KR101634952B1 - External skin preparation for beauty treatment, Manufacturing method thereof, Cosmetics containg that and Ointment of skin containing that - Google Patents

Abstract

The present invention relates to an external preparation for skin and a method for producing the same, and more specifically, it relates to a skin external preparation having excellent storage stability against an object to be transferred such as a plant conversion extract and a vitamin derivative, A cosmetic product using the same, and a skin ointment agent.

Description

[0001] The present invention relates to a skin external preparation for cosmetic use, a method for producing the same, a cosmetic product containing the same, and a skin ointment for cosmetic use,

The present invention relates to an external preparation for skin, a method for producing the same, and a cosmetic and / or skin ointment using the same.

Functional cosmetics refers to cosmetics that have improved efficacy and safety, that is, products with enhanced functionality, which can be classified into wrinkle-improving, whitening, and ultraviolet screening products and existing between both groups of pharmaceuticals and cosmetics. Examples of the active ingredient which is active in functional cosmetics include vitamins and derivatives thereof, plant extracts, fragrances, enzymes, microbial extracts, minerals and ultraviolet light blocking agents. Exposure to external factors such as temperature, pH, light and air , The stability is lowered and the skin absorption rate is accordingly lowered, so that the functional effects such as improvement of wrinkles, whitening, and ultraviolet ray shielding of cosmetics are lowered.

Therefore, in the development of cosmetics, a technique for improving the solubility and dispersing efficiency of the active ingredient, a technique for efficiently delivering the active ingredient to the desired site, and a technique for improving the stability of the skin It is required to develop a stable delivery material which can ultimately exhibit its original function sufficiently at a desired site of the effective ingredient.

However, the high crystallinity of polycaprolactone reduces the compatibility with the tissue and exhibits a long-term decomposition period, but it can be overcome by copolymerization with other monomers. Thus, the non-toxic, flexible, hydrophilic and biocompatible polyester series Were introduced. Polyethylene glycol (PEG) is non-toxic and exhibits excellent biocompatibility and is approved for use in the human body by the US Food and Drug Administration (FDA), and is widely used in the pharmaceutical industry. Methoxypolyethylene glycol is a drug delivery system with many advantages in the field of drug delivery. It can easily incorporate and release active ingredients, has high solubility in water and organic solvents, is non-toxic, and has no rejection of immune function.

The methoxypolyethylene glycol-polycaprolactone (mPEG-PCL) copolymer obtained by copolymerizing methoxypolyethylene glycol and polycaprolactone having the above properties can be produced by dissolving in a human body, by chemical hydrolysis, by enzymatic decomposition, Decomposition proceeds as a metabolite, and the decomposition period can be controlled by controlling the molecular weight and chemical composition of the copolymer. In addition to polycaprolactone, biodegradable polyesters such as poly L-lactide (PLLA), polyglycolide (PGA), and poly lactide-co-glycolide (PLGA) Various biomaterials copolymerized with polyethylene glycol have been studied. Korean Patent Publication No. 0891260 discloses an invention relating to a triblock copolymer in the form of polyethylene glycol-polycaprolactone-polyethylene glycol (PEG: PCL: PEG). Two polyethylene glycol-polycaprolactones (PEG-PCL ) Diacrylate diisocyanate (HMDI) and then reacted to prepare an ABA-block type PEG-PCL-PEG triblock copolymer. The present invention provides a PEG-PCLPEG triblock copolymer having a molecular weight ratio of PEG: PCL: PEG of 1: 2: 1 to 1: 4: 1 using PEG and PCL having a molecular weight of 400 to 3,000 g / Function and transdermal absorption facilitating function, and can reduce the amount of stimulant emulsifier to encapsulate and stabilize safe and unstable physiologically active ingredients on the skin. However, as a result of preparing a water-in-oil type (O / W) formulation using the triblock copolymer of the present invention, there is a problem that the particles encapsulating the physiologically active ingredients are large and hardly absorbed by the skin.

Korean Patent Publication No. 0919766 discloses an invention relating to a triblock copolymer of polyethylene glycol-hydrophobic block-polyethylene glycol type. However, when the size of the particles encapsulated using the triblock copolymer is 100 to 170 Mu m, which is larger than the epidermal tissue gap of the skin, so that the skin is not absorbed by the skin.

Recently, there has been a growing demand for non-toxic, naturally occurring cosmetics due to concerns about toxicity of cosmetics, and studies on cosmetics based on safe plant-derived ingredients under such an atmosphere have been actively conducted (Korean Patent Publication No. 10-2012-0121232, etc.) . However, when botanical converted extract and / or vitamin derivative is used as a cosmetic ingredient, not only the storage stability is deteriorated but also techniques for transferring and absorbing the same to the skin are insufficient. , There is a problem that the absorbing power of the cosmetic ingredients is deteriorated.

Accordingly, the present inventors have studied for a long period of time and found out the composition of the external preparation for skin having high stability of the substance to be delivered, which has high skin absorption power, and the optimum composition ratio thereof, and thus completed the present invention. That is, the present invention provides an external preparation for skin, a method for producing the same, a cosmetic using the same, and a skin ointment agent.

Disclosure of the Invention In order to solve the above problems, the present invention relates to an external preparation for skin, which comprises polymethyl methacrylate, polycaprolactone, and pentaerythrityl tetra-di-t-butylhydroxycinnamate tetra-di-t-butylhydroxyhydrocinnamate); And a recipient material containing at least one selected from a vitamin derivative and a transgenic tree plant conversion extract.

Another aspect of the present invention relates to a method for producing the external preparation for skin, comprising the steps of: injecting and dissolving polymethyl methacrylate and polycaprolactone in a solvent to prepare a first dissolving solution; Adding and dissolving pentaerythrityl tetra-di-t-butylhydroxyhydrocinnamate and a substance to be delivered to the first dissolving liquid to prepare a second dissolving liquid; Dropping and mixing the second dissolving solution into an emulsifier to prepare a mixed solution; Distilling the mixed solution under reduced pressure to remove the solvent; Centrifuging the mixed solution from which the solvent has been removed to obtain microparticles; Drying the resulting microparticles under reduced pressure; And pulverizing the dried microparticles to prepare a powder, thereby preparing a skin external preparation.

Another aspect of the present invention relates to a cosmetic comprising the above-described external preparation for skin.

Another aspect of the present invention relates to a skin ointment agent comprising the above-described external preparation for skin.

Conventional cosmetic carrier has poor stability and skin absorbability against plant transformation extract, vitamin derivative and the like. However, the external preparation for skin of the present invention is excellent in storage stability against transferring substances such as plant transformation extract and vitamin derivative, .

Figs. 1 and 2 show the chromatogram measurement results obtained in Experimental Example 1. Fig.
Fig. 3 is a result of an evaluation test of the storage stability of the external preparation for skin performed in Experimental Example 2. Fig.
FIG. 4 and FIG. 5 are the results of the calibration curve and the chromatogram measurement of the content of the vitamin derivative measured in Experimental Example 2. FIG.
6 to 8 are the results of the evaluation of the storage stability of the subject to be delivered in the cosmetic according to Experimental Example 3, and FIGS. 6 to 8 show the measurement results of Comparative Preparation Examples 1 to 3, respectively.
Figs. 9 and 10 are the results of the evaluation of the storage stability of the subject to be delivered in the cosmetics conducted in Experimental Example 3, wherein Fig. 6 and Fig. 10 are measurement results for Production Example 1 and Production Example 2, respectively.
FIG. 11 shows the results of measurement of changes in the content of vitamin derivatives in Experimental Example 3. FIG.
12 is a schematic view of the external preparation for skin of the present invention.
13A and 13B are SEM photographs of the external preparation for skin prepared in Example 2. Fig.
14A and 14B are SEM photographs of the external preparation for skin prepared in Example 3. Fig.

Hereinafter, the present invention will be described in more detail.

The present invention relates to a skin external preparation having excellent transferability and absorption ability to the skin and excellent in stability, and as shown in the schematic diagram of the external preparation for skin of the present invention shown in FIG. 12, have.

The carrier material may be contained in an amount of 1 to 10 parts by weight, preferably 1 to 8 parts by weight, based on 100 parts by weight of the carrier material. If the carrier material exceeds 10 parts by weight, There is a problem that the stability of the external preparation for skin is inferior.

In the present invention, the carrier material may be selected from the group consisting of polymethyl methacrylate, polycaprolactone, and pentaerythrityl tetra-di-t-butyl (pentaerythrityl tetra-di-t-butyl hydroxyhydrocinnamate).

Among the above carrier materials, polymethylmethacrylate serves as a shell of a microsphere (drug carrier), and may include 85 to 95% by weight of the total weight of the carrier material. In this case, poly When the content of methyl methacrylate is less than 85% by weight, there may be a problem that the formation rate of microspheres is decreased. When the content of methyl methacrylate is more than 95% by weight, there is a problem that the loading amount of the drug decreases.

Of the carrier materials, polycaprolactone is used to easily disintegrate the microspheres to release the drug, and may include 2 to 10% by weight of the total weight of the carrier material. In this case, the content of the polycaprolactone If it is less than 2% by weight, there may be a problem that the collapse effect is small. If it exceeds 10% by weight, there may be a problem that the microspheres aggregate.

Among the above carrier materials, pentaerythrityl tetra-di-t-butylhydroxyhydrocinnamate, which serves as an antioxidant, may contain 1 to 5% by weight of the total weight of the carrier material, and pentaerythrityl If the content of tetra-di-t-butylhydroxyhydrocinnamate is less than 1% by weight, the antioxidative effect may be low. If the content is more than 5% by weight, It is good.

In the present invention, the substance to be delivered may include a skin cosmetic ingredient, a skin drug ingredient, and the like, and may preferably include one or more kinds selected from a vitamin derivative and an extract from a transgenic tree plant, The vitamin derivative, and the plant extract of Algae plant.

In the case of using the vitamin derivative and the extract of Ganoderma lucidum extract simultaneously, it is advantageous in terms of skin absorption power and delivery power to be used in a ratio of 1: 0.1 ~ 2, preferably 1: 0.5 ~ 1.

In the present invention, the vitamin derivative may include general vitamins and derivatives thereof known in the art, preferably a vitamin derivative represented by the following general formula (1), more preferably a vitamin Derivative.

[Chemical Formula 1]

In Formula 1, R ₁ , R ₂ and R ₃ are each independently a hydrogen atom or a methyl group, and R ₄ is an alkylene group having 1 to 20 carbon atoms.

(2)

In Formula 2, R ₁ , R _2, and R ₃ are each independently a hydrogen atom or a methyl group.

The vitamin derivative represented by the above formula (1) or (2) may be prepared by using a specific hydroxy acid-based material as an intermediate mediator, and at one end of the intermediate mediator, a compound such as? -,? -,? - or? -Tocopherol Vitamin E is ester-linked, and the other end of the vitamin C is ether-bonded to the hydroxyl group at position 2 or 3 of the vitamin C. The vitamin derivative represented by the above formula (1) or (2) is characterized in that the hydroxy group at position 2 or 3 of vitamin C is bonded to the mediator through an ether bond, Since the ether bond is very stable against acids and the like, the stability is remarkably improved, and not only the effects of vitamin C and vitamin E are simultaneously exhibited, but also the inherent physical properties as a single substance can be exhibited have.

In addition, the transgenic plant transformation extract of the above-mentioned transfected material may include an extract obtained by hot-water extracting a mixture solution of kiwi and pineapple-ground liquid and a dispersion of groundwood-thistle-ground wood pulp. The kiwi and pineapple may be contained in a weight ratio of 1: 0.1 to 10, preferably 1: 0.1 to 1, more preferably 1: 0.1 to 0.5.

Hereinafter, a method for producing the external preparation for skin of the present invention described above will be described.

The external preparation for skin of the present invention can be prepared by mixing and microparticulating the above-described carrier material and the substance to be delivered, and pulverizing the same. Specifically, it is possible to use polymethyl methacrylate and polycaprolactone as a solvent Adding and dissolving the mixture to prepare a first dissolving liquid; Adding and dissolving pentaerythrityl tetra-di-t-butylhydroxyhydrocinnamate and a substance to be delivered to the first dissolving liquid to prepare a second dissolving liquid; Dropping and mixing the second dissolving solution into an emulsifier to prepare a mixed solution; Distilling the mixed solution under reduced pressure to remove the solvent; Centrifuging the mixed solution from which the solvent has been removed to obtain microparticles; Drying the resulting microparticles under reduced pressure; And pulverizing the dried microparticles to prepare a powder.

In the present invention, the solvent may be at least one selected from the group consisting of methylene chloride, chloroform, tetrahydrofuran and acetone, preferably methylene chloride.

In the present invention, the step of preparing the first dissolving solution may be performed at 10 ° C to 40 ° C, preferably at 15 ° C to 35 ° C.

The emulsifier in the step of preparing the mixed solution may use at least one selected from the group consisting of polyvinyl alcohol and polyoxyethylene sorbitan monooleate, preferably polyvinyl alcohol And it is suitably used in an amount of 200 to 400 parts by weight, preferably 250 to 350 parts by weight, based on 100 parts by weight of the solvent. If the amount of the emulsifier is less than 200 parts by weight, the emulsifying power is weak. If the amount of the emulsifier is more than 400 parts by weight, a large amount of bubbles may be produced during the manufacturing process.

Further, the vacuum distillation in the step of removing the solvent is preferably carried out under reduced pressure at 40 ° C to 60 ° C and -70 cmHg to -78 cmHg, preferably at 40 ° C to 50 ° C and -75 cmHg to -78 cmHg good.

The dried external microparticles may be pulverized by distillation under reduced pressure to produce the external preparation for skin of the present invention in powder form. The average particle size of the powder is 5 to 150 탆, preferably 5 to 120 탆, May be ground to 5 to 100 탆, and more preferably 5 to 50 탆, to prepare a powdery external preparation for skin. At this time, when the average particle diameter of the powder exceeds 150 탆, the skin absorbing ability may deteriorate. When the average particle diameter exceeds 5 탆, the production yield may decrease. Therefore, it is advantageous to pulverize the powder to have an average particle diameter within the above range.

As described above, the target material may include a skin cosmetic ingredient, a skin medicine ingredient and the like. Preferably, it may include at least one selected from a vitamin derivative and an extract from a plant extract May include the vitamin derivatives and the gentian plant transformation extract. The above-mentioned vitamin derivatives and plant extracts are the same as those described above, and a method of preparing them will be described in more detail below.

[Production method of vitamin derivative]

The vitamin derivative represented by the above formula (1) and / or (2), which can be used as a carrier in the present invention described above, can be obtained by treating a compound represented by the following formula (3) with an acid catalyst and water to remove an acetal group . ≪ / RTI >

(3)

In Formula 3, R ₁ , R _2, and R ₃ are each independently a hydrogen atom or a methyl group, and R ₄ is an alkylene group having 1 to 20 carbon atoms.

The water in the step of removing the acetal group is preferably used in an amount of 2 to 5 equivalents based on the compound represented by the general formula (3), and the acid catalyst is preferably used in an amount of 0.01 to 1 N , Preferably from 0.05 to 0.2 N.

The acid catalyst may be at least one selected from sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, and trifluoroacetic acid.

The compound represented by Formula 3 may be prepared by reacting a compound represented by Formula 4 and a compound represented by Formula 5 with an organic base; And hydrogen compounds of inorganic bases or inorganic bases; In the presence of one or two kinds of bases selected from the group consisting of: And organic bases; And a hydrogen compound of an inorganic base or an inorganic base are preferably used in an equivalent ratio of 1: 1 when they are used in combination. More specifically, the compound represented by the formula (3) can be prepared by introducing an ether linkage with the compound represented by the formula (5) in the -OH group at the 3-position of the compound represented by the formula (4). Reacting tocopheryl haloacylate of formula (5) with 5,6-isopropylidene-L-ascorbic acid of formula (4) to form tocopheryl acylate of formula Tocopheryl acyl-5,6-isopropylidene-L-ascorbic acid can be prepared by reacting 5,6-isopropylidene-L-ascorbic acid.

[Chemical Formula 4]

The 5,6-isopropylidene-L-ascorbic acid of Formula 4 is obtained by applying an acetal group to the hydroxyl groups at positions 5 and 6 of vitamin C. In the synthesis method of the present invention, considering the reactivity of vitamin C itself, By applying the form of formula (6), it is possible to induce a selective reaction to a desired position in the hydroxyl group at position 2 or 3 of vitamin C.

The 5,6-isopropylidene-L-ascorbic acid represented by the general formula (4) can be prepared by a general method known to those skilled in the art, for example, by mixing pure vitamin C with acetone or And the mixture is suspended in 2,2-dimethoxypropane, suspended, and then treated with an acid catalyst such as sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid or acetyl chloride.

Then, by controlling the molar ratio of equivalents of the base or hydride and 5,6-isopropylidene-L-ascorbic acid, the number of the 5,6-isopropylidene-L-ascorbic acid represented by the above formula (4) The reaction can be selectively induced in the hydroxyl group at the 3-position. Specifically, when the equivalent ratio of the base and the like to 5,6-isopropylidene-L-ascorbic acid is 1: 1, And an ether bond is formed at the position 2 when the equivalent ratio is 2: 1.

The equivalent ratio of tocopheryl halocarboxylate to 5,6-isopropylidene-L-ascorbic acid is 1: 0.1 to 10, preferably 1: 1 to 1.2. Examples of organic bases include triethylamine, pyridine, Or 4-dimethylaminopyridine (DMAP). As the inorganic base, sodium carbonate, sodium hydrogen carbonate or potassium carbonate, preferably sodium hydrogen carbonate, can be used.

The organic solvent is preferably a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a ketone solvent such as acetone or methyl ethyl ketone or an organic solvent such as acetonitrile, An aprotic solvent such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc) or dimethylsulfoxide (DMSO), more preferably an aprotic solvent such as DMF, DMAc or DMSO May be suitably changed depending on the solvent used, but the reaction temperature in the above step can be preferably 20 ° C to 60 ° C, more preferably 40 ° C to 60 ° C. If the reaction temperature is higher than 60 ° C, a large amount of oxides is produced due to lack of thermal stability of the reactants. If the reaction temperature is lower than 20 ° C, the reaction is not smoothly performed or the reaction time becomes long.

[Chemical Formula 5]

In Formula 5, X ₁ is I, Br, or Cl, R ₁ , R _2, and R ₃ are each independently a hydrogen atom or a methyl group, and R ₄ is an alkylene group having 1 to 20 carbon atoms.

The compound represented by Chemical Formula 5 may be prepared by reacting acyl halogenate compounds represented by Chemical Formula 6 with vitamin E such as? -,? -,? -, or? -Tocopherol in an organic solvent in the presence of an organic base And then reacting them. More specifically, an ester bond is formed between the hydroxy value of vitamin E and the acyl halogenate compound represented by formula (6). At this time, the equivalent ratio of the vitamin E to the acyl halogenate compound may be 1: 0.1 to 10, preferably 1: 1 to 1.3. The reaction may be carried out at a temperature of 10 ° C to 60 ° C, preferably 20 ° C to 30 ° C, more preferably 25 ° C to 30 ° C. Preferred examples of the organic base include triethylamine or pyridine. Preferred examples of the organic solvent include chloroform, dimethyl chloride, dimethylformamide or tetrahydrofuran.

[Chemical Formula 6]

Wherein X ₁ and X ₂ are each independently I, Br or Cl, and R ₄ is an alkylene group having 1 to 20 carbon atoms.

The acylhalogenate compound represented by Formula 6 may be prepared from a hydroxyacid-based substance used as an agent for binding vitamin C and E as a starting material. Specific examples thereof include a hydroxy acid or an isomer thereof having an alkyl chain having 1 to 20 carbon atoms and having a hydroxyl group and a carboxyl group at both terminals thereof, more preferably a glycolic acid, 4-hydroxybutyric acid, Hydroxyhexanoic acid, 6-hydroxyhexanoic acid, 9-hydroxynonanoic acid, hydroxypentadecanoic acid, hydroxyhexadecanoic acid, 18-hydroxyoctanoic acid, Hydroxyoctadecanoic acid or an isomer thereof may be used as an intermediate mediator, and the hydroxy group and the carboxyl group at both ends of the intermediate mediator may be respectively subjected to a halogen substitution reaction by halogen, Halogenated compounds can be prepared. The hydroxy acid-based material may be a Lewis acid catalyst such as ZnCl ₂ . In addition, the halogen substitution reaction may induce a halogen substitution reaction of a carboxyl group by directly mixing thionyl chloride (SOCl ₂ ), phosphorus trichloride, Br ₂ , or the like with the hydroxy acid-based substance.

In addition to the above method, the acyl halogenate compound represented by the above formula (6) may also be prepared by treating each hydroxy acid-based material through a solvent condition suitable for its physical properties.

[Preparation method of extracts of transgenic tree plants]

In the present invention, the above-described algae plant transformation extract can be prepared by mixing and aging a dispersion of a ground lump of kiwifruit and pineapple and a ground lump of lycopersicum, and then hydrolyzing the aged liquor.

The reaction can be carried out by mixing the milling liquid and the dispersion and then aging at 1 ° C to 10 ° C for 4 days to 10 days, preferably for 3 days to 7 days. At this time, If it is less than 1 day, the effect of the extract may be deteriorated, and it may be preferable to leave a mixture of the washing liquid and the dispersion for the above period, since it may be difficult to keep the liquid for 10 days. The aging temperature is preferably 1 to 10 ° C, more preferably 2 to 5 ° C. If the aging temperature exceeds 10 ° C, a problem of corruption may occur. If the aging temperature is less than 1 ° C, It is preferable to perform aging within the temperature range.

The hot water extraction is preferably performed at 65 ° C to 80 ° C. If the hot water extraction temperature is less than 65 ° C, the efficacy of the plant extract can be deteriorated. If the temperature exceeds 80 ° C, It is advantageous to perform hot water extraction within the temperature range.

Hereinafter, the present invention will be described in detail with reference to the preferred embodiments, which will be readily apparent to those skilled in the art to which the present invention pertains. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[ Example ]

Preparation Example  1: Manufacture of the extracts of Ganoderma lucidum

100 g of kiwi, 1,000 g of water and 20 g of pineapple were prepared and polished together to form a solution (this was called a solution A). 2,000 g of water was added to 100 g of ground wood crushed powder (hereinafter referred to as B solution).

Next, the solution A and the solution B were mixed at a weight ratio of 1: 1, and the mixture was aged in a refrigerator (4 ° C) for 1 week to prepare an aging solution. Next, the aged solution was subjected to extraction by hot water extraction at 70 캜 for 3 hours to obtain an extract, which was then centrifuged and filtered (0.2 탆) to prepare a ganoderma plant conversion extract.

Example  1: Preparation of external preparation for skin

Polymethyl methacrylate and polycaprolactone were added to methylene chloride as a solvent and dissolved at 25 占 폚 to prepare a first dissolution solution. Next, pentaerythrityl tetra-di-t-butylhydroxyhydrocinnamate and the plant extract obtained from Preparation Example 1 were added to the first dissolution solution, followed by dissolution at 25 ° C to obtain a second dissolution Lt; / RTI > At this time, 92 wt.%, 5.7 wt.% And 2.3 wt.% Of the total weight of the three components of polymethyl methacrylate, polycaprolactone and pentaerythrityl tetra-di-t-butylhydroxycinnamate were respectively.

And, 2 parts by weight of the extract of Algae plant transformation extract was used with respect to 100 parts by weight of the total of the weights of polymethyl methacrylate, polycaprolactone and pentaerythrityl tetra-di-t-butylhydroxyhydrocinnamate.

Next, the emulsifier was stirred and mixed at a stirring speed of 2,500 rpm for 3 minutes in a homomixer while dropwise adding the second dissolving solution to polyvinyl alcohol having a concentration of 2% to prepare a mixed solution.

Next, the mixed solution was distilled under reduced pressure at 45 캜 to completely remove methylene chloride, which was then centrifuged to obtain microparticles. At this time, the reduced pressure distillation was carried out at 45 ° C and -76 cmHg.

Next, the obtained microparticles were dried under reduced pressure at 45 DEG C to obtain dried microparticles, which were then pulverized using a hammer mill to obtain an average particle diameter of 30 to 80 mu m Sized powdery external preparation for skin was prepared.

Preparation Example  2: Preparation of vitamin derivatives

(1) α- Tocopheryl Bromoacetate  synthesis

50 g (0.116 mol) of alpha -tocopherol was dissolved in 100 mL of chloroform, and then 15 g (0.148 mol) of triethyl alcohol was added to the solution in an ice bath. Amine (TEA) was added slowly. The mixture was stirred at low temperature for 30 minutes, and 20 g (0.127 mol) of bromoacetyl chloride was taken and dropped by dropping funnel for 20 minutes. The addition continued at low temperature. After the addition was completed, the mixture was stirred for about 20 minutes while maintaining the low temperature, and the mixture was allowed to react for 3 hours in a shade state at room temperature. After completion of the reaction, the solution was transferred to a separating funnel with 100 mL of chloroform, washed with a diluted hydrochloric acid solution and distilled water, and the organic layer was separated and sufficiently dehumidified with MgSO4. After the desiccant was removed, the filtrate was concentrated under reduced pressure to obtain 58.9 g (yield: 92%) of? -Tocopheryl bromoacetate as a dark brown syrup.

TLC (ethyl acetate: hexane = 4: 6) Rf = 0.59

¹ H NMR (CDCl ₃ , 500 MHz) d (ppm): 4.31-4.34 (2H, t), 1.92, 1.95, 2.02 (3H, s), 2.48-2.58 ), 1.37 (3H, t) 0.79-0.86 (3H, t), 1.01-1.3 (2H, s)

(2) 3- (α- Tocopheryl  Acetyl) -5,6- Isopropylidene Synthesis of -L-ascorbic acid

A 500 mL three-necked round-bottom flask equipped with a dropping funnel was charged with Ar gas, and 26.5 g (0.123 mol) of 5,6-isopropylidene-L-ascorbic acid was taken and dissolved in 100 mL of DMSO . 10.34 g (0.123 mol) of NaHCO ₃ was added slowly at room temperature and stirred vigorously. And stirring was continued until the outflow of CO ₂ gas generated by interrupting the inflow of Ar gas was almost eliminated. After 1 hour, the solution was kept at a low temperature and a solution of 56.1 g (0.102 mol) of? -Tocopheryl bromoacetate dissolved in 120 mL of DMSO was transferred to a dropping funnel and slowly added dropwise with vigorous stirring. After the addition was completed, the reaction was allowed to proceed while the reaction temperature was raised to about 40 DEG C and the Ar gas was refluxed for 4 hours with vigorous stirring. After completion of the reaction, 150 mL of cold distilled water was added to neutralize with 1 M HCl solution while measuring the pH, and the mixture was stirred at room temperature for 30 minutes. The organic layer was recovered using ethyl acetate (300 mL), washed again with 1 M HCl and distilled water, and dehydrated with MgSO ₄ . The filtrate from which the desiccant was removed was concentrated and purified by silica gel column chromatography (ethyl acetate: hexane = 4: 6) to obtain 50.4 g (yield: 72%) of the target compound as a clear pale yellow viscous liquid.

TLC (ethyl acetate: hexane = 4: 6) Rf = 0.39

_{^{1 H NMR (CDCl 3, 500MHz}} ) d (ppm): 1.34 ~ 1.41 (3H, td) 5.24 ~ 5.3 (2H, d), 3.8 ~ 4.1 (2H, s) 4.1 ~ 4.3 (1H, t), 4.94 ~ (2H, t), 1.37 (3H, t), 2.48-2.58 (2H, t), 4.98 (1H, s), 5.3-5.46 , 0.79-0.86 (3H, t), 1.01-1.3 (2H, s)

(3) 3- (α- Tocopheryl  Acetyl) -L-ascorbic acid < / RTI >

50 g (0.0728 mol) of 3- (α-tocopheryl acetyl) -5,6-isopropylidene-L-ascorbic acid prepared above was taken in a 500 mL round-bottomed flask and dissolved in 200 mL of tetrahydrofuran ) And 60 mL of distilled water, and then 10 mL of trifluoroacetic acid was added slowly at a low temperature. After stirring for 10 minutes, the mixture was slowly heated to 60 DEG C and reacted for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, and residual distilled water was subjected to azeotropic distillation by adding alcohols such as isopropyl alcohol to obtain a pale yellow solid residue. The residue thus obtained was recrystallized from water, ethanol and methanol, and recovered to obtain 45.1 g (yield> 95.5%) of alpha -tocopheryl acetyl-L-ascorbic acid represented by the following formula (2) as a pale yellow powder (crystal).

TLC (ethyl acetate: hexane = 4: 6) Rf = 0.046.

Melting point: 182.98 ℃

Elemental analysis: C ₃₇ H ₅₈ O ₉ (calcd. C 68.70%, H 9.04%) detected C 68.63%, H 9.05%.

_{^{1 H NMR (DMSO-d 6}} , 500MHz) d: 3.40 ~ 3.51 (2H, m), 3.67 ~ 3.74 (1H, t), 4.94 ~ 4.98 (1H, s), 9.22 (H, t), 5.3 ~ 5.46 (2H, t), 1.37 (3H, t) 0.79-0.86 (3H, t), 1.72-1.78 1.01 ~ 1.3 (2H, s)

(2)

In Formula 2, R ₁ , R _2, and R ₃ are all hydrogen atoms.

Experimental Example  One : Preparation Example  Identification of vitamin derivatives of 2

Chromatograms were performed to evaluate the properties of the vitamin derivatives prepared in Preparative Example 2, and the results are shown in FIGS. 1 and 2.

As a result of the measurement, the vitamin derivatives prepared in Preparative Example 2 had intermediate properties of vitamin C and vitamin E, and chromatograms different from those of vitamin C and vitamin E were confirmed through FIG. 1 and FIG.

Example  2: Preparation of external preparation for skin

A skin external preparation for skin was prepared in the same manner as in Example 1 except that 2.1 parts by weight of the vitamin derivative prepared in Preparation Example 2 was replaced by 15 parts by weight of vitamin D derivatives, A skin external preparation for skin of 50 mu m in size was prepared. The SEM of the manufactured external preparation for skin was measured, and the results are shown in Figs. 13A and 13B.

Experimental Example  2: Experiment to evaluate stability of external preparation for skin

The stability test of the external preparation for skin prepared in Example 2 was measured by the following method, and the results are shown in Table 1 and FIG.

The stability test was carried out for 3 months in a constant temperature bath (40 ℃), and the stability evaluation experiment was carried out by observing changes in the content of the vitamin derivative as a carrier substance in the external preparation for skin.

3 and Table 1, it can be seen that the content of the vitamin derivative, which is a substance to be transferred, is hardly changed for 3 months, and it is confirmed that the stability of the external preparation for skin of the present invention is excellent.

ingredient Early 1 month 2 months 3 months Changes in vitamin content 86.68 ppm 87.23 ppm 86.33 ppm 87.81 ppm 100% 100.63% 99.59% 101.30%

Example  3

Using 2 parts by weight of the extract obtained from Preparatory Example 1 and 2 parts by weight of the vitamin derivative prepared in Preparation Example 2, the extracts of Phytophthora infestans and vitamin derivatives were prepared in the same manner as in Example 1, A powdered external preparation for skin having an average particle size of 70 to 110 mu m including all of the carrier was prepared, and SEM photographs thereof are shown in Figs. 14A and 14B.

Manufacturing example  1 to 2 and Comparative Manufacturing Example  1 ~ 3: Manufacture of cosmetics

Production examples 1 to 2 were carried out by using the external preparation for skin prepared in Example 2, respectively, to produce cream and essence type cosmetics.

Separately, Comparative Production Examples 1 to 3 were carried out by respectively preparing the vitamin derivatives prepared in Preparation Example 2, that is, the cream, the lotion and the essence type cosmetics respectively using the vitamin derivatives without using the carrier substance.

Experimental Example  3: In cosmetics To the subject  Storage stability evaluation experiment

In the stability evaluation test for cosmetics, each of the cosmetics prepared in the above Preparation Example was stored in a constant temperature bath (40 ° C) for 3 months to measure changes in the content of vitamin derivatives in the cosmetics of Production Examples 1 to 2 and Comparative Production Examples 1 to 3 .

The analytical method is to measure each sample to be 100 ppm of the vitamin derivative, dissolve in a mixed solution of tetrahydrofuran and methanol (40:60 by volume), and make a total of 100 ml. Respectively. After the extraction with ultrasound, 10 μl of the test solution and the standard solution were subjected to an experiment according to the liquid chromatographic method under the following conditions, and the content of the vitamin derivative was measured.

The results of the calibration curve and the chromatogram measurement of the standard solution of the vitamin derivative are shown in FIG. 4 and FIG. 5, respectively.

The measurement results of Comparative Production Examples 1 to 3 are shown in FIGS. 6 to 8, and the measurement results of Production Example 1 and Production Example 2 are shown in FIG. 9 and FIG. 10, respectively.

1) Detector: Ultraviolet absorptiometer (measuring wavelength 215 nm)

2) Column: A stainless steel tube having an inner diameter of about 4.6 mm and a length of about 15 cm and filled with octadecylsilylated silica gel for a liquid chromatograph of 5 μm was used

3) Column temperature: 30 DEG C

4) Mobile phase: methanol and distilled water (94: 6 by volume)

5) Flow rate: 1.5 ml / min

Table 2 and Fig. 11 show the results of summarizing the results of measurement of changes in the content of vitamin derivatives.

Formulation Early 1 month 2 months 3 months Comparative Preparation Example 1 87.15ppm 81.32 ppm 69.88 ppm 56.81 ppm 100.00% 93.31% 80.18% 65.18% Comparative Production Example 2 87.46 ppm 75.64 ppm 58.29 ppm 30.92 ppm 100.00% 86.49% 66.65% 35.35% Comparative Production Example 3 86.92 ppm 70.42 ppm 48.81 ppm 22.12 ppm 100.00% 81.02% 56.16% 25.44% Production Example 1 97.02 ppm 97.16 ppm 96.61 ppm 96.33 ppm 100.00% 100.14% 99.58% 99.29% Production Example 2 89.46 ppm 90.17 ppm 87.59 ppm 86.77 ppm 100.00% 100.79% 97.91% 96.99%

In the measurement results of Table 2 and FIG. 11, in the case of Preparation Example 1 and Preparation Example 2 of the cosmetics manufactured using the external preparation for skin of the present invention, it was confirmed that the content of the vitamin derivative was very slight. Term storage stability of 95% or more.

However, in the case of Comparative Preparation Examples 1 to 3 prepared using only the vitamin derivative without the delivery material of the present invention, the problem that the long-term stability is greatly lowered as compared with Production Examples 1 and 2 of the present invention there was.

Through the above Examples and Experimental Examples, it was confirmed that the external preparation for skin of the present invention has excellent storage stability against the substance to be delivered. Thus, through the external preparation for skin of the present invention, Cosmetics, and so on.

Claims (24)

A carrier material containing polymethyl methacrylate, polycaprolactone, and pentaerythrityl tetra-di-t-butylhydroxyhydrocinnamate; And
A vitamin derivative, and a transgenic plant extract,
Wherein the vitamin derivative is at least one selected from vitamin derivatives represented by the following formula (1) and vitamin derivatives represented by the following formula (2)
Wherein the extract of Phytophthora algae plant extract is a hot-water extract of a mixture of a liquid obtained by pulverizing kiwi and pineapple and a dispersion of pulverized product of algae wood;
[Chemical Formula 1]

Wherein R ₁ , R ₂ and R ₃ are each independently a hydrogen atom or a methyl group, R ₄ is an alkylene group having 1 to 20 carbon atoms,
(2)

In Formula 2, R ₁ , R _2, and R ₃ are each independently a hydrogen atom or a methyl group. The external preparation for cosmetic dermatology according to claim 1, wherein the carrier material is contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of the carrier material. The method of claim 1, wherein the carrier material is selected from the group consisting of 85 to 95% by weight of polymethylmethacrylate, 2 to 10% by weight of polycaprolactone and 1 to 5% by weight of pentaerythrityltetra-di-t-butylhydroxyhydrocinnamate, Wherein the external preparation for skin for cosmetics contains the composition. delete delete delete The method of claim 1,
A vitamin derivative and a graft extract of woody plant at a weight ratio of 1: 0.1 ~ 2. A cosmetic dermatological external preparation according to any one of claims 1 to 3 and 7, which is in powder form. A cosmetic comprising the external preparation for skin according to any one of claims 1 to 3 and 7. 7. A skin toning composition for cosmetic use, which comprises an external preparation for skin according to any one of claims 1 to 3 and 7. Adding and dissolving polymethyl methacrylate and polycaprolactone to a solvent containing at least one selected from methylene chloride, chloroform, tetrahydrofuran and acetone to prepare a first dissolving solution;
Adding and dissolving pentaerythrityl tetra-di-t-butylhydroxyhydrocinnamate and a substance to be delivered to the first dissolving liquid to prepare a second dissolving liquid;
Dropping and mixing the second dissolving solution into an emulsifier containing at least one selected from the group consisting of polyvinyl alcohol and polyoxyethylene sorbitan monooleate to prepare a mixed solution;
Distilling the mixed solution under reduced pressure to remove the solvent;
Centrifuging the mixed solution from which the solvent has been removed to obtain microparticles;
Drying the resulting microparticles under reduced pressure; And
Pulverizing the dried microparticles to prepare a powder,
Wherein the substance to be delivered comprises at least one selected from the group consisting of a vitamin derivative represented by the following formula (1), a vitamin derivative represented by the following formula (2)
The method for producing a topical skin preparation according to any one of claims 1 to 3, wherein the extract is prepared by mixing and reacting a dispersion of a crushed and ground pineapple and a dispersion of crushed pine tree, and then subjecting the reaction mixture to hot water extraction.
[Chemical Formula 1]

Wherein R ₁ , R ₂ and R ₃ are each independently a hydrogen atom or a methyl group, R ₄ is an alkylene group having 1 to 20 carbon atoms,
(2)

In Formula 2, R ₁ , R _2, and R ₃ are each independently a hydrogen atom or a methyl group. delete delete 12. The composition of claim 11, wherein the emulsifier comprises
Is 200 to 400 parts by weight based on 100 parts by weight of the solvent in the step of preparing the first dissolving liquid. The method of manufacturing an external preparation for skin according to claim 11, wherein the step of preparing the first dissolving liquid is performed at a temperature of from 10 캜 to 40 캜. 12. The method for producing an external preparation for skin according to claim 11, wherein the reduced pressure distillation is carried out at 40 to 60 DEG C and -70 to 100 cmHg. 12. The method according to claim 11, wherein the powder has an average particle diameter of 5 to 150 mu m. delete delete 12. The pharmaceutical composition according to claim 11, wherein the vitamin derivative represented by the formula (1)
Treating a compound represented by the following formula (3) with an acid catalyst and water to remove an acetal group; and a process for producing an external preparation for skin, comprising the steps of:
(3)

In Formula 3, R ₁ , R _2, and R ₃ are each independently a hydrogen atom or a methyl group, and R ₄ is an alkylene group having 1 to 20 carbon atoms. delete The method according to claim 11, wherein the kiwifruit and pineapple are contained in a weight ratio of 1: 0.1 to 10: 1. 12. The process of claim 11,
Wherein the milling liquid and the dispersion are mixed and aged for 4 days to 10 days at 1 占 폚 to 10 占 폚. The method according to claim 11, wherein the hot water extraction is carried out at 65 ° C to 80 ° C.

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