WO2000058347A1 - Cosmetic or dermopharmaceutical compositions containing tripeptide n-biotinyl-gly-his-lys for the prevention, reduction or suppression of hair loss and stimulation of regrowth - Google Patents

Abstract

The invention relates to the production of novel tripeptide N-biotinyl-gly-his-lys and the use thereof in cosmetic or dermopharmaceutical compositions. Said tripeptide can be obtained by synthesis, biotechnology or controlled hydrolysis of plant proteins. The inventive compositions are applied topically for the prevention, reduction or suppression of hair loss and to stimulate regrowth.

Description

TITLE Cosmetic or dermopharmaceutical compositions containing the tripeptide N-Biotinyl-Gly-His-Lys, to prevent, reduce or suppress hair loss as well as to promote their regrowth.

The media coverage of our society, through advertising, film and television, increasingly imposes an exacerbated image of bodily youth, and its morphological characteristics, which becomes a kind of ideal, each and everyone try to get closer.

Hair, an important component of this image, is one of the physical characteristics that any individual exhibits in the eyes of others. Indeed, at any age, the ideal appearance of the hair can be altered by many physiological or pathological dysfunctions. The best known example is the gradual and / or local loss of hair, of which baldness is the last step. Men being preferentially affected by baldness at any age, the role of androgen hormones was very quickly suspected and demonstrated (for example Jahoda CA (1998) Exp. Dermatol.l: 235-248) and confirmed by the observed hair loss. in women after menopause and its procession of hormonal disturbances (for example Rubin MB et al. (1997) Postgrad. - -.102.-129-131). Since then, a significant number of physiological or pathological dysfunctions have been identified: psychological stress in both women and men (for example: Cash T.F. (1993) J Am. Acad. Dermatol. 29: 568-

575); consequences of trivial medical acts (e.g. Wise R.P. et al. (1997) J.A.M.A.219: 117-118); genetic factors linked, or not, to other specific pathologies such as the risks of infarction (for example Herrera CR et al. (1995) Am. J. Epidemiol. l42 828.833) or of prostate cancer (for example: Pan HJ. Et al. (1998) Endocrine9: 39-43).

Furthermore, chemotherapy is well known to cause rapid and total alopecia through a mechanism, now identified, which results in an acceleration of apoptosis of the hair follicle (for example Cece R. et al. (1996) Invest. Lab 75: 601-609). To date, to correct the appearance of alopecia, many solutions have been used: local application of plant or mineral extracts of all kinds, hormonal treatment by topical or general route, prosthesis and other hairpieces or wigs, implants, autografts.

Recently, a type of pharmacological treatment has appeared with a new class of molecules: potassium channel activators which, originally, were intended for the treatment of cardiovascular and non-capillary problems (for example Buhl AE (1993) J Invest . E> erwαto / .101: 148S-152S).

The cosmetic industry is therefore completely in its role when it is constantly looking for new concepts and products capable of preventing, reducing or eliminating hair loss or promoting their regrowth. The object of this patent application lies in the discovery, and in the demonstration, that a new approach to the problem of regulating hair loss and regrowth can be proposed.

To understand the interest of our discovery, some brief reminders of the mechanism and physiology of hair formation (in Dermatology, Collection Consultation, ^Dr. Michel Jossey, MA Editions Paris, 1993: 107-114) are given below.

The hair consists of a root and a stem.

The first is formed by several layers of keratin and its lower end swells in the shape of a bulb, thus encapsulating the papilla, rich in blood vessels and nerve endings. The root, or hair follicle, is anchored in the mesh of the skin tissue formed by different types of collagens: types I, II, II V and XI, fibrillar forms, fill in the empty spaces while type IV forms the lattice networks. the basal lamina and the type VII is the anchoring fibrils of the stratified squamous epithelia (eg Albert B et al., Molecular Biology of the cell, ^3rd ed., Science, Medicine, Flammarion ed.

Paris, 1997: 979-980).

The stem, or free part of the hair is made of keratin and can be compared to a nail (dander).

At birth, we have around 100,000 pilosebaceous follicles and as there cannot be others during life, it is natural that this number decreases with age. With the exception of the poodle and the merino sheep, the hairs of mammals evolve cyclically. In humans, each follicle evolves independently of its neighbor according to three main phases:

• Anagen, or growth phase, which lasts about two years and which affects, at a given time, about 75% of the scalp. The anagen hair has a large dark stem with a straight proximal end and a pigmented bulb.

• Catagen which lasts about 2 weeks and affects 5% of the hair. It corresponds to the stopping of cell divisions. The hair, slightly dark in color, then has a rounded club-shaped proximal end. • Telogen which lasts 3 to 4 months and affects around 20% of the hair. It is a phase of rest and death which necessarily leads to the fall of the hair. After this cycle, the fallen hair is replaced by another, on the condition that the follicle has remained active and therefore, that it is maintained in a normal or at least satisfactory tissue and physiological context. For this, there are at least two essential conditions which seem obvious:

• the hair follicle must bathe in an environment rich in blood vessels to be nourished properly and therefore, receive the nutrients it needs and eliminate the catabolites produced by its metabolism,

• the hair follicle must be well anchored in the skin tissue thanks to an effective mesh established by molecules of constitution such as collagens, in particular those of types I, II, III and IV (for example Almond-Roesler N. et al.

(1997) Arch. Derm Res. 289: 698-704). The object of this patent application lies in the discovery, and in the demonstration, that the optimal conditions for maintaining the hair follicle of the hair in an environment favorable to its survival were obtained by the topical use of our new molecule, N -Biotinyl-Glycine-Histidine-Lysine (or N- Biotinyl-Gly-His-Lys or even N-Biotinyl-GHK).

This N-Biotinyl-GHK is obtained by grafting a biotin molecule on the N-terminal part of the tripeptide Gly-His-Lys, thus creating a new molecule. Surprisingly, and being an integral part of our patent application as an inventive step, we discovered that the effect against hair loss and favorable on their regrowth with our new product obtained by grafting biotin on the tripeptide Gly-His -Lys, is much superior to that which one could hope for by the simple additivity of the known effects for the only GH-

K and for biotin alone, but which had thus created a very strong unpredictable synergy even by one skilled in the art.

An additional interest brought by the grafting of a Biotin on the tripeptide Gly-His-Lys lies in a better cutaneous penetration of the product towards the hair follicle and in a better stability of the product after its incorporation in the great galenic diversity of final product to which he is destined. Gly-His-Lys sequence - Summary of knowledge (literature - patents) To date the Gly-His-Lys sequence is described in the literature as promoting the formation of neo-vessels, very general angiogenic effect such as for example: • Peptides containing the Gly-His-Lys sequence and synthesis of type I collagen:

Sage E.H. et al. (1994) J Hypertens. \ 2S \ 45-S \ 52,

• Gly-Ηis-Lys sequence and neovascularization: Raju K.S. et al. (1984) Cancer ResΛ4: l519-l5 4,

• Gly-Ηis-Lys + Cu ⁺⁺ sequence and collagen synthesis: Macquard FX et al. (1988) FERS 1988: 343-346,

This sequence has been the subject of patents including:

WO 89/12441 (1989): cosmetic compositions intended to thicken the subcutaneous adipose tissue of warm-blooded animals and / or the skin in general,

• Among other peptide sequences, N-acylated or not, in 1990, we had described (FR90 / 13349) Gly-Ηis-Lys usable in cosmetic preparations, without however claiming any particular physiological activity. Since the filing of our patent, certain documents have claimed, for the tripeptide Gly-Ηis-Lys, a general cosmetic activity:

• excluding the possibility of N-acylation with palmitic acid (FR-95 13543 dated 15/11/95), • by mentioning that a non-N-acylated tripeptide must contain any possible association of amino acids found in thymulin or in thymopoietin

AA (FR-95 13544) without the Gly-His-Lys sequence being mentioned, glycosylated and preferably linked to a metal atom such as zinc, • by only describing the use of 3-methyl-L-His, linked or not to another indeterminate molecule to facilitate transcutaneous passage, in topical use against collagen alterations due to UV (WO 90/06102),

By only mentioning a peptide sequence of 1 to n amino acids, one of which must be a His, which can be grafted to a fatty acid chain of 6 to 24 carbons, and claiming emulsifying, antioxidant, bactericidal activities, chelating or as a sun filter (JP 24655/91).

This same Gly-His-Lys sequence is used in a more or less specific way

(patent FR95 / 13543 of 15.11.95) in medicaments and compositions for the preventive and curative treatment of wrinkles of the face, neck and hands, in the form of lotions, gels when applied locally, as well as as an activating and potentiation of physiological mechanisms of cellular cooperation. This patent also claims the use of the Gly-His-Lys sequence alone or in combination with αMSH activators, for the acceleration of melanogenesis .... obtaining a natural tan and total protection against solar radiation (UV).

All these documents therefore refer to fields very far from the problem posed and resolved in this patent application.

Biotin - Summary of knowledge (literature - patents)

Biotin is a group B vitamin, also called vitamin H or Bios II, which was isolated by Kôgl F. and Tonnis B. in 1936 from egg yolk.

It directly stimulates the differentiation of keratinocytes and must be provided by food because the human body cannot synthesize it. Biotin deficiency is manifested in animals and humans, by symptoms such as: alopecia, dermatitis, anemia, hypercholesterolemia and disorders of the reproductive system. The uses of biotin can be grouped into two groups: medical applications and as a co-reagent (with avidin) in ELISA type reactions which are used to measure different biochemical constituents.

Among the medical applications of Biotin, one can cite among many other examples:

• As a constituent of a mixture to be used in alopecia and in the activation of hair growth or the maintenance of integuments, composed of other products such as a plant extract (for example patent WO9713492 or US5750107) or animal ( for example US5827510), • As an addition to the ration of people with symptoms of mental retardation, comas of ketotic acidosis, chronic candidiasis and alopecia (for example Munnich et al. (1980) Ann. Med. Internal - Paris 131: 435-437,

• As an oral treatment for Dupré syndrome, known as hair straightening (for example Shelley WB et al. J Am. Acad. Dermatol. 13: 97-102. Among the diagnostic methods, we can cite commercial kits of different brands such as Boërhinger , Sigma ...., as well as more specific applications (Bettens F. et al. (1991) Ewr. J. Clin. Chem. Clin. Biochem. 29: 685-688; Chevrier D. et al. (1995) , FEMS Immunol. Med. Microbiol. 10: 245-501; (Chomel JJ et al., J. Virol. Method 68: 97-104). All these documents refer either to domains very far from the problem posed and resolved in this patent application, that is to say to different solutions since if biotin is mentioned for the same type of problem, it is part of an association of products the exact contribution of which cannot be specified for each final activity claimed. The object of our discovery is therefore that we have brought together three characteristics in the one and only that new N-Biotinyl-Gly-His-Lys molecule:

• the tripeptide's own action on: the neoformation of blood vessels or on the maintenance of the hair follicle in a very well vascularized context to ensure its metabolism efficient and therefore correct functioning ensuring the survival or regrowth of the hair,

> the synthesis of a quality collagen ensuring a correct anchoring of the hair follicle in the cutaneous matrix, • the proper action of Biotin on the supply of vitamin and enzymatic cofactor at the very place of its use and where its deficiency macroscopically results in the loss and / or lack of hair regrowth, • the grafting of these two molecules into one which,

> improves the anchoring of the hair follicle thanks to the increase in collagen synthesis, increases the stability of these two molecules in the final product, increases the bioavailability in the targeted environment that is the hair follicle,

> simplifies the work of a person skilled in the art in galenical formulation because it has only one molecule to incorporate in a complex composition instead of two as well as by the great stability of Biotinyl-Gly-His-Lys ,

> creates an obvious synergy in relation to the specific activities observed for Biotin and for the tripeptide Gly-His-Lys when used either alone or in combination with one another. The N-Biotinyl-Gly-His-Lys, the subject of this patent application, can be obtained either by conventional chemical synthesis (in heterogeneous phase or in homogeneous phase), or by enzymatic synthesis (Kullman et al., J. Biol. Chem. 1980, 255, 8234) from the constituent amino acids or their derivatives, then by grafting on the N-terminal part of the Glycine of the tripeptide Gly-His-Lys with a molecule of Biotin. The small size of the Gly-His-Lys tripeptide allows its industrial synthesis, at an advantageous cost and its grafting with Biotin represents a low additional cost compared to the synergy thus created. Its large demonstrated activity authorizes commercial use in a large number of financially acceptable cosmetic or dermopharmaceutical products. The tripeptide Gly-His-Lys can also be obtained by fermentation of a strain of bacteria, modified or not by genetic engineering, to produce the desired sequences or their different fragments.

The tripeptide Gly-His-Lys can be obtained by extraction of proteins of animal or vegetable origin, preferably vegetable, capable of containing these sequences within their structure, followed by a controlled hydrolysis, enzymatic or not, which releases the fragment peptide of sequence Gly-His-Lys in plants which are likely to contain these sequences within their structure. The controlled hydrolysis makes it possible to release these peptide fragments. From this tripeptide obtained according to any process mentioned above, it is easy for a person skilled in the art to produce the product of the invention by grafting, by any process, a biotin molecule onto the N-terminal part of the glycine of the tripeptide. Without being exhaustive, by way of example, we indicate below two possibilities. Biotin is attached to the amino functions of a peptide by reacting activated esters of biotin (for example: paranitrophenyl ester or N-hydroxy-succinimide ester), or by any other form of activation. biotin (EtOCOCl, DCC, TBTU, BOP, ...). The reaction is then followed by purification by the conventional methods of peptide chemistry, for example crystallization, chromatography.

The attachment can also be done directly during the solid phase synthesis of the peptide (Lobl et al: Anal. Biochem., 1988, 170, pl055-1060). In this case, an excess of reagent is used and the coupling time is increased to compensate for the low reactivity. The last step of cleavage of the peptide is not modified due to the presence of biotin on the peptide.

In both cases, due to the low solubility of biotin in conventional organic solvents, the reaction must be carried out in dimethylformarnide (DMF). Finally, it is also possible, without losing the activity claimed in this patent, to esterify the carboxyl group of N-Biotinyl-Gly-His-Lys to increase its stability and tissue availability by facilitating the passage of the lipid barrier skin of this type of essentially hydrophilic structure. By way of example illustrating the invention, a few cosmetic formulas which are representative but not limiting of the invention are cited: Example No. 1: Gel

> Carbopol 1342 ^R 0.3 Propylene glycol 2.0

> Glycerin 1.0

> White petrolatum 1.5

> Cylomethicone 6.0 Cetyl alcohol 0.5> Lubrajel ^R MS 10 Triethanolamine 0.3

> N-Biotinyl-Gly-His-Lys 0.0005 Water, preservatives, perfume qs 100 g. Example 2: Cream> Brij ^R 721 2.4

> Volopo ^R S72 2.6

> Prostéayl-15

> Beeswax 0.5

> Abil ^R ZP 2434 3.0> Propylene glycol 3.0

> Carbopol ^R 941 0.25 Triethanolamine 0.25

> N-Biotinyl-Gly-His-Lys 0.005 Water, preservatives, perfumes qs 100 g Example n ° 3: Hair lotion against hair loss

> DEBLOO 10 Ethanol

> Castor oil 1.5

> Incronam 30 1.0 Crodure 40 1.0> PVP k90 0.4

> Crotein K 0.3 > Gafquat 755N 0.2

> N-Biotinyl-Gly-His-Lys 0.010 Water, preservatives, perfumes qs 100 g Example n ° 4: Shampoo against hair loss> Empicol EBS3 / M 43.0

> Incronam 30 10.0

> Empilan CDE 3.0

> Castor oil 1.5

> Citrol EGMS 2.0 Lactic acid = pH 6.5-7.0

> N-Biotinyl-Gly-His-Lys 0.005 Water, preservatives, perfumes qs 100 g

The activities described at the beginning of this request are illustrated by the following examples. Example 5: Increase in collagen synthesis: in vitro

The method chosen is a variant of that described by Augustin C. et al. (Skin Pharmacol. (1997) 10: 63-70) in that we used human skin explants instead of human pulmonary fibroblasts, in order to make our results directly usable in cosmetology. These explants, originating from breast plasty, are incubated, for 72 hours in the presence of H-proline, with N-Biotinyl-Gly-His-Lys in three final concentrations in the culture medium (1.10 ^"4 %, 3.10 ^{" 4} % and 1.10 ^{* 3} %; i.e. 1, 3 and 10 ppm). The explants are then washed, the dermis and the epidemic of each explant are separated, homogenized and lysed. The measurement of the incorporation of ³ H-proline is then carried out in each lysate. The tests are carried out in triplicate.

At the same time, negative controls are carried out under the same conditions but in the absence of the tripeptide. Positive controls, for their part, are carried out by replacing the tripeptide tested with vitamin C. In the presence of 1, 3 or 10 ppm of N-Biotinyl-Gly-His-Lys, the incorporation of ³ H-proline which translates the synthesis of collagen, is increased by 12.5 ± respectively 0.8%, 36.3 ± 2.2% and 65.1 ± 3.2% p.ar compared to what is observed in the control experiments (without the N-Biotinyl-Gly-His-Lys).

Under the same conditions, the reference product, ascorbic acid, at a concentration of 0.5 mM, increases the synthesis of collagen by 37.4 (± 4.4)%. Finally, and this is very important in the capillary application because facilitating the anchoring of the follicle, a complementary measurement was carried out using a polyclonal anti-collagen IV antibody (Rockland 600-401-106) and an anti-immunoglobulin conjugate of rabbit peroxidase (Tébu <L42007). If there is production, and therefore, presence of collagen IV at the end of incubation with N-Biotinyl-Gly-His-Lys, there is formation of a complex whose peroxidase activity can be quantified on Kodak film MP by the ECL method ("enhanced chemiluminescence", Amersham). In this additional experiment, in the presence of the concentrations of N-Biotinyl-Gly-His-Lys previously tested (1, 3 and 10 ppm), the synthesis of collagen IV was increased by 21, 29 and 37% respectively compared to the experiments controls, therefore without N-Biotinyl-Gly-His-Lys, increases comparable to those obtained with vitamin C under the same conditions. Example No. 6: Effect on Hair Loss and Regrowth: In Vivo The study involving 15 male volunteers, aged 26 to 50 and having hair problems, started by cutting the hair very closely. of the skin, over an area of a few square centimeters.

A microphotograph of the area thus delimited is then carried out.

Three days later, a new macro photograph of the same area is taken from the same angle.

During the following eleven weeks, to the exclusion of any cosmetic product other than their usual shampoo, the fifteen volunteers used daily a lotion containing 10 ppm of N-Biotinyl-Gly-His-Lys.

At the end of this period, the same protocol as above was used: haircut, very close to the skin, over an area of a few square centimeters followed by taking a photomicrograph of the area thus delimited immediately and 3 days after. After analyzing these images, as some natural regrowth took place during this period, it is possible to count the distribution of hair in anagen, catagen and telogen groups. As the photos are superimposable, it is possible to distinguish the places where the hair has grown (anagen), where the hair has not undergone any change (catagen) and the places where the hair has disappeared (telogen).

The following table shows the percentages of hair present in the 3 phases (average ± SEM) for each group, before and after eleven weeks of treatment. It should be noted, on the one hand, that the percentages obtained before treatment correspond to the ranges of values found in the literature, which validates the panel chosen and the measurement method, and that, on the other hand, this improvement was observed in the 15 study volunteers.

Anagen Catagen Telogen

Before treatment 72.6 ± 3.38 19.9 ± 0.3 4.2 ± 1.73 After treatment 86.6 ± 2.91 12.5 ± 3.02 0.9 + 1.24

These results point towards an improvement in the health of the hair since we observe a decrease in the scores of the two phases of latency and hair loss (respectively - 37% and -78% for the catagen and telogen groups) while the hair regrowth phase increases (anagen group: + 19%). The computer processing of the previous microphotographs makes it possible to measure two other significant parameters: the apparent capillary volume and the speed of hair regrowth.

The following table shows the differences (After treatment - Before treatment) between the variations observed during the 2 periods of three days (arbitrary units, average ± SEM) on these two parameters: apparent capillary volume and speed of hair regrowth for each group .

Apparent volume Regrowth speed

Before treatment 4500 ± 569 7.4 ± 1.8

After treatment 7600 ± 634 9.9 ± 2.7 These results clearly show the improvement in hair health since there is an increase in the apparent volume (+ 68.8%) and in the speed of this regrowth of hair (+ 33.8%).

The last two examples clearly demonstrate the efficacy in vitro and, more importantly for the problem posed here, in vivo, of N-Biotinyl-Gly-His-Lys on all the mechanisms which maintain the environment of the hair bulb in the best possible conditions and that results in improving the quality and quantity of hair. On the basis of the results shown in Examples 5 and 6, the beneficial effect on the synthesis of quality collagen and on the skin tone allows the use of N-

Biotinyl-Gly-His-Lys for all skin care in general, for example when looking for an anti-wrinkle, firming and toning effect, without this list being exhaustive. The same tests were carried out on Biotin alone or on the tripeptide Gly-His-Lys alone. The results are not shown here but, examination of the figures shows the presence of a significant synergy created by the grafting of Biotin on the tripeptide. For example, in the case of the example on the synthesis of collagen, in the presence of respectively 5 ppm of the tripeptide Gly-His-Lys or 5 ppm of Biotin (which represents approximately the contribution of each molecule in 10 ppm of Biotinyl -GHK), increases were 18.2 ± 0.3% and 4.1

± 0.2%. From these results, on the basis of the additivity of the effects, it was possible to expect an increase of approximately 22%, however, the result found in Example No. 3 is 65.2 ± 3 , 2% or about 3 times the expected value, which corresponds to the creation of a strong synergy between the specific effects of the two molecules by their chemical grafting.

N-Biotinyl-Gly-His-Lys can be used at concentrations varying between 0.5 and 1000 ppm (w / w), preferably between 1 and 20 ppm (w / w) in the finished cosmetic or dermopharmaceutical product. N-Biotinyl-Gly-His-Lys can be used in the form of a solution, dispersion, emulsion, or encapsulated in vectors such as macro-, micro- or nanocapsules, liposomes or chylomicrons, or included in macro-, micro- or nanoparticles, or in micro-sponges, or adsorbed on powdery organic polymers, talcs, bentonites and other mineral supports. N-Biotinyl-Gly-His-Lys can be used in any dosage form: O / W and HE emulsions, milks, lotions, ointments, hair lotions, shampoos, soaps, powders, sticks and pencils, sprays, body oils.

N-Biotinyl-Gly-His-Lys can be used with any other ingredient usually used: extraction and / or synthetic lipids, gelling and viscosifying polymers, surfactants and emulsifiers, hydro- or liposoluble active principles, plant extracts, extracts tissues, marine extracts, sun filters, antioxidants. On the basis of the results shown in Examples 5 and 6, the beneficial effect on the synthesis of quality collagen and therefore on the skin tone, authorizes the use of N-Biotinyl-Gly-His-Lys for all skin care. the skin in general as, for example, when one seeks an anti-wrinkle, firming, toning effect, without this list being limiting; as well as to prevent, reduce or suppress hair loss and to promote their regrowth.

N-Biotinyl-Gly-His-Lys is used in cosmetic and dermopharmaceutical applications for all skin care (anti-wrinkle, firming, toning ....), without this list being exhaustive; and particularly to prevent, reduce or suppress hair loss and to promote their regrowth.

N-Biotinyl-Gly-His-Lys is used either alone or previously incorporated in cosmetic or dermopharmaceutical preparations in the preparation of a drug, for all skin care (anti-wrinkle, firming, toning ....) , without this list being exhaustive, and in particular to prevent, reduce or eliminate hair loss and to promote their regrowth.

Claims

claims 1. N-Biotinyl-Gly-His-Lys product obtained by grafting a Biotin molecule on the N-terminal part of the Gly-His-Lys tripeptide, thus creating a synergy compared to the simple additivity of the proper effects of these two products. 2. Product according to claim 1, esterified on the carboxyl group of lysine. 3. Use of the biotinyl-tripeptide according to claims 1 to 2 in cosmetic or dermopharmaceutical compositions. 4. Cosmetic dermopharmaceutical compositions according to claim 3, characterized in that the Gly-His-Lys tripeptide is obtained by chemical synthesis, by enzymatic route, by fermentation or by extraction of proteins of vegetable origin. 5. Cosmetic or dermopharmaceutical compositions according to claims 3 to 4, characterized in that the tripeptide Gly-His-Lys is used by conventional peptide synthesis in homogeneous or heterogeneous phase or by enzymatic synthesis from the constituent amino acids. 6. Cosmetic or dermopharmaceutical compositions according to claims 3 to 5 characterized in that the N-Biotinyl-Gly-His-Lys according to claims 1 to 2 is obtained either • by grafting the biotin onto the tripeptide by reaction of activated esters biotin (for example: ester of paranitrophenyl or ester of N-hydroxysuccinimide), or by any other form of activation of biotin (EtOCOCl, DCC, TBTU, BOP, etc.); the reaction then being followed by a purification step carried out for example by crystallization or by chromatography, • by attachment of the biotin to the N-terminal part of the glycine directly during the solid phase synthesis of the tripeptide; in the presence of an excess of reagent; the last step of cleavage of the peptide not being modified due to the presence of biotin on the peptide; knowing that in both cases, due to the low solubility of biotin in conventional organic solvents, the reaction must be carried out in dimethylformamide (DMF). 7. Cosmetic or dermopharmaceutical compositions according to claims 3 to 6 characterized in that the N-Biotinyl-Gly-His-Lys according to claims 1 to 2 is used at concentrations varying between 0.5 and 1000 ppm (w / w) , preferably between 1 and 20 ppm (w / w) in the finished product. 8. Cosmetic or dermopharmaceutical compositions according to the claims 3 to 7, characterized in that the N-Biotinyl-Gly-His-Lys according to Claims 1 to 2 is used in the form of a solution, dispersion, emulsion, or encapsulated in vectors such as macro-, micro- or nanocapsules, liposomes or chylomicrons, or included in macro-, micro- or nanoparticles, or in micro-sponges, or adsorbed on powdery organic polymers, talcs, bentonites and other mineral supports. 9. Cosmetic or dermopharmaceutical compositions according to claims 3 to 8, characterized in that the N-Biotinyl-Gly-His-Lys according to claims 1 to 2 is used in any galenical form: H E emulsions and W / O, milks, lotions, ointments, hair lotions, shampoos, soaps, powders, sticks and pencils, sprays, body oils. 10. Cosmetic or dermopharmaceutical compositions according to claims 3 to 9, characterized in that the N-Biotinyl-Gly-His-Lys according to claims 1 to 2 is used with any other ingredient usually used: extraction and or synthetic lipids, gelling and viscosifying polymers, surfactants and emulsifiers, water- or liposoluble active principles, plant extracts, tissue extracts, marine extracts, sun filters, antioxidants. 11. Cosmetic or dermopharmaceutical compositions according to claims 3 to 10 intended for skin care, in order to obtain an anti-wrinkle, firming, toning effect and in particular for preventing, reducing or suppressing hair loss and also for promoting their regrowth. 12. Cosmetic or dermopharmaceutical compositions according to claims 3 to 10 used for the preparation of medicament intended for skin care, to obtain an anti-wrinkle, firming, toning and particularly effect. to prevent, reduce or suppress hair loss and to promote regrowth. 13. Use of the only N-Biotinyl-Gly-His-Lys according to claims 1 to 2, obtained according to claims 4 to 6 at concentrations according to claim 7, for the preparation of a medicament intended for skin care, to obtain an anti-wrinkle, firming, toning effect and in particular to prevent, reduce or suppress hair loss and to promote their regrowth.