EP2459158A2 - Pharmaceutical, cosmetic or dietetic composition for skin bleaching - Google Patents

Pharmaceutical, cosmetic or dietetic composition for skin bleaching

Info

Publication number
EP2459158A2
EP2459158A2 EP10752401A EP10752401A EP2459158A2 EP 2459158 A2 EP2459158 A2 EP 2459158A2 EP 10752401 A EP10752401 A EP 10752401A EP 10752401 A EP10752401 A EP 10752401A EP 2459158 A2 EP2459158 A2 EP 2459158A2
Authority
EP
European Patent Office
Prior art keywords
spermidine
composition according
cosmetic
pharmaceutical
skin
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10752401A
Other languages
German (de)
French (fr)
Inventor
Ralf Paus
Giammaria Giuliani
Yuval Ramot
Astrid Becker
Sergio Baroni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Giuliani SpA
Original Assignee
Giuliani SpA
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 Giuliani SpA filed Critical Giuliani SpA
Publication of EP2459158A2 publication Critical patent/EP2459158A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines

Definitions

  • the present invention relates to the use of a skin bleaching composition.
  • melanin characterize a large number of skin diseases, such as acquired hyperpigmentation, for example melasma, post-inflammatory melanodermia, sun freckles.
  • Skin and dermal hyperpigmentation may depend on a larger number of melanocytes or on the activity of melanogenic enzymes.
  • An ideal depigmenting compound must have a bleaching and powerful, quick and selective effect on hyperactivated melanocytes and no short- or long-term side effects and lead to a removal of the undesired pigment acting in one or more steps of the pigmenting process.
  • the spermidine compound that is N-(3-aminopropyl)butan-1 ,4-diamine, as such or in the form of a pharmaceutically acceptable derivative such as a salt, is provided with a pigmentation inhibition activity in the skin basal layer, and can therefore be effectively used to promote a skin bleaching effect.
  • Such activity allows configuring the use of the active compound in man as a natural skin depigmenting agent free from negative side effects.
  • the object of the invention is also a pharmaceutical or cosmetic or dietetic composition suitable to promote such skin bleaching effect and therefore containing spermidine as active principle, as such or in the form of a pharmaceutically acceptable derivative such as a salt.
  • a preferred salt according to the invention is spermidine trichlorohydrate, namely N-(3-aminopropyl)butan-1 ,4-diamine ⁇ 3HCI.
  • a composition of the invention preferably comprises spermidine trichlorohydrate formulated for topical use on the skin.
  • Suitable forms for topical use are, for example, a cream or a mask or an emulsion or a solution.
  • Spermidine as such or in the form of a pharmaceutically acceptable derivative, as a salt, is contained in a composition of the invention formulated for topical use according to a concentration preferably comprised between 10 '5 and 1 g/100 ml, corresponding to 0.4 to 4-10 4 ⁇ M.
  • composition of the invention comprises spermidine trichlorohydrate formulated for oral use.
  • Spermidine as such or in the form of a pharmaceutically acceptable derivative, as a salt, is contained in a composition of the invention formulated for oral use according to an amount comprised between 0.125 and 25 mg spermidine as such, or base, per single administration unit.
  • the component amounts are expressed in grams or milligrams and in the case of examples 1 to 3, by concentration ranges.
  • the tissues subject to biopsy with 3-4 mm cylindrical scalpel were cultured at 37°C for 6 days in Williams E medium (Biochrom, Cambridge, U.K.), integrated with 100
  • Spermidine HCI or the vehicle as a reference substance, was then administered at a concentration of 0.1 ⁇ M; 0.5 ⁇ M; 1 ⁇ M once at each medium change (i.e., every 48 hours).
  • the Masson-Fontana staining was carried out for the histochemical display of melanin on frozen sections. Melanin was stained in the form of brown granules and the pigmentation level was determined through the quantitative Masson- Fontana technique (Ito N., lto T., Kromminga A., Bettermann A., Takigawa M., Kees F., Straub R. H., and Paus R. (2005): Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize Cortisol. FASEB J 19, 1332-4).
  • This method is a particularly sensitive and reliable indicator of melanin synthesis variations, as proven by enzymatic activity assays and standard tyrosinase expression (Kauser S., Slominski A., Wei E. T., and Tobin D. J. (2006): Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides. FASEB J 20, 882-95).
  • the staining intensity was analyzed in a defined reference region of the skin pigmentation unit using the ImageJ software (National Institute of Health).
  • the TUNEL (terminal dUTP nick-end labeling) dual staining method with Ki-67 was used.
  • the cryostat sections were fixed in paraformaldehyde and ethanol- acetic acid (2:1 ) and marked with a digoxigenin-deoxy-UTP (kit for the identification of apoptosis in situ with ApopTag fluorescein; Intergen, Purchase, NY) in the presence of terminal deoxynucleotidyl transferase, followed by incubation with a murine anti-Ki-67 antiserum (1 :20 in PBS overnight at 4°C; Dako, Glostrup, Denmark).
  • TUNEL-positive cells were displayed by a conjugate isothiocyanate fluorescein anti digoxigenin antibody (kit ApopTag), whereas Ki-67 was detected by a goat anti-mouse antibody marked with rhodamine (Jackson ImmunoResearch, West Grove, PA). Negative controls were carried out omitting the terminal deoxynucleotidyl transferase and the Ki-67 antibody. The counter- staining was carried out with 4',6-diamidino-2-phenylindole (DAPI) (Roche Molecular Biochemicals GmbH, Mannheim, Germany). The quantitative histomorphometric assessment was carried out; Ki-67, TUNEL or DAPI-positive cells were counted in a reference region defined beforehand of the skin matrix and the percentage of positive Ki-67/TUNEL cells was determined.
  • DAPI 4',6-diamidino-2-phenylindole
  • tyramide signal amplification method described before was used for examining the expression of keratin K15 (Kloepper et al., 2008).
  • cryosections fixed with acetone were washed three times for 5 minutes using the TNT (tris-HCL NaCI Tween) buffer (0.1 mol/l Tris-HCI, pH 7.5; containing 0.15 mol/l NaCI and 0.05% Tween 20). Radish peroxidase was then blocked through wash with 3% H 2 O 2 in an isotonic phosphate buffer (PBS) for 15 minutes.
  • PBS isotonic phosphate buffer
  • Preincubation was carried out with the incubation of avidin and biotin for 15 minutes and with 5% normal goat serum in TNT for 30 minutes with intermediate washing steps.
  • Murine anti-human K15 (clone LHK15, Chemicon, Billerica, USA) were diluted in TNT and incubated overnight at 4°C, followed by a secondary goat anti-mouse biotinylate antibody (1 :200 in TNT) for 45 minutes at room temperature. Radish streptavidin-peroxidase was then administered (kit TSA; Perkin-Elmer, Boston, MA, USA) (1 :100 in TNT) for 30 minutes at room temperature. The reaction was amplified with a FITC-tyramide amplification agent at room temperature for 5 minutes (1 :50 in an amplification diluent supplied with the kit). The intensity of this immuno-staining was quantified by the ImageJ (National Institutes of Health) software. The staining intensity of reference regions in the skin basal layer was measured and compared between the control groups treated with vehicle only and the groups treated with spermidine.
  • the statistical analysis was carried out using a bilateral Student t-test for unpaired samples.
  • Fig. 1 shows the relevant images taken from the hystochemical display of melanin through Masson-Fontana staining, compared between the control groups treated with vehicle only and the groups treated with spermidine HCI at the concentrations of 0.1 ⁇ M; 0.5 ⁇ M; 1 ⁇ M.
  • Fig. 2 shows a corresponding diagram relating to the pigmentation intensity found in the skin basal layer.
  • a pigmentation inhibition effect is clear from both figures in the case of treatment with spermidine HCI, depending on the concentration and therefore in progressive increase from the concentration of 0.1 ⁇ M to 1 ⁇ M.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to the use of spermidine, as such or in the form of a pharmaceutically acceptable derivative, as the active principle in a pharmaceutical or cosmetic or dietetic composition suitable to promote skin bleaching, and to a composition suitable to promote such effect containing spermidine as active principle, as such or in the form of a pharmaceutically acceptable derivative such as a salt.

Description

PHARMACEUTICAL, COSMETIC OR DIETETIC COMPOSITION SUITABLE TO PROMOTE SKIN BLEACHING FIELD OF THE INVENTION
The present invention relates to the use of a skin bleaching composition.
BACKGROUND ART
The non-physiological production and build-up of melanin characterize a large number of skin diseases, such as acquired hyperpigmentation, for example melasma, post-inflammatory melanodermia, sun freckles.
Skin and dermal hyperpigmentation may depend on a larger number of melanocytes or on the activity of melanogenic enzymes. Ultraviolet light, chronic inflammations and skin friction, as well as an abnormal release of the α- melanotrope hormone (α-MSH), are breaking factors of these disorders.
Due to the main location in photo-exposed areas, acquired hyperpigmentation is important from several points of view, psychological, social and aesthetic, and the efforts aimed at selecting recognized and putative depigmenting agents have been multiple. Moreover, since known bleaching compounds have often proved to be ineffective towards the melanin skin build-up, physical therapies have been proposed as alternatives, for example by laser.
An ideal depigmenting compound must have a bleaching and powerful, quick and selective effect on hyperactivated melanocytes and no short- or long-term side effects and lead to a removal of the undesired pigment acting in one or more steps of the pigmenting process.
SUMMARY OF THE INVENTION
It has now surprisingly been found, and this is the object of the present invention, that the spermidine compound, that is N-(3-aminopropyl)butan-1 ,4-diamine, as such or in the form of a pharmaceutically acceptable derivative such as a salt, is provided with a pigmentation inhibition activity in the skin basal layer, and can therefore be effectively used to promote a skin bleaching effect.
Such activity allows configuring the use of the active compound in man as a natural skin depigmenting agent free from negative side effects.
The object of the invention is also a pharmaceutical or cosmetic or dietetic composition suitable to promote such skin bleaching effect and therefore containing spermidine as active principle, as such or in the form of a pharmaceutically acceptable derivative such as a salt.
DETAILED DESCRIPTION OF THE INVENTION
A preferred salt according to the invention is spermidine trichlorohydrate, namely N-(3-aminopropyl)butan-1 ,4-diamine■ 3HCI.
A composition of the invention preferably comprises spermidine trichlorohydrate formulated for topical use on the skin. Suitable forms for topical use are, for example, a cream or a mask or an emulsion or a solution.
Spermidine, as such or in the form of a pharmaceutically acceptable derivative, as a salt, is contained in a composition of the invention formulated for topical use according to a concentration preferably comprised between 10'5 and 1 g/100 ml, corresponding to 0.4 to 4-104 μM.
Another composition of the invention comprises spermidine trichlorohydrate formulated for oral use.
Spermidine, as such or in the form of a pharmaceutically acceptable derivative, as a salt, is contained in a composition of the invention formulated for oral use according to an amount comprised between 0.125 and 25 mg spermidine as such, or base, per single administration unit.
The following formulation examples illustrate the invention, but are not intended to be limiting in any manner.
The component amounts are expressed in grams or milligrams and in the case of examples 1 to 3, by concentration ranges.
EXAMPLE 1
DAY CREAM
EXAMPLE 2
SEBUM BALANCING CREAM
EXAMPLE 3
INTENSIVE FACE CREAM
EXAMPLE 4
Capsule
EXAMPLE 5
Soft gelatine capsule
EXAMPLE 6
Tablet
EXAMPLE 7
Slow-release coated tablet
EXAMPLE 8
Effervescent granulate in sachet for making an improptu solution
Below is the description of an experimental study relating to the activity in the use of spermidine according to the present invention.
ACTIVITY STUDY
Tissue samples
A sample of normal human skin was taken from a woman who had undergone a routine face lifting surgery after receiving the informed consent. All the experiments were carried out according to the Helsinki principles, with the ethical committee's approval.
Skin organ culture with complete thickness
The tissues subject to biopsy with 3-4 mm cylindrical scalpel were cultured at 37°C for 6 days in Williams E medium (Biochrom, Cambridge, U.K.), integrated with 100
IU mL'1 penicillin, 10 μg mL'1 streptomycin (Gibco, Karlsruhe, Germany), 10 μg ml_"1 insulin (Sigma, Taukfirchen, Germany), 10 ng mL"1 hydrocortisone (Sigma) and 2mmol L'1 (L-glutamine (Invitrogen, Paisley, U.K.).
Spermidine HCI, or the vehicle as a reference substance, was then administered at a concentration of 0.1 μM; 0.5 μM; 1 μM once at each medium change (i.e., every 48 hours).
Skin pigmentation
The Masson-Fontana staining was carried out for the histochemical display of melanin on frozen sections. Melanin was stained in the form of brown granules and the pigmentation level was determined through the quantitative Masson- Fontana technique (Ito N., lto T., Kromminga A., Bettermann A., Takigawa M., Kees F., Straub R. H., and Paus R. (2005): Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize Cortisol. FASEB J 19, 1332-4).
This method is a particularly sensitive and reliable indicator of melanin synthesis variations, as proven by enzymatic activity assays and standard tyrosinase expression (Kauser S., Slominski A., Wei E. T., and Tobin D. J. (2006): Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides. FASEB J 20, 882-95).
The staining intensity was analyzed in a defined reference region of the skin pigmentation unit using the ImageJ software (National Institute of Health).
Proliferation and apoptosis measurement
In order to evaluate the apoptotic cells in co-location with a proliferation marker Ki- 67, the TUNEL (terminal dUTP nick-end labeling) dual staining method with Ki-67 was used. The cryostat sections were fixed in paraformaldehyde and ethanol- acetic acid (2:1 ) and marked with a digoxigenin-deoxy-UTP (kit for the identification of apoptosis in situ with ApopTag fluorescein; Intergen, Purchase, NY) in the presence of terminal deoxynucleotidyl transferase, followed by incubation with a murine anti-Ki-67 antiserum (1 :20 in PBS overnight at 4°C; Dako, Glostrup, Denmark). TUNEL-positive cells were displayed by a conjugate isothiocyanate fluorescein anti digoxigenin antibody (kit ApopTag), whereas Ki-67 was detected by a goat anti-mouse antibody marked with rhodamine (Jackson ImmunoResearch, West Grove, PA). Negative controls were carried out omitting the terminal deoxynucleotidyl transferase and the Ki-67 antibody. The counter- staining was carried out with 4',6-diamidino-2-phenylindole (DAPI) (Roche Molecular Biochemicals GmbH, Mannheim, Germany). The quantitative histomorphometric assessment was carried out; Ki-67, TUNEL or DAPI-positive cells were counted in a reference region defined beforehand of the skin matrix and the percentage of positive Ki-67/TUNEL cells was determined.
Quantitative immunohistochemistry of K15
The tyramide signal amplification method described before was used for examining the expression of keratin K15 (Kloepper et al., 2008). In brief, cryosections fixed with acetone were washed three times for 5 minutes using the TNT (tris-HCL NaCI Tween) buffer (0.1 mol/l Tris-HCI, pH 7.5; containing 0.15 mol/l NaCI and 0.05% Tween 20). Radish peroxidase was then blocked through wash with 3% H2O2 in an isotonic phosphate buffer (PBS) for 15 minutes. Preincubation was carried out with the incubation of avidin and biotin for 15 minutes and with 5% normal goat serum in TNT for 30 minutes with intermediate washing steps. Murine anti-human K15 (clone LHK15, Chemicon, Billerica, USA) were diluted in TNT and incubated overnight at 4°C, followed by a secondary goat anti-mouse biotinylate antibody (1 :200 in TNT) for 45 minutes at room temperature. Radish streptavidin-peroxidase was then administered (kit TSA; Perkin-Elmer, Boston, MA, USA) (1 :100 in TNT) for 30 minutes at room temperature. The reaction was amplified with a FITC-tyramide amplification agent at room temperature for 5 minutes (1 :50 in an amplification diluent supplied with the kit). The intensity of this immuno-staining was quantified by the ImageJ (National Institutes of Health) software. The staining intensity of reference regions in the skin basal layer was measured and compared between the control groups treated with vehicle only and the groups treated with spermidine.
Statistical analysis
The statistical analysis was carried out using a bilateral Student t-test for unpaired samples.
Results
The figures of the annexed drawings show the results of the experimental study described.
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 shows the relevant images taken from the hystochemical display of melanin through Masson-Fontana staining, compared between the control groups treated with vehicle only and the groups treated with spermidine HCI at the concentrations of 0.1 μM; 0.5 μM; 1 μM.
Fig. 2 shows a corresponding diagram relating to the pigmentation intensity found in the skin basal layer.
A pigmentation inhibition effect is clear from both figures in the case of treatment with spermidine HCI, depending on the concentration and therefore in progressive increase from the concentration of 0.1 μM to 1 μM.

Claims

1. Use of spermidine, as such or in the form of a pharmaceutically acceptable derivative, as the active principle in a pharmaceutical or cosmetic or dietetic composition suitable to promote skin bleaching.
2. Pharmaceutical, cosmetic or dietetic composition to be used according to Claim 1 , suitable to promote skin bleaching and containing spermidine as active principle, as such or in the form of a pharmaceutically acceptable derivative, such as a salt.
3. Composition according to Claim 2, comprising said active principle formulated with any suitable excipient for topical administration on the skin.
4. Composition according to Claim 2, comprising said active principle formulated with any suitable excipient for oral administration.
5. Composition according to Claim 3 in the form of a cream or a mask or an emulsion or a solution.
6. Composition according to Claim 4 in the form of a capsule or a tablet or a granulate or a solution.
7. Composition according to Claim 3, comprising spermidine in an amount in a range between 0.4 to 4-104 μM, corresponding to an amount between 5.7-106 and 0.57 g/100 ml.
8. Composition according to Claim 4, comprising spermidine in an amount comprised in the range between 0.125 and 25 mg per administration unit.
9. Composition according to Claim 2, wherein spermidine is in the form of spermidine trichlorohydrate, namely N-(3-aminopropyl)butan-1 ,4-diamine■ 3HCI.
10. Composition according to Claim 9, comprising an amount of spermidine trichlorohydrate in a range from 10"5 to 1g/100 ml.
EP10752401A 2009-07-29 2010-07-29 Pharmaceutical, cosmetic or dietetic composition for skin bleaching Withdrawn EP2459158A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2009A001362A IT1395123B1 (en) 2009-07-29 2009-07-29 PHARMACEUTICAL, COSMETIC OR DIETETIC COMPOSITION TO PROMOTE A LIGHTENING EFFECT OF THE EPIDERMIDE
PCT/IB2010/053449 WO2011013086A2 (en) 2009-07-29 2010-07-29 Pharmaceutical, cosmetic or dietetic composition suitable to promote skin bleaching

Publications (1)

Publication Number Publication Date
EP2459158A2 true EP2459158A2 (en) 2012-06-06

Family

ID=42008599

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10752401A Withdrawn EP2459158A2 (en) 2009-07-29 2010-07-29 Pharmaceutical, cosmetic or dietetic composition for skin bleaching

Country Status (3)

Country Link
EP (1) EP2459158A2 (en)
IT (1) IT1395123B1 (en)
WO (1) WO2011013086A2 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7421695B2 (en) * 2019-09-26 2024-01-25 株式会社ファンケル Melanin production inhibitors and skin whitening agents or skin external preparations containing the same

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20031570A1 (en) * 2003-07-31 2005-02-01 Giuliani Spa COMPOSITION FOR DIETARY, PHARMACEUTICAL OR COSMETIC USE
NO20044818D0 (en) * 2004-11-05 2004-11-05 Bioforsk As Spermine in cosmetic preparations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2011013086A2 *

Also Published As

Publication number Publication date
WO2011013086A2 (en) 2011-02-03
IT1395123B1 (en) 2012-09-05
ITMI20091362A1 (en) 2011-01-30
WO2011013086A3 (en) 2011-07-21

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