EP1686977A1

EP1686977A1 - Use of a bigaunide derivative for protecting skin against uvb radiation

Info

Publication number: EP1686977A1
Application number: EP04767816A
Authority: EP
Inventors: Pierre Jean-Paul Potier; Nobumichi-André Sasaki; Maria Conception Achab; Gisèle FRANCK; Joanna Bakala; Françoise PICOT
Original assignee: PHARMAMENS
Current assignee: PHARMAMENS
Priority date: 2003-07-29
Filing date: 2004-07-29
Publication date: 2006-08-09
Also published as: WO2005011663A8; FR2858232A1; FR2858232B1; US20070041915A1; JP2007500173A; CA2534067A1; WO2005011663A1

Abstract

The invention relates to the use of a bigaunide derivative for protecting skin against UVB radiation harmful effects and/or for protecting skin against undesirable and/or inaesthetic effects of UVB radiation.

Description

Title: Use of a biguanide derivative to protect the skin from UVB radiation.

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.

It is known that ultraviolet (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. Wavelength rays between 280 nm and 320 nm, called UVB, are very energetic but penetrate little deep into the skin. They are the cause of erythema and skin burns, and thus prevent the development of tanning. Their erythemal power is 1000 times greater than UVA and their participation in the genesis of cancers is not negligible.

We also know that 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.

Many sun filters are known to date. However, due to the growing need for such filters in order to protect themselves from the sun while tanning, the search for new products protecting the skin against UVB is still current.

Surprisingly, the inventors have discovered that a biguanide derivative, advantageously metformin, has a protective effect on the skin against UVB.

Pharmaceutical 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. In fact, the action of 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. These effects result, in part, from the power of metformin to enhance the action of existing insulin by an increase in the activity of the insulin receptor enzyme tyrosine kinase, which triggers the signaling cascade " post-receptor ".

Metformin is also known in topical compositions for promoting healing and as having an angiogenic action (FR 2 809 310).

In addition, certain derivatives of biguanides are also known to have an anti-inflammatory action (US 4,163,800).

However, none of these documents describes or suggests the use of a biguanide derivative to protect the skin against UVB.

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 Cι-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.

By the term "C ₁ -C ₇ alkyl group" is meant in the sense of the present invention any Cι ~ C ₇ alkyl group, linear or branched, such as for example methyl, ethyl, propyl, isopropyl or butyl groups as well as their isomers. By the term "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.

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.

By the term "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. By the term "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. By the term "heteroaryl group" is meant 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. Examples of heteroaryl groups are furyl, isoxazyl, pyridyl, pyrimidyl.

By the term "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. By the term "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. Advantageously, hydrochloric acid is used.

In one embodiment of the invention, the medicament is intended to protect the skin against sunburn and skin cancers. Advantageously, the medicament has a protective activity with respect to the photo immunosuppressive effect induced by UVB irradiation on Langerhans cells.

In a particular embodiment of the invention, the group R3 represents the secondary amine of the following formula:

In an advantageous embodiment of the invention, the group R3 represents NH ₂ . In another embodiment of the invention, the groups R1 and R2 represent, independently of one another, a hydrogen atom or a C ₁ -C ₇ alkyl group.

Advantageously, the biguanide derivative is metformin, even more advantageously in the form of a hydrochloride.

In particular, 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.

Advantageously, 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. These 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. Finally, it is within the reach of any person skilled in the art to add various 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.

Advantageously, 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). Furthermore, 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. We know in particular that 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).

In order to improve the properties of the medicament according to the present invention, it is also advantageous to introduce into the latter thickening polymers with emulsifying properties and among which mention may particularly be made of crosslinked copolymers of acrylic acid / C ₁₀ -C ₃₀ alkyl acrylates type, such as those known under the brand names "PEMULEN TR-1" and "CARBOPOL 1342 ”from Goodrich, whose use is in fact today most widespread.

In a particular embodiment of the invention, 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:

(I) in which: 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).

The examples below of compositions according to the invention and of activity study are given by way of illustration and without limitation.

EXAMPLES

Several pharmaceutical forms have been prepared without a preservative. The percentages are expressed by weight.

Example of formulation 1: Metformin: 1%.

Neutral hydroxypropylcellulose gel (Klucel d'Aqualon type 99 MF EP) with

2.9%: complement to 100%.

Example of formulation 2:

Metformin: 1%. Gel loaded with sodium carboxymethylcellulose (Aqualon) at 4.5%: 100% complement.

Example of formulation 3:

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%. STUDY OF THE PROTECTIVE ACTIVITY OF AN OINTMENT COMPRISING METFORMIN WITH RESPECT TO AN IMMUNOSUPRESSANT EFFECT ON LANGERHAN CELLS

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).

Irradiation:

3 batches (control, excipient and ointment) are exposed to UVB irradiation of 4 J / cm ² , three batches (control, excipient and ointment) to UVB irradiation of 6 J / cm ² and the last three batches are placed in the darkness during irradiation.

Application of products in preventive mode:

The daily application of ointment is 4 mg per explant, for 3 days before irradiation. Histology:

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.

Results

Explants Non-irradiated witnesses:

The Langerhans cells observed are very large, very dendritic, rising well in the epidermis.

Control explants irradiated with UVB at 4 J / cm ² and 6 J / cm ² :

The number of Langerhans cells is significantly lower compared to the non-irradiated controls. They have condensed cell bodies and a sharp decrease in dendricity.

Explants treated with excipients alone irradiated at 4 J / cm ² and 6 J / cm ² .

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

The results of histological studies and in particular the immunostaining of Langerhans cells in explants subjected to observations 24 hours after irradiation show the protective action of metformin. When the ointment is applied preventively, its protective activity is very significant, which results in a large number of Langerhans cells kept intact.

Based on these results, we can therefore consider the use of metformin for the prevention of attacks from the sun's rays.

Claims

CLAIMS 1. Use of a biguanide derivative of general formula I as follows:

CM NH NH ^R1 N II II _/ NCNC-R3 R2 I ^H 0) in which: the groups R1 and R2 represent, independently of one another, a hydrogen atom, a Cι-C ₇ alkyl group ₎ a cycloalkyl group, a heterocycle, a C ₂ -C ₇ 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 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.

2. Use according to claim 1 intended to protect the skin against sunburn and skin cancer.

3. Use according to claim 1 or 2 for manufacturing a medicament having a protective activity with respect to the photo immunosuppressive effect induced by UVB irradiation on Langerhans cells.

4. Use according to any one of the preceding claims, characterized in that the groups R1 and R2 represent, independently of one another, a hydrogen atom or a C1-C7 alkyl group.

5. Use according to any one of the preceding claims, characterized in that the group R3 represents NH ₂ .

6. Use according to claim 5 characterized in that the biguanide derivative is metformin, advantageously in the form of a hydrochloride.

7. Use according to any one of the preceding claims taken separately, characterized in that the medicament is in a pharmaceutical form for local use.

8. Use according to any one of the preceding claims taken separately, characterized in that the medicament contains from 0.02 to 2% by weight of the biguanide derivative or of its pharmaceutically acceptable salt and an appropriate excipient.

9. Use according to any one of the preceding claims, characterized in that the biguanide derivatives or its pharmaceutically acceptable salt is combined with at least one other active principle.

10. Cosmetic use of a biguanide derivative of general formula I below:

_C NH NH ^R s II II ^ NCNC-R3 R2 IH (I) in which: 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 ₂ -C ₇ 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 more 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 protect the skin from the undesirable and / or unsightly effects of UVB radiation.