WO2009020314A2 - Stabilized alpha-lipoic acid particles, composition comprising the same and method for preparing the same - Google Patents

Stabilized alpha-lipoic acid particles, composition comprising the same and method for preparing the same Download PDF

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Publication number
WO2009020314A2
WO2009020314A2 PCT/KR2008/004505 KR2008004505W WO2009020314A2 WO 2009020314 A2 WO2009020314 A2 WO 2009020314A2 KR 2008004505 W KR2008004505 W KR 2008004505W WO 2009020314 A2 WO2009020314 A2 WO 2009020314A2
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particles
lipoic acid
stabilized
fine particles
group
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PCT/KR2008/004505
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French (fr)
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WO2009020314A3 (en
Inventor
Chul Hwan Kim
Chan Jae Shin
Han Joon Kim
Jung Ae Kwon
Choa Jin Kim
Chang Hun Ji
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Biogenics, Inc.
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Publication of WO2009020314A2 publication Critical patent/WO2009020314A2/en
Publication of WO2009020314A3 publication Critical patent/WO2009020314A3/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/062—Oil-in-water emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/11—Encapsulated compositions
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A61K9/5057—Gelatin

Definitions

  • the present invention relates to stabilized ⁇ -lipoic acid particles, a composition including the same, and a method for preparing the same, and more particularly, to stabilized ⁇ -lipoic acid particles, each of which includes a core consisting of ⁇ -lipoic acid particles having a volume average particle diameter of 3 to 30 ⁇ m and a first coating layer formed on the surface of the core wherein the first coating layer includes fine particles of an amino acid or an amino acid derivative or the like having a volume average particle diameter of 0.01 to 2.5 ⁇ m, a composition including the same, and a method for preparing the same.
  • ⁇ -lipoic acid has various pharmacological effects such as improving immune function, reducing blood sugar level, and suppressing appetite in human body. Furthermore, ⁇ -lipoic acid facilitates collagen generation, and reduces and eliminates skin wrinkles when applied to skin.
  • ⁇ -lipoic acid is readily reduced to dihydrolipoic acid which has unpleasant odor and cannot be easily applied to an aqueous composition due to its high lipophilicity.
  • a method of encapsulating ⁇ -lipoic acid using liposome has been introduced in order to overcome this problem, it is difficult to encapsulate a large amount of ⁇ -lipoic acid.
  • ⁇ -lipoic acid derivatives prepared by introducing a variety of substituents into a carboxylic acid of ⁇ -lipoic acid using esterification have been introduced. However, since additional processes such as chemical reaction, purification, or the like are required, it is not preferable in the light of economical aspects.
  • ⁇ -lipoic acid Due to the above-described problems of ⁇ -lipoic acid, ⁇ -lipoic acid has been used in solid formulations and the use of ⁇ -lipoic acid has been limited in formulations including an aqueous medium, even though ⁇ -lipoic acid has excellent efficacy. Therefore, there is a need to develop an economical method of easily using ⁇ -lipoic acid in formulations including an aqueous medium.
  • the present inventors conducted various researches in order to develop formulation methods for improving stability of ⁇ -lipoic acid, particularly in an aqueous medium. As a result, the present inventors found that, when ⁇ -lipoic acid is dry-coated with specific fine particles to form a coating layer, stability of the obtained ⁇ -lipoic acid-containing particles is remarkably increased, particularly in an aqueous medium.
  • the present invention provides stabilized ⁇ -lipoic acid particles, each of which includes a core consisting of ⁇ -lipoic acid particles and a first coating layer formed by coating with specific fine particles on the surface of the core.
  • the present invention also provides a composition including the stabilized ⁇ -lipoic acid particles.
  • the present invention also provides a method for preparing the stabilized ⁇ -lipoic acid particles.
  • stabilized ⁇ -lipoic acid particles each of which comprises a core consisting of ⁇ -lipoic acid particles having a volume average particle diameter of 3 to 30 ⁇ m and a first coating layer formed on the surface of the core, wherein the first coating layer comprises fine particles of at least one compound selected from the group consisting of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose;
  • a composition comprising the stabilized ⁇ -lipoic acid particles.
  • the composition may be in the form of a food composition, a cosmetic composition, or a pharmaceutical composition.
  • a method for preparing stabilized ⁇ -lipoic acid particles comprising stirring a mixture of ⁇ -lipoic acid particles having a volume average particle diameter of 3 to 30 ⁇ m and fine particles having a volume average particle diameter of 0.01 to 2.5 ⁇ m at 1000 to 1500 rpm, wherein the fine particles are formed of at least one compound selected from the group consisting of of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternaryl
  • the stabilized ⁇ -lipoic acid particles according to the present invention include a coating layer formed by dry-coating with specific fine particles, and alternatively a water insoluble polymer-coating layer, thereby having excellent stability in an aqueous medium.
  • the stabilized ⁇ -lipoic acid particles can be usefully applied to various compositions including food compositions, pharmaceutical compositions, and cosmetic compositions, since those can minimize denaturation caused by environmental factors such as temperature, light, oxygen, and water, even when being stored in an aqueous composition for a long period of time.
  • the present invention provides stabilized ⁇ -lipoic acid particles, each of which comprises a core consisting of ⁇ -lipoic acid particles having a volume average particle diameter of 3 to 30 ⁇ m and a first coating layer formed on the surface of the core, wherein the first coating layer comprises fine particles of at least one compound selected from the group consisting of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose; a cellulose derivative selected from the
  • the fine particles may be fine particles of a compound selected from the group consisting of lysine, chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid.
  • the fine particles may be obtained by dissolving the compound in water, mixing the solution with an oil such as triglyceride (alternatively and a surfactant such as twin 80), stirring the mixture to form an emulsion, drying the emulsion, and washing the resultant with an organic solvent such as hexane and ether.
  • the obtained fine particles may be incorporated into the first coating layer in form coated on inorganic particles such as zeolite, silica, and alumina. That is, the fine particles incorporated into the first coating layer may be provided in the form obtained by coating inorganic particles with the fine particles of the compound.
  • the ⁇ -lipoic acid particles, forming the core of the stabilized ⁇ -lipoic acid particles of the present invention have a volume average particle diameter of 3 to 30 ⁇ m, and the fine particles, contained in the first coating layer, have a volume average particle diameter of 0.01 to 2.5 ⁇ m. If the volume average particle diameter of the ⁇ -lipoic acid particles is greater than 30 ⁇ m, the ⁇ -lipoic acid core may break due to strong shear force. In addition, if the volume average particle diameter of the fine particles is greater than 2.5 ⁇ m, coating may not be smoothly performed. Preferably, the volume average particle diameter of the fine particles may be less than 1/5 of the volume average particle diameter of ⁇ -lipoic acid particles.
  • volume average particle diameter of the fine particles Due to the relative difference of the volume average particle diameters, small particles (i.e., fine particles) are coated on large particles (i.e., ⁇ -lipoic acid particles) to form a layer when they are mixed and stirred at a high speed.
  • the volume average particle diameter of the fine particles is less than 0.01 ⁇ m, an apparent density of the fine particles may be decreased, which results in insufficient collision between the fine particles and the core and thus incomplete coating.
  • the amount of the fine particles may vary according to types of the compound forming the fine particles and desired stabilization effects, but may be in the range of 1 to 50 parts by weight, and preferably 5 to 30 parts by weight based on 100 parts by weight of ⁇ -lipoic acid forming the core. If the amount of the fine particles is too small, a desired coating layer may not be formed. On the other hand, if the amount of fine particles is too large, strength of the particles is increased so much that desired formulations, for example emulsions, may not be obtained.
  • the first coating layer may further include inorganic particles having an apparent density greater than that of the fine particles.
  • the inorganic particles may be zeolite, silica, alumina, titania, barium titania, or a mixture thereof. If the first coating layer includes the inorganic particles, flowability is increased, and thus a uniform coating layer may be formed.
  • the inorganic particles may have a nano-sized particle diameter, for example a particle diameter of less than 20 nm, and the amount of the inorganic particles may be in the range of 5 to 40 parts by weight based on 100 parts by weight of ⁇ -lipoic acid, but is not limited thereto.
  • Each of the stabilized ⁇ -lipoic acid particles may further include a second coating layer including a water insoluble polymer, which is formed on the surface of the first coating layer.
  • the water insoluble polymer may be at least one selected from the group consisting of polysilane, polysiloxane (e.g., poly(dimethyl-methylhydrogen)siloxane), cellulose (e.g., hydroxypropylmethyl cellulose phthalate or hydroxypropyl methyl cellulose), and polycaprolactone.
  • the second coating layer may further increase stability of the ⁇ -lipoic acid particles.
  • the amount of the water insoluble polymer may be in the range of 5 to 50 parts by weight based on 100 parts by weight of the ⁇ -lipoic acid particles forming the first coating layer.
  • the second coating layer may also further include inorganic particles having an apparent density greater than that of the fine particles, for example, zeolite, silica, alumina, titania, and barium titania.
  • the second coating layer may be a single layer or a multilayer having at least two layers.
  • the second coating layer may have a single layered structure formed by coating the water insoluble polymer and the inorganic particles in a single layer, or a multilayered structure formed by coating the water insoluble polymer, and then coating the inorganic particles as a separate layer.
  • the present invention also provides a composition comprising the stabilized ⁇ -lipoic acid particles.
  • the composition may be in the form of a food composition, a cosmetic composition, or a pharmaceutical composition.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated into various forms for oral or external use, such as powders, granules, tablets, capsules, suspensions, emulsions, syrup, and aerosols, in accordance with a conventional method.
  • the pharmaceutically acceptable carrier includes lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, poly vinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, or the like.
  • the pharmaceutical composition may include diluents or additives, such as filler, a bulking agent, binder, a wetting agent, disintegrant, surfactant.
  • Solid oral dosage form includes tablets, pills, powders, granules, capsules, or the like.
  • the solid oral dosage form may include at least one additive such as starch, calcium carbonate, sucrose, lactose, and gelatin, and further include a lubricant such as magnesium stearate and talc.
  • Liquid oral dosage form includes suspensions, oral solutions, emulsions, syrup, or the like.
  • the liquid oral dosage form may also include a diluting agent such as water and liquid paraffin, a wetting agent, a sweetener, a fragrance, a preservative, or the like.
  • a dose of the stabilized ⁇ -lipoic acid particles contained in the pharmaceutical composition may vary according to the status and body weight of patients, degree of disease, dosage form, administration route, and term of administration, and may be appropriately adjusted.
  • the stabilized ⁇ -lipoic acid particles may be administered at a dose of 1 to 1000 mg/kg/day, and preferably 1 to 100 mg/kg/day.
  • the stabilized ⁇ -lipoic acid particles may be administered once or several times a day.
  • the pharmaceutical composition may be administered to mammals such as human beings via various administration routes such as oral administration, intravenous injection, intramuscular administration, or hypodermic injection.
  • the composition of the present invention may be in the form of a cosmetic composition comprising the stabilized ⁇ -lipoic acid particles as an active ingredient.
  • the cosmetic composition may be prepared using the stabilized ⁇ -lipoic acid particles to various forms using a conventional method.
  • the cosmetic composition may be prepared in the form of facial cosmetics, shampoo, hair lotion, hair cream, hair gel, foundation, eye shadow, blusher, nail enamel, eye liner, mascara, lipstick, fancy powder, or the like including the stabilized ⁇ -lipoic acid particles, and the cosmetic composition may be diluted using a conventional cleansing solution, astringent, and moisturizer.
  • the cosmetic composition may further include a conventional adjuvant such as stabilizers, solubilizers, vitamins, pigments, and fragrances.
  • the present invention also provides a method for preparing the stabilized ⁇ -lipoic acid particles, and preferably a method for preparing the stabilized ⁇ -lipoic acid particles using dry-coating. That is, the present invention includes A method for preparing stabilized ⁇ -lipoic acid particles, the method comprising stirring a mixture of ⁇ -lipoic acid particles having a volume average particle diameter of 3 to 30 iM and fine particles having a volume average particle diameter of 0.01 to 2.5 ⁇ m at 1000 to 1500 rpm, wherein the fine particles are formed of at least one compound selected from the group consisting of of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl me
  • the fine particles may be fine particles of a compound selected from the group consisting of lysine, chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid.
  • the fine particles may be provided in the form obtained by coating inorganic particles with the fine particles of the compound, the form of which may be prepared by dispersing the fine particles in an organic solvent such as hexane, mixing with inorganic particles such as nano silica, and then spay-drying the resultant using a twin-fluid nozzle or a spray drier to form a fine particles coated on the inorganic particles, having a particle diameter of 0.3 to 2.5 ⁇ m, and preferably 1.5 to 2.5 ⁇ m.
  • the method of the present invention may further include adding inorganic particles having an apparent density greater than that of the fine particles to the previously stirred mixture and then stirring the mixture at 1000 to 1500 rpm.
  • the inorganic particles may be zeolite, silica, alumina, titania, barium titania, or a mixture thereof.
  • the method may further include dispersing the obtained ⁇ -lipoic acid particles in a solution of a water insoluble polymer dissolved in an organic solvent and then drying the resultant to form a second coating layer.
  • the water insoluble polymer may be at least one selected from the group consisting of polysilane, polysiloxane (e.g., poly(dimethyl-methylhydrogen)siloxane), cellulose (e.g., hydroxypropylmethyl cellulose phthalate or hydroxypropyltnethyl cellulose), and polycaprolactone.
  • the organic solvent may be dichloromethane, acetone, or the like.
  • the method may further include adding inorganic particles having an apparent density greater than that of the fine particles after forming the second coating layer and then stirring the mixture at 1000 to 1500 rpm.
  • the inorganic particles may be zeolite, silica, alumina, titania, barium titania, or a mixture thereof
  • the stabilized ⁇ -lipoic acid particles according to the present invention include a coating layer formed by dry-coating with the above fine particles, and alternatively a water insoluble polymer-coating layer, thereby having excellent stability in an aqueous medium.
  • the mechanism of increasing stability is not clearly proven, but may be assumed as follows.
  • the fine particles contained in the first coating layer form an acid-base complex (or an addictive) or an acid-ion complex with evaporated dihydrolipoic acid so that vapor pressure of the dihydrolipoic acid is decreased to eliminate unpleasant odor.
  • lysine 100 g was dissolved in 50 ml of water, and the solution was dispersed in 500 ml of triglyceride.
  • the dispersion was mixed with 1 g of Twin 80 (Aldrich Co., Inc.), and the mixture was stirred at room temperature (at about 25 " C) at 1000 rpm for 30 minutes.
  • the obtained emulsion was heated to evaporate water, and 300 ml of hexane was added thereto.
  • the resultant was filtered to obtain lysine fine particles having an average particle diameter of 1 to 2 ⁇ m.
  • Preparation Example 7 95 g of lysine fine particles prepared in Preparation Example 1 was dispersed in 200 ml of hexane and the dispersion was mixed with nano silica to be in concentration of 10% by weight of nano silica. The mixture was stirred at room temperature (at about 25 0 C) at 1100 rpm for 30 minutes. The obtained dispersion was sprayed at a high pressure using a spray drier through a twin-fluid nozzle to obtain silica fine particles coated with lysine, having a particle diameter of 1.5 to 2.5 ⁇ m.
  • Preparation Examples 8 to 12 Fine particles coated with each of chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid were prepared in the same manner as in Preparation Example 7, except that 90 g of each of fine particles of chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid prepared in Preparation Examples 2 to 6 was used instead of lysine fine particles.
  • Example 1 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating 50% by weight of the lysine fine particles prepared in Preparation Example 1 and 45% by weight of ⁇ -lipoic acid particles having an average particle diameter of 7 ⁇ m were stirred at a high speed of 1800 rpm in a Henschel mixer. The stirring was performed six times, and each of the stirrings was performed at 30 Hz for 10 seconds and stopped for 50 seconds. Finally, 5% by weight of silica nano particles were added thereto, and the mixture was stirred at 1800 rpm to obtain stabilized ⁇ -lipoic acid particles.
  • Example 2 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating Stabilized ⁇ -lipoic acid particles were prepared in the same manner as in Example 1 , except for using 60% by weight of chitosan fine particles prepared in Preparation Example 2 and 35% by weight of ⁇ -lipoic acid particles having an average particle diameter of 7 ⁇ m.
  • Example 3 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating Stabilized ⁇ -lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of arginine fine particles prepared in Preparation Example 3 instead of lysine fine particles.
  • Example 4 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating Stabilized ⁇ -lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of poly(zinc acrylate) fine particles prepared in Preparation Example 4 instead of lysine fine particles.
  • Example 5 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating Stabilized ⁇ -lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of silica fine particles coated with lysine prepared in Preparation Example 7 instead of lysine fine particles.
  • Example 6 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating Stabilized ⁇ -lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of silica fine particles coated with chitosan prepared in Preparation Example 8 instead of lysine fine particles.
  • Example 7 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating Stabilized ⁇ -lipoic acid particles were prepared in the same manner as in Example 1, except for using 50% by weight of silica fine particles coated with arginine prepared in Preparation Example 9 instead of lysine fine particles.
  • Example 8 Preparation of stabilized ⁇ -lipoic acid particles using dry-coating Stabilized ⁇ -lipoic acid particles were prepared in the same manner as in
  • Example 1 except for using 50% by weight of silica fine particles coated with poly(zinc acrylate) prepared in Preparation Example 10 instead of lysine fine particles.
  • Example 9 Preparation of stabilized ⁇ -lipoic acid particles including a second coating layer 100 parts by weight of the stabilized ⁇ -lipoic acid particles prepared in
  • Example 1 was mixed with a solution prepared by dissolving 10 parts by weight of poly(dimethyl-methylhydrogen)siloxane in 50 parts by weight of hexane, and the mixture was stirred at 200 rpm for 10 minutes. The mixture was dried at 60 ° C in an oven for 1 hour to obtain stabilized ⁇ -lipoic acid particles including a second coating layer. 1.5 parts by weight of hydrophobic silica was added to the prepared stabilized ⁇ -lipoic acid particles, and the mixture was uniformly stirred to obtain stabilized ⁇ -lipoic acid particles having double coating layers.
  • Example 10 Stabilized ⁇ -lipoic acid particles having double coating layers were prepared in the same manner as in Example 9, except for using 10 parts by weight of polycaprolactone instead of poly(dimethyl-methylhydrogen)siloxane.
  • An o/w cream was prepared in the composition as shown in Table 1 below, respectively using the ⁇ -lipoic acid particles prepared in Examples 1 to 10, and then stored at 45 ° C for 4 weeks. Then, stability test (measurement of the remaining ⁇ -lipoic acid amount) and sensory test were performed.
  • the amount of ⁇ -lipoic acid in the each of o/w cream was measured three times using high performance liquid chromatography to calculate the mean values.
  • Conditions for the high performance liquid chromatography are as follows.
  • the obtained particles show high stability in an aqueous medium such as an O/W cream and denature into dihydrolipoic acid is significantly inhibited.

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Abstract

The present invention provides stabilized α-lipoic acid particles, each of which includes a core consisting of α-lipoic acid particles having a volume average particle diameter of 3 to 30 μm and a first coating layer formed on the surface of the core wherein the first coating layer includes fine particles of an amino acid or an amino acid derivative or the like having a volume average particle diameter of 0.01 to 2.5 μm, a composition including the same, and a method for preparing the same.

Description

[DESCRIPTION] [Invention Title]
STABILIZED ALPHA-LIPOIC ACID PARTICLES, COMPOSITION COMPRISING THE SAME AND METHOD FOR PREPARING THE SAME
[TECHNICAL FIELD]
The present invention relates to stabilized α-lipoic acid particles, a composition including the same, and a method for preparing the same, and more particularly, to stabilized α-lipoic acid particles, each of which includes a core consisting of α-lipoic acid particles having a volume average particle diameter of 3 to 30 μm and a first coating layer formed on the surface of the core wherein the first coating layer includes fine particles of an amino acid or an amino acid derivative or the like having a volume average particle diameter of 0.01 to 2.5 μm, a composition including the same, and a method for preparing the same.
[BACKGROUND ART]
It is known that α-lipoic acid has various pharmacological effects such as improving immune function, reducing blood sugar level, and suppressing appetite in human body. Furthermore, α-lipoic acid facilitates collagen generation, and reduces and eliminates skin wrinkles when applied to skin.
However, α-lipoic acid is readily reduced to dihydrolipoic acid which has unpleasant odor and cannot be easily applied to an aqueous composition due to its high lipophilicity. Although a method of encapsulating α-lipoic acid using liposome has been introduced in order to overcome this problem, it is difficult to encapsulate a large amount of α-lipoic acid. In addition, α-lipoic acid derivatives prepared by introducing a variety of substituents into a carboxylic acid of α-lipoic acid using esterification have been introduced. However, since additional processes such as chemical reaction, purification, or the like are required, it is not preferable in the light of economical aspects.
Due to the above-described problems of α-lipoic acid, α-lipoic acid has been used in solid formulations and the use of α-lipoic acid has been limited in formulations including an aqueous medium, even though α-lipoic acid has excellent efficacy. Therefore, there is a need to develop an economical method of easily using α-lipoic acid in formulations including an aqueous medium.
[DETAILED DESCRIPTION OF THE INVENTION]
[TECHNICAL PROBLEM]
The present inventors conducted various researches in order to develop formulation methods for improving stability of α-lipoic acid, particularly in an aqueous medium. As a result, the present inventors found that, when α-lipoic acid is dry-coated with specific fine particles to form a coating layer, stability of the obtained α-lipoic acid-containing particles is remarkably increased, particularly in an aqueous medium. Thus, the present invention provides stabilized α-lipoic acid particles, each of which includes a core consisting of α-lipoic acid particles and a first coating layer formed by coating with specific fine particles on the surface of the core.
The present invention also provides a composition including the stabilized α-lipoic acid particles.
The present invention also provides a method for preparing the stabilized α-lipoic acid particles.
[TECHNICAL SOLUTION]
According to an aspect of the present invention, there is provided stabilized α-lipoic acid particles, each of which comprises a core consisting of α-lipoic acid particles having a volume average particle diameter of 3 to 30 μm and a first coating layer formed on the surface of the core, wherein the first coating layer comprises fine particles of at least one compound selected from the group consisting of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose; a cellulose derivative selected from the group consisting of cellulose acetate and carboxymethyl cellulose; and a metal hydroxide, wherein the fine particle has a volume average particle diameter of 0.01 to 2.5 μm. According to another aspect of the present invention, there is provided a composition comprising the stabilized α-lipoic acid particles. The composition may be in the form of a food composition, a cosmetic composition, or a pharmaceutical composition. According to still another aspect of the present invention, there is provided a method for preparing stabilized α-lipoic acid particles, the method comprising stirring a mixture of α-lipoic acid particles having a volume average particle diameter of 3 to 30 μm and fine particles having a volume average particle diameter of 0.01 to 2.5 μm at 1000 to 1500 rpm, wherein the fine particles are formed of at least one compound selected from the group consisting of of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose; a cellulose derivative selected from the group consisting of cellulose acetate and carboxymethyl cellulose; and a metal hydroxide.
[ADVANTAGEOUS EFFECTS]
The stabilized α-lipoic acid particles according to the present invention include a coating layer formed by dry-coating with specific fine particles, and alternatively a water insoluble polymer-coating layer, thereby having excellent stability in an aqueous medium. Thus, the stabilized α-lipoic acid particles can be usefully applied to various compositions including food compositions, pharmaceutical compositions, and cosmetic compositions, since those can minimize denaturation caused by environmental factors such as temperature, light, oxygen, and water, even when being stored in an aqueous composition for a long period of time.
[BEST MODE FOR CARRYING OUT THE INVENTION]
The present invention provides stabilized α-lipoic acid particles, each of which comprises a core consisting of α-lipoic acid particles having a volume average particle diameter of 3 to 30 μm and a first coating layer formed on the surface of the core, wherein the first coating layer comprises fine particles of at least one compound selected from the group consisting of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose; a cellulose derivative selected from the group consisting of cellulose acetate and carboxymethyl cellulose; and a metal hydroxide, wherein the fine particle has a volume average particle diameter of 0.01 to 2.5 μm. In the stabilized α-lipoic acid particles of the present invention, the fine particles may be fine particles of a compound selected from the group consisting of lysine, chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid.
The fine particles may be obtained by dissolving the compound in water, mixing the solution with an oil such as triglyceride (alternatively and a surfactant such as twin 80), stirring the mixture to form an emulsion, drying the emulsion, and washing the resultant with an organic solvent such as hexane and ether. In addition, the obtained fine particles may be incorporated into the first coating layer in form coated on inorganic particles such as zeolite, silica, and alumina. That is, the fine particles incorporated into the first coating layer may be provided in the form obtained by coating inorganic particles with the fine particles of the compound.
The α-lipoic acid particles, forming the core of the stabilized α-lipoic acid particles of the present invention, have a volume average particle diameter of 3 to 30 μm, and the fine particles, contained in the first coating layer, have a volume average particle diameter of 0.01 to 2.5 μm. If the volume average particle diameter of the α-lipoic acid particles is greater than 30 μm, the α-lipoic acid core may break due to strong shear force. In addition, if the volume average particle diameter of the fine particles is greater than 2.5 μm, coating may not be smoothly performed. Preferably, the volume average particle diameter of the fine particles may be less than 1/5 of the volume average particle diameter of α-lipoic acid particles. Due to the relative difference of the volume average particle diameters, small particles (i.e., fine particles) are coated on large particles (i.e., α-lipoic acid particles) to form a layer when they are mixed and stirred at a high speed. On the other hand, if the volume average particle diameter of the fine particles is less than 0.01 μm, an apparent density of the fine particles may be decreased, which results in insufficient collision between the fine particles and the core and thus incomplete coating. The amount of the fine particles may vary according to types of the compound forming the fine particles and desired stabilization effects, but may be in the range of 1 to 50 parts by weight, and preferably 5 to 30 parts by weight based on 100 parts by weight of α-lipoic acid forming the core. If the amount of the fine particles is too small, a desired coating layer may not be formed. On the other hand, if the amount of fine particles is too large, strength of the particles is increased so much that desired formulations, for example emulsions, may not be obtained.
In the stabilized α-lipoic acid particles, the first coating layer may further include inorganic particles having an apparent density greater than that of the fine particles. The inorganic particles may be zeolite, silica, alumina, titania, barium titania, or a mixture thereof. If the first coating layer includes the inorganic particles, flowability is increased, and thus a uniform coating layer may be formed. The inorganic particles may have a nano-sized particle diameter, for example a particle diameter of less than 20 nm, and the amount of the inorganic particles may be in the range of 5 to 40 parts by weight based on 100 parts by weight of α-lipoic acid, but is not limited thereto.
Each of the stabilized α-lipoic acid particles may further include a second coating layer including a water insoluble polymer, which is formed on the surface of the first coating layer. The water insoluble polymer may be at least one selected from the group consisting of polysilane, polysiloxane (e.g., poly(dimethyl-methylhydrogen)siloxane), cellulose (e.g., hydroxypropylmethyl cellulose phthalate or hydroxypropyl methyl cellulose), and polycaprolactone. The second coating layer may further increase stability of the α-lipoic acid particles.
The amount of the water insoluble polymer may be in the range of 5 to 50 parts by weight based on 100 parts by weight of the α-lipoic acid particles forming the first coating layer. Like the first coating layer, the second coating layer may also further include inorganic particles having an apparent density greater than that of the fine particles, for example, zeolite, silica, alumina, titania, and barium titania. The second coating layer may be a single layer or a multilayer having at least two layers. For example, the second coating layer may have a single layered structure formed by coating the water insoluble polymer and the inorganic particles in a single layer, or a multilayered structure formed by coating the water insoluble polymer, and then coating the inorganic particles as a separate layer.
The present invention also provides a composition comprising the stabilized α-lipoic acid particles. The composition may be in the form of a food composition, a cosmetic composition, or a pharmaceutical composition. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated into various forms for oral or external use, such as powders, granules, tablets, capsules, suspensions, emulsions, syrup, and aerosols, in accordance with a conventional method. The pharmaceutically acceptable carrier includes lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, poly vinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, or the like. In addition, the pharmaceutical composition may include diluents or additives, such as filler, a bulking agent, binder, a wetting agent, disintegrant, surfactant. Solid oral dosage form includes tablets, pills, powders, granules, capsules, or the like. The solid oral dosage form may include at least one additive such as starch, calcium carbonate, sucrose, lactose, and gelatin, and further include a lubricant such as magnesium stearate and talc. Liquid oral dosage form includes suspensions, oral solutions, emulsions, syrup, or the like. The liquid oral dosage form may also include a diluting agent such as water and liquid paraffin, a wetting agent, a sweetener, a fragrance, a preservative, or the like. A dose of the stabilized α-lipoic acid particles contained in the pharmaceutical composition may vary according to the status and body weight of patients, degree of disease, dosage form, administration route, and term of administration, and may be appropriately adjusted. For example, the stabilized α-lipoic acid particles may be administered at a dose of 1 to 1000 mg/kg/day, and preferably 1 to 100 mg/kg/day. The stabilized α-lipoic acid particles may be administered once or several times a day. The pharmaceutical composition may be administered to mammals such as human beings via various administration routes such as oral administration, intravenous injection, intramuscular administration, or hypodermic injection. The composition of the present invention may be in the form of a cosmetic composition comprising the stabilized α-lipoic acid particles as an active ingredient. The cosmetic composition may be prepared using the stabilized α-lipoic acid particles to various forms using a conventional method. For example, the cosmetic composition may be prepared in the form of facial cosmetics, shampoo, hair lotion, hair cream, hair gel, foundation, eye shadow, blusher, nail enamel, eye liner, mascara, lipstick, fancy powder, or the like including the stabilized α-lipoic acid particles, and the cosmetic composition may be diluted using a conventional cleansing solution, astringent, and moisturizer. Furthermore, the cosmetic composition may further include a conventional adjuvant such as stabilizers, solubilizers, vitamins, pigments, and fragrances.
The present invention also provides a method for preparing the stabilized α-lipoic acid particles, and preferably a method for preparing the stabilized α-lipoic acid particles using dry-coating. That is, the present invention includes A method for preparing stabilized α-lipoic acid particles, the method comprising stirring a mixture of α-lipoic acid particles having a volume average particle diameter of 3 to 30 iM and fine particles having a volume average particle diameter of 0.01 to 2.5 μm at 1000 to 1500 rpm, wherein the fine particles are formed of at least one compound selected from the group consisting of of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose; a cellulose derivative selected from the group consisting of cellulose acetate and carboxymethyl cellulose; and a metal hydroxide.
In the method of the present invention, the fine particles may be fine particles of a compound selected from the group consisting of lysine, chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid. The fine particles may be provided in the form obtained by coating inorganic particles with the fine particles of the compound, the form of which may be prepared by dispersing the fine particles in an organic solvent such as hexane, mixing with inorganic particles such as nano silica, and then spay-drying the resultant using a twin-fluid nozzle or a spray drier to form a fine particles coated on the inorganic particles, having a particle diameter of 0.3 to 2.5 μm, and preferably 1.5 to 2.5 μm.
The method of the present invention may further include adding inorganic particles having an apparent density greater than that of the fine particles to the previously stirred mixture and then stirring the mixture at 1000 to 1500 rpm. The inorganic particles may be zeolite, silica, alumina, titania, barium titania, or a mixture thereof.
In addition, the method may further include dispersing the obtained α-lipoic acid particles in a solution of a water insoluble polymer dissolved in an organic solvent and then drying the resultant to form a second coating layer. The water insoluble polymer may be at least one selected from the group consisting of polysilane, polysiloxane (e.g., poly(dimethyl-methylhydrogen)siloxane), cellulose (e.g., hydroxypropylmethyl cellulose phthalate or hydroxypropyltnethyl cellulose), and polycaprolactone. The organic solvent may be dichloromethane, acetone, or the like. In addition, the method may further include adding inorganic particles having an apparent density greater than that of the fine particles after forming the second coating layer and then stirring the mixture at 1000 to 1500 rpm. The inorganic particles may be zeolite, silica, alumina, titania, barium titania, or a mixture thereof
The stabilized α-lipoic acid particles according to the present invention include a coating layer formed by dry-coating with the above fine particles, and alternatively a water insoluble polymer-coating layer, thereby having excellent stability in an aqueous medium. The mechanism of increasing stability is not clearly proven, but may be assumed as follows. When α-lipoic acid is reduced to dihydrolipoic acid, the dihydrolipoic acid has unpleasant odor. The fine particles contained in the first coating layer form an acid-base complex (or an addictive) or an acid-ion complex with evaporated dihydrolipoic acid so that vapor pressure of the dihydrolipoic acid is decreased to eliminate unpleasant odor.
The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Preparation Example 1 : Preparation of fine particles
100 g of lysine was dissolved in 50 ml of water, and the solution was dispersed in 500 ml of triglyceride. The dispersion was mixed with 1 g of Twin 80 (Aldrich Co., Inc.), and the mixture was stirred at room temperature (at about 25 "C) at 1000 rpm for 30 minutes. The obtained emulsion was heated to evaporate water, and 300 ml of hexane was added thereto. The resultant was filtered to obtain lysine fine particles having an average particle diameter of 1 to 2 μm.
Preparation Examples 2 to 6: Preparation of fine particles Fine particles were prepared in the same manner as in Preparation Example
1 , except that 100 g of each of chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid were used instead of lysine.
Preparation Example 7 95 g of lysine fine particles prepared in Preparation Example 1 was dispersed in 200 ml of hexane and the dispersion was mixed with nano silica to be in concentration of 10% by weight of nano silica. The mixture was stirred at room temperature (at about 250C) at 1100 rpm for 30 minutes. The obtained dispersion was sprayed at a high pressure using a spray drier through a twin-fluid nozzle to obtain silica fine particles coated with lysine, having a particle diameter of 1.5 to 2.5 μm.
Preparation Examples 8 to 12 Fine particles coated with each of chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid were prepared in the same manner as in Preparation Example 7, except that 90 g of each of fine particles of chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid prepared in Preparation Examples 2 to 6 was used instead of lysine fine particles.
Example 1 : Preparation of stabilized α-lipoic acid particles using dry-coating 50% by weight of the lysine fine particles prepared in Preparation Example 1 and 45% by weight of α-lipoic acid particles having an average particle diameter of 7 μm were stirred at a high speed of 1800 rpm in a Henschel mixer. The stirring was performed six times, and each of the stirrings was performed at 30 Hz for 10 seconds and stopped for 50 seconds. Finally, 5% by weight of silica nano particles were added thereto, and the mixture was stirred at 1800 rpm to obtain stabilized α-lipoic acid particles. Example 2: Preparation of stabilized α-lipoic acid particles using dry-coating Stabilized α-lipoic acid particles were prepared in the same manner as in Example 1 , except for using 60% by weight of chitosan fine particles prepared in Preparation Example 2 and 35% by weight of α-lipoic acid particles having an average particle diameter of 7 μm.
Example 3: Preparation of stabilized α-lipoic acid particles using dry-coating Stabilized α-lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of arginine fine particles prepared in Preparation Example 3 instead of lysine fine particles.
Example 4: Preparation of stabilized α-lipoic acid particles using dry-coating Stabilized α-lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of poly(zinc acrylate) fine particles prepared in Preparation Example 4 instead of lysine fine particles.
Example 5: Preparation of stabilized α-lipoic acid particles using dry-coating Stabilized α-lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of silica fine particles coated with lysine prepared in Preparation Example 7 instead of lysine fine particles.
Example 6: Preparation of stabilized α-lipoic acid particles using dry-coating Stabilized α-lipoic acid particles were prepared in the same manner as in Example 1 , except for using 50% by weight of silica fine particles coated with chitosan prepared in Preparation Example 8 instead of lysine fine particles. Example 7: Preparation of stabilized α-lipoic acid particles using dry-coating Stabilized α-lipoic acid particles were prepared in the same manner as in Example 1, except for using 50% by weight of silica fine particles coated with arginine prepared in Preparation Example 9 instead of lysine fine particles.
Example 8: Preparation of stabilized α-lipoic acid particles using dry-coating Stabilized α-lipoic acid particles were prepared in the same manner as in
Example 1 , except for using 50% by weight of silica fine particles coated with poly(zinc acrylate) prepared in Preparation Example 10 instead of lysine fine particles.
Example 9: Preparation of stabilized α-lipoic acid particles including a second coating layer 100 parts by weight of the stabilized α-lipoic acid particles prepared in
Example 1 was mixed with a solution prepared by dissolving 10 parts by weight of poly(dimethyl-methylhydrogen)siloxane in 50 parts by weight of hexane, and the mixture was stirred at 200 rpm for 10 minutes. The mixture was dried at 60 °C in an oven for 1 hour to obtain stabilized α-lipoic acid particles including a second coating layer. 1.5 parts by weight of hydrophobic silica was added to the prepared stabilized α-lipoic acid particles, and the mixture was uniformly stirred to obtain stabilized α-lipoic acid particles having double coating layers.
Example 10 Stabilized α-lipoic acid particles having double coating layers were prepared in the same manner as in Example 9, except for using 10 parts by weight of polycaprolactone instead of poly(dimethyl-methylhydrogen)siloxane.
Experimental Example: Stability test and sensory test
An o/w cream was prepared in the composition as shown in Table 1 below, respectively using the α-lipoic acid particles prepared in Examples 1 to 10, and then stored at 45 °C for 4 weeks. Then, stability test (measurement of the remaining α-lipoic acid amount) and sensory test were performed.
Table 1
Figure imgf000017_0001
Figure imgf000018_0001
Sensory tests were performed as follows: 10 healthy women in late twenties estimated odor intensity of samples to calculate the mean values of average odor intensity. The odor intensity is established as in the following Table 2.
Table 2
Figure imgf000018_0002
In order to evaluate stability, the amount of α-lipoic acid in the each of o/w cream was measured three times using high performance liquid chromatography to calculate the mean values. Conditions for the high performance liquid chromatography are as follows.
* Column: Zorbax Eclipse XDB-C18(2.1 * 150 mm, 5 urn)
* Guard column: Zorbax Eclipse XDB(2.1 * 12.5 mm, 5 urn) * Mobile Phase: 0.1 % Acetic acid in water-Acetonitrile=60-40
* Detector & Wavelength: UV 205,340nm (UV-DAD)
* Flow rate: 0.2 ml/min
* Injection volume: 1 ul
* Column oven temp.: 300C
* Run time: 20 min
The results of stability test (measurement of the remaining antioxidant amount) and sensory test are shown in Tables 3 and 4.
Table 3
Figure imgf000019_0001
Figure imgf000020_0001
Table 4
Figure imgf000020_0002
Figure imgf000021_0001
Referring to the results shown in Tables 3 and 4, when the coating layer(s) is formed according to the present invention, the obtained particles show high stability in an aqueous medium such as an O/W cream and denature into dihydrolipoic acid is significantly inhibited.

Claims

[CLAIMS]
1. Stabilized α-lipoic acid particles, each of which comprises a core consisting of α-lipoic acid particles having a volume average particle diameter of 3 to 30 μm and a first coating layer formed on the surface of the core, wherein the first coating layer comprises fine particles of at least one compound selected from the group consisting of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose; a cellulose derivative selected from the group consisting of cellulose acetate and carboxymethyl cellulose; and a metal hydroxide, wherein the fine particle has a volume average particle diameter of 0.01 to 2.5 μm.
2. The stabilized α-lipoic acid particles of claim 1 , wherein the fine particles are fine particles of a compound selected from the group consisting of lysine, chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid.
3. The stabilized α-lipoic acid particles of claim 1 , wherein the fine particles are provided in the form obtained by coating inorganic particles with the fine particles of the compound.
4. The stabilized α-lipoic acid particles of claim 1 , wherein the first coating layer further comprises inorganic particles having an apparent density greater than that of the fine particles.
5. The stabilized α-lipoic acid particles of claim 4, wherein the inorganic particles are zeolite, silica, alumina, titania, barium titania, or a mixture thereof.
6. The stabilized α-lipoic acid particles of claim 1 , further comprising a second coating layer formed on the surface of the first coating layer, wherein the second coating layer comprises a water insoluble polymer.
7. The stabilized α-lipoic acid particles of claim 6, wherein the water insoluble polymer is at least one selected from the group consisting of polysilane, polysiloxane, cellulose, and polycaprolactone.
8. The stabilized α-lipoic acid particles of claim 6, wherein the second coating layer further comprises inorganic particles having an apparent density greater than that of the fine particles.
9. The stabilized α-lipoic acid particles of claim 8, wherein the inorganic particles are zeolite, silica, alumina, titania, barium titania, or a mixture thereof.
10. A composition comprising the stabilized α-lipoic acid particles according to any one of claims 1 to 9.
11. The composition of claim 10, being a food composition, a cosmetic composition, or a pharmaceutical composition.
12. A method for preparing stabilized α-lipoic acid particles, the method comprising stirring a mixture of α-lipoic acid particles having a volume average particle diameter of 3 to 30 μm and fine particles having a volume average particle diameter of 0.01 to 2.5 μm at 1000 to 1500 rpm, wherein the fine particles are formed of at least one compound selected from the group consisting of of an amino acid selected from the group consisting of arginine, cystine, lysine, tryptophane, cysteine, glutamic acid, and carnitine, or a derivative thereof; a cationic polymer selected from the group consisting of polyethyleneimine and polyvinyl pyrrolidone; an acrylic polymer selected from the group consisting of a quaternary ammonium of poly(methyl methacrylate), polyacrylic acid, and poly(zinc acrylate); chitosan; gelatin; hyaluronic acid; alginic acid or a metal salt thereof; starch or oxidized starch; cellulose; a cellulose derivative selected from the group consisting of cellulose acetate and carboxymethyl cellulose; and a metal hydroxide.
13. The method of claim 12, wherein the fine particles are fine particles of a compound selected from the group consisting of lysine, chitosan, arginine, poly(zinc acrylate), carnitine, and glutamic acid.
14. The method of claim 12, wherein the fine particles are provided in the form obtained by coating inorganic particles with the fine particles of the compound.
15. The method of claim 12, further comprising adding inorganic particles having an apparent density greater than that of the fine particles to the previously stirred mixture and then stirring the resulting mixture at 1000 to 1500 rpm.
16. The method of claim 15, wherein the inorganic particles are zeolite, silica, alumina, titania, barium titania, or a mixture thereof.
17. The method of any one of claims 12 to 16, further comprising dispersing the stabilized α-lipoic acid particles prepared according to any one of claims 12 to 16 in a solution of a water insoluble polymer dissolved in an organic solvent and then drying the resultant to form a second coating layer.
18. The method of claim 17, wherein the water insoluble polymer is at least one selected from the group consisting of polysilane, polysiloxane, cellulose, and polycaprolactone.
19. The method of claim 17, further comprising adding inorganic particles having an apparent density greater than that of the fine particles after forming the second coating layer and then stirring the resulting mixture at 1000 to 1500 rpm.
20. The method of claim 19, wherein the inorganic particles are zeolite, silica, alumina, titania, barium titania, or a mixture thereof.
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CN103690492A (en) * 2013-12-16 2014-04-02 常熟富士莱医药化工有限公司 Preparation method of lipoic acid particles
WO2016180769A1 (en) * 2015-05-13 2016-11-17 Unilever N.V. Benefit delivery particle and composition comprising the particle
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US11471396B2 (en) 2016-10-28 2022-10-18 Conopco, Inc. Personal care compositions comprising surface-modified particles and non-volatile funcationalised silicone

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