WO2018024902A1 - Utilisations d'acide hyaluronique modifié de manière hydrophobe par des liaisons amide et/ou hydrazide en cosmétique et/ou en dermatologie - Google Patents

Utilisations d'acide hyaluronique modifié de manière hydrophobe par des liaisons amide et/ou hydrazide en cosmétique et/ou en dermatologie Download PDF

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Publication number
WO2018024902A1
WO2018024902A1 PCT/EP2017/069844 EP2017069844W WO2018024902A1 WO 2018024902 A1 WO2018024902 A1 WO 2018024902A1 EP 2017069844 W EP2017069844 W EP 2017069844W WO 2018024902 A1 WO2018024902 A1 WO 2018024902A1
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hyaluronic acid
skin
particle
particles
modified
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PCT/EP2017/069844
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English (en)
Inventor
Manuel Silva
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Biokawthar Technologies
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Publication of WO2018024902A1 publication Critical patent/WO2018024902A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • 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
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns

Definitions

  • the present invention relates to the field of cosmetics and pharmaceuticals such as dermatology.
  • the present invention relates to particles of hyaluronic acid hydrophobically modified by amidation with hydrophobic groups having an amine or a hydrazine function; and their use as a stimulating agent in the epidermis and/or in the dermis.
  • the particles of the invention are useful for restoring the endogenic production of hyaluronic acid and providing a lasting effect thanks to their slow degradation in vivo.
  • the present invention also refers to a skin improvement method comprising applying the particles of the invention.
  • the skin plays many fundamental biologic functions such as thermal regulation, barrier against the external environment or hormonal synthesis.
  • the skin also ensures a psychosocial role that impacts the social interactions between individuals.
  • the epidermis refers to the superficial layer of the skin made of keratinocyte cells, melanocytes cells or Langerhans cells. Its role is mainly directed to protection (immunity function).
  • the dermis Located under the epidermis, the dermis is the resistant part of the skin and is made of water, glycosaminoglycans (such as hyaluronic acid) and fibers of proteins (such as, elastin and collagen). These proteins, and glycosaminoglycans (and particularly endogenic hyaluronic acid), allow ensuring good physical properties to the skin (i.e. toughness, elasticity and smoothness).
  • these products (1) either contain hyaluronic acid having high molar weight mat cannot diffuse through the deepest layer of the skin; or (2) contain shorter hyaluronic acid that induces inflammatory phenomenon after its application on the skin.
  • these products only aim to be used as filling agents and/or as hydrating agents, and they do not focuse on the provision of an efficient way to reactivate the production of endogenic hyaluronic acid.
  • the hyaluronic acid chains are easily degraded by the human organism over time. This degradation implies a regular administration of the product by the subject that may be uncomfortable.
  • the hyaluronic acid modified by hydrophobic groups through an amide and/or a hydrazide bond is under the form of particles.
  • the hydrophobically modified hyaluronic acid particles of the invention are able to efficiently diffuse in the epidermis and the dermis; especially, in the papillary dermis, in the upper reticular dermis and in the lower reticular dermis. Furthermore, the particles of the invention do not provoke any inflammatory side-effects.
  • the particles of the invention are able to increase the expression of collagen HI and/or elastin in the skin; preferably, in the epidermis and/or the dermis; more preferably, in the papillary dermis, in the upper reticular dermis and in the lower reticular dermis.
  • the amide and the hydrazide linkages are more resistant to degradation by hydrolysis of hyaluronidase enzymes in the skin compared to esters linkages. Consequently, the particles of the invention allow a lasting action, even after a sole application, contrary to the hyotaphobic-modified HA having ester linkage, hyaluronic acid or any salt thereof such as sodium hyahironate.
  • the present invention thus concerns the use as a long lasting antiaging agent of a particle comprising at least one hyaluronic acid derivative of general formula (I):
  • Z represents a single bond or -NH-;
  • R represents a C1-C20 alkyl group; preferably, a C6-C18 alkyl group;
  • n represents the number of disaccnaride units of D- glucuronic acid and iV-acetyl-D- glucosamine and is a positive integer; and wherein the particle has a mean hydrodynamic diameter ranging from 200 nm to 500 nm; preferably, from 250 nm to 400 nm; more preferably, from 320 nm to
  • the degree of substitution (DS) of the hyaluronic acid derivatives of formula (I) ranges from 0.1 % to 55 %.
  • the molecular weight of the hyaluronic acid derivatives of formula (I) ranges from 100 kDa to 4 000 kDa; preferably, from 200 kDa to 3 000 kDa.
  • the long lasting antiaging agent is a long lasting skin plumping agent, a long lasting skin hydrating agent and/or a long lasting stimulating agent of the endogenic production of hyaluronic acid.
  • the present invention also concerns a particle comprising at least one hyaluronic acid derivative of general formula (I):
  • Z represents -NH-;
  • R represents a C1-C20 alkyl group; preferably, a C6-C18 alkyl group; more preferably, a C18 alkyl group;
  • n represents the number of disaccharide units of D- glucuronic acid and iV-acetyl-D- glucosamine and is a positive integer; and wherein the particle has a mean hydrodynamic diameter ranging from 200 nm to
  • 500 nm preferably, from 250 nm to 400 nm; more preferably, from 320 nm to 360 nm
  • the present invention also concerns a particle as defined above, for use as a medicament
  • the particle as defined above is for use in the treatment and/or the prevention of dermatological conditions; preferably as a healing agent
  • the present invention also concerns a cosmetic and/or fascia composition
  • a cosmetic and/or fascia composition comprising at least one particle as defined above, and a cosmetically acceptable base.
  • the cosmetic and/or dermo-cosmetic composition of the invention is under an injectable form
  • the present invention also concerns a skin improvement method comprising using the cosmetic and/or dermo-cosmetic composition of the invention in a subject in need thereof.
  • the skin improvement method of the invention is for restoring the production of endogenic hyaluronic acid in the epidermis and/or the dermis.
  • the skin improvement method of the invention is for limiting the shortcomings of the skin; preferably, for improving the hydration of the skin.
  • composition of the invention is administered to the skin of a subject in need thereof, once per week.
  • composition of the invention is administered to the epidermis and/or the dermis of a subject in need thereof, by a topical application or by injection.
  • “amidatkra reaction” relates to the reaction between the carboxylic function of the hyaluronic acid with (1) either the amine function of a hydrophobic compound or (2) the hydrazine function of a hydrophobic compound.
  • the resulting linkage may be either an amide linkage or a hydrazide linkage;
  • antiaging agent relates to a compound mat limits the effects of the age on the skin; preferably, it relates to skin plumping agent and/or skin hydrating agent;
  • alkyl relates to any saturated linear or branched hydrocarbon chain, with 1 to 20 carbon atoms, preferably 6 to 18 carbon atoms, preferably hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl; more preferably, octadecyl;
  • alkenyl relates to any unsaturated linear or branched hydrocarbon chain, with 1 to 20 carbon atoms, preferably 6 to 18 carbon atoms, preferably hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecyl, hexadecyl, heptadecyl, octadecenyl; more preferably, tetradecenyl, octadecenyl;
  • cycloalkyT relates to a substituted or not substituted cyclic alkyl substituent such as cyclopropyl, cyclopentyl, or cyclohexyl;
  • a cosmetically acceptable base relates to any compound for use in contact with the epidermis and/or the dermis, and which does not provoke any side effects such as toxicity, irritation, inflammation or allergic response.
  • a cosmetically acceptable base includes base for topical administration and/or injection;
  • cosmetic use refers to the use in order to improve the esthetic appearance of the body
  • degree of substitution relates to me number of me carboxylic functions of the hyaluronic acid that have been modified after amidation with at least one hydrophobic group having an amine or a hydrazine function;
  • - relates to the conjunctive tissue forming with the epidermis and the hypodermis, the skin.
  • the dermis is constituted of the papillary dermis and the reticular dermis;
  • “healing agent” relates to a compound able to favor the decrease of wounds; preferably, of superficial wounds; more preferably, of the superficial wounds of the skin or the mucous;
  • long-lasting agent relates to a compound able to provide its effects for a long time.
  • a 'long-lasting antiaging agent refers to a compound having antiaging properties, said properties being maintained or improved for a long time compared to the effects of a non-long-lasting antiaging agent;
  • particle relates to an assembly of the hyaluronic acid derivatives of the invention organized by weak bonds, i.e. an assembly of hyaluronic acid modified by amidation with at least one hydrophobic group having an amine or a hydrazine function.
  • the term “particle” comprises nanoparticles and/or microparticles obtained from hydrophobically modified hyaluronic acid of the invention.
  • the term “particles” does not comprise polymersomes or liposomes.
  • the term “particles” does not comprise aggregates;
  • ''pharmaceutically acceptable base relates to any ingredients of a pharmaceutical composition that are compatible with each other and not deleterious to the subject to which it is adrninistered;
  • hydrophobic relates to a compound or a chemical group that has no affinity for water or aqueous medium
  • skin plumping agent relates to a compound able to provide a measurable increase of the skin density; especially, of the epidermis and/or the dermis.
  • the "skin plumping effect” may be analyzed by echography or by the implementation of techniques suitable of the human body area for which the effect is analyzed;
  • skin hydrating agent relates to a compound able to overcome the dry skin; especially, to overcome the dry of the epidermis and/or the dermis and/or the mucous.
  • This invention relates to a hyaluronic acid derivative; especially, a hyaluronic acid modified by amidation with at least one hydrophobic group through an amine or a hydrazine function, of general formula (I):
  • Z represents a single bond or -NH-
  • R represents a C1-C20 alkyl or C1-C20 alkenyl group; preferably, a C6-C18 alkyl group; more preferably, a C18 alkyl group; and
  • n represents the number of disaccharide units of D- glucuronic acid and iV-acetyl-D- glucosamine and is a positive integer.
  • the hyaluronic acid salt is a hyaluronate, preferably sodium hyaluronate.
  • hydrophobic groups are grafted on sodium hyaluronate.
  • R represents a linear CI -20 alkyl group or a linear Cl- C20 alkenyl group, preferably a linear C6-C18 alkyl group, more preferably a linear C18 alkyl group.
  • R represents a C1-C20 alkyl group.
  • R represents a C6, C7, C8, C9, CIO, CI 1, C12, C13, C14, C15, C16, C17 or C18 alkyl group, preferably a linear C6, C7, C8, C9, CIO, CI 1, C12, C13, C14, C15, C16, C17 or C18 alkyl group.
  • preferred compounds are of formula (la):
  • R represents a C1-C20 alkyl or C1-C20 alkenyl group; preferably, a C6-C18 alkyl group; more preferably, a C18 alkyl group; and
  • n represents the number of disaccharide units of D- glucuronic acid and iV-acetyl-D- glucosamine and is a positive integer.
  • preferred compounds are of formula (lb):
  • R represents a C1-C20 alkyl or C1-C20 alkenyl group; preferably, a C6-C18 alkyl group; more preferably, a C18 alkyl group; and
  • n represents the number of disaccharide units of D- glucuronic acid and iV-acetyl-D- glucosamine and is a positive integer.
  • the present invention relates to a hyaluronic acid modified by amidation with at least one hydrophobic group through an amine or a hydrazine function, of general formula ( ⁇ ):
  • Z represents a single bond or -NH-
  • n represents the number of disaccharide units of D- glucuronic acid and iV-acetyl-D- glucosamine and is a positive integer.
  • R when Z is a single bond, R is not a C1-, CIS-, C16- or C20-alkyl group.
  • R when Z is a single bond, R is not a C8- , C12- or C16-alkyl group.
  • R does not represent a C8- alkyl group.
  • R does not represent a C12-alkyl group.
  • R does not represent a C16-alkyl group.
  • hyaluronic acid is not partially deacetylated. According to one embodiment, hyaluronic acid is not deacetylated. According to one embodiment, hyaluronic acid derivatives of formula (I) or (II) nave a molecular weight ranging from 3 kDa to 4000 kDa; preferably from 200 kDa to 3 000 kDa. According to one embodiment, hyaluronic acid derivatives of formula (I) or (II) have a molecular weight ranging from 100 kDa to 4000 kDa; preferably from 200 kDa to 3 000 kDa.
  • hyaluronic acid derivatives of formula (I) or (II) have a molecular weight of about 200 kDa or of about 3000 kDa. According to one embodiment, hyaluronic acid derivatives of formula (I) or (II) have a molecular weight of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900 or 4000 kDa.
  • the degree of substitution (DS) of the hyaluronic acid by the hydrophobic groups ranges from 0.01 % to 55 %; preferably, from 1 % to 15%; more preferably, from 1 to 5 %; more preferably, from 10 to 15 %. According to one embodiment, the degree of substitution (DS) of the hyaluronic acid by the hydrophobic groups ranges from 0.1 % to 55 %; preferably, from 1 % to 15 %; more preferably, from 1 to 5 %; more preferably, from 10 to 15 %. According to one embodiment, the degree of substitution (DS) is about 1.5 %. According to one embodiment, the degree of substitution (DS) is about 12 %.
  • the degree of substitution (DS) of the hyaluronic acid by the hydrophobic groups was detemiined by NMR (Nuclear Magnetic Resonance) analysis by comparing the area of cyclic protons of the hyaluronic acid or the sodium hyaluronate (10 protons between 3.5 and 54.3 ppm), with the terminal CH3 of the aliphatic graft (3 protons at around 1.57 ppm for 100 % of substitution). The calculation may be also done by comparing the areas of the terminal CH3 of the aliphatic graft (3 protons around 1.57 ppm for 100 % substitution) and the CH3 of N-acetyl glucosamine (3 protons around 1.47 ppm).
  • the degree of substitution (DS) of the hyaluronic acid by the hydrophobic groups ranges from 0.1 % to 5 %; preferably from 0.1 % to 4 % preferably from 0.1 % to 3 % preferably from 0.1 % to 2 % preferably from 0.1 % to 1 %. According to one embodiment, the degree of substitution (DS) of the hyaluronic acid by the hydrophobic groups ranges from 0.1 % to 10 %.
  • the degree of substitution (DS) of the hyaluronic acid by the hydrophobic groups is about 1 %, 5 %, 10 %, IS %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 % or 55 %. According to one embodiment, the degree of substitution (DS) of the hyaluronic acid by the hydrophobic groups is about 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 11 %, 12 %, 13 %, 14 % or 15 %.
  • the hydrophobic groups are grafted to the hyaluronic acid by a covalent linkage; especially, by an amide linkage or a hydrazide linkage.
  • the hydrophobic groups are grafted to the hyaluronic acid or any salts and solvates thereof, by a covalent linkage; especially, by an amide linkage or a hydrazide linkage.
  • the hyaluronic acid is modified by an amidation between the carboxylic acid function of hyaluronic acid and the amine function of the hydrophobic compounds to be grafted.
  • the hyaluronic acid salt which is a hyaluronate is modified by an amidation between the carboxylate function of said hyahironate and the amine function of the hydrophobic compounds to be grafted.
  • the hydrophobic compound is selected from the organic compounds having at least one amine function or having at least one hydrazine function, i.e. a function having the following structure:
  • Z represents a single bond or -NH-
  • R represents a C1-C20 alkyl or C1-C20 alkenyl group; preferably, a C6-C18 alkyl group; more preferably, a C18 alkyl group.
  • the hydrophobic compound is not hydrazine molecule, i.e. compound of formula: NH2-NH2.
  • the modified hyaluronic acid does not comprise free- hydrazido groups, i.e. - NH-NH2 or -NR'-NIfc pendent groups wherein R' is an organic functional group as for example an alkyl, an aryl, or an alkene.
  • me modified hyaluronic acid does not comprise oxalic hydrazido groups.
  • the hyaluronic acid is modified by an alkylamine; preferably, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, dodecylamine, tridecylamine, tetradecylamine, pentadecylamine, hexadecylamine, heptadecylamine, octadexylamine; nonadecylamine, eicosylamine; more preferably, hexylamine, heptylamine, octylamine, nonylamine, decylamine, undecylamine, dodecylamine, tridecylamine, tetradecylamine, pentadecylamine, hexadecylamine, eicosyl
  • the hyaluronic acid is not modified by octylamine. According to one embodiment, the hyaluronic acid is not modified by dodecylamine. According to one embodiment, the hyaluronic acid is not modified by hexadecylamine.
  • the hyaluronic acid is modified by alkenylamine; preferably, ethylenylamine, propylenylamine, butylenylamine, pentenylamine, hexenylamine, heptenylamine, octenylamine, nonenylamine, decenylamine, undecenylamine, dodecenylamine, tridecenylamine, tetradecenylamine, pentadecenylamine, hexadecenylamine, heptadecenylamine, octadecenylamine; nonadecenylamine, eicosenylamine; more preferably, hexenylamine, heptenylamine, octenylamine, nonenylamine, decenylamine, undecenylamine, dodecenylamine, tridecenylamine, t
  • the hyaluronic acid is modified by octadecylamine.
  • the amine is not octylamine, hexadecylamine or octadecylamine.
  • the amine compound does not comprise more than one amine function.
  • the amine compound does not comprise emylarnine.
  • the amine compound does not comprise any amino- acids or derivatives.
  • the amine compound does not comprise any amino- acid ester derivatives.
  • the amine compound does not comprise a hydroxyl group.
  • me amine compound does comprise other chemical functional groups than amino group.
  • the hyaluronic acid is modified by an alkylhydrazine; preferably, methylhydrazine, ethylhydrazine, propylhydrazine, butylhydrazine, pentylhydrazine, hexylhydrazine, heptylhydrazine, octylhydrazine, nonylhydrazine, decylhydrazine, undecylhydrazine, dodecylhydrazine, tridecylhydrazine, tetradecylhydrazine, pentadecylhydrazine, hexadecylhydrazine, heptadecylhydrazine, octadexylhydrazine; nanodecylhydrazine, eicosylhydrazine; more preferably, hexylhydrazine, heptylhydrazine,
  • the hyaluronic acid is modified by octadecylhydrazine.
  • the hyaluronic acid is modified by octadecylhydrazine (also called stearylhydrazine).
  • the hyaluronic acid is modified by an alkenylhydrazine; preferably, ethylenylhydrazine, propylenylhydrazine, butylenylhydrazine, pentylenylhydrazine, hexylenylhydrazine, heptylenylhydrazine, octylenylhydrazine, nonylenylhydrazine, decylenylhydrazine, undecylenylhydrazine, dodecylenylhydrazine, tridecylenylhydrazine, tetradecylenylhydrazine, pentadecylenylhydrazine, hexadecylenylhydrazine, heptadecylenylhydrazine, octadecylenylhydrazine
  • the hydrazine compound does not comprise more than one hydrazine function.
  • the hydrazine compound is a linear hydrophobic compound having one hydrazine function.
  • the hydrophobically-modified HA derivative is a HA of 200 kDa grafted with a C8 alkyl group via a hydrazide linkage.
  • the hydrophobically-modified HA derivative is a HA of 200 kDa grafted with a C6 alkyl group via an amide linkage.
  • the hydrophobically-modified HA derivative is a HA of 3000 kDa grafted with a C8 alkyl group via a hydrazide linkage.
  • the hydrophobically- modified HA derivative is a HA of 3000 kDa grafted with a C6 alkyl group via an amide linkage.
  • the hydrophobically-modified HA derivative is a HA of 3000 kDa grafted with a C18 alkyl group via an amide linkage.
  • the hydrophobically-modified HA derivative is a HA of 3000 kDa grafted with a C18 alkyl group via a hydrazide linkage. According to one embodiment, the hydrophobically-modified HA derivative is a HA of 200 kDa grafted with a C18 alkyl group via an amide linkage. According to one embodiment, the hydrophobically-modified HA derivative is a HA of 200 kDa grafted with a C18 alkyl group via a hydrazide linkage.
  • the hydrophobically-modified HA derivative is a HA of 3000 kDa grafted with a C12 alkyl group via an amide linkage. According to one embodiment, the hydrophobically-modified HA derivative is a HA of 200 kDa grafted with a C12 alkyl group via an amide linkage. According to one embodiment, the hydrophobically-modified HA derivative is a HA of 200 kDa grafted with a C18 alkyl group via an amide linkage. According to one embodiment, the hydrophobically-modified HA derivative is a HA of 200 kDa grafted with a C18 alkyl group via a hydrazide linkage.
  • the hydrophobically-modified HA derivative is a HA of 3000 kDa grafted with a C18 alkyl group via a hydrazide linkage. According to one embodiment, the hydrophobically-modified HA derivative is a HA of 3000 kDa grafted with a C18 alkyl group via an amide linkage.
  • the hydrazine compound does not comprise a hydroxy 1 group. According to one embodiment, the hydrazine compound does comprise other chemical functional groups than hydrazine group. According to one embodiment, the hydrophobic compound does not comprise more man one amine or hydrazine function. According to one embodiment, the hydrophobic compound does not comprise aryl compounds.
  • the hyaluronic acid derivative is N- stearylamine-modified hyaluronic acid, i.e. a hyaluronic acid modified by amidation reaction with stearylamine (also called octadecylamine) by amide linkage.
  • the hyaluronic acid derivative is -V-stearyl hydrazine- modified hyaluronic acid, i.e. a hyaluronic acid modified by amidation reaction with stearylhydrazine (also called octadecylhydrazine) by hydrazide linkage.
  • the hyaluronic acid is not crosslinked.
  • the modified hyaluronic acid is not crosslinked.
  • the invention also relates to a particle comprising at least one hyaluronic acid derivative of formula (I) and/or (II), and salts and/or solvates thereof.
  • the particle of the invention has a size (i.e. a mean hydrodynamic diameter) ranging from 200 nm to 500 nm; preferably, from 250 nm to 400 nm; more preferably, from 320 nm to 360 nm.
  • the mean hydrodynamic diameter is measured in a mixture of water/phosphate buffer (S0/S0, v/v) by using a nanosizer apparatus.
  • the size of the particle of the invention is about 327 nm.
  • the size of the particle of the invention is about 357 nm.
  • the particle of the invention has a size of about 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm or 500 nm. According to one embodiment, the particle of the invention has a size of about 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm or 360 nm.
  • the particle of the invention does not comprise cyclodextrin. According to one embodiment, the particle of the invention does not comprise alpha-cyclodextrin. According to one embodiment, the particle of the invention does not comprise beta-cyclodextrin. According to one embodiment, the particle is constituted of hyaluronic acid derivatives of formula (I) and/or ( ⁇ ), and salts and/or derivatives thereof. According to one embodiment, the particle of the invention does not comprise other kind of particle such as for example but not limited to, inorganic particles, hybrid particles and/or metallic particles. According to one embodiment, the particle of the invention does not comprise other polymer than hyaluronic acid. According to one embodiment, the particle of the invention does not comprise other polymer than the modified hyaluronic acid of the invention.
  • hyaluronic acid derivatives of formula (I) and/or ( ⁇ ), and salts and/or derivatives thereof are not associated with cyclodextrin.
  • hyaluronic acid derivatives of formula (I) and/or ( ⁇ ), and salts and/or derivatives thereof are not associated with alpha-cyclodextrin.
  • hyaluronic acid derivatives of formula (I) and/or ( ⁇ ), and salts and/or derivatives thereof are not associated with beta-cyclodextrin.
  • the hyaluronic acid derivatives of the invention have been characterized by spectroscopy and/or by Nuclear Magnetic Resonance (NMR).
  • NMR Nuclear Magnetic Resonance
  • the hyaluronic acid derivatives of the invention have been characterized by Fourier Transform Infrared (FT-IR) spectroscopy.
  • the invention also relates to a composition
  • a composition comprising at least one hyaluronic acid derivative of formula (I) and/or ( ⁇ ), and salts and/or derivatives thereof; and at least one cosmetically acceptable base.
  • the invention also relates to a cosmetic and/or dermo-cosmetic composition
  • a cosmetic and/or dermo-cosmetic composition comprising at least one particle of the invention as defined above, and at least one cosmetically acceptable base.
  • the composition of the invention comprises at least one particle having a size (i.e. a mean hydrodynamic diameter) ranging from 200 nm to 500 nm; preferably, from 250 nm to 400 nm; more preferably, from 320 nm to 360 nm.
  • the mean hydrodynamic diameter is measured in a mixture of water/phosphate buffer (S0/S0, v/v) by using a nanosizer apparatus.
  • the size of the particle of the invention is about 327 nm.
  • the size of the particle of the invention is about 357 nm.
  • the invention also relates to a pharmaceutical composition, preferably a dermatological composition, comprising at least one hyaluronic acid derivative of formula (I) and/or ( ⁇ ), and salts and/or derivatives thereof; and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition preferably a dermatological composition, comprising at least one hyaluronic acid derivative of formula (I) and/or ( ⁇ ), and salts and/or derivatives thereof; and at least one pharmaceutically acceptable carrier.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one particle of the invention as defined above, and at least one pharmaceutically acceptable carrier.
  • the composition does not comprise cyclodextrin. According to one embodiment, the composition does not comprise alpha-cyclodextrin. According to one embodiment, the composition does not comprise beta-cyclodextrin.
  • the composition comprises the particles of the invention in an amount ranging from 0.01 % to 100 % by weight to the total weight of the composition; preferably from 0.1 to 20 %; more preferably, from 0.5 % to 1 %.
  • the composition comprises the particles of the invention in an amount ranging from 1 % to 100 %, preferably from 10 % to 100 %, preferably from 20 % to 100 %, preferably from 30 % to 100 %, preferably from 40 % to 100 %, preferably from SO % to 100 %, by weight to the total weight of the composition.
  • the composition comprises the particles of the invention in an amount ranging from 1 % to 100 %, preferably from 1 % to 20 %, preferably from 5 % to 20 %, preferably from 10 % to 20 %, preferably from 15 % to 20 % by weight to the total weight of the composition.
  • the composition comprises the particles of the invention in an amount of about 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7 %, 8 %, 9 %, 10 %, 11 %, 12 %, 13 %, 14 %, 15 %, 16 %, 17 %, 18 %, 19 % or 20 % by weight to the total weight of the composition.
  • the composition comprises the particles of the invention in an amount of about 0.5 %, 0.6 %, 0.7 %, 0.8 %, 0.9 %, or 1 % by weight to the total weight of the composition.
  • the composition is under the form of a solid, a solution, a suspension or an emulsion.
  • the composition is selected from oil-in-water emulsion (O/W) and water-in-oil emulsion (W/O), wherein the oil may be sourced from vegetal oil or mineral oil.
  • the composition further comprises a solvent; preferably, a biocompatible solvent
  • the composition further comprises an aqueous solution or a hydro-alcoholic solution.
  • the composition further comprises at least one cosmetically acceptable base under the form of a gel, a paste, a cream, a lotion, a milk, a stick, a shampoo, a powder, an aerosol, a film or a patch.
  • compositions of the invention may be used in combination of at least one cosmetic agent selected from fatty acids, organic solvents, gelling agents, softening agents, surfactants, detergents, gelling agents, fragrances, emulsifying agents, opacifying agents, stabilizing agents, foaming agents, chelating agents, preservative agents, sunscreens, essential oils, dyes, mineral loads, or any compound used in cosmetics.
  • at least one cosmetic agent selected from fatty acids, organic solvents, gelling agents, softening agents, surfactants, detergents, gelling agents, fragrances, emulsifying agents, opacifying agents, stabilizing agents, foaming agents, chelating agents, preservative agents, sunscreens, essential oils, dyes, mineral loads, or any compound used in cosmetics.
  • compositions of the invention may be used in combination of at least one active ingredient
  • compositions of the invention are topically administrated. According to one embodiment the compositions of the invention are administrated by a direct topical mean. According to one embodiment, the compositions of the invention are administrated by an indirect topical mean. In the present invention, "indirect topical mean" refers to the use of a textile support or a material for administering the composition of the invention. According to another embodiment the composition of the invention is injected; preferably, by transdermal injection.
  • the invention also relates to a process for preparing hyaluronic acid derivatives of formula (I):
  • Z represents a single bond or -NH-
  • R represents a C1-C20 alkyl or C1-C20 alkenyl group; preferably, a C6-C18 alkyl group; more preferably, a C18 alkyl group; and
  • n represents the number of disaccharide units of D- glucuronic acid and iV-acetyl-D- glucosamine and is a positive integer
  • a suitable symmetric carbodiirnide compound has the following formula:
  • the caibodiimide compound is ethyl carbodiirnide.
  • the process for preparing hyaluronic acid derivatives of formula (I) is carried out at a temperature ranging from 0°C to 40°C; preferably, from 10°C to 30°C; more preferably, at a temperature ranging from 20°C to 2S°C.
  • the process for preparing hyaluronic acid derivatives of formula (I) is carried out at room temperature.
  • the process for preparing hyaluronic acid derivatives of formula (I) is carried out at atmospheric pressure.
  • the concentration of the hyaluronic acid ranges from 10 mg/mL to 70 mg/mL; preferably, from 20 mg/mL to 60 mg/mL; more preferably, ranges from 30 mg/mL to SO mg/mL.
  • the process is carried out for a period ranging more than 0 to 12 hours; preferably, from 1 hour to 6 hours; more preferably, the time of the process is carried out about 5 hours.
  • the invention also relates to a process for preparing particles of hyaluronic acid derivatives of formula (I):
  • Z represents a single bond or -NH-
  • R represents a C1-C20 alkyl or C1-C20 alkenyl group; preferably, a C6-C18 alkyl group; more preferably, a C18 alkyl group; n represents the number of disaccnaride units of D- glucuronic acid and JV-acetyl-D- glucosamine and is a positive integer; and comprising solubilizing hyaluronic acid derivatives or formula (I) in an aqueous dissolution medium at a concentration ranging from 0.25 to 2 % wt Especially, the invention relates to a process for preparing particles of hyaluronic acid derivatives of formula (II):
  • Z represents a single bond or -NH-
  • n represents the number of disaccnaride units of D- glucuronic acid and JV-acetyl-D- glucosamine and is a positive integer; and comprising solubilizing hyaluronic acid derivatives of formula (II) in an aqueous dissolution medium at a concentration ranging from 0.25 to 2 % wt
  • the particle has a size (i.e.
  • a mean hydrodynamic diameter ranging from 100 nm to 2000 nm; preferably, from 200 nm to 500 nm; preferably, from 250 nm to 400 nm; more preferably, from 320 nm to 360 nm
  • the mean hydrodynamic diameter is measured in a mixture of water/phosphate buffer (S0/S0, v/v) by using a nanosizer apparatus.
  • the size of the particle of the invention is about 327 nm.
  • the size of the particle of the invention is about 3S7 nm.
  • the particle has a size (i.e. a mean hydrodynamic diameter) depending on the substitution degree of modified hyaluronic acid.
  • the aqueous dissolution medium is selected from MilliQ* water, phosphate buffer or mixture of MilliQ* water and phosphate buffer (SO/SO; v/v).
  • the phosphate buffer comprises monosodium phosphate, dis odium phosphate and sodium chloride. According to one embodiment, the phosphate buffer comprises monosodium phosphate at the concentration of 0.045 g/L. According to one embodiment, the phosphate buffer comprises disodium phosphate at the concentration of 0.S63 g/L. According to one embodiment, the phosphate buffer comprises sodium chloride at the concentration of 8.5 g/L.
  • the aqueous dissolution medium has a pH ranging from 5 to 8; preferably from 5.6 to 6.9. According to one embodiment, the aqueous dissolution medium has a pH ranging from about 4 to about 8; preferably is about 4.S.
  • the concentration in the aqueous dissolution medium of hyaluronic acid derivatives is about 0.25 %, 0.S % or 1 %wt According to one embodiment, the concentration in the aqueous dissolution medium of hyaluronic acid derivatives wherein Z is single bond, is about 1 %wt According to one embodiment, the concentration in the aqueous dissolution medium of hyaluronic acid derivatives wherein Z is -NH-, is about 025 %wt or about 5 %wt.
  • the hyaluronic acid derivatives of formula (I) are completely solubilized in the aqueous dissolution medium.
  • the hyaluronic acid modified with a hydrophobic compound having (1) at least one amine function or at least one hydrazine function, and (2) a C18- alkyl chain allows improving the association of hyaluronic acid derivatives in particulate form.
  • the invention also relates to die use of hyaluronic acid derivatives or die particles of the invention, as described above.
  • the invention relates to the use of hyaluronic acid derivatives of formula (I) or particles thereof, in the field of cosmetics and/or pharmaceuticals . More especially, the invention relates to the use of hyaluronic acid derivatives of formula (I) or particles thereof, as a long-lasting anti-aging agent
  • the hyaluronic acid derivatives or particles thereof are useful in the field of cosmetics and/or fasciocosmetics.
  • the hyaluronic acid derivatives or particles thereof are useful as cosmetic and/or dermocosmetic agents, preferably as long lasting cosmetic and/or dermocosmetic agent; more preferably as long lasting anti-aging agents.
  • the long lasting anti-aging effect is observed more than 3 days, preferably more man 5 days, more preferably more than 7 days after the application of the hyaluronic acid derivatives of the invention or particles thereof on the skin of a subject in need thereof.
  • the hyaluronic acid derivatives or particles thereof increase the surface occupied by glycosaminoglycans (GAGs) in the skin (epidermis and/or dermis). According to one embodiment, the hyaluronic acid derivatives or particles thereof increase the surface occupied by glycosaminoglycans (GAGs) in the skin (epidermis and/or dermis). According to one embodiment, the hyaluronic acid derivatives or particles thereof increase the surface occupied by glycosaminoglycans (GAGs) in the skin (epidermis and/or dermis) in papillary dermis.
  • GAGs glycosaminoglycans
  • the hyaluronic acid derivatives or particles thereof are useful for increasing the surface occupied by glycosaminoglycans (GAGs) in the skin (epidermis and/or dermis), preferably in a range from 0.1 % to ISO %, preferably 1 % to ISO %, preferably from 10% a ISO %, preferably from 20 % to 150 %, preferably from 30 % to ISO %, preferably from 40 % to 150 %, preferably from 50 % to ISO %, preferably from 60 % to 150 %, preferably from 70 % to 150 %, preferably from 80 % to ISO %, preferably from 90 % to 150 %, preferably from 100 % to 150 % compared to the surface occupied by glycosaminoglycans (GAGs) in an untreated skin.
  • GAGs glycosaminoglycans
  • the hyaluronic acid derivatives or particles thereof are useful for increasing the surface occupied by glycosaminoglycans (GAGs) in the skin (epidermis and/or dermis) of a subject of about 3 %, 15 %, 30 % or 119 %, compared to the surface occupied by glycosaminoglycans (GAGs) in an untreated skin.
  • GAGs glycosaminoglycans
  • the hyaluronic acid derivatives or particles thereof are useful for increasing the surface occupied by glycosaminoglycans (GAGs) in the skin of a subject (epidermis and/or dermis) of about 1 %, 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 %, 10 %, 105 %, 110%, 115 %, 120 %, 125 %, 130 %, 135 %, 140 %, 145 %, 150 %, compared to the surface occupied by glycosaminoglycans (GAGs) in an untreated skin.
  • GAGs glycosaminoglycans
  • the particle has a size (i.e. a mean hydrodynamic diameter) ranging from 100 nm to 2000 nm; preferably, from 200 nm to 500 nm; preferably, from 250 nm to 400 nm; more preferably, from 320 nm to 360 nm.
  • the mean hydrodynamic diameter is measured in a mixture of water/phosphate buffer (50/50, v/v) by using a nanosizer apparatus.
  • the size of the particle of the invention is about 327 nm.
  • the size of the particle of the invention is about 357 nm.
  • the hyaluronic acid derivatives of the invention and/or the particles thereof are for use as a medicament
  • the present invention relates to the use of the hyaluronic acid derivatives of the invention and/or the particles thereof for the manufacture of a medicament
  • the hyaluronic acid derivatives and/or the particles of the invention are for use in the treatment and/or the prevention of dermatological conditions.
  • the hyaluronic acid derivatives and/or the particles of the invention are for use as a healing agent According to one embodiment the hyaluronic acid derivatives and/or the particles of the invention are for use as a long-lasting healing agent
  • the present invention relates to a method of treatment of dermatological diseases and/or conditions comprising the administration to a patient in need thereof, of the hyaluronic acid derivatives of the invention and/or the particles thereof.
  • the invention concerns the use as a cosmetic agent of a particle comprising at least one hyaluronic acid derivative of general formula (I) as defined above.
  • the invention concerns the use as a cosmetic agent of a particle comprising at least one hyaluronic acid derivative of general formula (la), (lb) or (II) as defined above.
  • the hyaluronic acid derivatives or the invention and/or the particles thereof are useful as cosmetic agents; preferably; as an anti-aging agent; more preferably, as a skin plumping agent, a skin hydrating agent and/or a stimulating agent of the endogenic production of hyaluronic acid.
  • the hyaluronic acid derivatives or the invention and/or the particles thereof are useful as long-lasting cosmetic agents; preferably as a long-lasting anti-aging agent; more preferably, as a long-lasting skin plumping agent, a long-lasting skin hydrating agent and/or a long-lasting stimulating agent of the endogenic production of hyaluronic acid.
  • the hyaluronic acid derivatives or the invention and/or the particles thereof are useful for stimulating the expression of endogen glycosaminoglycans (GAGs), preferably for stimulating the expression of endogen elastin, collagen and/or hyaluronic acid.
  • the invention concerns a method for stimulating the expression of endogen glycosaminoglycans (GAGs), preferably for stimulating the expression of endogen elastin, collagen and/or hyaluronic acid, said method comprising applying at least one hyaluronic acid derivative of the invention and/or the particles thereof, on the skin of a subject in need thereof.
  • glycosaminoglycans is stimulated at least during 2 days, preferably during 5 days, more preferably during 7 days, after the application of hyaluronic acid derivatives of the invention and/or the particles thereof, on the skin of a subject in need thereof.
  • glycosaminoglycans is improved in a range from 0.1 % to 150 %, preferably 1 % to 150 %, preferably from 10 % a 150 %, preferably from 20 % to 150 %, preferably from 30 % to 150 %, preferably from 40 % to 150 %, preferably from 50 % to 150 %, preferably from 60 % to 150 %, preferably from 70 % to 150 %, preferably from 80 % to 150 %, preferably from 90 % to 150 %, preferably from 100 % to 150 %, compared to the expression of glycosaminoglycans (GAGs) in an untreated skin.
  • GAGs glycosaminoglycans
  • glycosaminoglycans in the skin of a subject treated with the hyaluronic acid derivatives or particles of the invention, is improved of about 3 %, 15 %, 30 % or 119 %, compared to the expression of glycosaminoglycans in an untreated skin.
  • glycosaminoglycans (GAGs) in the skin of a subject treated with the hyaluronic acid derivatives or particles of the invention.
  • the invention also relates to a skin improvement method comprising administering the composition as defined above, to the skin of a subject in need thereof.
  • administering refers to a topical application or injection means.
  • the skin improvement method comprises applying the composition as defined above, on the skin of a subject in need thereof.
  • the skin improvement method comprises applying in a sole application the composition as defined above, on the skin of a subject in need thereof.
  • the composition is applied via a device comprising said composition; preferably, said device is a syringe, a patch, a film, a stick, a plaster, a stupe or a bandage.
  • the skin improvement method comprises applying the composition as defined above, on the skin of a subject in need thereof, once a week.
  • the skin improvement method comprises applying the composition as defined above, on the skin of a subject in need thereof, once a month.
  • the skin improvement method comprises applying the composition as defined above, on the skin of a subject in need thereof, twice a month.
  • the skin improvement method comprises the injection of the composition as defined above to a subject in need thereof.
  • the injection is a transdermal injection.
  • the skin improvement method is for restoring the production of endogenic hyaluronic acid in the epidermis and/or the dermis.
  • the skin improvement method is for limiting the shortcomings of the skin; preferably, for improving the hydration of the skin.
  • the composition is applied on the skin of a subject in need thereof, in a sole application.
  • the composition is applied on the skin of a subject in need thereof, at least once a month, preferably, twice a month; more preferably, once a week; more preferably, the composition of the invention is applied only once a week.
  • the invention also relates to a device comprising at least one hyaluronic acid derivative of formula (I) and/or ( ⁇ ); or comprising at least one particle of the invention.
  • the device is selected from a syringe, a patch, a film, a stick, a plaster, a stupe or a bandage.
  • Figure 1 is FT-IR spectra of N- stearylarnine-modified hyaluronic acid (Figure 1A) and iV-steaiymydrazme-modified hyaluronic acid ( Figure IB).
  • Figure 2 is a histogram showing the percentage of the surface occupied glycosaminoglycans (GAGs) in papillary dermis.
  • HA hyaluronic acid
  • FT-IR Fourier-Transform Infra-Red spectroscopy
  • Mw molecular weight
  • the mean hydrodynamic diameter of the particles of the invention was determined at 2S°C using a Zetasizer Nanoseries Nano-ZS90 (Malvern Instruments, France).
  • Colagen III immunostaining has been realized on frozen sections with a polyclonal anti- collagen III antibody (SBA, Ref: 1330-01) diluted at 1:20 in PBSBSA 0.3 %-Tween 20, 0.0S % during lh at room temperature using a Vectastain Kit Vector amplifier system avidin/biotin, and revealed by VIP (Vector laboratories, Ref: SK-4600). The immunostaining was assessed by microscopic observation.
  • Elastin immunostaining has been realized on paraffinized sections with a polyclonal anti- eslatin antibody (Noviotec, Ref.:25011) diluted at 1:400 during lh at room temperature, and revealed by AlexaFluor 488 (Lif etechnologies , Ref: A11008). Nuclei were post stained with propidium iodide. The immunostaining was assessed by microscopic observation. PART 1: CHFMISTPV
  • Example 1 Synthesis of the hyaluronic acid derivatives from hydrophobic compounds having at least one amine or hydrazine function
  • Typical procedures for grafting hydrophobic groups onto sodium hyaluronate are described hereinafter from an amine compound (point 1.1) or from a hydrazine compound (point 1.2).
  • sodium chloride 0.5 M
  • the grafted HA is precipitated using a water/ethanol mixture (2/3; v/v) and can be further purified by washing it with more hydrophobic water/ethanol mixtures (up to 19/1; v/v). Drying is performed under vacuum between at around 30°C. A white powder is obtained.
  • a hydrazine compound such as for example octadecylhydrazine
  • the grafted HA is precipitated using a water/ethanol mixture (2/3; v/v) and can be further purified by washing it with more hydrophobic water/ethanol mixtures (up to 19/1; v/v). Drying is performed under vacuum between at around 30°C. A white powder is obtained.
  • the product was characterized by FT-IR spectroscopy.
  • the spectrum of HA grafted with octadecylhydrazine is presented Figure IB. This analysis evidenced the presence of the bands corresponding to the grafting of the alkyl chain compared to non-modified HA.
  • Hydrophobically-modified hyaluronic acids of example 1 were dispersed into a mixture of MilliQ* water and phosphate buffer (S0/S0 %: v/v) at room temperature under magnetic stirring.
  • the formulation of die phosphate buffer is presented Table 2:
  • the final concentration of hydrophobically-modified hyaluronic acids was modified from 0.25 to 2 %wt depending on the solubility of HA derivatives and to keep the formulation liquid for size measurement
  • the particles were characterized by quasi-elastic light scattering in order to determine their mean hydrodynarnic diameter.
  • the mean hydrodynamic diameter is 327 nm for .V-stearylamine modified HA having 200 kDa and is 357 nm for N- stearylamine modified HA (3000 kDa).
  • the aim is to show that the particles of the invention are able to deliver in the papillary dermis by a sole application, a large amount of hyaluronic acid derivatives while limiting the degradation of the product in the skin over time.
  • PI 1 particles of .V-stearylamine modified HA having 200 kDa (amide linkage); P14: particles of .V-stearylamine modified HA having 3000 kDa (amide linkage); and
  • - PO particles of 0-stearoyle modified HA which are HA modified with stearic acid (ester linkage).
  • PI 1 and P14 are the particles of the invention whereas PO are particles for comparison, said particles PO comprising hydrophobically-modified HA through ester bond.
  • the skin human explants have an average diameter of 11 nm ( ⁇ 1 mm) and were collected after abdominoplasty from a 44-year-old woman. The explants were kept in survival in a culture medium at 37°C in a humid, 5 % CO2 atmosphere.
  • glycosaminoglycan GAG
  • C a witness sample
  • day 0 corresponds to the day where a topical administration of the formulation has been carried out on the explant (4 mg/cm 2 ).
  • the histogram shows that:
  • the aim is to show that the particles of the invention are able to be diffused until the deepest layer of the skin.
  • three formulations were studied during 7 days on ex vivo human skin abdomen explants:
  • PI 1 particles of .V-stearylamine modified HA having 200 kDa (amide linkage); P14: particles of -V-stearylamine modified HA having 3000 kDa (amide linkage); and
  • - PO particles of O-stearoyle modified HA which are HA modified with stearic acid (ester linkage).
  • glycosaminoglycan For each of these formulations, the total content of glycosaminoglycan (GAG) has been quantified over time (day 3, day 5 and day 7) through 3 different compartments of dermis: the papillary dermis, the upper reticular dermis and the lower reticular dermis. These results have been compared to a witness sample (no treated sample, noted "W").
  • the studied formulations are:
  • R sodium hyaluronate
  • PI 1 particles of -V-stearylamine modified HA having 200 kDa (amide linkage); P14: particles of -V-stearylamine modified HA having 3000 kDa (amide linkage); and
  • PO particles of 0-stearoyle modified HA which are HA modified with stearic acid (ester linkage).
  • the collagen ⁇ and elastin contents have been quantified in the papillary dermis after 7 days compared to a witness sample (no treated sample, noted "C").
  • the quantification has been carried out by an image analysis of collagen ⁇ and elastin after specific immunological labelling of samples.
  • the aim is to show that the particles of modified-HA comprising hydrazide linkages, are able to deliver in the papillary dermis by a sole application, a large amount of hyaluronic acid derivatives while limiting the degradation of the product in the skin over time.
  • the aim is also to compare the efficiency as a long lasting anti-aging agent of particles made of modified-HA comprising hydrazide linkages and of particles made of modified-HA comprising amide linkages.
  • the following formulations were studied during 7 days on ex vivo human skin abdomen explants:
  • P13 particles of N- steary lhydrazine modified HA having 3000 kDa (hydrazide linkage).
  • PI 1 particles of .V-stearylamine modified HA having 200 kDa (amide linkage).
  • the skin human explants have an average diameter of 11 nm ( ⁇ 1 mm) and were collected after abdominoplasty from a 51-year-old woman. The explants were kept in survival in a culture medium at 37°C in a humid, 5 % CO2 atmosphere.

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Abstract

La présente invention concerne le domaine de la cosmétique et des produits pharmaceutiques tels que la dermatologie. En particulier, la présente invention concerne des particules constituées d'acide hyaluronique modifié par amidation avec des groupes hydrophobes ayant une fonction amine ou hydrazine, de formule générale (I) : (I) où Z, R et n sont tels que définis dans les revendications. En particulier, les particules de l'invention sont utiles pour restaurer la production endogène d'acide hyaluronique et produire un effet durable grâce à leur dégradation lente in vivo. La présente invention concerne également une méthode de soin cosmétique consistant à appliquer les particules de l'invention sur la peau d'un sujet en ayant besoin.
PCT/EP2017/069844 2016-08-04 2017-08-04 Utilisations d'acide hyaluronique modifié de manière hydrophobe par des liaisons amide et/ou hydrazide en cosmétique et/ou en dermatologie WO2018024902A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021209645A1 (fr) * 2020-04-17 2021-10-21 Pvac Medical Technologies Ltd Composition pour le traitement de tissu kératinique

Citations (6)

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Publication number Priority date Publication date Assignee Title
WO2000001733A1 (fr) * 1998-07-06 2000-01-13 Fidia Advanced Biopolymers S.R.L. Amides d'acide hyaluronique, derives de ce dernier et leurs procede de preparation
WO2006113668A1 (fr) * 2005-04-15 2006-10-26 University Of South Florida Procede de delivrance d’un medicament par voie transdermique en utilisant des nanoparticules d’acide hyaluronique
WO2007102149A2 (fr) * 2006-03-07 2007-09-13 Prochon Biotech Ltd. Dérivés hydrazido de l'acide hyaluronique
WO2013150193A1 (fr) * 2012-04-06 2013-10-10 Centre National De La Recherche Scientifique Microparticules et nanoparticules constituées de polysaccharides hydrophobisés et d'une alpha-cyclodextrine
US20150080333A1 (en) * 2012-01-18 2015-03-19 University Of Kansas Hyaluronic acid particles and their use in biomedical applications
WO2016135430A1 (fr) * 2015-02-27 2016-09-01 Centre National De La Recherche Scientifique Particules d'acide hyaluronique pour des applications cosmétiques ou dermatologiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001733A1 (fr) * 1998-07-06 2000-01-13 Fidia Advanced Biopolymers S.R.L. Amides d'acide hyaluronique, derives de ce dernier et leurs procede de preparation
WO2006113668A1 (fr) * 2005-04-15 2006-10-26 University Of South Florida Procede de delivrance d’un medicament par voie transdermique en utilisant des nanoparticules d’acide hyaluronique
WO2007102149A2 (fr) * 2006-03-07 2007-09-13 Prochon Biotech Ltd. Dérivés hydrazido de l'acide hyaluronique
US20150080333A1 (en) * 2012-01-18 2015-03-19 University Of Kansas Hyaluronic acid particles and their use in biomedical applications
WO2013150193A1 (fr) * 2012-04-06 2013-10-10 Centre National De La Recherche Scientifique Microparticules et nanoparticules constituées de polysaccharides hydrophobisés et d'une alpha-cyclodextrine
WO2016135430A1 (fr) * 2015-02-27 2016-09-01 Centre National De La Recherche Scientifique Particules d'acide hyaluronique pour des applications cosmétiques ou dermatologiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021209645A1 (fr) * 2020-04-17 2021-10-21 Pvac Medical Technologies Ltd Composition pour le traitement de tissu kératinique

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