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
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • 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
  • A61K8/43—Guanidines
• • 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
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants

Definitions

• the present invention relates to the use of a biguanide derivative to protect the skin against the harmful effects of UVB radiation and / or to protect the skin against the undesirable and / or unsightly effects of UVB radiation.
• UV radiation of wavelengths between 280 nm and 400 nm which arrive on the skin from the sun, are of 2 types, namely UVA and UVB.
• Their erythemal power is 1000 times greater than UVA and their participation in the genesis of cancers is not negligible.
• sensitivity to solar radiation varies widely depending on the individual. It is a function of what is called the “phototype” of the individual. It is also necessary to differentiate the effects of UV at the usual doses according to the frequency of exposure. In fact, exposure to medium-energy UVA rays only causes pigmentation, while exposure to medium-energy UVB rays only causes sunburn. On the other hand, long and chronic exposure to UVB leads to skin senescence and skin cancers. Indeed in the long term, the sun's rays are responsible for the aging of the skin (wrinkles, rosacea, thinning of the skin), and especially for skin cancers. 95% of these cancers are located in the places most often exposed to the sun. Severe sunburn during youth can lead to serious cancer in adulthood.
• a biguanide derivative advantageously metformin, has a protective effect on the skin against UVB.
• compositions based on biguanides are already known. They are used in oral form in the treatment of certain forms of diabetes, and mainly non-insulin-dependent type II diabetes, as antihyperglycemic agents which promote the return to glycemic control.
• Metformin is the most widely used biguanide derivative in this type of treatment. This medication is taken by mouth as tablets containing 500, 850 mg or 1 g. active ingredient.
• the daily dosage is between 1 and 2 g. a few more times.
• the clinical evaluation of metformin in phase I showed the absence of toxicity of the molecule studied at hypoglycemic doses. Tolerance to the product appears to be good, its chronic toxicity almost zero. There is no change in the growth or behavior of the animals; blood count, uremia and liver function are not altered.
• the antihyperglycemic effect of metformin is due on the one hand to the increase in the activity of endogenous insulin and on the other hand to the action of metformin through mechanisms independent of insulin.
• metformin results in a decrease in the intestinal absorption of glucose, an increase in cellular absorption of blood glucose and a decrease in the production of glucose by the liver (suppression neoglucogenesis) as well as the amount of insulin needed to normalize blood sugar.
• Metformin is also known in topical compositions for promoting healing and as having an angiogenic action (FR 2 809 310).
• the present invention therefore relates to the use of a biguanide derivative of general formula I below:
• R 1 NH NH R N II II / NCNC-R3 R2 IH 0) in which: the groups R1 and R2 represent, independently of one another, a hydrogen atom, a C ⁇ -C 7 alkyl group, a cycloalkyl group, a heterocycle, a C 2 -C alkenyl group, an aryl group, an aralkyl group, an aryloxylalkyl group or a heteroaryl group or R1 and R2 taken together represent a C 2 -C 7 alkylene which may contain one or several heteroatoms and the group R3 represents a primary, secondary or tertiary amine or its pharmaceutically acceptable salt with the exception of the compound of formula to make a medicine to protect the skin from the harmful effects of UVB radiation.
• C 1 -C 7 alkyl group is meant in the sense of the present invention any C ⁇ ⁇ C 7 alkyl group, linear or branched, such as for example methyl, ethyl, propyl, isopropyl or butyl groups as well as their isomers.
• cycloalkyl group is meant in the sense of the present invention any cycloalkyl group containing from 3 to 7 carbon atoms, such as for example the cyclohexanyl group.
• heterocycle By the term of “heterocycle”, one understands within the meaning of the present invention any cycle containing from 3 to 7 atoms, one or more of them being a heteroatom such as for example the atom of nitrogen, oxygen or of sulfur, the others being carbon atoms.
• C 2 -C 7 alkenyl group is meant in the sense of the present invention any C 2 -C 7 alkenyl group, linear or branched such as vinyl or allyl groups.
• aryl group is meant in the sense of the present invention any aromatic hydrocarbon group such as for example the phenyl group, which may contain one or more substituents, such as for example, a C 1 -C 7 alkyl group as defined above, a C 2 -C 7 alkenyl group as defined above, or a halogen.
• heteroaryl group in the sense of the present invention any aromatic hydrocarbon group containing one or more heteroatoms, such as for example nitrogen or oxygen sulfur atoms, and which may carry one or more substituents, such as for example , a C 1 -C 7 alkyl group as defined above, a group C 2 -C 7 alkenyl as defined above, or halogen.
• heteroaryl groups are furyl, isoxazyl, pyridyl, pyrimidyl.
• C 2 -C 7 alkylene group is meant in the sense of the present invention any C 2 -C 7 alkylene group such as for example the ethylene, trimethylene, tetramethylene or pentamethylene groups.
• pharmaceutically acceptable salt is meant in the sense of the present invention any salt prepared from any pharmaceutically acceptable non-toxic acid, including organic and inorganic acids.
• Such acids include acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, tartaric. and paratoluenesulfonic.
• hydrochloric acid is used.
• the medicament is intended to protect the skin against sunburn and skin cancers.
• the medicament has a protective activity with respect to the photo immunosuppressive effect induced by UVB irradiation on Langerhans cells.
• the group R3 represents the secondary amine of the following formula:
• the group R3 represents NH 2 .
• the groups R1 and R2 represent, independently of one another, a hydrogen atom or a C 1 -C 7 alkyl group.
• the biguanide derivative is metformin, even more advantageously in the form of a hydrochloride.
• the medicament may be in a pharmaceutical form for local use, advantageously of the oil, cream, foam, unit, lotion, ointment, liquid, gel, milk or "spray" type.
• the forms can be single-phase vehicles consisting of a neutral hydroxypropylcellulose gel or a charged gel formed of sodium carboxymethylcellulose. It is also possible to prepare creams, forms with a biphasic vehicle, comprising a hydrophilic phase dispersed in a lipophilic phase.
• the medicament contains from 0.02 to 2% by weight of the biguanide derivative of general formula I or of its pharmaceutically acceptable salt and an appropriate excipient.
• excipients can be chosen from compounds having good compatibility with this active principle. These are, for example, water-soluble polymers of the natural polymer type, such as polysaccharides (xanthan gum, locust bean gum, peptine, etc.) or polypeptides, cellulose derivatives of methylcellulose type, hydroxypropylcellulose, hydroxypropyl-methylcellulose or also synthetic polymers, polaxamers, carbomers, PVA or PVP.
• cosolvent type excipients such as ethanol, glycerol, benzyl alcohol, humectants (glycerol), agents facilitating the diffusion to this cosmetic composition ( transcurol, urea), or antibacterial preservatives (0.15% methyl p-hydroxybenzoate). It can also contain surfactants, stabilizing agents, emulsifiers, thickeners, other active ingredients leading to a complementary or possibly synergistic effect, trace elements, essential oils, perfumes, dyes, collagen, chemical or mineral filters, moisturizers or thermal waters.
• this sunscreen medication is in the form of an oil-in-water type emulsion (that is to say a pharmaceutically acceptable carrier consisting of a continuous aqueous dispersing phase and an oily dispersed discontinuous phase) which contains, at various concentrations, the biguanide derivative according to the present invention alone or in combination with one or more conventional organic filters, lipophilic and / or hydrophilic, capable of selectively absorbing harmful UV radiation, the biguanide derivative and optionally these filters (and their quantities) being selected according to the sun protection factor sought (the sun protection factor expressed mathematically by the ratio of the time of irradiation necessary to reach the erythematogenic threshold with the UV filter to the time necessary to reach the erythematogenic threshold without UV filter).
• the sun protection factor sought expressed mathematically by the ratio of the time of irradiation necessary to reach the erythematogenic threshold with the UV filter to the time necessary to reach the erythematogenic threshold without UV filter.
• mineral (nano) pigments (“nanopigments” are understood to mean pigments whose average size of the primary particles generally does not exceed 100 nm, this size preferably being between 5 nm and 100 nm, and even more preferably (between 10 and 50 nm) based on metal oxides, and in particular titanium oxide, can be used in the medicament according to the present invention.
• these substances whether or not combined with conventional organic filters absorbing UVA and / or UVB, are capable of providing the sunscreen compositions which contain them with a certain own or complementary photoprotective power, however quite limited, and this by acting by simple physical blocking of UV rays (mechanisms of reflection and / or diffusion of radiation).
• the biguanide derivative or its pharmaceutically acceptable salt is combined with at least one other active principle.
• the present invention also relates to the cosmetic use of a biguanide derivative of general formula I below:
• the groups R1 and R2 represent, independently of one another, a hydrogen atom, a C 1 -C 7 alkyl group, a cycloalkyl group, a heterocycle, a C alkenyl group 2 -C 7 , an aryl group, an aralkyl group, an aryloxylalkyl group or a heteroaryl group or R1 and R2 taken together represent a C 2 -C 7 alkylene which may contain one or more heteroatoms and the group R3 represents a primary, secondary amine or tertiary or its pharmaceutically acceptable salt with the exception of the compound of formula to protect the skin against the undesirable and / or unsightly effects of UVB radiation, such as for example sunburn, aging, (appearance of wrinkles and dark spots).
• UVB radiation such as for example sunburn, aging, (appearance of wrinkles and dark spots).
• compositions according to the invention and of activity study are given by way of illustration and without limitation.
• Example of formulation 1 Metformin: 1%.
• Metformin 1%. Gel loaded with sodium carboxymethylcellulose (Aqualon) at 4.5%: 100% complement.
• Metformin 1% by weight relative to the lipophilic phase.
• Hydrocerin emulsion (fatty excipient from Roc® containing petrolatum, paraffin oil, triglycerides, polyoxyethylene ethers and cerisine) at 33% (H / L): complement to 100%.
• the aim of this study is to demonstrate the protective activity of metformin vis-à-vis a photo immunosuppressive effect (depletion of Langerhans cells) induced by UVB irradiation, on a model of human skin maintained in survival.
• the photo immunosuppressive activity induced by UVB is evaluated by counting Langerhans cells in separate epidermis and in tissue sections after anti-CD1a labeling.
• Explants procedure 27 explants of human skin were prepared and put into survival in culture medium. They are divided into 9 lots of three explants: three control lots, three excipient lots and three ointment lots containing 1% metformin (formulation example 3).
• the analysis of the control and treated explants was carried out 24 h after the irradiation.
• the immunostaining of Langerhans cells with anti-CD1a was carried out in separate epidermis and in tissue sections.
• the Langerhans cells observed are very large, very dendritic, rising well in the epidermis.
• Langerhans cells are significantly lower compared to the non-irradiated controls. They have condensed cell bodies and a sharp decrease in dendricity.
• Langerhans cells are depleting. Their morphology is identical to that seen in the explants irradiated at 4 J / cm 2 and 6 J / cm 2 and not treated.
• Explants treated with the ointment and irradiated at 4 J / cm 2 and at 6 J / cm 2 The number of Langerhans cells is greater in explants irradiated and treated with the ointment containing metformin, than in untreated irradiated explants . In addition, these cells are well dendritic and have a general morphology close to that observed in non-irradiated explants. conclusions

Landscapes

• 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)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Immunology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Dermatology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Birds (AREA)
• Toxicology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Cosmetics (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=34043630

Family Applications (1)

Country Status (6)

Families Citing this family (5)

Family Cites Families (4)

• 2003
  • 2003-07-29 FR FR0309306A patent/FR2858232B1/fr not_active Expired - Fee Related
• 2004
  • 2004-07-29 WO PCT/FR2004/002041 patent/WO2005011663A1/fr not_active Application Discontinuation
  • 2004-07-29 JP JP2006521626A patent/JP2007500173A/ja active Pending
  • 2004-07-29 US US10/566,490 patent/US20070041915A1/en not_active Abandoned
  • 2004-07-29 CA CA002534067A patent/CA2534067A1/fr not_active Abandoned
  • 2004-07-29 EP EP04767816A patent/EP1686977A1/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events