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WO2003030814A2 - Composition de reguline croisee de tetrahydrocurcuminoides derives du curcuma pour le blanchissement de la peau et la protection de la peau contre les rayons uvb - Google Patents

Composition de reguline croisee de tetrahydrocurcuminoides derives du curcuma pour le blanchissement de la peau et la protection de la peau contre les rayons uvb Download PDF

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Publication number
WO2003030814A2
WO2003030814A2 PCT/US2002/029846 US0229846W WO03030814A2 WO 2003030814 A2 WO2003030814 A2 WO 2003030814A2 US 0229846 W US0229846 W US 0229846W WO 03030814 A2 WO03030814 A2 WO 03030814A2
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WO
WIPO (PCT)
Prior art keywords
mixture
cross
linking
thc
random
Prior art date
Application number
PCT/US2002/029846
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English (en)
Other versions
WO2003030814A3 (fr
Inventor
Majeed Muhammed
Vladimir Badmaev
Original Assignee
Sabinsa Corporation
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
Priority claimed from US09/972,150 external-priority patent/US6653327B2/en
Application filed by Sabinsa Corporation filed Critical Sabinsa Corporation
Priority to AU2002341741A priority Critical patent/AU2002341741A1/en
Publication of WO2003030814A2 publication Critical patent/WO2003030814A2/fr
Publication of WO2003030814A3 publication Critical patent/WO2003030814A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

  • curcuminoids yellow phenolic compounds derived from turmeric roots ⁇ Curcuma longa, fam. Zingiberaceae
  • Curcuminoids are reported to protect normal human keratinocytes from hypoxanthine/xanthine oxidase injury in in vitro studies, and they can protect the skin against a broad range of physical, chemical and biological factors injuring the skin . Free radicals on the surface of the skin, generated through exposure to ultraviolet radiation, especially the UVB rays, chemicals or other environmental stress factors catalyze aging of the skin.
  • Curcuminoids prevent free radical formation and scavenge free radicals in biological systems. This combined action was previously described as a Bioprotectant mechanism that protects the integrity of the living cell e.g. skin cell.
  • Curcuminoids have also been found to inhibit the activity of tyrosinase, an enzyme that participates in melanogenesis, thereby preventing melanin formation with resultant lightening of the skin tone. 2
  • Tetrahydrocurcuminoids are color-free compounds derived from curcuminoids, the yellow, parent compounds of THC, in the process of hydrogenation.
  • the process of hydrogenation of curcuminoids can also occur naturally in the gastrointestinal tract. 3
  • THC Like the curcuminoids, THC have also shown significant antioxidant action in a number of in vitro and preclinical studies. 4"9 THC are valued as the ultimate metabolites of the curcuminoids in vivo. Several independent studies validated the significant antioxidant effects of the tetrahydrocurcuminoids and protection of skin against free radicals and UVB rays. 0
  • TPA induces many biochemical and morphological changes in mouse skin, which appear to be associated with inflammation and skin tumor promotion.
  • topical application of TPA to the skin of mice rapidly induced skin inflammation, increased epidermal ornithine decarboxylase activity, increased epidermal DNA synthesis, and increased the number of epidermal cell layers.
  • Ornithine decarboxylase (ODC) the first enzyme in polyamine biosynthesis, is highly regulated by many trophic stimuli, and changes in its levels and organization correlate with cytoskeletal changes in human keratinocytes. Therefore, compounds which inhibit TPA and affect ODC synthesis will also affect the organization of the cytoskeleton and related events of post-translatational modification of proteins and crosslinking of proteins in the cytosol.
  • the crossregulin composition of the invention is an optimal composition for protecting and preserving healthy living cells and for preventing cytoskeletons of the healthy living cells from being damaged by TPA and TPA-like tumor promoters.
  • THCl Tetrahydrocurcuminoids of the invention
  • THC2 Tetrahydrocurcuminoids
  • THC3 Tetrahydrocurcumin
  • mice Five hours later the mice were sacrificed and ear punches were weighted (the higher the weight, score the more severe the inflammation of the treated ear-skin). Based on the weight score of the ear punches, the percent of inflammation inhibition was calculated. Protection against inflammation in decreasing order was furnished by THCl of the invention, followed by THCl of the prior art, and finally followed by THC3. The protective effect was dose-dependent concerning THCl and THC2, while THC3 showed less protection at a dose of 0.36 mg compared to a dose of 0.12 mg.
  • Prior art as exemplified by the research data, cannot accomplish inhibition of the TPA induced ear edema above 80%.
  • crossregulin action is not an inherent part of just any composition of THCs, but it is a specific composition that affords inhibition of the TPA mechanism by more than 80%. Definition of crossregulin's action:
  • crossregulin 's action is based on an anti-inflammatory and cancer preventive mechanism which is limited to any compound that inhibits the inflammatory process by at least 80% in two tested doses (i.e. 0.12 mg and 0.36 mg).
  • Table 1 Effects of THC on TPA-induced ear edema
  • mice Female CF-1 mice were treated topically with 20 ul acetone, TPA (lnmol) in acetone or TPA (lnmol) and test compound in acetone on both ears. Five hours later the mice were sacrificed and ear punches were weighted. Data are expressed as the mean SE
  • THCl- invention THC2 - prior art Mimura,et al., US patent 5,266,344 issued Nov. 30, 1993, THC3 - Pure (synthetic) tetrahydrocurcumin.
  • Crossregulin action of the invention in prevention of UVB damage to the skin was tested against UVB-induced damage to the mouse epidermis. Exposure of unprotected skin to UVB causes sunburn, which in principle is an inflammatory reaction to thermal injury to the epidermis.
  • the number of epidermal cells with wild-type p53 and p21 increases at 1 hour after UVB exposure and reaches maximum levels by 8 to 12 hours.
  • the number of p53 and p21 -positive cells decline markedly between 24 and 48 hours after UVB exposure.
  • Topical application of liposomes containing the DNA repairing enzyme, photolyase to UVB-irradiated skin and subsequent exposure to photoreactivating light decreased the number of UVB radiation-induced dimers by 40-45%.
  • the UVB dose administered resulted in the suppression of the intercellular adhesion molecule- 1 (ICAM-1), a molecule required for immunity and inflammatory events in the epidermis.
  • ICM-1 intercellular adhesion molecule- 1
  • Photolyase-induced dimer repair completely prevented these UVB radiation-induced immunosuppressive effects as well as erythema and sunburn-cell formation.
  • DBM dibenzoylme thane
  • mice Treatment No. mice % thymine dimer cells % protection
  • mice Female SKH-1 mice (8-9 weeks old) were treated topically with 100 ul acetone or the test compound in 100 ul acetone. Five minutes later, the mice were irradiated with a single dose of UVB (30mJ/cm2). The mice were killed one hour later, and skin samples were stored in a 10%) formalin-phosphate buffer for thymine dimmers assay.
  • mice Female SKH-1 mice (8-9 weeks old; 8 mice per group) were irradiated with UVB (180 mJ/cm2) once a day for 3 days. The mice were treated topically with vehicle or THC 1 in vehicle once a day for 3 days at 10 min before UVB treatment. The 100 ul vehicle or THCl treatments were continued once a day until the end of the experiment. The area of sunburn lesion (red color) were measured: (-) no sunburn; (+) slight sunburn; (++) sunburn; (+++) strong sunburn; (++++) very strong sunburn lesion.
  • mice Female Sencar mice (5 mice per group) were treated topically with 100 ul acetone or inhibitor in acetone at 5 min before a single dose of UVB (60 mJ/cm2) irradiation. The mice were killed 8 hours after UVB irradiation, and the skin biopsies were evaluated for sunburn cells and p21 protein.
  • UVB 60 mJ/cm2
  • THCl has an UVB-protective effect comparable to DMB; however it may differ from DMB in the way it accomplishes that goal, and specifically in how it regulates Ras p21 protein (Ras p21 protein, an enzyme ubiquitous in the body cells, is central in the cell- signaling system). In cancer cells, this enzyme can undergo uncontrolled cross-linking which locks it in a cancer cell growth-promoting state.
  • Ras p21 protein an enzyme ubiquitous in the body cells, is central in the cell- signaling system. In cancer cells, this enzyme can undergo uncontrolled cross-linking which locks it in a cancer cell growth-promoting state.
  • UVB epidermal damage is associated with an increase in the number of p21 positive cells the sunburn-protective mechanism of THCl (without increasing the p21 marker) is a favorable finding for the invention.
  • the invention protects the epidermis against UVB exposure, resulting in significantly less sunburn which lasted one day less compared to the control group treated with vehicle (Table 3). Therefore the mechanism of the invention is unexpected and differs from prior art quantitatively and qualitatively. It is postulated that shortening the time of epidermal damage by the invention is due to stimulation of several defense compounds including photolyase and ICAM-1, which leads to epidermal DNA repair. It is further postulated that inhibition of tyrosinase, which furnishes a normalizing effect on photolyase, ICAM-1 and p21 protein is unique to the invention's crossregulin mechanism (i.e. post-translation modification of proteins).
  • transglutaminases form a family of proteins that have evolved for specialized functions such as post-translational modification of proteins.
  • tissue homeostasis e.g. blood clotting, replacement of old cells to give room for a new body cells.
  • Crosslinking of proteins or its inhibition has been suggested as one of the mechanisms in post-translational modification of proteins.
  • transglutaminase induced crosslinking activity has been proposed for its possible involvement in cell proliferation, differentiation and programmed death.
  • Transglutaminases exhibit true multifunctionality at the molecular level.
  • the crosslinking activity can promote disparate biological phenomena depending on the state of health of the organism. For example, the oncogenes of certain types of skin moles undergo conversion to melanoma when UV rays trigger the crosslinking of ras proteins. In that case, inhibition of crosslinking will prevent initiation and progression of the malignancy.
  • activation of tissue transglutaminases in poorly differentiated melanoma may give rise to crosslinked protein which may result in apoptosis or cancerous cell death. In this example, crosslinking of proteins would have a positive impact on the clinical course of the neoplastic disease.
  • THCl has least inhibitory effect on tyrosinase than either THC2 or THC3 (Table 5).
  • Epidermal melanin is known as a photoprotective agent which attenuates UV radiation. 12"14 Photoprotective action of melanin results in diminished erythema of skin exposed to UV rays. Melanin may play an important role in the absorption and scattering of UV light, which may be part of the mechanism in preventing skin cancer as well as an integral part of phototherapy in psoriasis.
  • UVB radiation produces suppresses normal immune responses. Immune suppression is important in the development of nonmelanoma skin cancer, and it may influence the development and course of infectious skin diseases. It has been postulated that melanin can provide protection against immune suppression by UVB. There is a consensus that high pigment content in skin is photoprotective against skin cancer, but induced pigment, as in tanning, may not be. The results of an in vitro study show that induced pigment is photoprotective and chemoprotective, but it is less effective in protection against mutagenesis by polychromatic UVB + UVA light.
  • the invention proposes a practical and safe solution to regulate functions of tyrosinase activity.
  • THCl has considerable potential in inhibiting the process of melanogenesis, and this effect is explained by post-translational modification of tyrosinase by THCl.
  • the ability of the invention to inhibit melanogenesis is combined with its superior to the prior art ability to prevent the action of mutagenic compounds on skin cells and protect against sunburn.
  • This combined mechanism of crossregulin is unique to a composition of this invention. This mechanism emphasizes the regulatory action of the invention rather than the inhibitory or stimulatory actions.
  • a comparative study of the invention (THCl) and prior art (THC2 and THC3) in the inhibition of tyrosinase has been conducted.
  • THCl THCl
  • THC2 and THC3 prior art

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Birds (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un mélange de tetrahydrocurcuminoïdes pouvant être utilisé pour réguler la réticulation protéique intracellulaire aléatoire et pour optimiser le potentiel électrique des cellules chez un patient.
PCT/US2002/029846 2001-10-09 2002-10-09 Composition de reguline croisee de tetrahydrocurcuminoides derives du curcuma pour le blanchissement de la peau et la protection de la peau contre les rayons uvb WO2003030814A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002341741A AU2002341741A1 (en) 2001-10-09 2002-10-09 Cross-regulin composition of turmeric-derived tetrahydrocurcuminoids for skin lightening and protection against uvb rays

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US09/972,150 2001-10-09
US09/972,150 US6653327B2 (en) 1999-04-09 2001-10-09 Cross-regulin composition of tumeric-derived tetrahydrocurcuminoids for skin lightening and protection against UVB rays

Publications (2)

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WO2003030814A2 true WO2003030814A2 (fr) 2003-04-17
WO2003030814A3 WO2003030814A3 (fr) 2003-10-16

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Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5861415A (en) * 1996-07-12 1999-01-19 Sami Chemicals & Extracts, Ltd. Bioprotectant composition, method of use and extraction process of curcuminoids

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AU2002341741A1 (en) 2003-04-22

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