CN103930089B - 口腔护理组合物 - Google Patents
口腔护理组合物 Download PDFInfo
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- CN103930089B CN103930089B CN201280057118.7A CN201280057118A CN103930089B CN 103930089 B CN103930089 B CN 103930089B CN 201280057118 A CN201280057118 A CN 201280057118A CN 103930089 B CN103930089 B CN 103930089B
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- Prior art keywords
- calcium carbonate
- total weight
- abrasive
- oral care
- particulate calcium
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Abstract
本发明提供了一种口腔护理组合物,其包含:(a)包含水或多元醇或其混合物的连续相,和(b)由初级颗粒组成的微粒碳酸钙磨料,所述初级颗粒是针状的并且具有2微米或更大的长度;其中微粒碳酸钙磨料的含量为10-70%,优选20-60%,更优选30-40%,基于组合物的总重量以微粒碳酸钙的总重量计。本发明的组合物显示出令人满意水平的清洁,但不过度磨损和对牙齿造成损害。
Description
发明领域
本发明涉及口腔护理组合物。更具体地,本发明涉及包含碳酸钙作为磨料的口腔护理组合物,并且具有低磨损性同时保持理想的清洁性能。
背景技术
用于口腔护理组合物例如洁齿剂的磨料要求能够有效移除外来污渍、牙菌斑和在牙齿表面表膜上积聚的食物残渣。
通常,污渍、牙菌斑和食物残渣的物理移除效率可以通过使用具有增强的磨损性的磨料来提高。然而,增强的磨损性也增加了牙齿表面可能被破坏的危险。
因此,对于表明令人满意水平的清洁但又不过度磨损和对牙齿造成破坏的口腔护理组合物存在持续不断的需求。
本发明人已经发现这一问题可以通过使用具有特定粒径和形状的碳酸钙磨料解决。
US4,743,274涉及改性晶体形态以提供高清洁性、低磨损磨料用于口腔组合物。其描述了在由无水磷酸氢钙(仲无水磷酸钙)组成的磨料的情况下,降低平均晶体尺寸如何制备符合满足高牙齿清洁能力和低牙齿表面磨损性二者的要求的材料。
US2004/0161388提及了碳酸钙材料的洁齿剂相关性能是如何与其形态和粒径相关,并且描述了小的偏三角面形状的碳酸钙颗粒是如何倾向于具有相对不显著的清洁效果,而大的菱形(有时称为“立方体”)碳酸钙颗粒具有增加的清洁性和磨损益处,但通常磨损过大:它们的磨损性导致可能破坏牙齿和牙龈的问题。作为这一问题的一个解决方案,US2004/0161388提出了一种具有约1-4微米的初级粒径的磨损性、沉淀碳酸钙。这些初级颗粒本身可以聚在一起并且通过共价键彼此结合形成具有约3-10微米粒径的聚集体。该材料具有方解石晶体形式和基本上立方晶体结构。
发明概述
本发明提供了一种口腔护理组合物,其包含:
(a) 包含水或多元醇或其混合物的连续相,和
(b) 由初级颗粒组成的微粒碳酸钙磨料,所述初级颗粒是针状的并且具有2微米或更大的长度;
其中微粒碳酸钙磨料的含量为10-70%,优选20-60%,更优选30-40%,基于组合物的总重量以微粒碳酸钙的总重量计。
发明详述
微粒碳酸钙磨料
本发明的组合物尤其包含一种由具有如上所述的特定形状和尺寸的初级颗粒组成的微粒碳酸钙磨料。
“初级颗粒”是指单独的颗粒。为了本发明的目的,微粒碳酸钙磨料的初级颗粒是针状的并且具有2微米或更大的长度。
初级颗粒可以在某些条件下联合以形成更大的二级结构例如聚集体或团聚体。
如果需要,可以对初级颗粒进行表面改性,例如通过用疏水性材料,如乙基纤维素、羟丙基纤维素、蜡(如虫胶,巴西棕榈蜡或蜂蜡)和脂肪或脂肪酸(如硬脂酸和油酸)涂覆。涂覆可以使用例如利用溶剂或温度变化的胶体沉淀来实现。
为了本发明的目的,合适种类的微粒碳酸钙磨料包括结晶碳酸钙,其中晶体是针状的并且具有2微米或更大的长度。
术语“晶体”是指由以通过平面表面(其是内部结构的外在表现)限制的有序重复阵列排列的原子组成的基本上完全致密的固体。
碳酸钙可以天然存在或可以以三种特别的结晶形态(方解石、霰石以及较少见的球霰石)合成制备。球霰石形式的碳酸钙是亚稳定的并且不可逆地转变成方解石和霰石。对于这些结晶形式中的每一个,存在许多不同的多晶型(晶体习性)。方解石结晶形态是最常用的碳酸钙晶体形式。在文献中已经报道了超过300种方解石的结晶形式。
在上下文中,术语“针状的”是指晶体的形状。通常,晶体在三个方向(长、宽和高)上生长。然而一些晶体具有一个或多个优选的生长方向。针状晶体在一个方向上具有优选的晶体生长。实例为呈针、棒、纤维、晶须或柱等形式的晶体。为了本发明的目的,优选的针状晶体是具有通常均匀的,典型地通常圆形的,横截面形状的棒状或针状。
对于针状晶体,晶体长度和宽度之间的比,所谓的长径比高于1:1。长径比越高,晶体越长。为了本发明的目的,所述长径比优选为至少2.5:1,更优选至少10:1。例如,所述长径比可以通常为2.5:1至200:1,和优选为10:1至60:1,更优选为20:1至30:1。
针状结晶形式的碳酸钙是天然可获得的,也可以通过沉淀制备技术制备。通常,沉淀碳酸钙是通过将氢氧化钙浆料暴露于碳化反应制备的。
用于本发明的优选的针状碳酸钙晶体具有2-100微米的长度,更优选10-30微米和0.1-4.0微米的宽度,更优选0.5-1.0微米。
晶体形态和结构可以通过本领域技术人员已知的标准技术例如扫描电子显微术(SEM)测定。SEM是基于检测当通过扫描电子束照射时由材料发出的电子和X-射线的成像和分析技术。成像允许用户区别初级颗粒和团聚体尺寸。
使用计算机软件的自动图像分析使得用户能够测定粒径分布。扫描电子显微术(SEM)是一种颗粒计数技术并且产生了数加权的粒径分布。因此,本文提到的对于颗粒长度和宽度的数字将通常表示大量颗粒的平均值,更具体地分别表示颗粒长度或颗粒宽度的D[1,0]数长平均。
适用于本发明的一种具体类别的材料包括霰石晶体形式碳酸钙,如那些例如在US5164172中描述的。根据US5164172,具有针状形状的霰石晶体形式碳酸钙通过以下步骤制备:将霰石碳酸钙和Ca(OH)2预混以制备水性浆料,将水可溶的磷酸化合物(例如磷酸或其水溶性盐)加入到水性浆料中,和将CO2气体引入到水性浆料中以引起发生碳化反应。在该方法中,霰石碳酸钙与Ca(OH)2浆料的摩尔比优选为1:7至1:5000。得到的霰石碳酸钙晶体具有针状形状并且具有10-100微米(长度)乘以0.5-4.0微米(宽度)的颗粒尺寸。示例的晶体通过显微镜显示呈具有10-100微米长度的棒状或针状。所述棒或针通常是均匀的并且通常在横截面上为圆形,横截面直径为0.5-4.0微米。为了本发明的目的,最优选的霰石碳酸钙晶体是如上所述的棒状或针状,具有10-30微米的长度,0.5-1.0微米的宽度并且长径比为20:1至30:1。
适用于本发明的霰石晶体形式碳酸钙是可商购的并且包括由Maruo Calcium Company Limited,日本以商品名WHISCAL®销售的那些。
也可以使用任何上述材料的混合物。
微粒碳酸钙磨料(如上所述)的含量通常为10-70%,优选20-60%,更优选30-40%,基于组合物的总重量以微粒碳酸钙磨料(如上所定义)的总重量计。
本发明的口腔护理组合物展现了令人满意水平的清洁性,又不过度磨损和对牙齿造成损害。本发明的口腔护理组合物的另一个优点是它们对于用于假牙架、假牙和其它形式的人工牙齿(其由比天然牙釉质软得多的聚合物,例如丙烯酸树脂(PMMA)制成)足够温和。
本发明组合物的清洁能力水平可以通过评估其在积累薄膜上的效果测量,例如通过使用例如由Pickles等描述的方法(International Dental Journal 55 (2005), 第197–202页)。该模型使用包埋在甲基丙烯酸酯树脂中的从牛门牙上切下的釉质板。将釉质表面使用在玻璃块上的氧化铝糊状物用手来打光(smooth)并且轻微酸蚀以促进污渍积累和粘着。釉质块放置在设置为50℃恒定温度的培养箱中并且缓慢旋转以在染色肉汤(由茶、咖啡和粘蛋白组成)和空气干燥之间交替。每天变换肉汤并且五天后取出该板并且用蒸馏水洗涤以移除任何松散残渣。随后将玷污的板在机械刷洗机中用蒸馏水刷洗以移除任何松散粘结的污渍。随后将它们干燥并且用L*a*b*模式的色度计测量CIE L*a*b*颜色体系的L*值(L*玷污)。为了评价清洁性能,随后将玷污的样品安置在机械刷洗机上并且将所需的载荷施加到每一个刷子上。将测试组合物分散在水性稀释剂中以形成浆料(通常38.5g测试组合物和61.5g的蒸馏水)并且一组数目的洗刷行程用10ml的浆料刷洗玷污的样品。在洗刷之后,用蒸馏水冲洗釉质板,干燥并且再次测量L*值(L*洗刷)。在最后阶段,使用研磨/抛光机在软布上使用浮石粉从釉质板上移除所有污渍痕迹。随后用蒸馏水冲洗釉质板、干燥并且测量和记录L*值(L*浮石去污)。相比于通过浮石粉的完全移除,通过测试组合物移除的污渍的百分比(此后称为薄膜清洗率或PCR)可以使用以下等式计算:
PCR = [(L*洗刷)-(L*玷污)/ (L*浮石去污)-(L*玷污)] x 100。
本发明的组合物优选具有至少30%,更优选至少40%,最优选至少50%的PCR值。
本发明组合物的磨损性水平可以评价其放射性牙质磨损测试(RDA)值。测量这些值的标准测试程序遵循美国牙医协会推荐的洁齿剂磨损性评价方法(Journal
of Dental Research 55(4) 563, 1976)。在该程序中,用中子流照射提取的人类牙齿并且使其经受标准洗刷制度。在根部从牙质移除的放射性磷32被用作测试组合物的磨损指数。还测量了在50cm3的0.5%的羧甲基纤维素钠水溶液中包含10g焦磷酸钙的参考浆料并且该混合物的RDA被任意地(arbitrarily)取为100。为了测量测试组合物的RDA,制备了25g测试组合物在40 cm3水中的浆料并且进行相同的洗刷制度。
本发明的组合物优选具有不超过100的RDA值,更优选不超过80,最优选不超过60。
本发明的组合物优选具有至少0.5的PCR:RDA比,更优选至少0.6,最优选至少0.8。
产品形式
在本发明的上下文中的优选类型的产品形式是洁齿剂。术语“洁齿剂”表示用于清洁口腔表面的组合物。洁齿剂是一种口腔组合物,其不意在吞服用于治疗剂全身给药的目的,而是在口腔中保留足够的时间以充分接触所有的牙齿表面和/或粘膜组织用于口腔活动的目的。优选地,洁齿剂适于使用牙刷施加并且在使用后冲洗掉。优选地,所述洁齿剂呈可挤出的半固体形式,例如膏状、糊剂或凝胶(或它们的混合物)。
基于洁齿剂的总重量,根据本发明的洁齿剂组合物将通常包含40-99wt%的液体连续相。这种液体连续相将通常包含水与多元醇的多种相对量的混合物,水的量通常为10-45wt%(基于洁齿剂的总重量),多元醇的量通常为30-70%(基于洁齿剂的总重量)。典型的多元醇包括湿润剂,例如甘油、山梨醇、聚乙二醇、聚丙二醇、丙二醇、木糖醇(和其它可食用的多元醇)、氢化的部分水解的多糖和它们的混合物。
根据本发明的洁齿剂组合物将通常包含另外的成分以提高性能和/或消费者的接受度。
例如,所述洁齿剂可以包含其它磨料材料(除了上述微粒碳酸钙磨料之外的)。基于洁齿剂的总重量,这种其它磨料材料将通常以3-75wt%的量存在。合适的其它磨料材料包括磨料二氧化硅、其它碳酸钙(其不同于上述微粒碳酸钙磨料)、磷酸二钙、磷酸三钙、煅烧氧化铝、偏磷酸钠和偏磷酸钾、焦磷酸钠和焦磷酸钾、三偏磷酸钠、六偏磷酸钠、微粒羟基磷灰石和它们的混合物。
此外,基于洁齿剂的总重量,所述洁齿剂将通常包含0.5-10wt%的粘合剂或增稠剂。合适的粘合剂或增稠剂包括羧乙烯基聚合物(例如用聚烯丙基蔗糖或聚烯丙基季戊四醇交联的聚丙烯酸)、羟乙基纤维素、羟丙基纤维素、纤维素醚的水可溶性盐(例如羧甲基纤维素钠和羧甲基羟乙基纤维素钠)、天然树胶(如角叉菜胶、刺梧桐树胶、瓜尔胶、黄原胶、阿拉伯胶和黄蓍胶)、细碎二氧化硅、锂蒙脱石、胶态硅酸镁铝和它们的混合物。
此外,基于洁齿剂的总重量,所述洁齿剂通常将包含0.2-5wt%的表面活性剂。合适的表面活性剂包括阴离子表面活性剂,例如以下物质的钠、镁、铵或乙醇胺盐:C8-C18烷基硫酸盐(例如十二烷基硫酸钠)、C8-C18烷基磺基琥珀酸盐(例如二辛磺化琥珀酸钠)、C8-C18烷基磺基乙酸盐(例如十二烷基磺基乙酸钠)、C8-C18烷基肌氨酸盐(例如十二烷基肌氨酸钠)、C8-C18烷基磷酸盐(其可以任选地包含最多10个氧化乙烯和/或氧化丙烯单元)和硫酸化单甘酯。其它合适的表面活性剂包括非离子表面活性剂,例如任选地聚乙氧基化脂肪酸山梨醇酯、乙氧基化的脂肪酸、聚乙二醇的酯、脂肪酸单甘油酯和二甘油酯的乙氧基化物、以及氧化乙烯/氧化丙烯嵌段聚合物。其它合适的表面活性剂包括两性表面活性剂,例如甜菜碱或磺基甜菜碱。也可以使用任何上述材料的混合物。
本发明的组合物(例如特别是洁齿剂)还可以包含本领域惯用的其它任选成分,例如氟离子源、抗牙结石剂、缓冲剂、调味剂、甜味剂、着色剂、遮光剂、防腐剂、抗过敏剂和抗微生物剂。
本发明将参照以下非限制性的实施例进一步阐明。
实施例
实施例
1
和对比实施例
A-G
制备了8种口腔护理组合物,掺入了一系列不同的微粒碳酸钙磨料。组合物的成分在以下表 1 和 2 中显示。实施例1表示了一种根据本发明的组合物。其余的组合物是对比实施例(非根据本发明的)。
表
1
成分 | 实施例 1 | 对比实施例 A | 对比实施例 B | 对比实施例 C |
水 | 至100 | 至100 | 至100 | 至100 |
山梨醇 | 21 | 21 | 21 | 21 |
增稠型二氧化硅 | 2.4 | 2.4 | 2.4 | 2.4 |
十二烷基硫酸钠 | 1.6 | 1.6 | 1.6 | 1.6 |
调味剂 | 1.2 | 1.2 | 1.2 | 1.2 |
单氟磷酸钠 | 1.09 | 1.09 | 1.09 | 1.09 |
磷酸三钠 | 1.07 | 1.07 | 1.07 | 1.07 |
二氧化钛(锐钛矿) | 1 | 1 | 1 | 1 |
羧甲基纤维素钠 | 0.7 | 0.7 | 0.7 | 0.7 |
糖精钠 | 0.27 | 0.27 | 0.27 | 0.27 |
尼泊金甲酯 | 0.15 | 0.15 | 0.15 | 0.15 |
尼泊金丙酯 | 0.05 | 0.05 | 0.05 | 0.05 |
碳酸钙棒(1) | 40 | - | - | - |
STURCAL® F(2) | - | 40 | - | - |
OMYACARB® 5-AV(3) | - | - | 40 | - |
VICRON® 食品级 45-3(4) | - | - | - | 40 |
(1) 沉淀碳酸钙 获自Maruo
Calcium Company Limited,由具有10-30微米长度和0.5-1.0微米直径的霰石棒/针组成。
(2) 沉淀碳酸钙 获自Speciality
Minerals Inc.,由针状霰石晶体的团聚体组成,晶体长度约为1微米或更小。所述团聚体具有约2.5微米的平均粒径(d50)(当量球径)。
(3) 研磨碳酸钙 获自Omya,其是来自Avenza ,意大利的细磨天然大理石,具有不规则菱形颗粒形状和5μm的中值粒径。
(4) 研磨碳酸钙 获自Speciality
Minerals Inc.,其是来自Adams,MA的细磨天然石灰石,具有不规则菱形颗粒形状和10.0微米的平均粒径。
表
2
成分 | 对比实施例 D | 对比实施例 E | 对比实施例 F | 对比实施例 G |
水 | 至100 | 至100 | 至100 | 至100 |
山梨醇 | 21 | 21 | 21 | 21 |
增稠型二氧化硅 | 2.4 | 2.4 | 2.4 | 2.4 |
十二烷基硫酸钠 | 1.6 | 1.6 | 1.6 | 1.6 |
调味剂 | 1.2 | 1.2 | 1.2 | 1.2 |
单氟磷酸钠 | 1.09 | 1.09 | 1.09 | 1.09 |
磷酸三钠 | 1.07 | 1.07 | 1.07 | 1.07 |
二氧化钛(锐钛矿) | 1 | 1 | 1 | 1 |
羧甲基纤维素钠 | 0.7 | 0.7 | 0.7 | 0.7 |
糖精钠 | 0.27 | 0.27 | 0.27 | 0.27 |
尼泊金甲酯 | 0.15 | 0.15 | 0.15 | 0.15 |
尼泊金丙酯 | 0.05 | 0.05 | 0.05 | 0.05 |
ViCALity®Extra Heavy(5) | 40 | - | - | - |
ViCALity® GF4(6) | - | 40 | - | - |
CalEssence® 450 (7) | - | - | 40 | - |
CalEssence® 1500 (8) | - | - | - | 40 |
(5) 沉淀碳酸钙 获自Speciality
Minerals Inc.,由群集的立方颗粒组成,所述群集的立方颗粒具有方解石晶体习性、立方颗粒形状和4.5微米的中值粒径。
(6) 研磨碳酸钙 获自
Speciality Minerals Inc.,具有不规则的菱形颗粒形状和4微米的中值粒径。
(7) 沉淀碳酸钙 获自
Speciality Minerals Inc.,由群集的立方颗粒组成,所述群集的立方颗粒具有方解石晶体习性、立方颗粒形状和4.5微米的中值粒径。
(8) 沉淀碳酸钙 获自
Speciality Minerals Inc.,由半正棱柱颗粒组成,所述半正棱柱颗粒具有方解石晶体习性、半正棱柱形状和12.0微米的中值粒径。
对于以上每一个组合物测量了PCR和RDA,并且计算了它们的比。PCR使用Pickles等的方法测量(International Dental Journal 55 (2005), 第197–202)。RDA使用由美国牙医协会推荐的洁齿剂耐磨评价方法测量(Journal of Dental Research 55(4) 563,
1976)。
结果在以下表3中显示。
测试组合物 | PCR | RDA | PCR:RDA |
实施例1 | 48 | 56 | 0.857 |
对比实施例A | 47 | 172 | 0.273 |
对比实施例B | 48 | 156 | 0.308 |
对比实施例C | 54 | 214 | 0.252 |
对比实施例D | 58 | 178 | 0.325 |
对比实施例E | 62 | 169 | 0.367 |
对比实施例F | 59 | 206 | 0.286 |
对比实施例G | 46 | 233 | 0.197 |
结果清楚地显示相比于对比实施例,实施例1具有出众的性能。实施例1的清洁性能(如通过PCR测量所表明的)不显著劣于任何对比实施例,但磨损性(如通过RDA测量所表明的)显著降低。
实施例
2
和对比实施例
H
制备了两种口腔护理组合物,掺入不同的微粒碳酸钙磨料。所述组合物的成分在以下表 4中显示。实施例2代表了根据本发明的组合物。另一个组合物是对比实施例(非根据本发明的)。
表
4
成分 | 实施例 2 | 对比实施例 H |
水 | 至100 | 至100 |
山梨醇 (70%) | 31.00 | 31.00 |
增稠型二氧化硅 | 7.1 | 7.1 |
十二烷基硫酸钠 | 1.6 | 1.6 |
调味剂 | 1.2 | 1.2 |
单氟磷酸钠 | 1.09 | 1.09 |
磷酸三钠 | 1.07 | 1.07 |
二氧化钛 (锐钛矿) | 1 | 1 |
羧甲基纤维素钠 | 1.0 | 1.0 |
糖精钠 | 0.27 | 0.27 |
尼泊金甲酯 | 0.15 | 0.15 |
尼泊金丙酯 | 0.05 | 0.05 |
脆的二氧化硅颗粒 | 0.96 | 0.96 |
珍珠岩 | 0.7 | 0.7 |
改性碳酸钙棒(9) | 41.7 | - |
Chalk 800M | - | 15 |
(9) 碳酸钙棒(1),通过将棒分散到油酸的乙醇溶液中改性,随后过滤并且用蒸馏水洗涤以获得浆料(36% a.i.)。
将假牙(由PMMA制成)包埋在自固化树脂中然后用测试组合物刷洗,如下:
第1组:仅用清洁的水刷洗
第2组:用对比实施例H的组合物刷洗
第3组:用实施例2的组合物刷洗
第4组:首先用对比实施例H的组合物刷洗,然后用实施例2的组合物刷洗。
刷洗介质由测试组合物和水以1:2的重量比组成。刷洗机(Martindale M235)提供有总共275g的集料器。第1-3组的牙齿在150rpm的速度下洗刷15分钟然后取出进行观察。第4组的牙齿用对比实施例H的组合物在150rpm的速度下洗刷15分钟,随后用实施例2的组合物在150rpm的速度下洗刷15分钟,然后取出进行观察。
通过SLR(Canon 550D)摄取经刷洗后的牙齿的数码照片,其在各组之间显示了光泽度的差别。第2组牙齿显示缺少光泽,表明表面损伤。第3组牙齿显示了比第2组高的光泽度。第4组牙齿也显示了比第3组牙齿更高的光泽度。
还通过Tabletop SEM(Hitachi
TM-3000)观察经过洗刷的牙齿的表面形态。结果在附图 1中显示,并且可以总结如下:
图像A(对照牙齿,未洗刷): 表面非常平坦不具有褶皱。
图像B(第1组牙齿): 可以观察到一些微小的划痕。
图像C(第1组牙齿): 图像显示对平坦假牙表面的划伤,一些
划痕最高至几微米
图像D(第3组牙齿): 相比于第2组牙齿观察到少得多的划痕
表明对于假牙表面更低的损伤。相比于第
1组牙齿,也观察到更轻的划痕
表明当在牙刷和表面之间刷洗时,
棒起润滑作用
图像E(第4组牙齿): 划痕的数量以及深度比第2组牙齿观察到
的少,这表明棒具有修复作用。
Claims (4)
1.一种口腔护理组合物,其包含:
(a) 包含水或多元醇或其混合物的连续相,和
(b) 微粒碳酸钙磨料,其为结晶碳酸钙,其中晶体是具有10-30微米的长度和0.5-1微米的宽度的针状物;
其中微粒碳酸钙磨料的含量为10-70%,基于组合物的总重量以微粒碳酸钙磨料的总重量计。
2.根据权利要求1的口腔护理组合物,其中微粒碳酸钙磨料的含量为20-60%,基于组合物的总重量以微粒碳酸钙磨料的总重量计。
3.根据权利要求1的口腔护理组合物,其中微粒碳酸钙磨料的含量为30-40%,基于组合物的总重量以微粒碳酸钙磨料的总重量计。
4.根据权利要求1的口腔护理组合物,其呈洁齿剂的形式,并且其进一步包含湿润剂、粘合剂或增稠剂、以及表面活性剂。
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CN1313750A (zh) * | 1998-08-24 | 2001-09-19 | 荷兰联合利华有限公司 | 包含细碳酸钙和粗碳酸钙的牙膏 |
CN1375275A (zh) * | 2001-03-14 | 2002-10-23 | 花王株式会社 | 牙粉 |
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WO2013041419A1 (en) | 2013-03-28 |
US9220665B2 (en) | 2015-12-29 |
CL2014000697A1 (es) | 2015-01-09 |
US20150050322A1 (en) | 2015-02-19 |
CN103930089A (zh) | 2014-07-16 |
PH12014500554A1 (en) | 2014-04-21 |
MX2014003524A (es) | 2014-07-14 |
EP2758026B1 (en) | 2015-08-26 |
BR112014006689B1 (pt) | 2018-11-21 |
EP2758026A1 (en) | 2014-07-30 |
BR112014006689A2 (pt) | 2017-04-04 |
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