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WO2002060404A1 - Composition de miconazole pour application externe et decoloration de la peau - Google Patents

Composition de miconazole pour application externe et decoloration de la peau Download PDF

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Publication number
WO2002060404A1
WO2002060404A1 PCT/KR2001/000615 KR0100615W WO02060404A1 WO 2002060404 A1 WO2002060404 A1 WO 2002060404A1 KR 0100615 W KR0100615 W KR 0100615W WO 02060404 A1 WO02060404 A1 WO 02060404A1
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WO
WIPO (PCT)
Prior art keywords
miconazole
skin
whitening
composition
melanin
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Ceased
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PCT/KR2001/000615
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English (en)
Inventor
Wonhong Woo
Yeunja Mun
Jounghoon Kim
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Classifications

    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • 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
    • 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 an externally applied skin-whitening composition containing miconazole, and more particularly, to a composition having an excellent skin whitening effect by containing miconazole as an effective ingredient, wherein the miconazole inhibits tyrosinase activity and melanin production.
  • Melanin is synthesized in melanocytes, being initiated by tyrosinase enzyme activated by internal and external regulatory factors. Tyrosinase acts on tyrosine to generate dihydroxyphenylalanine (DOPA), and oxidizes DOPA to give dopaquinone. Dopaquinone undergoes a non-enzymatic and spontaneous redox process to yield melanin pigment. Melanin is packaged in organelles called melanosomes, which distributed to neighboring keratinocytes and translocate to epidermal surface through a keratinization process, where melanin pigment protects skin from UN radiation.
  • melanosomes which distributed to neighboring keratinocytes and translocate to epidermal surface through a keratinization process, where melanin pigment protects skin from UN radiation.
  • melanin pigment functions as a free radical scavenger which removes various radicals modifying biological macromolecules such as proteins, lipids, and nucleic acids.
  • melanin is excessively synthesized at some area, or normal physiological functions of the body are impaired owing to aging and skin lesion, synthesized melanin is accumulated, resulting in various pigmentary deposits such as freckles, black spots, and ephelides.
  • depigmenting agents having inhibitory effects on tyrosinase activity or other reactions in the melanin synthesis process in cosmetics and pharmaceutical fields.
  • Examples of the depigmenting agents include tocopherol, vitamin, ascorbic acid, kojic acid, and hydroquinone.
  • the inhibitors of prior arts are not suitable for clinical or cosmetic application. That is, ascorbic acid is not useful as a melanin synthesis inhibitor because of its low inhibitory effect versus tyrosinase activity, and its instability.
  • Kojic acid shows high inhibitory activity against tyrosinase, but it is very unstable because it causes a color change when mixed with pharmaceutical compositions and decreases in titer with the lapse of time. Additionally, kojic acid exhibits so high irritation of the skin as to modify melanin pigment or melanocytes.
  • hydroquinone shows an excellent inhibitory effect on melanin synthesis
  • its use is generally limited because of hypersensitivity of skin to it.
  • the known depigmenting agents have serious problems that freckles remain in some areas even after treatment, harmful side effects occur, and a long time, generally at least 6 months, is required for expected results to be achieved.
  • peeling or laser therapy which are commonly used for removal of epidermal freckles of a depth of 0.1 mm, also can cause mechanical wounds and aggravate freckles.
  • miconazole has an excellent inhibitory effect on tyrosinase activity and melanin formation and is also capable of being used as an effective ingredient of external compositions for skin whitening.
  • miconazole functions as an antifungal agent.
  • Korean Pat. Publication No. 96-03321 discloses that econazole and miconazole, imidazole derivatives, are useful therapeutic agents for skin diseases induced by pathogenic fungi, Trichophyton and Candida species, where skin diseases including tinea ungium, tinea capitis, and tinea corporis result from infection of Trichophyton.
  • miconazole can be applied to a composition for treating and protecting skin against acute inflammation, as described in Korean
  • a optimal treatment concentration of miconazole was determined by analyzing viability of melanocyte cell line B16, and using the optimal concentration of miconazole, there were investigated effects of miconazole on tyrosinase activity, melanin formation and expression of tyrosinase, where hyperpigmentation was induced by increasing cAMP concetration by the treatment with ⁇ -melanocyte stimulating hormone ( ⁇ -MSH) and forskolin, and miconazole was found to have a skin whitening effect and an inhibitory effect on melanin formation.
  • ⁇ -MSH ⁇ -melanocyte stimulating hormone
  • Fig. 1 shows cell viability of melanocyte cell line B16 incubated with miconazole at a concentration of 0.1-50.0 ⁇ g/ml;
  • Fig. 2 shows tyrosinase activity in melanocyte cell line B16 incubated with miconazole at a concentration of 0.1 - 10.0 ⁇ g/ml;
  • Fig. 3 shows tyrosinase activity in melanocyte cell line B 16 incubated with miconazole at a concentration of 0.1-10.0 ⁇ g/ml as well as hyperpigmentation produced by treatment with ⁇ -MSH;
  • Fig. 4 shows tyrosinase activity in melanocyte cell line B16 incubated with miconazole at a concentration of 0.1-10.0 ⁇ g/ml as well as hyperpigmentation produced by the treatment of forskolin;
  • Fig. 5 shows inhibitory effects of miconazole and hydroquinone on tyrosinase activity
  • Fig. 6 shows synthesized melanin amount in melanocyte cell line B16 incubated with miconazole at a concentration of 0.1 - 10.0 ⁇ g/ml
  • Fig. 7 is a western blot showing protein expression level of tyrosinase in melanocyte cell line B16 incubated with miconazole at a concentration of 0.1-10.0 ⁇ g/ml.
  • Mouse melanocyte cell line B16 which synthesizes melanin, is used for investigating effects of miconazole on melanogenesis.
  • Miconazole is prepared by being dissolved in dimethyl sulfoxide (DMSO), and its optimal treatment concentration is determined by investigating cell viability of B 16 melanoma cells incubated with miconazole at varying concentrations of 0.1 to 50.0 ⁇ g/ml using sulphorhodamine-B (SRB) assay.
  • DMSO dimethyl sulfoxide
  • miconazole has an inhibitory effect on the activity of tyrosinase, which initiates melanin synthesis in melanocyte cells. Moreover, miconazole inhibits tyrosinase activity in B16 melanoma cells being stimulated by ⁇ -MSH ( ⁇ -melanocyte stimulating hormone), which induces hyperpigmentation by increasing melanin synthesis through stimulation of associated signal transduction pathways by increasing the intracellular concentration of cAMP. Also, miconazole displays an inhibitory effect on tyrosinase activity in B16 melanoma cells where hyperpigmentation is induced by forskolin.
  • ⁇ -MSH ⁇ -melanocyte stimulating hormone
  • Such an inhibitory effect of miconazole on tyrosinase activity is observed to be very strong in comparison with that of hydroquinone, a conventional depigmenting agent.
  • the synthesized melanin amount and the expression level of tyrosinase are reduced in B16 melanoma cells that have been treated with miconazole.
  • a new use of miconazole as a skin- whitening agent is provided on the basis of its strong inhibitory effects on tyrosinase activity and melanin formation.
  • a composition containing miconazole can be applied to external uses including cosmetics and pharmaceutical compositions with a skin whitening effect.
  • an externally applied skin- whitening composition containing miconazole as an effective ingredient and the composition contains miconazole at an amount of 0.05-5.0 % by weight, and preferably, at an amount of 0.1-2.0%) by weight. If the composition of the present invention contains miconazole at less than 0.05%, skin-whitening effect may be poor.
  • the composition of the present invention contains miconazole at an amount of 0.1-2.0%) by weight, and most preferably, at an amount of 2.0% by weight.
  • the externally applied skin- whitening composition of the present invention can also contain other substances used in conventional cosmetics and medical products for treatment, such as other whitening agents, moisturizers, antioxidants, oils, UV absorbents, surfactants, thickeners, alcohols, powders, dyes, perfumes, hydrophilic materials, water, and nutrient creams.
  • the skin- whitening composition of the present invention can also be formulated to various forms, such as cream, fluid cream, ointment, lotion, or pack, but the formulation is not limited to these.
  • Mouse melanoma cell line B16 was purchased from Korean Cell Line Bank. 1X10 5 of B16 melanoma cells per culture flask were incubated in 10% fetal bovine serum (FBS)-containing DMEM medium for 24 hours at 37°C under 5% CO 2 , and miconazole was then added at various concentrations of 0.1-10 ⁇ g/ml, and incubation was proceeded for 3 more days.
  • FBS fetal bovine serum
  • the cultured cells were used in the following Examples to investigate effects of miconazole on sulphorhodamine- B production, tyrosinase activity, melanin production, protein expression level, etc.
  • Sulphorhodamine-B (SRB) assay Sulphorhodamine-B (Sigma, USA) assay was performed to determine viable cell number when Bl ⁇ melanoma cells were exposed to miconazole.
  • B16 melanoma cells was seeded to a 96- well plate at a density of lxlO 4 cells per well and incubated for 24 hours, and after addition of miconazole in various amounts, further incubated for 48 hours.
  • Each of test and control groups incubated respectively with or without minaconazole was composed of three wells.
  • the cultivated cells were then fixed with a solution of 50% trichloroacetate (TCA) at 4°C for 1 hour, stained with a mixture of 0.4% sulphorhodamine-B (SRB) and 1% acetic acid, and after four washes with 1% acetic acid, dried.
  • TCA trichloroacetate
  • SRB sulphorhodamine-B
  • the dried cells were dissolved with protein stain in 10 mM Tris base to measure absorbance at 540 nm.
  • B16 melanoma cells incubated with or without miconazole which is a test or a control group, were harvested and lysed with 100 ⁇ l of lysis buffer (1% Triton X-100, 10 mM sodium phosphate, pH 7.0, 0.1 mM PMSF at 4°C with shaking once every 30 min, and then centrifuged.
  • lysis buffer 1% Triton X-100, 10 mM sodium phosphate, pH 7.0, 0.1 mM PMSF at 4°C with shaking once every 30 min, and then centrifuged.
  • the obtained supernatant was used for the tyrosinase activity assay, in which 50 ⁇ l supernatant was supplemented with 100 ⁇ l of 100 mM sodium phosphate buffer (pH 7.0), and after incubation for 5 min at 30°C and then addition of 50 ⁇ l of 100 mM L-DOPA, change in optical density was measured at 405 nm over 1 hour.
  • Inhibition level for tyrosinase activity by miconazole was calculated according to the below formula.
  • EXAMPLE 1 Effect of miconazole on viability of B16 melanoma cells Viability of B16 melanoma cells was investigated in order to determine a treatment concentration of miconazole.
  • the miconazole as prepared above was added to B16 melanoma cells at various concentrations of 0.1 to 50 ⁇ g/ml, and cell viability was measured using Sulphorhodamine-B (SRB) assay, which shows proliferation of cells by measuring cellular protein concentration.
  • SRB Sulphorhodamine-B
  • proliferation of B16 melanoma cells was inhibited at miconazole concentratons over 20 ⁇ g/ml, while proliferation of melanoma treated with miconazole at 50 ⁇ g/ml was reduced to 45% of that of a control group.
  • SRB Sulphorhodamine-B
  • EXAMPLE 2 Inhibitory effect of miconazole on tyrosinase activity
  • Step 1 Inhibitory effect of miconazole on tyrosinase activity
  • activity of tyrosinase which is the most important enzyme in the melanin synthesis pathway, was investigated.
  • test groups B16 melanoma cells were treated with miconazole of from 0.1 to 10 ⁇ g/ml, and a control group was incubated without miconazole. After incubation for 48 hours, tyrosinase activity was examined according to the procedure described in Reference Example 4.
  • Test groups incubated with miconazole at 0.1, 1, 5, and 10 ⁇ g/ml showed reduced tyrosinase activities of 86, 75, 67, and 4.6 %, respectively, compared to the control group. Accordingly, tyrosinase activity was significantly inhibited in proportion to increase in miconazole concentration (refer to Fig. 2).
  • Step 2 Inhibitory effect of miconazole on tyrosinase activity when hyperpigmentation is induced by ⁇ -MSH
  • ⁇ -MSH ⁇ -melanocyte stimulating hormone
  • B16 melanoma cell were treated with or without miconazole of from 0.1 to 10 ⁇ g/ml, and after 30 min, ⁇ -MSH was added to 10 nM and incubation was continued for 48 hours.
  • the melanoma cells treated with only ⁇ -MSH showed the increased tyrosinase activity of about 2.3 times higher than a control group.
  • tyrosinase activities were reduced to 64, 21, or 1.1 %, respectively, compared to the cells treated with only ⁇ -MSH. Accordingly, it was found that miconazole significantly inhibits tyrosinase activity upon hyperpigmentation being induced by ⁇ -MSH (refer to Fig. 3).
  • Step 3 Inhibitory effect of miconazole on tyrosinase activity when hyperpigmentation is induced by forskolin
  • the effect of miconazole on tyrosinase activity was investigated when B16 melanoma cells were stimulated with forskolin, which mimics the action of ⁇ - MSH by increasing intracellular cAMP concentration through activation of adenylate cyclase enzyme.
  • B16 melanoma cells were treated with or without miconazole of from 0.1 to 10 ⁇ g/ml, and after 30 min, forskolin was added to 20 nM and incubation was continued for 48 hours.
  • the cells with only forskolin exhibited increased tyrosinae activity of about 6 times higher than a control group, whereas the cells treated with both forskolin and miconazole of 0.1, 1, 5, or 10 ⁇ g/ml displayed reduced tyrosinase activities of 88.6, 64.8, 15.9, or 1.5 %, respectively, in comparison with the cells treated with only forskolin. Accordingly, it was confirmed that miconazole significantly inhibited tyrosinase activity in cells exhibiting hyperpigmentation induced by forskolin (refer to Fig. 4).
  • Step 4 Comparison of inhibitory effects of miconazole and hydroquinone on tyrosinase activity In cultivated B 16 melanoma cells using the same method as in Reference
  • Example 2 tyrosinase activities were analyzed accordingly to various concentrations of miconazole and hydroquinone, and the results are given in Fig. 5. As demonstrated in Fig. 5, miconazole strongly inhibited tyrosinase activity in the mouse melanoma cells. Especially, in comparison with hydroquinone, a known whitening agent, miconazole showed very strong inhibition of tyrosinase activity at the cellular level.
  • EXAMPLE 4 Inhibitory effect of miconazole on expression of tyrosinase Expression level of tyrosinase was investigated by Western blotting using anti-tyrosinase antibody.
  • NC membrane 10 % SDS-polyacrylamide gel, and then transferred to a nitrocellulose (NC) membrane.
  • NC membrane was incubated with a blocking buffer (5% skim milk) for 2 hours at room temperature (RT), and then with anti-tyrosinase antibody
  • test groups treated with miconazole showed lower protein expression levels of tyrosinase than the control group, and the expression level of tyrosinase was more significantly reduced at higher miconazole concentrations, indicating that miconazole significantly inhibits the expression of tyrosinase as well as enzyme activity of tyrosinase.
  • miconazole can prevent hyperpigmentation thanks to its excellent inhibitory effects on tyrosinase activity and melanin formation.
  • the externally applied skin-whitening compositions containing miconazole as an effective ingredient were prepared as creams in Preparation Example 1 and Comparative Preparation Example 1, below, and also, a cream without miconazole was prepared as Comparative Preparation Example 1 described below, followed by tests for stability and inhibitory effect on hyperpigmentation.
  • the externally applied skin-whitening composition containing miconazole was formulated as creams according to Table 1, below.
  • a cream of Preparation Example 1 was prepared according to Table 1 , and a composition for a cream of Comparative Preparation Example 1 was the same as that of Preparation Example 1 with the exception of sodium hydrogen sulfite.
  • the obtained creams were then separately put into a transparent glass vessel, covered, and maintained at room temperature to observe changes in color, where the observation was carried out on the first day, and the second, the fourth and the sixth weeks. The results are shown in Table 2, below.
  • EXAMPLE 6 Inhibitory effect of an externally applied skin- whitening composition on pigment deposition
  • the externally applied skin- whitening composition containing miconazole prepared in Preparation Example 1 displayed a whitening effect in 17 of 20 volunteers, especially an excellent whitening effect in comparison with the cream-type composition prepared in Comparative Preparation Example 2, which contains ascorbic acid as a known whitening agent, and exhibited no side effects to skin, demonstrating that minaconazole is an excellent whitening agent having stability while reducing hyperpigmentation, such as freckles and ephelides.
  • EXAMPLE 7 Whitening effect of the skin- whitening ointment on freckles
  • miconazole as a skin-whitening agent, which is widely known as antifungal agent, was demonstrated by confirming its inhibitory effects on tyrosinase activity, melanin formation and expression of tyrosinase enzyme. Moreover, in cosmetic application, miconazole showed high stability, no side effects and rapid whitening effect. Accordingly, the externally applied skin-whitening composition containing miconazole of the present invention is very useful for cosmetic and pharmaceutical applications.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Epidemiology (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition à usage externe pour la décoloration de la peau, contenant du miconazole. Ladite composition est stable, ne provoque pas d'effets secondaires nuisibles, et s'avère extrêmement efficace pour restreindre la formation du pigment mélanique et pour empêcher un dépôt pigmentaire de la peau, la composition contenant 0,05 % à 5,0 % de miconazole, ledit miconazole permettant de restreindre l'activité de la tyrosinase, enzyme principal dans la formation du pigment mélanique, et de restreindre la formation du pigment mélanique.
PCT/KR2001/000615 2001-01-31 2001-04-13 Composition de miconazole pour application externe et decoloration de la peau Ceased WO2002060404A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR2001/4701 2001-01-31
KR1020010004701A KR20010103057A (ko) 2001-01-31 2001-01-31 미코나졸 함유 피부 미백용 외용제 조성물

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010074052A1 (fr) 2008-12-22 2010-07-01 ポーラ化成工業株式会社 Inhibiteur de la production de mélanine
JP2017007999A (ja) * 2015-06-25 2017-01-12 花王株式会社 美白剤
EP4226911A1 (fr) * 2022-02-09 2023-08-16 CUTANEON - Skin & Hair Innovations GmbH Agent actif modulant l'activité d'un canal ionique utilisé pour la régulation de la pigmentation de la peau

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5648399A (en) * 1988-05-03 1997-07-15 Perio Products, Ltd. Liquid polymer composition and method of use
US5994372A (en) * 1995-09-12 1999-11-30 Regents Of The University Of California Peripherally active anti-hyperalgesic opiates
US6036966A (en) * 1998-02-17 2000-03-14 Youssefyeh; Rena T. Skin treatment compositions comprising protein and enzyme extracts
US6063397A (en) * 1996-10-25 2000-05-16 The Procter & Gamble Company Disposable cleansing products for hair and skin
US6153208A (en) * 1997-09-12 2000-11-28 The Procter & Gamble Company Cleansing and conditioning article for skin or hair

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5648399A (en) * 1988-05-03 1997-07-15 Perio Products, Ltd. Liquid polymer composition and method of use
US5994372A (en) * 1995-09-12 1999-11-30 Regents Of The University Of California Peripherally active anti-hyperalgesic opiates
US6063397A (en) * 1996-10-25 2000-05-16 The Procter & Gamble Company Disposable cleansing products for hair and skin
US6153208A (en) * 1997-09-12 2000-11-28 The Procter & Gamble Company Cleansing and conditioning article for skin or hair
US6036966A (en) * 1998-02-17 2000-03-14 Youssefyeh; Rena T. Skin treatment compositions comprising protein and enzyme extracts

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010074052A1 (fr) 2008-12-22 2010-07-01 ポーラ化成工業株式会社 Inhibiteur de la production de mélanine
KR20110098839A (ko) 2008-12-22 2011-09-01 포라 가세이 고교 가부시키가이샤 멜라닌 생산 억제제
US8846012B2 (en) 2008-12-22 2014-09-30 Pola Chemical Industries Inc. Melanin production inhibitor
EP3009123A1 (fr) 2008-12-22 2016-04-20 Pola Chemical Industries Inc. Inhibiteur de production de mélamine
JP2017007999A (ja) * 2015-06-25 2017-01-12 花王株式会社 美白剤
EP4226911A1 (fr) * 2022-02-09 2023-08-16 CUTANEON - Skin & Hair Innovations GmbH Agent actif modulant l'activité d'un canal ionique utilisé pour la régulation de la pigmentation de la peau
WO2023151931A1 (fr) * 2022-02-09 2023-08-17 Cutaneon - Skin & Hair Innovations Gmbh Agent actif modulant l'activité d'un canal ionique destiné à être utilisé dans la régulation de la pigmentation de la peau

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