WO2018202028A1 - 一种组合物用于制备促进个体毛发生长、预防毛发脱落或促进个体毛囊干细胞生成的药物的用途 - Google Patents

一种组合物用于制备促进个体毛发生长、预防毛发脱落或促进个体毛囊干细胞生成的药物的用途 Download PDF

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WO2018202028A1
WO2018202028A1 PCT/CN2018/085282 CN2018085282W WO2018202028A1 WO 2018202028 A1 WO2018202028 A1 WO 2018202028A1 CN 2018085282 W CN2018085282 W CN 2018085282W WO 2018202028 A1 WO2018202028 A1 WO 2018202028A1
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hair
composition
sodium salt
medicament
use according
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PCT/CN2018/085282
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English (en)
French (fr)
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吉冈亨
许文俐
颜佳蓉
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高雄医学大学
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Priority to JP2019539971A priority Critical patent/JP6996775B2/ja
Publication of WO2018202028A1 publication Critical patent/WO2018202028A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

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  • the present invention relates to the use of a composition for the preparation of a medicament for promoting hair growth, preventing hair loss or promoting hair follicle stem cell production in an individual, wherein the composition comprises an effective dose of Derinat, a deoxyribose Sodium nucleate, as the main active ingredient.
  • Hair follicles are important appendages of the skin used to grow hair, and they are composed of many types of cells such as hair follicle stem cells.
  • the cycle experienced by the hair follicles includes the anagen stage, the catagen stage, and the telogen stage, and the three stages are repeated.
  • the activation period is characterized by the activation of hair follicle stem cells. During this period, hair follicle stem cells continue to proliferate and grow in the direction of subcutaneous tissue. By the middle of the activation phase, the hair follicle stem cells stopped dividing and entered a state of hibernation.
  • the hair growth work was carried out by the outer root sheath, the inner root sheath, and the matrix differentiated from the hair follicle stem cells. The cells are responsible for the fact that these cells eventually differentiate into a structure with hair scales to form a hair shaft that is visible to the naked eye.
  • the Derinat composition is a natural deoxyribonucleic acid (DNA) sodium salt composition extracted from fish eggs (mostly salmon or trout), which is composed of more than 90% of the DNA sodium salt.
  • the composition is about 100 to 300 base pairs in size.
  • the present invention discloses that the Dali sodium salt is not toxic to human skin keratinocytes (KC) and human dermal fibroblasts (HDF) at high skin cell dose (1.5 mg/ml (mg/ml)). .
  • the Dali sodium salt of the invention can reduce the concentration of calcium ions in the skin cells, and can protect the skin cells and reduce the production of reactive oxygen species (ROS) in the skin cells.
  • ROS reactive oxygen species
  • experiments with nude mice revealed that the nude mice were exposed to the back with an effective dose of the Dyna Sodium salt composition for two hours, and the hair on the back of the nude mice increased after one week; then the nude mice were sacrificed to take the back skin.
  • H&E Stain hematoxylin-eosin staining
  • IHC immunohistochemical staining
  • the Dyna sodium salt can also reduce the production of reactive oxygen species in hair follicle cells, and has the function of protecting skin and hair follicle cells.
  • Dali sodium salt is not only non-toxic to skin cells, but can further promote hair follicle proliferation and activate hair follicle stem cells; in addition, it can also reduce the production of reactive oxygen species in skin tissue, thereby protecting skin cells and hair follicle cells. efficacy.
  • the present invention relates to the use of a composition for the manufacture of a medicament for promoting hair growth or preventing hair loss in an individual, wherein the composition comprises an effective amount of Derinat.
  • the composition comprises from 10 to 1500 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition comprises from 10 to 150 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition refers to a pharmaceutical composition for transdermal administration.
  • the unit dose of the dean sodium salt contained in each unit of the drug is 10 to 1500 micrograms ( ⁇ g), more preferably 10 to 150 micrograms ( ⁇ g).
  • the subject comprises a mammal having hair that is not growing, hair loss, or at risk of hair growth or hair loss.
  • the hair is located on the scalp, face, beard, head, torso, limbs, pubic, upper lip, eyebrows or eyelids.
  • the invention further relates to the use of a composition for the manufacture of a medicament for promoting the production of hair follicle stem cells in an individual, wherein the composition comprises an effective amount of a Daryl sodium salt.
  • the composition comprises from 10 to 1500 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition comprises from 10 to 150 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition refers to a pharmaceutical composition for transdermal administration.
  • the unit dose of the dean sodium salt contained in each unit of the drug is 10 to 1500 micrograms ( ⁇ g), more preferably 10 to 150 micrograms ( ⁇ g).
  • the individual comprises a mammal having hair that is not growing, hair loss, or at risk of hair growth or hair loss.
  • the hair is located on the scalp, face, beard, head, torso, limbs, pubic, upper lip, eyebrows or eyelids.
  • the invention also provides a method of promoting hair growth or preventing hair loss in an individual comprising topically administering to the individual a composition comprising an effective amount of a dehydrogenated sodium salt.
  • the composition comprises from 10 to 1500 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition comprises from 10 to 150 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition refers to a pharmaceutical composition for transdermal administration.
  • the individual comprises a mammal having hair that is not growing, hair loss, or at risk of hair growth or hair loss.
  • the hair is located on the scalp, face, beard, head, torso, limbs, pubic, upper lip, eyebrows or eyelids.
  • the invention also provides a method of promoting the production of hair follicle stem cells in an individual comprising topically administering to the individual a composition comprising an effective amount of a dehydrogenated sodium salt.
  • the composition comprises from 10 to 1500 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition comprises from 10 to 150 micrograms per milliliter ( ⁇ g/mL) of the Daryl sodium salt.
  • the composition refers to a pharmaceutical composition for transdermal administration.
  • the individual comprises a mammal having hair that is not growing, hair loss, or at risk of hair growth or hair loss.
  • the hair is located on the scalp, face, beard, head, torso, limbs, pubic, upper lip, eyebrows or eyelids.
  • compositions of the present invention comprise compositions for application to topical and regional effects.
  • topical as used herein relates to the incorporation into a suitable pharmaceutical carrier using the compositions described herein and applied to the area where the hair is thinned or hair loss to effect a topical action.
  • topical compositions include those in which the compound is applied from the outside by direct contact with the surface of the skin to be treated.
  • Conventional pharmaceutical forms for this purpose include ointments, wipes, creams, shampoos, lotions, pastes, gels, sprays, aerosols, and the like, and may be patched depending on the body part to be treated or Apply in the form of an impregnation dressing.
  • formulations encompasses formulations (including creams) having an oily base, a water soluble base, and an emulsion base selected from the group consisting of petrolatum, lanolin, polyethylene glycols, and mixtures of these combinations.
  • the drug can be formulated in an aqueous solution, cream, ointment or oil by the addition of a pharmacologically acceptable buffer and salt.
  • a pharmacologically acceptable buffer and salt may or may not contain preservatives (eg, benzalkonium chloride, chlorhexidine, chlorobutanol, p-hydroxybenzoic acid) and phenylmercuric salts (eg, nitrates, chlorides, acetates, and boron). Acid salts) or antioxidants and additives (such as EDTA, sorbitol, boric acid, etc.).
  • the aqueous solution may comprise a tackifier such as a polysaccharide such as methylcellulose, a mucopolysaccharide such as hyaluronic acid and chondroitin sulfate or a polyol such as polyvinyl alcohol.
  • a tackifier such as a polysaccharide such as methylcellulose, a mucopolysaccharide such as hyaluronic acid and chondroitin sulfate or a polyol such as polyvinyl alcohol.
  • compositions For topical application to the skin and scalp, it may be advantageous to formulate a pharmaceutical composition using an ointment, cream, trowel or patch as the active ingredient carrier. Additionally, these pharmaceutical compositions may or may not contain a preservative. Such preservatives include the above pharmaceutical compositions as well as methyl, propyl- or butyl-p-hydroxybenzoic acid, betaines, chlorhexidine, benzalkonium chloride, and the like.
  • the pharmaceutical compositions can also be delivered by sustained release from different matrices. To achieve a daily dosage of the pharmaceutical composition, the composition can be administered one or more times per day in the presence or absence of an antioxidant.
  • the condition of reducing the amount of hair caused by hair growth or hair loss according to the present invention may be caused by hair loss (e.g., androgenetic alopecia, alopecia areata, etc.), hereditary baldness, scarring, burns, radiation therapy, chemotherapy, disease-related Hair loss due to hair loss, accidental injury, hair follicle damage, surgical trauma, incisional injury or skin graft.
  • hair loss e.g., androgenetic alopecia, alopecia areata, etc.
  • hereditary baldness e.g., hereditary baldness, scarring, burns, radiation therapy, chemotherapy, disease-related Hair loss due to hair loss, accidental injury, hair follicle damage, surgical trauma, incisional injury or skin graft.
  • compositions of the invention are applicable to all mammalian species, including both humans and animals.
  • the compositions of the invention may be applied to the scalp, face, beard, head, torso, limbs, pubic, upper lip, eyebrows or eyelids.
  • the compositions of the invention can be applied to the entire body surface for commercial reasons to improve the entire fur.
  • the compositions of the invention may be applied to animals, for example, to the skin of a dog or cat having a certain degree of baldness due to rickets or having bald spots due to other diseases.
  • a derivative encompasses a plurality of such derivatives, and the reference to “a” includes reference to one or more individual or the like.
  • FIG. 1 is a discussion of the toxicity of deli sodium salt on human skin cells, and the results show that in the skin keratinocytes (KC) and skin fibroblasts (HDF), at a high concentration of 1.5 mg / ml (mg / ml) of the Dye sodium salt Under the treatment, the cells showed no obvious death.
  • KC skin keratinocytes
  • HDF skin fibroblasts
  • Figure 2 is a treatment of low concentrations of 15 ⁇ g/ml ( ⁇ g/mL) and 150 ⁇ g/ml ( ⁇ g/mL) of Dylan sodium in skin keratinocytes (KC) and dermal fibroblasts (HDF), respectively. It can inhibit the activation of calcium ions ([Ca 2+ ] i ).
  • FIG. 3 is a discussion of the effect of Daryl sodium salt on the back hair growth of nude mice.
  • the mice were exposed to 14 ⁇ g/ml ( ⁇ g/mL) or 60 ⁇ g/mL ( ⁇ g/mL) of the sodium salt on the back of the nude for one week. After a few hours, it was found that the hair on the back of the nude mice of the Dairy sodium salt group increased.
  • Fig. 4 shows that the nude mice were sacrificed to take the back skin, and hematoxylin-eosin staining (H&E Stain) was used to find that the hair follicles of the Dairy sodium salt group proliferated, and more hair follicles were activated.
  • H&E Stain hematoxylin-eosin staining
  • FIG. 5 shows that the proliferation of hair follicles is related to the activation of hair follicle stem cells. Therefore, immunohistochemical staining (IHC) staining was used to observe the molecular markers CD49f and Oct-3/4 expressed by two hair follicle stem cells. After salt treatment, more hair follicle stem cells were expressed.
  • IHC immunohistochemical staining
  • Fig. 6A is a graph showing the expression level of reactive oxygen species (ROS) in skin tissue or hair follicle cells by living tissue staining.
  • ROI reactive oxygen species
  • Fig. 6B is a graph showing the expression level of reactive oxygen species (ROS) in skin tissue or hair follicle cells by living tissue staining.
  • Figure 6B shows that the Dylan sodium salt reduces reactive oxygen free radicals in hair follicle cells, the dashed line indicates the extent of the hair follicle, and the arrow points to the hair follicle cells.
  • ROS reactive oxygen species
  • Example 1 Discussion on the toxicity of Dali sodium salt to human skin cells
  • Daryl sodium salt was applied to human skin keratinocytes and dermal fibroblasts to test their toxicity to human skin cells.
  • the results showed no significant death of skin keratinocytes (KC) and dermal fibroblasts (HDF) at high concentrations of 1.5 mg/ml (mg/ml) of Dye-sodium salt (Fig. 1).
  • Example 2 Test of the inhibition of intracellular calcium ion concentration by Dali sodium salt
  • Example 4 Effect of Dali sodium salt on the generation of reactive oxygen species in skin tissue
  • Daryl sodium salt can reduce the production of reactive oxygen species, thereby improving the efficacy of skin cells and hair follicle cells ( Figure 6A and Figure 6B).

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Abstract

本发明公开了一种组合物用于制备促进个体毛发生长、预防毛发脱落或促进个体毛囊干细胞生成的药物的用途，其中该组合物包含有效剂量的戴理钠盐(Derinat)，一种脱氧核醣核酸钠盐，作为主要活性成分。

Description

一种组合物用于制备促进个体毛发生长、预防毛发脱落或促进个体毛囊干细胞生成的药物的用途 技术领域
本发明是关于一种组合物用于制备促进个体毛发生长、预防毛发脱落或促进个体毛囊干细胞生成的药物的用途，其中该组合物包含有效剂量的戴理钠盐(Derinat)，一种脱氧核醣核酸钠盐，作为主要活性成分。
背景技术
毛囊是用来生长毛发的皮肤重要附属器官，其由毛囊干细胞(hair follicle stem cell)等多种类型细胞组成。毛囊经历的周期包含活化期(anagen stage)、退化期(catagen stage)及休止期(telogen stage)，三个阶段的不断重复。活化期的特征就是毛囊干细胞的活化，此时期的毛囊干细胞不断增生，往皮下组织的方向生长。到了活化期的中期，毛囊干细胞停止分裂而进入了冬眠的状态，毛发生长的工作就交由毛囊干细胞所分化出来的外根鞘(outer root sheath)、内根鞘(inner root sheath)、和基质细胞(matrix cell)负责，这些细胞最终分化出具有毛鳞片的结构而构成肉眼可见的发干(hair shaft)。
毛囊周期异常往往导致严重的毛发不生长或毛发脱落，秃发为其中最常见的状况之一。秃发不分男女的影响了个体的身心、自尊的减弱进而影响其生活的许多层面，令人备感困扰。
目前市面上并无任何产品能有效地使毛发增生，顶多只能增加毛 发结构的稳定度，减少掉发几率，或是抑制5α还原酶(5α-reductase)，使二氢睪固酮(dihydrotestosterone，DHT)产量减少，来达到治疗秃发的目的，然而后者有性功能障碍的不良副作用。因此，提供一有效且无毒并且相对来说不具有不良副作用的组合物或方法以促进毛发生长或预防毛发脱落有其必要性。
发明内容
戴理钠盐(Derinat)组合物为自鱼卵(大多为鳟鱼或鲑鱼)萃取而出的一种天然的脱氧核醣核酸(DNA)钠盐组合物，其由90％以上的DNA钠盐所组成，大小约100～300碱基对左右。本发明揭露此戴理钠盐在高皮肤细胞剂量(1.5毫克/毫升(mg/ml))对于人类的皮肤角质细胞(keratinocytes，KC)及皮肤纤维母细胞(human dermal fibroblasts，HDF)并无毒性。本发明的戴理钠盐可降低皮肤细胞内的钙离子浓度，并达到保护皮肤细胞、降低皮肤细胞活性氧自由基(reactive oxygen species，ROS)产生的作用。更进一步，以裸鼠进行实验发现每日使裸鼠背部接触包含有效剂量的戴理钠盐组合物两个小时，一周后裸鼠背部的毛发有增多的情形；接着将裸鼠处死取背部皮肤，利用苏木素-伊红染色(H&E Stain)发现毛囊有增生的情形，且使较多的毛囊呈现活化期(anagen stage)。由于毛囊的增生与干细胞的活化有关，因此利用免疫组化染色(immunohistochemistry(IHC)staining)，观察两个干细胞会表达的分子标记CD49f及Oct-3/4，结果发现以该戴理钠盐处理后，有较多的毛囊干细胞表达。不仅如此，该 戴理钠盐也可降低毛囊细胞中活性氧自由基的产生，具有保护皮肤及毛囊细胞的功能。综合以上实验结果，戴理钠盐不仅对皮肤细胞没有毒性，并可进而促进毛囊增生以及活化毛囊干细胞；此外也可降低皮肤组织中活性氧自由基的产生，进而达到保护皮肤细胞与毛囊细胞的功效。
本发明是关于一种组合物用于制备促进个体毛发生长或预防毛发脱落的药物的用途，其中该组合物包含一有效剂量的戴理钠盐(Derinat)。
在一实施例中，该组合物包含10-1500微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物包含10-150微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物是指经皮肤施用的医药组合物。该组合物被制备成药物时，每一单位药物所含的戴理钠盐的单位剂量为10-1500微克(μg)，更佳为10-150微克(μg)。
在一实施例中，该个体(subject)包含具毛发不生长、毛发脱落或处于毛发不生长或毛发脱落风险中的哺乳动物。
在一实施例中，其中该毛发位于头皮、面部、胡须、头部、躯干、四肢、耻部、上唇、眉毛或眼睑。
本发明还关于一种组合物用于制备促进个体毛囊干细胞生成的药物的用途，其中该组合物包含一有效剂量的戴理钠盐。
在一实施例中，该组合物包含10-1500微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物包含10-150微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物是指经皮肤施用的医药组合物。
该组合物被制备成药物时，每一单位药物所含的戴理钠盐的单位剂量为10-1500微克(μg)，更佳为10-150微克(μg)。
在一实施例中，该个体包含具毛发不生长、毛发脱落或处于毛发不生长或毛发脱落风险中的哺乳动物。
在一实施例中，其中该毛发位于头皮、面部、胡须、头部、躯干、四肢、耻部、上唇、眉毛或眼睑。
本发明也提供促进个体毛发生长或预防毛发脱落的方法，其包含向该个体局部投与包含有效剂量的戴理钠盐的组合物。
在一实施例中，该组合物包含10-1500微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物包含10-150微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物是指经皮肤施用的医药组合物。
在一实施例中，该个体包含具毛发不生长、毛发脱落或处于毛发不生长或毛发脱落风险中的哺乳动物。
在一实施例中，其中该毛发位于头皮、面部、胡须、头部、躯干、 四肢、耻部、上唇、眉毛或眼睑。
本发明还提供促进个体毛囊干细胞生成的方法，其包含向该个体局部投与包含有效剂量的戴理钠盐的组合物。
在一实施例中，该组合物包含10-1500微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物包含10-150微克/毫升(μg/mL)的戴理钠盐。
在一实施例中，该组合物是指经皮肤施用的医药组合物。
在一实施例中，该个体包含具毛发不生长、毛发脱落或处于毛发不生长或毛发脱落风险中的哺乳动物。
在一实施例中，其中该毛发位于头皮、面部、胡须、头部、躯干、四肢、耻部、上唇、眉毛或眼睑。
本发明所述的组合物包含施用于局部和区域作用的组合物。本文所用的术语“局部”涉及使用本文所述的组合物掺入合适的药用载体中且施涂在头发变薄或脱发的部位，以实施局部作用。因此，此类局部用组合物包含其中通过与待处理皮肤表面直接接触来自外部施涂的化合物的那些药物形式。用于此目的的常规药物形式包含软膏剂、抹剂、乳膏、洗发剂、乳液、糊剂、凝胶剂、喷剂、气溶胶等，并且可以根据待治疗的身体部位以贴片或浸溃敷料形式施用。术语“软膏剂”包含具有油性基质、水溶性基质和乳液型基质的制剂(包含乳膏)，所述基质选自如凡士林、羊毛脂、聚乙二醇类以及这些组合的混合物。
就眉毛或眼睑的局部应用而言，可通过添加药理学上可接受的缓冲剂和盐，将药物配置于水溶液、乳膏、油膏剂或油剂中。此类医药组合物可以包含或不包含防腐剂(例如苯扎氯铵、氯己定、氯丁醇、对羟基苯甲酸)和苯基汞盐(例如硝酸盐、氯化物、乙酸盐和硼酸盐)或抗氧化剂以及添加剂(如EDTA、山梨糖醇、硼酸等)。此外，特别是水溶液可以包含增粘剂，例如多糖(如甲基纤维素)、黏多糖(如透明质酸和硫酸软骨素)或多元醇(如聚乙烯醇)。根据形成原位凝胶(in situ gel，是指以溶液状态给药后，能在用药部位发生相转变，由液态转化成为半固体凝胶态的制剂)的物质，并可以使用不同缓释凝胶和基质，以及可溶性和不溶性眼用嵌入剂。在实际情况下，不同药物量和不同剂量可被应用以制剂。
就皮肤和头皮的局部应用而言，可有利地使用软膏剂、乳膏、抹剂或贴片作为活性成分载体配制医药组合物。另外，这些医药组合物可以包含或不包含防腐剂。此类防腐剂包含上述医药组合物以及甲基、丙基-或丁基-对羟基苯甲酸、甜菜碱、氯己定、苯扎氯铵等。本医药组合物并可以借由不同基质进行缓释递送。要达到医药组合物的每日使用剂量，可以在存在或不存在抗氧化剂的情况下，每天一次或多次施用组合物。
本发明所涉及的因毛发不生长或毛发脱落而导致的毛发量减少的状况可由脱发(例如雄激素性脱发，斑秃等)、遗传性秃顶、瘢痕、烧伤、放射治疗、化学治疗、疾病相关性脱发、意外伤害、毛囊损伤、 手术创伤、切口伤或皮肤移植的接受部位创伤所致。
本发明可应用于所有哺乳动物物种，包含人和动物两者。在人类中，本发明的组合物可施用于头皮、面部、胡须、头部、躯干、四肢、耻部、上唇、眉毛或眼睑。在为取得毛皮而饲养的动物中，出于商业原因可将本发明的组合物施用于整个身体表面以改善整个毛皮。出于美观原因，并可将本发明的组合物应用于动物，例如施用于因螨病导致一定程度的秃毛，或因其他疾病而具有秃斑的狗或猫的皮肤上。
除非上下文另有明确说明，否则本说明书以及权利要求书中所使用的单数形式“一”及“该”包含复数个提及物。举例而言，提及“一衍生物”包含复数种该等衍生物，且提及“一个体”包含提及一或多位个体等。
又，除非另有说明，否则使用“或”意为“及/或”。类似地，“包含”，“包含”可互换使用且不意为具有限制性。
进一步应理解，当各实施例的描述使用术语“包含”时，本领域技术人员应理解在一些特定情况下，或者可使用语言“基本上由......组成”或“由......组成”来描述实施例。
除非另有定义，否则本文中所使用的所有技术及科学术语均具有与熟习本发明所属的技术领域的普通技术人员通常所理解含义相同的。虽然与本文中所述的方法及物质类似或等效的方法及物质可用于实施所揭示的方法及组合物，但本文中仅对例示性方法、装置及物质加以描述。
上文及整篇文章中所讨论的公开案仅针对本申请案的申请日期之前的已公开内容而提供。本文在任何方面皆不应理解为承认本发明者由于先前公开而无权使本发明具有优先权。
附图说明
图1是探讨戴理钠盐对于人类皮肤细胞的毒性，结果显示在皮肤角质细胞(KC)与皮肤纤维母细胞(HDF)中，在高浓度1.5毫克/毫升(mg/ml)戴理钠盐处理下，细胞皆无明显死亡。
图2是在仅处理低浓度15微克/毫升(μg/mL)与150微克/毫升(μg/mL)戴理钠盐分别于皮肤角质细胞(KC)与皮肤纤维母细胞(HDF)中，即可抑制钙离子([Ca 2+] i)的激化(motivation)。
图3是探讨戴理钠盐对于裸鼠背部毛发生长的影响，维持一周，每天让裸鼠背部接触14微克/毫升(μg/mL)或60微克/毫升(μg/mL)戴理钠盐两个小时，结果发现戴理钠盐组的裸鼠背部的毛发皆有增多的情形。
图4是将裸鼠处死取背部皮肤，利用苏木素-伊红染色(H&E Stain)，发现戴理钠盐组毛囊有增生的情形，且使较多的毛囊呈现活化期。
图5是毛囊的增生与毛囊干细胞的活化有关，因此利用免疫组化染色(immunohistochemistry(IHC)staining)，观察两个毛囊干细胞会表达的分子标记CD49f及Oct-3/4，结果发现戴理钠盐处理后，有较多的毛囊干细胞表达。
图6A是以活组织染色检测皮肤组织或毛囊细胞的活性氧自由基(reactive oxygen species，ROS)的表达量。图6A呈现戴理钠盐可降低皮肤细胞中的活性氧自由基。
图6B是以活组织染色检测皮肤组织或毛囊细胞的活性氧自由基(reactive oxygen species，ROS)的表达量。图6B呈现戴理钠盐可降低毛囊细胞中的活性氧自由基，虚线标示出毛囊的范围，而箭头所指处为毛囊细胞。
具体实施方式
以下的实施例非为限定用途，仅用以呈现此发明的多种方面。
实施例一：戴理钠盐对于人类皮肤细胞的毒性的探讨
将戴理钠盐施用于人类皮肤角质细胞与皮肤纤维母细胞以测试其对于人类皮肤细胞的毒性。结果显示在高浓度1.5毫克/毫升(mg/ml)戴理钠盐处理下皮肤角质细胞(KC)与皮肤纤维母细胞(HDF)皆无明显死亡(图1)。
实施例二：戴理钠盐对于抑制胞内钙离子浓度变化的测试
已知当皮肤细胞内钙离子浓度升高时，过多的钙离子会影响粒线体，使粒线体产生活性氧自由基(reactive oxygen species，ROS)，并进而造成对皮肤细胞的伤害。为了观察戴理钠盐(Derinat)对皮肤细胞钙离子通道活性及胞内钙离子浓度的影响，首先以戴理钠盐处理原代人类皮肤角质细胞和皮肤纤维母细胞24小时，之后再利用钙离子染剂(Fluo-4-AM)以检测细胞内钙离子浓度的变化。在观察Derinat对 钙离子通道的影响时，由于钙离子通道的特性并更精确检测钙离子通道，在检测细胞内钙离子的动态变化时利用ATP刺激细胞打开钙离子通道。首先在无钙离子的缓冲溶液中利用ATP去刺激钙离子通道打开，之后洗去ATP，再换为含有2毫摩尔浓度(mM)钙离子的缓冲溶液，随后检测曲线高度，并再做高度面积的定量。图2显示相较于未施予Derinat的对照组以及施予DMSO的组别，低浓度的15微克/毫升(μg/mL)与150微克/毫升(μg/mL)戴理钠盐即可抑制皮肤角质细胞及皮肤纤维母细胞的钙离子通道活性，并因而降低细胞内钙离子浓度，而达到保护皮肤细胞的效果。
实施例三：戴理钠盐对于裸鼠毛发生长的影响
为探讨戴理钠盐对于裸鼠毛发生长的影响，以14微克/毫升(μg/mL)(即3.5微克/平方公分(μg/cm 2))或60微克/毫升(μg/mL)(即14微克/平方公分(μg/cm 2))的戴理钠盐每日施用至裸鼠背部使其接触两个小时，在为期一周的试验后结果发现戴理钠盐组的裸鼠背部的毛发皆有增多的情形(图3)。由于14微克/毫升(μg/mL)的戴理钠盐即有效果，后续实验便以此剂量为主。将裸鼠处死后取下背部皮肤并以苏木素-伊红染色进行切片观察，发现戴理钠盐组毛囊有增生的情形，且使较多的毛囊呈现活化期(anagen stage)(图4)。由于毛囊的增生与干细胞的活化有关，因此利用免疫组化染色以观察两种毛囊干细胞会表达的分子标记CD49f及Oct-3/4，结果发现经戴理钠盐处理后，分子标记CD49f及Oct-3/4的表达量均增加，表示有较多的毛囊 干细胞生成(图5)。
实施例四：戴理钠盐对于皮肤组织中活性氧自由基生成的影响
为更进一步了解戴理钠盐对于皮肤组织中活性氧自由基生成的影响，以活组织染色检测皮肤细胞与毛囊细胞中活性氧自由基的表达量，同样发现不论是对于皮肤细胞或毛囊细胞，戴理钠盐皆能降低其活性氧自由基的产生，进而达到保护皮肤细胞与毛囊细胞的功效(图6A及图6B)。
为使此发明所属技术领域中普通技术人员得以了解制作以及使用这项技艺的方法，此发明已描述并已充分详细举例说明，然而，各式各样的变体、修改或改进应被视为无异于此项发明的精神与范围。
本发明所属技术领域中普通技术人员易于理解并实现本发明的目的，并获得先前所提到的结果及优点。本发明所使用的细胞、动物、材料以及生产它们的过程和方法为代表最佳实施例，是示例性质，而不作为限制本发明的范围用途。本领域的技术人员与制作或使用此项技艺时所将产生的修改或其他用途皆涵盖于本发明的精神之内，并且由权利要求范围所限定。

Claims (10)

  1. 一种组合物用于制备促进个体毛发生长或预防毛发脱落的药物的用途，其中所述组合物包含一有效剂量的戴理钠盐(Derinat)。
  2. 根据权利要求1所述的用途，其中所述组合物包含一有效剂量为10-1500微克/毫升的所述戴理钠盐。
  3. 根据权利要求1所述的用途，其中所述组合物包含一有效剂量为10-150微克/毫升的所述戴理钠盐。
  4. 根据权利要求1所述的用途，其中所述组合物是指经皮施用的医药组合物。
  5. 根据权利要求1所述的用途，其中所述毛发位于头皮、面部、胡须、头部、躯干、四肢、耻部、上唇、眉毛或眼睑。
  6. 一种组合物用于制备促进个体毛囊干细胞生成的药物的用途，其中所述组合物包含一有效剂量的戴理钠盐。
  7. 根据权利要求6所述的用途，其中所述组合物包含一有效剂量为10-1500微克/毫升所述戴理钠盐。
  8. 根据权利要求6所述的用途，其中所述组合物包含一有效剂量为10-150微克/毫升的所述戴理钠盐。
  9. 根据权利要求6所述的用途，其中所述组合物是指经皮施用的医药组合物。
  10. 根据权利要求6所述的用途，其中所述毛发位于头皮、面部、胡须、头部、躯干、四肢、耻部、上唇、眉毛或眼睑。
PCT/CN2018/085282 2017-05-04 2018-05-02 一种组合物用于制备促进个体毛发生长、预防毛发脱落或促进个体毛囊干细胞生成的药物的用途 WO2018202028A1 (zh)

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