JP2007500172A - Cosmetic use of biguanide derivatives as skin anti-aging agents - Google Patents

Abstract

  The present invention relates to the cosmetic use of biguanide derivatives as skin anti-aging actives. According to the invention, metformin is particularly suitable for use.

Description

Field of Invention

  The present invention relates to the cosmetic use of biguanide derivatives as skin anti-aging and remodeling agents.

Background of the Invention

  Generally in mammals, especially humans, the skin consists of two main parts: the outer epidermis and the inner dermis.

  The epidermis is responsible for the impermeability of the skin and its resistance. It regenerates about every 4 weeks due to the detachment of dead cells near the surface. The epidermis mainly comprises three types of cells: keratinocytes, melanocytes and Langerhans cells, which occupy almost the majority. Each of these cell types contributes to the essential role that skin plays in living organisms with unique functions.

  The dermis forms a solid support for the epidermis. It is also a nourishment source. It is referred to as the extracellular matrix and is itself composed of fibroblasts dispersed in a complex medium, which mainly comprises collagen fibers, elastin, hyaluronic acid and proteoglycans.

  Collagen acts as a “cement” for the dermis. It imparts firmness and resistance to the skin and is responsible for moisture retention (and hence its flexibility). Elastin provides elasticity and tension. Hyaluronic acid maintains volume and is involved in moisturizing.

  With age, especially on the face, the skin ages due to the appearance of wrinkles, then muscles, and / or sagging skin.

  Aging first affects the epidermis and its thickness decreases. The basal layer cell division ability is reduced, and the regeneration time in the surface layer of the cornea is prolonged.

  The maturity of these cells is incomplete and keratinization is no longer successful in creating a regular homogeneous corneal layer. Tissue collapse in the deep part of the skin, delayed cell regeneration, and decreased production of collagen and elastin are observed at the same time.

  In addition to the clock biological factors of aging, there are also external factors such as sunlight, tobacco, sleep deprivation and vitamin deficient diet.

  It is also known that changes in hormone production associated with menopause (mainly estrogen deficiency) amplify skin aging. These changes lead to a decrease in collagen and elastin in the dermis and weak cell regeneration in the epidermis. Thus, the skin becomes less flexible, thinner, and becomes dry and sagging.

  The structural elements of the skin (collagen, elastin and keratin) are most involved in our appearance. Indeed, changes in elastin and keratin levels and the density of the collagen network are responsible for loss of elasticity, wrinkles and skin sagging. It is some of these that cosmetics play.

  Cosmetics have been known for many years in the fight against skin aging. To date, however, nothing was satisfactory.

  Surprisingly, however, the inventors have found that biguanide derivatives, preferably metformin, have anti-aging and remodeling effects on the epidermis and dermal papilla and thus the skin.

  Pharmaceutical compositions containing biguanides are already known. They are used orally to treat certain types of diabetes, mainly type II non-insulin dependent diabetes, as antihyperglycemic agents that promote restoration of blood glucose balance.

  Metformin is the biguanide derivative most used in this type of therapy.

  This medicament is administered orally in the form of tablets containing 500 mg, 850 mg or 1 g of active ingredient.

  The daily dose is in the range of 1-2 g.

  A phase I clinical evaluation of metformin showed that the molecule tested on blood glucose levels was not toxic. The product is found to be well tolerated and its chronic toxicity is virtually zero. There is no change in animal behavior or growth; blood counts, uremia, and liver function have not deteriorated.

  The antihyperglycemic effect of metformin arises from the action of metformin through firstly increased activity of endogenous insulin and secondly through an insulin-independent mechanism. The action of metformin is to reduce the intestinal absorption of glucose, increase the cellular absorption of blood glucose, and reduce the amount of insulin required to normalize glucose production in the liver (disappearance of new sugar formation) and glycemia Appears as These effects are due in part to the ability of metformin to amplify the action of existing insulin through increased activity of the tyrosine kinase enzyme of the insulin receptor that induces a 'post-reception' signal response.

  Metformin is also known to promote healing in topical compositions and is known to have an angiogenic effect (FR 2809310).

  In addition, some biguanide derivatives are also known to have anti-inflammatory effects (US 4163800).

  However, all of these documents show that biguanide derivatives, in particular metformin, have a cosmetic anti-aging and remodeling action in the epidermis and dermal papilla, and the use of a composition comprising them in III It does not describe or suggest increasing type collagen production, stimulating keratinocyte proliferation in the epidermis, and / or increasing epidermal thickness.

Summary of the Invention

（上記式中：
Ｒ１およびＲ２基は、互いに独立して、水素原子、Ｃ_１‐Ｃ_７アルキル基、シクロアルキル基、ヘテロ環式基、Ｃ_２‐Ｃ_７アルケニル基、アリール基、アラルキル基、アリールオキシアルキル基またはヘテロアリール基を表すか；
あるいはＲ１およびＲ２は一緒になって、可能であれば１以上のヘテロ原子を含有した、Ｃ_２‐Ｃ_７アルキレンを表し；かつ
Ｒ３基は、一級、二級または三級アミンを表す；
但し下記式の化合物：

を除く）。 The present invention relates to the cosmetic use of biguanide derivatives having the following general formula I or cosmetically acceptable salts thereof as anti-aging and remodeling agents for the epidermis and dermal papilla:

(In the above formula:
R1 and R2 groups, independently of one another, _hydrogen, C 1 -C ₇ alkyl group, a cycloalkyl group, heterocyclic _group, C 2 -C ₇ alkenyl group, an aryl group, an aralkyl group, an aryloxy group or Represents a heteroaryl group;
Or R 1 and R 2 taken together represent C ₂ -C ₇ alkylene, possibly containing one or more heteroatoms; and the R 3 group represents a primary, secondary or tertiary amine;
However, the compound of the following formula:

except for).

The term “C ₁ -C ₇ alkyl group” in the sense of the present invention means a linear or branched C ₁ -C ₇ group, for example a methyl, ethyl, propyl, isopropyl or butyl group and isomers thereof.

  In the sense of the present invention, the term “cycloalkyl group” means a cycloalkyl group containing from 3 to 7 carbon atoms, such as a cyclohexanyl group.

  The term “heterocyclic group” in the sense of the present invention means a cyclic group containing from 3 to 7 atoms, one or more of these atoms being heteroatoms such as nitrogen, oxygen or sulfur atoms. And others are carbon atoms.

In the sense of the present invention, the term “C ₂ -C ₇ alkenyl group” means a linear or branched C ₂ -C ₇ alkenyl group such as a vinyl or allyl group.

The term “aryl group” in the sense of the present invention contains, for example, one or more substituents, for example a C ₁ -C ₇ alkyl group as described above, a C ₂ -C ₇ alkenyl group or halogen as described above. It means a hydrocarbon aromatic group such as a phenyl group.

The term “heteroaryl group” in the sense of the present invention contains one or more heteroatoms such as nitrogen, oxygen or sulfur atoms and contains one or more substituents, for example C ₁ -C ₇ alkyl as defined above. group, C ₂ -C ₇ alkenyl group or halogen as described above, may have means a hydrocarbon aromatic radical. Examples of heteroaryl groups are furyl, isoxazyl, pyridyl, pyrimidyl groups.

The term _"C 2 -C ₇ alkylene group" in the sense of the present invention, means such as ethylene, trimethylene, a _C 2 -C ₇ alkylene group such as tetramethylene or pentamethylene group.

  The term “cosmetically acceptable salt” in the sense of the present invention means a salt prepared from non-toxic cosmetically acceptable acids including organic and inorganic acids. As this acid, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, There are mucinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, tartaric acid and p-toluenesulfonic acid. Advantageously, hydrochloric acid is used.

  In one embodiment of the present invention, a biguanide derivative according to the present invention is used to increase type III collagen production in the dermal papilla, stimulate keratinocyte proliferation in the epidermis, and / or increase epidermal thickness.

  Advantageously, the biguanide derivative has a tensor or toning effect on the skin.

  It is also used to prevent, reduce and / or suppress the appearance of wrinkles in the skin.

In one specific embodiment of the invention, the R3 group represents a secondary amine having the formula:

In one advantageous embodiment of the present invention, R3 group represents NH _2.

In another aspect of the present invention, R1 and R2 groups are, independently of each other, represent a hydrogen atom or a _C 1 -C ₇ alkyl group.

  Advantageously, the biguanide derivative is metformin, more preferably in the form of the hydrochloride.

  In particular, the derivatives take the form of topical cosmetic compositions, advantageously of the oil, cream, foam, coating, lotion, ointment, liquid, gel, emulsion or spray type. The form may have a single phase vehicle consisting of a neutral hydroxypropylcellulose gel or a gel containing sodium carboxymethylcellulose. The cream may be made with a two-phase vehicle comprising a hydrophilic phase dispersed in a lipophilic phase.

  Advantageously, the composition contains 0.02 to 2% by weight of a biguanide derivative having the general formula I or a cosmetically acceptable salt thereof and a suitable excipient. These excipients are selected from among compounds that have good compatibility with the active ingredient. They are, for example, natural polymer-type water-soluble polymers such as polysaccharides (xanthan gum, carnauba gum, peptin ...) or polypeptides, methylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose type cellulose derivatives, or other synthetic polymers. , Poloxamer, carbomer, PVA or PVP.

  Finally, various cosolvent type excipients such as ethanol, glycerol, benzyl alcohol, humectants (glycerol), diffusion enhancers (transcroll, urea) or another antimicrobial preservative (0.15% p-hydroxy The addition of methyl benzoate) to this cosmetic composition is within the knowledge of all those skilled in the art. It is a surfactant, stabilizer, emulsifier, thickener, auxiliary or other active ingredient that exerts a synergistic effect, trace element, essential oil, fragrance, colorant, collagen, chemical or inorganic sunscreen, wettable powder And hot spring water.

  In one specific embodiment of the invention, the biguanide derivative or a cosmetically acceptable salt thereof is combined with at least one other active ingredient.

（上記式中：
Ｒ１およびＲ２基は、互いに独立して、水素原子、Ｃ_１‐Ｃ_７アルキル基、シクロアルキル基、ヘテロ環式基、Ｃ_２‐Ｃ_７アルケニル基、アリール基、アラルキル基、アリールオキシアルキル基またはヘテロアリール基を表すか；
あるいはＲ１およびＲ２は一緒になって、可能であれば１以上のヘテロ原子を含有する、Ｃ_２‐Ｃ_７アルキレンを表し；かつ
Ｒ３基は、一級、二級または三級アミンを表す；
但し下記式の化合物：

を除く）。 The invention also relates to a method for the cosmetic treatment of skin aging by application of a composition comprising a biguanide derivative of general formula I or a cosmetically acceptable salt thereof:

(In the above formula:
R1 and R2 groups, independently of one another, _hydrogen, C 1 -C ₇ alkyl group, a cycloalkyl group, heterocyclic _group, C 2 -C ₇ alkenyl group, an aryl group, an aralkyl group, an aryloxy group or Represents a heteroaryl group;
Or R1 and R2 taken together represent C ₂ -C ₇ alkylene, possibly containing one or more heteroatoms; and the R3 group represents a primary, secondary or tertiary amine;
However, the compound of the following formula:

except for).

  The examples given below for the compositions of the invention and testing of their activity are for demonstration and not for limitation.

Examples Several dosage forms were made without preservatives. The percentage is% by weight.
Formulation Example 1 :
Metformin: 1%
2.9% neutral hydroxypropyl cellulose gel (Alucon type 99 MF EP Klucel): up to 100% final
Formulation Example 2 :
Metformin: 1%
Gel containing 4.5% sodium carboxymethyl cellulose (Aqualon): up to 100% final
Formulation Example 3 :
Metformin: 1% by weight based on the lipophilic phase
33% (H / L) hydroserine emulsion (Roc ™ fat excipient containing petrolatum, paraffin oil, triglycerides, polyoxyethylene ether and sericin): up to 100% final

Test of remodeling and anti-aging activity of metformin-containing ointment The purpose of this test was to examine the general morphology after panoramic staining and to assess the number of mitotic keratinocytes and the density of collagen III by immunolabeling, 1% metformin It is to evaluate the reconstruction and anti-aging activity of the containing ointment (Formulation Example 3).

Procedure <br/> Preparation of explants:
Adipose tissue was removed from a 59-year-old woman by mammodermoplasty, and 39 explants were prepared and kept alive in the medium. They were divided into 3 batches of 12 explants (ointment, excipient alone, untreated control) and 1 batch of 3 explants.

Product application:
The product to be tested (ointment and excipients alone) was applied to the explants at a rate of 4 mg / explant for 10 days by topical route, and the untreated batch was not treated.

Histology:
At time T0, 3 explants were removed and fixed (normal Bouin's) or frozen. On days 3, 5, 7 and 10, 3 explants were removed from each batch and processed as described above.

Histological examination was performed as follows:
-Sections stained with Masson's Trichrome and then fixed in paraffin for general morphology observation-frozen sections for the following immunolabeling:
I. Immunolabeling of mitotic cells with anti-Ki67 monoclonal antibody (clone 7B11) counterstaining nuclei with propidium iodide
II. Immunolabeling of type III collagen with anti-collagen III polyclonal antibody developed with DAB (chromogenic chromogen for immunolabeling)

Result 1. General form:
Changes in skin structure were examined in various parts: epidermis, epidermis junction (DEJ) and dermal papilla.
Observations made on all explants indicate that application of metformin-containing ointment induces irritation of the epidermal structure resulting in an increase in its thickness and a more significant relaxation of the DEJ. This represents an image of a young epidermis structure. In fact, a clear epidermal thickening response (increase in epidermal thickness) was observed up to a thickness of 6-7 cell layers, starting with the 5th day of treatment for the batches coated with metformin-containing ointment. It should be emphasized that the vehicle alone has no clear effect on the skin structure of the treated explant.

2. Keratinocyte mitosis index The keratinocytes during mitosis labeled with anti-Ki67 were counted in the length direction of the epidermis in the taken sections.
The mitotic index, in terms of the values obtained, is 5 days for explants treated with metformin-containing ointment compared to control explants and explants treated with excipients. It was twice as expensive. In addition, the mitotic index on day 5 was increased by 25% in the treated explants compared to that measured on day 3.
On the 7th and 10th days, this index corresponds to the normal value of the explants in this survival stage.
These data clearly show that application of metformin-containing ointment stimulates keratinocyte proliferation, especially after 5 days of treatment. This observation is completely related to the simultaneously seen epidermal thickening.

3. Type III collagen density:
The labeling of type III collagen made it possible to examine its expression in the dermal papilla and along the DEJ. The results obtained were already on the third day, in the case of batches of explants coated with metformin-containing ointment, compared to those seen with untreated explants and those treated with excipients. It shows that the sign is somewhat clear along DEJ.
From day 5 to day 10, the markings in the batch of explants to which the ointment has been applied are more distinct in the dermal papilla, especially along the DEJ. These results indicate that the application of metformin-containing ointment induces increased expression of type III collagen in the dermal papilla, especially along the DEJ. This overexpression reaches its maximum on day 7 and is still quite present on day 10.

Conclusion Application of 1% metformin-containing ointment to human skin explants over 10 days induced an increase in epidermal thickness, which is visible after 5 days of treatment, but on day 7 It is still very clearly seen on the 10th day. This epidermal thickening is supported by an increase in the mitotic index of keratinocytes, which is twice that seen with the control and excipients on day 5 with the ointment, about 25% compared to day 3 Is an increase. This index returns to the normal value on the 7th to 10th days.
Metformin-containing ointment also induces an increase in type III collagen expression in the dermal papilla and along the DEJ, which reaches its maximum on day 7 and remains very clear on day 10.

  These observations as a whole represent the stimulation of the epidermal structure and the remodeling of the epidermis and dermal papilla by metformin. These types of changes represent a reference for young skin.

Claims (11)

Cosmetic use of biguanide derivatives of the following general formula I or their cosmetically acceptable salts as anti-aging and remodeling agents for the epidermis and dermal papilla:

(In the above formula:
R1 and R2 groups, independently of one another, _hydrogen, C 1 -C ₇ alkyl group, a cycloalkyl group, heterocyclic _group, C 2 -C ₇ alkenyl group, an aryl group, an aralkyl group, an aryloxy group or Represents a heteroaryl group;
Or R1 and R2 taken together represent C ₂ -C ₇ alkylene, possibly containing one or more heteroatoms; and the R3 group represents a primary, secondary or tertiary amine;
However, the compound of the following formula:

except for).   Use according to claim 1, for increasing the production of type III collagen in the dermal papilla, stimulating keratinocyte proliferation in the epidermis and / or increasing the thickness of the epidermis.   Use according to claim 1 or 2 for preventing, reducing and / or suppressing the appearance of wrinkles in the skin.   4. Use according to any one of claims 1 to 3 for a tensor or toning effect on the skin. R1 and R2 groups, independently of one another, represent a hydrogen atom or a _C 1 -C ₇ alkyl group, Use according to any one of claims 1 to 4. R3 group represents NH _2, Use according to any one of claims 1 to 5.   7. Use according to claim 6, wherein the biguanide derivative is metformin, preferably in the form of the hydrochloride.   8. Use according to any one of the preceding claims, wherein the biguanide derivative takes the form of a topical cosmetic composition.   Use according to claim 8, wherein the composition contains 0.02 to 2% by weight of a biguanide derivative or a cosmetically acceptable salt thereof and a suitable excipient.   10. Use according to any one of the preceding claims, wherein a biguanide derivative or a cosmetically acceptable salt thereof is combined with at least one other active ingredient. A method for cosmetic treatment of skin aging using a composition comprising a biguanide derivative of the following general formula I or a cosmetically acceptable salt thereof:

(In the above formula:
R1 and R2 groups, independently of one another, _hydrogen, C 1 -C ₇ alkyl group, a cycloalkyl group, heterocyclic _group, C 2 -C ₇ alkenyl group, an aryl group, an aralkyl group, an aryloxy group or Represents a heteroaryl group;
Or R1 and R2 taken together represent C ₂ -C ₇ alkylene, possibly containing one or more heteroatoms; and the R3 group represents a primary, secondary or tertiary amine;
However, the compound of the following formula:

except for).