WO2019145541A1 - Nano-objets métalliques à usage cosmétique - Google Patents

Nano-objets métalliques à usage cosmétique Download PDF

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Publication number
WO2019145541A1
WO2019145541A1 PCT/EP2019/052012 EP2019052012W WO2019145541A1 WO 2019145541 A1 WO2019145541 A1 WO 2019145541A1 EP 2019052012 W EP2019052012 W EP 2019052012W WO 2019145541 A1 WO2019145541 A1 WO 2019145541A1
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Prior art keywords
cosmetic
nanoobject
combination
metal
skin
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PCT/EP2019/052012
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English (en)
Inventor
Joaquín QUEROL SASTRE
Joaquín ESCUDERO CANO
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Endor Technologies, S.L.
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Publication of WO2019145541A1 publication Critical patent/WO2019145541A1/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
    • A61K8/02—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
    • 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
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • 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
    • A61Q19/06—Preparations for care of the skin for countering cellulitis
    • 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
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm
    • 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
    • A61K2800/60—Particulates further characterized by their structure or composition
    • A61K2800/61—Surface treated
    • A61K2800/614—By macromolecular compounds
    • 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
    • A61K2800/81—Preparation or application process involves irradiation
    • 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
    • A61K2800/82—Preparation or application process involves sonication or ultrasonication
    • 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
    • A61K2800/94—Involves covalent bonding to the substrate

Definitions

  • the present invention relates to the field of cosmetics, in particular it relates to the use of a metal nanoobject, or a cosmetic composition comprising thereof, in combination with cosmetic-type radiation for the topical skin cosmetic treatment, wherein the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis.
  • Invasive methods are used in cosmetics in order to treat cellulitis and in anti-age treatments, as is the case of liposuction and cosmetic treatments wherein the agent is usually injected into the dermis or hypodermis of the patient.
  • Cosmetic applications for radiation skin therapy are numerous, and include for example radiofrequency (RF), laser, visible light, infrared, ultraviolet, led light and ultrasound radiation.
  • RF energy treatment is often used for non-surgical body contouring, fat and cellulite reduction.
  • RF works as an anti-cellulite agent through a deep controlled heating of the fatty layers under the skin. RF stimulates tissue tightening, and increases blood circulation, which makes fatty deposits be drained through the lymphatic system.
  • NPs Metal nanoparticles
  • AU201 1293132 describes the subdermal application of metal NPs in combination with light irradiation for skin rejuvenation, wrinkle reduction and fat ablation
  • US2014358068 discloses lipolysis by injecting a photo- absorbing NP and irradiating with near infrared light
  • Invasive cosmetic treatments that use metal NP show several problems as the metal NPs can be accumulated in the body of the patient, in particular in the kidney and produce acute nephrotoxicity. The problem is increased when the patient receives several cosmetic treatment sessions, which is normally the case.
  • NPs metal nanoparticles conjugated with a cosmetic agent which binds to a component forming part of the epidermis were effectively retained in the epidermis, when they were topically applied on skin surface, as it is shown in Example 5. And that this retainment was due to the binding of the conjugated cosmetic agent, exemplified by hyaluronic acid (HA), to the hyaluronic acid receptors found in the epidermis.
  • HA hyaluronic acid
  • the inventors applied cosmetic-type radiation, after the topical application of the nanoparticle, it was found that the nanoparticle, even being retained in the epidermis, was able to exert a cosmetic effect in the dermis.
  • the hyaluronic-conjugated metal nanoparticles in combination with the radiation, were able to efficiently treat cellulite and age skin conditions such as wrinkles, and produced amelioration in skin tightness.
  • the conjugated metal NPs which are retained in the epidermis, absorb the energy of the applied radiation, emit heat and trigger the production of hyaluronic acid and collagen in the dermis.
  • the cosmetic effect obtained with the conjugated metal nanoobjects combined with radiofrequency was also obtained with the conjugated metal nanoobjects combined with other cosmetic-type radiations, such as laser and ultrasound.
  • Example 6 the inventors have also found, as shown in Example 6, that the own organism expels the NP in the 24 hours following its application.
  • the cosmetic combination therapy of the invention means a great advance in the field of topical skin cosmetics because it is reported, for the first time, a nanoparticle- based topical skin cosmetic treatment which is non-invasive and which further overcomes the toxicity drawbacks of the prior art due to nanoparticle’s accumulation in kidney.
  • a first aspect of the present invention refers to the use of a metal nanoobject for the topical cosmetic treatment of skin, in combination with cosmetic-type radiation, wherein the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis.
  • the first aspect can be alternatively formulated as a cosmetic method for the treatment of skin, said method comprising: - topical administering to a person in need thereof a cosmetically effective amount of a metal nanoobject, and - application of cosmetic-type radiation; wherein the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis.
  • a second aspect of the present invention refers to the use of a cosmetic composition that comprises an effective amount of the metal nanoobject as defined in the first aspect of the invention together with one or more appropriate topical cosmetically acceptable excipients or carriers, for the cosmetic treatment of skin, in combination with a cosmetic-type radiation source.
  • This aspect can be alternatively formulated as a cosmetic method for the treatment of skin, said method comprising: - topical administering to a person in need thereof an effective amount of a cosmetic composition comprising an effective amount of the metal nanoobject as defined in the first aspect of the invention together with one or more appropriate topical cosmetically acceptable excipients or carriers, and - application of cosmetic-type radiation.
  • Fig. 1 shows a schematic representation of the metal NP conjugated with derivatized HA.
  • A schema of the linking of the metal NP to the HA through a linker that contains a sulphur group (cystamine dyhydrochloride);
  • B left, metal NP before conjugation with the derivatised HA, right, metal NP after conjugation with the derivatised HA (top figures, schematic representation; bottom figures, TEM images)
  • Fig. 2 represents a TEM image of Au NPs size, shape and distribution (left panel). Right panel is the corresponding analysis of average diameter size.
  • Fig. 3 shows the SPR (UV-Vis spectrophotometry) of the Au NPs.
  • Fig. 4 shows the hyaluronic acid oligomers NMR spectrum: A, initial spectrum; B, after derivatization.
  • Fig. 5 represents the UV-Vis spectrophotometry (SPR) of the conjugated Au NPs.
  • Fig. 6 shows cellulite reduction comparing the treatments of gold NP conjugated with derivatized HA (gold NP-HA) combined with RF (gold NP-HA + RF) versus placebo combined with RF (placebo + RF).
  • Fig. 7 shows the increase in echogenic density in dermis comparing the treatments of gold NP-HA combined with RF (gold NP-HA + RF) versus placebo combined with RF (placebo + RF).
  • Fig. 8 shows the collagen staining of biopsies taken from volunteers at day 0 from the beginning of the treatment (DO), at day 49 (D49) after the 6 weekly sessions with the gold NP-HA combined with RF (gold NP-HA + RF) or with placebo combined with RF (placebo + RF).
  • the rectangles show similar zones in the dermis between the images.
  • Fig. 9 shows the hyaluronic acid stain in biopsies taken at day 0 from the beginning of the treatment (DO), at day 49 (D49) after the 6 weekly sessions with the gold NP-HA combined with RF (gold NP-HA + RF) or with placebo combined with RF (placebo + RF).
  • the rectangles show similar zones in the dermis between the images.
  • any ranges given include both the lower and the upper end-points of the range. Ranges given, such as weights, ratios, and the like, should be considered approximate, unless specifically stated.
  • the first aspect of the invention refers to the use of a metal nanoobject for the topical cosmetic treatment of skin in combination with a cosmetic-type radiation, wherein the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis.
  • the cosmetic agent which binds to a component forming part of the epidermis comprises one or more of: a polysaccharide, an
  • the cosmetic-type radiation is selected from the list consisting of: radiofrequency, laser, infrared, ultraviolet, led light, microwave, ultrasound and electrical cosmetic radiation.
  • nanoobject refers to a primary particle (non- agglomerated single particle) with one, two or three external dimensions in the nanoscale, as already recognized by International Organization for Standardization in the document with the reference number ISO/TS 27687:2008(E).
  • nanoobjects are: nanoparticles, which are nanoobjects with all three external dimensions in the nanoscale (if the lengths of the longest to the shortest axes of the nanoobject differ significantly, typically by more than three times, the terms nanofibre or nanoplate are intended to be used instead of the term nanoparticle); nanosheets (or nanoplates or nanolayers), which are nanoobjects with one external dimension in the nanoscale and the two other external dimensions significantly larger, wherein the smallest external dimension is the thickness of the nanosheets, the two significantly larger dimensions are considered to differ from the nanoscale dimension by more than three times, and the larger external dimensions are not necessarily in the nanoscale; nanofibres, which are nanoobjects with two similar external dimensions in the nanoscale and the third dimension significantly larger, wherein the nanofibres can be flexible or rigid and the two similar external dimensions are considered to differ in size by less than three times and the significantly larger external dimension is considered to differ from the other two by more than three times, and the largest external dimension is not necessarily in
  • conjuggated encompasses both the covalent binding (including covalent-like binding) between the nanoobject and the cosmetic agent, but also the absorption in particle surface due to electrostatic interactions.
  • the metal nanoobject is made of a single metal.
  • the nanoparticle is made from a single metal, which is selected from the group consisting of: gold, copper, silver, platinum, cobalt, iron, titanium, nickel, zinc, chromium, palladium, cadmium, ruthenium, rhodium, iridium and oxides thereof.
  • the metal nanoobject is a gold nanoobject.
  • the metal nanoobject is made from different metals.
  • the nanoobject is made from two or three different metals selected from gold, copper, silver, platinum, cobalt, iron, titanium, nickel, zinc, chromium, palladium, cadmium, ruthenium, rhodium, iridium, and oxides thereof.
  • the metal nanoobject is a metal nanoparticle (NP).
  • the metal nanoobject is a nucleus-shield NP, wherein the nucleus and the shield may be independently composed of a material selected from the group formed by the metals Au, Ag, Pt, Co, Fe, oxides thereof, Ti0 2 , and any combination thereof.
  • the metal nanoobject is a Au nanoparticle (NP).
  • Metal nanoobjects and nanoparticles can be obtained using well-known methods in the state of the art.
  • the preparation is performed, with shape and size control, by means of chemical reactions that are well known to those skilled in the art.
  • gold nanoparticles are prepared, and the method used to do so is based on synthetic methods that are broadly described in the literature, such as the so-called sodium citrate method (Turkevich, J., P. C. Stevenson, et al. (1951 ). "The nucleation and growth processes in the synthesis of colloidal gold.” Discussions of the Faraday Society 11 : 55-75 ), or by reduction with NaBH 4 (Haiss, W., N. T. Thanh, et al. (2007). "Determination of size and concentration of gold nanoparticles from UV-vis spectra.” Anal Chem 79(1 1 ): 4215-21 ).
  • the metal nanoobject has an average diameter size between 2 and 100 nm.
  • the term“particle size” when referred to the nanoobject of the invention refers to a characteristic physical dimension of the primary particle.
  • the size corresponds to the diameter of the nanoobject.
  • the“particle size” of the nanoobject corresponds to the diameter of the cross-section of the nanoobject.
  • the size of the nanoobject corresponds to the thickness.
  • the set of nanoobjects can have a distribution of sizes around the specified size.
  • the skilled person in the art, using the general knowledge, can achieve the different sizes and shapes of the nanoobjects.
  • the size of the nanoobjects of the invention can be determined using well-known techniques in the state of the art such as Transmission Electron Microscopy (TEM).
  • TEM Transmission Electron Microscopy
  • the metal nanoobject is a spherical metal NP. In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the metal nanoobject is a nanorod metal NP.
  • the metal nanoobject has an average diameter size of 4 to 50 nm. In another embodiment, optionally in combination with any of the embodiments provided above or below, the metal nanoobject has an average diameter size of 6-30 nm. In another embodiment, optionally in combination with any of the embodiments provided above or below, the metal nanoobject has an average diameter size of 8-15nm. In another embodiment, the metal NP has an average diameter size of 10-14 nm, in yet another embodiment is of 10-12nm.
  • The“component forming part of the epidermis” is any protein, lipid or polysaccharide located in the epidermis.
  • the component is on the epidermal cell-surface.
  • the component is an epidermal cell receptor.
  • the component forming part of the epidermis is a growth factor receptor.
  • the component forming part of the epidermis is the cell receptor of a polysaccharide, an oligossacharide, an amino acid, a peptide or a protein.
  • the component forming part of the epidermis is a vitamin or a hormone receptor.
  • the component forming part of the epidermis is the cell receptor of a polysaccharide.
  • the component is a glycosaminoglycan receptor.
  • the component is a hyaluronic acid (HA) receptor.
  • HA hyaluronic acid
  • the component is a HA receptor located in the keratinocytes.
  • the HA receptor is selected for the group consisting of: CD44, keratinocyte intercellular adhesion molecule-1 (ICAM-1 ) and the receptor for HA-mediated motility (RHAMM).
  • CD44 is also known as HCAM (homing cell adhesion molecule), Pgp-1 (phagocytic glycoprotein-1 ), Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.
  • the metal nanoobject is a Au NP and binds to a HA cell-receptor of the epidermis.
  • the metal nanoobject is a Au NP and binds to CD44 of the epidermis.
  • the cosmetic active agent comprises one or more of: a polysaccharide, an oligosaccharide, an amino acid, a peptide and a protein.
  • the cosmetic active agent comprises a vitamin and/or a hormone.
  • the active agent consists of a polysaccharide, an oligossacharide, an amino acid, a peptide or a protein.
  • the active agent consists of a vitamin, a hormone or a growth factor.
  • the active agent is a HA hydrolysis inhibitor (HA hydrolysis inhibitors produced by an enzyme from the hyaluronidase family).
  • the polysaccharide is a glycosaminoglycan.
  • the glycosaminoglycan is a HA polysaccharide.
  • Hyaluronic acid is a polysaccharide formed by alternating disaccharide units of D- glucuronic acid and N-acetyl-D-glucosamine bound by b-1 -3 and b-1 -4 glycosidic bonds. It may be of animal origin (for example from hens' combs and fish's eyeballs) or of microbiological origin (for example, from bacterial culture extracts).
  • HA polysaccharide used in this invention can refer to a natural HA oligomer and may be acquired from various companies that commercialize it. "HA polysaccharide” is interchangeable with the term“HA polymer”.
  • HA polymer and HA oligomer refer to the same compound, when they have the same number of monomers and the same structure; likewise, occasionally their respective derivatives, "derivatised HA polymer” and “derivatised HA oligomer”, are the same.
  • the "HA polymer” may has not been subject to enzymatic hydrolysis or may have been subject to enzymatic hydrolysis.
  • the aspects and embodiments referring to“HA” embraces both the non-derivatised and the derivatised forms of the molecule.
  • the HA polysaccharide is derivatised in accordance with one of the following alternatives:
  • the HA oligomer or the derivatised HA oligomer generally comprises between 1 and a maximum number of monomers, determined by the biological nature of HA itself. In general, this maximum number is about 50,000 HA monomers. In a particular
  • the hyaluronic acid oligomer comprises between 1 -1 ,000 HA monomers; in another particular embodiment, it comprises between 1 -100 HA monomers, and, in another particular embodiment, it comprises between 2-25 HA monomers.
  • the derivatised HA comprises 3 monomers.
  • HA refers to a unit formed by two consecutive residues of bound D- glucuronic acid and N-acetyl-D-glucosamine.
  • the metal nanoobject is a Au NP
  • the cosmetic active agent is HA.
  • the HA- conjugated NP is retained in epidermis because the HA oligomer binds to the HA receptor displayed in epidermal cells.
  • the HA polysaccharide has a molecular weight from 2 to 15 kDa.
  • the term“molecular weight” refers both to the number average molecular weight (Mn) and the weight average molecular weight (Mw) as the HA polysaccharide composition is homogeneous, therefore the Mn and Mw are equivalent and their value is the same.
  • the HA polysaccharide has a molecular weight from 4 to 10 kDa.
  • the cosmetic active agent is a HA polysaccharide having a molecular weight from 2 to 15 kDa and the metal nanoobject has an average particle size from 4 to 50 nm.
  • the cosmetic active agent is a HA polysaccharide having a molecular weight from 2 to 15 kDa and the metal nanoobject is a Au NP having an average particle size from 4 to 50 nm.
  • optionally in combination with any of the embodiments provided above or below the cosmetic active agent is a HA polysaccharide having a molecular weight from 2 to 15 kDa and the metal nanoobject is a Au NP having an average particle size from 4 to 50 nm.
  • the cosmetic active agent is a HA polysaccharide having a molecular weight from 4 to 10 kDa and the metal nanoobject has an average particle size from 10 to 14 nm.
  • the cosmetic active agent is a HA polysaccharide having a molecular weight from 4 to 10 kDa and the metal nanoobject is a Au NP having an average particle size from 10 to 14 nm.
  • the average particle size of the HA-conjugated nanoobject is from 15 to 25 nm.
  • the average particle size of the HA- conjugated Au NP is from 15 to 25 nm.
  • the number of metal nanoobject (for example metal NPs) in the conjugate compound generally ranges between 1 and a maximum number that may be determined by physical characterization techniques, and which depends on various factors, such as the total number of linkers in the cosmetic agent (for example, HA oligomer).
  • the weight ratio between the nanoobject and the HA is from 4 and 2,000; in another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the weight ratio between the HA and the nanoobject is from 400:1 to 600:1 (for example 500:1 ), from 4:1 to 200:1 ; or from 4:1 to 50:1.
  • the molecular ratio of the cosmetic agent:nanoobject is 1 :1.
  • the molecular ratio of the HA anoobject is 1 :1.
  • the molecular ratio of HA:NP is 1 :1.
  • the surface of the nanoobject is conjugated at 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% by the cosmetic agent
  • the surface of the nanoobject, which is a NP is conjugated at 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% by the cosmetic agent
  • the surface of the NP is conjugated at 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% by the cosmetic agent
  • the surface of the NP is conjugated at 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91 %, 92%, 93%,
  • the conjugation can be performed by mixing and stirring in a water suspension the metal nanoobject and the cosmetic active agent.
  • the nanoobject is conjugated to the cosmetic active agent by a covalent binding.
  • the nanoobject is covalently bound to the cosmetic active agent by a linker birradical.
  • the nanoobject is a metal nanoobject and it is conjugated to the cosmetic active agent via a -S- atom contained in a linker birradical (i.e. a birradical has at least one -S-).
  • the nanoobject is a gold nanoobject and it is conjugated to the cosmetic active agent via a -S- atom contained in a linker birradical (i.e. a birradical has at least one -S-).
  • the nanoobject is a gold NP and it is conjugated to the cosmetic active agent via a -S- atom contained in a linker birradical (i.e. a birradical has at least one -S-).
  • linker refers to an organic molecule that covalently binds to an HA oligomer, as explained further below, and binds said HA oligomer to the metal nanoobject (for example a metal NP).
  • the linker in this invention contains at least one sulfur atom that binds to the metal nanoobject (for example a metal NP).
  • the linker may have numerous different chemical structures, provided that it fulfils the function of binding the HA oligomer and the metal nanoobject (for example a metal NP). Said structures may be variable and are easily recognised by a person skilled in the art.
  • the nanoobject is a gold NP and it is conjugated to HA via a -S- atom contained in a linker birradical (i.e. a birradical has at least one -S-).
  • the linker is a -NH(Ci-Cio)alkyl-S- birradical, the -S- atom being bound to the NP and the -NH- to the HA.
  • alkyl refers to a saturated linear or branched hydrocarbon chain containing the number of carbon atoms indicated in the claims and in the description.
  • alkyl groups include, but are not limited to: methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonanyl and decanyl.
  • the linker is a -NH(Ci- C 5 )alkyl-S- birradical, the -S- atom being bound to the NP and the -NH- to the HA.
  • the linker is a -NH(CH 2 ) 2 -S- birradical, the - S- atom being bound to the NP and the -NH- to the HA.
  • the conjugate has a structure that comprises: one metal nanoparticle and one or more HA oligomers, wherein each of the HA oligomers is derivatised with one linker through one chemical bond, and wherein each linker binds each HA oligomer to the metal NP.
  • the conjugate has a structure that comprises: one metal nanoparticle and one or more HA oligomers, wherein each of the oligomers is derivatised with at least two linkers, which bind each HA oligomer to the metal NP.
  • the conjugate has a structure that comprises: one or more HA oligomers derivatised with more than one linker each, which bind each HA oligomer to one or more metal NP.
  • the conjugated nanoobject is purified and subsequently isolated by dialysis.
  • cosmetic-type radiation refers to a radiation that does not produce tissue ablation and does not injury any tissue of the treated person.
  • the characteristics of the cosmetic-type radiation to be not harmful can be easily adjusted by the expert, such as, for example, wavelength, intensity, potency, pulse and pulse width.
  • the cosmetic-type radiation is a light source.
  • one or more light sources of any type that emits light i.e. an emitter light outputs
  • the light cosmetic treatment occurs by the use of an emitter or light- generating device such as for example a laser; a lamp for instance a flash lamp (as used in an intense pulsed light); or a light output device.
  • the light source is a laser, visible light, infrared, ultraviolet or led light.
  • the cosmetic radiation is laser.
  • lasers that emit specific wavelengths within the UV, visible and IR portions of the electromagnetic spectrum can be used.
  • lasers commonly used include, but it is not limited to Q-switched Nd:YAG laser, Q-switched ruby laser, Q- switched Alexandrite laser.
  • laser therapy treatments can be performed mantaining the fluence of laser during the entire treatment, or alternatively modifying the fluence from a relative low fluence to a high fluence.
  • the light therapy is a laser therapy.
  • the treatment is performed mantaining the fluence of the laser during the entire treatment.
  • a light application may include one or more exposures of a treatment area of one or more emitter light outputs.
  • multiple outputs may be necessary to obtain full treatment. That is, if an emitter output for instance appears relatively small and circular in shape at the surface of the treatment area, clinicians or others may use two or more overlapping outputs, which may be fully or partially overlapping, to treat a larger and/or non-circular treatment area.
  • a treatment area may receive or be exposed to sufficient outputs in such manner as to achieve the desired result.
  • the skin treatment area is exposed to a number of light outputs.
  • the cosmetic-type radiation is selected from the list consisting of: radiofrequency, laser, visible light, infrared, ultraviolet, led light, microwave, ultrasound or electrical cosmetic radiation.
  • the cosmetic-type radiation is radiofrequency (RF).
  • the cosmetic radiation is radiofrequency, laser and/or ultrasound, or any combinations thereof.
  • the metal nanoobject is a gold nanoobject
  • the cosmetic active agent is HA
  • the cosmetic-type radiation is RF.
  • the metal nanoobject is a gold NP
  • the cosmetic active agent is HA
  • the cosmetic-type radiation is RF.
  • the metal nanoobject is a gold nanoobject
  • the cosmetic active agent is HA
  • the NP being conjugated to HA via a -S- (Ci-Cio)alkyl-NH- linker, wherein the -S- atom is bound to the NP and the -NH- to the HA
  • the cosmetic-type radiation is RF.
  • the metal nanoobject is a gold NP
  • the cosmetic active agent is HA
  • the NP is conjugated to HA via a -S- (C CioJalkyl-NH- linker, wherein the -S- atom is bound to the NP and the -NH- to the HA
  • the cosmetic-type radiation is RF.
  • the metal nanoobject is a gold NP
  • the cosmetic active agent is HA
  • the NP is conjugated to HA via a -S- (CH 2 ) 2 -NH- linker, wherein the -S- atom is bound to the NP and the -NH- to the HA
  • the cosmetic-type radiation is RF.
  • the cosmetic treatment can alternate different cosmetic radiations, for example, in one treatment round the cosmetic radiation is one from the ones disclosed herein and in a following round of treatment is a different one.
  • the cosmetic radiation is always radiofrequency.
  • RF energy/power can be applied or coupled to skin by at least one electrode or by two or more electrodes.
  • Application of RF energy to skin heats the segment of skin or tissue located near the electrodes.
  • bipolar RF power/energy is applied is applied between a pair (or pairs) of adjacent RF electrodes, leading to increase of the skin segment temperature.
  • An electrical contact improving gel could be used between RF electrodes and skin to avoid formation of air pockets or to wet the outer dry layer of skin thereby reducing the electrical impedance.
  • the RF is applied with a potency of 45-75W, during 5-20 minutes, with a pulse frequency of 0.50-0.78 Hz and with a pulse width of 100-300 us.
  • the cosmetic radiation is ultrasound.
  • the cosmetic radiation is ultrasound of 1 to 3 MHz.
  • the use of the metal nanoobject in combination with the cosmetic-type radiation produces hyperthermia, wherein said hyperthermia is of about a range from 32 to 52°C, in a more particular embodiment the hyperthermia is of about 42°C.
  • the nanoobject is a gold NP with an average diameter size between 10-12nm conjugated with a derivatised HA polysaccharide of a molecular weight of a range from 4 to 10kDa, wherein the HA polysaccharide is derivatised through, at least, one chemical bond with at least one linker that comprises an -S- group, whereby the derivatised HA polysaccharide binds to the gold NP; wherein the radiation source is RF, wherein the RF is applied with a potency of 45- 75W, during 5-20 minutes, with a pulse frequency of 0.50-0.78 Hz and with a pulse width of 100-300 us; and the hyperthermia is of about 42°C.
  • first aspect of the invention optionally in combination with any of the embodiments provided above or below, comprises the use of a substance to improve the radiation source action prior to or after the administration of the cosmetic-type radiation.
  • a substance to improve the radiation source action prior to or after the administration of the cosmetic-type radiation.
  • said substance is glycerin.
  • glycerin is used before the cosmetic-type radiation treatment.
  • glycerin is used before the RF radiation.
  • the treatment is applied weekly during 4-8 weeks.
  • the treatment is applied weekly during 6 weeks.
  • the treatment is applied weekly during 6 weeks with daily application of the conjugated metal nanoobject and weekly application of the cosmetic-type radiation.
  • the treatment is applied weekly during 6 weeks with daily application of the Au NP conjugated with HA and weekly application of RF.
  • the cosmetic treatment is selected from cellulite reduction, skin tightness amelioration and wrinkle reduction.
  • the cosmetic applications described herein can be applied also to other cosmetic agents which binds to a component forming part of the epidermis.
  • the cosmetic treatment of skin is performed by increasing collagen and/or hyaluronic acid production in the dermis.
  • the cosmetic treatment of skin is performed by increasing collagen and/or hyaluronic acid production in the dermis.
  • the treated skin is the skin of the legs, arms, abdomen or face.
  • the cosmetic treatment is performed on undamaged skin.
  • “Undamaged skin” refers to a skin with its integrity maintained in the area to be treated.
  • the present invention also refers to a cosmetic method for the treatment of cellulite, wrinkles and/or improving skin tightness, said method comprising topical administering to a person in need thereof a cosmetically effective amount of the metal nanoobject of the first aspect of the invention and application of cosmetic-type radiation. From now on is referred to as the“cosmetic method of the invention”.
  • the cosmetic method comprises the steps of:
  • composition that comprises the metal nanoobject as defined in the first aspect of the invention together with topical cosmetically acceptable excipients or carriers;
  • the cosmetic-type radiation source is selected from the list consisting of: RF, visible light, infrared, ultraviolet, led light, microwave, ultrasound or electrical cosmetic radiation.
  • the cosmetic-type radiation source is RF.
  • the RF is applied with a potency of 45-75W, during 5-20 minutes, with a pulse frequency of 0.50-0.78 Flz and with a pulse width of 100-300 us.
  • the“cosmetic method of the invention additionally comprises the measurement of skin temperature in the treated skin.
  • the hyperthermia is of about a range from 32 to 52°C.
  • the hyperthermia is of about 42°C.
  • the nanoobject is a gold NP with an average diameter size between 10-12nm conjugated with a derivatised HA polysaccharide of a molecular weight of a range from 4 to 10kDa, wherein the HA polysaccharide is derivatised through, at least, one chemical bond with at least one linker that comprises an -S- group, whereby the derivatised HA oligomer binds to the metal NP; wherein the radiation source is RF, wherein the RF is applied with a potency of 45-75W, during 5-20 minutes, with a pulse frequency of 0.50-0.78 Hz and with a pulse width of 100-300 us; and the hyperthermia is of about 42°C.
  • a substance is put in contact
  • glycerin is topically administered between steps a) and b).
  • the cosmetic treatment is applied weekly during 4-8 weeks. In another embodiment, it is applied weekly during 6 weeks.
  • the treated skin is skin of the legs, arms, abdomen or face.
  • the cosmetic treatment is not a tissue ablation treatment.
  • the invention refers to a topical use of a cosmetic composition that comprises an effective amount of the metal nanoobject of the firs aspect of the invention, together with one or more appropriate topical cosmetically acceptable excipients or carriers, for the cosmetic treatment of the skin, in combination with a cosmetic-type radiation.
  • the second aspect of the invention can be reformulated as the use of a cosmetic composition that comprises an effective amount of a metal nanoobject, wherein the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis; together with one or more appropriate topical cosmetically acceptable excipients or carriers, for the cosmetic treatment of skin, in combination with a cosmetic- type radiation source.
  • the metal nanoobject is a metal NP.
  • the component forming part of the epidermis is a receptor of the cosmetic agent.
  • the component forming part of the epidermis is a receptor of hyaluronic acid.
  • the cosmetic active agent comprises one or more of: a polysaccharide, an oligossacharide, an amino acid, a peptide or a protein.
  • the cosmetic agent is a hyaluronic acid (HA) polysaccharide.
  • the HA polysaccharide has a molecular weight from 2 to 15 kDa.
  • the HA polysaccharide has a molecular weight from 4 to 10 kDa and the metal nanoobject has an average particle size from 4 to 50 nm.
  • the nanoobject is an Au nanoobject.
  • the HA polysaccharide is conjugated to the Au nanoobject by a linker birradical of formula -NH(Ci-Ci 0 )alkyl-S-.
  • the cosmetic-type radiation is selected from the list consisting of: radiofrequency, laser, infrared, ultraviolet, led light, microwave, ultrasound and electrical cosmetic radiation.
  • the cosmetic-type radiation is radiofrequency, ultrasound and/or laser.
  • the cosmetic-type radiation is radiofrequency. In an embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the cosmetic-type radiation is ultrasound.
  • the cosmetic-type radiation is laser.
  • the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis
  • the cosmetic agent which binds to a component forming part of the epidermis comprises one or more of: a polysaccharide, an oligossacharide, an amino acid, a peptide or a protein
  • the cosmetic-type radiation is selected from the list consisting of: radiofrequency, laser, infrared, ultraviolet, led light, microwave, ultrasound and electrical cosmetic radiation.
  • An embodiment of the second aspect of the invention refers to the use of a cosmetic composition that comprises an effective amount of a metal nanoobject, wherein the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis; wherein the cosmetic active agent comprises one or more of: a polysaccharide, an oligossacharide, an amino acid, a peptide or a protein; together with one or more appropriate topical cosmetically acceptable excipients or carriers, for the cosmetic treatment of skin, in combination with a cosmetic-type radiation source; wherein the cosmetic-type radiation is selected from the list consisting of: radiofrequency, laser, infrared, ultraviolet, led light, microwave, ultrasound and electrical cosmetic radiation.
  • the treatment is selected from cellulite reduction, skin tightness amelioration and wrinkle reduction.
  • the second aspect of the invention optionally in combination with any of the embodiments provided above or below, it is treated the skin of the neck, the neckline, the hands, the back or the feet.
  • an “effective amount” of the composition refers to the amount of active ingredients which provide a cosmetic effect after its application.
  • cosmetically acceptable or “dermatological acceptable” which is herein used interchangeably refers to that excipients or carriers suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, among others.
  • the topical compositions defined above comprise appropriate excipients or carriers for topical administration that can be pharmaceutical or cosmetic excipients, including, but not limited to, repairing cutaneous barrier function agent, a hydrating agent, an emollient, an emulsifier, a thickener, a humectant, a pH-regulating agent, an antioxidant, a preservative agent, a vehicle, or their mixtures.
  • excipients or carriers used have affinity for the skin, are well tolerated, stable, and are used in an amount adequate to provide the desired consistency, and ease application.
  • topical skin barrier recovery agent examples include, but are not limited to, ceramides, cholesterol, fatty acids, and precursors of these lipids including cerebrosides, sphingoid bases such as phytosphingosine or sphingosine, or phospholipids including phosphatidylcholine, and agents that promote the synthesis of epidermal lipids like urea, dexpanthenol, and alpha- hydroxyacids including lactic acid among others.
  • ceramides are selected from the group consisting of ceramide 1 , ceramide 3, and ceramide 6 II.
  • the amount of skin barrier recovery agent in the compositions of the present invention is comprised between 0.05 and 10%.
  • topical hydrating agent examples include, but are not limited to, collagen, collagen amino acids, dimethiconol, glycine, hyaluronic acid, dimethylsilanol hyaluronate, magnesium stearate, maltitol, maltose, pyrrolidone carboxylic acid (PCA), manganese PCA, sodium PCA, mannitol, trehalose, trilactin, glucose, glutamic acid, hydrolyzed caesalpinia spinosa gum, caesalpinia spinosa gum, prunus persica extract, prunus serotina extract, echinacea angustifolia extract, Echinacea purpurea extract, methyl gluceth, hydrolyzed wheat gluten, erythritol, aluminium stearoyl glutamate, copper acetylmethionate, or ditridecyl dimmer dilinoleate.
  • the hydrating agent is selected from the group consisting of glucose, glycine, lysine, glutamic acid, hydrolyzed caesalpinia spinosa gum, caesalpinia spinosa gum, sodium PCA, and their mixtures.
  • the amount of hydrating agent in the compositions of the present invention is comprised between 0.1 and 15%.
  • topical emollient agents include, but are not limited to, octyl hydroxystearate, lanolin, caprylic/capric triglyceride, cetyl palmitate, octyldodecanol, cetyl alcohol, isopropyl isostearate, glyceryl dilaurate, isopropyl myristate, palm alcohol, dimethicone, squalane, plukenetia volubilis seed oil, butyrospermum parkii butter, sucrose cocoate, or their mixtures.
  • the emollient is selected from the group consisting of dimethicone, squalane, plukenetia volubilis seed oil, butyrospermum parkii butter, caprylic/capric triglyceride, octyldodecanol, or their mixtures.
  • the amount of emollient agent in the compositions of the present invention is comprised between 10 and 30%.
  • emulsifier examples include, but are not limited to, glyceryl trioleate, glyceryl oleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene monostearate, glycerol monooleate, sucrose distearate, polyethylene glycol
  • the emulsifier is selected group consisting of glyceryl oleate, lecithin, sodium lauroyi lactylate, sodium stearoyi lactylate, glyceryl stearate, candelilla/jojoba/rice bran polyglyceryl-3 esters, and their mixtures.
  • the amount of the emulsifier in the compositions of the present invention is comprised between 0.5 and 10%.
  • appropriate surfactant agents include, but are not limited to, non- ionic, ionic (either anionic or cationic) or zwitterionic (or amphoteric wherein the head of the surfactant contains two oppositely charged groups) surfactants.
  • anionic surfactants include, but are not limited to, those based on sulfate, sulfonate or carboxylate anions such as perfluorooctanoate (PFOA or PFO), alkyl benzene sulfonate, soaps, fatty acid salts, or alkyl sulfate salts such as perfluorooctanesulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, or sodium lauryl ether sulfate (SLES).
  • PFOA or PFO perfluorooctanoate
  • SDS sodium dodecyl sulfate
  • SLES sodium lauryl ether sulfate
  • cationic surfactants include, but are not limited to, those based on quaternary ammonium cations such as or alkyltrimethylammonium including cetyl trimethylammonium bromide (CTAB) a.k.a., or hexadecyl trimethyl ammonium bromide, cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), or benzethonium chloride (BZT).
  • CTAB cetyl trimethylammonium bromide
  • CPC cetylpyridinium chloride
  • POEA polyethoxylated tallow amine
  • BAC benzalkonium chloride
  • BZT benzethonium chloride
  • zwitterionic surfactants include, but are not limited to dodecyl betaine, cocamidopropyl betaine, or coco ampho glycinate.
  • Poloxamers commercially called Poloxamers or Poloxamines
  • alkyl polyglucosides including octyl glucoside and decyl maltoside
  • fatty alcohols including cetyl alcohol and oleyl alcohol
  • cocamide MEA cocamide MEA
  • cocamide DEA cocamide DEA
  • polysorbates including tween 20, tween 80, or dodecyl dimethylamine oxide.
  • the surfactant is foaming and skin friendly, including polysorbate 20 or 40, coco glucoside, lauryl glucoside, decyl glucoside, lauryl sulfates such as ammonium, sodium, magnesium, MEA, triethylamine (TEA), or mipa lauryl sulfate, cocamidopropyl betain, or sodium alkyl sulfosucci nates.
  • the amount of the surfactant in the compositions of the present invention is comprised between 0.5 and 10%.
  • topical humectants include, but are not limited to, glycerin, diglycerin, ethylhexylglycerin, glucose, honey, lactic acid, polyethylene glycol, propylene glycol, sorbitol, sucrose, or threalose.
  • the humectant is selected group consisting of glycerin, diglycerin, ethylhexylglycerin, and their mixtures.
  • the amount of the humectants in the compositions of the present invention is comprised between 0.5-10%.
  • topical pH-regulating agents include, but are not limited to, acetic acid, lactic acid, citric acid, ethanolamine, formic acid, oxalic acid, potassium hydroxide, sodium hydroxide, triethanolamine, or their mixtures.
  • the pFI-regulating agent is selected group consisting of triethanolamine, sodium hydroxide, lactic acid, and citric acid.
  • the amount of the pH- regulating agent in the compositions of the present invention is comprised between 0.01 and 1 %.
  • antioxidants include, but are not limited to, free radical scavengers or reducing agents such as, acetyl cysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene, green tea extract, caffeic acid, cysteine, tocopherol, ubiquinone, propyl gallate, butylated hydroxytoluene (BHT), and their mixtures.
  • the antioxidant agent is selected group consisting of ascorbyl palmitate, and tocopherol.
  • the amount of the antioxidants in the compositions of the present invention is comprised between 0.001 and 0.25%.
  • appropriate preservative agents include, but are not limited to, benzoic acid,
  • the preservative agent is selected group consisting of potassium sorbate, sodium benzoate, and phenoxyethanol.
  • the amount of the preservatives in the compositions of the present invention is comprised between 0.1 and 3%.
  • viscosity agents include, but are not limited to, cellulose or their derivatives such as hydroxypropyl methylcellulose, polyethylene glycol, microcrystalline cellulose, cetearyl alcohol, alginates, branched polysaccharides, fumed silica, xanthan gum, carbomer, and polyacrylates.
  • the viscosity agent is selected group consisting of microcrystalline cellulose, cetearyl alcohol, cellulose, xanthan gum, and carbomer.
  • the amount of the viscosity agents in the compositions of the present invention is comprised between 0.5 and 10%.
  • compositions mentioned above also include a vehicle.
  • vehicles include, but are not limited to, water, propylene glycol, butylene glycol, ethanol, isopropanol, or silicones.
  • the vehicle is water.
  • compositions of the present invention may contain other ingredients, such as fragrances, colorants, and other components known in the state of the art for use in topical formulations.
  • compositions of the invention can be formulated in several forms that include, but are not limited to, solutions, aerosols and non-aerosol sprays, shaving creams, powders, mousses, lotions, gels, sticks, ointments, pastes, creams, shampoos, shower gel, body washes or face washes.
  • the topical composition used is formulated as an emulsion.
  • An emulsion is a dispersed system comprising at least two immiscible phases, one phase dispersed in the other as droplets. The above mentioned emulsifying agents are included to improve stability.
  • water is the dispersed phase and oil is the dispersion medium
  • the emulsion is termed a water-in-oil emulsion (w/o).
  • oil is dispersed as droplets throughout the aqueous phase
  • the emulsion is termed an oil-in-water emulsion (o/w).
  • emulsions known in the art are multiple emulsions, such as water-in- oil-in-water emulsions (w/o/w), GELTRAP emulsions, where the aqueous intern phase is gelified and it is covered by the oil phase, and SWOP emulsions, also known as inversion emulsions.
  • the emulsions used are preferably oil-in water emulsions.
  • the emulsions for use in the sense of the present invention are compatible with creams and lotions.
  • surfactant base is a blend of at least two surfactants.
  • Surfactants are commonly used in cleaning products, breaking up stains and keeping the dirt in the water solution to prevent its re-deposition onto the surface.
  • Surfactants disperse dirt that normally does not dissolve in water, becoming it dispersible in water, and removable with the wash water.
  • the above mentioned surfactants are included to lower the surface tension.
  • surfactant bases for use in the sense of the present invention are compatible with shampoos, shower gel, and body or face washes.
  • Topical compositions of the present invention can be prepared according to methods well known in the state of the art.
  • the appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared.
  • the cosmetic composition of the invention can be used for the care of the skin.
  • another embodiment of the second aspect of the invention is the topical use of the cosmetic composition as defined above, for the skin care.
  • the cosmetic composition of the present invention is used for the skin care comprises ameliorating at least one of the following symptoms: roughness, flakiness, dehydration, tightness, chapping, and lack of elasticity.
  • the cosmetic composition as defined above is used as a skin care agent, wherein the skin care comprises ameliorating at least one of the following symptoms: roughness, flakiness, dehydration, tightness, chapping, and lack of elasticity.
  • the topical cosmetic composition of the present invention is designed to be applied to the body to improve its appearance or to beautify, preserve, condition or protect the skin. Therefore, the above cosmetic compositions are adjectivally used for a non-medical application.
  • the topical cosmetic compositions of the present invention is a moisture agent.
  • the topical composition of the present invention comprises also non-conjugated hyaluronic acid.
  • the topical composition of the present invention comprises a concentration of conjugated nanoobjects of a range from 1x10 12 to 5x10 12 per ml.
  • the topical composition of the present invention comprises a concentration of conjugated gold NPs of a range from 1x10 12 to 5x10 12 NP/ml, the concentration of HA (conjugated and non-conjugated) is from 0.1 to 1 mg/ml and wherein gold is present at 10-50 ppm.
  • the topical cosmetic compositions comprises: aqua, glycerin, gold thioethylamino hyaluronic acid (nano), methylsilanol hydroxyproline aspartate, propylene glycol, peg-40 hydrogenated castor oil, butylene glycol, diazolidinyl urea, tocopheryl acetate, xanthan gum, glyceryl polyacrylate, sodium benzoate, potassium sorbate, perfume, triethanolamine, triticum vulgare germ extract, hydrolized vegetable protein, phenoxy ethanol, caprylic glycol, limonene,
  • ethylhexylglycerin calcium chloride, glycine soja protein, hexyl cinnamal, pectin, butylphenyl methylpropional, linalool, arginine, proline, serine, alpha-isomethyl ionone, glucose, citronellol, citral and carragenan.
  • the topical cosmetic compositions consists of: aqua, glycerin, gold thioethylamino hyaluronic acid (nano), methylsilanol hydroxyproline aspartate, propylene glycol, peg-40 hydrogenated castor oil, butylene glycol, diazolidinyl urea, tocopheryl acetate, xanthan gum, glyceryl polyacrylate, sodium benzoate, potassium sorbate, perfume, triethanolamine, triticum vulgare germ extract, hydrolized vegetable protein, phenoxy ethanol, caprylic glycol, limonene,
  • ethylhexylglycerin calcium chloride, glycine soja protein, hexyl cinnamal, pectin, butylphenyl methylpropional, linalool, arginine, proline, serine, alpha-isomethyl ionone, glucose, citronellol, citral and carragenan.
  • Gold nanoparticles were synthesised in water solution following the process of Turkevich J., P. C. Stevenson, et al. "The nucleation and growth processes in the synthesis of colloidal gold.” Discussions of the Faraday Society 1951 (11 ): 55-75 , which allowed an accurate control over shape and size. Briefly, a water solution of gold containing salt, HAuCU at 25 mM was rapidly injected into a solution at 100°C where sodium citrate acted as reductor agent. The reaction remains under intense agitation during 3 minutes after which agitation was interrupted and temperature was decreased under 85°C in order to stop nanoparticle growth. The size of the nanoparticle was finally fixed within the interval of 10-12 nm of diameter. Final concentration of 6x10 12 NP/ml was achieved.
  • the resulting Gold nanoparticles were characterised by using transmission electron microscopy (TEM) (JEOL J1010 measuring at 80 Kv) and ultraviolet-visible (UV-Vis) (Biotek Powerwave XS, measuring as scanning from 450 nm to 650 nm) techniques. Size, shape and monodispersity were obtained from TEM images and crystalline structure was characterised by the absorbance spectrum given by UV-Vis.
  • TEM transmission electron microscopy
  • UV-Vis ultraviolet-visible
  • Example 2 Functionalization of HA
  • the cleaning process through ultrafiltration consisted in dyalising the resulted synthesis in a buffer (5I of water with 1 ml 1 M of HCI) during 2 days. After this time, the solution was recovered. A sample of the solution was mixed with gold nanoparticles (6 ml of nanoparticles with 1 ml of solution). As it is known that Gold nanoparticles aglomerate in contact with cystamine unless nanoparticles are completely coated, this fact was used to characterise the correct cleaning process of the solution. If when nanoparticles got in contact with the solution aglomeration did not take place, it meaned that purification process had been correct.
  • the final S-functionalized oligomer was characterised by using NMR (see FIGs 4A and 4B). Compared to the spectrum of the starting material (the N-acetyl methyl protons were at a) d 1 95)(FIG. 4A), new peaks appeared at b) d 2.8 and c) d 3.1 (FIG. 4B), corresponding to the two side chain methylenes (CH 2 CH 2 SH).
  • Derivatised HA had a MW of 10 ⁇ 2KDa, a particle size of 2.5 ⁇ 0.5 nm (water 1 mg/ml) and composition of 38.3% C; 5.73% H; 3.47 N; 0.4% S.
  • Thiolated hyaluronic acid resulting from Example 2 was added to the Au nanoparticles water suspension resulting from Example 1 in a concentration that ensured the complete coating of every single nanoparticle (by using 0.5 g of derivatised HA per liter of NP), which transported around 500 oligomers/NP. Conjugation process was performed at room temperature (due to the affinity of sulphur with Au, only with mixing and stirring the conjugation was obtained) and the remaining hyaluronic acid oligomers that had not been conjugated to any nanoparticle were included into the final formulation and no filtration was performed due to the beneficial properties of hyaluronic acid for skin moisturising.
  • the preservatives (Dermosoft® OMP) were added at this stage of the manufacturing process. Also an alternative formulation was performed without preservatives. Both formulations were sterilised and stored.
  • FIG. 1 for a schematic representation of the conjugated product (gold NP-HA or AuNP-HA).
  • the active ingredient used in the experiments was a water suspension of gold nanoparticles conjugated to 6-10 KDa HA (gold thioethylamino hyaluronic acid, or Gold, 4-deoxy-4-((2-mercaptoethyl)amino) hyaluronate complexes), wherein Au was present at 33 ⁇ 3 ppm, the concentration of NPs was 1.88x10 12 ⁇ 1.7x10 11 NP/ml and the concentration of HA was 0.5 mg/ml.
  • Au gold thioethylamino hyaluronic acid, or Gold, 4-deoxy-4-((2-mercaptoethyl)amino) hyaluronate complexes
  • Example 4 Clinical study using gold nanoparticles conjugated with HA in combination with radiofrequency
  • RF radio frequency
  • the topical composition comprised a 5% of the active ingredient and other components.
  • the complete cosmetic composition used for the clinical study was, in descencent order, the following: aqua, glycerin, gold thioethylamino hyaluronic acid (nano), methylsilanol hydroxyproline aspartate, propylene glycol, peg-40 hydrogenated castor oil, butylene glycol, diazolidinyl urea, tocopheryl acetate, xanthan gum, glyceryl polyacrylate, sodium benzoate, potassium sorbate, perfume, triethanolamine, triticum vulgare germ extract, hydrolized vegetable protein, phenoxy ethanol, caprylic glycol, limonene, ethylhexylglycerin, calcium chloride, glycine soja (soybean) protein, hexyl cinnamal, pectin, butylphenyl methylpropional, linalool, arginine, proline, serine, alpha-isomethyl ion
  • the cellulite was evaluated by image analysis of the treated areas. Measures were taken one week after completing six treatment sessions. The scheduled measurement procedures were as follows: at day 0 before the application of the products was performed the following: clinical observation and description of the quality of the skin at the measuring areas, location of the measuring areas, weight measurement, thigh circumference measurement, clinical photography, 3D analysis of dimples with FOITS, 50 mhz high frequency ultrasound evaluation of the epidermis and dermis, biopsies and mass spectrometry.
  • HFUS High Frequency Ultrasounds
  • the subject lied on a bed on their belly and the measurements were performed on both thighs. Water was put on the transducer after the probe was placed on the skin without compressing it. Dozens of captures were recorded on a given measurement site, at each time point of the study. Each one corresponded to 12mm of scanned skin. Three captures with optimal signal ratio were selected. The software analysed the amplitude of the signal though all points of the scan and established an amount of echo based on. This amount of echo was called echogenic density and was proportional to the amount of extracellular matrix present in the tissue. The software provided the average echogenic density of the epidermis and dermis (in Arbitrary Units) of the 12mm of scanned skin in each capture. The skin thickness was expressed in Arbitrary Units and was subdivided in two
  • the 3D topometry was performed using Fast Optical In vivo Topometry of human Skin (FOITS), which allowed to objectify the modifications of the cutaneous topography. Thighs cellulite under the buttocks was selected as the area of choice. The measurements were taken using an optical system dedicated to the metrology of the relief of surfaces. This system included a measurement sensor associating a projector and a high resolution CCD camera (Dermatop system (Breuckmann, Germany - EoTech, France); field of view : 50 x 60 mm) - linked to the acquisition software Optocat (EoTech, France). The average axial and lateral resolutions were 10 pm.
  • FOITS Fast Optical In vivometry of human Skin
  • the evaluation was carried out in a dark room.
  • the subject must worn as only garments clinical disposable underwear and a white t-shirt, keeping the arms resting on the column and looking straight ahead.
  • the positioning of the sensor and of the subject was made with the use of a measurement bench (Visio4D) enabling the body to be kept in the same position and a reproducible positioning of the sensor.
  • the subject placed his/her feet over two foot-shaped markings on a circular platform. This platform was then elevated until a fixed-position horizontal laser line reaches the Region of Interest.
  • the elevation height was noted in the CRF in order order to place the subject in the same position on the following visit.
  • a ruler allowed to place it exactly at the same height every time while a protractor ruler placed in the border of the platform allowed to place it at the same angle every time. In this case the height was 36cm and the angles were ⁇ 30°C.
  • the analysis of the cutaneous topography of the surface consisted in calculating the shape and size of“objects” (in this case the big depressions of the skin known as dimples) in order to obtain their volume, area, circumference, maximum depth and minimal depth. It also involveed calculating typical roughness parameters used in metrology. In cellulite skin, roughness parameters not only correlated with the intrinsic quality of the skin but also with the nodules associated with the orange peel texture that characterizes cellulite. Concretely, SA, SQ and Stm. All these parameters were extracted from a surface of 50 x 60mm (30 cm2). The analysis of the data obtained by fringe projection on the studied areas was carried out using the Optocat analysis software. The analysis was performed on the“SDF” files obtained from the“ABS” files. The principle involved quantifying the objects and micro-relief of the studied area by analyzing the deformation of high contrast networks of lines on this surface. Mathematical treatment of the raw data:
  • Dimple areas were detected after the use of several filters and a polynomial correction in order to remove the local shape and flatten the Region of Interest (ROI).
  • Mean circumference (CIRC) of the dimples (mm) this parameter corresponded to the mean perimeter of the objects detected in the ROI.
  • Mean maximum depth (Max. D.) of the dimples (mm 2 ) this parameter corresponded to the mean of the maximum depths of the objects detected in the ROI.
  • Mean average depth (Mean. D.) of the dimples (mm 2 ) this parameter corresponded to the average of the mean depths of the objects detected in the ROI.
  • Verification of the normality of the distributions was carried out using the Shapiro-Wilk and Kolomogorov-Smirnov tests.
  • the statistical analysis of the evolution of the measured parameters during the study for each product was performed using the Student test (normality of distributions checked) or with the Wilcoxon test (normality of the distributions rejected).
  • the significance threshold was fixed at 5%.
  • Verification of the normality of the distribution was carried out using the ShapiroWilk and Kolomogorov-Smirnov tests for the comparison of the two products at DO and at D49-D0.
  • topical composition comprising gold NP-HA with RF provided an improved skin firmness and efficiency in the reduction of cellulite (stage 1-2 Nurnberger- Mijller scale), revealing younger and healthier-looking skin.
  • FIG. 7 shows the echogenic effect in dermis obtained by 50 Mz Frequency ultrasound evaluation.
  • Collagen denaturation was taken place when placebo + RF was used, while when using gold NP-HA + RF new collagen was synthesized on the skin. Moreover, when placebo + RF was used, a high amount of nuclei from neutrophils and macrophages taking care of the collagen removal was visible in biopsies. There were less nuclei visible on the biopsies where the gold NP-HA + RF was applied.
  • Collagen stain was perfomed in biopsies as pointed out above. Collagen stain showed a significant increase of the collagen content after the 6 weekly sessions using gold NP-HA +RF compared to Placebo +RF (see FIG. 8). Collagen synthesis was demostrated for the gold NP-HA + RF as explained before for the ultrasound results.
  • the topical composition comprising the HA-conjugated Au NPs as active ingredient enhanced the effect of RF treatments, resulting in an intense effect that improved skin firmness and the reduction of cellulite.
  • the skin localization of the gold NP conjugated with HA resulting from Example 3 was evaluated.
  • the Franz test was performed to verify that the active substance did not penetrate beyond the epidermis. Briefly, this test was done by applying the active ingredient on a pig skin wafer in which the conditions of human skin were simulated. After 24 hours, histological sections of the wafer were made and the amount of gold layer by layer was quantified. Since it was an in vitro test and therefore can take as much skin as required, the accuracy in detection was very high.
  • 0.1 g of the histological section (in this example also referred as“sample”) was digested in 1 ml HN0 3 (“Baker Instra”), 1 ml H 2 0 2 (“Merck Suprapur”) and 0.2 ml of aqua regia (HCI -
  • HN0 3 (“Baker Instra”) inside closed Teflon reactor, heating to 90°C all night. Digested sample was diluted in 7.8 ml of 1 % HCI and 200 ppm of thiourea solution. Final volume was calculated using the weigth and the weight/volume ratio of the sample.
  • Dermis (“M1 D”) once digested upon 0.1 1749 g of sample
  • liquid receptor (“M1 FR”) (which was the liquid recovered from the dermis), duplicate digested upon 0.1 g of sample.
  • Gold quantity in samples was evaluated using the technique ICP-MS (Inductively coupled plasma mass spectrometry) in a“Perkin Elmer ELAN 6000” device in standard conditions in the Unity of Analysis of Metals of the University of Barcelona. Device was calibrated with five patterns prepared with 200 ppm of tiourea in 1 % HCI solution, utilizing Rh as internal pattern. Gold pattern of 1 g/L was traced with NIST. Digested samples were directly analyzed with rhodium on line addition (FIA system).
  • ICP-MS Inductively coupled plasma mass spectrometry
  • Example 6 In vivo analysis to verify that gold nanoparticles conjugated with hyaluronic acid did not accumulate on the skin
  • the conjugated metal NPs of Example 3 were applied to a human volunteer, following the protocol described in Example 4 (gold NP-HA + RF), and 24 hours later a skin biopsy was performed.
  • Example 7 Clinical study using gold nanoparticles conjugated with HA without RF
  • the gold NP conjugated with HA resulting from Example 3 were applied without the combination with RF.
  • the desired anti-cellulite effect was achieved when two applications for 28 days were applied. A total of 56 applications daily applied contrast with the just six applications of nanoparticles that were enough to obtain similar result when such nanoparticles were administered in combination with radiofrequency (see example 4). This comparison demonstrates that a surprising effect was achieved when the conjugated nanoparticles were combined with radiofrequency.
  • Non Patent Literature Haiss, W., N. T. Thanh, et at. "Determination of size and concentration of gold
  • Clause 1 Use of a metal nanoobject for the topical cosmetic treatment of skin in combination with a cosmetic-type radiation, wherein the metal nanoobject is conjugated to a cosmetic agent which binds to a component forming part of the epidermis.
  • Clause 2. The use of clause 1 wherein the metal nanoobject is a metal nanoparticle (NP).
  • Clause 3 The use of clauses 1 or 2, wherein the component forming part of the epidermis is a receptor of the cosmetic agent. Clause 4. The use of clause 3, wherein the component forming part of the epidermis is a receptor of hyaluronic acid.
  • Clause 13 The use of any one of clauses 1 to 12, wherein the treatment is selected from cellulite reduction, skin tightness amelioration and wrinkle reduction.
  • Clause 14 The use of any one of clauses 1 to 13, wherein it is treated the skin of the legs, arms, abdomen or face.
  • Clause 15 Use of a cosmetic composition that comprises an effective amount of the metal nanoobject as defined in any of the clauses 1 to 14 together with one or more appropriate topical cosmetically acceptable excipients or carriers, for the cosmetic treatment of skin, in combination with a cosmetic-type radiation source.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
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  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Epidemiology (AREA)
  • Gerontology & Geriatric Medicine (AREA)
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  • Inorganic Chemistry (AREA)
  • Cosmetics (AREA)

Abstract

La présente invention concerne l'utilisation d'un nano-objet métallique, et une composition cosmétique qui le comprend, pour le traitement cosmétique topique de la peau en combinaison avec un rayonnement de type cosmétique, le nano-objet métallique étant conjugué à un agent cosmétique qui se lie à un composant formant une partie de l'épiderme.
PCT/EP2019/052012 2018-01-29 2019-01-28 Nano-objets métalliques à usage cosmétique WO2019145541A1 (fr)

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WO2007015105A2 (fr) * 2005-08-04 2007-02-08 Thomas William Rademacher Nanoparticules comprenant des ligands antibacteriens
EP2228393A1 (fr) * 2008-01-04 2010-09-15 Endor Nanotechnologies, S.L. Conjugué d'acide hyaluronique destiné au traitement cosmétique et procédé de préparation
EP2343047A2 (fr) * 2000-02-08 2011-07-13 Rice University Nanoparticules actives optiquement à utiliser dans les procédés thérapeutiques et de diagnostic
AU2011293132A1 (en) 2010-08-27 2013-03-14 Sebacia, Inc. Compositions and methods for targeted thermomodulation
US20140316387A1 (en) * 2010-08-27 2014-10-23 Sienna Labs, Inc. Ultrasound delivery of nanoparticles
US20140358068A1 (en) 2012-05-08 2014-12-04 The Regents Of The University Of California Selective lipolysis using nir light and nanoparticles
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EP2343047A2 (fr) * 2000-02-08 2011-07-13 Rice University Nanoparticules actives optiquement à utiliser dans les procédés thérapeutiques et de diagnostic
US20030093092A1 (en) 2001-09-26 2003-05-15 West Jennifer L. Optically-absorbing nanoparticles for enhanced tissue repair
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