CN101102763A - 刺激真皮乳头细胞生长及促进毛囊生长的、含有维生素c衍生物的组合物 - Google Patents
刺激真皮乳头细胞生长及促进毛囊生长的、含有维生素c衍生物的组合物 Download PDFInfo
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Abstract
本发明公开一种含有维生素C衍生物的组合物，该组合物可用于刺激真皮乳头细胞生长及促进毛囊生长。
Description
技术领域
本发明涉及一种含有维生素C衍生物的组合物，该组合物可用于刺激真皮乳头细胞生长及促进毛囊生长。
背景技术
通常，哺乳动物的毛囊是一种组织严密的、多层且动态的器官。毛囊包括诸如内根鞘细胞和外根鞘细胞之类的上皮细胞、衍生自上皮组织的基质和毛干、以及衍生自间充组织的真皮乳头细胞和真皮鞘细胞。上皮组织和间充组织之间的相互作用对于出生后毛发的生长以及毛囊的发育是十分必要的。
出生后毛发的生长具有以下细胞周期：生长期、退化期和毛发生长终期。人们已经知道真皮乳头在生长期期间被上皮基质细胞包围，并且真皮乳头所分泌的生长因子(例如胰岛素样生长因子1(IGF-1)、角化细胞生长因子(KGF)等)在该生长期期间被分化出来，促使上皮细胞的增殖和毛干的生成(参见文献：Itami S等人，“Biochen BiophysRes Commun”，212：第988-94页，1995年；Werner S等人，“Science”，266：第819-22页，1994年)。
同时，人们发现上皮细胞在退化期因真皮乳头内所分泌的生长抑制因子(例如肿瘤生长因子β(TGF-β))而发生程序性细胞死亡(凋亡)(参见文献：Soma等人，“J Invest Dermatol”，111：第948-54页，1998年；Hibino和Nishiyama，“J Dermatol Sci”，35：第9-18页，2004年)。因此，人们已知真皮乳头细胞分泌的因子控制毛发的生长。同时真皮乳头的尺寸也与毛囊的尺寸成比例(参见文献：Stenn和Paus，“Physiol Rev”，81：第449-494页，2001年)。此外，可以预测能够控制真皮乳头细胞生长或其基因表达的天然提取物或化学品，在控制毛发生长中发挥重要的作用。
维生素C(L-抗坏血酸)在胶原蛋白的合成中表现出辅助因子的活性，并可用作培养基中的补充成分。然而，由于维生素C在水溶液、特别是在通常的培养条件下被快速氧化和降解，所以，维生素C的这种应用受到了限制。维生素C衍生物L-抗坏血酸-2-磷酸酯镁盐(也称作Asc 2-P)是一种比维生素C更稳定的制品，并且已经在多种培养基中被用作补充成分。与维生素C一样，Asc 2-P也刺激人真皮成纤维细胞和成骨细胞的生长(参见文献：Hata等人，“Eur J Biohem”，173：第261-267页，1988年)。但是人们根本不知道维生素C或Asc2-P对毛发和真皮乳头细胞的生长有什么影响。
发明内容
因此，本发明被设计用来解决现有技术中的问题，由此本发明的目的就是提供一种治疗脱发症的药剂，该药剂能够刺激真皮乳头细胞和/或毛囊的生长。
为了实现上述目的，本发明提供一种刺激真皮乳头细胞生长及促进毛囊生长的组合物，该组合物含有维生素C衍生物作为有效成分。
在本发明中，优选的是，维生素C衍生物选自L-抗坏血酸-2-磷酸酯镁盐、L-抗坏血酸棕榈酸酯和L-抗坏血酸硬脂酸酯，并且下面化学式1所示的L-抗坏血酸-2-磷酸酯镁盐是最优选的。
而且，本发明的维生素C衍生物的特征在于它们促进毛囊的生长、刺激真皮乳头细胞的生长、刺激真皮乳头细胞内胰岛素样生长因子1(IGF-1)的产生、增强真皮乳头细胞和毛囊内多功能蛋白聚糖的表达以及增强真皮乳头细胞内碱性磷酸酶的表达。
附图简要说明
下文将参照附图，将更充分地说明本发明优选实施方案的以上这些或其它特征、方面和优点。在附图中：
图1是显示Asc 2-P对体外孵育的毛囊的生长的影响的图。将毛囊在Asc 2-P存在下孵育9天后，测量毛囊的生长长度(*，P＜0.05)。
图2是显示Asc 2-P对孵育的真皮乳头细胞的生长的影响的图。将真皮乳头细胞在含有Asc 2-P的培养基中孵育5天后，使用MTT法计量细胞的数量(*，P＜0.05)。
图3是显示Asc 2-P对真皮乳头细胞中生长因子(A)、胶原蛋白(B)、多功能蛋白聚糖(C)和碱性磷酸酶(D)的表达的影响的图。在使用Asc 2-P对真皮乳头细胞处理5天后，测量mRNA的含量。
图4是显示Asc 2-P对毛囊中的多功能蛋白聚糖的表达的影响的图。在使用Asc 2-P对毛囊处理5天后，对其进行免疫染色。
实施本发明的最佳方式
下文将参照附图详细说明本发明的非限制性实施例。
实施例1：细胞培养和人毛囊的生长
在患有雄激素性脱发症的患者到达Kyungpook国立大学医院进行头发移植手术期间，在其同意的前提下，从他们的后脑部头皮获得活体解剖样本。根据已知的方法(参见文献：Philpott等人，“J CellSci”，97：第463-471页，1990年)分离并孵育毛囊。使用立体双目显微镜从头皮中分离出处于生长期的毛囊。将分离出的处于生长期的毛囊从上部切掉三分之一，所余三分之二部分置于Williams E培养基中(得自位于美国的Sigma公司)在37℃及5％CO2气氛下孵育。该毛囊在含有Asc 2-P的培养基中孵育9天，然后使用立体显微镜测量其长度。
实施例2：细胞培养和真皮乳头细胞的生长
使用双目显微镜从病情严重的毛囊球部分离出真皮乳头，然后将其转移至组织培养皿中。该真皮乳头在补加有青霉素(100U/ml)、链霉素(100μg/ml)和20％热灭活的胎牛血清(FBS，得自于美国的Hyclone公司)的DMEM培养基中，在37℃及5％CO2气氛下孵育5天，然后在相同的条件下传代培养。在传代培养后，将真皮乳头细胞保存在含有10％FBS的DMEM培养基中。本发明使用二次传代的培养细胞。
将真皮乳头细胞在密度为5,000个细胞/孔的96孔培养板中孵育过夜，该培养板的孔中装有补加有10％FBS的DMEM培养基。然后将培养基更换为含有各种浓度的Asc 2-P的DMEM培养基并孵育5天，再使用MTT法测量细胞的数量。
实施例3：真皮乳头细胞中各种基因的表达
将真皮乳头细胞在含有0.25mM的Asc 2-P的培养基中孵育5天，然后使用TRIzol试剂(得自位于美国纽约州Grand Island市的Gibco-BRL公司)分离出它们的RNA。使用包含Superscript II逆转录酶和六碱基随机引物(得自Gibco-BRL公司)的cDNA合成试剂盒，由RNA合成cDNA。使用表1所示的成套的特定基因扩增引物对cDNA进行扩增。RT-PCR引物和它们的条件列于下面的表1中。
在本发明中分析了IGF-1(胰岛素样生长因子1)、HGF(肝细胞生长因子)、VEGF(血管内皮细胞生长因子)、KGF(角质细胞生长因子)、I型胶原蛋白、III型胶原蛋白、多功能蛋白聚糖和碱性磷酸酶(ALP)的基因的表达水平。
表1
| 基因 | 正向(5’-3’) | 反向(5’-3’) | 预期大小 | 循环次数 | D | A | P |
| IGF-1IIGFKGFVEGFCollagcnICollagcnIIIVersicanActin | TCAACAAGCCCACAGGGTATCGAGGCCATGGTGCTATACTGACATGGATCCTGCCAACTTTCTTCAAGCCATCCTGTGTGCCCACCAATCACCTGCGTACAGAGAGATGTCTGGAAGCCAGAACCATTCAACATCTCATGTTCCTCCCGGACTTCGAGCAAGAGATGG | ACTCGTGCAGAGCAAAGGATACACCAGGGTGATTCAGACCAATTCCAACTGCCACTGTCCGCGAGTCTGTGTTTTTGCAGTTCTTGGTCGGTGGGTGACTCTGAGATCTCCCTTGGGGCCTTGAGGTTTCTTCACTGTGGGTATAGGTCTAAGCACTGTGTTGGCGTACAG | 307296304297214207405234 | 4040304030253025 | 9494949494949494 | 5858585862625558 | 7272727268687272 |
实施例4：毛囊中多功能蛋白聚糖的免疫染色
将毛囊在分别添加有0.1mM和1mM的Asc 2-P的培养基中孵育5天，然后对多功能蛋白聚糖进行免疫染色试验。
实施例5：统计分析
使用t-检验进行统计偏差分析。概率(P)值为小于或等于0.05被认为该试验结果具有统计学意义。
发明人从上述实施例中获得的结果如下：
在体外Asc 2-P对毛囊生长的刺激作用
发明人研究了Asc 2-P对从头皮中分离出的人生长期毛囊的影响。结果表明当毛囊在分别含有0.05mM和0.25mM的Asc 2-P的Williams E培养基中孵育9天时，毛囊均显著地生长(如图1所示)。
在体外Asc 2-P对真皮乳头细胞生长的刺激作用
当使用的Asc 2-P的浓度分别为0.05mM、0.25mM、1mM和5mM时，Asc 2-P可显著地刺激真皮乳头细胞的生长(如图2所示)。特别地是，当使用的Asc 2-P的浓度为0.25mM时，Asc 2-P所刺激的真皮乳头细胞的生长与对照组相比较，要高出2.4倍。
Asc 2-P对真皮乳头细胞的基因表达的影响
当使用的Asc 2-P的浓度为0.25mM时，Asc 2-P使IGF-1、多功能蛋白聚糖和碱性磷酸酶(ALP)的mRNA的浓度增加。但是Asc 2-P对HGF、VEGF、KGF、I型胶原蛋白和III型胶原蛋白不起作用(如图3所示)。
上述免疫染色试验揭示出，在用Asc 2-P处理的毛囊中，多功能蛋白聚糖的表达增加(如图4所示)。
工业适用性
如从上述说明中可见的那样，本发明的维生素C衍生物Asc2-P由于能够刺激真皮乳头细胞和/或毛囊的生长，因此可用作治疗脱发症的药剂。
序列表
<110>毛发基因有限公司(Trichogene.Inc)
<120>刺激真皮乳头细胞生长及促进毛囊生长的、含有维生素C衍生物的组合物
<130>2006-01-06
<150>10-2005-0003091
<151>2005-01-13
<160>16
<170>PatentIn version 3.3
<210>1
<211>20
<212>DNA
<213>IGF-1 正向引物
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<210>2
<211>20
<212>DNA
<213>IGF-1 反向引物
<400>2
actcgtgcag agcaaaggat 20
<210>3
<211>20
<212>DNA
<213>HGF 正向引物
<400>3
cgaggccatg gtgctatact 20
<210>4
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<212>DNA
<213>HGF 反向引物
<400>4
acaccagggt gattcagacc 20
<210>5
<211>20
<212>DNA
<213>KGF 正向引物
<400>5
gacatggatc ctgccaactt 20
<210>6
<211>20
<212>DNA
<213>KGF 反向引物
<400>6
aattccaact gccactgtcc 20
<210>7
<211>20
<212>DNA
<213>VEGF 正向引物
<400>7
tcttcaagcc atcctgtgtg 20
<210>8
<211>20
<212>DNA
<213>VEGF 反向引物
<400>8
gcgagtctgt gtttttgcag 20
<210>9
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<212>DNA
<213>I型胶原蛋白正向引物
<400>9
cccaccaatc acctgcgtac aga 23
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<211>24
<212>DNA
<213>I型胶原蛋白反向引物
<400>10
ttcttggtcg gtgggtgact ctga 24
<210>11
<211>24
<212>DNA
<213>III型胶原蛋白正向引物
<400>11
gagatgtctg gaagccagaa ccat 24
<210>12
<211>23
<212>DNA
<213>III型胶原蛋白反向引物
<400>12
gatctccctt ggggccttga ggt 23
<210>13
<211>21
<212>DNA
<213>多功能蛋白聚糖正向引物
<400>13
tcaacatctc atgttcctcc c 21
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<213>多功能蛋白聚糖反向引物
<400>14
ttcttcactg tgggtatagg tcta 24
<210>15
<211>20
<212>DNA
<213>肌动蛋白正向引物
<400>15
ggacttcgag caagagatgg 20
<210>16
<211>20
<212>DNA
<213>肌动蛋白反向引物
<400>16
agcactgtgt tggcgtacag 20
Claims (7)
1.一种治疗脱发症的组合物，该组合物含有维生素C衍生物作为有效成分。
2.根据权利要求1所述的组合物，其中所述维生素C衍生物选自L-抗坏血酸-2-磷酸酯镁盐、L-抗坏血酸棕榈酸酯和L-抗坏血酸硬脂酸酯。
3.根据权利要求1或2所述的组合物，其中所述维生素C衍生物促进毛囊的生长。
4.根据权利要求1或2所述的组合物，其中所述维生素C衍生物刺激真皮乳头细胞的生长。
5.根据权利要求1或2所述的组合物，其中所述维生素C衍生物刺激真皮乳头细胞中胰岛素样生长因子-1(IGF-1)的产生。
6.根据权利要求1或2所述的组合物，其中所述维生素C衍生物增强真皮乳头细胞和毛囊中多功能蛋白聚糖的表达。
7.根据权利要求1或2所述的组合物，其中所述维生素C衍生物增强真皮乳头细胞中碱性磷酸酶的表达。
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| Application Number | Priority Date | Filing Date | Title |
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| KR1020050003091 | 2005-01-13 | ||
| KR1020050003091A KR100645090B1 (ko) | 2005-01-13 | 2005-01-13 | 비타민 ｃ 및 그 유도체를 포함하는 탈모 치료제 조성물 |
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| US (1) | US20080269173A1 (zh) |
| EP (1) | EP1835904A4 (zh) |
| JP (1) | JP2008526955A (zh) |
| KR (1) | KR100645090B1 (zh) |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112245312A (zh) * | 2020-10-23 | 2021-01-22 | 介一生物工程技术（大连）有限公司 | 一种防脱发组合物及其应用 |
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| ITTO20050800A1 (it) * | 2005-11-11 | 2007-05-12 | Univ Degli Studi Torino | Composizioni utili per il recupero del trofismo e della pigmentazione originari e per la stimolazione della crescita degli apparati tegumentari, relativi usi e prodotti |
| KR100796904B1 (ko) * | 2006-05-04 | 2008-01-22 | 신석봉 | 안정화된 비타민 ｃ 또는 비타민 ｃ 유도체의 복합체를함유하는 발모제 조성물 |
| KR101113806B1 (ko) * | 2009-05-08 | 2012-03-02 | (주)트리코진 | 트레오네이트를 유효성분으로 하는 탈모 예방 또는 치료용 조성물 |
| KR101124441B1 (ko) * | 2009-11-23 | 2012-03-21 | 영남대학교 산학협력단 | 마그네슘 아스코르빌 포스페이트(ｍａｐ) 및 메틸설포닐메탄(ｍｓｍ) 혼합물을 유효성분으로 함유하는 탈모 방지 및 발모 개선용 조성물 |
| JP2018203681A (ja) * | 2017-06-07 | 2018-12-27 | 日本メナード化粧品株式会社 | くせ毛改善剤 |
| KR102166356B1 (ko) * | 2018-12-07 | 2020-10-15 | 주식회사 넥스모스 | 압타민 c를 유효성분으로 포함하는 탈모증의 예방, 치료 또는 개선용 조성물 |
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| US6150405A (en) * | 1985-07-18 | 2000-11-21 | Proctor; Peter H. | Hair loss treatment with ascorbates |
| JP2926432B2 (ja) | 1990-06-11 | 1999-07-28 | 株式会社林原生物化学研究所 | 養毛剤 |
| US5494667A (en) | 1992-06-04 | 1996-02-27 | Kabushiki Kaisha Hayahibara | Topically applied hair restorer containing pine extract |
| KR100308491B1 (ko) * | 1999-07-21 | 2001-09-26 | 김유채 | 모발 성장 조성물 |
| KR20030062605A (ko) * | 2002-01-17 | 2003-07-28 | (주)바우코스켐 | 자연 발효 추출물을 함유하는 탈모방지, 비듬방지 및모발성장 조성물 |
| FR2835429B1 (fr) * | 2002-02-07 | 2006-02-10 | Oreal | Utilisation d'acide ascorbique pour renforcer la cohesion de la jonction dermo-epidermique |
| US6908941B2 (en) * | 2002-06-06 | 2005-06-21 | Nicholas V. Perricone | Hair and nail treatments using alkanolamines |
| KR20060014433A (ko) * | 2003-06-04 | 2006-02-15 | 에버사이츠, 엘엘씨 | 신규의 피부의학 조성물 |
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| CN112245312A (zh) * | 2020-10-23 | 2021-01-22 | 介一生物工程技术（大连）有限公司 | 一种防脱发组合物及其应用 |
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| EP1835904A4 (en) | 2008-01-23 |
| EP1835904A1 (en) | 2007-09-26 |
| KR20060110017A (ko) | 2006-10-24 |
| WO2006075854A1 (en) | 2006-07-20 |
| JP2008526955A (ja) | 2008-07-24 |
| US20080269173A1 (en) | 2008-10-30 |
| KR100645090B1 (ko) | 2006-11-23 |
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