg/ml (0,0001 %) a 10 μg/ml (0,001 %)), Zn-FWAHKK (1,35 μg/ml (0,000135 %) a 13.5 μg/ml (0,00135 %)) (oboje připraveno, jak je popsáno v příkladu 1), ZnSO4*7H2O (Zn, 0,35 μg/ml (0,000035 %) a 3.5 μg/ml (0,00035 %)), a 10 μΜ retinolu (v DMSO, finální koncentrace DMSO byla 0,1 %) 24 h. Kontrolní buňky byly neošetřeny nebo ošetřeny 0,1% DMSO v případě retinolové kontroly.HaCaT keratinocytes (CLS collection, Germany) were cultured as described in Example 3. Cells seeded at the appropriate density in 6-well plates were washed in PBS and irradiated with 10 mJ/cm 2 UVB using a 300 W xenon arc lamp (Oriel Arc Lamp Housing, Newport, CA, USA) and a 300 ±10 nm optical filter (Newport, CA, USA). Then they were treated with FWAHKK (1 μg/ml (0.0001%) and 10 μg/ml (0.001%), Zn-FWAHKK (1.35 μg/ml (0.000135%) and 13.5 μg/ml (0. 00135%)) (both prepared as described in Example 1), ZnSO4*7H2O (Zn, 0.35 μg/ml (0.000035%) and 3.5 μg/ml (0.00035%)), and 10 μΜ of retinol (in DMSO, final DMSO concentration was 0.1%) for 24 h. Control cells were untreated or treated with 0.1% DMSO in the case of retinol control.
IL1A genová exprese byla stanovena real-time qRT-PCR, jak je popsáno v příkladu 5, použitím specifické TaqMan genové expresní metody pro IL6 (Hs00174131_m1), IL8 (Hs00174103_m1), a RPL13A (Hs04194366_g1) jako referenčního genu (vše Thermo Fisher Scientific, MA, USA). Data byla analyzována použitím metody 2-AACt. Data byla normalizována na UV B neošetřené kontroly nebo v případě retinolu na UVB DMSO kontroly. T-test byl použit pro statistické vyhodnocení výsledků.IL1A gene expression was determined by real-time qRT-PCR as described in Example 5 using the specific TaqMan gene expression method for IL6 (Hs00174131_m1), IL8 (Hs00174103_m1), and RPL13A (Hs04194366_g1) as a reference gene (all Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2 -AACt method. Data were normalized to UVB untreated controls or, in the case of retinol, to UVB DMSO controls. T-test was used for statistical evaluation of the results.
Zánět je klíčovou událostí v patogenezi akné. Indukovali jsme zánětlivé procesy jako zvýšená exprese prozánětlivých interleukinů IL-6 a IL-8 v HaCaT keratinocytech použitím UVB záření (obr. 7.) Pozorovali jsme významnou inhibici UVB-indukované IL6 a IL8 genové exprese po FWAHKK a Zn-FWAHKK ošetření podobně jako u 10 μM retinolu, zatímco zinek v odpovídajících koncentracích neukázal žádný účinek (obr. 7).Inflammation is a key event in the pathogenesis of acne. We induced inflammatory processes as increased expression of pro-inflammatory interleukins IL-6 and IL-8 in HaCaT keratinocytes using UVB radiation (Fig. 7.) We observed a significant inhibition of UVB-induced IL6 and IL8 gene expression after FWAHKK and Zn-FWAHKK treatment similar to 10 μM retinol, while zinc at the corresponding concentrations showed no effect (Fig. 7).
Příklad 9. Antimikrobiální aktivita FWAHKK a Zn-FWAHKK proti C. acnesExample 9. Antimicrobial activity of FWAHKK and Zn-FWAHKK against C. acnes
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Cutibacterium acnes (kmen DSM 1897, DSZM sbírka, Německo) byl udržován v suspenzi v tryptickém sójovém vývaru (TSB) při 37 °C. Bakterie byly potom inokulovány ve vhodné hustotě do TSB obsahujícího FWAHKK (10 až 80 μg/ml (0,001 až 0,008 %)), Zn-FWAHKK (13,5 až 108,2 μg/ml (0,00135 až 0,01082 %)) (oboje připraveno, jak je popsáno v příkladu 1) a ZnSO4*7H2O (Zn; 3,5 až 28,2 μg/ml (0,00035 až 0,00282 %)) v 96-jamkových destičkách. Bakterie byly kultivovány 72 h při 37 °C a potom byla změřena optická hustota při 590 nm (OD590) spektrofotometrem (EnVision® 2105 Multimodální destičkový reader, PerkinElmer, USA). T-test byl použit pro statistické vyhodnocení výsledků.Cutibacterium acnes (strain DSM 1897, DSZM collection, Germany) was maintained in suspension in tryptic soy broth (TSB) at 37°C. Bacteria were then inoculated at an appropriate density into TSB containing FWAHKK (10 to 80 μg/ml (0.001 to 0.008%)), Zn-FWAHKK (13.5 to 108.2 μg/ml (0.00135 to 0.01082%) ) (both prepared as described in Example 1) and ZnSO4*7H2O (Zn; 3.5 to 28.2 μg/ml (0.00035 to 0.00282%)) in 96-well plates. The bacteria were cultured for 72 h at 37 °C and then the optical density at 590 nm (OD590) was measured with a spectrophotometer (EnVision® 2105 Multimodal plate reader, PerkinElmer, USA). T-test was used for statistical evaluation of the results.
Oboje - zinek a hexapeptid FWAHKK - měly slabou antimikrobiální aktivitu proti C. acnes (Obr. 8). Komplex Zn-FWAHKK byl účinnější než jednotlivé sloučeniny v odpovídajících koncentracích (obr. 8).Both zinc and the hexapeptide FWAHKK had weak antimicrobial activity against C. acnes (Fig. 8). The Zn-FWAHKK complex was more effective than the individual compounds at the corresponding concentrations (Fig. 8).
Příklad 10. Stimulace produkce kolagenu FWAHKK a Zn-FWAHKKExample 10. Stimulation of collagen production by FWAHKK and Zn-FWAHKK
NIH-3T3 myší embryonální fibroblasty (ATCC sbírka, USA) byly kultivovány stejným způsobem jako HaCaT keratinocyty, jak je popsáno v příkladu 3. Buňky nasazené ve vhodné hustotě do 6-jamkových destiček byly ošetřeny FWAHKK (1 μg/ml (0,0001 %) a 10 pg/ml (0,001 %)), Zn-FWAHKK (1,35 pg/ml (0,000135 %) a 13.5 pg/ml (0,00135 %)) (oboje připraveno, jak je popsáno v Příkladu 1), ZnSO4*7H2O (Zn, 0,35 pg/ml (0,000035 %) a 3,5 pg/ml (0,00035 %)), a 10 μΜ retinol (v DMSO, finální koncentrace DMSO byla 0,1 %) 72 h. Kontrolní buňky byly neošetřeny nebo ošetřeny 0,1% DMSO v případě retinolové kontroly.NIH-3T3 mouse embryonic fibroblasts (ATCC collection, USA) were cultured in the same manner as HaCaT keratinocytes as described in Example 3. Cells seeded at an appropriate density in 6-well plates were treated with FWAHKK (1 μg/ml (0.0001% ) and 10 pg/ml (0.001%)), Zn-FWAHKK (1.35 pg/ml (0.000135%) and 13.5 pg/ml (0.00135%)) (both prepared as described in Example 1 ), ZnSO4*7H2O (Zn, 0.35 pg/ml (0.000035%) and 3.5 pg/ml (0.00035%)), and 10 μΜ retinol (in DMSO, final DMSO concentration was 0.1 %) 72 h. Control cells were untreated or treated with 0.1% DMSO in case of retinol control.
COL1A1 genová exprese byla stanovena real-time qRT-PCR, jak je popsáno v příkladu 5, použitím specifické TaqMan genové expresní metody pro COL1A1 (Mm00801666_g1), a RPL13A (Mm05910660_g1) jako referenčního genu (oboje Thermo Fisher Scientific, MA, USA). Data byla analyzována použitím metody 2AACt. Data byla normalizována na neošetřené kontroly nebo v případě retinolu na DMSO kontroly. T-test byl použit pro statistické vyhodnocení výsledků.COL1A1 gene expression was determined by real-time qRT-PCR as described in Example 5, using the specific TaqMan gene expression method for COL1A1 (Mm00801666_g1), and RPL13A (Mm05910660_g1) as a reference gene (both Thermo Fisher Scientific, MA, USA). Data were analyzed using AACt method 2. Data were normalized to untreated controls or, in the case of retinol, to DMSO controls. T-test was used for statistical evaluation of the results.
Výsledky ukázaly významnou stimulaci exprese genu kolagenu 1 po ošetření FWAHKK a ZnFWAHKK, zatímco zinek v odpovídajících koncentracích a 10 μΜ retinol neukázaly žádný účinek (obr. 9).The results showed a significant stimulation of collagen 1 gene expression after treatment with FWAHKK and ZnFWAHKK, while zinc at the corresponding concentrations and 10 μΜ retinol showed no effect (Fig. 9).
Příklad 11 Zn-FWAHKK zlepšuje vzhled pokožky náchylné k akné a má také účinek proti stárnutí in vivoExample 11 Zn-FWAHKK improves the appearance of acne-prone skin and also has an antiaging effect in vivo
Provedli jsme dvojitě slepou, placebo-kontrolovanou, in vivo studii s rozdělením tváře na 40 lidských dobrovolnících (Běloši, Fitzpatrikův typ kůže I-III, ženy/muži 36/4, 18 až 49 let, průměr 30,5 roku) s mastnou, problematickou pokožkou náchylnou k akné. Tato studie byla provedena v souladu s principy Helsinské deklarace Světové lékařské asociace. Tato studie byla schválena etickým výborem Contipro a.s. a informovaný souhlas byl získán od všech dobrovolníků. Pouze zdravé subjekty bez akutních kožních poruch na tváři byly zahrnuty do studie. Další výlučná kritéria byla těhotenství, kojení, invazivní kosmetické obličejové procedury (face lift, botox, atd.) a silné kouření (> 10 cigaret na den). Aplikace jakýchkoli obličejových produktů pro péči o pokožku a také umývání obličeje nebylo dovoleno během dne měření.We conducted a double-blind, placebo-controlled, in vivo face-splitting study in 40 human volunteers (Caucasian, Fitzpatrick skin type I-III, female/male 36/4, 18 to 49 years, mean 30.5 years) with oily, problematic skin prone to acne. This study was conducted in accordance with the principles of the Declaration of Helsinki of the World Medical Association. This study was approved by the ethical committee of Contipro a.s. and informed consent was obtained from all volunteers. Only healthy subjects without acute facial skin disorders were included in the study. Other exclusive criteria were pregnancy, breastfeeding, invasive cosmetic facial procedures (face lift, botox, etc.) and heavy smoking (> 10 cigarettes per day). Application of any facial skin care products as well as face washing was not allowed during the measurement day.
Všichni dobrovolníci dostali dvě emulze: 30 dobrovolníků (ženy/muži 27/3, 18 až 48 let, průměr 31,0 roku) obdrželi emulze s 0,00135% Zn-FWAHKK (13,5 μg/ml; připravenou, jak je popsáno v příkladu 1) a placebo, a 10 dobrovolníků (ženy/muži 9/1, 24 až 49 let, průměr 28,9 roku) obdrželo emulze s 0,2% retinolem a placebo. Kompozice emulzí je popsána v tabulce 1. Dvě emulze byly aplikovány na dvě jednotlivé poloviny obličeje jednou denně večer 6 týdnů. Měření parametrů pokožky bylo provedeno na počátku studie a potom po 2, 4 a 6 týdnech.All volunteers received two emulsions: 30 volunteers (female/male 27/3, 18 to 48 years, mean 31.0 years) received an emulsion with 0.00135% Zn-FWAHKK (13.5 μg/ml; prepared as described in Example 1) and placebo, and 10 volunteers (female/male 9/1, 24 to 49 years, mean 28.9 years) received 0.2% retinol emulsions and placebo. The composition of the emulsions is described in Table 1. Two emulsions were applied to two individual halves of the face once a day in the evening for 6 weeks. Skin parameters were measured at the beginning of the study and then after 2, 4 and 6 weeks.
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Měření byla provedena po 30 min aklimatizace dobrovolníků v místnosti s kontrolovanými podmínkami (T: 20 až 22 °C; RH 40 až 45 %). Počet lézí akné byl stanoven analýzou obrázku celoobličejových obrazů získaných VisiaCR, fotoaparátem s vysokým rozlišením (Canfield Scientific, USA). Kvantifikace byla provedena použitím Image-Pro 10 analysis softwaru (Media Cybernetics, USA). Hloubka vrásek vraních nožek byla stanovena pomocí fotoaparátu Primos Lite 3D (Canfield Scientific, USA).The measurements were performed after 30 min of acclimatization of the volunteers in a room with controlled conditions (T: 20 to 22 °C; RH 40 to 45%). The number of acne lesions was determined by image analysis of full-face images acquired by VisiaCR, a high-resolution camera (Canfield Scientific, USA). Quantification was performed using Image-Pro 10 analysis software (Media Cybernetics, USA). Crow's feet wrinkle depth was determined using a Primos Lite 3D camera (Canfield Scientific, USA).
Výsledky ukázaly zlepšení vzhledu pokožky náchylné k akné reprezentované snížením počtu lézí akné (obr. 10A). Také se ukázalo, že Zn-FWAHKK má aktivitu proti stárnutí snížením vrásek (obr. 10B). V obou případech byl Zn-FWAHKK účinnější než 0,2% retinol.The results showed an improvement in the appearance of acne-prone skin represented by a reduction in the number of acne lesions (Fig. 10A). Zn-FWAHKK was also shown to have antiaging activity by reducing wrinkles (Fig. 10B). In both cases, Zn-FWAHKK was more effective than 0.2% retinol.
Tabulka 1 Kompozice emulzí použitých v in vivo studiiTable 1 Composition of the emulsions used in the in vivo study
Příklad 12. Kompozice emulzí s FWAHKK, Zn-FWAHKK, acetyl-FWAHKK nebo palmitoylFWAHKKExample 12. Composition of emulsions with FWAHKK, Zn-FWAHKK, acetyl-FWAHKK or palmitoylFWAHKK
Příklad krémů (olej ve vodě emulze) obsahujících hexapeptidy stávajícího vynálezu FWAHKK, Zn-FWAHKK, acetyl-FWAHKK nebo palmitoyl-FWAHKK připravené, jak je popsáno v příkladu 1.Example of creams (oil-in-water emulsion) containing hexapeptides of the present invention FWAHKK, Zn-FWAHKK, acetyl-FWAHKK or palmitoyl-FWAHKK prepared as described in Example 1.
Tabulka 2.Table 2.
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Tabulka 3Table 3
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Tabulka 4Table 4
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Tabulka 5Table 5
Olejová a vodná fáze byly připraveny a zahřátý na 70 °C. Dále byly obě fáze smíchány a emulgovány za míchání (290 rpm/min). Potom byla emulze ochlazena na 40 °C a byla přidána fáze ve vodě rozpustných aktivních složek a/nebo vitamín E a konzervant. Konečně bylo změřeno pH a upraveno na hodnoty mezi 2,2 a 6,5 1 až. 50% kyselinou citrónovou nebo 1 až 50% KOH nebo NaOH.The oil and water phases were prepared and heated to 70°C. Next, both phases were mixed and emulsified under stirring (290 rpm/min). The emulsion was then cooled to 40°C and a phase of water-soluble active ingredients and/or vitamin E and a preservative was added. Finally, the pH was measured and adjusted to values between 2.2 and 6.5 1 to. 50% citric acid or 1 to 50% KOH or NaOH.
oO
Příklad 13. Kompozice sér s FWAHKK, Zn-FWAHKK a acetyl-FWAHKKExample 13. Composition of sera with FWAHKK, Zn-FWAHKK and acetyl-FWAHKK
Příklad sér obsahujících hexapeptidy stávajícího vynálezu FWAHKK a Zn-FWAHKK připravené, jak je popsáno v příkladu 1.Example of sera containing hexapeptides of the present invention FWAHKK and Zn-FWAHKK prepared as described in Example 1.
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Tabulka 6Table 6
Tabulka 7Table 7
Tabulka 8Table 8
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Tabulka 9Table 9
Nejdříve byly přidány hexapeptid FWAHKK nebo Zn-FWAHKK nebo acetyl-FWAHKK a aktivní složky kromě hyaluronátu sodného a kroslinkovanéhoHA do vody a míchány, dokud se zcela nerozpustily. Dále byla přidána zahušťovadla a/nebo hyaluronát sodný a kroslinkovanýHA a směs míchána, dokud se složky zcela nerozpustily. Potom byl přidán konzervant. Konečně bylo změřeno pH a upraveno na hodnoty mezi 5,2 a 6,5 1 až 50% kyselinou citrónovou nebo 1 až 50% KOH nebo NaOH.First, hexapeptide FWAHKK or Zn-FWAHKK or acetyl-FWAHKK and active ingredients except sodium hyaluronate and croslink HA were added to water and stirred until completely dissolved. Next, thickeners and/or sodium hyaluronate and croslink HA were added and the mixture was mixed until the components were completely dissolved. A preservative was then added. Finally, the pH was measured and adjusted to values between 5.2 and 6.5 with 1 to 50% citric acid or 1 to 50% KOH or NaOH.
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PCT/CZ2023/050016 WO2023186193A1 (en) | 2022-03-31 | 2023-03-31 | Hexapeptide, composition comprising thereof and topical use thereof |
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