CN118307691A - 透明质酸赖氨酸铜螯合物及其应用 - Google Patents
透明质酸赖氨酸铜螯合物及其应用 Download PDFInfo
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- CN118307691A CN118307691A CN202410478415.3A CN202410478415A CN118307691A CN 118307691 A CN118307691 A CN 118307691A CN 202410478415 A CN202410478415 A CN 202410478415A CN 118307691 A CN118307691 A CN 118307691A
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- CN
- China
- Prior art keywords
- chelate
- copper
- lysine
- hyaluronic acid
- hyaluronate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 title claims description 31
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (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-carboxylic acid Chemical compound 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 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 44
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Abstract
本发明提供一种具有控油、修复和促进毛发生长作用的透明质酸赖氨酸铜螯合物及其在化妆品和医药领域的应用。本发明螯合物的特征在于铜的含量为1%~9%(质量百分比),赖氨酸和铜离子按摩尔比为1:0.4~0.6;透明质酸双糖单位和赖氨酸按摩尔比为1:0.1~2。本发明螯合物可用于制备改善皮肤和预防脱发的化妆品和医疗产品。
Description
技术领域
本发明涉及具有控油、修复和促进毛发生长作用的透明质酸赖氨酸铜螯合物,以及所述螯合物在化妆品和医药领域的应用。
背景技术
矿物质是一类无机营养物质,是人体必需的元素,能够维持皮肤最佳的健康状态。矿物离子在皮肤中起到细胞间信息传递、催化生物反应、促进电子转移等多种功能。金属离子在皮肤组织中在维持皮肤屏障稳态、抵御外部环境应激、抗炎舒缓、改善衰老方面具有相当重要的作用。在人体皮肤中,钠、氯、钾、镁、钙含量较高,分布从角质层延伸至真皮层;铁、铜、锌等则含量相对较低。铜作为人体内含量低于0.01%的重要微量元素之一,铜的缺乏可造成身体虚弱和皮肤溃疡[参考文献:胡文玉。化妆品中的微量元素,广东微量元素科学,1999,6(10):,13-15] 。
铜离子能够调控皮肤内源性抗氧体系中超氧化物歧化酶、谷胱甘肽过氧化物酶等抗氧化酶及谷胱甘肽等小分子抗氧化物质的活性,清除体内自由基;辅助维生素c氧化及在皮肤上合成弹性蛋白,上调TGF-β1的水平,并通过激活赖氨酸氧化酶刺激细胞外基质蛋白的合成,与钙离子协同作用,增强真皮乳头/表皮交界处的纤维强度、改善面部衰老;下调IL-6和IL-8等促炎细胞因子在皮肤损伤后的急剧增加,抑制炎症、缓解热损伤[参考文献:马晓瑜,严晓娟,鲍熹珺。金属矿物离子的皮肤生物学效应及其在化妆品领域的应用。日用化学工业(中英文),2023, 53(11):1315-1324]。
此外,有报告公开铜能够调节酪氨酸酶活性,调控黑色素细胞产生黑色素维持皮肤自然颜色;能在角质层中产生二硫化物交联物,可促进头发生长; 铜离子对I型和II型5α-还原酶均有抑制作用,而后者与良性前列腺增生、寻常痤疮、女性多毛症、脂溢性皮炎、男性型秃顶和假性雌雄同体症等雄激素依赖性疾病有关[参考文献:Yasuro Sugimoto, etal. Cations Inhibit Specifically Type I 5α-Reductase Found in Human Skin.Invest Dermatol. 1995,104(5):775-778 ]。
透明质酸(hyalouronic acid,HA)又名玻璃酸,是由(1-β-4)D-葡糖醛酸和(1-β-3)N-乙酰基-D-氨基葡糖双糖单位重复连接组成的链状聚阴离子黏多糖,是构成皮肤细胞外基质的主要成分之一,在皮肤组织中具有保水、维持细胞外空间、调节细胞外阳离子的流动和浓度、调节表皮角蛋白细胞的分化和迁移、促进表皮细胞的正常分化、清除自由基等作用。WO00/08061公开了透明质酸和天然氨基酸的反应产物及其在化妆品和药物组合物中的应用。透明质酸与赖氨酸可以通过成盐和酰胺键两种方式结合,结合物在化妆品中主要用作保湿剂,在医疗领域可用于促进伤口愈合和褥疮的恢复、损伤鼻黏膜和干眼症角膜受损上皮细胞的修复以及骨和软骨的再生[参考文献:①Giuseppe Alonci,et al. Physico-Chemical Characterization and In Vitro Biological Evaluation of a BionicHydrogel Based on Hyaluronic Acid and L -Lysine for Medical Applications.Pharmaceutics, 2021,13, 1194; ②Giorgio Felzani,et al. Effect of LysineHyaluronate on the Healing of Decubitus Ulcers in Rehabilitation Patients.Adv Ther, (2011) 28(5):439-445; ③Adriana Di Benedetto,,et al. Osteogenic andChondrogenic Potential of the Supramolecular Aggregate T-LysYal®. Frontiersin Endocrinology,2020,11,285],HA与包括赖氨酸在内的多种氨基酸复合制备的三类医疗器械产品可用于治疗和预防皮肤皱纹[F. Svolacchia, et al.Evaluation of theefficacy and safety of hyaluronic acid and supplemented with amino acids, andglutathione or colin, for the prevention and treatment of wrinkles on theface, neck, décolleté and hands.European Review for Medical andPharmacological Sciences, 2023,27 (3 Suppl) : 99-108]
近年来,多种含铜化合物用于制备具有皮肤修护、舒缓、抗皱、紧致等功效的护肤品。但目前已有的无机铜盐能破坏化妆品常用的乳化体系,小分子有机铜化合物在皮肤表面流失较快。
本发明提供一种有机大分子铜螯合物,赖氨酸铜螯合物与透明质酸的结合物有利于化妆品配方体系的稳定性,具有高保湿性能和更好的皮肤黏附性,具有更强的功效,可广泛用于制备具有控油、修复和促进毛发生长作用的化妆品和医疗产品。
发明内容
本发明的目的是提供一种具有控油、修复和促进毛发生长作用的透明质酸赖氨酸铜螯合物,以及该螯合物在改善皮肤和预防脱发的化妆品和医药领域的应用。
本发明透明质酸赖氨酸铜螯合物,其特征在于:
①铜离子含量为1%~9%(g/g);
②赖氨酸和铜离子按摩尔比为1:0.4~0.6;
和③透明质酸双糖单位和赖氨酸按摩尔比为1:0.1~2。
本发明透明质酸赖氨酸铜螯合物,其特征还在于赖氨酸铜螯合物与透明质酸以盐的方式结合,以通式(1)表示,
(1)
其中X,Y和Z表示透明质酸双糖单位的数量,X>Y>Z。
本发明透明质酸赖氨酸铜螯合物,其特征还在于赖氨酸铜螯合物与透明质酸以酰胺的方式结合,以通式(2)表示,
(2)
其中X,Y和Z表示透明质酸双糖单位的数量,X>Y>Z。
本发明透明质酸赖氨酸铜螯合物,其特征还在于所述铜离子含量为5%~7%(g/g)
本发明透明质酸赖氨酸铜螯合物权利要求1所述的螯合物,其特征还在于所述透明质酸双糖单位和赖氨酸按摩尔比为1:0.2~1.5,优选摩尔比为1:0.8~1.2。
本发明透明质酸赖氨酸铜螯合物,其特征还在于与赖氨酸铜螯合物结合的透明质酸的平均分子量是指采用高效分子排阻色谱-多角激光散射法(GPC-MALLS)测定的平均分子量,其范围在5 kDa~2000 kDa,优选平均分子量范围在10 kDa~800 kDa,更优选平均分子量范围为200 kDa~500 kDa。
具有本发明技术特征的透明质酸赖氨酸铜螯合物,除了具有高保湿性能和更好的皮肤黏附性,对5α-还原酶有显著抑制作用,能够有效控油,预防和治疗寻常痤疮,改善皮肤水油平衡,预防脂溢性脱发和提高毛发的质量、修复皮肤和粘膜损伤,促进弹性蛋白、胶原蛋白的生成,预防和减轻皮肤皱纹,使皮肤光洁而富有弹性,起到抗皱紧致的功效,改善面部衰老。
本发明透明质酸赖氨酸铜螯合物可用于制备具有控油、修复和促进毛发生长作用的皮肤外用产品,包括化妆品和医疗产品。其中化妆品包括皮肤护理产品和洗浴用品,医疗产品包括预防和治疗寻常痤疮、脂溢性脱发、褥疮、皮肤和粘膜损伤以及面颈部皮肤皱纹的医疗器械和药品。
将本发明透明质酸赖氨酸铜螯合物添加于化妆品常用的成分,配制成为溶液、凝胶、膏、霜或乳液等多种形式,可以制备日常使用洗浴产品,例如沐浴液、洗发水、护发素、洁面乳、洗发膏、护发乳、剃须膏、剃须泡沫、剃须水等;也可以制备日常使用的护理产品,例如平衡保湿露、平衡保湿喷雾、平衡保湿面膜、控油爽肤水、化妆水、柔肤水、去角质啫喱、祛痘凝胶、平衡保湿乳、面霜、体霜、护手霜、脚霜、修复精华液、保湿膏、修复乳、保湿唇膏、唇彩、唇釉、染发膏、生发水、头皮护理液等。
将本发明透明质酸赖氨酸铜螯合物添加于医药领域常用的辅料,配制成为溶液、凝胶、乳膏等多种剂型,可以制备皮肤外用产品,例如祛痘膏、生发乳、祛痘凝胶、生发水等;也可以制备用于皮肤和黏膜的修复材料,例如创口贴、褥疮垫、瘢痕贴、牙科和鼻腔冲洗液、妇科洗剂、水光针等医疗器械产品。
附图说明
图1 透明质酸透明质酸钠的红外图谱。3385 cm-1为 O-H的伸缩振动, 2895 cm-1为C-H的伸缩振动
图2 透明质酸赖氨酸铜螯合物(本发明实施例一样品1-3)的红外图谱。以成盐方式结合的透明质酸赖氨酸铜螯合物IR谱图呈现与Lys-Cu-Lys类似的特征峰。
图3 透明质酸赖氨酸铜螯合物(本发明实施例一样品1-9)的红外图谱。以酰胺键结合的透明质酸赖氨酸铜螯合物IR谱图,O-H的伸缩振动谱带扩展延伸变宽,位移至3420cm-1左右,C-H的伸缩振动位移至2929cm-1左右。
图4 成盐和酰胺键两种方式结合的透明质酸赖氨酸铜螯合物和透明质酸钠的红外图谱叠加图。以成盐方式结合的透明质酸赖氨酸铜螯合物IR谱图显示,O-H的伸缩振动和C-H的伸缩振动分别在3445cm-1,3263cm-1,3045cm-1,2946cm-1;不对称的C=O伸缩振动分别在1661cm-1和1585cm-1,呈现与Lys-Cu-Lys类似的特征峰;指纹区613cm-1,仍呈现HA特征峰。以酰胺键结合的透明质酸赖氨酸铜螯合物IR谱图显示,透明质酸O-H的伸缩振动谱带扩展延伸变宽, 3385 cm-1峰向高波数位移至3420 cm-1左右,C-H的伸缩振动, 2895 cm-1峰该峰向高波数位移至2929cm-1左右,指纹区仍呈现HA特征峰。
图5 透明质酸赖氨酸铜螯合物、硫酸铜和盐酸赖氨酸铜螯合物对5α-还原酶的相对抑制率的比较。以阳性对照为0.2mM的度他雄胺(DTS)溶液作为参照,三种供试品均对5α-还原酶有显著抑制作用,本发明透明质酸赖氨酸铜螯合物的抑制作用好于硫酸铜和盐酸赖氨酸铜螯合物。
图6 盐酸赖氨酸铜螯合物、透明质酸铜和透明质酸赖氨酸铜螯合物的皮肤黏附性比较:a. 皮肤试验区域铜离子的流失量(ug);b.皮肤试验区域铜离子在的累计流失量%。经12次擦拭后,测定铜离子的累计流失量,盐酸赖氨酸铜螯合物为95.68%、透明质酸铜为86.68%,透明质酸赖氨酸铜螯合物为71.50%。本发明透明质酸赖氨酸铜螯合物的皮肤黏附性好于盐酸赖氨酸铜螯合物和透明质酸铜。
具体实施方式
以下实施例是为了更好地说明本发明,不是限制本发明。
实施例1 透明质酸赖氨酸铜螯合物
将透明质酸钠和盐酸赖氨酸铜螯合物混合溶解均匀后,加入适量乙醇沉淀和纯化,过滤,无水乙醇脱水后减压干燥,获得蓝色颗粒状粉末,即为本发明以成盐的方式结合得到的透明质酸赖氨酸铜螯合物(样品1-1~1-5)。
将透明质酸钠和盐酸赖氨酸铜螯合物混合溶解均匀,加入催化剂N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDCI)和N-羟基琥珀酰亚胺(NHS),保温反应后加入适量乙醇沉淀和纯化,过滤,无水乙醇脱水后减压干燥,获得蓝色颗粒状粉末,即为本发明以酰胺键结合的方式得到的透明质酸赖氨酸铜螯合物(样品1-6~1-10)。
在以上制备过程中,调整透明质酸钠和盐酸赖氨酸铜螯合物的比例、催化剂EDCI和NHS的投入量以及反应液的pH值,可获得铜离子含量不同的样品,如下表。
对比化合物透明质酸铜的制备:将透明质酸钠和氯化铜混合溶解均匀后,加入适量乙醇沉淀和纯化,过滤,无水乙醇脱水后减压干燥,即得。
铜离子[Cu2+%(g/g)]含量测定方法:
取样品适量,精密称定,加水完全溶解,配制浓度约1% 的溶液,滴加2~3滴 1-(2-吡啶偶氮)-2-萘酚(PAN)指示剂,用0.01mol/L的乙二胺四乙酸二钠(EDTA-2Na)标准溶液滴定溶液颜色由深蓝色变为浅绿色即为滴定终点,并将滴定的结果用空白试验校正。
样品中Cu2+含量以质量百分数计,按下式计算:
式中:
V0:滴定空白溶液所消耗EDTA-2Na标准滴定液的体积,ml;
V1:滴定样品溶液所消耗EDTA-2Na标准滴定液的体积,ml;
c:EDTA-2Na标准滴定液的浓度,mol/L;
m:样品的质量,g;
h(%):供试品干燥失重。
赖氨酸[Lys%(g/g)]含量测定方法:
柠檬酸缓冲液(0.2mol/l,pH5.5):称取3.84g柠檬酸和5.16g柠檬酸三钠,分别溶于100mL蒸馏水,取柠檬酸溶液15.21g,柠檬酸三钠溶液93g,混匀,即得。
茚三酮试剂:称取1g茚三酮溶于25mL 95%乙醇中,另称取40mg二氯化锡溶于25mL柠檬酸缓冲液中,将两液混合摇匀置于棕色瓶中,置冰箱保存备用。
赖氨酸标准液:准确称取50mg赖氨酸标准品,加蒸馏水稀释定容至1000ml,得浓度为50μg/ml的标准液。
供试品溶液:取本品约0.1 g(m1),精密称定,加水溶解至100mL,再取7.0 g(m2)(按溶液密度为1.000 g/ml计,为7.0ml),加水稀释至50 mL,即得。
标准曲线:取赖氨酸标准液0、0.2、0.4、0.6、0.8、1.0mL,补加水至1.0mL, 分别加入茚三酮试剂2mL,混匀,80℃保温30min,水浴冷却至室温,再加水稀释至10mL,混匀,以0管为空白,于570nm测定吸光度。以赖氨酸浓度为横坐标,吸光度为纵坐标,绘制标准曲线,并进行线形回归。
供试品测定:取供试品溶液1.0mL,加入茚三酮试剂2mL,混匀,80℃保温30min,水浴冷却至室温,再加水稀释至10mL,混匀,于570nm测定吸光度。按下式计算
式中:Ci为由回归方程得到的赖氨酸的浓度,μg/ml;
m1为供试品的质量,g;
m2为供试品稀释液的质量,g;
h(%)为供试品的干燥失重。
根据文献(Bitter T,Muir H M.A modif ied uronic acid carbarbazolereationl J J.Anal Biochem .1962.4:330—333.),采用改良咔唑法测定样品的葡萄糖醛酸含量T%(g/g)。
氯离子[Cl-%(g/g)]含量测定方法:
取样品约0.1g,精密称定,置于滴定管中,加50ml超纯水使溶解,照电位滴定法,用硝酸银滴定液(0.1mol/L)滴定,并将滴定结果用空白实验校正。每1ml硝酸银滴定液(0.1mol/L)相当于3.55mg的氯离子。
铜离子与赖氨酸的摩尔比[Cu2+/ Lys(mol/mol)]按下式计算:
赖氨酸与透明质酸双糖单位的摩尔比[Lys/ HA(mol/mol)]按下式计算:
实施例2 透明质酸赖氨酸铜螯合物的红外分析
采用溴化钾压片,对以成盐和酰胺键两种方式结合的透明质酸赖氨酸铜螯合物(本发明实施例一样品1-3和样品1-9)进行红外分析,并与透明质酸钠的红外图谱作对比,结果见图1~图4。
以上谱图分析:
以酰胺键结合的透明质酸赖氨酸铜螯合物与透明质酸钠IR谱图对比,由于赖氨酸与透明质酸羰基以酰胺键结合,受其化学键的影响,1)O-H的伸缩振动,其谱带扩展延伸变宽,透明质酸中的3385 cm-1峰向高波数位移至3420 cm-1左右。2)C-H的伸缩振动,透明质酸中的2895 cm-1峰该峰向高波数位移至2929cm-1左右。
以成盐方式结合的透明质酸赖氨酸铜螯合物与透明质酸钠IR谱图对比,由于赖氨酸铜盐的存在,1)其O-H的伸缩振动和C-H的伸缩振动分别在3445cm-1,3263cm-1,3045cm-1,2946cm-1。2)不对称的C=O伸缩振动分别在1661cm-1和1585cm-1,呈现与Lys-Cu-Lys类似的特征峰[参考文献:刘飞飞,李群,于岚,Cu2+-Lys螯合物的合成和表征。应用化工,2009,38(11):1631-1634]。3)其指纹区613cm-1,仍呈现HA特征峰。
实施例3 透明质酸赖氨酸铜螯合物对5α-还原酶的抑制作用
根据文献方法(潘继飞等.5α-还原酶抑制剂体外评价体系的建立及其应用.日用化学工业(中英文),2023,53(11):1280-1284)测定本发明透明质酸赖氨酸铜螯合物(HA-lys-Cu)(本发明实施例一样品1-9)、硫酸铜(CuSO4)和盐酸赖氨酸铜螯合物(lys-Cu-lys·2HCl)对5α-还原酶(5AR)相对抑制率,对其控油功效进行体外评价。将三种化合物加水溶解并稀释为含铜离子0.5mM的溶液作为供试样品,以阳性对照为0.2mM的度他雄胺(DTS)溶液作为参照,测定并计算相对抑制率,结果(图5)表明三种供试品均对5α-还原酶有显著抑制作用,本发明透明质酸赖氨酸铜螯合物的抑制作用好于硫酸铜和盐酸赖氨酸铜螯合物。体外控油功效评价结果说明,与无机铜盐--硫酸铜和小分子有机铜化合物--盐酸赖氨酸铜螯合物比较,本发明透明质酸赖氨酸铜螯合物的控油效果提高。
实施例4 透明质酸赖氨酸铜螯合物的皮肤黏附性
分别称取适量盐酸赖氨酸铜螯合物、透明质酸铜(本发明实施例一样品2-1)和本发明透明质酸赖氨酸铜螯合物(本发明实施例一样品1-3),加水配制成铜离子含量为6.87mg/ml的溶液。在皮肤上选取2cm×2cm的试验区域,分别涂抹上述盐酸赖氨酸铜螯合物、透明质酸铜和透明质酸赖氨酸铜螯合物溶液各0.3ml。干燥后,每5min用棉棒擦拭试验区域皮肤,测定棉棒中擦拭掉的铜离子含量,与涂抹于皮肤试验区皮肤铜离子的总量相比,计算铜离子多次擦拭后的累计流失量(%)。结果(图6)表明经12次擦拭后,盐酸赖氨酸铜螯合物铜的累计流失量95.68%、透明质酸铜86.68%,透明质酸赖氨酸铜螯合物为71.50%。说明本发明透明质酸赖氨酸铜螯合物的皮肤黏附性好于盐酸赖氨酸铜螯合物和透明质酸铜。
Claims (10)
1.一种透明质酸赖氨酸铜螯合物,其特征在于:
①铜离子含量为1%~9%(g/g);
②赖氨酸和铜离子按摩尔比为1:0.4~0.6;
和③透明质酸双糖单位和赖氨酸按摩尔比为1:0.1~2。
2.权利要求1所述的螯合物,其特征还在于赖氨酸铜螯合物与透明质酸以盐的方式结合,以通式(1)表示,
(1)
其中X,Y和Z表示透明质酸双糖单位的数量,X>Y>Z。
3.权利要求1所述的螯合物,其特征还在于赖氨酸铜螯合物与透明质酸以酰胺键的方式结合,以通式(2)表示,
(2)
其中X,Y和Z表示透明质酸双糖单位的数量,X>Y>Z。
4.权利要求1所述的螯合物,其特征还在于所述铜离子含量为5%~7%(g/g)。
5.权利要求1所述的螯合物,其特征还在于所述透明质酸双糖单位和赖氨酸按摩尔比为1:0.2~1.5。
6.权利要求1,2和3所述的螯合物,其特征还在于与赖氨酸铜螯合物结合的透明质酸的平均分子量为5 kDa~2000 kDa。
7.权利要求1,2和3所述的螯合物,其特征还在于与赖氨酸铜螯合物结合的透明质酸的平均分子量为200 kDa~500 kDa。
8.权利要求1,2和3所述的螯合物,用于制备具有控油、修复和促进毛发生长作用的皮肤外用产品。
9.权利要求1,2和3所述的螯合物,用于制备具有控油、修复和促进毛发生长作用的化妆品。
10.权利要求1,2和3所述的螯合物,用于制备具有控油、修复和促进毛发生长作用的医疗产品。
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