ITMI991895A1 - SKIN DEPIGMENTANTS - Google Patents

Description

DESCRIPTION

Attached to an INDUSTRIAL INVENTION patent application entitled:

SKIN DEPIGMENTANTS

The present invention relates to cosmetic compositions containing substances with hydroxystylbene and pyr (id) onic structure.

In particular, the present invention relates to cosmetic compositions useful in the depigmentation treatment of skin hyperchromias of a melanic or hemosiderin nature.

Some of the substances with a hydroxystylbene or pyr (id) onic structure have been synthesized for the first time and therefore constitute a further inventive object.

The hyperpigmentative etiology is linked to heterogeneous events, which include local drug hyperpigmentation (for example by Ca-antagonists), cyanic melasma, gravidaric chiasm, senile melasma, heterologous melanic over-response following scleroderma, response post-inflammatory or traumatic, or responds to the need to reduce the ethnic coloration of individuals of Afro or Asian stock.

The first depigmenting cream appeared in Korea 50 years ago, and corresponded to the aesthetic need of oriental women to exhibit a pale complexion. It contained a mercurial compound, the action of which. it was based on the substitution of copper, an essential trace element as a co-factor of tyrosinase. The mercurial compound is currently banned for its nephrotoxic effects.

Various natural compounds are able to perform a partial inhibiting action of the synthesis or tyrosinase activity, for example glucosamines, galactosamines, mannosamines, and some plant extracts, whose activity is presumably linked to the blocking of free radicals that stimulate melanogenesis.

Even antioxidants such as vitamins C and E and their esters have mild depigmenting abilities, due to partial inhibition of melanogenesis, however with insufficient effects for the required aesthetic purposes.

Azelaic acid, introduced as an anti-acne treatment such as Azelex <®> (Allergan, Irvine, USA), finds extemporaneous use as a depigmentant having demonstrated the competitive inhibition of tyrosinase and DNA synthesis at the melanosomal site.

Currently the most used product are compositions with 2% hydroquinone, a substrate with an antagonistic and competitive action of tyrosine against the enzyme tyrosinase, frequently associated with alpha hydroxy acids.

In particular, glycolic acid has been used successfully in combination with hydroquinone (Lim JT, Tham SN Dermatol Surg, 23 (3): 177-179, 1997), with tretinoin (Lawrence N, Cox SE, Brody HJ , J. Am. Acad. Dermatol., 36 (4). 589-93, 1997) and with kojic acid (Garcia A, Fulton JE, Dermatol Surg, 22 (5): 443-7, 1996).

However, kojic acid appears to be an irritant and a possible source of chronic hypochromias (Iurassich S, Santoro M, Rossi E, G. Ital. Venereol., 132: 443-4, 1997), as well as the prolonged use of 2% hydroquinone coincides with a high frequency of granular-localized hyperpigmentation and formation of elastotic fibers (Sylla R et al, Dakar Med., 3, 223-6, 1994), with cases of hypopigmentation and vitiligo from prolonged use.

Depigmenting substances are therefore either partially effective or have contraindications in topical application.

The Applicant has found that substances with a stilbenic (polyhydroxy) structure are effective in the treatment of hyperpigmentative forms, in particular of melanic origin.

An object of the present invention relates to a cosmetic composition containing substances of general formula:

where R <1>, R <2>, R <3>, R <4>, each independently, is equal to H or OH, and with a number of R = OH between 2 and 3;

said substances useful for the preparation of cosmetic compositions with depigmenting action.

A particular type of hyperpigmentation concerns the hemosiderin deposits from trauma, hematomas, or the after-effects of the scleroderma operation. In the aesthetic treatment of venous-varicose and capillary sclerosis, the incidence of unresolved local hyperpegmentative events is around 20% of the patients treated.

In this context, the formation of pigmented spots appears to be the result of the combination of hemoglobin extravasation, with the formation of hemosiderin deposit, and melanic hyperactivity mediated by the inflammatory process resulting from the extravasation itself. An increase in the incidence of pigmentation was observed for the treatment of blue venulectasis, as opposed to the treatment of red telengiectasis, with indications regarding capillary fragility as a predisposing cause.

This condition can occur in other traumatic conditions, for example as a result of hematomas, the treatment of folliculosis, the incision of tattoos, etc.

The treatment of hemosiderin deposits involved the use of exfoliation (for example with trichloroacetic acid), cryotherapy, retinoic acid, while specific treatments aimed at the chelation of hemosiderin iron have turned to the application of creams containing EDTA, or the intradermal injection of a specific iron ketant, desferoxamine. None of these gave definitive results on hyperpigmentative imperfections.

The Applicant has now also found that some substances such as 4-hydroxy-3-pyrones, -pyridones, jointly defined as 4-hydroxy-3-pir (id) oni, which prove effective in the treatment of hyperpigmentative forms, in particular of hemosiderin.

An object of the present invention relates to a cosmetic composition containing substances of general formula:

where: X is O or N - Y,

R <5> is H, methyl or ethyl;

Y is an amino acid or R <6>;

R <6> is a linear or branched or cyclic, saturated or unsaturated or hydroxylated alkyl; said substances useful for the preparation of cosmetic compositions with depigmenting action.

Some of the substances with depigmenting action of the present invention are known, others have been synthesized for the first time in this context, therefore they constitute a further inventive object.

Among the (polyhydroxy) stilbenes, lossiresveratrol (2.3 ', 4.5'-tetrahydroxystilbene,

which has been extracted and characterized in the mulberry tree (Morus alba).

New structural analogs with a (polyhydroxy) stilbenic structure object of the present invention include, among others, 2,2 ', 4,4'-tetrahydroxystilbene, 2, 3', 4, 4'-tetrahydroxystilbene and 2,3 ' , 4,5 ', 6'-pentahydroxystylbene.

The (polyhydroxy) stilbenes are obtained by the Wittig reaction between the O-protected derivatives (such as dimethyl-terbutyl-silane) of the phosphorus ilide of 2,4-dihydroxybenzyl chloride and the aldehyde 3,5- 2,4- or 3,4-dihydrosibenzoic or gallic aldehyde, with subsequent release of the protections by hydrogenation at 5 atm on Pd / C in methanol.

From the 4-hydroxy-3-pyrones series, pyromeconic acid is known, obtained by heating the comenic acid of fermentative origin, maltol

contained in chicory, pine needles and larch bark; ethylmaltol

known food fragrance.

Given the commercial unavailability of comenic acid, we have developed a process for the synthesis of pyromeconic acid starting from furfuryl alcohol by treatment with chlorine in a hydromethanolic solution.

Said process was not known, and therefore constitutes a further inventive object.

Deferiprone is known from the 1,2-dialkyl-4-hydroxy-3-pyridones series.

and a series of linear alkyl homologs tested in therapy

ketant for removing sideremias from polytransfusion, sometimes spontaneously formed by 4-hydroxy-3-pyrons by Mannich reaction, for example of maltol with primary animins or glyein, when cooking food.

Starting from pyrochomenic acid by reaction with primary amines and amino acids in aqueous or hydroalcoholic solution we have developed the series of N-substituted 4-hydroxy-3-pyridones with alkyl or amino acid group, not known until now, which therefore constitute a further inventive object.

The new substances include, however not exclusively, the substituted 4-hydroxy-3-pyridones such as 1-methyl, 1-ethyl, 1-isopropyl, 1-N-valine, 1-N-leucine, 1-N-isoleucine .

The composition according to the invention may also comprise a cosmetically acceptable carrier which acts as a dilutant, dispersant or carrier of the substances of interest in the cosmetic composition.

The amount of the carrier can vary from 50% to 99.9%, preferably from 95% to 99% by weight of the total composition. Vehicles other than water may include liquid or solid emollients, silicones and solvents.

The depigmenting agents of the present invention can be applied to the skin in a solution of solvents such as DMSO, or they can benefit from the presence of cosmetic ingredients capable of improving their applicability, facilitating their penetration and / or increasing the effectiveness of the depigmenting treatment.

Oils and lipids can be combined with water by means of emulsifiers ("surfactants"), to give emulsions either / to or to / or in function of the average hydrophilic-lipophilic balance (HLB) of the emulsifying system. The surfactants can be incorporated in quantities ranging from 0.5% to 30%, preferably from 1% to 15% by weight.

Cationic, nonionic, anionic, amphoteric surfactants and their combinations can be usefully employed. Among the nonionic surfactants, the alkoxylates of alcohols and fatty acids or sorbitals, polyoxypropylene and polyoxyethylene, alkyl polyglycosides are mentioned; among the anionic surfactants, fatty acid soaps, sodium lauryl sulfate or lauryl ether sulfate, alkyl benzenesulfonates, mono and / or dialkyl phosphates and the like; among the amphoteric surfactants the dialkylamine oxides, the various types of betaines, phospholipids and natural ceramides.

A thickener can be present in an amount from 0.1% to 10% by weight of an aqueous-based composition, preferably from 0.5% to 5% by weight. Examples of thickeners are cross-linked polyacrylates (Carbopol <®>), and gums such as xanthan, carrageenan, gelatin, karaia, and pectin.

Aqueous cosmetic compositions must be preserved with preservatives from the growth of microorganisms, for example with hydroxybenzoic acid alkyl esters, hydantoins, parabens, imidazolidinyl urea, sodium dehydroacetate, benzyl alcohol, and a range of quaternary ammonium compounds, in quantities between 0.2% and 1% by weight.

In the anhydrous cosmetic compositions, silicones can be present, for example those with viscosities ranging from 10 to 10 <7> centistokes at 25 ° C, and their mixtures, in quantities ranging from 5% to 95% by weight.

The sunscreens can be incorporated in the cosmetic compositions of the present invention, for example the derivatives of PABA, benzophenone, and cinnamates, in an amount depending on the desired degree of UV protection.

Other additional ingredients can be further incorporated, which can include dyes and pigments, opacifiers, perfumes, etc. The amount of these materials can vary from 0.001% to 20% by weight of the composition.

In a preferred embodiment of the present invention, the depigmenting substances of the present invention are used in combination with other functional substances. An example of functional substances are alpha- and beta-hydroxy acids. At average concentrations, hydroxy acids act by inhibiting the enzymatic action of sulfate transferase, phosphotransferase and phosphokinase of mucopolysaccharides, resulting in a reduction of the cohesion forces asocytes, thus facilitating the action of depigmenting agents.

Among the alpha hydroxy acids glycolic acid is preferred, due to the characteristics of excellent penetrating capacity due to the limited serum bulk of the molecule, in quantities from 1% to 50%, preferably from 5% to 12% by weight.

Among the beta-hydroxyacids, salicylic acid is preferred due to its qualities as an energetic exfoliator of the epidermal layer, inactive and therefore non-irritating at the level of the dermis, in quantities from 0.1% to 10%, preferably from 1% to 5% in weight.

Another preferred combination in the present invention consists of other depigmentants, for example hydroquinone, arbutin and kojic acid.

Other types of active ingredients are considered in the present invention. Although not limited to these categories, they include anti-wrinkle and anti-inflammatory drugs, such as glycyrrhizin derivatives, flavonoids, alpha-bisabolol, rosmarinic acid, azulene, asiaticoside, ruscogenin, lescin, betulinic acid. , retinol and its derivatives, tocopherol and its derivatives.

The compositions of the present invention can be used formulated in the form of cosmetic compositions such as ointments, creams, ointments, gels, tinctures, milks, lipogels, and other triphasic preparations either / a or a / or commonly usable for topical treatment.

An example of compositions are creams or gels containing liposomes or microemulsions, due to their excellent bioavailability with intracutaneous diffusion, therefore usable in deep alterations of hemosiderin or methane pigmentation.

The incorporation of the active ingredients in compositions in controlled transdermal release forms, such as plasters, bandages and dressings, are indicated for prolonged applications in limited areas.

For sebum or hyperkeratin skins, the aqueous compositions with a low oily content, for example gels or gelled microdispersions (lipogels), capable of releasing depigmenting substances carried by an alpha- or beta-hydroxy acid, are of particular interest.

The depigmenting substances can be present in cosmetic compositions in quantities ranging from 0.001% to 20%, preferably from 0.1% to 2% by weight.

The overall dosages can vary from 5 mg up to 5000 mg / day, based on the individual response and extension of the affected skin area to forms of senile melasma, chiasma gravidarum, post-inflammatory and traumatic hyperpigmentation, for the treatment of pigmentation. ethnic, hemosiderin deposits resulting from scleroderma, hematoma and tactile.

Obvious results can be obtained in degenerative diseases that require a constant supply of the active ingredient in sufficient quantity to produce the required effects.

The following examples serve to further illustrate the invention and should not be considered absolutely limiting.

Preparative Example I - Synthesis of polyhydroxystilbenes

The synthesis is carried out according to the procedure described by Orsini F et al. (J Nat Prod, 60, 11, 1997), applying the Wittig reaction of the O-protected derivatives (such as dimethylterbutyl-silane) of the phosphorus ilide of 2,4-dihydroxybenzyl chloride and aldehyde 3,5-2, 4- or 3,4-dihydrosibenzoic or gallic aldehyde, with subsequent release of the protections by hydrogenation at 5 atm on Pd / C in methanol to give, respectively, 2, 3 ', 4,4'-tetrahydroxystilbene and 2,3 ', 4,5', 6'-pentahydroxystilbene.

Preparative Example II - Synthesis of pyromeconic acid

74.6 g of chlorine gas (1.05 moles) are bubbled under stirring at the bottom of a reactor containing 15 ml of methanol: water 2: 3 (v / v), previously cooled to -10 ° C.

At the same time, a solution of 49 g of furfuryl alcohol (0.5 moles) dissolved in 50 ml of methanol: water 5: 1 (v / v) is added. When the addition of furfuryl alcohol is completed, the chlorine introduced amounts to 2/3 of the total, the remaining portion (1/3) is subsequently introduced, keeping the system at a temperature not exceeding -5 ° C.

Then it is heated to 90 ° C, distilling part of the methanol, and continuing the heating at 90-50 ° C for about 3 hours.

The solution is cooled to room temperature, about 7 g of pitchy material are separated, and then adjusted to pH 2.2 with 50% NaOH (about 45 ml), maintaining at a temperature not exceeding 40 ° C under stirring.

By cooling to 5 ° C pyromeconic acid precipitates, which is filtered and re-crystallized twice by methanol, giving 25 g of a semi-crystalline white product (yield 51%).

Preparative Example 1H - Synthesis of 1-alkyl-3-hydroxy-4-pyridone

0.98 g of pyromeconic acid (10 mmoles) are dissolved in 40 ml of water containing 2.4 ml of 40% methylamine (about 3 equivalents).

The mixture is refluxed for 7 hours, then it is cooled and activated carbon is added, and it is left to stand for 30 minutes. The solution, with the appearance of a dark brown solution, is filtered and then evaporated under vacuum by heating, to give a dark brown solid, which is recrystallized 3 times by water, to give 0.42 g of white acicular product, yield 38%.

The oven dried and ground product is 1-methyl-3-hydroxy-4-pyridone, M = 111. Preparative Example VI - Synthesis of 3-hydroxy-4-pyridone. 1-N-amino acids

The procedure of Preparative Example ΙI is followed but replacing the methylamine with 3 g of gliein, to give 1-carboxymethyl-3-hydroxy-4-pyridone with yields of 23%.

Example I - Inhibition of tyrosinase in vitro

In 120 ul of 67 mM phosphate buffer (pH 6.8) dissolve 0.197 mg of L-dopa (1 umole), to which 40 ul of the sample solution at various concentrations in the buffer solution are added. They are placed in plates, to which 40 ul of mushroom tyrosinase (Sigma-Aldrich, USA) are added at 125 U / ml, mixed and left to incubate at 37 ° C for 20 minutes.

The optical density is then measured in microcuvettes at 492 nm, calculating the percentage of inhibition with respect to the value provided by a solution of 120 ul of phosphate buffer and 40 ul of tyrosinase on 1 umole of L-DOPA. For comparison, kojic acid is used, whose depigmenting properties are known.

The value of IC50 is obtained through the MacALLFIT program. The results are shown in Table I.

TABLE I

From the table it is observed that the (polyhydroxy) stilbenes and the 3-hydroxy-4-pir (id) oni without substituent in position 2 possess a tyrosinase inhibition activity from 2 to 30 times greater than kojic acid.

The inactivity of 2-alkyl-3-hydroxy-4-pyridonium is highlighted, which will turn out to be potential candidates for the removal of hemosiderin stains.

Example I - Melanic depigmentation with controlled release forms

100 g of an adhesive mass are prepared, each containing respectively:

Adhesive mass (A) (B) (C) (D)

the adhesive film is then spread on a base film and a covering film, obtaining patches capable of releasing the depigmenting substances in the course of 24 hours, ensuring their continuous administration.

2 volunteers of Afro stock (from Senegal) are supplied with patches with a surface of 12 cm of composition from A to D, delimiting the 4 areas of application on the ventral area, with the instruction to renew the application of the patch every 48 hours After 40 days of treatment, the subjects are examined, comparing the 4 application areas with the color of the surrounding, untreated skin. The results are shown in Table I.

TABLE Π

Therefore, a high methane depigmenting activity of (polyhydroxy) stilbenes and deferiprone is observed, in partial agreement with the results of the tyrosinase inhibition test.

Example 111 - Depigmentation of hemosiderin spots with glycolic gel

100 g of gel with 2% of active ingredient are prepared, which respectively contain:

Gel (A) Gel (B) Gel (C)

2 female volunteers, who have some persistent hemosiderin spots on their legs (more than 6 months after scleroderma surgery) are provided with 3 Gels A, B, C, with the instruction to apply them separately and repeatedly on 3 distinct areas .

After 30 days of treatment with 3 daily applications of 30 minutes, followed by washing the affected area with water, the results are evaluated, Gel A did not make any substantial changes to the iron stain, Gel B a moderate improvement, while the area treated with Gel C it is devoid of hyperpigmentative trace.

In practice it has been found that the present invention achieves the intended purposes. It is evident that the compositions and methods according to the invention are susceptible to variants that fall within the scope of the inventive concept.

The object of the invention is better defined by the claims, rather than by the examples reported above.

Claims (14)

CLAIMS 1. Depigmenting cosmetic composition containing a stilbenic (polyhydroxy) structured substance of general formula: where R <1> R <2>, R <3>, R <4>, each independently, is equal to H or OH, and with a number of R = OH between -2 and 3. 2. Depigmenting cosmetic composition containing a substance according to Claim 1 in an amount comprised between 0.001% and 20%, preferably between 0.1% and 2% by weight, said composition used for the topical treatment of skin hyperpegmentative forms, senile melasma, chiasm gravidarum, post-inflammatory hyperpigmentation, ethnic pigmentation 3. Substance according to Claim 1 con 4. Substance according to Claim 1 con 5. Substance according to Claim 1 con 6. Depigmenting cosmetic composition containing a substance with a pyri (id) inonic structure of general formula: where: X is O or N - Y; R <5> is H, methyl or ethyl, Y is an amino acid or R <6>; R <6> is a linear or branched or cyclic, saturated or unsaturated or hydroxylated alkyl. 7. Cosmetic composition containing a substance according to Claim 6 in a quantity comprised between 0.001% and 20%, preferably between 0.1% and 2% by weight, said composition used for the topical treatment of cutaneous hyperpegmentative forms, senile melasma, chiasma gravidarum , post-inflammatory hyperpigmentation, ethnic pigmentation, or hemosiderin deposits resulting from scleroderma, hematoma or tattoo. 8. Substance according to Claim 6 with N-amino acid group (excluding N-glycine). 9. Substance according to claim 6 with linear or branched or cyclic, saturated or unsaturated or hydroxylated alkyl. 10. Substance according to claim 6 where R <6> is methyl, ethyl or isopropyl. 11. Cosmetic composition according to the preceding claims further containing cosmetically acceptable ingredients. 12. Cosmetic composition according to claim 11 containing one or more alpha hydroxy acids. 13. Cosmetic composition according to Claim 11 containing salicylic acid. 14. Cosmetic composition according to Claim 11 containing further depigmentants selected from kojic acid, hydroquinone and its glycosides, ascorbic acid and its esters, tocopherol and its esters, azelaic acid and its esters, and relative mixtures.