WO2022195228A1 - Injectable composition comprising a peptide conjugate - Google Patents

Injectable composition comprising a peptide conjugate Download PDF

Info

Publication number
WO2022195228A1
WO2022195228A1 PCT/FR2022/050481 FR2022050481W WO2022195228A1 WO 2022195228 A1 WO2022195228 A1 WO 2022195228A1 FR 2022050481 W FR2022050481 W FR 2022050481W WO 2022195228 A1 WO2022195228 A1 WO 2022195228A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
condensate
composition according
peptide conjugate
peptide
Prior art date
Application number
PCT/FR2022/050481
Other languages
French (fr)
Inventor
Nicolas Riviere
Original Assignee
Rpm Dermatologie
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rpm Dermatologie filed Critical Rpm Dermatologie
Publication of WO2022195228A1 publication Critical patent/WO2022195228A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/736—Chitin; Chitosan; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection

Definitions

  • composition for injection comprising a peptide conjugate
  • the present invention relates to a composition comprising at least one peptide conjugate of formula (I) and at least one vector, its use for restructuring or preserving the appearance of the skin, its method of application, as well as its kit.
  • the aging of the skin is a complex phenomenon having various origins, which can be external (exposure to the sun, to cold, oxidizing agents, etc.) or intrinsic (genetics, proteins, etc.).
  • the skin is a tissue, consisting of layers (epidermis, dermis, and hypodermis, dermis and epidermis being linked by the dermo-epidermal junction “JDE”), having the role of protective barrier between the interior and exterior environment.
  • JDE dermo-epidermal junction
  • the Ac-SDKP-OH molecule is a natural tetrapeptide (Acetyl-Serine-Aspartic acid-Lysine-Proline-OH) identified for its cosmetic properties on the skin during topical use (EP 1 786 386, Bakala et al.).
  • this molecule is very easily hydrolyzed, which makes its commercial exploitation difficult, in particular for common-use cosmetic compositions (i.e. stored at room temperature, opened and closed at the convenience of the patient).
  • the molecule is also very sensitive to enzymatic hydrolysis. The same is true for its analogues covered by EP 1 786 386.
  • EP3416730 is a formulation of the emulsion/nanoemulsion type to overcome these difficulties.
  • the anti-wrinkle effect is not instantaneous and the anti-wrinkle composition needs to be applied for several days, weeks or months in order to obtain the effect and maintain it.
  • composition comprising: a. at least one peptide conjugate of the following formula (I):
  • R1 being on the N-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
  • X1 is a condensate of (L)-serine
  • X2 is a condensate of (L) and/or (D) aspartic acid
  • X3 is a condensate of (L) and/or (D) lysine, ,
  • X4 is a condensate of (L) and/or (D) proline
  • X4 or X3 and X4, being optionally absent, the bonds linking X1 to X2, X2 to X3 where applicable, and X3 to X4 where applicable, possibly being peptide or pseudopeptide bonds,
  • A1 is a covalent bond, an NH group or an oxygen atom
  • R2 being on the C-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
  • R1 and R2 cannot be hydrogen atoms together, or one of its pharmaceutically acceptable salts, and b. at least one vector chosen from aqueous solutions or biocompatible filling biomaterials.
  • the invention relates to the non-therapeutic use of the composition according to the present invention for restructuring or preserving the appearance of the skin, in particular in depth at the dermal level.
  • the invention in a third aspect, relates to a kit comprising the composition according to the present invention and a device for administering said composition.
  • the invention relates to a non-therapeutic treatment method for restructuring or preserving the appearance of the skin, in particular in depth at the dermal level, said method comprising:
  • peptide conjugate refers to a conjugated peptide strand, i.e. linked, to a molecular fragment of another nature, for example a linear or branched, substituted or unsubstituted C1 to C50 alkyl group, preferably C2, C12 or C16. It is accepted in the art that a peptide comprises X number of amino acids, it is actually X number of condensed amino acids, i.e. having each lost a molecule of water (if they are connected to each other by a peptide bond, typically).
  • peptide strand refers to a polymer of amino acids, which amino acids are linked together by at least one peptide or pseudopeptide bond.
  • a peptide comprising two amino acid residues is a dipeptide
  • a peptide comprising three amino acid residues is a tripeptide
  • a peptide comprising four amino acid residues is a tetrapeptide
  • peptide bond refers to a CO carbonyl group and an NH amino group in a peptide.
  • the peptide bond is therefore an amide bond linking two amino acids together.
  • amino acids are said to be “condensed” because they have lost at least one molecule of water to form the peptide bond(s) in which they are involved.
  • polypeptide bond refers to a bond which engages between the carbonyl group CO or the amino group NH of the alpha carbon of the peptide and another methyl group CH3, carbonyl CO or amino group NH of another molecule which is not a peptide, for example a C1 to C50 hydrocarbon chain.
  • SDKP refers to a peptide strand of structure:
  • the amino acids are of L configuration:
  • Functional groups eg NH2, OH, COOH
  • NH2, OH, COOH can be in protonated or deprotonated form depending on the surrounding pH.
  • These groups can also be protected by conventional protective groups such as found in the works “Protective Groups in Organic Synthesis”, Wiley, New York, 2007 4th edition and/or Harrison et al. "Compendium of Synthetic Organic Methods", Vol. 1 to 8 (J. Wiley & sons, 1971 to 1996).
  • the COOH functions can be protected by an ester group such as O-tert-Butyl (OtBu), O-Methyl (OMe), O-Ethyl (OEt), or even O-benzyl, the OH function by an ether of tert-Butyl, Methyl, Ethyl, or benzyl, and NH2 by an acid-labile group such as Boc or baso-labile group such as Fmoc.
  • an ester group such as O-tert-Butyl (OtBu), O-Methyl (OMe), O-Ethyl (OEt), or even O-benzyl
  • the OH function by an ether of tert-Butyl, Methyl, Ethyl, or benzyl, and NH2 by an acid-labile group such as Boc or baso-labile group such as Fmoc.
  • linear or branched, substituted or unsubstituted C1-C50 alkyl represents a saturated hydrocarbon chain, linear or branched, comprising from 1 to 50 carbon atoms, such as for example a methyl (C1), ethyl (C2), propyl or isopropyl (C3), butyl, isobutyl or tert-butyl (C4), pentyl (C5), hexyl (C6), heptyl (C7), octyl C8), nonyl (C9), decyl (C10), undecyl (C11), dodecyl or lauroyl (C12), n-tridecyl (C13), n-tetradecyl (C14), n-pentadecyl (C15), n-hexadecyl (16), n-heptadecyl (C17), n-octadecy
  • the alkyls may or may not be substituted.
  • the alkyls can be substituted by one or more halogens such as F, Cl, Br, I, or by other fragments such as OH, SH, N02, NH2, COOH.
  • physiologically acceptable salt is understood to mean, within the meaning of the present invention, any salt prepared from any physiologically acceptable non-toxic acid, including organic and inorganic acids.
  • Such acids include acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, tartaric acid and paratoluenesulfonic.
  • hydrochloric acid is used.
  • biocompatible is meant according to the invention compatible with the human or animal body.
  • a biocompatible biomaterial is, according to the invention, a material meeting the criteria given by the ISO 10993 standard relating to medical devices.
  • fibrous tissue is meant according to the invention a subcutaneous space of essentially fibrous nature, and capable of being filled with fillers.
  • subcutaneous is meant according to the hypodermic invention, therefore under the dermis.
  • intradermal is meant according to the invention in the thickness of the dermis.
  • gel we mean a three-dimensional physical structure having viscosifying, rheological and thixotropic properties.
  • vector fluid is understood to mean a compound in fluid form which can convey the peptide conjugate, in particular if the latter is in lyophilized form, and/or a biocompatible filling biomaterial which occurs naturally in the form of solid powder.
  • hydrogel is understood to mean a gel obtained by dissolving at least one biocompatible filling biomaterial in water (for example by means of an aqueous solvent).
  • injection within the meaning of the present invention, is meant an injection performed with a needle, such as with a syringe adapted according to the type of administration or performed without a needle, such as for example using any device or technique capable of crossing the epidermal barrier, such as barophoresis.
  • barophoresis or “needleless injection” we mean the propulsion at supersonic speed of a mixture of air and compounds via a handpiece.
  • This mixture subjected to high pressure, arrives on the skin in the form of microscopic droplets. The pores will then open, allowing the penetration of said compound(s).
  • the mixture is a mixture of air and the composition according to the present invention.
  • the term “approximately” denotes a content expressed in % or in mol/L or in ml or in mm, with a margin of +/- 20%, preferably +/- 10%, more preferably +/- 5%.
  • composition according to the present invention comprises: a. at least one peptide conjugate of the following formula (I):
  • R1 being on the N-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
  • X1 is a condensate of (L)-serine
  • X2 is a condensate of (L) and/or (D) aspartic acid
  • X3 is a condensate of (L) and/or (D) lysine, ,
  • X4 is a condensate of (L) and/or (D) proline
  • X4 or X3 and X4, being optionally absent, the bonds linking X1 to X2, X2 to X3 where applicable, and X3 to X4 where applicable, possibly being peptide or pseudopeptide bonds,
  • A1 is a covalent bond, an NH group or an oxygen atom, R2, being on the C-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
  • R1 and R2 cannot be hydrogen atoms together, or one of its pharmaceutically acceptable salts, and b. at least one vector chosen from aqueous solutions or biocompatible filling biomaterials.
  • alkyl groups particularly suitable for the implementation of the present invention linear or branched C1 -C12 alkyl groups and more particularly C2 alkyl groups such as acetyl and C12 such as lauroyl will be preferred. .
  • the object of the present invention relates to a composition in which the sequence X1 -X2-X3-X4 of the peptide conjugate can be (L)serine-(L)aspartic acid (SD), (L)serine -(L)aspartic acid-(L)lysine (SDK) or (L)serine-(L)aspartic acid-(L)lysine-(L)proline (SDKP).
  • the sequence X1-X2-X3-X4 of the peptide conjugate is SDKP.
  • a peptide conjugate of formula (I) which is particularly suitable for implementing the present invention is the natural tetrapeptide CH3CO-Ser-Asp-Lys-Pro, also called acetyl-SDKP (AcSDKP).
  • the natural tetrapeptide AcSDKP was isolated from fetal calf bone marrow (WO-88/00594). It can also be obtained by conventional peptide-type synthesis.
  • the peptides or pseudopeptides of formula (I) related to the compound AcSDKP can also be obtained by peptide or pseudopeptide synthesis, as described in document WO-97/28183.
  • peptide conjugate of formula (I) which is particularly suitable for the implementation of the present invention is lauroyl-SDKP, as described in document EP3416730.
  • the at least one peptide conjugate of formula (I) is present in the composition at a concentration of between 10 11 mol/l and 10 3 mol/l, preferably between 10 9 mol/l and 10 5 mol/l. l, and more particularly about 10 8 mol/L.
  • the quantity of the latter is between 5.10 -1 % and 5.10 -4 % by weight, preferably between 5.10 -9 % and 5.10 -6 % by weight, more preferably d about 5.10 _7 % by weight relative to the total weight of the composition.
  • the amount of the latter is between 6.10 -1 % and 6.10 -4 % by weight, preferably between 6.10 -9 % and 6.10 -6 % by weight, more preferably about 6.10 _7 % by weight relative to the total weight of the composition.
  • the at least one peptide conjugate of formula (I) is present in the composition in lyophilized form or in liquid form such as a solution, preferably an aqueous solution, or in the form of lipid nanoparticles as described in EP3416730 .
  • the at least one peptide conjugate of formula (I) is present in a form compatible with administration by injection.
  • the at least one peptide conjugate is present in liquid form.
  • the at least one peptide conjugate is present in the form of nanoparticles and is present at a content of between 1.10 9 % and 10% by weight relative to the total amount of said composition.
  • the composition according to the present invention contains the peptide conjugate in a content of between 1.10 _7 % and 1% by weight, more advantageously in a content of between 1.10 _6 % and 0.1% by weight, or even in a content of between 2.10 _6 % and 0.01% by weight.
  • the content of peptide conjugate according to the present invention is approximately 5.10 -6 % by weight.
  • the composition comprises at least one vector chosen from aqueous solutions or biocompatible filling biomaterials.
  • aqueous solutions comprise water, preferably water having an acceptable osmotic pressure for injection of the saline type or water for injection (WFI), or buffered water , preferably phosphate buffered water at a physiologically acceptable pH.
  • the at least one biocompatible filling biomaterial according to the present invention makes it possible, for example, to fill wrinkles, fine lines, pitting or depressions in the skin with at least one biocompatible filling biomaterial, simple and effective, with practically total bioresorbability, and this without the release of toxic secondary products. Indeed, the degradation products of such a biocompatible filling biomaterial in vivo must be biocompatible and non-toxic. Consequently, a biocompatible non-absorbable filler biomaterial is not desirable.
  • the at least one biocompatible filling biomaterial in accordance with the invention degrades or dissolves practically completely after administration, then is practically completely eliminated from the body by natural processes such as enzymatic hydrolysis.
  • the at least one biocompatible filling biomaterial is a natural polymer chosen from the list comprising polysaccharides and polymers of protein origin.
  • Polysaccharides include glycosaminoglycans such as hyaluronic acid or one of its salts or a derivative of one of its salts; cellulose derivatives such as Carboxy Methyl Cellulose, HPMC (Hydroxy Propyl Methyl Cellulose) and HPC (Hydroxy Propyl Cellulose); and chitosan.
  • Polymers of protein origin include, in particular, collagen.
  • the at least one biocompatible filling biomaterial is more or less viscous hyaluronic acid, crosslinked or not, and more particularly crosslinked hyaluronic acid.
  • Chitosan is a polysaccharide composed of the random distribution of D-glucosamine linked at b-(1-4) (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is produced by chemical (in an alkaline medium) or enzymatic deacetylation of chitin, the component of the arthropod exoskeleton (crustaceans) or the endoskeleton of cephalopods (squid%) or even the wall of fungi. Chitosan has been shown to be biologically renewable, biodegradable, biocompatible, non-antigenic, non-toxic and biofunctional. Chitosan can be formulated as hydrogels.
  • Hyaluronic acid is a non-sulfated glycosaminoglycan (GAG) and one of the major components of the extracellular matrix of most connective tissues such as cartilage, vitreous humor of the eye, synovial fluid or the umbilical cord. It is a polysaccharide which has the advantage of being in the same chemical form regardless of its source. It consists of alternating monosaccharide units of D-glucuronic acid and D-N-acetylglucosamine linked by b 1 -3 glycosidic bonds. Hyaluronic acid is usually found in the form of sodium hyaluronate gel.
  • Hyaluronic acid has been used in various medical and cosmetic applications because it is a major component of the extracellular matrix. Indeed, its ease of injection and its safety of use, but above all its biocompatibility and its absence of toxicity, as well as its physico-chemical properties, make it a compound of choice in various biomedical applications. These same gels are used in dermatology and plastic surgery in the treatment of skin aging as fillers, but have the disadvantage of degrading quickly, hence the need to remedy repeated injections.
  • Carboxymethyl cellulose (CMC), hydroxy propyl methyl cellulose (HPMC) and hydroxy propyl cellulose (HPC) are derivatives of cellulose.
  • Cellulose is the main constituent of plant cell walls, cellulose is the main component of wood and plants in general. Thus, cellulose represents 50% of biomass, making it the most abundant organic matter on Earth. It is a linear homopolymer with the molecular formula (C6Hio05)n consists of D-anhydroglucopyranose units (cyclic form of glucose) linked together by b1 -4 glycosidic bonds. The repeating unit is cellobiose, consisting of two anhydroglucopyranose units.
  • hydroxyl groups of cellulose can react partially or totally with various reagents to give various cellulose derivatives, and in particular cellulose ethers as described above.
  • Cellulosic derivatives are known in particular for their uses in the form of hydrogels as non-toxic, visco-elastic, biodegradable and long-term stable filling gel for breast implants.
  • Collagen is the major protein making up the extracellular matrix of bone. In its native environment, collagen interacts with cells in connective tissues and allows the transduction of signals essential for the regulation of cell anchorage, migration, proliferation, differentiation and survival. There are 27 types, but type 1 collagen being the most abundant, it is also the most studied. Its structure is composed of three polypeptide chains arranged in a triple helix. It gives fabrics their mechanical resistance to stretching. It can be degraded by the action of specific enzymes such as collagenases or metalloproteinases. Thanks to its physico-chemical, mechanical and biological properties, it has been used in many biomedical applications.
  • the at least one biocompatible filling biomaterial is present in the composition in fluid form.
  • the term fluid here includes a gel, for example viscoelastic.
  • a so-called vector fluid such as water, preferably water for injection (WFI), or buffered water, preferably phosphate buffered water at a physiologically acceptable pH and osmotic pressure, in order to rehydrate it.
  • WFI water for injection
  • buffered water preferably phosphate buffered water at a physiologically acceptable pH and osmotic pressure
  • the at least one biocompatible filling biomaterial will be in the form of a gel, for example viscoelastic.
  • a biocompatible filler biomaterial is present in a form compatible with administration by injection. More particularly, the at least one biocompatible biomaterial of filler has sufficient intrinsic viscosity to be preferably injected through a 7G to 34G, preferably 18G to 32G, more preferably 25G to 30G gauge needle.
  • the at least one biocompatible filling biomaterial according to the invention is particularly preferably a biocompatible hydrogel, soluble in water for injectable preparation added with a sodium chloride or directly an isotonic sodium chloride solution. or in an injectable grade buffer solution such as phosphate buffer. More particularly, a biocompatible filling biomaterial such as cross-linked hyaluronic acid hydrogel is preferred.
  • the at least one biocompatible filling biomaterial according to the invention when it is injectable, advantageously combines the convenience of use, possibly the syringeability of the product, the resorbability in a controlled time.
  • the at least one biocompatible filling biomaterial is present in the composition at a content of 0.2% to 5% by weight relative to the total amount of said composition.
  • the composition according to the invention may also comprise an active ingredient.
  • the active agents can in particular comprise all the active agents known for their activity on skin ageing, such as keratolytic or prodesquamating agents, for example [alpha]-hydroxy acids, such as glycolic, lactic, malic, citric, tartaric, mandelic and their derivatives; [beta]-hydroxy acids such as salicylic acid and its derivatives; [alpha]-acetoacids such as ascorbic acid or vitamin C and their derivatives; [beta]-keto acids; retinoids such as retinol (vitamin A) and its esters (palmitate), retinal, retinoic acid and mixtures thereof.
  • keratolytic or prodesquamating agents for example [alpha]-hydroxy acids, such as glycolic, lactic, malic, citric, tartaric, mandelic and their derivatives; [beta]-hydroxy acids such as salicylic acid and its derivatives; [alpha]-acetoa
  • the active ingredients can also include molecules commonly used in aesthetics such as local anesthetics for example lidocaine, vitamins for example A, C, E, amino acids, zinc, polyols, antiseptics for example chlorhexidine, glycerol and their mixtures.
  • the presence and quantity of the active ingredient depends on the desired end use.
  • the amount can range, for example, from about 0.001 to about 30% by weight, preferably from about 0.05 to about 15% by weight and more preferably from about 0.5 to about 5% by weight based on the total weight of the composition.
  • composition according to the present invention is particularly intended for administration by injection.
  • the composition is administered parenterally.
  • Parental administration may be subcutaneous administration, intradermal administration, intraepidermal administration, but is not limited thereto.
  • the composition is administered subcutaneously or intradermally.
  • the administration is intradermal, it is preferentially carried out in the fibrous tissue.
  • the administration of the composition according to the invention is carried out via a syringe adapted according to the type of administration or via any device or technique capable of crossing the epidermal barrier, such as barophoresis, also called “needleless injection”.
  • a syringe adapted according to the type of administration or via any device or technique capable of crossing the epidermal barrier, such as barophoresis, also called “needleless injection”.
  • barophoresis also called “needleless injection”.
  • the user will be able to adapt the type of syringe in accordance with his professional practice.
  • the administration when the administration is intraepidermal or intradermal, it can be carried out by mesotherapy consisting of intraepidermal or intradermal micro injections using one or a multitude of needles or a mesotherapy gun, for example the TechDent Meso Tech Classic. The user will know how to adapt the needle size in accordance with his professional practice.
  • the at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials can be administered separately, simultaneously or sequentially.
  • the active ingredient when the vector is an aqueous solution, the active ingredient is present in the latter.
  • “separately” means an application of at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials at places and/or at separate times.
  • “simultaneously” means that the at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials are mixed beforehand before being administered to a given location, preferably extemporaneously, such as for example by withdrawing each component in one and the same syringe which is then shaken or by withdrawing one of the components which is added to the container of the other component and that the are mixed by suction and discharge.
  • the order of sampling can be done in a first direction, by first taking the at least one peptide conjugate of formula (I) to add it to the container of the vector and then by carrying out the mixing by suction and discharge, or in the opposite direction.
  • “sequentially” means that one of the components is administered first at a given location and that the other component is administered at the same location as the first component.
  • the administration of the second component is either done directly after the first, that is to say without latency, or the administration of the second component can be done remotely, that is to say with a latency time which can be from 1 min to 30J, preferably from 5 min to 15J.
  • the at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials, any two components of the composition according to the present invention can be packaged separately in any means suitable for its application, such as a syringe, a jar, a vial, a tube, a bottle, a pressure-dosed bottle, a bottle with integrated pipette, or a box.
  • a syringe it is designated according to the present invention, according to separate containers.
  • the composition according to the present invention will be prepared just before extemporaneous administration.
  • the at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials can also be packaged in unit form.
  • unit it is designated according to the present invention, in the same container.
  • the composition according to the present invention will be prepared in advance before administration and packaged in any means suitable for its application, such as a syringe, a jar, a vial, a tube, a bottle, a bottle pressure dispenser, a bottle with integrated pipette, or a box.
  • the components of the composition according to the present invention are packaged in unit form, preferably in a syringe.
  • the present invention relates to a kit comprising the composition as described above.
  • the kit may comprise the composition according to the present invention in unit or separate form, and a device for administering said composition, for example, a syringe adapted to the type of administration such as a syringe comprising a needle gauge of 7G to 34G, preferably 18G to 32G, more preferably 25G to 30G.
  • the present invention also relates to the non-therapeutic use, for example, for cosmetic or aesthetic purposes, of the composition according to the present invention for restructuring or preserving the appearance of the skin. More particularly, the composition according to the present invention can be used to improve the elasticity and/or the tone of the skin, and/or to prevent, reduce and/or eliminate the appearance of wrinkles and fine lines on the skin. In one embodiment, the non-therapeutic use of the composition is for anti-aging and skin restructuring use.
  • composition according to the invention makes it possible to obtain improved results compared to topical application and that the combination of at least one compound of formula (I) and of the vector chosen from aqueous solutions or of the biocompatible filling biomaterial acts synergistically so that the effect of the two components separately is less than when they are combined.
  • the composition according to the invention is used as a filling material to supplement a cavity, to restructure an unharmonious volume.
  • Such a filling comprises the filling of wrinkles, fine lines, cutaneous depressions and scars of the human body, including the filling of cutaneous defects secondary to taking a treatment that can lead to lipodystrophy, most often characterized by facial lipoatrophy.
  • the composition according to the invention overcomes the drawbacks of the prior art since it makes it possible to obtain a preservation of the appearance of the skin that is more noticeable and immediate than with a topical composition. It also allows restructuring and preservation of the appearance of the skin that lasts over time beyond fillers used alone.
  • the association between the conjugated peptide according to the present invention and the biocompatible filling biomaterial makes it possible to have an almost instantaneous effect by the injection of the biocompatible filling biomaterial, this effect lasting thanks to the action of the conjugated peptide which provides a smoothing, anti-wrinkle, restructuring, redensifying, moisturizing and toning effect.
  • the combination of the two components makes it possible to obtain a result which lasts, reducing the frequency of the injections.
  • the biocompatible filling biomaterials resorb after a given time, ranging from 3 to 9 months depending on the subject. The subject must therefore return for at the end of this time to have an additional injection and therefore maintain the aesthetic effect which remains ephemeral.
  • the peptide conjugate When the peptide conjugate is used in combination with the biocompatible filling biomaterial in the form of a gel, the latter is trapped in the three-dimensional physical structure of the gel.
  • the biocompatible filling biomaterial being resorbable, as its resorption progresses, the peptide conjugate will be released, then causing a prolonged release over time of the latter.
  • This release according to a slow, so-called prolonged kinetics, makes it possible to increase the T1/2 life of the peptide conjugate and to maintain the aesthetic effects of the biocompatible filling biomaterial while intensifying it.
  • Due to the presence of the conjugated peptide in the physical structure three-dimensional of the gel the degradation of the biocompatible filling biomaterial by the enzymes will be slowed down because it is less immediately available to the enzymes.
  • the composition according to the invention acts both from a mechanical point of view by filling, but also from a biological point of view by preserving the appearance of the subject's skin.
  • the composition according to the present invention makes it possible to obtain the aforementioned effects for at least 6 months, preferably for at least 9 months, more preferably for at least 12 months and even more preferably for at least 18 months.
  • the at least one biocompatible filling biomaterial will not degrade before 3 months, preferably 6 months, but will be degraded after 18 months. Even if the biocompatible filling biomaterial is resorbed after 18 months, the effect of the peptide conjugate will continue to last over time by acting directly on the tissues.
  • the at least one biocompatible filling biomaterial is cross-linked hyaluronic acid and the at least one peptide conjugate is acetyl-SDKP.
  • the hyaluronidase enzymes will degrade the injected cross-linked hyaluronic acid, the in vivo degradation products being the biocompatible and non-toxic hyaluronic acid monomers.
  • acetyl-SDKP will also be released because it will be less and less trapped in the three-dimensional physical structure of the hydrogel. This allows it to play its smoothing, anti-wrinkle, restructuring, redensifying, moisturizing and toning action at the site where the composition is administered.
  • this hydrogel will not degrade for at least 6 months but will be degraded after 18 months.
  • the at least one biocompatible filling biomaterial is cross-linked hyaluronic acid in the form of a hydrogel and the at least one peptide conjugate is lauroyl SDKP in the form of a nanoparticle.
  • the SDKP will have an effect that is all the more prolonged over time.
  • the shape of the peptide conjugate and the cross-linked form of hyaluronic acid, the composition makes it possible to obtain the aforementioned effects for at least 6 months, preferably for at least 9 months, more preferably for at least 12 months and even more preferably for at least 18 month.
  • the non-therapeutic treatment process for restructuring or preserving the appearance of the skin comprises:
  • composition or the kit when the composition or the kit is in a syringe, preferably ready for use, it will not be necessary to withdraw the quantity of the composition according to the invention.
  • composition according to the present invention is administered in an amount ranging from 0.2 mL to 10 mL, preferably from 0.5 mL and 3 mL, more preferably 1 mL.
  • the user will be able to adapt this quantity according to the administration area.
  • the sample is taken using any material suitable for sampling, such as a syringe.
  • the quantity of the composition is taken directly from this container.
  • the composition when each component of the composition is in separate containers, the composition must first be prepared extemporaneously.
  • the first component for example the vector chosen from aqueous solutions or biocompatible filling biomaterials
  • the second component for example the peptide conjugate is sampled. The whole is mixed by shaking the sampling device or by suction and discharge.
  • the amount of vector chosen from aqueous solutions or biocompatible filling biomaterials taken is between 0.1 to 5 mL, preferably from 0.2 to 3 mL, more preferably about 0.5 mL and the amount of at least one peptide conjugate is between 0.1 to 5 mL, preferably 0.2 to 3 mL, more preferably about 0.5 mL.
  • the description relating to the mode of administration of the composition as described above is also applicable for the non-therapeutic treatment method.
  • the non-therapeutic treatment method is an anti-aging and skin restructuring method.
  • the invention therefore also proposes a non-therapeutic treatment method for tightening and smoothing the skin to immediately reduce wrinkles and/or fine lines.
  • Other characteristics and advantages of the invention will emerge better from the examples which follow, given by way of non-limiting illustration.
  • Example 1 Sterile composition in accordance with the invention for injection by mesotherapy [0093] [Table 1]
  • composition preparation The hyaluronic acid is used in the form of sodium hyaluronate of injectable grade and of molecular weight (Mw) of 1.5 MDa.
  • the sodium sodium hyaluronate is dissolved in the solution of EPPI, NaCl and AcSDKP above, with gentle stirring, for 24 hours. After stirring, the pH is checked and adjusted if necessary to pH 7 by adding 0.25N NaOH. The mixture is then sterilized in an autoclave at 121°C so as to obtain an FO sterilization value greater than 15 and filled into a 1 ml pre-filled syringe.
  • This composition is very interesting for mesotherapy treatments and allows the redensification of the dermis, the improvement of the radiance of the skin, the reduction in the depth of wrinkles and fine lines and the hydration of the skin.
  • the composition is used for treating the epidermis by the multipoint injection technique with a syringe fitted with a 30G gauge needle and at a depth of approximately 0.5 mm below the surface area.
  • the excess composition remaining on the surface of the skin is removed by dabbing.
  • composition The properties of the composition were the subject of a test versus the same composition but not comprising Ac-SDKP (“Control composition”).
  • the number of patients included was calculated in order to obtain at least 5 patients treated per injection zone and per product.
  • Example 2 Sterile composition in accordance with the invention for injection by mesotherapy
  • the hyaluronic acid fibers are dissolved in I ⁇ RRI and the other components above with gentle stirring for 10 hours and then left to stand in the refrigerator for 12 hours.
  • the viscous solution thus obtained is then sterilized by filtration and filled into a sterile 5ml bottle.
  • This composition is very advantageous for mesotherapy treatments and allows redensification of the dermis, improvement in the radiance of the skin, reduction in the depth of wrinkles and fine lines and hydration of the skin.
  • composition is used for treating the epidermis by the multipoint injection technique, also called mesotherapy.
  • Example 3 Sterile composition in accordance with the invention based on cross-linked hyaluronic acid
  • compositions of examples 1 and 2 can be formed based on crosslinked hyaluronic acid (HA).
  • the crosslinked HA is obtained by bringing together HA and a crosslinking agent.
  • This crosslinking agent may be chosen from epoxy, aldehyde, polyamines, polyphosphates, divinyl sulfone, and mixtures thereof.
  • the crosslinking agent may be chosen from epoxy and preferentially 1,4-butanediol diglycidyl ether (BDDE).
  • the pH is checked and adjusted to 7.2 if necessary.
  • the composition is then distributed in 1 ml syringes and then sterilized with moist heat by autoclaving so as to obtain an FO sterilizing value greater than 15.
  • the composition is particularly indicated in the treatment of wrinkles by filling as well as for the revitalization of the dermis and prevention of skin aging processes.
  • composition obtained is injectable through 27G to 30G hypodermic needles. It is indicated for the filling, at the level of the middle dermis, of wrinkles and cutaneous breaks as well as for long-term revitalization.
  • Example 4 Sterile composition in accordance with the invention based on hyaluronic acid and carboxymethylcellulose
  • compositions of Examples 1 and 2 can be formed based on hyaluronic acid (FIA) and carboxymethylcellulose (CMC) according to the following table:
  • the pH is checked and adjusted to 7.2 if necessary.
  • the composition is then distributed in 1 ml syringes and then sterilized with moist heat by autoclaving so as to obtain an FO sterilizing value greater than 15.
  • the composition is particularly indicated in the treatment of wrinkles by filling as well as for the revitalization of the dermis and the prevention of skin aging processes.
  • composition obtained is injectable through 27G to 30G hypodermic needles. It is indicated for the filling, at the level of the middle dermis, of wrinkles and cutaneous breaks as well as for long-term revitalization.

Abstract

The present invention relates to a composition comprising: a) at least one peptide conjugate of formula (I) below: R1-X1-X2-X3-X4-A1-R2 (I) wherein: R1, being on the N-terminal side, is a hydrogen atom, or a substituted or unsubstituted, linear or branched C1-C50 alkyl group, X1 is a condensate of (L)-serine, X2 is a condensate of (L) and/or (D) aspartic acid, X3 is a condensate of (L) and/or (D) lysine, X4 is a condensate of (L) and/or (D) proline, X4, or X3 and X4, being optionally absent, the bonds connecting X1 to X2, X2 to X3 where appropriate, and X3 to X4 where appropriate, possibly being peptide or pseudopeptide bonds, A1 is a covalent bond, an NH group or an oxygen atom, R2, being on the C-terminal side, is a hydrogen atom, or a substituted or unsubstituted, linear or branched C1-C50 alkyl group, R1 and R2 not being able to both be hydrogen atoms, or a physiologically acceptable salt thereof, and b) at least one carrier chosen from aqueous solutions or biocompatible filling biomaterials.

Description

Description Description
Titre : Composition pour injection comprenant un conjugué peptidique Title: Composition for injection comprising a peptide conjugate
[0001] La présente invention concerne une composition comprenant au moins un conjugué peptidique de formule (I) et au moins un vecteur, son utilisation pour restructurer ou préserver l’aspect de la peau, son procédé d’application, ainsi que son kit. The present invention relates to a composition comprising at least one peptide conjugate of formula (I) and at least one vector, its use for restructuring or preserving the appearance of the skin, its method of application, as well as its kit.
Domaine technique Technical area
[0002] Le vieillissement de la peau est un phénomène complexe ayant des origines diverses, qui peuvent être extérieures (exposition au soleil, au froid, agents oxydants, etc.) ou intrinsèques (génétique, protéiques, etc.). [0002] The aging of the skin is a complex phenomenon having various origins, which can be external (exposure to the sun, to cold, oxidizing agents, etc.) or intrinsic (genetics, proteins, etc.).
[0003] La peau est un tissu, constitué de couches (épiderme, derme, et hypoderme, derme et épiderme étant liés par la jonction dermo-épidermique « JDE »), ayant le rôle de barrière de protection entre le milieu intérieur et extérieur. [0003] The skin is a tissue, consisting of layers (epidermis, dermis, and hypodermis, dermis and epidermis being linked by the dermo-epidermal junction “JDE”), having the role of protective barrier between the interior and exterior environment.
[0004] Le vieillissement de la peau se traduit en surface par l’apparition de rides et ridules. Ceci est dû en partie par un relâchement et une perte de densité et épaisseur des tissus cutanés et sous cutanés et à une perte d’élasticité de ces derniers. Ainsi, le derme assure la fonction fondamentale de cohésion de la peau et constitue une cible privilégiée du traitement antirides. [0004] The aging of the skin is reflected on the surface by the appearance of fine lines and wrinkles. This is partly due to a relaxation and a loss of density and thickness of the cutaneous and subcutaneous tissues and a loss of elasticity of the latter. Thus, the dermis ensures the fundamental function of cohesion of the skin and constitutes a privileged target of the anti-wrinkle treatment.
[0005] La perte d’élasticité du derme/épiderme s’explique par la conjoncture de plusieurs phénomènes. Elle est due en partie à la diminution de la quantité de collagène et la réduction du taux de fibronectine dans le derme. De plus, les fibroblastes se transforment en fibrocytes ou disparaissent. A ceci, s’ajoute un aplatissement de la JDE qui perd ainsi progressivement ses ondulations caractéristiques diminuant en conséquence l’interface épiderme-derme. Les réseaux moléculaires de la peau se déstructurent : le squelette protéique se fragilise, les kératinocytes basaux montrent une adhérence moindre, ce qui a pour conséquence une altération des fonctions biologiques et de soutien de la JDE. [0006] Des moyens variés ont été proposés contre le vieillissement cutané, allant de la composition cosmétique anti-rides aux injections pour le comblement de rides. [0005] The loss of elasticity of the dermis/epidermis is explained by the combination of several phenomena. It is partly due to the decrease in the amount of collagen and the reduction in the level of fibronectin in the dermis. In addition, fibroblasts turn into fibrocytes or disappear. To this is added a flattening of the JDE which thus gradually loses its characteristic undulations, consequently reducing the epidermis-dermis interface. The molecular networks of the skin are destructured: the protein skeleton becomes fragile, the basal keratinocytes show less adherence, which results in an alteration of the biological and support functions of the JDE. [0006] Various means have been proposed against skin ageing, ranging from anti-wrinkle cosmetic compositions to injections for filling in wrinkles.
[0007] La molécule Ac-SDKP-OH est un tétrapeptide naturel (Acétyl- Sérine-Acide aspartique-Lysine-Proline-OH) identifiée pour ses propriétés cosmétiques au niveau de la peau lors d’un usage topique (EP 1 786 386, Bakala et al.). Toutefois, cette molécule s’hydrolyse très facilement, ce qui rend son exploitation commerciale délicate en particulier pour des compositions cosmétiques d’usage commun (i.e. stockées à température ambiante, ouvertes et refermées à la convenance du patient). La molécule est en outre très sensible à l’hydrolyse enzymatique. Il en est de même pour ses analogues couverts par EP 1 786 386. Ainsi, de par sa fragilité, l’accès aux couches les plus profondes de la peau par cette molécule est limité, restreignant ainsi l’effet du traitement. Une solution proposée par EP3416730, est une formulation de type émulsion/nanoémulsion pour surmonter ces difficultés. Cependant, l’effet anti-rides n’est pas instantané et la composition anti-ride nécessite d’être appliquée pendant plusieurs jours, semaines ou mois afin d’obtenir l’effet et de l’entretenir. [0007] The Ac-SDKP-OH molecule is a natural tetrapeptide (Acetyl-Serine-Aspartic acid-Lysine-Proline-OH) identified for its cosmetic properties on the skin during topical use (EP 1 786 386, Bakala et al.). However, this molecule is very easily hydrolyzed, which makes its commercial exploitation difficult, in particular for common-use cosmetic compositions (i.e. stored at room temperature, opened and closed at the convenience of the patient). The molecule is also very sensitive to enzymatic hydrolysis. The same is true for its analogues covered by EP 1 786 386. Thus, due to its fragility, access to the deepest layers of the skin by this molecule is limited, thus restricting the effect of the treatment. A solution proposed by EP3416730 is a formulation of the emulsion/nanoemulsion type to overcome these difficulties. However, the anti-wrinkle effect is not instantaneous and the anti-wrinkle composition needs to be applied for several days, weeks or months in order to obtain the effect and maintain it.
[0008] Parmi les méthodes d'élimination des rides par injection, la méthode consistant à paralyser les muscles qui provoquent les rides avec le Botox est largement utilisée, mais elle crée une expression non naturelle et est difficile à utiliser sous les yeux, la lèvre inférieure, les plis nasogéniens, etc. Le problème est que l'effet n'est que de 3 à 6 mois et nécessite de répéter les injections. Une autre méthode consiste à utiliser un produit de comblement tel que l’acide hyaluronique ou le collagène. Cependant, la résorption de ce type de produit, de 3 à 6 mois chez la plupart des sujets, est telle que les injections doivent être répétées à intervalles proches et réguliers pour préserver les effets. [0008] Among the methods of removing wrinkles by injection, the method of paralyzing the muscles that cause wrinkles with Botox is widely used, but it creates an unnatural expression and is difficult to use under the eyes, lip inferior, nasolabial folds, etc. The problem is that the effect is only 3-6 months and requires repeated injections. Another method is to use a filler such as hyaluronic acid or collagen. However, the resorption of this type of product, from 3 to 6 months in most subjects, is such that the injections must be repeated at close and regular intervals to preserve the effects.
[0009] Les demandeurs ont découvert qu’en associant un vecteur avec un conjugué peptidique il était possible d’obtenir un effet antirides immédiat qui se prolonge dans le temps réduisant donc la fréquence des injections. [0009] The applicants have discovered that by combining a vector with a peptide conjugate, it is possible to obtain an immediate anti-wrinkle effect which is prolonged over time, thus reducing the frequency of injections.
Résumé de l’invention [0010] En conséquence, dans un premier aspect de l'invention, il est fourni une composition comprenant : a. au moins un conjugué peptidique de formule (I) suivante : Summary of the invention Accordingly, in a first aspect of the invention there is provided a composition comprising: a. at least one peptide conjugate of the following formula (I):
R1 -X1 -X2-X3-X4-A1 -R2 (I) dans laquelle : R1 -X1 -X2-X3-X4-A1 -R2 (I) in which:
R1 , étant du côté N-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, R1, being on the N-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
X1 est un condensât de (L)-sérine, X1 is a condensate of (L)-serine,
X2 est un condensât de (L) et/ou (D) acide aspartique, X2 is a condensate of (L) and/or (D) aspartic acid,
X3 est un condensât de (L) et/ou (D) lysine, , X3 is a condensate of (L) and/or (D) lysine, ,
X4 est un condensât de (L) et/ou (D) proline, X4 is a condensate of (L) and/or (D) proline,
X4, ou X3 et X4, étant optionnellement absents, les liaisons reliant X1 à X2, X2 à X3 le cas échéant, et X3 à X4 le cas échéant, pouvant être des liaisons peptidiques ou pseudopeptidiques, X4, or X3 and X4, being optionally absent, the bonds linking X1 to X2, X2 to X3 where applicable, and X3 to X4 where applicable, possibly being peptide or pseudopeptide bonds,
A1 est une liaison covalente, un groupement NH ou un atome d’oxygène,A1 is a covalent bond, an NH group or an oxygen atom,
R2, étant du côté C-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, R2, being on the C-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
R1 et R2 ne pouvant être conjointement des atomes d’hydrogène, ou l’un de ses sels pharmaceutiquement acceptables, et b. au moins un vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement. R1 and R2 cannot be hydrogen atoms together, or one of its pharmaceutically acceptable salts, and b. at least one vector chosen from aqueous solutions or biocompatible filling biomaterials.
[0011] Dans un second aspect, l’invention concerne l’utilisation non thérapeutique de la composition selon la présente invention pour restructurer ou préserver l’aspect de la peau, en particulier en profondeur au niveau dermique. In a second aspect, the invention relates to the non-therapeutic use of the composition according to the present invention for restructuring or preserving the appearance of the skin, in particular in depth at the dermal level.
[0012] Dans un troisième aspect, l’invention concerne un kit comprenant la composition selon la présente invention et un dispositif d’administration de ladite composition. In a third aspect, the invention relates to a kit comprising the composition according to the present invention and a device for administering said composition.
[0013] Dans un dernier aspect, l’invention porte sur un procédé de traitement non thérapeutique de restructuration ou de préservation de l’aspect de la peau, en particulier en profondeur au niveau dermique, ledit procédé comprenant : In a final aspect, the invention relates to a non-therapeutic treatment method for restructuring or preserving the appearance of the skin, in particular in depth at the dermal level, said method comprising:
- la fourniture de la composition ou du kit selon l’invention, - le prélèvement d’une quantité de la composition selon l’invention, et - the supply of the composition or the kit according to the invention, - the removal of a quantity of the composition according to the invention, and
- l’administration par injection de manière séparée ou séquentielle ou simultanée, de préférence simultanée, de la dite composition. - administration by injection separately or sequentially or simultaneously, preferably simultaneously, of said composition.
Exposé de l’invention Disclosure of Invention
[0014] Définitions [0014] Definitions
[0015] Par « Conjugué peptidique », il est fait référence à un brin peptidique conjugué, i.e. lié, à un fragment moléculaire d’une autre nature, par exemple un groupement alkyle linéaire ou ramifié, substitué ou non substitué en C1 à C50, de préférence en C2, en C12 ou en C16. Il est admis dans l’art qu’un peptide comprend un nombre X d’acides aminés, il s’agit en réalité d’un nombre X d’acides aminés condensés, i.e. ayant chacun perdu une molécule d’eau (s’ils sont reliés les uns aux autres par une liaison peptidique, typiquement). [0015] The term "peptide conjugate" refers to a conjugated peptide strand, i.e. linked, to a molecular fragment of another nature, for example a linear or branched, substituted or unsubstituted C1 to C50 alkyl group, preferably C2, C12 or C16. It is accepted in the art that a peptide comprises X number of amino acids, it is actually X number of condensed amino acids, i.e. having each lost a molecule of water (if they are connected to each other by a peptide bond, typically).
[0016] Par « brin peptidique » il est fait référence à un polymère d'acides aminés, lesquels acides aminés sont reliés entre eux par au moins une liaison peptidique ou pseudopeptidique. Ainsi, un peptide comprenant deux résidus d’acides aminés est un dipeptide ; un peptide comprenant trois résidus d’acides aminés est un tri peptide; un peptide comprenant quatre résidus d’acides aminés est un tétrapeptide ; et ainsi de suite. [0016] The term "peptide strand" refers to a polymer of amino acids, which amino acids are linked together by at least one peptide or pseudopeptide bond. Thus, a peptide comprising two amino acid residues is a dipeptide; a peptide comprising three amino acid residues is a tripeptide; a peptide comprising four amino acid residues is a tetrapeptide; And so on.
[0017] Par « liaison peptidique » il est fait référence à un groupement carbonyle CO et un groupement aminé NH dans un peptide. La liaison peptidique est donc une liaison amide reliant deux acides aminés entre eux. Ainsi les acides aminés sont dits « condensés » car ils ont perdu au moins une molécule d'eau pour former la ou les liaisons peptidiques dans lesquels ils sont impliqués. [0017] The term “peptide bond” refers to a CO carbonyl group and an NH amino group in a peptide. The peptide bond is therefore an amide bond linking two amino acids together. Thus amino acids are said to be “condensed” because they have lost at least one molecule of water to form the peptide bond(s) in which they are involved.
[0018] Par « liaison pseudo peptidique » il est fait référence à une liaisons qui s’engage entre le groupement carbonyle CO ou le groupement aminé NH du carbone alpha du peptide et un autre groupement méthyle CH3, carbonyle CO ou groupement aminé NH d’une autre molécule qui n’est pas un peptide, par exemple une chaîne hydrocarbonée de C1 à C50. [0019] Par « SDKP »il est fait référence à un brin peptidique de structure :
Figure imgf000006_0001
The term "pseudo-peptide bond" refers to a bond which engages between the carbonyl group CO or the amino group NH of the alpha carbon of the peptide and another methyl group CH3, carbonyl CO or amino group NH of another molecule which is not a peptide, for example a C1 to C50 hydrocarbon chain. [0019] The term "SDKP" refers to a peptide strand of structure:
Figure imgf000006_0001
Avantageusement les acides aminés sont de configuration L :
Figure imgf000006_0002
Les groupements fonctionnels (e.g. NH2, OH, COOH) peuvent être sous forme protonée ou déprotonée selon le pH environnant. Ces groupements peuvent également être protégés par des groupements protecteur classiques tels que trouvés dans les ouvrages "Protective Groups in Organic Synthesis", Wiley, New York, 2007 4e édition et/ou Harrison et al. "Compendium of Synthetic Organic Methods", Vol. 1 à 8 (J. Wiley & sons, 1971 to 1996). Ainsi typiquement, les fonctions COOH peuvent être protégées par un groupement ester tel que O-tert- Butyle (OtBu), O-Méthyle (OMe), O-Ethyle (OEt), ou encore O-benzyle, la fonction OH par un éther de tert-Butyle, Méthyle, Ethyle, ou benzyle, et NH2 par un groupement acido-labile tel que Boc ou baso-labile tel que Fmoc. [0020] L'expression « alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué», représente une chaîne hydrocarbonée saturée, linéaire ou ramifiée, comportant de 1 à 50 atomes de carbone, comme par exemple un méthyle (C1), éthyle (C2), propyle ou isopropyle (C3), butyle, isobutyle ou tertbutyle (C4), pentyle (C5), hexyle (C6), heptyle (C7), octyle C8), nonyle (C9), décyle (C10), undécyle (C11), dodécyle ou lauroyle (C12), n-tridécyle (C13), n-tétradécyle (C14), n- pentadécyle (C15), n-hexadécyle (16), n-heptadécyle (C17), n-octadécyle (C18), n- nonadécyle (C19), n-eicosyle (C20), 1-méthyl-dodécyle (C13), 2-méthyl-dodécyle (C13), 1 -éthyl-undécyle (C13), 2-éthyl-undécyle (C13), etc. Les alkyles peuvent être substitués ou non. Préférentiellement les alkyles peuvent être substitués par un ou plusieurs halogènes tels que F, Cl, Br, I, ou par d’autres fragments tels que OH, SH, N02, NH2, COOH. Advantageously, the amino acids are of L configuration:
Figure imgf000006_0002
Functional groups (eg NH2, OH, COOH) can be in protonated or deprotonated form depending on the surrounding pH. These groups can also be protected by conventional protective groups such as found in the works “Protective Groups in Organic Synthesis”, Wiley, New York, 2007 4th edition and/or Harrison et al. "Compendium of Synthetic Organic Methods", Vol. 1 to 8 (J. Wiley & sons, 1971 to 1996). Thus typically, the COOH functions can be protected by an ester group such as O-tert-Butyl (OtBu), O-Methyl (OMe), O-Ethyl (OEt), or even O-benzyl, the OH function by an ether of tert-Butyl, Methyl, Ethyl, or benzyl, and NH2 by an acid-labile group such as Boc or baso-labile group such as Fmoc. The expression "linear or branched, substituted or unsubstituted C1-C50 alkyl" represents a saturated hydrocarbon chain, linear or branched, comprising from 1 to 50 carbon atoms, such as for example a methyl (C1), ethyl (C2), propyl or isopropyl (C3), butyl, isobutyl or tert-butyl (C4), pentyl (C5), hexyl (C6), heptyl (C7), octyl C8), nonyl (C9), decyl (C10), undecyl (C11), dodecyl or lauroyl (C12), n-tridecyl (C13), n-tetradecyl (C14), n-pentadecyl (C15), n-hexadecyl (16), n-heptadecyl (C17), n-octadecyl (C18), n-nonadecyl (C19), n-eicosyl (C20), 1-methyl-dodecyl (C13), 2-methyl-dodecyl (C13), 1-ethyl-undecyl (C13), 2-ethyl-undecyl (C13), etc. The alkyls may or may not be substituted. Preferably, the alkyls can be substituted by one or more halogens such as F, Cl, Br, I, or by other fragments such as OH, SH, N02, NH2, COOH.
[0021] Par le terme « de sel physiologiquement acceptable », on entend au sens de la présente invention tout sel préparé à partir de tout acide non toxique physiologiquement acceptable, y compris les acides organiques et inorganiques. De tels acides incluent l'acide acétique, benzènesulfonique, benzoïque, citrique, éthanesulfonique, fumarique, gluconique, glutamique, bromhydrique, chlorhydrique, lactique, maléique, malique, mandélique, méthanesulfonique, mucique, nitrique, pamoique, pantothénique, phosphorique, succinique, tartarique et paratoluènesulfonique. Avantageusement, on utilise l'acide chlorhydrique. The term “physiologically acceptable salt” is understood to mean, within the meaning of the present invention, any salt prepared from any physiologically acceptable non-toxic acid, including organic and inorganic acids. Such acids include acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, tartaric acid and paratoluenesulfonic. Advantageously, hydrochloric acid is used.
[0022] Par « biocompatible », on entend selon l’invention compatible avec le corps humain ou animal. En particulier un biomatériau biocompatible est, selon l’invention, un matériau répondant aux critères donnés par la norme ISO 10993 relative aux dispositifs médicaux. By "biocompatible" is meant according to the invention compatible with the human or animal body. In particular, a biocompatible biomaterial is, according to the invention, a material meeting the criteria given by the ISO 10993 standard relating to medical devices.
[0023] Par « tissu fibreux », on entend selon l’invention un espace sous-cutané de nature essentiellement fibreuse, et apte à être rempli par des produits de comblement. By "fibrous tissue" is meant according to the invention a subcutaneous space of essentially fibrous nature, and capable of being filled with fillers.
[0024] Par « sous-cutanée », on entend selon l’invention hypodermique, donc sous le derme. [0024] By "subcutaneous" is meant according to the hypodermic invention, therefore under the dermis.
[0025] Par « intradermique », on entend selon l’invention dans l’épaisseur du derme. By "intradermal" is meant according to the invention in the thickness of the dermis.
[0026] Par « gel », on entend une structure physique tridimensionnelle ayant des propriétés viscosifiantes, rhéologiques et thixotropiques. [0026] By “gel”, we mean a three-dimensional physical structure having viscosifying, rheological and thixotropic properties.
[0027] On entend par « fluide vecteur » selon l’invention un composé sous forme fluide qui peut véhiculer le conjugué peptidique, notamment si celui-ci est sous forme lyophilisée, et/ou un biomatériau biocompatible de comblement se présentant naturellement sous forme de poudre solide. [0028] On entend par « hydrogel » un gel obtenu par solubilisation de l’au moins un biomatériau biocompatible de comblement dans de l’eau (par exemple par l’intermédiaire d’un solvant aqueux). The term “vector fluid” according to the invention is understood to mean a compound in fluid form which can convey the peptide conjugate, in particular if the latter is in lyophilized form, and/or a biocompatible filling biomaterial which occurs naturally in the form of solid powder. The term “hydrogel” is understood to mean a gel obtained by dissolving at least one biocompatible filling biomaterial in water (for example by means of an aqueous solvent).
[0029] Par « injection » au sens de la présente invention, on entend une injection effectuée avec aiguille, comme par exemple avec une seringue adaptée en fonction du type d’administration ou effectuée sans aiguille, comme par exemple à l’aide de tout dispositif ou technique capable de faire franchir la barrière épidermique tel que la barophorèse. By "injection" within the meaning of the present invention, is meant an injection performed with a needle, such as with a syringe adapted according to the type of administration or performed without a needle, such as for example using any device or technique capable of crossing the epidermal barrier, such as barophoresis.
[0030] Par « barophorèse » ou « injection sans aiguille », on entend la propulsion à une vitesse supersonique d’un mélange d’air et de composés par l’intermédiaire d’une pièce à main. Ce mélange, soumis à une haute pression, arrive sur la peau sous forme de gouttelettes microscopiques. Les pores vont alors s’ouvrir, permettant la pénétration dudit/desdits composé(s). Préférentiellement, le mélange est un mélange d’air et de la composition selon la présente invention. [0030] By “barophoresis” or “needleless injection”, we mean the propulsion at supersonic speed of a mixture of air and compounds via a handpiece. This mixture, subjected to high pressure, arrives on the skin in the form of microscopic droplets. The pores will then open, allowing the penetration of said compound(s). Preferably, the mixture is a mixture of air and the composition according to the present invention.
[0031] Par « environ » il est désigné une teneur exprimée en % ou en mol/L ou en ml ou en mm, avec une marge de +/- 20%, de préférence +/- 10%, plus préférentiellement +/- 5%. [0031] The term “approximately” denotes a content expressed in % or in mol/L or in ml or in mm, with a margin of +/- 20%, preferably +/- 10%, more preferably +/- 5%.
[0032] Ainsi, la composition selon la présente invention comprend : a. au moins un conjugué peptidique de formule (I) suivante : Thus, the composition according to the present invention comprises: a. at least one peptide conjugate of the following formula (I):
R1 -X1 -X2-X3-X4-A1 -R2 (I) dans laquelle : R1 -X1 -X2-X3-X4-A1 -R2 (I) in which:
R1 , étant du côté N-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, R1, being on the N-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
X1 est un condensât de (L)-sérine, X1 is a condensate of (L)-serine,
X2 est un condensât de (L) et/ou (D) acide aspartique, X2 is a condensate of (L) and/or (D) aspartic acid,
X3 est un condensât de (L) et/ou (D) lysine, , X3 is a condensate of (L) and/or (D) lysine, ,
X4 est un condensât de (L) et/ou (D) proline, X4 is a condensate of (L) and/or (D) proline,
X4, ou X3 et X4, étant optionnellement absents, les liaisons reliant X1 à X2, X2 à X3 le cas échéant, et X3 à X4 le cas échéant, pouvant être des liaisons peptidiques ou pseudopeptidiques, X4, or X3 and X4, being optionally absent, the bonds linking X1 to X2, X2 to X3 where applicable, and X3 to X4 where applicable, possibly being peptide or pseudopeptide bonds,
A1 est une liaison covalente, un groupement NH ou un atome d’oxygène, R2, étant du côté C-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, A1 is a covalent bond, an NH group or an oxygen atom, R2, being on the C-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
R1 et R2 ne pouvant être conjointement des atomes d’hydrogène, ou l’un de ses sels pharmaceutiquement acceptables, et b. au moins un vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement. R1 and R2 cannot be hydrogen atoms together, or one of its pharmaceutically acceptable salts, and b. at least one vector chosen from aqueous solutions or biocompatible filling biomaterials.
[0033] Conjugué peptidique de formule (I) [0033] Peptide conjugate of formula (I)
[0034] Parmi les groupements alkyles particulièrement adaptés à la mise en œuvre de la présente invention, on préférera les groupements alkyles C1 -C12 linéaires ou ramifiés et plus particulièrement les groupements alkyles en C2 tel que l’acétyle et en C12 tel que le lauroyle. Among the alkyl groups particularly suitable for the implementation of the present invention, linear or branched C1 -C12 alkyl groups and more particularly C2 alkyl groups such as acetyl and C12 such as lauroyl will be preferred. .
[0035] Plus précisément, l’objet de la présente invention concerne une composition dans laquelle la séquence X1 -X2-X3-X4 du conjugué peptidique peut être (L)sérine- (L)acide aspartique (SD), (L)sérine-(L)acide aspartique-(L)lysine (SDK) ou (L)sérine-(L)acide aspartique-(L)lysine-(L)proline (SDKP). De manière préférée, la séquence X1 -X2-X3-X4 du conjugué peptidique est SDKP. More specifically, the object of the present invention relates to a composition in which the sequence X1 -X2-X3-X4 of the peptide conjugate can be (L)serine-(L)aspartic acid (SD), (L)serine -(L)aspartic acid-(L)lysine (SDK) or (L)serine-(L)aspartic acid-(L)lysine-(L)proline (SDKP). Preferably, the sequence X1-X2-X3-X4 of the peptide conjugate is SDKP.
[0036] Un exemple de conjugué peptidique de formule (I) convenant particulièrement bien à la mise en œuvre de la présente invention est le tétrapeptide naturel CH3CO-Ser-Asp-Lys-Pro, aussi appelé acétyle-SDKP (AcSDKP). Le tétrapeptide naturel AcSDKP a été isolé de la moelle osseuse de veau foetal (WO- 88/00594). Il peut également être obtenu par une synthèse de type peptidique classique. Les peptides ou pseudopeptides de formule (I) apparentés au composé AcSDKP peuvent également être obtenus par une synthèse peptidique ou pseudopeptidique, comme décrit dans le document WO-97/28183. An example of a peptide conjugate of formula (I) which is particularly suitable for implementing the present invention is the natural tetrapeptide CH3CO-Ser-Asp-Lys-Pro, also called acetyl-SDKP (AcSDKP). The natural tetrapeptide AcSDKP was isolated from fetal calf bone marrow (WO-88/00594). It can also be obtained by conventional peptide-type synthesis. The peptides or pseudopeptides of formula (I) related to the compound AcSDKP can also be obtained by peptide or pseudopeptide synthesis, as described in document WO-97/28183.
[0037] Un autre exemple de conjugué peptidique de formule (I) convenant particulièrement bien à la mise en œuvre de la présente invention est le lauroyl- SDKP, comme décrit dans le document EP3416730. Another example of a peptide conjugate of formula (I) which is particularly suitable for the implementation of the present invention is lauroyl-SDKP, as described in document EP3416730.
[0038] L’au moins un conjugué peptidique de formule (I) est présent dans la composition à une concentration comprise entre 1011 mol/l et 103 mol/l, de préférence entre 109 mol/l et 105 mol/l, et plus particulièrement d’environ 108 mol/L. Préférentiellement lorsque le conjugué peptidique de formule (I) est le AcSDKP, la quantité de ce dernier est comprise entre 5.10-1 °% et 5.10_4% en poids, de préférence entre 5.10_9% et 5.10_6% en poids, plus préférentiellement d’environ 5.10_7% en poids par rapport au poids total de la composition. Lorsque le conjugué peptidique de formule (I) est le lauroyl-SDKP, la quantité de ce dernier est comprise entre 6.10-1 °% et 6.10_4% en poids, de préférence entre 6.10_9% et 6.10_6% en poids, plus préférentiellement d’environ 6.10_7% en poids par rapport au poids total de la composition. The at least one peptide conjugate of formula (I) is present in the composition at a concentration of between 10 11 mol/l and 10 3 mol/l, preferably between 10 9 mol/l and 10 5 mol/l. l, and more particularly about 10 8 mol/L. Preferably, when the peptide conjugate of formula (I) is AcSDKP, the quantity of the latter is between 5.10 -1 % and 5.10 -4 % by weight, preferably between 5.10 -9 % and 5.10 -6 % by weight, more preferably d about 5.10 _7 % by weight relative to the total weight of the composition. When the peptide conjugate of formula (I) is lauroyl-SDKP, the amount of the latter is between 6.10 -1 % and 6.10 -4 % by weight, preferably between 6.10 -9 % and 6.10 -6 % by weight, more preferably about 6.10 _7 % by weight relative to the total weight of the composition.
[0039] L’au moins un conjugué peptidique de formule (I) est présent dans la composition sous forme lyophilisée ou sous forme liquide telle qu’une solution, de préférence une solution aqueuse, ou sous forme de nanoparticules lipidiques tel que décrit dans EP3416730. De préférence, l’au moins un conjugué peptidique de formule (I) est présent sous une forme compatible avec une administration par injection. The at least one peptide conjugate of formula (I) is present in the composition in lyophilized form or in liquid form such as a solution, preferably an aqueous solution, or in the form of lipid nanoparticles as described in EP3416730 . Preferably, the at least one peptide conjugate of formula (I) is present in a form compatible with administration by injection.
[0040] Dans un mode de réalisation, l’au moins un conjugué peptidique est présent sous forme liquide. In one embodiment, the at least one peptide conjugate is present in liquid form.
[0041] Dans un autre mode de réalisation, l’au moins un conjugué peptidique est présent sous forme de nanoparticules et est présent à une teneur comprise entre 1 .109% et 10% en poids relatif à la quantité totale de ladite composition. Préférentiellement, la composition selon la présente invention contient le conjugué peptidique à une teneur comprise entre 1.10_7% et 1 % en poids, plus avantageusement à une teneur comprise entre 1.10_6% et 0.1 % en poids, voire à une teneur comprise entre 2.10_6% et 0.01 % en poids. De manière toute préférée, la teneur en conjugué peptidique selon la présente invention est d’environ 5.10_6% en poids. In another embodiment, the at least one peptide conjugate is present in the form of nanoparticles and is present at a content of between 1.10 9 % and 10% by weight relative to the total amount of said composition. Preferably, the composition according to the present invention contains the peptide conjugate in a content of between 1.10 _7 % and 1% by weight, more advantageously in a content of between 1.10 _6 % and 0.1% by weight, or even in a content of between 2.10 _6 % and 0.01% by weight. Most preferably, the content of peptide conjugate according to the present invention is approximately 5.10 -6 % by weight.
[0042] Vecteur [0042] Vector
[0043] Au sens de la présente invention, la composition comprend au moins un vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement. [0044] Les solutions aqueuses selon la présentation comprennent de l’eau, de préférence de l’eau présentant une pression osmotique acceptable pour injection de type sérum physiologique ou de l’eau pour préparation injectable (EPPI), ou de l’eau tamponnée, de préférence de l’eau tamponnée phosphate à un pH physiologiquement acceptable. Within the meaning of the present invention, the composition comprises at least one vector chosen from aqueous solutions or biocompatible filling biomaterials. [0044] The aqueous solutions according to the presentation comprise water, preferably water having an acceptable osmotic pressure for injection of the saline type or water for injection (WFI), or buffered water , preferably phosphate buffered water at a physiologically acceptable pH.
[0045] L’au moins un biomatériau biocompatible de comblement selon la présente invention permet, par exemple, de combler les rides, ridules, citatrices ou dépressions cutanées par au moins un biomatériau biocompatible de comblement, simple et efficace, à biorésorbabilité pratiquement totale, et ce sans libération de produits secondaires toxiques. En effet, les produits de dégradation d’un tel biomatériau biocompatible de comblement in vivo doivent êtres biocompatibles et atoxiques. En conséquence, un biomatériau biocompatible de comblement non résorbable n’est pas souhaitable. The at least one biocompatible filling biomaterial according to the present invention makes it possible, for example, to fill wrinkles, fine lines, pitting or depressions in the skin with at least one biocompatible filling biomaterial, simple and effective, with practically total bioresorbability, and this without the release of toxic secondary products. Indeed, the degradation products of such a biocompatible filling biomaterial in vivo must be biocompatible and non-toxic. Consequently, a biocompatible non-absorbable filler biomaterial is not desirable.
[0046] Ainsi, avantageusement selon l’invention, l’au moins un biomatériau biocompatible de comblement conforme à l’invention se dégrade ou se solubilise pratiquement totalement après administration, puis est pratiquement totalement éliminé de l’organisme par les processus naturels tels que l’hydrolyse enzymatique. Thus, advantageously according to the invention, the at least one biocompatible filling biomaterial in accordance with the invention degrades or dissolves practically completely after administration, then is practically completely eliminated from the body by natural processes such as enzymatic hydrolysis.
[0047] L’au moins un biomatériau biocompatible de comblement est un polymère naturel choisi dans la liste comprenant les polysaccharides et les polymères d’origine protéique. Les polysaccharides comprennent les glycosaminoglycannes tels qu’un acide hyaluronique ou un de ses sels ou un dérivé d’un de ses sels ; les dérivés cellulosiques tels que la Carboxy Méthyl Cellulose, l’HPMC (Hydroxy Propyl Méthyl Cellulose) et l’HPC (Hydroxy Propyl Cellulose) ; et le chitosan. Les polymères d’origine protéique comprennent notamment le collagène. De préférence l’au moins un biomatériau biocompatible de comblement est l’acide hyaluronique plus ou moins visqueux, réticulé ou non et plus particulièrement l’acide hyaluronique réticulé. The at least one biocompatible filling biomaterial is a natural polymer chosen from the list comprising polysaccharides and polymers of protein origin. Polysaccharides include glycosaminoglycans such as hyaluronic acid or one of its salts or a derivative of one of its salts; cellulose derivatives such as Carboxy Methyl Cellulose, HPMC (Hydroxy Propyl Methyl Cellulose) and HPC (Hydroxy Propyl Cellulose); and chitosan. Polymers of protein origin include, in particular, collagen. Preferably, the at least one biocompatible filling biomaterial is more or less viscous hyaluronic acid, crosslinked or not, and more particularly crosslinked hyaluronic acid.
[0048] Le chitosan est un polysaccharide composé de la distribution aléatoire de D-glucosamine liée en b-(1 -4) (unité désacétylée) et de N-acétyl-D-glucosamine (unité acétylée). Il est produit par désacétylation chimique (en milieu alcalin) ou enzymatique de la chitine, le composant de l'exosquelette des arthropodes (crustacés) ou de l'endosquelette des céphalopodes (calmars...) ou encore de la paroi des champignons. Il a été montré que le chitosane est biologiquement renouvelable, biodégradable, biocompatible, non-antigénique, non-toxique et biofonctionnel. Le chitosane peut être formulé sous forme d’hydrogels. Chitosan is a polysaccharide composed of the random distribution of D-glucosamine linked at b-(1-4) (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is produced by chemical (in an alkaline medium) or enzymatic deacetylation of chitin, the component of the arthropod exoskeleton (crustaceans) or the endoskeleton of cephalopods (squid...) or even the wall of fungi. Chitosan has been shown to be biologically renewable, biodegradable, biocompatible, non-antigenic, non-toxic and biofunctional. Chitosan can be formulated as hydrogels.
[0049] L’acide hyaluronique est un glycosaminoglycane (GAG) non-sulfaté et l’un des composants majeurs de la matrice extracellulaire de la plupart des tissus conjonctifs tels que le cartilage, l’humeur vitrée de l’œil, le liquide synovial ou le cordon ombilical. C’est un polysaccharide qui présente l’avantage de se trouver sous la même forme chimique quelle que soit sa source. Il est constitué d’une alternance d’unités de monosaccharides d'acide D-glucuronique et de D-N- acétylglucosamine reliées par des liaisons glycosidiques b 1 -3. L’acide hyaluronique se rencontre habituellement sous la forme d’un gel de hyaluronate de sodium. De plus, il peut être modifié chimiquement de façon covalente sur ses fonctions hydroxyle ou carboxylate afin notamment d’améliorer ses propriétés mécaniques par réticulation et de diminuer sa vitesse de dégradation, celui-ci étant dégradable de façon enzymatique par la hyaluronidase et résorbable à travers de multiples voies métaboliques. L’acide hyaluronique a été utilisé dans diverses applications médicales et cosmétiques parce qu’il s’agit d’un composant majeur de la matrice extracellulaire. En effet, sa facilité d’injection et sa sécurité d’emploi, mais surtout sa biocompatibilité et son absence de toxicité, ainsi que ses propriétés physico-chimiques, en font un composé de choix dans diverses applications biomédicales. Ces mêmes gels sont utilisés en dermatologie et chirurgie plastique dans le traitement du vieillissement cutané comme produit de comblement, mais présentent l’inconvénient de se dégrader rapidement, d’où la nécessité de remédier à des injections répétées. [0049] Hyaluronic acid is a non-sulfated glycosaminoglycan (GAG) and one of the major components of the extracellular matrix of most connective tissues such as cartilage, vitreous humor of the eye, synovial fluid or the umbilical cord. It is a polysaccharide which has the advantage of being in the same chemical form regardless of its source. It consists of alternating monosaccharide units of D-glucuronic acid and D-N-acetylglucosamine linked by b 1 -3 glycosidic bonds. Hyaluronic acid is usually found in the form of sodium hyaluronate gel. In addition, it can be chemically modified covalently on its hydroxyl or carboxylate functions in order in particular to improve its mechanical properties by crosslinking and to reduce its rate of degradation, the latter being enzymatically degradable by hyaluronidase and resorbable through multiple metabolic pathways. Hyaluronic acid has been used in various medical and cosmetic applications because it is a major component of the extracellular matrix. Indeed, its ease of injection and its safety of use, but above all its biocompatibility and its absence of toxicity, as well as its physico-chemical properties, make it a compound of choice in various biomedical applications. These same gels are used in dermatology and plastic surgery in the treatment of skin aging as fillers, but have the disadvantage of degrading quickly, hence the need to remedy repeated injections.
[0050] La carboxy méthyl cellulose (CMC), l’hydroxy propyl méthyl cellulose (HPMC) et l’hydroxy propyl cellulose (HPC) sont des dérivés de la cellulose. La cellulose est le principal constituant des parois cellulaires des plantes, la cellulose est la principale composante du bois et des végétaux en général. Ainsi, la cellulose représente 50% de la biomasse, ce qui en fait la matière organique la plus abondante sur la Terre. Il s’agit d’un homopolymère linéaire de formule brute (C6Hio05)n constitué d’unités D-anhydroglucopyranose (forme cyclique du glucose) liées entre elles par des liaisons glycosidiques b1 -4. Le motif répétitif est la cellobiose, constituée de deux unités anhydroglucopyranoses. Les groupements hydroxyles de la cellulose peuvent réagir partiellement ou totalement avec différents réactifs pour donner divers dérivés cellulosiques, et notamment des éthers de cellulose tels que décrits ci-dessus. Les dérivés cellulosiques sont notamment connus pour leurs utilisations sous forme d’hydrogels comme gel de remplissage non toxique, visco-élastique, biodégradable et stable à long terme des implants mammaires. Carboxymethyl cellulose (CMC), hydroxy propyl methyl cellulose (HPMC) and hydroxy propyl cellulose (HPC) are derivatives of cellulose. Cellulose is the main constituent of plant cell walls, cellulose is the main component of wood and plants in general. Thus, cellulose represents 50% of biomass, making it the most abundant organic matter on Earth. It is a linear homopolymer with the molecular formula (C6Hio05)n consists of D-anhydroglucopyranose units (cyclic form of glucose) linked together by b1 -4 glycosidic bonds. The repeating unit is cellobiose, consisting of two anhydroglucopyranose units. The hydroxyl groups of cellulose can react partially or totally with various reagents to give various cellulose derivatives, and in particular cellulose ethers as described above. Cellulosic derivatives are known in particular for their uses in the form of hydrogels as non-toxic, visco-elastic, biodegradable and long-term stable filling gel for breast implants.
[0051] Le collagène est la protéine majeure composant la matrice extracellulaire de l’os. Dans son milieu d'origine, le collagène interagit avec les cellules dans les tissus conjonctifs et permet la transduction de signaux essentiels pour la régulation de l'ancrage des cellules, leur migration, prolifération, différenciation et survie. Il en existe 27 sortes mais le collagène de type 1 étant le plus abondant, il est aussi le plus étudié. Sa structure est composée de trois chaînes polypeptidiques agencées en triple hélice. Il confère aux tissus leur résistance mécanique à l’étirement. Il peut être dégradé par l’action d’enzymes spécifiques telles que les collagénases ou métalloprotéinases. Grâce à ses propriétés physico-chimiques, mécaniques et biologiques, il a été utilisé dans de nombreuses applications biomédicales. Collagen is the major protein making up the extracellular matrix of bone. In its native environment, collagen interacts with cells in connective tissues and allows the transduction of signals essential for the regulation of cell anchorage, migration, proliferation, differentiation and survival. There are 27 types, but type 1 collagen being the most abundant, it is also the most studied. Its structure is composed of three polypeptide chains arranged in a triple helix. It gives fabrics their mechanical resistance to stretching. It can be degraded by the action of specific enzymes such as collagenases or metalloproteinases. Thanks to its physico-chemical, mechanical and biological properties, it has been used in many biomedical applications.
[0052] L’au moins un biomatériau biocompatible de comblement est présent dans la composition sous forme de fluide. Le terme fluide comprend ici un gel par exemple viscoélastique. Lorsque l’au moins un biomatériau biocompatible de comblement n’est pas présent naturellement sous forme de fluide, mais sous forme sèche par exemple, ce dernier peut être ajouté à un fluide dit vecteur tel que l’eau, de préférence de l’eau pour préparation injectable (EPPI), ou de l’eau tamponnée, de préférence de l’eau tamponnée phosphate à un pH et une pression osmotique physiologiquement acceptable, afin de le réhydrater. Après réhydratation, l’au moins un biomatériau biocompatible de comblement se présentera sous forme de gel, par exemple viscoélastique. De préférence, un biomatériau biocompatible de comblement est présent sous une forme compatible avec une administration par injection. Plus particulièrement, l’au moins un biomatériau biocompatible de comblement présente une viscosité intrinsèque suffisante pour être de préférence injecté à travers une aiguille de gauge de 7G à 34G, de préférence de 18G à 32G, plus préférentiellement de 25G à 30G. The at least one biocompatible filling biomaterial is present in the composition in fluid form. The term fluid here includes a gel, for example viscoelastic. When the at least one biocompatible filling biomaterial is not naturally present in the form of a fluid, but in a dry form for example, the latter can be added to a so-called vector fluid such as water, preferably water for injection (WFI), or buffered water, preferably phosphate buffered water at a physiologically acceptable pH and osmotic pressure, in order to rehydrate it. After rehydration, the at least one biocompatible filling biomaterial will be in the form of a gel, for example viscoelastic. Preferably, a biocompatible filler biomaterial is present in a form compatible with administration by injection. More particularly, the at least one biocompatible biomaterial of filler has sufficient intrinsic viscosity to be preferably injected through a 7G to 34G, preferably 18G to 32G, more preferably 25G to 30G gauge needle.
[0053] L’au moins un biomatériau biocompatible de comblement selon l’invention est de façon particulièrement préférée un hydrogel biocompatible, soluble dans de l’eau pour préparation injectable additionnée d’un chlorure de sodium ou directement une solution de chlorure de sodium isotonique ou dans une solution tampon de qualité injectable tel que le tampon phosphate. Plus particulièrement, un biomatériau biocompatible de comblement tel que l’hydrogel d’acide hyaluronique réticulé est préféré. The at least one biocompatible filling biomaterial according to the invention is particularly preferably a biocompatible hydrogel, soluble in water for injectable preparation added with a sodium chloride or directly an isotonic sodium chloride solution. or in an injectable grade buffer solution such as phosphate buffer. More particularly, a biocompatible filling biomaterial such as cross-linked hyaluronic acid hydrogel is preferred.
[0054] En outre, l’au moins un biomatériau biocompatible de comblement selon l’invention, lorsqu’il est injectable, allie avantageusement la commodité d’emploi, éventuellement la seringabilité du produit, la résorbabilité en un temps contrôlé. In addition, the at least one biocompatible filling biomaterial according to the invention, when it is injectable, advantageously combines the convenience of use, possibly the syringeability of the product, the resorbability in a controlled time.
[0055] Dans un mode de réalisation, l’au moins un biomatériau biocompatible de comblement est présent dans la composition à une teneur de 0,2% à 5% en poids relatif à la quantité totale de ladite composition. In one embodiment, the at least one biocompatible filling biomaterial is present in the composition at a content of 0.2% to 5% by weight relative to the total amount of said composition.
[0056] Composition selon la présente invention Composition according to the present invention
[0057] Selon un mode de réalisation particulier, la composition selon l’invention peut comprendre en outre un actif. Les actifs peuvent comprendre notamment tous les actifs connus pour leur activité sur le vieillissement cutané, tels que les agents kératolytiques ou prodesquamants, par exemple les [alpha] -hydroxyacides, tels que les acides glycolique, lactique, malique, citrique, tartrique, mandélique et les leurs dérivés; les [bêta] -hydroxyacides tels que l'acide salicylique et ses dérivés; les [alpha] -acétoacides tels que l'acide ascorbique ou la vitamine C et leurs dérivés; [bêta]-cétoacides; les rétinoïdes tels que le rétinol (vitamine A) et ses esters (palmitate), le rétinien, l'acide rétinoïque et leurs mélanges. Les actifs peuvent aussi comprendre des molécules couramment utilisées en esthétique telles que des anesthésiques locaux par exemple la lidocaïne, des vitamines par exemples A, C, E, des acides aminés, du zinc, des polyols, des antiseptiques par exemple la chlorhexidine, du glycérol et leurs mélanges. [0058] La présence et la quantité de l’actif dépend de l'utilisation finale souhaitée. Lorsque qu’un actif est utilisé, la quantité peut aller par exemple d'environ 0,001 à environ 30% en poids, de préférence d'environ 0,05 à environ 15% en poids et plus préférablement d'environ 0,5 à environ 5% en poids sur la base du poids total de la composition. According to one particular embodiment, the composition according to the invention may also comprise an active ingredient. The active agents can in particular comprise all the active agents known for their activity on skin ageing, such as keratolytic or prodesquamating agents, for example [alpha]-hydroxy acids, such as glycolic, lactic, malic, citric, tartaric, mandelic and their derivatives; [beta]-hydroxy acids such as salicylic acid and its derivatives; [alpha]-acetoacids such as ascorbic acid or vitamin C and their derivatives; [beta]-keto acids; retinoids such as retinol (vitamin A) and its esters (palmitate), retinal, retinoic acid and mixtures thereof. The active ingredients can also include molecules commonly used in aesthetics such as local anesthetics for example lidocaine, vitamins for example A, C, E, amino acids, zinc, polyols, antiseptics for example chlorhexidine, glycerol and their mixtures. The presence and quantity of the active ingredient depends on the desired end use. When an active is used, the amount can range, for example, from about 0.001 to about 30% by weight, preferably from about 0.05 to about 15% by weight and more preferably from about 0.5 to about 5% by weight based on the total weight of the composition.
[0059] La composition selon la présente invention est particulièrement destinée à une administration par injection. La composition est administrée par voie parentérale. L'administration parentale peut être une administration sous-cutanée, une administration intra-dermique, une administration intra-épidermique, mais n'y est pas limitée. Préférentiellement, la composition est administrée par voir sous- cutanée ou intra-dermique. Lorsque l’administration est intradermique, elle est préférentiellement effectuée dans le tissu fibreux. The composition according to the present invention is particularly intended for administration by injection. The composition is administered parenterally. Parental administration may be subcutaneous administration, intradermal administration, intraepidermal administration, but is not limited thereto. Preferably, the composition is administered subcutaneously or intradermally. When the administration is intradermal, it is preferentially carried out in the fibrous tissue.
[0060] Dans un mode de réalisation l’administration de la composition selon l’invention est effectuée via une seringue adaptée en fonction du type d’administration ou via tout dispositif ou technique capable de faire franchir la barrière épidermique tel que la barophorèse aussi appelée « injection sans aiguille ». L’utilisateur saura adapter le type de seringue conformément à sa pratique professionnelle. In one embodiment, the administration of the composition according to the invention is carried out via a syringe adapted according to the type of administration or via any device or technique capable of crossing the epidermal barrier, such as barophoresis, also called “needleless injection”. The user will be able to adapt the type of syringe in accordance with his professional practice.
[0061] Dans un mode de réalisation lorsque l’administration est intraépidermique ou intradermique, elle peut être réalisée par mésothérapie consistant en des micro injections intra-épidermiques ou intra-dermiques à l'aide d'une ou d'une multitude d'aiguilles ou d'un pistolet de mésothérapie, par exemple le TechDent Meso Tech Classic. L’utilisateur saura adapter la taille d’aiguille conformément à sa pratique professionnelle. In one embodiment when the administration is intraepidermal or intradermal, it can be carried out by mesotherapy consisting of intraepidermal or intradermal micro injections using one or a multitude of needles or a mesotherapy gun, for example the TechDent Meso Tech Classic. The user will know how to adapt the needle size in accordance with his professional practice.
[0062] L’au moins un conjugué peptidique de formule (I) et le vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement peuvent être administrés séparément, simultanément ou séquentiellement. The at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials can be administered separately, simultaneously or sequentially.
[0063] Dans un mode de réalisation, lorsque le vecteur est une solution aqueuse, l’actif est présent dans cette dernière. [0064] Au sens de la présente invention « séparément » signifie une application de l’au moins un conjugué peptidique de formule (I) et le vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement à des endroits et/ou à des moments séparés. In one embodiment, when the vector is an aqueous solution, the active ingredient is present in the latter. Within the meaning of the present invention, "separately" means an application of at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials at places and/or at separate times.
[0065] Au sens de la présente invention « simultanément » signifie que l’au moins un conjugué peptidique de formule (I) et le vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement sont au préalable mélangés avant d’être administrés à un endroit donné, de préférence de manière extemporanée, comme par exemple en prélevant chaque composant dans une et même seringue qui est ensuite agitée ou un prélevant l’un des composant que l’on ajoute dans le contenant de l’autre composant et que l’on mélange par aspiration et refoulement. L’ordre de prélèvement peut se faire dans un premier sens, en prélevant d’abord l’au moins un conjugué peptidique de formule (I) pour l’ajouter dans le contenant du vecteur et ensuite en effectuant le mélange par aspiration et refoulement, ou dans le sens inverse. Within the meaning of the present invention, "simultaneously" means that the at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials are mixed beforehand before being administered to a given location, preferably extemporaneously, such as for example by withdrawing each component in one and the same syringe which is then shaken or by withdrawing one of the components which is added to the container of the other component and that the are mixed by suction and discharge. The order of sampling can be done in a first direction, by first taking the at least one peptide conjugate of formula (I) to add it to the container of the vector and then by carrying out the mixing by suction and discharge, or in the opposite direction.
[0066] Au sens de la présente invention « séquentiellement » signifie que l’un des composants est administré en premier à un endroit donné et que l’autre composant est administré au même endroit que le premier composant. Selon cet aspect, l’administration du deuxième composant est soit faite directement après le premier, c’est-à-dire sans temps de latence, ou l’administration du deuxième composant peut être faite à distance, c’est-à-dire avec un temps de latence qui peut être de 1 min à 30J, préférentiellement de 5 min à 15J. Within the meaning of the present invention, "sequentially" means that one of the components is administered first at a given location and that the other component is administered at the same location as the first component. According to this aspect, the administration of the second component is either done directly after the first, that is to say without latency, or the administration of the second component can be done remotely, that is to say with a latency time which can be from 1 min to 30J, preferably from 5 min to 15J.
[0067] L’au moins un conjugué peptidique de formule (I) et le vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement tout deux composants de la composition selon la présente invention, peuvent être conditionnés séparément dans tout moyen apte à son application, tel qu’une seringue, un pot, une fiole, un tube, un flacon, un flacon doseur à pression, un flacon avec pipette intégrée, ou une boite. Par « séparée », il est désigné selon la présente invention, selon des contenants distincts. Dans ce cas, la composition selon la présente invention sera préparée juste avant administration de manière extemporanée. [0068] L’au moins un conjugué peptidique de formule (I) et le vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement peuvent aussi être conditionnés sous forme unitaire. Par « unitaire », il est désigné selon la présente invention, sous un même contenant. Dans ce cas, la composition selon la présente invention sera préparée à l’avance avant l’administration et conditionnée dans tout moyen apte à son application, tel qu’une seringue, un pot, une fiole, un tube, un flacon, un flacon doseur à pression, un flacon avec pipette intégrée, ou une boite. The at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials, any two components of the composition according to the present invention, can be packaged separately in any means suitable for its application, such as a syringe, a jar, a vial, a tube, a bottle, a pressure-dosed bottle, a bottle with integrated pipette, or a box. By “separate”, it is designated according to the present invention, according to separate containers. In this case, the composition according to the present invention will be prepared just before extemporaneous administration. The at least one peptide conjugate of formula (I) and the vector chosen from aqueous solutions or biocompatible filling biomaterials can also be packaged in unit form. By “unit”, it is designated according to the present invention, in the same container. In this case, the composition according to the present invention will be prepared in advance before administration and packaged in any means suitable for its application, such as a syringe, a jar, a vial, a tube, a bottle, a bottle pressure dispenser, a bottle with integrated pipette, or a box.
[0069] De préférence les composants de la composition selon la présente invention sont conditionnés sous forme unitaire, de préférence dans une seringue. Preferably, the components of the composition according to the present invention are packaged in unit form, preferably in a syringe.
[0070] Selon un autre aspect, la présente invention concerne un kit comprenant la composition telle que décrite précédemment. Le kit peut comporter la composition selon la présente invention sous forme unitaire ou séparée, et un dispositif d’administration de ladite composition, par exemple, une seringue adaptée au type d’administration comme une seringue comprenant une aiguille de gauge de 7G à 34G, de préférence de 18G à 32G, plus préférentiellement de 25G à 30G. According to another aspect, the present invention relates to a kit comprising the composition as described above. The kit may comprise the composition according to the present invention in unit or separate form, and a device for administering said composition, for example, a syringe adapted to the type of administration such as a syringe comprising a needle gauge of 7G to 34G, preferably 18G to 32G, more preferably 25G to 30G.
[0071] Utilisation de la composition selon la présente invention [0071] Use of the composition according to the present invention
[0072] La présente invention concerne également l’utilisation non thérapeutique, par exemple, à visée cosmétique ou esthétique, de la composition selon la présente invention pour restructurer ou préserver l’aspect de la peau. Plus particulièrement, la composition selon la présente invention peut être utilisée pour améliorer l'élasticité et/ou la tonicité de la peau, et/ou pour prévenir, diminuer et/ou supprimer l'apparition des rides et ridules sur la peau. Dans un mode de réalisation, l’utilisation non thérapeutique de la composition est une utilisation antivieillissement et restructurante de la peau. The present invention also relates to the non-therapeutic use, for example, for cosmetic or aesthetic purposes, of the composition according to the present invention for restructuring or preserving the appearance of the skin. More particularly, the composition according to the present invention can be used to improve the elasticity and/or the tone of the skin, and/or to prevent, reduce and/or eliminate the appearance of wrinkles and fine lines on the skin. In one embodiment, the non-therapeutic use of the composition is for anti-aging and skin restructuring use.
[0073] Les présents inventeurs ont trouvé que l’utilisation par injection de la composition selon l’invention permet l’obtention de résultats améliorés par rapport à une application topique et que la combinaison de l’au moins un composé de formule (I) et du vecteur choisi parmi les solutions aqueuses ou du biomatériau biocompatible de comblement agit de façon synergique de telle sorte que l’effet des deux composants séparément est moindre que lorsqu’ils sont combinés. [0074] La composition selon l’invention est utilisée en tant que matériau de comblement pour supplémenter une cavité, restructurer un volume non harmonieux. Un tel comblement comprend le comblement des rides, ridules, dépressions cutanées et cicatrices du corps humain, y compris le comblement des défects cutanés secondaires à la prise d’un traitement pouvant entraîner une lipodystrophie se caractérisant le plus souvent par une lipoatrophie faciale. The present inventors have found that the use by injection of the composition according to the invention makes it possible to obtain improved results compared to topical application and that the combination of at least one compound of formula (I) and of the vector chosen from aqueous solutions or of the biocompatible filling biomaterial acts synergistically so that the effect of the two components separately is less than when they are combined. The composition according to the invention is used as a filling material to supplement a cavity, to restructure an unharmonious volume. Such a filling comprises the filling of wrinkles, fine lines, cutaneous depressions and scars of the human body, including the filling of cutaneous defects secondary to taking a treatment that can lead to lipodystrophy, most often characterized by facial lipoatrophy.
[0075] Avantageusement, la composition selon l’invention pallie les inconvénients de l’art antérieur puisqu’elle permet d’obtenir une préservation de l’aspect de la peau plus notable et immédiat qu’avec une composition topique. Elle permet également une restructuration et une préservation de l’aspect de la peau qui dure dans le temps au-delà des produits de comblement utilisés seuls. En effet l’association entre le peptide conjugué selon la présente invention et le biomatériau biocompatible de comblement, permet d’avoir un effet quasi instantané par l’injection du biomatériau biocompatible de comblement, cet effet perdurant grâce à l’action du peptide conjugué qui apporte un effet lissant, anti-rides, restructurant, redensifiant, hydratant et tonifiant. Advantageously, the composition according to the invention overcomes the drawbacks of the prior art since it makes it possible to obtain a preservation of the appearance of the skin that is more noticeable and immediate than with a topical composition. It also allows restructuring and preservation of the appearance of the skin that lasts over time beyond fillers used alone. Indeed the association between the conjugated peptide according to the present invention and the biocompatible filling biomaterial, makes it possible to have an almost instantaneous effect by the injection of the biocompatible filling biomaterial, this effect lasting thanks to the action of the conjugated peptide which provides a smoothing, anti-wrinkle, restructuring, redensifying, moisturizing and toning effect.
[0076] Les demandeurs ont découvert que l’association des deux composants permet d’obtenir un résultat qui perdure, réduisant la fréquence des injections. En effet, les biomatériaux biocompatibles de comblement se résorbent après un temps donné, allant de 3 à 9 mois selon les sujets. Le sujet doit donc revenir pour au bout de ce temps pour avoir une injection supplémentaire et donc entretenir l’effet esthétique qui reste éphémère. The applicants have discovered that the combination of the two components makes it possible to obtain a result which lasts, reducing the frequency of the injections. Indeed, the biocompatible filling biomaterials resorb after a given time, ranging from 3 to 9 months depending on the subject. The subject must therefore return for at the end of this time to have an additional injection and therefore maintain the aesthetic effect which remains ephemeral.
[0077] Lorsque le conjugué peptidique est utilisé en association avec le biomatériau biocompatible de comblement se présentant sous forme de gel, ce dernier est piégé dans la structure physique tridimensionnelle du gel. Le biomatériau biocompatible de comblement étant résorbable, au fur et à mesure de sa cette résorption, le conjugué peptidique sera relargué provoquant alors une libération prolongée dans le temps de ce dernier. Ce relargage selon une cinétique lente, dite prolongée, permet d’augmenter la T1/2 vie du conjugué peptidique et de maintenir les effets esthétiques du biomatériau biocompatible de comblement tout en l’intensifiant. De par la présence du peptide conjugué dans la structure physique tridimensionnelle du gel, la dégradation biomatériau biocompatible de comblement par les enzymes se trouvera ralenti car moins immédiatement disponible aux enzymes. Ainsi la composition selon l’invention agit tant d’un point de vue mécanique en comblant, mais aussi d’un point de vue biologique en préservant l’aspect de la peau du sujet. When the peptide conjugate is used in combination with the biocompatible filling biomaterial in the form of a gel, the latter is trapped in the three-dimensional physical structure of the gel. The biocompatible filling biomaterial being resorbable, as its resorption progresses, the peptide conjugate will be released, then causing a prolonged release over time of the latter. This release according to a slow, so-called prolonged kinetics, makes it possible to increase the T1/2 life of the peptide conjugate and to maintain the aesthetic effects of the biocompatible filling biomaterial while intensifying it. Due to the presence of the conjugated peptide in the physical structure three-dimensional of the gel, the degradation of the biocompatible filling biomaterial by the enzymes will be slowed down because it is less immediately available to the enzymes. Thus the composition according to the invention acts both from a mechanical point of view by filling, but also from a biological point of view by preserving the appearance of the subject's skin.
[0078] De préférence, la composition selon la présente invention permet d’obtenir les effets précités pendant au moins 6 mois, de préférence pendant au moins 9 mois, plus préférentiellement pendant au moins 12 mois et encore plus préférentiellement pendant au moins 18 mois. Tout particulièrement, l’au moins un biomatériau biocompatible de comblement ne se dégradera avant 3 mois, de préférence 6 mois, mais sera dégradée au bout de 18 mois. Même si le biomatériau biocompatible de comblement est résorbé au bout de 18 mois, l’effet du conjugué peptidique continuera de perdurer dans le temps en agissant directement sur les tissus. Preferably, the composition according to the present invention makes it possible to obtain the aforementioned effects for at least 6 months, preferably for at least 9 months, more preferably for at least 12 months and even more preferably for at least 18 months. In particular, the at least one biocompatible filling biomaterial will not degrade before 3 months, preferably 6 months, but will be degraded after 18 months. Even if the biocompatible filling biomaterial is resorbed after 18 months, the effect of the peptide conjugate will continue to last over time by acting directly on the tissues.
[0079] Dans un mode de réalisation particulier, l’au moins un biomatériau biocompatible de comblement est l’acide hyaluronique réticulé et l’au moins un conjugué peptidique est l’acétyle-SDKP. Dans ce cas particulier, les enzymes hyaluronidases vont dégrader l’acide hyaluronique réticulé injecté, les produits de dégradation in vivo étant les monomères d’acide hyaluronique biocompatibles et atoxiques. A côté des produits de dégradation de l’acide hyaluronique, l’acétyle- SDKP sera aussi relargué car il sera de moins en moins piégé dans la structure physique tridimensionnelle de l’hydrogel. Ceci lui permet de jouer son action lissante, anti-rides, restructurante, redensifiante, hydratante et tonifiante à l’endroit où la composition est administrée. Dans ce mode particulier, de par la forme réticulée de l’acide hyaluronique, cet hydrogel ne se dégradera pas pendant au moins 6 mois mais sera dégradé au bout de 18 mois. In a particular embodiment, the at least one biocompatible filling biomaterial is cross-linked hyaluronic acid and the at least one peptide conjugate is acetyl-SDKP. In this particular case, the hyaluronidase enzymes will degrade the injected cross-linked hyaluronic acid, the in vivo degradation products being the biocompatible and non-toxic hyaluronic acid monomers. Alongside the degradation products of hyaluronic acid, acetyl-SDKP will also be released because it will be less and less trapped in the three-dimensional physical structure of the hydrogel. This allows it to play its smoothing, anti-wrinkle, restructuring, redensifying, moisturizing and toning action at the site where the composition is administered. In this particular mode, due to the cross-linked form of hyaluronic acid, this hydrogel will not degrade for at least 6 months but will be degraded after 18 months.
[0080] Dans un autre mode de réalisation particulier, l’au moins un biomatériau biocompatible de comblement est l’acide hyaluronique réticulé sous forme d’hydrogel et l’au moins un conjugué peptidique est le lauroyle SDKP sous forme de nanoparticule. Dans ce mode particulier, de par la forme du conjugué peptidique sous forme de nanoparticule tel que décrit dans EP3416730 le SDKP aura un effet d’autant plus prolongé dans le temps. Dans ce mode particulier, la forme du conjugué peptidique et la forme réticulée de l’acide hyaluronique, la composition permet d’obtenir les effets précités pendant au moins 6 mois, de préférence pendant au moins 9 mois, plus préférentiellement pendant au moins 12 mois et encore plus préférentiellement pendant au moins 18 mois. In another particular embodiment, the at least one biocompatible filling biomaterial is cross-linked hyaluronic acid in the form of a hydrogel and the at least one peptide conjugate is lauroyl SDKP in the form of a nanoparticle. In this particular mode, due to the form of the peptide conjugate in the form of a nanoparticle as described in EP3416730, the SDKP will have an effect that is all the more prolonged over time. In this particular mode, the shape of the peptide conjugate and the cross-linked form of hyaluronic acid, the composition makes it possible to obtain the aforementioned effects for at least 6 months, preferably for at least 9 months, more preferably for at least 12 months and even more preferably for at least 18 month.
[0081] Procédé de traitement non thérapeutique [0081] Non-therapeutic treatment method
[0082] Au sens de la présente invention, le procédé de traitement non thérapeutique de restructuration ou de préservation de l’aspect de la peau, comprend : Within the meaning of the present invention, the non-therapeutic treatment process for restructuring or preserving the appearance of the skin comprises:
- la fourniture de la composition ou du kit selon la présente invention, - the supply of the composition or the kit according to the present invention,
- éventuellement, le prélèvement de la quantité de la composition selon l’invention, et - optionally, the withdrawal of the quantity of the composition according to the invention, and
- l’administration par injection de manière séparée, séquentielle ou simultanée, de préférence simultanée, de ladite composition. - administration by injection separately, sequentially or simultaneously, preferably simultaneously, of said composition.
[0083] Dans un mode de réalisation, lorsque la composition ou le kit se trouve dans une seringue, de préférence prête à l’emploi, il ne sera pas nécessaire de prélever la quantité de la composition selon l’invention. In one embodiment, when the composition or the kit is in a syringe, preferably ready for use, it will not be necessary to withdraw the quantity of the composition according to the invention.
[0084] La composition selon la présente invention est administrée en une quantité allant de 0,2mL à 10mL, de préférence de 0,5mL et 3mL, plus préférentiellement 1 mL. L’utilisateur saura adapter cette quantité en fonction de la zone d’administration. The composition according to the present invention is administered in an amount ranging from 0.2 mL to 10 mL, preferably from 0.5 mL and 3 mL, more preferably 1 mL. The user will be able to adapt this quantity according to the administration area.
[0085] Dans un mode de réalisation le prélèvement s’effectue à l’aide de tout matériel apte au prélèvement tels qu’une seringue. In one embodiment, the sample is taken using any material suitable for sampling, such as a syringe.
[0086] Dans un mode de réalisation lorsque la composition se présente sous un contenant unitaire autre qu’une seringue, la quantité de la composition est directement prélevée dans ce contenant. In one embodiment, when the composition is presented in a unitary container other than a syringe, the quantity of the composition is taken directly from this container.
[0087] Dans un autre mode de réalisation, lorsque chaque composant de la composition se présente dans des contenants séparés, la composition doit au préalable être préparée de manière extemporanée. Dans ce cas, le premier composant, par exemple le vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement est prélevé de son contenant à l’aide d’un dispositif de prélèvement adapté, par exemple une seringue, puis avec ce même dispositif, le deuxième composant, par exemple le conjugué peptidique est prélevé. Le tout est mélangé par agitation du dispositif de prélèvement ou par aspiration et refoulement. La quantité du vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement prélevée est comprise entre 0,1 à 5 mL, de préférence de 0,2 à 3 mL, plus préférentiellement d’environ 0,5mL et la quantité de l’au moins un conjugué peptidique est comprise entre 0,1 à 5 mL, de préférence de 0,2 à 3 mL, plus préférentiellement d’environ 0,5mL. [0088] La description relative au mode d’administration de la composition telle de décrite précédemment est aussi applicable pour le procédé de traitement non thérapeutique. In another embodiment, when each component of the composition is in separate containers, the composition must first be prepared extemporaneously. In this case, the first component, for example the vector chosen from aqueous solutions or biocompatible filling biomaterials, is taken from its container using a suitable sampling device, for example a syringe, then with this same device, the second component, for example the peptide conjugate is sampled. The whole is mixed by shaking the sampling device or by suction and discharge. The amount of vector chosen from aqueous solutions or biocompatible filling biomaterials taken is between 0.1 to 5 mL, preferably from 0.2 to 3 mL, more preferably about 0.5 mL and the amount of at least one peptide conjugate is between 0.1 to 5 mL, preferably 0.2 to 3 mL, more preferably about 0.5 mL. The description relating to the mode of administration of the composition as described above is also applicable for the non-therapeutic treatment method.
[0089] Le procédé selon l’invention permet d’améliorer l'élasticité et/ou la tonicité de la peau, et/ou pour prévenir, diminuer et/ou supprimer l'apparition des rides et ridules sur la peau. Dans un mode de réalisation, le procédé de traitement non thérapeutique est un procédé antivieillissement et restructurant de la peau. The method according to the invention makes it possible to improve the elasticity and/or the tone of the skin, and/or to prevent, reduce and/or eliminate the appearance of wrinkles and fine lines on the skin. In one embodiment, the non-therapeutic treatment method is an anti-aging and skin restructuring method.
[0090] L'invention propose donc également un procédé de traitement non thérapeutique pour tendre et lisser la peau pour atténuer immédiatement les rides et/ou les ridules. [0091] D'autres caractéristiques et avantages de l'invention ressortiront mieux des exemples qui suivent, donnés à titre illustratif et non limitatif. The invention therefore also proposes a non-therapeutic treatment method for tightening and smoothing the skin to immediately reduce wrinkles and/or fine lines. Other characteristics and advantages of the invention will emerge better from the examples which follow, given by way of non-limiting illustration.
Exemples Examples
[0092] Exemple 1 : Composition stérile conforme à l’invention pour injection par mésothérapie [0093] [Tableau 1]
Figure imgf000021_0001
[0092] Example 1: Sterile composition in accordance with the invention for injection by mesotherapy [0093] [Table 1]
Figure imgf000021_0001
Ό094] Préparation de la composition [0095] L’acide hyaluronique est utilisé sous forme de hyaluronate de sodium de grade injectable et de poids moléculaire (Mw) de 1 ,5 MDa. Ό094] Composition preparation The hyaluronic acid is used in the form of sodium hyaluronate of injectable grade and of molecular weight (Mw) of 1.5 MDa.
[0096] Le hyaluronate de sodium de sodium est mis à dissoudre dans la solution d’EPPI, NaCI et AcSDKP si dessus, sous agitation douce, pendant 24 heures. Après agitation, le pH est contrôlé et ajusté si nécessaire à pH 7 par addition de NaOH 0,25N. Le mélange est ensuite stérilisé en autoclave à 121 °C de manière à obtenir une valeur stérilisatrice FO supérieure à 15 et rempli dans une seringue préremplie de 1 ml. The sodium sodium hyaluronate is dissolved in the solution of EPPI, NaCl and AcSDKP above, with gentle stirring, for 24 hours. After stirring, the pH is checked and adjusted if necessary to pH 7 by adding 0.25N NaOH. The mixture is then sterilized in an autoclave at 121°C so as to obtain an FO sterilization value greater than 15 and filled into a 1 ml pre-filled syringe.
[0097] Utilisation de la composition en mésothérapie [0097] Use of the composition in mesotherapy
[0098] Cette composition est très intéressante pour les traitements de mésothérapie et permet la redensification du derme, l’amélioration de l’éclat de la peau, la diminution de la profondeur des rides et ridules et l’hydratation de la peau. This composition is very interesting for mesotherapy treatments and allows the redensification of the dermis, the improvement of the radiance of the skin, the reduction in the depth of wrinkles and fine lines and the hydration of the skin.
[0099] La composition est utilisée pour le traitement de l’épiderme par la technique d’injection multi points avec une seringue munie d’une aiguille de gauge 30G et à une profondeur d’environ 0,5 mm sous la zone de surface. L’excédent de composition restant à la surface de la peau est éliminé par tamponnage. The composition is used for treating the epidermis by the multipoint injection technique with a syringe fitted with a 30G gauge needle and at a depth of approximately 0.5 mm below the surface area. The excess composition remaining on the surface of the skin is removed by dabbing.
[0100] Les volontaires ayant reçu le traitement font tous état d’un très bon effet esthétique par notamment une amélioration significative de l’éclat de la peau et une réduction significative des irrégularités cutanés. The volunteers who received the treatment all report a very good aesthetic effect, in particular a significant improvement in the radiance of the skin and a significant reduction in skin irregularities.
[0101] Les propriétés de la composition ont fait l’objet d’un test versus la même composition mais ne comprenant pas d’Ac-SDKP ( « Composition témoin »). The properties of the composition were the subject of a test versus the same composition but not comprising Ac-SDKP (“Control composition”).
[0102] L’étude s’est déroulée selon un protocole prévoyant 3 séances d’injection et de contrôle à 3 semaines d’intervalle puis d’une dernière visite 3 semaines après la dernière injection. The study took place according to a protocol providing for 3 injection and control sessions 3 weeks apart, then a final visit 3 weeks after the last injection.
[0103] Le nombre de patients inclus a été calculé afin d’obtenir au moins 5 patients traités par zone d’injection et par produit. The number of patients included was calculated in order to obtain at least 5 patients treated per injection zone and per product.
[0104] Les objectifs de l’étude sont d’évaluer : [0104] The objectives of the study are to assess:
-l’acceptabilité et la sécurité du traitement. Vérification de l’absence d’effets secondaires ; - l’efficacité des compositions au regard de l’indication considérée ; et -la durabilité des effets aux différentes visites. - the acceptability and safety of the processing. Verification of the absence of side effects; - the efficacy of the compositions with regard to the indication considered; and - the durability of the effects at different visits.
[0105] Résultats [0105] Results
[0106] La comparaison des deux compositions ci-dessus a permis de démontrer un taux d’amélioration des différents paramètres testés systématiquement en faveur de la composition contenant Ac SDKP. The comparison of the two compositions above made it possible to demonstrate a rate of improvement of the various parameters tested systematically in favor of the composition containing Ac SDKP.
[0107] Exemple 2 : Composition stérile conforme à l’invention pour injection par mésothérapie Example 2: Sterile composition in accordance with the invention for injection by mesotherapy
[0108] Dans cet exemple on prépare un flacon de 5ml d’une solution d’Ac-SDKP dé composition : In this example, a 5ml bottle of an Ac-SDKP solution of composition is prepared:
[0109] [Tableau 2]
Figure imgf000023_0001
physiologique par agitation douce durant au moins 30 minutes. Le mélange est ensuite stérilisé par filtration et rempli dans un flacon de 5ml stérile. [0111] D’autre part on prépare une solution d’acide Hyaluronique de composition : [0109] [Table 2]
Figure imgf000023_0001
physiological by gentle shaking for at least 30 minutes. The mixture is then sterilized by filtration and filled into a sterile 5ml bottle. On the other hand, a hyaluronic acid solution of composition is prepared:
[0112] [Tableau 3]
Figure imgf000023_0002
[0112] [Table 3]
Figure imgf000023_0002
Ό113] Les fibres d’acide hyaluronique sont dissoutes dans IΈRRI et les autres composants ci-dessus sous agitation douce durant 10 heures puis laissées au repos au réfrigérateur 12 heures. La solution visqueuse ainsi obtenue est ensuite stérilisée par filtration et rempli dans un flacon de 5ml stérile. [0114] Cette composition est très intéressante pour les traitements de mésothérapie et permet la redensification du derme, l’amélioration de l’éclat de la peau, la diminution de la profondeur des rides et ridules et l’hydratation de la peau. Ό113] The hyaluronic acid fibers are dissolved in IΈRRI and the other components above with gentle stirring for 10 hours and then left to stand in the refrigerator for 12 hours. The viscous solution thus obtained is then sterilized by filtration and filled into a sterile 5ml bottle. This composition is very advantageous for mesotherapy treatments and allows redensification of the dermis, improvement in the radiance of the skin, reduction in the depth of wrinkles and fine lines and hydration of the skin.
[0115] Mélange extemporané et administration [0116] Le praticien prélève à part égale, à l’aide d’une seringue stérile, 0.5 ml de la solution d’acide hyaluronique et 0.5 ml de la solution d’Ac-SDKP. La seringue de prélèvement est ensuite agitée par retournement puis équipée d’une aiguille 30G / longueur d’environ 0,5 mm pour injection intra-épidermique chez le sujet. [0115] Extemporaneous mixing and administration [0116] The practitioner takes an equal part, using a sterile syringe, of 0.5 ml of the hyaluronic acid solution and 0.5 ml of the Ac-SDKP solution. The sampling syringe is then shaken by inversion then fitted with a 30G needle / length of approximately 0.5 mm for intraepidermal injection in the subject.
[0117] La composition est utilisée pour le traitement de l’épiderme par la technique d’injection multi points aussi appelée mésothérapie. The composition is used for treating the epidermis by the multipoint injection technique, also called mesotherapy.
[0118] Les volontaires ayant reçu le traitement font tous état d’un très bon effet esthétique par une amélioration significative de la redensification du derme, l’amélioration de l’éclat de la peau, la diminution de la profondeur des rides et ridules et l’hydratation de la peau. [0119] Exemple 3 : Composition stérile conforme à l’invention à base d’acide hyaluronique réticulé [0118] The volunteers who received the treatment all report a very good aesthetic effect by a significant improvement in the redensification of the dermis, the improvement in the radiance of the skin, the reduction in the depth of wrinkles and fine lines and skin hydration. Example 3: Sterile composition in accordance with the invention based on cross-linked hyaluronic acid
[0120] L’une des compositions des exemples 1 et 2 peut être formée à base d’acide hyaluronique (HA) réticulé. One of the compositions of examples 1 and 2 can be formed based on crosslinked hyaluronic acid (HA).
[0121] L’HA réticulé s’obtient par la mise en présence d’HA et d’un agent réticulant. Cet agent réticulant peut-être choisi parmi l’époxyde, l’aldéhyde, les polyamines, les polyphosphates, le divinyl sulfone, et leurs mélanges. De préférence, l’agent réticulant peut-être choisi parmi l’époxyde et préférentiellement le 1 ,4-butanediol diglycidyl éther (BDDE). The crosslinked HA is obtained by bringing together HA and a crosslinking agent. This crosslinking agent may be chosen from epoxy, aldehyde, polyamines, polyphosphates, divinyl sulfone, and mixtures thereof. Preferably, the crosslinking agent may be chosen from epoxy and preferentially 1,4-butanediol diglycidyl ether (BDDE).
[0122] L’obtention d’un HA réticulé par mise en présence d’HA et de BDDE en milieu basique puis suivi d’une phase de chauffage puis de dialyse est connu de l’homme de l’art. Obtaining a crosslinked HA by bringing together HA and BDDE in a basic medium then followed by a phase of heating and then dialysis is known to those skilled in the art.
[0123] [Tableau 4]
Figure imgf000024_0001
Figure imgf000025_0001
[0123] [Table 4]
Figure imgf000024_0001
Figure imgf000025_0001
Ό124] Après fabrication et avant stérilisation de la composition, le pH est contrôlé et ajusté à 7,2 si nécessaire. La composition est ensuite répartie dans des seringues de 1 ml puis stérilisée à la chaleur humide par autoclavage de manière à obtenir une valeur stérilisatrice FO supérieure à 15. [0125] La composition est notamment indiquée dans le traitement des rides par comblement ainsi que pour la revitalisation du derme et la prévention des processus de vieillissement cutané. Ό124] After manufacture and before sterilization of the composition, the pH is checked and adjusted to 7.2 if necessary. The composition is then distributed in 1 ml syringes and then sterilized with moist heat by autoclaving so as to obtain an FO sterilizing value greater than 15. The composition is particularly indicated in the treatment of wrinkles by filling as well as for the revitalization of the dermis and prevention of skin aging processes.
[0126] La composition obtenue est injectable au travers d’aiguilles hypodermique de 27G à 30G. Elle est indiquée pour le comblement, au niveau du derme moyen, des rides et cassures cutanées ainsi que pour la revitalisation à long terme. The composition obtained is injectable through 27G to 30G hypodermic needles. It is indicated for the filling, at the level of the middle dermis, of wrinkles and cutaneous breaks as well as for long-term revitalization.
[0127] Exemple 4 : Composition stérile conforme à l’invention à base d’acide hyaluronique et de carboxyméthylcelullose Example 4: Sterile composition in accordance with the invention based on hyaluronic acid and carboxymethylcellulose
[0128] L’une des compositions des exemples 1 et 2 peut être formée à base d’acide hyaluronique (FIA) et de carboxyméthylcelullose (CMC) selon le tableau suivant : One of the compositions of Examples 1 and 2 can be formed based on hyaluronic acid (FIA) and carboxymethylcellulose (CMC) according to the following table:
[0129] [Tableau 5]
Figure imgf000025_0002
[0129] [Table 5]
Figure imgf000025_0002
Ό130] Après fabrication et avant stérilisation de la composition, le pH est contrôlé et ajusté à 7,2 si nécessaire. La composition est ensuite répartie dans des seringues de 1 ml puis stérilisée à la chaleur humide par autoclavage de manière à obtenir une valeur stérilisatrice FO supérieure à 15. [0131] La composition est notamment indiquée dans le traitement des rides par comblement ainsi que pour la revitalisation du derme et la prévention des processus de vieillissement cutané. Ό130] After manufacture and before sterilization of the composition, the pH is checked and adjusted to 7.2 if necessary. The composition is then distributed in 1 ml syringes and then sterilized with moist heat by autoclaving so as to obtain an FO sterilizing value greater than 15. The composition is particularly indicated in the treatment of wrinkles by filling as well as for the revitalization of the dermis and the prevention of skin aging processes.
[0132] La composition obtenue est injectable au travers d’aiguilles hypodermique de 27G à 30G. Elle est indiquée pour le comblement, au niveau du derme moyen, des rides et cassures cutanées ainsi que pour la revitalisation à long terme. The composition obtained is injectable through 27G to 30G hypodermic needles. It is indicated for the filling, at the level of the middle dermis, of wrinkles and cutaneous breaks as well as for long-term revitalization.

Claims

Revendications Claims
[Revendication 1] Composition comprenant : a. au moins un conjugué peptidique de formule (I) suivante : [Claim 1] A composition comprising: a. at least one peptide conjugate of the following formula (I):
R1 -X1 -X2-X3-X4-A1 -R2 (I) dans laquelle : R1 -X1 -X2-X3-X4-A1 -R2 (I) in which:
R1 , étant du côté N-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, R1, being on the N-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
X1 est un condensât de (L)-sérine, X1 is a condensate of (L)-serine,
X2 est un condensât de (L) et/ou (D) acide aspartique, X2 is a condensate of (L) and/or (D) aspartic acid,
X3 est un condensât de (L) et/ou (D) lysine, , X3 is a condensate of (L) and/or (D) lysine, ,
X4 est un condensât de (L) et/ou (D) proline, X4 is a condensate of (L) and/or (D) proline,
X4, ou X3 et X4, étant optionnellement absents, les liaisons reliant X1 à X2, X2 à X3 le cas échéant, et X3 à X4 le cas échéant, pouvant être des liaisons peptidiques ou pseudopeptidiques, X4, or X3 and X4, being optionally absent, the bonds linking X1 to X2, X2 to X3 where applicable, and X3 to X4 where applicable, possibly being peptide or pseudopeptide bonds,
A1 est une liaison covalente, un groupement NH ou un atome d’oxygène,A1 is a covalent bond, an NH group or an oxygen atom,
R2, étant du côté C-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, R2, being on the C-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
R1 et R2 ne pouvant être conjointement des atomes d’hydrogène, ou l’un de ses sels physiologiquement acceptables, et b. au moins un vecteur choisi parmi l’acide hyaluronique et le chitosan. R1 and R2 cannot jointly be hydrogen atoms, or one of its physiologically acceptable salts, and b. at least one vector chosen from hyaluronic acid and chitosan.
[Revendication 2] Composition selon la revendication 1 , dans laquelle la séquence X1 -X2-X3-X4 de l’au moins un conjugué peptidique de formule (I) est (L)sérine- (L)acide aspartique-(L)lysine-(L)proline (SDKP). [Claim 2] Composition according to claim 1, in which the sequence X1 -X2-X3-X4 of the at least one peptide conjugate of formula (I) is (L)serine-(L)aspartic acid-(L)lysine -(L)proline (SDKP).
[Revendication 3] Composition selon les revendications 1 ou 2, dans laquelle l’au moins un conjugué peptidique de formule (I) est l’acétyle-SDKP ou le lauroyl-SDKP. [Claim 3] A composition according to claims 1 or 2, wherein the at least one peptide conjugate of formula (I) is acetyl-SDKP or lauroyl-SDKP.
[Revendication 4] Composition selon les revendications 1 à 3, dans laquelle l’au moins un vecteur est un biomatériau biocompatible de comblement est l’acide hyaluronique. [Claim 4] Composition according to claims 1 to 3, in which the at least one vector is a biocompatible filler biomaterial is hyaluronic acid.
[Revendication 5] Composition selon les revendications 1 à 4, comprenant en outre au moins un actif choisi dans la liste comprenant les agents kératolytiques ou prodesquamants, des vitamines, des acides aminés, du zinc, des polyols, du glycérol et leurs mélanges. [Claim 5] Composition according to Claims 1 to 4, further comprising at least one active ingredient chosen from the list comprising keratolytic agents or prodesquamers, vitamins, amino acids, zinc, polyols, glycerol and mixtures thereof.
[Revendication 6] Composition selon les revendications 1 à 5, dans laquelle l’au moins un conjugué peptidique de formule (I) se présente sous forme liquide ou de nanoparticules lipidiques et l’au moins un biomatériau biocompatible de comblement se trouve sous forme de fluide. [Claim 6] Composition according to Claims 1 to 5, in which the at least one peptide conjugate of formula (I) is in the form of liquid or of lipid nanoparticles and the at least one biocompatible filling biomaterial is in the form of fluid.
[Revendication 7] Utilisation non thérapeutique par injection d’une composition comprenant : a. au moins un conjugué peptidique de formule (I) suivante : [Claim 7] Non-therapeutic use by injection of a composition comprising: a. at least one peptide conjugate of the following formula (I):
R1 -X1 -X2-X3-X4-A1 -R2 (I) dans laquelle : R1 -X1 -X2-X3-X4-A1 -R2 (I) in which:
R1 , étant du côté N-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, R1, being on the N-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
X1 est un condensât de (L)-sérine, X1 is a condensate of (L)-serine,
X2 est un condensât de (L) et/ou (D) acide aspartique, X2 is a condensate of (L) and/or (D) aspartic acid,
X3 est un condensât de (L) et/ou (D) lysine, X3 is a condensate of (L) and/or (D) lysine,
X4 est un condensât de (L) et/ou (D) proline, X4 is a condensate of (L) and/or (D) proline,
X4, ou X3 et X4, étant optionnellement absents, les liaisons reliant X1 à X2, X2 à X3 le cas échéant, et X3 à X4 le cas échéant, pouvant être des liaisons peptidiques ou pseudopeptidiques, X4, or X3 and X4, being optionally absent, the bonds linking X1 to X2, X2 to X3 where applicable, and X3 to X4 where applicable, possibly being peptide or pseudopeptide bonds,
A1 est une liaison covalente, un groupement NH ou un atome d’oxygène,A1 is a covalent bond, an NH group or an oxygen atom,
R2, étant du côté C-terminal, est un atome d’hydrogène, ou un groupement alkyle en C1-C50 linéaire ou ramifié, substitué ou non substitué, R2, being on the C-terminal side, is a hydrogen atom, or a linear or branched, substituted or unsubstituted C1-C50 alkyl group,
R1 et R2 ne pouvant être conjointement des atomes d’hydrogène, ou l’un de ses sels physiologiquement acceptables, et b. au moins un vecteur choisi parmi les solutions aqueuses ou les biomatériaux biocompatibles de comblement. R1 and R2 cannot jointly be hydrogen atoms, or one of its physiologically acceptable salts, and b. at least one vector chosen from aqueous solutions or biocompatible filling biomaterials.
[Revendication 8] Utilisation non thérapeutique selon la revendication 7, caractérisée en ce qu’il s’agit d’une utilisation antivieillissement et restructurante de la peau. [Claim 8] Non-therapeutic use according to Claim 7, characterized in that it is an anti-ageing and restructuring use of the skin.
[Revendication 9] Kit comprenant la composition selon les revendications 1 à 6 et un dispositif d’administration de ladite composition. [Claim 9] Kit comprising the composition according to claims 1 to 6 and a device for administering said composition.
[Revendication 10] Procédé de traitement non thérapeutique de restructuration ou de préservation de l’aspect de la peau, ledit procédé comprenant : - la fourniture de la composition selon les revendications 1 à 6 ou du kit selon la revendication 9, [Claim 10] Non-therapeutic treatment method for restructuring or preserving the appearance of the skin, said method comprising: - providing the composition according to claims 1 to 6 or the kit according to claim 9,
- éventuellement, le prélèvement de la quantité de la composition selon les revendications 1 à 6, et - optionally, the withdrawal of the quantity of the composition according to claims 1 to 6, and
- l’administration par injection de manière séparée, séquentielle ou simultanée, de préférence simultanée, de ladite composition. - administration by injection separately, sequentially or simultaneously, preferably simultaneously, of said composition.
PCT/FR2022/050481 2021-03-16 2022-03-17 Injectable composition comprising a peptide conjugate WO2022195228A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR2102600A FR3120794B1 (en) 2021-03-16 2021-03-16 Composition for injection comprising a peptide conjugate
FRFR2102600 2021-03-16

Publications (1)

Publication Number Publication Date
WO2022195228A1 true WO2022195228A1 (en) 2022-09-22

Family

ID=76159521

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR2022/050481 WO2022195228A1 (en) 2021-03-16 2022-03-17 Injectable composition comprising a peptide conjugate

Country Status (2)

Country Link
FR (1) FR3120794B1 (en)
WO (1) WO2022195228A1 (en)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988000594A1 (en) 1986-07-18 1988-01-28 Institut National De La Sante Et De La Recherche M Tetrapeptide inhibiting the proliferation cycle of haematopoietic strain cells, methods of production and applications thereof
WO1997028183A1 (en) 1996-02-01 1997-08-07 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Peptide inhibitors of hematopoietic cell proliferation
FR2872040A1 (en) * 2004-06-23 2005-12-30 Centre Nat Rech Scient COSMETIC USE OF AT LEAST ONE AC-N-SER-ASP-LYS-PRO NATURAL TETRAPEPTIC OR ONE OF ITS ANALOGUES AS AN ANTI-AGING AND RESTRUCTURING AGENT OF THE SKIN
KR101110317B1 (en) * 2009-06-30 2012-02-15 고려대학교 산학협력단 Smart releasing scafford of Thymosin beta-4 originated Ac-SDKP peptides for tissue regeneration
FR3047990A1 (en) * 2016-02-18 2017-08-25 Rpm Dermatologie SKIN COSMETIC COMPOSITION COMPRISING AN SDKP PEPTIDE OR AN ANALOGUE THEREOF
CN111658573A (en) * 2020-06-17 2020-09-15 广州艾尔亿医药有限公司 Human-like serum protein preparation for regenerative medicine cosmetology
WO2020227526A1 (en) * 2019-05-08 2020-11-12 ALASTIN Skincare, Inc. Compositions and methods for improving bruising and rejuvenating skin
FR3112687A1 (en) * 2020-07-23 2022-01-28 Rpm Dermatologie Personalized and customizable skin care kit

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2882256B1 (en) * 2005-02-18 2007-05-25 Centre Nat Rech Scient COSMETIC USE OF AT LEAST ONE AC-N-SER-ASP-LYS-PRO NATURAL TETRAPEPTIDE OR ONE OF ITS ANALOGUES AS AN AGENT TO SLOW DOWN THE FALL OF HAIR AND / OR STIMULATE THEIR GROWTH
KR20180002228A (en) * 2016-06-29 2018-01-08 세종대학교산학협력단 enhancer for radiotheraphy comprising Ac-SDKP originated from thymosin

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988000594A1 (en) 1986-07-18 1988-01-28 Institut National De La Sante Et De La Recherche M Tetrapeptide inhibiting the proliferation cycle of haematopoietic strain cells, methods of production and applications thereof
WO1997028183A1 (en) 1996-02-01 1997-08-07 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Peptide inhibitors of hematopoietic cell proliferation
FR2872040A1 (en) * 2004-06-23 2005-12-30 Centre Nat Rech Scient COSMETIC USE OF AT LEAST ONE AC-N-SER-ASP-LYS-PRO NATURAL TETRAPEPTIC OR ONE OF ITS ANALOGUES AS AN ANTI-AGING AND RESTRUCTURING AGENT OF THE SKIN
EP1786386A1 (en) 2004-06-23 2007-05-23 CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) Etablissement Public Cosmetic use of at least one type of natural ac-n-ser-asp-lys-pro tetrapeptide or one of the analogs thereof in the form of a skin antiaging and restructuring agent
KR101110317B1 (en) * 2009-06-30 2012-02-15 고려대학교 산학협력단 Smart releasing scafford of Thymosin beta-4 originated Ac-SDKP peptides for tissue regeneration
FR3047990A1 (en) * 2016-02-18 2017-08-25 Rpm Dermatologie SKIN COSMETIC COMPOSITION COMPRISING AN SDKP PEPTIDE OR AN ANALOGUE THEREOF
EP3416730A1 (en) 2016-02-18 2018-12-26 RPM Dermatologie Dermatological cosmetic composition comprising an sdkp peptide or an analog thereof
WO2020227526A1 (en) * 2019-05-08 2020-11-12 ALASTIN Skincare, Inc. Compositions and methods for improving bruising and rejuvenating skin
CN111658573A (en) * 2020-06-17 2020-09-15 广州艾尔亿医药有限公司 Human-like serum protein preparation for regenerative medicine cosmetology
FR3112687A1 (en) * 2020-07-23 2022-01-28 Rpm Dermatologie Personalized and customizable skin care kit

Also Published As

Publication number Publication date
FR3120794B1 (en) 2023-11-24
FR3120794A1 (en) 2022-09-23

Similar Documents

Publication Publication Date Title
JP6995946B2 (en) Dermal filler composition containing antioxidants
EP2861301B1 (en) Composition, in an aqueous medium, including at least one hyaluronic acid and at least one sucrose octasulphate water-soluble salt
CA2857946C (en) Homogeneous aqueous solution of injectable chitosan
CN106999625A (en) Dermal augmentation agent based on cross-linking type sodium hyaluronate and carboxymethyl cellulose
WO2006021644A1 (en) Water-soluble crosslinked hyaluronic acid, a method for the preparation thereof, implant containing said crosslinked hyaluronic acid and the use thereof
FR2909560A1 (en) HYALURONIC ACID GEL FOR INTRADERMAL INJECTION
CA2686558A1 (en) Pharmaceutical or cosmetic preparations for topical and/or parenteral application, preparation methods thereof and use of same
EP2890360A1 (en) Sterilised composition comprising at least one hyaluronic acid and magnesium ascorbyl phosphate
EP3285781B1 (en) Homogeneous aqueous solution of injectable chitosan having a ph close to physiological ph
US20130004546A1 (en) Hydrogel of microspheres
CA2985695A1 (en) Compositions comprising at least one polyol and at least one anaesthetic
EP3976663A1 (en) Chitosan and applications thereof
CA2686556A1 (en) Pharmaceutical or cosmetic preparations for topical and/or parenteral application, methods for the preparation thereof, and uses thereof
EP3386496B1 (en) Novel injectable composition; method for preparing said composition; use of said composition
WO2017009346A1 (en) Chitosan for mixing with a coagulable fluid
FR3116534A1 (en) Chitosan-based beads, preparation, compositions and applications
WO2022195228A1 (en) Injectable composition comprising a peptide conjugate
EP3532113A1 (en) Novel compositions that act on adipocytes
FR2919999A1 (en) Cosmetic/pharmaceutical composition, useful to treat e.g. loss of dermal/epidermal volume, for filling depressions on skin surface and to treat wrinkles, and/or restore facial fullness, comprises hyaluronic acid and divalent cation
EP3416652B1 (en) Injectable composition, method for preparing said composition, and use of said composition
EP3315130B1 (en) Hyaluronic acid composition including mepivacaine
FR3091995A1 (en) Chitosan gel massage
WO2019121694A1 (en) Injectable compositions of cross-linked hyaluronic acid and bupivacaine, and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22714484

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE