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WO2016006732A1 - Composition contenant des fragments de peptide dérivés de facteur de croissance épidermique pour cicatrisation ou inhibition de la formation de ride cutanée - Google Patents

Composition contenant des fragments de peptide dérivés de facteur de croissance épidermique pour cicatrisation ou inhibition de la formation de ride cutanée Download PDF

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Publication number
WO2016006732A1
WO2016006732A1 PCT/KR2014/006169 KR2014006169W WO2016006732A1 WO 2016006732 A1 WO2016006732 A1 WO 2016006732A1 KR 2014006169 W KR2014006169 W KR 2014006169W WO 2016006732 A1 WO2016006732 A1 WO 2016006732A1
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WO
WIPO (PCT)
Prior art keywords
seq
skin
peptide
growth factor
epidermal growth
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Application number
PCT/KR2014/006169
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English (en)
Korean (ko)
Inventor
한장희
고인영
류연호
김유리
김민서
Original Assignee
강원대학교산학협력단
(주) 수파드엘릭사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 강원대학교산학협력단, (주) 수파드엘릭사 filed Critical 강원대학교산학협력단
Priority to PCT/KR2014/006169 priority Critical patent/WO2016006732A1/fr
Publication of WO2016006732A1 publication Critical patent/WO2016006732A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention relates to a wound healing composition
  • a wound healing composition comprising peptide fragments (small peptides or small peptides) derived from epidermal growth factor (EGF); And it relates to a composition for inhibiting skin aging or wrinkle formation.
  • the peptide activates the epidermal growth factor receptor and also has activity to promote skin keratinocyte proliferation and angiogenesis.
  • Wounds are sometimes referred to as wounds, and their symptoms include pain, bleeding, and dysfunction. Wounds create a unique microenvironment consisting of growth factors, cytokines, neurohormones, and extracellular matrix secreted from surrounding cells, blood derived cells, and sensory neurons. Some factors in the wound microenvironment persist long enough to spread into peripheral blood and then affect stem cells in the bone marrow, causing the bone marrow cells to migrate into peripheral blood, supply to the wound site, and participate in wound healing. It is known.
  • Extracellular matrix such as collagen I, III (Type I, III collagens), elastin, and fibronectin present in the skin to maintain its elasticity and strength without breaking the connective tissue of the skin Extracellular matrix (ECM) proteins are important.
  • Natural aging or chronic exposure to UV rays reduces the loss of ECM proteins and the elasticity and strength of skin tissues, which are strongly associated with characteristic skin aging such as wrinkles.
  • Matrix metalloproteinases (MMPs) are important enzymes in the degradation of dermal ECM. Under stress conditions such as UV irradiation, overexpression of MMPs in keratinocytes and dermal fibroblasts contributes to the degradation of ECM proteins, thereby forming wrinkles on the skin.
  • epidermal growth factor is one of growth factors that bind to epidermal growth factor receptor (EGFR) and regulate the proliferation, differentiation and survival of various cells.
  • EGFR epidermal growth factor receptor
  • EGF is secreted from platelets, macrophages and fibroblasts, and acts as a paracrine fashion to keratinocytes. EGF increases the expression of keratin K6 and K16 and activates cell proliferation signaling.
  • epidermal growth factor receptor When the epidermal growth factor receptor is activated, it stimulates the growth of keratinocytes and fibroblasts by inducing the production of growth factors such as VEGF and HGF, and also induces the production of extracellular matrix such as collagen in fibroblasts. Or improve skin wrinkles.
  • the present inventors have designed various small peptide fragments that activate epidermal growth factor receptors expressed in keratinocytes and fibroblasts of the skin, and surprisingly, specific peptide fragments or small peptides derived from epidermal growth factor are found to be epidermal growth factor receptors. It has been found that it can promote the re-epithelialization of the epidermis by activating and promoting the proliferation and angiogenesis of keratinocytes.
  • an object of the present invention is to provide a pharmaceutical composition for treating wounds or promoting wound treatment comprising a specific peptide fragment derived from epidermal growth factor as an active ingredient.
  • an object of the present invention is to provide a cosmetic composition for inhibiting skin aging or inhibiting skin wrinkle formation comprising the specific peptide fragment.
  • a pharmaceutical composition for treating wounds or promoting wound healing comprising a peptide selected from the group consisting of the peptides of SEQ ID NOs: 1 to 15 as an active ingredient, and comprising a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising the peptide of SEQ ID NO: 9 as an active ingredient.
  • a cosmetic composition for inhibiting skin aging or inhibiting skin wrinkles comprising a peptide selected from the group consisting of the peptides of SEQ ID NOs: 1 to 15 as an active ingredient.
  • a cosmetic composition comprising a peptide of SEQ ID NO: 9 as an active ingredient is provided.
  • peptide fragments derived from epidermal growth factor promote epidermal re-epithelialization by activating epidermal growth factor receptors and promoting proliferation and angiogenesis of keratinocytes. Therefore, the peptides may be usefully applied to pharmaceutical compositions for treating wounds or promoting wound healing, and cosmetic compositions for inhibiting skin aging or inhibiting skin wrinkle formation.
  • 1 and 2 show the results of evaluating the activation of the epidermal growth factor receptor by the peptide according to the present invention.
  • FIG. 3 and 4 show the results of evaluation of phosphorylation of ERK and Akt by peptides according to the present invention in human keratinocytes HaCaT (FIG. 3) and mouse fibroblast NIH3T3 (FIG. 4), respectively.
  • Figure 5 shows the results of evaluating the effect of the peptides according to the invention on the proliferation of keratinocytes.
  • Figure 6 shows the results of evaluating the angiogenic activity by the peptides according to the present invention.
  • wound refers to damage of epithelial and connective tissue caused by intrinsic and external factors, and may preferably be damage to skin.
  • skin aging refers to aging of the skin caused by intrinsic and external factors, preferably skin photoaging accompanied with the formation of skin wrinkles, more preferably skin Skin photoaging due to ultraviolet irritation accompanied by wrinkle formation.
  • skin wrinkle refers to wrinkle formation on skin.
  • the present invention provides a pharmaceutical composition for promoting wound healing or wound treatment comprising a peptide selected from the group consisting of the peptides of SEQ ID NOs: 1 to 15 as an active ingredient, and comprising a pharmaceutically acceptable carrier.
  • the present invention provides a cosmetic composition for inhibiting skin aging or skin wrinkle formation comprising a peptide selected from the group consisting of peptides of SEQ ID NO: 1 to 15 as an active ingredient.
  • the peptides according to the invention have excellent activity on wound healing and skin regeneration.
  • the present invention may be usefully applied to cosmetic compositions for improving skin aging and / or suppressing skin wrinkle formation accompanying skin irritation caused by external stimuli such as ultraviolet rays.
  • the peptide fragments are shown in Table 1 below.
  • the peptide of the present invention may be a peptide of SEQ ID NO: 9.
  • the pharmaceutical composition of the present invention may include excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, tonicity agents, and the like which are well known, and may be used in parenteral dosage forms, preferably It may be formulated in parenteral dosage forms including external dermal preparations.
  • excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, tonicity agents, and the like which are well known, and may be used in parenteral dosage forms, preferably It may be formulated in parenteral dosage forms including external dermal preparations.
  • a sterile solution of the active ingredient is usually prepared and may comprise a buffer which can suitably adjust the pH of the solution, and for intravenous administration isotonic in the formulation. May be included to impart this.
  • the pharmaceutical composition of the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4, and may be locally introduced into the patient's intramuscular blood flow in the form of a solution. have.
  • a pharmaceutically acceptable carrier such as saline having a pH of 7.4
  • it may be formulated into a transdermal dosage form such as an external preparation, an emulsion, an ointment, a patch and the like according to conventional pharmaceutical methods.
  • the pharmaceutical composition of the present invention can be administered to patients with various wounds at a dose of about 1 to 2000 mg / kg per day. Appropriate dosages will generally vary depending on the age, weight and symptoms of the patient.
  • the cosmetic composition of the present invention may be in the form of a functional cosmetic composition comprising the peptide as an active ingredient.
  • the cosmetic composition may be prepared in various forms according to a conventional cosmetic preparation method.
  • the cosmetic composition may be prepared in the form of a cosmetic product containing the peptide, lotion, cream, lotion, etc., which may be diluted with a conventional cleansing liquid, astringent liquid and moisturizing liquid.
  • the cosmetic composition may include conventional adjuvants such as stabilizers, solubilizers, vitamins, pigments, and flavorings commonly used in the field of cosmetic compositions.
  • the content of the peptide may be contained in an amount effective to achieve an effect of inhibiting skin aging, in particular, skin wrinkle formation, for example, in an amount of 0.001 to 10% by weight based on the total weight of the composition. It may be contained in an amount of about 0.01 to 1% by weight.
  • Peptides of SEQ ID NOs: 1 to 15 were synthesized by the FMOC solid-phase method using an automated synthesizer (PeptrEx-R48, Peptron, Daejeon, Korea). The synthesized peptide was purified and analyzed by reverse-phase HPLC using a C18 analytical RP column (Shiseido capcell pak) (Prominence LC-20AB, Shimadzu, Japan), and mass spectrometer (HP 1100 Series). LC / MSD, Hewlett-Packard, Roseville, USA).
  • Peptides of SEQ ID NO: 1 to 15 were dissolved in PBS, respectively, to prepare a concentration of 1 M.
  • the obtained protein solution was used in the following test example.
  • In situ proximity ligation assay was used to confirm whether the peptide of the present invention activates the epidermal growth factor receptor. The test was performed by purchasing Duolink In Situ reagent from Olink Bioscience, Sweden.
  • DMEM medium 1 mL was added to a 24-well plate coated with 12 mm glass, and 4.5 ⁇ 10 4 human keratinocyte line HaCaT cells (DKFZ, Heidelberg, Germany) were plated and stabilized for 24 hours.
  • Anti-Gab1 Rabbit Polyclonal Antibody (Gab1 Antibody, Cell Signaling Technology, INC., USA) and Anti-Shp2 Mouse Monoclonal Antibody (SH-) to measure the degree of interaction between Gab1 and Shp2 increased by epidermal growth factor receptor activation PTP2 (B-1): sc-7384 mouse mAb, Santa Cruz Biothecnology, INC., USA) was treated with cells at 37 ° C. After 30 minutes, treated with PLA probe solution and incubated at 37 ° C. for 1 hour, then treated with ligation solution and incubated for 30 minutes. Treated with amplication solution and incubated for 100 minutes.
  • FIGS. 1 and 2 After the cells treated as described above were washed with washing buffer, the number of red spots was measured using confocal microscopy, and the results are shown in FIGS. 1 and 2.
  • Figure 1 when treated with the peptide of SEQ ID NOS: 1 to 7 having 4 amino acids, the interaction between Gab1 and Shp2 increased by about 50 to 100% compared to the control.
  • Figure 2 when treated with the peptide of SEQ ID NOS: 8 to 15 having three amino acids, the interaction between Gab1 and Shp2 was increased by about 30 to 170% compared to the control. This indicates that the peptides according to the invention activate the epidermal growth factor receptor, which plays a major role in skin regeneration.
  • the peptide of SEQ ID NO. Human keratinocytes HaCaT (DKFZ, Heidelberg, Germany) and mouse fibroblast NIH3T3 (ATCC CRL-1658, USA) were treated with a solution (1 ml) obtained by lysis at a concentration of ⁇ M. After 15 minutes, Western blotting analysis was performed on the cell extracts to measure changes in phosphorylation of ERK and Akt, and the results are shown in FIGS. 3 and 4.
  • the phosphorylation degree of ERK and Akt was increased in a concentration-dependent manner by the peptide of SEQ ID NO. Therefore, it can be seen that the peptide according to the present invention activates the epidermal growth factor receptor expressed in keratinocytes and fibroblasts.
  • the effect of the peptides according to the invention on angiogenesis was evaluated as follows.
  • the interaction between the vascular endothelial component and vascular endothelial cells is an important factor in the formation and maintenance of neovascularization.
  • matrigel which is a complex of the bottom membrane component
  • a polymerization reaction occurs and a plug .
  • Human umbilical vein endothelial cells (HUVECs) were inoculated into a 24 well cell culture plate coated with Matrigel at a density of 8 x 10 4 cells / well, and the peptide of SEQ ID NO: 9 was serum-free M199 medium.
  • VEGF Vascular Endothelial Growth Factor

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition contenant des fragments de peptide ou des petits peptides dérivés du facteur de croissance épidermique (EGF) pour la cicatrisation et l'inhibition du vieillissement de la peau ou de la formation de rides cutanées. Les peptides activent des récepteurs EGF et ont des activités favorisant la prolifération de kératinocytes et l'angiogenèse dans la peau. En conséquence, les peptides peuvent être utilisés efficacement pour la cicatrisation et l'inhibition du vieillissement de la peau ou de la formation de rides cutanées.
PCT/KR2014/006169 2014-07-09 2014-07-09 Composition contenant des fragments de peptide dérivés de facteur de croissance épidermique pour cicatrisation ou inhibition de la formation de ride cutanée WO2016006732A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2014/006169 WO2016006732A1 (fr) 2014-07-09 2014-07-09 Composition contenant des fragments de peptide dérivés de facteur de croissance épidermique pour cicatrisation ou inhibition de la formation de ride cutanée

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2014/006169 WO2016006732A1 (fr) 2014-07-09 2014-07-09 Composition contenant des fragments de peptide dérivés de facteur de croissance épidermique pour cicatrisation ou inhibition de la formation de ride cutanée

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5492894A (en) * 1991-03-21 1996-02-20 The Procter & Gamble Company Compositions for treating wrinkles comprising a peptide
US20060148706A1 (en) * 2005-01-03 2006-07-06 Blue Blood Biotech Corp. Composition for wound healing and use thereof
WO2008044846A1 (fr) * 2006-10-10 2008-04-17 Caregen Co., Ltd Peptides à activités de facteur de croissance épidermique et utilisations de ceux-ci
KR20100092150A (ko) * 2009-02-12 2010-08-20 주식회사 웰스킨 다이펩타이드를 포함하는 피부 미백용 조성물
WO2012121428A1 (fr) * 2011-03-07 2012-09-13 주식회사 웰스킨 Composition pour la croissance de fibroblastes comprenant un dipeptide à titre de principe actif, et produit la contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5492894A (en) * 1991-03-21 1996-02-20 The Procter & Gamble Company Compositions for treating wrinkles comprising a peptide
US20060148706A1 (en) * 2005-01-03 2006-07-06 Blue Blood Biotech Corp. Composition for wound healing and use thereof
WO2008044846A1 (fr) * 2006-10-10 2008-04-17 Caregen Co., Ltd Peptides à activités de facteur de croissance épidermique et utilisations de ceux-ci
KR20100092150A (ko) * 2009-02-12 2010-08-20 주식회사 웰스킨 다이펩타이드를 포함하는 피부 미백용 조성물
WO2012121428A1 (fr) * 2011-03-07 2012-09-13 주식회사 웰스킨 Composition pour la croissance de fibroblastes comprenant un dipeptide à titre de principe actif, et produit la contenant

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