JP2005213170A - Nano particle-containing composition and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing a nano particle-containing composition which contains combined nano particles, gives a good sense of use, and can easily be charged into a container in a high density. <P>SOLUTION: The method for producing medicine-containing combined particles comprising a medicine and a biocompatible polymer is characterized by having a nano particle-forming process for adding a fat-soluble vitamin C (VC-IP), PLGA and an organic solvent to a 0.2 wt.% polyvinyl alcohol aqueous solution to form the medicine-containing biocompatible nano particles, a distilling process for distilling away the organic solvent from the solution after the nano particle-forming process, and a combination process for combining the nano particles. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a nanoparticle-containing composition in which primary particles containing nanoparticles are formed, and further, the primary particles are combined so that the primary particles are reversibly assembled. The present invention relates to a nanoparticle-containing composition suitable for application to a skin.

  In recent years, vitamin C and its derivatives are attracting attention to prevent the formation of stains and freckles. Such vitamin C (VC-IP or the like) exerts its effect by being supplied deep into the skin. This is because when the deep skin is damaged by ultraviolet A waves, sebum oxidation, or microorganisms, vitamin C works on the deep epidermis to recover the damage. Specifically, vitamin C exerts an effect of acting on melanocytes (pigment cells) in the deep part of the skin to bring a whitening effect and working on fibroblasts of the dermis to bring about collagen construction. Furthermore, vitamin C improves lipid metabolism of adipocytes (adipocytes) deep in the skin that are involved in cellulite.

  However, a vitamin preparation such as vitamin C hardly penetrates deep into the skin by simply applying it externally on the skin surface. Therefore, as a method of promoting penetration into the deep part of the skin, a method of permeating while flowing an electric current (about 0.4 mA) with an iontophoresis device, a method of permeating while applying ultrasonic waves with an ultrasonic cosmetic device, or applying goggles IPL (instantaneous strobe light) photofacial methods that penetrate while receiving IPL irradiation are used. Furthermore, as a method of penetrating into the deep part of the skin, peeling and oscillophoresis (P & O) is used to peel the deteriorated stratum corneum by finely vibrating the skin in three dimensions with pumice-like alumina, and impregnated oily vitamin C (/ It is also known to strike E) deep into the skin.

  However, in the method of applying such mechanical irritation, there is a great risk that the irritation to the skin is great and the skin is adversely affected. For example, in an ultrasonic cosmetics device, skin crushing due to cavitation (cavity phenomenon, bubbles) occurs when conditions are bad. Another drawback is that vitamin C is decomposed by ultrasound and the effect of vitamin C is reduced.

  Therefore, there is a demand for a method for allowing a vitamin preparation to penetrate into the skin without causing physical damage to the skin. As such a method, Patent Document 1 describes a method for producing an emulsion capable of improving permeability into skin and hair. Patent Document 2 describes that a vitamin agent (active agent) is captured on fine particles (such as nanospheres) of a biodegradable polymer of 1 to 1000 nm and applied to the skin.

  Patent Document 3 discloses a method for stably producing nanoparticles containing an active ingredient, Patent Document 4 discloses a nanosphere having excellent stability and no stickiness, and Patent Document 5 has good touch and slipperiness. Cosmetics containing fine particles are described. Furthermore, in Patent Document 6, as a method for producing nanospheres, the initial release of the contained drug can be prevented by adding a biodegradable polymer to an organic solvent containing 0.5% to 20% by weight of polyvinyl alcohol. Is described.

On the other hand, nanoparticles are highly reactive, but have a problem of difficulty in handling during storage and administration before use because of high surface adhesion. In this regard, Patent Document 7 discloses a method for producing nanocomposite particles in which nanoparticles containing a drug are compounded. By combining nanoparticles with this method, the nanoparticles are gathered and easily handled before use, and when exposed to moisture during use, they return to the nanoparticles and recover properties such as high reactivity. Nanocomposite particles can be made. This solves the above problem.
JP 7-165530 A (publication date: June 27, 1995) Japanese Patent No. 3001821 (registration date: November 12, 1999) Special table 2001-510790 (Publication date: August 7, 2001) JP 2000-178129 (release date: June 27, 2000) JP2003-073233 (release date: March 12, 2003) JP-A-9-110678 (release date: April 28, 1997) JP 2003-275281 (release date: September 30, 2003) Japanese Patent Publication No. 2720247 (registration date: November 21, 1997) Norika Akagi, Kikuko Yoshimitsu, Haruko Mimura, Nobuhiko Miwa, “Chapter 28 Evaluation Method of Drug Penetration Using Human Skin”, Nobuhiko Miwa, “Beautiful Skin / Skin Protection and Biotechnology” , 1st edition, CMC Publishing Co., Ltd., August 31, 2003, p. 301-304

  However, the nanocomposite particles of Patent Document 7 are mainly intended for oral preparations and transpulmonary preparations, and further improvements are required when applied to the skin.

  Specifically, first, since it will be applied directly to the skin, the feeling of use becomes important. Therefore, it is necessary to study to improve the feeling of use.

  In addition, when the nanocomposite particles are externally applied to the skin as a cosmetic or dermatological agent, it can be considered to be mixed with a liquid material such as an emulsion. Since the nanocomposite particles need to be stored in a dry state until just before use due to their characteristics, when the mixture with the emulsion is commercialized, it is mixed with the emulsion just before use. In this case, for example, it is considered that an effective means is to fill and sell a single-use portion in a small container. At this time, nanocomposite particles having a high bulk density that are excellent in fluidity and can be easily filled in a small container and can be filled more in a small container are required.

  The present invention has been made in view of the above-mentioned problems, and the object thereof is a nanoparticle-containing composition that includes particles obtained by complexing nanoparticles, has a good feeling of use, and can be easily and densely filled into a container. It is to realize a method for efficiently manufacturing the process.

  In order to solve the above-described problems, a method for producing a nanoparticle-containing composition according to the present invention includes a polyvinyl alcohol in an amount of less than 0.5% by weight in the method for producing a drug-containing composite particle containing a drug and a biocompatible polymer. A step of forming a nanoparticle-containing solution by adding at least a drug, a biocompatible polymer, and an organic solvent to an aqueous solution to form a drug-containing biocompatible nanoparticle to form a nanoparticle-containing solution, and the organic solvent from the nanoparticle-containing solution It has the distillation process of distilling off, and the compounding process which combines the said nanoparticle, It is characterized by the above-mentioned.

  Thus, by making the polyvinyl alcohol aqueous solution to which the drug, the biocompatible polymer and the organic solvent are added 0.5% by weight or less, the tension when applied to the skin can be suppressed, and the liquid state such as emulsion can be reduced. It becomes a nanoparticle-containing composition that is familiar. Moreover, since this nanoparticle containing composition has a large bulk density, it is excellent in fluidity | liquidity, can be easily filled into a small container, and can be filled with high density.

  This effect is further increased by setting the concentration of polyvinyl alcohol to 0.2% by weight or less.

  Conventionally, after using a high-concentration polyvinyl alcohol aqueous solution, the nanoparticle was washed by centrifugation or the like to prevent this problem. Time can be greatly reduced.

  In the method for producing a nanoparticle-containing composition according to the present invention, it is preferable to add water to the nanoparticle-containing solution for at least a predetermined time from the beginning of the distillation step.

  When the concentration of polyvinyl alcohol is low, the dispersibility of the nanoparticles in the solution decreases, and aggregation and a liquid surface film are likely to be generated. Therefore, it is necessary to perform the distillation step slowly over time. However, by distilling off the organic solvent while adding water at a constant rate, even if the organic solvent is rapidly distilled off, aggregation of the nanoparticles and generation of the liquid film surface are prevented. Therefore, the distillation time can be shortened.

  Here, the predetermined time is a period from the start of the distilling process until no aggregation or film formation occurs even if the distilling is performed without adding water. Since the addition of water is intended to prevent agglomeration by suppressing a rapid increase in the concentration of nanoparticles, in order to exert the effect of preventing the agglomeration described above, The addition of water is important. Therefore, after dilution to some extent, the addition of water may be stopped.

  The addition of water is preferably performed at a constant rate. Thereby, aggregation of a nanoparticle and the production | generation of a liquid film surface can be prevented favorably.

  Further, the drug is characterized by being a vitamin or a vitamin derivative. Nanoparticles can reach the dermis when applied to the skin. Vitamin C, which is a vitamin or vitamin derivative, acts on the dermis and has a whitening effect that prevents spots and freckles. Therefore, it is expected that a high whitening effect can be obtained by adding it to nanoparticles and acting on the skin. it can. In addition, since the drug contained in the nanoparticles is gradually released for a long time, a long-term effect can be expected.

  Furthermore, the method for producing a nanoparticle-containing composition according to the present invention is characterized in that in the complexing step, vitamins or vitamin derivatives are complexed with the nanoparticles. According to this, it can be set as the nanoparticle containing composition which contains more vitamins or vitamin derivatives. In addition, since the complexed vitamin or vitamin derivative starts to act after being dispersed immediately after use, it acts at a timing and place different from those contained in the above nanoparticles. Therefore, when vitamins or vitamin derivatives are contained in nanoparticles and combined, they are expected to have a two-stage effect of fast action and slow action.

  Moreover, in the said composite process, it is preferable to composite sugar alcohol with a nanoparticle. This is because the dispersibility and heat resistance of the composite nanoparticles are improved by combining the sugar alcohol. In addition, some sugar alcohols, such as trehalose, exhibit an effect of improving whitening / beauty effects.

  Moreover, it is preferable that the said composite process is performed by freeze-drying. According to this, the composite of the nanoparticles is favorably performed.

  Moreover, the nanoparticle containing composition manufactured by the manufacturing method of said nanoparticle containing composition is suitable as what is applied to skin as mentioned above. Therefore, it is preferably used as a cosmetic or as a transdermal drug.

  In addition, the nanoparticle-containing composition of the present invention is characterized by comprising nanocomposite particles in which nanoparticles containing vitamins or vitamin derivatives are combined with water-soluble vitamins or vitamin derivatives.

  According to this, the water-soluble vitamin or vitamin derivative adhering to the surface of the nanocomposite particles dissolves immediately after administration and exhibits a fast-acting action, and then the vitamin or vitamin derivative contained in the nanoparticles gradually increases. Exerts a sustained release action. Therefore, it becomes a nanoparticle containing composition with which the effect of a vitamin is exhibited over a long period of time.

  In the method for producing a nanoparticle-containing composition according to the present invention, a drug-containing biocompatible nanoparticle is formed by adding at least a drug, a biocompatible polymer and an organic solvent to an aqueous solution of polyvinyl alcohol of less than 0.5% by weight. And forming a nanoparticle-containing solution, a distillation step of distilling off the organic solvent from the nanoparticle-containing solution, and a compounding step of compositing the nanoparticles.

  As a result, it is possible to produce a nanoparticle-containing composition that suppresses a feeling of tension when applied to the skin and is well-familiar with a liquid state such as an emulsion. Further, since the produced nanoparticle-containing composition has a large bulk density, it is excellent in fluidity and can be easily and densely filled into a small container. In addition, manufacturing effort and time can be greatly reduced.

  An embodiment of the present invention will be described below with reference to FIGS.

  The method for producing drug-containing composite particles according to the present embodiment is a method of forming primary particles including nanoparticles, and further compositing the primary particles so that the primary particles aggregate reversibly. .

  The method for producing drug-containing composite particles according to the present invention is suitably used in a wide range of fields such as the development of various new materials. For example, it can be suitably used for the purpose of producing powder as a cosmetic material. This is because, in use, the composite particles pass through the primary particles, disperse into nanoparticle units, penetrate into the deep part of the skin, and gradually release the drug from the nanoparticles at the deep part of the skin.

  The material of the nanoparticles in the present invention is not particularly limited as long as it is a substance that can be made into nanoparticles. The method for producing nanoparticles is not particularly limited as long as the target substance can be processed into particles having an average particle diameter of less than 1000 nm. In the case of crystallization, it is very preferable to use a spherical crystallization method.

  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. The spherical crystallization method can be divided into a spherical granulation method (SA method) and an emulsion solvent diffusion method (ESD method) depending on the generation / aggregation mechanism of crystals to be crystallized.

  The SA method is a method of forming a spherical granulated crystal by precipitating drug crystals using two kinds of solvents. Specifically, first, a poor solvent that hardly dissolves the target drug and a good solvent that can dissolve the drug well and can be mixed and diffused in the poor solvent are prepared. Then, the drug solution dissolved in the good solvent is dropped into the poor solvent with stirring. At this time, by utilizing the shift of the good solvent to the poor solvent and the decrease in solubility due to the temperature effect or the like, the drug crystal 51 is precipitated in the system as shown in the leftmost diagram of FIG.

  Furthermore, when a small amount of liquid (liquid cross-linking agent) that has affinity for the drug and is not miscible with the poor solvent is added to the system, the liquid cross-linking agent 52 becomes as shown in the leftmost diagram of FIG. Liberate. Then, a bridge is formed between the crystals 51, and the crystals 51 begin to aggregate non-randomly as shown in the second diagram from the left in FIG. 2A due to the interfacial tension and the capillary force. This state is called a funicular state.

  When a mechanical shearing force is further applied to the system in the funicular state, the aggregated crystals 51 are consolidated, and as shown in the third diagram from the left in FIG. It becomes. This state is called a capillary state. When the granulated material 53 in the capillary state is randomly united, a final spherical granulated crystal 54 is formed as shown in the rightmost diagram of FIG.

  The kind of the good solvent and the poor solvent and the kind of the liquid crosslinking agent 52 are determined according to the kind of the target drug and the like and are not particularly limited. Further, the conditions at the time of crystal precipitation and the method of applying mechanical shearing force are not particularly limited, and the type of the target drug, the particle size of the spherical granulated crystal 54 (in the case of the present invention, nano-order), etc. What is necessary is just to determine suitably according to.

  The ESD method is also a method using two types of solvents, but unlike the SA method, it is a method in which an emulsion is formed and then the drug is crystallized in a spherical shape by utilizing mutual diffusion between a good solvent and a poor solvent. is there. Specifically, first, a drug solution dissolved in a good solvent is dropped into a poor solvent under stirring. At this time, since the drug and the good solvent have an affinity, the transition of the good solvent to the poor solvent is delayed, and emulsion droplets 55 are formed as shown in the left diagram of FIG.

  Then, as shown in the middle diagram of FIG. 2 (b), cooling of the emulsion droplet 55 and mutual diffusion of the good solvent and the poor solvent (in the figure, the black arrow indicates the good solvent diffusion and the white arrow indicates the poor solvent diffusion). 2), the solubility of the drug decreases in the emulsion droplet 55, and the spherical crystal particles 56 of the drug precipitate while retaining the shape of the emulsion droplet 55, as shown in the right diagram of FIG. ,grow up.

  The types of the good solvent and the poor solvent are not particularly limited and are determined according to the type of the target drug and the like, as in the SA method. In addition, the conditions for forming the emulsion and the cooling conditions at the time of crystal precipitation are not particularly limited, depending on the type of the target drug, the particle size of the spherical crystal particles 55 (in the nano-order in the present invention), and the like. What is necessary is just to determine suitably.

  In the above spherical crystallization method, nanoparticles can be formed by a physicochemical method, and the resulting nanoparticles are almost spherical, so there is no need to consider the problem of catalyst or raw material compound residue from homogeneous nanoparticles. Can be easily formed. In addition, when applying nanoparticles to a living body, the nanoparticles may be modified with a biocompatible polymer, but the spherical crystallization method only dissolves the drug and the biocompatible polymer in a good solvent. Therefore, it is very preferable because nanoparticles in which both are combined can be formed.

  The biocompatible polymer as a material constituting the biocompatible nanoparticle obtained by the spherical crystallization method has low irritation and toxicity to the living body, is biocompatible, is decomposed and metabolized after administration. Biodegradable materials are desirable. Moreover, it is preferable that it is the particle | grain which discharge | releases the medicine to include continuously and gradually. Examples of such a material include polylactic acid / glycolic acid (PLGA). It is known that PLGA can contain a drug and can be stored for a long time while maintaining the efficacy of the drug. Furthermore, from the characteristics of hydrolysis and long-term half-life of PLGA, it is considered that sustained release can be performed in units of several days to one month. Other biocompatible polymers include polyglycolic acid (PGA), polylactic acid (PLA), and the like. Further, these copolymers may be used, and may have a charged group such as an amino acid or a group that can be functionalized.

  Other biocompatible polymers include polyalkylenes such as polyamide, polycarbonate, polyethylene, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl compounds such as polyvinyl alcohol, polyvinyl ether and polyvinyl ester, acrylic acid and Polymers with methacrylic acid, cellulose and other polysaccharides, and peptides or proteins, or copolymers or mixtures thereof.

  As the biocompatible polymer, polylactic acid / glycolic acid can be particularly preferably used. The molecular weight of polylactic acid / glycolic acid is preferably in the range of 5,000 to 200,000, and more preferably 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 preferably 0.333 of glycolic acid with respect to lactic acid 1. The PLGA having a content of lactic acid and glycolic acid in the range of 25% to 65% by weight is preferably used because it is amorphous and soluble in an organic solvent such as acetone. .

  Examples of drugs encapsulated in the biocompatible nanoparticles include vitamins, provitamins (vitamin derivatives) and various drugs. As will be described later, the nanoparticle-containing composition of the present invention is excellent in penetration from the skin and can be suitably used as a cosmetic or transdermal drug. However, provitamin (particularly provitamin C) has a whitening effect due to skin application or the like. Since it attracts attention, if provitamin-encapsulated PLGA is produced as the biocompatible nanoparticles, a provitamin-containing cosmetic product that works efficiently can be obtained.

  Examples of provitamins to be encapsulated in nanoparticles include vitamin A, B, C, and E derivatives, specifically VC-IP (ascorbyl tetrahexyldecanoate), VE (tocopherol acetate), VA (vitamin A). -Retinol, vitamin A precursor: β-carotene). The encapsulating rate in these nanoparticles can be set to VC-IP 15% and VE 20% when the spherical solvent crystallization method is used.

  In particular, provitamin C (VC-IP or the like) is suitable as a drug to be encapsulated in nanoparticles because its effect is improved by being supplied deep into the skin. Provitamin C is required to be supplied deep into the skin when the deep skin is damaged by ultraviolet A waves (UVA), sebum oxidation, and microorganisms, and vitamin C acts on the deep skin to cause damage. It is to recover. Specifically, vitamin C works on melanocytes (pigment cells) in the deep part of the skin to bring about a whitening effect, and works on dermal fibroblasts to bring about collagen construction. In addition, vitamin C improves lipid metabolism in the skin epidermis and deep adipocytes (adipocytes) involved in cellulite. Furthermore, VC-IP, an oily provitamin C, is expected to protect against UVA-induced DNA strand breakage of human skin keratinocytes HaCaT, or to protect against skin cell DNA strand breakage caused by ultraviolet B wave (UVB). Has been.

  Examples of the transdermal drug include fentanyl citrate as an anesthetic, bifonazole as a drug for parasitic skin diseases (such as athlete's foot), and minoxidil as a hair restorer. In addition, insulin (diabetic drug) as a pulmonary drug, calcitonin (drug for osteoporosis), and the like are also included. In addition, when this drug was encapsulated by using the spherical crystallization method using an in-oil phase inversion method, the encapsulation rate was 6 to 10% for insulin and 6 to 10% for calcitonin.

  The nanoparticle may have a particle size of 1000 nm or less, but more preferably 250 nm or less. In addition, it is preferable that the particle diameter of the nanoparticles is 100 nm or less because the nanoparticles have very high permeability to the skin.

  The nanoparticles obtained as described above can be formed into aggregated particles that can be redispersed when powdered by freeze drying or the like (can be combined). Further, compressive force and shear force are applied by fluidized bed dry granulation method or dry mechanical particle compositing method (for example, by the apparatus described in Patent Document 7, specifically, Mechanofusion AMS (Hosokawa Micron)). Even if they are combined, they can be integrated in a separable state. As a result, the nanoparticles are gathered and easily handled before use, and nanocomposite particles that return to the nanoparticles and restore characteristics such as high reactivity can be obtained by touching moisture during use.

  In order to improve the properties of the cosmetic product, the biocompatible nanoparticles are preferably combined with an organic or inorganic substance so as to be redispersible when combined. For example, by applying sugar alcohol or sucrose, sugar alcohol or the like can be used as an excipient to improve the handleability. Examples of the sugar alcohol include mannitol, trehalose, sorbitol, erythritol, maltose, and xylitol. Among them, mannitol is particularly preferable. Mannitol is chemically stable, non-oxidized, moisture resistant and suitable for carrier particles. In particular, trehalose is very suitable because it enhances the whitening effect when used in combination with a whitening agent such as vitamin C and its derivatives (see Patent Document 8).

  Further, chitosan for enhancing mucoadhesiveness may be complexed on the surface of the nanoparticles, or phospholipid (lecithin / phosphadylcholine) may be complexed to enhance the skin affinity. In addition, by combining polyethylene glycol (PEG), it becomes easier to dissolve in water, and the permeability to the skin can be improved. Furthermore, by combining talc, the slipperiness of the particles can be improved and the feeling on the skin can be enhanced.

  In addition, by attaching a drug such as provitamin to the surface of the composite particle (nanocomposite) at the time of compounding, it is immediately after skin penetration, apart from the contained drug that is released slowly from the nanoparticle. A fast-acting drug that dissolves from the surface of the composite particles can act. Examples of such drugs include water-soluble provitamins such as VC-PMG (water-soluble ascorbyl phosphate Mg), AA2G (ascorbyl glucoside), panthenol (water-soluble vitamin B5), and L-cysteine. . By adopting such a configuration, the PLGA composite particles can be given further quick permeability (fast-acting penetrating action). In addition, it is more preferable that the compounded drug is water-soluble because it dissolves quickly and exhibits a fast-acting effect.

  In addition, by having the drug contained in the nanoparticles and the drug to be combined, both the fast-acting effect and the slow-acting effect can be obtained, so that permeation can be performed for a long period after application to the skin.

  The composite particles produced in this way can penetrate into the skin as it is attached to the skin as it is, and have the effect of transporting the contained or attached drug to the deep part of the skin. Produces good permeability. However, PLGA is hydrolyzed when mixed with moisture, and the transport performance of the composite particles is lost in a short time. Therefore, when using as such an emulsion, the emulsion and powder are filled and stored in separate containers as shown in FIG. 3, and the containers are separated from each other just before use. It is preferable to use a container that can mix the powder.

  Next, the process from the production of PLGA particles to the production of composite particles will be described with reference to FIG.

[Nanoparticle formation process]
A 0.2 wt% aqueous solution obtained by diluting 8 g of polyvinyl alcohol (PVA) with 4000 ml of water is placed in a beaker. The PVA aqueous solution was stirred at 40 ° C. and 400 rpm, and in the stirred PVA aqueous solution, 80 g of polylactic acid glycolic acid (PLGA: PLGA7520 manufactured by Wako Pure Chemical Industries, Ltd.), acetone 1600 ml, ethanol 800 ml, and fat-soluble tetratetrahydrochloride C A solution consisting of 12 g of ascorbyl hexyldecanoate (VC-IP: manufactured by Nikko Chemical) was added dropwise at a rate of 15 ml / min. This produced a nanoparticle-containing solution.

[Distillation step]
While adding a total of 320 ml of purified water at 4 ml / min to the nanoparticle-containing solution, the organic solvent was distilled off while stirring at 40 ° C. and 100-200 rpm.

[Freeze drying process]
To the PLGA suspension from which the organic solvent has been distilled off, 80 g of mannitol as an excipient, 40 g of water-soluble ascorbyl phosphate (VC-PMG), which is a water-soluble vitamin, and 200 ml of purified water are added. And then lyophilized at −80 ° C. and a vacuum of 10 torr. Thereby, PLGA composite particles (composite particles) were obtained.

  The obtained PLGA composite particles have a powder-side container and a solution-side container in FIG. 3 integrated, and 160 mg is filled in a powder-side container (capacity 1.5 cc) of an event-dispersed container that can be mixed at the time of use. The solution side container (capacity 5.5 cc) was filled with emulsion. Thereby, it mixes just before using and the emulsion containing PLGA composite particle | grains is made.

  Although the detailed setting in the above method may be changed as appropriate, the PVA concentration in the mixing step is less than 0.5% by weight, preferably 0.4% by weight or less, more preferably 0.2% by weight or less. Is preferred. Moreover, it is preferable to set it as 0.1 weight% or more, and it is more preferable to set it as 0.2 weight%.

  The reason for this is that when high-concentration PVA is used, PVA is excessively contained in the freeze-dried product (may be contained more than the PLGA solid content if there are many), which is an obstacle when applied to cosmetics. .

Specifically, the failure is as follows.
-Since PVA is hydrophilic and hygroscopic, the PLGA composite particles on which excess PVA is adsorbed are sticky and the quality is impaired.
・ As the amount of PVA added increases, the bulk density decreases and the filling property (ease of filling into the container) deteriorates. In addition, the filling property and the feeling of use are also impaired from the point that the needle shape tends to be formed.
・ When applied on the skin, the skin feels tight (smooth) due to the “paste” characteristic of PVA.

  In order to prevent this, for example, it is necessary to remove excess PVA after crystallization and solvent distillation. Usually, in order to remove PVA, it is considered that particles are isolated by centrifugation, the supernatant liquid containing excess PVA is discarded, replaced with purified water, and centrifuged again to remove PVA. It is done. However, this centrifugation operation is a very time-consuming operation, and from the viewpoint of industrialization, it becomes an obstacle to the efficient production of nanoparticles.

  Therefore, as a result of examining a manufacturing method that does not perform this removal operation (centrifugation, etc.) (see Example 6), PLGA composite particles in a solution containing only the amount of PVA that should be contained in the final PLGA composite particles It has been found that the removal work can be made unnecessary by producing The amount of PVA to be contained in the final PLGA composite particles is about 0.2% by weight as the PVA concentration, and less than 0.5% by weight, preferably 0.2% by weight or less. It is preferable to use it.

  When the PVA concentration is as low as 0.2%, if the distillation step after the crystallization operation is performed slowly over time, no agglomeration or film is formed, but this is an obstacle to industrialization. On the other hand, in the case of rapid distillation (for example, a distillation rate of 80 ml / min or more), as the solution is concentrated while the solvent is distilled off, partial re-dissolution of PLGA in the remaining good solvent is caused. Since a strong agglomerate or film is formed, redispersion cannot be performed.

  Therefore, for the purpose of suppressing the aggregation and film formation, water is supplied together with the concentration to maintain the dispersibility of the PLGA particles in water. In this case, as shown in Example 6 below, it is necessary to add water at a constant addition rate together with distillation.

  The water to be added at this time may continue to be added for a predetermined period from the beginning of the distillation step, that is, until no aggregation or film formation occurs even if distillation is performed without adding water from the start of the distillation step. preferable. In addition, the amount of water added at this time is preferably 1% by weight or more, more preferably 4% by weight or more, of the amount distilled off for 1 minute. Moreover, it is preferable to add at 10 weight% or less of the amount of distillation for 1 minute, and it is more preferable to add at 5 weight% or less.

  Also, by adding an aqueous solution of sugar alcohol, vitamins, etc. immediately before the freeze-drying process and freeze-drying, PLGA is mixed with sugar alcohol and vitamins (water-soluble provitamins, etc.) around the PLGA particles. Particles can be combined. By adding sugar alcohol, heat resistance is given to heat-sensitive PLGA particles, PLGA composite particles can be stored stably, and the redispersibility of the composite particles is improved so that they can penetrate deep into the skin. become. Moreover, by adding a vitamin preparation, more vitamins can be included in the PLGA composite particles, and the effect of the vitamin preparation can be enhanced.

  The vitamin preparation may be lyophilized to form PLGA composite particles, and then pulverized to a particle size of about 10 μm and mixed. According to this, the compounding quantity of a vitamin preparation can be raised further.

  The structure of the composite particles produced as described above will be described with reference to FIG. 4. PVA is attached to the surface of PLGA particles containing VC-IP (drug) (the rightmost figure). However, it forms composite particles with mannitol and water-soluble vitamins (middle figure). The composite particles are further aggregated so as to be redispersible to form giant particles (the leftmost figure).

  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.

  In accordance with the method of the above-described embodiment, PLGA particles in which fluorescent-labeled coumarin is encapsulated instead of VC-IP are produced by spherical crystallization method (emulsion solvent diffusion method in water), and are permeable to human skin. I investigated. As a comparative example, the permeability of a 10% coumarin solution into human skin was examined. As the coumarin, coumarin 6 (COUMARIN6), that is, [C20H18N2O2S 3- (2-Benzothiazolyl) -7-N, N-diethylaminocoumarin] was used, and it was enclosed so that PLGA: coumarin = 2000: 1. The excitation wavelength of coumarin is 458 nm and the fluorescence wavelength is 505 nm.

  After applying this aqueous dispersion of PLGA particles (coumarin concentration in aqueous solution: 0.00005%) or coumarin solution to the skin of the subject, the fluorescence of the coumarin was followed to observe the permeability of the PLGA particles into the skin. .

  FIG. 5 shows that the coumarine-containing PLGA aqueous dispersion (FIG. 5 (b)) or the coumarin solution (FIG. 5 (a)) was applied to the side skin of a 35-year-old woman 2 hours later, 3 hours later, The photograph of the cross-sectional view of the epidermis after time is shown. In the coumarin solution, the fluorescent dye coumarin penetrates into the dermis through the stratum corneum (0.01 mm from the skin surface) and epidermis (from the skin surface to 0.1 mm) with time, but the fluorescently stained range and amount penetrates little. Sex is not good. On the other hand, the coumarin-containing PLGA aqueous dispersion is dyed extensively to a depth of about 1 mm after 2 hours, and it can be seen that it reaches a large amount of the skin deeply (8 mm or more from the skin) quickly. Moreover, it is guessed that the periphery of the pore is darkly dyed after 4 hours, and penetrates deeply into the skin deeply from the pore (FIG. 5B is an enlarged view of the diagram after 4 hours). 5 (c)). That is, it seems that the penetration effect is enhanced by using pores as a bypass as one of the drug penetration routes into the deep skin.

  In accordance with the method of the above-described embodiment, an aqueous dispersion of PLGA particles (average particle size 240 nm) containing VC-IP at an encapsulation rate of 13 to 15% (the concentration of VC-IP in the dispersion is 1%) The skin penetration test was carried out by the modified Bronov diffusion chamber method. As a comparative example, a VC-IP solution (concentration 1%) was used.

The process of the modified Bronov diffusion chamber method will be described below (see Non-Patent Document 1).
1) Remove a piece of skin from the subject (an upper arm of a 52-year-old female) and remove about 1 mm of subcutaneous tissue.
2) Divide the skin piece into several small pieces in the vertical direction.
3) Wrap the cut side of the skin piece with biocompatible TG polymer.
4) Install in the housing of a sterilized modified Bronov diffusion chamber.
5) Place the chamber in a 24-well microplate and place serum-free DMEM medium.
6) Aerate 5% carbon dioxide to maintain pH at 7.2-7.3.
7) Add the sample to the skin surface side.
8) After a certain period (0.5 hours, 2 hours, 4 hours), remove the skin pieces.
9) The reference skin piece is stained by EvG staining, and the thickness of the stratum corneum, epidermis and dermis is measured.
10) Separate skin pieces into epidermis and dermis with trypsin.
11) Appropriately crush the separated epidermis and dermis.
12) Each cell lysate is HPLC-separated by a conventional method and quantified with a fluorescence / coulometric ECD / UV detector.

  After 0.5 hour, 2 hours and 4 hours, the amount of vitamin C in the tissues of the epidermis (E) and dermis (D) was measured. In addition, PLGA7520 made from Wako Purechemical was used as PLGA, and the product made from Nikko Chemical was used as provitamin C (VC-IP).

  The results are shown in the lower bar graph of FIG. When the VC-IP solution of Comparative Example was applied, about 80 nmol was present in the epidermis (E) after 0.5 hours, but decreased to 20 nmol after 2 hours and 4 hours. Moreover, only about 4 nmol penetrated into the dermis (D) at any time.

  On the other hand, the amount of vitamin C when the aqueous dispersion of VC-IP-encapsulated PLGA particles prepared according to the present invention was applied was about 70 nmol, about 0.5 nm, 2 hours, and 4 hours, respectively, for the epidermis (E). It changed to 10 nmol and about 50 nmol, and in the dermis (D), the penetration amount gradually increased to about 2.1 nmol, about 8 nmol, and about 14 nmol.

  When both are compared, the vitamin C value in the dermis after 4 hours when the aqueous dispersion of VC-IP-encapsulated PLGA particles is applied is 3 as compared with the value after 4 hours of the VC-IP solution. It was a very high value of 5 times. That is, it was found that the VC-IP solution hardly penetrates into the dermis, whereas the inclusion in PLGA particles penetrates into the dermis. Considering the results of Example 1, it is presumed that the PLGA particles also have a pore bypass effect and are well delivered to the dermis. Moreover, since VC-IP flows out from PLGA particle | grains gradually, it is thought that VC-IP contained in PLGA particle | grains is discharge | released slowly to skin over a long continuous time.

  In addition, when an aqueous dispersion of VC-IP-encapsulated PLGA particles was applied, VC-IP in the epidermis once decreased after 0.5 hours and then increased again after 4 hours. This may indicate that, after 4 hours, the outflow of VC-IP from the PLGA particles that have penetrated deep into the skin has increased, and the outflowed VC-IP has moved from the deep to the epidermis.

  Furthermore, the upper graph of FIG. 6 shows the ratio of reduced vitamin C (ascorbic acid) to the total vitamin C in the epidermis and dermis (Asc / t-vitamin C). This value indicates the proportion of effective vitamin C that has not been oxidatively decomposed in the total amount of vitamin C (reduced vitamin C), and indicates resistance to oxidative degradation. In other words, it is considered that the higher the value, the less oxidative degradation of vitamin C is, and the higher the efficacy of vitamin C. According to the upper graph of FIG. 6, in the case of VC-IP-encapsulated PLGA particles, reduced vitamin C remained well in the dermis even after 2 hours or 4 hours. This value is good even after 4 hours of the VC-IP solution, but the permeation amount itself is low in the VC-IP solution, so the total amount of reduced vitamin C is low.

  FIG. 7 shows values representing the amount of reduced vitamin C in the dermis (Asc / t-vitamin C) by multiplying the numerical values in the lower bar graph of FIG. 6 with the numerical values in the upper graph. According to this, in the case of PLGA particles encapsulating VC-IP, it is 6.7 times as high as the value after 2 hours and nearly 4 times as high as 4 hours after the VC-IP solution. It can be seen that it has an amount of vitamin C. Therefore, it was shown that PLGA particles can permeate a large amount of VC-IP in an effective reduced vitamin C state. That is, it can be said that the PLGA particles exhibit an effect as a “VC-IP penetrant”.

  Even if VC-IP is enclosed in a reservoir type in the PLGA particles, VC-IP is released so much from the PLGA particles of the sustained release substrate within a short time after several hours of penetration of the PLGA particles. It is considered that VC-IP derived from this is not detected in the skin. Therefore, in the above skin penetration experiment, it is presumed that VC-IP on the surface of PLGA particles, which are monolithic nanospheres, rapidly penetrated the skin and increased the amount of vitamin C deep in the skin.

  According to the manufacturing method of the embodiment, PLGA composite particles were manufactured. As an example of the PLGA composite particles, PLGA composite particles having the following blending ratio (weight ratio) were obtained.

PLGA: 1.00 vs.
Fat-soluble provitamin VC-IP: 0.15
PVA: 0.10 to 0.30
Excipient (mannitol or erystole): 1.00
Water-soluble provitamin VC-PMG: 1.125

  In the production method of the embodiment, the concentration (% by weight) of the poor solvent PVA aqueous solution to which the PLGA (VC-IP) / ethanol / acetone solution is dropped during crystallization (in-water emulsion solvent diffusion method) is 0.2%, The drug-containing PLGA composite particles were manufactured by changing to 0.4% and 0.6%, and composited. The conditions of crystallization and lyophilization other than the PVA concentration are all the same. In addition, in the conventional PLGA composite particles, it is standard that the concentration of PVA is about 3% by weight, and in Patent Document 6, the concentration is 0.5% by weight or more. Furthermore, here, in the distillation step, purified water was added for 300 minutes at a constant rate of 4 ml / min.

  The redispersibility, bulk density, and container filling properties of the composite particles were measured, and the results are shown in Table 1. Here, in this experiment, when the concentration (% by weight) of the PVA aqueous solution was 0.2%, 0.4%, and 0.6%, the PLGA (VC-IP) / ethanol / acetone solution was added dropwise. In the PVA solution, the PVA concentration with respect to the PLGA composite particles is 10% by weight, 20% by weight, and 30% by weight.

  The redispersibility is obtained by measuring the particle size of dispersed particles obtained by dispersing composite particles in purified water. Here, since the particle size of the PLGA composite particles is about 0.22 μm, the particle size in the purified water is close to this value if the redispersibility is good. According to Table 1, any PLGA composite particles having a PVA aqueous solution concentration of 0.2%, 0.4%, and 0.6% can be redispersed to a particle size of 0.2 to 0.3 μm. It can be seen that even if the PVA aqueous solution concentration is made thinner than before, the redispersibility is not affected.

  The bulk density is a value obtained by measuring the weight of 1 cc PLGA composite particles. As a method, put the PLGA composite particles in the screw tube bottle loosely (to the extent that they are blended after weighing the sample) or caulk (180 times tapping), measure the height and weight, and calculate the weight per cc. did. Here, too, the bulk density was 0.02 to 0.05 g / cc, which was loose, and about 0.04 to 0.09 g / cc.

  However, comparing the ease of filling the PLGA composite particles into the container (container fillability), as shown in Table 1, there was a problem when the concentration of the PVA aqueous solution was high. This is because the produced PLGA composite particles change from a round shape to a needle shape as the PVA aqueous solution concentration increases to 0.2%, 0.4%, and 0.6%. If the PLGA composite particles are needle-shaped, the fluidity is low and bulky, making it difficult to handle and filling the container. This container filling property is particularly important in view of the work of filling a small container necessary for selling as a cosmetic.

  According to the above measurement results, it can be said that the concentration of the PVA aqueous solution to be used is preferably 0.4% or less and more preferably 0.2% or less from the viewpoint of container filling.

  Next, the characteristics when the PLGA composite particles of Example 1 were mixed with an emulsion having the following blending ratio (weight ratio) were measured.

For lecithin milk: 1.000,
Lipidure: 0.005
Pullulan: 0.005
The characteristics measured include ease of familiarity when mixed with emulsion, permeability to skin when PLGA composite particles are applied to the skin, and a mixture of 180 mg of PLGA composite particles in 5 g of emulsion (hereinafter referred to as PLGA emulsion). ) Is applied to the skin and penetrates into the skin, and the feeling of use of the PLGA emulsion.

  The lecithin emulsion contains water (approximately 80% by weight), hydrogenated lecithin (approximately 10% by weight), butylene glycol (approximately 10% by weight), and other minor components include mineral oil, glycerin, and trioctanoin. , Isopentyldiol, cetanol, carbomer, hydroxypropylmethylcellulose, and sodium hydroxide in appropriate amounts.

  The ease of fitting the PLGA composite particles with the emulsion is a visual observation of whether the PLGA composite particles are immediately dispersed in the emulsion. The results are shown in Table 2. According to this, when the PVA concentration is 0.2%, it is accustomed to the emulsion without problems, but when it is 0.4%, it may not be accustomed, and when it becomes 0.6%, the water-soluble vitamin on the surface of the composite particles is It did not melt well and dispersed after a while.

  In addition, as a feeling of use, when only an appropriate amount (several tens of mg) of PLGA composite particles is accustomed to the skin, or when the PLGA emulsion (300 mg) is accustomed to the skin, the penetration into the skin, and the feeling of tightness of the skin I investigated. The results are shown in Table 2. These are average values based on monitor evaluation of 12 women in their 20s to 50s.

  Permeability to the skin is an investigation of whether particles or emulsions are quickly absorbed by the skin after being applied to the skin. When PLGA composite particles were directly blended into the skin, when mannitol was used as an excipient, it penetrated well when the PVA concentration was 0.4%, and penetrated very well at 0.2% or less. . When erythrol was used as an excipient, a certain degree of permeability was observed when the PVA concentration was 0.4% or 0.2%. On the other hand, when the concentration of PVA was 0.6%, the particles remained on the skin like red and hardly penetrated with either excipient. Therefore, when the PLGA composite particles are directly applied to the skin, it is preferable to use mannitol as an excipient, and the PVA concentration is preferably 0.4% or less, preferably 0.2% or less. I can say that.

  The PLGA emulsion penetrated the skin well without depending on the excipient or PVA concentration. However, when the PVA concentration was 0.2%, the permeability to the skin was particularly high. Therefore, when used as a PLGA emulsion, a relatively good permeability can be obtained regardless of the PVA concentration and excipient, but the permeability with a PVA concentration of 0.2% or less was particularly good.

  In addition, when the skin tension feeling when PLGA emulsion was applied to the skin was investigated, it was felt that the skin was moderate when the PVA concentration was 0.2%, and the skin tension was slightly felt at 0.4%. At 6%, the sense of tension was clear. Therefore, it was found that the PVA concentration was preferably 0.4% or less, more preferably 0.2% or less, from the feeling of skin firmness.

  Various distillation methods (methods A to I) were changed in the distillation step, and the state of formation of PLGA particle aggregates after distillation, particle size, and redispersibility in water after lyophilization, in the order of microns The presence or absence of aggregates was observed.

  Method B is a case in which PLGA 40 g is mixed with the solvent shown in Table 3 (PVA concentration is 0.2% by weight) according to the embodiment, and a distillation method in which water is not added at the time of distillation is adopted. In the case of this method B, in order to obtain particles having no aggregation, it was necessary to distill off slowly (25 hours) at a distillation rate of 48 ml / h. However, from the viewpoint of efficiency, such a long-time production is an obstacle to industrialization (see Table 5). This problem can be solved by increasing the concentration of PVA to 8 g (PVA solution concentration 0.4 wt%, method H) or 12 g (PVA solution concentration 0.6 wt%, method I). Although nanoparticles can be formed well in a short time of 11 hours (see Table 5), such a high PVA concentration is used in cosmetics such as emulsions as shown in the results of Example 2. Is a problem.

  Therefore, as a result of investigating a method of reducing the PVA concentration and shortening the distillation time, it has been found that the method of adding purified water in the distillation step is effective. Therefore, purified water was added at various timings in the distillation step (Methods C to F). Table 4 shows the method of adding each purified water. The conditions other than the addition of purified water are the same as B. The purified water to be added was unified to 1200 ml.

  C is added all at once in the middle of the distillation time, D is added in the first half of the distillation time (400 ml of purified water) and just in the middle (800 ml of purified water). did. And E added all the water at once just after the start of distillation. In these three methods, when distilled off in a short time, as shown in Table 5, when the liquid after distillation was passed through a 23 μm filter paper, micron particles or a liquid surface film was formed. The particle size of the particles after lyophilization was 230 nm to 260 nm, which was larger than the conventional one (B is 220 nm), and aggregates on the order of microns were detected even after lyophilization. Method F is a method of supplying purified water at a constant rate of 4 ml / min until 200 minutes after the start, and then supplying purified water at a constant rate of 2 ml / min for 300 minutes. When distilled off, micron particles were formed after the distillation. Further, the particle size after freeze-drying was 250 nm, and aggregates of micron order were generated after freeze-drying.

  On the other hand, in the distillation method in which purified water is supplied at a constant rate of 4 ml / min over 300 minutes from the start of the distillation of Method G, even if it is distilled in a short time of 12 hours, it is lyophilized after distillation. Later, micron particles, liquid surface film, and micron-order aggregates were hardly formed, and the particle size after freeze-drying was as good as 220 nm. Therefore, as a distillation method that does not generate micron order particles, a method of distilling while supplying purified water at a constant rate for a while from the start of the distillation is effective.

  Furthermore, under the condition that the purified water is continuously added at a constant rate in the distillation step, even if the PLGA is reduced to 5 g (Method A), 100 g (Method J), or even if it is distilled in a short time. No agglomerates or liquid surface films were produced. The mixing ratio of the solvents is shown in Table 3. Specifically, as shown in Table 4, the addition rate of purified water was 2 ml / min for 5 g of PLGA composite particles. When PLGA was 100 g, water was supplied at 4 ml / min for 250 minutes.

  Furthermore, methods G and J only add purified water for the first few hours of the distillation time (G is the first 5 hours of 12 hours, J is the first of 30 hours). The result was good. Therefore, it can be seen that the purified water does not need to be added over the entire period of the distillation step, and only a predetermined time from the beginning. Further, from the results of Method J, it was found that when the prescription amount of PLGA particles was increased, the amount of purified water (added purified water amount / distilled solvent amount) relative to the amount of solvent to be distilled out was smaller. It was.

  As described above, purified water can be added in small portions at a constant rate for a short time compared to the case where purified water is added several times in the middle of the distillation process or the one that is put together at the beginning. It was found that good quality PLGA particles can be produced.

  The reason for this is that if the concentration rate of PLGA particles increases too much during distillation, contact between the crystallized PLGA particles becomes active, and a solvent such as acetone that dissolves PLGA evaporates between the PLGA particles. It can be estimated that the PLGA is partially redissolved while moving. If the PVA concentration is increased in advance as in the examples of H and I, sufficient PVA particles are adsorbed around the PLGA particles, and acetone can be prevented from redissolving the PLGA particles, so that water is not added. It can be distilled off in a short time. However, when the PVA concentration is 0.2% or less, this re-dissolution with acetone cannot be completely suppressed. Therefore, for the short-time distillation, the purified water is added at a constant rate to remove the PLGA particles. It is desirable to reduce the concentration.

  PLGA composite particles obtained by adding an excipient and a water-soluble vitamin VC-PMG aqueous solution to the PLGA particle suspension after the distillation step and freeze-drying the whole have a bulk density of 0.044 to 0.087 g / cc. Because it is a fluffy powder, it is difficult to fill the small container with high density. Therefore, it is conceivable to increase the bulk density by the following method.

  VC-PMG is ground in advance with a mortar or the like and powdered so that the particle size is about several tens of μm. By mixing this VC-PMG with freeze-dried PLGA composite particles, the bulk density is increased by about 4 to 5 times compared to the case of adding VC-PMG aqueous solution and freeze-drying.

As an experimental example, VC-PMG crushed as described above is used.
PLGA: VC-IP: PVA: Mannitol (excipient): VC-PMG (freeze-dried): VCPMG (pulverized) = 1: 0.15: 0.1: 1: 1.125: 6.0525
As a result, PLGA composite particles were prepared. The bulk density of the composite particles and those freeze-dried by adding a VC-PMG aqueous solution were measured as follows. The above two types of PLGA composite particles were weighed and placed in a screw tube bottle having a body diameter of 30 mm and an inner diameter of 27 mm so as to have a height of about 15 mm in the screw. Height measurements were taken from five locations around the tube. Further, the measurement was performed under two conditions: a case where the sample was loosened (to the extent that the sample was weighed) and the height was 15 mm, and a sample was placed (after 180 times tapping) and the height was 15 mm. The results are shown in Table 6.

  As shown in the table, when VC-PMG ground is used, the bulk density is high, the fluidity is good, the filling into a small container is excellent, and vitamin C is supplied to the emulsion in a high content. it can.

  As described above, when commercializing as a milky lotion, it is necessary to sell it in a container in which the powder and the milky milk are put separately, and it is desired to make the milky milk effective in a small amount. Such containers typically have a filling volume of 1.5 cc. However, the composite particles produced by the above method are easy to fill into a container, have a high vitamin C concentration, and sufficiently contain vitamin C when mixed in an emulsion.

  Specifically, when 164 mg of PLGA composite particles produced as described above is filled in a 1.5 cc container, it is mixed with the emulsion contained in the emulsion container (5.5 ml), and the amount of vitamin C is mixed. (VC-PMG + VC-IP) is about 2.4% by weight, and becomes an emulsion containing vitamin C at a sufficiently effective level. In addition, when it is necessary to raise the compounding quantity of vitamin C more, the weight% of vitamin C can also be raised by raising the mixing amount of the grinded vitamin C.

  The nanoparticle-containing composition produced by the method for producing a nanoparticle-containing composition of the present invention has excellent skin permeability, can be easily filled in a container at a high density, and has a good feeling of use. It can also be applied to uses such as medical drugs or drugs for transdermal administration. Moreover, since it mixes well with a milky lotion etc., it can also be mixed and used for a milky lotion.

  Furthermore, by containing or combining vitamins or vitamin derivatives in the nanoparticles, it can be induced to the deep part of the skin, so that it is also suitable for use as a whitening agent or cosmetic liquid. Moreover, since the nanoparticle of this invention discharge | releases the chemical | medical agent contained gradually, it can supply a chemical | medical agent to the skin deep part over a long period of time. Therefore, it can be used as a nanoparticle-containing composition of a drug that acts for a long time. In addition, if vitamins and vitamin derivatives are added to the nanoparticles and then combined, the combined vitamins or vitamin derivatives exhibit a fast-acting action, and those contained in the nanoparticles act slowly. It can be used as a nanoparticle-containing composition.

It is drawing which shows the process of the manufacturing method of the nanoparticle containing composition concerning embodiment of this invention. (A) * (b) is a schematic diagram explaining the spherical crystallization method used for the manufacturing method of the medicine containing composite particles concerning one embodiment of the present invention, and (a) (B) shows the granulation process of the emulsion solvent diffusion method. It is drawing which shows the container of the nanoparticle containing composition concerning embodiment of this invention. It is drawing which shows the structure of the nanoparticle containing composition concerning embodiment of this invention. It is drawing which shows the experimental result which measured the permeability to the skin of the nanoparticle containing composition concerning embodiment of this invention, (a) is a comparative example, (b) is an Example, (c) is (b). The enlarged view of a part of is shown. It is drawing which shows the result of having measured the ratio of the reduced vitamin C in the amount of vitamin C at the time of making the nanoparticle containing composition concerning embodiment of this invention osmose | permeate skin, and vitamin C total amount. It is drawing which shows the result of having measured the quantity of the reduced vitamin C at the time of making the nanoparticle containing composition concerning embodiment of this invention osmose | permeate skin.

Claims (11)

A method for producing a drug-containing composite particle comprising a drug and a biocompatible polymer, comprising:
A nanoparticle formation step of adding at least a drug, a biocompatible polymer, and an organic solvent to an aqueous solution containing less than 0.5% by weight of polyvinyl alcohol to form drug-containing biocompatible nanoparticles to form a nanoparticle-containing solution; ,
A distillation step of distilling off the organic solvent from the nanoparticle-containing solution;
A method for producing a nanoparticle-containing composition, comprising: a compositing step for compositing the nanoparticles.   The method for producing a nanoparticle-containing composition according to claim 1, wherein the concentration of the polyvinyl alcohol is 0.2% by weight or less.   3. The method for producing a nanoparticle-containing composition according to claim 1, wherein water is added to the nanoparticle-containing solution for at least a predetermined period from the beginning of the distillation step.   The method for producing a nanoparticle-containing composition according to claim 3, wherein water is added at a constant rate in the distillation step.   The method for producing a nanoparticle-containing composition according to any one of claims 1 to 4, wherein the drug is a vitamin or a vitamin derivative.   The method for producing a nanoparticle-containing composition according to any one of claims 1 to 5, wherein in the complexing step, vitamins or vitamin derivatives are complexed together with the nanoparticles.   The method for producing a nanoparticle-containing composition according to any one of claims 1 to 6, wherein in the complexing step, sugar alcohol is complexed with the nanoparticles.   8. The method for producing a nanoparticle-containing composition according to any one of 1 to 7, wherein the complexing step is performed by freeze-drying.   A cosmetic comprising the nanoparticle-containing composition produced by the method for producing a nanoparticle-containing composition according to any one of claims 1 to 8.   A transdermal drug comprising the nanoparticle-containing composition produced by the method for producing a nanoparticle-containing composition according to any one of claims 1 to 8.   A nanoparticle-containing composition comprising nanocomposite particles in which nanoparticles containing vitamins or vitamin derivatives are combined with water-soluble vitamins or vitamin derivatives.

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