WO2017183901A1 - 코엔자임 q10 가용화 조성물 및 이의 제조방법 - Google Patents
코엔자임 q10 가용화 조성물 및 이의 제조방법 Download PDFInfo
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- WO2017183901A1 WO2017183901A1 PCT/KR2017/004182 KR2017004182W WO2017183901A1 WO 2017183901 A1 WO2017183901 A1 WO 2017183901A1 KR 2017004182 W KR2017004182 W KR 2017004182W WO 2017183901 A1 WO2017183901 A1 WO 2017183901A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/35—Ketones, e.g. benzophenone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
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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
Definitions
- the present invention relates to a coenzyme Q10 solubilizing composition and a method for preparing the same, wherein the solubility of coenzyme Q10 is poorly soluble.
- Coenzyme Q10 a poorly soluble drug and physiologically active substance called ubiquinone or ubidecarenone, is a coenzyme that is biologically active and is located in the electron transport system of the mitochondria, an energy generating organ in the cell, to produce ATP. It is known to play an important role, widely distributed in the human body, by converting the sugar into energy to reduce blood sugar and antioxidants, such as vitamin E to prevent the oxidation of the cell membrane and to increase the oxygen utilization rate.
- Coenzyme Q10 is an antioxidant that protects cells from harmful oxygen and helps the activity of vitamin E with antioxidant function.It is effective in preventing carcinogenesis caused by antioxidant activity, anti-aging action, and inhibiting LDL (low density lipoprotein) oxidation in blood. This has been reported and is known to be effective as an adjuvant for cardiovascular diseases such as congestive heart failure, angina or high blood pressure, and heart disease. Furthermore, there are clinical trial reports that Coenzyme Q10 delays functional decline in various neurodegenerative diseases such as Huntington's disease, Friedreich's ataxia, and in particular Parkinson's disease.
- the coenzyme Q10 is very poorly soluble in water, so the versatility of the drug, health functional food or food is very low in general use, in particular, to solve the problem that is very limited in the application to water-soluble liquids, such as beverages It is dissolved in hydrophobic lipids such as omega-3 fatty acids and orally administered, but its absorption rate in vivo is low.
- a poorly soluble drug means a drug that is difficult to dissolve in water because it contains a hydrophobic part in the structure of the compound, and its practical use is often limited due to poor solubility. For example, about 41% of drugs that are developed as new drugs are given up due to poor solubility, and about 8% of drugs listed in the US Pharmacopeia are classified as poorly soluble drugs.
- the present inventors have improved the solubility of coenzyme Q10 by encapsulating coenzyme Q10 by encapsulating coenzyme Q10 as a poorly soluble drug in micelles containing glycyrrhinic acid or glycyrrhinic acid salts, bile acids or salts of bile acids, and unsaturated fatty acids.
- the efficiency was improved, and thus the coenzyme Q10 solubilizing composition of the present invention and the preparation method thereof were completed.
- an object of the present invention is to provide a coenzyme Q10 solubilizing composition characterized in that coenzyme Q10 is encapsulated in micelles containing glycyrrhinic acid or salts of glycyrrhinic acid, salts of bile acids or bile acids, and unsaturated fatty acids.
- another object of the present invention is to prepare a suspension by (1) adding a salt of glycyrrhinic acid or glycyrrhinic acid, a salt of a bile acid or a bile acid, an unsaturated fatty acid and coenzyme Q10 to the solvent, followed by stirring to prepare a suspension; And (2) it provides a method for producing a coenzyme Q10 solubilizing composition comprising a homogenization step of homogenizing the suspension by ultrasonication (sonication) or ultra-high pressure (microfluidizer).
- the present invention is coenzyme Q10 is characterized in that the coenzyme Q10 is enclosed in micelles (micelle) containing glycyric acid or salts of glycyrrhinic acid, salts of bile acids or bile acids, and unsaturated fatty acids Provides a Q10 solubilizing composition.
- micelles micelles containing glycyric acid or salts of glycyrrhinic acid, salts of bile acids or bile acids, and unsaturated fatty acids.
- the coenzyme Q10 solubilizing composition may further include ascorbic acid.
- the bile acid may be any one or more selected from the group consisting of cholic acid (cholic acid), deoxycholic acid (deoxycholic acid) and ursodeoxycholic acid.
- the unsaturated fatty acid is an omega-3 fatty acid, myristoleic acid, palmitoleic acid, oleic acid, alpha-linolenic acid, gamma-linolenic acid, linoleic acid, conjugated linoleic acid And arachidonic acid may be any one or more selected from the group consisting of.
- the omega-3 fatty acid may be EPA (Eicosapentaenoic acid) or DHA (Docosa hexaenoic acid).
- the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition may be 1 to 50% by weight relative to the total weight of the composition.
- the coenzyme Q10 solubilizing composition may be included in a concentration of 0.05 to 3 mg / mL coenzyme Q10.
- the mixing ratio of the glycyric acid or the salt of glycyrrhinic acid, the salt of the bile acid or the bile acid, the unsaturated fatty acid, and coenzyme Q10 is 0.1-5: 0.1-5: 0.1-5: 0.1 by weight. It can be mixed in the range of -5.
- the coenzyme Q10 solubilizing composition may have a particle size of 10 ⁇ 200 nm.
- the composition may be a pharmaceutical composition.
- the composition may be a food composition.
- the composition may be a cosmetic composition.
- Another object of the present invention is to prepare a suspension by (1) adding a salt of glycyrrhinic acid or glycyrrhinic acid, a salt of a bile acid or a bile acid, an unsaturated fatty acid, and coenzyme Q10 to a solvent, followed by stirring to prepare a suspension; And (2) it provides a method for producing a coenzyme Q10 solubilizing composition comprising a homogenization step of homogenizing the suspension by ultrasonication (sonication) or ultra-high pressure (microfluidizer).
- the method for preparing the coenzyme Q10 solubilizing composition may further comprise the step (3) of purifying the coenzyme Q10 solubilizing composition formed in the homogenization step (2) through a filter.
- the method for preparing the coenzyme Q10 solubilizing composition is a purification step (4) of purifying the coenzyme Q10 solubilizing composition in the form of a solution filtered in the purification step (3) after storage at 0 ⁇ 5 ° C through a filter It may further include.
- the suspension may further include ascorbic acid.
- Coenzyme Q10 solubilizing composition and a preparation method thereof according to the present invention is a micelle comprising a salt of glycyrrhizinic acid or glycyrrhizin acid, bile acid (cholic acid, deoxycholic acid or ursodeoxycholic acid) and unsaturated fatty acid, coenzyme Q10 is a poorly soluble drug Encapsulation improved the encapsulation efficiency and improved the water solubility of coenzyme Q10.
- a micelle containing ascorbic acid excellent in promoting collagen synthesis, UV protection, antioxidant effect and melanin production inhibitory effect to the composition was imparted functionality to the bioavailability of the composition.
- the preparation of the composition can be easily prepared in a large amount of the composition through the ultrasonic grinding (sonication) or ultra-high pressure (microfluidizer), the particle size of the composition encapsulated coenzyme Q10 can be adjusted, using ethanol and organic solvents It is expected that it can be usefully used as a pharmaceutical, food and cosmetic composition, which can be formulated on the basis of natural products without any toxicity, thereby ensuring stability.
- the present invention has various physiological activities such as anti-inflammatory activity, but due to the low water solubility and low absorption in the digestive tract, the biopharmaceutical characteristics (solubilization of coenzyme Q10 and / or unsaturated fatty acids, which are known to have low bioavailability) By improving PK properties, pharmacological applications in the art are expected.
- coenzyme Q10 solubilizing composition consisting of glycyrrhizin, bile acid (cholic acid, deoxycholic acid or ursodeoxycholic acid), unsaturated fatty acids, and coenzyme Q10.
- Figure 2 shows a method for producing a coenzyme Q10 solubilizing composition using ultrasonic sonication
- Figure 2a shows a method for producing a coenzyme Q10 solubilizing composition in an unsaturated state
- Figure 2b shows a coenzyme Q10 solubilizing composition in a supersaturated state It shows a manufacturing method.
- Figure 3 shows a simple filtration of the composition after the two-step preparation of the preparation method of the coenzyme Q10 solubilizing composition.
- Figure 4 is a method of preparing a coenzyme Q10 solubilizing composition (Fig. 2b) of the three-saturated composition in the manufacturing step 3 after storage for 12 hours at 4 °C, precipitated excipients and stabilizers that did not form micelles (left) and this The filtered coenzyme Q10 solubilizing composition (right) is shown.
- Figure 10 is the result of analyzing the particle distribution in the autoclave conditions (right) of the coenzyme Q10 solubilization composition (left) prepared by ultrasonic grinding (sonication).
- FIG. 11 illustrates a method for preparing a coenzyme Q10 solubilizing composition using a microfluidizer
- FIG. 11A illustrates a method for preparing a coenzyme Q10 solubilizing composition in an unsaturated state
- FIG. 11B illustrates a coenzyme Q10 solubilizing composition in a supersaturated state. It shows a manufacturing method.
- FIG. 12 shows coenzyme Q10 solubilizing composition prepared by microfluidizer.
- FIG. 15 is a result of analyzing a quantitative graph of a coenzyme Q10 solubilizing composition prepared by a microfluidizer.
- 16 is a result of analyzing the particle distribution of the coenzyme Q10 solubilizing composition including ascorbic acid prepared by a microfluidizer.
- FIG. 17 is a result of analyzing a quantitative graph of a coenzyme Q10 solubilizing composition including ascorbic acid prepared by a microfluidizer.
- FIG. 18 is a result of analyzing a graph for quantifying ascorbic acid of a coenzyme Q10 solubilizing composition including ascorbic acid prepared by a microfluidizer.
- the present invention relates to a coenzyme Q10 solubilizing composition and a method for preparing the same, wherein coenzyme Q10 is encapsulated in micelles containing salts of glycyrrhinic acid or glycyrrhinic acid, salts of bile acids or bile acids, and unsaturated fatty acids to coenzyme as a poorly soluble drug.
- coenzyme Q10 is encapsulated in micelles containing salts of glycyrrhinic acid or glycyrrhinic acid, salts of bile acids or bile acids, and unsaturated fatty acids to coenzyme as a poorly soluble drug.
- the water solubility of Q10 was improved and the encapsulation efficiency of coenzyme Q10 was improved.
- the present invention was completed.
- the present invention provides a coenzyme Q10 solubilizing composition characterized in that coenzyme Q10 is encapsulated in micelles comprising glycyrrhinic acid or salts of glycyrrhinic acid, salts of bile acids or bile acids, and unsaturated fatty acids.
- the bile acid in the present invention may be any one or more selected from the group consisting of cholic acid (cholic acid), deoxycholic acid (deoxycholic acid) and ursodeoxycholic acid, but is not limited thereto. .
- the unsaturated fatty acid may be omega-3 fatty acid, myristoleic acid, palmitoleic acid, oleic acid, alpha-linolenic acid, gamma-linolenic acid, linoleic acid, conjugated linoleic acid or arachidonic acid, Preferably it may be an omega-3 fatty acid, but is not limited thereto.
- omega-3 fatty acid may be any one or more selected from the group consisting of Eicosapentaenoic acid (EPA) and Docosa hexaenoic acid (DHA), but is not limited thereto.
- EPA Eicosapentaenoic acid
- DHA Docosa hexaenoic acid
- bile acids, omega-3 fatty acids and glycyrrhizin are substances derived from natural products, used as excipients or stabilizers for the solubilization of coenzyme Q10 by forming micelles, ethanol as an excipient or stabilizer Or, since no organic solvent is used, natural product-based formulation is possible, and there is little toxicity.
- the term "excipient” in the present invention refers to a substance added to the drug or food to give a suitable form or increase the amount to facilitate the use, "stabilizer” is used for the purpose of preventing the alteration of the drug or food Will be. Therefore, the coenzyme Q10 solubilizing composition of the present invention can increase the solubility of the composition through a natural-derived biostable material by using the bile acid, omega-3 fatty acid or glycyrrhizin, and can improve long-term stability.
- the content of coenzyme Q10 encapsulated in the coenzyme Q10 solubilizing composition may be 15 to 40% by weight based on the total weight of the composition, but is not limited thereto.
- coenzyme Q10 solubilization composition is coenzyme Q10 may be included in the coenzyme Q10 solubilizing composition aqueous solution of 0.05 ⁇ 3 mg / mL, but is not limited thereto.
- the mixing ratio of the salt of the glycyrrhinic acid or glycyrrhinic acid, bile acid, omega-3 fatty acid and coenzyme Q10 may be mixed in the range of 0.1 to 5: 0.1 to 5: 0.1 to 5 by weight, Preferably, it may be mixed in the range of 0.1 to 5: 1: 1: 1, but is not limited thereto.
- the coenzyme Q10 solubilizing composition may further include ascorbic acid, salts of the glycyrrhizin acid or glycyrrhizinic acid, bile acid, omega-3 fatty acid, ascorbic acid and coenzyme
- the mixing ratio of Q10 is preferably in the range of 0.1 to 5: 0.1 to 5: 0.1 to 5: 0.1 to 5, more preferably 6: 2: 2: 2: by weight. It may be mixed in the range of 1, but is not limited thereto.
- coenzyme Q10 solubilizing composition comprising ascorbic acid may be included in the concentration of 0.05 to 3 mg / mL ascorbic acid in the aqueous solution of coenzyme Q10 solubilizing composition comprising the ascorbic acid, but is not limited thereto.
- the coenzyme Q10 solubilizing composition may have a particle size of 10 ⁇ 200 nm, but is not limited thereto. More specifically, the particle size of the coenzyme Q10 solubilizing composition may be controlled through the concentration of glycyrrhizinic acid.
- coenzyme Q10 solubilizing composition may be a pharmaceutical composition.
- Coenzyme Q10 is found in mitochondria, a cell's energy generator, and is widely distributed in the body. It is an antioxidant that protects cells from harmful oxygen and helps the activity of vitamin E with antioxidant function. It is excellent for anti-aging, anti-inflammatory, fatigue recovery, strengthening of immune system, and for cardiovascular diseases such as congestive heart failure, angina or high blood pressure. It is also known to be effective as an adjuvant. Furthermore, there are clinical trial reports that Coenzyme Q10 delays functional decline in various neurodegenerative diseases such as Huntington's disease, Friedreich's ataxia, and in particular Parkinson's disease.
- the coenzyme Q10 solubilizing composition of the present invention is not limited to a pharmaceutical composition for preventing, ameliorating or treating a specific disease, and may be used as an additional effective ingredient in a drug to obtain the above effects.
- it can be used as a composition useful for heart disease, high blood pressure, rheumatic valve disease, alveolar inflammation, congestive heart failure, cerebrovascular disorders, and anticancer drug side effects (heart failure caused by adriamycin). It is not limited to this.
- the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
- the pharmaceutically acceptable carrier is commonly used in the preparation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
- it may further include a lubricant, wetting agent, sweetener, flavoring agent, emulsifier, suspending agent, preservative and the like.
- Formulation forms of the pharmaceutical compositions of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or slow-release preparations of injectable liquids and active compounds, and the like.
- the coenzyme Q10 solubilizing composition of the present invention can be utilized as a sustained release medicine as the poorly soluble coenzyme Q10 encapsulated in micelles is gradually released.
- compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
- 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 the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field.
- the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
- the effective amount of the pharmaceutical composition of the present invention may vary according to the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day.
- the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.
- the pharmaceutical composition of the present invention may be administered to mammals such as primates, mice, rats, dogs, cats, horses, and cattle, which are human or non-human, but are not limited thereto.
- the coenzyme Q10 solubilizing composition may be a food composition, there is no particular limitation on its use, it can be added to all kinds of food.
- the coenzyme Q10 solubilizing composition of the present invention is used as a food additive, the compound may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
- the mixed amount of the active ingredient may be appropriately determined depending on the purpose of use (prevention, health or therapeutic treatment).
- the compounds of the invention are added in an amount of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
- the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
- Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcoholic beverages and vitamin complexes, and the like and include all foods in a conventional sense.
- the coenzyme Q10 solubilizing composition of the present invention may contain various flavors or natural carbohydrates, etc. as additional components, as in a general beverage.
- Natural carbohydrates described above are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
- sweetening agent natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame, and the like can be used.
- the proportion of the natural carbohydrate is generally about 0.01 to 0.20 g, preferably about 0.04 to 0.10 g per 100 ml of the composition of the present invention.
- the composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, And carbonating agents used in carbonated drinks.
- the composition of the present invention may contain a pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components can be used independently or in combination. The proportion of such additives is not critical but is usually selected in the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.
- coenzyme Q10 solubilizing composition may be a cosmetic composition.
- Coenzyme Q10 provides antioxidant, anti-inflammatory, fatigue recovery, skin moisturizing and anti-aging effects.
- the coenzyme Q10 solubilizing composition of the present invention can be used as a cosmetic composition, and the bile acids, omega-3 fatty acids or used in the coenzyme Q10 solubilizing composition.
- glycyrrhizin it is expected to provide sufficient skin improvement effect because it does not cause skin irritation due to its excellent biocompatibility through a natural-derived biostable substance.
- the cosmetic composition of the present invention may include not only coenzyme Q10 solubilizing composition, but also components commonly used in cosmetic compositions, and are not particularly limited in its formulation, and skin lotion, skin softener, skin toner, Astringent, Lotion, Milk Lotion, Moisture Lotion, Nutrition Lotion, Massage Cream, Nutrition Cream, Moisture Cream, Hand Cream, Essence, Nutrition Essence, Pack, Soap, Shampoo, Cleansing Foam, Cleansing Lotion, Cleansing Cream, Body Lotion, Body Cleanser It can be formulated as a, latex, lipstick, makeup base, foundation, press powder, loose powder, eye shadow and the like.
- Such cosmetics may include conventional ingredients such as aqueous vitamins, oily vitamins, polymer peptides, polymer polysaccharides, sphingolipids, and the like, and may be readily prepared according to techniques well known to those skilled in the art.
- compositions of each formulation may be appropriately selected and blended by those skilled in the art according to the formulation or purpose of use of the cosmetic.
- Conventional adjuvants such as antioxidants, sunscreens, stratum corneum exfoliants, surfactants, flavors, pigments, preservatives, pH adjusters, chelating agents, stabilizers, solubilizers, vitamins, pigments and flavorings, and carriers.
- the present invention provides a method for preparing a coenzyme Q10 solubilizing composition. More specifically, (1) a suspension preparation step of preparing a suspension by adding and stirring a glycyrrhizinic acid or a salt of glycyrrhizinic acid, bile acid, omega-3 fatty acid and coenzyme Q10 to a solvent; And (2) a homogenization step of homogenizing the suspension using sonication or ultrafluidizer as the principle of the composition preparation method; In the case of supersaturated micelles, (3) further comprises a purification step of purifying the coenzyme Q10 solubilizing composition formed in the homogenization step through a filter, wherein the coenzyme Q10 solubilizing composition in the form of the solution filtered in the purification step (3) is 0 to 5 ° C.
- the preparation method of the coenzyme Q10 solubilizing composition by ultrasonication dissolves glycyric acid or salt of glycyrrhizin acid, bile acid, omega-3 fatty acid and coenzyme Q10 in distilled water or phosphate buffered saline (PBS) at pH 7.4 in one step.
- the pretreatment may be performed by using ultrasonic waves with low energy of 300 W, and micelles may be formed by using ultrasonic waves with high energy of 500 W in two steps.
- the composition formed in step 2 may be purified using a 0.22 ⁇ m syringe filter.
- the fourth step after the composition purified in the three-step process for 12 hours at a low temperature of 0 ⁇ 5 °C, more preferably 4 °C and stored for 12 hours, it can be subjected to the purification process using a syringe filter of 0.22 ⁇ m as well, 1 Optimization may be performed in four stages, two stages, and / or three stages, but is not limited thereto.
- the preparation method of the coenzyme Q10 solubilizing composition by using a microfluidizer is a mixture of glycyrrhizin or a salt of glycyrrhizin acid, bile acid, omega-3 fatty acid and coenzyme Q10 mixture in distilled water or phosphate buffered saline (PBS) at pH 7.4 in one step.
- the micelle may be formed by crushing the fluidized bed mixer at a high pressure of 800 to 2000 bar (780 to 1970 atm) for 1 hour.
- the supersaturated composition formed in step 2 may be purified using a 0.22 ⁇ m syringe filter.
- the fourth step after the composition purified in the three-step process for 12 hours at a low temperature of 0 ⁇ 5 °C, more preferably 4 °C and stored for 12 hours, it can be subjected to the purification process using a syringe filter of 0.22 ⁇ m as well, 1 Optimization may be performed in four stages, two stages, and / or three stages, but is not limited thereto.
- the coenzyme Q10 solubilization composition was prepared using ultrasonic sonication, and the characteristics were confirmed through the encapsulation efficiency of the prepared composition (see Example 1).
- Example 3-2 Reference confirmed the stability of the coenzyme Q10 solubilizing composition through autoclaving (see Example 3-1), and confirmed the particle distribution of the coenzyme Q10 solubilizing composition subjected to autoclaving.
- a coenzyme Q10 solubilizing composition was prepared by using a microfluidizer to prepare a large amount of the coenzyme Q10 solubilizing composition (see Example 4-1), from which the coenzyme Q10 solubilizing composition was prepared. The particle distribution was confirmed (see Examples 4-2 and 4-3) and the coenzyme Q10 solubilizing composition was quantified (see Example 4-4).
- solubilizing composition By using the coenzyme Q10 solubilizing composition and a preparation method thereof, it is possible to prepare a solubilizing composition with a high encapsulation efficiency of 0.05 ⁇ 0.1% (w / v), the preparation of the composition through ultrasonic grinding (sonication) or ultra-high pressure grinding method (microfluidizer) through the mass production of the composition can be easily produced, the water solubility is increased, and can be utilized as a pharmaceutical, food and cosmetic composition is secured stability.
- a coenzyme Q10 solubilizing composition according to glycyrizine concentration
- the preparation method described in FIG. 2 was performed. More specifically, after injecting phosphate buffered saline (PBS) into the reactor, glycyrizine, icosapentaenoic acid (EPA), choline acid and coenzyme Q10, which are poorly soluble drugs for micelle formation, are used in the amounts shown in Table 2 below. Stir to add and disperse evenly. The reaction solution was dispersed evenly by performing an ultrasonic treatment corresponding to an output of 300 W at 4 ° C. for 30 minutes, and then subjected to an ultrasonic treatment corresponding to an output of 500 W at 4 ° C. for 30 minutes to coenzyme through micelle formation. Enclosure of Q10 was performed (see FIG. 2A).
- the co-saturated reaction solution which was not encapsulated in an aqueous solution, was removed using a 0.22 ⁇ m syringe filter, and the filtered solution was filtered again using a 0.22 ⁇ m syringe filter after storing for 12 hours at 4 ° C.
- the solution was cooled and lyophilized at ⁇ 80 ° C. for at least 2 days to prepare a coenzyme Q10 solubilizing composition (see FIG. 2B).
- a quantitative graph of coenzyme Q10 was prepared through HPLC analysis at absorbance of 210 nm wavelength.
- HPLC analysis was performed using Waters 2695 HPLC model of Waters, the column was Xbridge C18 (4.6 x 250 mm, 5 ⁇ m; Waters), the mobile phase solvent was a mixture of Methanol: isopropanol (40:60) at a rate of 1 mL / min By shedding.
- the quantitative graph of coenzyme Q10 of FIG. 5 was confirmed.
- the particle distribution of the coenzyme Q10 solubilization composition was measured using the coenzyme Q10 solubilization composition prepared in Table 2 described in Example 2-1, and measured three times at room temperature using a Nano ZS90 device of MALVERN, followed by coenzyme Particle distribution of the Q10 solubilizing composition was analyzed.
- the surface charge of the coenzyme Q10 solubilizing composition was measured using the sample of Table 1 (conditional) described in Example 2-1, and measured at room temperature using a Nano ZS90 device of MALVERN, and then the coenzyme Q10 solubilizing composition The surface charge of was analyzed.
- Coenzyme comprising 10 mg of dipotassium glyziric acid in 10 mL of distilled water, which is the condition A composition of Table 1 described in Example 1-1, E10: Chloic acid: The content of dipotassium glycyrizine is 1: 1: At 1: 1 conditions, coenzyme Q10 solubilizing compositions were prepared using the preparation method described in FIG. 2. In order to confirm the stability of the prepared coenzyme Q10 solubilizing composition, autoclaving was performed for 15 minutes at a high temperature of 120 °C.
- the particle distribution of the coenzyme Q10 solubilizing composition which was sterilized by autoclaving using Nano ZS90 equipment of MALVERN, was prepared using the coenzyme Q10 solubilizing composition prepared by the method described in Example 3-1.
- the composition prepared by confirming that the particle size of the coenzyme Q10 solubilizing composition was about 20 nm even after autoclaving and did not change significantly compared to about 10 nm, which is a uniform particle size before autoclaving. It was confirmed that the stability of the high.
- the preparation method described in FIG. 11 was performed to prepare a large amount of coenzyme Q10 solubilizing composition containing high concentrations of coenzyme Q10. More specifically, after distilled water is injected into the reactor, dipotassium glycyrrhizinate, icosapentaenoic acid (EPA), choline acid, and coenzyme Q10, which are poorly soluble drugs, are used to form micelles. Each was added at a content of 10 mg (1: 1: 1: 1) and stirred at 4000 rpm to distribute evenly.
- the reaction solution was encapsulated with coenzyme Q10 through micelle formation for 1 hour at a high pressure of 1500 bar using APV-2000 fluidized bed mixer (APV), and micelles were obtained using a 0.22 ⁇ m syringe filter.
- AAV fluidized bed mixer
- the coenzyme Q10 not encapsulated in the aqueous solution was removed using a 0.22 ⁇ m syringe filter, and the filtered solution was stored at 4 ° C. for 12 hours and then again 0.22 ⁇ m syringe. The filter was filtered and the filtered solution was stored at 4 ° C. at low temperature.
- the coenzyme Q10 solubilizing composition containing coenzyme Q10 which is a poorly water-soluble substance was obtained.
- Particle distribution of the coenzyme Q10 solubilization composition was analyzed using the coenzyme Q10 solubilization composition prepared by the method described in Example 4-1.
- a fluidized bed mixer was used for mass production, and measurement was performed using MALVERN's Nano ZS90 instrument.
- the coenzyme Q10 solubilizing composition showed a uniform particle size of about 30 nm.
- the coenzyme Q10 solubilizing composition prepared by the method described in Example 4-1 was analyzed for particle size through transmission electron microscope analysis, which is a more precise device than a particle size analyzer.
- the coenzyme Q10 solubilizing composition confirmed a particle size of about 30 nm, which is the same result as the particle size analyzer shown in FIG. 13. Eggplant confirmed the result value.
- Coenzyme Q10 prepared using 1 liter of distilled water from glycyrrhizinic acid: coenzyme Q10: icosapentaenoic acid: choline acid (3.6 g: 1.2 g: 1.2 mL: 0.6 grma) by the method described in Example 4-1. Quantitative determination of coenzyme Q10 was performed using 6.2 g / L solubilizing composition.
- the above conditions are the glycosirinic acid: coenzyme Q10: Aicosapentaenoic acid: choline acid (0.1-5: 0.1-5: 0.1-5: 0.1-5) using the solubilizing composition prepared during the preparation of the solubilizing composition
- the mixing range may be changed based on the embodiment 2-1 or the embodiment 4-1.
- Coenzyme Q10 solubilizing composition containing high concentrations of coenzyme Q10 comprising ascorbic acid was carried out according to the preparation method described in FIG. 11.
- Coenzyme Q10 was added at a content of 3.6 g, 1.2 mL, 1.2 g, 0.6 g, and 1.2 g (6: 2: 2: 1: 2), respectively, and stirred for 10 minutes at 4000 rpm at 45 ° C. for uniform dispersion.
- the solution was encapsulated with coenzyme Q10 through micelle formation for 1 hour at a high pressure of 1500 bar using APV-2000 fluidized bed mixer (APV), and micelles were obtained using a 0.22 ⁇ m syringe filter.
- AAV fluidized bed mixer
- the coenzyme Q10 not encapsulated in the aqueous solution was removed using a 0.22 ⁇ m syringe filter, and the filtered solution was stored at 4 ° C. for 12 hours and then again 0.22 ⁇ m syringe. The filter was filtered and stored at 4 ° C. at low temperature.
- glycyrrhizinic acid coenzyme Q10: icosapentaenoic acid: ascorbic acid: choline acid (3.6 g: 1.2 g: 1.2 mL: 1.2 g: 0.6 g) was added to 1 liter of distilled water. Quantitative determination of coenzyme Q10 was carried out using 6.4 g / L coenzyme Q10 solubilizing composition prepared using.
- the above conditions are glycyrrhizinic acid: coenzyme Q10: Aicosapentaenoic acid: ascorbic acid: choline acid (0.1-5: 0.1-5: 0.1-5: 0.1-5: 0.1-5) to prepare a solubilizing composition
- the mixing condition may be changed based on Example 2-1 or Example 4-1.
- glycyrrhizinic acid coenzyme Q10: icosapentaenoic acid: ascorbic acid: choline acid (3.6 g: 1.2 g: 1.2 mL: 1.2 g: 0.6 g) was added to 1 liter of distilled water.
- Ascorbic acid was quantified using 6.4 g / L coenzyme Q10 solubilizing composition prepared using.
- a solvent 0.075% TFA in Water B solvent: 0.1% TFA in ACN 0 to 5 minutes 90% 10% 5 to 10 minutes 20% 80% 10 to 15 minutes 20% 80% 15 to 16 minutes 90% 10% 16 to 20 minutes 90% 10%
- PK property Pharmacokinetic characteristics through solubilization of coenzyme Q10 and / or unsaturated fatty acids, which are known to have low bioavailability due to various physiological activities such as anti-inflammatory activity but low water solubility and low absorption in the digestive tract.
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Abstract
Description
시간 | A 용매 : 0.075% TFA in Water | B 용매 : 0.1% TFA in ACN |
0 ~ 5 분 | 90% | 10% |
5 ~ 10 분 | 20% | 80% |
10 ~ 15 분 | 20% | 80% |
15 ~ 16 분 | 90% | 10% |
16 ~ 20 분 | 90% | 10% |
Claims (16)
- 글리시리진산 또는 글리시리진산의 염, 담즙산 또는 담즙산의 염, 및 불포화 지방산을 포함하는 마이셀(micelle)에 코엔자임 Q10이 봉입되는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 코엔자임 Q10 가용화 조성물은 아스코르브산 (ascorbic acid)을 더 포함하는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 담즙산은 콜린산(cholic acid), 디옥시콜린산(deoxycholic acid) 및 우루소디옥시콜린산(ursodeoxycholic acid)으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 불포화 지방산은 오메가-3 지방산, 미리스톨레인산, 팔미톨레인산, 올레인산, 알파-리놀레닌산, 감마-리놀레닌산, 리놀레인산, 공액 리놀레인산 및 아라키돈산으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것을 특징으로 하는, 코엔자입 Q10 가용화 조성물.
- 제 4 항에 있어서, 상기 오메가-3 지방산은 EPA(Eicosapentaenoic acid) 또는 DHA(Docosa hexaenoic acid)인 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 코엔자임 Q10 가용화 조성물에 봉입되는 코엔자임 Q10의 함량이 조성물 총 중량에 대하여 1∼50 중량%인 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 코엔자임 Q10은 코엔자임 Q10 가용화 조성물 수용액에 0.05∼3 mg/mL의 농도로 포함되는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 글리시리진산 또는 글리시리진산의 염, 담즙산, 불포화 지방산, 및 코엔자임 Q10의 혼합 비율은 중량기준으로 0.1∼5:0.1∼5:0.1∼5:0.1∼5의 범위로 혼합되는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 코엔자임 Q10 가용화 조성물은 10∼200 nm의 입자크기를 갖는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 조성물은 약제학적 조성물인 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 조성물은 식품 조성물인 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- 제 1 항에 있어서, 상기 조성물은 화장료 조성물인 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물.
- (1) 글리시리진산 또는 글리시리진산의 염, 담즙산 또는 담즙산의 염, 불포화 지방산, 및 코엔자임 Q10을 용매에 첨가한 후 교반하여 현탁액을 제조하는 단계; 및(2) 상기 현탁액을 초음파 분쇄법(sonication) 또는 초고압 분쇄법(microfluidizer)을 이용하여 균질화하는 단계를 포함하는, 코엔자임 Q10 가용화 조성물의 제조방법.
- 제 13 항에 있어서, 상기 코엔자임 Q10 가용화 조성물의 제조방법은 상기 균질화 단계(2)에서 형성된 코엔자임 Q10 가용화 조성물을 필터를 통해 정제하는 단계(3)를 더 포함하는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물의 제조방법.
- 제 14 항에 있어서, 상기 코엔자임 Q10 가용화 조성물의 제조방법은 상기 정제 단계(3)에서 걸러진 용액 형태의 코엔자임 Q10 가용화 조성물을 0∼4 ℃에서 보관 후 필터를 통해 정제하는 정제 단계(4)를 더 포함하는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물의 제조방법.
- 제 13 항에 있어서, 상기 현탁액은 아스코르브산 (ascorbic acid)을 더 포함하는 것을 특징으로 하는, 코엔자임 Q10 가용화 조성물의 제조방법.
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