WO2012169518A1 - Composition liquide, et produit cosmétique et agent de croissance des cheveux comprenant chacun la composition liquide - Google Patents

Composition liquide, et produit cosmétique et agent de croissance des cheveux comprenant chacun la composition liquide Download PDF

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WO2012169518A1
WO2012169518A1 PCT/JP2012/064540 JP2012064540W WO2012169518A1 WO 2012169518 A1 WO2012169518 A1 WO 2012169518A1 JP 2012064540 W JP2012064540 W JP 2012064540W WO 2012169518 A1 WO2012169518 A1 WO 2012169518A1
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liquid composition
nanoparticles
acid
plga
extract
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PCT/JP2012/064540
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Japanese (ja)
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愛子 安武
香織 原
辻本　広行
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ホソカワミクロン株式会社
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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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • 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
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • 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
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85—Polyesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • 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
    • A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
    • 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
    • A61K2800/60—Particulates further characterized by their structure or composition
    • A61K2800/65—Characterized by the composition of the particulate/core
    • A61K2800/654—The particulate/core comprising macromolecular material

Definitions

  • the present invention relates to a liquid composition in which biocompatible nanoparticles carrying a physiologically active substance inside or on the surface of a particle are dispersed in a dispersion, a cosmetic using the same, and a hair restorer, and in particular, a dispersion
  • the present invention relates to a method for stabilizing nanoparticles in a liquid.
  • DDS Drug Delivery System
  • the hair-restoring and moisturizing ingredients are brought to the target site.
  • a method of supplying can be considered.
  • One of the main technologies in DDS is to carry a small amount of drug inside or on the surface of a biocompatible polymer to form nanoparticles with a high drug introduction efficiency into cells of several tens to several hundreds of nanometers.
  • Technology. These drug-supporting nanoparticles deliver the drug stably and reliably to the target affected area, and control the drug release rate (sustained release) according to the type of polymer and the elapsed time after administration.
  • the drug can be released when it reaches the site, and exhibits high effects not only for use as an injection or oral preparation, but also for external preparations that have heretofore been difficult to penetrate deeply into the skin.
  • Patent Document 1 discloses a hair growth agent for scalp containing biocompatible nanoparticles encapsulating stevia extract, ceramide precursor, ceramide, and blood flow promoting component as hair growth components.
  • Patent Document 2 discloses a cosmetic prepared by blending hyaluronic acid-carrying nanoparticles carrying hyaluronic acid inside or on the surface of biocompatible nanoparticles.
  • Patent Document 3 discloses a method for producing a microsphere in which an active substance is encapsulated. Further, Patent Documents 1 to 3 describe PLGA (lactic acid / glycol as a biocompatible polymer that forms biocompatible nanoparticles), which can contain a drug and can be stored for a long period of time while retaining the efficacy of the drug. It is described that acid copolymers are preferred.
  • JP 2009-107941 A JP 2010-150151 A JP-T 9-504026
  • the PLGA nanoparticle powder and the liquid in which it is dispersed are filled in separate containers and stored before use. Prior to use, a predetermined amount of PLGA nanoparticle powder and dispersion were mixed and used as a dispersion.
  • Patent Document 3 it is described that the pH of a preparation containing PLGA microspheres is usually about 5 to 8, preferably 6.5 to 7.5. The relationship of pH was not specifically examined. In addition, there is a similar problem when nanoparticles formed of polylactic acid or polyglycolic acid containing an ester bond having the same properties as PLGA are dispersed in a dispersion.
  • the present invention suppresses hydrolysis in a dispersion liquid of nanoparticles formed of either polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer for a desired period of time.
  • An object of the present invention is to provide a liquid composition that can be used, and a cosmetic and a hair restorer using the same.
  • the present invention provides a living body in which a physiologically active substance is carried on at least one of the inside or the surface of a nanoparticle formed of either polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer. It is a liquid composition containing compatible nanoparticles and a buffer solution having a pH of 7 or more and 10 or less.
  • the present invention is characterized in that, in the liquid composition having the above-described configuration, the buffer solution is a phosphate-citrate buffer solution having a pH of 7 or more and 8 or less.
  • the present invention is characterized in that, in the liquid composition having the above-described configuration, the buffer solution is a phosphate buffer solution having a pH of 7 or more and 10 or less.
  • the present invention is characterized in that, in the liquid composition having the above-described configuration, a thickener is further added to the buffer solution.
  • the present invention is also characterized in that, in the liquid composition having the above structure, the thickener is a water-soluble polymer.
  • the present invention provides the liquid composition having the above structure, wherein the water-soluble polymer is xanthan gum, hyaluronic acid, sodium hyaluronate, acetylated sodium hyaluronate, carboxyvinyl polymer, carbomer, alginic acid, hydroxypropylcellulose, carrageenan, locust It is at least one selected from the group consisting of bean gum, guar gum, and hydrophobic polyether urethane.
  • the water-soluble polymer is xanthan gum, hyaluronic acid, sodium hyaluronate, acetylated sodium hyaluronate, carboxyvinyl polymer, carbomer, alginic acid, hydroxypropylcellulose, carrageenan, locust It is at least one selected from the group consisting of bean gum, guar gum, and hydrophobic polyether urethane.
  • the present invention is also characterized in that, in the liquid composition having the above-described configuration, the biocompatible nanoparticles have an average particle size of 10 nm to 300 nm.
  • the present invention is characterized in that in the liquid composition having the above-described configuration, the polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer has a weight average molecular weight of 5,000 or more and 100,000 or less.
  • the present invention is a cosmetic comprising the liquid composition having the above-described configuration or blending the liquid composition.
  • the present invention is a cosmetic for hair comprising the liquid composition having the above-mentioned constitution or blending the liquid composition.
  • the present invention is a hair restorer comprising the liquid composition having the above-described structure or blending the liquid composition.
  • the liquid composition for the production of lactic acid and glycolic acid accompanying hydrolysis of biocompatible nanoparticles formed of either polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer.
  • the resulting decrease in pH of the liquid composition is suppressed by the buffering action of the buffer solution. Therefore, the liquid composition can effectively suppress the hydrolysis of the nanoparticles for a predetermined period.
  • a buffering action of the buffer solution is obtained by using a phosphate-citrate buffer solution having a pH of 7 or more and 8 or less as the buffer solution.
  • a phosphate-citrate buffer solution having a pH of 7 or more and 8 or less as the buffer solution.
  • the combination of disodium hydrogen phosphate and citric acid, which is a buffer has high solubility in water, so that the buffering effect can be easily increased by increasing the concentration of the buffer.
  • the pH of the liquid composition is suppressed to 8 or less, the safety to the human body is further improved.
  • a phosphate buffer solution having a pH of 7 or more and 10 or less is used as a buffer solution, whereby the pH of the buffer solution is increased by the buffering action.
  • the reduction and the accompanying hydrolysis of the nanoparticles can be suppressed.
  • pH is suppressed to 10 or less, it becomes a liquid composition with few bad influences with respect to a human body.
  • the fourth configuration of the present invention in the liquid composition having the first configuration described above, by further adding a thickening agent to the buffer solution, aggregation or sedimentation of nanoparticles in the buffer solution can be performed. Generation
  • production can be suppressed and it becomes a liquid composition which can maintain the stable dispersion state of a nanoparticle for a predetermined period.
  • the water-soluble polymer that is easily dissolved in the buffer solution by adding a water-soluble polymer as a thickener in the liquid composition of the fourth configuration. It is possible to easily and effectively suppress the aggregation and sedimentation of nanoparticles.
  • the sixth configuration of the present invention in the liquid composition of the fifth configuration, xanthan gum, hyaluronic acid, sodium hyaluronate, acetylated sodium hyaluronate, carboxyvinyl polymer, carbomer,
  • xanthan gum, hyaluronic acid, sodium hyaluronate, acetylated sodium hyaluronate, carboxyvinyl polymer, carbomer By using at least one selected from the group consisting of alginic acid, hydroxypropylcellulose, carrageenan, locust bean gum, guar gum, and hydrophobic polyether urethane, a liquid composition having no adverse effects on the living body and having high safety is obtained.
  • the average particle diameter of the biocompatible nanoparticles is set to 10 nm or more and 300 nm or less, thereby being used as a cosmetic or a hair restorer.
  • it becomes a liquid composition which a nanoparticle osmose
  • the weight average molecular weight of the polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer forming the nanoparticles is 5 In the range of 1,000 to 100,000, the bioactive substance can be stored for a predetermined period while being supported on the nanoparticles, and the bioactive substance can be gradually released in units of several hours to several tens of hours when used. It becomes a possible liquid composition.
  • the liquid composition having any one of the first to eighth configurations is used as a cosmetic, or a cosmetic containing the liquid composition is used.
  • a one-pack type cosmetic that is excellent in usability and can be stably stored for a certain period of time is provided.
  • or 8 structure is used as hair cosmetics, or the cosmetics for hair in which the said liquid composition was mix
  • a one-pack type cosmetic for hair that is excellent in usability and can be stably stored for a certain period of time by previously dispersing the nanoparticle powder in the liquid is provided.
  • the liquid composition having any one of the first to eighth configurations is used as a hair restorer, or a hair restorer in which the liquid composition is blended.
  • a hair restoration agent that is excellent in usability and can be stably stored for a certain period of time is provided.
  • the liquid composition of the present invention is obtained by dispersing biocompatible nanoparticles in which a physiologically active substance is encapsulated or supported on the particle surface in a dispersion.
  • This nanoparticle penetrates from the pores and skin surface to the deep part of the skin, so that the bioactive substance can reach the deep part of the skin, and the bioactive substance can be gradually released from the nanoparticle in the deep part of the skin.
  • it can be suitably used as a raw material for cosmetics intended to moisturize the skin, cosmetics for hair that acts on the scalp to suppress dandruff and itching, hair growth, and a hair growth agent that exhibits a hair growth effect.
  • Biocompatible polymer The biocompatible polymer used to form the biocompatible nanoparticle used in the liquid composition of the present invention is desirably biodegradable having low irritation and toxicity to the living body and being decomposed and metabolized after administration. Moreover, it is preferable that it is the particle
  • a lactic acid / glycolic acid copolymer (PLGA) can be particularly preferably used. It is known that PLGA can contain various drugs and can be stored for a long period of time while maintaining its efficacy. Furthermore, although depending on the type of drug encapsulated and the molecular weight of PLGA, it is considered that sustained release can be performed in units of several hours to several months due to the characteristics of hydrolysis and long-term half-life of PLGA.
  • the weight average molecular weight of PLGA is preferably in the range of 5,000 to 100,000, taking into consideration the ease of preparation of the nanoparticles, the skin permeability of the prepared nanoparticles, and the degradability within the skin. More preferably, it is in the range of 15,000 to 25,000.
  • the composition ratio (molar ratio) of lactic acid to glycolic acid may be 1:99 to 99: 1, but is preferably 1/3 of glycolic acid with respect to lactic acid 1.
  • PLGA polyethylene glycol
  • PGA polyglycolic acid
  • the physiologically active substance encapsulated inside the nanoparticles or supported on the surface of the nanoparticles can be selected according to the use of the liquid composition of the present invention.
  • a hair matrix cell active agent, ceramide and ceramide precursor as hair components, anti-inflammatory agent, androgen antagonist, blood circulation promoter, bactericidal agent, moisturizer, topical
  • physiologically active substances having a hair-growth effect such as stimulants and antiseborrheic agents.
  • Hair matrix cell activators activate cell division by acting directly on hair matrix cells and hair root cells, or by increasing ATP, which is an energy source for cell division.
  • Specific examples of such hair matrix cell activators include stevia extract, panthenol, calcium pantothenate, pantothenate derivatives such as ethyl pantothenate, pantothenyl ethyl ether, hinokitiol, potassium aspartate, pentadecanoic acid glyceride, photosensitivity Element 301, N-acetyl-L-methionine, 5-mononitroguaiacol, mononitroguaiacol sodium, chlorhexidine gluconate, biotin, netacanal, chixetsuninjin, taisou extract, placenta extract, carrot extract, royal jelly extract, garlic component, etc. Is mentioned.
  • Ceramide 2 and ceramide 5 which are hair components can effectively improve hair damage and hair strength in a short period of time, and can produce healthy hair with firmness and stiffness.
  • glucosylceramide having a high ability to produce ceramide 2 and ceramide 5 is preferable, and among them, commercially available glycosphingoglycolipid which is easily available industrially is preferable.
  • An anti-inflammatory agent suppresses inflammation of the scalp and suppresses dandruff and itching.
  • anti-inflammatory agents include ⁇ -glycyrrhetinic acid and derivatives thereof, lipophilic glycyrrhetinic acids, glycyrrhizic acid and dipotassium glycyrrhizinate, glycyrrhizic acid derivatives such as monoammonium glycyrrhizinate, diphenhydramine hydrochloride, hydrocortisone acetate, bradnisolone, salicylic acid , Azulene, Guai Azulene, Licorice extract, Ages extract, Ogon extract, Shikon extract, Kawaramugi extract, Kyary extract, Kyonin extract, Gardenia extract, Kumagus extract, Gentiana extract, Comfrey extract, Hawthorn extract, Birch extract, Achillea millefolium extract, Zenia oil Extract, tonin extract, peach
  • An androgen antagonist suppresses the activity of androgen that slows the division of hair matrix cells, such as a 5 ⁇ reductase inhibitor.
  • Specific examples of such androgen antagonists include estradiol, ethinyl estradiol, spironolactone, oxendron, diethylstilbestrol, epitestosterone, estrone, cyproterone acetate, 11 ⁇ -hydroxyprogesterone, flutamide, 3-deoxyadenosine, acetic acid Chlormadinone, hop extract, peppermint extract, clove extract, quina extract, aloe extract, salamander extract, ginseng extract and the like.
  • the blood circulation promoter increases blood flow by expanding capillaries and promotes nutritional supplementation to the hair papilla.
  • Specific examples of such blood circulation promoters include nicotinic acid and nicotinic acid amide, nicotinic acid derivatives such as benzyl nicotinate, cephalanthin, carpronium chloride, acetylcholine, ⁇ -oryzanol, cerretin, cromakalim, nicorandil, pinacidil, phthalides, Dialkyl monoamine derivatives, Ginkgo biloba extract, Chamomile extract, Japanese cypress extract, Senkyu extract, Rosemary extract, Senburi extract, Safflower extract, Pepper tincture, Chimpi extract, Ginseng extract, Carrot extract, Ginger extract, Yakusei extract, Yuzu extract, etc. Is mentioned.
  • Bactericides prevent the growth of germs that have an adverse effect on hair growth.
  • Specific examples of such bactericides include hinokitiol, isopropylmethylphenol, menthol, salicylic acid, benzalkonium chloride, octopirox, chlorohexidine, zinc pyrithione, potassium sorbate, biozol, cucumber extract, mucrothi extract, amber extract and the like. It is done.
  • the moisturizer prepares the hair growth environment by making the scalp dry and soft.
  • moisturizers include trehalose, mayifa, sorbitol, soluble collagen, glycerin, chondroitin sulfate, tuberose polysaccharides, cordyceps, trisaccharide, urea, biohyaluronic acid, hyaluronic acid, vitamin C phosphate calcium salt , Sodium pyrrolidone carboxylate, Propylene glycol, Buttonpi extract, Aloe extract, Placenta extract, Plum extract, Hypericum extract, Oat extract, Barley extract, Orange extract, Seaweed extract, Cucumber extract, Burdock extract, Shiitake extract, Giant extract , Duke extract, loquat extract, grape leaf extract, prune extract, loofah extract, maikai extract, mini sasanishiki, lily extract, apple extract, etc. And the like.
  • Local stimulants have effects such as activation of scalp metabolism, strengthening of the scalp, and prevention of itching.
  • Specific examples of such a local stimulant include camphor, capsicum tincture, nonylic acid vanillylamide, menthol, pepper tincture, Dutch mustard extract, cantalis tincture, salamander extract, peppermint oil, horseradish radish extract and the like.
  • Antiseborrheic agent excludes excessively secreted sebum that promotes hair loss or suppresses sebaceous gland activity.
  • Specific examples of such an antiseborrheic agent include licorice extract, licorice extract, sulfur, thioxolone, vanside, polysorbates, lecithin and the like.
  • liquid composition of the present invention When using the liquid composition of the present invention as a hair cosmetic or a skin cosmetic, vitamins, vitamin derivatives and the like are added as necessary in addition to the above bactericides, topical stimulants and moisturizers.
  • the method for producing nanoparticles is not particularly limited as long as it is a method capable of processing a physiologically active substance and a biocompatible polymer into particles having an average particle size of less than 1,000 nm.
  • a spherical crystallization method can be suitably used.
  • the spherical crystallization method is a method in which spherical crystal particles can be designed and processed by directly controlling their physical properties by controlling the crystal generation and growth process in the final process of compound synthesis.
  • One of the spherical crystallization methods is an emulsion solvent diffusion method (ESD method).
  • the ESD method is a technology for producing nanoparticles (nanospheres) based on the following principle.
  • two types of solvents are used: a good solvent that can dissolve the biocompatible polymer serving as the base polymer, and a poor solvent that does not dissolve the biocompatible polymer.
  • a good solvent an organic solvent such as acetone that dissolves the biocompatible polymer and is miscible with the poor solvent is used.
  • a polyvinyl alcohol aqueous solution etc. are normally used for a poor solvent.
  • PLGA lactic acid / glycolic acid copolymer
  • a solution of a physiologically active substance is added and mixed in the good solvent so that PLGA does not precipitate.
  • this mixed liquid containing PLGA and a physiologically active substance is dropped into a poor solvent while stirring, the good solvent (organic solvent) in the mixed liquid rapidly diffuses and moves into the poor solvent.
  • self-emulsification of the good solvent occurs in the poor solvent (Marangoni effect), and emulsion droplets of the good solvent of submicron size are formed.
  • the organic solvent continuously diffuses from the emulsion to the poor solvent, so that the solubility of PLGA and the physiologically active substance in the emulsion drops is lowered, and finally, PLGA nanoparticles of crystal particles encapsulating a physiologically active substance are generated (nanoparticle formation step).
  • nanoparticles can be formed by a physicochemical method, and the resulting nanoparticles are substantially spherical, so that homogeneous nanoparticles can be formed without considering the problem of catalyst and raw material residue. Can be easily formed. Then, the organic solvent which is a good solvent is depressurizingly distilled (solvent distillation process), and nanoparticle powder is obtained by drying.
  • the methods for evaporating the solvent are roughly classified into a vacuum method and an outside air introduction method.
  • the vacuum method the vacuum pump is controlled ON / OFF so that the degree of vacuum in the closed crystallization vessel becomes a specified value, or a leak valve is provided on the primary side of the vacuum pump to adjust the amount of leakage.
  • Control the degree of vacuum in the analysis vessel it is important in terms of quality to minimize hydrolysis of PLGA also in the solvent distillation step, and it is desirable to remove the solvent in as short a time as possible while increasing the degree of vacuum to such an extent that the solvent does not bump.
  • the temperature at this time needs to be about 45 ° C. or less which is the glass transition point of PLGA. Specifically, it is used under a temperature condition of 30 to 40 ° C., and the degree of vacuum is controlled so that the boiling point of the solvent is close to the temperature.
  • a leak valve is provided in the upper part of the crystallization vessel, so that the solvent is distilled off while taking the outside air into the crystallization vessel. It can be distilled off over time.
  • this method has the disadvantage that additional devices such as vacuum pumps and cooling devices are increased, the vacuum method is too high in the vacuum method, which causes quality problems such as particle agglomeration and leakage of encapsulated drugs.
  • it is advantageous in that the degree of vacuum in the container can be adjusted within an appropriate range. Therefore, it can be adopted as a solvent distillation method from a nanoparticle suspension in which a drug is encapsulated.
  • the kind of the good solvent and the poor solvent used in the nanoparticle formation step is not particularly limited, but it is necessary to use a solvent that is highly safe for the human body and has a low environmental load.
  • a poor solvent for example, an aqueous polyvinyl alcohol solution is suitably used, and examples of the surfactant other than polyvinyl alcohol include polyethylene glycol, cyclodextrin, lecithin, hydroxymethyl cellulose, hydroxypropyl cellulose and the like.
  • halogenated alkanes which are low-boiling organic solvents, acetone, methanol, ethanol, ethyl acetate, diethyl ether, cyclohexane, benzene, toluene, etc.
  • acetone methanol, ethanol, ethyl acetate, diethyl ether, cyclohexane, benzene, toluene, etc.
  • acetone classified as Class 3 or a mixture of acetone and ethanol is preferably used.
  • the concentration of the polyvinyl alcohol aqueous solution may also be appropriately determined according to the concentration of the biocompatible polymer, etc., but the higher the concentration of the polyvinyl alcohol aqueous solution, the better the adhesion of the polyvinyl alcohol to the nanoparticle surface, but the drying Later redispersibility in water decreases.
  • concentration of the polyvinyl alcohol aqueous solution is below a predetermined level, the dispersibility in the poor solvent is adversely affected. Therefore, although it varies depending on the polymerization degree and saponification degree of polyvinyl alcohol, it is preferably 0.1% by weight or more and 10% by weight or less, more preferably about 2% by weight.
  • the nanoparticles produced in the present invention are not particularly limited as long as they have an average particle diameter of less than 1,000 nm, but generally, the pore diameter is about 200 ⁇ m, so that the effect of penetrating deep into the skin is enhanced.
  • the average particle size is preferably 300 nm or less.
  • the skin cell size is 15,000 nm and the skin cell interval varies between shallow and deep skin, it is considered to be about 70 nm. If the diameter is about 300 nm, the nanoparticles penetrate into the epidermis and dermis through the cell gap route (skin keratinocyte gap), and the physiologically active substance can be effectively delivered to the deep part of the skin.
  • the smaller the particle size of the nanoparticles the lower the encapsulation rate of the physiologically active substance. Therefore, the average particle size is preferably 10 nm or more.
  • the amount of the physiologically active substance encapsulated in the nanoparticles can be adjusted by adjusting the amount of the physiologically active substance added at the time of nanoparticle formation, the type and molecular weight of the biocompatible polymer forming the nanoparticles.
  • the weight ratio to the biocompatible polymer is preferably 0.001 or more and 1.0 or less. When the weight ratio with respect to the biocompatible polymer is less than 0.001, the concentration of the physiologically active substance in the good solvent is too low and the encapsulation rate in the nanoparticles becomes low. On the other hand, when it exceeds 1.0, formation of nanoparticles is inhibited.
  • the physiologically active substance encapsulated in the nanoparticles is an anionic physiologically active substance that exists as an anion molecule in an aqueous solution
  • a cationic polymer by adding a cationic polymer to a poor solvent in the nanoparticle formation step, The encapsulation rate of the physiologically active substance in the nanoparticles can be increased.
  • the surface of the nanoparticles produced by the conventional spherical crystallization method generally has a negative zeta potential.
  • the cell adhesion of the nanoparticles deteriorated. Therefore, as in the present invention, using a cationic polymer to charge the surface of the nanoparticle so as to have a positive zeta potential increases the adhesion of the nanoparticle to the negatively charged cell wall, resulting in an anionic physiological activity. It is also preferable from the viewpoint of improving the intracellular transferability of the substance.
  • the zeta potential is the potential of the surface (sliding surface) where the above movement occurs when the potential of an electrically neutral region sufficiently separated from the particle is used as a reference. If the absolute value of the zeta potential is increased, the repulsive force between the particles is increased and the stability of the particles is increased. Conversely, as the zeta potential approaches 0, the particles are likely to aggregate. Therefore, the zeta potential is used as an index of the dispersed state of particles.
  • Examples of the cationic polymer used in the present invention include chitosan and chitosan derivatives, cationized cellulose obtained by binding a plurality of cationic groups to cellulose, polyamino compounds such as polyethyleneimine, polyvinylamine and polyallylamine, polyornithine and polylysine.
  • a cation group such as a quaternary ammonium salt is bonded to a polymer having 2-methacryloyloxyethyl phosphorocholine (MPC) as a structural unit, which has both a group (phosphorylcholine group) and a highly polymerizable methacryloyl group.
  • Cationic polymers e.g., MPC and 2-hydroxy-3-methacryloyloxy propyl copolymers with trimethylammonium chloride
  • Chitosan is a cationic natural polymer in which many glucosamines, one of the sugars with amino groups, contained in shrimp, crabs, and insect shells are bound. Emulsification stability, shape retention, biodegradability Since it has characteristics such as biocompatibility and antibacterial properties, it is widely used as a raw material for cosmetics, foods, clothing, pharmaceuticals and the like. By adding this chitosan into a poor solvent, highly safe nanoparticles can be produced without adverse effects on the living body.
  • the nanoparticles thus obtained are used as they are, or are compounded as necessary (compositing step).
  • This composite makes the composite particles easy to handle, in which nanoparticles are collected before use, and returns to the nanoparticles by touching moisture at the time of use, and characteristics such as high reactivity can be restored.
  • a freeze drying method for example, vacuum freeze drying using a drying shelf type freeze dryer (Takara Seisakusho) or Nauta mixer NXV (Hosokawa Micron)
  • a fluidized bed dry granulation method for example, fluid granulation is performed using Agromaster AGM (manufactured by Hosokawa Micron)) or a dry mechanical particle compounding method (for example, Mechanofusion System AMS (manufactured by Hosokawa Micron))
  • Agromaster AGM manufactured by Hosokawa Micron
  • a dry mechanical particle compounding method for example, Mechanofusion System AMS (manufactured by Hosokawa Micron)
  • the nanoparticle surface In order to electrostatically support the anionic physiologically active substance on the nanoparticle surface, it is necessary to charge the nanoparticle surface so that it has a positive zeta potential.
  • the cationic polymer When the cationic polymer is added to the poor solvent in the nanoparticle formation step, the surface of the formed nanoparticle is modified (coated) with the cationic polymer, and the zeta potential of the nanoparticle surface becomes positive. Therefore, when complexing nanoparticles by lyophilization, an anionic physiologically active substance is added to the nanoparticle suspension before lyophilization, so that the physiologically active substance that has become negatively charged anionic molecules can be obtained. A predetermined amount is supported (attached) on the surface of the nanoparticles by electrostatic interaction.
  • a chitosan derivative such as N- [2-hydroxy-3- (trimethylammonio) propyl] chitosan having a higher cationic property by quaternizing a part of chitosan which is originally cationic ( Cationic chitosan) is preferably used.
  • the amount of the physiologically active substance supported on the nanoparticle surface can be changed by adjusting the type and amount of the cationic polymer and the amount of the physiologically active substance added to the nanoparticle suspension before lyophilization.
  • the amount of the physiologically active substance added to the nanoparticle suspension is preferably 0.001 or more and 1.0 or less with respect to the biocompatible polymer. When the weight ratio with respect to the biocompatible polymer is less than 0.001, the concentration of the physiologically active substance is too low and the loading rate on the nanoparticle surface is low. On the other hand, if it exceeds 1.0, the amount that can be electrostatically supported is exceeded, and an excess physiologically active substance that is not supported on the nanoparticle surface is generated.
  • the physiologically active substance first supported on the surface of the nanoparticle, and then the physiologically active substance encapsulated in the nanoparticle Are released in this order. Therefore, the release rate of the physiologically active substance can be controlled in two stages.
  • polyvinyl alcohol is hydrophilic and hygroscopic
  • the composite particles after freeze-drying contain excessive polyvinyl alcohol, the composite particles become sticky and the quality is impaired.
  • the filling property (ease of filling into a container) becomes worse as the addition amount of polyvinyl alcohol increases.
  • the skin feels tight (smooth) when applied to the skin. In order to solve these problems, it is preferable to provide a removal step.
  • the surface of the nanoparticle encapsulating the bioactive substance is further supported with the bioactive substance, but the bioactive polymer is not added to the good solvent in the nanoparticle formation step.
  • a physiologically active substance may be supported on the surface of nanoparticles formed by agglomerating only the above-mentioned method.
  • composite particles in which nanoparticles carrying physiologically active substances are combined with a binder will be described.
  • composite particles having excellent dispersibility and heat resistance in addition to redispersibility can be obtained.
  • other physiologically active substances can be supported on the composite particles including nanoparticles.
  • the binder improves the dispersibility and heat resistance of the composite particles by forming a layer that separates the nanoparticles from each other during the composite.
  • the physiologically active substance encapsulated in the nanoparticles is water-soluble, once the encapsulated physiologically active substance leaks to the nanoparticle surface, it is re-dissolved in the surrounding water. When this water is removed by freeze-drying or the like, the physiologically active substance is reduced by that amount, and the content rate is varied. Therefore, it is preferable to combine organic or inorganic substances so that they can be redispersed, and to dry them together with the nanoparticles without removing the water in which the physiologically active substance is dissolved.
  • binders examples include sugar alcohols such as mannitol, trehalose, sorbitol, erythritol, maltose, and xylitol, sucrose, polymer polymer powders such as acrylic polymer and ethyl cellulose, and the like. If a sugar alcohol having a weak crystallinity is used as a binder, it may become amorphous during compounding and may not be formed into particles satisfactorily. Therefore, it is preferable to use mannitol having strong crystallinity.
  • the nanoparticles or composite particles thus produced are dispersed in a dispersion to obtain a liquid composition.
  • this liquid composition as a hair restorer or cosmetic, or by blending it as a raw material for the hair restorer or cosmetic, the nanoparticles penetrate efficiently from the pores or the skin surface to the deep part of the skin. That is, the droplets containing nanoparticles applied to the skin surface are likely to move in the direction in which the interfacial energy decreases (the direction of penetration into the skin) because the surface tension is reduced by the nanoparticles. Furthermore, adsorption from the inside of the skin also occurs with respect to the nanoparticles or water in the droplets, so that the nanoparticles are efficiently delivered to the deep part of the skin. As a result, the physiologically active substance carried on the nanoparticles is gradually released in the skin over a predetermined period immediately after administration.
  • a liquid formulation is mentioned as a dosage form of the hair restorer of this invention.
  • the dosage form of the cosmetic of the present invention include hair cosmetics such as hair tonics, hair liquids, shampoos, rinses and hair conditioners, and skin care cosmetics such as emulsions, lotions and skin creams.
  • the mixing ratio of the nanoparticles or composite particles in the liquid composition can be arbitrarily set according to the required effect, dosage form, and the like.
  • Dispersion liquid As the dispersion liquid, it is necessary to use nanoparticles that uniformly disperse instantaneously and have high safety to the human body, and water or a mixture of water and ethanol is preferably used. In addition, since aggregation of nanoparticles occurs when the volume ratio of ethanol to water becomes 1/2 or more, the range of 1/10 to 3/10 is preferable. Moreover, the skin permeation effect of the nanoparticles can be further enhanced by using an emulsion as the dispersion.
  • PLGA nanoparticles are hydrolyzed when exposed to moisture for a long time, and the transport performance of physiologically active substances by the nanoparticles is lost.
  • PLGA nanoparticles are hydrolyzed, lactic acid and glycolic acid constituting PLGA are produced, so that the dispersion gradually becomes acidic and the pH (hydrogen ion concentration) decreases. This pH decrease further promotes the hydrolysis of PLGA.
  • a buffer solution having a pH of 7 to 10 is used as the dispersion.
  • the pH of the dispersion is maintained at 7 to 10 by the buffering action, the pH does not decrease due to the hydrolysis of the PLGA nanoparticles. Therefore, hydrolysis of PLGA nanoparticles in the dispersion can be effectively suppressed by using the dispersion as a buffer.
  • buffer solution in this specification refers to a solution obtained by adding an excess weak base to a salt composed of a strong acid and a weak base, such as a phosphate buffer or a phosphate-citrate buffer, or a weak acid and a strong buffer.
  • buffer solution in which an excess of weak acid is added to a salt consisting of a base, a buffer solution or solution, and several specific substances are dissolved at a certain ratio to reduce pH buffering capacity. It shall also contain what became the solution which has (for example, magnesium hydroxide aqueous solution).
  • the pH of the buffer solution When the pH of the buffer solution is smaller than 7, further decrease in pH is suppressed by the buffering action, but the acid hydrolysis of PLGA proceeds because the buffer solution is originally acidic. Moreover, when pH exceeds 10, while an alkali hydrolysis of PLGA advances, there is also a concern about the bad influence on a human body. Therefore, the pH of the buffer solution needs to be 7 to 10, and pH 7 to 8 is more preferable in consideration of safety.
  • the buffer used in the liquid composition of the present invention includes a phosphate-citrate buffer using a combination of disodium hydrogen phosphate and citric acid as a buffering agent, disodium hydrogen phosphate and sodium dihydrogen phosphate.
  • a phosphate buffer solution using a combination is mentioned.
  • the phosphate-citrate buffer is preferably used when adjusting to pH 7-8, and the phosphate buffer is preferably used when adjusting to pH 7-10.
  • the buffer action of the buffer increases as the concentration of the buffer in the buffer increases, but the combination of disodium hydrogen phosphate and citric acid is more than the combination of disodium hydrogen phosphate and sodium dihydrogen phosphate. Because of its high solubility in water, a high concentration buffer solution can be prepared. Therefore, by using a phosphate-citrate buffer, it is possible to increase the buffering action and enhance the hydrolysis inhibiting effect.
  • PLA and PGA other than PLGA are similar to PLGA in that lactic acid or glycolic acid is generated by hydrolysis and the pH gradually decreases. Therefore, a buffer solution having a pH of 7 to 10 should be used as a dispersion. Thus, hydrolysis of PLA and PGA nanoparticles in the dispersion can be effectively suppressed.
  • the buffer action of the buffer increases in proportion to the concentration of the buffer, it is preferable to increase the concentration of the buffer in the dispersion in order to suppress hydrolysis of the nanoparticles over a long period of time.
  • concentration of the buffering agent is increased, the hydrated water on the surface of the nanoparticles is dehydrated and the nanoparticles are easily aggregated. As a result, nanoparticles settle and aggregate, making it difficult to maintain a stable dispersed state for a long period of time.
  • a thickener added to the liquid composition of the present invention, xanthan gum, hyaluronic acid, sodium hyaluronate, sodium acetylated hyaluronate, carboxyvinyl polymer, carbomer, alginic acid, hydroxypropylcellulose, carrageenan, locust bean gum, guar gum,
  • xanthan gum hyaluronic acid, sodium hyaluronate, sodium acetylated hyaluronate, carboxyvinyl polymer, carbomer, alginic acid, hydroxypropylcellulose, carrageenan, locust bean gum, guar gum
  • water-soluble polymers selected from hydrophobic polyether urethanes may be mentioned.
  • hydrophobic polyether urethane is (PEG-240 / decyltetradeceth-20 / HDI) copolymer.
  • hectorite which is a kind of water-swellable clay mineral, can be mentioned. Hectorite has a smectite structure rich in swelling properties, and has a thickening action when dissolved in water.
  • the lower limit (minimum effective addition amount) of the addition amount of the above thickener varies depending on the period for maintaining the dispersed state of the nanoparticles, the concentration and combination of the buffering agent, the blending amount of the nanoparticles, and the type of the thickener. Therefore, it may be appropriately adjusted according to the formulation of the liquid composition.
  • the upper limit (maximum effective addition amount) of the thickener addition amount there is no particular limitation on the upper limit (maximum effective addition amount) of the thickener addition amount, but as the thickener addition amount increases, the viscosity of the liquid composition increases, and it is used as a cosmetic or hair restorer. The feeling of use when doing is worsened. Therefore, it is preferable to make it the addition amount of the range which does not impair the usability as a cosmetic or hair restorer.
  • the bioactive substances in the dispersion adsorbed on the nanoparticle surface are delivered to the skin at the same time as the nanoparticles penetrate into the skin. Therefore, more physiologically active substance can be supplied to the deep part of the skin.
  • the physiologically active substances to be blended in the dispersion include brown algae extract, burdock extract,retea root extract, serine, betaine, sorbitol, trehalose, glycine, alanine, proline, threonine, arginine, lysine, glutamic acid, maltodextrin, squalane, Moisturizing ingredients such as inositol, biotin, yeast extract, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin F, vitamin K, vitamin P, vitamin U, carnitine, ferulic acid, ⁇ -oryzanol, ⁇ -lipo Acid, orotic acid and their components or derivatives, such as retinol acetate, riboflavin acetate, pyridoxine dioctanoate, L-ascorbic acid dipalmitate, L-ascorbic acid-2-sodium sulfate, L-ascorbic acid phosphate ester DL-
  • the liquid composition of the present invention includes talc, mica, sericite, titanium oxide, silicic anhydride, kaolin, zinc oxide, mica titanium, iron oxide and other inorganic powders, polyester, polyethylene, polystyrene, polyurethane, acrylic acid resin , Various resin powders such as phenol resin, fluororesin, divinylbenzene, styrene copolymer or copolymer resin powders composed of two or more thereof, organic powders such as acetylcellulose, polysaccharides, proteins, red 202, red 226 No., Yellow 205, Yellow 401, Blue No. 1, Blue No. 204, Blue No.
  • metal soap such as zinc stearate, magnesium stearate, zinc palmitate, dimethicone, methicone, cyclomethicone, poly Silicon compounds such as ether-modified silicon and fluorine-modified silicon
  • Minerals such as ester oil such as lioctanoin, neopentyl glycol dicaprylate, glyceryl tri (capryl / capric acid), dipentaerythrityl (hydroxystearic acid / stearic acid / rosinic acid), isostearic acid hydrogenated castor oil, mineral oil, petroleum jelly and polybutene Oils, carnauba wax, candelilla wax, beeswax and other waxes, jojoba oil, olive oil, aloe, safflower and other natural raw materials, any inorganic or organic raw materials, or any ingredient normally blended in cosmetics, for example ethanol Alcohols such as polyhydric alcohols, surfactants, fats and oils,
  • the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and can be obtained by appropriately combining technical means disclosed in different embodiments. Embodiments are also included in the technical scope of the present invention.
  • the production method of the nanoparticles used in the liquid composition of the present invention and the effect of suppressing the hydrolysis of the nanoparticles in the liquid composition will be described more specifically with reference to Examples, Comparative Examples, and Test Examples.
  • the reference example showing the preparation method of nanoparticles dispersed in the test solution is nano The bioactive substance is not supported on the particles.
  • PVA EG05 polyvinyl alcohol
  • the particle size distribution of the PLGA nanoparticles when the obtained composite particles were redispersed in water was measured by a dynamic light scattering method (measuring device: MICROTRAC UPA-150, manufactured by Nikkiso Co., Ltd.). The average particle size was 160 nm. there were.
  • PLGA nano-particles prepared in Reference Example were mixed with 79.6 wt% water and 20 wt% ethanol adjusted to pH 7.0 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 200 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of the particles.
  • a liquid composition was prepared by the same procedure as in Example 1 using 79.6% by weight of water prepared by dissolving citric acid and disodium hydrogen phosphate at a concentration of 200 mmol / L and adjusting the pH to 7.6. did.
  • Liquid composition was prepared in the same manner as in Example 1, using 79.6% by weight of water prepared by dissolving sodium dihydrogen phosphate and disodium hydrogen phosphate at a concentration of 200 mmol / L and adjusting the pH to 7.7. A product was prepared.
  • the liquid composition was prepared in the same manner as in Example 1. Prepared.
  • the liquid composition was prepared by the same procedure as in Example 1. Prepared.
  • the PLGA nano-particles prepared in the Reference Example were mixed in a mixed solution of 79.2 wt% water and 20 wt% ethanol adjusted to pH 7.5 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 750 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles and 0.4% by weight of hyaluronic acid as a thickener.
  • PLGA nano-particles prepared in Reference Example were mixed in a mixed solution of 79.3% water and 20% ethanol by dissolving citric acid and disodium hydrogen phosphate as a buffering agent at a concentration of 750 mmol / L and adjusting the pH to 7.5.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles and 0.3% by weight of hyaluronic acid as a thickener.
  • PLGA nano-particles prepared in Reference Example were mixed with 79.5 wt% water and 20 wt% ethanol adjusted to pH 7.5 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 750 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles and 0.1% by weight of hyaluronic acid as a thickener.
  • the PLGA nano-particles prepared in the Reference Example were mixed in a mixed solution of 79.2 wt% water and 20 wt% ethanol adjusted to pH 7.5 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 750 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles and 0.4% by weight of xanthan gum as a thickener.
  • PLGA nano-particles prepared in Reference Example were mixed with 79.5 wt% water and 20 wt% ethanol adjusted to pH 7.5 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 750 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles and 0.1% by weight of xanthan gum as a thickener.
  • PLGA nano-particles prepared in Reference Example were mixed with a mixture of 79.55 wt% water and 20 wt% ethanol adjusted to pH 7.5 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 750 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles and 0.05% by weight of xanthan gum as a thickener.
  • PLGA nano-particles prepared in Reference Example were mixed with 79.49 wt% water and 20 wt% ethanol adjusted to pH 7.5 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 750 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles, 0.01% by weight of hyaluronic acid as a thickener, and 0.1% by weight of xanthan gum.
  • PLGA nano-particles prepared in Reference Example were mixed with 79.5 wt% water and 20 wt% ethanol adjusted to pH 7.5 by dissolving citric acid and disodium hydrogen phosphate at a concentration of 750 mmol / L as buffering agents.
  • a liquid composition was prepared by dispersing 0.4% by weight of particles, 0.05% by weight of hyaluronic acid and 0.05% by weight of xanthan gum as thickeners.
  • a liquid composition was prepared by the same procedure as in Example 1 using 79.6% by weight of water adjusted to pH 6.3 by dissolving citric acid and sodium citrate at a concentration of 200 mmol / L as a buffering agent.
  • a liquid composition was prepared by the same procedure as in Example 1 using 79.6% by weight of water having a pH of 6.8 and not dissolving the buffer.
  • a liquid composition is prepared by dispersing 0.4% by weight of PLGA nanoparticles in 79.6% by weight of water prepared by dissolving citric acid and disodium hydrogen phosphate as a buffering agent at a concentration of 750 mmol / L and adjusting the pH to 7.5. Prepared. [Hydrolysis inhibition effect of PLGA nanoparticles]
  • Example 1 The liquid compositions prepared in Examples 1 to 5 and Comparative Examples 1 and 2 were stored as a test solution at 20 ° C. for a predetermined period, and then the pH of each test solution and the molecular weight of PLGA in each test solution were measured. .
  • Table 1 summarizes the initial set values of the composition, storage temperature, and pH of each test solution.
  • the pH of the test solution was measured using a pH meter (D-51, manufactured by Horiba, Ltd.).
  • the molecular weight of PLGA was obtained by adding 2.0 mL of chloroform to a powder obtained by lyophilizing ethanol in a test solution under reduced pressure and dissolving only PLGA. This solution was filtered with a 0.2 ⁇ m filter, and the filtrate was measured using GPC (gel permeation chromatography, detector: manufactured by Shimadzu Corporation, differential refractometer).
  • the molecular weight retention of PLGA was calculated by the following formula.
  • PLGA molecular weight retention rate (%) (PLGA molecular weight after storage for a certain period) / (PLGA molecular weight before start of test) ⁇ 100 The results are shown in FIGS.
  • the test solutions of Examples 1 to 5 adjusted to have an initial pH value of 7.0 to 10.0 using a buffering agent ( ⁇ , ⁇ , ⁇ , In the data series of ⁇ and ⁇ , the pH is almost the same as the initial setting value after storage for 12 months at 20 ° C., and the molecular weight retention rate of PLGA after 90 months storage at 20 ° C. is also 90. % Or more. Furthermore, as shown in FIG. 3, in the test solution of Example 2 (circle data series), the molecular weight retention is almost 100% even after storage for 8 months, and the PLGA nanoparticles in the test solution are almost hydrolyzed. There wasn't.
  • the molecular weight retention after storage for 12 months was 96%
  • the molecular weight retention after storage for 18 months was 88%
  • a high molecular weight retention was maintained even after 18 months.
  • the pH after storage at 20 ° C. for 2 months is maintained at 10
  • the molecular weight retention rate is 90%. Therefore, the upper limit of the pH of the buffer solution exhibiting a practical hydrolysis inhibiting effect of PLGA is estimated to be 10.
  • the dispersion state of PLGA nanoparticles is ⁇ when no aggregation or sedimentation of particles is observed, no aggregation of particles is observed, ⁇ when a small amount of particles is sedimenting, and no aggregation of particles is observed.
  • ⁇ is marked, and in the case where both the aggregation and settling of particles are recognized, x is marked.
  • Table 3 The observation results are shown in Table 3 together with the pH and molecular weight retention.
  • Example 6 to 8 where sodium hyaluronate alone was used as the thickener, no aggregation or sedimentation of particles was observed in Example 6 where the addition amount was 0.4% by weight, and the dispersibility was the best. Met. In Examples 7 and 8 in which the amount of sodium hyaluronate added was 0.3% by weight or less, particle aggregation was not observed, but precipitation of PLGA nanoparticles was gradually observed. On the other hand, in Examples 9 to 11 where xanthan gum was used alone as a thickener, the dispersibility was the best in Example 9 where the addition amount was 0.4% by weight, and the addition amount of xanthan gum was 0.1% by weight. In Examples 10 and 11 in which the percentage was less than or equal to%, the precipitation of PLGA nanoparticles was gradually observed.
  • Example 12 in which sodium hyaluronate and xanthan gum were used in combination as a thickener, good dispersibility was exhibited with a lower addition amount than when sodium hyaluronate or xanthan gum was used alone, particularly sodium hyaluronate.
  • Example 12 in which 0.01% by weight and 0.1% by weight of xanthan gum were added, aggregation and sedimentation of PLGA nanoparticles were not observed at all.
  • either PGA, PLA, or PLGA is used as a material for forming nanoparticles, and in a dispersion of biocompatible nanoparticles in which a physiologically active substance is supported on at least one of the inside of the particle or the surface thereof. It becomes a liquid composition which can suppress hydrolysis of for a long period of time.
  • a thickener to the liquid composition, it is possible to suppress dispersion of nanoparticles and improve dispersion stability. Accordingly, a liquid composition that can be suitably used as a one-component cosmetic or hair restorer in which nanoparticle powder is dispersed in a dispersion in advance is provided.

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Abstract

Des nanoparticules biocompatibles sont dispersées dans une solution tampon ayant une valeur de pH de 7-10, chacune des nanoparticules biocompatibles comprenant n'importe lequel choisi parmi l'acide polylactique, l'acide polyglycolique et un copolymère (acide lactique)-(acide glycolique) et comprenant une substance physiologiquement active dans celle-ci ou ayant la substance physiologiquement active supportée sur la surface de celle-ci.
PCT/JP2012/064540 2011-06-07 2012-06-06 Composition liquide, et produit cosmétique et agent de croissance des cheveux comprenant chacun la composition liquide WO2012169518A1 (fr)

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WO2017151595A1 (fr) 2016-02-29 2017-09-08 Michelman, Inc. Dispersion à base aqueuse hydrolytiquement stable d'un polymère biodégradable
WO2017155020A1 (fr) * 2016-03-10 2017-09-14 大日本住友製薬株式会社 Composition contenant de fines particules, et procédé de production associé
KR101921246B1 (ko) 2017-01-04 2018-11-22 주식회사 베스트앤퍼스트바이오텍 탈모 방지 및 양모를 위한 헤어 필러 조성물 및 그 제조 방법
US10806692B2 (en) 2016-10-03 2020-10-20 The Procter & Gamble Company Skin cleansing compositions comprising color stable abrasive particles
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WO2016175216A1 (fr) * 2015-04-27 2016-11-03 株式会社 資生堂 Produit cosmétique pour la peau
JPWO2016175216A1 (ja) * 2015-04-27 2018-02-15 株式会社 資生堂 皮膚化粧料
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WO2023171588A1 (fr) * 2022-03-08 2023-09-14 国立大学法人大阪大学 Préparation de plga contenant un antimicrobien

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