WO2016153229A1 - 글루타치온을 함유하는 미백용 피부 외용제 조성물 및 이의 제조 방법 - Google Patents

글루타치온을 함유하는 미백용 피부 외용제 조성물 및 이의 제조 방법 Download PDF

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WO2016153229A1
WO2016153229A1 PCT/KR2016/002763 KR2016002763W WO2016153229A1 WO 2016153229 A1 WO2016153229 A1 WO 2016153229A1 KR 2016002763 W KR2016002763 W KR 2016002763W WO 2016153229 A1 WO2016153229 A1 WO 2016153229A1
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Prior art keywords
glutathione
buffer
metal oxide
whitening
skin
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PCT/KR2016/002763
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English (en)
French (fr)
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배형진
이해신
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한국과학기술원
주식회사 비에이치랩
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Publication of WO2016153229A1 publication Critical patent/WO2016153229A1/ko

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/27—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/29—Titanium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

  • the present invention relates to a skin whitening composition containing glutathione and a method for producing the same.
  • Melanin plays an important role in determining human skin color. Melanin can be divided into eumelanin and peomelanin, and it is reported that melanin, which blackens the skin color, is mainly due to the production of eumelanin. In melanosomes, bioresponse begins with Tyrosine as a substrate and is converted to dopa (DOPA) form by tyrosinase.DOPA-Quinone ,
  • Glutathione is a tripeptide containing glutamate, cysteine and glycine, which has strong antioxidant properties, detoxification properties of toxic substances, immune enhancing properties and especially whitening properties. It is reported to be effective, and it is reported to be due to cysteine with free-thiol group. Specifically, it prevents the conversion of substrate tyrosine to waveguide by reducing the activity of tyrosinase, which is essential for the formation of eumelanin, It has been reported that whitening properties appear due to the principle of the formation of cysteinylDOPA, a precursor of pheomelanin, through inhibition of eumelanin production.
  • the object of the present invention is to provide a whitening skin external composition containing glutathione with significantly improved whitening properties and stability, and a method for producing the same.
  • the present invention uses the equilibrium relationship between glutathione monomer and glutathione dimer to adjust the pH of the aqueous phase to induce reaction in the direction of glutathione dimer to improve the stability in the form of the formulation.
  • the reaction is in the reverse direction of the reaction to the whitening skin external preparation composition to improve the whitening properties.
  • a whitening agent comprising the steps of: a) adjusting the pH of an aqueous phase to 6 to 8; and b) adding glutathione to the pH-adjusted water.
  • the present invention relates to a skin external composition preparation method and a whitening skin external preparation prepared by the above method.
  • the water phase of step a) includes a buffer, and the releasing agent includes a citrate buffer, a bis-tris buffer, and a MOPS buffer.
  • MOPS buffer phosphate buffer (PHOSPHATE buffer), CARBONATE buffer, HEPES buffer (HEPES buffer), tricine It may include a TRICINE buffer, a TRIS buffer, a BICINE buffer or a TAPS buffer.
  • the method for preparing a whitening skin external composition of the present invention includes the steps of c) adding a metal oxide particle to the water of step a ) or b) to prevent the metal oxide particle from being applied to the functional group of the glutathi silver or the glutameric dimer. It may further comprise a step of stabilizing by covalent bonding.
  • the metal oxide particles are used to achieve the object of the present invention.
  • metal oxides such as titanium dioxide and zinc oxide.
  • composition is not limited to the purpose of the present invention.
  • the total weight may include, for example, 0.01 to 5% by weight glutathione and 0.01 to 10% by weight of metal oxide particles.
  • a) adjusting the pH of the water phase to 6 to 8 b) preparing a glutathione dimer by injecting glutathione into the pH adjusted water and c) the a It relates to a method of stabilizing glutathione comprising the step of stabilizing the metal oxide particles by covalently bonded to the functional group of the glutathione or the glutathione dimer by introducing a metal oxide particles in the water of the step or b).
  • the functional group may include any one or more than one selected from -SH, -COOH, and -NH 2 functional group.
  • the metal oxide particles are used to achieve the object of the present invention.
  • metal oxides such as titanium dioxide and zinc oxide.
  • the whitening skin external composition of the present invention can be prepared by adjusting pH.
  • the whitening skin external composition of the present invention can be applied to UV-blocking skin external preparations, and has additionally improved UV-blocking properties while improving stability and whitening properties.
  • topical skin preparation for whitening of the present invention can be applied to various skin external preparations such as cosmetics or whitening agents in various dosage forms.
  • FIG. 2 is a spectrum showing the results obtained by using an ultraviolet-visible spectrometer to measure the dopamine oxidation characteristics according to the glutathione concentration of Experimental Example 2.
  • FIG. 3 is an image showing the result of measuring color change in order to measure the degree of phamine oxidation according to the glutathione concentration of Experimental Example 2.
  • FIG. 3 is an image showing the result of measuring color change in order to measure the degree of phamine oxidation according to the glutathione concentration of Experimental Example 2.
  • FIG. 5 is a graph showing the whitening characteristics of the composition according to Experimental Example 4 in relative ratios.
  • glutathione is present in the glutathione monomer of Formula 1, the glutathyl dimer of Formula 2, or in a mixed state depending on the pH environment.
  • the glutathione dimer increases more than the probability that the glutathione is present in the water.
  • Glutathione dimers are chemically more stable than glutathione monomers, and have relatively low whitening properties, making glutathione dimers unsuitable for use as external skin whitening agents.
  • the principle of improving whitening properties is to control the free-thiol group of glutathione by adjusting the pH, ie the increase in the ratio of glutathione monomers with free-thiol groups increases the activity of tyrosinase, which is essential for eumelanin formation. This reduces the whitening properties and prevents the conversion of tyrosine, which is a substrate, into the waveguide, and forms cysteinyl waveguides, which are precursors of pheomelanin, by inhibiting eumelanin production. do.
  • the method for preparing a whitening skin external composition of the present invention comprises the steps of a) adjusting the pH of the water phase to 6 to 8; and b) adding glutathione to the pH-adjusted water phase.
  • a) adjusting the pH of the water phase to 6 to 8; and b) adding glutathione to the pH-adjusted water phase comprises the steps of a) adjusting the pH of the water phase to 6 to 8; and b) adding glutathione to the pH-adjusted water phase.
  • the hydrogen ion concentration in the aqueous phase of step a) and step b) may be independently acidic, neutral or basic, and may be adjusted by a releasing agent or a pH adjuster.
  • the pH of step a) is preferably 6 to 8. Since the formation of glutathione dimer according to the reaction equilibrium from the pH above 6 is enhanced, the chemical stability of glutathione is improved, so the pH above 6 is appropriate. On the other hand, if the pH is less than 6, most of the glutathione monomer is present, and the reaction equilibrium toward the glutathione dimer rarely proceeds. If the pH exceeds 8, the pH level exceeds the appropriate pH level as an external skin preparation. In addition, skin irritation and cosmetic problems may occur, making it difficult to manufacture and use external skin preparations.
  • step a) is a step of adjusting the pH of the water phase
  • step b) a glutathione dimer is produced by inducing a conversion reaction of glutathione to a glutathione dimer. This is a pretreatment step.
  • the glutathione monomer when the glutathione monomer is reacted and converted to a glutamic dimer to form a liquid such as a liquid, the chemical deformation or side reaction is minimized, thereby improving stability.
  • the skin environment lipophilic
  • the skin environment lipophilic
  • a pH of 5 to 6 is automatically reacted to the glutathione and absorbed into the skin, thereby improving the whitening properties.
  • the step a) is not limited to a method of controlling pH, but specifically, a step of adjusting the pH by adding a buffer to the water, a ⁇ control agent, or these can be illustrated.
  • the buffer is, for example, acetate
  • buffers may be exemplified.
  • the citrate is not limited to the purpose of the present invention but can be adjusted to a pH corresponding to pH 6 to 8.
  • CITRATE buffer BIS-TRIS buffer
  • MOPS Buffers MOPS buffer
  • Phosphate buffers PHOSPHATE buffer
  • CARBONATE buffers HEPES buffers
  • Tricine Tricine
  • TRICINE buffer TRIS buffer, BICINE buffer or TAPS buffer
  • TRIS buffer TRIS buffer
  • BICINE buffer TAPS buffer
  • Internal buffers can be used.
  • the content of the buffer is, for example, the total weight of the composition.
  • the content can be adjusted for adjustment to the target pH, which is not greatly limited.
  • the pH adjusting agent is not limited to the purpose of the present invention, for example, lactic acid or salts thereof, pyrrolidone carboxylic acid or salts thereof and amino acid groups (lysine, histidine, arginine, aspartic acid).
  • Threonine, Serine, Glutamic Acid, Proline, Glycine, Alanine, Valine, Methionine, Isoleucine, Leucine, Tyrosine, Phenylalanine, Half cysteine, Cysteine, Asparagine, Glutamine or Tryptophan May contain
  • the pH adjusting agent is not limited to the purpose of the present invention, for example, citric acid, lactic acid, glycolic acid, sodium citrate, ascorbic acid, benzoic acid, salicylic acid It may contain any one or more selected from constituents such as phosphoric acid, succinic acid, maleic acid, hydrochloric acid, quenoic acid, sodium quenoate, edetic acid, sodium edate, sodium chloride, sodium hydroxide, potassium hydroxide and triethanolamine.
  • known pH regulators may be used.
  • pH regulators within the content range without cytotoxicity may be used.
  • the method for preparing a whitening skin external composition of the present invention includes the steps of c) injecting a metal oxide particle into the water of step a) or b) so that the metal oxide particle is covalently bonded to the functional group of the glutathione or the glutathione dimer. This can further include stabilizing steps.
  • the metal oxide particles may be selected from one or more functional groups selected from glutathione monomers and glutathione dimers such as -SH, -COOH, and -NH 2 .
  • metal oxide particles-glutathione monomers or metal oxide particles-glutathione dimers Due to the covalent property, the probability of existence of metal oxide particles-glutathione monomers or metal oxide particles-glutathione dimers is very high. Such metal oxide particles-glutathione monomers and metal oxide particles-glutathione dimers.
  • the improved chemical and physical stability also acts as a carrier, with a synergistic effect that simultaneously reveals the properties of the metal oxide particles.
  • metal oxide particles-glutathione monomers and metal oxide particles-glutathione dimers when contacted to the skin, automatically lose covalent bonds with the metal oxide particles and glutathione due to the weak acidic pH environment of the skin, resulting in glutathione other than metal oxides. As it is selectively absorbed into the skin, Will be improved.
  • the step c) is to add the metal oxide particles
  • the metal oxide particles may be added to the water of the step a) or b).
  • step b) when the metal oxide particles are added to the water before step b) which does not contain glutathione, glutathione is introduced thereafter.
  • the metal oxide particle-glutathione monomer is more than likely because the functional group that can react with the metal oxide particles in comparison with the glutathione dimer increases the probability that the reaction will proceed.
  • the glutathione dimer having a relatively smaller functional group capable of reacting with the metal oxide particles than the monomers with glutathione increases the probability of the reaction being proceeded. Therefore, the probability of the presence of the metal oxide particles-glutathione dimer is significantly higher.
  • the relative ratios of the metal oxide particles-glutathione monomers or metal oxide particles-glutathione dimers can be adjusted, and thus the relative effects of the stability of the formulation state and the whitening characteristics due to skin contact can be determined. I can regulate it.
  • the covalent bond with the glutathione is broken and the glutathione is selectively absorbed into the skin, resulting in a significant improvement in the whitening properties.
  • the average particle diameter of the metal oxide particles is not limited to the purpose of the present invention, but may be, for example, 1 nm to 10 mm 3, preferably 1 ntn to 1,000.
  • the average particle diameter of the oxide particles can be adjusted.
  • the metal oxide particles are not limited to the purpose of the present invention, but may include any one or more selected from metal oxides such as titanium dioxide and zinc oxide. If the particle is one or more metal oxide particles selected from metal oxides such as titanium dioxide and zinc oxide, the skin preparations of the present invention will have the effect of improving the stability and whitening properties as well as the additive effect of UV blocking properties.
  • the present invention is not limited by the type of the metal oxide particles, and the present invention is not limited to those having the same principles and characteristics.
  • the composition is not limited to achieving the object of the present invention, but may include, for example, 0.01 to 5 wt.
  • the glutathion may be comprised between 0.05 and 4% by weight and between 0.05 and 8% by weight of metal oxide particles, but this is only an example and the present invention is not limited thereto.
  • the skin external preparation is a melanin inhibitor, anti-aging agent, preservative, isotonic agent, stabilizer, disinfectant, wound protector, wound healing agent, purulent disease agent, anti-inflammatory agent, immunosuppressive agent, Parasitic skin disease agents, skin softeners, vitamins, herbals, moisturizers, astringents, coolants, antioxidants-agents, ultraviolet absorbers, ultraviolet scatterers, preservatives, antibacterial agents, chelating agents, surfactants, foaming agents, stabilizers, penetrants, preparations, It may further comprise any one or two or more selected from ingredients such as emulsifiers, emulsions, adhesives, adhesives, flavorings and pigments. The above ingredients may also be appropriately selected by those of ordinary skill in the art.
  • it may further contain various ingredients for improving physical properties as external skin preparations.
  • the whitening skin external composition of the present invention is a softening converging cosmetic cream, a nourishing cosmetic cream, BB cream, eye cream, nourishing cream, ultraviolet cream, cleansing foam, cleansing water, etc. It can be manufactured and used in a variety of formulations such as liquids, solids, powders, hydrogels, essences, sprays, patches, ointments, lotions or packs.These formulations can be used in any suitable form. It may contain various bases and additives necessary for formulation, and the types and amounts of these components can be easily adjusted, and the manufacturing methods of the above formulations are widely known, so the known methods may be used. Do.
  • Example 1 The procedure of Example 1 was repeated except that 1 N HC1 or 1 N NaOH was added so that the pH of Example 1 was 8 instead of 6. [Example 3]
  • a pH-controlled aqueous solution was prepared.
  • a glutathione aqueous solution was prepared by injecting glutathione into the aqueous solution, thereby preparing a whitening skin external preparation containing glutathione dimer and glutathione-metal oxide particle complex.
  • Aqueous solution adjusted to pH 6 was prepared by adding glutathione to the aqueous solution. After preparing a glutathione aqueous solution, 5 wt% of Ti0 2 particles having an average particle diameter of 60 nm were added based on the total weight of the aqueous solution to prepare a whitening skin external preparation composition containing a glutathione dimer and a glutathione-metal oxide particle complex.
  • Example 1 The pH of Example 1 was adjusted using a citrate releasing agent so that the pH was 5 instead of 6.
  • Ti0 2 particles having an average particle diameter of 60 nm based on the total weight of the aqueous solution in an aqueous solution 5
  • a weight ⁇ 3 ⁇ 4 was added.
  • a glutathione aqueous solution was prepared by adding glutathione to the aqueous solution, thereby preparing a whitening skin external composition containing a glutathione dimer and a glutathione-metal oxide particle complex.
  • compositions according to Examples 1 and 2 were measured using reverse-phase liquid chromatography. . Water and acetonitrile were used as the mobile phases at a volume ratio of 9: 1 respectively.
  • the glutathione monomer absorbed at 220 nm and the glutathione dimer absorbed at 280 nm the 4.44 min region, which is the retention time of the main peak, was observed.
  • the spectrum was measured using an ultraviolet-visible spectrometer and the color change over time was observed.
  • the results of the spectrum measurement are shown in FIG. 2, and the color change is shown in FIG. 3.
  • each composition 0.5, 1, and 2 mM glutathione having a pH of 6, each composition, 0.5, 1, and 2 mM glutathione having a ⁇ of 8 did not contain each composition, glutathione.
  • a pH 6 composition and a glutathione-free composition were prepared.
  • dopamine was added to make 10 mM dopamine solution, followed by treatment in an incubator for 24 hours. Spectral measurements and color change over time were observed.
  • mice treated with the composition prepared with 20 mM glutathione aqueous solution were treated as a control group, and mice treated with no treatment were used as a control group.
  • the back part of the composition-coated mouse was applied with a 360 nm ultraviolet lamp 2/3 from the head and a total of 37.4 kJ / m 2 was used. The light was irradiated for 9 days.
  • the whitening effect of the y-axis value of FIG. 5 is defined as 5 showing the best skin discoloration based on the degree of skin discoloration of the control group of Experimental Example 3 as 0, and as a relative ratio.
  • the degree of skin discoloration (whitening effect) was measured visually with a value of 0-5.
  • Example 3 and Example 5 containing glutathione and metal oxide particles that the whitening properties are improved than those of Example I and Comparative Example 1 containing no metal oxide particles. This is believed to be due to the synergistic effect of the combination of glutathione and metal oxide particles.
  • 0.1 weight% of hydroxyethyl sal was mixed and stirred at 43 :, and then emulsified by adding 10% by weight of soybean phospholipid, 5% by weight of sodium hyaluronate and purified water using an emulsifier. After finishing, use a stirrer to stir to 35 ° C while stirring to obtain 7% by weight of the whitening skin preparation composition of Example 2.
  • Nutritional serum was prepared.
  • the ratio 4% by weight of dicetylphosphate and 5% by weight of glycerin in a silver-based amphiphilic lipid mixture were mixed and homogenized at 25 ° C., passed through a microfluidizer, and then 15 % by weight of macadamia oil.
  • the second embodiment means baekyong topical composition 7 wt ⁇ 3 ⁇ 4, xanthan gum 11% by weight and benzoin 0.2 ⁇ 3 ⁇ 4 and carboxyvinyl Essence was prepared by dispersing and stabilizing by adding 0.3 weight% of polymer (weight average molecular weight 1,200,000) and aging at 25 ° C. for 2 days.

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Abstract

본 발명은 수상의 pH를 6 내지 8로 조절하는 단계, pH가 조절된 상기 수상에 글루타치온을 투입하여 글루타치온 이량체를 제조하는 단계를 포함하는 미백용 피부 외용제 조성물 제조방법 및 상기 방법으로 제조된 미백용 피부 외용제 조성물에 관한 것으로, 안정성이 보다 우수하고, 미백 효과가 뛰어난 특징이 있다.

Description

명세서
발명의명칭：글루타치온을함유하는미백용피부외용제조성물 및이의제조방법
기술분야
[1] 본발명은글루타치온을함유하는미백용피부외용제조성물및이의제조 방법에관한것이다.
[2]
배경기술
[3] 멜라닌 (Melanin)은사람의피부색을결정하는데에있어중요한역할을한다. 멜라닌은유멜라닌 (Eumelanin)과페오멜라닌 (Pheomelanin)으로구분될수 있는데，피부색을검게하는멜라닌은주로유멜라닌의생성에의한것으로 보고되어있다.유멜라닌은멜라닌을합성하는멜라노사이트 (Melanocyte)내의 멜라노좀 (Melanosome)에서타이로신 (Tyrosine)을기질로하여생체반웅이 시작되며,타이로시나아제에의하여도파 (DOPA)형태로전환된다.도파는생체 내에서자가산화반웅을통해도파퀴논 (DOPA-Quinone),
하이드록시인돌 (Hydroxyindole),인돌퀴논 (Indolequinone)등의형태로전환되어 최종적으로멜라닌올형성하게된다.
[4] 그러므로미백효과를주기위해서는 1)타이로신에서도파로의전환을
막아주고， 2)도파에서도파크름 (DOPA chrome)형태로유멜라닌이아닌 페오멜라닌을형성하도록유도시켜야한다.
[5] 한편글루타치온 (Glutathione)은글루타메이트 (Glutamate),시스테인 (Cystein)및 글라이신 (Glycine)을포함하는트라이펩타이드 (Tripeptide)로강력한항산화 특성,독성물질의해독특성，면역력강화특성및특히미백특성에효과가있는 것으로알려져있으며，이는자유-티올기를가진시스테인에기인한것으로 보고되어있다.상세하게,유멜라닌의형성에필수적인타이로시나아제의 활성을감소시킴으로써기질인타이로신의도파로의전환을막아주며, 도파와의결합올통해페오멜라닌의전구체인시스테닐도파 (CysteinylDOPA)를 형성하여유멜라닌생성을저해하는원리에의해미백특성이나타나는것으로 보고되어있다.
[6] 따라서글루타치온을이용한피부외용제의연구가활발히진행되고있다. 예컨대일본공개특허 1998-114670A, 1997-2910ΠΑ및 1996-099820A에는 글루타치온을함유하는미백용외용제조성물에대하여공지되어있다.또한 일본공개특허 2007-176798A등과같이다양한화합물을흔합하여글루타치온을 안정화시키는방법에대한연구도보고된바있으나,자유-티을기의부족으로 인하여유멜라닌의형성을효과적으로저해하지못해，결과적으로미백특성이 저하되는문제가발생한다. [7] 상기문제등으로인하여높은효율의미백특성을가지도록피부외용제에 글루타치온을적용하는것은실질적으로많은어려움이따른다.구체적으로， 글루타치온은특히액상에서안정성이저하되므로,실제화장료등의액상의 미백제에적용할경우，미백특성이현저히감소하는문제가발생한다.
[8] 이는글루타치은이포함된피부외용제의경우，미백특성이우수하면
안정성이저하되고，안정성이우수하면미백특성이저하되는
상충 (Trade-off)되는원리로서설명될수있다.
[9] 또한글루타치은은태양광에의해서도쉽게그화학적구조가쉽게변형될수 있어화학적또는물리적안정성이떨어지므로，실제자외선차단용화장료등에 적용할경우미백특성이효과적으로발현되지못하는문제가있다.
[10] 따라서우수한미백특성이피부에그대로적용되어유지될수있도록안정성 또한함께향상시키기위한연구가필요하며 ,또한다양한복합기능성피부 외용제에도적용이가능한글루타치온을포함하는피부외용제의연구가 필요하다.
[11]
발명의상세한설명
기술적과제
[12] 본발명의목적은미백특성과안정성이현저히향상된글루타치온을함유하는 미백용피부외용제조성물및이의제조방법을제공하는것이다.
[13] 또한본발명의목적은자외선차단용피부외용제에글루타치온을적용함에도 우수한안정성에기인하여미백특성및자외선차단특성이향상된미백용피부 외용제조성물및이의제조방법을제공하는것이다.
[14]
과제해결수단
[15] 본발명은글루타치온단량체와글루타치은이량체간의평형관계를이용하여 수상의 pH가조절됨으로써,글루타치온이량체로의반웅방향으로유도되어 제형상태에서는안정성이향상되고，사용시 (피부접촉)에는상기반웅의 역방향으로반웅이진행되어미백특성이향상되는미백용피부외용제 조성물에관한것이다.
[16] 구체적인일예에따른본발명은 a)수상의 pH를 6내지 8로조절하는단계및 b) pH가조절된상기수상에글루타치온을투입하여글루타치은이량체를 제조하는단계를포함하는미백용피부외용제조성물제조방법및상기 방법으로제조된미백용피부외용제조성물에관한것이다.
[17] 본발명의일예에있어서,상기 a)단계의수상은완충제를포함하며，상기 완층제는시트레이트완층제 (CITRATE buffer),비스-트리스완층제 (BIS-TRIS buffer), MOPS완충제 (MOPS buffer),포스페이트완충제 (PHOSPHATE buffer), 카보네이트완층제 (CARBONATE buffer), HEPES완층제 (HEPES buffer),트리신 완층제 (TRICINE buffer),트리스완층제 (TRIS buffer),바이신완충제 (BICINE buffer)또는 TAPS완층제 (TAPS buffer)를포함할수있다.
[18] 본발명의미백용피부외용제조성물제조방법은 c)상기 a)단계또는상기 b) 단계의수상에금속산화물입자를투입하여상기금속산화물입자가상기 글루타치은또는상기글루타치은이량체의작용기에공유결합하여안정화되는 단계를더포함할수있다.
[19] 본발명의일예에있어서，상기금속산화물입자는본발명의목적달성에
한해서는제한되지않으나,예컨대이산화티타늄및산화아연등의금속산화물 중에서선택되는어느하나이상을포함할수있다.
[20] 본발명의일예에있어서 ,상기조성물은본발명의목적달성에한해서는
제한되지않으나，예컨대전체중량기준，글루타치온 0.01내지 5중량 %및 금속산화물입자 0.01내지 10증량 %를포함할수있다.
[21] 또한본발명다른일양태로, a)수상의 pH를 6내지 8로조절하는단계， b) pH가조절된상기수상에글루타치온을투입하여글루타치온이량체를 제조하는단계및 c)상기 a)단계또는상기 b)단계의수상에금속산화물입자를 투입하여상기금속산화물입자가상기글루타치온또는상기글루타치온 이량체의작용기에공유결합하여안정화되는단계를포함하는글루타치온의 안정화방법에관한것이다.
[22] 본발명의일예에있어서,상기작용기는 -SH, -COOH및 -NH2작용기등에서 선택되는어느하나또는둘이상을포함할수있다
[23] 본발명의일예에있어서，상기금속산화물입자는본발명의목적달성에
한해서는제한되지않으나,예컨대이산화티타늄및산화아연등의금속산화물 둥에서선택되는어느하나이상을포함할수있다.
[24]
발명의효과
[25] 본발명의미백용피부외용제조성물은 pH조절을통하여상대적으로
안정성이높은글루타치온이량체를적용함으로써 ,안정성의향상과동시에 미백특성이향상되는효과가있다.
[26] 또한본발명의미백용피부외용제조성물은자외선차단용피부외용제에 적용이용이하고，안정성및미백특성이향상되면서도부가적으로향상된 자외선차단특성또한함께갖는효과가있다.
[27] 또한본발명의미백용피부외용제조성물은다양한제형형태로서 ,화장료 또는미백제등의다양한피부외용제로서의적용이가능한효과가있다.
[28]
도면의간단한설명
[29] 도 1은실험예 1의 pH에따른글루타치온단량체및글루타치은이량체의형성 특성을측정하기위해역상고효율액체크로마토그래피 (Reverse-phase liquid chromatography)를이용하여측정한결과를나타낸스펙트럼이며，
[30] 도 2는실험예 2의글루타치온농도에따른도파민산화특성을측정하기위해 자외선-가시광선분광기를이용하여측정한결과를나타낸스펙트럼이며，
[31] 도 3은실험예 2의글루타치은농도에따른도파민산화특성을측정하기위해 색변화를측정한결과를나타낸이미지이며,
[32] 도 4는실험예 3의처리군및대조군의시간에따른피부변색특성을측정하여 그결과를나타낸이미지이며,
[33] 도 5는실험예 4에따른조성물의미백특성을상대적비로나타낸그래프이다.
[34]
발명의실시를위한형태
[35] 이하첨부한도면들을참조하여본발명의글루타치온올함유하는미백용피부 외용제조성물및이의제조방법을상세히설명한다.
[36] 본발명에기재되어있는도면은당업자에게본발명의사상이충분히전달될 수있도록하기위해예로서제공되는것이다.따라서본발명은제시되는 도면들에한정되지않고다른형태로구체화될수도있으며，상기도면들은본 발명의사상을명확히하기위해과장되어도시될수있다.
[37] 또한본발명에서특별한언급없이불분명하게사용된 %의단위는중량 %를 의미한다.
[38]
[39] 수상에서글루타치온은 pH환경에따라하기화학식 1의글루타치온단량체, 화학식 2의글루타치은이량체또는이들이흔합된상태로존재하게된다.
구체적으로，상기 pH가 6이상일경우，상기글루타치온단량체들이서로 결합하여글루타치온이량체로의반웅평형방향으로반응이진행되므로，상기 글루타치온이량체가수상에존재할확률이상대적으로상승하게된다.
[40] [화학식 1J
[41 ]
Figure imgf000005_0001
[42] [화학식 2] [43]
Figure imgf000006_0001
[44] 글루타치온이량체는글루타치온단량체에비해화학적으로안정성이높은 물질인반면，상대적으로낮은미백특성을갖기때문에글루타치온이량체를 미백용피부외용제로서사용하기에는적합하지않다.
[45] 하지만상술한바와같이글루타치온은 pH환경에따라가역적으로
글루타치온이량체또는글루타치온단량체로존재하기때문에，하기화학식 3과같이 pH를조절하여액상등의제형상태에서는화학적으로안정적인 글루타치온이량체로존재하도록하고，실제피부에접촉되는상태에서는피부 접촉에기인한 pH감소에의해자동적으로 pH가조절되어향상된미백특성을 갖는글루타치온단량체로전환되도록하여,높은안정성및높은미백특성을 동시에갖는획기적인발명이라할수있다.
[46] [화학식 3]
[47] 피부접촉 A 제형상태
Figure imgf000006_0002
+2H +
[48] (GSH：글루타치온단량체, GSSG：글루타치온이량체)
[49] 미백특성이향상되는원리는 pH의조절을통해글루타치은의자유-티올기를 조절하여，즉,자유-티올기를가진글루타치온단량체의비가증가할수록 유멜라닌형성에필수적인타이로시나아제의활성을감소시켜미백특성이 향상되는원리이다.따라서기질인타이로신이도파로전환되는것을방지하고, 도파와의결합을통해페오멜라닌의전구체인시스테닐도파를형성하여 유멜라닌생성을저해하므로미백특성이향상되게된다. 상기원리를적용하기위한구체적인방법으로서 ,본발명의미백용피부 외용제조성물제조방법은 a)수상의 pH를 6내지 8로조절하는단계및 b) pH가 조절된상기수상에글루타치온을투입하여글루타치온이량체를제조하는 단계를포함할수있다.
[52] 본발명의일예에있어서，상기 a)단계및상기 b)단계의수상의수소이온 농도는독립적으로산성，중성또는염기성일수있으며 ,완층제또는 pH조절제 등에의해조절될수있다.
[53] 본발명의일예에있어서,상기 a)단계의 pH는 6내지 8인것이바람직하다. 6 이상의 pH에서부터반응평형에따른글루타치온이량체형성이보다우세하게 되어글루타치온의화학적안정성이향상되기때문에 6이상의 pH가적절하다. 반면상기 pH가 6미만일경우대부분글루타치온단량체가존재하게되며， 글루타치온이량체방향으로의반응평형이상대적으로거의진행되지않게 된다.또한 pH가 8을초과할경우，피부외용제로서적합한 pH수준을넘어서게 되어，피부자극성및제형상문제등이발생할수있어피부외용제로서제조및 사용이어려운문제가발생할수있다.
[54] 따라서상기 pH범위내를만족하는경우，미백특성이우수한글루타치온 단량체가존재하면서동시에안정성이우수한글루타치온이량체가상대적으로 다량존재하므로,안정성과함께미백특성이보다우수한효과가있다.
[55] 본발명의일예에있어서,상기 a)단계는수상의 pH를조절하는단계로서 , 이후의상기 b)단계에서글루타치온을글루타치온이량체로의전환반응을 유도하여글루타치은이량체를제조하기위한전처리단계이다.
[56] 앞서상술한바와같이 pH환경을조절하여글루타치온단량체를글루타치은 이량체로반웅및전환시켜액체등의제형상태로제조하게되면，화학적변형 또는부반응이최소화되어안정성이향상되게된다.따라서최종적으로피부에 사용 (접촉)시， pH가 5내지 6정도인피부환경 (지용성)에의해자동적으로 글루타치온단량체로의반웅이진행되어피부에흡수되므로，미백특성이다시 향상되게된다.
[57] 본발명의일예에있어서,상기 a)단계는 pH를조절할수있는방법이라면 크게제한되지않으나，구체적인일예로,수상에완충제 , ρΗ조절제또는이들을 투입하여 pH를조절하는단계를예시할수있다.
[58] 본발명의일예에있어서，상기완충제는예컨대아세테이트
완층제 (ACETATE buffer), MES완층제 (MES buffer),시트레이트
완층제 (CITRATE buffer),비스-트리스완층제 (BTS-TRIS buffer), MOPS 완충제 (MOPS buffer),포스페이트완층제 (PHOSPHATE buffer),카보네이트 완충제 (CARBONATE buffer), HEPES완충제 (HEPES buffer),트리신
완층제 (TRICINE buffer),트리스완충제 (TRIS buffer),바이신완층제 (BICINE buffer), TAPS완충제 (TAPS buffer),타우린완층제 (TAURINE buffer),보레이트 완충제 (BORATE buffer)또는 CAPS완충제 (CAPS buffer)등의완충제를예시할 수있다.구체적으로,본발명의목적달성에한해서는크게제한되지않으나， 예컨대 pH 6내지 8에해당하는 pH로조절이가능한시트레이트
완충제 (CITRATE buffer),비스-트리스완층제 (BIS-TRIS buffer), MOPS 완충제 (MOPS buffer),포스페이트완충제 (PHOSPHATE buffer),카보네이트 완층제 (CARBONATE buffer), HEPES완층제 (HEPES buffer),트리신
완충제 (TRICINE buffer),트리스완층제 (TRIS buffer),바이신완층제 (BICINE buffer)또는 TAPS완충제 (TAPS buffer)를사용하는것이바람직하다.하지만 이는바람직한일예일뿐,이외의인체에유해하지않는함량내의완충제를 사용할수있다.
[59] 본발명의일예에있어서，상기완충제의함량은예컨대조성물전체중량
기준， 0.001내지 5중량%인것일수있으나，목표 pH로의조절을위해상기 함량은조절될수있으므로，크게제한되지않는다.
[60] 본발명의일예에있어서，상기 pH조절제는본발명의목적달성에한해서는 제한되지않으나，예컨대젖산또는그의염,피롤리돈카르복시산또는그의염 및아미노산군 (라이신,히스티딘,아르기닌，아스파르트산，트레오닌，세린， 글루탐산,프롤린,글리신,알라닌，발린，메티오닌，이소로이신,로이신，티로신, 페닐알라닌,하프시스테인,시스테인，아스파라긴，글루타민또는트립토판등) 등의성분중에서선택되는어느하나또는둘이상올포함할수있다.
[61] 보다구체적인일예로,상기 pH조절제는본발명의목적달성에한해서는 제한되지않으나，예컨대시트릭산，락틱산，글라이콜릭산,소듐시트레이트， 아스코르빅산,벤조익산，살리실릭산，인산，숙신산，말레익산，염산，쿠엔산， 쿠엔산나트륨，에데트산，에데트산나트륨,염화나트륨，수산화나트륨， 수산화칼륨및트리에탄올아민등의성분증에서선택되는어느하나또는둘 이상올포함수있다.또한이외에도공지된 pH조절제를사용할수있다.이 외에도세포독성이없는함량범위내의 pH조절제가사용될수있다.
[62] 본발명의미백용피부외용제조성물제조방법은 c)상기 a)단계또는상기 b) 단계의수상에금속산화물입자를투입하여상기금속산화물입자가상기 글루타치온또는상기글루타치온이량체의작용기에공유결합하여안정화되는 단계를더포함할수있다.
[63] 상기금속산화물입자는글루타치온단량체또는글루타치온이량체의 -SH, -COOH및 -NH2등에서선택되는어느하나또는둘이상의작용기에
공유결합하는특성이있으므로,금속산화물입자 -글루타치온단량체또는 금속산화물입자 -글루타치온이량체로존재할확률이매우높아진다.이러한 금속산화물입자 -글루타치은단량체및금속산화물입자 -글루타치온이량체를 포함하는복합체에의해화학적및물리적안정성이보다향상되는것은물론， 전달체의역할도하며，동시에금속산화물입자의특성까지발현되는동반상승 효과가나타난다.
[64] 특히금속산화물입자-글루타치온단량체및금속산화물입자-글루타치온 이량체는피부에접촉시，피부의약산성 pH환경변화에의하여자동적으로 금속산화물입자및글루타치온과의공유결합이끊어져금속산화물외의 글루타치온이선택적으로피부에흡수되므로,미백특성이상대적으로 향상되게된다.
[65] 본발명의일예에있어서，상기 c)단계는금속산화물입자를투입하는
단계로서,상기금속산화물입자는상기 a)단계또는상기 b)단계의수상에 투입될수있다.
[66] 구체적인일예로，글루타치온을함유하지않는상기 b)단계이전의수상에 금속산화물입자를투입할경우,이후에글루타치온이투입되므로,
글루타치온이글루타치온이량체로전환되는동시에금속산화물
입자 -글루타치온복합체반응이일어나게된다.따라서글루타치온이량체에 비해금속산화물입자와반응할수있는작용기가상대적으로많은글루타치온 단량체와도상기반웅이진행될확률이상승하기때문에,금속산화물 입자 -글루타치온단량체가존재할확률이상대적으로높아진다.반면， 글루타치온을함유하는상기 b)단계이후의수상에금속산화물입자를투입할 경우,글루타치은단량체에비해금속산화물입자와반응할수있는작용기가 상대적으로적은글루타치온이량체와상기반웅이진행될확률이상승하기 때문에，금속산화물입자 -글루타치온이량체가존재할확률이상대적으로 높아진다.
[67] 상기와같은원리및방법에의하여，금속산화물입자 -글루타치온단량체또는 금속산화물입자 -글루타치온이량체의상대적비를조절할수있으므로，제형 상태의안정성및피부접촉에의한미백특성의상대적효과정도를조절할수 있다.
[68] 또한앞서상술한바와같이피부에접촉시，금속산화물입자및
글루타치온과의공유결합이끊어져글루타치온이선택적으로피부에 흡수되므로，미백특성이상대적으로향상되게된다.
[69] 본발명의일예에있어서，상기금속산화물입자의평균입경은본발명의목적 달성에한해서는크게제한되지않으나，예컨대 1 nm내지 10卿인것을예시할 수있다.바람직하게는 1 ntn내지 1,000 nm,보다바람직하게는 I nm내지 500 nm의평균입경을가지는보다미세한금속산화물입자를사용하는것이상기 조건들에있어서보다바람직한형태일수있다.예컨대제형의형태및자외선 차단효율등의조건에따라금속산화물입자의평균입경올조절하여사용할수 있다.
[70] 본발명의일예에있어서，상기금속산화물입자는본발명의목적달성에 한해서는크게제한되지않으나，예컨대이산화티타늄및산화아연등의 금속산화물중에서선택된어느하나이상을포함할수있다.상기금속산화물 입자가이산화티타늄및산화아연등의금속산화물증에서선택된어느하나 이상의금속산화물입자일경우，본발명의피부외용제조성물은안정성의향상 및미백특성향상과동시에자외선차단특성의부가적효과까지갖게된다. 하지만상기금속산화물입자의종류에의해본발명이제한되는것은아니며， 이와같은원리및특성을갖는것이라면크게제한되지않는다. [71] 본발명의일예에있어서，상기조성물은본발명의목적달성에한해서는 제한되지않으나,예컨대전체중량기준,글루타치온 0.01내지 5중량 <¾및 금속산화물입자 0.01내지 10중량 %를포함할수있다.바람직하게는 글루타치은 0.05내지 4중량 %및금속산화물입자 0.05내지 8중량 %를 포함하는것을예시할수있지만,이는바람직한일예일뿐，본발명이이에 제한되는것은아니다.
[72] 본발명의일예에있어서，상기피부외용제조성물은멜라닌합성저해제， 항노화제，보존제，등장화제，안정화제，살균소독약,창상보호제,창상치유제， 화농성질환용제,소염제，면역억제제,기생성피부질환용제,피부연화제, 비타민제，생약류，보습제,수렴제，청량제，항산회 -제,자외선흡수제，자외선 산란제,방부제,항균제，킬레이트제,계면활성제，발포제，안정제,침투제,조제， 유화제,유탁제，점착제，접착제,향료및색소등의성분중에서선택된어느 하나또는둘이상을더포함할수있다.또한상기성분들은본발명이속하는 기술분야에서통상의지식을가진자에의해적절히선택될수있는
부분으로서，이외에도피부외용제로서물성의개선을위한다양한성분들이더 포함될수있다.
[73] 본발명의일예에있어서，본발명의미백용피부외용제조성물은유연화장수 수렴화장수，영양화장수，비비크림,아이크림，영양크림,마사지크림， 클린징크림，자외선차단크림，클린징폼，클린징워터，액체，고체，파우더 , 하이드로젤,에센스,스프레이,패취，연고,로션또는팩등의다양한제형으로 제조하여사용될수있다.이외에도적합한어떠한형태로든제형화하여사용할 수있으며，이들각제형은그제형의제제화에필요하고적절한각종의기제와 첨가물을함유할수있으며 ,이들성분의종류와양은용이하게조절할수 있으므로제한되지않는다.또한상기제형의제조방법은널리공지되어 있으므로，공지된방법을이용해도무방하다.
[74]
[75] 이하본발명을실시예，실험예및제형예를통해상세히설명하나，이들은본 발명을보다상세하게설명하기위한것으로，본발명의권리범위가하기의 실시예에의해한정되는것은아니다.
[76]
[77] [실시예 1 ]
[78] 100 mM Tris-HCl완층제수용액에 I N HC1또는 1 N NaOH를 pH가 6이되도록 투입하여 pH가 6으로조절된수용액을제조하였다.이어서상기수용액에 글루타치온을투입하여 2 mM글루타치온수용액을제조하여 ,글루타치온 이량체를함유하는미백용피부외용제조성물을제조하였다.
[79] [실시예 2]
[80] 실시예 1의 pH가 6대신 8이되도록 1 N HC1또는 1 N NaOH를투입한것을 제외하고，실시예 1과동일하게실시하였다. [81 ] [실시예 3]
[82] 100 mM Tris-HCl완층제수용액에상기수용액전체중량기준，평균입경이 60 nm인 Ti02입자 5중량 %를투입하였다.이어서 1 N HC1또는 1 N NaOH를 pH가 6이되도록투입하여 pH가 6으로조절된수용액을제조하였다.이어서상기 수용액에글루타치온을투입하여 2 mM글루타치온수용액을제조하여， 글루타치은이량체및글루타치온 -금속산화물입자복합체를함유하는미백용 피부외용제조성물을제조하였다.
[83] [실시예 4]
[84] 실시예 3의 Ti02입자대신평균입경이 100 nm인 ΖηΟ입자를사용한것을
제외하고,실시예 3과동일하게실시하였다.
[85] [실시예 5]
[86] 100 mM Tris-HCl완층제수용액에 1 N HC1또는 1 N NaOH를 pH가 6이되도록 투입하여 pH가 6으로조절된수용액을제조하였다.이어서상기수용액에 글루타치온을투ᅳ입하여 2 mM글루타치온수용액을제조한후,상기수용액전체 중량기준，평균입경이 60 nm인 Ti02입자 5중량 %를투입하여글루타치온 이량체및글루타치온 -금속산화물입자복합체를함유하는미백용피부외용제 조성물을제조하였다.
[87] [비교예 I ]
[88] 실시예 1의 pH가 6대신 5가되도록시트레이트완층제를사용하여 pH를
조절한것을제외하고,실시예 1과동일하게실시하였다.
[89] [비교예 2]
[90] 수용액에상기수용액전체중량기준，평균입경이 60 nm인 Ti02입자 5
중량 <¾를투입하였다.이어서상기수용액에글루타치온을투입하여 2 mM 글루타치온수용액을제조하여，글루타치온이량체및글루타치온 -금속산화물 입자복합체를함유하는미백용피부외용제조성물을제조하였다.
[91]
[92] [실험예 1]
[93] pH에따른글루타치온단량체및글루타치온이량체의형성특성을확인하기 위해,실시예 1및실시예 2에따른조성물을역상고효율액체크로마토그래피 (Reverse-phase liquid chromatography)를이용하여스팩트럼을측정하였다. 이동상으로서물과아세토나이트릴를각각 9: 1의부피비로사용하였다.
[94] 구체적으로，글루타치온단량체는 220 nm에서흡광하며,글루타치은이량체는 280 nm에서흡광하므로,주피크 (Main peak)의유지시간 (Retention time)인 4.44 min영역대를관찰하였다.
[95] 이에대한결과는도 1에도시하였으며， pH 6의조건에서는자유-티올기를 갖는글루타치온단량체가다량존재하는것을확인하였으나,자유-티올기가 이황화결합 (Disulfide bond)한글루타치온이량체는미량존재하는것을 확인하였다.반면 pH 8의조건에서는자유-티올기를갖는글루타치온단량체와 함께 ,자유-티올기가이황화결합 (Disulfide bond)한글루타치온이량체가다량 존재하는것을확인하였다.
[96]
[97] [실험예 2]
[98] pH및글루타치온농도에따른도파민산화특성을측정하기위해
자외선-가시광선분광기를이용하여스펙트럼을측정하고，시간에따른색 변화를관찰하였다.스팩트럼측정결과는도 2에도시하였으며，색변화는도 3에도시하였다.
[99] 구체적으로，실시예 1과동일한방법으로， pH가 6인 0.5, 1및 2 mM글루타치은 각각의조성물 , ρΗ가 8인 0.5， 1및 2 mM글루타치은각각의조성물, 글루타치온을함유하지않는 pH가 6인조성물및글루타치온을함유하지않는 pH가 8인조성물을제조하여，각각의조성물모두에도파민 (Dopamine)을 투입하여 10 mM도파민수용액이되도록한후,인큐베이터에서 24시간동안 처리한후,스펙트럼측정및시간에따른색변화를관찰하였다.
[100] 이에대한결과는도 2에도시하였으며, pH가 6인 0.5， 1및 2 mM글루타치온 조성물및 pH가 8인 0.5, 1및 2 mM글루타치온조성물각각모두글루타치온의 저해 (Inhibition)가우수한것을확인할수있다.또한 1 mM이상의글루타치온 농도에서는미백특성의변화량이크지않으므로, 0.5내지 L mM의농도의 글루타치온을사용하는것이보다바람직함을확인할수있다.
[101] 또한시간에따른색의변화는도 3에도시되어있으며 , ρΗ가 6인 0.5, 1및 2 mM글루타치온조성물은변화가없었으나， pH가 8인 0.5， 1및 2 mM글루타치온 조성물은변색이나타났다.이는도파민의관능기인카테콜 (Catechol)기가 염기성조건에서탈수소화 (Deprotonation)되면서반웅성이좋은
카테콜퀴논 (Catecholquinone)형태가되면서가교반웅이진행되는것에 기인한다.
[102] 이때글루타치온을함유하지않은경우，마이크로이상의입자가형성되어 용액이탁하고부유물이관찰되나,글루타치온을함유한경우，상대적으로 부유물이적고,맑은형태의용액이형성됨을확인할수있었다.
[103]
[104] [실험예 3]
[105] 시간에따른피부변색특성을측정하기위하여，멜라닌이포함된 Hairless HRM2 (HR-l/Hos x C3H/He Hos)누드마우스를이용하여피부변색정도를 육안으로측정하였다.상기마우스는일반누드마우스보다피부가얇고,사람의 피부와가장유사한것으로보고되었으며,자외선조사시에검버섯및주름이 생기는특징을갖는다.
[106] 구체적으로,실시예 1과동일한방법으로,피부변색의차이를명확하게
확인하기위하여 20 mM글루타치온수용액으로제조된조성물이도포된 마우스를처리군으로，아무처리도하지않은마우스를대조군으로하여 실험하였다.그리고자외선조사로인한마우스피부의변색정도를명확히비교 확인하기위하여，상기조성물이도포된마우스의등부분을머리로부터 2/3 지점에 360 nm의자외선램프를이용하여전체 37.4 kJ/m2이되도록빛을 9일 동안조사하였다.
[107] 이에대한결과는도 4에도시하였으며,대조군에비하여처리군의미백특성의 효과가현저히향상된것을확인하였다.
[108]
[109] [실험예 4]
[1 10] 실시예 1 ,실시예 3,실시예 5,비교예 1및비교예 2의조성물의안정성및
미백특성의효과를측정하기위하여가속화실험을하였으며,실험예 3의 조성물대신상기조성물을직사광선및 40°C이상의온도를포함하는조건에서 7일동안방치한후얻은조성물을사용한것을제외하고，실험예 3과동일한 • 방법으로피부변색을측정하였다.또한변화의차이를명확하게확인하기 위하여,상기각각의조성물은 20 mM글루타치온수용액으로제조되었다.상기 조건은글루타치온의안정성에영향을주어물리적또는화학적변화를가속화 할수있는조건으로,상기조건하에일정시간방치된조성물의피부변색미백 특성은안정성판단의기준이될수있다.
[1 1 1] 이에대한결과는미백특성의각조성물에따른상대적비로서도 5에
그래프로도시되어있다ᅳ구체적으로，상기도 5의 y축값인미백효과는실험예 3의대조군의피부변색정도를 0으로기준하여가장우수한피부변색을보인 정도를 5로정의하였으며,이의상대적비로서 0내지 5의값으로피부변색 정도 (미백효과)를육안으로측정하였다.
[1 12] 이로부터글루타치온및금속산화물입자를함유하는실시예 3및실시예 5의 경우，금속산화물입자를함유하지않는실시예 I및비교예 1의경우보다 향상된미백특성을갖는것을확인할수있다.이는글루타치온및금속산화물 입자의결합에따른동반상승효과에기인한것으로판단된다.
[113] 하지만비교예 2의경우로부터，글루타치온및금속산화물입자의결합에따른 동반상승효과는 pH조절이수반되어야보다효과적임을확인할수있다.즉, pH 조절을하지않아안정성이떨어지는글루타치온단량체의상대적비가많은 것에기인하여，미백특성이저하되는것으로판단된다.
[114] 또한실시예 3및실시예 5의경우로부터 , ρΗ가조절된수상에글루타치온투입 후에금속산화물을투입하여제조된조성물의미백특성이보다향상돠는것을 확인할수있다.
[1 15]
[116] [제형예 1]
[117] 정제수에화장수전체중량기준，글리세린 3중량 부틸렌글리콜 2중량 %， 프로필렌글리콜 2중량 %및벤조인 0.2중량 %를순서대로반웅용기에투입및 교반하여용해시킨후,폴리옥시에틸렌경화피마자유 1증량%를 60°C로 가열하여 '용해시켰다.이후，실시예 2의미백용피부외용제조성물 7중량 에탄올 10중량 %및잔량의정제수를투입하여충분히교반및흔합한후， 25°C에서 2일동안숙성시켜화장수를제조하였다.
[118] [제형예 2]
[119] 정제수에영양크림전체중량기준，프로필렌글리콜 3중량 %，텍스트린
베헤네이트 0.5중량 %및벤조인 0.2중량 %를 82°C에서흔합및교반하였다. 이어서유화기를이용하여밀납 1증량 %,폴리솔베이트 60 1.5증량 솔비탄 세스퀴올레이트 0.5중량 %,유동파라핀 10중량 %，소르비탄스테아레이트 1 중량 친유형모노스테아린산글리세린 0.5중량 %,스테아린산 1 .5중량 %및 글리세릴스테아레이트 1중량 %를 82°C에서유화시켰다.유화가끝난후， 교반기를이용하여교반하면서 50°C까지냉각하였다.이어서실시예 2의미백용 피부외용제조성물 7중량 %를투입하여 250C까지다시냉각하였다.이후， 25°C에서 2일동안숙성시켜영양크림을제조하였다.
[120] [제형예 3]
[121] 영양세럼전체중량기준，잔탄검 0.02중량 %，부틸렌글리콜 10중량 %및
하이드록시에틸샐를로오즈 0.1중량 %를 43 ：에서흔합및교반한후,유화기를 이용하여소이빈포스포리피드 10증량 %>,소듐히아루로네이트 5중량 %및 정제수를투입하여유화시켰다ᅳ유화가끝난후,교반기를이용하여교반하면서 35°C까지넁각하고실시예 2의미백용피부외용제조성물 7중량%를
투입하였다.이어서 25°C까지냉각한후, 25°C에서 2일동안숙성시켜
영양세럼을제조하였다.
[122] [제형예 4]
[123] 시토스테롤 1.7중량 %，폴리에틸¾글리콜 1.5중량 세라마이드 0.7증량 %, 스테아르산 L2중량 %및콜레스테롤 1.5중량 %를 250C에서균질화하여 비이온계양친매성지질흔합물을제조하였다.상기비이은계양친매성지질 흔합물에디세틸포스페이트으4중량 %및글리세린 5중량 %를 25°C에서흔합및 균질화하여마이크로플루이다이져에통과시킨후,마카다미아오일 15중량 %를
550C에서서서히첨가하여균질화한후다시마이크로플루이다이져에재 통과시켰다.이후,실시예 2의미백용피부외용제조성물 7중량 <¾，산탄검 11 중량 %，벤조인 0.2중량 <¾및카르복시비닐폴리머 (중량평균분자량 1 ,200,000) 0.3 중량 %를투입하여분산및안정화시키고， 25°C에서 2일동안숙성시켜에센스를 제조하였다.

Claims

청구범위
[청구항 1] a)수상의 pH를 6내지 8로조절하는단계；및
b) pH가조절된상기수상에글루타치온올투입하여글루타치온 이량체를제조하는단계;
를포함하는미백용피부외용제조성물제조방법.
[청구항 2] 제 1항에있어서,
상기 a)단계의수상은완충제를포함하며,상기완충제는시트레이트 완층제 (CITRATE buffer),비스-트리스완층제 (BIS-TRIS buffer), MOPS 완충제 (MOPS buffer),포스페이트완층제 (PHOSPHATE buffer), 카보네이트완충제 (CARBONATE buffer), HEPES완충제 (HEPES buffer), 트리신완충제 (TRICINE buffer),트리스완충제 (TRIS buffer),바이신 완충제 (BICINE buffer)또는 TAPS완층제 (TAPS buffer)를포함하는것인 미백용피부외용제조성물제조방법 .
[청구항 3] 제 1항에있어서，
c)상기 a)단계또는상기 b)단계의수상에금속산화물입자를투입하여 상기금속산화물입자가상기글루타치온또는상기글루타치온 이량체의작용기에공유결합하여안정화되는단계；
를더포함하는미백용피부외용제조성물제조방법.
[청구항 4] 제 3항에있어서，
상기금속산화물입자는이산화티타늄및산화아연중에서선택된어느 하나이상을포함하는것인미백용피부외용제조성물제조방법 .
[청구항 5] 제 3항에있어서,
상기조성물은전체증량기준，글루타치온 0.01내지 5중량 %및 금속산화물입자 0.01내지 10중량 %를포함하는것인미백용피부 외용제조성물제조방법.
[청구항 6] 제 1항내지제 5항중에서선택된어느한항의제조방법으로제조된 글루타치온이량체를함유하는미백용피부외용제조성물.
[청구항 7J a)수상의 pH를 6내지 8로조절하는단계;
b) pH가조절된상기수상에글루타치온을투입하여글루타치온 이량체를제조하는단계;및
c)상기 a)단계또는상기 b)단계의수상에금속산화물입자를투입하여 상기금속산화물입자가상기글루타치온또는상기글루타치온 이량체의작용기에공유결합하여안정화되는단계;
를포함하는글루타치온의안정화방법.
[청구항 8] 제 7항에있어서,
상기작용기는 -SH, -COOH및 -NH2중에서선택된어느하나또는둘 이상을포함하는것인글루타치온의안정화방법 . [청구항 9] 제 8항에있어서，
상기금속산화물입자는이산화티타늄및산화아연중에서선텍된어느 하나이상을포함하는것인글루타치온의안정화방법.
PCT/KR2016/002763 2015-03-20 2016-03-18 글루타치온을 함유하는 미백용 피부 외용제 조성물 및 이의 제조 방법 WO2016153229A1 (ko)

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