Depigmentation composition comprising l-cysteamine, ascorbic acid and phytic acid

Abstract

The present application relates to a depigmentation composition, a depigmentation composition for use as a drug, and the non-therapeutic use of a depigmentation composition.

Description

[0001] DEPIGMENTING COMPOSITION COMPRISING L-CYSTEAMINE, ASCORBIC ACID AND PHYTIC ACID

[0002] Field of invention

[0003] The present patent application relates to a depigmentation composition, a depigmentation composition for use as a medicament, as well as the non-therapeutic use of a depigmentation composition.

[0004] Back-

[0005] Human skin pigmentation is highly variable and originates from melanin, a macromolecule synthesized in melanocytes located in the stratum basale, the innermost layer of the epidermis. Once synthesized, melanin accumulates in melanosomes. These melanosomes are transported to the skin surface by the action of dendrites that link melanocytes to keratinocytes, thus protecting the genetic integrity of cells against the mutagenic effects of UV rays.

[0006] Depigmentation compositions can have a medical action, to prevent or treat a pigmentation disorder, or a purely cosmetic action, to lighten the natural coloring of black or tanned skin. Among the medical applications, we can notably cite the lightening of dark spots on the skin and the homogenization of irregularities in skin coloring. This particularly concerns hyperpigmentation which manifests itself in the form of dark and irregular spots on the skin. Also concerned are melasma or chloasma, spots which generally appear during or after pregnancy, but which can also be caused by medications, particularly hormonal ones, or acne. We can also cite lentigo (solar or senile) which appears on parts of the skin exposed to the sun in a predominantly elderly population.Finally, post-inflammatory hyperpigmentation can occur as a result of any inflammatory skin condition, such as photoallergic reactions or laser therapy.

[0007] The most widely used molecule today to reduce skin pigmentation is hydroquinone. This molecule is generally formulated at between 0.5 and 10% in creams or lotions. However, the irritant and cytotoxic properties of hydroquinone limit its use in many countries. Indeed, even at concentrations below 2%, hydroquinone is both irritating and cytotoxic to melanocytes, notably causing exogenous ochronosis.

[0008] Many alternative depigmentation compositions have been developed to overcome these irritation problems, but with unsatisfactory results.

[0009] Sulfur molecules such as cysteamine (L-cysteamine) with a strong reducing action are among the most effective.

[0010] Cysteamine (beta-mercaptoethylamine) is an aminothiolated compound with antioxidant and depigmenting properties. It is produced naturally in mammals by intracellular degradation of L-cysteine.

[0011] However, a major disadvantage of these sulfur molecules is that, due to their instability in aqueous solution, these molecules develop an unpleasant odor and a brown coloring, which strongly limits their use for the preparation of cosmetic or therapeutic compositions.

[0012] One proposed method to overcome these problems is to encapsulate or derivatize cysteamine (Atallah, C. et al. Challenges for cysteamine stabilization, quantification, and biological effects improvement. Journal of Pharmaceutical Analysis. 2020; 10: 499-516). However, these techniques are complex to implement and may affect the therapeutic or cosmetic activity of cysteamine.

[0013] Furthermore, ascorbic acid is also known for its depigmenting properties by inhibiting the migration of melanosomes through dendrites to the skin surface. However, ascorbic acid is also rapidly oxidized in aqueous solution, causing a yellow discoloration, which limits its cosmetic and / or therapeutic action (Boo YC Ascorbic Acid (Vitamin C) as a Cosmeceutical to Increase Dermal Collagen for Skin Antiaging Purposes: Emerging Combination Therapies. Antioxidants. 2022; 11, 1663).

[0014] An alternative method described in patent CH706226B1 consists of combining cysteamine with ascorbic acid derivatives (sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl palmitate). According to the inventors, these chemical derivatives of ascorbic acid made it possible to stabilize cysteamine while avoiding the stability problems of pure ascorbic acid, and thus obtain formulations with a good odor and a light color.

[0015] However, the clinical efficacy of these formulations has been shown to be lower than that of hydroquinone at equivalent dosage (Lima PB et al. A comparative study of topical 5% cysteamine versus 4% hydroquinone in the treatment of facial melasma in women). This is explained in particular by the fact that chemical derivatives of ascorbic acid do not have the same depigmenting properties as ascorbic acid itself.

[0016] There is therefore a need for the provision of formulations that are low or non-irritant (and have no other undesirable side effects) and that nevertheless have a depigmentation activity comparable to or even superior to that of hydroquinone. These formulations must be able to be produced on an industrial scale and have a pleasant odor, a light color and be stable under commercial storage conditions (have an acceptable shelf life).

[0017] Summary of the invention

[0018] The inventors have surprisingly discovered that the present invention addresses the above-mentioned problems.

[0019] According to a first aspect, the present invention relates to a depigmentation composition [composition (D), hereinafter] in the form of a serum comprising, relative to the total weight of composition (D): from 0.2 to 10.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts, from 1.0 to 20.0% by weight of ascorbic acid, preferably from 2.0 to 20.0% by weight of ascorbic acid, and from 0.1 to 5.0% by weight of phytic acid, wherein the pH of said composition is less than 5.0.

[0020] According to another aspect, the present invention relates to the depigmentation composition (D) for use as a medicament, in particular for use in the treatment or prevention of at least one skin pigmentation disorder linked to excessive production of melanin and / or an abnormally high number of melanocytes.

[0021] According to another aspect, the present invention also relates to the non-therapeutic use of the depigmentation composition (D) for reducing normal pigmentation of the skin and / or hair.

[0022] Detailed description of the invention

[0023] The term “comprising,” as used in the context of the invention, should not be construed as being limited to the means listed thereafter; it does not exclude the presence of other elements or steps. It should be interpreted as specifying the presence of the listed features, elements, steps, or components referred to, but does not exclude the presence or addition of one or more other features, elements, steps, or components, or groups thereof. Thus, the scope of the expression “a composition comprising A and B” should not be limited to the composition composed solely of A and B. This means that, in the context of the present invention, the only relevant elements are A and B. Accordingly, the terms “comprising” and “including” encompass the more restrictive terms “consisting essentially of” and “consisting of.”

[0024] In the context of the present invention, the term "subject" is used herein to refer to a mammal, preferably a human. In some embodiments, the subject is a subject in need of treatment or a subject having a skin pigmentation disease or disorder, such as hyperpigmentation. However, in other embodiments, the subject is a normal subject who has healthy, normal skin and needs to lighten their skin and / or healthy, normal hair and needs to lighten their hair.

[0025] In the context of the present invention, the term "depigmentation" is used to refer to the lightening of skin and / or hair, or the loss of pigment. Depigmentation compositions are generally referred to as "lighteners", "whiteners" or "equalizers". Regardless of the terminology used, the general principle is that they relate to a reduction in the melanization or rate of melanization of skin and / or hair, resulting in a loss of pigment.

[0026] The present invention relates to a depigmentation composition [composition (D), hereinafter] in the form of a serum comprising, relative to the total weight of composition (D): from 0.2 to 10.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts, from 1.0 to 20.0% by weight of ascorbic acid, preferably from 2.0 to 20.0% by weight of ascorbic acid and from 0.1 to 5.0% by weight of phytic acid, wherein the pH of said composition is less than 5.0.

[0027] L-cysteamine and ascorbic acid are generally known for their depigmenting properties. However, these two active molecules are unstable in aqueous solution, which until now prevents their combined use in cosmetic formulations. The inventors have surprisingly found that, in composition (D) as described above, both L-cysteamine and ascorbic acid are stable during storage under commercial conditions. This allows composition (D) to exhibit a pleasant odor and a light color over an extended period, and moreover to develop a depigmenting action superior to that of the gold standard in the field, hydroquinone.

[0028] It appears that, when ascorbic acid and cysteamine are stabilized in composition (D), a synergy develops between their depigmenting activities.

[0029] As described above, composition (D) comprises, relative to the total weight of composition (D), from 0.2 to 10.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts.

[0030] In the context of the present invention the terms "cysteamine" and "L-cysteamine" are used interchangeably to refer to the compound which can be synthesized by mammals by degradation of Coenzyme A, of general formula C2N7NS and also known as beta-mercaptoethylamine.

[0031] In the context of the present invention, the term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic or organic acid salts of cysteamine. These salts may be prepared in situ during the preparation or isolation of cysteamine, or by separately reacting purified cysteamine with a suitable organic or inorganic acid, and isolating the salt thus formed. Examples of pharmaceutically acceptable salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oxalate, benzoate, lactate, phosphate, tosylate, citrate, fumarate, tartrate, succinate salts. Preferably, the pharmaceutically acceptable salt of cysteamine is cysteamine hydrochloride.

[0032] Preferably, said composition (D) comprises, relative to the total weight of the composition (D), at least 0.5% by weight, preferably at least 1.0% by weight, even more preferably at least 2.0% by weight, more preferably at least 3.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts.

[0033] Preferably, said composition (D) comprises, relative to the total weight of the composition (D), at most 9.0% by weight, preferably at most 8.0% by weight, even more preferably at most 7.0% by weight, more preferably at most 6.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts.

[0034] According to a preferred variant of the present invention, said composition (D) comprises, relative to the total weight of the composition (D), at least 0.5% by weight and at most 9.0% by weight, preferably at least 1.0% by weight and at most 8.0% by weight, even more preferably at least 2.0% by weight and at most 7.0% by weight, preferably at least 3.0% by weight and at most 6.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts.

[0035] According to the invention, said composition (D) comprises, relative to the total weight of the composition (D), from 2.0 to 20.0% by weight of ascorbic acid.

[0036] In the context of the present invention the term "ascorbic acid" refers to the organic compound of general formula CeHsOe also known as hexuronic acid. Ascorbic acid exists in two enantiomeric forms (L and D). Preferably, ascorbic acid is the L-enantiomer of ascorbic acid.

[0037] Preferably, said composition (D) comprises, relative to the total weight of the composition (D), at least 3.0% by weight, preferably at least 4.0% by weight, even more preferably at least 5.0% by weight, more preferably at least 6.0% by weight of ascorbic acid.

[0038] Preferably, said composition (D) comprises, relative to the total weight of the composition (D), at most 15.0% by weight, preferably at most 12.0% by weight, even more preferably at most 10.0% by weight, preferably at most 8.0% by weight of ascorbic acid.

[0039] According to a preferred variant of the present invention, said composition (D) comprises, relative to the total weight of the composition (D), at least 3.0% by weight and at most 15.0% by weight, preferably at least 4.0% by weight and at most 12.0% by weight, even more preferably at least 5.0% by weight and at most 10.0% by weight, preferably at least 6.0% by weight and at most 8.0% by weight of ascorbic acid.

[0040] According to the invention, said composition (D) comprises, relative to the total weight of the composition (D), from 0.1 to 5.0% by weight of phytic acid.

[0041] In the context of the present invention the term "phytic acid" refers to inositol hexaphosphate (IP6). However, since IP6 generally does not exist in pure form, the term also encompasses inositol phosphates that are catabolites of IP6, including inositol pentaphosphate (IP5), inositol tetraphosphate (IP4), inositol triphosphate (IP3), inositol diphosphate (IP2) and inositol monophosphate (IP1), their salts and mixtures thereof. The term "phytic acid" does not refer to inositol, the fully hydrolyzed product of phytic acid (IP0). Thus, the term "phytic acid" encompasses catabolites, hydrolysis products, salts and analogs (e.g., esters and salts). As used herein, the terms IP6, IP5, IP4, IP3, IP2, IP1, and their salts, refer to any isomer of that particular inositol phosphate.Furthermore, while IP6, IP5, IP4, IP3, IP2, and IP1 in salt form are typically referred to as "phytates," the term "phytic acid" as used herein also includes these phytates. An example of a counterion of phytate is sodium (such as sodium phytate). However, the counterion may be, for example, calcium, magnesium, iron, copper, or zinc.

[0042] Therefore, the term "phytic acid" as used herein includes both the acid form and the salt form of phytic acid. In some embodiments, the phytic acid is the acid form or combinations of acid forms. In some instances, the phytic acid is the salt form or combinations of salt forms. In some instances, the phytic acid is a combination of the acid form (or combinations of acid forms) and the salt form (or combinations of salt forms).

[0043] Preferably, said composition (D) comprises, relative to the total weight of the composition (D), at least 0.2% by weight, preferably at least 0.3% by weight, even more preferably at least 0.4% by weight, preferably at least 0.5% by weight of phytic acid.

[0044] Preferably, said composition (D) comprises, relative to the total weight of the composition (D), at most 4.0% by weight, preferably at most 3.0% by weight, even more preferably at most 2.0% by weight, preferably at most 1.5% by weight of phytic acid.

[0045] According to a preferred variant of the present invention, said composition (D) comprises, relative to the total weight of the composition (D), at least 0.2% by weight and at most 4.0% by weight, preferably at least 0.3% by weight and at most 3.0% by weight, even more preferably at least 0.4% by weight and at most 2.0% by weight, preferably at least 0.5% by weight and at most 1.5% by weight of phytic acid.

[0046] According to the invention, said composition (D) has a pH of less than 5.0.

[0047] The inventors have surprisingly discovered that the presence of phytic acid in combination with a pH below 5.0 makes it possible to stabilize both cysteamine and ascorbic acid in a composition, and thus produce a depigmentation composition having a potent, rapid and selective activity on melanocytes, while not exhibiting harmful side effects, not having the unpleasant odor characteristic of cysteamine and having an acceptable shelf life.

[0048] Preferably, the pH of composition (D) is at most 4.5, preferably at most 4.0. Preferably, the pH of composition (D) is at least 3.0, preferably at least 3.2.

[0049] According to a preferred variant of the invention, the pH of composition (D) is at least 3.2 and at most 4.0. Advantageously, the pH of composition (D) is approximately 3.8.

[0050] According to a preferred variant of the invention, composition (D) is buffered using a weak acid present in composition (D). Advantageously, the weak acid comprises citric acid.

[0051] The inventors have surprisingly discovered that the presence of a buffer makes it possible to maintain the pH of the composition (D) according to the invention at acceptable values, even after its application to the area to be treated in the subject. Thus, the composition (D) maintains its pleasant odor for several hours after application. In contrast, the compositions of the prior art are not buffered and must be washed off the treated area quickly (so-called "fleeting" applications) after application in order to avoid the development of the unpleasant odor characteristic of the degradation of L-cysteamine. The composition (D) according to the invention therefore has great stability after application to the area to be treated, in particular great cutaneous stability.

[0052] According to the invention, said composition (D) is in the form of a serum. In the context of the present invention, the term "serum" refers to an essentially liquid composition having the capacity to be easily absorbed by the skin. Typically, serums are marketed in the form of bottles equipped with a dropper.

[0053] Unlike creams or ointments, serums allow better skin penetration of active ingredients.

[0054] According to a preferred variant of the invention, said composition (D) in the form of a serum comprises, relative to the total weight of said composition (D): from 3.0 to 6.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts, from 6.0 to 8.0% by weight of ascorbic acid, and from 0.5 to 1.5% by weight of phytic acid, in which the pH of said composition is between 3.2 and 4.0.

[0055] Advantageously, said composition (D) further comprises, relative to the total weight of said composition (D), from 1.0 to 20.0% by weight of an extract of Ginkgo biloba leaves.

[0056] In the context of the present invention, the term "Ginkgo biloba leaf extract" corresponds to its usual meaning known in the prior art. In general, a Ginkgo biloba leaf extract can be obtained by extraction using an organic solvent (such as propylene glycol and / or ethanol) from Ginkgo biloba leaves. The extraction process may also contain additional steps. Generally, Ginkgo biloba leaf extracts are rich in flavone glycosides and terpene lactones, and contain bilobalides, Ginkgolides (A, B and C), quercetin and kaempferol.

[0057] Extracts are generally obtained by extraction using a solvent and are then concentrated and / or dried. Therefore, in the context of the present invention, the term "extract" includes both solid and liquid extracts. Preferably, the Ginkgo biloba leaf extract is a liquid extract.

[0058] Advantageously, said composition (D) comprises, relative to the total weight of the composition (D), at least 2.0% by weight, even more advantageously at least 4.0% by weight, even more advantageously at least 5.0% by weight of an extract of Ginkgo biloba leaves.

[0059] Advantageously, said composition (D) comprises, relative to the total weight of the composition (D), at most 15.0% by weight, even more advantageously at most 12.0% by weight, even more advantageously at most 10.0% by weight of an extract of Ginkgo biloba leaves.

[0060] According to a preferred variant of the invention, said composition (D) comprises, relative to the total weight of said composition (D), from 5.0 to 10.0% by weight of an extract of Ginkgo biloba leaves.

[0061] According to a preferred variant of the invention, said composition (D) in the form of a serum comprises, relative to the total weight of said composition (D): from 3.0 to 6.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts, from 6.0 to 8.0% by weight of ascorbic acid, from 0.5 to 1.5% by weight of phytic acid, and from 5.0 to 10.0% by weight of an extract of Ginkgo biloba leaves, in which the pH of said composition is between 3.2 and 4.0.

[0062] Advantageously, said composition (D) further comprises, relative to the total weight of said composition (D), from 0.1 to 5.0% by weight, more advantageously from 0.3 to 3.0% by weight, even more advantageously from 0.5% to 2.0% by weight of a depigmenting peptide. Advantageously, said depigmenting peptide is acetyl glycyl beta-alanine.

[0063] Advantageously, said composition (D) further comprises, relative to the total weight of said composition (D), from 10.0 to 60.0% by weight, more advantageously from 20.0 to 50.0% by weight, even more advantageously from 30.0% to 40.0% by weight of a thickener. Advantageously, said thickener is propylene glycol and / or a polyethylene glycol ether of glycerin.

[0064] Advantageously, said composition (D) further comprises, relative to the total weight of said composition (D), from 5.0 to 30.0% by weight, more advantageously from 10.0 to 20.0% by weight, even more advantageously from 12.0% to 18.0% by weight of water.

[0065] Advantageously, said composition (D) further comprises, relative to the total weight of said composition (D), from 10.0 to 40.0% by weight, more advantageously from 12.0 to 30.0% by weight, even more advantageously from 15.0% to 25.0% by weight of a water-miscible organic solvent. Advantageously, said water-miscible organic solvent is isopentyldiol and / or ethoxydiglycol.

[0066] Advantageously, said composition (D) further comprises, relative to the total weight of said composition (D), from 0.1 to 50% by weight, more advantageously from 0.2 to 3.0% by weight, even more advantageously from 0.5% to 2.0% by weight of a silicone emollient agent. Advantageously, said silicone emollient agent is PEG-8 dimethicone.

[0067] Advantageously, said composition (D) further comprises, relative to the total weight of said composition (D), from 0.1 to 50% by weight, more advantageously from 0.2 to 3.0% by weight, even more advantageously from 0.5% to 2.0% by weight of an alkanolamine. Advantageously, said alkanolamine is aminomethyl propanol.

[0068] According to a preferred variant of the invention, the composition (D) according to the invention is intended for topical administration, preferably on the skin and / or hair.

[0069] In another aspect, the present invention relates to the composition (D) according to the invention for use as a medicament.

[0070] All the definitions, preferences and preferred aspects described above for the composition (D) according to the invention also apply mutatis mutandis to its use as a medicament.

[0071] Advantageously, the composition (D) according to the invention is used in the treatment and / or prevention of at least one skin pigmentation disorder, preferably a skin pigmentation disorder linked to excessive production of melanin and / or an abnormally high number of melanocytes.

[0072] Thus, the present invention therefore relates to the composition (D) according to the invention for use in the treatment and / or prevention of at least one pigmentation disorder. In particular, the pigmentation disorder, such as non-cosmetic conditions, lesions or damages, are linked to excessive production of melanin or an abnormally high number of melanocytes.

[0073] According to another aspect, the present invention also relates to a method for reducing and / or preventing at least one pigmentation disorder, comprising topical administration of the depigmentation composition (D), to a subject in need thereof.

[0074] Many skin pigmentation disorders are characterized by increased production and / or accumulation of melanin. Ultraviolet light, hormones, chronic inflammation, friction, and abnormal production of alpha melanoctye stimulating hormone (alpha-MSH) are triggers for such disorders.

[0075] Non-limiting examples of such pigmentation disorders include, but are not limited to, hyperpigmentation, melasma, post-inflammatory hyperpigmentation, radiodermatitis, solar or senile lentigo, light-induced hyperpigmentation, and chemical exposure-induced hyperpigmentation.

[0076] The inventors have surprisingly discovered that such pigmentation disorders can be effectively treated by the complex or composition according to the invention, and with an activity superior to that of the gold standard in the field, hydroquinone.

[0077] In another aspect, the present invention relates to the non-therapeutic, cosmetic use of the composition (D) according to the invention for reducing normal pigmentation of the skin and / or hair.

[0078] In the context of the present invention, the expression "normal pigmentation of the skin and / or hair" refers to healthy skin and / or healthy hair, not exhibiting a pigmentation disorder.

[0079] The inventors have in fact surprisingly discovered that the general appearance of a subject can be improved following the use of composition (D) according to the invention.

[0080] Composition (D) according to the invention can be used to make hair lighter compared to the natural hair color. For example, it can make hair brown, red or blond compared to the natural hair color.

[0081] Said composition (D) according to the invention can be used to reduce normal pigmentation of the skin and / or hair, preferably the skin and / or hair of the face.

[0082] Said composition (D) according to the invention can be used for treating and / or preventing dark circles. According to another aspect, the present invention also relates to a method for reducing normal pigmentation of the skin and / or hair, comprising the topical administration of the depigmentation composition (D), to a subject in need thereof.

[0083] All the definitions, preferences and preferred aspects described above for the composition (D) according to the invention also apply mutatis mutandis for their non-therapeutic use in reducing the natural pigmentation of the skin and / or hair.

[0084] The present invention further relates to a method for producing said composition (D) according to the invention, said method comprising the steps of: contacting from 1.0 to 20.0% by weight of ascorbic acid, preferably from 2.0 to 20.0% by weight of ascorbic acid; and from 0.5 to 2.0% by weight of phytic acid, relative to the total weight of said composition, so as to obtain a first mixture, and contacting said first mixture with from 0.2 to 20.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts.

[0085] All the definitions, preferences and preferred aspects described above for the composition (D) according to the invention also apply mutatis mutandis to the method of producing said composition.

[0086] The invention will now be described in more detail with reference to the following examples, which detail non-limiting illustrations of different aspects of the invention. Preparation of a depigmentation composition (D) according to the invention.

[0087] A depigmentation composition (D) according to the invention was prepared by mixing the different ingredients listed in Table 1, below. The formulation of the composition is detailed below and is in the form of a serum. Table 1

[0088] The citrate buffer consists of a mixture of 0.7 M citric acid and 0.7 M trisodium citrate. The pH of composition (D) is measured at 3.8.

[0089] Ginkgo biloba leaf extract is a brownish liquid composed of 75.0% propylene glycol and 25.0% dry Ginkgo biloba leaf extract. The specifications of said dry Ginkgo biloba leaf extract are shown in Table 2 below.

[0090] Table 2

[0091] Cysteamine is a very smelly compound that gives a rotten egg odor to cosmetic formulations containing it. Although some formulations containing cysteamine with reduced odor exist, they still have a certain odor that is unpleasant for users. In contrast, composition (D) above produces no odor, which is a distinct advantage over other topical formulations containing cysteamine.

[0092] Example 2: Evaluation of the stability of composition (D) according to the invention.

[0093] The stability of composition (D) described in Example 1 is evaluated over a period of 6 months.

[0094] A calibration curve was performed by dissolving cysteamine hydrochloride in milliQ water at concentrations of 0.1, 0.2, 1.0, and 2.0 mg / mL. The calibration curve was performed from these four points by plotting the areas under the peaks measured in HPLC at 215 nm as a function of the mass of cysteamine injected onto the HPLC column and the concentrations of the standards, respectively. Each standard solution was analyzed three times in HPLC to perform an average over the integrations of the area under the signal corresponding to cysteamine.

[0095] A sample of composition (D) of 136.9 mg was weighed into a 10 mL flask and then diluted in 5 mL of milliQ water. The resulting aqueous solution was transferred into a separating funnel and the aqueous phase was washed twice with 2 mL of diethyl ether. The aqueous phase was recovered and centrifuged for 10 minutes at 4,500 rpm. Finally, 1 mL of the centrifuged solution was placed in a pillbox for HPLC analysis.

[0096] The conditions of the analysis are as follows:

[0097] - Equipment: Agilent 1100 series HPLC connected to a DAD detector Column: Agilent Eclipse Plus C18 (3.5 pm) - 4.6 x 100 mm Flow: 1.0 mL / min Injection volume: 2 pL

[0098] Eluent: H2O / CH3CN - 85 / 15 (v / v). The mobile phase is an aqueous solution (4mM) of sodium 1-heptanesulfonate containing 0.1% by weight of HCOOH

[0099] Column temperature: 40°C

[0100] Selected wavelengths: 215 nm and 254 nm

[0101] The cysteamine content in composition (D) was evaluated over a period of 6 months. For this purpose, the amount of cysteamine was measured at regular intervals. Stability was evaluated under normal storage conditions (25°C and 60% relative humidity).

[0102] The results of these experiments are shown in Table 3, below.

[0103] Table 3

[0104] The results obtained demonstrate that the composition (D) according to the invention has a compliant quantity of cysteamine (> 90%) over the entire duration of the stability study, i.e. 6 months under commercial conditions. Furthermore, over the entire duration of the test, no alteration of the color or odor of the composition (D) could be observed. These observations are surprising given that cysteamine and ascorbic acid are generally oxidized within a few hours in cosmetic formulations of this type.

[0105] Clinical evaluation of the depigmentation activity of composition (D) according to the invention on melasma in comparison with a serum dosed at 4% hydroquinone.

[0106] The treatment of choice (gold standard) for skin pigmentation disorders is hydroquinone, usually dosed at 4%. These experiments aim to compare the efficacy of composition (D) with a serum dosed at 4% hydroquinone in a clinical group with a randomized, double-blind hemifacial application.

[0107] This hemifacial clinical trial is conducted on subjects aged 20 to 70 years, phototypes II, III or IV and completed by subjects of phototypes V and VI. Composition (D) is applied to the right side of the face and the serum dosed at 4% hydroquinone on the left side of the patient. The results are evaluated 3 times by a practitioner on days 0, 60 and 120 with standard photographs, Wood lamp photographs, and colorimetry for the mMasi and MELASqol indices. The Global Aesthetic Improvement Scale is also used to evaluate the difference in skin appearance using standardized photographs. This study is conducted in the Northern Hemisphere.

[0108] Exclusion criteria are pregnancy, sensitivity to some of the active ingredients, facial skin conditions (skin infections, eczema, psoriasis, rosacea, herpes, etc.) or severe allergies.

[0109] The products are applied once a day, in the evening, to the specified area. The treated area is not washed after application. 20 patients are enrolled in the study, for a duration of 4 months.

[0110] Each operator receives two batches of twenty treatments each for twenty patients labeled "Right Side Product" and "Left Side Product." They give the patient an evaluation sheet and a treatment kit. They complete the practitioner's observation sheet themselves.

[0111] The practitioner takes a photo of the face and performs a colorimetric assessment of the visits, the day of the start (T0 marking), after 2 months (T60 marking) and a final photo after 4 months of intervention (T120 marking). The photographs are both standard and under Wood light to classify the melasma between superficial, medium, and dermal.

[0112] A fragrance-free moisturizing preparation called is provided to each patient and a 50+ SPF sunscreen is used each morning.

[0113] All the data collected demonstrate that treatment with composition (D) reduces hyperpigmentation (mMasi and MELASqol indices) of the skin evenly and without side effects, with superior performance to the reference treatment with hydroquinone and other alternatives containing cysteamine. Furthermore, the odor of the product remains acceptable over the duration of the study, despite the fact that composition (D) is not washed off after application to the treated area. Comparative tests of compositions according to the invention with the compositions described in document CH706226B1. a) The following compositions were compared in terms of stability over time:

[0114] Formulation according to example 1 of document CH706226B1: 3% L-cysteamine + 1% sodium ascorbyl phosphate + 0.5% citric acid + 95.5% water;

[0115] Formulation according to the invention: 3% L-cysteamine + 1% ascorbic acid + 0.5% phytic acid + 95.5% water.

[0116] An HPLC analysis was carried out starting from 1 mL of each of the formulations with the same apparatus and according to the same parameters as those described in example 2. The results obtained are presented in table 4 below. Table 4

[0117] As can be seen, a formulation (composition) according to the invention has increased stability compared to that determined for a formulation according to example 1 of document CH706226B1.

[0118] Note that for the formulation according to example 1 document CH706226B1 the degradation product of cysteamine, namely cystamine, was systematically detected. On the contrary, for the formulation according to the invention, no trace of cystamine was detected, which confirms the stability of a formulation (composition) according to the invention compared to those described in the state of the art. b) The following compositions were compared in terms of stability over time:

[0119] Formulation according to example 2 of document CH706226B1: 4.8% L-cysteamine + 0.5% sodium ascorbyl phosphate + 0.5% ascorbyl palmilate + 0.2% glycolic acid + 94% water;

[0120] Formulation according to the invention: 4.8% L-cysteamine + 1% ascorbic acid + 0.2% phytic acid + 94% water.

[0121] An HPLC analysis was carried out starting from 1 mL of each of the formulations with the same apparatus and according to the same parameters as those described in example 2. The results obtained are presented in table 5 below. Table 5

[0122] As can be seen, a formulation (composition) according to the invention has increased stability compared to that determined for a formulation according to example 2 of document CH706226B1.

[0123] Note that for the formulation according to example 2 document CH706226B1 the degradation product of cysteamine, namely cystamine, was systematically detected. On the contrary, for the formulation according to the invention, no trace of cystamine was detected, which confirms the stability of a formulation (composition) according to the invention compared to those described in the state of the art. c) The following compositions were compared in terms of stability over time:

[0124] Formulation according to example 3 of document CH706226B1: 8% L-cysteamine + 1% sodium ascorbyl phosphate + 1.5% ascorbyl palmilate + 0.5% lactic acid + 89% water;

[0125] Formulation according to the invention: 8% L-cysteamine + 2.5% ascorbic acid + 0.5% phytic acid + 89% water.

[0126] An HPLC analysis was carried out starting from 1 mL of each of the formulations with the same apparatus and according to the same parameters as those described in example 2. The results obtained are presented in table 6 below. Table 6

[0127] As can be seen, a formulation (composition) according to the invention has increased stability compared to that determined for a formulation according to example 3 of document CH706226B1.

[0128] Note that for the formulation according to example 3 document CH706226B1 the degradation product of cysteamine, namely cystamine, was systematically detected. On the contrary, for the formulation according to the invention, no trace of cystamine was detected, which confirms the stability of a formulation (composition) according to the invention compared to those described in the state of the art.

Claims

Claims 1. Depigmentation composition [composition (D), hereinafter] in the form of a serum comprising, relative to the total weight of composition (D): - from 0.2 to 10.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts; - from 1.0 to 20.0% by weight of ascorbic acid, preferably from 2.0 to 20.0% by weight of ascorbic acid; - from 0.1 to 5.0% by weight of phytic acid; and wherein the pH of said composition (D) is less than 5.

0.

2. The depigmentation composition according to claim 1, comprising from 2.0 to 8.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts, relative to the total weight of the composition (D).

3. The depigmentation composition according to any one of the preceding claims, comprising from 5.0 to 10.0% by weight of ascorbic acid, relative to the total weight of the composition (D).

4. The depigmentation composition according to any one of the preceding claims, comprising from 0.4 to 2.0% by weight of phytic acid, relative to the total weight of the composition (D).

5. The depigmentation composition according to any one of the preceding claims, wherein the pH of said composition is between 3.2 and 4.

0.

6. The depigmentation composition according to any one of the preceding claims, comprising relative to the total weight of the composition (D): - from 2.0 to 8.0% by weight of L-cysteamine; - from 5.0 to 10.0% by weight of ascorbic acid; - from 0.4 to 2.0% by weight of phytic acid; and wherein the pH of said composition is between 3.2 and 4.

0.

7. The depigmentation composition according to any one of the preceding claims, further comprising from 1.0 to 20.0% by weight of a Ginkgo biloba leaf extract.

8. The depigmentation composition according to any one of the preceding claims, said composition being intended for topical administration, preferably on the skin and / or on the hair.

9. A depigmentation composition according to any one of the preceding claims, for use as a medicament.

10. The depigmentation composition for use according to claim 9, for use in the treatment or prevention of at least one skin pigmentation disorder.

11. The depigmentation composition for use according to claim 9 or 10, wherein the skin pigmentation disorder is selected from the group consisting of hyperpigmentation, melasma and solar or senile lentigo.

12. Non-therapeutic cosmetic use of a depigmentation composition (D) according to any one of claims 1 to 8 for reducing the natural pigmentation of the skin and / or hair.

13. A method for producing the depigmentation composition (D) according to any one of claims 1 to 8, said method comprising the steps of: (i) contacting from 1.0 to 20.0% by weight of ascorbic acid, preferably from 2.0 to 20.0% by weight of ascorbic acid, and from 0.5 to 2.0% by weight of phytic acid, relative to the total weight of said composition, so as to obtain a first mixture, and (ii) contacting said first mixture with from 0.2 to 20.0% by weight of L-cysteamine or one of its pharmaceutically acceptable salts.

Images