CN117342971B - 一类脂肪酰凝血酸盐及其制备方法和应用 - Google Patents
一类脂肪酰凝血酸盐及其制备方法和应用 Download PDFInfo
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- CN117342971B CN117342971B CN202311275809.0A CN202311275809A CN117342971B CN 117342971 B CN117342971 B CN 117342971B CN 202311275809 A CN202311275809 A CN 202311275809A CN 117342971 B CN117342971 B CN 117342971B
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- aqueous solution
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- tranexamic acid
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Abstract
本发明提供了一类脂肪酰凝血酸盐及其制备方法和应用,所述的脂肪酰凝血酸盐由下述结构式(I)表示,其中e选自正整数且1≤e≤23,t选自正整数且1≤t≤5,M选自金属元素Au、Ag、Al、Ba、Bi、Ca、Ce、Co、Cr、Cu、Fe、Ge、Hg、K、Li、Mg、Mn、Na、Pt、Sn、Sr、Ti、Zn或Zr。本发明的脂肪酰凝血酸盐作为原料药应用在医药领域中,用于治疗黄褐斑、炎症后色素沉着、血管性水肿、玫瑰痤疮等疾病,也可以应用在日化领域中,具有美白、舒缓、修护的功效,且可以作为表面活性剂使用,发挥清洁、乳化或分散的功能。
Description
技术领域
本发明属于化学药品原料药、制剂制造领域,具体地说,是关于一类脂肪酰凝血酸盐及其制备方法和应用。
背景技术
凝血酸及其片剂、胶囊、注射液,作为止血药,被收录在《中华人民共和国药典》(2020年版)中。凝血酸是一种人工合成的抗纤溶药物,具有抗炎、免疫调节、减轻血管内皮损伤等作用,其通过抑制纤溶酶原和抑制酪氨酸酶的激活,来减少黑色素和新血管的形成,常用来治疗黄褐斑、炎症后色素沉着、血管性水肿、玫瑰痤疮等疾病。凝血酸还可以促进表皮更新,降低皮肤的经表皮失水率,维护和修复皮肤屏障功能。
凝血酸以口服、外用为主,但长期口服可导致血栓形成、视力缺陷、肝肾功能损害等多种不良反应,外用凝血酸的溶液、乳霜等制剂安全性较高,但凝血酸的亲水性和氢键作用比较强,较难通过皮肤角质层屏障,需要通过对凝血酸进行改性来提高其经皮渗透性,增强功效。
公开号为昭57-59847的发明专利申请公开了一种环烷基酰凝血酸酯;公开号为CN101253148A的发明专利申请公开了一种烷基酰氧基烷基凝血酸酯,作为凝血酸前药治疗出血或皮肤疾病;公开号为CN 101925353 A的发明专利申请公开了一种凝血酰胺衍生物,通过促进血管内皮生长因子产生来缓解水肿或皱纹;公开号为EP 0604667 A1的发明专利申请公开了一种具有美白功能的外用组合物,其中的有效成分为凝血酸酯或凝血酰胺;公开号为CN 105085364A的发明专利申请公开了一种药用化合物,马来酰凝血酸的制备方法;公开号为CN 113952326 A的发明专利申请公开了一种PEG酰凝血酸,可以延长凝血酸药效时间;公开号为CN 114751858 A的发明专利申请公开了一种喹啉基凝血酰胺,具有抗肿瘤活性。以上发明专利申请都对凝血酸的氨基或羧基进行了改性,但未发现用与皮肤中油脂结构相近的中长直链脂肪酰基对凝血酸的氨基进行修饰,且同时将凝血酸的羧基进行成盐处理的方案;以上发明专利申请着重于凝血酸药物作用的发挥,未赋予凝血酸衍生物其它的作用,例如表面活性作用,从而规避掉药品、护肤品存在的一些问题。
在药品、护肤品等制品中,传统的表面活性剂应用非常广泛,且不可或缺,因为其具有乳化、分散、润湿、增溶、去污的作用。但表面活性剂应用在制品中时,存在着留存在皮肤上的问题,例如使用驻留型制品时,其中所含的表面活性剂大部分沉积皮肤上;使用洗去型制品清洁皮肤时,由于其中的表面活性剂含量较高,无法被完全冲洗干净而造成残留。所以药品、护肤品的使用不当或者使用频繁,会使表面活性剂在皮肤上长期残留或累积,从而引发皮肤屏障受损、皮肤刺激或皮肤敏感等问题。
发明内容
为了解决上述的凝血酸亲水性和氢键作用强导致皮肤吸收性差的不足,以及传统表面活性剂残留引起皮肤问题的缺点,本申请提供了一类新型凝血酸衍生物,即脂肪酰凝血酸盐,其对皮肤的亲和性强,且具备表面活性,使得相关药品、护肤品中不需要再添加额外的表面活性剂。
因此,本发明的目的在于提供一类脂肪酰凝血酸盐及其制备方法和应用。
为了达到上述目的,本发明提供了如下的技术方案:
一类脂肪酰凝血酸盐,由结构式(I)表示:
其中,e选自正整数且1≤e≤23,t选自正整数且1≤t≤5,M选自金属元素Au、Ag、Al、Ba、Bi、Ca、Ce、Co、Cr、Cu、Fe、Ge、Hg、K、Li、Mg、Mn、Na、Pt、Sn、Sr、Ti、Zn或Zr。
根据本发明的优选实施例,所述结构式(I)中的e选自正整数且1≤e≤11,t选自正整数且1≤t≤4,M选自金属元素Al、Ca、Cu、Fe、K、Li、Mg、Mn、Na或Zn。
优选的,所述结构式(I)中的t为1,M选自金属元素K、Li或Na。
同样优选的,所述结构式(I)中的t为2,M选自金属元素Ca、Cu、Fe、Mg、Mn或Zn。
同样优选的,所述结构式(I)中的t为3,M选自金属元素Al或Fe。
同样优选的,所述结构式(I)中的t为4,M为金属元素Mn。
根据本发明,所述的脂肪酰凝血酸盐的制备方法,包括以下步骤:
(1)在反应釜中加入凝血酸、水、有机溶剂A,搅拌至凝血酸完全溶解;
(2)向反应釜中滴加碱性水溶液,调节体系的pH值在9.0-11.0;
(3)维持反应釜的温度在15-35℃,边搅拌边向其中缓慢滴加脂肪酰卤,同时继续滴加碱性水溶液使体系的pH值维持在9.0-11.0;
(4)脂肪酰卤滴加完毕后,继续搅拌2-6h,升温蒸馏回收有机溶剂A;
(5)向反应釜中边搅拌边滴加无机酸水溶液,调节体系pH值在5-7,过滤除去析出的脂肪酸;
(6)向滤液中继续边搅拌边滴加无机酸水溶液,调节体系pH值在1-2,进行减压抽滤,水洗至滤液呈中性,将得到的固体烘干,再将烘干的固体置于有机溶剂B中进行重结晶,得到脂肪酰凝血酸;
(7)用溶剂将脂肪酰凝血酸溶解,与金属M的氧化物、氢氧化物或无机盐溶液进行成盐反应,再经分离、洗涤或干燥,得到脂肪酰凝血酸盐。
根据本发明,所述的脂肪酰凝血酸盐的制备方法,其特征在于,所述步骤(1)中的凝血酸与水的质量比为(14-18)∶100,水与有机溶剂A的体积比为1∶(1-3),有机溶剂A选自乙醇、丙酮、四氢呋喃。
所述步骤(2)中的碱性水溶液选自KOH水溶液、NaOH水溶液、K2CO3水溶液、Na2CO3水溶液,所述步骤(5)中的无机酸水溶液为稀盐酸、稀硫酸,步骤(6)中的有机溶剂B选自石油醚、乙醇、四氢呋喃,所述步骤(7)中的所述溶剂选自水、乙醇,溶液选自KOH、NaOH、K2CO3、Na2CO3的水溶液或乙醇溶液。
根据本发明,所述的脂肪酰凝血酸盐作为原料药应用在医药领域中,用于治疗黄褐斑、炎症后色素沉着、血管性水肿、玫瑰痤疮等疾病。
根据本发明,所述的脂肪酰凝血酸盐应用在日化领域中,具有美白、舒缓、修护的功效,且可以作为表面活性剂使用,发挥清洁、乳化或分散的功能。本发明的有益效果:
凝血酸用于治疗黄褐斑、炎症后色素沉着、血管性水肿、玫瑰痤疮等疾病,且本身具有舒缓、美白、修护的功效,但其亲水性和氢键作用太强,不容易被皮肤吸收,本发明的脂肪酰凝血酸盐是凝血酸的衍生物,在其氨基上引入了与皮肤中油脂结构相近的中长直链脂肪酰基,大大增强了其亲脂性和亲肤性,将羧基进行成盐处理,减弱了氢键作用,更利于皮肤的吸收和凝血酸功效的发挥;传统的表面活性剂在药品和护肤品中应用广泛,长期使用相关制品会使表面活性剂在皮肤上残留或积累,引起肌肤问题,而脂肪酰凝血酸盐具有表面活性,可以替代传统的表面活性剂,发挥乳化、分散或清洁的功能,则药品、护肤品制剂中不需要再添加额外的表面活性剂,避免了传统表面活性剂残留引起的肌肤问题。脂肪酰凝血酸盐因其具有舒缓、美白或修护的功效,不仅不会刺激皮肤,反而会改善肌肤问题。
此外,本发明的脂肪酰凝血酸盐制备方法可操作性强,易于工业化生产,可代替凝血酸或传统的表面活性剂,广泛应用于医药或日化等领域中。
具体实施方式
以下结合具体实施例,对本发明做进一步说明。应理解,以下实施例仅用于说明本发明而非用于限制本发明的范围。
除特别注明外,以下实施例中所用原料皆市售可得。
以下实施例中涉及性能功效的检测方法如下:
稳定性测试方法(离心实验、耐热耐寒实验、室温留样观察)的参考文献:陈思,张轶.红色诺卡氏菌细胞壁骨架乳液的制备及其安全性研究[J].日用化学品科学,2023,46(01):4-8.
治疗黄褐斑效果测试方法的参考文献:皮子欣,邱湘宁,邓前程等.外用烟酰胺治疗黄褐斑临床观察[J].中国医疗美容,2019,9(11):49-53.
治疗炎症后色素沉着效果测试方法的参考文献:班超.多磺酸粘多糖乳膏治疗炎症后色素沉着的疗效观察[J].中外女性健康研究,2016(12):48-56.
舒缓功效测试方法(泛红参数测量)的参考文献:郭沈涛,徐文枫,崔玉矫等.几种化妆品舒缓功效评价方法的应用研究[J].日用化学品科学,2023,46(06):37-40+44.
美白功效测试方法(人体皮肤白度L*测量)的参考文献:张雷,杨淑琴,郭秀茹等.覆盆子酮葡糖苷的功效评价研究[J].日用化学品科学,2022,45(03):43-47.
修护功效测试方法(乳酸刺痛实验、经表皮失水率TEWL值测试)的参考文献:雷翠婷,郑木创,陈楚微.皮肤修护类化妆品功效评价方法探讨[J].日用化学品科学,2021,44(12):28-30.
实施例1
本实施例的脂肪酰凝血酸盐的结构式如下:
即硬脂酰凝血酸钠。制备方法为:
(1)向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的1L五口夹层烧瓶中加入凝血酸(50.00g,0.1758mol)、水(333.33g,18.50mol)、丙酮(394.95g,6.80mol),搅拌至凝血酸完全溶解;向烧瓶中滴加20%的NaOH水溶液,调节体系的pH值在9.0-11.0;开启循环水浴,维持烧瓶内的温度在30℃,边搅拌边向其中缓慢滴加硬脂酰氯(42.59g,0.1406mol),同时继续滴加20%的NaOH水溶液使体系的pH值维持在9.0-11.0;硬脂酰氯滴加完毕后,继续搅拌2-6h,升温至58-60℃蒸馏回收丙酮;向烧瓶中边搅拌边滴加15%的稀盐酸,调节体系pH值在5-7,过滤除去生成的硬脂酸;向滤液中继续边搅拌边滴加15%的稀盐酸,调节体系pH值在1-2,出现大量白色固体,进行减压抽滤,水洗白色固体至滤液呈中性,将得到的白色固体置于烘箱中50℃烘干(56.57g);再将白色固体转入到500mL烧瓶中,加入300mL石油醚,50℃加热搅拌,趁热过滤,滤液冷却静置进行重结晶,抽滤,滤渣置于烘箱中50℃烘干,得到硬脂酰凝血酸(53.16g)。
制备得到的硬脂酰凝血酸为白色固体,收率89.25%。1H NMR(400MHz,DMSO-d6)δ:12.32(s,1H),8.05(brd,1H),3.10(d,J=7.0Hz,2H),2.35-2.29(m,1H),2.17(m,J=7.1Hz,2H),2.12-2.00(m,1H),1.80-1.70(m,4H),1.63-1.44(m,6H),1.40-1.20(m,28H),0.89(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:178.3,171.7,42.5,42.3,37.4,36.9,31.7,29.8,29.4,28.8,28.5,27.6,26.8,25.6,22.6,13.9;[M-H]-m/z:422.36。
向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的500mL五口夹层烧瓶中加入硬脂酰凝血酸(30.00g,0.0708mol),加入300mL乙醇,50℃加热搅拌使将硬脂酰凝血酸溶解,再向烧瓶中加入14.16mL 20%的NaOH的乙醇溶液,搅拌1-2h,冷却后析出白色固体,抽滤,50℃烘干,得到硬脂酰凝血酸钠(30.30g)。
制备得到的硬脂酰凝血酸钠为白色固体,收率96.10%。1H NMR(400MHz,DMSO-d6)δ:8.03(brd,1H),3.12(d,J=7.0Hz,2H),2.35-2.29(m,1H),2.16(m,J=7.1Hz,2H),2.12-2.00(m,1H),1.80-1.70(m,4H),1.63-1.44(m,6H),1.40-1.20(m,28H),0.90(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:178.1,171.4,42.6,42.3,37.5,36.8,31.7,29.5,29.2,28.8,28.5,27.8,26.8,25.5,22.6,13.8;[M-H]-m/z:422.36。
将制备得到的硬脂酰凝血酸钠应用到如下精华霜配方中,对照配方中将硬脂酰凝血酸钠替换成等质量的表面活性剂鲸蜡硬脂醇聚醚-25。
配制方法为:按质量分数称取所述A相各组分,混合,于85℃下加热搅拌,得到分散均匀且无肉眼可见团聚颗粒的A相;将相应质量的B相各组分混合,于85℃下加热搅拌,得到分散均匀且无肉眼可见团聚颗粒的B相;85℃下,将分散好的A相逐渐加入到分散好的B相中,6000rpm均质乳化5min,然后600rpm搅拌至料体冷却至室温,得到精华霜料体。
按照参考文献提供的方法测试精华霜料体的稳定性和舒缓功效。
该精华霜料体经过离心后,未出现出油、沉淀、分层现象;经过耐寒耐热的料体恢复至室温后,未出现出油、破乳、沉淀、分层、变色等现象;常温留样3个月内也未出现出油、破乳、沉淀、分层、变色等现象,对照样品料体出油,以上说明该精华霜料体具有良好的稳定性,以及硬脂酰凝血酸钠的具有良好的乳化性能。30例敏感肌肤受试者的初始泛红均值分别为24.36和24.94,使用精华霜和对照样品(使用前摇匀)28天的泛红均值分别为21.82(显著性P<0.01)和24.43(显著性P>0.05),说明该精华霜料体具有舒缓功效,且硬脂酰凝血酸钠具有舒缓功效。精华霜样品试用组第4周的ΔL*为2.13(显著性P<0.05),对照样品试用组第4周的ΔL*为0.12(显著性P>0.05),说明该精华霜料体具有美白功效,且硬脂酰凝血酸钠具有美白功效。
实施例2
本实施例的脂肪酰凝血酸盐的结构式如下:
即月桂酰凝血酸钾。制备方法为:
(1)向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的1L五口夹层烧瓶中加入凝血酸(50.00g,0.1758mol)、水(333.33g,18.50mol)、丙酮(394.95g,6.80mol),搅拌至凝血酸完全溶解;向烧瓶中滴加20%的NaOH水溶液,调节体系的pH值在9.0-11.0;开启循环水浴,维持烧瓶内的温度在20℃,边搅拌边向其中缓慢滴加月桂酰氯(27.06g,0.1231mol),同时继续滴加20%的NaOH水溶液使体系的pH值维持在9.0-11.0;月桂酰氯滴加完毕后,继续搅拌2-6h,升温至58-60℃蒸馏回收丙酮;向烧瓶中边搅拌边滴加15%的稀盐酸,调节体系pH值在5-7,过滤除去生成的月桂酸;向滤液中继续边搅拌边滴加15%的稀盐酸,调节体系pH值在1-2,出现大量白色固体,进行减压抽滤,水洗白色固体至滤液呈中性,将得到的白色固体置于烘箱中50℃烘干(39.72g);再将白色固体转入到500mL烧瓶中,加入250mL石油醚,50℃加热搅拌,趁热过滤,滤液冷却静置进行重结晶,抽滤,滤渣置于烘箱中50℃烘干,得到月桂酰凝血酸(37.76g)。
制备得到的月桂酰凝血酸为白色固体,收率90.34%。1H NMR(400MHz,DMSO-d6)δ:12.60(s,1H),8.07(brd,1H),3.15(d,J=7.0Hz,2H),2.35-2.30(m,1H),2.18(m,J=7.0Hz,2H),2.11-2.01(m,1H),1.81-1.70(m,4H),1.65-1.45(m,6H),1.41-1.20(m,16H),0.92(t,J=8.1Hz,3H);13C NMR(100MHz,DMSO-d6)δ:177.5,169.4,42.6,42.1,38.1,37.2,32.0,29.8,29.6,28.5,28.3,27.4,26.8,25.7,22.9,13.9;[M-H]-m/z:338.27。
向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的500mL五口夹层烧瓶中加入月桂酰凝血酸(20.00g,0.0589mol),加入200mL乙醇,50℃加热搅拌使将月桂酰凝血酸溶解,再向烧瓶中加入11.78mL 20%的NaOH的乙醇溶液,搅拌1-2h,冷却后析出白色固体,抽滤,50℃烘干,得到月桂酰凝血酸钾(21.57g)。
制备得到的月桂酰凝血酸钾为白色固体,收率96.98%。1H NMR(400MHz,DMSO-d6)δ:8.05(brd,1H),3.20(d,J=7.0Hz,2H),2.35-2.30(m,1H),2.19(m,J=7.0Hz,2H),2.11-2.01(m,1H),1.81-1.70(m,4H),1.65-1.45(m,6H),1.41-1.20(m,16H),0.94(t,J=8.1Hz,3H);13C NMR(100MHz,DMSO-d6)δ:177.5,169.5,42.7,41.8,38.1,37.5,32.1,29.6,29.3,28.5,28.2,27.5,26.8,25.6,22.9,14.1;[M-H]-m/z:338.27。
将制备得到的月桂酰凝血酸钾应用到如下洁面配方中,对照样品配方中将月桂酰凝血酸钾替换成等质量的表面活性剂椰油酰肌氨酸钠。
配制方法为:按质量分数称取所述A相各组分,混合,于常温下搅拌,得到无色透明的A相;将相应质量的B相各组分依次加入混合好的A相中,常温搅拌至体系无色透明;得到洁面泡沫料体。
按照参考文献提供的方法测试洁面泡沫料体的稳定性和舒缓功效。
该洁面泡沫料体经过离心后,未出现沉淀、分层现象;经过耐寒耐热的料体恢复至室温后,未出现沉淀、分层、变色等现象;常温留样3个月内也未出现沉淀、分层、变色等现象,对照样品料体亦无沉淀、分层、变色等现象,以上说明该洁面料体具有良好的稳定性。30例敏感肌肤受试者的初始泛红均值分别为23.98和24.16,使用精华霜和对照样品28天的泛红均值分别为22.12(显著性P<0.01)和24.73(显著性P<0.01),说明该洁面料体具有舒缓功效,且月桂酰凝血酸钾具有舒缓功效。另外在使用过程中洁面泡沫料体的起泡丰富,可以洗去皮肤污垢,说明月桂酰凝血酸钾具有清洁功效。
实施例3
本实施例的脂肪酰凝血酸盐的结构式如下:
即二辛酰凝血酸锌。制备方法为:
(1)向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的1L五口夹层烧瓶中加入凝血酸(50.00g,0.1758mol)、水(333.33g,18.50mol)、四氢呋喃(445.00g,6.17mol),搅拌至凝血酸完全溶解;向烧瓶中滴加20%的KOH水溶液,调节体系的pH值在9.0-11.0;开启循环水浴,维持烧瓶内的温度在15℃,边搅拌边向其中缓慢滴加辛酰氯(17.16g,0.1055mol),同时继续滴加20%的KOH水溶液使体系的pH值维持在9.0-11.0;辛酰氯滴加完毕后,继续搅拌2-6h,升温至68-70℃蒸馏回收四氢呋喃;向烧瓶中边搅拌边滴加15%的稀盐酸,调节体系pH值在5-7,过滤(过滤温度13-15℃)除去生成的辛酸;向滤液中继续边搅拌边滴加15%的稀盐酸,调节体系pH值在1-2,出现大量白色固体,进行减压抽滤,水洗白色固体至滤液呈中性,将得到的白色固体置于烘箱中50℃烘干(29.39g);再将白色固体转入到500mL烧瓶中,加入300mL石油醚,50℃加热搅拌,趁热过滤,滤液冷却静置进行重结晶,抽滤,滤渣置于烘箱中50℃烘干,得到辛酰凝血酸(28.81g)。
制备得到的辛酰凝血酸为白色固体,收率96.35%。1H NMR(400MHz,DMSO-d6)δ:12.53(s,1H),8.10(brd,1H),3.17(d,J=7.0Hz,2H),2.35-2.25(m,1H),2.15(m,J=7.1Hz,2H),2.10-2.00(m,1H),1.81-1.70(m,4H),1.65-1.45(m,6H),1.35-1.25(m,6H),0.89(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:178.7,170.9,41.9,41.6,37.4,35.8,30.6,27.8,27.5,26.9,25.1,21.9,14.3;[M-H]-m/z:282.21。
向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的500mL五口夹层烧瓶中加入辛酰凝血酸(20.00g,0.0706mol),加入282.40mL 1%的NaOH水溶液,50℃加热搅拌使将辛酰凝血酸溶解,再向烧瓶中加入56.99mL 10%的硫酸锌水溶液,出现白色浑浊现象,继续搅拌1-2h,冷却后抽滤,50℃烘干,得到二辛酰凝血酸锌(21.58g)。
制备得到的二辛酰凝血酸锌为白色固体,收率88.7%。1H NMR(400MHz,DMSO-d6)δ:8.09(brd,1H),3.17(d,J=7.0Hz,2H),2.35-2.25(m,1H),2.14(m,J=7.1Hz,2H),2.10-2.00(m,1H),1.81-1.70(m,4H),1.65-1.45(m,6H),1.35-1.25(m,6H),0.90(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:178.5,171.0,42.1,41.5,37.2,35.8,30.3,27.8,27.5,26.6,25.3,21.9,14.7;[M-H]-m/z:282.21。
将制备得到的二辛酰凝血酸锌应用到如下乳膏中,对照配方中将二辛酰凝血酸锌替换成等质量的凝血酸。
配制方法为:按质量分数称取所述A相各组分,混合,于70℃下加热搅拌,得到分散均匀且无肉眼可见团聚颗粒的A相;将相应质量的B相各组分混合,于70℃下加热搅拌,得到分散均匀且无肉眼可见团聚颗粒的B相;70℃下,将分散好的A相逐渐加入到分散好的B相中,7000rpm均质乳化5min,然后600rpm搅拌至料体冷却至室温,得到乳膏料体。
按照参考文献提供的方法测试乳膏料体的稳定性和治疗黄褐斑和炎症后色素沉着的功效。
该乳膏料体经过离心后,未出现出油、沉淀、分层现象;经过耐寒耐热的料体恢复至室温后,未出现出油、破乳、沉淀、分层、变色等现象;常温留样3个月内也未出现出油、破乳、沉淀、分层、变色等现象,对照样品料体有轻微出油现象,以上说明该精华霜料体具有良好的稳定性,以及二辛酰凝血酸锌的具有良好的乳化性能。乳膏样品试用组第12周的mMASI分值下降率为65.42±15,73(显著性P<0.01),对照样品试用组第12周的mMASI分值下降率为41.31±11.29(显著性P<0.01),说明该乳膏料体对黄褐斑治疗确实有效,且二辛酰凝血酸锌比凝血酸的功效更强。乳膏样品试用组第8周对验证后色素沉着的满意度为72%(显著性P<0.05),对照样品的满意度为48%(显著性P<0.05),说明乳膏样品对炎症后色素沉着确实有效,且二辛酰凝血酸锌比凝血酸的作用更强。
实施例4
本实施例的脂肪酰凝血酸盐的结构式如下:
即二肉豆蔻酰凝血酸镁。制备方法为:
(1)向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的1L五口夹层烧瓶中加入凝血酸(50.00g,0.1758mol)、水(333.33g,18.50mol)、四氢呋喃(445.00g,6.17mol),搅拌至凝血酸完全溶解;向烧瓶中滴加20%的KOH水溶液,调节体系的pH值在9.0-11.0;开启循环水浴,维持烧瓶内的温度在15℃,边搅拌边向其中缓慢滴加肉豆蔻酰氯(30.38g,0.1231mol),同时继续滴加20%的KOH水溶液使体系的pH值维持在9.0-11.0;肉豆蔻酰氯滴加完毕后,继续搅拌2-6h,升温至68-70℃蒸馏回收四氢呋喃;向烧瓶中边搅拌边滴加15%的稀盐酸,调节体系pH值在5-7,过滤除去生成的肉豆蔻酸;向滤液中继续边搅拌边滴加15%的稀盐酸,调节体系pH值在1-2,出现大量白色固体,进行减压抽滤,水洗白色固体至滤液呈中性,将得到的白色固体置于烘箱中50℃烘干(42.99g);再将白色固体转入到500mL烧瓶中,加入400mL石油醚,50℃加热搅拌,趁热过滤,滤液冷却静置进行重结晶,抽滤,滤渣置于烘箱中50℃烘干,得到肉豆蔻酰凝血酸(40.41g)。
制备得到的肉豆蔻酰凝血酸为白色固体,收率89.31%。1H NMR(400MHz,DMSO-d6)δ:12.45(s,1H),8.10(brd,1H),3.17(d,J=7.0Hz,2H),2.35-2.29(m,1H),2.19(m,J=7.1Hz,2H),2.10-2.01(m,1H),1.81-1.70(m,4H),1.66-1.46(m,6H),1.41-1.25(m,20H),0.94(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:176.4,170.7,43.1,42.3,37.1,35.9,31.4,29.3,28.6,28.1,27.5,27.1,25.0,23.1,13.9。[M-H]-m/z:366.30。
向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的500mL五口夹层烧瓶中加入肉豆蔻酰凝血酸(30.00g,0.0816mol),加入326.40mL 1%的NaOH水溶液,50℃加热搅拌使将肉豆蔻酰凝血酸溶解,再向烧瓶中加入49.11mL 10%的硫酸镁水溶液,出现白色浑浊现象,继续搅拌1-2h,冷却后抽滤,50℃烘干,得到二肉豆蔻酰凝血酸镁(29.98g)。
制备得到的二肉豆蔻酰凝血酸镁为白色固体,收率97.01%。1H NMR(400MHz,DMSO-d6)δ:8.09(brd,1H),3.15(d,J=7.0Hz,2H),2.35-2.29(m,1H),2.18(m,J=7.1Hz,2H),2.10-2.01(m,1H),1.81-1.70(m,4H),1.66-1.46(m,6H),1.41-1.25(m,20H),0.96(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:176.8,170.5,43.3,42.5,37.3,36.0,31.3,29.3,28.5,28.0,27.7,27.3,24.8,23.4,14.0。[M-H]-m/z:366.30。
将制备得到的二肉豆蔻酰凝血酸镁应用到如下隔离霜配方中,对照配方中将二肉豆蔻酰凝血酸镁替换成等质量的肉豆蔻酸镁。
配制方法为:按质量分数称取所述A相各组分,混合,于75℃下加热搅拌,得到分散均匀且无肉眼可见团聚颗粒的A相;将相应质量的B相各组分混合,于75℃下加热搅拌,得到分散均匀且无肉眼可见团聚颗粒的B相;75℃下,将分散好的B相逐渐加入到分散好的A相中,7000rpm均质乳化5min,然后600rpm搅拌至料体冷却至室温,得到隔离霜料体。
按照参考文献提供的方法测试隔离霜料体的稳定性。
该隔离霜料体经过离心后,未出现出水、沉淀、分层现象;经过耐寒耐热的料体恢复至室温后,未出现出水、破乳、沉淀、分层、变色等现象;常温留样3个月内也未出现出水、破乳、沉淀、分层、变色等现象,对照样品料体稍有出水,以上说明该隔离霜料体具有良好的稳定性,以及二肉豆蔻酰凝血酸镁的具有良好的辅助乳化性能。另外在使用过程中隔离霜料体的滑感明显优于对照样品,说明二肉豆蔻酰凝血酸镁还具有分散润滑的功效。
实施例5
本实施例的脂肪酰凝血酸盐的结构式如下:
即二棕榈酰凝血酸锰。制备方法为:
(1)向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的1L五口夹层烧瓶中加入凝血酸(50.00g,0.1758mol)、水(333.33g,18.50mol)、四氢呋喃(445.00g,6.17mol),搅拌至凝血酸完全溶解;向烧瓶中滴加20%的KOH水溶液,调节体系的pH值在9.0-11.0;开启循环水浴,维持烧瓶内的温度在15℃,边搅拌边向其中缓慢滴加棕榈酰氯(44.14g,0.1606mol),同时继续滴加20%的KOH水溶液使体系的pH值维持在9.0-11.0;棕榈酰氯滴加完毕后,继续搅拌2-6h,升温至68-70℃蒸馏回收四氢呋喃;向烧瓶中边搅拌边滴加15%的稀盐酸,调节体系pH值在5-7,过滤除去生成的棕榈酸;向滤液中继续边搅拌边滴加15%的稀盐酸,调节体系pH值在1-2,出现大量白色固体,进行减压抽滤,水洗白色固体至滤液呈中性,将得到的白色固体置于烘箱中50℃烘干(59.10g);再将白色固体转入到1L烧瓶中,加入600mL石油醚,50℃加热搅拌,趁热过滤,滤液冷却静置进行重结晶,抽滤,滤渣置于烘箱中50℃烘干,得到棕榈酰凝血酸(57.31g)。
制备得到的棕榈酰凝血酸为白色固体,收率90.20%。1H NMR(400MHz,DMSO-d6)δ:12.48(s,1H),3.18(d,J=7.0Hz,2H),2.35-2.31(m,1H),2.17(m,J=7.1Hz,2H),2.10-2.00(m,1H),1.80-1.70(m,4H),1.65-1.45(m,6H),1.40-1.20(m,24H),0.94(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:180.7,174.6,43.2,42.3,38.3,35.7,32.4,29.6,29.2,29.0,27.4,27.1,27.0,25.9,23.1,14.3。[M-H]-m/z:394.33。
向装有电磁加热搅拌器、温度计、pH计、冷凝回流管、滴液漏斗的500mL五口夹层烧瓶中加入棕榈酰凝血酸(30.00g,0.0816mol),加入228.91mL 2%的KOH水溶液,50℃加热搅拌使将棕榈酰凝血酸溶解,再向烧瓶中加入61.61mL 10%的硫酸锰水溶液,出现淡红色浑浊现象,继续搅拌1-2h,冷却后抽滤,50℃烘干,得到二棕榈酰凝血酸锰(32.70g)。
制备得到的二棕榈酰凝血酸锰为淡红色固体,收率94.94%。1H NMR(400MHz,DMSO-d6)δ:8.03(brd,1H),3.15(d,J=7.0Hz,2H),2.35-2.31(m,1H),2.15(m,J=7.1Hz,2H),2.10-2.00(m,1H),1.80-1.70(m,4H),1.65-1.45(m,6H),1.40-1.20(m,24H),0.94(t,J=8.0Hz,3H);13C NMR(100MHz,DMSO-d6)δ:180.5,173.8,43.5,42.4,38.6,35.8,32.4,29.8,29.3,28.9,27.4,27.2,26.9,26.0,23.2,14.7。[M-H]-m/z:394.33。
将制备得到的二棕榈酰凝血酸锰应用到如下油膏配方中,对照配方中将二棕榈酰凝血酸锰替换成等质量的棕榈酸锰。
配制方法为:按质量分数称取所述A相各组分,混合,于85℃下加热搅拌,得到无色透明的A相;依次相应质量的B相各组分加入到混合好的A相中,于85℃下加热搅拌,至体系分散均匀且无肉眼可见团聚颗粒;然后500rpm搅拌至料体冷却到60℃时,加入C相的组分,继续搅拌至料体冷却到室温,得到粉红色油膏料体。
按照参考文献提供的方法测试油膏料体的稳定性和修护功效。
该油膏料体经过离心后,未出现出油、沉淀、分层现象;经过耐寒耐热的料体恢复至室温后,未出现出油、沉淀、分层、变色、变味等现象;常温留样和对照样品3个月内也未出现出油、沉淀、分层、变色、变味等现象,以上说明该油膏料体具有良好的稳定性。30例肌肤受试者的初始乳酸刺痛均值分别为2.86和2.82,使用油膏料体和对照样品28天的乳酸刺痛均值分别为0.35(显著性P<0.01)和2.67(显著性P<0.01);30例肌肤受试者的初始皮肤TEWL均值分别为17.73和17.69,使用油膏料体和对照样品28天的皮肤TEWL均值分别为16.17(显著性P<0.01)和17.51(显著性P<0.01);以上说明该油膏料体具有较强的修护功效,且二棕榈酰凝血酸锰具有修护功效。
实施例6
本实施例的脂肪酰凝血酸盐的结构式如下:
即脂肪酰凝血酸钠。
参照实施例1的方法制备了三十一酰凝血酸钠、三十酰凝血酸钠、肉豆蔻酰凝血酸钠、月桂酰凝血酸钠、辛酰凝血酸钠、庚酰凝血酸钠。
参照实施例1,将制备得到的三十一酰凝血酸钠、三十酰凝血酸钠、肉豆蔻酰凝血酸钠应用到如下精华霜配方中,按照参考文献提供的方法测试精华霜料体的稳定性。
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参照实施例2,将制备得到的月桂酰凝血酸钠、辛酰凝血酸钠、庚酰凝血酸钠应用到如下洁面配方中,按照参考文献提供的方法测试洁面泡沫料体的稳定性,并进行试用。
含有三十酰凝血酸钠、肉豆蔻酰凝血酸钠的精华霜料体经过离心后,未出现出油、沉淀、分层现象;经过耐寒耐热的料体恢复至室温后,未出现出油、破乳、沉淀、分层、变色等现象;常温留样3个月内也未出现出油、破乳、沉淀、分层、变色等现象,含有三十一酰凝血酸钠的精华霜出油、分层。洁面泡沫料体经过离心后,未出现沉淀、分层现象;经过耐寒耐热的料体恢复至室温后,未出现沉淀、分层、变色等现象;常温留样3个月内也未出现沉淀、分层、变色等现象,试用时含有月桂酰凝血酸钠、辛酰凝血酸钠的洁面泡沫泡沫较为丰富,但含有庚酰凝血酸钠的洁面泡沫明显稀少。以上说明当1≤e≤23时,对应的脂肪酰凝血酸钠具有较好的表面活性。
Claims (9)
1.一类脂肪酰凝血酸盐,其特征在于,由结构式(I)表示:
其中,e选自正整数且1≤e≤23,t选自正整数且1≤t≤2,M选自金属元素Ba、Ca、K、Li、Mg、Mn、Na、Zn。
2.根据权利要求1所述的脂肪酰凝血酸盐,其特征在于,所述结构式(I)中的e选自正整数且1≤e≤11,t选自正整数且1≤t≤2,M选自金属元素Ca、K、Li、Mg、Mn、Na或Zn。
3.根据权利要求2所述的脂肪酰凝血酸盐,其特征在于:
所述结构式(I)中的t为1,M选自金属元素K、Li或Na;或者
所述结构式(I)中的t为2,M选自金属元素Ca、Mg、Mn或Zn。
4.根据权利要求3所述的脂肪酰凝血酸盐,其特征在于:
所述结构式(I)中的t为1,M选自金属元素K或Na;或者
所述结构式(I)中的t为2,M选自金属元素Mg或Zn。
5.权利要求1-4任一项所述的脂肪酰凝血酸盐的制备方法,包括以下步骤:
(1)在反应釜中加入凝血酸、水、有机溶剂A,搅拌至凝血酸完全溶解;
(2)向反应釜中滴加碱性水溶液,调节体系的pH值在9.0-11.0;
(3)维持反应釜的温度在15-35℃,边搅拌边向其中缓慢滴加脂肪酰卤,同时继续滴加碱性水溶液使体系的pH值维持在9.0-11.0;
(4)脂肪酰卤滴加完毕后,继续搅拌2-6h,升温蒸馏回收有机溶剂A;
(5)向反应釜中边搅拌边滴加无机酸水溶液,调节体系pH值在5-7,过滤除去析出的脂肪酸;
(6)向滤液中继续边搅拌边滴加无机酸水溶液,调节体系pH值在1-2,进行减压抽滤,水洗至滤液呈中性,将得到的固体烘干,再将烘干的固体置于有机溶剂B中进行重结晶,得到脂肪酰凝血酸;
(7)用溶剂将脂肪酰凝血酸溶解,与金属M的氧化物、氢氧化物或无机盐溶液进行成盐反应,再经分离、洗涤或干燥,得到脂肪酰凝血酸盐。
6.权利要求5所述的制备方法,所述步骤(1)中的凝血酸与水的质量比为(14-18)∶100,水与有机溶剂A的体积比为1∶(1-3),有机溶剂A选自乙醇、丙酮、四氢呋喃。
7.权利要求5所述的制备方法,所述步骤(2)中的碱性水溶液选自KOH水溶液、NaOH水溶液、K2CO3水溶液、Na2CO3水溶液,所述步骤(5)中的无机酸水溶液为稀盐酸、稀硫酸。
8.权利要求5所述的制备方法,所述步骤(6)中的有机溶剂B选自石油醚、乙醇、四氢呋喃,所述步骤(7)中的溶剂选自水、乙醇,所述步骤(7)中的溶液选自KOH、NaOH、K2CO3、Na2CO3的水溶液或乙醇溶液。
9.权利要求1-4任一所述的脂肪酰凝血酸盐在日化领域中的应用,所述脂肪酰凝血酸盐作为表面活性剂使用,发挥清洁、乳化或分散的功能。
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