JP2010150151A - Hyaluronic acid-supported nanoparticles and hyaluronic acid-containing composite particles and cosmetic using them - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide bio-compatible hyaluronic acid-supported nanoparticles and hyaluronic acid-containing composite particles, having a hyaluronic acid infiltration effect into skins and a hyaluronic acid sustained release effect, and to provide a cosmetic using them and high in a moisture-retaining effect. <P>SOLUTION: The bio-compatible hyaluronic acid-supported nanoparticles 1 involve the hyaluronic acid 4a in nanoparticles formed from a bio-compatible polymer 2. The surfaces of the nanoparticles are further coated with a cationic polymer 5, and the hyaluronic acid 4b is electrostatically supported. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a hyaluronic acid-carrying nanoparticle in which hyaluronic acid is carried on at least one of the inside or the surface of a biocompatible nanoparticle, a hyaluronic acid-containing composite particle obtained by compounding this, and a cosmetic using the same. It is.

  Hyaluronic acid is a heteropolysaccharide in which D-glucuronic acid and N-acetylglucosamine are alternately bound. This hyaluronic acid has a function of enhancing the skin's moisturizing power and improving the elasticity of the skin, or a function as a lubricant for articular cartilage, but is known to decrease with age. Therefore, development of various cosmetics and pharmaceuticals for suppressing the decrease of hyaluronic acid due to aging and supplementing from outside the body has been actively carried out.

  However, hyaluronic acid is degraded by digestive enzymes (amylases) in the body, so oral BA (bioavailability) is remarkably low, and since it is a hydrophilic polymer substance, it is hardly absorbed from the skin. Not expected. Therefore, the present condition is that the formulation which can fully suppress the reduction | decrease of the hyaluronic acid by aging is hardly practically used.

  In recent years, low-molecular-weight hyaluronic acid having a molecular weight reduced to tens of thousands has been developed in order to enhance hyaluronic acid absorption from the skin. However, since the molecular weight of hyaluronic acid correlates with the water retention capacity in the body, this method is not expected to provide a sufficient water retention effect, and development of a method for effectively delivering high molecular weight hyaluronic acid into the skin is not possible. It was sought after.

  Therefore, there is a method of supplying hyaluronic acid to a target site by using a technique for effectively administering a drug, so-called drug delivery system (hereinafter referred to as DDS) so that the drug is not absorbed and decomposed until reaching the affected part. Conceivable. 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-containing nanoparticles deliver the drug stably and reliably to the target affected area, and control the release rate (sustained release) of the drug according to the type of polymer and the elapsed time after administration. The drug can be released at the time of reaching the point, and exhibits high effects not only for use as an injection or oral preparation, but also for external preparations that have conventionally been difficult to penetrate deeply into the skin.

As a DDS using hyaluronic acid, for example, Patent Document 1 discloses a controlled release system for applying an active ingredient locally to hair or skin using solid spheres (fine particles) containing an active ingredient and a cationic control ingredient. As disclosed, hyaluronic acid is described as an example of an active ingredient encapsulated in nanospheres. Patent Documents 2 to 4 describe hyaluronic acid as lactic acid. A method of using a polymer bonded with a glycolic acid copolymer as a substrate for nanoparticles is disclosed. Furthermore, Patent Document 5 discloses a method using hyaluronic acid itself as a base material for nanoparticles.
JP 2006-510580 A Japanese translation of PCT publication No. 2004-521152 No. 2005-23906 No. 2006-95668 JP 2005-59991 A

  In order to express the moisturizing effect of hyaluronic acid more reliably, in addition to the reliable arrival of hyaluronic acid to the site of action, it releases hyaluronic acid over a predetermined period immediately after arrival, so-called immediate effect and sustained release It is desirable to have However, the above-mentioned Patent Document 1 describes an example in which nanospheres for hair and nanospheres for clothes are introduced into hair care products and detergents, and the nanospheres are burst by natural drying or heat of blow or iron to release internal fragrances. However, there was no description of the penetration of nanospheres into the skin and the release of hyaluronic acid from the nanospheres. In addition, the methods of Patent Documents 2 to 5 use hyaluronic acid as a nanoparticle substrate, and are not used as a physiologically active component, and do not describe anything about the function and effect of hyaluronic acid as a moisturizing component. Absent.

  In view of the above problems, the present invention provides biocompatible hyaluronic acid-carrying nanoparticles and hyaluronic acid-containing composite particles that have both hyaluronic acid penetration effect and sustained release effect into the skin, and moisturizing effect using them. The purpose is to provide high cosmetics.

  In order to achieve the above object, the present invention provides a hyaluronic acid having hyaluronic acid supported on at least one of the inside and the surface of nanoparticles formed of any of polylactic acid, polyglycolic acid, and lactic acid / glycolic acid copolymer. Supported nanoparticles.

  Further, the present invention is characterized in that the hyaluronic acid-carrying nanoparticles having the above-described configuration have an average molecular weight of the hyaluronic acid of 1,000,000 to 5,000,000.

  Further, the present invention is characterized in that the hyaluronic acid-carrying nanoparticles having the above-described configuration have an average molecular weight of the hyaluronic acid of 1,000,000 to 2,000,000.

  The present invention is also characterized in that in the hyaluronic acid-carrying nanoparticles having the above structure, the nanoparticles are formed of a lactic acid / glycolic acid copolymer.

  The present invention is also characterized in that in the hyaluronic acid-carrying nanoparticles having the above structure, the nanoparticles are coated with a cationic polymer.

  In the hyaluronic acid-carrying nanoparticles having the above structure, the present invention is characterized in that the cationic polymer is chitosan.

  Further, the present invention is a hyaluronic acid-containing composite particle obtained by combining the hyaluronic acid-carrying nanoparticles having the above structure with a binder.

  Further, the present invention is characterized in that in the hyaluronic acid-containing composite particle having the above-described configuration, another physiologically active component is encapsulated in the binder.

  The present invention is also a cosmetic comprising the hyaluronic acid-carrying nanoparticles having the above structure.

  The present invention is also a cosmetic comprising the hyaluronic acid-containing composite particles having the above-described structure.

  Further, the present invention is characterized in that the hyaluronic acid-carrying nanoparticles or the hyaluronic acid-containing composite particles are dispersed in a liquid in the cosmetic having the above-described configuration.

  Moreover, the present invention is characterized in that the liquid is an emulsion in the cosmetic having the above-described configuration.

  Further, the present invention is characterized in that in the cosmetic having the above-described configuration, another physiologically active ingredient is blended in the liquid.

  According to the first configuration of the present invention, hyaluronic acid is supported on at least one of the inside or the surface of nanoparticles formed of any one of polylactic acid, polyglycolic acid, and lactic acid / glycolic acid copolymer. Thus, highly safe hyaluronic acid-carrying nanoparticles with an increased total hyaluronic acid content without increasing the diameter of the particles are provided. In addition, when hyaluronic acid is supported on both the inside and the surface of the nanoparticle, the hyaluronic acid is diffused from the nanoparticle surface and released from the inside of the nanoparticle for a certain period immediately after administration. Hyaluronic acid-carrying nanoparticles capable of releasing

  In addition, according to the second configuration of the present invention, in the hyaluronic acid-carrying nanoparticles having the first configuration, the average molecular weight of hyaluronic acid is set to 1,000,000 to 5,000,000, so that the nanoparticles The excluded volume effect of hyaluronic acid in the preparation process can be suppressed. As a result, it is possible to prepare nanoparticles encapsulating hyaluronic acid having an average particle size of several hundred nm or less, high skin permeability, and sufficient water retention ability.

  According to the third configuration of the present invention, in the hyaluronic acid-carrying nanoparticles having the second configuration, the average molecular weight of hyaluronic acid is 1,000,000 to 2,000,000. It becomes possible to prepare nanoparticles encapsulating hyaluronic acid having a diameter of 200 nm or less and excellent in skin permeability.

  Further, according to the fourth configuration of the present invention, in the hyaluronic acid-carrying nanoparticles of any one of the first to third configurations, by forming nanoparticles using a lactic acid / glycolic acid copolymer, It is possible to provide hyaluronic acid-carrying nanoparticles that have low irritation and toxicity to the living body, are excellent in in vivo degradability, and can be stored for a long period of time. Further, by selecting the molecular weight and the contents of lactic acid and glycolic acid in the copolymer, the skin permeability of the prepared nanoparticles and the release rate of hyaluronic acid can be controlled.

  According to the fifth configuration of the present invention, in the hyaluronic acid-carrying nanoparticles having any one of the first to fourth configurations, the surface of the nanoparticles is coated with a cationic polymer, so that the hyaluronic acid is nano-sized. The particles can be electrostatically supported on the surface of the particles. Moreover, the cationic polymer which coat | covers a nanoparticle interacts with the hyaluronic acid which exists in the emulsion droplet surface, can suppress the leakage of hyaluronic acid in a poor solvent, and can also raise the encapsulation rate to a nanoparticle.

  In addition, according to the sixth configuration of the present invention, hyaluronic acid having high safety and no adverse effects on the living body by using chitosan as the cationic polymer in the hyaluronic acid-carrying nanoparticles of the fifth configuration. It becomes a supported nanoparticle.

  According to the seventh configuration of the present invention, the hyaluronic acid-carrying nanoparticles of any one of the first to sixth configurations are combined with a binder to form hyaluronic acid-containing composite particles. Is easy to handle and becomes redispersible composite particles when used. Also, the dispersibility and heat resistance of the composite nanoparticles are improved.

  Further, according to the eighth configuration of the present invention, in the hyaluronic acid-containing composite particle of the seventh configuration, the hyaluronic acid released from the nanoparticles by encapsulating another physiologically active component in the binder is Separately, a physiologically active ingredient that dissolves from the surface of the composite particle immediately after permeation of the skin can act immediately.

  Further, according to the ninth configuration of the present invention, by blending the hyaluronic acid-carrying nanoparticles having any one of the first to sixth configurations, the hyaluronic acid-carrying nanoparticles are penetrated to the deep part of the skin, Alternatively, a cosmetic that can effectively exhibit a moisturizing effect by releasing hyaluronic acid supported on the surface is provided.

  Further, according to the tenth configuration of the present invention, by blending the hyaluronic acid-containing composite particles of the seventh or eighth configuration, the hyaluronic acid-carrying nanoparticles are penetrated to the deep part of the skin, and the inside or the surface of the particles There is provided a cosmetic that can effectively release a moisturizing effect by releasing the supported hyaluronic acid. In addition, since composite particles having excellent handleability, dispersibility, and heat resistance are used, it is advantageous in terms of cosmetics manufacturability and user usability.

  Further, according to the eleventh configuration of the present invention, in the cosmetic of the ninth or tenth configuration, hyaluronic acid-carrying nanoparticles are dispersed by dispersing hyaluronic acid-carrying nanoparticles or hyaluronic acid-containing composite particles in a liquid. The moisturizing effect can be effectively expressed. In addition, by storing the dispersion and particle powder in separate containers and mixing and using a predetermined amount of the dispersion and powder immediately before use, long-term storage is possible and excellent usability Become a cosmetic.

  According to the twelfth configuration of the present invention, in the cosmetic composition of the eleventh configuration, the skin penetration effect of the hyaluronic acid-carrying nanoparticles can be further enhanced by using the liquid as an emulsion. In the present specification, the emulsion means a liquid in which a water-soluble component and an oil-soluble component are blended. In the emulsion, the oil-soluble component is present in an emulsified state with a surfactant or the like.

  Further, according to the thirteenth configuration of the present invention, in the cosmetic composition of the eleventh or twelfth configuration, by blending other physiologically active ingredients into the liquid, along with the penetration of nanoparticles into the deep skin, Since the physiologically active ingredient in the liquid is also delivered to the deep skin along with the nanoparticles, more physiologically active ingredient can be supplied to the deep skin.

  The hyaluronic acid-carrying nanoparticles of the present invention are those in which hyaluronic acid having a moisturizing effect is encapsulated in nanoparticles formed of a biocompatible polymer or supported on the surface of the nanoparticles. This nanoparticle penetrates from the pores and skin surface to the deep part of the skin, so that the hyaluronic acid or its derivative as a moisturizing component reaches the deep part of the skin and gradually releases the hyaluronic acid from the nanoparticle in the deep part of the skin. Therefore, it can be suitably used as a raw material for cosmetics for the purpose of moisturizing the skin.

  FIG. 1 is a schematic diagram showing the structure of hyaluronic acid-carrying nanoparticles according to the first embodiment of the present invention. The hyaluronic acid-carrying nanoparticles 1 are formed by aggregation of a large number of biocompatible polymers 2, and the particle surfaces are coated with polyvinyl alcohol 3. Further, hyaluronic acid 4a is encapsulated in the matrix of the biocompatible polymer 2. In the following description, hyaluronic acid encapsulated in nanoparticles is referred to as hyaluronic acid 4a.

  The biocompatible polymer used in the present invention is desirably a biodegradable polymer that has low irritation and toxicity to the living body and is decomposed and metabolized after administration. Further, it is preferably a particle that continuously and gradually releases the encapsulated hyaluronic acid. 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 average molecular weight of PLGA is preferably in the range of 5,000 to 200,000, considering the ease of nanoparticle preparation, 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 of lactic acid and glycolic acid may be 1:99 to 99: 1, but glycolic acid is preferably 1/3 of lactic acid 1.

  When encapsulating water-soluble hyaluronic acid, it is preferable to modify the surface of PLGA with polyethylene glycol (PEG) in order to increase the amount of encapsulation. Other biocompatible polymers include polylactic acid (PLA), polyglycolic acid (PGA), polyaspartic acid, and the like. In addition, aspartic acid / lactic acid copolymer (PAL) and aspartic acid / lactic acid / glycolic acid copolymer (PALG), which are these copolymers, may be used, and charged groups such as amino acids or functionalizable groups may be used. You may have.

  Next, hyaluronic acid supported on biocompatible nanoparticles will be described. Hyaluronic acid is a kind of glycosaminoglycan (mucopolysaccharide) and has a structure in which disaccharide units of N-acetylglucosamine and glucuronic acid are linked. Hyaluronic acid has the effect of gelling the moisture in the skin and binding it to elastin that supports the collagenous tissue, which is believed to prevent skin dryness. Therefore, by supplying hyaluronic acid to the inside of the skin, it is possible to increase the moisture retention of the skin and maintain firmness and moisture.

  In addition, the higher the molecular weight of hyaluronic acid, the better the water retention capacity. However, when hyaluronic acid having an extremely large average molecular weight of 6 to 7 million is used, significant aggregation of particles occurs in the nanoparticle preparation process described later. . This is presumed that hyaluronic acid is a group of molecules having different chain lengths, and high molecular weight (long chain length) hyaluronic acid that was not encapsulated in nanoparticles induced aggregation of the particles.

  Furthermore, a polymer occupying a large volume in a solution exhibits steric hindrance in the solution due to its molecular structure and molecular weight, and forms a space in which other molecules cannot enter (excluded volume effect). Since this effect is thought to increase as the number of branches and molecular weight in the three-dimensional structure of the polymer increases, it is possible to encapsulate hyaluronic acid having a large average molecular weight in nanoparticles formed of a biocompatible polymer such as PLGA. It becomes difficult.

  Therefore, by using hyaluronic acid having an average molecular weight of about 1,000,000 to 5,000,000, it becomes possible to suppress the excluded volume effect of hyaluronic acid in the preparation process of the nanoparticles to a level that can be ignored. It is possible to prepare hyaluronic acid-carrying nanoparticles having high permeability and sufficient water retention ability. In particular, when hyaluronic acid having an average molecular weight of 1,000,000 to 2,000,000 is used, it is more preferable because hyaluronic acid-carrying nanoparticles having an average particle diameter of 200 nm or less and extremely excellent skin permeability can be prepared.

  Next, a method for producing hyaluronic acid-carrying nanoparticles will be described. The method for producing hyaluronic acid-carrying nanoparticles is not particularly limited as long as hyaluronic acid and biocompatible polymer can be processed 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 hyaluronic acid is used as a drug and lactic acid / glycolic acid copolymer (PLGA) is used as a biocompatible polymer will be described in detail.

  First, after dissolving PLGA in a good solvent, a hyaluronic acid solution is added and mixed in the good solvent so that PLGA does not precipitate. When the mixed solution containing PLGA and hyaluronic acid is dropped into a poor solvent while stirring, the good solvent (organic solvent) in the mixed solution 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 hyaluronic acid in the emulsion droplets is lowered, and finally hyaluronic acid. PLGA nanoparticles of crystal particles encapsulating acid 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.

  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%.

  The hyaluronic acid-carrying 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 it penetrates deep into the skin. In order to enhance the effect, the average particle diameter 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 200 nm, the nanoparticles penetrate into the epidermis and dermis through the cell gap route (skin keratinocyte gap), and hyaluronic acid can be effectively delivered to the deep part of the skin. On the other hand, the smaller the particle diameter of the nanoparticles, the lower the encapsulation rate of hyaluronic acid, so the average particle diameter is preferably 30 nm or more.

  The amount of hyaluronic acid encapsulated in the nanoparticles can be adjusted by adjusting the amount of hyaluronic acid added during nanoparticle formation, the type and molecular weight of the biocompatible polymer that forms the nanoparticles, and the like. As the amount of hyaluronic acid mixed in a good solvent at the time of nanoparticle formation, the weight ratio with respect 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 hyaluronic acid 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.

  In addition, since hyaluronic acid encapsulated in nanoparticles is an anionic drug that exists as an anionic molecule in an aqueous solution, by adding a cationic polymer to a poor solvent in the nanoparticle formation step, The encapsulation rate of hyaluronic acid can be increased.

  When trying to produce nanoparticles containing an anionic drug using the conventional spherical crystallization method, the water-soluble anionic drug dispersed and mixed in a good solvent leaks and dissolves in the poor solvent, resulting in nanoparticles. Since only the biocompatible polymer that forms the slag is deposited, the anionic drug was 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 drug present on the emulsion droplet surface, resulting in poor quality. It is considered that leakage of an anionic drug into the 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, charging the surface of the nanoparticle so as to have a positive zeta potential using a cationic polymer as in the present invention increases the adhesion of the nanoparticle to the negatively charged cell wall, and the anionic drug cell. It is also preferable from the viewpoint of improving the inward transferability.

  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 in which a plurality of cationic groups are bonded 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 to a poor solvent, hyaluronic acid-carrying nanoparticles with high safety and no adverse effects on the living body can be produced.

  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 the nanoparticles are collected before use, and can return to the nanoparticles by touching moisture during use and restore characteristics such as high reactivity.

  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 hyaluronic acid on the surface of the nanoparticles will be described. Here, a method of electrostatically supporting hyaluronic acid on the nanoparticle surface having a positive zeta potential will be described as an example.

  In order to electrostatically support hyaluronic acid on the nanoparticle surface, it is necessary to charge the nanoparticle surface so that it has 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, by adding hyaluronic acid to the nanoparticle suspension before freeze-drying when the nanoparticles are combined by freeze-drying, the hyaluronic acid that has become a negatively charged anion molecule is caused by electrostatic interaction. A predetermined amount is supported (externally attached) on the nanoparticle surface.

  FIG. 2 is a schematic view showing the structure of hyaluronic acid-carrying nanoparticles according to the second embodiment in which hyaluronic acid is electrostatically carried on the particle surface. The surface of the nanoparticles 1 is coated with polyvinyl alcohol 3, and the outside thereof is coated with a cationic polymer 5. The cationic polymer 5 has a positive zeta potential. Hyaluronic acid 4 is encapsulated in nanoparticles 1 (4a) and is also electrostatically supported on the particle surface. In FIG. 2, hyaluronic acid supported on the nanoparticle surface is 4b (the same applies to FIG. 3).

  In addition, since the zeta potential becomes a larger positive value by using a more cationic polymer among the cationic polymers, it becomes possible to carry more hyaluronic acid 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 hyaluronic acid supported on the nanoparticle surface can be changed by adjusting the type and amount of the cationic polymer and the amount of hyaluronic acid added to the nanoparticle suspension before lyophilization. The amount of hyaluronic acid 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 hyaluronic acid is too low and the loading 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 surplus hyaluronic acid that is not supported on the nanoparticle surface is generated.

  In this way, by combining the inclusion of hyaluronic acid in the nanoparticles and electrostatic loading on the surface of the nanoparticles, first the hyaluronic acid supported on the surface of the nanoparticles and then the hyaluronic acid encapsulated in the nanoparticles are released in this order. Is done. Accordingly, the hyaluronic acid release rate can be controlled in two stages.

  If surplus polyvinyl alcohol or chitosan remains in the nanoparticle suspension before lyophilization, polyvinyl alcohol or chitosan and hyaluronic acid are adsorbed, and hyaluronic acid is efficiently supported on the nanoparticle surface. become unable. Therefore, it is preferable to provide a step (removal step) for removing polyvinyl alcohol and chitosan by centrifugation before adding the hyaluronic acid solution 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.

  In addition, although the case where hyaluronic acid is further supported on the surface of nanoparticles encapsulating hyaluronic acid was described here, hyaluronic acid was not added to a good solvent in the nanoparticle formation process, and only the biocompatible polymer was aggregated. Hyaluronic acid may be supported on the surface of the nanoparticles formed by the above method.

  Next, composite particles obtained by combining hyaluronic acid-carrying nanoparticles 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 ingredient in the binder, other physiologically active ingredients can be supported on the composite particles containing nanoparticles. FIG. 3 is a schematic diagram showing the structure of hyaluronic acid-containing composite particles in which hyaluronic acid-carrying nanoparticles are combined with a binder. The composite particle 6 is a composite of the nanoparticle 1 with a binder 7, and a physiologically active component 8 is encapsulated in the binder 7.

  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. Further, since hyaluronic acid encapsulated in the nanoparticles is water-soluble, once the hyaluronic acid encapsulated therein leaks to the nanoparticle surface, it is re-dissolved in the water existing around it. When this water is removed by lyophilization or the like, the amount of hyaluronic acid is reduced by that amount, resulting in a variation in content. 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 hyaluronic acid 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.

  In addition, by encapsulating other physiologically active ingredients in the binder, the physiologically active ingredients that are dissolved from the surface of the composite particles immediately after skin permeation can act immediately, in addition to the hyaluronic acid released from the nanoparticles. it can. By adopting such a configuration, the composite particles can be given immediate effect.

The physiologically active ingredients encapsulated in the binder include vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin F, vitamin K, vitamin P, vitamin U, carnitine, ferulic acid, γ-oryzanol, α- Lipoic 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 diester dipotassium, pantothenyl ethyl ether, D-pantothenyl alcohol, acetyl pantothenyl ethyl ether, ergocalciferol, cholecalciferol, tocopherol acetate, tocopherol nicotinate Rolls, vitamins such as tocopherol succinate or vitamin derivatives, or water-soluble compounds such as VC-PMG (water-soluble ascorbyl phosphate Mg), AA2G (ascorbic acid glucoside), panthenol (water-soluble vitamin B ₅ ), L-cysteine, etc. Provitamins are listed.

  An effective moisturizing effect can be obtained by using the hyaluronic acid-supported nanoparticles or hyaluronic acid-containing composite particles produced as described above as a raw material for cosmetics. Examples of the dosage form of the cosmetic of the present invention include skin care cosmetics such as milky lotion, lotion and skin cream. The blending ratio of the nanoparticles or composite particles in the cosmetic can be arbitrarily set according to the required moisturizing effect, the dosage form of the cosmetic, and the like.

  In addition, PLGA will be hydrolyzed when it touches moisture for a long time, and the transport performance of nanoparticles will be lost. Therefore, when used as such a cosmetic, the nanoparticle powder and a liquid for dispersing the nanoparticle powder (hereinafter referred to as a dispersion) are filled and stored in separate containers, and the nanoparticle powder and the liquid just before use are stored. It is preferable that a predetermined amount of the dispersion is mixed and used as a 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.

  When the cosmetic thus obtained is applied to the skin, the nanoparticles efficiently penetrate from the pores and 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, hyaluronic acid supported on the nanoparticles is gradually released in the skin over a predetermined period immediately after administration.

  In addition, by blending other bioactive ingredients in the dispersion or emulsion, the bioactive ingredients in the lotion adsorbed on the nanoparticle surface are also absorbed deep into the skin as the nanoparticles penetrate into the skin. Since it is delivered, more physiologically active ingredients can be supplied deep into the skin. The bioactive ingredients to be blended are the same as the bioactive ingredients encapsulated in the binder, brown algae extract, burdock extract, altea root extract, serine, betaine, sorbitol, trehalose, glycine, alanine, proline, threonine, Moisturizing ingredients such as arginine, lysine, glutamic acid, maltodextrin, squalane, inositol, biotin, yeast extract and the like can be mentioned.

  In addition, the cosmetics of the present invention include 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 , Yellow 205, Yellow 401, Blue 1, Blue 204, Blue 404, etc., metal soap such as zinc stearate, magnesium stearate, zinc palmitate, dimethicone, methicone, cyclomethicone, polyether Silicon compounds such as modified silicon and fluorine-modified silicon, trio Minerals such as tanoin, neopentyl glycol dicaprylate, tri (capryl / capric acid) glyceryl, (hydroxystearic acid / stearic acid / rosinic acid) dipentaerythrityl, isostearic acid hydrogenated 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 and action effect of the hyaluronic acid-carrying nanoparticles of the present invention will be described more specifically with reference to Examples, Comparative Examples, and Test Examples.
[Preparation of hyaluronic acid-supported PLGA nanoparticles]

  10 g of a 2 wt% aqueous solution of chitosan (manufactured by NOF Corporation) was mixed with 400 mL of an aqueous solution of 4 wt% polyvinyl alcohol (PVA EG05, manufactured by Nippon Synthetic Chemical Industry) to make a poor solvent. Also, 2 g of lactic acid / glycolic acid copolymer (average molecular weight 20,000, polymerization ratio 75:25, PLGA7520 manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in a mixture of 215 mL of acetone and 50 mL of ethanol, and 0.5 wt. 30 mL of an aqueous solution of% hyaluronic acid (average molecular weight 2,000,000, bio hyaluronic acid manufactured by Maruha Nichiro) was added and mixed uniformly to obtain a good solvent.

  The good solvent was added dropwise at a constant rate (4 mL / min) while stirring the poor solvent at 40 ° C. and 400 rpm. After stirring for 5 minutes after completion of dropping, the organic solvent was distilled off in 4 hours while stirring at 200 rpm under reduced pressure. Next, excess polyvinyl alcohol and chitosan were removed by centrifugation, and 45 mL of a 0.1 wt% hyaluronic acid aqueous solution was added to the obtained nanoparticle suspension. Thereafter, freeze-drying was performed for about 1 day to obtain 2.2 g of freeze-dried powder of hyaluronic acid-carrying PLGA nanoparticles.

  It was 195 nm when the average particle diameter at the time of re-dispersing the obtained nanoparticle in water was measured with the dynamic light scattering method (measuring device: MICROTRAC 9340-UPA (brand name), Nikkiso Co., Ltd. make). The zeta potential on the particle surface after lyophilization was -63 mV as measured using a zeta electrometer (ZETASIZER Nano-Z (trade name), manufactured by Malvern Instruments). Furthermore, the hyaluronic acid content in the particles (weight ratio of hyaluronic acid to PLGA nanospheres) in the particles was quantified using an ultraviolet-visible spectrophotometer (V-530 (trade name), manufactured by JASCO Corporation, measurement wavelength 270 nm). .2% by weight.

  Hyaluronic acid-carrying PLGA nanoparticles were prepared by the same procedure as in Example 1 except that hyaluronic acid having an average molecular weight of 1,000,000 was used. The average particle diameter when the obtained nanoparticles were redispersed in water was 180 nm as measured by a dynamic light scattering method.

  Hyaluronic acid-carrying PLGA nanoparticles were prepared by the same procedure as in Example 1 except that hyaluronic acid having an average molecular weight of 5,000,000 was used. The average particle size when the obtained nanoparticles were redispersed in water was measured by a dynamic light scattering method to be 350 nm.

Comparative Example 1

Hyaluronic acid-carrying PLGA nanoparticles were prepared by the same procedure as in Example 1 except that hyaluronic acid having an average molecular weight of 6,000,000 was used. As a result, aggregation of particles occurred in the step of dropping the good solvent into the poor solvent, and hyaluronic acid-carrying PLGA nanoparticles could not be obtained.
[Preparation of emulsion]

  Table 1 shows the formulation of the emulsion in which the hyaluronic acid-carrying PLGA nanoparticles are dispersed.

Since this emulsion can satisfactorily disperse hyaluronic acid-carrying PLGA nanoparticles, filling the nanoparticle powder and the emulsion in separate containers can be used as a time-dispersed cosmetic. It has become possible. In addition, about the kind and compounding quantity of a component mix | blended in an emulsion, it is an example and can be suitably changed according to the objective.
[Evaluation of skin penetration and retention effect using skin culture model]

Test example 1

The skin permeation / retention effect of the hyaluronic acid-carrying PLGA nanoparticles prepared in Example 1 was measured using three-dimensional artificially cultured human skin cells (TESTSKIN LSE-high (trade name), manufactured by Toyobo Co., Ltd., hereinafter abbreviated as skin model). And evaluated. As test solutions, purified water, hyaluronic acid aqueous solution (hereinafter abbreviated as HA aqueous solution), hyaluronic acid-supported nanoparticle dispersion (hyaluronic acid-supported nanoparticles were dispersed in purified water at a particle concentration of 1.0% by weight). Three types of liquid (hereinafter abbreviated as HA nanoparticle dispersion) were used. The hyaluronic acid concentrations in the HA aqueous solution and the HA nanoparticle dispersion were both 3.2 × 10 ⁻² wt%. The test method is shown below.

1) Constant temperature water (35 ± 0.5 ° C.) was circulated in a jacket 11 of a Franz diffusion cell 10 (effective transmission area: 0.64 cm ² ) as shown in FIG.
2) The receiver part 12 of the Franz diffusion cell 10 is filled with PBS (phosphate buffered saline, pH 7.4, 5.2 ± 0.1 mL), and the skin having a diameter of 24 mm is provided between the donor part 13 and the receiver part 12. The model 14 was inserted so that the tissue side (corneal side) was the donor side and the polycarbonate membrane side (dermis layer side) was the receiver side.
3) After clamping the donor part 13 and the receiver part 12 with a clamp to fix the skin model 14, the test solution was administered to the donor part 13 while gently stirring the PBS in the receiver part 12 with a magnetic stirrer (each test group). N = 5).
4) After 24 hours, the skin model 14 was removed from the diffusion cell 10 and washed with purified water.
5) Hyaluronic acid contained in the skin model 14 and the liquid in the receiver unit 12 was quantified, and an average value was calculated for each test group. For the quantification of hyaluronic acid, an HA quantification kit (manufactured by Seikagaku Corporation) was used and quantified by an inhibition method using hyaluronic acid binding protein. The results are shown in FIG.

  As shown in FIG. 5, the amount of hyaluronic acid that permeated and stayed in the skin model (light-colored portion of the graph) was about 450 to 500 ng in both the HA aqueous solution administration group and the HA nanoparticle dispersion administration group. On the other hand, the amount of hyaluronic acid penetrating from the donor part into the skin model and permeating through the receiver part (dark colored part of the graph) was 871 ng in the HA aqueous solution administration group and 1187 ng in the HA nanoparticle dispersion administration group.

  Here, since hyaluronic acid is originally contained in the skin model, hyaluronic acid is detected from the skin model 14 and the liquid in the receiver unit 12 even when purified water is used as the test liquid. Therefore, the amount obtained by subtracting the detection amount (475 ng) of hyaluronic acid when purified water is used from the detection amount when using an HA aqueous solution and HA nanoparticle dispersion is the hyaluronic acid that actually permeates the skin model from the donor part. Estimated to be a quantity.

  Accordingly, it is considered that hyaluronic acid of 871-475 = 396 (ng) in the HA aqueous solution administration group and 1187-475 = 712 (ng) of the HA nanoparticle dispersion administration group permeated through the skin model from the donor part. From this result, it was revealed that the HA nanoparticle dispersion liquid administration group showed better skin permeability than the HA aqueous solution administration group.

Test example 2

By using the same apparatus and operation procedure as in Test Example 1, a HA nanoparticle dispersion and a hyaluronic acid-carrying nanoparticle-containing emulsion (as a test solution) The skin penetration / retention effect of hyaluronic acid-supported PLGA nanoparticles when using two types of liquids (hereinafter abbreviated as HA nanoparticle emulsions) was compared. The hyaluronic acid concentration in the HA nanoparticle dispersion and the HA nanoparticle emulsion was 3.2 × 10 ⁻² wt%. The results are shown in FIG.

  As shown in FIG. 6, the amount of hyaluronic acid that permeated the skin model and permeated the receiver part (dark portion of the graph) was about 200 ng in both the HA nanoparticle dispersion administration group and the HA nanoparticle emulsion administration group. There was no significant difference. On the other hand, the amount of hyaluronic acid retained in the skin model (light-colored portion of the graph) was about 400 ng in the HA nanoparticle dispersion administration group and about 800 ng in the HA nanoparticle emulsion administration group. Since the retention amount of hyaluronic acid in the skin model when purified water was used in Test Example 1 was small (100 ng or less), the HA nanoparticle emulsion administration group compared to the HA nanoparticle dispersion administration group. It was revealed that the skin retention was good.

  From the above, it was confirmed that hyaluronic acid was supported on PLGA nanoparticles to enhance the permeability and retention in the skin. In addition, these effects are higher in the HA nanoparticle emulsion administration group than in the HA nanoparticle dispersion administration group, and it is confirmed that the emulsion is more suitable than using the nanoparticles dispersed in purified water. It was done.

  According to the present invention, hyaluronic acid-carrying nanoparticles that are supported on at least one of the inside or the surface of the nanoparticles and that can be suitably used as a raw material for cosmetics are provided. In particular, the total content of hyaluronic acid, which is a water-soluble drug, can be increased. In addition, as a material for forming hyaluronic acid-carrying nanoparticles, any of PGA, PLA, and PLGA, which has low irritation and toxicity to the living body and is decomposed and metabolized after administration, has high safety to the human body. Can be secured.

  Moreover, when the molecular weight of hyaluronic acid is large, inclusion in nanoparticles becomes difficult due to the excluded volume effect, but skin permeation can be achieved by using hyaluronic acid having an average molecular weight of 1,000,000 to 5,000,000. Hyaluronic acid-encapsulated nanoparticles having a high water content and sufficient water retention ability can be prepared. In particular, when hyaluronic acid having an average molecular weight of 1,000,000 to 2,000,000 is used, it is possible to prepare hyaluronic acid-encapsulating nanoparticles having an average particle diameter of 200 nm or less and excellent in skin permeability.

  In addition, the nanoparticle surface is coated with a cationic polymer such as chitosan, and the hyaluronic acid release rate is controlled in two steps by combining the inclusion of hyaluronic acid in the nanoparticle and electrostatic loading on the nanoparticle surface. it can. Furthermore, leakage of hyaluronic acid into the poor solvent can be suppressed and the encapsulation rate in the nanoparticles can be increased.

  In addition, if the hyaluronic acid-carrying nanoparticles are combined with a binder to form hyaluronic acid-containing composite particles, the dispersibility and heat resistance of the composite particles are improved, and the hyaluronic acid once encapsulated in the nanoparticles is applied to the particle surface. Leakage can be prevented. Further, by incorporating a physiologically active ingredient in the binder, immediate effect due to elution of the physiologically active ingredient encapsulated in the binder can be expected.

  Then, just before use, a predetermined amount of the composite particles are mixed and dispersed in the liquid and used as a cosmetic, thereby producing an effective moisturizing effect. In addition, if a physiologically active ingredient is blended in the liquid, it is adsorbed on the nanoparticle surface and delivered to the skin deeper along with the nanoparticle, so more physiologically active ingredients with different mechanisms of action are supplied to the skin deeper. it can. Furthermore, if a physiologically active ingredient that acts on the skin surface is formulated, the immediate effect of these ingredients on the skin surface is ensured, while hyaluronic acid from the nanoparticles is gradually released in the deep part of the skin. A long-term moisturizing effect can be expected.

These are the schematic diagrams which show the hyaluronic acid carrying | support nanoparticle which concerns on 1st Embodiment of this invention. These are the schematic diagrams which show the hyaluronic acid carrying | support nanoparticle which concerns on 2nd Embodiment of this invention with which the hyaluronic acid was carry | supported electrostatically on the particle | grain surface. These are the schematic diagrams which show the hyaluronic acid containing composite particle | grains of this invention in which the other bioactive component was enclosed with the binder. FIG. 3 is a schematic view of a Franz diffusion cell used in Test Examples 1 and 2. These are the graphs which show the amount of hyaluronic acid which permeated and stayed in the skin model in Test Example 1. These are the graphs which show the amount of hyaluronic acid that permeated and stayed in the skin model in Test Example 2.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Hyaluronic acid carrying nanoparticle 2 Biocompatible polymer 3 Polyvinyl alcohol 4a Hyaluronic acid (encapsulation)
4b Hyaluronic acid (external)
DESCRIPTION OF SYMBOLS 5 Cationic polymer 6 Composite particle 7 Binder 8 Physiologically active ingredient 10 Franz diffusion cell 11 Jacket 12 Receiver part 13 Donor part 14 Skin model

Claims (13)

  Hyaluronic acid-carrying nanoparticles in which hyaluronic acid is supported on at least one of the inside or the surface of nanoparticles formed of any of polylactic acid, polyglycolic acid, and lactic acid / glycolic acid copolymer.   The hyaluronic acid-carrying nanoparticles according to claim 1, wherein the hyaluronic acid has an average molecular weight of 1,000,000 to 5,000,000.   The hyaluronic acid-carrying nanoparticles according to claim 2, wherein the hyaluronic acid has an average molecular weight of 1,000,000 to 2,000,000.   The hyaluronic acid-carrying nanoparticle according to any one of claims 1 to 3, wherein the nanoparticle is formed of a lactic acid / glycolic acid copolymer.   The hyaluronic acid-carrying nanoparticle according to any one of claims 1 to 4, wherein the nanoparticle is coated with a cationic polymer.   The hyaluronic acid-carrying nanoparticles according to claim 5, wherein the cationic polymer is chitosan.   Hyaluronic acid-containing composite particles obtained by combining the hyaluronic acid-carrying nanoparticles according to any one of claims 1 to 6 with a binder.   The hyaluronic acid-containing composite particle according to claim 7, wherein another physiologically active ingredient is encapsulated in the binder.   A cosmetic comprising the hyaluronic acid-carrying nanoparticles according to any one of claims 1 to 6.   A cosmetic comprising the hyaluronic acid-containing composite particles according to claim 7 or 8.   The cosmetic according to claim 9 or 10, wherein the hyaluronic acid-carrying nanoparticles or hyaluronic acid-containing composite particles are dispersed in a liquid.   The cosmetic according to claim 11, wherein the liquid is an emulsion.   The cosmetic according to claim 11 or 12, wherein another physiologically active ingredient is blended in the liquid.

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