JPWO2012169518A1 - Liquid composition and cosmetic and hair restorer using the same - Google Patents

Abstract

Biocompatible nanoparticles formed of either polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer encapsulating a physiologically active substance inside the particle or supported on the particle surface in a pH 7-10 buffer solution Disperse.

Description

  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.

  In recent years, a large number of hair-restoring agents containing hair-restoring ingredients for the purpose of preventing hair loss and hair growth have been put on the market. In addition, many cosmetics containing moisturizing ingredients such as hyaluronic acid to prevent the skin from drying are on the market. In such hair growth agents and cosmetics, in order to fully develop the hair growth effect by the hair growth ingredient and the moisturizing effect by the moisture retention ingredient, in addition to the reliable arrival of the active ingredient to the action site, It is desirable to have a so-called immediate effect and sustained release that is released over a predetermined period.

  Therefore, by using a technique that effectively administers the drug so that the drug is not absorbed and decomposed until it reaches the site of action, the so-called Drug Delivery System (hereinafter referred to as DDS), the hair-restoring and moisturizing ingredients are applied 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.

  For example, 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, in Patent Documents 1 to 3, PLGA (lactic acid / glycol) that can contain a drug as a biocompatible polymer that forms biocompatible nanoparticles and can be stored for a long period of time while maintaining the efficacy of the drug. It is described that acid copolymers are preferred.

JP 2009-107941 A JP 2010-150151 A Japanese National Patent Publication No. 9-504026

  By the way, since PLGA contains an ester bond in the molecule, PLGA nanoparticles have a property of being easily hydrolyzed in an aqueous solution. Therefore, in the hair restorer of Patent Document 1 or the cosmetic of Patent Document 2, the PLGA nanoparticle powder and the liquid in which it is dispersed (hereinafter referred to as a dispersion) 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.

  However, in this method, since the user mixes the PLGA nanoparticle powder and the dispersion liquid, there is a possibility that the mixing amount is wrong or the PLGA nanoparticle powder or dispersion liquid may be spilled during mixing, which is sufficient in terms of usability. I could not say. Therefore, it has been desired to develop a one-part product in which nanoparticle powder is dispersed in a dispersion in advance.

  In addition, Patent Document 3 describes 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.

  In view of the above problems, 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.

  In order to achieve the above object, 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.

  Further, 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.

  Further, 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.

  Further, 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.

  Further, 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.

  Further, the present invention is 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 liquid composition of the present invention is characterized in that the polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer has a weight average molecular weight of 5,000 to 100,000.

  Further, the present invention is a cosmetic comprising the liquid composition having the above-described configuration or blending the liquid composition.

  Moreover, this invention is cosmetics for hair which consist of the liquid composition of the said structure, or mix | blend the said liquid composition.

  Further, the present invention is a hair restorer comprising the liquid composition having the above-described configuration or comprising the liquid composition.

  According to the first configuration of the present invention, 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.

  Further, according to the second configuration of the present invention, in the liquid composition of the first configuration, 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. By this, it is possible to suppress the decrease in pH and the accompanying hydrolysis of the nanoparticles. In addition, 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. Furthermore, since the pH of the liquid composition is suppressed to 8 or less, the safety to the human body is further improved.

  Further, according to the third configuration of the present invention, in the liquid composition of the first configuration, 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. Moreover, since pH is suppressed to 10 or less, it becomes a liquid composition with few bad influences with respect to a human body.

  Further, according to 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 | occurrence | production can be suppressed and it becomes a liquid composition which can maintain the stable dispersion state of a nanoparticle for a predetermined period.

  Further, according to the fifth configuration of the present invention, 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.

  According to 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, 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.

  According to the seventh configuration of the present invention, in the liquid composition having the first configuration, 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. When it does, it becomes a liquid composition which a nanoparticle osmose | permeates from the crevice part of skin cells other than a pore and a pore to the deep part of skin.

  According to the eighth configuration of the present invention, in the liquid composition having the first configuration, the weight average molecular weight of the polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer forming the nanoparticles is 5 In a state where the physiologically active substance is supported on the nanoparticles, the biologically active substance can be stored for a predetermined period of time, and when used, the physiologically active substance can be gradually released in units of several hours to several tens of hours. It becomes a possible liquid composition.

  According to the ninth configuration of the present invention, 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. In addition, by dispersing the nanoparticle powder in the liquid in advance, a one-pack type cosmetic that is excellent in usability and can be stably stored for a certain period of time is provided.

  Moreover, according to the 10th structure of this invention, the liquid composition of the said any one of the said 1st thru | or 8 structure is used as hair cosmetics, or the cosmetics for hair in which the said liquid composition was mix | blended Thus, 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.

  According to the eleventh configuration of the present invention, 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. In addition, by dispersing the nanoparticle powder in the liquid in advance, a one-part hair restoration agent that is excellent in usability and can be stably stored for a certain period of time is provided.

The graph which shows transition of pH of each test liquid of Examples 1-5 and Comparative Examples 1 and 2 which were stored for 12 months at 20 ° C. in Test Example 1 The graph which shows transition of the molecular weight retention rate of PLGA of each test liquid of Examples 1-5 and Comparative Examples 1 and 2 which were stored for 2 months at 20 ° C. in Test Example 1 The graph which shows transition of the molecular weight retention rate of PLGA of each test liquid of Example 2 and Comparative Example 2 which were stored for 18 months at 20 ° C. in Test Example 1

  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. In particular, 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 | grains which release the physiologically active substance to include continuously and gradually. As such a material, 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 nanoparticles, skin permeability of the prepared nanoparticles, and degradability inside the skin. More preferably, it is in the range of 15,000 to 25,000. The composition ratio (molar ratio) of lactic acid and glycolic acid may be 1:99 to 99: 1, but is preferably 1/3 of glycolic acid with respect to lactic acid 1.

  When encapsulating a water-soluble physiologically active substance, it is preferable to modify the surface of PLGA with polyethylene glycol (PEG) because the amount of encapsulation can be increased. Other biocompatible polymers include polylactic acid (PLA) and polyglycolic acid (PGA). Moreover, you may have the group which can be charged or functionalized like an amino acid.

(Bioactive substance)
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. When the liquid composition of the present invention is used as a hair growth agent, a hair matrix active agent, ceramide and ceramide precursor as hair components, anti-inflammatory agent, androgen antagonist, blood circulation promoter, bactericidal agent, moisturizer, topical Examples thereof include physiologically active substances having a hair-growth effect, such as stimulants and antiseborrheic agents.

  The hair matrix activator activates cell division by directly acting on hair matrix cells or hair root cells or increasing ATP as 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. As the ceramide precursor, 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.

  The anti-inflammatory agent suppresses inflammation of the scalp and suppresses dandruff and itching. Specific examples of such anti-inflammatory agents include β-glycyrrhetinic acid and derivatives thereof, fat-soluble glycyrrhetinic acids, glycyrrhizic acid and dipotassium glycyrrhizinate, 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 leaf extract, loquat leaf extract and the like.

  A male hormone antagonist suppresses the activity of male hormones that slow down the division of hair matrix cells, such as 5α reductase inhibitors. Specific examples of such androgen antagonists include estradiol, ethinyl estradiol, spironolactone, oxendron, diethylstilbestrol, epitestosterone, estrone, cyproterone acetate, 11α-hydroxyprogesterone, flutamide, 3-deoxyadenosine, acetic acid Chlormadinone, hop extract, peppermint extract, clove extract, quina extract, aloe extract, salamander extract, ginseng extract and the like.

  A blood circulation promoter increases blood flow by expanding capillaries and promotes nutritional supplementation to the hair papilla. Specific examples of such a blood circulation promoter include nicotinic acid and nicotinic acid amide, nicotinic acid derivatives such as benzyl nicotinate, cephalanthin, carpronium chloride, acetylcholine, γ-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.

  A disinfectant prevents the growth of germs that have a negative 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 moisturizing agent adjusts the hair growth environment by preventing the scalp from drying and making it soft. Specific examples of such 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.

  The local stimulant has effects such as activation of scalp metabolism, strengthening of the scalp, 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.

  Anti-seborrheic agents exclude excess sebum that promotes hair loss, or suppress sebaceous gland activity. Specific examples of such an antiseborrheic agent include licorice extract, licorice extract, sulfur, thioxolone, vanside, polysorbates, lecithin and the like.

  When the liquid composition of the present invention is used 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.

(Nanoparticle production method)
Next, a method for producing nanoparticles encapsulating or carrying a physiologically active substance will be described. 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. For example, in this embodiment, a spherical crystallization method can be suitably used. Spherical crystallization 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 technique for producing nanoparticles (nanospheres) based on the following principle. In this method, 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. As the good solvent, an organic solvent such as acetone that dissolves the biocompatible polymer and is miscible with the poor solvent is used. And a polyvinyl alcohol aqueous solution etc. are normally used for a poor solvent. Hereinafter, the operation procedure when lactic acid / glycolic acid copolymer (PLGA) is used as the biocompatible polymer will be described in detail.

  First, after dissolving PLGA in a good solvent, a solution of a physiologically active substance is added and mixed in the good solvent so that PLGA does not precipitate. When 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. As a result, 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. Furthermore, due to the mutual diffusion of the good solvent and the poor solvent, 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).

  In the above spherical crystallization method, 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 method for distilling off the solvent is roughly divided into a vacuum method and an outside air introduction method. In 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. However, 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.

  On the other hand, in the outside air introduction method, 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. Although 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. In this case, 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.

  Although the kind of good solvent and poor solvent used in the nanoparticle formation step is not particularly limited, it is necessary to use a solvent that is highly safe for the human body and has a low environmental load. As such 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.

  Examples of good solvents include halogenated alkanes, which are low-boiling organic solvents, acetone, methanol, ethanol, ethyl acetate, diethyl ether, cyclohexane, benzene, toluene, etc. About the guideline (March 30, 1998, Pharmaceutical Trial No. 307), only 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. On the other hand, when the 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 μm, so that the effect of penetrating deep into the skin is enhanced. For this purpose, the average particle size is preferably 300 nm or less. In addition, although 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. On the other hand, 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. As the amount of the physiologically active substance to be mixed with the good solvent at the time of nanoparticle formation, 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.

  Further, when the physiologically active substance encapsulated in the nanoparticles is an anionic physiologically active substance that exists as an anion molecule in an aqueous solution, 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.

  When trying to produce nanoparticles encapsulating anionic physiologically active substances using the conventional spherical crystallization method, water-soluble physiologically active substances dispersed and mixed in a good solvent leak into and dissolve in poor solvents. Since only the biocompatible polymer forming the nanoparticles is deposited, the physiologically active substance is hardly encapsulated. In contrast, when a cationic polymer is added to a poor solvent in the nanoparticle formation step, the cationic polymer that coats the nanoparticle surface interacts with the anionic physiologically active substance present on the emulsion droplet surface. Thus, it is considered that leakage of the physiologically active substance into the poor solvent can be suppressed.

  In addition, although the cell wall in the living body is negatively charged, the surface of the nanoparticles produced by the conventional spherical crystallization method generally has a negative zeta potential. There was a problem that 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.

  Note that the zeta potential is a potential of a 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. Polyamino acid, polyvinylimidazole, polyvinylpyridinium chloride, alkylaminomethacrylate quaternary salt polymer (DAM), alkylaminomethacrylate quaternary salt / acrylamide copolymer (DAA), phospholipid polarity which is a constituent of cell membrane (biological membrane) A cation group such as a quaternary ammonium salt is bonded to a polymer having 2-methacryloyloxyethyl phosphorcholine (MPC) as a structural unit, which has both a group (phosphorylcholine group) and a highly polymerizable methacryloyl group. Although such a cationic polymer (e.g., MPC and 2-hydroxy-3-methacryloyl copolymers of trimethylammonium chloride) and the like, is preferably used in particular chitosan or a derivative thereof.

  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.

  As a nanoparticle composite method, a freeze drying method (for example, vacuum freeze drying using a drying shelf type freeze dryer (Takara Seisakusho) or Nauta mixer NXV (Hosokawa Micron)) is preferably used. It is done. Further, 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)) And may be combined by applying compressive and shear forces. In particular, when using a fluidized bed drying granulation method in which a mixture containing the material to be granulated is sprayed into a flowing gas, a time-consuming and laborious freeze-drying step can be omitted, and composite particles can be produced easily and in a short time. This is advantageous for industrialization.

  Next, a method for further supporting an anionic physiologically active substance on the surface of the nanoparticles will be described. Here, a method for electrostatically supporting an anionic physiologically active substance on the surface of a nanoparticle having a positive zeta potential will be described as an example.

  In order to electrostatically support the anionic physiologically active substance on the nanoparticle surface, it is necessary to charge the nanoparticle surface so as to have a positive zeta potential. 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.

  In addition, since the zeta potential becomes a larger positive value by using a cationic polymer having a stronger cationic property, a larger amount of physiologically active substance can be supported on the nanoparticle surface, and between the nanoparticles. The repulsive force increases and the stability of the nanoparticles also increases. For example, 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.

  Thus, by combining the encapsulation of the physiologically active substance into the nanoparticles and the electrostatic loading onto the surface of the nanoparticles, 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.

  If surplus polyvinyl alcohol or chitosan remains in the nanoparticle suspension before lyophilization, polyvinyl alcohol or chitosan and the bioactive substance are adsorbed, and the bioactive substance is efficiently adsorbed to the nanoparticle surface. Can no longer be supported. Therefore, it is preferable to provide a step (removal step) for removing polyvinyl alcohol and chitosan by centrifugation before adding the solution of the physiologically active substance after the solvent distillation step.

  In particular, since polyvinyl alcohol is hydrophilic and hygroscopic, if the composite particles after freeze-drying contain excessive polyvinyl alcohol, the composite particles become sticky and the quality is impaired. Further, the filling property (ease of filling into a container) becomes worse as the addition amount of polyvinyl alcohol increases. Furthermore, due to the function of “glue” unique to polyvinyl alcohol, the skin feels tight (smooth) when applied to the skin. In order to solve these problems, it is preferable to provide a removal step.

  Specifically, a method of removing the polyvinyl alcohol by isolating the particles by a centrifugal separation operation, discarding the supernatant liquid containing excess polyvinyl alcohol, replacing it with purified water, and centrifuging again is conceivable.

  Here, the case where the surface of the nanoparticle encapsulating the bioactive substance is further supported with the bioactive substance has been described, but the bioactive polymer is not added to the good solvent in the nanoparticle formation step. Alternatively, a physiologically active substance may be supported on the surface of nanoparticles formed by agglomerating only the above-mentioned method.

  Next, composite particles obtained by combining nanoparticles carrying a physiologically active substance with a binder will be described. By combining the nanoparticles with the binder, composite particles having excellent dispersibility and heat resistance in addition to redispersibility can be obtained. Further, by adding a physiologically active substance in the binder, 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 when composited. In addition, since 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.

  Examples of such a binder include sugar alcohols such as mannitol, trehalose, sorbitol, erythritol, maltose, and xylitol, sucrose, and polymer compound powders such as an acrylic polymer and ethyl cellulose. 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.

(Liquid composition)
The nanoparticles or composite particles thus produced are dispersed in a dispersion to obtain a liquid composition. By using 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 deep into 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.

  Therefore, it becomes a hair restorer or cosmetic that is easy to handle and can obtain an effective hair-restoring effect and moisturizing effect. A liquid formulation is mentioned as a dosage form of the hair restorer of this invention. Examples of 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)
As the dispersion liquid, it is necessary to use nanoparticles that uniformly disperse instantaneously and have high safety for the human body, and water, a mixed liquid of water and ethanol are 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.

  By the way, it is known that 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. When 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.

  Therefore, in the liquid composition of the present invention, a buffer solution having a pH of 7 to 10 is used as the dispersion. In this case, since 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.

  The “buffer solution” in the present specification means 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. In addition to the usual buffer solution (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).

  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.

  As the buffer used in the liquid composition of the present invention, a phosphate-citrate buffer solution using a combination of disodium hydrogen phosphate and citric acid as a buffer, disodium hydrogen phosphate and sodium dihydrogen phosphate are used. 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.

  In addition, 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, the buffering action can be increased and the hydrolysis inhibiting effect can be further enhanced.

  In addition, 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 is used as a dispersion. Thus, hydrolysis of PLA and PGA nanoparticles in the dispersion can be effectively suppressed.

(Thickener)
Since 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. However, when the concentration of the buffering agent is increased, the water of hydration on the nanoparticle surface is dehydrated, and the nanoparticles tend to aggregate. As a result, nanoparticles settle and aggregate, making it difficult to maintain a stable dispersed state for a long period of time.

  Therefore, by adding a thickener to the dispersion, a liquid composition capable of maintaining the dispersed state of the nanoparticles for a predetermined period is obtained. As 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, One type or two or more types of water-soluble polymers selected from hydrophobic polyether urethanes may be mentioned. Representative examples of hydrophobic polyether urethanes include (PEG-240 / decyltetradeceth-20 / HDI) copolymers. Further, as a thickener other than the water-soluble polymer, 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-described thickener varies depending on the period for maintaining the dispersed state of the nanoparticles, the concentration and combination of the buffer, 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. Moreover, 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.

In addition, by mixing other bioactive substances in the dispersion, 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, altea 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, γ-oryzanol, α-lipo Acid, orotic acid and their components or derivatives, retinol acetate, riboflavin acetate, pyridoxine dioctanoate, L-ascorbic acid dipalmitate, L-ascorbic acid-2-sodium sulfate, L-ascorbic acid phosphate ester DL-tocopherol-L-ascorbic acid phosphoric diester dipotassium, pantothenyl ethyl ether, D-pantothenyl alcohol, acetyl pantothenyl ethyl ether, ergocalciferol, cholecalciferol, tocopherol acetate, tocopherol nicotinate, tocopherol succinate And water-soluble provitamins such as VC-PMG (water-soluble ascorbyl phosphate Mg), AA2G (ascorbic acid glucoside), panthenol (water-soluble vitamin B ₅ ), and L-cysteine. It is done.

  In addition, 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. 404, etc., 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 octanoin, neopentyl glycol dicaprylate, glyceryl tri (capryl / capric acid), (hydroxystearic acid / stearic acid / rosinic acid) dipentaerythrityl, hydrogenated isostearic acid castor oil, mineral oil, petrolatum, polybutene, etc. 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, ultraviolet absorbers, colorants, fragrances, preservatives, and the like can be blended within a range that does not hinder the effects of the present invention.

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. Hereinafter, 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. In the following test examples, in order to investigate the molecular weight retention effect (hydrolysis suppression effect) and dispersion stabilization effect of PLGA nanoparticles, 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.
[Preparation of PLGA nanoparticles]

Reference example

  Acetone, a good solvent, is 10 g of a lactic acid / glycolic acid copolymer (PLGA: PLGA 7520, average molecular weight 20,000, lactic acid / glycolic acid polymerization molar ratio = 75: 25, manufactured by Wako Pure Chemical Industries, Ltd.), which is a biocompatible polymer. It melt | dissolved in 200 mL, ethanol 100mL was added and mixed, and the solution was prepared. Moreover, 400 mL of 0.25 wt% polyvinyl alcohol (PVA EG05, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.), which is a poor solvent for PLGA, was prepared. While stirring this polyvinyl alcohol aqueous solution at 40 ° C. and 400 rpm, the previous PLGA solution was dropped at a constant rate to obtain a suspension of PLGA nanoparticles.

  After completion of the dropwise addition, acetone and ethanol were distilled off under reduced pressure. Next, 11.7 g of trehalose (manufactured by Hayashibara) and 2.1 g of ascorbyl magnesium phosphate (manufactured by Wako Pure Chemical Industries, Ltd.) are added to the resulting nanoparticle suspension, and the composite of PLGA nanoparticles is lyophilized. Particle powder was obtained.

When 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.
[Preparation of liquid composition]

  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.

  Using 79.6% by weight of water prepared by dissolving sodium dihydrogen phosphate and sodium hydroxide at a concentration of 200 mmol / L as a buffer and adjusting the pH to 9.0, the liquid composition was prepared in the same manner as in Example 1. Prepared.

  Using 79.6% by weight of water prepared by dissolving sodium dihydrogen phosphate and sodium hydroxide at a concentration of 200 mmol / L and adjusting the pH to 10.0 as a buffering agent, 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.

Comparative Example 1

  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.

Comparative Example 2

  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.

Comparative Example 3

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]

Test 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 (Horiba, Ltd., D-51). Regarding the molecular weight of PLGA, ethanol in the test solution was distilled off under reduced pressure, and then 2.0 mL of chloroform was added to the powder obtained by lyophilization to dissolve only PLGA. This solution was filtered with a 0.2 μm 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.

  As shown in FIG. 1 and FIG. 2, the test solutions of Examples 1 to 5 adjusted to have an initial pH value of 7.0 to 10.0 using a buffer (●, ○, Δ, In the data series of ▲ and □, the pH is almost the same as the initial setting value after storage at 20 ° C. for 12 months, and the molecular weight retention rate of PLGA after storage at 20 ° C. for 2 months 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. Further, the molecular weight retention after storage for 12 months was 96%, the molecular weight retention after storage for 18 months was 88%, and a high molecular weight retention was maintained even after 18 months. In addition, in the test solution of Example 5 (data series of □) having an initial pH value of 10.0, the pH after storage at 20 ° C. for 2 months is maintained at 10, and 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.

  On the other hand, in the test solution of Comparative Example 1 (x data series) adjusted so that the initial pH value was 6.3 using a buffering agent, it was stored at 20 ° C. for 8 months due to the buffering effect. The pH was maintained at 6.1, which was almost the same as the initial setting value, but because the test solution was acidic, PLGA hydrolysis progressed over time, and the molecular weight of PLGA after storage at 20 ° C. for 2 months The retention rate was 70% or less. Moreover, pH after storing for 12 months fell to 5.5. This is considered to be because the buffering effect was weakened by the increase in lactic acid and glycolic acid produced by hydrolysis.

  In addition, in the test solution of Comparative Example 2 (data series of *) in which no buffer was added, the pH after storage for 8 months at 20 ° C. with lactic acid and glycolic acid generated by hydrolysis of PLGA was 3.3. The molecular weight retention of PLGA after storage for 2 months at 20 ° C. was also 70% or less. Furthermore, as shown in FIG. 3, the molecular weight retention after storage at 20 ° C. for 8 months was 0%, and the PLGA nanoparticles in the test solution were completely hydrolyzed.

From the above results, it was confirmed that hydrolysis of PLGA nanoparticles was significantly suppressed over a long period of time in a buffer solution having a pH of 7.0 to 10.0.
[Dispersion stabilization effect of PLGA nanoparticles]

Test example 2

  The liquid compositions prepared in Examples 6 to 13 and Comparative Example 3 were stored as test solutions at 20 ° C. for 3 months, and then the pH of each test solution and each test were performed using the same apparatus and operation procedure as in Test Example 1. The molecular weight of PLGA in the liquid was measured. Moreover, the dispersion state of the PLGA nanoparticles in each test solution was visually observed. Table 2 summarizes the initial settings of the composition, storage temperature, and pH of each test solution.

  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. In the case where a small amount of particles are settling, Δ is marked, and in the case where both the aggregation and settling of particles are recognized, x is marked. The observation results are shown in Table 3 together with the pH and molecular weight retention.

  As shown in Table 3, in the test solutions of Examples 6 to 13 and Comparative Example 3, the pH after storage for 3 months at 20 ° C. is maintained at 7.5, which is the same as the initial setting value, and PLGA. The molecular weight retention of was 100%.

  In Examples 6 to 8 where sodium hyaluronate was used alone as a 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%. In Examples 10 and 11 in which the percentage was less than or equal to%, the precipitation of PLGA nanoparticles was gradually observed.

  Furthermore, in Examples 12 and 13 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. In 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.

  On the other hand, in Comparative Example 3 where no thickener was added, both aggregation and sedimentation of PLGA nanoparticles were observed. From the above, the dispersion state of PLGA nanoparticles in the buffer solution is effectively maintained by adding 0.4% by weight or more of sodium hyaluronate and 0.4% by weight or more of xanthan gum as thickeners. It was confirmed that the addition amount can be reduced by using sodium hyaluronate and xanthan gum together.

  According to the present invention, 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. In addition, by adding 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.

In order to achieve the above object, 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. A compatible nanoparticle , a buffer containing phosphoric acid having a pH of 7 to 10, and xanthan gum, hyaluronic acid, sodium hyaluronate, acetylated sodium hyaluronate, carboxyvinyl polymer, carbomer, alginic acid, hydroxypropyl cellulose as a thickener, And at least one selected from the group consisting of carrageenan, locust bean gum, guar gum, and hydrophobic polyether urethane .

Further, the present invention is characterized in that 0.01% by weight or more of sodium hyaluronate is added as the thickener in the liquid composition having the above structure.

Moreover, the present invention is characterized in that 0.05% by weight or more of xanthan gum is added as the thickener in the liquid composition having the above-described configuration.

Further, the present invention is characterized in that in the liquid composition having the above-described configuration , both sodium hyaluronate and xanthan gum are added as the thickener .

The present invention is also characterized in that the total amount of sodium hyaluronate and xanthan gum added is 0.1% by weight or more in the liquid composition having the above structure.

According to the first configuration of the present invention, 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. In addition, by using a buffer solution containing phosphoric acid having a pH of 7 or more and 10 or less as the buffer solution, it is possible to suppress the decrease in pH and the accompanying hydrolysis of the nanoparticles due to the buffer action of the buffer solution. Moreover, since pH is suppressed to 10 or less, it becomes a liquid composition with few bad influences with respect to a human body. Moreover, from the group consisting of xanthan gum, hyaluronic acid, sodium hyaluronate, acetylated sodium hyaluronate, carboxyvinyl polymer, carbomer, alginic acid, hydroxypropyl cellulose, carrageenan, locust bean gum, guar gum, hydrophobic polyether urethane as a thickener By using at least one selected, it is possible to easily and effectively suppress the occurrence of aggregation and sedimentation of the nanoparticles by maintaining a stable dispersion state of the nanoparticles for a predetermined period, and to adversely affect the living body. And a highly safe liquid composition.

Further, according to the third configuration of the present invention, in the liquid composition having the first or second configuration , 0.01% by weight or more of sodium hyaluronate is added as a thickener, thereby providing a buffer solution. It is possible to more effectively suppress the aggregation and sedimentation of nanoparticles inside .

Moreover, according to the 4th structure of this invention, in the liquid composition of the said 1st or 2nd structure, by adding 0.05 weight% or more of xanthan gum as a thickener , in a buffer solution Ru can be more effectively suppress the occurrence of aggregation or precipitation of the nanoparticles.

Further, according to the fifth configuration of the present invention, in the liquid composition of the first configuration, by adding both sodium hyaluronate and xanthan gum as thickeners , the nanoparticles in the buffer solution Ru can be very effectively suppress the occurrence of aggregation and sedimentation.

Further, according to the sixth configuration of the present invention, in the liquid composition of the fifth configuration, the total addition amount of sodium hyaluronate and xanthan gum is 0.1% by weight or more, so that Sodium hyaluronate and xanthan gum to be used can be added in an amount necessary to effectively suppress aggregation and sedimentation of nanoparticles.

According to the seventh configuration of the present invention, in the liquid composition having any one of the first to sixth configurations, the average particle diameter of the biocompatible nanoparticles is set to 10 nm or more and 300 nm or less. When used as a preparation or hair restorer, a liquid composition is obtained in which the nanoparticles penetrate from the pores and gaps between the skin cells other than the pores to the deep part of the skin.

According to the eighth configuration of the present invention, in the liquid composition having any one of the first to seventh configurations, polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer forming nanoparticles The weight average molecular weight of 5,000 to 100,000 can be stored for a predetermined period in a state in which the physiologically active substance is supported on the nanoparticles, and when used, the physiology in units of several hours to several tens of hours is possible. A liquid composition capable of sustained release of the active substance is obtained.

In order to achieve the above object, 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. A compatible nanoparticle, a buffer containing phosphoric acid having a pH of 7 or more and 10 or less, and one of xanthan gum and sodium hyaluronate as a thickener, and the addition amount of xanthan gum is 0.05% by weight or more, sodium hyaluronate Is a liquid composition having an addition amount of 0.1% by weight or more .

Further, the present invention is characterized in that the amount of xanthan gum or sodium hyaluronate added in the above-described liquid composition is 0.4% by weight or more .

The present invention also provides biocompatible nanoparticles in which a bioactive substance is supported on at least one of the inside or the surface of nanoparticles formed of either polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer, It is a liquid composition containing both a buffer solution containing phosphoric acid having a pH of 7 or more and 10 or less and sodium hyaluronate and xanthan gum as thickeners, and the total amount of sodium hyaluronate and xanthan gum added is 0.1% by weight or more. .

Further, the present invention is characterized in that, in the liquid composition having the above-described configuration, the amount of sodium hyaluronate added is 0.01% by weight or more and the amount of xanthan gum added is 0.1% by weight or more .

Further, 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 .

According to the first configuration of the present invention, 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. In addition, by using a buffer solution containing phosphoric acid having a pH of 7 or more and 10 or less as the buffer solution, it is possible to suppress the decrease in pH and the accompanying hydrolysis of the nanoparticles due to the buffer action of the buffer solution. Moreover, since pH is suppressed to 10 or less, it becomes a liquid composition with few bad influences with respect to a human body. In addition, by containing 0.05% by weight or more of xanthan gum or 0.1% by weight or more of sodium hyaluronate as a thickener, a stable dispersion state of the nanoparticles is maintained for a predetermined period of time, and aggregation or sedimentation of the nanoparticles is prevented. Generation | occurrence | production can be suppressed easily and effectively, and there is no bad influence on a biological body, and it becomes a highly safe liquid composition.

Further, according to the second configuration of the present invention, in the liquid composition of the first configuration, the addition amount of xanthan gum or sodium hyaluronate is 0.4% by weight or more, so that the aggregation and sedimentation of the nanoparticles are performed. Can be more effectively suppressed .

Further, according to the third configuration of the present invention, lactic acid or glycolic acid accompanying hydrolysis of biocompatible nanoparticles formed of either polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer is used. A decrease in pH of the liquid composition resulting from the generation 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. In addition, by using a buffer solution containing phosphoric acid having a pH of 7 or more and 10 or less as the buffer solution, it is possible to suppress the decrease in pH and the accompanying hydrolysis of the nanoparticles due to the buffer action of the buffer solution. Moreover, since pH is suppressed to 10 or less, it becomes a liquid composition with few bad influences with respect to a human body. In addition, both sodium hyaluronate and xanthan gum are included as thickeners, and the total amount of sodium hyaluronate and xanthan gum added is 0.1% by weight or more to maintain a stable dispersion state of nanoparticles for a predetermined period. Thus, the aggregation of the nanoparticles and the occurrence of sedimentation can be easily and effectively suppressed, and the liquid composition is highly safe without adversely affecting the living body.

According to the fourth configuration of the present invention, in the liquid composition of the third configuration, the amount of sodium hyaluronate added is 0.01 wt% or more, and the amount of xanthan gum added is 0.1 wt% or more. By doing so, the stable dispersion state of the nanoparticles can be maintained for a predetermined period, and the occurrence of aggregation and sedimentation of the nanoparticles can be further effectively suppressed.

Further, according to the fifth structure of the present invention, in the first to fourth liquid composition of any one of the, as a buffer solution, phosphate pH7 to 8 - The use of citric acid buffer In addition, the buffering action of the buffer solution can suppress the decrease in pH and the accompanying hydrolysis of the nanoparticles. In addition, 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. Furthermore, since the pH of the liquid composition is suppressed to 8 or less, the safety to the human body is further improved.

According to the sixth configuration of the present invention, in the liquid composition having any one of the first to fifth configurations, the average particle size of the biocompatible nanoparticles is set to 10 nm or more and 300 nm or less. When used as a preparation or hair restorer, a liquid composition is obtained in which the nanoparticles penetrate from the pores and gaps between the skin cells other than the pores to the deep part of the skin.

According to the seventh configuration of the present invention, in the liquid composition having any one of the first to sixth configurations, polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer forming nanoparticles The weight average molecular weight of 5,000 to 100,000 can be stored for a predetermined period in a state in which the physiologically active substance is supported on the nanoparticles, and when used, the physiology in units of several hours to several tens of hours is possible. A liquid composition capable of sustained release of the active substance is obtained.

Moreover, according to the 8th structure of this invention, by using the liquid composition of the said any one of the said 1st thru | or 7 structure as cosmetics, or setting it as the cosmetics by which the said liquid composition was mix | blended. In addition, by dispersing the nanoparticle powder in the liquid in advance, a one-pack type cosmetic that is excellent in usability and can be stably stored for a certain period of time is provided.

According to the ninth configuration of the present invention, the liquid composition having any one of the first to seventh configurations is used as a hair cosmetic, or a hair cosmetic containing the liquid composition. Thus, 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.

Moreover, according to the 10th structure of this invention, by using the liquid composition of the said any one of the said 1st thru | or 7 structure as a hair restorer, or setting it as the hair restorer with which the said liquid composition was mix | blended. In addition, by dispersing the nanoparticle powder in the liquid in advance, a one-part hair restoration agent that is excellent in usability and can be stably stored for a certain period of time is provided.

Claims (11)

  A biocompatible nanoparticle carrying a bioactive substance inside or on the surface of a nanoparticle formed of any of polylactic acid, polyglycolic acid, or lactic acid / glycolic acid copolymer, and a pH of 7-10 A liquid composition comprising a buffer solution.   The liquid composition according to claim 1, wherein the buffer solution is a phosphate-citrate buffer solution having a pH of 7 or more and 8 or less.   The liquid composition according to claim 1, wherein the buffer solution is a phosphate buffer solution having a pH of 7 or more and 10 or less.   The liquid composition according to claim 1, further comprising a thickener added to the buffer solution.   The liquid composition according to claim 4, wherein the thickener is a water-soluble polymer.   The water-soluble polymer is a group consisting of xanthan gum, hyaluronic acid, sodium hyaluronate, acetylated sodium hyaluronate, carboxyvinyl polymer, carbomer, alginic acid, hydroxypropylcellulose, carrageenan, locust bean gum, guar gum, hydrophobic polyether urethane The liquid composition according to claim 5, wherein the liquid composition is at least one selected from the group.   The liquid composition according to claim 1, wherein the biocompatible nanoparticles have an average particle size of 10 nm to 300 nm.   2. The liquid composition according to claim 1, wherein 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.   A cosmetic comprising the liquid composition according to any one of claims 1 to 8, or a mixture of the liquid composition.   A cosmetic for hair comprising the liquid composition according to any one of claims 1 to 8, or a mixture of the liquid composition.   A hair restorer comprising the liquid composition according to any one of claims 1 to 8, or a blend of the liquid composition.

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