KR101799050B1 - Nanoparticles prepared from amphipilic star polymer with self-assembling and containing non-soluble compounds, and the skin external composition comprising the nanoparticles - Google Patents

Abstract

The present invention relates to a nanoparticle prepared by collecting a poorly soluble substance using an amphiphilic polymer having magnetic association and a cosmetic composition containing the nanoparticle. More particularly, the present invention relates to a nanoparticle comprising a core part having a plurality of branches made of a hydrophobic polymer; And an arm portion composed of a hydrophilic polymer which is combined with the hydrophobic polymer of the core portion to form a double block copolymer, and a nanoparticle prepared by incorporating a physiologically active component into the amphiphilic polymer having a stereostructure and having a self- As an active ingredient.

Description

TECHNICAL FIELD The present invention relates to a nanoparticle prepared by collecting a poorly soluble substance using an amphipathic star polymer having self-assembling properties and a cosmetic composition containing the nanoparticle. external composition comprising the nanoparticles}

The present invention relates to a nanoparticle prepared by collecting a poorly soluble substance using an amphiphilic polymer having magnetic association and a cosmetic composition containing the nanoparticle. More particularly, the present invention relates to a nanoparticle comprising a core part having a plurality of branches made of a hydrophobic polymer; And an arm portion composed of a hydrophilic polymer which is combined with the hydrophobic polymer of the core portion to form a double block copolymer, and a nanoparticle prepared by incorporating a physiologically active component into the amphiphilic polymer having a stereostructure and having a self- As an active ingredient.

In the field of cosmetics and pharmaceuticals, there has been a demand for development of formulations capable of stably collecting various substances having efficacy on the skin and effectively acting on the skin to improve the condition of the skin. However, many physiologically active substances are poorly soluble or unstable in water phase, and often bind or react with other substances to make the whole system unstable.

In order to overcome this problem, it has been appreciated as a core technology that techniques utilizing emulsified particles having a size of nanometer to micrometer size to stably and easily collect an effective substance in a formulation. As a representative example, a nanoemulsion is prepared by preparing a semi-dosage form using a surfactant having a specific hydrophilic-hydrophobic ratio value, and then treating it with a high-pressure emulsifier or the like to form fine emulsified particles. , Which is a spherical or other type of particle structure in which single or multiple membranes are formed while collecting an efficacious substance. Also, techniques for producing nano-sized emulsified particles using a microemulsion in which three phases of an emulsifier, oil and water are formed at optimal concentrations are reported.

These emulsion particles are in dynamic equilibrium with the outer surface of the emulsion layer, so that the active ingredient in the emulsion continuously comes into contact with water, which causes a problem of denaturation due to oxidation or decomposition. In addition, since the emulsion layer is very weak and unstable physically and chemically, the emulsion layer is destroyed due to contamination with an organic or inorganic substance having a salt or electric charge, and the emulsion layer is very weak against heat or light, which is unstable in long-term storage. As described above, the nanoparticles containing an active ingredient using a low molecular weight emulsifier are not only unsuitable for capturing an active ingredient having an unstable tendency in an aqueous solution, but also considerably restricted in formulation of emulsified particles.

In order to overcome the instability of the nanoparticles and to develop nanoparticles capable of trapping and transferring physiologically active components more stably and effectively, a linear amphiphilic polymer having self-assembly prepared by bonding a hydrophobic polyester polymer with a hydrophilic polymer Has been reported as a method for producing nanoparticles. The nanoparticles can be stably produced at a nanoscale level by the self-assembly force of the polymer itself without adding various additives, dispersants or surfactants to overcome the mechanical process requiring high energy, which is a disadvantage of conventional nanoparticles, Of particles can be formed. However, nanoparticles formed of such linear amphiphilic polymers have a disadvantage in that the stability of the nanoparticles in a formulation is greatly reduced due to disadvantages such as a particle size of several hundred nanometers and a large particle size distribution when a large amount of physiologically active substance is contained Lt; / RTI > In addition, the disadvantages common to the conventional techniques developed so far include that the stability of the colloid is lowered by the colloid instability mechanism such as Ostwald ripening, precipitation and aggregation, and the colloid instability increases as the solid content increases It can not contain a high content of nanodispersions.

Accordingly, the present inventors have made efforts to produce nanoparticles that stabilize the active ingredient more efficiently and stably, and as a result, they have found that the conventional linear polymer structure having one hydrophobic group and one hydrophilic group in one molecule is removed and a three- Thereby forming smaller and more uniform nanoparticles with a smaller amount of use, thereby improving the stability of the active ingredients in the formulation. Thus, the present invention has been completed.

Accordingly, an object of the present invention is to provide nanoparticles in which an active ingredient is stabilized using a polymer having a three-dimensional structure and a cosmetic composition containing the same.

In order to achieve the above object, the present invention provides a polymer electrolyte fuel cell comprising: a core part having a plurality of branches made of a hydrophobic polymer; And an arm portion composed of a hydrophilic polymer which forms a double block copolymer by bonding with the hydrophobic polymer of the core portion, the nanoparticles prepared by incorporating a physiologically active component into the amphiphilic polymer having a three-dimensional structure do.

In addition, the present invention provides a cosmetic composition containing the nanoparticles.

The nanoparticles prepared by using the amphipathic star polymer having self-assembly prepared according to the present invention are polymer nanoparticles containing a physiologically active substance insoluble in water at a high concentration and require no mechanical force The nanoparticles of the present invention can be used in various formulations as well as being excellent in colloidal stability and uniform in particle size of several tens of nanometers. PCG-404, which is an amphipathic star polymer, is biodegradable in vivo and is harmless to the human body. In addition, the star polymer surfactant having a plurality of hydrophilic groups and plural hydrophobic groups in one molecule is excellent in solubility in water and exhibits an interfacial property showing a critical micelle formation ability (CMC) at a lower concentration, Not only the physical properties but also the emulsifying power, the dispersing ability, the washing power, the mixing property with other compounds and the like can be improved.

Fig. 1 shows the particle size distribution of the nanoparticles prepared in Example 3. Fig.

Hereinafter, the present invention will be described more specifically.

The present invention relates to a nanoparticle prepared by preparing an amphipathic star polymer having a three-dimensional structure with magnetic crystallization and incorporating an insoluble physiologically active ingredient therein.

The amphipathic star polymer having a three-dimensional structure used in the present invention has a core portion having a plurality of branches made of a hydrophobic polymer (A); And an arm portion composed of a hydrophilic polymer (B) which forms a double-block copolymer (A-B) by bonding with the hydrophobic polymer of the core portion. At this time, the number of branches of the polymer chain (A-B) constituting the polymer is preferably 3 to 8. If the number of branches is less than 3, it is impossible to form a three-dimensional structure because it is a conventional linear structure. If the number of branches is more than 8, there is a high possibility of occurrence of aggregation due to the complexity of the structure and precise control of the polymer structure is difficult Problems arise.

The hydrophobic polymer (A) forming the core portion is a polymer having a molecular weight of 1,000 to 100,000 Da, and examples thereof include poly-caprolactone, poly-L-lactic acid, poly-D, L-lactic acid, poly- poly-L-lactic acid-co-glycolic acid, poly-L-lactic acid-co-glycolic acid, poly-D, L-lactic acid-co-glycolic acid and copolymers thereof. At this time, as a reaction initiator for preparing the core part, TMP (trimethylol propane), PTOL (Pentaerythritol), Cyclotriphosphazene, Prochloroglucinol, Silsesquioxane (Silsesquioxane), or cubic silsesquioxane.

The hydrophilic polymer (B) forming the arm portion may be selected from the group consisting of polyethylene glycol, polyvinyl pyrrolidone and polyethylene imine, and has a molecular weight of 1,000 to 100,000 Da.

The hydrophobic polymer (A) in the core portion and the hydrophilic polymer (B) in the arm portion may be combined at a weight ratio of 1 to 9 to 9 to 1 to form a double block copolymer. The form of the bond is not particularly limited, For example, a covalent bond such as an ester bond, an anhydride bond, a carbamate bond, a carbonate bond, an imine bond or an amide bond, a secondary amine bond, a urethane bond, a phosphodiester bond or a hydrazone bond.

There are no particular restrictions on various physiologically active ingredients which can be solubilized in the stereostructured amphoteric star polymer having the above-mentioned self-association, but examples thereof include rhubarb, generic, hesperitin, hesperidin, catechin, isoflavone, Vitamin D and derivatives thereof, vitamin A and derivatives thereof, pro-vitamin D ₃ and derivatives thereof, urzol, and derivatives thereof, such as fucose, fucose, isosorbide dinitrate, chloramphenicol, sulfamethosazole, caffeine, cimetidine, sodium diclofenac, coenzyme Q ₁₀ , vitamin E and its derivatives, But are not limited to, lactic acid, oleic acid, rosmarinic acid, 18-beta licoric acid, gabridine, allylic acid, polyphenol, esculine, epigallocatechin gallate, tumeric acid, ginsenoside, tetrahydrocurcuminoid, Asiatica, beta-carotene, Asian ticoside, fenesol, beta-sitosterol, linoleic acid, gamma linoleic acid, resveratrol, , Ginkgo biloba, triclosan, minoxidil, natural essential oil, ceramide, sphingosine, white porcelain extract, Sasa extract, licorice extract, yulmu extract, finasteride, ginsenoside or Compound K :

In one embodiment of the present invention, the compound K, which is one of the ginseng saponin derivatives, is incorporated in the amphoteric star polymer having the three-dimensional structure having the self-rotation property to prepare nanoparticles. The compound K is a ginsenoside having a structure in which a sugar (glucose) is attached to uglycon among saponin components of ginseng, and has a pharmacological action such as inhibiting cancer cell proliferation, inhibiting tumor growth, and enhancing anticancer activity of an anticancer drug ought.

The process for preparing nanoparticles according to the present invention comprises the following steps:

a) preparing an amphiphilic star polymer having a three-dimensional structure having a self-assembly and dissolving the polymer in an organic solvent;

b) dissolving and stirring the active ingredient in the polymer melt; And

c) introducing the mixed solution prepared in steps a) and b) into an aqueous solution to form nanoparticles;

d) evaporating the organic solvent.

The content of the physiologically active ingredient trapped in the nanoparticles may be adjusted depending on the purpose and the case, and it is generally preferable to use 1 to 50% by weight based on the total weight of the nanoparticles. The average particle diameter of the prepared nanoparticles is 1 to 1,000 nm, more preferably 10 to 500 nm.

Examples of the organic solvent that can be used when the polymer nanoparticles are prepared in an aqueous solution using the biodegradable star polymer block of the present invention include acetone, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane, tetra A solvent selected from the group consisting of methanol, ethanol, ethyl ether, diethyl ether, hexane and petroleum ether, or a mixture thereof may be used as the organic solvent, for example, ethanol, ethyl acetate, acetonitrile, methyl ethyl ketone, methylene chloride, In the case of manufacturing by this production method, the physiologically active component is collected in the hydrophobic core portion of the self-assembled star-shaped polymer particle, and the hydrophilic polymer chain is oriented on the surface of the particle, and is stably dispersed in the water phase. The dispersed nanoparticles have a particle diameter of several tens to several hundreds of nanometers depending on the composition and manufacturing method of the polymer. When the nanoparticles are added to cosmetics, the physiologically active ingredients do not directly contact the emulsified product or the skin product, As well as various cosmetic compositions such as creams, milky lotions, and lotions.

The cosmetic composition according to the present invention contains the nanoparticles as an active ingredient, and the content thereof may be 1 to 50% by weight based on the total weight of the composition. There are no particular restrictions on its formulation, and there are no particular restrictions on the formulation, and there are no particular restrictions on the formulation of hair tonics, scarf treatments, hair creams, general ointments, softening liquors, convergent lotions, nutritional lotions, eye creams, nutritional creams, massage creams, cleansing creams, cleansing foams, Such as powder, essence, pack, body lotion, body cream, body oil, body essence, makeup base, foundation, hair dye, shampoo, rinse, body cleanser, toothpaste, mouthwash, lotion, gel, patch or spray .

Hereinafter, the present invention will be described more specifically with reference to examples and test examples. It is to be understood that the scope of the present invention is not limited to these embodiments and that variations, substitutions, and insertions conventionally known in the art can be carried out, And this is included in the scope of the present invention.

[Example 1] Production of polycaprolactone-block-polyethylene glycol star polymer of steric structure

1) Production of core part using hydrophobic polymer

0.34 g of pentaerythritol (reaction initiator) represented by the formula (2) having four terminal hydroxyl groups in a dried 250 mL flask, 50 g of caprolactone monomer and 0.04 mL of a catalyst octanoate tin were added. After charging the magnetic bar and connecting the condenser, the process of adding vacuum and filling with nitrogen was repeated three times. The flask was sealed, placed in an oil bath at 110 DEG C, and polymerized for 12 hours while stirring. After the polymerization was completed, the temperature was lowered to room temperature, and then 100 mL of methylene chloride was added thereto to completely dissolve and precipitate in an excess amount of methanol. This process was repeated three times to remove unreacted monomers and oligomers. After the precipitation, the obtained sample was dried under reduced pressure at room temperature for 12 hours or more to obtain 45 g of a star polymer copolymer composed of polycaprolactone evenly grown on four branches. Hydrogen ( ¹ H) nuclear magnetic resonance analysis confirmed that caprolactone was normally opened at each end of the initiator to form a copolymer. It was confirmed that the number average molecular weight was 12,000 Da and the amount of residual monomers and catalyst was negligible through the integration ratio of ethylene peak of polycaprolactone and chain end group.

2) Formation of dark area using hydrophilic polymer

19.1 g of the polycaprolactone star polymer (core part) prepared in 1) above and 20 g of monomethoxy polyethylene glycol substituted with a carboxyl group at one end were added to a 500 mL flask. Then, a magnetic bar was charged and a capacitor was connected And sealed. Vacuum was applied at 80 DEG C for two hours, dried and filled with nitrogen. 1.2 g of DPTS catalyst and 50 mL of methylene chloride were added, followed by heating gradually to obtain a homogeneous phase, which was then cooled to room temperature. 0.916 mL of DIPC was added, and the esterification reaction was conducted for 72 hours while stirring at room temperature. After the reaction was completed, diisopropyl urea was removed by filtration. 50 mL of methylene chloride was added to dilute and then precipitated in excess ethyl ether. The sample obtained after the precipitation was dried under reduced pressure at room temperature for 12 hours or more to obtain a star polymer block copolymer (hereinafter referred to as "PCG-404") of the following formula 3 in which polyethylene glycol was bonded to the terminal ends of four polycaprolactones by an esterification reaction g. Hydrogen ( ¹ H) nuclear magnetic resonance (NMR) analysis confirmed the formation of an ester bond in the final product. The number average molecular weight was 38,000 Da through the integration of polycaprolactone and ethylene glycol peak.

Wherein A is a compound represented by the following formula 4:

In the above formula, m and n are integers of 2 to 500.

[Comparative Example 1] Production of linear polycaprolactone-block-polyethylene glycol copolymer

10 g of monomethoxypolyethylene glycol (molecular weight: 5,000) and 10 g of? -Caprolactone monomer each having a hydroxyl group at one end were added to a dried 50 mL flask, and 0.05 g of tin octoate as a catalyst was added. The magnetic bar coated with Teflon was placed in a flask, and a vacuum was applied to the flask containing the reactant for 30 minutes and then sealed. The sealed flask was placed in an oil bath at 150 캜 and polymerization was carried out for about 6 hours.

The mixed solution in the flask completed polymerization was completely dissolved by adding 20 mL of methylene chloride as a solid solid, and precipitated in excess of ethyl ether. This process was repeated three times to remove unreacted monomers and oligomers. The sample obtained by the precipitation was dried under reduced pressure at room temperature for 12 hours to finally obtain 17.3 g of a linear polycaprolactone-block-polyethyleneglycol block copolymer.

Hydrogen ( ¹ H) nuclear magnetic resonance analysis confirmed that caprolactone was opened at the terminal of monomethoxypolyethylene glycol to form a copolymer. It was confirmed that the number average molecular weight was about 9,200 Da through the integral ratio of peaks corresponding to monomethoxy polyethylene glycol and polycaprolactone.

[Examples 2 to 5 and Comparative Example 2] Preparation of nanoparticles

Example 1 (PCG-404), Comparative Example 1 and Compound K were added to 50 g of ethanol in the amounts shown in Table 1, respectively, and stirred to dissolve uniformly. After confirming that it was dissolved, it was slowly added to 50 g of distilled water and stirred. The mixture was stirred for about 1 minute, the ethanol was evaporated while warming to 50 to 60 DEG C, and finally, the dispersion of nanoparticles of Examples 2 to 5 and Comparative Example 2 containing Compound K was prepared.

ingredient Example 2 Example 3 Example 4 Example 5 Comparative Example 2 Example 1 (PCG-404) 0.5 g 0.5 g 0.5 g 0.5 g - Compound K 0.1 g 0.25 g 0.4 g 0.5 g 0.5 g Comparative Example 1 - - - - 0.5 g

[Test Example 1] Size measurement by dynamic light scattering of nanoparticles

The average particle size of the nanoparticles prepared in Examples 2 to 5 and Comparative Example 2 was measured using Zetasizer 3000 Hsa manufactured by Malvern, UK. The scattering angle was fixed at 90 ° and the temperature was measured while keeping the temperature at 25 ° C. The results are shown in Table 2 below, and the particle size distribution of Example 3 is shown in FIG.

Test substance Average particle size (nm) Critical micelle formation capacity (CMC) Example 2 29.8 4.56E-04 Example 3 28.2 4.21E-04 Example 4 64.5 4.75E-04 Example 5 39.6 3.91E-04 Comparative Example 2 120.0 6.17E-04

[Formulation Example 1] Underwater emulsifier type

The composition of the water-in-oil emulsion type containing the star-shaped polymer copolymer prepared in Example 1 is shown in Table 3 below (Unit: wt%).

ingredient content Cetearyl Alcohol (CETOS KD) One Hydrogenated C6-14 olefin polymer (Puresyn 4) 10 Triethanolamine (TEA) 0.08 Carbopol (Carbopol 981 (1%)) 8 Methylparaben (DANISOL- M) 0.2 Propylparaben (DANISOL- P) 0.1 Distilled water Balance Example 1 (PCG-404) One

Claims (10)

A core portion having a plurality of branches made of poly-caprolactone as a hydrophobic polymer; And
An arm portion made of polyethylene glycol which is a hydrophilic polymer which forms a double block copolymer by binding with the hydrophobic polymer of the core portion
A nanoparticle prepared by incorporating a physiologically active component into an amphiphilic polymer having a three-dimensional structure,
The nanoparticles having the number of branches consisting of the double-block copolymer constituting the amphipathic polymer having the three-dimensional structure having the self-assembly. delete The method according to claim 1,
The hydrophobic polymer has a molecular weight of 1,000 to 100,000 Da. The method according to claim 1,
A nanoparticle prepared by using pentaerythritol (PTOL) as a reaction initiator for producing the core part. The method according to claim 1,
The hydrophilic polymer has a molecular weight of 1,000 to 100,000 Da. The method according to claim 1,
Wherein the hydrophobic polymer and the hydrophilic polymer are mixed in a weight ratio of 1: 9 to 9: 1. The method according to claim 1,
Wherein the hydrophobic polymer and the hydrophilic polymer form a double block through an ester bond. The method according to claim 1,
Wherein the physiologically active ingredient is incorporated in an amount of 1 to 50% by weight based on the total weight of the nanoparticles. 9. A cosmetic composition comprising nanoparticles according to any one of claims 1 to 8 as an active ingredient. 10. The method of claim 9,
The composition can be used as a hair tonic, a scarf treatment, a hair cream, a general ointment, a softening agent, a convergent lotion, a nutritional lotion, an eye cream, a nutritional cream, a massage cream, a cleansing cream, a cleansing foam, a cleansing water, a powder, Wherein the composition is formulated into a lotion, a body cream, a body oil, a body essence, a makeup base, a foundation, a hair dye, a shampoo, a rinse, a body cleanser, a toothpaste, an oral cleanser, a lotion, a gel, a patch or a spray.

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