WO2022170940A1 - Extrait de graisse exempt de cellules destiné à être utilisé pour améliorer le vieillissement et favoriser le rajeunissement de la peau - Google Patents

Extrait de graisse exempt de cellules destiné à être utilisé pour améliorer le vieillissement et favoriser le rajeunissement de la peau Download PDF

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WO2022170940A1
WO2022170940A1 PCT/CN2022/073020 CN2022073020W WO2022170940A1 WO 2022170940 A1 WO2022170940 A1 WO 2022170940A1 CN 2022073020 W CN2022073020 W CN 2022073020W WO 2022170940 A1 WO2022170940 A1 WO 2022170940A1
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skin
cell
preparation
extract
another preferred
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PCT/CN2022/073020
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English (en)
Chinese (zh)
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张文杰
蔡宜佐
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上海萨美细胞技术有限公司
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Publication of WO2022170940A1 publication Critical patent/WO2022170940A1/fr

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    • 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
    • A61K35/35—Fat tissue; Adipocytes; Stromal cells; Connective tissues
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • 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
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • 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
    • A61P17/18—Antioxidants, e.g. antiradicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B1/00—Production of fats or fatty oils from raw materials
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the field of medicine, in particular to the use of cell-free fat extracts for improving aging and promoting skin rejuvenation.
  • Skin aging is an inevitable process.
  • the early manifestations of skin aging are mainly reflected in periorbital aging, manifested as periorbital wrinkles, skin sagging, decreased elasticity and pigmentation.
  • the current treatment of skin aging (such as periorbital aging) mainly includes surgical treatment and non-surgical treatment.
  • non-surgical treatment due to the problems of long recovery period and scarring in surgical treatment, the research focus is on non-surgical treatment.
  • Non-surgical treatment includes physical therapy and biological therapy.
  • the former is mainly laser therapy, which can produce thermal effects on tissues and stimulate local collagen synthesis through selective photothermal action, thereby achieving the effect of treating periorbital aging.
  • laser therapy can produce thermal effects on tissues and stimulate local collagen synthesis through selective photothermal action, thereby achieving the effect of treating periorbital aging.
  • the purpose of the present invention is to provide the use of a cell-free fat extract in improving skin aging and/or promoting skin rejuvenation.
  • a first aspect of the present invention provides the use of a cell-free fat extract for preparing a composition or formulation for improving skin aging and/or promoting skin rejuvenation.
  • the skin aging includes periorbital skin aging.
  • described skin aging includes one or more manifestations selected from the following group:
  • the wrinkles include fine lines and/or coarse lines.
  • the improvement of skin aging and/or the promotion of skin rejuvenation comprises one or more methods selected from the following group:
  • the improving skin aging and/or promoting skin rejuvenation has one or more characteristics selected from the group consisting of:
  • the cell-free fat extract is a cell-free fat extract prepared from human or non-human mammalian fat.
  • the non-human mammal is monkey, orangutan, cow, pig, dog, sheep, mouse or rabbit.
  • compositions or preparations include pharmaceutical compositions or preparations, food compositions or preparations, health product compositions or preparations, or dietary supplements.
  • composition or preparation further includes a pharmaceutically, food, health product or dietary acceptable carrier.
  • composition or preparation further includes other drugs for improving skin aging and/or promoting skin rejuvenation.
  • the other drugs for improving skin aging and/or promoting skin rejuvenation are selected from the group consisting of skin fillers, anti-wrinkle drugs, and ingredients for nourishing skin
  • the skin filling material is selected from the group consisting of hyaluronic acid, collagen, or a combination thereof.
  • the anti-wrinkle drug includes botulinum toxin.
  • the ingredients for nourishing the skin include vitamins.
  • the vitamin component is selected from the group consisting of vitamin B1, vitamin B2, vitamin B12, vitamin C, vitamin D, vitamin E, or a combination thereof.
  • the dosage form of the composition or preparation is an oral preparation, an external preparation or an injection preparation.
  • the injection preparation is an intravenous injection or an intramuscular injection.
  • the injection preparation is an intradermal injection preparation.
  • the injection preparation is an intradermal injection preparation of periorbital skin.
  • the dosage form of the composition or preparation is a solid dosage form, a semi-solid dosage form, or a liquid dosage form, such as solution, gel, cream, lotion, ointment, cream, paste, cake, powder, Patches etc.
  • the dosage form of the composition or preparation is powder, granule, capsule, injection, tincture, oral liquid, tablet or lozenge.
  • composition or preparation is administered externally, topically, or by injection.
  • the injection preparation is an intradermal injection preparation.
  • the injection preparation is an intradermal injection preparation of periorbital skin.
  • the cell-free fat extract does not contain cells and does not contain lipid droplets.
  • the lipid droplets are oil droplets released after fat cells are disrupted.
  • the "does not contain lipid droplets" means that in the cell-free fat extract, the volume of oil droplets accounts for less than 1% of the total liquid, preferably less than 0.5%, more preferably less than 0.1%.
  • the cells are selected from the group consisting of endothelial cells, adipose stem cells, macrophages, and stromal cells.
  • the "cell-free” refers to the average number of cells in 1 ml of cell-free fat extract ⁇ 1, preferably ⁇ 0.5, more preferably ⁇ 0.1, or 0.
  • the cell-free fat extract is a naturally-obtained nano-fat extract without added components.
  • the "no added components” means that, except for the rinsing step, no solution, solvent, small molecule, chemical agent, and biological additive are added during the preparation of the fat extract.
  • the cell-free adipose extract is prepared by centrifuging adipose tissue after emulsification.
  • the cell-free fat extract contains one or more components selected from the group consisting of IGF-1, BDNF, GDNF, TGF- ⁇ 1, HGF, bFGF, VEGF, TGF- ⁇ 1 , PDGF, EGF, NT-3, GH, G-CSF, or a combination thereof.
  • the cell-free fat extract contains, but is not limited to, one or more components selected from the group consisting of IGF-1, BDNF, GDNF, bFGF, VEGF, TGF- ⁇ 1, HGF , PDGF, or a combination thereof.
  • the cell-free fat extract is a cell-free fat extract.
  • the concentration of the IGF-1 is 5000-30000pg/ml, preferably 6000-20000pg/ml, more preferably 7000-15000pg/ml , more preferably 8000-12000pg/ml, more preferably 9000-11000pg/ml, more preferably 9500-10500pg/ml.
  • the concentration of BDNF is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more Preferably 1400-2000 pg/ml, more preferably 1600-2000 pg/ml, more preferably 1700-1850 pg/ml.
  • the concentration of GDNF is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more Preferably 1400-2000 pg/ml, more preferably 1600-2000 pg/ml, more preferably 1700-1900 pg/ml.
  • the concentration of the bFGF is 50-600pg/ml, preferably 100-500pg/ml, more preferably 120-400pg/ml, more Preferably 150-300 pg/ml, more preferably 200-280 pg/ml, more preferably 220-260 pg/ml.
  • the concentration of the VEGF is 50-500pg/ml, preferably 100-400pg/ml, more preferably 120-300pg/ml, more Preferably 150-250 pg/ml, more preferably 170-230 pg/ml, more preferably 190-210 pg/ml.
  • the concentration of TGF- ⁇ 1 is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml , more preferably 800-1200pg/ml, more preferably 800-1100pg/ml, more preferably 900-1000pg/ml.
  • the concentration of the HGF is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more Preferably 600-1200 pg/ml, more preferably 800-1000 pg/ml, more preferably 850-950 pg/ml.
  • the concentration of PDGF is 50-600pg/ml, preferably 80-400pg/ml, more preferably 100-300pg/ml, more Preferably 140-220 pg/ml, more preferably 160-200 pg/ml, more preferably 170-190 pg/ml.
  • the weight ratio of IGF-1 to VEGF is 20-100:1, preferably 30-70:1, more preferably 40-60:1, most preferably 45-55: 1.
  • the weight ratio of BDNF to VEGF is 2-20:1, preferably 4-15:1, more preferably 6-12:1, and most preferably 8-9.5:1.
  • the weight ratio of GDNF to VEGF is 2-20:1, preferably 4-15:1, more preferably 6-12:1, and most preferably 8.5-9.5:1.
  • the weight ratio of bFGF to VEGF is 0.2-8:1, preferably 0.5-5:1, more preferably 0.6-2:1, more preferably 0.8-1.6:1, Optimally 1-1.5:1.
  • the weight ratio of TGF- ⁇ 1 to VEGF is 1-20:1, preferably 1-15:1, more preferably 1-10:1, more preferably 2-8: 1, preferably 4-6:1.
  • the weight ratio of HGF to VEGF is 1-20:1, preferably 1-15:1, more preferably 1-10:1, more preferably 2-8:1, More preferably 4-5.5:1.
  • the weight ratio of PDGF to VEGF is 0.1-3:1, preferably 0.2-2:1, more preferably 0.4-1.5:1, and most preferably 0.7-1.2:1.
  • the cell-free fat extract is prepared by the following method:
  • Emulsifying the intermediate layer to obtain an emulsified fat mixture also referred to as nano-fat
  • a second aspect of the present invention provides a method for preparing a cell-free fat extract, the method comprising the steps of:
  • Emulsifying the intermediate layer to obtain an emulsified fat mixture also referred to as nano-fat
  • the cell-free fat extract is as described in the first aspect of the present invention.
  • the centrifugation is performed at 800-2500g, preferably 800-2000g, more preferably 1000-1500g, and most preferably 1100-1300g.
  • the centrifugation time is 1-15 minutes, preferably 1-10 minutes, more preferably 1-8 minutes, and optimally 1-5 minutes.
  • the temperature of the centrifugation is 2-6°C.
  • the emulsification is mechanical emulsification.
  • the mechanical emulsification is performed mechanically by repeated blowing through a syringe (eg 20-200 times, preferably 20-150 times, more preferably 20-100 times, more preferably 30-50 times). emulsification.
  • the method of blowing and beating is that two 10ml injection syringes are connected with a tee tube to repeatedly push and beat at a constant speed.
  • the emulsification is a method of crushing by a tissue homogenizer.
  • the emulsified fat mixture is further frozen and then thawed.
  • the thawed mixture is used for centrifugation after thawing after freezing.
  • the freezing temperature is -50°C to -120°C, preferably -60°C to -100°C, more preferably -70°C to -90°C.
  • the thawing temperature is 20-40°C, preferably 25-40°C, more preferably 37°C.
  • the number of cycles of thawing after freezing is 1-5 times (preferably 1, 2, 3 or 4 times).
  • the emulsified fat mixture is layered into four layers, the first layer is an oil layer, the second layer is a residual adipose tissue layer, and the third layer is a liquid layer layer (ie, the middle liquid layer), and the fourth layer is the cell/tissue debris sedimentation layer.
  • the centrifugation is performed at 800-2500g, preferably 800-2000g, more preferably 1000-1500g, and most preferably 1100-1300g.
  • the centrifugation time is 1-15 minutes, preferably 1-10 minutes, more preferably 2-8 minutes, and optimally 3-7 minutes.
  • the temperature of the centrifugation is 2-6°C.
  • the first layer, the second layer, the third layer and the fourth layer are arranged in order from top to bottom.
  • the intermediate liquid layer is a transparent or substantially transparent layer.
  • the filtration and sterilization are performed through a filter (eg, a 0.22 ⁇ m microporous membrane).
  • a filter eg, a 0.22 ⁇ m microporous membrane
  • the filter is a microporous membrane filter.
  • the pore size of the microporous filter membrane is 0.05-0.8 ⁇ m, preferably 0.1-0.5 ⁇ m, more preferably 0.1-0.4 ⁇ m, more preferably 0.15-0.3 ⁇ m, more preferably 0.2-0.25 ⁇ m, optimally 0.22 ⁇ m.
  • the filtration and sterilization are firstly passed through a first filter that can filter out cells, and then passed through a second filter that can filter out pathogens (such as bacteria).
  • filter eg, 0.22 ⁇ m filter.
  • the step (6) further includes sub-packaging the fat extract to form a sub-packaged product.
  • the subpackaged extract can be stored at -20°C for later use; it can be used directly after thawing at low temperature (such as -4°C) or normal temperature, or it can be stored at low temperature (such as 4°C) for a period of time after thawing, and then used ).
  • the third aspect of the present invention provides a cell-free fat extract, which is prepared by the method described in the second aspect of the present invention.
  • the fourth aspect of the present invention provides a composition or preparation for improving skin aging and/or promoting skin rejuvenation, the composition or preparation comprising (a) the acellular fat according to the third aspect of the present invention an extract; and (b) a pharmaceutically, food, nutraceutical or dietary acceptable carrier or excipient.
  • the composition is a pharmaceutical composition, a food composition, a health product composition or a dietary supplement.
  • the dosage form of the composition or preparation is an oral preparation, an external preparation or an injection preparation.
  • the dosage form of the composition or preparation is powder, granule, capsule, injection, tincture, oral liquid, tablet or lozenge.
  • the injection is an intravenous injection or an intramuscular injection.
  • the injection preparation is an intradermal injection preparation.
  • the injection preparation is an intradermal injection preparation of periorbital skin.
  • the dosage form of the composition or preparation is a solid dosage form, a semi-solid dosage form, or a liquid dosage form, such as solution, gel, cream, lotion, ointment, cream, paste, cake, powder, Patches etc.
  • the mass percentage of the cell-free fat extract is 5 wt %, preferably 1-20 wt %, based on the total weight of the composition or preparation.
  • the fifth aspect of the present invention provides a method for preparing the composition or preparation according to the fourth aspect of the present invention, the method comprising the steps of: mixing the cell-free fat extract according to the third aspect of the present invention with a pharmaceutical It is mixed with acceptable carriers or excipients on food, health product or diet to form a composition or preparation.
  • the sixth aspect of the present invention provides a method for improving skin aging and/or promoting skin rejuvenation, by applying the cell-free fat extract according to the third aspect of the present invention to a subject in need.
  • the subject is a human or a non-human mammal.
  • the non-human mammals include rodents, such as rats and mice.
  • the administration mode is oral administration, topical administration or injection administration.
  • the injection is intradermal injection.
  • the injection is intradermal injection of the periorbital skin.
  • the dose administered by injection is 0.05-0.2 mL of acellular fat extract/1 cm of skin.
  • Figure 1 is a photo of the periorbital skin after CEFFE treatment, where Pre-treatment is before treatment, 3M-fellow up, 6M-fellow up and 12M-fellow up are follow-up at 3, 6 and 12 months after treatment, respectively.
  • Figure 2 shows the change in skin roughness of the periorbital skin after CEFFE treatment, where Pre represents before CEFFE administration, 1st, 2nd, 3rd, 4th and 5th are the 1st, 2nd, 3rd, 4th and 5th CEFFE administration, respectively Medication time, 3m, 6m and 12m were 3, 6 and 12 months after the end of treatment, respectively.
  • Figure 3 shows the changes of skin elasticity of the periorbital skin after CEFFE treatment, where Pre represents the time before CEFFE administration, 1st, 2nd, 3rd, 4th and 5th are the 1st, 2nd, 3rd, 4th and 5th times of CEFFE administration, respectively , 3m, 6m and 12m were 3, 6 and 12 months after the end of treatment, respectively.
  • Figure 4 shows the water loss of the periorbital skin after CEFFE treatment.
  • Pre represents the time before CEFFE administration
  • 1st, 2nd, 3rd, 4th, and 5th are the 1st, 2nd, 3rd, 4th, and 5th times of CEFFE administration, respectively
  • 3m, 6m, and 12m are the 3rd, 6th, and 6th time after the treatment, respectively. and December.
  • a cell-free fat extract has an excellent improving effect on skin aging.
  • the research of the examples of the present invention shows that the cell-free fat extract of the present invention has an excellent therapeutic effect on skin aging.
  • the present invention has been completed on this basis.
  • the terms “comprising,” “including,” and “containing” are used interchangeably to include not only open definitions, but also semi-closed, and closed definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • IGF-1 insulin-like growth factors-1
  • BDNF brain-derived neurotrophic factor
  • GDNF glial cellline-derived neurotrophic factor
  • bFGF basic fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • TGF- ⁇ 1 is referred to as transforming growth factor- ⁇ 1.
  • HGF Hepatocyte Growth Factor
  • PDGF Platelet derived growth factor
  • EGF Epidermal Growth Factor
  • NT-3 As used in the text, the term "NT-3" is referred to as neurotrophins-3.
  • GH Growth Hormone
  • G-CSF granulocyte colony stimulating factor
  • CEFFE Cell free fat extract
  • the terms "cell-free adipose extract of the present invention”, “extract of the present invention”, “fat extract of the present invention” and the like are used interchangeably to refer to the process during the preparation of the fat extract (other than the rinsing step) )
  • An adipose tissue-derived extract (or extract) prepared without the addition of any solutions, solvents, small molecules, chemicals, and biological additives.
  • a typical method for preparing the extract of the present invention is as described above in the second aspect of the present invention.
  • the extract of the present invention does not have to add any additives (or added components) during the preparation process, some or small amounts of safe substances (such as small amounts) that do not negatively or adversely affect the activity of the extract of the present invention may also be added. water).
  • the cell-free fat extract of the present invention can be derived from human adipose tissue, which is purified from nano-fat by removing oil and cell/extracellular matrix fractions after centrifugation, and is a cell-free, easy-to-prepare, rich in various growth factor liquid.
  • the cell-free fat extract is a cell-free fat extract.
  • the cell-free adipose extract of the present invention various cytokines may be included.
  • the cell-free adipose extract comprises IGF-1, BDNF, GDNF, TGF- ⁇ , HGF, bFGF, VEGF, TGF- ⁇ 1, PDGF, EGF, NT-3, GH and G-CSF one or more.
  • the concentration of the IGF-1 is 5000-30000pg/ml, preferably 6000-20000pg/ml, more preferably 7000-15000pg/ml , more preferably 8000-12000pg/ml, more preferably 9000-11000pg/ml, more preferably 9500-10500pg/ml.
  • the concentration of BDNF is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more Preferably 1400-2000 pg/ml, more preferably 1600-2000 pg/ml, more preferably 1700-1850 pg/ml.
  • the concentration of GDNF is 800-5000pg/ml, preferably 1000-4000pg/ml, more preferably 1200-2500pg/ml, more Preferably 1400-2000 pg/ml, more preferably 1600-2000 pg/ml, more preferably 1700-1900 pg/ml.
  • the concentration of the bFGF is 50-600pg/ml, preferably 100-500pg/ml, more preferably 120-400pg/ml, more Preferably 150-300 pg/ml, more preferably 200-280 pg/ml, more preferably 220-260 pg/ml.
  • the concentration of the VEGF is 50-500pg/ml, preferably 100-400pg/ml, more preferably 120-300pg/ml, more Preferably 150-250 pg/ml, more preferably 170-230 pg/ml, more preferably 190-210 pg/ml.
  • the concentration of TGF- ⁇ 1 is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml , more preferably 800-1200pg/ml, more preferably 800-1100pg/ml, more preferably 900-1000pg/ml.
  • the concentration of the HGF is 200-3000pg/ml, preferably 400-2000pg/ml, more preferably 600-1500pg/ml, more Preferably 600-1200 pg/ml, more preferably 800-1000 pg/ml, more preferably 850-950 pg/ml.
  • the concentration of PDGF is 50-600pg/ml, preferably 80-400pg/ml, more preferably 100-300pg/ml, more Preferably 140-220 pg/ml, more preferably 160-200 pg/ml, more preferably 170-190 pg/ml.
  • the weight ratio of IGF-1 to VEGF is 20-100:1, preferably 30-70:1, more preferably 40-60:1, most preferably 45-55: 1.
  • the weight ratio of BDNF to VEGF is 2-20:1, preferably 4-15:1, more preferably 6-12:1, and most preferably 8-9.5:1.
  • the weight ratio of GDNF to VEGF is 2-20:1, preferably 4-15:1, more preferably 6-12:1, and most preferably 8.5-9.5:1.
  • the weight ratio of bFGF to VEGF is 0.2-8:1, preferably 0.5-5:1, more preferably 0.6-2:1, more preferably 0.8-1.6:1, Optimally 1-1.5:1.
  • the weight ratio of TGF- ⁇ 1 to VEGF is 1-20:1, preferably 1-15:1, more preferably 1-10:1, more preferably 2-8: 1, preferably 4-6:1.
  • the weight ratio of HGF to VEGF is 1-20:1, preferably 1-15:1, more preferably 1-10:1, more preferably 2-8:1, More preferably 4-5.5:1.
  • the weight ratio of PDGF to VEGF is 0.1-3:1, preferably 0.2-2:1, more preferably 0.4-1.5:1, and most preferably 0.7-1.2:1.
  • the cell-free fat extract of the present invention is prepared by the method as described in the second aspect of the present invention.
  • the cell-free fat extracts of the present invention are prepared by the following methods:
  • Emulsifying the intermediate layer to obtain an emulsified fat mixture also referred to as nano-fat
  • the centrifugation is performed at 800-2500g, preferably 800-2000g, more preferably 1000-1500g, and most preferably 1100-1300g.
  • the centrifugation time is 1-15 minutes, preferably 1-10 minutes, more preferably 1-8 minutes, and optimally 1-5 minutes.
  • the emulsification is mechanical emulsification.
  • the mechanical emulsification is performed mechanically by repeated blowing through a syringe (eg 20-200 times, preferably 20-150 times, more preferably 20-100 times, more preferably 30-50 times). emulsification.
  • the blowing method is to repeatedly push and beat at a constant speed with two 10ml injection syringes connected to a tee tube.
  • the emulsification is a method of crushing by a tissue homogenizer.
  • the emulsified fat mixture is further frozen and then thawed.
  • the thawed mixture is used for centrifugation after thawing after freezing.
  • the freezing temperature is -50°C to -120°C, preferably -60°C to -100°C, more preferably -70°C to -90°C.
  • the thawing temperature is 20-40°C, preferably 25-40°C, more preferably 37°C.
  • the number of cycles of thawing after freezing is 1-5 times (preferably 1, 2, 3 or 4 times).
  • the emulsified fat mixture is layered into four layers, the first layer is an oil layer, the second layer is a residual adipose tissue layer, and the third layer is a liquid layer layer (ie, the middle liquid layer), and the fourth layer is the cell/tissue debris sedimentation layer.
  • the centrifugation is performed at 800-2500g, preferably 800-2000g, more preferably 1000-1500g, and most preferably 1100-1300g.
  • the centrifugation time is 1-15 minutes, preferably 1-10 minutes, more preferably 2-8 minutes, and optimally 3-7 minutes.
  • the first layer, the second layer, the third layer and the fourth layer are arranged in order from top to bottom.
  • the intermediate liquid layer is a transparent or substantially transparent layer.
  • the filter bag in the step (6), can remove the adipocytes in the primary fat extract.
  • the filtration and sterilization are performed through a filter (eg, a 0.22 ⁇ m microporous membrane).
  • a filter eg, a 0.22 ⁇ m microporous membrane
  • the filter is a microporous membrane filter.
  • the pore size of the microporous filter membrane is 0.05-0.8 ⁇ m, preferably 0.1-0.5 ⁇ m, more preferably 0.1-0.4 ⁇ m, more preferably 0.15-0.3 ⁇ m, more preferably 0.2-0.25 ⁇ m, optimally 0.22 ⁇ m.
  • the filtration and sterilization are firstly passed through a first filter that can filter out cells, and then passed through a second filter that can filter out pathogens (such as bacteria).
  • filter eg, 0.22 ⁇ m filter.
  • the step (6) further includes sub-packaging the fat extract to form a sub-packaged product.
  • the subpackaged extract can be stored at -20°C for later use; it can be used directly after thawing at low temperature (such as -4°C) or normal temperature, or it can be stored at low temperature (such as 4°C) for a period of time after thawing, and then used ).
  • the present invention provides the use of a cell-free fat extract for the preparation of a composition or formulation for improving skin aging and/or promoting skin rejuvenation.
  • the term “improving” includes prevention and/or treatment.
  • prevention refers to a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease. "Prevention” as used herein also includes delaying the onset of the disease and/or its attendant symptoms and reducing the risk of the disease in a subject.
  • Treatment includes delaying and stopping the progression of the disease, or eliminating the disease, and does not require 100% inhibition, elimination and reversal.
  • the cell-free fat extract of the present invention reduces, inhibits and/or reverses skin aging, eg, by at least about 10%, at least about 30%, at least about 50%, or at least about 80%.
  • the aging skin site is not particularly limited.
  • the skin aging includes periorbital skin aging.
  • described skin aging includes one or more manifestations selected from the following group:
  • the wrinkles include fine lines and/or coarse lines.
  • the improvement of skin aging and/or the promotion of skin rejuvenation comprises one or more methods selected from the group consisting of:
  • the present invention also provides a method of improving skin aging and/or promoting skin rejuvenation by administering the cell-free fat extract of the present invention to a subject in need thereof.
  • the subject is a human or a non-human mammal.
  • the non-human mammals include rodents, such as rats and mice.
  • the administration mode is oral administration, topical administration or injection administration.
  • the injection is intradermal injection.
  • the injection is intradermal injection of the periorbital skin.
  • compositions described in the present invention include (but are not limited to): pharmaceutical compositions, food compositions, health care compositions, dietary supplements, and the like.
  • the cell-free fat extracts of the present invention can be prepared into pharmaceutical compositions such as tablets, capsules, powders, microparticles, solutions, lozenges, jellies, creams, elixirs, suspensions, Dosage forms such as tinctures, poultices, liniments, lotions, and aerosols.
  • Pharmaceutical compositions can be prepared by generally known preparation techniques, and suitable pharmaceutical additives can be added to the medicament.
  • composition of the present invention may also include a pharmaceutically, food, health product or dietary acceptable carrier.
  • “Pharmaceutically, food, nutraceutical or dietary acceptable carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
  • “Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • acceptable carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.) , gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol) etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular), topical, and preferred modes of administration are oral administration and injection.
  • the injection administration is intradermal injection, preferably intradermal injection of the periorbital skin.
  • the dosage form of the composition or preparation of the present invention is an oral preparation, an external preparation or an injection preparation.
  • solid dosage forms for oral administration or administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as sodium citrate
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents.
  • Liquid dosage forms for oral administration or administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the injection preparation is an intradermal injection preparation, preferably, the injection preparation is an intradermal injection preparation of the periorbital skin.
  • Dosage forms for topical administration or administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the cell-free adipose extract of the present invention may be administered or administered alone, or in combination with other drugs for preventing and/or treating fatty liver and/or its complications.
  • a safe and effective amount of the cell-free fat extract of the present invention is suitable for human or non-human animals (such as rats, mice, dogs, cats, cows, chickens, ducks, etc.) in need of treatment, wherein the administration
  • the current dose is the effective dose that can be considered as acceptable in pharmacy, food or health care products.
  • the term "safe and effective amount” refers to an amount that produces function or activity in humans and/or animals and is acceptable to humans and/or animals. Those of ordinary skill in the art should understand that the "safe and effective amount” may vary with the form of the pharmaceutical composition, the route of administration, the excipients of the drug used, the severity of the disease, and the combination with other drugs, etc. different.
  • the daily dose is usually 0.1 to 1000 mg, preferably 1 to 600 mg, more preferably 2 to 300 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention finds for the first time that the cell-free fat extract has an excellent therapeutic effect on skin aging and promotes skin rejuvenation.
  • the cell-free fat extract of the present invention is a cell-free component that can avoid cell-related problems in clinical applications, including, for example, genetic stability after cell processing, cell viability and viability after injection, The multiple administration and storage of cells, and the immunogenicity of cells when using allogeneic fat, the cell-free fat extract of the present invention has the advantages of higher safety and lower side effects in the preparation and prevention of skin aging .
  • Adipose tissue was obtained from 6 healthy women who underwent conventional liposuction, with an average age of 31 years (24-36 years). After local injection of tumescent fluid anesthesia, a 3mm liposuction cannula with a large lateral hole (2mm x 7mm) was used to connect a 20mL syringe, and radial suction was performed under artificial negative pressure. Rinse 3 times with normal saline.
  • the middle layer ie, the fat layer containing adipocytes
  • the mechanically emulsified fat mixture was placed in a -80°C refrigerator for freezing, and then thawed in a 37°C water bath. After a single freeze-thaw cycle, the thawed fat mixture was centrifuged at 1200g at 4°C for 5 minutes to obtain fractions.
  • the layered mixture is divided into 4 layers, the first layer is the oil layer, the second layer is the residual adipose tissue layer, the third layer is the liquid layer, and the fourth layer is the cell/tissue debris precipitation layer, remove the oil layer and For the residual adipose tissue layer, the liquid layer is sucked, and the contamination of the cell/tissue debris sediment layer is avoided during the sucking process, so as to obtain the initial fat extraction solution.
  • the content of cytokines including IGF-1, BDNF, GDNF, bFGF, VEGF, TGF- ⁇ 1, HGF and PDGF, was detected by ELISA immunosorbent assay kit.
  • the average concentrations of 6 samples were as follows: IGF-1 (9840.6pg/ml), BDNF (1764.5pg/ml), GDNF (1831.9pg/ml), bFGF (242.3pg/ml), VEGF (202.9pg/ml), TGF- ⁇ 1 (954.5 pg/ml), HGF (898.4 pg/ml) and PDGF (179.9 pg/ml).
  • the injection was performed 1 hour after the periorbital topical anesthetic was applied.
  • the intradermal drip injection technique was used to inject 0.1 mL of CEFFE every 1 cm from the lateral orbital canthus to the medial canthus, and from the lower eyelid margin to the infraorbital margin from 0.5 cm.
  • treatment was performed with a total of 5 injections, followed by follow-up at 3, 6, and 12 months after the end of treatment.
  • the Vivoscan skin detector (CK, Germany) was used to detect the three points of the infraorbital inside and outside.
  • SEr periorbital skin roughness parameters
  • SEsm skin smoothness parameters
  • the skin elasticity of the medial and lateral orbital skin was measured by MPA580 skin measuring instrument (CK, Germany), and the total elasticity value R2, net elasticity value R5 and elasticity were recorded. The data of the value number R7. Also according to the above calculation formula, the change of skin elasticity around the orbit after operation was calculated with the preoperative as the base point.
  • the water loss of the medial and lateral skin in the periorbital periorbital area will be detected by the water loss test probe Tewameter TM300 instrument (CK, Germany) at each visit, and the data of transepidermal water loss (TEWL (transepidermal waterloss)) value will be recorded. to evaluate skin barrier function.
  • TEWL transepidermal water loss
  • SEr is the skin roughness parameter, representing the roughness of the skin, the smaller the value, the less rough the skin
  • SEsm is the skin smoothness parameter, representing the fineness of the skin, the smaller the value, the smoother and finer the skin.
  • the elasticity data recorded by the MPA580 skin measuring instrument at each visit was analyzed, including the data of total elasticity value R2, net elasticity value R5 and elasticity value R7.
  • R2 is the overall elasticity degree of the skin. The larger the value, the more representative the skin. The better the elasticity.
  • R5 is the net elasticity of the skin, that is, the ratio of the retracted part of the skin to the part attracted by the negative pressure when the skin is released from the negative pressure. The larger the value, the better the skin retraction ability and the more elastic the skin.
  • R7 is the skin elasticity value, which represents the ratio of the retracted part of the skin to the maximum lifting amount of the skin under the release of negative pressure. The larger the value, the better the skin elasticity. It was observed that the skin elasticity increased slowly after 3 treatments, especially at the 6-month follow-up, and an increase in skin elasticity was still observed at the 12-month follow-up (as shown in Figure 3).
  • Non-surgical treatment includes laser treatment and minimally invasive treatment, but the efficacy is uncertain, so there are few treatment options for patients to choose.
  • the cell-free fat extract is obtained by further physical purification on the basis of nano-fat in fat derivatives. After testing by Elisa, it was found that it contains a large amount of active growth factors. Such as angiogenic growth factors VEGF, bFGF, TGF- ⁇ ; neurotrophic factors GDNF and BDNF; In the present study, we directly injected acellular fat extract into the periorbital dermis of patients, and by comparing preoperative and postoperative standardized photographs, we found that the number of infraorbital fine lines was reduced and the skin was neat (Figure 1).
  • the objective wrinkle evaluation also confirmed that after multiple treatments, the suborbital skin roughness parameter SEr and skin smoothness parameter SEsm both showed a downward trend, indicating a trend of gradual smoothness and smooth and neat wrinkles (Figure 2).
  • the periorbital wrinkles were significantly reduced and the skin was delicate, while at the third visit, the wrinkles slightly increased and the skin was slightly rough, but with the increase of the number of treatments, the wrinkles gradually decreased and the skin was smoother.
  • the effect continued until 12 months of follow-up, and although there was a trend of mild recurrence, it was still improved compared with before treatment. Increased skin elasticity was observed after treatment (Fig.

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Abstract

L'invention concerne un extrait de graisse exempt de cellules et son utilisation pour améliorer le vieillissement et favoriser le rajeunissement de la peau. L'extrait de graisse sans cellule peut être utilisé pour préparer une composition ou une préparation, et la composition ou la préparation est utilisée pour améliorer le vieillissement de la peau et/ou favoriser le rajeunissement de la peau.
PCT/CN2022/073020 2021-02-10 2022-01-20 Extrait de graisse exempt de cellules destiné à être utilisé pour améliorer le vieillissement et favoriser le rajeunissement de la peau WO2022170940A1 (fr)

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