EP2155186A2

EP2155186A2 - Pharmaceutical or cosmetic preparations for topical and/or parenteral application, preparation methods thereof and use of same

Info

Publication number: EP2155186A2
Application number: EP08788214A
Authority: EP
Inventors: Marc Moutet; Jean-Claude Yadan
Original assignee: Galderma Research and Development SNC
Current assignee: Galderma Research and Development SNC
Priority date: 2007-05-11
Filing date: 2008-04-22
Publication date: 2010-02-24
Also published as: WO2008139124A2; WO2008139124A3; US20100298249A1; CA2686511A1

Abstract

The invention relates to a pharmaceutical or cosmetic composition for topical and/or parenteral application, containing, in a physiologically acceptable medium, at least one retinoid or the salts and derivatives thereof and at least one inhibitor of hyaluronic acid degradation. The invention is particularly suitable for use in human dermatology and plastic surgery.

Description

PHARMACEUTICAL OR COSMETIC PREPARATIONS FOR

TOPICAL AND / OR PARENTERAL APPLICATION, THEIR METHODS OF

PREPARATION AND USES THEREOF

The present invention relates to compositions for topical and / or parenteral application comprising, in a physiologically acceptable medium, a retinoid and / or its salts and / or derivatives, and an inhibitor of the degradation of hyaluronic acid. manufacturing such compositions, and their uses as pharmaceutical compositions, especially of pharmaceutical, or cosmetic. Said compositions are intended for the treatment of dermatological conditions, in particular, the filling treatment of wrinkles, fine lines, fibroblastic depletions and any scarring.

The aging of the skin is one of the most visible changes in the senescence process. In addition, the skin is exposed to many factors that can accelerate this physiological process. There are two different types of skin aging. On the one hand, intrinsic aging, which is easier to evaluate in areas that are normally not exposed to the sun and, on the other hand, extrinsic aging, caused by the interaction of environmental factors, in particular UV rays. These environmental factors have a much greater effect on sun-exposed body parts, especially in light-skinned people. We also speak of actinic aging. Other factors such as eating habits, smoking, excessive alcohol consumption, Chronic diseases and dysfunctions of the endocrine glands also contribute to this aging.

During the intrinsic aging of the skin, the stratum corneum is little modified. The epidermis is atrophic and the dermal-epidermal junction is flattened, so that adhesion to the dermis is less good, facilitating the formation of bubbles. The thickness of the dermis is significantly reduced; there are fewer blood vessels. There are also fewer fibroblasts and their biosynthesis and proliferation abilities are diminished. The elastic fibers undergo modifications first, and then disappear.

As far as extrinsic aging is concerned, there is an irregular epidermis, sometimes atrophic, sometimes hyperplastic, with signs of disorganization and dysplasia. Melanocytes are more numerous in some places, and fewer in number. There is also an irregular distribution of melanin in the epidermis, following problems of melanosome transfer. The number of Langerhans cells decreases. The small blood vessels are first dilated, then thin and atrophy.

Wrinkles are the most visible signs of aging. We can distinguish it from several natures, in particular superficial and deep wrinkles. Deep wrinkles may be due to dermo-hypodermic changes, while superficial wrinkles could be explained by dermal and possibly epidermal changes. Wrinkles are mainly due to the loss of elasticity of the skin. The reaching of the network elastic subepidermal gives rise to a superficial laxity of the aged skin and a fold of its surface. The destruction of elastic fibers in the reticular dermis is responsible for the loss of elasticity and the ability of the skin to regain its shape after stretching. Depending on the type, intensity and topography, a suitable treatment will be possible.

The treatment of unsightly skin changes related to aging has made tremendous progress in recent years.

A relatively large number of natural or synthetic substances have already been described as dermal implants, that is to say as substances injected directly into the skin, in order to remedy the skin changes resulting from aging. , trauma or disease.

Other therapeutic alternatives for these applications include the local injection of botulinum toxin inactivated (Botox ®) or the use of laser techniques. These different types of treatment are not exclusive and their combination has even been recommended. Among the natural substances of human origin, collagen and hyaluronic acid are the ones that are at the origin of the majority of the products available on the market.

Hyaluronic acid is a ubiquitous natural polysaccharide that exists in the same form from the simplest bacterium to humans. It is a polysaccharide composed alternately of D-glucuronic acid and N- acetylglucosamine, linked together by alternating glycosidic bonds beta-1,4 and beta-1,3. According to Saari H et al. Differential effects of reactive oxygen species on a native synovial fluid and purified human umbilical cord hyaluronate. Inflammation 17 (1993): 403-415, the polymers of this repeating unit can have a size between 10 ² and 10 ⁴ kDa in vivo, the hyaluronic acid taken from the umbilical cord having a weight of 2500 kDa.

Hyaluronic acid is a natural component of the dermis where it plays an important role in the hydration and elasticity of the skin. However, it decreases in quantity and quality with age, resulting in drying of the skin that wrinkles. It is highly water soluble and forms high viscosity solutions in water. Because of these particular properties, hyaluronic acid is one of the most widely used pharmaceutical products.

However, in humans, hyaluronic acid is very quickly eliminated from the plasma by degradation. Its plasma half-life after intravenous injection is very short, between 2.5 and 5.5 minutes, while in the skin, its half-life is 0.5 to 2 days depending on its concentration. Urinary excretion is low, less than 1% of total clearance. In rabbits, the rate of elimination in the skin was measured (Reed RK, Laurent UB, JR Fraser, Laurent TC., Removal rate of [3H] hyaluronan injected subcutaneously in rabbits.) Am J Physiol 1990 Aug; 259 (2Pt 2): H532-5). It is non-exponential with a half-life of 0.5 to 1 day when its concentration is 5 mg / ml. The tolerance of hyaluronic acid is very good and no immunogenicity has been associated with this substance. This has a very low incidence of side effects.

The use of hyaluronic acid, alone or in combination, has thus been described for several medical applications, such as, for example, the treatment of osteoarthritis as well as rheumatoid arthritis. Injectable compositions such as, for example, hyaluronic acid alone, collagen alone or the combination "hyaluronic acid and collagen" have already been used in reconstructive surgery, in the context of treatment by filling wrinkles, fine lines, fibroblastic depletions and all scars.

Currently, many dermal implants are used but none has yet been considered ideal for safe and healthy tissue augmentation.

(Naoum C, Dasiou-Plakida Dermal Filler Materials and Botulinum toxin Int J Dermatol 2001 Oct; 40 (10): 609-21).

However, hyaluronic acid, because of its low bioavailability after injection and its too high injection frequency, can not be used as such.

Of course, attempts have been made to develop compositions based on hyaluronic acid having a very good bioavailability and likely to better withstand the action of degradation enzymes. This allows, in particular, to space interventions and reduce their number.

These compositions used as a dermal implant are all composed of stabilized hyaluronic acid and many of them comprise hyaluronic acid chemically modified for this purpose. In addition, the hyaluronic acid included in these products is predominantly of non-human origin such as for example of avian or bacterial origin.

There are thus in these compositions numerous hyaluronic acid derivatives chemically modified in the form, in particular of esters, of amides, as well as derivatives having "intra and / or interchain bridges"

(cross-linked).

However, these modifications affect the physico-chemical characteristics and the biological properties of hyaluronic acid, its potential immunogenicity and its fate after administration. These structural modifications of hyaluronic acid can lead to inflammatory reactions as reported by Sopaar CNS, Patrinely JR Ophthalmic Plastic and Reconstructive Surgery 2005 Mar; 21 (2): 151-53.

In view of the foregoing, a problem to be solved by the invention is to provide compositions which make it possible to ensure that hyaluronic acid has a better bioavailability while retaining its physico-chemical characteristics and its biological properties, as well as a method of manufacturing such compositions. The solution of the invention to this problem has as its first object a pharmaceutical or cosmetic composition, especially for topical and / or parenteral application comprising, as sole active ingredients, in a physiologically acceptable medium:

at least one compound chosen from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid.

Preferably, the composition does not comprise an oligosaccharide.

The composition according to the invention indeed contains as active ingredients only the retinoid (s) and the (s) inhibitor (s) of the degradation of hyaluronic acid; any other active ingredient is excluded.

Its second object is a process for the manufacture of such a pharmaceutical or cosmetic composition, comprising a step of mixing at least one compound chosen from retinoids, their salts and derivatives, and at least one degradation inhibitor. hyaluronic acid with a physiologically acceptable medium. Preferably, the method according to the invention also comprises a step of preparing a physiologically acceptable medium, in which the active ingredients are mixed.

Finally, its third object is the use of at least one compound chosen from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid, or a composition according to the invention, for the manufacture of a medicament for the treatment and / or prevention of dermatological conditions.

A pharmaceutical or cosmetic composition according to the invention significantly increases the bioavailability of a hyaluronic acid, which is further included in said composition, or which is administered separately. The composition according to the invention makes it possible to space the applications of hyaluronic acid and to reduce the number thereof and it has a significant effectiveness in the filling of wrinkles, fine lines, fibroblastic depletions and all scars.

The Applicant has demonstrated a decrease in the catabolism of hyaluronic acid in human keratinocytes in vivo on which hyaluronic acid, an inhibitor of hyaluronic acid degradation and a retinoid, are applied in the absence of oligosaccharide. Thus, surprisingly, the absence of oligosaccharide in a composition comprising a hyaluronic acid degradation inhibitor and a retinoid confers on hyaluronic acid also applied a better stability and a better bioavailability. Such a composition is more effective than the compositions of the prior art, and in particular compositions comprising oligosaccharides, in the filling of wrinkles, fine lines, fibroblastic depletions and all scars, as well as in the hydration of the skin.

The invention will be better understood on reading the nonlimiting description which follows. The composition according to the invention comprises, in a physiologically acceptable medium, at least one retinoid and / or its salts and / or derivatives and an inhibitor of the degradation of hyaluronic acid. In particular, it does not include an oligosaccharide.

The composition according to the invention may further comprise hyaluronic acid. Alternatively, the composition according to the invention may be administered to a subject to whom hyaluronic acid is independently administered. In this case, the hyaluronic acid may be included in a separate composition, which may be administered simultaneously or in a different time from that of the administration of the composition according to the invention. The distinct composition comprising hyaluronic acid can be administered topically, orally or parenterally, for example by injection.

Physiologically acceptable medium according to the invention means a medium compatible with the skin and optionally with its integuments (eyelashes, nails, hair) and / or mucous membranes.

In the compositions according to the invention, the retinoid and / or its salts and / or its derivatives, and the inhibitor of the degradation of hyaluronic acid and, where appropriate, hyaluronic acid, are present in proportions that can go from 0.0000001% to 10%, preferably from 0.00001% to 1% by weight, relative to the total weight of the composition. In this description, and unless otherwise specified, it is understood that where intervals of concentrations are given, they include the upper and lower bounds of that range.

The compositions according to the invention may comprise hyaluronic acid.

By hyaluronic acid is meant a ubiquitous natural polysaccharide existing in the same form from the simplest bacterium to humans. It is a polysaccharide composed alternately of D-glucuronic acid and N-acetylglucosamine, linked together by alternating glycoside bonds beta-1,4 and beta-1,3. According to Saari H et al. Differential effects of reactive oxygen species on a native synovial fluid and purified human umbilical cord hyaluronate. Inflammation 17 (1993): 403-415, the polymers of this repeating unit can have a size between 10 ² and 10 ⁴ kDa in vivo, the hyaluronic acid taken from the umbilical cord having a weight of 2500 kDa.

Advantageously, hyaluronic acid is natural.

By natural hyaluronic acid is meant an unstabilized hyaluronic acid, not chemically modified in the form, in particular of esters, amides, or in the form of derivatives having "intra and / or interchain bridges"

(cross linked), such modifications affecting the physico-chemical characteristics and the biological properties of said hyaluronic acid, as well as its fate after administration. The compositions according to the invention comprise a retinoid and / or its salts and / or its derivatives, taken alone or as a mixture.

Among the retinoids that may be used in the compositions according to the invention, retinol, retinal, retinoic acid (or tretinoin), adapalene or their salts and derivatives, taken alone or as a mixture, more preferably, will be chosen more preferentially. retinol.

By retinoid salt is meant in particular an alkali metal salt, or an alkaline earth salt, or an organic amine salt. By retinoid derivative is meant in particular the esters, such as retinyl palmitate, retinyl acetate, retinyl stearate, retinyl oleate, retinyl propionate or retinyl linoleate.

Advantageously, the retinoids used in the compositions according to the invention are retinoids naturally occurring in the human body.

The compositions according to the invention do not comprise in particular any oligosaccharide.

By oligosaccharide is meant polymers formed of a number n (with n less than or equal to 100) of monosaccharides by glycosidic bonding, in particular any oligosaccharide limiting the penetration of hyaluronic acid into skin cells, in particular keratinocytes and fibroblasts. Among the oligosaccharides, mention may be made of the oligomers of hyaluronic acid, such as di- to dodecamers of the acid hyaluronic acid, said dimer comprising a disaccharide unit component of hyaluronic acid, and the dodecamer comprising six of these disaccharide units, in particular the tetra-to-hexamers of hyaluronic acid, in particular the pentamer of hyaluronic acid. The molecular weight of a disaccharide unit of hyaluronic acid is about 400 Da. An oligomer of one to six disaccharide units of hyaluronic acid therefore has a molecular weight of between 400 and 2400 Da. Oligomer means, according to IUPAC in Pure Appl. Chem., Vol. 68, No.12, pp. 2287-2311, 1996, a molecule of intermediate molecular weight, the structure of which comprises a small amount of molecules having a lower molecular weight. We will speak of a molecule having an intermediate molecular mass, when the removal of one or a few constituent units will significantly modify the properties of the molecule.

The compositions according to the invention further comprise an inhibitor of the degradation of hyaluronic acid.

By inhibitor of the degradation of hyaluronic acid is meant a compound capable of reducing, or even blocking, the catabolism either extracellular or intracellular of hyaluronic acid, preferably a compound capable of reducing or even blocking the extracellular catabolism of hyaluronic acid, more preferably a compound capable of inhibiting the extracellular hyaluronidase present in the skin. Among the inhibitors of the degradation of hyaluronic acid, taken alone or as a mixture, which may be used in the compositions according to the invention, 1,2,3,4,6-penta-O-galloylglucose will be chosen in particular. apigenin, beta-escin, caltrin, cis-Hinokiresinol (CHR), echinacin, eicosatrienoic acid (C20: 3), fenoprofen, GoId sodium thiomalate, gossypol, heparin, Hesperidin phosphate, indomethacin, L-ascorbic acid, L-ascorbic acid 6-hexadecanoate, L-carnitine, L-aminocarnitine, myocrisin (sodium aurothiomalate), N-tosyl-L- phenyl-alanine-chloromethyl ketone (TPCK) and N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), phosphorylated hesperidin, poly (sodium 4-styrenesulfonate) (T-PSS), polyestradiol phosphate polyphloretin phosphate, PS53 (a hydroquinone-sulphonic acid-formaldehyde polymer), sodium polystyrene sulphonate (N-PSS), sulphated 2-hydroxyphenyl monolactobioside, hydroquinone digalactoside sulphaté, oligosaccharides sulphates verbascose, planteose and neomycin, tetradecyl sodium sulphate

(TDSS), a C14: 1 to C24: 1 unsaturated fatty acid with a double bond, the urinary trypsin inhibitor

(UTI), urolithin B, WSG, glycyrrhizin or glycyrrhetinic acid, their derivatives and / or analogues. Glycyrrhizin, glycyrrhetinic acid, their derivatives and / or analogues are preferred.

Advantageously, the inhibitors of the degradation of hyaluronic acid used in the compositions according to the invention are natural. In the compositions according to the invention, the inhibitor is used at concentrations of between 10 ^-9 M and 10 ^-2 M, preferentially between 10 ^-6 M and 10 ^-3 M.

By derivatives of glycyrrhizin or of glycyrrhetinic acid is meant in particular the salts, substituted derivatives, enantiomers and racemates of said compounds.

As salts of said compounds, mention may be made of the salts obtained by addition of said compounds with an inorganic base, chosen in particular from the hydroxides of sodium, lithium, calcium, potassium, magnesium, ammonium or zinc, the carbonates of alkali or alkaline earth metals such as carbonates and bicarbonates of sodium, lithium, calcium, potassium, magnesium, ammonium or zinc, or with an organic base, chosen in particular from methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, procein, lysine, arginine, histidine, N-methylglucamine or even phosphonium salts such as alkylphosphonium salts, arylphosphonium salts, alkylarylphosphonium salts, alkenylarylphosphonium salts or quaternary ammonium salts such as tetra-n-butylammonium salts. Such salts are in particular the potassium salt of glycyrrhetinic acid, the sodium salt of glycyrrhetinic acid, or the salt monoammonium of glycyrrhetinic acid (ammonium glycyrrhetinate).

"Analogous" is understood to mean, in particular, the enzymatic or biomimetic analogs of said compounds, capable of binding to the catalytic or non-catalytic site of hyaluronidases and of thus inhibiting their activation. Such analogs can be selected in vitro by hyaluronidase binding or inhibition tests according to conventionally used techniques.

Advantageously, the derivatives and / or analogues must be of natural origin.

The compounds and their derivatives and / or analogues of natural origin are compounds in the pure state or in solution at different concentrations, obtained by various methods of extraction or hydrolysis of biological material of natural origin.

In known manner, the compositions according to the invention may also contain the usual adjuvants well known to those skilled in the art.

The compositions according to the invention may be formulated for topical and / or parenteral application.

Topically, the compositions may be in any dosage form normally used for topical administration. By way of nonlimiting example of topical compositions, mention may be made of compositions in liquid form, pasty, or solid and, more particularly, in the form of ointments, aqueous, hydroalcoholic or oily solutions, dispersions of the lotion type which may be biphasic, serum, aqueous, anhydrous or lipophilic gels, powders, soaked swabs, syndets, wipes, sprays, foams, sticks, shampoos, compresses, washing bases, emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), a microemulsion, suspensions or emulsions of soft, semi-liquid or solid consistency of the white or colored cream, gel or ointment type, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, or microcapsules, microparticles or nanoparticles or polymeric or gelled patches allowing controlled release.

Parenterally, the compositions according to the invention can be applied subcutaneously or intradermally. By way of nonlimiting example of parenteral compositions, mention may be made of compositions in the form of solutions or suspensions for infusion or for injection.

By way of non-limiting example given merely by way of illustration and which in no way limits the scope of the invention, hyaluronic acid may be administered in the form of an injectable aqueous solution, a composition according to the invention. invention comprising retinol, and glycyrrhizin being administered as a cream. In the context of a combined administration of hyaluronic acid and a composition according to the invention, the administration frequencies may be identical or different.

Advantageously in the context of the invention, the frequency of administration of hyaluronic acid injected in the form of an aqueous solution for injection may vary from 4 to 24 months, preferably from 4 to 16 months, while those of composition according to the invention, administered topically, for example in cream form, may vary from 1 to 7 days, preferably from 1 to 3 days.

According to one particular embodiment of the invention, the method of manufacturing a composition comprises the steps of preparing a physiologically acceptable medium and mixing an effective amount of retinol, and glycyrrhizin and / or its derivatives and / or like.

The invention also relates to the use of at least one compound chosen from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid, or a composition such as previously described for the manufacture of a cosmetic or pharmaceutical composition for the treatment, improvement and / or prevention of dermatological conditions.

More particularly, the invention relates to the use of at least one compound chosen from retinoids, their salts and their derivatives, and at least one inhibitor of the degradation of hyaluronic acid, or of a composition as described above for the manufacture of a cosmetic or pharmaceutical composition for the treatment, improvement and / or prevention of skin aging. Skin aging is understood to mean wrinkles, fine lines, fibroblastic depletions and scars. Such a medicine is adapted to the treatment of wrinkled and / or aged skin, and aims in particular to prevent and / or reduce the effects. The treatment of wrinkles, fine lines, fibroblastic depletions and all scars is done by filling.

In particular, the composition according to the invention can be applied to the areas of the face or forehead marked by expression lines.

The invention also relates to the use of at least one compound chosen from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid, or a composition such as previously described for the manufacture of a cosmetic or pharmaceutical composition for use in reconstructive surgery.

The present invention will now be illustrated by the following examples.

Example 1 Inhibitory Effect of Glycyrrhizin (GLZ) on Hyaluronidase Activity of Bovine Origin

Determination of IC50 of GLZ, with or without pre-incubation at 37 ° C: The GLZ, at different concentrations, is preincubated or not 20 minutes at 37 ° C in the presence of the enzyme. The enzymatic reaction is triggered by adding the hyaluronic acid solution (TO time). After 20 minutes of incubation, the unhydrolysed hyaluronic acid is precipitated by adding the acid solution of bovine albumin.

In order to verify that the pre-incubation step does not affect the stability of the hyaluronidase, an aliquot of a solution of the enzyme is placed at 37 ° C for 20 minutes. Another aliquot is kept in an ice bath for 19 minutes, then incubated at

37 ⁰ C for 1 minute. A solution of hyaluronic acid is then added to each aliquot (TO). After 15, 30 or 45 minutes of incubation, the unhydrolysed hyaluronic acid is precipitated by addition of the acid solution of bovine albumin.

Measurement of hyaluronidase activity of bovine origin:

After the precipitation step, the turbidimetry of the solutions is determined spectrophotometrically at a wavelength of 600 nm. The optical density (OD) of these solutions is deduced from the OD of a control solution of hyaluronic acid (of the same concentration) not hydrolyzed by the enzyme. This difference in OD, which is inversely proportional to the concentration of hyaluronic acid, is used to measure the activity of hyaluronidase. The inhibitory effect of GLZ on bovine hyaluronidase is illustrated in Figure 1 (semi-logarithmic representation).

The results obtained show that this effect is dose-dependent and that the concentration of GLZ inhibiting at 50% (IC50) the hyaluronidase activity is 400 μM without pre-incubation with the enzyme.

When the GLZ is preincubated for 20 minutes at 37 ° C. in the presence of the enzyme, the IC50 is 350 μM.

Example 2 Composition No. 1

Solution for injection no.

This composition is prepared in a conventional manner for the person skilled in the art:

Glycyrrhizin 0.02%

Retinol 0.00001%

Water qs 100%

Example 3: Composition No. 2

Solution for injection No. 2 hyaluronic acid coupled to a cream according to the invention

Injection solution Hyaluronic acid 2%

Water qs 100%

Cream Glycyrrhizin 0.02%

Retinol 0.00001%

Stearic acid 3.00% mixture of glyceryl monostearate and PEG stearate (100 EO) 2.5%

PEG Stearate (20 EO) 1.0%

Cyclopentadimethylsiloxane 10, 00%

Vegetable oils 7.00% Synthetic oils 6.00%

Silicone gum 0,20%

Stearic alcohol 1.00%

Water qs 100%

Claims

1. A pharmaceutical or cosmetic composition comprising, in a physiologically acceptable medium, as sole active ingredients:

at least one compound chosen from retinoids, their salts and their derivatives, and

at least one inhibitor of the degradation of hyaluronic acid chosen from 1, 2, 3, 4, 6-penta-O-galloylglucose, apigenin, beta-escin, caltrin, cis-Hinokiresinol), echinacin, eicosatrienoic acid, fenoprofen,, GoId sodium thiomalate, gossypol, heparin, Hesperidin phosphate, L-ascorbic acid, L-ascorbic acid 6-hexadecanoate, L-ascorbic acid, carnitine, L-aminocarnitine, myocrisin (sodium aurothiomalate), N-tosyl-L-phenylalanine-chloromethyl ketone and N-alpha-p-tosyl-L-lysine chloromethyl ketone, phosphorylated hesperidin, poly (sodium 4-styrenesulfonate)), polyestradiol phosphate, polyphloretin phosphate, PS53, sodium polystyrene sulfonate, 2-hydroxyphenyl monolactobioside sulphated, hydroquinone digalactoside sulphated, oligosaccharides sulphated verbascose, plantose and neomycin, tetradecyl sodium sulfate , a C14: 1 to C24: 1 unsaturated fatty acid with a double bond, inhibits it urinary trypsin, urolithin B, WSG, glycyrrhizin, glycyrrhetinic acid and their derivatives and the like.

2. Composition according to claim 1, characterized in that the retinoid is selected from retinol, tretinoin and adapalene.

3. Composition according to one of claims 1 or 2, characterized in that the inhibitor of the degradation of hyaluronic acid is selected from glycyrrhizin, glycyrrhetinic acid and their derivatives and the like.

4. Composition according to any one of claims 1 to 3, characterized in that it is formulated for topical application.

5. Composition according to one of claims 1 to 3, characterized in that it is formulated for parenteral application.

6. Parenteral composition according to claim 5, characterized in that it is in the form of solutions or suspensions for infusion or injection.

7. A method of manufacturing a composition according to one of claims 1 to 6, comprising a step of mixing at least one compound selected from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid with a physiologically acceptable medium.

8. Use of at least one compound chosen from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid, for the manufacture of a pharmaceutical or cosmetic composition intended for treatment, prevention or improvement of skin aging.

9. Use of at least one compound chosen from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid for the manufacture of a pharmaceutical or cosmetic composition intended for treatment by filling wrinkles, fine lines, fibroblast depletions and scars.

10. Use of at least one compound chosen from retinoids, their salts and derivatives, and at least one inhibitor of the degradation of hyaluronic acid for the manufacture of a pharmaceutical or cosmetic composition for use in Reconstructive surgery.