WO2007145395A1

WO2007145395A1 - Method of stabilization of active ingredients that have low solubility, using hollow type multi-layered microcapsule made of hydrophobic polymer/polyhydric alcohols and preparation method thereof, and cosmetic composition containing the microcapsules

Info

Publication number: WO2007145395A1
Application number: PCT/KR2006/003149
Authority: WO
Inventors: Dong-Hwan Lee; Jin-Hui Kim; Bum-Chun Lee; Hyeong-Bae Pyo
Original assignee: HAN-BUL COSMETICS Co Ltd
Current assignee: HAN-BUL COSMETICS Co Ltd
Priority date: 2006-06-13
Filing date: 2006-08-11
Publication date: 2007-12-21
Anticipated expiration: 2008-12-13
Also published as: KR100781604B1

Abstract

The present invention relates to a method of stabilizing active ingredients that have low solubility, using hollow-type, multi-layered microcapsules made of hydrophobic polymer/polyols, a method preparing the hollow-type, mult i layered microcapsules, and a cosmetic composition containing the microcapsules.

Description

[DESCRIPTION] [Invention Title]

METHOD OF STABILIZATION OF ACTIVE INGREDIENTS THAT HAVE LOW SOLUBILITY, USING HOLLOW TYPE MULTI-LAYERED MICROCAPSULE MADE OF HYDROPHOBIC POLYMER/POLYHYDRIC ALCOHOLS AND PREPARATION METHOD THEREOF, AND COSMETIC COMPOSITION CONTAINING THE MICROCAPSULES [Technical Field]

<i> The present invention relates to a preparing method of hollow-type multi-layered microcapsules containg copious amounts of low-soluble cosmetic ingredients with low solubility, and a cosmetic composition containing the microcapsules. [Background Art]

<2> Polyphenols are one of the most important natural substances that possess anti-free radical and anti-oxidant activities ( 'Polyphenol ic Phenomena¹, A. SCALBERT, Editor, INRA Editions, Paris, 1993). Polyphenol compounds containing flavonoids have valuable biological features related to anti-free radical activity. These compounds can prevent the harmful effects of free radicals on skin, and can protect against accelerated skin aging resulting from sunlight exposure. They also are useful as antitumor agents. The compounds can prevent the onset of diseases that are caused by free radicals, such as cancer. Polyphenols containing flavonoids also are used to preserve foods owing to their antioxidant properties.

<3> Flavonoids, one class of polyphenols, have a 2-phenyl-benzo-r-pyrone ring, namely a flavone structure, "flavonoids is a generic term for flavans, flavonones, flavones, anthocyanins, etc. At present, about 3,000 species of flavonoids are known, and they commonly have 2-phenyl-chroman linkage as their basic structure. Flavonoids can be classified into several groups according to the degree to which the central pyran ring is oxidized. In nature, flavonoids occasionally exist in free form, but more often they are present in the glycoside form, linked with rhamnose, glucose, rutinose, etc.

<4> Flavonoids, a group of phytochemicals renowned for their anti-candiosis properties, have additional disease-fighting properties, including antioxidant, tumor, thrombotic, inflammatory, allergic and microbial activities. Discovery of the physiological functions of flavonoids led to the development of foods, pharmaceuticals and cosmetics containing the compound. Flavonoids possess antioxidant and enzyme-inhibiting activities. Therefore, the compound is used in cosmetics, pharmaceuticals and foods. Various forms of flavonoids are used in cosmetics because of their anti-wrinkle, whitening, antioxidant and moisturizing effects.

<5> However, the most important characteristic of a cosmetic ingredient is stability. The stability of flavonoids is influenced by various physical and chemical factors in the environment, such as oxygen, light, high temperature, extreme pH, and presence of other cosmetic ingredients. In addition, the stability of flavonoids may deteriorate depending on what environmental factors are present during manufacturing, circulation, consumer's use, and storage.

<6> If the flavonoid is simply mixed with other cosmetic ingredients, it is difficult to preserve its inherent structure and function. Moreover, the color may change as a result of deterioration of the active ingredient. A decrease in the content of active ingredient results in deterioration of function. Therefore, many researchers are seeking effective methods of containing the active ingredients in cosmetics.

<7> Another problem is the very poor solubility in water or oil of the active ingredient. Since the type of flavonoid that is used as a cosmetic ingredient, has poor solubility in water or oil, exceeding the apporopriate concentration causes the ingredient to form needle-shaped crystals, and the cosmetic feels abrasive.

<8> The tendency of flavonoids to form crystals results from the strong interactions among the molecules, making the solubility in solvents poor. As a result, it is not easy to formulate cosmetics containing polyphenols such as flavonoids. Therefore, improvements in the solubility of insoluble active ingredients are needed. <9> As an example, triterphenoid, which is known to possess anti-aging, anti-inflammatory, moisturizing and anti-fungal activities, cannot be used at a concentration greater than 0.02 wt% because of its poor solubility either in water or in solvents.

<io> Quercetin, a representative flavonoid, which has powerful antioxidant, free-radicals scavenging, liver-protective, inhibition of platelet- aggregation, anti-allergy, and anti-inflammatory effects, has solubilities of 0.0003% in water, 0.012% in myristic acid isopropyl, and 0.156% in oleyl alcohol- all common cosmetic solvents.

<ii> Therefore, many researchers have explored ways to increase the stability and solubility of these insoluble ingredients. Representative stabilization methods include the following: the physical method, which stabilizes the active ingredients by isolating them from water or solvent via encapsulation; and, the chemical method, which stabilizes the active ingredients by adding antioxidants or by transforming them into derivatives.

<12> Another solution is liposomes, which are widely used in pharmaceuticals, cosmetics and foods. Liposomes are classified into multi lamella vesicles (MLV) and uni lamella vesicles (ULV), which are further reclassified into large (LUV) and small unilamella vesicles (SUV). Among these liposomes, LUV contains the largest number of active molecules, but are unstable; SUV are the most stable, but cannot contain many molecules. Furthermore, the stability of liposomes in cosmetics has not been sufficiently verified.

<i3> As a stabilization method, microcapsulation has many advantages. Microcapsules protect sensitive molecules from deterioration and control delivery of active molecules.

<14> As detailed examples, a microcapsule preparation method using natural macromolecules, such as albumin, gelatin and starch, ethylcellulose or polyalkylcyanoacrylate [J. of Pharm. Sci. 1970, vol.59, 1367; J. of Pharm. Pharmacol. 1988, vol.40, 754; J. of Microencapsulation 1991, vol.8, 335; J. of Microencapsulation 1989, vol. 6, 1; Polymer Eng. & Sci. 1989, vol. 29, 1746], to coat and encapsulate active molecules, thereby separating them from the external environment [Advanced Drug Delivery Reviews 1997, vol.28, 25-42; US patent 4,954,298; US patent 5,788,687; US patent 5,916,598] has been reported. Among others, multi-emulsion method [US patent 4,954,298] also has been reported.

<i5> However, the inner structures of microcapsules are dense. Therefore, the microcapsules have poor active molecule content. Porous microcapsules are problematic because solvent water filters into the capsule and deteriorates active molecules.

<16> To apply microcapsules for cosmetics, not only is physicochemical stability of the microcapsule against environmental factors, such as water, surfactant, light, etc., required, but the encapsulated active molecules also must be stable. Until now, no solution to this problem has been proposed. Capsulation using coacervation by changing temperature or pH, or by adding counterpart ions or solvents is widely known. In the coacervation method, gelatin and acarcia gum are generally used as the counterpart ions or solvent. In addition to coacervation between macromolecules, a method using anionic and cationic surfactants has been proposed. The aforementioned methods require that major bases of the capsule are hydrophilic. The base is dispersed and dissolved in water- phase to produce an emulsion", the emulsion is then added to another water- phase containing counter-ionic macromolecules or salt to induce coacervation. Or the emulsion is added to counter-ionic macromolecular or surfactant aqueous solution to induce coacervation.

<17> Therefore, lipophilic or hydrophilic active ingredients can be encapsulated, but active molecules with low solubility in water or oil, such as flavonoids, cannot be sufficiently encapsulated. Because an excess amount of water negatively affects the stability of flavonoids, coacervation is not effective for encapsulation and stabilization of low-soluble active ingredients.

<I8> Moreover, when active ingredients such as flavonoids, which are known to be heavily influenced by metal salts or ionic substances, are encapsulated by coacervation-a process that relies on ionic macromolecules or ionic salts as the base, they become difficult to stabilize.

<i9> In usual encapsulation methods, lipophilic molecules generally are encapsulated in hydrophobic macromolecules, and water-soluble molecules are encapsulated in hydrophilic macromolecules. However, water permeates the hydrophilic macromolecular capsules in which water-soluble molecules are encapsulated, and the encapsulated active molecules are eluted and subsequently deteriorate.

<20> To improve the stability of water-soluble compounds, Jeffery et al . proposed a double- emulsion-solvent vaporization method in 1993. This method improves the stability of encapsulated, water-soluble compounds compared with the simple water-in-oil (w/o) emulsion-solvent vaporization method. However, because water-soluble molecules disperse into the outer water- phase, high encapsulation yield cannot be expected.

<2i> Encapsulation yields for active molecules that rarely dissolve in water are very low by this method. In addition, because the active molecules dissolved in water using this method, the improvement in stability is only marginal .

<22> Therefore, studies of hollow-type microcapsules have been performed to solve the aforementioned problems. Korean patent No. 537952 (2005.12.14.) describes hollow-type hydrophobic macromolecular microcapsules and a method for preparing them, but, the capsule could only encapsulate water-soluble active molecules. And, since bases of the inner water-phase and the outermost water-phase are water, this method is not appropriate for dissolving and encapsulating low-soluble active molecules, such as polyphenols. In addition to this problem, osmotic pressure causes inner active molecules to be eluted to the outermost water-phase. [Disclosure] [Technical Probleml

<23> It is an object of the present invention to provide hollow-type, multi- layered microcapsules which could improve the stability of low-soluble active ingredients and contain large amounts of low-soluble active ingredients, especially at least one selected from polyphenol compounds, flavonoids, linoleic acid, coenzyme Q-IO and lipoic acid.

<24> It is another object of the present invention to provide method for preparing hollow-type, multi-layered microcapsules using polyhydric alcohol.

<25> It is another object of the present invention to provide a cosmetic composition containing hollow-type, multi-layered microcapsules made using polyhydric alcohol . [Technical Solution]

<26> Therefore, to solve these problems and overcome the difficulties caused by crystallization of insoluble active molecules, the present inventors prepared hollow-type, multi-layered microcapsules using hydrophobic macromolecules, polyhydric alcohols (hereafter synonymous with 'polyol' and hydrophilic or amphiphilic macromolecules. The hollow-type, multi-layered microcapsules were able to encapsulate a large number of low-soluble active molecules and to improve the stability of encapsulated low-soluble active molecules by separating them from environmental factors, such as high temperature, oxygen and ultra-violet ray, and from factors in the inner cosmetic base, such as water and surfactant.

<27> In particular, the cosmetic composition of the present invention encapsulated polyphenols such as flavonoids and triterphenoid, which possess low solubilities in water and oil, into hollow-type, multi-layered microcapsules. The low-soluble active molecules encapsulated in hollow-type, multi-layered microcapsules of the present invention can be separated from factors in the inner cosmetic base, such as water and surfactant, and also from factors in the outer environment, such as high temperature, oxygen, UV and so on. Therefore, the cosmetics formulated in the present invention are stabilized and inhibit deterioration, change in color, and crystallization of the active molecule.

<28> In another preferable example of the present invention, the aforementioned polyphenol compound is at least one or its derivative selected from a group containing flavonoids; isoflavonoids; neoflavonoids; gallotannins and ellagitannins; cathechols and their derivatives, such as caffeic acid, dihydrocaffeic acid, protocatechuic acid, chlorogenic acid, isochlorogenic acid, gentisic acid, homogentisic acid, garlic acid, hexahydroxydiphenic acid, ellagic acid, rosemaric acid or litospermic acid; phenolic acid derivatives, especially containing their esters or heterosides', curcumin." polyhydroxylated coumarine," monocyclic or polycyclic polyphenols, such as polyhydroxylated lignans, neolignans, or silymarin. These polyphenols may be the extracts of plants.

<29> In addition, the aforementioned polyphenol may be selected from a group comprising flavones, such as apigenol or luteolol ; flavonols, such as quercetin or kaempferol; flavones or flavonol heterosides, such as rutin or its derivatives; flavanones, such as naringenin or hesperetin; flavanone heterosides, such as naringin, hesperidin or diosmin; flavanone derivatives, such as diosmoside and abiflavonoid; flavone or flavone dimmers, such as amentoflavon; calcones, such as isoliquirtigenin or hesperidin methylealcone; flavonol ignan such as silybin, silichristin or silidianin; flavan-3-ols, such as (+)-cathechol or (-)-epichathechol ; polymers consisting of basic monomers, generally known as 'proantocyanidin or 'polymerized tanin' especially, procyanidolic oligomer (PCO) consisting of 2 - 8 units of proantocyanidin; or antocianosides, such as malvoside. The aforementioned flavonoids may be extracts of plants.

<30> Another object and feature of the present invention will be apparent to person skilled in the art according to the description of the present invention.

<3i> To achieve the objects of the present invention, the hollow-type, multi-layered microcapsules of the present invention are characterized to be stabilized and dissolved low-soluble active ingredient using polyol. The microcapsule is characterized to contain large amounts of low-soluble active ingredients, and to have a multi-layer structure using either hydrophilic or amphiphilic macromolecules. The present invention is about the hollow-type, O

multi-layered microcapsules of the present invention in which the outer coat is made of hydrophobic macromolecule, a hollow is formed in the outer coat, and, in the hollow, at least one microsphere encapsulating low-soluble active ingredient in hydrophilic or amphiphilic macromolecules; a method of preparing the microcapsules; and, a cosmetic composition containing the microcapsules.

<32> The hollow-type, multi-layered microcapsules of the present invention were prepared using a multi-emulsion method with polyhydric alcohol and volatile organic solvent. A polyol pase 1-in-oil (Pl/O) type first emulsion was prepared from polyol phase 1 (Pl), which was prepared by dissolving low- soluble active ingredients and hydrophilic or amphiphilic macromolecules, and an oil-phase (O), which consists of a volatile organic solvent containing hydrophobic macromolecules. A polyol phase 1-in-oil-in polyol phase 2 (P1/0/P2) type multi-emulsion was prepared by adding the Pl/O type first emulsion to a polyol phase 2 (P2), which contained at least one emulsion stabilizer. Subsequently, the volatile organic solvent was removed by solvent evaporation-solvent extraction and the hollow-type, multi-layered microcapsules of the present invention were formed.

<33> The cosmetic composition of the present invention is characterized to contain 0.001-25.0 wt% hollow-type, multi-layered microcapsules of the present invention.

<34> The size of the hollow-type, multi-layered microcapsules of the present invention can be varied by changing the synthesis methods, such as stirring method, stirring instrument, rotating speed, temperature and so on, as is well-known to person skilled in the art. The synthesized microcapsules of the present invention range in diameter approximately 0.01 j^n ~ 500 im-

<35> The preparation method of the hollow-type, multi-layered microcapsule of the present invention is explained in detail.

<36> (1) Preparation of polyol phase 1 by adding the low-soluble active ingredient and hydrophilic or amphiphilic macromolecules to polyol-'

<37> 0.1-20 wt% of hydrophilic or amphiphilic macromolecules was added and stirred to the polyol phase 1 to form a homogeneous dispersion by heating or by mechanical method. Then, 0.01-40 wt% of the low-soluble active ingredient was added to polyol phase 1, gently stirred, and prepared poly phase 1 containing low-soluble active ingredient and hydrophilic or amphiphilic macromolecule.

<38> Polyol is at least one selected from low-molecular weight alcohols'- polyethyleneglycol , polypropyleneglycol , and their copolymers, butyleneglycol , propyleneglycol , glycerin, ether containing hydric group, such as diethyleneglycol monoethyl ether. The appropriate content of the polyol is 40-99.8 wt% of total polyol phase 1. The appropriate glycerin content is 20-95 wt% of total polyol phase 1. If less than 20 wt% is added, it is difficult to form the polyol-in-oil (P/0) type first emulsion of the present invention since the alcohol phase cannot be separated from the volatile organic solvent. If more than 95 wt% glycerin is added, low-soluble active molecules cannot be effectively dissolved or dispersed.

<39> The content of the active ingredient dissolved in polyol phase 1 can be varied according to the intended purpose. But, to form a stable first emulsion, 0.01-40 wt% of the total polyol phase 1, preferably 1-10 wt% should be added.

<40> The hydrophilic or amphiphilic macromolecules dispersed into the polyol phase 1 may vary between 0.1-20 wt%, preferably 0.1-10 wt% of the total polyol phase 1 to form a stable first emulsion.

<4i> (2) Preparation of the oil-phase by adding hydrophobic macromolecules and surfactant to a volatile organic solvent:

<42> 1.0-20 wt% of the hydrophobic macromolecules was dissolved into a volatile organic solvent to prepare oil-phase. If less than 1.0 wt% was added, the microcapsules of the present invention did not form. If more than 20 wt% was added, the P/0 first emulsion did not form because the high viscosity prevent the macromolecules from dispersing in the organic solvent. Therefore, the appropriate content of the hydrophobic macromolecules is 1.0-20 wt% of the total oil-phase, preferably 5-15 wt%. <43> (3) Preparation of the P/0 type first emulsion by adding the polyol phase 1 to the oil-phase:

<44> The P/O-type first emulsion was prepared by adding and homogenizing the oil-phase with the polyol phase 1. The content of the oil-phase may vary according to the species of hydrophobic macromolecule. The oil-phase should contain l~15-fold polyol phase 1, preferably 2~10-fold. If less than 1-fold is added, the P/O-type emulsion cannot form efficiently, and the encapsulation rate of the low-soluble active ingredient is lowered. If more than 15-fold is added, the inner capacity of the hollow-type, multi-layered microcapsules and the content of the active ingredient are reduced.

<45> (4) Preparation of the polyol phase 2 by adding emulsion stabilizer to the polyol and water mixture'•

<46> Polyol phase 2 was prepared by adding 0.05-10 wt% of the emulsion stabilizer to the mixture of polyol and water. The polyol contained 20-99.95 wt% glycerin and 60-99.95 wt% of at least one selected from polyethyleneglycol , polypropyleneglycol , their copolymer and their derivatives; low molecular weight alcohol compounds, such as butyleneglycol and propyleneglycol ; and, ether containing hydric group, such as diethyleneglycol monoethyl ether. If less than 20 wt% glycerin is added, P/0/P-tyρe multi-emulsion will not form effectively because phase-separation is difficult to maintain. The proper water content is 0-30 wt% of the total polyol phase 2. If more than 30 wt% water is added, crystals form because the osmotic pressure of polyol phase 1 and polyol phase 2 cause elution of the low-soluble active ingredients into polyol phase 2.

<47> The proper content of the emulsion stabilizer is 0.05-10 wt%. If less than 0.05 wt% is added, the P/0/P-type multi-emulsion cannot form effectively and coagulation of the hollow-type, multi-layered microcapsules occur. If more than 10 wt% is added, it is difficult to handle.

<48> (5) Preparation of P/0/P-type multi-layered emulsion by adding the P/O- type first emulsion to polyol phase 2'

<49> The P/0/P-type multi-layered emulsion was prepared by adding 2~15-fold of polyol phase 2, prepared according to step (4), to the P/O-type first emulsion, prepared according to step (3), and mixing with a homogenizer etc. The proper mixing ratio of the P/O-type first emulsion to polyol phase 2 is 1:2-15. If the ratio is less than 1:2, the P/O/P-type mult i-emulsion cannot form effectively. If the ratio is more than 1:15, the content of the active ingredient is low and ineffective.

<50> (6) Preparation of hollow-type, multi-layered microcapsules by hardening the multi-layered emulsion using solvent evaporation-solvent extraction".

<5i> The hollow-type, multi-layered microcapsules of the present invention were prepared by removing the volatile organic solvent from the P/O/P-type multi-emulsion, prepared according to step (4). The volatile organic solvent was removed using the solvent extraction-solvent evaporation method. Briefly, the solvent was diffused slowly due to the concentration disparity of volatile solvent between capsule membrane and polyol phase 2 in extraction process. The solvent in polyol phase 2 diffuses into the boundary layer between polyol phase 2 and the outer air, where it then evaporates, removing solvent which had dissolved the hydrophobic macromolecules in evaporation process. Heating slowly or reducing the pressure of polyol phase 2 increased the rate of extraction and evaporation, thereby, increasing the rate at which hollow-type multi layered microcapsules were produced.

<52> After completely removing the volatile organic solvent, the microcapsules of the present invention can be directly applied to cosmetic composition without other collecting processes such as centrifugation, filtration or drying.

<53> Because the outermost continuous phase of microcapsules produced using former multi-emulsion methods contain copious amounts of water after solvent removal, the active ingredient encapsulated in the microcapsules is not stable and is eluted into the outermost continuous phase by osmotic pressure. So, the active ingredient content decreases, crystals form, and coagulation occurs. Therefore, microcapsules produced using the former multi-emulsion method should be collected by other means.

<54> In contrast, because the outermost continuous phase of the microcapsules of the present invention contains polyol after evaporating the volatile solvent, the microcapsules can be directly applied to cosmetic composition without other collecting processes. If needed, the microcapsules of the present invention can be collected using centrifugation, filtration or drying and applied to cosmetic composition.

<55> The present invention will be explained in more detail.

<56> The present invention is about a method of preparing hollow-type, multi layered microcapsules using polyol, a stabilizing method of low-soluble active ingredients, and a cosmetic composition containing the microcapsules. In detail, in preparing hollow-type, multilayered microcapsules from hydrophobic macromolecules, the inventors used polyol to increase the solubility of the low-soluble active ingredient and hydrophilic or amphiphilic macromolecules to stabilize the active ingredient in the multilayered structures.

<57> The hollow-type, multilayered microcapsules of the present invention using polyol separates the low-soluble active ingredients from external environmental factors, such as high temperature, oxygen or ultra violet and internal environment such as water and surfactant, thereby stabilizing the low-soluble active ingredients and preventing deterioration, discoloration and crystallization.

<58> The low-soluble active ingredient, which could be encapsulated in the microcapsule of the present invention, contain molecules generally used in cosmetics, such as at least one selected from a group containing, but not limited to, linoleic acid, coenzyme Q-IO, lipoic acid and so on.

<59> The low-soluble active ingredient, which can be encapsulated in the microcapsule, may be seledted from a group of polyphenol or its derivative as follows"- flavonoids; isoflavonoids; neoflavonoids! gallotannins and ellagitannins," cathechol and their derivatives, such as caffeic acid, dihydrocaffeic acid, protocatechuic acid, chlorogenic acid, isochlorogenic acid, gentisic acid, homogentisic acid, garlic acid, hexahydroxydiphenic acid, ellagic acid, rosemaric acid or litospermic acid; phenolic acid derivatives, especially containing their esters or heterosides; curcumin; polyhydroxylated coumarine; and, monocyclic or polycyclic polyphenols, such as polyhydroxylated lignans, neolignans, or silymarin. The aforementioned polyphenols may be the extracts of plants.

<60> The said vegetable flavonoid may be selected from the following types of polyphenols: flavones, such as apigenol or luteololl flavonols, such as quercetin or kaempferol; flavones or flavonol heterosides, such as rutin or its derivatives; flavanones, such as naringenin or hesperetin; flavanone heterosides, such as naringin, hesperidin or diosmin," flavanone derivatives, such as diosmoside, abiflavonoid; flavone or flavone dimmers, such as amentoflavon; calcones, such as isoliquirtigenin or hesperidin methylcalcone; flavonolignan, such as silybin, silichristin or silidianin; flavan-3-ols, such as (+)-cathechol or (-)-epichathechol ; polymers consist of basic monomers, generally known as 'proantocyanidin' or 'polymerized tanin' especially, procyanidolic oligomer(PCO) consisting of 2 - 8 units of proantocyanidin; and antocianosides, such as malvoside. The aforementioned flavonoids may be extracts of plants.

<6i> Polyol of the present invention is used to encapsulate and stabilize copious amounts of low-soluble active ingredients. The alcohol is at least one selected from low-molecular weight alcohol compounds: polyethyleneglycol , polypropyleneglycol, and their copolymers; butyleneglycol, propyleneglycol and glycerin; ether containing at least one hydric group, such as diethyleneglycol monoethyl ether. The appropriate content is 20-95 wt% of total polyol phase 1. If less than 20 wtfo is added, it is difficult to form the P/O-type first emulsion of the present invention because the alcohol- phase cannot be separated from the volatile organic solvent. If more than 95 wt% is added, the low-soluble active molecule cannot be effectively dissolved or dispersed.

<62> Biocompatible macromolecules available for external application can be used as hydrophobic macromolecules for the synthesis of the multi-layered microcapsules of the present invention.

<63> For example, polystyrene, poly p- or m-methylstyrene, poly p- or m- ethylstyrene, poly p- or m-chlorostyrene, poly p- or m-chloromethylstyrene, polystyrene sulfonic acid, poly p- or m- or t-butoxystyrene, polymethyl(meta)acrylate, polyethyl(meta)acrylate, polypropyl(meta)acrylate, poly n-butyl(meta)acrylate, polyisobutyl(meta)acrylate, poly t- butyl(meta)acrylate, poly 2-ethylhexyl(meta)acrylate, poly n- octyl(mata)acrylate, poly1auryl(meta)acrylate, polystearyl(meta)acrylate, poly 2-hydroxyethyl(meta)acrylate, polyethyleneglycol(meta)acrylate, methoxypolyethyleneglycol(meta)acrylate, polyglysidyl(meta)acrylate, polydimethylaminoethyl(meta)acrylate, polydiethylaminoethyl(meta)acrylate, acrylate-metaerylate copolymer, polyamide, polyethyleneterephthalare, polyaminoacid, silicone macromolecules, dextran stearate, ethyl cellulose, acetyl cellulose, nitrocellulose, polyurethane, maleic anhydride copolymer, ethylene-vinylacetate copolymer, polymers, copolymers or mixture of polyvinylacetate, polyvinylalcohol , polyacrylamide are available.

<64> Biodegradable hydrophobic aliphatic polyester available for the present invention contains poly-L-latate, poly-D,L-glycolate, poly-L-lactate-co- glycolate, poly-D,L-lactate-co-glycolate, polycaprolactone, polyvalerolactone, polyhydroxybutyrate, polyhydroxyvalerate, polyorthoester and copolymers produced from the monomers. Mixtures of polymethyl(meta)acrylate, polyethyl(meta)acrylate, poly-L-lactate, poIy-L- lactate-co-glycolate or polycaprolactone are desirable. The appropriate hydrophobic macromolecule content is 1.0-20 wt% of the total oil-phase. If less than 1.0 wt% is added, it is difficult to form microcapsules. If more than 20 wt% is added, the content of active molecules is inadequate.

<65> In producing the P/O-type first emulsion, appropriate surfactants can be added. Available surfactants are sorbitansesquioleate, sorbitanmonooleate, sorbitanmonostearate and so on.

<66> The volatile organic solvent used in producing the hollow-type, multi- layered microcapsules of the present invention should have a solubility similar to that of the selected macromolecule. Specific examples of appropriate solvents are as follows: linear alkanes, such as hexane, heptane, octane, nonane and decane; alkyl ester not less than 7 carbons, such as n- hexylacetate, 2-ethylhexyl acetate, methyl oleate, dibutyl sebacate, dibutyl adibate or ebutyl carbamate; aliphatic ketones, such as methyl isobutylketone, and isobutylketone; aromatic carbohydrates, such as benzene, toluene, o~ and p-xylene! and, chlorine-containing compounds, such as methylene chloride, chloroform, carbon tetrachloride, etc. Methylenechloride, chloroform or acetone are well-suited to this method due to their low boiling points, high volatility, and propensity to form capsules.

<67> The emulsion stabilizer used in the present invention may be selected from one of the following types of compounds: natural gums, such as gum arabic, irish moss, karaya gum, gum tragacanth, gum guaiac, xanthan gum, locust bean gum,' casein; gelatin; collagen; albumin (ex, human serum albumin); globulin", fibrin; cellulose; cellulose derivatives, such as dextrin, pectin, starch, agar and mannan; polyvinyl compounds, such as polyvinylpyrrolidone, polyvinylalcohol , polyvinylmethylether , polyvinylether ; polycarboxylic acids, such as polyacrylater or carbopol; polysaccharides, such as polysucrose, polyglucose, polylactose, and their salts. The appropriate emulsion stabilizer content is 0.05-10 wt% of the total polyhydric alcohol phase 2. If less than 0.05 wt% is added, P/0/P-type multi- emulsion cannot form effectively and coagulation of hollow-type, multi- layered microcapsules occurs. If more than 10 wt% is added, it is difficult to handle.

<68> The hydrophilic or amphiphatic macromolecules used in the present invention should dissolve and disperse homogeneously in the polyol phase 1, which consists of glycerin and polyol. Possible hydrophilic or amphiphatic macromolecules are as follows: natural gums, such as gum arabic, irish moss, karaya gum, gum tragacanth, gum guaiac, xanthan gum, locust bean gum; gelatin; collagen; albumin (ex, human serum albumin); globulin! fibrin; cellulose", cellulose derivatives, such as dextrin, pectin, starch, agar or mannan; polyvinyl compounds, such as polyvinylpyrrolidone, polyvinylalcohol , polyvinylmethylether, polyvinylether ; polycarboxylic acids, such as polyacrylater and carbopol ; polysaccharides, such as polysucrose, polyglucose, polylactose, and their salts; and, polyoxyethylene polyoxypropylene block polymers (ex, poloxamer series), and acrylate/alkylacrylate crosspolymer (ACRYLATES/C10-30 ALKYL ACRYLATE CROSSPOLYMER, Pemulen series). The appropriate hydrophilic or amphiphatic macromolecule content for stable formation of the P/O-type first emulsion, is 0.05-20 wt%, desirably 0.1-10 wt% of the total polyol phase 1.

<69> The hollow-type mult i layered macromolecule microcapsules of the present invention constituted 0.001-25.0 wt%, desirably 0.01-10.0 wt% of total cosmetic composition. If more than 25 wt% is added, the stability of the emulsion cannot be guaranteed and the texture of the formulation is not so good.

<70> The hollow-type multi layered macromolecule microcapsules of the present invention can be varied in formulation. Formulation of the cosmetics can be water-phase, water phase-alcohol or oily solution, oil-in-water, water-in-oil or mult i layered emulsion, aqueous or oily gel, liquid, paste, solid anhydride, or oil dispersion in water-phase using microspheres, or more desirably, an ionic and/or nonionic lipid reticulum.

<7i> The cosmetic formulation of the present invention may be fluid, a white or ivory cream, ointment, milk lotion, serum, essence, paste or mousse. The cosmetic of the present invention can be applied as an aerosol spray, solid form e.g. stick, and so on. The cosmetic of the present invention can be formulated as skin care and/or make-up products.

<72> The composition of the present invention may contain general adjuvants known to skilled person in the art, such as hydrophilic or lipophilic gelation agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, fragrances, fillers, blockers, pigments, deodorants and dyes. The adjuvant content is known to skilled person in the art, generally, 0.01 -20 wt%. Depending on their property, adjuvants may be present in the oil-, water-, or polyol-phases. In any case, the content of the adjuvant should be such that it does not to deteriorate the beneficial properties of the cosmetic composition.

<73> Composition of the present invention may also contain general cosmetic carriers, such as water, saline, glycerol and so on.

<74> The cosmetic composition of the present invention can be formulated as basic cosmetics, such as skin lotion, milk lotion, nourishing cream, massage cream, essence, cleansing form, cleansing water, pack or body oil, and color cosmetics, such as foundation, lipstick, mascara or make-up base. The formulation may be applied as a cleanser for either the face or the body. [Advantageous Effects]

<75> The hollow-type, mult i layered microcapsules using polyol have enhanced solubility and stability from their low-soluble active ingredients. The low- soluble active ingredients are captured in the hollow structure by an outer membrane made of hydrophobic macromolecules. [Description of Drawings]

<76> Fig. 1 is an optical microscopic image of the hollow-type, multi layered microcapsules of the present invention.

<77> Fig. 2 and Fig. 3 show the surface morphology of the hollow-type, multi layered microcapsules of the present invention obtained using scanning electron microscopy.

<78> Fig. 4 is a cross-sectional image of the hollow-type, multilayered microcapsules of the present invention obtained using scanning electron microscopy.

<79> Fig. 5 shows cross-sectional images of the hollow-type, multilayered microcapsules of the present invention obtained using scanning electron microscopy.

<80> Fig. 6 shows surface images of the hollow-type, multilayered microcapsules of the present invention obtained using scanning electron microscopy. [Best Mode]

<8i> Quercetin, a flavonoid, was selected as the low-soluble active ingredient. Polymethyl metacrylate was used as the hydrophobic macromolecule. A P/O-type first emulsion was produced.

<82> Glycerin, butyleneglycol , and diethyleneglycol monoethylether were mixed in a 5:4:1 weight ration to prepare the polyol mixture. 0.5 wt% of pemulen, an acrylate/alkylacrylate crosspolymer, was added to the polyol mixture and stirred to prepare a homogeneous polyol phase 1.

<83> 10 wt% of polymethyl metacrylate, 3 wt% of sorbitan sesquioleate, and 87 wt% of methylene chloride were homogenized to prepare the oil-phase. Polyol phase 1 and the oil-phase were mixed slowy in a ratio of 1:5 (w/w), and emulsified using an homogenizer at 10,000 rpm for 5 min at room temperature to prepare a polyol-in-oil (P/O)-type first emulsion. Various polyol phase 2 listed in Table 3 were slowly mixed into the P/O-type first emulsion in a 1:8 (w/w) ratio, and emulsified using a homogenizer at 2,500 rpm for 10 min at room temperature to prepare a polyol-in-polyol (P/O/P)-type multilayered emulsion. The emulsion was stirred for 24hr at 3O⁰C, and then evaporated by rotary vacuum evaporator for 30 min at room temperature to produce hollow-type, multilayered microcapsules. [Mode for Invention]

<84> The present invention will be explained in more detail with reference to the following embodiments. However, it is to be noted that the present invention can be utilized in various ways and it is not intended to be confined to the embodiments.

<85> <Materials>

<86> The following chemicals were obtained from commercial sources and were used as received. Quercetin dihydrate, polyethylene glycol (M.W. 300) and polyvinyl alcohol (PVA) were obtained from Sigma-Aldrich Cheme GmbH (Steinheim, Germany). This PVA exhibits a molecular weight of 30 to 70 kd. Polymethyl methacrylate (PMMA) was supplied by Nihon Junyaku Co., LTD. (Japan). This PMMA has a molecular weight of 500 to 1,000 kd. Acrylates/CIO- 30 alkyl acrylate crosspolymers (Pemulen TR-2) were obtained from BF Goodrich Company (OH, USA). Sorbitan sesquioleate (Arlacel 83), a lipophilic surfactant, was purchased from Uniqema Inc (USA).

<87> <Examples 1 - 5>

<88> Quercetin, a flavonoid, was selected as the low-soluble active ingredient. Polymethyl metacrylate was used as the hydrophobic macromolecule. A P/O-type first emulsion was produced, and its features were evaluated according to the composition of the polyol phase.

<89> 0.5 wt% pemulen, an acrylate/alkylacrylate crosspolymer , and 2 wt% quercetin were added to the polyol composition shown in Table 1 and mixed fully to prepare polyol phase 1. The oil-phase was prepared by dispersing 0.3 wt% sorbitan sesquioleate (Arlacel 83) and 10 wt% polymethyl methacrylate into methylene chloride. The polyol phase 1 and the oil-phase were slowly mixed at a ratio of 1:5 (w/w). Before being sealed, they were emulsified using a homogenizer at 10,000rpm for 5 min. After lhr, the P/O-type 1st emulsion was observed by both the naked eye and with a microscope. The results are shown in Table 2.

<90> The molecular weight of polymethyl methacrylate ranged from 3-100 kd, more properly 3-20 kd.

<9i> [Table 1]

<92> <93>

<94> In Examples 1 and 2, which used less than 20 wt% glycerin in the polyol phase, stable P/0 emulsion did not form because the polyol mixture could not be separated from the oil-phase (Table 2). In Example 5, in which 20 wt% pure water was added to the polyol phase, needle-shaped crystals, rather than a stable P/O-type emulsion, formed because of the low solubility of quercetin.

<95> <Examples 6 - IO <96> Polymethyl metacrylate hollow-type, multi layered microcapsules containing various polyol phase 2 compositions were produced.

<97> Glycerin, butyleneglycol , and diethyleneglycol monoethylether were mixed in 5"-4:l weight ratio to prepare a polyol mixture. 0.5 wt% of pemulen, an acrylate/alkylacrylate crosspolymer , was added to the polyol mixture and stirred to prepare homogeneous polyol phase 1.

<98> 10 wt% of polymethyl metacrylate, 3 wt% of sorbitan sesquioleate and 87 wt% of methylene chloride were homogenized to prepare the oil-phase. A 1:5 ratio of the polyol phase 1 and oil-phase were slowly mixed, and emulsified using a homogenizer at 10,000 rpm for 5 min at room temperature to prepare a polyol-in-oil (P/0)-tyρe first emulsion. Various polyol phase 2 composition, listed in Table 3, were slowly mixed into the P/0-tyρe first emulsion in a 1:8 (w/w) ratio and emulsified using a homogenizer at 2,500 rpm for 10 min at room temperature to prepare a polyol-in-polyol (P/0/P)-type, multi layered emulsion. The emulsion was stirred for 24 hr at 30^°C, and then evaporated by rotary vacuum evaporator for 30 min at room temperature to prepare hollow- type, mult i layered microcapsules which were observed by both the naked eye and with a microscope. The results are shown in Table 4.

<99> [Table 3]

<100> <101> [Table 4]

:io2> Microscopic examination of Examples 6 and 7 revealed mult i layered microcapsules (Fig. 1). In Example 8, with a water content of more than 40 wt%, multi layered microcapsules formed. The capsules coagulated, however, and after a short time needle-shaped quercetin crystals were observed external to the capsules. If the water content is high in polyol phase 2, the hydrophobic macromolecular membrane will not harden completely and quercetin elutes from the inner polyol phase 1 due to osmotic pressure between the inner and outer polyol phases. In Example 10, in which in the polyol phase 2 contained 20 wt% glycerin, only a few multi layered microcapsules formed and a small number of needle-shaped quercetin crystals were observed. These results indicate that the polyol phase 2 cannot separate from the polyol-in-oil (P/0) emulsion and form a P/0/P-type, multi layered emulsion, and that the quercetin in the inner polyol phase 1 was eluted to the outer polyol phase 2.

<1O3> <Examples 11 - 14>

<i04> Hollow-type, multilayered microcapsules containing various amounts of sorbitan sesquioleate, a surfactant, were produced.

<io5> 0.5 wt% pemulen, an acrylate/alkylacrylate crosspolymer, and 5 wt% quercetin were added and dispersed homogeneously into a 5:4:1 (w/w/w) mixture of glycerin, butyleneglycol , diethyleneglycol monoethylether to produce a polyol phase 1.

<iO6> Sorbitan sesquioleate (Arlacel 83) and polymethylmetacrylate were dispersed in methylenechloride, as shown in Table 5, to produce an oil-phase. 5-fold (w/w) polyol phase 1 was added little very gradually to the oil-phase, then emulsified using a homogenizer at 10,000 rpm for 5min at room temperature to produce a polyol-in-oil (P/0)-type first emulsion.

107> 1 wt% polyvinylalcohol (average degree of saponification 80-90%) was dispersed in a mixture of 90 wt% glycerin and 10 wt% pure water to produce polyol phase 2. The P/O-type first emulsion was added to the polyol phase 2 at a ratio of first emulsion : polyol phase 2 = 1:8 (w/w) , and homogenized at 2,500 rpm for 10 min at room temperature to produce a polyol-in-oil-in-polyol (P/0/P)-type mult i layered emulsion. The emulsion was stirred at 30°C for 24hr, and the methylenechloride was evaporated completely by rotary vacuum evaporator at room temperature for 30 min. Hollow mult i layered microcapsules were mixed and washed in excess pure water, filtered by 0.45μm filter paper, and then freeze-dried. clO8> [Table 5]

<109> Samples produced according to Table 5 were observed by scanning electrone microscopy (SEM). Samples of Examples 11 - 14 were homogeneous and continuous microcapsules; the size of microcapsules was reduced when the amount of sorbitan sesquioleate was increased (Fig. 2, 3).

<110> When a section of Example 14 was ground and then observed by SEM, a mult i layered structure was evident in hollow microcapsules (Fig. 4).

<111> <Examples 15 - 18> <1 )2> Hollow-type, multilayered microcapsules containing various hydrophilic and amphiphilic macromolecules of polyol phase 1 were produced.

<1 13> 0.5 wt% various hydrophilic or amphiphilic macromolecules, listed in Table 6, and 5 wt% quercetin were added and dispersed homogeneously into a 5^'.4:l mixture of glycerin, butyleneglycol , and diethyleneglycol monoethylether to produce polyol phase 1.

:1 14> 3 wt% sorbitan sesquioleate (Arlacel 83), 10 wt% polymethylmetacrylate and 87 wt% methylenechloride were mixed to homogeneity, producing oil-phase. 5-fold (w/w) of polyol phase 1 was added very gradually to the oil-phase, then emulsified using a homogenizer at 10,000 rpm for 5 min at room temperature to produce a polyol-in-oil (P/0)-type first emulsion.

:115> The other steps in the process were the same as those used in Examples 11 - 14, and hollow-type, multi layered microcapsules were produced.

:116> [Table 6)

<1 17> Ground samples according to Table 6 were observed by SEM. Samples of Examples 15 17 were observed to have hollow, multi layered microcapsules, and a sample of Example 18 was determined to have formed monolayered microcapsules (Fig. 5).

<1 18> <Examples 19 - 20> <U9> Hollow-type, multi layered microcapsules were produced from the hydrophobic macromolecules, polycaprolactone (average MW 80,000) and poly- D,L-lactate-co-glycolate (MW 40,000-75,000, lactate : glycolate=65:35).

<120> Hollow-type, multilayered microcapsules were produced as described for Example 14, with the exception of the hydrophobic macromolecules and surfactant that were dispersed in methylenechloride, as shown in Table 7, to produce a polyol-in-oil (P/O)-tyρe first emulsion. The other steps in the process were the same as those used in Example 14, yielding hollow-type, mult i layered microcapsules, polycaprolactone hollow, multi layered microcapsules, and poly-D,L-lactate-co-glycolate hollow, mult i layered microcapsules.

:121> [Table 7]

cl22> Samples produced according to Table 7 were observed by SEM. Samples of Examples 19 and 20 were identified to be homogeneous and continuous microcapsules (Fig. 6). cl23> Experimental Example 1> Analysis of quercetin content <124> (A) Analytic conditions cl25> (D solvent: methanol : acetonitrile : acetic acidCpH 4.5)= 40 : 20 : 40 <126> (2) condition: RP-C18 column(250x4.6 mm, 5.0 /zm), 1.0 ntf/min, UV detector 370 nm, retention time: 6.3 minutes

<127> CD Analytical instrument: Waters 2695 alliance separation module, Waters 996 PDA detector <128> (D Sample preparation: 9 mi of methanol was added to 1 g of sample, The mixture was ultrasonicated for 30 min, and filtered using 0.2 μm filter paper. The filtered solution was diluted properly and quantified.

<129> <Experimental Example 2> Determination of the stability of quercetin encapsulated in hollow-type, multi layered microcapsules

<130> 10 g of hollow-type, multilayered microcapsules containing quercetin that were produced by Example 14, and had the same concentration of free quercetin, were added to 50% butylenes glycol, mixed to homogeneity, sealed and stored at 4°C , 25°C and 42°C . According to time lapse, the contents of quercetin of the samples were quantified according to Experimental Example 1. The results are shown in Table 8.

131 > [Table 81

<132> As shown in Table 8, quercetin dissolved in 50% butylene glycol deteriorated suddenly at room temperature and at high temperatures. However, quercetin in the hollow-type, mult i layered microcapsules of the present invention remained stable even at high temperatures. Therefore, the hollow- type, mult i layered microcapsules of the present invention proved to remarkably improve the stability of the low-soluble active ingredient.

<133> <Experimental Example 3> Stability of quercetin encapsulated in hollow- type, multi-layered microcapsules in milk lotion

<134> A milk lotion containing hollow-type, multilayered microcapsules of the present invention were prepared as shown in Table 9. The A) phase of Table 9 was heated and kept at 70°C . The B) phase was added, pre-emulsified and emulsified with the A) phase using a homomixer. And then, the C) phase was added and cooled slowly. After cooling, hollow-type, multi layered microcapsules encapsulating quercetin, as prepared in Example 14, or free quercetin was added and to the mixture to prepare homogeneous milk lotion (Example 21 and comparative Example 1).

:135> [Table 9]

<136> The serums produced were sealed and kept at 4^°C, 25°C and 42^°C, respectively. According to time lapse, the quercetin content of the samples was quantified according to Experimental Example 1. The results are shown in Table 10.

:137> [Table 10]

d38> As shown in Table 10, quercetin content in serum changed dramatically at room temperature and high temperatures. However, quercetin in hollow-type, multilayered microcapsules possessed excellent stability at high temperatures. [Industrial Applicability] cl39> In the cosmetics containing hollow-type, multilayered microcapsules of the present invention, low-soluble active molecules encapsulated in hollow- type, multi-layered microcapsules can be separated from inner cosmetic bases, such as water and surfactant, and from outer environmental factors, such as high temperature, oxygen and UV. Therefore, the cosmetics of the present invention are stabilized and deterioration, change of color, and crystallization of the active molecules are inhibited.

Claims

[CLAIMS] [Claim 1] Method for producing hollow-type multilayered microcapsules using polyols containing the following steps:

(1) Polyol phase 1 preparing step by adding 0.01-40 wt% low-soluble active ingredient and 0.1-20 wt% hydrophilic or amphiphilic macromolecules to 40-99.89 wt% polyhydric alcohol containing 20-95 wt% glycerin;

(2) Oil-phase preparing step by adding 1.0-20 wt% hydrophobic macromolecule and surfactant to volatile organic solvent;

(3) Polyol-in-oil type first emulsion preparing step by adding the oil- phase, prepared according to step (2), to polyol phase 1, prepared according to step (1), in a ratio of 1:1-15 (w/w);

(4) Polyol phase 2 preparing step by adding 0.05-10 wt% emulsion stabilizer to a mixture of 0-30 wt% water and 60-99.95 wt% polyol containing 20-99.95 vιt% glycerin;

(5) Polyol-in-oil-in-polyol-type multi-emulsion producing step by adding the polyol phase 2, prepared according to step (4) to the polyol-in- oil-type first emulsion, prepared according to step (3), in a ratio of 1:2-15;

(6) Hollow-type, multi layered microcapsule producing step by hardening the multi-emulsion made in step (5) by solvent evaporation-solvent extraction.

[Claim 2)

The method of claim 1, wherein said low-soluble active ingredient is at least one selected from a group comprising: linoleic acid, coenzyme Q-10, lipoic acid, gallotannin, ellagitannin, cathechol and their derivative, caffeic acid, dihydrocaffeic acid, protocatechuic acid, chlorogenic acid, isochlorogenic acid, gentisic acid, homogentisic acid, garlic acid, hexahydroxydiphenic acid, ellagic acid, rosemaric acid, litospermic acid, phenolic acid ester, phenolic acid heteroside, curcumin, polyhydroxylated coumarine, monocyclic polyphenol, polyeyelie polyphenols, polyhydroxylated lignans, polyhydroxylated neolignans, silymarin, apigenol , luteolol, flavonol, quercetin, kaempferol, flavone, flavonol heteroside, rutin, rutin derivative, flavanone, naringenin, hesperetin, flavanone heteroside, naringin, hesperidin, diosmin, flavanone derivative, diosmoside, abiflavonoid, flavone, flavone dimer, amentoflavon, calcone, isoliquirtigenin, hesperidin methylcalcone, flavonolignan, silybin, silichristin, silidianin, flavan-3-ol, (+)-cathechol , (-)-epichathechol , flavan-3-ol polymer, proantocyanidin, procyanidolic oligomer, antocianoside and malvoside. [Claim 3]

The method of claim 1, wherein said polyol phase 1 contains at least one selected from a group comprising: polyethyleneglycol , polypropyleneglycol , their copolymers and copolymer derivatives; butyleneglycol , propyleneglycol , glycerin and diethyleneglycol monoethyl ether. [Claim 4]

The method of claim 1, wherein said hydrophobic macromolecule is at least one selected from a group comprising: polystyrene, poly p- or m-methylstyrene, poly p- or m- ethylstyrene, poly p- or m-chlorostyrene, poly p- or m-chloromethylstyrene, polystyrene sufonic acid, poly p- or m- or t-butoxystyrene, ρolymethyl(meta)acrylate, polyethyl(meta)acrylate, polypropyl(meta)acrylate, poly n-butyl(meta)acrylate, polyisobutyl(meta)acrylate, poly t- butyl(meta)acrylate, poly 2-ethylhexyl(meta)acrylate, poly n- octyl(mata)acrylate, poly1auryl(meta)acrylate, polystearyl(meta)acrylate, poly 2-hydroxyethyl(meta)acrylate, ρolyethyleneglycoi(meta)acrylate, methoxypolyethyleneglycol(meta)acrylate, ρolyglysidyl(meta)acrylate, polydimethylaminoethyl(meta)acrylate, ρolydiethylaminoethyl(meta)acrylate, aerylate-metaerylate copolymer, poiyamide, polyethyleneterephthalare, polyaminoacid, silicone macromolecule, dextran stearate, ethyl cellulose, acetyl cellulose, nitrocellulose, polyurethane, maleic anhydride copolymer, ethylene-vinylacetate copolymer, copolymers or mixtures of polyvinylacetate, polyvinylalcohol and polyacrylamide, poly-L-latate, poly-D,L-glycolate, poly- L-lactate-co-glycolate, poly-D,L-lactate-co-glycolate, polycaprolactone, polyvalerolactone, polyhydroxybutyrate, polyhydroxyvalerate, polyorthoester and copolymers produced from L-latate, D,L-glycolate, L-lactate-co-glycolate, D,L-lactate-co-glycolate, caprolactone, valerolactone, hydroxybutyrate, hydroxyvalerate and orthoester. [Claim 5]

The method of claim 1, wherein said hydrophilic or amphiphilic macromolecule is at least one selected from a group comprising: gum arabic, irish moss, karaya gum, gum tragacanth, gum guaiac, xanthan gum, locust bean gum, gelatin, collagen, albumin, globulin, fibrin, cellulose, cellulose derivatives, dextrin, pectin, starch, agar, mannan, polyvinyl compound, polyvinylpyrrolidone, polyvinylalcohol, polyvinylmethylether, polyvinylether , polycarboxylic acid, polyacrylate, carbopol, polysaccharide, polysucrose, polyglucose, polylactose, salts of polysaccharides, polysucrose, polyglucose and polylactose, polyoxyethylene polyoxypropylene block polymer, and acrylate/alkylacrylate crosspolymer . [Claim 6]

The method of claim 1, wherein said polyol phase 2 contains at least one selected from a group comprising: glycerin, polyethyleneglycol , polypropyleneglycol , copolymer and copolymer derivatives of polyethyleneglycol and polypropyleneglycol, butyleneglycol , propyleneglycol and diethyleneglycol monoethyl ether. [Claim 7]

The method of claim 1, wherein said volatile organic solvent is at least one selected from a group comprising", hexane, heptane, octane, nonane, decane, linear alkanes, n- hexylacetate, 2-ethylhexyl acetate, methyl oleate, dibutyl sebacate, dibutyl adibate, ebutyl carbamate, alkyl esters not less than 7 carbons, aliphatic ketones, methylisobutylketone, isobutylketone, aromatic carbohydrates, benzene, toluene, o-χylene, p-xylene, chlorine-containing compounds, methylene chloride, chloroform, carbon tetrachloride and acetone. [Claim 8]

Hollow-type mult i layered microcapsule containing: outer membrane made of hydrophobic macromolecules; hollow formed in the outer membrane; and at least one microsphere in which the low-soluble active ingredient is encapsulated by hydrophilic or amphiphilic macromolecule in the hollow. [Claim 9]

The capsule of claim 8, wherein said low-soluble active ingredient is at least one selected from a group comprising: linoleic acid, coenzyme Q-IO, lipoic acid, gallotannin, ellagitannin, cathechol and their derivatives, caffeic acid, dihydrocaffeic acid, protocatechuic acid, chlorogenic acid, isochlorogenic acid, gentisic acid, homogentisic acid, garlic acid, hexahydroxydiphenic acid, ellagic acid, rosemaric acid, litospermic acid, phenolic acid esters, phenolic acid heteroside, curcumin, polyhydroxylated coumarine, monocyclic polyphenols, polycyclic polyphenols, polyhydroxylated lignans, polyhydroxylated neolignans, silymarin, apigenol, luteolol, flavonols, quercetin, kaempferol , flavones, flavonol heteroside, rutin, rutin derivatives, flavanones, naringenin, hesperetin, flavanone heterosides, naringin, hesperidin, diosmin, flavanone derivatives, diosmoside, abiflavonoid, flavones, flavone dimers, amentoflavon, calcone, isoliquirtigenin, hesperidin methylcalcone, flavonolignan, silybin, silichristin, silidianin, flavan-3-ol, (+)-cathechol , (-)-epichathechol , flavan-3-ol polymer, proantocyanidin, procyanidolic oligomer, antocianoside and malvoside. [Claim 10]

The capsule of claim 8, wherein said hydrophobic macromolecule is at least one selected from a group comprising: polystyrene, poly p- or m-methylstyrene, poly p- or m- ethylstyrene, poly p- or m-chlorostyrene, poly p- or m-chloromethylstyrene, polystyrene sufonic acid, poly p- or m- or t-butoxystyrene, polymethyl(meta)acrylate, polyethyl(meta)acrylate, polypropyl(meta)acrylate, poly n-butyl(meta)acrylate, polyisobutyl(meta)acrylate, poly t- butyl(meta)acrylate, poly 2-ethylhexyl(meta)acrylate, poly n- octyl(mata)acrylate, polylauryl (meta)acrylate, polystearyl(meta)acrylate, poly 2-hydroxyethyl(meta)acrylate, polyethyleneglycol(meta)acrylate, methoxypolyethyleneglycol(meta)acrylate, polyglysidyl(meta)acrylate, polydimethylaminoethyl(meta)acrylate, polydiethylaminoethyl(meta)acrylate, acrylate-metacrylate copolymer, polyamide, polyethyleneterephthalare, polyaminoacid, silicone macromolecules, dextran stearate, ethyl cellulose, acetyl cellulose, nitrocellulose, polyurethane, maleic anhydride copolymer, ethylene-vinylacetate copolymer, copolymers or mixture of polyvinylacetate, polyvinylalcohol and polyacrylamide, poIy-L-Iatate, poly-D,L-glycolate, poly- L-lactate-co-glycolate, poly-D,L-lactate-co-glycolate, polycaprolactone, polyvalerolactone, polyhydroxybutyrate, polyhydroxyvalerate, polyorthoester and copolymers produced from L-latate, D,L-glycolate, L-lactate-co-glycolate, D,L-lactate-co-glycolate, caprolactone, valerolactone, hydroxybutyrate, hydroxyvalerate and orthoester. [Claim H]

The capsule of claim 8, wherein said hydrophilic or amphiphilic macromolecule is at least one selected from a group comprising: gum arabic, irish moss, karaya gum, gum tragacanth, gum guaiac, xanthan gum, locust bean gum, gelatin, collagen, albumin, globulin, fibrin, cellulose, cellulose derivative, dextrin, pectin, starch, agar, mannan, polyvinyl compounds, polyvinylpyrrolidone, polyvinylalcohol, polyvinylmethylether , polyvinylether , polyearboxylie acid, polyacrylate, carbopol, polysaccharide, polysucrose, polyglucose, polylactose and salts of polysaccharide, polysucrose, polyglucose and polylactose, polyoxyethylene polyoxypropylene block polymer, and acrylate/alkylacrylate crosspolymer . [Claim 12]

The capsule of claim 8, wherein said polyol is at least one selected from a group comprising: glycerin, polyethyleneglycol , polypropyleneglycol , copolymer and copolymer derivatives of polyethyleneglycol and polypropyleneglycol, butyleneglycol , propyleneglycol and diethyleneglycol monoethyl ether. [Claim 13]

A cosmetic composition containing 0.001-25 wt% hollow-type multi- layered microcapsules according to one selected from claims 8- 12.