WO2023243447A1 - 環状コラーゲンの形成を制御する美容方法 - Google Patents

環状コラーゲンの形成を制御する美容方法 Download PDF

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Publication number
WO2023243447A1
WO2023243447A1 PCT/JP2023/020684 JP2023020684W WO2023243447A1 WO 2023243447 A1 WO2023243447 A1 WO 2023243447A1 JP 2023020684 W JP2023020684 W JP 2023020684W WO 2023243447 A1 WO2023243447 A1 WO 2023243447A1
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Prior art keywords
collagen
skin
dermal matrix
expression
wnt16
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English (en)
French (fr)
Japanese (ja)
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智暢 江連
伸彦 大野
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Shiseido Co Ltd
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Shiseido Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H23/00—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H7/00—Devices for suction-kneading massage; Devices for massaging the skin by rubbing or brushing not otherwise provided for
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the technical field of suppressing skin aging.
  • Sagging skin has a major impact on the appearance of one's age, and maintaining skin firmness and improving sagging is a major cosmetic issue.
  • Skin firmness is mainly due to the thickness of the dermal layer, and firm skin contains abundant elastic fibers such as collagen and elastin that fill the dermal layer.
  • collagen and elastin that fill the dermal layer.
  • the function of dermal fibroblasts declines and the production of elastic fibers decreases, and matrix metalloproteinases are activated and degrade elastic fibers. This causes the dermal layer to thin, causing sagging or moss.
  • the amount of collagen tends to decrease with age, but the amount of collagen is also affected by skin care, exposure to ultraviolet rays, and diet.
  • sagging and moss do not necessarily depend only on the amount of collagen in the dermis.
  • the amount of collagen does not necessarily decrease, and it is thought that the symptoms of sagging are affected by some influence other than the amount of collagen.
  • Other known causes besides the amount of collagen include weakening of facial muscles and increase in subcutaneous fat.
  • conventional beauty methods have focused on increasing collagen and elastic fibers by activating dermal fibroblasts, or suppressing the decomposition of collagen and elastic fibers.
  • Patent Document 1 JP 2012-144499 and Patent Document 2: Publication No. 2013-014555.
  • the purpose of this study is to clarify the internal structure of the skin related to sagging, and to provide a new beauty method to prevent and improve sagging.
  • the present inventors conducted intensive research to elucidate the internal structure of the skin that causes facial sagging, and found that in the dermis of the face, structures with elasticity are not spread evenly, and there are areas with high elasticity, It was found that there were scattered areas with low elasticity. After conducting a more detailed analysis, we found that there was a ring-shaped part with high elasticity surrounding the part with low elasticity, and the collagen arranged in a ring contracted toward the center. It was found that it causes tension on the skin and prevents it from sagging. We have also found that by applying mechanical stimulation and/or thermal stimulation to hair follicles, the formation of dermal matrix can be promoted and the formation of annularly arranged collagen can be controlled.
  • the invention therefore relates to: [1] A cosmetic method comprising promoting the formation of dermal matrix and/or controlling the formation of circular collagen in facial skin by mechanical stimulation and/or thermal stimulation of hair follicles. [2] The cosmetic method according to item 1, wherein the annular collagen refers to collagen formed in an annular shape around the hair follicle. [3] The cosmetic method according to item 1 or 2, which improves skin firmness by forming circular collagen. [4] The cosmetic method according to any one of items 1 to 3, wherein mechanical stimulation to the hair follicle is applied by bringing a probe into contact with the skin.
  • the dermal matrix is at least one selected from the group consisting of tenascin C, versican, and periostin.
  • the circular collagen is collagen formed in a circular shape around the hair follicle.
  • FIG. 1A is a heat map showing the difference in tension in a horizontal section of the dermis when the skin is deformed and analyzed. Points with strong tension (orange to red in the heat map) are shown with dotted arrows, and points with weak tension (green to light blue in the heat map) are shown with solid arrows.
  • FIG. 1B shows a heat map of the difference in tension in a horizontal section of the dermis and its surrounding tissue superimposed.
  • FIG. 2 shows enlarged photographs of horizontal sections of the dermis of facial skin specimens obtained from young and elderly subjects using X-ray CT.
  • Figure 3 shows that expression of tenascin-C was increased in fibroblasts by humoral factors secreted from hair follicle epithelial cells.
  • FIG. 10A is a graph showing changes in circular collagen diameter when organ culture is performed with thermal stimulation applied.
  • FIG. 10B is an immunostaining photograph showing the expression of Wnt16 and versican in organ culture with thermal stimulation applied.
  • FIG. 10C is a graph showing changes in the expression level of Wnt16 in human outer root sheath cells cultured under thermal stimulation.
  • the present invention provides a cosmetic method that includes promoting the formation of dermal matrix and/or controlling the formation of cyclic collagen in facial skin by mechanical stimulation and/or thermal stimulation of hair follicles.
  • the dermal matrix and fibers do not exist uniformly, but that a dermal matrix region exists just below the hair follicle, and collagen is formed in a ring shape surrounding the dermal matrix. ( Figure 1).
  • the dermal matrix can be determined by measuring the expression of contained components such as fibronectin, tenascin C, versican, and periostin. The diameter of the circular collagen increases depending on the amount of dermal matrix.
  • the amount of circular collagen can be measured based on morphology and/or collagen as a component. While there is a positive correlation between the amount of circular collagen and tension, there is an inverse correlation between the amount of circular collagen and sagging.
  • the tension in the plane direction differs depending on whether the collagen has a circular collagen structure or exists uniformly (FIG. 2 and Table 1). Therefore, when cyclic collagen is lost due to aging, it becomes impossible to maintain tension in the plane direction, and the skin as a whole is pulled downward without being able to resist gravity, resulting in sagging. Furthermore, there is a correlation between the diameter of the circular collagen and the diameter of the microhair, and the thicker the diameter of the microhair, the larger the diameter of the circular collagen (FIG. 6).
  • Stromal components are produced by fibroblasts.
  • the present inventors have shown that humoral factors from hair follicle epithelial cells increase the amount of dermal matrix produced (FIG. 3).
  • humoral factors secreted from hair follicle cells such as Wnt16, activate fibroblasts in the perifollicular and deep regions of the hair follicle, leading to the activation of fibroblasts in the dermal matrix. Production increases. Activated fibroblasts also increase collagen production. During the maturation process, the produced collagen changes its structure into a circular collagen that surrounds the dermal matrix.
  • Mechanical stimulation to the hair follicle tissue may be applied by any method as long as it is applied so as to deform the shape of the hair follicle.
  • mechanical stimulation of hair follicular tissue can be achieved with a device that includes a probe that contacts the skin.
  • the mechanical stimulus it is preferable to apply a stretching stimulus that stretches the skin.
  • the stretching stimulus is applied by moving a probe applied to the skin in a horizontal direction with respect to the skin surface while it is in contact with the skin.
  • it can be applied by moving two or more probes to be applied to the skin so as to separate them while they are in contact with the skin.
  • Stretching stimulation can be applied by moving the probe, more specifically by vibration. Mechanical stimulation allows the promotion of dermal matrix formation and/or the control of circular collagen formation.
  • the formation of circular collagen is promoted, which improves firmness.
  • At least one action selected from activation of hair follicle cells, promotion of dermal matrix formation, and control of circular collagen formation by mechanical stimulation is a performance indication of a device that applies mechanical stimulation, especially stretching stimulation, on packages, catalogs, It may be displayed on promotional materials, manuals, the screen of the device, etc., or may be used to advertise the provision of services using such devices.
  • the beauty method according to the present invention may be provided as a service in cosmetic medicine, beauty treatment, etc., or may be provided by a device that applies mechanical stimulation.
  • the beauty method according to the present invention may be displayed on a catalog, promotional material, instruction manual, or monitor screen.
  • the cosmetic method according to the present invention may be displayed together with its mechanism of action and/or effects.
  • Another aspect of the present invention also relates to a method of evaluating cyclic collagen based on the amount of dermal matrix.
  • Cyclic collagen differs from normal collagen fibers in that it has a structure formed by aggregation of collagen fibers, so it cannot be measured by measuring the amount of collagen protein or mRNA. Cyclic collagen can be evaluated based on the shape of aggregated collagen fibers by tissue staining, etc., but such evaluation methods lack quantitative properties.
  • cyclic collagen is formed so as to surround the dermal matrix containing proteoglycans, there is a relationship in which as the amount of dermal matrix increases, the amount of cyclic collagen also increases. Therefore, cyclic collagen can be evaluated based on the amount of dermal matrix.
  • annular collagen annular collagen formed around the hair follicle or in the subfollicular region can be evaluated.
  • the amount of dermal matrix can be determined by measuring the expression level of any component of the dermal matrix, such as tenascin C, fibronectin, versican, periostin, etc. Tenascin C, versican, or periostin is preferably used.
  • the expression level of protein and/or mRNA can be measured using techniques well known in the art, such as immunological techniques or quantitative PCR, respectively.
  • cyclic collagen By evaluating cyclic collagen, current or future skin tightness can be determined. It is possible to predict future sagging, wrinkles, and moss caused by skin tension. As an example, when the amount of circular collagen is lower than a predetermined threshold value, there is a high probability that sag will be formed even if no sag is currently formed.
  • the threshold value can be appropriately determined by large-scale investigation of the amount of cyclic collagen in living organisms.
  • a threshold value can be set based on the relationship between sagging and the amount of annular collagen in the skin using a sagging determination method known in this technical field such as cutometer or photo judgment. Further, by conducting a follow-up survey after a predetermined period of time, it becomes possible to set the threshold value more accurately.
  • the present invention also relates to a method of screening for a cyclic collagen production promoter using dermal matrix protein and/or Wnt16 expression as an indicator in a fibroblast culture.
  • the screening method of the present invention more specifically includes the following: cultivating a fibroblast culture in a medium containing the candidate component; measuring the expression of dermal matrix protein and/or Wnt16 in the fibroblast culture after culturing; and comparing the measured dermal matrix protein and/or Wnt16 expression with a control dermal matrix protein and/or Wnt16 expression.
  • candidate components can be screened as cyclic collagen production promoters.
  • the screening method may include a step of selecting a candidate component as a cyclic collagen production promoter when dermal matrix protein and/or Wnt16 expression is increased.
  • the cyclic collagen production promoter thus screened can promote cyclic collagen production by enhancing dermal matrix protein and/or Wnt16 expression.
  • the cyclic collagen production promoter can also be called a sagging improving agent.
  • As the dermal matrix protein at least one selected from the group consisting of tenascin C, versican, and periostin can be used.
  • the control dermal matrix protein and/or Wnt16 expression can be used to express dermal matrix protein and/or Wnt16 in fibroblast cultures that differ only in that they do not contain the candidate component.
  • a threshold value may be set based on the expression of dermal matrix protein and/or Wnt16 in the control group, or culture and measurement steps may be performed in parallel.
  • the expression of dermal matrix protein and/or Wnt16 may be the protein amount or mRNA amount of dermal matrix protein and/or Wnt16 in fibroblast culture, and can be expressed by the present technical field such as immunological method or quantitative PCR, respectively. It can be measured using a well-known method.
  • any library of cosmetic materials, food materials, pharmaceutical materials, etc. can be used.
  • a library a compound library, an extract library, etc. may be used.
  • compounds and extracts included in each library commercially available compounds and extracts may be used, or synthesized compounds and prepared extracts may be used.
  • Example 1 Reconstruction of skin dynamics The excess skin was deformed, images were acquired with X-ray CT, skin dynamics were reconstructed on a computer, and the height of tension in the horizontal section of the skin was measured ( Figure 1A). Furthermore, in order to investigate the causes of high and low tension regions in the horizontal section of the dermis, we observed the shallow and deep regions of the dermis in the horizontal section ( Figure 1B). Regions of low tension were shown to be surrounded by regions of high tension. It was also shown that the region of low tension was the lower region of the hair follicle.
  • Example 2 Changes in circular collagen due to aging Facial skin specimens were obtained from excess facial skin of young people (under 40 years old) and elderly people (over 60 years old). A cylindrical skin section several millimeters in diameter was cut from the skin specimen and photographed using X-ray CT ( Figure 2). In skin specimens from young people, the dermal matrix region and the circular collagen surrounding the dermal matrix region could be clearly distinguished, whereas in skin specimens from elderly patients, it was difficult to distinguish between the dermal matrix region and the circular collagen, and the collagen had an amorphous shape. (A typical example is shown in Figure 2).
  • Example 3 Relationship between cyclic collagen and skin tension and sagging
  • the amount of cyclic collagen was quantified using a hair follicle condition grading method.
  • the tension in the cheek area of the subject's face was measured using a Cutometer.
  • the degree of sagging in the cheeks of the subject's face was evaluated with photographs.
  • Statistical analysis was performed on the state of circular collagen and the degree of tension and sagging of the cheeks using Spearman's correlation coefficient. The results are shown in the table below.
  • Example 4 Induction of dermal matrix by hair follicle cells Hair follicle epithelial cells and fibroblasts were seeded in a Boyden chamber, and the influence of hair follicle epithelial cells on fibroblasts was investigated. More specifically, fibroblasts (established from human biopsy skin) were seeded in the upper chamber at 5,000 cells/ml in DMEM medium, and hair follicle epithelial cells (established from human biopsy skin) were seeded in DMEM medium. The cells were seeded at 250,000 cells/ml in the lower chamber and cultured at 37°C under a CO 2 atmosphere for 48 hours. Fibroblasts in the upper chamber after culture were collected, and mRNA was extracted using an RNA extraction kit (Qiagen).
  • RNA extraction kit Qiagen
  • a reverse transcription reaction was performed using a Superscript kit (Invitrogen) and subjected to quantitative PCR.
  • a control (Cont.) was prepared similarly, differing only in that the lower chamber did not contain hair follicle epithelial cells.
  • the following primer set was used for quantitative PCR.
  • the expression level of TenascinC is shown in FIG.
  • Example 5 Production of dermal matrix by hair follicle stimulation Stretching stimulation was applied to cylindrically cut skin sections (young subjects and elderly subjects). Organ culture was performed in DMEM medium at 37° C. in a 5% CO 2 atmosphere for 7 days while applying stretching stimulation. The skin samples after culture were fixed with acetone and washed with PBS. Paraffin embedding was then performed, and skin sections with a thickness of 5 ⁇ m were obtained. After incubating the skin sections in a blocking solution (1% BSA) for 0.5 hours, the primary antibodies were anti-tenascin C antibody (Abcam), anti-versican antibody (Abcam), and anti-periostin antibody (Abcam) diluted x200.
  • a blocking solution 1% BSA
  • FIG. 4 It was shown that tenascin-C is expressed in the area from around the hair follicle to under the hair follicle. Furthermore, after stretching stimulation, it was shown that the expression of tenascin-C increased in the area from around the hair follicle to under the hair follicle.
  • Example 6 Relationship between fine hair and collagen on the body and face Skin specimens were obtained from excess skin from the body and from the face, and examined using an X-ray CT machine (sold by Zeiss). It was subjected to measurement and a three-dimensional structure was constructed. In particular, fine hair and collagen in the dermis were visualized (FIGS. 5A and B). From the three-dimensional construct, the amount of collagen contained in the dermis was determined and compared between the body and face ( Figure 5C). Next, the diameter of microhairs and the diameter of circular collagen in the excess skin were measured and plotted on a graph (FIG. 6). The density of fine hair was higher on the face than on the body. Collagen content was high in the body, and collagen was uniformly present in the dermis.
  • Example 7 Factors that induce proteoglycan layers Screening was performed for factors that induce proteoglycan layers in fibroblast cultures. More specifically, fibroblasts (established from human biopsied skin) were seeded in a 24-well plate culture vessel at 1 ⁇ 10 4 cells/ml in DMEM medium supplemented with 10% FBS. 1 ⁇ g/ml of Wnt16 (R&D Co., Ltd.) was added to the medium and cultured at 37° C. in a CO 2 atmosphere for 48 hours. The fibroblasts after culture were collected, and mRNA was extracted using an RNA extraction kit (Qiagen). A reverse transcription reaction was performed using a Super script kit (Invitrogen) and subjected to quantitative PCR. The following primer set was used for quantitative PCR. The expression levels of periostin and versican are shown in FIG. Addition of Wnt16 increased the expression levels of periostin and versican.
  • Example 8 Expression of Wnt16 around hair follicles in young and elderly subjects Facial skin specimens were obtained from excess facial skin of young people (under 40 years old) and elderly people (over 60 years old). A cylindrical skin section with a diameter of several millimeters was cut from the skin specimen, fixed with acetone, and washed with PBS. Paraffin embedding was then performed, and skin sections with a thickness of 5 ⁇ m were obtained. After incubating the skin sections in a blocking solution (1% BSA) for 0.5 h, they were incubated overnight at 4°C using a x200 dilution of anti-Wnt16 antibody (LS-bio) as the primary antibody, followed by Envision (1% BSA).
  • a blocking solution 1% BSA
  • LS-bio anti-Wnt16 antibody
  • FIG. 8A the expression of Wnt16 was evaluated using 4-level grading, and the results are shown in FIG. 8B.
  • Wnt16 expression around hair follicles decreased.
  • Example 10 Effects of thermal stimulation
  • Abdominal skin specimens young subjects under 40 years of age cut into cylinders were subjected to organ culture in a DMEM medium. Thermal stimulation was applied at 42°C for 60 minutes, and then culture was performed at 37°C in a 5% atmosphere for 7 days. Skin samples after organ culture were fixed with acetone and washed with PBS. Paraffin embedding was then performed, and skin sections with a thickness of 5 ⁇ m were obtained. After incubating the skin sections in a blocking solution (1% BSA) for 0.5 hours, they were incubated overnight using anti-versican antibody (Abcam) and anti-Wnt16 antibody (anti-Wnt16 antibody) diluted 1:200 as primary antibodies.
  • Abcam anti-versican antibody
  • anti-Wnt16 antibody anti-Wnt16 antibody
  • human outer root sheath cells were obtained from fine hair sites in the dermis and cultured in kSFM medium at 42°C for 60 minutes. As a control, the cells were cultured at 37°C. Human outer root sheath cells after culture were collected, and mRNA was extracted using an RNA extraction kit (Qiagen). A reverse transcription reaction was performed using a Superscript kit (Invitrogen) and subjected to quantitative PCR. A control (Cont.) was prepared similarly, differing only in that the lower chamber did not contain hair follicle epithelial cells. The following primer set was used for quantitative PCR. The expression level of Wnt16 is shown in FIG. 10C.

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007520285A (ja) * 2004-02-06 2007-07-26 バロレ，ダニエル 哺乳類組織の治療方法及び装置
JP2021508453A (ja) * 2017-12-20 2021-03-11 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ ボツリヌス毒素細胞結合ドメインポリペプチドおよび皮膚の若返りのための使用方法
WO2021167097A1 (ja) * 2020-02-19 2021-08-26 株式会社 資生堂 立毛筋細胞の賦活化による老化改善方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007520285A (ja) * 2004-02-06 2007-07-26 バロレ，ダニエル 哺乳類組織の治療方法及び装置
JP2021508453A (ja) * 2017-12-20 2021-03-11 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ ボツリヌス毒素細胞結合ドメインポリペプチドおよび皮膚の若返りのための使用方法
WO2021167097A1 (ja) * 2020-02-19 2021-08-26 株式会社 資生堂 立毛筋細胞の賦活化による老化改善方法

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