CN101500550A - 增强促弹性活性的组合物 - Google Patents
增强促弹性活性的组合物 Download PDFInfo
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- CN101500550A CN101500550A CNA2007800296579A CN200780029657A CN101500550A CN 101500550 A CN101500550 A CN 101500550A CN A2007800296579 A CNA2007800296579 A CN A2007800296579A CN 200780029657 A CN200780029657 A CN 200780029657A CN 101500550 A CN101500550 A CN 101500550A
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Abstract
公开了用于在怀孕的最后三个月过程中改善阴道和会阴弹性的组合物,其包括将硫醇盐化合物或其混合物与有机酸的酯或其混合物组合。本发明的组合物在增加延展性和弹性回复更快的两个方面都改善阴道的和/或会阴组织的弹性。本发明的组合物可以降低生产过程中会阴组织创伤的危险,以及降低作为分娩后的短期/中期/长期并发症的直肠或膀胱失禁的危险。
Description
发明领域
本发明涉及可用于增强对阴道和/或会阴组织的促弹性性能的组合物,其包括与有机酸的酯结合的硫醇盐化合物。
发明背景
在本领域中,具有游离SH基团的硫醇盐化合物以及具有由官能团封端的S原子的硫醇盐化合物都具有通过打破二硫键而引起蛋白质分子的延展性增强来降低蛋白质结构刚性的能力。这种结果是通过作用于三级和四级结构实现的,而不影响一级和二级结构,因此是可逆的。这种作用是充分已知的,并且其被应用于两个大的领域,如在人类中治疗支气管炎、降低痰液粘度和在急性和慢性支气管炎中都可以改善支气管和气管的廓清;另一方面,其在美容产业中被用于改善具有皱纹或条纹的受试者的皮肤柔软性。事实上,在作为皮肤主要成分的角蛋白的结构中富含二硫键,是由于氨基酸链中的两个不相邻的半胱氨酸(cisteine)之间的相互作用的结果。在痰液中情况也是这样,其组分也是富含二硫键。通过将-SS-桥还原为两个-SH游离基团来破坏二硫键,使得蛋白质通过失去由于共价键产生的刚性而得以伸展。另一方面,这种现象是可逆的,事实上,两个SH游离基团可以再相互作用并且形成-SS-桥。
醇和有机酸的酯是本领域中已知的,并且被用作皮肤护理和营养物用于预防和减少拉伸斑纹。它们充分地起作用,并且同时保持主动软化和促弹性的实质的润肤作用。甘油三酯是甘油的酯,其生理学存在于动物和植物组织中。所述酯由碳原子链为6-18个碳原子的有机脂肪酸组成,并且可以是饱和的或不饱和的,所述不饱和主要是单不饱和、双不饱和、或三不饱和。链长和双键的存在影响脂肪酸及其酯的熔点。降低熔点使得这些化合物为半固体或液体状态,可由于它们的润肤和润湿性能而有用。胆固醇酯是胆固醇与脂肪酸的酯,其也是天然存在的,主要存在于动物的脂肪和神经组织中。它们还由于其润肤性能而被用于制备乳膏剂和软膏。植物甾醇酯是蔬菜中的对应物,其中作为植物油成分的植物甾醇酯中的甾醇组分是β-谷甾醇、菜油甾醇、和豆甾醇。植物油植物甾醇酯的这些组分已经由于其润肤性能而作为皮肤护理产品的化妆品中的成分存在,因此它们具有与胆固醇酯和甘油三酯类似的预定用途。在酯与甾醇的组合物中的脂肪酸也具有6-18个碳原子,可以是饱和的或不饱和(主要是单不饱和、双不饱和、或三不饱和)的脂肪酸。醇和有机酸的酯可以是合成的,例如肉豆蔻酸异丙酯和棕榈酸异丙酯。肉豆蔻酸异丙酯是异丙醇和肉豆蔻酸(饱和的14碳脂肪酸)的酯,其广泛用于美容和制药工业,也用于阴道制备物。
本发明的组合物包含至少硫醇盐化合物和有机酸的酯,其协同地起作用以便在增强延展性和弹性回复方面改善组织弹性。这个特征对于在怀孕的最后三个月过程中增强阴道的远端部分和会阴组织的弹性是很重要的。由于在生产的排出阶段过程中的过分伸展,自然分娩经常发生会阴组织的撕裂。短期-中期的并发症是在30-50%的女性中发生经常疼痛、性交疼痛和尿失禁(Lukacz ES等人,Obst Gynecol.2006;Olsen LO等人Obstet.Gynecol.1997)。
进行外阴切开术可能在撕裂的几率和严重程度方面减少自发的撕裂,但是也不能避免并发症,如产后女性的性交疼痛和直肠失禁。根据新近的系统性证据复查,尽管在美国在大约30-35%的阴道生产中进行了外阴切开术,但是对于严重的阴道或会阴创伤、性交疼痛或尿失禁来说没有发现统计上显著的差异(ACOG Practice Bulletin.Episiotomy.Clinical Management Guidelines for Obstet.Gynecol.2006)。
在怀孕的最后一周进行会阴按摩是本领域中已知的作法,使得所述组织为自然分娩过程中增加的对伸展的要求做好准备。在生产之前的最后6-8过程中进行十-十五分钟的按摩,大体上是每天一次或每周三次进行。使用杏仁油作为润滑剂。这种作法的有效性是有争论的:根据文献,进行会阴按摩能够改善会阴组织的延展性,在未经历过阴道生产的女性中显著降低需要缝合的创伤发生率和外阴切开术的数量,但是与没有经过会阴按摩的女性相比发生1度或2度会阴撕破或3度到4度会阴创伤的发生率没有差异(Beckmann MM等人,Birth2006)。
发明内容
现在已经表明,包含至少硫醇盐化合物和有机酸的酯以及适当的赋形剂的组合物通过两种组分(即,硫醇盐化合物和有机酸的酯)的协同作用改善皮肤的弹性。此外,定期应用包含至少硫醇盐化合物和有机酸的酯以及适当的赋形剂的组合物能够增加阴道远端部分和会阴组织的弹性。
所述组合物优选为乳膏剂、软膏、凝胶剂或洗液的形式,并且优选通过会阴按摩局部施用,以便增加成分深入渗透到会阴组织中,以及调理阴道和会阴的肌肉适应生产时的排出阶段。
所述组合物包含相对于组合物的总重量的比例为0.1-25重量%、优选0.5-15重量%、更优选1.0-10重量%的至少硫醇盐化合物。所述硫醇盐化合物优选为含硫的氨基酸,更优选为半胱氨酸的衍生物,最优选为羧甲基半胱氨酸的盐。根据一个优选实施方案,所述含硫氨基酸选自1-甲硫氨酸、1-半胱氨酸、1-胱氨酸、牛磺酸、4-噻唑烷羧酸、羧甲基半胱氨酸和/或甲基磺酰基甲烷(sulphonylmethane)、或其生理学可接受的盐。
所述组合物包含相对于组合物的总重量的比例为1-95重量%、优选5-70重量%、更优选10-45重量%的至少有机酸的酯。所述有机酸的酯优选为甘油的酯或动物或植物甾醇(例如胆固醇)的酯、或其混合物。
所述有机酸包含2-30个碳原子,优选6-18个碳原子,更优选12-18个碳原子。所述有机酸是饱和的或不饱和的。
所述组合物根据常规方法制备并且可以包括相容的赋形剂和药学可接受的载体,例如离子化剂、抗氧剂、螯合剂、增湿剂、减充血剂、消毒剂和/或抗微生物剂、调味剂和着色剂。
所述组合物也可以组合地包含具有互补活性或任何有用活性的其它活性成分。根据本发明制备的这些组合物的实例包括:乳膏剂、软膏、凝胶剂、洗液或泡沫剂。
下面通过以下实施例更完全地描述本发明的药物组合物和应用。然而,需要指出的是,这种实施例只是用于说明而非用于限制。
具体实施方式
实施例1
制备具有以下w/w%组成的脂质凝胶(=均质的疏水性软膏)制剂:
1)赖氨酸羧甲基半胱氨酸盐1 5.00%
2)聚甘油基-3蜂蜡2 7.50%
3)Prunus amygdalus var.dulcis3 12.00%
4)维生素E、卵磷脂、棕榈酸抗坏血酸酯、
柠檬酸4 0.05%
5)矿脂5 15.00%
6)氢化蓖麻油6 2.00%
7)液体石蜡7 调节到100.00%
2Cera Bellina(其中游离脂肪酸已经转化为聚甘油酯的蜂蜡的亲水性衍生物);3Sweet Almond Oil(包含约65%的油酸甘油酯);4Aperoxid TLA;5白色软石蜡;HR Powder(主要由羟基硬脂酸(C18)的甘油三酯组成);7Pharma 55
将液体石蜡、聚甘油基-3蜂蜡、Prunus amygdalus var.dulcis、Aperoxid TLA和矿脂在涡轮乳化器中混合并且在70℃加热。在物质熔化时,在适度的搅拌下加入氢化蓖麻油,直到完全分散。
然后将熔融的物质在45℃冷却并且在搅拌下加入赖氨酸羧甲基半胱氨酸盐,直到得到均质的凝胶。
得到的凝胶包含21.50%的本发明的酯,其外观为乳白色并且为均质的。
实施例2
制备具有以下w/w%组成的脂质凝胶(=均质的疏水性软膏)制剂:
1)赖氨酸羧甲基半胱氨酸盐 7.50%
2)聚甘油基-3蜂蜡 5.00%
3)乙酰化羊毛脂* 2.00%
4)维生素E、卵磷脂、棕榈酸抗坏血酸酯、
柠檬酸 0.05%
5)矿脂 38.50%
6)液体石蜡 14.00%
7)氢化蓖麻油 3.00%
8)大豆油** 调节到100.00%
*ModulanTM羊毛脂衍生物(Noveon)乙酰化羊毛脂醇;**在甘油酯中包含亚油酸(50-57%)、亚麻酸(5-10%)、油酸(17-26%)、棕榈酸(9-13%)、和硬脂酸(3-6%)。
得到的凝胶包含39.95%的本发明的酯。
使用与实施例1中所述相同的方法制备制剂。
实施例3
制备具有以下w/w%组成的脂质凝胶(=均质的疏水性软膏)制剂:
1)赖氨酸羧甲基半胱氨酸盐 5.00%
2)聚甘油基-3蜂蜡 5.00%
3)Prunus amygdalus var.dulcis 12.00%
4)维生素E、卵磷脂、棕榈酸抗坏血酸酯、
柠檬酸 0.10%
5)矿脂 15.00%
6)植物甾醇酯* 15.00%
7)氢化蓖麻油 3.50%
8)二氧化硅 1.50%
9)液体石蜡 调节到100.00
*Vegapure(Cognis)
得到的凝胶包含35.5%的本发明的酯。
使用与实施例1中所述相同的方法制备制剂。
实施例4
制备具有以下w/w%组成的脂质凝胶(=均质的疏水性软膏)制剂:
1)赖氨酸羧甲基半胱氨酸盐 5.00%
2)聚甘油基-3蜂蜡 7.50%
3)Prunus amygdalus var.dulcis 7.00%
4)肉豆蔻酸异丙酯* 5.00%
5)维生素E、卵磷脂、棕榈酸抗坏血酸酯、
柠檬酸 0.10%
6)矿脂 15.00%
7)氢化蓖麻油 4.50%
8)二氧化硅 1.50%
9)液体石蜡 调节到100.00%
*Crodamol IPM(Croda,异丙醇和肉豆蔻酸(饱和的C14脂肪酸)的酯)
得到的凝胶包含24.00%的本发明的酯。
使用与实施例1中所述相同的方法制备制剂。
实施例5:
制备具有以下w/w%组成的脂质凝胶(=均质的疏水性软膏)制剂:
1)L-甲硫氨酸 5.00%
2)合成的蜂蜡* 8.50%
3)Prunus amygdalus var.dulcis 12.00%
4)维生素E、卵磷脂、棕榈酸抗坏血酸酯、
柠檬酸 0.05%
5)矿脂 15.00%
6)氢化蓖麻油 4.00%
7)二氧化硅 2.50%
8)印度楝树油** 1.00%
9)芝麻籽油*** 2.00%
10)液体石蜡 调节到100.00%
*Syncrowax BB4(Croda)
**包含亚油酸、油酸、棕榈酸和硬脂酸的甘油三酯的混合物
***包含花生酸(0.8%)、亚油酸(40.4%)、油酸(45.4%)、棕榈酸(9.1%)、和硬脂酸(4.3%)的甘油酯。
得到的凝胶包含27.50%的本发明的酯。
使用与实施例1中所述相同的方法制备制剂。
实施例6:
制备具有以下w/w%组成的脂质凝胶(=均质的疏水性软膏)制剂:
1)甲磺酰甲烷(Methylsulfonyl 5.00%
methane)
2)合成的蜂蜡 5.00%
3)Prunus amygdalus var.dulcis 12.00%
4)维生素E、卵磷脂、棕榈酸抗坏血酸
酯、柠檬酸 0.10%
5)矿脂 15.00%
6)氢化植物油* 3.50%
7)二氧化硅 1.50%
8)液体石蜡 调节到100.00%
得到的凝胶包含20.50%的本发明的酯。
使用与实施例1中所述相同的方法制备制剂。
实施例7
制备具有以下w/w%组成的脂质凝胶(=均质的疏水性软膏)制剂:
1)赖氨酸羧甲基半胱氨酸盐 5.00%
2)合成的蜂蜡 5.00%
3)Prunus amygdalus var.dulcis 6.00%
4)维生素E、卵磷脂、棕榈酸抗坏血酸酯、
柠檬酸 0.10%
5)矿脂 15.00%
6)羊毛脂醇* 3.50%
7)羊毛脂USP** 6.00%
8)二氧化硅 1.50%
9)液体石蜡 调节到100.00%
*Super Hartolan(Croda,药物级羊毛脂的富含胆固醇的固体部分);**MedilanTM(Croda,包含胆固醇和几种脂肪酸的酯的混合物
得到的凝胶包含20.50%的本发明的酯。
使用与实施例1中所述相同的方法制备制剂。
实施例8
对比性临床试验
已经对健康志愿者进行了临床研究,目的是研究3种不同的组合物与由白色软石蜡组成的标准对照产品相比在急性试验中的促皮肤弹性活性。研究的目的是将包含硫醇盐化合物(如羧甲基半胱氨酸盐)以及脂肪酸和甘油的酯的混合物的制剂与包含单独的硫醇盐化合物或单独的酯混合物的不同制剂进行活性比较。
所述志愿者是21名女性,年龄为24-55岁(平均45岁)。每个产品通过温和的按摩随机施用一次在前臂的手掌表面上。如SparavignaA,Setaro M,Misurazione delle proprietà meccaniche della cutemediant emetod id itorsione,“Diagnostica non invasiva indermatologia”a cura di Stefania Seidenari,EDRA MedicalPublishing & New Media,Milano,1998,第323-328页中所述通过用Dermal Torque Meter(Dia-Stron LTD)测量扭转力(torsiometry)在基线和施用每种产品之后的30分钟进行弹塑性测量。
这个方法的主要原理在于利用存在于通过双面胶带粘附于皮肤的两个同心圆中的装置在活体中在皮肤表面上进行扭转。两个圆之间的距离(1mm)限制了发生扭转的区域。内圆通过相对于外圆旋转而对皮肤施加恒定的扭矩,其在皮肤的对抗作用力平衡所述施加的扭转力矩(9mNm)时停止。扭转的持续时间是1秒。所述装置测量在机械诱导时期以及其停止时的扭转角θ。
通过a.m.技术测量的参数是弹性回复和皮肤弹性,其如下测量:
Ue:瞬间延展性
Uf:最大延展性
Uv:粘弹性
Ur:瞬间弹性恢复
Ur/Ue:弹性回复
Ur/Uf:皮肤弹性
Uv/Uc:粘度
τon和τoff时间在曲线“继续(go on)”和“返回(go back)”上为恒定的。
使用的组合物如下:
产品1:脂质凝胶LPOL514,实施例1的组合物
产品2:水凝胶LPOL513,具有如下的w/w%组成:
1)赖氨酸羧甲基半胱氨酸盐1 7.50%
2)对羟基苯甲酸丙酯钠 0.04%
3)对羟基苯甲酸甲酯钠 0.37%
4)咪唑烷基脲2 0.20%
5)EDTA二钠 0.10%
6)羟乙基纤维素3 1.50%
7)角叉菜胶4 5.00%
8)柠檬酸 调节到pH5.5
9)水 调节到100.00%
产品3:水凝胶LPOL520,具有如下的w/w%组成:
1)氢化大豆磷脂酰胆碱1 1.03%
2)胆固醇USP 0.26%
3)丁羟茴醚(BHA) 0.10%
4)抗坏血酸 7.10%
5)甘油 5.00%
6)EDTA二钠2 0.10%
7)对羟基苯甲酸甲酯钠3 0.37%
8)对羟基苯甲酸丙酯钠4 0.04%
9)咪唑烷基脲5 0.21%
10)羟乙基纤维素6 0.70%
11)黄原胶7 1.00%
12)水 调节到100.00%
1LipoidS 100-3;2Dissolvine NA-2;3Nipagin M sodium;4NipasolM sodium;5Gram 1;6Natrosol 250M;7Rhodigel Ultra
产品4:参照标准,具有以下组成:
1)矿脂(=白色软石蜡)CAS n°8009-03-8 100%
结果概括在以下表1中:
表1:在21名健康志愿者的前臂皮肤上施用不同的研究产品或对
照产品之后30分钟得到的扭转力参数相对于基线的百分比改变
(Student′检验)。
扭转力参数 | 产品1脂质凝胶LPOL514 | 产品2水凝胶LPOL513 | 产品3阴道用凝胶POL520 | 产品4对照 |
Ur/Uf皮肤弹性 | +24%** | +1% | -4% | +13%* |
Ur/Ue弹性回复 | +23%*** | -1% | 0% | +13%* |
*相对于基线P<0.05
**相对于基线P<0.01
***相对于基线P<0.001
结果表明,在产品1和2中包含的硫醇盐化合物与在产品1、3、和4中包含的酯有协同的活性。事实上,在两种主要组分(硫醇盐化合物和酯)如在产品2(无活性)或产品3(无活性)中单独存在时,或在产品4中(对照白色软石蜡,具有轻微的活性),促弹性活性不存在或轻微存在(不高于13%)。相反地,在将硫醇盐化合物和酯合并在同一制剂中时,如在产品1中,得到的促弹性活性强(弹性+24%,弹性回复+23%)并且优于单独的酯所得到的促弹性活性。实现的作用是协同的,组合优于单独两种成分之和。
实施例9
对比性临床试验
已经对孕妇进行了临床研究,目的在于研究在怀孕的最后两个月过程中定期施用实施例3的制剂对会阴组织的促弹性活性和预防生产过程中会阴的创伤性损伤的能力。研究是开放的,相对于历史组进行比较。
总的说来,在这项研究中包括36名孕妇。所有的女性都是初产孕妇(第一次怀孕),它们中没有一个处于需要剖腹分娩的危险中。从第30周开始,通过每天进行定期的会阴按摩施用产品,直到自然分娩。产品的施用(2-5g)如下进行:用制剂润湿会阴,然后通过在阴唇上和在阴道的远端部分上的圆周运动进行温和的按摩,持续约15分钟。
在生产时评价的参数为:由妇科医生判断的表示为从0(没有)到100(最大)的视觉相似性比例(VAS)的延展性和弹性回复、外阴切开术的百分比、撕裂的比例和程度、不利事件和效力的总体判断。
结果如下:延展性为平均±SD 78.81±8.59,弹性回复为78.04±12.4,没有进行外阴切开术,8.3%的I度撕裂,没有II度或III度撕裂。将外阴切开术和/或会阴撕裂的结果与425名自然生产的历史组相比较,包括了在整个2004年在同一研究中心进行的所有生产。数据概括在以下表2中。
表2:与历史组女性相比的研究组的自然分娩过程中外阴切开术
和撕裂的比例
2004年的自然生产(%,n=425) | 研究组(%,n=36) | |
外阴切开术 | 23.3 | 0 |
1度撕裂(涉及外阴阴道粘膜和会阴皮肤) | 22.8 | 8.3 |
2度撕裂(涉及会阴肌肉和会阴筋膜) | 11.5 | 0 |
3度撕裂(涉及肛门括约肌) | 0.8 | 0 |
作出的结论是,所述产品对于改善会阴的弹性以及预防生产过程中会阴组织的创伤性并发症非常有效。
Claims (15)
1.以下物质:
a)至少硫醇盐化合物,和
b)至少有机酸的酯或其混合物;
用于生产局部用组合物的用途,所述局部用组合物用于改善孕妇的阴道和会阴的促弹性化。
2.权利要求1的用途,其中组分a)选自含硫氨基酸及其衍生物。
3.权利要求1的用途,其中所述组分a)选自1-甲硫氨酸、1-半胱氨酸、1-胱氨酸、牛磺酸、4-噻唑烷羧酸、羧甲基半胱氨酸和/或甲基磺酰基甲烷、或其生理学可接受的盐。
4.权利要求1的用途,其中组分a)以0.1-25重量%的量存在。
5.权利要求1的用途,其中组分a)以0.5-15重量%的量存在。
6.权利要求1的用途,其中组分a)以1.0-10重量%的量存在。
7.权利要求1的用途,其中组分b)是甘油的酯或动物甾醇或植物甾醇的酯、或其混合物。
8.权利要求7的用途,其中所述甾醇是胆固醇。
9.权利要求1的用途,其中所述有机酸包含2-30个碳原子,优选6-18个碳原子,更优选12-18个碳原子。
10.权利要求1的用途,其中所述有机酸是饱和的或不饱和的。
11.权利要求1的用途,其中组分b)以1.0-95重量%的量存在。
12.权利要求1的用途,其中组分b)以5-70重量%的量存在。
13.权利要求1的用途,其中组分b)以10-45重量%的量存在。
14.权利要求1的用途,其特征在于包括一种或多种药学可接受的赋形剂。
15.权利要求14的用途,其中所述赋形剂选自:离子化剂、抗氧剂、螯合剂、增湿剂、热粘化剂(thermoviscosizing agents)、减充血剂、消毒剂、和/或抗微生物剂、调味剂和着色剂。
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PCT/EP2007/053793 WO2008017521A2 (en) | 2006-08-09 | 2007-04-18 | Compositions with enhanced elasticizing activity |
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US4296130A (en) * | 1979-08-30 | 1981-10-20 | Herschler R J | Methylsulfonylmethane and methods of use |
GB9213472D0 (en) * | 1992-06-25 | 1992-08-12 | Unilever Plc | Cosmetic composition |
WO1995034280A1 (en) * | 1994-06-15 | 1995-12-21 | The Procter & Gamble Company | Methods of lightening hyperpigmented regions in mammalian skin |
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US20050266064A1 (en) * | 2004-05-29 | 2005-12-01 | Mccarthy Kathryn J | Cosmetic compositions and methods |
US20060088496A1 (en) * | 2004-10-25 | 2006-04-27 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Personal care compositions with salts of hydroxypropyl trialkylammonium substituted mono-saccharide |
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