WO1997042970A1 - Agent de depigmentation pour le traitement du melasme - Google Patents

Agent de depigmentation pour le traitement du melasme Download PDF

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Publication number
WO1997042970A1
WO1997042970A1 PCT/KR1997/000081 KR9700081W WO9742970A1 WO 1997042970 A1 WO1997042970 A1 WO 1997042970A1 KR 9700081 W KR9700081 W KR 9700081W WO 9742970 A1 WO9742970 A1 WO 9742970A1
Authority
WO
WIPO (PCT)
Prior art keywords
dexamethasone
melanoma cells
depigmenting
lincomycin hydrochloride
depigmenting agent
Prior art date
Application number
PCT/KR1997/000081
Other languages
English (en)
Inventor
Dae-Ghon Kim
Kyung-Ran You
Eun-Sil Kim
Hong-Yong Kim
Original Assignee
Kim Dae Ghon
You Kyung Ran
Kim Eun Sil
Kim Hong Yong
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kim Dae Ghon, You Kyung Ran, Kim Eun Sil, Kim Hong Yong filed Critical Kim Dae Ghon
Priority to AU27137/97A priority Critical patent/AU2713797A/en
Publication of WO1997042970A1 publication Critical patent/WO1997042970A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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

  • This invention relates to a type depigmenting agent for the melanoderma of patients with melasma.
  • This depigmenting agent containing a combination of corticosteroid and lincosamide, exhibits remarkable depigmenting effect with less side effects.
  • Melasma is defined as a facial hypermelanosis of light to dark brown color, occurring commonly on sun-exposed areas that develops slowly and symmetrically. Although no sex or race is spared, melasma appears to be more common in female.
  • Epidermal hyperpigmentation is charachterized by an increase in the number of active melanocytes and also by increased melanin synthesis.
  • the biosynthesis of melanin is initiated by catalytic oxidation of tyrosine to dihydroxylphenyialanine (DOPA), which is oxidized to dopaquinone and dopachrome.
  • DOPA dihydroxylphenyialanine
  • Tyrosinase is a rate-limiting enzyme in melanin biosysnthesis that catalizes the conversion of tyrosine to DOPA, DOPA to DOPAquinone.
  • Melasma can be a cosmetically disfiguring and psychologically devasting disease. Despite numerous claims that depigmneting agents give effective results in up to 80 percent of users, most clinician continue to express dissatifaction with presently available bleaching and depigmenting agents.
  • phenol compounds such as hydroquinone, monobenzyl ether of hydroquinone (MBEH), 4- isopropylcatechol, paratertiarybutyl and amyl phenol, 4-hydroxyanisole have demonstrated potent depigmenting effects in the treatment of melasma and other disoders of skin pigmentation. However, these treatments are not completely satisfactory because high concentrations are required, which results in side effects such as local irritation and irreversibile depigmentation of surrounding normal skin.
  • Hydroquinone is the most commonly used depigmenting agent for the treatment of melasma. It can be used in combination with 0.1% tretinoin (retinoic acid) with or withtout a corticosteroid. Kligman and
  • Topical application of azelaic acid at concnetration of 20% has also been reported to be effective in the treatment of several disoders of hyperpigmwntation including melasma and lentigo maligna.
  • formulation revealed adverse reactions including pruritus, mild and transient erythema, scaling, and burning.
  • tretinoin alone or in combination with hydroxyanisole has been considered as a depigmenting agents in the therapy of of postinflammatory hyperpigmentation and mealsma. Butit it has also been encountered with severe cutaneous side effects such as erthema and/or peeling in the area of application.
  • the object of this invention is to provide a new agent for improved efficacy and reduced toxicity.
  • the depigmenting agent of this invention contains the combination of corticosteroid and lincosamide.
  • the corticosteroid contained in the depigmenting agent of this invention may include cortisol, cortisone, cortisterone, deoxycortisterone, aldosterone, prednisolone, triamcinolone, paramethasone, betamethasone, or dexamethasone. It is preferred to select betamethasone valerate or dexamethasone.
  • the content ofthe corticosteroid is in the range of 0.01 to 10%, and preferably in the range of 0.04 to 1%.
  • the lincosamide contained in the depigmenting agent of this invention may also include lincomycin hydrochloride or clindamycin. The content of the linconsamide is in the range of 0.1 to 50%, and preferably in the range of 1 to 5%.
  • the molar concentration ratio between corticosteroid and lincosamide is in the range of 1 : 1 to 1 : 1000, preferably in the range of 1 : 10 to 1 : 100.
  • depigmenting agent of this invention may be used as a skin cream where hydrophilic ointment base is added to a combination of corticosteroid and lincosamide
  • other formulation may include lotion, solution, suspension, ointment, aerosol (spray), foam, paste, gel, or patch.
  • the depigmenting agent of this invention has some advantages in that a) it may inhibit the melanin synthesis with no effect on tyrosinase activity in melanoma cells, and b) at the same time, it may inhibit the proliferation of melanoma cells, thus demonstrating better depigmenting effects with less side effects.
  • this depigmenting agent containing a combination of corticosteroid and lincosamide may have synergic or additional effects on melanogenesis, compared with a single-drug regimen.
  • the depigmenting agent of this invention has no effect on tyrosinase activity in melanoma cells, it is beneficial since the rebound phenomenon of melanin overproduction is not expected to occur after discontinuation, and this is very important in maintaining homeostasis.
  • therapeutic effects of topical corticosteroid may mediated immunological suppression of hypermelanogesis, and simultaneous treatment of lincosamide may counteract corticosteroid-induced melanogenesis.
  • the combination of these drugs may turn out to be ideal in the better depigmenting effects.
  • the depigmenting agent of this invention is a novel which has not been used as a depigmenting agent in the past, and any experimental findings of this agent have not been published yet.
  • Fig. 1 show the comparison of clinical improvement of a patient between before treatment (A) and after treatment (B), There is a marked improvement of mealsma after topical application of the skin cream(Example 2) for 6 weeks.
  • Fig. 2 show the comparison of clinical improvement of a patient between before treatment (A) and after treatment (B), There is a complete loss of melasma after topical application of the skin cream (Example 2) for 6 weeks.
  • Fig. 3 show the comparison of clinical improvement of a patient before treatment (A) and one year after drug discontinuation (B), There is a marked improvement and no recurrence after drug discontinuation.
  • a skin cream of this invention was prepared by the combination of 0.05% dexamethasone and 2% lincomycin hydrochloride.
  • Example 2 A skin cream was prepared by mixing a skin-hydrophilic ointment base with 0.05% betamethasone valerate and 2% lincomycin hydrochloride and topically applied on the melanoderma of the melasma patients by a double blind method.
  • Melanoma cells were treated with dexamethasone, lincomycin hydrochloride, or dexamethasone/lincomycin hydrochloride (1 : 1) in various concentration ranges of 10 "9 M to 10 "4 to investigate the inhibitory effects of these drugs on the growth of melanoma cells. Also, so as to determine the optimum concentration ratio between dexamethasone and lincomycin hydrochloride, cells treated with fixed dose of 10 "6 M lincomycin hydrochloride in conjuntin with various dose of dexamethasone, in the range of 10 "9 M to lO ⁇ M.
  • B16 murine melanoma cells (Fiedler IJ, Nature, 242:148-149, 1973),were routinely cultured in a minimum essential medium (MEM) supplemented with 5% fetal bovine serum (FBS).
  • MEM minimum essential medium
  • FBS fetal bovine serum
  • Cells were seeded in 24-well plates at 2 X IO 3 cells/well, treated with drugs on next day and cultured at 37 ° C for 4 days in air containing 5% CO2. Every 2 days, the media was freshly changed. The growth rate of melanoma cells was determined by MTT assay 4 days after drug treatment, and expressed as a percentage of untreated cells.
  • MTT assay was performed as follows: MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] was dissolved in phosphate-buffered saline (PBS) and 50 ⁇ i of this solution was added to each well of 24-well plate. After 4 hrs, 200 ⁇ i dimethylsulfoxide (DMSO) and 50 ⁇ £ glycin buffer (pH 10.5) were added to the well and agitated for 10 min.
  • PBS phosphate-buffered saline
  • DMSO dimethylsulfoxide
  • pH 10.5 glycin buffer
  • Melanoma cells were treated with dexamethasone, lincomycin hydrochloride, or dexamethasone/lincomycin hydrochloride ( 1 : 1 ) in each concentration range of 10 "9 M to 10 '4 M to investigate the inhibitory effects of these drugs on the melanin synthesis in melanoma cells. Also, so as to determine the optimum concentration ratio between dexamethasone and lincomycin hydrochloride, the concentration of lincomycin hydrochloride was fixed to 10 '6 M and that of dexamethasone was in the range of 10 "9 M to 10 "4 M for this experiment. Hence, the melanin content was quantified according to the procedure described by Hosoi et al. (Cancer Res, 45; 1474-1478, 1985).
  • B16 murine melanoma cells were seeded in petri dish at 2 X I O 4 cells/ml. The cells were treated with above drugs and cultured for 4 days.
  • the melanin content was calculated and expressed in ⁇ g /mg protein.
  • Table 2 Inhibition of melanin synthesis in melanoma cells treated with dexamehtasone, lincomycin hydrochloride, or dexamethasone/lincomycin hydrochloride at various concentration
  • melanin synthesis in melanoma cells was inhibited in a dose response curve and melanin synthesis was most significantly inhibited at 10 '7 M or 1 O ⁇ M.
  • Melanoma cells were treated with dexamethasone, lincomycin hydrochloride,or dexamethasone/lincomycin hydrochloride (1 : 1) in various concentration ranges of 10 '8 M to I O "4 M to investigate the effects of these drugs on tyrosinase activity in melanoma cells. Also, so as to determine the optimum concentration ratio between dexamethasone and lincomycin hydrochloride, the eel treated with the fixed dose of 10 " 6 M lincomycin hydrochloride in conjunction with various dose of dexamethasone in the range of 10 "9 M to 10 '4 M. Tyrosinase activity of melanoma cells was measured by a method of Bouchard et al. (J. Exp. Med., 169; 2029-2042, 1989).
  • B16 murine melanoma melanoma cells were seeded in 100 mm of petri dish at 2 X IO 4 cells/ml. The cells were treated with above drugs at indicated concentrations and cultured for 4 days.
  • reaction mixture was left on ice for 30 mins and centrifuged at
  • Table 4 Tyrosine activity in melanoma cells treated with dexamethasone, lincomycin hydrochloride, or dexamethasone/lincomycin hydrochlorie at various concentration
  • Melanoma cells were treated with dexamethasone, lincomycin hydrochloride, or dexamethasone/lincomycin hydrochloride (1 : 1) in various concentration ranges of 10 "8 M to 10 "4 to investigate the effects of these drugs on the tyrosinase mRNA level in melanoma cells by Nothern blot analysis.
  • mRNA in melanoma cells were extracted from oligo (dT) cellulose column chromatography, fractionated on 1% formaldehyde gel via electrophoresis, and transferred to a Gene Screen Plus membrane. After UV cross-linking and prehydbridization in Church buffer, the blots were hybridized with a radiolabeled probe which were isolated from the clone MTY81 IC . Next day, the filters were washed twice at 65 ° C in 2 X SSC/0.1% SDS for 20 min each, then washed twice at 65 ° C in 2 X SSC/0.1% SDS each. The band intensity of the autoradiogram was measured using a personal densitometer SI (Molecular Dynamics, Sunnyvale, CA, USA). The tyrosinase mRNA transcript level was expressed as a percentage of untreated control.
  • the level of mRNA for beta-actin was determined in the same manner as described above. The results were demonstrated in the following table 6.
  • Table 6 Tyrosinase mRNA transcript level in melanoma cells treated with dexamethasone, lincomycin hydrochloride or dexamethasone/lincomycin hydrochloride at various concentration
  • tyrosinase mRNA transcript level in melanoma cells was increased in a dose dependent manner.
  • melanoma cells were treated with lincomycin hydrochloride alone, there was no increase in tyrosinase mRNA transcript level in melanoma cells.
  • a combination of dexamethasone and lincomycin hydrochloride has several advantages in that a) it may inhibit the melanin biosynthesis wihtout change of tyrosinase activity in melanoma cells, and b) at the same time, it may inhibit the growth of melanoma cells.
  • this combination seems to be better than any other previous agent in depigmenting effects and side effects.
  • Experimental example 5 Double blind control trials using a skin cream containing dexamethasone and lincomycin hydrochloride.
  • a skin cream containing betamethasone valerate and lincomycin hydrochloride must be safe and have remarkable depigmenting effects with less side effects.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un agent de dépigmentation, notamment un composé entraînant une dépigmentation, qui contient une combinaison d'un corticostéroïde et d'une lincosamide. Le corticostéroïde peut être choisi entre le cortisol, la cortisone, la corticostérone, la désoxycorticostérone, l'aldostérone, la prednisolone, le triamcinolone, la paraméthasone, la bétaméthasone ou la dexaméthasone; de préférence, on choisit la bétaméthasone ou la dexaméthasone; et son taux est compris entre 0,01 et 10 %, de préférence entre 0,04 et 1 %. La lincosamide peut être choisie entre la lincomycine ou la clindamycine, et son taux est compris entre 0,1 et 50 %, de préférence entre 0,1 et 5 %. La formulation de l'agent de dépigmentation peut être une crème à base d'onguent, ou bien une lotion, une solution, une suspension, un onguent, un aérosol (spray), une mousse, une pâte, un gel ou une pastille adhésive. L'agent entraîne une dépigmentation remarquable avec peu d'effets secondaires.
PCT/KR1997/000081 1996-05-10 1997-05-10 Agent de depigmentation pour le traitement du melasme WO1997042970A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27137/97A AU2713797A (en) 1996-05-10 1997-05-10 Depigmentating agent in the treatment of melasma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1996/15303 1996-05-10
KR19960015303 1996-05-10

Publications (1)

Publication Number Publication Date
WO1997042970A1 true WO1997042970A1 (fr) 1997-11-20

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KR (1) KR100200240B1 (fr)
AU (1) AU2713797A (fr)
WO (1) WO1997042970A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8148327B2 (en) * 2007-06-06 2012-04-03 Human Matrix Sciences, Llc Aldosterone induced elastin production
US8618084B2 (en) 2008-06-06 2013-12-31 Human Matrix Sciences, Llc Aldosterone induced vascular elastin production

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100668492B1 (ko) * 2000-04-08 2007-01-12 김대곤 기미 치료제 조성물

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3856934A (en) * 1970-06-24 1974-12-24 A Kligman Skin depigmentation
FR2383663A1 (fr) * 1977-03-18 1978-10-13 Nemet Pierre Procede d'obtention d'une creme a action depigmentante et creme obtenue par ce procede

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3856934A (en) * 1970-06-24 1974-12-24 A Kligman Skin depigmentation
FR2383663A1 (fr) * 1977-03-18 1978-10-13 Nemet Pierre Procede d'obtention d'une creme a action depigmentante et creme obtenue par ce procede

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8148327B2 (en) * 2007-06-06 2012-04-03 Human Matrix Sciences, Llc Aldosterone induced elastin production
US8470774B2 (en) 2007-06-06 2013-06-25 Human Matrix Sciences, Llc Deoxycorticosterone induced elastin production
US9492462B2 (en) 2007-06-06 2016-11-15 Human Matrix Sciences, Llc Composition for elastin production
US8618084B2 (en) 2008-06-06 2013-12-31 Human Matrix Sciences, Llc Aldosterone induced vascular elastin production
US9283236B2 (en) 2008-06-06 2016-03-15 The Hospital For Sick Children Aldosterone induced vascular elastin production

Also Published As

Publication number Publication date
KR970073592A (ko) 1997-12-10
KR100200240B1 (ko) 1999-06-15
AU2713797A (en) 1997-12-05

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