WO2021187944A1 - Therapeutic use of coenzyme q10 solubilizing composition - Google Patents

Therapeutic use of coenzyme q10 solubilizing composition Download PDF

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WO2021187944A1
WO2021187944A1 PCT/KR2021/003428 KR2021003428W WO2021187944A1 WO 2021187944 A1 WO2021187944 A1 WO 2021187944A1 KR 2021003428 W KR2021003428 W KR 2021003428W WO 2021187944 A1 WO2021187944 A1 WO 2021187944A1
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coq10
coenzyme
composition
micelles
arthritis
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PCT/KR2021/003428
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French (fr)
Korean (ko)
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박성환
조미라
곽승기
이선영
전주연
나현식
조근형
문영미
정상전
강효진
김주환
김가현
Original Assignee
가톨릭대학교 산학협력단
앱티스 주식회사
성균관대학교산학협력단
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Publication of WO2021187944A1 publication Critical patent/WO2021187944A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • 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
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds
    • A23V2250/314—Ubiquinone, coenzyme Qn

Definitions

  • the present invention relates to the use of a coenzyme Q10 solubilizing composition for treating immune diseases.
  • Autoimmune disease refers to a disease in which the body's immune system attacks normal and healthy tissues, organs, or other body components. Many autoimmune diseases result from an abnormal immune response in the body and cause self-destruction. Famous examples include rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), Sjogren's syndrome, and the like. Primary biliary cirrhosis (PBC), chronic active hepatitis, and other diseases such as Hashimoto's thyroiditis are all associated with autoimmune diseases. Among them, Sjogren's syndrome is a multi-system chronic inflammatory disease affecting the lacrimal and salivary glands (NIAMS. November 2014.
  • Sjogren's syndrome is the most prevalent autoimmune disease affecting 1-3% of the world's population, including 4,000,000 patients in the United States. More than 90% of patients with Sjogren's syndrome are female, and the disease may be accompanied by a variety of other autoimmune phenomena (Ferri, Fred F. (2010). Ferri's differential diagnosis: a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders (2nd ed.) Philadelphia, PA: Elsevier/Mosby. p. Chapter S. ISBN 978-0323076999.). The physiological causes of Sjogren's syndrome are not precisely understood, but two distinct phenomena are believed to occur.
  • the initiation phase when autoreactive lymphocyte activation is induced, and the infiltration and accumulation of pathogenic lymphocytes in the lacrimal and salivary glands, respectively, in which the effect of reducing the amount of tears and saliva is shown.
  • the initiation phase when autoreactive lymphocyte activation is induced, and the infiltration and accumulation of pathogenic lymphocytes in the lacrimal and salivary glands, respectively, in which the effect of reducing the amount of tears and saliva is shown.
  • it is divided into primary Sjogren's syndrome and secondary Sjogren's syndrome according to the stage of symptom progression.
  • tears do not come out, and there is a feeling of redness or fatigue.
  • this condition is left as it is, it leads to damage to the cornea and conjunctiva, and the lack of salivation in the mouth causes a lot of tartar to occur, and tooth decay and periodontitis frequently occur.
  • Inflammatory diseases appearing in the joints are chronic joint rheumatism, which is understood to be caused by autoimmunity, infectious arthritis caused by bacterial infection, osteoarthritis in which degeneration or destruction of articular cartilage or bone due to various causes, and degenerative changes in connective tissue are soluble It can be broadly classified into crystalline arthritis, in which metabolites are deposited as crystals in the connective tissue around the joint.
  • degeneration such as aging occurs in the chondrocytes constituting the joint, and the synthesis of type II collagen and proteoglycan, which are substrate materials of the joint, is inhibited in the chondrocytes, and at the same time,
  • inflammatory cytokines such as interleukin-1 and tumor necrosis factor- ⁇ are produced, the synthesis of matrix metalloproteinase (MMP) and It is a disease caused by destruction of joint tissue due to increased activity in joint cells.
  • MMP matrix metalloproteinase
  • arthritis is further exacerbated by the induced synthesis of more MMPs due to the production of nitric oxide by inflammatory cytokines and the production of self-amplifying cytokines by the produced nitric oxide, thereby promoting the decomposition of the joint matrix.
  • inflammatory cytokines increase the production of prostaglandin E2, a lipid metabolite, to induce an inflammatory response in arthritis.
  • Osteoarthritis also called degenerative arthritis, is a type of arthritis that occurs mainly in old age without a specific organic cause. Rheumatoid arthritis and degenerative arthritis are characterized by infiltration of inflammatory cells into the joint synovial tissue, which is mediated by chemokines.
  • Chemokines such as monocyte chemoattractant protein-1 (MCP-1) are expressed in the synovial tissue of arthritis, and these are known to be produced in synovial fibroblasts. Excess MCP-1 produced by arthritis invites monocytes and macrophages to the site of inflammation, and by activating these cells, it promotes the production of inflammatory cytokines, thereby exacerbating inflammation.
  • MCP-1 monocyte chemoattractant protein-1
  • Another object of the present invention is to provide a method for preventing or treating an immune disease, comprising administering to an individual a pharmaceutically effective amount of the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition for preventing or treating immune diseases, comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
  • the present invention provides a food composition for preventing or improving immune diseases comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
  • the present invention provides a method for preventing or treating an immune disease, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition.
  • CoQ10 micelles in which coenzyme Q10 is encapsulated in micelles inhibit the infiltration of inflammatory cells.
  • it by suppressing the expression of inflammatory cytokines and increasing the expression of anti-inflammatory cytokines, it showed a therapeutic effect in rheumatoid arthritis, osteoarthritis, Sjogren's syndrome and rheumatic diseases accompanied by obesity. Therefore, it can be usefully used for the prevention or treatment of immune diseases.
  • Figure 5a is the result of confirming the therapeutic effect of rheumatoid arthritis of the CoQ10 solubilizing composition (CoQ10 micelles) as an arthritis index.
  • 5B is a result of analyzing the rheumatoid arthritis treatment effect of the CoQ10 solubilizing composition (CoQ10 micelles) in terms of prevalence.
  • 6a is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of IgG, which is a rheumatoid arthritis-specific antibody.
  • 6b is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of IgG2a, a rheumatoid arthritis-specific antibody.
  • 6c is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of CII specific IgG, which is a rheumatoid arthritis-specific antibody.
  • 6d is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of CII specific IgG, which is a rheumatoid arthritis-specific antibody.
  • 7a is a diagram confirming the inhibitory effect of CoQ10 micelles on joint destruction caused by rheumatoid arthritis by H&E staining.
  • 7b is a diagram confirming the inhibitory effect of CoQ10 micelles on cartilage damage caused by rheumatoid arthritis by H&E staining.
  • Figure 7c is a numerical view of the inhibitory effect of CoQ10 micelles on inflammation caused by joint destruction and cartilage damage caused by rheumatoid arthritis.
  • 7d is a diagram quantifying the inhibition of joint destruction caused by rheumatoid arthritis of CoQ10 micelles as a joint damage value.
  • Figure 7e is a diagram quantifying the inhibition of cartilage damage caused by rheumatoid arthritis of CoQ10 micelles as cartilage damage values.
  • 8A is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (IL-1 ⁇ ) caused by rheumatoid arthritis.
  • 8B is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (IL-6) caused by rheumatoid arthritis.
  • 8c is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (IL-17) caused by rheumatoid arthritis.
  • 8d is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (TNF- ⁇ ) by rheumatoid arthritis.
  • Figure 9a is a diagram confirming the osteoarthritis pain relief effect of CoQ10 micelles with paw withdrawal latency.
  • Figure 9b is a diagram confirming the osteoarthritis pain relief effect of CoQ10 micelles with the paw withdrawal threshold.
  • 9c is a diagram confirming the osteoarthritis pain relief effect of CoQ10 micelles by weight-bearing evaluation.
  • 10a is a diagram confirming the effect of CoQ10 micelles on the inhibition of bone destruction and bone surface damage caused by osteoarthritis by micro-CT.
  • 10B is a diagram quantifying the effect of CoQ10 micelles on inhibiting bone destruction and bone surface damage caused by osteoarthritis.
  • Figure 11a is a view confirming the chondroprotective effect of CoQ10 micelles on osteoarthritis by safranin O (Safranin O) staining.
  • 11B is a diagram quantifying the chondroprotective effect of CoQ10 micelles on osteoarthritis by OARSI score.
  • 11C is a diagram quantifying the chondroprotective effect of CoQ10 micelles on osteoarthritis by the Mankin score.
  • 12a is a diagram confirming the effect of CoQ10 micelles on the expression level of inflammatory cytokine (IL-1 ⁇ ) caused by osteoarthritis through immunochemical staining analysis.
  • 12B is a diagram illustrating the quantification of the expression level of inflammatory cytokine (IL-1 ⁇ ) in CoQ10 micelles due to osteoarthritis.
  • 12c is a diagram confirming the effect of CoQ10 micelles on the expression level of inflammatory cytokine (IL-6) caused by osteoarthritis through immunochemical staining analysis.
  • 12d is a diagram illustrating the quantification of the expression level of inflammatory cytokine (IL-6) caused by osteoarthritis in CoQ10 micelles.
  • 12e is a diagram confirming the effect of CoQ10 micelles on the expression level of inflammatory cytokine (IL-17) caused by osteoarthritis through immunochemical staining analysis.
  • 12f is a diagram illustrating the quantification of the expression level of inflammatory cytokines (IL-17) caused by osteoarthritis in CoQ10 micelles.
  • 12g is a diagram confirming the effect of CoQ10 micelles on the expression level of anti-inflammatory cytokine (IL-10) caused by osteoarthritis through immunochemical staining analysis.
  • 12h is a diagram illustrating the quantification of the expression level of anti-inflammatory cytokine (IL-10) caused by osteoarthritis in CoQ10 micelles.
  • 12i is a diagram confirming the effect of CoQ10 micelles on the expression level of oxidative factor (iNOS) caused by osteoarthritis through immunochemical staining analysis.
  • 12j is a diagram illustrating the quantification of the expression level of oxidative factor (iNOS) in CoQ10 micelles due to osteoarthritis.
  • iNOS oxidative factor
  • 12k is a diagram confirming the effect of CoQ10 micelles on the expression level of the protein (MMP13) involved in catabolism caused by osteoarthritis through immunochemical staining analysis.
  • 12L is a diagram illustrating the quantification of the expression level of the protein (MMP13) involved in the catabolic action of CoQ10 micelles due to osteoarthritis.
  • 13a is a diagram confirming the effect of increasing salivary secretion by CoQ10 micelles in Sjogren's syndrome.
  • 13B is a diagram confirming the serum glucose maintenance effect by CoQ10 micelles in Sjogren's syndrome.
  • 14a is a diagram confirming that CoQ10 micelles inhibit inflammatory immune cell infiltration in salivary gland tissue of a Sjogren's syndrome mouse model by H&E staining.
  • 14B is a diagram quantifying the inhibition of CoQ10 micelles on inflammatory immune cell infiltration in the salivary gland tissue of the Sjogren's syndrome mouse model.
  • Figure 15a is a diagram confirming the expression change of inflammatory cytokine (IL-6) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
  • 15B is a diagram confirming the expression change of inflammatory cytokine (IL-17) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
  • 15c is a diagram confirming the expression change of inflammatory cytokine (TNF- ⁇ ) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
  • 15D is a diagram confirming the expression change of anti-inflammatory cytokine (IL-10) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
  • IL-10 anti-inflammatory cytokine
  • 16a is a diagram confirming the treatment effect of obesity-related arthritis by CoQ10 micelles as an arthritis index:
  • Figure 16b is a diagram confirming the prevalence of obesity-related arthritis treatment effect by CoQ10 micelles.
  • 17A is a diagram showing the process of confirming the effect of inhibiting immune inflammatory cell infiltration, bone destruction, and cartilage damage in an animal model of obesity-related arthritis.
  • 17B is a diagram confirming the effect of inhibiting bone destruction by CoQ10 micelles by H&E staining in an animal model of obesity-related arthritis.
  • 17c is a diagram confirming cartilage damage in an animal model of obesity-related arthritis by safranin O staining.
  • Figure 17d is a diagram confirming the cartilage damage inhibition effect by CoQ10 in an animal model of obesity-related arthritis by safranin O staining.
  • 17e is a diagram confirming the cartilage damage inhibitory effect of CoQ10 micelles by safranin O staining in an animal model of obesity-related arthritis.
  • 17f is a diagram illustrating the quantification of the anti-inflammatory effect of CoQ10 micelles in an animal model of obesity-related arthritis.
  • 17G is a diagram illustrating the quantification of the effect of inhibiting bone destruction by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 17h is a diagram illustrating the quantification of the cartilage damage inhibition effect by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18a is a diagram confirming the effect of suppressing the expression of inflammatory cytokines (IL-17) by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18B is a diagram confirming the effect of suppressing the expression of inflammatory cytokines (IL-6) by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18c is a diagram confirming the effect of suppressing the expression of inflammatory cytokines (IL-1 ⁇ ) by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18D is a diagram confirming the effect of inhibiting inflammatory cytokine (TNF- ⁇ ) expression by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18E is a diagram quantifying the effect of inhibiting the expression of inflammatory cytokines (IL-17) by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18f is a diagram quantifying the effect of inhibiting inflammatory cytokine (IL-6) expression by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18G is a diagram illustrating the quantification of the effect of inhibiting the expression of inflammatory cytokines (IL-1 ⁇ ) by CoQ10 micelles in an animal model of obesity-related arthritis.
  • 18h is a diagram illustrating the quantification of the inflammatory cytokine (TNF- ⁇ ) expression inhibitory effect by CoQ10 micelles in an animal model of obesity-related arthritis.
  • the present invention relates to a pharmaceutical composition for preventing or treating immune diseases, comprising as an active ingredient a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles.
  • inhibiting the infiltration of inflammatory cells reducing or inhibiting the expression of inflammatory cytokines IL-17, IL-6, TNF- ⁇ and IL-1 ⁇ , the expression of the anti-inflammatory cytokine IL-10 , and can reduce or inhibit the expression of iNOS, an oxidative factor, and MMP13, which is involved in catabolism.
  • the glycyrrhizic acid according to the present invention may be used in the form of a salt thereof, preferably a pharmaceutically acceptable salt.
  • the salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid.
  • the organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid and aspartic acid.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
  • the curcumin compound according to the present invention may be isolated from nature or prepared by a chemical synthesis method known in the art.
  • the pharmaceutical composition of the present invention may further include an adjuvant.
  • the adjuvant may be used without limitation as long as it is known in the art, and for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the immunity thereof.
  • treatment means, unless otherwise stated, the disease or condition to which the term applies, or one or more symptoms of the disease or disorder, which reverses, ameliorates, inhibits the progression, or It means to prevent, and the term treatment as used in the present invention refers to the act of treating. Accordingly, treatment or therapy for immune disorders in mammals may include one or more of the following:
  • mammal refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
  • a composition is indicated to be "pharmaceutically or physiologically acceptable” if the recipient animal can tolerate administration of the composition, or if administration of the composition to that animal is suitable.
  • the agent can be said to have been administered in a "therapeutically effective amount”.
  • An agent is physiologically meaningful if the presence of the agent results in a physiologically detectable change in the recipient patient.
  • the therapeutically effective amount of the composition of the present invention may vary depending on several factors, for example, the administration method, the target site, the condition of the patient, and the like. Therefore, when used in the human body, the dosage should be determined as an appropriate amount in consideration of both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. These considerations in determining effective amounts are, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's Health status, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concurrently, and other factors well known in the medical field can be determined according to
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • compositions of the present invention may also include carriers, diluents, excipients or combinations of two or more commonly used in biological agents.
  • a pharmaceutically acceptable carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc.
  • Compounds described in , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used as needed. Conventional additives may be added.
  • diluents such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • it can be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
  • the pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. have.
  • the term “pharmaceutically acceptable” refers to exhibiting non-toxic properties to cells or humans exposed to the composition.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive includes starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate. , lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, sucrose, dextrose, sorbitol and talc and the like can be used.
  • the pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
  • the term "administration” means providing a predetermined substance to a patient by any suitable method, and parenteral administration (eg, intravenous, subcutaneous, intraperitoneal or topical administration according to a desired method) ) or oral administration, and the dosage varies according to the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
  • parenteral administration eg, intravenous, subcutaneous, intraperitoneal or topical administration according to a desired method
  • oral administration varies according to the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
  • composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) or orally, depending on the desired method, and the dosage may vary depending on the subject's age, weight, sex, physical condition, etc. is selected taking into account.
  • concentration of the active ingredient included in the pharmaceutical composition can be variously selected depending on the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 ⁇ g/ml to 50 mg/ml. If the concentration is less than 0.01 ⁇ g/ml, pharmaceutical activity may not appear, and if it exceeds 50 mg/ml, it may be toxic to the human body.
  • compositions of the present invention may be formulated in various oral or parenteral dosage forms.
  • Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like.
  • the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid. or disintegrants such as sodium salts thereof or effervescent mixtures and/or absorbents, coloring, flavoring and sweetening agents.
  • the formulation may be prepared by conventional mixing, granulating or coating methods.
  • a representative formulation for parenteral administration is an injection formulation, and water, Ringer's solution, isotonic saline, or suspension may be mentioned as a solvent for the injection formulation.
  • the sterile, fixed oil of the injectable preparation may be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides may be used for this purpose.
  • the injection preparation may use a fatty acid such as oleic acid.
  • prevention refers to any action that suppresses or delays the occurrence, spread, and recurrence of immune diseases by administration of the pharmaceutical composition according to the present invention.
  • the present invention relates to a food composition for the prevention or improvement of immune diseases comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
  • the micelles may comprise glycyrrhizic acid or a salt of glycyrrhizic acid, and EPA or DHA.
  • the mixing ratio of glycyrrhizic acid or a salt of glycyrrhizic acid, EPA or DHA, and coenzyme Q10 may be in the range of 0.1 to 5:0.1 to 5:0.1 to 5 by weight.
  • the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition may be 1 to 50% by weight based on the total weight of the composition.
  • coenzyme Q10 may be included in an aqueous solution of coenzyme Q10 solubilizing composition at a concentration of 0.05 to 3 mg/mL.
  • the coenzyme Q10 solubilizing composition may have a particle size of 10-200 nm.
  • the immune disease may be any one or more selected from the group consisting of an autoimmune disease, an inflammatory disease, and a cell, tissue or organ transplant rejection disease.
  • the immune disease is arthritis, ankylosing spondylitis, asthma, dermatitis, psoriasis, cystic fibrosis, late and chronic rejection of solid organ transplantation, multiple sclerosis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroid, polymyositis, scleroderma, adi Son's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, inflammatory bowel disease, autoimmune diabetes, diabetic retinopathy, rhinitis, tongue blood-reperfusion injury, restenosis after angioplasty, chronic obstructive heart disease, Grave's disease, gastrointestinal allergy, conjunctivitis , atherosclerosis, coronary artery disease, angina pectoris, may be any one or more selected from the group consisting of cancer metastasis and arteriole disease.
  • the arthritis is senile arthritis, degenerative arthritis, autoimmune arthritis, osteoarthritis, obese arthritis, rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, psoriatic arthritis, gout, bacterial arthritis, juvenile rheumatoid arthritis, lupus, scleroderma, multiple Sclerosis, fibromyalgia, polymyositis, dermatomyositis, Behcet's disease, Reiter's syndrome, Lyme arthritis, adhesive capsulitis, frozen shoulder, tendon synovitis, elbow capsulitis, de Quervain's tendon synovitis, rerheumatism, polymyalgia rheumatica and adult still It may be any one or more selected from the group consisting of bottles.
  • the composition of the present invention when used as a food composition, the composition may be added as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the composition may contain a food additive that is pharmaceutically acceptable, and the mixing amount of the active ingredient may be suitably determined according to the purpose of use (prevention, health or therapeutic treatment).
  • food supplement additive used in the present invention refers to a component that can be added to food as an auxiliary, and is added to the manufacture of health functional food of each formulation, and those skilled in the art can appropriately select and use it.
  • food supplement additives include various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners , pH adjuster, stabilizer, preservative, glycerin, alcohol, carbonation agent used in carbonated beverages, etc., but the above examples are not limited to the type of food supplement additive of the present invention.
  • the food composition of the present invention may include a health functional food.
  • health functional food refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful in the human body.
  • the term 'functionality' refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological effects on the structure and function of the human body.
  • the health functional food of the present invention can be prepared by a method commonly used in the ordinary technical field, and at the time of the preparation, it can be prepared by adding raw materials and components commonly added in the conventional technical field.
  • the formulation of the health functional food is also recognized as a health functional food, it can be prepared without limitation.
  • composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur during long-term administration of the drug using food as a raw material, and has excellent portability, and the present invention health functional food can be taken as an adjuvant to enhance the effect of immune disease treatment.
  • compositions comprising the extract of the present invention or a fraction thereof as an active ingredient can be prepared by mixing known additives with other suitable auxiliary ingredients that may be contained in health functional foods according to the selection of those skilled in the art.
  • suitable auxiliary ingredients include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and There are vitamin complexes and the like, and it can be prepared by adding the extract according to the present invention as a main component to juice, tea, jelly, juice, and the like.
  • composition of the present invention is made from natural materials, side effects may be less than that of general synthetic compounds even when used as a pharmaceutical composition or a food composition, so it can be safely included in pharmaceutical compositions and health functional foods to be usefully used.
  • the invention relates to a kit comprising a composition of the invention in one or more unit dosage forms.
  • the dosage forms described herein may be packaged in a bottle or as a blister pack with instructions for use of the dosage form.
  • instructions may be provided as a package insert or may be provided directly on a blister pack, label affixed to the bottle, or on a secondary packaging material from which the blister pack or bottle was provided to a human subject.
  • Instructions may include, for example, the number of doses, administration of the dosage form to be administered with or without food, the active ingredient constituting the dosage form, and the dosage form.
  • the present invention relates to a method for preventing or treating an immune disease, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition.
  • the pharmaceutical composition of the present invention is administered in a therapeutically effective amount or a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the subject type and severity, age, sex, activity of the drug, and the drug. It can be determined according to factors including sensitivity, administration time, administration route and excretion rate, duration of treatment, concurrent drugs, and other factors well known in the medical field.
  • CoQ10 solubilized composition containing CoQ10 (Coenzyme Q10) at a high concentration
  • the preparation method described in FIG. 1 was performed under the conditions shown in Table 1 below. More specifically, after injecting distilled water into the reactor, glycyrrhizinate dipotassium salt (Dipotassium glycyrrhizinate), eicosapentaenoic acid (EPA), poorly soluble drug CoQ10 for micelle formation, It was added in the amount shown in Table 1 and stirred to evenly disperse. In order to generate micelles smoothly in the reactor, the mixture was stirred at 10,000 rpm for 10 minutes while each raw material was included in a bath at 60 to 70 °C.
  • the reaction solution was encapsulated with CoQ10 for micellar formation for 1 hour at a high pressure of 1200 bar using APV-2000 fluid bed mixer (microfluidizer, SPX Flow, UK) of APV, and micelles were removed using a 0.45 ⁇ m syringe filter. secured.
  • APV-2000 fluid bed mixer microfluidizer, SPX Flow, UK
  • micelles were removed using a 0.45 ⁇ m syringe filter.
  • CoQ10 not encapsulated in the aqueous phase after solubilization of the composition using a fluidized bed mixer was removed using a 0.45 ⁇ m syringe filter.
  • the CoQ10 solubilizing composition had a uniform particle size of about 80 nm. Appearance was confirmed.
  • CoQ10 eicosapentaenoic acid (EPA): glycyrrhizic acid (1 g: 1 mL: 1 g) using 1 liter of distilled water
  • CoQ10 solubilizing composition 2.4 g/L using CoQ10 was analyzed by HPLC. HPLC conditions are shown in Table 2 below, and it was confirmed that a peak appeared at 6.9 minutes on HPLC of CoQ10 detected through the following conditions, which is shown in FIG. 3 .
  • Example 2 Treatment effect of CoQ10 solubilizing composition for rheumatoid arthritis
  • an animal model of rheumatoid arthritis was prepared. Specifically, normal DBA/1 mice were first inoculated with Type II collagen, followed by a second inoculation 14 later. An animal model was prepared by selecting a group showing a disease index of 1 or more on the 21st day after induction of rheumatoid arthritis. After that, after inducing obesity-related arthritis in an animal model, the excipient controls micelles, CoQ10 (10 mg/kg) and CoQ10-micelles (3 mg/kg or 10 mg/kg) were orally administered once a day, respectively, from the 21st day.
  • CoQ10 micelles 3 mg/kg and 10 mg/kg showed a statistically significant rheumatoid arthritis treatment effect compared to micelles (micelle vs. CoQ10-micelle 3 mg/kg 8w2, 9w1, **P ⁇ 0.001, 10w2, *P ⁇ 0.05; micelle vs. CoQ10 10 mg/kg, 6w1, 6W2, 10w1, *P ⁇ 0.05) ( FIGS. 5A and 5B ).
  • the degree of joint destruction was analyzed histopathologically using H&E staining, and the degree of damage and immune cell infiltration were determined It was evaluated on a scale of 0-5, and the joint tissues of the navicular and tibia were paraffin-blocked and sectioned to a thickness of 5 ⁇ , and the degree of cartilage damage was confirmed through Safranin O tissue staining.
  • osteoarthritis animal model 5-week-old male Wistar rats weighing 200 to 250 g were bred at a temperature of 21 to 22 ° C in a light-dark cycle at 12 hour intervals, and sterilized water and feed were supplied. brought up Thereafter, osteoarthritis was induced by administering monosodium iodoacetate (MIA, Sigma, ST. Louis, MO) at a dose of 3 mg/50 ⁇ l to the knee joint of a rat to induce osteoarthritis. MIA was administered by dissolving it in physiological saline. After 4 days of osteoarthritis induction, pain was measured to select an osteoarthritis-induced animal model.
  • MIA monosodium iodoacetate
  • the osteoarthritis-positive control drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles, respectively, were orally administered to the animal model of osteoarthritis prepared in Example 3-1 4 days after induction of osteoarthritis 6 times a week. After 2 days, a net plate was placed on the Dynamic plantat aesthsiometer (Ugo Basile, Comerio, Italy), and the rats of each group were placed in an acrylic animal holder on the top.
  • the pain measurement graph was derived by automatically measuring the paw withdrawal latency (s, seconds) and the amount of weight applied to the paw withdrawal threshold (g). In addition, an incapacitance tester was used to compare and measure the force applied to the left and right feet of the rat.
  • the rat was placed in a plastic chamber, and the left and right paws of the rat were placed on each plate on a separate plate of the incapacitance tester, and the average value of the force applied to each paw was obtained for 3 seconds.
  • the weight bearing (%) obtained in this way was substituted into Equation 2 below to obtain a result.
  • the osteoarthritis-positive drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles were orally administered 6 times a week, respectively, and bone destruction and damage of the femur (Femur).
  • the degree was confirmed by analyzing the bone volume (%) through micro-CT imaging.
  • micro-CT equipment skyscan1272 ex-vivo micro-CT was used, and in the case of resolution, imaging was performed with 8.19 ⁇ m pixels.
  • the osteoarthritis-positive control drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles were orally administered 6 times a week, respectively, and the navicular ) and the joint tissue of the tibia were paraffin-blocked and sectioned to a thickness of 5 ⁇ m, and the degree of cartilage damage was confirmed through Safranin O tissue staining.
  • the osteoarthritis-positive control drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles were orally administered 6 times a week, respectively, and the joint tissue and synovial membrane of each group of rats
  • the expression level of inflammatory cytokines (IL-1 ⁇ , IL-6 and IL-17), anti-inflammatory cytokines (IL-10), oxidative factor (iNOS) and catabolic protein (MMP13) in tissues was measured by immunohistochemical staining method. , and positive cells for each marker were counted.
  • the inflammatory cytokines IL-1 ⁇ , IL-6 and IL-17 were found to be decreased in the CoQ10 administration group, the CoQ10 micellar administration group and the celecoxib administration group compared to the micellar administration group (Figs. 12a to 12f), IL-10, an anti-inflammatory cytokine, was significantly increased in the CoQ10 micellar administration group compared to the excipient control group and the CoQ10 administration group ( FIGS. 12G and 12H ).
  • the expression of oxidative factor iNOS and MMP13 involved in catabolism showed a tendency to decrease in the CoQ10 administration group, the CoQ10 micellar administration group and the celecoxib administration group ( FIGS. 12i to 12l ).
  • both the CoQ10 micelles 3 mg/kg or 10 mg/kg administration group showed decreased infiltration of immune cells (FIG. 14a), and histological score analysis showed that the infiltration of inflammatory immune cells was reduced in the CoQ10 micelles administration group. was found (Fig. 14b).
  • IL-6, IL-17 and TNF- ⁇ were reduced in the CoQ10 micelles 3 mg/kg or 10 mg/kg administration group.
  • TNF- ⁇ is CoQ 10 micelles in 3 mg / kg and 10 mg / kg administration group showed a statistical significance (vehicle compared * P ⁇ 0.05) (Fig. 15a to Fig. 15c).
  • IL-10-expressing cells were increased in CoQ10 micelles administered at 3 mg/kg and at 10 mg/kg ( FIG. 15D ).
  • Example 5 Treatment effect of CoQ10 solubilizing composition for rheumatoid arthritis accompanied by obesity
  • CoQ10 micelles In order to confirm the therapeutic effect of CoQ10 micelles (CoQ10-micelle) on the treatment of obesity-related arthritis, the degree of infiltration of immune inflammatory cells in the synovial tissue caused by the administration of CoQ10 micelles, the degree of bone destruction, and the degree of cartilage damage were checked. Specifically, as in the above example, CoQ10 or CoQ10- micelles were administered to a mouse model of obesity-related arthritis, and synovial tissues obtained therefrom were fixed overnight with 4% paraformaldehyde. Thereafter, dehydration with alcohol, embedding with paraffin, cutting, and H&E and Safranin O staining were performed, and observed with an Olympus microscope (Tokyo, Japan).
  • the expression level of inflammatory cytokines in the synovial membrane of joint tissues was checked. Specifically, after administration of CoQ10 or CoQ10- micelles to a mouse model of obesity-related arthritis as in the above example, the synovial tissue obtained therefrom was stained with the inflammatory cytokines IL-17, IL-6, IL- The expression of 1 ⁇ and TNF- ⁇ was analyzed.

Abstract

The present invention pertains to the use of a coenzyme Q10 solubilizing composition for treating immune diseases. CoQ10 micelles, in which a coenzyme C10 according to the present invention is encapsulated, were found to inhibit the infiltration of inflammatory cells. In addition, the coenzyme Q10 solubilizing composition was found to inhibit the expression of inflammatory cytokines and increase the expression of anti-inflammatory cytokines, thus having therapeutic effects on rheumatoid arthritis, osteoarthritis, Sjogren's syndrome, and rheumatic diseases accompanying obesity. Therefore, the coenzyme Q10 solubilizing composition can be advantageously used for preventing or treating immune diseases.

Description

코엔자임 Q10 가용화 조성물의 치료학적 용도Therapeutic use of coenzyme Q10 solubilizing composition
본 발명은 코엔자임 Q10 가용화 조성물의 면역질환 치료 용도에 관한 것이다.The present invention relates to the use of a coenzyme Q10 solubilizing composition for treating immune diseases.
자가면역질환은 체내의 면역체계가 정상적이고 건강한 조직이나 기관 또는 기타 체내 성분 등을 공격하게 되는 질환을 의미한다. 다수의 자가면역 질병은 인체의 면역이상 반응으로부터 기인하며 자가 파괴를 유발한다. 유명한 예는 류마티스 관절염(Rheumatoid arthritis, RA), 전신경화증(Systemic sclerosis, SSc), 전신홍반루푸스(Systemic lupus erythematosus, SLE) 쇼그렌 증후군(Sjogren's syndrome) 등을 포함한다. 원발 쓸개관 간경화증 (Primary biliary cirrhosis, PBC), 만성 활성 간염, 및 하시모토 갑상선염과 같은 기타 질병은 모두 자가면역 질병과 관련된다. 이 중, 쇼그렌 증후군은 눈물샘(lacrimal gland)과 침샘(salivary gland)에 영향을 미치는 다양성 만성 염증(system chronic inflammatory) 질병이다 (NIAMS. November 2014. Archived from the original on 4 July 2016.). 쇼그렌 증후군은 미국에 4,000,000명의 환자를 포함하여 전세계 인구의 1-3%에 달하는 가장 널리 분포하는 자가면역질환이다. 쇼그렌 증후군을 가지고 있는 환자의 90% 이상이 여성이며, 이 질병은 다양한 다른 자가 면역현상과 동반되어 나타날 수도 있다 (Ferri, Fred F. (2010). Ferri's differential diagnosis : a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders (2nd ed.). Philadelphia, PA: Elsevier/Mosby. p. Chapter S. ISBN 978-0323076999.). 쇼그렌 증후군의 생리학적인 원인에 대해서는 정확히 이해되지 않고 있지만 두 개의 구별되는 현상이 일어나는 것으로 보고 있다. 자가 반응성 림프세포의 활성이 유도되는 시작단계와 눈물샘과 침샘에 병원성의 림프세포가 침투하여 누적하게 됨으로써 각각 눈물의 양과 침의 양을 감소시키는 효과가 나타나는 두 가지 구별되는 시기가 있다. 즉, 증상의 진행단계에 따라 1차성 쇼그렌 증후군과 2차성 쇼그렌 증후군으로 구별되는데, 1차성 쇼그렌 증후군은 주로 안구, 구강, 피부 건조증이 나타나며, 눈의 건조감의 느낌이 있고 이물질이 들어있는 듯한 느낌이 들며 더 진행되면 눈이 따갑고 눈물이 나오지 않으며 충혈되거나 피로감이 있다. 그러나, 이러한 상태를 그대로 두면 각막과 결막 손상으로 이어지며 입은 침 분비 부족으로 치석이 많이 생기고 충치와 치주염도 자주 발생하게 된다. 또한, 피부의 땀샘과 피지선의 분비도 감소하여 피부가 마르는 것도 특징 중 하나이다. 2차성 쇼그렌 증후군은 류마티스 관절염, 루푸스, 전신성 경화증, 피부근염이 동반되기도 하는데, 병이 진행되면서 호흡기, 위장, 취장 등 소화기 내분비계 손상과 신장, 심장 등의 신경계에 손상이 온다. 또한 쇼그렌 증후군 환자의 약 5% 정도에서는 림프종이 발생하는 것으로 알려져 있고, 쇼그렌 증후군 환자는 일반인에 비해 약 2.7배정도 사망률이 높은 것으로 알려져 있다.Autoimmune disease refers to a disease in which the body's immune system attacks normal and healthy tissues, organs, or other body components. Many autoimmune diseases result from an abnormal immune response in the body and cause self-destruction. Famous examples include rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), Sjogren's syndrome, and the like. Primary biliary cirrhosis (PBC), chronic active hepatitis, and other diseases such as Hashimoto's thyroiditis are all associated with autoimmune diseases. Among them, Sjogren's syndrome is a multi-system chronic inflammatory disease affecting the lacrimal and salivary glands (NIAMS. November 2014. Archived from the original on 4 July 2016.). Sjogren's syndrome is the most prevalent autoimmune disease affecting 1-3% of the world's population, including 4,000,000 patients in the United States. More than 90% of patients with Sjogren's syndrome are female, and the disease may be accompanied by a variety of other autoimmune phenomena (Ferri, Fred F. (2010). Ferri's differential diagnosis: a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders (2nd ed.) Philadelphia, PA: Elsevier/Mosby. p. Chapter S. ISBN 978-0323076999.). The physiological causes of Sjogren's syndrome are not precisely understood, but two distinct phenomena are believed to occur. There are two distinct phases: the initiation phase, when autoreactive lymphocyte activation is induced, and the infiltration and accumulation of pathogenic lymphocytes in the lacrimal and salivary glands, respectively, in which the effect of reducing the amount of tears and saliva is shown. In other words, it is divided into primary Sjogren's syndrome and secondary Sjogren's syndrome according to the stage of symptom progression. As it progresses further, the eyes sting, tears do not come out, and there is a feeling of redness or fatigue. However, if this condition is left as it is, it leads to damage to the cornea and conjunctiva, and the lack of salivation in the mouth causes a lot of tartar to occur, and tooth decay and periodontitis frequently occur. In addition, the secretion of sweat glands and sebaceous glands of the skin is also decreased, so that the skin becomes dry. Secondary Sjogren's syndrome is also accompanied by rheumatoid arthritis, lupus, systemic sclerosis, and dermatomyositis. In addition, it is known that about 5% of patients with Sjogren's syndrome develop lymphoma, and it is known that patients with Sjogren's syndrome have a mortality rate of about 2.7 times higher than that of the general public.
관절에 나타나는 염증성 질환은 자가면역이 원인인 것으로 이해되는 만성 관절 류마티스, 세균 감염에 의한 감염성 관절염, 여러 원인으로 인하여 관절 연골이나 뼈에 변성이나 파괴가 일어나는 변형성 관절염, 결합 조직의 퇴행성 변화로 인하여 가용성 대사 산물이 관절 주변의 결합 조직 내에 결정으로 침착되는 결정성 관절염 등으로 크게 구분될 수 있다. 퇴행성 관절염, 즉 골관절염은 관절을 구성하는 연골세포(chondrocytes)에 노화 등의 퇴행이 발생하여, 연골세포에서 관절의 기질 물질들인 유형II 콜라겐(type II collagen) 및 프로테오글리칸 등의 합성이 저해됨과 동시에, 인터루킨-1(interleukin-1) 및 종양괴사인자-α(tumor necrosis factor-α) 등의 염증성 사이토카인이 생성됨에 따라, 관절기질을 분해하는 기질 금속단백질 분해효소 (matrix metalloproteinase; MMP)의 합성 및 활성이 관절세포에서 증가됨으로 인해 관절조직이 파괴됨으로써 유발되는 질병이다. 또한, 관절염은 염증성 사이토카인에 의한 일산화질소의 생성과, 생성된 일산화질소에 의한 자가 증폭적인 사이토카인의 생성으로 인해 더욱 많은 MMP의 합성이 유발되어 관절기질의 분해가 촉진됨으로써 더욱 악화된다. 이와 동시에, 염증성 사이토카인은 지질 대사산물인 프로스타글란딘 E2의 생성을 증가시켜 관절염에서의 염증반응을 유발시킨다. 골관절염은 퇴행성 관절염으로도 명명되는 관절염의 일종으로서, 특정한 기질적 원인이 없이 주로 노년에 많이 발생되며 만성적으로 진행되면 관절구조의 변형으로 보행 장애 등의 운동 장애를 수반한다. 류마티스와 퇴행성 관절염은 관절 활막조직 내로의 염증세포 침윤이 그 특징이며, 이는 chemokine에 의해서 매개된다. 관절염의 활막조직에는 MCP-1(monocyte chemoattractant protein-1) 등의 chemokine이 발현되며, 이들은 활막섬유아세포(synovial fibroblast) 등에서 생성되는 것으로 알려져 있다. 관절염에 의해 생성된 과잉의 MCP-1은 염증부위로 단구세포와 거식세포를 불러들이고, 이들세포들을 활성화함으로써 염증성 사이토카인의 생성을 촉진하여 염증을 더욱 악회시키는 역할을 한다.Inflammatory diseases appearing in the joints are chronic joint rheumatism, which is understood to be caused by autoimmunity, infectious arthritis caused by bacterial infection, osteoarthritis in which degeneration or destruction of articular cartilage or bone due to various causes, and degenerative changes in connective tissue are soluble It can be broadly classified into crystalline arthritis, in which metabolites are deposited as crystals in the connective tissue around the joint. In degenerative arthritis, that is, osteoarthritis, degeneration such as aging occurs in the chondrocytes constituting the joint, and the synthesis of type II collagen and proteoglycan, which are substrate materials of the joint, is inhibited in the chondrocytes, and at the same time, As inflammatory cytokines such as interleukin-1 and tumor necrosis factor-α are produced, the synthesis of matrix metalloproteinase (MMP) and It is a disease caused by destruction of joint tissue due to increased activity in joint cells. In addition, arthritis is further exacerbated by the induced synthesis of more MMPs due to the production of nitric oxide by inflammatory cytokines and the production of self-amplifying cytokines by the produced nitric oxide, thereby promoting the decomposition of the joint matrix. At the same time, inflammatory cytokines increase the production of prostaglandin E2, a lipid metabolite, to induce an inflammatory response in arthritis. Osteoarthritis, also called degenerative arthritis, is a type of arthritis that occurs mainly in old age without a specific organic cause. Rheumatoid arthritis and degenerative arthritis are characterized by infiltration of inflammatory cells into the joint synovial tissue, which is mediated by chemokines. Chemokines such as monocyte chemoattractant protein-1 (MCP-1) are expressed in the synovial tissue of arthritis, and these are known to be produced in synovial fibroblasts. Excess MCP-1 produced by arthritis invites monocytes and macrophages to the site of inflammation, and by activating these cells, it promotes the production of inflammatory cytokines, thereby exacerbating inflammation.
본 발명의 목적은 면역질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of immune diseases.
아울러, 본 발명의 목적은 면역질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.In addition, it is an object of the present invention to provide a food composition for preventing or improving immune diseases.
아울러, 본 발명의 다른 목적은 약학적으로 유효한 양의 상기의 약학적 조성물을 개체에 투여하는 단계를 포함하는, 면역질환의 예방 또는 치료 방법을 제공하는 것이다.In addition, another object of the present invention is to provide a method for preventing or treating an immune disease, comprising administering to an individual a pharmaceutically effective amount of the pharmaceutical composition.
상기 과제를 해결하기 위하여, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating immune diseases, comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
아울러, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving immune diseases comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
또한, 본 발명은 약학적으로 유효한 양의 상기의 약학적 조성물을 개체에 투여하는 단계를 포함하는, 면역질환의 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method for preventing or treating an immune disease, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition.
본 발명에 따르면, 코엔자임 Q10이 마이셀에 봉입된 CoQ10 마이셀은 염증성세포의 침윤을 억제하는 것을 확인하였다. 또한, 염증성 사이토카인의 발현을 억제하며, 항염증성 사이토카인의 발현을 증가시킴으로써 류마티스 관절염, 골관절염, 쇼그렌 증후군 및 비만 동반 류마티스 질환에 치료효과를 나타내었다. 따라서, 이를 면역질환의 예방 또는 치료 용도로 유용하게 활용할 수 있다.According to the present invention, it was confirmed that CoQ10 micelles in which coenzyme Q10 is encapsulated in micelles inhibit the infiltration of inflammatory cells. In addition, by suppressing the expression of inflammatory cytokines and increasing the expression of anti-inflammatory cytokines, it showed a therapeutic effect in rheumatoid arthritis, osteoarthritis, Sjogren's syndrome and rheumatic diseases accompanied by obesity. Therefore, it can be usefully used for the prevention or treatment of immune diseases.
도 1은 고압 균질 유화기를 이용한 CoQ10 가용화 조성물의 제조방법을 나타낸 것이다:1 shows a method for preparing a CoQ10 solubilizing composition using a high pressure homogeneous emulsifier:
a: 마이셀의 제조방법; 및a: a method for preparing micelles; and
b: CoQ10 마이셀의 제조방법.b: Method for producing CoQ10 micelles.
도 2는 CoQ10을 농도별로 HPLC 분석하여 정량 곡선을 작성한 결과이다.2 is a result of preparing a quantitative curve by HPLC analysis of CoQ10 for each concentration.
도 3은 고압 균질 유화기를 이용하여 제조된 CoQ10 가용화 조성물의 입자분포도를 분석한 결과이다.3 is a result of analyzing the particle distribution of the CoQ10 solubilizing composition prepared using a high-pressure homogeneous emulsifier.
도 4는 고압 균질 유화기를 이용하여 제조된 CoQ10 가용화 조성물의 표면전하를 분석한 결과이다.4 is a result of analyzing the surface charge of the CoQ10 solubilizing composition prepared using a high-pressure homogeneous emulsifier.
도 5a는 CoQ10 가용화 조성물 (CoQ10 마이셀)의 류마티스 관절염 치료 효과를 관절염 지수로 확인한 결과이다.Figure 5a is the result of confirming the therapeutic effect of rheumatoid arthritis of the CoQ10 solubilizing composition (CoQ10 micelles) as an arthritis index.
도 5b는 CoQ10 가용화 조성물 (CoQ10 마이셀)의 류마티스 관절염 치료 효과를 유병률로 분석한 결과이다.5B is a result of analyzing the rheumatoid arthritis treatment effect of the CoQ10 solubilizing composition (CoQ10 micelles) in terms of prevalence.
도 6a는 CoQ10 마이셀의 류마티스 관절염 특이적 항체인 IgG 생성 억제 효과를 확인한 도이다.6a is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of IgG, which is a rheumatoid arthritis-specific antibody.
도 6b는 CoQ10 마이셀의 류마티스 관절염 특이적 항체인 IgG2a 생성 억제 효과를 확인한 도이다.6b is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of IgG2a, a rheumatoid arthritis-specific antibody.
도 6c는 CoQ10 마이셀의 류마티스 관절염 특이적 항체인 CII specific IgG 생성 억제 효과를 확인한 도이다.6c is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of CII specific IgG, which is a rheumatoid arthritis-specific antibody.
도 6d는 CoQ10 마이셀의 류마티스 관절염 특이적 항체인 CII specific IgG 생성 억제 효과를 확인한 도이다.6d is a diagram confirming the inhibitory effect of CoQ10 micelles on the production of CII specific IgG, which is a rheumatoid arthritis-specific antibody.
도 7a는 CoQ10 마이셀의 류마티스 관절염에 의한 관절 파괴 억제 효과를 H&E 염색으로 확인한 도이다.7a is a diagram confirming the inhibitory effect of CoQ10 micelles on joint destruction caused by rheumatoid arthritis by H&E staining.
도 7b는 CoQ10 마이셀의 류마티스 관절염에 의한 연골 손상 억제 효과를 H&E 염색으로 확인한 도이다.7b is a diagram confirming the inhibitory effect of CoQ10 micelles on cartilage damage caused by rheumatoid arthritis by H&E staining.
도 7c는 CoQ10 마이셀의 류마티스 관절염에 의한 관절 파괴 및 연골 손상에 의한 염증 억제 효과를 수치화한것이다.Figure 7c is a numerical view of the inhibitory effect of CoQ10 micelles on inflammation caused by joint destruction and cartilage damage caused by rheumatoid arthritis.
도 7d는 CoQ10 마이셀의 류마티스 관절염에 의한 관절 파괴 억제를 관절 손상 수치로 정량화한 도이다.7d is a diagram quantifying the inhibition of joint destruction caused by rheumatoid arthritis of CoQ10 micelles as a joint damage value.
도 7e는 CoQ10 마이셀의 류마티스 관절염에 의한 연골 손상 억제를 연골 손상 수치로 정량화한 도이다.Figure 7e is a diagram quantifying the inhibition of cartilage damage caused by rheumatoid arthritis of CoQ10 micelles as cartilage damage values.
도 8a는 CoQ10 마이셀의 류마티스 관절염에 의한 염증성 사이토카인(IL-1β) 억제 효과를 확인한 도이다.8A is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (IL-1β) caused by rheumatoid arthritis.
도 8b는 CoQ10 마이셀의 류마티스 관절염에 의한 염증성 사이토카인(IL-6) 억제 효과를 확인한 도이다.8B is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (IL-6) caused by rheumatoid arthritis.
도 8c는 CoQ10 마이셀의 류마티스 관절염에 의한 염증성 사이토카인(IL-17) 억제 효과를 확인한 도이다.8c is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (IL-17) caused by rheumatoid arthritis.
도 8d는 CoQ10 마이셀의 류마티스 관절염에 의한 염증성 사이토카인(TNF-α) 억제 효과를 확인한 도이다.8d is a diagram confirming the inhibitory effect of CoQ10 micelles on inflammatory cytokines (TNF-α) by rheumatoid arthritis.
도 9a는 CoQ10 마이셀의 골관절염 통증 경감 효과를 paw withdrawal latency로 확인한 도이다.Figure 9a is a diagram confirming the osteoarthritis pain relief effect of CoQ10 micelles with paw withdrawal latency.
도 9b는 CoQ10 마이셀의 골관절염 통증 경감 효과를 paw withdrawal threshold로 확인한 도이다.Figure 9b is a diagram confirming the osteoarthritis pain relief effect of CoQ10 micelles with the paw withdrawal threshold.
도 9c는 CoQ10 마이셀의 골관절염 통증 경감 효과를 체중부하 평가로 확인한 도이다.9c is a diagram confirming the osteoarthritis pain relief effect of CoQ10 micelles by weight-bearing evaluation.
도 10a는 CoQ10 마이셀의 골관절염에 의한 골 파괴 및 골 표면 손상 억제 효과를 micro-CT로 확인한 도이다.10a is a diagram confirming the effect of CoQ10 micelles on the inhibition of bone destruction and bone surface damage caused by osteoarthritis by micro-CT.
도 10b는 CoQ10 마이셀의 골관절염에 의한 골 파괴 및 골 표면 손상 억제 효과를 정량화한 도이다.10B is a diagram quantifying the effect of CoQ10 micelles on inhibiting bone destruction and bone surface damage caused by osteoarthritis.
도 11a는 골관절염에 대한 CoQ10 마이셀의 연골 보호 효과 사프라닌 O(Safranin O) 염색으로 확인한 도이다.Figure 11a is a view confirming the chondroprotective effect of CoQ10 micelles on osteoarthritis by safranin O (Safranin O) staining.
도 11b는 골관절염에 대한 CoQ10 마이셀의 연골 보호 효과를 OARSI 스코어로 정량화한 도이다.11B is a diagram quantifying the chondroprotective effect of CoQ10 micelles on osteoarthritis by OARSI score.
도 11c는 골관절염에 대한 CoQ10 마이셀의 연골 보호 효과를 Mankin 스코어로 정량화한 도이다.11C is a diagram quantifying the chondroprotective effect of CoQ10 micelles on osteoarthritis by the Mankin score.
도 12a는 CoQ10 마이셀이 골관절염에 의한 염증성 사이토카인(IL-1β)의 발현 정도에 미치는 영향을 면역화학염색 분석법을 통해 확인한 도이다.12a is a diagram confirming the effect of CoQ10 micelles on the expression level of inflammatory cytokine (IL-1β) caused by osteoarthritis through immunochemical staining analysis.
도 12b는 CoQ10 마이셀이 골관절염에 의한 염증성 사이토카인(IL-1β)의 발현 정도를 정량화한 도이다.12B is a diagram illustrating the quantification of the expression level of inflammatory cytokine (IL-1β) in CoQ10 micelles due to osteoarthritis.
도 12c는 CoQ10 마이셀이 골관절염에 의한 염증성 사이토카인(IL-6)의 발현 정도에 미치는 영향을 면역화학염색 분석법을 통해 확인한 도이다.12c is a diagram confirming the effect of CoQ10 micelles on the expression level of inflammatory cytokine (IL-6) caused by osteoarthritis through immunochemical staining analysis.
도 12d는 CoQ10 마이셀이 골관절염에 의한 염증성 사이토카인(IL-6)의 발현 정도를 정량화한 도이다.12d is a diagram illustrating the quantification of the expression level of inflammatory cytokine (IL-6) caused by osteoarthritis in CoQ10 micelles.
도 12e는 CoQ10 마이셀이 골관절염에 의한 염증성 사이토카인(IL-17)의 발현 정도에 미치는 영향을 면역화학염색 분석법을 통해 확인한 도이다.12e is a diagram confirming the effect of CoQ10 micelles on the expression level of inflammatory cytokine (IL-17) caused by osteoarthritis through immunochemical staining analysis.
도 12f는 CoQ10 마이셀이 골관절염에 의한 염증성 사이토카인(IL-17)의 발현 정도를 정량화한 도이다.12f is a diagram illustrating the quantification of the expression level of inflammatory cytokines (IL-17) caused by osteoarthritis in CoQ10 micelles.
도 12g는 CoQ10 마이셀이 골관절염에 의한 항염증성 사이토카인(IL-10)의 발현 정도에 미치는 영향을 면역화학염색 분석법을 통해 확인한 도이다.12g is a diagram confirming the effect of CoQ10 micelles on the expression level of anti-inflammatory cytokine (IL-10) caused by osteoarthritis through immunochemical staining analysis.
도 12h는 CoQ10 마이셀이 골관절염에 의한 항염증성 사이토카인(IL-10)의 발현 정도를 정량화한 도이다.12h is a diagram illustrating the quantification of the expression level of anti-inflammatory cytokine (IL-10) caused by osteoarthritis in CoQ10 micelles.
도 12i는 CoQ10 마이셀이 골관절염에 의한 산화인자(iNOS)의 발현 정도에 미치는 영향을 면역화학염색 분석법을 통해 확인한 도이다.12i is a diagram confirming the effect of CoQ10 micelles on the expression level of oxidative factor (iNOS) caused by osteoarthritis through immunochemical staining analysis.
도 12j는 CoQ10 마이셀이 골관절염에 의한 산화인자(iNOS)의 발현 정도를 정량화한 도이다.12j is a diagram illustrating the quantification of the expression level of oxidative factor (iNOS) in CoQ10 micelles due to osteoarthritis.
도 12k는 CoQ10 마이셀이 골관절염에 의한 이화 작용 관여 단백질(MMP13)의 발현 정도에 미치는 영향을 면역화학염색 분석법을 통해 확인한 도이다.12k is a diagram confirming the effect of CoQ10 micelles on the expression level of the protein (MMP13) involved in catabolism caused by osteoarthritis through immunochemical staining analysis.
도 12l는 CoQ10 마이셀이 골관절염에 의한 이화 작용 관여 단백질(MMP13)의 발현 정도를 정량화한 도이다.12L is a diagram illustrating the quantification of the expression level of the protein (MMP13) involved in the catabolic action of CoQ10 micelles due to osteoarthritis.
도 13a는 쇼그렌 증후군에서 CoQ10 마이셀에 의한 타액 분비능 증가 효과를 확인한 도이다.13a is a diagram confirming the effect of increasing salivary secretion by CoQ10 micelles in Sjogren's syndrome.
도 13b는 쇼그렌 증후군에서 CoQ10 마이셀에 의한 혈청 글루코즈 유지 효과를 확인한 도이다.13B is a diagram confirming the serum glucose maintenance effect by CoQ10 micelles in Sjogren's syndrome.
도 14a는 쇼그렌 증후군 마우스 모델의 침샘 조직 내 염증성 면역 세포 침윤을 CoQ10 마이셀이 억제하는 것을 H&E 염색으로 확인한 도이다.14a is a diagram confirming that CoQ10 micelles inhibit inflammatory immune cell infiltration in salivary gland tissue of a Sjogren's syndrome mouse model by H&E staining.
도 14b는 쇼그렌 증후군 마우스 모델의 침샘 조직 내 염증성 면역 세포 침윤을 CoQ10 마이셀이 억제하는 것을 정량화한 도이다.14B is a diagram quantifying the inhibition of CoQ10 micelles on inflammatory immune cell infiltration in the salivary gland tissue of the Sjogren's syndrome mouse model.
도 15a는 CoQ10 마이셀에 의한 쇼그렌 증후군 마우스 모델의 침샘 조직 내 염증성 사이토카인(IL-6)의 발현 변화를 확인한 도이다.Figure 15a is a diagram confirming the expression change of inflammatory cytokine (IL-6) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
도 15b는 CoQ10 마이셀에 의한 쇼그렌 증후군 마우스 모델의 침샘 조직 내 염증성 사이토카인(IL-17)의 발현 변화를 확인한 도이다.15B is a diagram confirming the expression change of inflammatory cytokine (IL-17) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
도 15c는 CoQ10 마이셀에 의한 쇼그렌 증후군 마우스 모델의 침샘 조직 내 염증성 사이토카인(TNF-α)의 발현 변화를 확인한 도이다.15c is a diagram confirming the expression change of inflammatory cytokine (TNF-α) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
도 15d는 CoQ10 마이셀에 의한 쇼그렌 증후군 마우스 모델의 침샘 조직 내 항염증성 사이토카인(IL-10)의 발현 변화를 확인한 도이다.15D is a diagram confirming the expression change of anti-inflammatory cytokine (IL-10) in the salivary gland tissue of the Sjogren's syndrome mouse model by CoQ10 micelles.
도 16a는 CoQ10 마이셀에 의한 비만 관련 관절염 치료 효과를 관절염 지수로 확인한 도이다:16a is a diagram confirming the treatment effect of obesity-related arthritis by CoQ10 micelles as an arthritis index:
CIA: Collagen Induced Arthritis.CIA: Collagen-Induced Arthritis.
도 16b는 CoQ10 마이셀에 의한 비만 관련 관절염 치료 효과를 유병률로 확인한 도이다.Figure 16b is a diagram confirming the prevalence of obesity-related arthritis treatment effect by CoQ10 micelles.
도 17a는 비만 관련 관절염 동물모델에서 면역 염증 세포의 침윤, 골 파괴 및 연골 손상 억제 효과를 확인하는 과정을 나타낸 도이다.17A is a diagram showing the process of confirming the effect of inhibiting immune inflammatory cell infiltration, bone destruction, and cartilage damage in an animal model of obesity-related arthritis.
도 17b는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 골 파괴 억제 효과를 H&E 염색으로 확인한 도이다.17B is a diagram confirming the effect of inhibiting bone destruction by CoQ10 micelles by H&E staining in an animal model of obesity-related arthritis.
도 17c는 비만 관련 관절염 동물모델의 연골손상을 사프라닌 O 염색으로 확인한 도이다.17c is a diagram confirming cartilage damage in an animal model of obesity-related arthritis by safranin O staining.
도 17d는 비만 관련 관절염 동물모델에서 CoQ10에 의한 연골 손상 억제 효과를 사프라닌 O 염색으로 확인한 도이다.Figure 17d is a diagram confirming the cartilage damage inhibition effect by CoQ10 in an animal model of obesity-related arthritis by safranin O staining.
도 17e는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 연골 손상 억제 효과를 사프라닌 O 염색으로 확인한 도이다.17e is a diagram confirming the cartilage damage inhibitory effect of CoQ10 micelles by safranin O staining in an animal model of obesity-related arthritis.
도 17f는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증 억제 효과를 정량화한 도이다.17f is a diagram illustrating the quantification of the anti-inflammatory effect of CoQ10 micelles in an animal model of obesity-related arthritis.
도 17g는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 골 파괴 억제 효과를 정량화한 도이다.17G is a diagram illustrating the quantification of the effect of inhibiting bone destruction by CoQ10 micelles in an animal model of obesity-related arthritis.
도 17h는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 연골 손상 억제 효과를 정량화한 도이다.17h is a diagram illustrating the quantification of the cartilage damage inhibition effect by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18a는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(IL-17) 발현 억제 효과를 확인한 도이다.18a is a diagram confirming the effect of suppressing the expression of inflammatory cytokines (IL-17) by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18b는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(IL-6) 발현 억제 효과를 확인한 도이다.18B is a diagram confirming the effect of suppressing the expression of inflammatory cytokines (IL-6) by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18c는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(IL-1β) 발현 억제 효과를 확인한 도이다.18c is a diagram confirming the effect of suppressing the expression of inflammatory cytokines (IL-1β) by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18d는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(TNF-α) 발현 억제 효과를 확인한 도이다.18D is a diagram confirming the effect of inhibiting inflammatory cytokine (TNF-α) expression by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18e는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(IL-17) 발현 억제 효과를 정량화한 도이다.18E is a diagram quantifying the effect of inhibiting the expression of inflammatory cytokines (IL-17) by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18f는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(IL-6) 발현 억제 효과를 정량화한 도이다.18f is a diagram quantifying the effect of inhibiting inflammatory cytokine (IL-6) expression by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18g는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(IL-1β) 발현 억제 효과를 정량화한 도이다.18G is a diagram illustrating the quantification of the effect of inhibiting the expression of inflammatory cytokines (IL-1β) by CoQ10 micelles in an animal model of obesity-related arthritis.
도 18h는 비만 관련 관절염 동물모델에서 CoQ10 마이셀에 의한 염증성 사이토카인(TNF-α) 발현 억제 효과를 정량화한 도이다.18h is a diagram illustrating the quantification of the inflammatory cytokine (TNF-α) expression inhibitory effect by CoQ10 micelles in an animal model of obesity-related arthritis.
이하, 첨부된 도면을 참조하여 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다. Hereinafter, the present invention will be described in detail as an embodiment of the present invention with reference to the accompanying drawings. However, the following embodiments are presented as examples of the present invention, and when it is determined that detailed descriptions of well-known techniques or configurations known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description may be omitted, and , the present invention is not limited thereby. Various modifications and applications of the present invention are possible within the scope of equivalents interpreted therefrom and the description of the claims to be described later.
또한, 본 명세서에서 사용되는 용어(terminology)들은 본 발명의 바람직한 실시예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다. 따라서, 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, the terms used in this specification are terms used to properly express the preferred embodiment of the present invention, which may vary according to the intention of a user or operator, or customs in the field to which the present invention belongs. Accordingly, definitions of these terms should be made based on the content throughout this specification. Throughout the specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본 발명에 도입된다.All technical terms used in the present invention, unless otherwise defined, have the meaning as commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention. The contents of all publications herein incorporated by reference are incorporated herein by reference.
일 측면에서, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating immune diseases, comprising as an active ingredient a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles.
일 구현예에서, 염증성세포의 침윤을 억제하고, 염증성 사이토카인인 IL-17, IL-6, TNF-α 및 IL-1β의 발현을 감소 또는 억제하며, 항염증성 사이토카인인 IL-10의 발현을 증가시키고, 산화 인자인 iNOS 및 이화작용에 관여하는 MMP13의 발현을 감소 또는 억제할 수 있다.In one embodiment, inhibiting the infiltration of inflammatory cells, reducing or inhibiting the expression of inflammatory cytokines IL-17, IL-6, TNF-α and IL-1β, the expression of the anti-inflammatory cytokine IL-10 , and can reduce or inhibit the expression of iNOS, an oxidative factor, and MMP13, which is involved in catabolism.
본 발명에 따른 상기 글리시리진산은 이의 염, 바람직하게는 약학적으로 허용 가능한 염의 형태로 사용될 수 있다. 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하며, 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다. 본 발명에 따른 커큐민 화합물은 천연으로부터 분리되거나 당업계에 공지된 화학적 합성법으로 제조된 것을 사용할 수 있다.The glycyrrhizic acid according to the present invention may be used in the form of a salt thereof, preferably a pharmaceutically acceptable salt. The salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid. The organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid and aspartic acid. In addition, the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. The curcumin compound according to the present invention may be isolated from nature or prepared by a chemical synthesis method known in the art.
본 발명의 약학적 조성물에는 보조제(adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트(Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 면역성을 증가시킬 수 있다.The pharmaceutical composition of the present invention may further include an adjuvant. The adjuvant may be used without limitation as long as it is known in the art, and for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the immunity thereof.
본 발명의 용어, "치료"란, 달리 언급되지 않는 한, 상기 용어가 적용되는 질환 또는 질병, 또는 상기 질환 또는 질병의 하나 이상의 증상을 역전시키거나, 완화시키거나, 그 진행을 억제하거나, 또는 예방하는 것을 의미하며, 본 발명에서 사용된 상기 치료란 용어는 치료하는 행위를 말한다. 따라서 포유동물에 있어서 면역질환의 치료 또는 치료요법은 하기의 하나 이상을 포함할 수 있다:As used herein, the term "treatment" means, unless otherwise stated, the disease or condition to which the term applies, or one or more symptoms of the disease or disorder, which reverses, ameliorates, inhibits the progression, or It means to prevent, and the term treatment as used in the present invention refers to the act of treating. Accordingly, treatment or therapy for immune disorders in mammals may include one or more of the following:
(1) 면역질환의 성장을 저해함, 즉, 그 발달을 저지시킴;(1) inhibit the growth of, ie, arrest the development of, an immune disease;
(2) 면역질환의 확산을 예방함, 즉, 전이를 예방함; (2) prevent the spread of immune diseases, ie, prevent metastasis;
(3) 면역질환을 경감시킴; (3) alleviating immune disorders;
(4) 면역질환의 재발을 예방함; 및 (4) prevent recurrence of immune diseases; and
(5) 면역질환의 증상을 완화함(palliating) (5) alleviating symptoms of immune diseases (palliating)
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.As used herein, the term "mammal" refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
만약, 수혜동물이 조성물의 투여에 견딜 수 있거나, 조성물의 그 동물에의 투여가 적합한 경우라면, 조성물은 "약학적으로 또는 생리학적으로 허용가능함"을 나타낸다. 투여된 양이 생리학적으로 중요한 경우에는 상기 제제는 "치료학적으로 유효량"으로 투여되었다고 말할 수 있다. 상기 제제의 존재가 수혜 환자의 생리학적으로 검출가능한 변화를 초래한 경우라면 상기 제제는 생리학적으로 의미가 있다.A composition is indicated to be "pharmaceutically or physiologically acceptable" if the recipient animal can tolerate administration of the composition, or if administration of the composition to that animal is suitable. When the amount administered is physiologically important, the agent can be said to have been administered in a "therapeutically effective amount". An agent is physiologically meaningful if the presence of the agent results in a physiologically detectable change in the recipient patient.
본 발명의 조성물의 치료적으로 유효한 양은 여러 요소, 예를 들면 투여방법, 목적부위, 환자의 상태 등에 따라 달라질 수 있다. 따라서, 인체에 사용 시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다. 동물실험을 통해 결정한 유효량으로부터 인간에 사용되는 양을 추정하는 것도 가능하다. 유효한 양의 결정시 고려할 이러한 사항은, 예를 들면 Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.(2001), Pergamon Press; 및 E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed.(1990), Mack Publishing Co.에 기술되어있다.The therapeutically effective amount of the composition of the present invention may vary depending on several factors, for example, the administration method, the target site, the condition of the patient, and the like. Therefore, when used in the human body, the dosage should be determined as an appropriate amount in consideration of both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. These considerations in determining effective amounts are, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's Health status, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concurrently, and other factors well known in the medical field can be determined according to The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 조성물은 또한 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 약학적으로 허용 가능한 담체는 조성물을 생체 내 전달에 적합한 것이면 특별히 제한되지 않으며, 예를 들면, Merck Index, 13th ed., Merck & Co. Inc. 에 기재된 화합물, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 이용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주이용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 당 분야의 적정한 방법으로 또는 Remington's Pharmaceutical Science(Mack Publishing Company, Easton PA, 18th, 1990)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.The compositions of the present invention may also include carriers, diluents, excipients or combinations of two or more commonly used in biological agents. A pharmaceutically acceptable carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc. Compounds described in , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used as needed. Conventional additives may be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to formulate into injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets. Furthermore, it can be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
본 발명의 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. have.
본 발명에서 사용되는 용어, "약학적으로 허용가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. As used herein, the term “pharmaceutically acceptable” refers to exhibiting non-toxic properties to cells or humans exposed to the composition.
본 발명의 약학적 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 중량부 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive includes starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate. , lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, sucrose, dextrose, sorbitol and talc and the like can be used. The pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
본 발명에서 사용되는 용어, "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 목적하는 방법에 따라 비 경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 주사 제형으로 적용)하거나 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다.As used herein, the term "administration" means providing a predetermined substance to a patient by any suitable method, and parenteral administration (eg, intravenous, subcutaneous, intraperitoneal or topical administration according to a desired method) ) or oral administration, and the dosage varies according to the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
본 발명의 조성물은 목적하는 방법에 따라 비경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 적용)하거나 경구 투여할 수 있으며, 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택된다. 상기 약학적 조성물 중 포함되는 유효성분의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학적 조성물에 0.01 ㎍/ml ~ 50 mg/ml의 농도로 포함되는 것이다. 그 농도가 0.01 ㎍/ml 미만일 경우에는 약학 활성이 나타나지 않을 수 있고, 50 mg/ml를 초과할 경우에는 인체에 독성을 나타낼 수 있다.The composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) or orally, depending on the desired method, and the dosage may vary depending on the subject's age, weight, sex, physical condition, etc. is selected taking into account. It is self-evident that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected depending on the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 μg/ml to 50 mg/ml. If the concentration is less than 0.01 μg/ml, pharmaceutical activity may not appear, and if it exceeds 50 mg/ml, it may be toxic to the human body.
본 발명의 약학적 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화될 수 있다. 경구 투여용 제형으로는 예를 들면 정제, 환제, 경질, 연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제 (예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제 (예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 추가로 포함할 수 있다. 또한, 상기 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다. 또한, 비경구 투여용 제형의 대표적인 것은 주사용 제제이며, 주사용 제제의 용매로서 물, 링거액, 등장성 생리식염수 또는 현탁액을 들 수 있다. 상기 주사용 제제의 멸균 고정 오일은 용매 또는 현탁 매질로서 사용할 수 있으며 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있다. 또한, 상기 주사용 제제는 올레산과 같은 지방산을 사용할 수 있다. The pharmaceutical composition of the present invention may be formulated in various oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg, silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). In addition, the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid. or disintegrants such as sodium salts thereof or effervescent mixtures and/or absorbents, coloring, flavoring and sweetening agents. The formulation may be prepared by conventional mixing, granulating or coating methods. In addition, a representative formulation for parenteral administration is an injection formulation, and water, Ringer's solution, isotonic saline, or suspension may be mentioned as a solvent for the injection formulation. The sterile, fixed oil of the injectable preparation may be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides may be used for this purpose. In addition, the injection preparation may use a fatty acid such as oleic acid.
본 발명에서, 용어 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 면역질환의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to any action that suppresses or delays the occurrence, spread, and recurrence of immune diseases by administration of the pharmaceutical composition according to the present invention.
일 측면에서, 본 발명은 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 식품 조성물에 관한 것이다.In one aspect, the present invention relates to a food composition for the prevention or improvement of immune diseases comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
일 구현예에서, 마이셀은 글리시리진산 또는 글리시리진산의 염, 및 EPA 또는 DHA를 포함할 수 있다.In one embodiment, the micelles may comprise glycyrrhizic acid or a salt of glycyrrhizic acid, and EPA or DHA.
일 구현예에서, 글리시리진산 또는 글리시리진산의 염, EPA 또는 DHA, 및 코엔자임 Q10의 혼합 비율은 중량기준으로 0.1 내지 5:0.1 내지 5:0.1 내지 5의 범위로 혼합될 수 있다.In one embodiment, the mixing ratio of glycyrrhizic acid or a salt of glycyrrhizic acid, EPA or DHA, and coenzyme Q10 may be in the range of 0.1 to 5:0.1 to 5:0.1 to 5 by weight.
일 구현예에서, 코엔자임 Q10 가용화 조성물에 봉입되는 코엔자임 Q10의 함량이 조성물 총 중량에 대하여 1∼50 중량%일 수 있다.In one embodiment, the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition may be 1 to 50% by weight based on the total weight of the composition.
일 구현예에서, 코엔자임 Q10은 코엔자임 Q10 가용화 조성물 수용액에 0.05∼3 mg/mL의 농도로 포함될 수 있다.In one embodiment, coenzyme Q10 may be included in an aqueous solution of coenzyme Q10 solubilizing composition at a concentration of 0.05 to 3 mg/mL.
일 구현예에서, 코엔자임 Q10 가용화 조성물은 10∼200 nm의 입자크기를 가질 수 있다.In one embodiment, the coenzyme Q10 solubilizing composition may have a particle size of 10-200 nm.
일 구현예에서, 면역질환은 자가면역질환, 염증성 질환, 및 세포, 조직 또는 기관의 이식거부질환으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다.In one embodiment, the immune disease may be any one or more selected from the group consisting of an autoimmune disease, an inflammatory disease, and a cell, tissue or organ transplant rejection disease.
일 구현예에서, 면역질환은 관절염, 강직성 척추염, 천식, 피부염, 건선, 낭섬유증, 고형장기 이식 후기 및 만성거부증, 다발성 경화증, 전신성 홍반성 루푸스, 쇼그렌 증후군, 하시모토 갑상선, 다발성근염, 경피증, 아디슨병, 백반증, 악성빈혈, 사구체신염, 폐섬유, 염증성장질환, 자가면역성 당뇨, 당뇨 망막증, 비염, 혀혈-재관류 손상, 혈관성형술후 재협착, 만성 폐색성 심장 질환, 그레이브병, 위장관 알러지, 결막염, 죽상경화증, 관상동맥질환, 협심증, 암 전이 및 소동맥 질환으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다.In one embodiment, the immune disease is arthritis, ankylosing spondylitis, asthma, dermatitis, psoriasis, cystic fibrosis, late and chronic rejection of solid organ transplantation, multiple sclerosis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroid, polymyositis, scleroderma, adi Son's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, inflammatory bowel disease, autoimmune diabetes, diabetic retinopathy, rhinitis, tongue blood-reperfusion injury, restenosis after angioplasty, chronic obstructive heart disease, Grave's disease, gastrointestinal allergy, conjunctivitis , atherosclerosis, coronary artery disease, angina pectoris, may be any one or more selected from the group consisting of cancer metastasis and arteriole disease.
일 구현예에서, 관절염은 노인성 관절염, 퇴행성 관절염, 자가면역관절염, 골관절염, 비만성 관절염, 류마티스관절염, 척추관절병증, 강직성 척추염, 건선관절염, 통풍, 세균성 관절염, 소아기 류마티스관절염, 루푸스, 경피증, 다발성 경화증, 섬유근통, 다발성 근염, 피부근염, 베체트병, 라이터 증후군, 라임 관절염, 유착 관절낭염, 오십견, 힘줄 활막염, 팔꿈치머리 주머니염, 드쿼베인 힘줄윤활막염, 재발류마티스, 류마티스 다발근육통증 및 성인형 스틸병으로 이루어진 군에서 선택되는 어느 하나 이상일 수 있다.In one embodiment, the arthritis is senile arthritis, degenerative arthritis, autoimmune arthritis, osteoarthritis, obese arthritis, rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, psoriatic arthritis, gout, bacterial arthritis, juvenile rheumatoid arthritis, lupus, scleroderma, multiple Sclerosis, fibromyalgia, polymyositis, dermatomyositis, Behcet's disease, Reiter's syndrome, Lyme arthritis, adhesive capsulitis, frozen shoulder, tendon synovitis, elbow capsulitis, de Quervain's tendon synovitis, rerheumatism, polymyalgia rheumatica and adult still It may be any one or more selected from the group consisting of bottles.
본 발명의 조성물을 식품 조성물로 사용하는 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상의 방법에 따라 적절하게 사용할 수 있다. 상기 조성물은 유효성분 이외에 식품학적으로 허용가능한 식품보조첨가제를 포함할 수 있으며, 유효성분의 혼합량은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When the composition of the present invention is used as a food composition, the composition may be added as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method. In addition to the active ingredient, the composition may contain a food additive that is pharmaceutically acceptable, and the mixing amount of the active ingredient may be suitably determined according to the purpose of use (prevention, health or therapeutic treatment).
본 발명에서 사용되는 용어 "식품보조첨가제"란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The term "food supplement additive" used in the present invention refers to a component that can be added to food as an auxiliary, and is added to the manufacture of health functional food of each formulation, and those skilled in the art can appropriately select and use it. Examples of food supplement additives include various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners , pH adjuster, stabilizer, preservative, glycerin, alcohol, carbonation agent used in carbonated beverages, etc., but the above examples are not limited to the type of food supplement additive of the present invention.
본 발명의 식품 조성물에는 건강기능식품이 포함될 수 있다. 본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 통상의 기술분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 면역질환 치료제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The food composition of the present invention may include a health functional food. The term "health functional food" as used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful in the human body. Here, the term 'functionality' refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be prepared by a method commonly used in the ordinary technical field, and at the time of the preparation, it can be prepared by adding raw materials and components commonly added in the conventional technical field. In addition, if the formulation of the health functional food is also recognized as a health functional food, it can be prepared without limitation. The composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur during long-term administration of the drug using food as a raw material, and has excellent portability, and the present invention health functional food can be taken as an adjuvant to enhance the effect of immune disease treatment.
또한, 본 발명의 조성물이 사용될 수 있는 건강식품의 종류에는 제한이 없다. 아울러 본 발명의 추출물 또는 이의 분획물을 활성성분으로 포함하는 조성물은 당업자의 선택에 따라 건강기능식품에 함유될 수 있는 적절한 기타 보조 성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림 류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 추출물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다.In addition, there is no limitation on the type of health food in which the composition of the present invention can be used. In addition, the composition comprising the extract of the present invention or a fraction thereof as an active ingredient can be prepared by mixing known additives with other suitable auxiliary ingredients that may be contained in health functional foods according to the selection of those skilled in the art. Examples of foods that can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and There are vitamin complexes and the like, and it can be prepared by adding the extract according to the present invention as a main component to juice, tea, jelly, juice, and the like.
본 발명의 조성물은 천연 재료를 원료로 하므로 약학적 조성물 또는 식품 조성물로 사용할 경우에도 일반적인 합성 화합물에 비하여 부작용이 덜할 수 있으므로, 안전하게 약학적 조성물 및 건강기능식품에 포함되어 유용하게 사용될 수 있다.Since the composition of the present invention is made from natural materials, side effects may be less than that of general synthetic compounds even when used as a pharmaceutical composition or a food composition, so it can be safely included in pharmaceutical compositions and health functional foods to be usefully used.
일 측면에서, 본 발명은 본 발명의 조성물을 하나 이상의 단위 투여 형태로 포함하는 키트에 관한 것이다.In one aspect, the invention relates to a kit comprising a composition of the invention in one or more unit dosage forms.
일 구현예에서, 본 발명에서 기술되는 투여 형태는 투여 형태의 사용에 대한 설명서와 함께 블리스터 팩으로서 또는 병에 포장될 수 있다. 예를 들어, 설명서는 패키지 삽입물로서 제공되거나 블리스터 팩, 병에 부착된 표지물 상 또는 블리스터 팩 또는 병이 사람 피험자에게 제공되었던 이차적인 포장재 상에 직접적으로 제공될 수 있다. 설명서는, 예를 들어, 투약 횟수, 음식과 함께 또는 음식 없이 투여되는 투여 형태의 투여, 투여 형태를 구성하는 활성 성분 및 투여 형태를 포함할 수 있다.In one embodiment, the dosage forms described herein may be packaged in a bottle or as a blister pack with instructions for use of the dosage form. For example, instructions may be provided as a package insert or may be provided directly on a blister pack, label affixed to the bottle, or on a secondary packaging material from which the blister pack or bottle was provided to a human subject. Instructions may include, for example, the number of doses, administration of the dosage form to be administered with or without food, the active ingredient constituting the dosage form, and the dosage form.
일 측면에서, 본발명은 약학적으로 유효한 양의 상기의 약학적 조성물을 개체에 투여하는 단계를 포함하는, 면역질환의 예방 또는 치료 방법에 관한 것이다.In one aspect, the present invention relates to a method for preventing or treating an immune disease, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition.
본 발명의 약학적 조성물은 치료적 유효량 또는 약학으로 유효한 양으로 투여한다. 용어"약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a therapeutically effective amount or a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the subject type and severity, age, sex, activity of the drug, and the drug. It can be determined according to factors including sensitivity, administration time, administration route and excretion rate, duration of treatment, concurrent drugs, and other factors well known in the medical field.
하기의 실시예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나 하기 실시예는 본 발명의 내용을 구체화하기 위한 것일 뿐 이에 의해 본 발명이 한정되는 것은 아니다.The present invention will be described in more detail through the following examples. However, the following examples are only for specifying the contents of the present invention, and the present invention is not limited thereto.
실시예 1. CoQ10 가용화 조성물 제조Example 1. Preparation of CoQ10 Solubilizing Composition
1-1. 고압 균질 유화기를 이용한 CoQ10 가용화 조성물 제조1-1. Preparation of CoQ10 Solubilizing Composition Using High Pressure Homogeneous Emulsifier
CoQ10(코엔자임 Q10)이 고농도로 함유된 CoQ10 가용화 조성물을 제조하기 위하여, 하기 표 1의 조건으로 도 1에 기재된 제조 방법을 수행하였다. 보다 구체적으로, 반응기에 증류수(Distilled water)를 주입한 후, 마이셀 형성을 위한 글리시리진산 이칼륨염(Dipotassium glycyrrhizinate), 아이코사펜타에노익산(Eicosapentaenoic acid, EPA), 난용성 약물인 CoQ10을 하기 표 1에 기재된 함량으로 첨가하여 고르게 분산되도록 교반하였다. 반응기에서 원활한 마이셀 생성을 위해 60 내지 70 ℃로 중탕된 상태로 각 원료가 포함된 상태에서 10,000 rpm으로 10분간 교반하였다. 상기 반응액을 APV사의 APV-2000 유동층 혼합기(microfluidizer, SPX Flow, UK)를 이용하여 1200 bar의 고압에서 1 시간 동안 마이셀 형성을 위한 CoQ10의 봉입을 수행하였으며, 0.45 ㎛ 시린지 필터를 이용하여 마이셀을 확보하였다. 이 때, 과포화 상태의 조성물의 경우, 유동층 혼합기를 이용한 조성물 가용화 수행 후 수용액상에서 봉입되지 않은 CoQ10은 0.45 ㎛ 시린지 필터를 이용하여 제거하였다.In order to prepare a CoQ10 solubilized composition containing CoQ10 (Coenzyme Q10) at a high concentration, the preparation method described in FIG. 1 was performed under the conditions shown in Table 1 below. More specifically, after injecting distilled water into the reactor, glycyrrhizinate dipotassium salt (Dipotassium glycyrrhizinate), eicosapentaenoic acid (EPA), poorly soluble drug CoQ10 for micelle formation, It was added in the amount shown in Table 1 and stirred to evenly disperse. In order to generate micelles smoothly in the reactor, the mixture was stirred at 10,000 rpm for 10 minutes while each raw material was included in a bath at 60 to 70 °C. The reaction solution was encapsulated with CoQ10 for micellar formation for 1 hour at a high pressure of 1200 bar using APV-2000 fluid bed mixer (microfluidizer, SPX Flow, UK) of APV, and micelles were removed using a 0.45 μm syringe filter. secured. At this time, in the case of the composition in the supersaturated state, CoQ10 not encapsulated in the aqueous phase after solubilization of the composition using a fluidized bed mixer was removed using a 0.45 μm syringe filter.
Figure PCTKR2021003428-appb-T000001
Figure PCTKR2021003428-appb-T000001
1-2. CoQ10 가용화 조성물의 입도 분석 1-2. Particle size analysis of CoQ10 solubilizing composition
상기에서 제조한 수용성 코엔자임 Q1의 마이셀 입자크기를 나타내는 입도분석 결과 (Zetasizer Nano ZS9, Malvern Instrument, Ltd., UK), 도 2에 나타낸 바와 같이, CoQ10 가용화 조성물은 80 nm 내외로 균일한 입자 크기가 나타남을 확인하였다.As shown in the particle size analysis results (Zetasizer Nano ZS9, Malvern Instrument, Ltd., UK) showing the micellar particle size of the water-soluble coenzyme Q1 prepared above, FIG. 2 , the CoQ10 solubilizing composition had a uniform particle size of about 80 nm. Appearance was confirmed.
1-3. CoQ10 가용화 조성물의 CoQ10 함유량 분석 1-3. Analysis of CoQ10 content of CoQ10 solubilizing composition
상기 실시예와 같이 CoQ10 : 아이코사펜타에노익산(EPA) : 글리시리진산 (1 g : 1 mL : 1 g)을 1 리터의 증류수를 이용하여 제조된 CoQ10 가용화 조성물 2.4 g/L을 이용하여 CoQ10의 정량을 HPLC로 분석하였다. HPLC 조건은 하기 표 2와 같으며, 하기 조건을 통해 검출한 CoQ10의 HPLC 상에서의 시간대는 6.9분에 피크가 나타나는 것을 확인하였으며, 이를 도 3에 도시하였다.As in the above example, CoQ10: eicosapentaenoic acid (EPA): glycyrrhizic acid (1 g: 1 mL: 1 g) using 1 liter of distilled water CoQ10 solubilizing composition 2.4 g/L using CoQ10 was analyzed by HPLC. HPLC conditions are shown in Table 2 below, and it was confirmed that a peak appeared at 6.9 minutes on HPLC of CoQ10 detected through the following conditions, which is shown in FIG. 3 .
Figure PCTKR2021003428-appb-T000002
Figure PCTKR2021003428-appb-T000002
이 때, 상기 조건은 CoQ10 : EPA : 글리시리진산 (0.1 내지 5 : 0.1 내지 5 : 0.1 내지 5)을 이용한 가용화 조성물 제작 중 최적의 조건을 표기한 것일 뿐, 그 혼합 범위는 변경될 수 있다. 그 결과, 도 4에 나타낸 바와 같이, CoQ10의 정량곡선을 통해, 유동층 혼합기를 이용한 CoQ10 가용화 조성물의 CoQ10의 가용화 정도를 하기 수학식 1을 통해 확인하였다. At this time, the above conditions are CoQ10: EPA: glycyrrhizic acid (0.1 to 5: 0.1 to 5: 0.1 to 5) is only indicated the optimum conditions during the preparation of the solubilizing composition, the mixing range can be changed. As a result, as shown in FIG. 4 , the degree of solubilization of CoQ10 in the CoQ10 solubilization composition using a fluidized bed mixer was confirmed through Equation 1 through the quantitative curve of CoQ10.
Figure PCTKR2021003428-appb-M000001
Figure PCTKR2021003428-appb-M000001
x = CoQ10 농도; 및 x = CoQ10 concentration; and
y = micelle 1 mg을 MeOH에 용해한 후 측정한 HPLC 상에서의 흡광 intensity.y = Absorption intensity on HPLC measured after dissolving 1 mg of micelles in MeOH.
그 결과, 상기 표 1에 나타낸 바와 같이, 난용성 물질인 CoQ10이 함유된 생체 친화적 마이셀 입자를 수득하였으며, 수율 100%의 CoQ10 가용화 조성물 (CoQ10 마이셀, CoQ10 micelle)을 제조하고, 봉입효율을 확인하였다.As a result, as shown in Table 1, biocompatible micellar particles containing CoQ10, a poorly soluble material, were obtained, and a CoQ10 solubilization composition (CoQ10 micelles, CoQ10 micelles) with a yield of 100% was prepared, and the encapsulation efficiency was confirmed. .
실시예 2. CoQ10 가용화 조성물의 류마티스 관절염 치료 효과Example 2. Treatment effect of CoQ10 solubilizing composition for rheumatoid arthritis
2-1. CoQ10 가용화 조성물의 류마티스 관절염 증상 치료 효과2-1. Effect of CoQ10 Solubilizing Composition for Treating Rheumatoid Arthritis Symptoms
상기 실시예 1의 CoQ10 가용화 조성물의 류마티스 관절염 치료 효과를 확인하기 위해, 류마티스 관절염 동물 모델을 제작하였다. 구체적으로, 정상 DBA/1 마우스에 Type Ⅱ 콜라겐을 1차 접종한 후 14 후 다시 2차 접종하였다. 류마티스 관절염 유발 후 21일에 1점 이상의 질환 지수를 보이는 군을 선별함으로써 동물 모델을 제작하였다. 그 후, 동물 모델에서 비만 관련 관절염을 유발하고 21일차부터 부형대조물질인 마이셀, CoQ10(10mg/kg) 및 CoQ10-마이셀(3mg/kg 또는 10mg/kg)을 각각 하루 1회 매일 경구 투여한 뒤, 각 군의 마우스를 3 명의 관찰자가 하기 표 3의 평가기준(Mean arthritic index)에 따라 점수로 평가하여 얻은 평균 점수로 관절염을 평가하였다(Current protocols in immunology. vol.2. p15.5-11. John Wiley & Sons, New Yo가 NY, 1996). 유발율 평가의 경우 하나의 발에서 부종이 발생될 시 25%로 네 다리의 합을 100%로 계산하여 평가하였다.In order to confirm the therapeutic effect of the CoQ10 solubilizing composition of Example 1 on rheumatoid arthritis, an animal model of rheumatoid arthritis was prepared. Specifically, normal DBA/1 mice were first inoculated with Type II collagen, followed by a second inoculation 14 later. An animal model was prepared by selecting a group showing a disease index of 1 or more on the 21st day after induction of rheumatoid arthritis. After that, after inducing obesity-related arthritis in an animal model, the excipient controls micelles, CoQ10 (10 mg/kg) and CoQ10-micelles (3 mg/kg or 10 mg/kg) were orally administered once a day, respectively, from the 21st day. , Arthritis was evaluated with the average score obtained by evaluating the mice in each group with a score according to the evaluation criteria (Mean arthritic index) of Table 3 below (Current protocols in immunology. vol.2. p15.5-11) (John Wiley & Sons, New Yo, NY, 1996). In the case of induced rate evaluation, when edema occurred in one foot, it was evaluated by calculating the sum of the four legs as 25% and the sum of the four legs as 100%.
점수score 평가기준Evaluation standard
0점0 points 부종이나 종창이 없다.There is no edema or swelling.
1점1 point 발 또는 발목관절에 국한된 경한 부종과 발적Mild swelling and redness localized to the foot or ankle joint
2점2 points 발목관절에서 족근골 (Metatarsal bone)에 걸친 경한 부종과 발적Mild swelling and redness from the ankle joint to the metatarsal bone
3점3 points 발목관절에서 족근골에 걸친 중등도의 부종과 발적Moderate swelling and redness from the ankle joint to the tarsal bone
4점4 points 발목에서 다리 전체에 걸쳐 부종과 발적이 있는 경우Swelling and redness from the ankle to the entire leg
상기와 같은 관절염 유효성 및 발병율 관찰 결과, CoQ10 마이셀(3㎎/㎏ 및 10㎎/㎏)이 마이셀에 비해 통계적으로 유의하게 류마티스관절염 치료 효과를 나타냈다(micelle vs. CoQ10-micelle 3 mg/kg 8w2, 9w1, **P<0.001, 10w2, *P<0.05; micelle vs. CoQ10 10 ㎎/㎏, 6w1, 6W2, 10w1,*P<0.05) (도 5a 및 도 5b).As a result of the observation of the arthritis efficacy and incidence rate as described above, CoQ10 micelles (3 mg/kg and 10 mg/kg) showed a statistically significant rheumatoid arthritis treatment effect compared to micelles (micelle vs. CoQ10-micelle 3 mg/kg 8w2, 9w1, **P <0.001, 10w2, *P <0.05; micelle vs. CoQ10 10 mg/kg, 6w1, 6W2, 10w1, *P <0.05) ( FIGS. 5A and 5B ).
2-2. CoQ10 가용화 조성물의 류마티스 관절염 특이적 항체 생성 억제 효과2-2. Inhibitory effect of CoQ10 solubilizing composition on rheumatoid arthritis-specific antibody production
상기 실시예 1의 CoQ10 가용화 조성물의 류마티스 관절염 치료 효과를 확인하기 위해, 상기 실시예에서와 같이 류마티스 관절염 동물 모델에 마이셀, CoQ10 및 CoQ10 마이셀을 투여한 뒤, 각 군의 마우스에서 혈청을 수득하고, 혈청 내 총 IgG, IgG2a, 타입 Ⅱ 콜라겐 특이적 IgG 및 타입 Ⅱ 콜라겐 특이적 IgG2a 항체를 효소결합 면역측정법(ELISA)을 통해 분석하였다.In order to confirm the rheumatoid arthritis therapeutic effect of the CoQ10 solubilizing composition of Example 1, micelles, CoQ10 and CoQ10 micelles were administered to the rheumatoid arthritis animal model as in the above Example, and then serum was obtained from mice in each group, Total IgG, IgG2a, type II collagen-specific IgG and type II collagen-specific IgG2a antibodies in serum were analyzed by enzyme-linked immunoassay (ELISA).
그 결과, 혈청 내 IgG, IgG2a, 타입 Ⅱ 콜라겐 특이적 IgG 및 타입 Ⅱ 콜라겐 특이적 IgG2a가 마이셀 또는 CoQ10를 투여한 군에 비해 CoQ10 마이셀을 투여한 군(3㎎/㎏ 또는 10㎎/㎏)에서 통계적으로 유의하게 항체 생성이 현저히 감소된 것으로 나타났다(*P<0.05, **P<0.001, ***P<0.005) (도 6a 내지 도 6d).As a result, serum IgG, IgG2a, type II collagen-specific IgG, and type II collagen-specific IgG2a were found in the group administered with CoQ10 micelles (3 mg/kg or 10 mg/kg) compared to the groups administered with micelles or CoQ10. It was found that the antibody production was significantly reduced statistically significantly ( *P <0.05, ** P <0.001, ***P <0.005) ( FIGS. 6A to 6D ).
2-3. CoQ10 가용화 조성물의 관절 파괴 억제 효과2-3. Inhibitory effect on joint destruction of CoQ10 solubilizing composition
상기 실시예 1의 CoQ10 가용화 조성물의 류마티스 관절염 치료 효과를 확인하기 위해, 상기 실시예에서와 같이 류마티스 관절염 동물 모델에 마이셀, CoQ10 및 CoQ10 마이셀을 투여한 뒤, 각 군의 마우스의 관절 파괴 정도를 조직병리학적으로 확인하였다. 구체적으로, 동물 모델 마우스 각 군의 발목뼈(tarsal bone), 활막 및 연골(cartilage)을 채취한 후 H&E 염색을 이용하여 관절 파괴 정도를 조직병리학적으로 분석하고 손상정도 및 면역세포 침윤 정도에 따라 0-5점으로 평가하여 수치화하였으며, 주상골(navicular) 및 정강이뼈(tibia)의 관절 조직을 파라핀 블록화하여 5 μ두께로 절편화한 뒤 연골 손상 정도를 Safranin O 조직염색을 통해 확인하였다.In order to confirm the rheumatoid arthritis therapeutic effect of the CoQ10 solubilizing composition of Example 1, micelles, CoQ10, and CoQ10 micelles were administered to the rheumatoid arthritis animal model as in Example 1, and then, the degree of joint destruction of mice in each group was assessed by tissue It was confirmed pathologically. Specifically, after collecting tarsal bone, synovial membrane, and cartilage from each group of animal model mice, the degree of joint destruction was analyzed histopathologically using H&E staining, and the degree of damage and immune cell infiltration were determined It was evaluated on a scale of 0-5, and the joint tissues of the navicular and tibia were paraffin-blocked and sectioned to a thickness of 5 μ, and the degree of cartilage damage was confirmed through Safranin O tissue staining.
그 결과, CoQ10 마이셀 처리군의 경우 발목뼈를 중심으로 활막에 염증 세포의 침윤과 골 파괴 정도가 다른 군에 비해(vehicle 및 마이셀) 현저히 낮게 나타났다 (도 7a 내지 도 7e).As a result, in the case of the CoQ10 micelles-treated group, the infiltration of inflammatory cells into the synovial membrane around the ankle bone and the degree of bone destruction were significantly lower than in other groups (vehicle and micelles) ( FIGS. 7A to 7E ).
2-4. CoQ10 가용화 조성물의 관절 조직 내 염증성 사이토카인 억제 효과2-4. Inhibitory effect of CoQ10 solubilizing composition on inflammatory cytokines in joint tissue
상기 실시예 1의 CoQ10 가용화 조성물의 류마티스 관절염 치료 효과를 확인하기 위해, 상기 실시예에서와 같이 류마티스 관절염 동물 모델에 마이셀, CoQ10 및 CoQ10 마이셀을 투여한 뒤, 각 군의 마우스의 관절 조직 및 활막 조직 내 염증성 사이토카인인 IL-17, TNFα, IL-6 및 IL-1β 양성 세포를 면역 조직 염색법을 이용하여 계수하였다. In order to confirm the rheumatoid arthritis therapeutic effect of the CoQ10 solubilizing composition of Example 1, micelles, CoQ10 and CoQ10 micelles were administered to the rheumatoid arthritis animal model as in Example 1, and then the joint tissue and synovial tissue of mice of each group Inflammatory cytokines, IL-17, TNFα, IL-6 and IL-1β positive cells were counted using immunohistochemistry.
그 결과, 염증성 사이토카인인 IL-17, IL-6, TNF-α 및 IL-1β의 발현이 CoQ10 마이셀 투여군에서 현저히 억제되는 것으로 나타났다(도 8a 내지 도 8d).As a result, the expression of inflammatory cytokines IL-17, IL-6, TNF-α and IL-1β was significantly inhibited in the CoQ10 micellar administration group ( FIGS. 8a to 8d ).
실시예 3. CoQ10 가용화 조성물의 골관절염 치료 효과Example 3. Osteoarthritis treatment effect of CoQ10 solubilizing composition
3-1. 골관절염 동물모델 제작3-1. Osteoarthritis animal model production
골관절염 동물모델을 제작하기 위해 200~250g인 5주령 수컷 Wistar 랫(rat)을 21~22℃의 온도에서 명암주기(light-dark cycle)를 12시간 간격으로 사육하였고 살균한 물과 사료를 공급하여 키웠다. 이후 골관절염 유도를 위해 랫(rat)의 슬관절에 3mg/50μl의 용량으로 모노소듐 아이도아세테이트(Monosodium iodoacetate, MIA, Sigma, ST. Louis, MO)를 투여하여 골관절염을 유도하였다. MIA는 생리식염수에 용해시켜 투여하였다. 골관절염 유발 4일 후에 통증 측정을 하여 골관절염 유발 동물모델을 선별하였다.To produce an osteoarthritis animal model, 5-week-old male Wistar rats weighing 200 to 250 g were bred at a temperature of 21 to 22 ° C in a light-dark cycle at 12 hour intervals, and sterilized water and feed were supplied. brought up Thereafter, osteoarthritis was induced by administering monosodium iodoacetate (MIA, Sigma, ST. Louis, MO) at a dose of 3 mg/50 μl to the knee joint of a rat to induce osteoarthritis. MIA was administered by dissolving it in physiological saline. After 4 days of osteoarthritis induction, pain was measured to select an osteoarthritis-induced animal model.
3-2. CoQ10 가용화 조성물의 골관절염 통증 경감 효과3-2. Osteoarthritis Pain Relief Effect of CoQ10 Solubilizing Composition
상기 실시예 3-1에서 제작한 골관절염 동물모델에 골관절염 유발 4 일 후 부터 골관절염 양성 대조약물(Celecoxib), 마이셀, CoQ10 및 CoQ10 마이셀을 각각 주 6회 구강투여하였다. 2일 후 Dynamic plantat aesthsiometer(Ugo Basile, Comerio, Italy) 위에 그물로 된 판을 얹고 그 위에 아크릴로 된 동물고정틀 안에 각 군의 랫을 넣고, 측정기계로 약물이 주입된 오른발을 찌른 후에 랫이 발을 떼는데 걸리는 시간(paw withdrawal latency) (s, 초)과 얼마만큼의 무게를 주었을 때 발을 떼는지(paw withdrawal threshold) (g)를 기계가 자동적으로 측정하여 통증 측정 그래프를 도출하였다. 또한, 랫트의 왼발과 오른발에 실리는 힘을 비교, 측정하기 위하여 Incapacitance tester를 이용하였다. 랫트를 플라스틱 챔버에 넣고 Incapacitance tester의 분리된 판 위에 랫트의 왼발과 오른발을 각 판위에 올려놓고 3초 동안 각 발에 실리는 힘의 평균값을 얻었다. 이렇게 얻은 Weight bearing (%)은 하기 수학식 2에 대입하여 결과를 얻었다.The osteoarthritis-positive control drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles, respectively, were orally administered to the animal model of osteoarthritis prepared in Example 3-1 4 days after induction of osteoarthritis 6 times a week. After 2 days, a net plate was placed on the Dynamic plantat aesthsiometer (Ugo Basile, Comerio, Italy), and the rats of each group were placed in an acrylic animal holder on the top. The pain measurement graph was derived by automatically measuring the paw withdrawal latency (s, seconds) and the amount of weight applied to the paw withdrawal threshold (g). In addition, an incapacitance tester was used to compare and measure the force applied to the left and right feet of the rat. The rat was placed in a plastic chamber, and the left and right paws of the rat were placed on each plate on a separate plate of the incapacitance tester, and the average value of the force applied to each paw was obtained for 3 seconds. The weight bearing (%) obtained in this way was substituted into Equation 2 below to obtain a result.
Figure PCTKR2021003428-appb-M000002
Figure PCTKR2021003428-appb-M000002
그 결과, 다른 모든 약물 투여군들에 비해 CoQ10 마이셀을 투여한 군의 통증이 현저히 완화된 것으로 나타났으며, 특히 종래의 골관절염 치료제(Celecoxib) 투 여군보다도 통증 경감에 현저한 효과를 나타났다(*P<0.05) (도 9a 및 도 9b). 또한, 체중부하(Weight bearing) 평가 결과에서도 CoQ10 마이셀을 투여한 군의 효과가 골관절염 치료제와 유사한 정도로 다른 군에 비해 현저히 우수한 것으로 나타났다 (micelle 대비 **P<0.01, ***P<0.001) (도 9c).As a result, it was found that the group administered with CoQ10 micelles was significantly relieved of pain compared to all other drug-administered groups, and in particular, the group treated with the conventional osteoarthritis treatment (Celecoxib) had a significant effect on pain relief ( *P <0.05). ) ( FIGS. 9A and 9B ). In addition, in the weight bearing evaluation result, the effect of the group administered with CoQ10 micelles was significantly superior to that of the other groups to a degree similar to the treatment for osteoarthritis ( **P< 0.01 compared to micelles, ***P <0.001) ( Fig. 9c).
3-3. CoQ10 가용화 조성물의 골 파괴 억제 효과3-3. Bone destruction inhibitory effect of CoQ10 solubilizing composition
상기 실시예 3-1에서 제작한 골관절염 동물모델에 골관절염 유발 4 일 후부터 골관절염 양성 대 조약물(Celecoxib), 마이셀, CoQ10 및 CoQ10 마이셀을 각각 주 6회 구강투여하고 대퇴골(Femur)의 골 파괴 및 손상 정도를 micro-CT 촬영을 통해 골 볼륨(%)을 분석함으로써 확인하였다. micro-CT 장비는 skyscan1272 ex-vivo micro-CT를 사용하였으며 해상도의 경우 8.19㎛ 픽셀로 촬영을 진행하였다.From 4 days after osteoarthritis induction to the osteoarthritis animal model prepared in Example 3-1, the osteoarthritis-positive drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles were orally administered 6 times a week, respectively, and bone destruction and damage of the femur (Femur). The degree was confirmed by analyzing the bone volume (%) through micro-CT imaging. For micro-CT equipment, skyscan1272 ex-vivo micro-CT was used, and in the case of resolution, imaging was performed with 8.19㎛ pixels.
그 결과, CoQ10 마이셀을 투여한 군에서 골 표면 손상 정도가 현저히 감소하 였다(도 10a 및 도 10b).As a result, the degree of bone surface damage was significantly reduced in the group administered with CoQ10 micelles ( FIGS. 10a and 10b ).
3-4. CoQ10 가용화 조성물의 염증성 사이토카 인 제어 효과3-4. Inflammatory cytokine control effect of CoQ10 solubilizing composition
상기 실시예 3-1에서 제작한 골관절염 동물모델에 골관절염 유발 4 일 후 부터 골관절염 양성 대조약물(Celecoxib), 마이셀, CoQ10 및 CoQ10 마이셀을 각각 주 6회 구강투여하고 각 군의 랫의 주상골(nav icular) 및 정강이뼈(tibia)의 관절 조직을 파라핀 블록화하여 5 μ 두께로 절편화한 뒤 연골 손상 정도를 Safranin O 조직염색을 통해 확인하였다.From 4 days after osteoarthritis induction to the osteoarthritis animal model prepared in Example 3-1, the osteoarthritis-positive control drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles were orally administered 6 times a week, respectively, and the navicular ) and the joint tissue of the tibia were paraffin-blocked and sectioned to a thickness of 5 μm, and the degree of cartilage damage was confirmed through Safranin O tissue staining.
그 결과, 부형제 대조군(Vehicle)에서는 연골의 섬유화 및 손상이 나타났고 골 파괴 증상까지 나타났고, 양성대조물질군인 Celecoxib에서도 섬유화 증상이 확인되었으나, CoQ10 마이셀 투여군에서는 연골의 섬유화 현상이 호전되었으며, CoQ10 투여군 및 마이셀 투여군에 비해 OA RSI 및 Mankin score의 유의적인 감소를 확인하였다(vehicle 대비 *P<0.05) (도 11a 내지 도 11c).As a result, in the vehicle control group, cartilage fibrosis and damage and even bone destruction symptoms were observed, and fibrosis symptoms were also confirmed in Celecoxib, a positive control group. And it was confirmed that a significant decrease in OA RSI and Mankin score compared to the micellar administration group (compared to vehicle * P <0.05) ( FIGS. 11a to 11c ).
3-5. CoQ10 가용화 조성물의 염증 성 사이토카인 제어 효과3-5. Inflammatory cytokine control effect of CoQ10 solubilizing composition
상기 실시예 3-1에서 제작한 골관절염 동물모델에 골관절염 유발 4 일 후부터 골관절염 양성 대조약물(Celecoxib), 마이셀, CoQ10 및 CoQ10 마이셀을 각각 주 6회 구강투여하고 각 군의 랫의 관 절 조직 및 활막 조직 내 염증성 사이토카인 (IL-1β, IL-6 및 IL-17), 항염증성 사이토카인(IL-10), 산화 인자(iNOS) 및 이화 작용 관여 단백질(MMP13)의 발현 정도를 면역조직화학염색법으로 확인하고, 각 마커의 양성 세포를 계수하였다. From 4 days after osteoarthritis induction to the osteoarthritis animal model prepared in Example 3-1, the osteoarthritis-positive control drug (Celecoxib), micelles, CoQ10 and CoQ10 micelles were orally administered 6 times a week, respectively, and the joint tissue and synovial membrane of each group of rats The expression level of inflammatory cytokines (IL-1β, IL-6 and IL-17), anti-inflammatory cytokines (IL-10), oxidative factor (iNOS) and catabolic protein (MMP13) in tissues was measured by immunohistochemical staining method. , and positive cells for each marker were counted.
그 결과, 염증성 사이토카인인 IL-1β, IL-6 및 IL-17은 마이셀 투여군에 비해 CoQ10 투여군, CoQ10 마이셀 투여군 및 셀레콕시브 투여군에서 감소하는 것으로 나타났으며(도 12a 내지 도 12 f), 항염 증성 사이토카인인 IL-10은 부형제 대조군 및 CoQ10 투여군에 비해 CoQ10 마이셀 투여군에서 현저히 증가하는 것으로 나타났다(도 12g 및 도 12h). 아울러, 산화 인자인 iNOS 및 이화작용에 관여하는 MMP13의 발현은 CoQ10 투여군, CoQ10 마이셀 투여군 및 셀레콕시브 투여군에서 감소하는 경향을 나타냈다(도 12i 내지 도12l).As a result, the inflammatory cytokines IL-1β, IL-6 and IL-17 were found to be decreased in the CoQ10 administration group, the CoQ10 micellar administration group and the celecoxib administration group compared to the micellar administration group (Figs. 12a to 12f), IL-10, an anti-inflammatory cytokine, was significantly increased in the CoQ10 micellar administration group compared to the excipient control group and the CoQ10 administration group ( FIGS. 12G and 12H ). In addition, the expression of oxidative factor iNOS and MMP13 involved in catabolism showed a tendency to decrease in the CoQ10 administration group, the CoQ10 micellar administration group and the celecoxib administration group ( FIGS. 12i to 12l ).
실시예 4. CoQ10 가용화 조성물의 쇼그렌 증후군 치료 효과Example 4. Sjogren's Syndrome Treatment Effect of CoQ10 Solubilizing Composition
4-1. CoQ10 가용화 조성물의 타액 분비능 증가 효과4-1. Effect of CoQ10 Solubilizing Composition to Increase Salivation
쇼그렌 증후군의 동물 모델인 NOD(Non-obese diabetic) 마우스가 10주령이 되는 시점부터 마이셀, CoQ10 및 CoQ10 마이셀을 각각 주 3회 피하 주사한 후, 마 우스의 쇼그렌 증후군의 발병척도인 타액분비능을 타액 분비율(sal iva/weight/7(minutes) 수치인 flow rate으로 측정)로 평가하여 평균±표준 편 차로 기록하였다. 타액량은 1 mg/ml의 필로카르핀(pilocarpine)을 100ul 피하 주사 1분 30초 후부터 7분 동안 타액을 수집하여 측정하였다. 또한, 마우스 모델의 혈액 내 글루코스 양을 분석하였다.After subcutaneous injection of micelles, CoQ10, and CoQ10 micelles, respectively, 3 times a week in non-obese diabetic (NOD) mice, an animal model of Sjogren's syndrome, from the age of 10 weeks, the salivation capacity, which is a measure of the onset of Sjogren's syndrome, of the mouse was measured with saliva. The secretion rate (measured by flow rate, which is a value of sal iva/weight/7 (minutes)) was evaluated and recorded as the mean ± standard deviation. The amount of saliva was measured by collecting saliva for 7 minutes from 1 minute and 30 seconds after 100ul subcutaneous injection of 1 mg/ml of pilocarpine. In addition, the amount of glucose in the blood of the mouse model was analyzed.
그 결과, 투여 기간(주, w)이 늘어남에 따라, 대조군(vehicle), 마이셀 처리군(micelle), CoQ10 10 mg/kg 투여군에서 타액 분비가 감소하였으나, CoQ10 마이셀 3 mg/kg 또는 10 mg/kg 투여군에서는 통계적으로 유의하게 타액 분비가 유지되는 것으로 나타났다(도 13a). 아울러, 혈청 내 글루코스의 농도가 마이셀 3 mg/kg 투여군 , CoQ10 마이셀 3 mg/kg 또는 10 mg/kg 투여군에서 통계적으로 유의하게 유 지되는 것으로 나타났다(도 13b).As a result, as the administration period (week, w) increased, salivation was decreased in the control group (vehicle), the micelles treated group (micelle), and the CoQ10 10 mg/kg administration group, but CoQ10 micelles 3 mg/kg or 10 mg/kg In the kg administration group, it was found that salivation was maintained statistically (Fig. 13a). In addition, it was found that the concentration of glucose in the serum was maintained statistically significantly in the micelles 3 mg/kg administration group, CoQ10 micelles 3 mg/kg or 10 mg/kg administration group (FIG. 13b).
4-2. CoQ10 가용화 조성물 의 침샘 조직 손상 억제 효과4-2. Inhibiting effect of CoQ10 solubilizing composition on salivary gland tissue damage
쇼그렌 증후군의 동물 모델 마우스에 마이셀, CoQ10 및 CoQ10 마이셀을 각각 주 3회 피하 주사한 후, 각 군의 마우스의 침샘(Salivary gland) 조직을 파라핀 블록 제작한 뒤, 세포의 형태 유지 여부 및 면역세포의 분포를 H&E 염색법을 통해 확인하고 면역세 포 침윤 결과를 조직학적 점수로 분석하여 평균±표준 편차로 기록하 였다.After subcutaneous injection of micelles, CoQ10, and CoQ10 micelles three times a week in an animal model of Sjogren's syndrome mice, paraffin blocks were prepared from the salivary gland tissues of each group of mice, The distribution was confirmed through H&E staining, and the results of immune cell infiltration were analyzed as histological scores and recorded as the mean ± standard deviation.
그 결과, CoQ10 마이셀 3 mg/kg 또는 10 mg/kg 투여군 모두 면역 세포의 침 윤이 감소하는 것으로 나타났으며(도 14a), 조직학적 점수 분석에서도 CoQ10 마이 셀 투여군에서 염증성 면역 세포의 침윤이 감소된 것으로 나타났다(도 14b).As a result, both the CoQ10 micelles 3 mg/kg or 10 mg/kg administration group showed decreased infiltration of immune cells (FIG. 14a), and histological score analysis showed that the infiltration of inflammatory immune cells was reduced in the CoQ10 micelles administration group. was found (Fig. 14b).
4-3. CoQ10 가용화 조성물의 침샘 조직 염증 억제 효과4-3. Inhibitory effect of CoQ10 solubilizing composition on inflammation of salivary gland tissue
쇼그렌 증후군의 동물 모델 마우스에 마이셀, CoQ10 및 CoQ10 마이셀을 각각 주 3회 피하 주사한 후, 각 군의 마우스의 침샘 조직을 IHC 염색하여 염증성 사이토카인(IL-17, IL-6 및 TNF-α) 발현 세포 및 항염증성 사이토카인(IL-10) 발현 세포를 분석하였다. After subcutaneous injection of micelles, CoQ10, and CoQ10 micelles three times a week to mice in an animal model of Sjogren's syndrome, IHC staining of the salivary gland tissues of mice in each group showed inflammatory cytokines (IL-17, IL-6 and TNF-α) Expressing cells and anti-inflammatory cytokine (IL-10) expressing cells were analyzed.
그 결과, CoQ10 마이셀 3 mg/kg 또는 10 mg/kg 투여군에서 염증성 사이토카인인 IL-6, IL-17 및 TNF-α을 발현하는 세포가 감소되었으며, 특히, IL-6는 CoQ10 마이셀 10 mg/kg 투여군에서, TNF-α는 CoQ 10 마이셀 3 mg/kg 및 10 mg/kg 투여군에서 통계적 유의성을 보였다(vehicle 대비 *P<0.05) (도 15a 내지 도 15c). 또한, IL-10 발현 세포는 CoQ10 마이셀 3 mg/kg 투여군 및 10 mg/kg 투여군에서 증가하였다(도 15d).As a result, cells expressing the inflammatory cytokines IL-6, IL-17 and TNF-α were reduced in the CoQ10 micelles 3 mg/kg or 10 mg/kg administration group. in kg administered group, TNF-α is CoQ 10 micelles in 3 mg / kg and 10 mg / kg administration group showed a statistical significance (vehicle compared * P <0.05) (Fig. 15a to Fig. 15c). In addition, IL-10-expressing cells were increased in CoQ10 micelles administered at 3 mg/kg and at 10 mg/kg ( FIG. 15D ).
실시예 5. CoQ10 가용화 조성물의 비만 동반 류마티스 관절염 치료 효과Example 5. Treatment effect of CoQ10 solubilizing composition for rheumatoid arthritis accompanied by obesity
5-1. CoQ10 가용화 조성물의 관절염 증상 치료 효과 5-1. Effect of CoQ10 Solubilizing Composition for Treating Arthritis Symptoms
CoQ10 마이셀의 비만 관련 관절염 치료 효과를 확인하기 위해, 정상 DBA/1 마우스에 Type Ⅱ 콜라겐을 1차 접종한 후 14 후 다시 2차 접종하였다. 그 후, 고지방 식이를 수행하여 비만 관련 관절염을 유발하고, 비만관절염 유발 후 21일에 1 점 이상의 질환 지수를 보이는 군을 선별함으로써 동물 모델을 제작하였다. 그 후, 동물 모델에서 비만 관련 관절염을 유발하고 21일차부터 CoQ10 및 CoQ10-마이셀을 각각 하루 1회 매일 경구 투여한 뒤, 각 군의 마우스를 3 명의 관찰자가 상기 표 3 의 평가기준(Mean arthritic index)에 따라 점수로 평가하여 평균 점수로 관절염을 평가하였다(Current protocols in immunology. vol.2. p15.5-11. John Wiley & Sons, New Yo가 NY, 1996). 유발율 평가의 경우 하나의 발에서 부종이 발생될 시 25%로 네 다리의 합을 100%로 계산하여 평가하였다.To confirm the therapeutic effect of CoQ10 micelles on obesity-related arthritis, normal DBA/1 mice were first inoculated with Type II collagen, followed by a second inoculation 14 later. Thereafter, a high-fat diet was performed to induce obesity-related arthritis, and an animal model was prepared by selecting a group showing a disease index of 1 or more on the 21st day after the induction of obesity-related arthritis. Thereafter, obesity-related arthritis was induced in an animal model, and CoQ10 and CoQ10- micelles were orally administered once a day from day 21, respectively, and then three observers of each group were evaluated by the evaluation criteria (Mean arthritic index in Table 3). ), and arthritis was evaluated with an average score (Current protocols in immunology. vol.2. p15.5-11. John Wiley & Sons, New Yo NY, 1996). In the case of induced rate evaluation, when edema occurred in one foot, the sum of the four legs was calculated as 25% and 100% was evaluated.
상기와 같은 관절염 유효성 및 발병율 관찰 결과, CoQ10 마이셀 10mg/kg의 농도에서 비만관절염군 대비 통계적으로 유의하게 질환 치료 효력을 나타냈다(비만관절염 군 대비 5주(*P<0.005) 6주~9주(***P<0.005) (도 16a 및 도 16b).As a result of the observation of the arthritis efficacy and incidence rate as described above, at a concentration of 10 mg/kg of CoQ10 micelles, it showed a statistically significant disease treatment effect compared to the obesity arthritis group (5 weeks ( *P <0.005 ) compared to the obesity arthritis group) 6 weeks to 9 weeks ( ***P<0.005 ) (FIGS. 16A and 16B).
5-2. CoQ10 가용화 조성물의 관절 및 연골 파괴 완화 효과5-2. Effect of CoQ10 Solubilizing Composition for Alleviating Joint and Cartilage Destruction
CoQ10 마이셀(CoQ10-micelle)의 비만 관련 관절염 치료 효과를 확인하기 위해, C oQ10 마이셀의 투여로 인한 활막 조직 내 면역 염증 세포의 침윤 정도, 골 파 괴 정도 및 연골 손상 정도를 확인하였다. 구체적으로, 상기 실시예에서와 같이 비 만 관련 관절염 마우스 모델에 CoQ10 또는 CoQ10-마이셀을 투여한 뒤 이들로부터 얻은 활막(synovium) 조직을 4% 파라포름알데히드로 밤새도록 고정하였다. 이 후, 알콜로 탈수시키고 파라핀으로 임베딩(embedding)하여 절단을 실시하고, H&E 및 Safranin O 염색을 진행하여, 올림푸스 현미경(Tokyo, Japan)으로 관찰하였다. In order to confirm the therapeutic effect of CoQ10 micelles (CoQ10-micelle) on the treatment of obesity-related arthritis, the degree of infiltration of immune inflammatory cells in the synovial tissue caused by the administration of CoQ10 micelles, the degree of bone destruction, and the degree of cartilage damage were checked. Specifically, as in the above example, CoQ10 or CoQ10- micelles were administered to a mouse model of obesity-related arthritis, and synovial tissues obtained therefrom were fixed overnight with 4% paraformaldehyde. Thereafter, dehydration with alcohol, embedding with paraffin, cutting, and H&E and Safranin O staining were performed, and observed with an Olympus microscope (Tokyo, Japan).
조직학 적 검사 결과, CoQ10 마이셀을 투여한 군에서는 활막 조직 내 면역 염 증 세포의 침윤이 통계적으로 유의하게 감소하였으며(**P<0.01), 통계적으로 유의 하게 골 파괴가 억제되었고(*P<0.05), 연골 손상이 억제됨을 확인하였다 (***P<0.005) (도 17a 내지 도 17h).As a result of histological examination, in the group administered with CoQ10 micelles, the infiltration of immune-inflammatory cells in the synovial tissue was significantly reduced (** P <0.01), and bone destruction was statistically significantly suppressed (* P <0.05). ), it was confirmed that cartilage damage was inhibited (*** P <0.005) ( FIGS. 17A to 17H ).
5-3. CoQ10 가용화 조성물의 관절 조직 내 염증성 사이토카인 발현 억제 효과5-3. Inhibitory effect of CoQ10 solubilizing composition on inflammatory cytokine expression in joint tissue
CoQ10 마이셀의 비만 관련 관절염 치료 효과를 확인하기 위해, 관절 조직 활 막 부위 내 염증성 사이토카인의 발현 정도를 확인하였다. 구체적으로, 상기 실시 예에서와 같이 비만 관련 관절염 마우스 모델에 CoQ10 또는 CoQ10-마이셀을 투여한 뒤, 이들로부터 얻은 활막 조직을 면역 조직 염색법을 이용하여 염증성 사이토카인 IL-17, IL-6, IL-1β 및 TNF-α의 발현을 분석하였다.In order to confirm the therapeutic effect of CoQ10 micelles on obesity-related arthritis, the expression level of inflammatory cytokines in the synovial membrane of joint tissues was checked. Specifically, after administration of CoQ10 or CoQ10- micelles to a mouse model of obesity-related arthritis as in the above example, the synovial tissue obtained therefrom was stained with the inflammatory cytokines IL-17, IL-6, IL- The expression of 1β and TNF-α was analyzed.
그 결과, CoQ10 마이셀을 투여한 군의 경우 IL-17, TNF-α, IL-1β 및 IL-6의 발현이 CoQ10 보다도 통계적으로 유의하게 현저히 감소하였다(도 18a 내지 도 18h).As a result, in the case of the group administered with CoQ10 micelles, the expression of IL-17, TNF-α, IL-1β and IL-6 was significantly significantly decreased than CoQ10 ( FIGS. 18A to 18H ).

Claims (21)

  1. 코엔자임 Q10이 마이셀(micelle)에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 면역질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating immune diseases, comprising a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles as an active ingredient.
  2. 제 1항에 있어서, 마이셀은 글리시리진산(Glycyrrhizinate) 또는 글리시리진산의 염, 및 EPA(Eicosapentaenoic acid) 또는 DHA(Docosa hexaenoic acid)를 포함하는, 면역질환의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition of claim 1, wherein the micelles include glycyrrhizinate or a salt of glycyrrhizinate, and Eicosapentaenoic acid (EPA) or Docosa hexaenoic acid (DHA).
  3. 제 2항에 있어서, 글리시리진산 또는 글리시리진산의 염; EPA 또는 DHA; 및 코엔자임 Q10;의 혼합 비율은 중량기준으로 0.1 내지 5 : 0.1 내지 5 : 0.1 내지 5의 범위로 혼합되는, 면역질환의 예방 또는 치료용 약학적 조성물.According to claim 2, glycyrrhizic acid or a salt of glycyrrhizic acid; EPA or DHA; and coenzyme Q10; the mixing ratio is 0.1 to 5: 0.1 to 5: 0.1 to 5 by weight, which is mixed in a range of 0.1 to 5, a pharmaceutical composition for the prevention or treatment of immune diseases.
  4. 제 1항에 있어서, 코엔자임 Q10 가용화 조성물에 봉입되는 코엔자임 Q10의 함량이 조성물 총 중량에 대하여 1 내지 50 중량%인, 면역질환의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating immune diseases according to claim 1, wherein the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition is 1 to 50% by weight based on the total weight of the composition.
  5. 제 1항에 있어서, 코엔자임 Q10은 코엔자임 Q10 가용화 조성물 수용액에 0.05 내지 3 mg/mL의 농도로 포함되는, 면역질환의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating immune diseases according to claim 1, wherein coenzyme Q10 is contained in an aqueous solution of coenzyme Q10 solubilizing composition at a concentration of 0.05 to 3 mg/mL.
  6. 제 1항에 있어서, 코엔자임 Q10 가용화 조성물은 10 내지 200 nm의 입자크기를 가지는, 면역질환의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating immune diseases according to claim 1, wherein the coenzyme Q10 solubilizing composition has a particle size of 10 to 200 nm.
  7. 제 1항에 있어서, 면역질환은 자가면역질환, 염증성 질환, 및 세포, 조직 또는 기관의 이식거부(transplantation rejection)질환으로 이루어진 군으로부터 선택되는, 면역질환의 예방 또는 치료용 약학적 조성물. The pharmaceutical composition of claim 1, wherein the immune disease is selected from the group consisting of autoimmune diseases, inflammatory diseases, and transplantation rejection diseases of cells, tissues or organs.
  8. 제 7항에 있어서, 면역질환은 관절염(Arthritis), 강직성 척추염(Ankylosing spondylitis), 천식(Asthma), 피부염(Dermititis), 건선(Psoriasis), 낭섬유증 (Cystic Fibrosis), 고형장기 이식 후기 및 만성거부증(Post transplantation late and chronic solid organ rejection), 다발성 경화증(Multiple Sclerosis), 전신성 홍반성 루푸스(systemic lupus erythematosus), 쇼그렌 증후군(Sjogren syndrome), 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 사구체신염(glomerulonephritis), 폐섬유증(pulmonary fibrosis), 염증성장질환(Inflammatory Bowel Dieseses), 자가면역성 당뇨(AutoimmuneDiabetes), 당뇨 망막증(Diabetic retinopathy), 비염(Rhinitis), 혀혈-재관류 손상(Ischemia-reperfusion injury), 혈관성형술후 재협착(Post-angioplasty restenosis), 만성 폐색성 심장 질환(Chronic obstructive pulmonary diseases; COPD), 그레이브병(Graves disease), 위장관 알러지(Gastrointestinal allergies), 결막염(Conjunctivitis), 죽상경화증(Atherosclerosis), 관상동맥질환(Coronary artery disease), 협심증(Angina), 암 전이 및 소동맥 질환으로 이루어진 군으로부터 선택되는, 면역질환의 예방 또는 치료용 약학적 조성물. The method of claim 7, wherein the immune disease is arthritis, ankylosing spondylitis, asthma (Asthma), dermatitis (Dermititis), psoriasis (Psoriasis), cystic fibrosis (Cystic Fibrosis), solid organ transplant late and chronic rejection (Post transplantation late and chronic solid organ rejection), Multiple Sclerosis, systemic lupus erythematosus, Sjogren syndrome, Hashimoto thyroiditis, polymyositis, scleroderma ( scleroderma, Addison disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, Inflammatory Bowel Dieseses, Autoimmune Diabetes , Diabetic retinopathy, Rhinitis, Ischemia-reperfusion injury, Post-angioplasty restenosis, Chronic obstructive pulmonary diseases (COPD), Selected from the group consisting of Graves disease, Gastrointestinal allergies, Conjunctivitis, Atherosclerosis, Coronary artery disease, Angina, cancer metastasis and arteriosclerosis , A pharmaceutical composition for the prevention or treatment of immune diseases.
  9. 제 8항에 있어서, 관절염은 노인성 관절염, 퇴행성 관절염, 자가면역관절염, 골관절염, 비만성 관절염, 류마티스관절염, 척추관절병증, 강직성 척추염, 건선관절염, 통풍, 세균성 관절염, 소아기 류마티스관절염, 루푸스, 경피증, 다발성 경화증, 섬유근통, 다발성 근염, 피부근염, 베체트병, 라이터 증후군, 라임 관절염, 유착 관절낭염, 오십견, 힘줄 활막염, 팔꿈치머리 주머니염, 드쿼베인 힘줄윤활막염, 재발류마티스, 류마티스 다발근육통증 및 성인형 스틸병으로 이루어진 군에서 선택되는, 면역질환의 예방 또는 치료용 약학적 조성물. The method of claim 8, wherein the arthritis is senile arthritis, degenerative arthritis, autoimmune arthritis, osteoarthritis, obese arthritis, rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, psoriatic arthritis, gout, bacterial arthritis, juvenile rheumatoid arthritis, lupus, scleroderma, Multiple sclerosis, fibromyalgia, polymyositis, dermatomyositis, Behcet's disease, Reiter's syndrome, Lyme arthritis, adhesive capsulitis, frozen shoulder, tendon synovitis, elbow capsulitis, de Quervain's tendon synovitis, rerheumatic rheumatism, polymyalgia rheumatica and adult form A pharmaceutical composition for the prevention or treatment of immune diseases, selected from the group consisting of Still's disease.
  10. 제 1항에 있어서, 염증성세포의 침윤을 억제하는, 면역질환의 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating immune diseases according to claim 1, which inhibits the infiltration of inflammatory cells.
  11. 제 1항에 있어서, 염증성 사이토카인인 IL-17, IL-6, TNF-α 및 IL-1β의 발현을 감소 또는 억제시키는, 면역질환의 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating immune diseases according to claim 1, which reduces or inhibits the expression of inflammatory cytokines IL-17, IL-6, TNF-α and IL-1β.
  12. 제 1항에 있어서, 항염증성 사이토카인인 IL-10의 발현을 증가시키는, 면역질환의 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating immune diseases according to claim 1, which increases the expression of IL-10, which is an anti-inflammatory cytokine.
  13. 제 1항에 있어서, 산화 인자인 iNOS 및 이화작용에 관여하는 MMP13의 발현을 감소 또는 억제시키는, 면역질환의 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating immune diseases according to claim 1, which reduces or suppresses the expression of iNOS, which is an oxidative factor, and MMP13, which is involved in catabolism.
  14. 코엔자임 Q10이 마이셀에 봉입된 코엔자임 Q10 가용화 조성물을 유효성분으로 포함하는 면역질환의 예방 또는 개선용 식품 조성물.A food composition for preventing or improving immune diseases, comprising as an active ingredient a coenzyme Q10 solubilizing composition in which coenzyme Q10 is encapsulated in micelles.
  15. 제 14항에 있어서, 마이셀은 글리시리진산 또는 글리시리진산의 염, 및 EPA(Eicosapentaenoic acid) 또는 DHA(Docosa hexaenoic acid)를 포함하는, 면역질환의 예방 또는 개선용 식품 조성물.The food composition of claim 14, wherein the micelles contain glycyrrhizic acid or a salt of glycyrrhizin, and EPA (Eicosapentaenoic acid) or DHA (Docosa hexaenoic acid).
  16. 제 15항에 있어서, 글리시리진산 또는 글리시리진산의 염; EPA 또는 DHA; 및 코엔자임 Q10;의 혼합 비율은 중량기준으로 0.1 내지 5:0.1 내지 5:0.1 내지 5의 범위로 혼합되는, 면역질환의 예방 또는 개선용 식품 조성물.16. The method according to claim 15, comprising: glycyrrhizic acid or a salt of glycyrrhizic acid; EPA or DHA; and coenzyme Q10; the mixing ratio is 0.1 to 5:0.1 to 5:0.1 to 5 by weight, which is mixed in the range of 5, preventing or improving immune diseases.
  17. 제 14항에 있어서, 코엔자임 Q10 가용화 조성물에 봉입되는 코엔자임 Q10의 함량이 조성물 총 중량에 대하여 1 내지 50 중량%인, 면역질환의 예방 또는 개선용 식품 조성물.The food composition for preventing or improving immune diseases according to claim 14, wherein the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition is 1 to 50% by weight based on the total weight of the composition.
  18. 제 14항에 있어서, 코엔자임 Q10은 코엔자임 Q10 가용화 조성물 수용액에 0.05 내지 3 mg/mL의 농도로 포함되는, 면역질환의 예방 또는 개선용 식품 조성물.The food composition for preventing or improving immune diseases according to claim 14, wherein coenzyme Q10 is contained in an aqueous solution of coenzyme Q10 solubilizing composition at a concentration of 0.05 to 3 mg/mL.
  19. 제 14항에 있어서, 코엔자임 Q10 가용화 조성물은 10 내지 200 nm의 입자크기를 가지는, 면역질환의 예방 또는 개선용 식품 조성물.The food composition for preventing or improving immune diseases according to claim 14, wherein the coenzyme Q10 solubilizing composition has a particle size of 10 to 200 nm.
  20. 제 14항에 있어서, 면역질환은 자가면역질환, 염증성 질환, 및 세포, 조직 또는 기관의 이식거부질환으로 이루어진 군으로부터 선택되는, 면역질환의 예방 또는 개선용 식품 조성물.The food composition for preventing or improving immune diseases according to claim 14, wherein the immune disease is selected from the group consisting of autoimmune diseases, inflammatory diseases, and transplant rejection diseases of cells, tissues or organs.
  21. 약학적으로 유효한 양의 제1항의 약학적 조성물을 개체에 투여하는 단계를 포함하는, 면역질환의 예방 또는 치료 방법.A method for preventing or treating immune diseases, comprising administering to an individual a pharmaceutically effective amount of the pharmaceutical composition of claim 1 .
PCT/KR2021/003428 2020-03-19 2021-03-19 Therapeutic use of coenzyme q10 solubilizing composition WO2021187944A1 (en)

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Citations (5)

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KR20140071262A (en) * 2012-12-03 2014-06-11 가톨릭대학교 산학협력단 Composition for preventing or treating inflammatory disease or immunological rejection comprising coenzyme Q10 as an effective component
CN106177227A (en) * 2016-08-25 2016-12-07 成都润馨堂药业有限公司 A kind of compositions containing coenzyme Q10 strengthening body immunity
KR20170119642A (en) * 2016-04-19 2017-10-27 동국대학교 산학협력단 A composition for solubilizing coenzyme Q10 and method for preparing the same
KR20170122573A (en) * 2016-04-27 2017-11-06 가톨릭대학교 산학협력단 Compositions comprising coenzyme Q10 or its derivatives for reducing or alleviating cytotoxic side effects induced by calcineurin inhibitors

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WO2013180253A1 (en) * 2012-05-31 2013-12-05 テルモ株式会社 pH-SENSITIVE CARRIER AND METHOD FOR PRODUCTION THEREOF, pH-SENSITIVE MEDICINE AND pH-SENSITIVE PHARMACEUTICAL COMPOSITION EACH CONTAINING SAID CARRIER, AND CULTURE METHOD USING SAID pH-SENSITIVE MEDICINE OR SAID pH-SENSITIVE PHARMACEUTICAL COMPOSITION
KR20140071262A (en) * 2012-12-03 2014-06-11 가톨릭대학교 산학협력단 Composition for preventing or treating inflammatory disease or immunological rejection comprising coenzyme Q10 as an effective component
KR20170119642A (en) * 2016-04-19 2017-10-27 동국대학교 산학협력단 A composition for solubilizing coenzyme Q10 and method for preparing the same
KR20170122573A (en) * 2016-04-27 2017-11-06 가톨릭대학교 산학협력단 Compositions comprising coenzyme Q10 or its derivatives for reducing or alleviating cytotoxic side effects induced by calcineurin inhibitors
CN106177227A (en) * 2016-08-25 2016-12-07 成都润馨堂药业有限公司 A kind of compositions containing coenzyme Q10 strengthening body immunity

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