EP1748758A1

EP1748758A1 - Spot-on formulation useful for cosmetology and dermatology

Info

Publication number: EP1748758A1
Application number: EP05770872A
Authority: EP
Inventors: Jean-Claude Allart; Jean-Marie Lefevre; Jacques Peyrot; Jean-Paul Marty
Original assignee: Dermaconcept JMC SARL
Current assignee: Girex SAS
Priority date: 2004-05-12
Filing date: 2005-05-12
Publication date: 2007-02-07
Also published as: FR2870125B1; WO2005115335A1; US20090010968A1; BRPI0510806A; JP2007537214A; IL178889A0; KR20070026580A; FR2870125A1; CA2562565A1

Abstract

The invention relates to a novel formulation useful for cosmetology and dermatology by using the storage capacity of sebaceous glands. The inventive spot-on formulation contains an active lipophilic principle selected from the vitamin A and E, a lipophilic antioxidant agent, ceramides or sphingoid bases and steroid hormones associated with one or several fatty acids unsaturated in C4-C26 and a liquid vehicle having sebaceous tropism. The inventive formulation is usable for local topical administration of the active lipophilic principles.

Description

SPOT-ON FORMULATION USEFUL IN COSMETOLOGY AND DERMATOLOGY.

The present invention relates to a new formulation with sebaceous tropism for localized topical application, useful in the field of cosmetology and dermatology, its use in cosmetics and dermatology as well as the associated cosmetic treatment methods. The sebaceous gland has long been considered by many authors as a fossil gland with the sole function of producing sebum and being involved in the pathophysiology of acne.

L0 Over the past ten years research has again become interested in this problem, which has made it possible to revise the initial derogatory judgment. In the light of this work, clarifications could be made on the important role played by the sebaceous gland

L5 in skin homeostasis. The sebaceous gland is part of a larger, more complex system, the pilosebaceous unit which includes the hair follicle, the excretion canal and the gland itself. This unit reaches its full development in the post-pubertal period under

.0 the influence of adrenal and gonadal hormonal secretions. The sebaceous gland therefore appears as a true secondary sexual organ capable of not only metabolizing a wide variety of androgens, but also, thanks to equipment

_5 specific enzyme, to use cholesterol as a substrate for the synthesis of androgen precursors. In addition, its richness in 5-reductase allows effective use of testosterone. Other hormone receptors are also present (retinoids, thyroid, vitamin D) which regulate its

30 physiological activity. Three successive events characterize it:

tiu ϋ - the holocrine secretion-production of sebum at the end of a 15-day cell cycle leading to the lysis of sebocytes, - the discharge of sebum within the infundibulum of the sebaceous unit, - regular excretion at the surface of the skin and on the hair (100 to 500 μg / cm ² ); it is a real reservoir. The sebum is composed of squalene (15%), waxes (25%) and triglycerides (60%) with completely specific fatty acid chains, genetically determined in their proportions for each individual. The originality of the sebaceous gland in lipid synthesis should therefore be emphasized. Sebum, because of its composition, can be considered as an oil in the physicochemical sense, which indicates a notable influence of the temperature on its flow. The role of sebum is becoming better known. It is involved in the organization of lipids within the stratum corneum and therefore participates in the barrier effect. Waxes reinforce the impermeability of the skin surface. Squalenes participate in UV protection like certain cyto ines which are spilled on its surface. Finally, the specific lipids of sebum, thanks to the action of an endogenous β-desaturase play a role in the modulation of inflammation. In addition, specific regulation of neuropeptides

(neuroendopeptidases) and a selective response to certain hormones, including retinoids, also occur in the sebum. It should also be noted that sebum constitutes the only route of excretion of vitamin E, that, by its supply of glycerol, it participates in skin hydration and, lastly, that it participates in the regulation of the ecosystem. (anti gram + activity of palmitoleic acid isomers). The anatomical position of the pilosebaceous unit places the follicular reservoir at the crossroads of two worlds: one internal and living, the other as an environment carrying germs and oxygen. This explains the constant transformation of the sebum excreted from its storage area, subsequently called the follicular reservoir. Furthermore, this position also makes it a privileged means of excretion of certain exogenous or endogenous molecules and a source of IL 1 alpha cytokines or neuropeptides. Finally, the sebaceous gland plays an important role in cutaneous-canopy homeostasis and in the immune system. In summary, the sebaceous gland simultaneously exhibits secretion and synthesis, storage and finally excretion properties. Numerous cosmetic and dermatological compositions for topical use have been proposed in the art for ensuring skin care in various indications, and for example application WO 0176538 describes a composition for protecting the lips comprising a mixture of lipids chosen from ceramides. , essential fatty acids and non-essential fatty acids. Patent GB 2004 741 relates to a composition for the treatment of alopecia, based on cholesterol, fatty acids and a phospho-aminolipid. The patent FR 2795960 is based on the observation that certain fatty acids can have a relaxing effect on the body, and it describes a stable microemulsion based on fatty acids with free carboxylic acid group which can be administered orally, injectable, topical, etc., for the treatment of anxiety. Another emulsion based on fatty acids is described in US Pat. No. 6,361,806, but this formulation is intended to cross the epidermis. Patent DE 4113346 describes an aqueous hair composition based on phospholipids, oils and alcohols. However, none of the compositions described in the art is suitable for using the properties of the sebaceous glands. Cosmetological or dermatological treatments are often very restrictive and can then lead to a phenomenon of weariness in the patient when the desired improvements are considered too slow to appear. There is therefore an increased need in the cosmetic and dermatological field to find alternative methods of administration, allowing good compliance on the part of the patients. The studies carried out by the applicant have shown that it is possible to use the storage capacity that constitutes the sebaceous gland, and more particularly the follicular reservoir, to release lipophilic active ingredients for a prolonged period. Thus, thanks to the continuous excretion of its content on the surface of the skin, it has been found that it is possible to act, by a gradual release of the active ingredient thus obtained, on a wide variety of skin disorders. To arrive at suitable formulations, the applicant has demonstrated that the vehicle must be compatible with human sebum, present no risk of modifying its physicochemical properties, and be chosen so as to be preferentially absorbed at the level of the sebaceous gland.

The present invention The invention therefore relates to a formulation for localized topical application, comprising an emulsion or saturated solution containing one or more lipophilic active principles, preferably lipidic, in a mixture of solvents comprising one or more unsaturated fatty acids in C ₄ -C ₂₆ and a polar liquid vehicle, with sebaceous tropism. The liquid vehicle preferably comprises a polar organic solvent. The formulation The presence of an unsaturated C ₄ -C ₂₆ fatty acid makes it possible both to ensure better vectorization of the active principle due to its compatibility with the lipids of the sebum and to facilitate the release of the latter during the excretion phase. The unsaturated C ₄ -C ₂₆ fatty acid may contain from 1 to 6 unsaturations, and preferably from 1 to 6 double bonds. It can for example be chosen from butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, acid stearic, oleic acid, sapienic acid, ricinoleic acid, α- and γ-linoleic acid, α- and γ-linolenic acid, steraidonic acid, arachidic acid and acid behenic. These fatty acids can be used individually or as a mixture between them. Sapienic acid is naturally found in abundance in the sebaceous gland in humans. It is a monounsaturated fatty acid having 16 carbon atoms and a single cis double bond at the ^6th carbon from the carboxyl terminus. The fatty acid and the active principle are preferably dissolved in an organic solvent to ensure preferential absorption in the sebaceous gland. Mention may be made, as preferred fatty acid, of sapienic acid, linolenic acid and linoleic acid. Linoleic acid, more precisely α- or γ-linoleic acid, is preferred. The present invention relates to a sebaceous tropism formulation which can advantageously be in the form of a simple solution, preferably anhydrous, or of a simple emulsion or of an emulsion of quaternary type, saturated with active principle. When it is in the form of a simple anhydrous oily solution, saturated with active principle, the vehicle is essentially composed of fatty acid and a polar organic solvent. When it is in the form of a quaternary type emulsion, typically a microemulsion, saturated with active principle, the polar liquid vehicle is a quaternary system comprising a hydrophilic phase, an oily phase, a surfactant and a cosurfactant. Such a microemulsion is liquid, translucent, and isotropic. In both cases, the formulation optionally contains a crystallization inhibitor and / or an antioxidant and / or any other excipient compatible with the mode of administration used according to the present invention, as detailed below. A “formulation for localized topical application” is also commonly called a “Spot-on” type formulation; the two terminologies can be used interchangeably in the context of the present invention; they mean that they are intended to treat, by means of a targeted application of the active principle, precise cutaneous zones, prone to a particular affection of the skin. This type of formulation, well known in the field of veterinary medicine, is characterized by the fact that the application of a single dose, typically of a single drop, without spreading, of said formulation to the skin allows, thanks to a phenomenon of dispersal, reaching a large amount of sebaceous glands from the affected area. Thus, a spot-on formulation containing a combination of 1-N-phenylpyrazoles and endectocidal macrocyclic lactones, useful for combating parasites in the field of veterinary medicine is described in US Pat. No. 6,426,333. After application of a spot-on type formulation according to the present invention, the active principle is stored in the sebaceous glands, and more particularly in the follicular reservoir, then gradually released into the sebaceous flow on the stratum corneum, according to the rhythm physiological excretion of the sebaceous glands. More specifically, the formulation according to the present invention has in particular the advantage of allowing easy incorporation of the lipophilic active principle into the follicular reservoir of the pilosebaceous unit and then of allowing not only a regular distribution of the active principle on the skin but also a release. spread over time of the active ingredient. In this way, the active ingredient can then exert a targeted action on the skin at the level of the stratum corneum. The formulations according to the present invention do not target the passage of the skin barrier. In other words, the passage through the blood is very limited. Of course, the cosmetic and / or dermatological treatment objectives vary depending on the active ingredient used. Thus, thanks to the formulations according to the present invention, it is possible to treat, separately or simultaneously, the skin conditions directly linked to dysregulations of the sebaceous glands themselves or even any other skin condition, provided that there is a lipophilic active ingredient to treat it. It is clearly understood in the latter case that the sebaceous glands are used exclusively as a storage reservoir for a slow release of the active principle at the level of the stratum corneum. This is the case, for example, when the active principle is a ceramide or one of its precursors, as indicated below. Thus, among the conditions linked to a dysregulation of the sebaceous glands, we find deficits or excess of sebaceous secretion. The deficit in sebaceous secretion can come from aging of the skin and result from localized atrophy conditions; excess, that is to say seborrhea, can be a source of acne or inflammatory dermatitis such as seborrheic dermatitis. The active ingredients suitable for the formulation Any active ingredient having lipophilic properties can be used, and preferably a lipid active ingredient. Mention may in particular be made of the following lipophilic active principles, suitable for the formulation according to the present invention: any fat-soluble vitamin, such as vitamin A and its derivatives, vitamin E and its derivatives; any lipophilic anti-radical agent; ceramides or their sphingoid base type precursors such as sphingosine or phytosphingosine; steroid hormones, such as estrogen or progesterone, and essential fatty acids, such as linoleic acid and linolenic acid. The natures and roles of the various active ingredients listed above are described below: Vitamin A, also known under the name of retinol, is a substance extremely used in cosmetology in particular because of its major physiological function, particularly in the regulation proliferation and differentiation of a number of cell types. It is known in particular that the topical application of retinol stabilizes the balance of vitamin A in the skin and that this balance can be altered in particular by exposure to UV light. Thus, vitamin A deficiency leads in particular to an increase in the formation of wrinkles, especially in the event of overexposure to the sun ("photoaging"). Insufficient vitamin A also leads to a loss of skin elasticity and weakens the barrier function of the skin against microorganisms. Finally, retinol is commonly used in the treatment of acne. Advantageously, vitamin A can be used in its natural form (retinol) or in the form of its acid (retinoic acid) or alternatively retinyl acetate, retinaldehyde, β-carotene or retinyl palmitate, in the context of the present invention. Vitamin E and its derivatives are substances which, by virtue of their presumed properties as anti-free radicals (free radical suppressants), are widely used in cosmetology and dermatology. Vitamin E, also called tocopherol, can advantageously be incorporated into the formulation according to the present invention pure (natural form) or in the form of an ester and in particular in the form of tocopherol acetate, tocopherol linoleate or tocopherol succinate . Mention may also be made, as lipophilic anti-radical agent, of lipoic acid derivatives, andrographolides, of lipophilic vitamin C derivatives such as esters, for example palmitate and ascorbyl stearate. Phytosphingosine and sphingosine, precursors of ceramides, present in human skin, have inhibitory properties of protein kinase C. These molecules also seem to be involved in the differentiation of keratinocytes of the epidermis. It has also been observed that sphingosines present in the stratum corneum and other layers of the epidermis inhibit the growth of certain undesirable microorganisms. They thus find their application in particular in the treatment of acne, seborrheic dermatitis and hyper-seborrhea. The sphingoid bases used in the formulations of the present invention can be obtained by known methods from various suitable sources, for example from natural sources or by chemical synthesis or by fermentation. Chemical synthesis methods are generally relatively expensive and do not always make it possible to obtain the sphingoid bases having the desired stereochemical configurations. The sphingoid bases can also be obtained from animal or plant tissues by extraction and purification, but these methods are generally Lely expensive and animal sources do not always have the desired bacteriological qualities. This is why the sphingoid bases used in the invention are preferably prepared by microbial fermentation, for example from a yeast such as Pichia ciferii, and the phytosphingosine obtained in this way has the advantage of being very close to that of the animal's skin. According to a preferred embodiment of the invention, as the sphingoid base, the phytosphigosine obtained from tetra-acetyl-phytosphingosine (TAPS) derived from Pichia ciferii by deacetylation is used. The deacetylation reaction can be carried out by chemical reaction, for example by hydrolysis in the presence of potassium hydroxide, or by enzymatic reaction. To obtain a high purity phytosphingosine, it is preferable to carry out a purification at the outlet of hydrolysis. Any purification method known in the art may be suitable. In the context of the present invention, the sphingoid base is advantageously chosen from sphingosine, sphinganine, phytosphingosine, tetracetylphytosphingosine, N-acetylphytosphingosine, phytosphingosine hydrochloride and phytosphingosine salicylate. Steroid hormones such as estrogens, antiandrogens or progesterone are known for their ability to combat certain forms of seborrhea, Fox and Fordyce disease, androgenic alopecia, acne and hirsutism.

The components of the formulation The formulation can be presented either in the form of a simple oily solution, or in the form of a simple or quaternary emulsion, the formulation being in both cases saturated with lipid active principle. It comprises, in addition to the fatty acid, a polar organic solvent which can be any polar organic solvent generally acceptable in a formulation for topical application, known to those skilled in the art. As polar organic solvents, acetone, ethyl acetate, methanol, ethanol, isopropanol, dimethylformamide, diethylene glycol, dichloromethane, monoethyl ether of diethylene glycol (Transcutol) can be used in particular. ). A solvent capable of facilitating or improving the penetration of the active ingredients into the skin can also be advantageously used in the compositions of the invention, and for example a non-ionic amphiphilic glycerol derivative such as 1, 2-O -isopropylidene glycerol (Solketal). These solvents can be supplemented with various excipients depending on the nature of the phases desired, such as the caprylic triglyceride / C8-C10 caprate (Estasan or Miglyol 812), or oleic acid. In the context of the present invention, use is preferably made of Transcutol and Solketal, known for their high non-selective lipophilicity. In the case of a simple solution, a volatile cosolvent can advantageously be associated with the main solvent, and for example an alcohol such as ethanol and glycol, to facilitate drying after application, and cause oversaturation of the active principle. In the case of a simple or quaternary emulsion, the formulation comprises an oily phase and a hydrophilic phase. This cosolvent can be non-polar and be constituted for example by linoleic acid. When applied to the skin, in contact with the stratum corneum in an area comprising sebaceous glands, the difference in partition coefficients existing between the supersaturated vehicle and the stratum corneum creates a diffusion of the lipid active principle towards the sebaceous lipids and its storage in the sebaceous glands. The anhydrous nature of the composition of the invention promotes its stability over time. However, in the case of emulsions an aqueous phase may be present but the water does not represent more than 5% by weight relative to the total weight of the composition. The oily phase is formed by the lipophilic active principle dissolved in the unsaturated fatty acid (s) in CC ₂₆ , optionally supplemented with mineral oils or vegetable oils, unsaturated polyglycosylated glycerides or triglycerides, or alternatively mixtures of such compounds. The hydrophilic phase can in particular be formed from glycol derivatives in general, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. Propylene glycol, diethylene glycol, monoethyl ether of diethylene glycol and monoethyl ether of dipropylene glycol are particularly preferred. The surface-active agents for the microemulsion can be chosen from monoethyl ether of diethylene glycol, monomethyl ether of dipropylene glycol, polyglycolysed Cβ-Cio glycerides and polyglyceryl 6-dioleate. More particularly when the formulation according to the present invention is in the form of a microemulsion, it is characterized by a stable dispersion of micro-droplets of the oily phase in the aqueous phase, or conversely of micro-droplets of the aqueous phase in the oily phase. The size of these micro-droplets is less than 200 nm (1,000 to 100,000 nm for emulsions). The interfacial film consists of an alternation of surfactant molecules (TA) and Co-surfactants (CoTa) which, by lowering the interfacial tension, allow the spontaneous formation of the microemulsion. In the microemulsion, the oily phase is present in a content which can be between 2 and 15%, more particularly between 7 and 10%, and preferably between 8 and 9% relative to the total volume of the formulation. Generally, the aqueous phase is present in a content which can be between 1 and 4% relative to the total volume of the formulation. The microemulsion preferably contains from 25 to 75% surfactant and 10 to 55% cosurfactant relative to the total volume of the formulation. Furthermore, the cosurfactant to surfactant ratio is preferably between 1/7 and 1/2. Thus the cosurfactants can be chosen from short-chain alcohols, such as ethanol and glycol. Some compounds are common to the three components discussed above, ie, hydrophilic phase, surfactant and cosurfactant. The crystallization inhibitor can prove to be very advantageous when there is a risk of crystallization of an active principle. It is then useful so that the active principle reaches the follicular reservoir easily, but also so that the release phase is facilitated, that is to say so that the active principle is effectively soluble in the sebum. The crystallization inhibitor can in particular be present in a content of 1 to 20% by weight relative to the total volume of the formulation, preferably from 5 to 15%. The crystallization inhibitors which can be used in the invention include: - polyvinylpyrrolidone (PVP), polyvinyl alcohols, copolymers of vinyl acetate and of vinyl pyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylene sorbitan esters; lecithin, sodium carboxymethyl cellulose; acrylic derivatives such as methacrylates and others; - anionic surfactants, such as alkali stearates, in particular sodium stearate, potassium stearate or ammonium stearate; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; dodecylbenzenesulfonate sodium, sodium dioctylsulfosuccinate; fatty acids, in particular those derived from coconut oil; cationic surfactants, such as the water-soluble quaternary ammonium salts represented by the formula N ⁺ RιR ₂ R ₃ R, Y ^" in which the radicals Ri to R ₄ , identical or different, are hydrocarbon radicals, optionally hydroxylated, and Y ^" is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyl trimethyl ammonium bromide is one of the cationic surfactants which can be used; - the amine salts of formula N ⁺ R 'R''R''' in which the radicals R, identical or different, are hydrocarbon radicals, optionally hydroxylated; octadecylamine hydrochloride is one of the cationic surfactants which can be used; - nonionic surfactants such as sorbitan esters, optionally polyoxyethylenated, in particular Polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenate derivatives of castor oil, polyglycerol esters, polyoxyethylenate fatty alcohols, polyoxyethylenate fatty acids, copolymers of ethylene oxide and propylene oxide; - amphoteric surfactants such as substituted lauryl compounds of betaine; - Or preferably a mixture of at least two of the compounds listed above. The formulation may also include an antioxidant intended to avoid any lipoperoxidation, this agent being in particular present in a content of between 0.005 to 1% (W / V), preferably between 0.01 to 0.05%. Any conventional antioxidant can be used for those skilled in the art. Mention may in particular be made of butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate or a mixture of not more than two of them. The components described above, useful for preparing the liquid vehicle of the formulation according to the present invention, are well known to those skilled in the art and can be obtained commercially or by known techniques. The formulations according to the present invention are generally prepared by the simple mixing of the components described above; advantageously, one begins by mixing the active principle in the organic solvent, and then the other components are added.

Application of the formulation The formulations according to the invention are extremely effective for long periods of time in the various treatments described above. The formulations according to the present invention can be packaged in bottles with suitable applicators. Typically the formulation can be applied in the form of one or more drops to be distributed over the areas to be treated. The dosage is adapted according to the active ingredient used and the condition to be treated. For example, it can be between 10 and 25 drops applied to the face, in the case of retinoic acid in 0.5% solution. It can also be noted that the flow of the sebum excretion phase depends on the temperature. This parameter can be advantageously used when seeking to administer a lipophilic anti-radical agent. Indeed, the temperature having a fluidifying effect on the sebum, the anti-free radical agent can be released more quickly when the skin is exposed to the sun. Use of the formulation The invention relates to a method of cosmetic treatment of the skin intended for the treatment or prevention of skin damage associated with aging of the skin which may consist of a loss of firmness of the skin, of the skin tone and the appearance of fine lines and wrinkles, consisting in applying to the affected areas of the skin a formulation according to the present invention containing vitamin A, for example in the form of retinyl acetate, retinyl palmitate, retinoic acid, retinaldehyde or β-carotene. The invention also relates to a cosmetic treatment method for the skin intended for the treatment or prevention of skin damage associated with photoaging of the skin, comprising applying to the affected areas of the skin a formulation according to the present invention containing vitamin A, for example in the form of retinyl acetate, retinyl palmitate, retinoic acid, retinaldehyde or β-carotene, vitamin E, for example in the form of tocopherol acetate or tocopherol succinate, or any lipophilic anti-free radical agent, for example in the form of lipoic acid, andro-grapholides, esters of vitamin C such as palmitate and ascorbyl stearate. In addition, the invention relates to a method of cosmetic treatment of the skin intended for exfoliation or peeling thereof, consisting in applying to the skin a formulation according to the present invention containing concentrated retinoic acid, preferably between 0, 1 and 1%. In addition, the invention relates to a spot-on type formulation according to the present invention for its use as a dermatological composition for human medicine. More particularly, the invention relates to: - a spot-on type formulation according to the present invention, comprising vitamin A, a steroid hormone dienne, a ceramide or one of its precursors of sphingoid base type or else an essential fatty acid, for its use as a dermatological composition intended for treating acne, - a formulation of spot-on type according to the present invention, comprising a ceramide or one of its precursors of sphingoid base type or else a steroid hormone, for its use as a dermatological composition intended for treating seborrhea, - a formulation of spot-on type according to the present invention, comprising a ceramide or one of its sphingoid base precursors or an essential fatty acid, for its use as a dermatological composition intended for treating seborrheic dermatitis, - a formulation of spot-on type according to the present invention, comprising vitamin E , vitamin A or glycerol, for its use as a dermatological composition intended to treat sebaceous deficit, - a formulation of spot-on type according to the present invention, comprising a steroid hormone for anti-inflammatory purposes, for its use as a dermatological composition intended to treat Fox and Fordyce disease, or an anti-androgenic hormonal substance in the context of androgenic alopecia and hirsutism, - a spot-on formulation according to the present invention, comprising a ceramide or one of its precursors of sphingoid base type, for its use as a dermatological composition intended for treating chronic folliculitis of leather scalp, - a spot-on type formulation according to the present invention, comprising an essential fatty acid, for its use as a dermatological composition intended for treating ichthyosis in its localization in the scalp. a spot-on type formulation according to the present invention, comprising a kojic acid ester, a licorice extract, a steroid hormone, vitamin A or else a ceramide or one of its sphingoid base type precursors, for its use as a dermatological composition intended to treat actinic lentigos, pigmentary disorders linked to aging and hypermelanosis. In addition, the invention relates to the use of a lipophilic active principle for cutaneous use for the preparation of a formulation for localized topical application in humans, intended to be absorbed by the sebaceous glands and then gradually released into the time by the latter on the stra tum corneum, according to its secretory flow. The invention relates to the use of an active principle chosen from vitamin A, for example in pure form (retinol) or in the form of retinyl acetate, palmitate or retinyl of retinoic acid, retinaldehyde or β - carotene; steroid hormones, for example estrogens, progesterone and antiandrogens; ceramides or their precursors such as sphingoid bases, for example sphingosine, sphinganine, phytosphingosine, tetracetylphytosphingosine, N-acetylphytosphingosine, phytosphingosine hydrochloride and phytosphingosine salicylate; essential fatty acids, for example linoleic acid and linolenic acid, for the preparation of a formulation according to the present invention, intended for treating acne. In addition, the invention relates to the use of an active principle chosen from ceramides or their precursors such as sphingoid bases, for example sphingosine, sphinganine, phytosphingosine, tetracetylphytosphingosine, N-acetylphytosphingosine, hydrochloride phytosphingosine and phytosphingosine salicylate; steroid hormones such as estrogen, progesterone or antiandrogens, for the preparation of a formulation according to the present invention, intended for treating seborrhea. The invention also relates to the use of an active principle chosen from ceramides or their precursors such as a sphingoid base, for example sphingosine, sphinganine, phytosphingosine, tetracetylphytosphingosine, N-acetylphytosphingosine, phytosphingosine hydrochloride and phytosphingosine salicylate; essential fatty acids, for example linoleic acid and linolenic acid, for the preparation of a formulation according to the present invention, intended for treating seborrheic dermatitis. In addition, the invention relates to the use of an active ingredient chosen from vitamin E, for example tocopherol acetate, tocopherol succinate; vitamin A, for example retinyl acetate, retinyl palmitate, retinoic acid, retinaldehyde or β-carotene and glycerol, for the preparation of a formulation according to the present invention, intended for treating deficit sebaceous. Another subject of the invention is the use of an active principle chosen from steroid hormones, for example estrogens, progesterone or antiandrogens such as cyproterone or finasteride, for the preparation of a formulation according to the present invention , intended to treat Fox and Fordyce disease, androgenic alopecia or hirsutism. The invention finally relates to the use of an active principle chosen from ceramides or their precursors such as a sphingoid base, for example sphingosine, sphinganine, phytosphingosine, tetracetylphytosphingosine, N-acetylphytosphingosine, hydrochloride of phytosphingosine and phytosphingosine salicylate, for the preparation of a formulation according to the present invention, intended for treating chronic folliculitis of the scalp. The subject of the invention is the use of an active principle chosen from essential fatty acids, for example linoleic acid and linolenic acid, for the preparation of a formulation according to the present invention, intended for treating ichthyosis in its location of the scalp. Finally, the subject of the invention is the use of an active ingredient chosen from kojic acid esters, for example kojic acid dipalmitate; licorice extracts (glabridin); steroid hormones, for example estrogens, progesterone and antiandrogens; vitamin A, for example retinyl acetate, retinyl palmitate, retinoic acid, retinaldehyde and β-carotene; ceramides or their precursors such as a sphingoid base, for example sphingosine, sphinganine, phytosphingosine, tetracetylphytosphingosine, N-acetylphytosphingosine, phytosphingosine hydrochloride and phytosphingosine salicylate, intended for treating actinic lentigos pigmentary disorders linked to aging and hypermelanosis. The examples which follow illustrate the present invention, without however limiting its scope.

Example 1: Study Protocol and Result (10 Cases) for Vitamin A This first example aims to illustrate the relevance of the concept of administration of lipophilic active principles in the follicular reservoirs before their prolonged release, according to the cycle physiological. To affirm this concept:

- The absorption speed of the active ingredient after local application has been determined,

- Its preferential storage at the pilosebaceous unit has been verified,

- Its gradual and continuous release and its duration have been controlled. An original methodology was used. A number of fluorescent lipids having compatibility with sebaceous lipids were selected. The skin was exposed to a Wood lamp. The dispersion surface was thus determined after application of a single dose of the solution to be studied ("cracking effect"). Rate of absorption by the sebaceous gland was also measured. According to a specific protocol for each active ingredient considered, the reality of salting out has been demonstrated by simple fluorescence. A more quantitative approach has also been implemented thanks to the Sebutest, which is intended to measure the sebaceous flow and to collect the sebum for analysis. These parameters make it possible to predict the duration of action of the active ingredient and therefore the dosage to be recommended. Variations in the number of sebaceous glands according to the topography were also taken into account when carrying out studies on different sites. This made it possible to adjust the dosage according to the application site, and the response according to age was evaluated.

IMPLEMENTATION: A comparative study was carried out on two formulations (a control formulation and a formulation according to the invention)

PREPARATION: Vitamin A palmitate 3,000,000 IU BHT 0.10 g PVP 4 g BHA 0.20 g Sodium fluoresceinate 020 g (or nile red 0.20 g) Linoleic acid 5 g Diethylene glycol QS 100 g WITNESS: Sodium Fluoresceinate 0.20 g Alcohol 60 ° QS 100 g

CHOICE OF APPLICATION SITES: Region rich in sebaceous glands: above-mentioned fold, nasogenic fold

Less rich region: forearm (anterior side) Hair region: scalp

PROTOCOL: A comparative study was carried out on symmetrical zones. A drop of 0.4 ml of the product to be studied was deposited on each zone retained. Natural drying was carried out without spreading. We studied - the dispersion by measuring the area covered after 15 minutes - the absorption by degree of fluorescence at 60 minutes and 6 hours - the afterglow by measuring the fluorescence at 24 hours, 48 hours, 96 hours. At the 168 ^th hour, the toilet of the skin or the scalp was done normally while avoiding too powerful surfactants. A surgras toilet roll and a mild shampoo were recommended. The extinction of fluorescence has also been studied. The active has been demonstrated by stripping the epidermis and specific coloring with antimony trichloride which gives a blue coloring under microscopy at 24 hours and 96 hours. Finally, we studied the absorption spectrum (characteristic band at 328 nanometers).

RESULTS: The results are identical in all subjects. The dispersion is better on the hairy areas and on the areas rich in sebaceous glands, it is in all cases greater than the control. The absorption is identifiable from the first hour with a dotted line at the level of the dispersion spot corresponding to the pilosebaceous orifices. This dotted line is not found at the witness level. This aspect is amplified at the 6 ^th hour while the fluorescence of the control spot decreases. The remanence is confirmed by a clear persistence of the fluorescence which is still observed at the 168 ^th hour. There is a total disappearance of the control spot, the remanence is greater on the areas rich in sebaceous glands. Therefore, the presence of vitamin A has been confirmed in the 4 ^th day on all areas and at ^day 7 on hairy areas. The extinction of the fluorescence is greater than a period of 9 days. Example 2: Retinoic acid formulation in a formulation according to the invention Retinoic acid 0.30 g BHT 0.10 g BHA 0.20 g Linoleic acid 5.00 g PVP 4.00 g Transcutol QS 100 g

Efficacy and tolerance study versus 0.1% Locacid® solution 5 patients received the spot-on formulation, the other 5 of Locacid®, the product was applied to the forehead, cheeks, nose wings and chin: only 1 application for the spot on formulation, 1 daily application for Locacid®. The observations were made on D1, D2, D3, D4, D5, D6 and D8. The skin types were identical, namely normal to oily tendency, the patients were between 35 and 50 years old. In patients treated with Locacid®, irritative phenomena with redness, burning sensation and dryness are noted from D2. Stopping treatment was necessary after the ^3rd application in 4 of 5 cases and 4 ^th day for the ^5th patient. In patients treated by the spot-on formulation, a gradual activity is found, without irritative phenomena, and visible as a fine peeling starting ^day 3 to extend to the ^6th day and an overall improvement of the skin surface. This study demonstrates that the spot-on formulation of the invention is superior to Locacid®, that the action is progressive and that it is spread over 8 days under conditions of remarkable tolerance, allowing us to be able to judge the real effects of the product. These findings make it possible to propose a new mode of administration of vitamin A acid (retinoic acid), much more effective than the known proposals available. The ease of treatment with a single application per week is a guarantee of compliance.

Example 3: Other examples of formulations according to the invention and results after treatment Other examples have been carried out to illustrate the variety of treatments which can be envisaged by means of the formulations according to the present invention. Spot-on based on linoleic acid 2 applications per week to treat retentional acne. Aim: correction of deficits in linoleic acid in the sebum of acne patients. The results have been very positive.

Spot-on based on phytosphingosine and linoleic acid versus ketoconazole and local corticosteroids in the management of seborrheic dermatitis. The formulation used was as follows: Salicyloyl phytosphingosine 0.5 G Tocopherol 0.5 G Triglyceride C8-C10 caprylic capric 10.0 ML Ethanol 13.5 ML PVP 5.0 G TWEEN 80 5.0 G TRANSCUTOL 60 ML Propylene glycol QS 100 ML 2 applications per week against a daily application of ketoconazole and local corticosteroids. The results have been very positive. Indeed, the effectiveness of the Spot-on formulation was faster than that based on ketoconazole and local corticosteroids. Thus, the withdrawal of corticosteroids could be facilitated. Furthermore, no rebound was observed when the treatment was stopped.

Spot-on based on phytosphingosine and linolenic acid in chronic scalp folliculitis The formulation used was as follows: Phytosphingosine hydrochloride 0.4 G Linolenic gamma acid 5.0 G Ethanol 20 ML TRANSCUTOL QS 100 ML 2 applications per week. It was observed an outcome from the ^2nd week of treatment.

Spot-on based on licorice extract and linoleic acid in the treatment of actinic lentigos The formulation used was as follows: PT40 (licorice extract) 0.80 G Linoleic acid 5.0 ML Polyglyceryl dioleate 4.5 ML Ethanol 15.0 ML TRANSCUTOL 60.0 ML TWEEN 80 50.0 G PVP 5.0 G Propylene glycol QS 100 ML 1 application every 5 days in the treatment of actinic lentigines of the face. A notable lightening is observed after 4 weeks of treatment.

Spot-on retinoic acid + palmitic acid in the peel versus AHA or trichloroacetic acid The formulation used was as follows: Retinoic acid 0.5 G Palmitic acid 4.0 G PVP 5.0 G BHT 0.1 G BHA 0.2 G TRANSCUTOL QS 100 ML Better results have been observed than with alpha-hydroxy acids (AHA) and equivalent to trichloroacetic acid

30% without social gene or post-peeling pigmentary disorder.

Spot-on tocopherol + palmitoleic acid in sun protection The formulation used was as follows: Alpha tocopherol 1.0 G Palmitoleic acid 5.0 G TWEEN 80 50.0 G PVP 5.0 G Ethanol 10 ML TRANSCUTOL QS 100 ML 1 application per week. There is an increase in natural photoprotection.

Spot-on linoleic acid in ichthyosis of the scalp 2 applications per week. Linoleic acid 5.0 G Tocopherol 0.5 G BHT 0.1 G BHA 0.2 G TWEEN 80 10.0 G Isopropanol 40 ML Diethylene glycol QS 100 ML There is a normalization of the desquamative state.

Claims

1. Spot-on type formulation for localized topical application, characterized in that it comprises an emulsion or saturated solution containing a lipophilic active principle in a mixture of solvents comprising one or more unsaturated C ₄ -C ₂₆ fatty acids and a polar liquid vehicle, with a sebaceous tropism.

2. Spot-on type formulation according to claim

1, characterized in that the active principle is chosen from vitamin A; vitamin E; a lipophilic anti-radical agent; ceramides or sphingoid bases; and steroid hormones.

3. Spot-on type formulation according to claim

2, characterized in that vitamin A is in natural form (retinol), in the form of its acid (retinoic acid) or else retinyl acetate, retinaldehyde, β-carotene or retinyl palmitate; vitamin E is present in pure form or of an ester such as tocopherol acetate, tocopherol linoleate or tocopherol succinate; the lipophilic radical agent is chosen from derivatives of α-lipoic acid, andrographolides, lipophilic derivatives of vitamin C such as palmitate and ascorbyl stearate; the sphingoid base is chosen from sphingosine, sphinganine, phytosphingosine, tetracetylphytosphingosine, N-acetylphytosphingosine, phytosphingosine hydrochloride and phytosphingosine salicylate and the steroid hormones are chosen from estrogens and antiestrogens, progesterone.

4. Spot-on type formulation according to any one of claims 1 to 3, characterized in that the unsaturated C ₄ -C ₂₆ fatty acid is chosen from sapienic acid, linolenic acid and acid linoleic.

5. A spot-on type formulation according to claim 4, characterized in that the unsaturated C ₄ -C ₂₆ fatty acid is α- or γ-linoleic acid.

6. formulation of spot-on type according to any one of claims 1 to 5, characterized in that it is in the form of a simple oily solution, of an emulsion or of an emulsion of quaternary type, saturated active ingredient.

7. Formulation of the spot-on type according to any one of claims 1 to 6, characterized in that it is in the form of a simple anhydrous oily solution, saturated with active principle and in that the polar liquid vehicle comprises an organic solvent.

8. Spot-on type formulation according to claim 7, characterized in that the organic solvent is chosen from acetone, ethyl acetate, methanol, ethanol, isopropanol, dimethylformamide, diethylene glycol, dichloromethane, 1, 2-O-isopropylidene glycerol (Solketal) and the diethylene glycol monoethyl ether (Transcutol).

9. A spot-on type formulation according to any one of claims 1 to 8 for its use as a dermatological composition for human medicine.

10. Use of a lipophilic active principle for cutaneous aiming for the preparation of a formulation for topical application localized in humans intended to be absorbed by the sebaceous glands and then gradually released into the sebaceous flow on the stratum corneum , according to the physiological rhythm of excretion of the sebaceous glands.

11. Use of a lipid active ingredient chosen from vitamin A, steroid hormones, ceramides or their precursors such as sphingoid bases and essential fatty acids, for the preparation of a spot-on type formulation intended for treat acne.

12. Use of a lipid active principle chosen from ceramides or their precursors such as bases sphingoids and steroid hormones, for the preparation of a spot-on type formulation, intended to treat seborrhea.

13. Use of a lipid active principle chosen from ceramides or their precursors such as a sphingoid base and essential fatty acids, for the preparation of a spot-on type formulation intended for treating seborrheic dermatitis.

14. Use of a lipid active principle chosen from vitamin E, vitamin A and glycerol, for the preparation of a formulation of the spot-on type, intended to treat the sebaceous deficit.

15. Use of a lipid active principle chosen from steroid hormones, for the preparation of a spot-on formulation, intended to treat Fox and Fordyce disease, androgenic alopecia or hirsutism.

16. Use of a lipid active principle chosen from ceramides or their precursors such as a sphingoid base, for the preparation of a spot-on type formulation intended for treating chronic folliculitis of the scalp.

17. Use of a lipid active ingredient chosen from essential fatty acids, for the preparation of a spot-on type formulation intended for treating ichthyosis of the scalp.

18. Use of a lipid active principle chosen from kojic acid esters, licorice extract, steroid hormones, vitamin A, ceramides or their precursors such as a sphingoid base, for the preparation of a formulation Spot-on type, intended to treat actinic lentigos, pigmentary disorders linked to aging and hypermelanosis.

19. Use according to any one of claims 10 to 18, characterized in that the spot-on formulation is according to any one of claims 1 to 8.

20. Cosmetic treatment method for the skin, characterized in that it consists in applying to the affected areas of the skin a formulation of the spot-on type according to any one of claims 1 to 8.