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WO2016006733A1 - Composition contenant des fragments peptidiques dérivés du facteur de croissance des fibroblastes pour la cicatrisation des plaies ou l'inhibition de la formation des rides - Google Patents

Composition contenant des fragments peptidiques dérivés du facteur de croissance des fibroblastes pour la cicatrisation des plaies ou l'inhibition de la formation des rides Download PDF

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Publication number
WO2016006733A1
WO2016006733A1 PCT/KR2014/006170 KR2014006170W WO2016006733A1 WO 2016006733 A1 WO2016006733 A1 WO 2016006733A1 KR 2014006170 W KR2014006170 W KR 2014006170W WO 2016006733 A1 WO2016006733 A1 WO 2016006733A1
Authority
WO
WIPO (PCT)
Prior art keywords
skin
peptide
seq
growth factor
fibroblast growth
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2014/006170
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English (en)
Korean (ko)
Inventor
한장희
고인영
김민서
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Industry Academic Cooperation Foundation of KNU
Original Assignee
Industry Academic Cooperation Foundation of KNU
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.)
Filing date
Publication date
Application filed by Industry Academic Cooperation Foundation of KNU filed Critical Industry Academic Cooperation Foundation of KNU
Priority to PCT/KR2014/006170 priority Critical patent/WO2016006733A1/fr
Publication of WO2016006733A1 publication Critical patent/WO2016006733A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 fibroblast growth factor (FGF); And it relates to a composition for inhibiting skin aging or wrinkle formation.
  • the peptide activates the fibroblast growth factor receptor to induce collagen synthesis, 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.
  • fibroblast growth factor is one of growth factors that control the proliferation, migration, differentiation and survival of various cells including fibroblasts, and is composed of a group of 23 proteins.
  • FGF is produced in keratinocytes, fibroblasts, vascular endothelial cells, striated myocytes, chondrocytes and mast cells and exhibits the above-described function by activating four kinds of fibroblast growth factor receptors (FGF Receptors) expressed in various cells.
  • FGF-2, FGF-7 and FGF-10 are known to play an important role in skin regeneration (Barrientos S, Stojadinovic O, Golinko M, Brem H, Vinay Tomic-Canic M. 2008.
  • FGF-2 increases the expression of acute wounds and functions as re-epithelialization of the epidermis, and acts on fibroblasts in the dermal layer to induce granulation tissue formation and tissue remodeling through the production of extracellular matrix such as collagen. It is also known to promote the expression of skin barrier components and hair growth.
  • FGF-7 and FGF-10 are involved in the re-epithelial process by promoting the proliferation of keratinocytes, and also plays a role in maintaining keratinocytes through the detoxification of free radicals. FGF-7 also stimulates the growth of fibroblasts and keratinocytes by inducing the production of growth factors such as VEGF and HGF.
  • the present inventors have designed various small peptide fragments that activate fibroblast growth factor receptors expressed in keratinocytes and fibroblasts of the skin, and surprisingly, specific peptide fragments or small peptides derived from fibroblast growth factor are derived from fibroblasts. It has been found that activating growth factor receptors and promoting the proliferation and angiogenesis of keratinocytes can promote epithelial re-epithelialization. In addition, it has been found that the formation of extracellular matrix such as collagen can be inhibited by acting on fibroblasts of the dermal layer to inhibit skin wrinkle formation.
  • an object of the present invention is to provide a pharmaceutical composition for treating wounds or promoting wound healing comprising a specific peptide fragment derived from fibroblast 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 the treatment of wounds or promoting wound healing comprising a peptide selected from the group consisting of the peptides of SEQ ID NOs: 1 to 13 as an active ingredient, and comprising a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising the peptide of SEQ ID NO: 1 as an active ingredient.
  • a cosmetic composition for inhibiting skin aging or skin wrinkle formation comprising a peptide selected from the group consisting of the peptides of SEQ ID NOs: 1 to 13 as an active ingredient.
  • a cosmetic composition comprising a peptide of SEQ ID NO: 1 as an active ingredient is provided.
  • peptide fragments derived from fibroblast growth factor promote the re-epithelialization of the epidermis by activating the fibroblast growth factor receptor and promoting the proliferation and angiogenesis of keratinocytes.
  • the formation of extracellular matrix such as collagen can be suppressed by acting on fibroblasts of the dermal layer to inhibit skin wrinkle formation. 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 evaluation of phosphorylation of ERK and Akt by the peptide according to the present invention in human keratinocytes HaCaT.
  • Figure 3 shows the results of the evaluation of phosphorylation of ERK and Akt by the peptide according to the invention in mouse fibroblast NIH3T3.
  • Figure 4 shows the results of evaluating the effect of the peptides according to the invention on the proliferation of keratinocytes.
  • Figure 5 shows the results of evaluating the effect of the peptides according to the invention on collagen synthesis in fibroblasts.
  • 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 13 as an active ingredient, and comprising a pharmaceutically acceptable carrier.
  • the present invention also provides 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 13 as an active ingredient.
  • 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: 1.
  • 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, emulsion, ointment, patch, etc. 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 13 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 13 were dissolved in PBS, respectively, to prepare a concentration of 1 M.
  • the obtained protein solution was used in the following test example.
  • Human keratinocytes HaCaT (DKFZ, Heidelberg, Germany) were prepared using the peptides of SEQ ID NOs. The solutions obtained by dissolving in each were treated to 10 ⁇ M. Control means untreated group. After 15 minutes, Western blotting analysis was performed on the cell extracts to measure the change in phosphorylation of ERK and Akt, and the results are shown in FIGS. 1 and 2. As can be seen in Figures 1 and 2, the degree of phosphorylation of ERK and Akt was significantly increased by the peptides of SEQ ID NOS: 1 to 13. Therefore, it can be seen that the peptide according to the present invention activates the fibroblast growth factor receptor expressed in keratinocytes.
  • the peptide of SEQ ID NO: 1 was prepared in serum-free DMEM medium of 0.05, 0.1, 0.5, 1, 5, 10 ⁇ M.
  • Mouse fibroblast NIH3T3 (ATCC CRL-1658, USA) was treated with a solution (1 ml) obtained by lysis at a concentration. After 15 minutes, Western blotting analysis was performed on the cell extracts to measure the change in phosphorylation of ERK and Akt, and the results are shown in FIG. 3.
  • the promotion of the synthesis of glue fibers is a major means to suppress skin aging caused by ultraviolet stimulation. It was evaluated using human dermal fibroblasts Detroit 551 (ATCC CCL-110, USA) to promote collagen synthesis in fibroblasts by treatment of the peptides of the present invention. Human dermal fibroblasts were treated with a solution (1 ml) obtained by dissolving the peptide of SEQ ID NO: 1 in serum-free DMEM medium at concentrations of 0.05, 0.1, 0.5, and 1 ⁇ M. After 48 hours, Western blotting analysis was performed on the cell extracts to measure the change in the expression level of procollagen type 1, and the results are shown in FIG. 5.
  • the expression level of procollagen type 1 was increased in a concentration-dependent manner by the peptide of SEQ ID NO: 1. Therefore, it can be seen that the peptide according to the present invention can suppress aging of the skin due to collagen loss, in particular, skin wrinkles.
  • the effect of the peptides according to the invention on angiogenesis was evaluated as follows.
  • the interaction of the vascular endothelial components with vascular endothelial cells is an important factor in the formation and maintenance of neovascularization.
  • matrigel which is a complex of the bottom membrane components
  • a polymerization reaction occurs and a plug .
  • Human umbilical vein endothelial cells (HUVECs) were inoculated in a 96 well cell culture plate coated with Matrigel at a density of 1.5 x 10 4 cells / well, and the peptide of SEQ ID NO: 1 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)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Dermatology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition contenant des fragments peptidiques ou de petits peptides dérivés du facteur de croissance des fibroblastes (FGF), destinée à favoriser la cicatrisation des plaies ou à inhiber le vieillissement de la peau ou la formation des rides de la peau. Les peptides activent les récepteurs du FCF, induisant ainsi la synthèse de collagène, et présentent des activités favorisant au niveau de la peau la prolifération des kératinocytes et l'angiogenèse. En conséquence, les peptides peuvent être efficacement utilisés pour la cicatrisation des plaies et pour inhiber le vieillissement de la peau ou la formation de rides de la peau.
PCT/KR2014/006170 2014-07-09 2014-07-09 Composition contenant des fragments peptidiques dérivés du facteur de croissance des fibroblastes pour la cicatrisation des plaies ou l'inhibition de la formation des rides Ceased WO2016006733A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2014/006170 WO2016006733A1 (fr) 2014-07-09 2014-07-09 Composition contenant des fragments peptidiques dérivés du facteur de croissance des fibroblastes pour la cicatrisation des plaies ou l'inhibition de la formation des rides

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Application Number Priority Date Filing Date Title
PCT/KR2014/006170 WO2016006733A1 (fr) 2014-07-09 2014-07-09 Composition contenant des fragments peptidiques dérivés du facteur de croissance des fibroblastes pour la cicatrisation des plaies ou l'inhibition de la formation des rides

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WO2016006733A1 true WO2016006733A1 (fr) 2016-01-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170143604A1 (en) * 2015-11-19 2017-05-25 Avon Products, Inc. Peptides and Their Use in The Treatment of Hair
WO2017183942A3 (fr) * 2016-04-21 2018-08-02 주식회사 젬백스앤카엘 Peptide efficace pour augmenter la génération de collagène et composition le comprenant
WO2025110754A1 (fr) * 2023-11-22 2025-05-30 한도숙 Composition pour traiter une plaie ou inhiber la formation de rides de la peau

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5155214A (en) * 1984-03-05 1992-10-13 The Salk Institute For Biological Studies Basic fibroblast growth factor
US20060217310A1 (en) * 2004-08-17 2006-09-28 Ing-Ming Chiu Fibroblast growth factor 1 (FGF-1) used for skin care
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
US8759300B2 (en) * 2007-06-14 2014-06-24 The Research Foundation For The State University Of New York Polypeptides and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5155214A (en) * 1984-03-05 1992-10-13 The Salk Institute For Biological Studies Basic fibroblast growth factor
US20060217310A1 (en) * 2004-08-17 2006-09-28 Ing-Ming Chiu Fibroblast growth factor 1 (FGF-1) used for skin care
US8759300B2 (en) * 2007-06-14 2014-06-24 The Research Foundation For The State University Of New York Polypeptides and methods of use
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

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170143604A1 (en) * 2015-11-19 2017-05-25 Avon Products, Inc. Peptides and Their Use in The Treatment of Hair
WO2017087034A1 (fr) * 2015-11-19 2017-05-26 Avon Products, Inc. Peptides et leur utilisation dans le traitement de la peau
US10080714B2 (en) * 2015-11-19 2018-09-25 Avon Products, Inc. Peptides and their use in the treatment of hair
WO2017183942A3 (fr) * 2016-04-21 2018-08-02 주식회사 젬백스앤카엘 Peptide efficace pour augmenter la génération de collagène et composition le comprenant
WO2025110754A1 (fr) * 2023-11-22 2025-05-30 한도숙 Composition pour traiter une plaie ou inhiber la formation de rides de la peau

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