WO2017171491A1 - Composition pharmaceutique comprenant un extrait de cellules souches pour la prévention ou le traitement d'une maladie inflammatoire - Google Patents

Composition pharmaceutique comprenant un extrait de cellules souches pour la prévention ou le traitement d'une maladie inflammatoire Download PDF

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WO2017171491A1
WO2017171491A1 PCT/KR2017/003577 KR2017003577W WO2017171491A1 WO 2017171491 A1 WO2017171491 A1 WO 2017171491A1 KR 2017003577 W KR2017003577 W KR 2017003577W WO 2017171491 A1 WO2017171491 A1 WO 2017171491A1
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inflammatory
disease
stem cell
cell extract
cells
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PCT/KR2017/003577
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English (en)
Korean (ko)
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최진
송지영
유진호
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재단법인 아산사회복지재단
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Publication of WO2017171491A1 publication Critical patent/WO2017171491A1/fr

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    • 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
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • 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
    • 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
    • A61K8/982—Reproductive organs; Embryos, Eggs
    • 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
    • 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
    • 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
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • 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
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat

Definitions

  • the present invention relates to a pharmaceutical composition having a prophylactic or therapeutic effect of an inflammatory disease comprising a stem cell extract, and more particularly, the present invention relates to a pharmaceutical composition for preventing or treating an inflammatory disease comprising a stem cell extract, using the pharmaceutical composition It relates to a method for preventing or treating an inflammatory disease, a food composition for improving an inflammatory disease comprising the stem cell extract and a cosmetic composition for preventing or improving an inflammatory skin disease comprising a stem cell extract.
  • Inflammation is a manifestation of normal and protective in vivo defense mechanisms that are localized to tissue damage caused by physical trauma, harmful chemicals, microbial infections or irritants in metabolites in vivo. This inflammation is triggered by various inflammatory mediators produced from damaged tissues and migrating cells. In normal cases, the living body restores normal structure and function by neutralizing or eliminating pathogens and regenerating upper and lower tissues through inflammatory reactions. Otherwise, the living body may progress to a disease state such as chronic inflammation. Among these, the pathological state of the abscess formed by the invasion of bacteria is called an inflammatory disease.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • the pathogenesis of the inflammatory bowel disease is not yet known in detail, but it is known that abnormalities in immune function are involved. Immunological factors involved in this include innate immunity, cytokine production, activation of CD4, and the like. This is known. In particular, cytokines play an important role. Tumor nerosis cytokine (TNF- ⁇ ), Interluekin (IL) -1, IL-6, and IL-8 production at the site of inflammation are ulcerative Significantly increased in patients with colitis and Crohn's disease.
  • TNF- ⁇ Tumor nerosis cytokine
  • IL-6 Interluekin
  • IL-8 Interluekin
  • Drugs used to treat these inflammatory bowel diseases include 5-aminosalicylic acid (5-ASA) -based drugs (eg, sulfasalazine) that block the production of steroidal immunosuppressants, prostaglandins, Mesalazine and the like are used, and they are not only effective in treating inflammatory bowel disease but also cause serious side effects such as fullness, headache, rash, liver disease, leukopenia, agranulocytosis, and male infertility. Use is limited. In order to solve this problem, studies are being actively conducted to develop ingredients that can treat inflammatory bowel disease using natural products having relatively no side effects. For example, International Patent Publication No.
  • 5-ASA 5-aminosalicylic acid
  • WO 2004/098624 discloses a technique for treating colitis using water extracts of the king, and Korean Patent Publication No. 2015-0142213 discloses inflammation comprising a water-soluble extract of three hundred seconds as an active ingredient.
  • a pharmaceutical composition for preventing or treating a growth disease is disclosed.
  • the therapeutic agents derived from these natural products are excellent in safety, the therapeutic effect shows a lower level than the conventional therapeutic agents with side effects, and does not recover the inflamed intestinal tissue.
  • the present inventors have diligently researched to develop an inflammatory disease treatment agent that can recover tissues damaged by inflammation without causing side effects, and as a result, stem cell extracts can recover tissues damaged by inflammation, The present invention has been completed.
  • One object of the present invention to provide a pharmaceutical composition for the prevention or treatment of inflammatory diseases comprising stem cell extract.
  • Still another object of the present invention is to provide a food composition for improving inflammatory disease comprising a stem cell extract.
  • Still another object of the present invention is to provide a cosmetic composition for preventing or improving inflammatory skin disease, comprising a stem cell extract.
  • Still another object of the present invention is to provide a stem cell extract for preventing or treating inflammatory diseases.
  • the pharmaceutical composition comprising the stem cell extract of the present invention can not only recover the cells damaged by inflammation, but also improve the symptoms of animals with inflammatory diseases, and thus are widely used for the development of safe and effective therapeutic agents for inflammatory diseases.
  • Figure 1a is a schematic diagram showing the co-culture method of Caco2 cells and Raw264.7 cells.
  • Figure 1b is a micrograph showing the results of E-cadherin fluorescence staining of caco2 cells and co-culture of Caco2 cells and Raw264.7 cells, and treated with LPS, and then treated with the extract of stem cells (hUC-MSC).
  • Figure 1c is a graph showing the level change of IL-17 in the culture medium according to the treatment of the stem cells (hUC-MSC) extract after co-culture of Caco2 cells and Raw264.7 cells, LPS treatment.
  • Figure 1d is a graph showing the change in the level of IL-10 in the culture medium according to the treatment of the stem cells (hUC-MSC) extract after co-culture of Caco2 cells and Raw264.7 cells, LPS treatment.
  • Figure 2a is a schematic diagram showing a method of treating stem cells or extracts thereof to Raw264.7 cells treated with LPS.
  • Figure 2b is a graph showing the change in the level of IL-17 in the culture after the treatment of stem cells or extracts thereof L26 treated Raw264.7 cells.
  • Figure 2c is a graph showing the change in the level of IL-10 in the culture after the treatment of stem cells or extracts thereof L26 treated Raw264.7 cells.
  • Figure 2d is a graph showing the change in the level of NO in the culture after the treatment of stem cells or extracts thereof L26 treated Raw264.7 cells.
  • Figure 3a is a graph showing the weight recovery level according to the administration of the stem cell (hUC-MSC) extract in chronic colitis model.
  • Figure 3b is a graph showing the change in DAI (disease activity index) according to the administration of the stem cell (hUC-MSC) extract in the chronic colitis model.
  • Figure 3c is a photograph and graph comparing the length of the colon according to whether the administration of the stem cell (hUC-MSC) extract in the chronic colitis model.
  • Figure 3d is a graph showing the change in MPO activity according to the administration of the stem cell (hUC-MSC) extract in chronic colitis model.
  • Figure 3e is a micrograph showing the tissue of the colon according to the administration of the stem cell (hUC-MSC) extract in the chronic colitis model.
  • Figure 4a is a graph showing the weight recovery level according to the administration of the stem cell (hUC-MSC) extract in the acute colitis model.
  • Figure 4b is a graph showing the change in DAI according to the administration of the stem cell (hUC-MSC) extract in the acute colitis model.
  • Figure 4c is a graph showing the change in MPO activity according to the administration of the stem cell (hUC-MSC) extract in the acute colitis model.
  • Figure 4d is a photograph and graph comparing the length of the large intestine according to the administration of the stem cell (hUC-MSC) extract in the acute colitis model.
  • Figure 5a is a graph showing the weight recovery level according to the administration of stem cells (hUC-MSC) or its extract (MSC-Ex) in the chronic colitis model.
  • Figure 5b is a graph showing the change in DAI according to the administration of stem cells (hUC-MSC) or its extract (MSC-Ex) in the chronic colitis model.
  • Figure 5c is a photograph and graph comparing the length of the colon according to the administration of stem cells (hUC-MSC) or its extract (MSC-Ex) in the chronic colitis model.
  • Figure 5d is a graph comparing the level of pathological symptoms according to the administration of stem cells (hUC-MSC) or its extract (MSC-Ex) in the chronic colitis model.
  • Figure 5e is a graph comparing the level of IL-17 according to the administration of stem cells (hUC-MSC) or its extract (MSC-Ex) in the chronic colitis model.
  • Figure 5f is a graph comparing the level of IL-10 according to the administration of stem cells (hUC-MSC) or its extract (MSC-Ex) in the chronic colitis model.
  • Figure 6a is a graph showing the change in the expression level of iNOS according to the treatment of the stem cell (hUC-MSC) extract in LPS-treated HaCaT cells.
  • Figure 6b is a graph showing the change in the expression level of IL-1 ⁇ according to the treatment of stem cells (hUC-MSC) extract in LPS-treated HaCaT cells.
  • Figure 6c is a graph showing the change in the expression level of TNF- ⁇ according to the treatment of stem cells (hUC-MSC) extract in LPS-treated HaCaT cells.
  • Figure 7 is a graph showing the change of sphingomyelin activity according to the treatment of stem cells (hUC-MSC) extract in LPS-treated HaCaT cells.
  • Figure 8a is a graph showing the change in the level of IL-6 expression according to the treatment of stem cells (hUC-MSC) extract in LPS-treated C2C12 cells.
  • Figure 8b is a Western blot analysis picture showing the change in the level of PPAR ⁇ according to the treatment of stem cells (hUC-MSC) extract in LPS-treated C2C12 cells.
  • the present inventors conducted various studies to develop an inflammatory disease therapeutic agent that can recover tissues damaged by inflammation without causing side effects, and thus, stem cell extracts were discovered.
  • the stem cell extract showed an effect of restoring the cells damaged by inflammation in the inflammatory cell model, and in view of the effect of restoring the cells damaged by the inflammation, the stem cell extract showed an improved effect than the stem cells. It was.
  • the inflammatory response can be treated in a disease model animal in which an inflammatory bowel disease used as an example of an inflammatory disease in which the inflammatory cells may appear.
  • stem cell extracts As such, in the treatment of inflammatory diseases, techniques using stem cell extracts have not been known so far and were first developed by the present inventors.
  • the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising a stem cell extract.
  • stem cell refers to a cell having the ability to differentiate into various tissues, that is, an 'undifferentiated cell'.
  • the stem cell is not particularly limited thereto, but may be, for example, embryonic stem cells, adult stem cells, pluripotent stem cells, pluripotent stem cells, induced pluripotent stem cells (induced pluripotent stem cells) As another example, it may be mesenchymal stem cells, mesenchymal stromal cells derived from human tissues, mesenchymal stem cells derived from human tissues, multipotent stem cells or amniotic epithelial cells, and the like.
  • Mesenchymal stem cells selected from the group consisting of umbilical cord, umbilical cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane and placenta, and as another example, human umbilical cord blood-derived intermediate Human stem cells (Human Umbilical Cord Blood Mesenchymal Stem Cell; hUCB-MSC) and the like.
  • stem cell extract refers to a stem cell suspension obtained by treating the stem cells by lysis, crushing, permeation, or the like, a liquid extract obtained by filtering the suspension, or a dry powder of the liquid extract. it means.
  • inflammatory disease refers to a tumor necrosis factor- (TNF- ⁇ ) secreted by immune cells such as macrophages by excessively promoting the human immune system due to harmful stimuli such as inflammation-inducing factors or irradiation.
  • proinflammatory substances inflammatory cytokines
  • ⁇ IL-1
  • IL-6 interleukin-1
  • NO nitric oxide
  • the inflammatory disease is not particularly limited thereto, but may be, for example, allergic inflammatory disease, inflammatory skin disease, inflammatory eye disease, inflammatory bone disease, inflammatory muscle disease, inflammatory bowel disease, and the like.
  • allergic inflammatory diseases such as allergic rhinitis, angioedema, allergic conjunctivitis
  • Inflammatory skin diseases such as atopic dermatitis, psoriasis, contact dermatitis, eczema dermatitis, photodermatitis, seborrheic dermatitis, herpes dermatitis, squamous gland, scleroderma, necrotic pneumonia, pemphigus, vesicular epidermal detachment
  • Inflammatory eye diseases such as blepharitis, degenerative or inflammatory ophthalmitis
  • Inflammatory bone disease such as arthritis, rheumatoid arthritis, spondylitis
  • Inflammatory muscle diseases such as systemic sclerosis, dermatitis,
  • IBD Inflammatory bowel disease
  • Ulcerative colitis mainly invades mucous membranes, and frequently causes ulcers or ulcers.
  • a type of diffuse nonspecific inflammation of unknown origin, which is accompanied by a variety of systemic symptoms, including bloody diarrhea, and Crohn's disease is the discontinuity of the entire gastrointestinal tract from the mucosa to the entire intestinal tract from the oral cavity to the anus.
  • atopic dermatitis refers to a chronic inflammatory skin disease characterized by dryness, pruritis, erythematous eczema, skin barrier dysfunction is also reported as a major cause. Specifically, when abnormalities in barrier function such as increased transepidermal water loss, decreased amount of water in the stratum corneum, and increased skin surface pH are observed, the results are reported to be related to the severity of the lesion. (Allergy Asthma Respir Dis 1 (1): 20-28, March 2013).
  • prevention means any action that inhibits or delays an inflammatory disease by administration of the pharmaceutical composition.
  • the term "treatment” refers to any activity that is clinically involved in altering the natural process of an individual or cell to be treated, which can be performed during or to prevent a clinical pathology.
  • the desired therapeutic effect includes preventing the occurrence or recurrence of the disease, alleviating the symptoms, reducing all direct or indirect pathological consequences of the disease, preventing metastasis, slowing the progression of the disease, and reducing the disease state. Or temporarily alleviate, drive off, or improve the prognosis.
  • the treatment may be interpreted as including all the actions of the symptoms of inflammatory diseases improved or cured by administration of the pharmaceutical composition, but is not particularly limited thereto.
  • the stem cell extract in the present invention can recover the damaged cells in the LPS-treated cell model (Fig. 1a to 1d), showing a superior recovery effect than the stem cells in the cell model ( 2a to 2c), it can be seen that it can be used for the treatment of various inflammatory diseases.
  • the inflammatory disease as a result of confirming the therapeutic effect of the stem cell extract against inflammatory bowel disease, the symptoms of chronic or acute inflammatory bowel inflammation model induced by the treatment of dextran sulphate sodium (DSS) can be improved. It was confirmed (Figs. 3a to 3d and 4a to 4c).
  • the pharmaceutical composition may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions, which carriers may be unnatural carriers.
  • the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • compositions of the present invention in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral formulations, external preparations, suppositories, and sterile injectable solutions, respectively, may be used according to conventional methods.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, and the like in the stem cell extract.
  • Liquid preparations for oral use may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have one formulation.
  • the content of the stem cell extract included in the pharmaceutical composition of the present invention is not particularly limited, but may be included in 0.0001 to 50% by weight relative to the total weight of the final composition, preferably in an amount of 0.001 to 10% by weight can do.
  • the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, the term "pharmaceutically effective amount" of the present invention, the amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment
  • Effective dose levels are well-known for individual types and severities, age, gender, drug activity, drug sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrently used drugs, and other medical fields. It can be determined according to known factors.
  • the pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. In consideration of all the above factors, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects.
  • the dosage of the pharmaceutical composition of the present invention can be determined by those skilled in the art in consideration of the purpose of use, the degree of addiction of the disease, the age, weight, sex, history, or type of substance used as an active ingredient of the patient.
  • the pharmaceutical composition of the present invention may be administered at about 0.1 ng to about 100 mg / kg, preferably 1 ng to about 10 mg / kg, per adult, and the frequency of administration of the composition of the present invention is specifically Although not limited, it can be administered once a day or several times in divided doses.
  • the present invention provides a method for preventing or treating an inflammatory disease, comprising administering the pharmaceutical composition to a subject having or likely to develop an inflammatory disease.
  • the term "individual" of the present invention means any animal which includes or is likely to develop the inflammatory disease.
  • an inflammatory disease can be alleviated or treated.
  • the term “relaxation” refers to any action by which administration of a composition according to the present invention improves or benefits an inflammatory disease.
  • treatment means any action by which the composition according to the present invention is administered to a subject in need of such treatment so that the treatment of the inflammatory disease is carried out or beneficially achieved.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • the term "administration" refers to introducing a pharmaceutical composition of the present invention to a subject in any suitable manner, and the route of administration may be administered via various routes, oral or parenteral, as long as the target tissue can be reached. .
  • the pharmaceutical composition may be appropriately administered to a subject according to conventional methods, routes of administration, and dosages used in the art, depending on the purpose or need.
  • routes of administration may be administered orally, parenterally, subcutaneously, intraperitoneally, pulmonary, and intranasally, and parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.
  • an appropriate dosage and frequency of administration may be selected according to methods known in the art, and the amount and frequency of administration of the pharmaceutical composition of the present invention to be actually administered may include the type of symptom to be treated, route of administration, sex, and health condition , Diet, the age and weight of the individual, and the severity of the disease may be appropriately determined.
  • the term “pharmaceutically effective amount” means an amount sufficient to inhibit or mitigate the increase in vascular permeability at a reasonable benefit / risk ratio applicable to medical use, and the effective dose level may include the type and severity, age, It may be determined according to sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrently used drugs, and other factors well known in the medical arts.
  • the compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art.
  • the present invention provides a food composition for improving inflammatory disease, comprising a stem cell extract.
  • the composition comprising the stem cell extract comprises 0.01 to 100% by weight, more preferably 1 to 80% by weight relative to the total weight of the food composition.
  • food When food is a beverage, it may be included in a ratio of 1 to 30 g, preferably 3 to 20 g, based on 100 ml.
  • the composition may include additional ingredients that are commonly used in food compositions to improve the smell, taste, time and the like. For example, it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like.
  • minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu) and chromium (Cr) may be included. It may also contain amino acids such as lysine, tryptophan, cysteine, valine and the like.
  • preservatives can be added.
  • the additive is selected according to the type of food
  • a food composition comprising the stem cell extract can be prepared for the functional food for the prevention or improvement of inflammatory diseases.
  • processed foods that improve the shelf life at the same time by modifying the properties of agricultural products, livestock products or aquatic products using the composition.
  • processed foods include, for example, sweets, beverages, alcoholic beverages, fermented foods, canned foods, milk processed foods, land processed foods, noodles and the like.
  • Confections include biscuits, pies, cakes, breads, candies, jelly, gum, cereals (including meal substitutes such as grain flour).
  • Beverages include carbonated drinks, functional hot drinks, juices (eg, apples, pears, grapes, aloes, citrus fruits, peaches, carrots, tomato juices, etc.), Sikhye, and the like.
  • Alcoholic beverages include sake, whiskey, shochu, beer, liquor, fruit wine, and the like.
  • Fermented foods include soy sauce, miso, and red pepper paste.
  • Canned food includes canned seafood (eg, canned tuna, mackerel, saury, canned seashells, etc.), canned livestock (eg beef, pork, chicken, turkey canned, etc.), canned produce (corn, peaches, canned apples, etc.).
  • Milk processed foods include cheese, butter, yogurt, and the like.
  • Processed meat products include pork cutlet, beef cutlet, chicken cutlet and sausage. Includes sweet and sour pork, nuggets, breadfruits and more. Noodles, such as sealed packaging fresh noodles, are included.
  • the composition may be used in retort food, soups and the like.
  • the term "functional food” of the present invention is the same term as a food for special health use (FOSHU), and in addition to the nutritional supply, the medical and medical effects are processed so that the bioregulatory function appears efficiently It means high food.
  • the term "health food” refers to a food having an active health maintenance or promotion effect compared to a general food
  • a health supplement food refers to a food for health supplement purposes. Accordingly, the terms functional foods, health foods, and dietary supplements are favored, and the foods may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. in order to obtain useful effects in preventing or improving inflammatory diseases. Can be.
  • the present invention provides a cosmetic composition for preventing or improving inflammatory skin disease, comprising a stem cell extract.
  • the stem cell extract preferably based on the total weight of the cosmetic composition may be contained in 0.0001% by weight to 10% by weight, more preferably 0.0005% by weight to 10% by weight It may be contained as.
  • the stem cell extract in an appropriate amount, there is an advantage that the economic and yet effective effect is sufficiently exhibited to achieve the object of the present invention.
  • the cosmetic composition according to the present invention is a solution, an external ointment, a cream, a foam, a nourishing lotion, a flexible lotion, a pack, a flexible water, an emulsion, a makeup base, an essence, a soap, a liquid detergent, a bath, a sunscreen cream, a sun oil, a suspension, Emulsions, pastes, gels, lotions, powders, soaps, surfactant-containing cleansing, oils, powder foundations, emulsion foundations, wax foundations, patches and sprays may be prepared in a formulation selected from the group consisting of, but not limited to It is not.
  • the cosmetic composition of the present invention may be preferably prepared as a semi-solid preparation, such as external ointment, lotion, but is not limited thereto.
  • the cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers formulated in general skin cosmetics, and as conventional components, for example, oil, water, surfactants, moisturizers, lower alcohols, thickeners , Chelating agents, pigments, preservatives, fragrances and the like may be appropriately blended, but is not limited thereto.
  • one or more cosmetically acceptable carriers formulated in general skin cosmetics, and as conventional components, for example, oil, water, surfactants, moisturizers, lower alcohols, thickeners , Chelating agents, pigments, preservatives, fragrances and the like may be appropriately blended, but is not limited thereto.
  • the cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the dosage form.
  • the formulation of the cosmetic composition of the present invention is an ointment
  • a paste, a cream or a gel as a carrier component, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, Zinc oxide or the like may be used, but is not limited thereto. These may be used alone or in combination of two or more thereof.
  • lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, etc. may be used as the carrier component, and in particular, in the case of a spray, additionally chloro Propellants, such as, but not limited to, fluorohydrocarbons, propane / butane or dimethyl ether. These may be used alone or in combination of two or more thereof.
  • a solvent, a solubilizer or an emulsifier may be used as the carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl Benzoate, propylene glycol, 1,3-butylglycol oil and the like can be used, and in particular, cottonseed oil, peanut oil, corn seed oil, olive oil, castor oil and sesame oil, glycerol aliphatic ester, polyethylene glycol or sorbitan Fatty acid ester of may be used, but is not limited thereto. These may be used alone or in combination of two or more thereof.
  • suspensions such as liquid diluents such as water, ethanol or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester as carrier components
  • liquid diluents such as water, ethanol or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester
  • microcrystalline cellulose, aluminum metahydroxyde, bentonite, agar or tracant may be used, but is not limited thereto. These may be used alone or in combination of two or more thereof.
  • the formulation of the present invention is a soap
  • alkali metal salts of fatty acids fatty acid hemiester salts, fatty acid protein hydrolyzates, isethionates, lanolin derivatives, aliphatic alcohols, vegetable oils, glycerol, sugars and the like
  • carrier components May be, but is not limited thereto. These may be used alone or in combination of two or more thereof.
  • hUC-MSC Human umbilical cord mesenchymal stem cells cultured in Petri dishes are scraped for cell harvesting after washing twice with physiological saline without trypsin to exclude the addition of foreign substances.
  • hUC-MSC Human umbilical cord mesenchymal stem cells
  • the obtained cells were suspended by adding 100 ⁇ l of saline per petri dish, and stabilized on ice for 15 minutes to stop various enzyme reactions in the cells.
  • Cold stabilized hUC-MSC was used to alternate the liquid nitrogen and constant temperature bath to freeze and thaw cells three times to crush the cells.
  • the crushed cells were centrifuged (13,000 rpm, 15 minutes), and the obtained supernatant was used as a stem cell extract.
  • protease inhibitor protease inhibitor
  • Caco2 cells Cold Epithelial Colorectal adenocarcin, colorectal adenocarcin cell line
  • Caco2 cells Cold Epithelial Colorectal adenocarcin, colorectal adenocarcin cell line
  • RAW264.7 cells macrophages
  • transwells with differentiated caco2 cells were mounted on top (FIG. 1A).
  • the lower culture was treated with LPS to induce an inflammatory response, and the stem cell extract prepared in Example 1 was treated at 30 ⁇ g / mL in the upper culture, followed by incubation for 24 hours.
  • the lower culture was collected to measure the amount of inflammatory cytokines IL-17 and anti-inflammatory cytokines IL-10, and cultured caco2 cells were subjected to E-cadherin (adherens junction) fluorescence staining (Fig. 1b to 1d).
  • the level of IL-10 was slightly increased when LPS was treated, but the level of IL-10 was rapidly increased when stem cell extract was treated.
  • the level of IL-17 increased by the treatment of LPS was decreased by the treatment of hUC-MSC or its extract, and IL-17 when treated with its extract rather than when treated with hUC-MSC. It is confirmed that the level of is relatively further reduced.
  • the level of IL-10 was slightly increased when LPS was treated, but the level of IL-10 was rapidly increased when hUC-MSC or its extracts were treated. When the extract was treated, it was confirmed that the level of IL-10 was further increased.
  • the level of NO increased by LPS treatment was reduced by the treatment of stem cells or stem cell extracts, the effect of reducing the level of NO shows a higher level of stem cell extract than stem cells It was confirmed.
  • the inflammatory response increased by the treatment of LPS could be recovered by using the stem cells or extracts thereof, it can be seen that the recovery effect is further improved when using the stem cell extract rather than the stem cells there was.
  • Example 4 DSS ( dextran sulphate sodium) induced chronic Enteritis Therapeutic Effect Analysis of Stem Cell Extracts Using Model
  • Examples 2 and 3 confirmed that the inflammatory response increased by the treatment of LPS can be recovered by using the stem cell extract, to confirm whether this effect can be applied to the actual inflammatory disease, DSS (dextran The treatment effect of inflammatory bowel disease was analyzed using sulphate sodium) induced chronic enteritis or DSS induced acute enteritis.
  • Example 4-1 DSS-induced Chronic Enteritis Therapeutic Effect Analysis of Stem Cell Extracts Using Model
  • the measured body weight was set as the reference weight (100%) before administration of DSS and scored by dividing the change in body weight after administration of DSS into five levels (0 points: 0-1%, 1 point: 1-to-1) 5%, 2 points: 5-10%, 3 points: 10-20% and 4 points: 20% or more).
  • the average value obtained from the scores obtained for the measured body weight, stool status, and the presence or absence of blood stool was set as the DAI (disease activity index).
  • MPO Myeloperoxidase
  • the rat group administered with the stem cell extract was confirmed that the weight gain rate is improved compared to the rat group (control) administered PBS.
  • MPO activity was reduced in the rat group administered with the stem cell extract, it was confirmed that the infiltration of inflammatory cells is reduced.
  • the cells showing the inflammatory response was observed in the colon tissue of the rat group administered PBS, but the cells showing the inflammatory response was not observed in the colon tissue of the rat group administered the stem cell extract.
  • Example 4-2 Acute DSS Induction Enteritis Therapeutic Effect Analysis of Stem Cell Extracts Using Model
  • C71BL / 6 rats were fed with 4% DSS for 5 days to prepare a DSS-induced acute enteritis model, and from the third day of feeding, PBS (Phosphate buffered saline, 100 ⁇ l) or the stem cell extract prepared in Example 1 (injection: 100 ⁇ g / 100 ⁇ l) was administered through the abdominal cavity over 5 days. During the whole procedure, body weight, stool status and blood stool were recorded daily, and the length of the colon was measured at the sacrifice of mice the day after the last injection (FIGS. 4A-4D).
  • the rat group administered with the stem cell extract was confirmed that the level of weight loss is somewhat reduced compared to the rat group administered with PBS.
  • Example 4-3 DSS-induced chronic Enteritis Anti-inflammatory Effects of Stem Cells and Stem Cell Extracts in Models
  • Example 4-1 The same experiment as in Example 4-1, except that the stem cell extract MSC-Ex (30 ⁇ g / mL) obtained from the same number of stem cells (1x10 ⁇ 5 cells) used in Example 1 was treated. Was performed (FIGS. 5A-5F).
  • the colon length between the stem group and the rat group to which the stem cell extract was administered was recovered compared to the colon length of the rat group to which the PBS was administered, and the colon length between the stem group and the rat group to which the stem cell extract was administered was It was confirmed that there was no particular difference.
  • the pathological symptoms between the stem cells and the rat group to which the stem cell extract was administered was reduced compared to the pathological symptoms of the rat group to which PBS was administered, and the stem rather than the pathological symptoms between the rat groups to which the stem cells were administered. It was confirmed that the pathological symptoms of the rat group to which the cell extract was administered were relatively reduced.
  • the level of IL-17 was lower in the rat group to which the stem cells and stem cell extracts were administered, compared to the rat group to which PBS was administered, and in the rat group to which the stem cells and stem cell extracts were administered. It was confirmed that the level of IL-17 did not show any particular difference.
  • IL-10 levels were higher in the rat group to which the stem cells and stem cell extracts were administered than to the rat group to which PBS was administered, and in the rat group to which the stem cells and stem cell extracts were administered. It was confirmed that the level of IL-10 showed no particular difference.
  • Example 5-1 expressed in keratinocytes On inflammation marker Effect of Stem Cell Extracts on
  • RNA was obtained from each cultured cell, and real-time PCR analysis was performed using the obtained total RNA and the following primers to analyze changes in expression levels of inflammatory markers iNOS, IL-1 ⁇ , and TNF- ⁇ (FIG. 6A). To 6c). At this time, GAPDH was used as the internal control group.
  • TNF ⁇ -F 5'-GGAGAAGGGTGACCGACTCA-3 '(SEQ ID NO: 1)
  • TNF ⁇ -R 5'-CTGCCCAGACTCGGCAA-3 '(SEQ ID NO: 2)
  • IL-1 ⁇ -F 5'-AAAAGCTTGGTGATGTCTGG-3 '(SEQ ID NO: 3)
  • IL-1 ⁇ -R 5'-TTTCAACACGCAGGACAGG-3 '(SEQ ID NO: 4)
  • iNOS-F 5'-TCAGCCAAGCCCTCACCTAC-3 '(SEQ ID NO: 5)
  • iNOS-R 5'-CCAATCTCTGCCTATCCGTCTC-3 '(SEQ ID NO: 6)
  • GAPDH-F 5'-GAAGGTGAAGGTCGGAGTC-3 '(SEQ ID NO: 7)
  • GAPDH-R 5'-GAAGATGGTGATGGGATTTC-3 '(SEQ ID NO: 8)
  • Example 5-2 Effect of Stem Cell Extracts on the Level of Ceramide Produced in Keratinocytes
  • ceramide which is a constituent of lipids produced in each cell obtained in Example 5-1
  • the protein extracted from each cell is applied to a spingomyelinase (SMase) assay kit (Cayman).
  • SMase spingomyelinase
  • the activity of sphingomyelinase producing ceramide was analyzed (FIG. 7).
  • C2C12 cells which are a kind of myoblasts, were treated with LPS (1 ⁇ g / mL), incubated for 4 hours, replaced with medium containing normal or stem cell extracts, and further cultured for 24 hours.
  • RNA was obtained from the cultured cells, and the change in the expression level of the inflammatory marker IL-6 was analyzed by real-time PCR analysis using the obtained total RNA and the following primers (FIG. 8A). At this time, GAPDH was used as the internal control group.
  • IL-6-F 5'-CCGGAGAGGAGACTTCACAG-3 '(SEQ ID NO: 9)
  • IL-6-R 5'-TCCACGATTTCCCAGAGAAC-3 '(SEQ ID NO: 10)
  • the L2 treatment of C2C12 cells induce an inflammatory response to increase the expression level of the inflammatory marker IL-6, after the stem cell extract was confirmed that the increased IL-6 expression level is reduced It was.
  • the stem cell extracts can restore the damage of inflammatory cells commonly found in inflammatory diseases, and the recovery effect is confirmed that stem cell extracts are superior to stem cells, and indeed inflammatory bowel disease is developed.
  • the stem cell extracts As a result of confirming the effect of the stem cell extract in the animal model, it was found that the symptoms of the animal model in which chronic or acute inflammatory bowel disease was developed.
  • the stem cell extract of the present invention may have an effect of preventing or treating various inflammatory diseases.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un extrait de cellules souches destinée à la prévention ou au traitement de maladies inflammatoires, un procédé de prévention ou de traitement de maladies inflammatoires à l'aide de la composition pharmaceutique, une composition alimentaire comprenant l'extrait de cellules souches destinée à améliorer la prise en charge des maladies inflammatoires, et une composition cosmétique comprenant un extrait de cellules souches destinée à la prévention ou au traitement de maladies inflammatoires de la peau. La composition pharmaceutique comprenant un extrait de cellules souches selon la présente invention peut non seulement restaurer des cellules lésées par une inflammation, mais également améliorer les symptômes d'animaux atteints de maladies inflammatoires, ce qui permet de trouver de nombreuses applications dans la mise au point d'agents thérapeutiques sûrs et efficaces pour des maladies inflammatoires.
PCT/KR2017/003577 2016-03-31 2017-03-31 Composition pharmaceutique comprenant un extrait de cellules souches pour la prévention ou le traitement d'une maladie inflammatoire WO2017171491A1 (fr)

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