WO2024043715A1 - Composition comprenant des exosomes dérivés de cellules souches pluripotentes induites et du collagène en tant que principes actifs, et leurs utilisations - Google Patents

Composition comprenant des exosomes dérivés de cellules souches pluripotentes induites et du collagène en tant que principes actifs, et leurs utilisations Download PDF

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WO2024043715A1
WO2024043715A1 PCT/KR2023/012557 KR2023012557W WO2024043715A1 WO 2024043715 A1 WO2024043715 A1 WO 2024043715A1 KR 2023012557 W KR2023012557 W KR 2023012557W WO 2024043715 A1 WO2024043715 A1 WO 2024043715A1
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skin
ipscs
exosomes
derived
collagen
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PCT/KR2023/012557
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English (en)
Korean (ko)
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황도원
기영욱
김신일
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(주) 테라베스트
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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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
    • A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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
    • A61K8/65—Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • A61K8/981—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of mammals or bird
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/59—Mixtures
    • A61K2800/591—Mixtures of compounds not provided for by any of the codes A61K2800/592 - A61K2800/596

Definitions

  • the present invention relates to a composition for treating skin diseases and/or improving skin condition, including a composition containing induced pluripotent stem cell-derived exosomes and collagen as active ingredients.
  • Extracellular vesicles are substances with a double lipid membrane structure secreted from cells. Depending on their size, they are classified into exosomes (30-150 nm), microvesicles (50-1,000 nm), and large oncosomes (1-10 ⁇ m).
  • exosomes were first identified in the 1980s and were considered simple cellular waste at the time, but since then, exosomes have been recognized as containing various bioactive substances such as proteins, lipids, and genetic materials, and the nature and state of origin from which they were derived are known. It has been confirmed that this is reflected. The importance of these exosomes has been revealed not only in information about biological functions, but also in disease pathogenesis and disease diagnosis. Exosomes are derived from various cells such as normal cells, cancer cells, stem cells, and immune cells (Ali Hazrati1 et.al. , Biomarker Research , 10(30):1-25, 2022).
  • iPSCs Induced pluripotent stem cells
  • iPSCs are a type of embryonic stem cell and are source stem cells without ethical issues.
  • iPSCs are cells induced to have pluripotent differentiation ability through an artificial dedifferentiation process from differentiated cells, and have almost the same characteristics as embryonic stem cells.
  • iPSCs are cells that have been dedifferentiated and reprogrammed into pluripotent stem cells by the introduction of specific genes such as Oct3/4, Sox2, c-Myc, and Klf4.
  • iPSCs show gene and protein expression similar to embryonic stem cells and have the ability to differentiate into all cell lineages in the body.
  • iPSCs In addition to exploiting the regenerative properties of iPSCs for disease treatment, iPSCs have also been found to produce some regulatory factors for direct regulation of neighboring cells. iPSCs have been proven to promote sciatic nerve recovery and regeneration by upregulating nerve growth factors, and it has been shown that these regulatory factors can be released in the form of extracellular vesicles such as exosomes. Accordingly, various studies have recently been conducted on applying exosomes secreted from iPSCs to various diseases such as cardiovascular disease, liver disease, neurological disease, bone disease, etc. (Aline Yen Ling Wang, Int J Mol Sci. , 22(4) ):1769, p.1-16, 2021).
  • Korean Patent Publication No. 10-2015-0039343 discloses the use of a composition containing human embryonic stem cell culture medium to improve skin condition.
  • a composition containing human embryonic stem cell culture medium to improve skin condition.
  • ethical issues in using human embryonic stem cells and there are also problems with the effect being minimal.
  • the present inventor continued research using exosomes derived from iPSCs, which have the same characteristics as embryonic stem cells, for improving skin conditions such as improving skin wrinkles, wound regeneration, and increasing elasticity, and for treating skin diseases such as atopic dermatitis.
  • iPSCs-derived exosomes The present invention was completed by confirming that it has excellent cell proliferation and wound healing ability through the development of a complex of biocompatible polymers such as collagen and hyaluronic acid.
  • one aspect of the present invention is an induced pluripotent stem cell-derived exosome; and a pharmaceutical composition for preventing or treating skin diseases comprising collagen, hyaluronic acid, or a salt thereof as an active ingredient.
  • Another aspect of the present invention provides a cosmetic composition for improving skin condition containing induced pluripotent stem cell-derived exosomes and collagen as active ingredients.
  • Another aspect of the present invention provides a use of the pharmaceutical composition for preventing or treating skin diseases.
  • Another aspect of the present invention provides the use of the pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of skin diseases.
  • Another aspect of the present invention provides a method for preventing or treating skin diseases comprising administering the pharmaceutical composition.
  • composition containing iPSCs-derived exosomes and biocompatible polymers such as collagen and hyaluronic acid as active ingredients according to the present invention has excellent cell proliferation and wound healing effects. Accordingly, the composition of the present invention can be widely used as a cosmetic material for improving skin conditions such as improving skin wrinkles, wound regeneration, and increasing elasticity, as well as a pharmaceutical material for preventing or treating skin diseases such as atopic dermatitis. there is.
  • Figure 1 is a diagram showing the results of particle size analysis of exosomes derived from iPSCs according to an embodiment of the present invention.
  • Figure 2 is a diagram schematically showing that applying iPSCs-derived exosomes to aging skin according to an embodiment of the present invention can improve aging, that is, induce skin regeneration.
  • Figure 3a is a diagram showing the results of evaluating the proliferation ability of human fibroblasts according to treatment with exosomes derived from iPSCs culture medium. Specifically, this is a photomicrograph of the degree of proliferation of human fibroblasts on the 3rd day after treatment with exosomes derived from iPSCs culture medium.
  • Figure 3b is a diagram showing the results of evaluating the proliferation ability of human fibroblasts according to treatment with exosomes derived from iPSCs culture medium. Specifically, this is a graph showing the quantification of the absorbance analysis results measuring the degree of cell proliferation over time (0 h, 24 h, 48 h, and 72 h) after treatment with exosomes derived from iPSCs culture medium.
  • Figure 4 is a diagram showing the results of evaluating the proliferation ability of human fibroblasts according to iPSCs-derived exosome treatment. Specifically, this is a graph showing the quantification of the absorbance analysis results measuring the degree of cell proliferation over time (24h, 48h, and 72h) after treatment with exosomes derived from iPSCs culture medium and exosomes derived from lyophilized iPSCs.
  • Figure 5 is a diagram showing the results of comparative evaluation of the cell proliferation effect between exosomes of different origins. Specifically, this is a graph showing the quantification of the absorbance analysis results measuring the degree of cell proliferation over time (24h, 48h, and 72h) after treatment with exosomes derived from iPSCs and exosomes derived from MSCs.
  • Figure 6a is a diagram showing micrographs taken over time of the degree of wound recovery according to treatment with exosomes derived from iPSCs culture medium.
  • Figure 6b is a diagram showing the results of evaluating wound healing efficacy according to exosome treatment derived from iPSCs culture medium, and the degree of wound recovery is graphically shown by measuring the gap between cell wound areas.
  • Figure 7 is a diagram schematically showing the conditions for establishing the mixing ratio of iPSCs-derived exosomes and HA complexes for evaluating the cell proliferation ability of iPSCs-derived exosomes and biocompatible polymer complexes and the schedule of experiments for evaluating cell proliferation ability.
  • Figure 8 is a diagram showing the results of evaluating cell proliferation ability according to treatment at various concentrations of iPSCs-derived exosomes and HA polymer complex.
  • Figure 9 is a diagram schematically showing the iPSCs-derived exosome and biocompatible polymer complex prepared according to an embodiment of the present invention, showing a schematic diagram of the iPSCs-derived exosome complex embedded with collagen polymer.
  • Figure 10 is a diagram schematically showing the experimental conditions and schedule for evaluating the cell proliferation ability of iPSCs-derived exosomes and biocompatible polymer complexes.
  • vehicle, iPSCs-derived exosomes (40 ⁇ g), HA (100 ⁇ g), and collagen (100 ⁇ g) each contain iPSCs-derived exosomes and HA complex (HA embedded iPSCs exosome) and iPSCs-derived exosomes and collagen complex.
  • collagen embedded iPSCs exosome was used as a control.
  • Figures 11a to 11c are diagrams showing the results of evaluating the proliferation ability of human fibroblasts according to treatment of iPSCs-derived exosomes and biocompatible polymer complex.
  • human fibroblast proliferation after 24 hours (Figure 11a), 48 hours ( Figure 11b), or 72 hours (Figure 11c) of exosomes derived from iPSCs culture medium and hyaluronic acid (HA) or collagen polymer complex treatment This is a photo taken under a microscope.
  • Figure 12 is a diagram showing the results of evaluating the proliferation ability of human fibroblasts according to treatment of iPSCs-derived exosomes and biocompatible polymer complex. Specifically, this is a graph showing the quantification of the absorbance analysis results of measuring the degree of cell proliferation over time (24h, 48h, and 72h) after treatment of exosomes derived from iPSCs culture medium and hyaluronic acid (HA) or collagen polymer complex.
  • HA hyaluronic acid
  • One aspect of the present invention is iPSCs-derived exosomes; and collagen and/or hyaluronic acid.
  • composition containing iPSCs-derived exosomes and collagen
  • One aspect of the present invention is an induced pluripotent stem cell-derived exosome; and a pharmaceutical composition for preventing or treating skin diseases comprising collagen, hyaluronic acid, or a salt thereof as an active ingredient.
  • the pharmaceutical composition may include induced pluripotent stem cell-derived exosomes and collagen as active ingredients. In another embodiment, the pharmaceutical composition may include induced pluripotent stem cell-derived exosomes and hyaluronic acid or a salt thereof as active ingredients. In another embodiment, the pharmaceutical composition includes induced pluripotent stem cell-derived exosomes; Collagen, hyaluronic acid or a salt thereof may be included as active ingredients.
  • induced pluripotent stem cells refers to cells induced to have pluripotent differentiation capacity through an artificial dedifferentiation process from differentiated cells, such as somatic cells. Also referred to as stem cells.
  • the induced pluripotent stem cells can be obtained by reprogramming cells using specific dedifferentiation inducers, such as Sox2, c-Myc, Klf4, Oct-4, etc., and can differentiate into cells of various organs.
  • the induced pluripotent stem cells of the present invention include induced pluripotent stem cells derived from all mammals such as humans, monkeys, pigs, horses, cattle, sheep, dogs, cats, mice, and rabbits, but preferably induced pluripotent stem cells derived from humans. It could be a cell.
  • exosome used herein may refer to nano-sized particles that are naturally secreted by being packaged in a lipid bilayer from living cells, and play a role in transferring information between cells.
  • the size of exosomes is known to be approximately 30 nm to 250 nm in diameter, and although it varies somewhat depending on the type of cell of origin, the exosome membrane contains surface proteins (surface markers) such as CD9, CD63, and CD81, It is known that exosomes contain proteins such as TSG101 and ALIX, which can be proven to be of endosomal origin.
  • stem cell-derived exosomes are known to have effects such as regulating the differentiation of stem cells, promoting regeneration, growth, and inducing specific immune responses.
  • the iPSCs-derived exosomes may be present in iPSCs or may be obtained by extracting exosomes secreted in the culture medium of iPSCs from the culture medium.
  • iPSCs-derived exosomes are not limited thereto, but can be prepared using an exosome extraction method known in the art as follows:
  • the method may further include, but is not limited to, the following steps:
  • collagen used herein is the most commonly found protein in the human body and the most abundant protein in mammals, accounting for approximately 25 to 35% of total proteins. In particular, it is a major component of bones, tendons, and ligaments, and mainly plays a role in maintaining the structure of organs.
  • the collagen can be easily extracted from the skin of mammals such as cows or pigs, and the collagen may include collagen derivatives in addition to pure collagen.
  • its origin is not particularly limited, and for example, various collagens derived from mammals, fish, such as bovine bone, bovine skin, pig bone, pig skin, etc. can be used.
  • Collagen I to collagen IV can be used as the collagen constituting the composition according to the present invention.
  • the collagen may be collagen I and collagen III.
  • the collagen may be atelocollagen of collagen I.
  • the atelocollagen refers to collagen from which telopeptide, an antigenic substance that can cause skin hypersensitivity reactions, has been removed.
  • the pharmaceutical composition of the present invention may additionally include hyaluronic acid or a salt thereof.
  • hyaluronic acid is a biopolymer material in which repeating units consisting of N-acetyl-D-glucosamine and D-glucuronic acid are linearly linked, and has a molecular weight of 100 kDa. It is a colorless, transparent, high-viscosity linear polysaccharide ranging from 13,000 kDa to 13,000 kDa, and is extracted and extracted from various species and tissues such as vitreous humor of the eye, synovial fluid of joints, and chicken comb using acid solubilization, alkaline solubilization, neutral solubilization, and enzyme solubilization methods. It can be purified and used.
  • Viscosity, elasticity, and moisturizing properties are determined depending on the molecular weight and concentration of hyaluronic acid in the aqueous solution, and as the concentration of hyaluronic acid increases, its properties increase.
  • Hyaluronic acid is known to have different functions depending on its molecular weight.
  • the hyaluronic acid constituting the composition of the present invention may be 1.0 KDa to 3.0 MDa, 10 KDa to 2.5 MDa, 50 KDa to 2.0 MDa, or 110 KDa to 1.81 MDa.
  • the “salt of hyaluronic acid” may include a cosmetically acceptable salt of hyaluronic acid within the range of having the same efficacy as hyaluronic acid.
  • the salt of hyaluronic acid may be, for example, sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, or cobalt hyaluronate.
  • the hyaluronic acid is not limited thereto, but may be a cross-linked hyaluronic acid gel.
  • the crosslinked hyaluronic acid gel is not limited thereto, but includes, but is not limited to, 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis (2,3-epoxypropoxy)butane, 1,4-bis Selected from the group consisting of glycidyloxybutane, 1,2-bis (2,3-epoxypropoxy) ethylene and 1- (2,3-epoxypropyl) -2,3-epoxycyclohexane or combinations thereof It may be a hyaluronic acid gel cross-linked with at least one cross-linking agent.
  • BDDE 1,4-butanediol diglycidyl ether
  • 1,4-bis (2,3-epoxypropoxy)butane 1,4-bis Selected from the group consisting of glycidyloxybutan
  • the pharmaceutical composition may include collagen in an amount of 0.1 to 30% by weight based on the total weight of the composition.
  • the pharmaceutical composition contains about 1 ⁇ g to about 1000 ⁇ g, about 10 ⁇ g to about 500 ⁇ g, about 30 ⁇ g to about 200 ⁇ g, or about 50 ⁇ g of collagen. It may contain from about 100 ⁇ g. More specifically, the pharmaceutical composition may contain about 100 ⁇ g of collagen.
  • the pharmaceutical composition may include hyaluronic acid or a salt thereof in an amount of 0.1 to 30% by weight based on the total weight of the composition.
  • the pharmaceutical composition contains about 1 ⁇ g to about 1000 ⁇ g, about 10 ⁇ g to about 500 ⁇ g, about 30 ⁇ g to about 200 ⁇ g, or about 50 ⁇ g of hyaluronic acid or a salt thereof. It may contain from about 100 ⁇ g. More specifically, the pharmaceutical composition may include about 100 ⁇ g of hyaluronic acid or a salt thereof.
  • the exosomes and collagen may be mixed at a weight ratio of 1:1 to 1:10.
  • the exosomes and collagen may be mixed at a weight ratio of 1:9 to 2:8.
  • the exosomes and hyaluronic acid or a salt thereof may be mixed at a weight ratio of 1:1 to 1:10.
  • the exosomes and hyaluronic acid or a salt thereof may be mixed at a weight ratio of 1:9 to 2:8.
  • the pharmaceutical composition may include the exosomes, collagen, and hyaluronic acid or a salt thereof at a weight ratio of 1:1:1 to 1:10:10.
  • the pharmaceutical composition may include exosomes, hyaluronic acid or a salt thereof, and collagen in a weight ratio of 1:2.5:2.5.
  • the pharmaceutical composition according to the present invention can be used for preventing or treating skin diseases.
  • the “skin disease” may be selected from the group consisting of atopic dermatitis, wounds, skin wrinkles, skin aging, weakened skin elasticity, dry skin, sensitive skin, acne, hair loss, skin pigmentation, and combinations thereof, but is not limited thereto. No.
  • prevention may comprehensively mean preventing a disease in advance or reducing the possibility or frequency of occurrence of a disease by administering the pharmaceutical composition in a pharmaceutically effective amount. For example, it may be to lower the probability of developing a skin disease or to reduce the probability of recurrence in patients who are likely to develop a skin disease or have previously had it.
  • the “pharmaceutically effective amount” has the same meaning as the “therapeutically effective amount,” including the type of disease, patient’s age, weight, health, gender, patient’s sensitivity to the drug, route of administration, method of administration, number of administrations, treatment period, It can be easily determined by a person skilled in the art according to factors well known in the medical field, such as combination or drugs used simultaneously.
  • treatment may comprehensively mean improving a disease by administering the pharmaceutical composition in a pharmaceutically effective amount, and may mean alleviating or curing the symptoms of the disease in a shorter time compared to natural cure. It may be something that improves one symptom or most of the symptoms caused by a disease.
  • the pharmaceutically effective amount is the same as described above.
  • the pharmaceutical composition of the present invention may itself be a composition for treating skin diseases, or may be administered together with other pharmacological ingredients and applied as a treatment adjuvant for the diseases. Accordingly, the term “treatment” includes the meaning of “treatment assistance.”
  • the pharmaceutical composition of the present invention is administered in a “therapeutically effective amount.”
  • the therapeutically effective amount is the same as described above.
  • the term "administration" means introducing a predetermined substance into an individual by an appropriate method, and the composition may be administered through any general route as long as it can reach the target tissue. . It may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, locally, intranasally, intrapulmonaryly, or rectally, but is not limited thereto. Additionally, the pharmaceutical composition of one embodiment of the present invention may be administered by any device that allows the active agent to move to target tissues or cells. Specifically, it may be administered parenterally, and more specifically, may be administered subcutaneously or transdermally. Additionally, the pharmaceutical composition can be applied directly to the skin. When applying the pharmaceutical composition to the skin, the pharmaceutical composition according to the present invention may be applied directly to the skin or sprayed depending on its form.
  • the subject to whom the pharmaceutical composition can be administered may be a mammal, specifically, a human.
  • the appropriate dosage of the pharmaceutical composition of the present invention may be prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity. You can.
  • the dosage of the pharmaceutical composition according to the present invention is 0.001 mg/kg to 100 mg/kg for adults, and can be administered in one to several divided doses. These dosages should not be construed as limiting the scope of the invention in any respect.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means that it does not inhibit the activity of the active ingredient and does not have any toxicity beyond what the subject of application (prescription) can adapt to.
  • the carrier may be included in an amount of about 1% by weight to about 99.99% by weight, preferably about 90% by weight to about 99.99% by weight, based on the total weight of the pharmaceutical composition of the present invention.
  • the pharmaceutically acceptable carrier may be any carrier that is a non-toxic material suitable for delivery to a patient. Distilled water, alcohol, fats, waxes and inert solids may be included as carriers. Pharmaceutically acceptable adjuvants (buffers, dispersants) may also be included in the pharmaceutical composition, but are not limited thereto. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed, 1995).
  • the pharmaceutical composition When the pharmaceutical composition is prepared as a parenteral formulation, it can be formulated in the form of injections, transdermal administration, nasal inhalation, and suppositories along with a suitable carrier according to methods known in the art.
  • the pharmaceutical composition of the present invention can be prepared as an injection.
  • the injection may be an aqueous injection, a non-aqueous injection, an aqueous suspension injection, a non-aqueous suspension injection, or a solid injection used by dissolving or suspending, but is not limited thereto.
  • distilled water for injection vegetable oil (e.g., peanut oil, sesame oil, camellia oil, etc.), monoglyceride, diglyceride, propylene glycol, camphor, estradiol benzoate, bismuth subsalicylate, sodium arsenobenzoate, or streptomycin sulfate, and may optionally include a stabilizer or preservative.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is prepared for external use on the skin, it may be formulated in the form of ointment, liquid, cream, spray, patch, etc. At this time, within the range that does not impair the effect of the present invention, ingredients commonly used in cosmetics or external skin preparations, such as moisturizers, antioxidants, oily ingredients, ultraviolet absorbers, emulsifiers, surfactants, thickeners, alcohols, powder ingredients, colorants , aqueous ingredients, water, and various skin nutrients can be appropriately mixed as needed.
  • ingredients commonly used in cosmetics or external skin preparations such as moisturizers, antioxidants, oily ingredients, ultraviolet absorbers, emulsifiers, surfactants, thickeners, alcohols, powder ingredients, colorants , aqueous ingredients, water, and various skin nutrients can be appropriately mixed as needed.
  • the pharmaceutical composition of the present invention can also be prepared in the form of an injection for filler.
  • an injection for filler for example, alginic acid, carboxymethyl cellulose, chitosan, dextran, collagen, gelatin, pectin, agar, amylose. It may contain one or more carriers selected from the group consisting of amylose, cyclodextrin, and elastin.
  • the injectable composition for filler contains hyaluronic acid
  • the hyaluronic acid may have a cross-linked structure.
  • biodegradable polymer scaffolds include, for example, hyaluronic acid, polyglycolic acid (PGA), polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), and poly- ⁇ -caprolactone. (PCL), polyamino acid, polyanhydride, polyorthoester, and copolymers thereof.
  • the filler injection according to the present invention may contain a local anesthetic, antihistamine, vitamin, etc.
  • Local anesthetics include, for example, lidocaine, etidocaine, bupivacaine, tetracaine, mepivacaine, procaine, and prilocaine ( prilocaine), ropivacaine, etc., but there is no particular limitation as long as it is a local anesthetic for injection.
  • Antihistamines may include, for example, plokon (piprinhydrinate), chlorpheniramine, diphenylpyraline (piprinhydrinate), diphenhydramine, cetirizine, etc., but antihistamines for injections If it is, there are no particular restrictions.
  • the pharmaceutical composition, skin disease, prevention and treatment are the same as described above.
  • the method for preventing or treating the skin disease may include administering the pharmaceutical composition according to the present invention to the skin of a subject in need thereof.
  • the pharmaceutical composition, skin disease, treatment and prevention are the same as described above.
  • Another aspect of the present invention is induced pluripotent stem cell-derived exosomes; and a cosmetic composition for improving skin condition containing collagen, hyaluronic acid, or a salt thereof as an active ingredient.
  • the cosmetic composition may additionally include hyaluronic acid and a salt thereof.
  • hyaluronic acid and a salt thereof.
  • the contents of exosomes, collagen, and hyaluronic acid are as described above.
  • the cosmetic composition of the present invention is used to improve skin condition.
  • skin condition improvement refers to a group consisting of inhibition of wrinkles, inhibition of skin aging, improvement of skin elasticity, skin regeneration, wound healing, cornea regeneration, skin irritation relief, and combinations thereof. It can be one selected from . In addition, it may be characterized by protecting the skin from deterioration or loss of skin cell function, improving skin condition, or preventing or improving skin diseases.
  • the cosmetic composition may be formulated into a cosmetic formulation commonly prepared in the art.
  • the cosmetic compositions can be formulated as, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing products, oils, powder foundations, emulsion foundations, wax foundations and sprays. It may be converted, but is not limited to this. More specifically, it can be formulated as a softening lotion, nourishing lotion, nourishing cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray, or powder. Additionally, it can be manufactured as a filler for cosmetics.
  • Cosmetic fillers can be applied by applying to the skin surface, and may include, for example, fragrance, xanthan gum, wax, butter, oil, surfactant, moisturizer, alcohol, etc. Cosmetics that may typically include Any component of the composition may be included without particular limitation. Additionally, when the cosmetic filler composition includes hyaluronic acid, the hyaluronic acid may have a non-crosslinked structure.
  • the formulation of the cosmetic composition according to the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide and It may include a carrier component selected from the group consisting of mixtures thereof.
  • the formulation of the cosmetic composition according to the present invention may include a carrier component selected from the group consisting of a solvent that is a solution or emulsion, a solvating agent, an emulsifying agent, and mixtures thereof.
  • a carrier component selected from the group consisting of a solvent that is a solution or emulsion, a solvating agent, an emulsifying agent, and mixtures thereof.
  • examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, sorbitan fatty acid ester, and mixtures thereof, etc.
  • liquid diluents such as water, ethanol or propylene glycol
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester
  • carrier component selected from the group consisting of microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof.
  • the cosmetic composition may further include various known additives in addition to the carrier depending on the formulation.
  • the additives include emulsifiers, moisturizers, surfactants, chelating agents, antioxidants, disinfectants, stabilizers, etc.
  • the emulsifier may include liquid paraffin, cetyl oltanoate, stearic acid, etc.
  • the moisturizing agent may include a polyol selected from the group consisting of glycerin, butylene glycol, propylene glycol, dipropylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol, sorbitol, and any combination thereof.
  • the chelating agent may include sodium ethylenediaminetetraacetate (EDTA), ⁇ -hydroxy fatty acid, lactoferrin, ⁇ -hydroxy acid, citric acid, lactic acid, malic acid, bilirubin, biliverdin, etc.
  • EDTA ethylenediaminetetraacetate
  • the antioxidant may include butylhydroxyanisole, dibutylhydroxytoluene, or propyl gallate.
  • ingredients that can be mixed in the cosmetic composition or external skin preparation include fat ingredients, emollients, organic and inorganic pigments, organic powders, ultraviolet absorbers, pH adjusters, alcohol, pigments, fragrances, blood circulation promoters, coolants, antiperspirants, and vitamins. etc.
  • the cell culture substrate iMatrix 511 (Takara) was used and reacted for more than 1 hour in an incubator at 37°C and 5% CO 2 conditions.
  • iPSCs were seeded in a flask coated with iMatrix 511. At this time, it was treated with 1% penicillin-streptomycin and 10 ⁇ M Y-27631, and the medium was changed every day.
  • the iPSCs cell culture supernatant was collected and 20 mL of medium was centrifuged at 300 rcf(g). After centrifugation, cell debris was removed. Afterwards, 4 mL of exosome enrichment reagent (Invitrogen, Cat. No.
  • Exosome/polymer complexes were prepared by mixing iPSCs-derived exosomes isolated by the method of Preparation Example 1 with collagen or hyaluronic acid (FIG. 9).
  • exosomes derived from the culture medium of the iPSCs 400 ⁇ g of exosomes derived from the culture medium of the iPSCs; and 1 mg of collagen powder (Dalimthyssen, BA06091) or 1 mg of hyaluronic acid powder (Lifecore, HA1M-5) were added to PBS or D.W. and mixed by vortexing for 2 minutes. After reacting the mixture at 4°C for 10 minutes, the bubbles were removed and the mixture was mixed with exosomes; and was used as a sample during combined treatment with collagen or hyaluronic acid.
  • Example 1 Evaluation of cell proliferation effect according to exosome treatment derived from induced pluripotent stem cell culture medium
  • iPSCs induced pluripotent stem cells
  • the BJ6 cell line a human fibroblast
  • the culture was maintained for 24 hours in a medium containing 10% FBS, and then the existing medium was removed.
  • the test material was treated with medium containing 1% FBS and further cultured for 72 hours.
  • exosomes 50 ⁇ g
  • the CCK-8 solution was diluted 1/10 using medium containing 1% FBS, and 100 ⁇ L of this was treated per well. After reacting in an incubator for 2 hours, the absorbance was measured at a wavelength of 450 nm using a spectrophotometer. After measuring the absorbance, the cell proliferation rate of each group was calculated as a percentage (%) compared to the control group.
  • the cell proliferation effect can be increased by iPSCs-derived exosomes. Accordingly, it was found that it can ultimately be used to improve skin conditions such as improving skin wrinkles and wound regeneration, and improving symptoms of skin diseases such as atopic dermatitis.
  • Example 2 Evaluation of cell proliferation effect according to exosome treatment derived from freeze-dried induced pluripotent stem cells
  • iPSCs-derived exosomes were iPSCs culture medium-derived exosomes (40 ⁇ g) and freeze-dried iPSCs-derived exosomes, respectively.
  • the cell proliferation rate of each group was calculated as a percentage (%) compared to the control group (vehicle). At this time, the control group was compared and calculated by fixing it at 100% as the relative comparison value.
  • the cell proliferation rate increased by 167% in the group treated with exosomes derived from iPSCs culture fluid and by 172% in the group treated with exosomes derived from lyophilized iPSCs.
  • Example 3 Comparative evaluation of cell proliferation effect between exosomes derived from induced pluripotent stem cells and exosomes derived from umbilical cord blood mesenchymal stem cells
  • iPSCs-derived exosomes 50 ⁇ g were obtained using the human fibroblast BJ6 cell line and Cell Counting Kit-8 (CCK-8) in the same manner as in Example 1.
  • CCK-8 Cell Counting Kit-8
  • MSC umbilical cord blood mesenchymal stem cell
  • the cell proliferation rate of the test group treated with the iPSCs-derived exosomes and MSC-derived exosomes was calculated as a percentage (%) compared to the control group. At this time, the control group was compared and calculated by fixing the relative comparison value at 100%.
  • Example 4 Evaluation of wound healing efficacy according to induced pluripotent stem cell-derived exosome treatment
  • the wound healing efficacy of iPSCs-derived exosomes was evaluated using the human fibroblast BJ6 cell line and wound healing assay technique.
  • the wound healing assay is a technique that proliferates human fibroblasts on a 35 mm flask and then creates a wound using a tip of 1 mm or less.
  • the wound healing efficacy evaluation results of this experiment are used as an indicator to evaluate the efficacy of improving skin conditions such as wrinkle improvement and wound regeneration, and improving symptoms of skin diseases such as atopic dermatitis.
  • the BJ6 cell line a human fibroblast
  • the existing medium was removed and a 35 mm flask was scraped using a tip to create a wound on the cells.
  • the test material was treated with medium containing 1% FBS and further cultured for 56 hours.
  • exosomes (50 ⁇ g) isolated from control (vehicle) and iPSCs culture medium were used as test substances.
  • the wound healing efficacy effect can be increased by iPSCs-derived exosomes. Accordingly, it was found that it can ultimately be used to improve skin conditions such as improving skin wrinkles and wound regeneration, and improving symptoms of skin diseases such as atopic dermatitis.
  • Example 5 Evaluation of cell proliferation effect according to treatment of induced pluripotent stem cell-derived exosomes and hyaluronic acid complex at different concentrations
  • HA- and iPSCs-derived exosomes were mixed at 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, and 2: 8, iPSCs-derived exosomes and HA complex were prepared by mixing at a ratio of 1:9 and 0:10. Afterwards, cell proliferation ability was evaluated according to treatment with iPSCs-derived exosomes and HA complex concentrations.
  • the cell proliferation ability of iPSCs-derived exosomes and HA complexes was evaluated using the human fibroblast BJ6 cell line and Cell Counting Kit-8 (CCK-8) in the same manner as in Example 1.
  • the cell proliferation rate of the iPSCs-derived exosome and HA complex treatment group at each mixing concentration was calculated as a percentage (%) compared to the control group. At this time, the control group was compared and calculated by fixing it at 100% as the relative comparison value.
  • the number of exosomes derived from iPSCs culture medium alone (HA 0 ⁇ g + iPSCs exo 100 ⁇ g) increased by 87% in the HA alone (HA 100 ⁇ g + iPSCs exo 0 ⁇ g) group, compared to 191% in the group treated with HA alone (HA 100 ⁇ g + iPSCs exo 0 ⁇ g).
  • the cell proliferation rate increased at the % level.
  • the group treated with HA and iPSCs-derived exosomes (HA 10 ⁇ g + iPSCs exo 90 ⁇ g) fused at a mixing ratio of 1:9 showed the best cell proliferation effect at 196% (Figure 8) .
  • Example 6 Evaluation of cell proliferation effect of induced pluripotent stem cell-derived exosomes and biocompatible polymer complex
  • Example 5 In order to confirm whether the biocompatible polymer applied in Example 5 shows an excellent cell proliferation effect even when using a polymer other than hyaluronic acid, a collagen complex containing exosomes derived from iPSCs was prepared using an additional collagen polymer (FIG. 9) . Based on the results derived in Example 5, exosomes and biocompatible polymer complexes derived from iPSCs culture fluid were prepared at the optimal mixing ratio and cell proliferation ability was evaluated.
  • a collagen complex containing exosomes derived from iPSCs culture medium 1 mg of collagen powder and 400 ⁇ g of exosomes derived from iPSCs were added to 1 mL of distilled water and mixed by vortexing for 2 minutes. Afterwards, it was maintained at 4°C for 10 minutes, and the bubbles generated by vortexing were removed.
  • the iPSCs-derived exosome complex (collagen embedded iPSCs driven exosome) prepared according to the same method as above was used to evaluate cell proliferation ability. At this time, the final combined concentration of the complex was 40 ⁇ g of iPSCs-derived exosomes and 100 ⁇ g of collagen.
  • the iPSCs-derived exosome (40 ⁇ g) and HA polymer (100 ⁇ g) complex tested in Example 5 was prepared to have the same final mixing concentration, and the complex of the two iPSCs-derived exosomes and the biocompatible polymer complex was prepared. The cell proliferation effect was compared and evaluated.
  • the experiment was conducted in the same manner as in Example 1, according to the experimental conditions and schedule as shown in Figure 10.
  • Cell proliferation ability was evaluated over 24 hours, 48 hours, and 72 hours using the BJ6 cell line and Cell Counting Kit-8 (CCK-8).
  • the control substances used were vehicle, hyaluronic acid alone (HA, 100 ⁇ g), exosomes derived from iPSCs culture (40 ⁇ g), and collagen alone (collagen, 100 ⁇ g), and the test substance was hyaluronic acid (HA, 100 ⁇ g).
  • 100 ⁇ g) and iPSCs culture medium-derived exosomes (40 ⁇ g) fusion material and collagen (100 ⁇ g) and iPSCs culture medium-derived exosomes (40 ⁇ g) were used.
  • Example 2 To measure the survival rate of cells, the same procedure as in Example 1 was performed except that 200 ⁇ L of CCK-8 solution was applied to each well, and after completion of the reaction, the absorbance was measured using a spectrophotometer. After measuring the absorbance, the cell proliferation rate of each experimental group was calculated as a percentage (%) compared to the control group (vehicle). At this time, the control group was compared and calculated by fixing it at 100% as the relative comparison value.
  • exosomes derived from iPSCs culture fluid alone increased by 130% in the HA-only (HA 100 ⁇ g) treatment group and 189% in the collagen-only (collagen 100 ⁇ g) treatment group.
  • the cell proliferation rate increased to 264%.
  • exosomes and collagen polymer complex derived from iPSCs culture medium showed a cell proliferation rate of 256%.
  • exosomes and HA polymer complex derived from iPSCs culture medium showed a cell proliferation rate of 280%.
  • iPSCs-derived exosomes especially iPSCs-derived exosomes, and HA complex as a biocompatible polymer can induce excellent cell proliferation effects. Accordingly, it was found that it can ultimately be used to improve skin conditions such as improving skin wrinkles and wound regeneration, and improving symptoms of skin diseases such as atopic dermatitis.

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Abstract

La présente invention concerne une composition et ses utilisations, la composition comprenant, en tant que principes actifs, des exosomes dérivés de cellules souches pluripotentes induites, et du collagène ou de l'acide hyaluronique ou des sels de ceux-ci. La composition selon la présente invention présente une excellente prolifération cellulaire et des effets de cicatrisation de plaie, et peut ainsi être efficacement utilisée en tant que matériau cosmétique pour une amélioration de l'état de la peau telle qu'une réduction des rides de la peau, une régénération de la peau au site de la plaie et une élasticité accrue, et peut également être utilisée dans un matériau médical pour prévenir ou traiter des maladies de la peau telles que la dermatite atopique.
PCT/KR2023/012557 2022-08-24 2023-08-24 Composition comprenant des exosomes dérivés de cellules souches pluripotentes induites et du collagène en tant que principes actifs, et leurs utilisations WO2024043715A1 (fr)

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