EP4329718A1 - Topische zusammensetzungen mit (glyco)sphingolipiden und/oder (glyco)ceramiden - Google Patents

Topische zusammensetzungen mit (glyco)sphingolipiden und/oder (glyco)ceramiden

Info

Publication number
EP4329718A1
EP4329718A1 EP22726199.7A EP22726199A EP4329718A1 EP 4329718 A1 EP4329718 A1 EP 4329718A1 EP 22726199 A EP22726199 A EP 22726199A EP 4329718 A1 EP4329718 A1 EP 4329718A1
Authority
EP
European Patent Office
Prior art keywords
skin
ceramide
individual
carbon
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22726199.7A
Other languages
English (en)
French (fr)
Inventor
Bruce Mcconnell
Cornelia PYKO
Feryel ADAM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Carbocode SA
Original Assignee
Carbocode SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Carbocode SA filed Critical Carbocode SA
Priority claimed from PCT/PT2022/050018 external-priority patent/WO2022231448A1/en
Publication of EP4329718A1 publication Critical patent/EP4329718A1/de
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • 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
    • 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
    • A61Q19/004—Aftersun preparations
    • 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
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention relates to a topical composition and to a cosmetic or medical use of a topical composition.
  • the skin is a critical barrier for the body. It prevents the loss of water and electrolytes and acts as a barrier to external assaults on the body, such as from ultra-violet light, pollution, infectious agents, etc.
  • the epidermis, or outer portion of the skin provides the primary barrier function of the skin.
  • the epidermis is made up of layers of which the stratum comeum is the outermost layer and the stratum basale is the innermost layer.
  • the epidermis contains no blood vessels, and cells in the deepest layers are nourished by diffusion from blood capillaries extending to the upper layers of the dermis.
  • the stratum basale of the epidermis contains keratinocytes which proliferate through mitosis.
  • the daughter cells move up through the layers of the epidermis, changing shape and composition as they undergo multiple stages of cell differentiation.
  • the daughter cells eventually become terminally differentiated when they reach the stratum comeum.
  • the terminally differentiated keratinocytes are referred to as comeocytes.
  • the corneocytes are filled with water-retaining keratin proteins and are attached together through comeodesmosomes. Comeocytes do not contain a nucleus.
  • the comeocytes are eventually shed from the surface of the skin, a process called desquamation.
  • the stratum corneum acts as the main barrier in the skin. It is made up of about 10 to 30 layers of comeocytes surrounded by lipid layers (lipid lamellae). The stratum comeum is thus described as a wall composed of bricks (comeocytes) and mortar (lipids). The main constituents of the lipid layers are ceramides, cholesterol, and free fatty acids in a 1:1:1 molar ratio. The ceramides play the most important role in the barrier function of the stratum comeum. Dismption or decrease of ceramides in the stratum corneum weakens the skin barrier function, thereby e.g. increasing transdermal water loss.
  • ceramide composition of the skin has generally involved incorporation of ceramides or pseudo-ceramides into topical skincare formulations.
  • ceramides are highly insoluble and have high melting points. This makes formulation difficult. Also, their tendency to recrystallise complicates their stable incorporation into topical formulations.
  • Efforts to overcome formulation difficulties have generally focussed on combining ceramides with other lipids. For example, WO 1999029293 describes a combination of a free sphingoid base and a ceramide.
  • WO2018177730 describes melting a mixture of, or a wax and a ceramide, and then incorporating the melt into an oil-containing formulation.
  • MSEF milk sphingolipid-enriched fraction
  • An alternative approach to modulate the ceramide composition of the stratum corneum is to apply a composition which induces epidermal lipid production and ceramides in particular.
  • a composition which induces epidermal lipid production and ceramides in particular.
  • application of an oat oil extract on keratinocytes is reported to increase lipid synthesis including ceramides; potentially through activation of peroxisome proliferator- activated receptors (Chon et al, Exp. Dermatol, 2015).
  • compositions that comprise ceramide species that are stereochemically and structurally identical to those found in the human stratum corneum.
  • the present invention relates to topical compositions comprising (glyco)sphingolipids and/or (glyco)ceramides that can be used in cosmetic and medical applications.
  • the present invention comprises the following aspects:
  • a topical composition comprising one or more compounds of formula I
  • X is hydrogen or a glycosyl moiety, the carbon-carbon bond noted - is a double or a single bond,
  • R 1 is an alkyl chain having 10 - 20 carbon atoms
  • R 2 is hydrogen or a substituted or unsubstituted acyl having 16-34 carbon atoms
  • R 3 is hydrogen when the carbon-carbon bond noted - is a double or a single bond, and R 3 is -OH when the carbon-carbon bond noted - is a single bond,
  • R 4 is hydrogen when the carbon-carbon bond noted - is a double or a single bond, and R 4 is hydrogen or -OH when the carbon-carbon bond noted - is a double bond, said composition is characterized in that at least one of the one or more compounds of formula I has a lactosyl moiety or a glucosyl moiety in the position X.
  • Topical compositions comprising one or more compounds of formula I administered onto skin of an individual for a period of time increase the ceramide content of the stratum corneum, increase keratinocyte terminal differentiation in the epidermis, upregulate enzymes in the epidermis associated with epidermal ceramide synthesis, and/or improve skin barrier function in said individual.
  • Beneficial effects cosmetic treatment with topical compositions comprising one or more compounds of formula I are one or more of following Improving skin complexion;
  • compositions comprising one or more compounds of formula I for use in treating a skin pathological condition or a skin disease in an individual, such as acne, ichthyosis, xeroderma, eczema, atopic dermatitis and/or psoriasis.
  • Method for non-pharmacological intervention for mitigation of a skin condition or a skin disease in an individual who has, or who is susceptible to developing an impaired skin barrier function comprising topically administering a composition comprising one or more compounds of formula I onto skin of an individual.
  • Figures 1 to 5 show heatmaps using a log2 scale with up- or downregulation of respective proteins upon treatment with 0,01 % (01), 0,03 % (03) and 0,15 % (15) of respective ceramide in vehicle as compared to vehicle without ceramide (VEH)
  • Fig. 1 LacCerNS
  • Fig. 2 GlcCerNS
  • Fig. 3 CerNP
  • Fig. 4 CerNG
  • Fig. 5 CerNS
  • one or more compounds of formula I may achieve this by upregulating enzymes in the epidermis associated with epidermal ceramide synthesis. Further, one or more compounds of formula I advantageously increase keratinocyte terminal differentiation in the epidermis and improve skin barrier function in skin of an individual.
  • the following terms have the following meanings:
  • Topical composition includes compositions suitable for topical application on keratinous tissue, especially on skin. Such compositions are typically dermatologically acceptable in that they do not have undue toxicity, incompatibility, instability, allergic response, and the like, when applied to skin. Topical compositions typically comprise a topically acceptable carrier. Topical skin care compositions of the present invention can have a selected viscosity to avoid significant dripping or pooling after application to skin. Accordingly, a topical cosmetic or medical composition of the invention comprising one or more compounds described herein, would typically comprise one or more other compounds that are useful for formulating these compositions. Typically, such “formulating” compounds do not possess the biological activity of the compounds of the invention.
  • Keratinous tissue includes keratin-containing layers disposed as the outermost protective covering of mammals and includes, but is not limited to, lips, skin, hair and nails.
  • reducing or any variation of the term such as “reduction” includes any measurable decrease to achieve a desired effect.
  • Effective amount means an amount sufficient to render a desired treatment or management outcome in a human. An effective amount can be administered in one or more doses to achieve the desired treatment or management outcome.
  • Preventive treatment means treatment given or action taken to diminish the risk of onset or recurrence of a cosmetic or medical condition, or of an effect related to an impairment in the visual appearance of a skin or of a skin disease.
  • Primary prevention means prevention of the initial onset of a cosmetic or a medical condition in an individual.
  • “Secondary prevention” means, in an individual who has a cosmetic or a medical condition or who has had a condition, (i) prevention of reoccurrence of the condition, (ii) increase in the duration of remission of the condition, and/or (iii) reduction in severity of symptoms of the condition.
  • Treat means to address a cosmetic or a medical condition or disease with the objective of improving or stabilising an outcome in the person being treated or addressing an underlying need. Treat therefore includes the topical management of the cosmetic or medical condition or disease by addressing dermatological needs of the person being treated. “Treating” and “treatment” have grammatically corresponding meanings.
  • “Therapy” means treatment given or action taken to reduce or eliminate symptoms of a disease or pathological condition.
  • a child as referred to herein denotes a human individual until the age of 12.
  • a teenager as referred to herein denotes a human individual having an age of between 13 and
  • the present invention relates to a topical composition
  • a topical composition comprising one or more compounds of formula I I, wherein
  • X is hydrogen or a glycosyl moiety, the carbon-carbon bond noted - is a double or a single bond,
  • R 1 is an alkyl chain having 10 - 20 carbon atoms
  • R 2 is hydrogen or a substituted or unsubstituted acyl having 16-34 carbon atoms
  • R 3 is hydrogen when the carbon-carbon bond noted - is a double or a single bond, and R 3 is -OH when the carbon-carbon bond noted - is a single bond,
  • R 4 is hydrogen when the carbon-carbon bond noted - is a double or a single bond, and R 4 is hydrogen or -OH when the carbon-carbon bond noted - is a double bond, said composition is characterized in that at least one of the one or more compounds of formula I has a lactosyl moiety or a glucosyl moiety in the position X.
  • alkyl refers to an acyclic straight hydrocarbyl group in which the carbon atoms may be saturated or contain one or more double and/or triple bonds (so, forming for example an alkenyl or an alkynyl).
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec -butyl, tert-butyl, isopentyl, n-pentyl, neo-pentyl, n-hexyl, ethenyl, propenyl, 1-butenyl, 2-butenyl, isobutenyl,l-pentenyl, 2-pentenyl, 2-methyl- 1-butenyl, 3 -methyl- 1-butenyl, 2-methyl-2- butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, methylpentenyl, dimethylbutenyl, ethynyl, propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl.
  • alkyl examples include,
  • acyl includes both saturated groups and groups having one or more double and/or triple bonds.
  • substituted means that the carbon atoms may be substituted one or several times, preferably 1 to 3 times, with functional group(s).
  • R 2 of compound I is an unsubstituted acyl group.
  • R 2 of compound I or II is a saturated fatty acyl group or a fatty acyl group having one or more double bonds.
  • the compounds of formula I may be obtained by any technique known to the skilled person.
  • the compounds of formula I may be obtained by a fermentation technique or by a biocatalytic process.
  • glycosphingoplipids such as lactosylceramide may be produced starting from the respective glycosyl fluoride, such as lactosyl fluoride, followed by coupling to a (acylated) sphingoid base by the use of an endoglycoceramide synthase, such as described in Rich et al., ChemComm (2011) 47:10806-10808.
  • Sphingoid bases may be produced by a fermentation process, such as e.g. described in WO 95/12683 Al, especially phytosphingosine or a precursor thereof (claim 1 of EP 0726 960 Bl).
  • the topical composition comprises one or more compounds of formula I, wherein the residue X is lactosyl.
  • the topical composition comprises at least two compounds of formula I, wherein for one compound of formula I the residue X is lactosyl and for the other compound of formula I the residue X is galactosyl.
  • the topical composition comprises at least two compounds of formula I, wherein for one compound of formula I the residue X is lactosyl and for the other compound of formula I the residue X is hydrogen.
  • the topical composition comprises at least two compounds of formula I, wherein for one compound of formula I the residue X is lactosyl and for the other compound of formula I the residue X is glucosyl.
  • the topical composition comprises at least three compounds of formula I, wherein for one compound of formula I the residue X is lactosyl for the second compound of formula I the residue X is galactosyl and for the third compound of formula I the residue X is glucosyl.
  • the topical composition comprises at least three compounds of formula I, wherein for one compound of formula I the residue X is lactosyl, for the second compound of formula I the residue X is galactosyl, and for the third compound of formula I the residue X is hydrogen.
  • the topical composition comprises at least three compounds of formula I, wherein for one compound of formula I the residue X is lactosyl, for the second compound of formula I the residue X is hydrogen, and for the third compound of formula I the residue X is glucosyl.
  • the topical composition comprises at least four compounds of formula I, wherein for one compound of formula I the residue X is lactosyl for the second compound of formula I the residue X is hydrogen, for the third compound of formula I the residue X is glucosyl, and for the fourth compound of formula I the residue X is galactosyl.
  • R 1 is -C12H25 and R 2 is hexadecanoyl, 2-hydroxyhexadecanoyl, octadecanoyl, 2- hydroxyoctadecanoyl, eicosanoyl, 2-hydroxyeicosanoyl, lignoceroyl, 2-hydroxytetracosanoyl or 30-(linoleyloxy)-triacontanoyl, preferably octadecanoyl or lignoceroyl.
  • the one or more compounds of formula I may be formulated into topical compositions suitable for application to the skin.
  • the topical compositions of the present invention will contain from about 0,0001 % to about 10% wt/wt of a compound of formula I, such as from about 0,005 % to about 5% wt/wt of a compound of formula I, or from 0,01 % to about 1% wt/wt of a compound of formula I.
  • the topical compositions of the present invention may contain from about 0,0001 to about 0,00025 % wt/wt of a compound of formula I, from about 0,0002 to about 0,0004 % wt/wt of a compound of formula I, from about 0,0003 to about 0,0005 % wt/wt of a compound of formula I, from about 0,0004 to about 0,0006 % wt/wt of a compound of formula I, from about 0,0005 to about 0,0008 % wt/wt of a compound of formula I, from about 0,0007 to about 0,001 % wt/wt of a compound of formula I, from about 0,001 to about 0,005 % wt/wt of a compound of formula I, from about 0,003 to about 0,008 % wt/wt of a compound of formula I, from about 0,005 to about 0,01 % wt/wt of a compound of formula I, from about 0,008 to about 0,0505
  • the topical compositions of the present invention contain an amount of about 0.01 % to 5% wt/wt of a compound of formula I. or an amount of about 0.02 % wt/wt to 1% wt/wt of a compound of formula I.
  • Examples are 0.05 % wt/wt, 0.1 % wt/wt or 0.2 % wt/wt of a compound of formula I.
  • Compounds of formula I in which the residue X is a glycosyl moiety selected from lactosyl, glucosyl and galactosyl may be present in an amount of 0.1 % wt/wt.
  • Compounds of formula I in which the residue X is hydrogen may be present in an amount of 0.2 % wt/wt.
  • the topical compositions can contain an amount of about 5 % to 10 % wt/wt of a compound of formula I.
  • the topical compositions according to the present invention may comprise a single compound of formula I, e.g. a compound comprising the lactosyl moiety in position X of formula I, in the ranges or amounts as listed above.
  • the topical composition according to the present invention comprises more than one compound of formula I, also termed herein as blend of compounds of formula I
  • each compound of formula I may be present in the same amount or in different amounts.
  • the ranges or amounts as listed above may relate to the total content of the blend in the topical composition, or to the amount of one compound in the blend in the topical composition.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0, 1 % wt/wt, wherein the blend has glucosylceramide in an amount of 0,02 % wt/wt and lactosylceramide in an amount of 0,08 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,2 % wt/wt, wherein the blend has lactosylceramide in an amount of 0,04 % wt/wt and ceramide NP in an amount of 0,16 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,2 % wt/wt, wherein the blend has lactosylceramide in an amount of 0,04 % wt/wt and ceramide NS in an amount of 0,16 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,2 % wt/wt, wherein the blend has lactosylceramide in an amount of 0,04 % wt/wt and ceramide NG in an amount of 0,16 % wt/wt.
  • Non-limiting exemplary embodiments are also depicted in Example 1.
  • the topical composition may comprise a blend of compounds of formula I, wherein X is hydrogen.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0, 1 % wt/wt, wherein the blend has ceramide NP in an amount of 0,06 % wt/wt, ceramide NS in an amount of 0,02 % wt/wt and ceramide NG in an amount of 0,02 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,2 % wt/wt, wherein the blend has ceramide NP in an amount of 0,11 % wt/wt, ceramide NS in an amount of 0,04 % wt/wt and ceramide NG in an amount of 0,05 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,5 % wt/wt, wherein the blend has ceramide NP in an amount of 0,28 % wt/wt, ceramide NS in an amount of 0,09 % wt/wt and ceramide NG in an amount of 0,13 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,1 % wt/wt, wherein the blend has ceramide NP in an amount of 0,075 % wt/wt, ceramide NS in an amount of 0,02 % wt/wt and ceramide NG in an amount of 0,005 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,2 % wt/wt, wherein the blend has ceramide NP in an amount of 0,15 % wt/wt, ceramide NS in an amount of 0,04 % wt/wt and ceramide NG in an amount of 0,01 % wt/wt.
  • the topical composition may comprise a blend of compounds of formula I with a total content of the blend of 0,2 % wt/wt, wherein the blend has ceramide NP in an amount of 0,1 % wt/wt, ceramide NS in an amount of 0,05 % wt/wt and glucosylceramide in an amount of 0,05 % wt/wt.
  • ceramide NP in an amount of 0,1 % wt/wt
  • ceramide NS in an amount of 0,05 % wt/wt
  • glucosylceramide in an amount of 0,05 % wt/wt.
  • the amount of the one or more compounds of formula I in a composition of the invention may vary depending upon factors such as the age of the person, the risk and severity of any underlying condition, the environment the person is exposed to, the form of the topical composition, its use for cosmetic or medical purposes, and any other skin care compositions being administered. Appropriate doses for any particular person or indication may be determined by methods known to skin care practitioners. The dose may also vary depending upon whether the topical composition is a “leave on” or “rinse off’ formulation with “rinse off’ formulations generally containing lower doses. Further, the dose may vary depending on whether the topical composition is applied in an intervention treatment phase or in a maintenance phase. Generally higher doses can be applied in an initial intervention phase than in a maintenance phase.
  • Topical composition according to the present invention may have a pH in the range of about 4.5 to about 8, e.g. from about 4.5 to about 6.
  • Topical compositions of the present invention can be structured or formulated into a variety of different forms.
  • Non-limiting examples include emulsions (e.g., water-in-oil, water-in-oil- in-water, oil-in-water, silicone-in-water, water-in-silicone, oil-in-water-in-oil, oil-in-water-in- silicone emulsions), creams, lotions, solutions (both aqueous and hydroalcoholic), anhydrous bases (such as lipsticks and powders), gels, masks, peelings, and ointments. Variations and other structures will be apparent to the skilled artisan and are appropriate for use in the present invention.
  • a topical composition may be formulated as an emulsion.
  • a topical composition of the present invention is typically intended for application on the face, on the body and/or on the hair.
  • the topical composition may be for application on the face or on the body.
  • a topical composition of the present invention may comprise a compound of formula I, which is selected from the group consisting of ceramide NS (CerNS or CNS), ceramide NG (CerNG or CNG), ceramide NP (CerNP or CNP), glucosyl ceramide or lactosyl ceramide, or a combination thereof.
  • Ceramide NS, ceramide NdS and ceramide NP are named according to the shorthand nomenclature developed by Motta et al., Biochim Biophys Acta., 1993, 1182:147-151 and expanded by Rabionet et al., Biochim Biophys Acta, 2014, 1841:422-434, and by Masukawa et al., Journal of Lipid Research , 2008, 49, 1466-1476. Ceramides NdS may also be referred to as ceramide NG. For each species, the number of carbons and unsaturations (if present) may be expressed in parentheses following the letters of N, A, E, and O.
  • the carbon chain length of the sphingoid base moiety of the ceramides mentioned herein is typically Cis.
  • the carbon chain length of the acyl moiety of the ceramides mentioned herein may be e.g. Ci6, Cis, C20, C22 or C24.
  • the glucosyl ceramide and the lactosyl ceramide as mentioned herein are preferably ceramide NS, typically with an acyl chain length of Cis.
  • Glucosyl ceramide which is ceramide NS and has an acyl chain length of Cis may be referred to herein also as GlcCNS.
  • Lactosyl ceramide which is ceramide NS and has an acyl chain length of Cis may be referred to herein also as LacCNS.
  • a topical composition described herein on skin of an individual increases the ceramide content of the stratum corneum, increases keratinocyte terminal differentiation in the epidermis, upregulates enzymes in the epidermis associated with epidermal ceramide synthesis and/or improves skin barrier function in said individual.
  • These effects may be determined by an upregulation of respective differentiation markers in vitro.
  • an increase of keratinocyte terminal differentiation in the epidermis may be determined by an upregulation of differentiation markers such as loricrin, filaggrin or involucrin.
  • Upregulation of enzymes in the epidermis associated with epidermal ceramide synthesis may be e.g. measured in vitro in keratinocytes as explained in Example 4.
  • the effects may also be measured with further other suitable standard technique known to the skilled person.
  • An increase of the ceramide content of the stratum corneum can be e.g. determined with the tape stripping procedure as e.g. described in Lademann et ah, European Journal of Pharmaceutics and Biopharmaceutics (2009) 72:317-323.
  • An improvement of skin barrier function may be e.g. determined by measuring TEWL and skin hydration with a corneometer or tewameter.
  • a topical composition of the present invention may advantageously be used for cosmetic treatment or medical treatment of keratinous tissue, especially skin, of an individual.
  • the topical composition according to the invention may be referred to as topical cosmetic composition or cosmetic composition.
  • Cosmetic treatment is herein defined as to improve the visual appearance of skin of the treated individual.
  • improved visual appearance of skin is meant that cosmetic treatment with a topical composition of the invention comprising one or more compounds of formular I, in particular comprising one or more of the following beneficial effects on the treated skin of an individual: reducing skin roughness. reducing skin flakiness. reducing the depth of wrinkles in the skin. strengthening the skin elasticity. increasing the tautness of the skin. increasing the thickness of the skin. increasing skin moisture. calming irritated skin normalizing and improving the skin tone.
  • the cosmetic compositions of the invention preferably improve skin complexion, i.e. color and texture of the skin, especially on the face; improve skin radiance, i.e. skin tone, luminosity, firmness, and discolouration (think dark circles and sun damage); improve skin tone, i.e. normalizing natural hue of the skin, reducing redness and reducing pigmentation; soothe the skin, i.e. calming irritated skin, e.g.
  • mitigating, assuaging, or allaying pain from sunburning or dehydrating of the skin reduce the signs of skin ageing, both chronological and premature, e.g the signs of ageing due to exposure of the skin to intrinsic and extrinsic factors, like decrease in production of essential molecules supporting the skin natural structure, loss of water, UV light damage, or exposure to chemical internal radicals generated in the body (due to unhealthy eating or life style, a disease, etc) or external pollutants hazardous for the skin; and/or smooth skin wrinkles, in particular, the face skin wrinkles, both fine surface lines and deeper furrows, i.e. lessen the appearance of wrinkled skin, smoothing the skin surface;
  • cosmetic compositions of the invention support and enhance healthy look of the skin, especially of the face and neck skin.
  • the skin may be an aged and/or a dry skin.
  • the cause of dryness of the skin may be of constitutional or acquired type.
  • Non-pathological acquired constitutional dry skin can be characterized by a deficiency in lipids constituting the barrier and/or the aqueous-lipid film, and/or an endogenous insufficiency of sebum production by the sebaceous glands.
  • Skin aging is a complex phenomenon responsible for progressive changes of the skin. Many factors contribute to skin aging and associated alterations in appearance and function of the skin, such as the actual age of a person, the amount of exposure to environmental factors (e.g., sun light, pollution, chemicals, smoke, etc.), and how well a person has taken care of their skin. In particular, skin aging concerns two processes - intrinsic aging, which is related to the natural aging process and genetic influences, and extrinsic aging, which is accumulated damage due to exposure to environmental factors.
  • Intrinsic aging process in cells and skin can be related to the loss of proper function of the skin in maintaining biochemical pathways. Such pathways can control the oxidative/reductive environment balance in the skin, the regulation of inflammation, and the maintenance of the moisture balance of the skin. Losses of proper function of the skin can lead to increased oxidative damage, increased inflammation, dry skin, loss of skin firmness, increased skin unevenness, and increased fine lines and wrinkles.
  • UV Factors that cause extrinsic aging can include exposure to ultraviolet (UV) rays, irritants, and pollutants, such as Polycyclic aromatic pollutants (PAH), Particulate Matter PM2.5 (micrometers), blue light, Ozone, or cigarette smoke.
  • UV rays through sun exposure or the use of ultraviolet lamps (for example, tanning beds), can induce oxidative stress, inflammation, production of melanin, and even genetic mutations that leads to skin damage.
  • the accumulation of oxidative stress through free radical formation can damage skin proteins leading to skin aging, which includes loss of elasticity, loss of dermal proteins, lines and wrinkles, and abnormal pigmentation.
  • accumulation of fine particles such as PM 2.5 (fine particles that have an aerodynamic diameter under 2.5 pm) on the skin can also induce oxidative stress and inflammation. These fine particles may also cause damage on barrier proteins of the skin, leading to loss of moisture and elasticity of the skin.
  • the appearance of aged skin targeted by the invention include thinning of the skin, a loss of firmness, a loss of elasticity, a loss of density or a loss of tonicity of the skin, the appearance of a marked microrelief of the skin, the appearance of roughness, the formation and/or presence of fine lines and/or of wrinkles, a modification of the radiance of the skin complexion, a wizened appearance of the skin, sagging of the skin, and/or withering of the skin.
  • the cosmetic treatment according to the present invention typically has one or more beneficial effects on skin of an individual. These beneficial effects include one or more of improving skin complexion, improving skin radiance, improving skin tone, skin soothing, reducing premature skin aging, wrinkle smoothing and/or supporting healthy look of skin.
  • Skin soothing or skin calming as used herein denote protection from skin irritation or reduction of skin irritation and typically has a gentle calming effect. Additionally to the above described biological effects, the present inventors have surprisingly found that application of lactosylceramide on the skin leads to an upregulation of syndecan-1, of ceramide synthase 4 and of phosphomevalonate kinase.
  • Syndecan-1 is known to play a role in keratinocyte proliferation and differentiation.
  • Ceramide synthase 4 catalyzes the formation of ceramides.
  • Phosphomevalonate kinase is involved in cholesterol synthesis.
  • the present invention relates to the use of lactosylceramide for increasing the ceramide content of the stratum corneum, increasing keratinocyte terminal differentiation in the epidermis, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis and/or improving skin barrier function in skin of an individual.
  • the present inventors have surprisingly found that application of ceramide NP on the skin leads to an upregulation of syndecan-1, long-chain-fatty-acid-CoA ligase 3, phosphopantothenate-cysteine ligase and phosphomevalonate kinase.
  • Long-chain-fatty-acid-CoA ligase 3 activates long-chain fatty acids for synthesis of cellular lipids.
  • Phosphopantothenate-cysteine ligase catalyzes the second step in the biosynthesis of coenzyme A from vitamin B5.
  • Coenzyme A is a very important molecule in lipid metabolism, it is converted to acetyl-CoA, which is a precursor in the synthesis of fatty acids, cholesterol and ceramides.
  • acetyl-CoA is a precursor in the synthesis of fatty acids, cholesterol and ceramides.
  • ceramide NP may help to provide free fatty acids, cholesterol and ceramides to maintain the skin barrier.
  • the present invention additionally relates to the use of ceramide NP for increasing the ceramide content of the stratum comeum, increasing keratinocyte terminal differentiation in the epidermis, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis and/or improving skin barrier function in skin of an individual.
  • the present inventors have also surprisingly found that application of ceramide NG on the skin leads to an upregulation of ceramide synthase 4, of loricrin, of repetin, of small proline- rich protein 2D and of phosphomevalonate kinase.
  • Loricrin is a major keratinocyte cell envelope protein.
  • Repetin is involved in the cornified cell envelope formation.
  • Small proline rich protein 2D is a cross-linked envelope protein of keratinocytes.
  • Cornification is an essential process to build the skin barrier, during which the cell membrane of keratinocytes is replaced by the cornified envelope.
  • the cornified envelope is an agglomeration of several structural proteins that are crosslinked. Loricrin (makes up to 70-80 % of protein content of cornified envelope), repetin & small proline-rich protein 2d are part of the cornified envelope and their upregulation indicates that ceramide NG triggers the formation of the cornified envelope and therefore the keratinocyte terminal differentiation and may improve the skin barrier function.
  • Ceramide Synthase 4 catalyzes the formation of ceramides and phosphomevalonate kinase is involved in cholesterol synthesis.
  • the upregulation of both enzymes indicates that ceramide NG helps to provide cholesterol and ceramides to maintain the skin barrier.
  • the present invention in one aspect relates to the use of ceramide NG for increasing the ceramide content of the stratum comeum, increasing keratinocyte terminal differentiation in the epidermis, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis and/or improving skin barrier function in skin of an individual.
  • the present inventors have surprisingly found that application of glucosyl ceramide on the skin leads to an upregulation of 3-ketodihydrosphingosine reductase, of acetyl-coenzyme A synthetase (cytoplasmic), of malonate-CoA ligase ACSF3 (mitochondrial) and of pho sphomevalonate .
  • 3-ketodihydrosphingosine reductase kinase catalyzes the reduction of 3- ketodihydrosphingosine to dihydro sphingo sine.
  • Acetyl-coenzyme A synthetase catalyzes the synthesis of acetyl-CoA from short-chain fatty acids.
  • Malonate— CoA ligase ACSF3 catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate into their respective CoA thioester.
  • Acetyl- CoA and Malonyl-CoA are both precursors of the synthesis of fatty acids, cholesterol and ceramides.
  • the Phosphomevalonate kinase is involved in the cholesterol synthesis and 3- ketodihydrosphingosine reductase in the ceramide synthesis.
  • the upregulation of those enzymes indicates that glucosyl ceramide CNS helps to provide free fatty acids, cholesterol and ceramides to maintain the skin barrier.
  • the present invention relates to the use of glucosyl ceramide for increasing the ceramide content of the stratum corneum, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis and/or improving skin barrier function in skin of an individual.
  • ceramide NS on the skin leads to an upregulation of cornifin-B, of filaggrin-2, of syndecan-1, of kallikrein-5 and of phosphomevalonate kinase.
  • Cornifin-B is a cross-linked envelope protein of keratinocytes.
  • Filaggrin-2 is important for proper integrity and mechanical strength of the stratum corneum of the epidermis, Essential for normal cell-cell adhesion in the cornified cell layers.
  • Kallikrein-5 is a protease that cleaves corneodesmosomes.
  • the cornification is an essential process to build the skin barrier, during which the cell membrane of keratinocytes is displaced by the cornified envelope.
  • the cornified envelope is an agglomeration of several structural proteins that are crosslinked.
  • Cornifin-B and Fillagrin- 2 are both parts of the cornified envelope and their upregulation indicates that ceramide NS may trigger the formation of the cornified envelope and therefore may improve the skin barrier function.
  • Desquamation is the last step of the keratinocytes terminal differentiation and Kallikrein-5 is a protease that cleaves the corneodesmosomes (cell-cell-adhesion of corneocytes) allowing the corneocytes to desquame.
  • Kallikrein-5 is a protease that cleaves the corneodesmosomes (cell-cell-adhesion of corneocytes) allowing the corneocytes to desquame.
  • the present invention relates to the use of ceramide NS for increasing keratinocyte terminal differentiation in the epidermis and/or improving skin barrier function in skin of an individual.
  • topical compositions according to the present invention may be used for medical treatment of skin of an individual.
  • the topical composition according to the invention may be referred to as a topical pharmaceutical composition or a pharmaceutical composition.
  • the pharmaceutical composition is for use in treating of a skin disease or of a skin pathological condition in an individual.
  • skin disease is a disorder of structure or function in a human or animal that produces specific symptoms or that affects a specific location, i.e. skin, and is not simply a direct result of physical injury.
  • skin diseases include acne, rosacea, erythrocouperosis, psoriasis, xeroderma, ichthyosis, vascular disorders, diaper rash, atopic dermatitis, eczema, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis.
  • pathological skin condition refers to abnormal anatomical or physiological conditions and objective or subjective manifestations of disease, not classified as disease or syndrome.
  • pathological skin conditions include: rosacea, which is characterized by small, red, pus-fil led bumps on the face and vitiligo, which results in large, irregular patches of skin.
  • a pharmaceutical composition of the present invention may in some embodiments consist of one or more compounds of formula I of the inventive topical composition (as any of the described above).
  • the topical pharmaceutical composition of the present invention may further include an additional ingredient that is pharmaceutically active for treating a skin disease or a pathological skin condition.
  • Non-limiting examples of such additional pharmaceutical active agents include anti-acne agents, agents used to treat rosacea, analgesics, anesthetics, anorectals, antihistamines, anti inflammatory agents including non-steroidal anti-inflammatory drugs, antibiotics, antifungals, antivirals, antimicrobials, anti-cancer actives, scabicides, pediculicides, antineoplastics, antiperspirants, antipruritics, antipsoriatic agents, antiseborrheic agents, biologically active proteins and peptides, burn treatment agents, cauterizing agents, depigmenting agents, depilatories, diaper rash treatment agents, enzymes, hair growth stimulants, hair growth retardants including DFMO and its salts and analogs, hemostatics, kerotolytics, canker sore treatment agents, cold sore treatment agents, dental and periodontal treatment agents, photosensitizing actives, skin protectant/barrier agents, steroids including hormones and corticosteroids, sun
  • Topical compositions of the invention may be advantageously administered onto skin of an individual for at least 7 days, such as for at least 14 days or for at least 21 days.
  • the topical composition is administered for at least 28 days.
  • the administration period of a cosmetic compositions of the invention there is no time limitation for the administration period of a cosmetic compositions of the invention.
  • the administration period would be typically determined by a medical practitioner for each individual patient.
  • a topical composition (either cosmetic or pharmaceutical) may be administered one time or several times per day, such as 2-3 times per day.
  • Topical compositions of the present invention typically include or are incorporated into different types of vehicles and carriers.
  • the topical composition of the present invention further comprises a topically acceptable carrier.
  • the vehicle or carrier can be a pharmaceutically and/or dermatologically acceptable vehicle or carrier.
  • Non-limiting examples of vehicles or carriers include water, glycerin, alcohol, oil, a silicon containing compound, a silicone compound, and wax. Variations and other appropriate vehicles will be apparent to the skilled artisan and are appropriate for use in the present invention.
  • the concentrations and combinations of the compounds, ingredients, and agents can be selected in such a way that the combinations are chemically compatible and do not form complexes which precipitate from the finished product.
  • a topical composition may contain a Ce -Cioo ester base which functions as an acceptable carrier for the one or more compounds of formula I.
  • ester bases include:
  • esters may be formed from the reaction between C1-C22 alkanoic acid with neopentyl alcohol, neopentyl glycol, 2- butyl-2-ethyl- 1,3-propanediol,
  • 2, 2, 4- lrimethyl- 1,3-pentane diol trimethylol propane, pentaerythritol, di-trimethylol propane, di-pentaerythritol or pentaerythritol-trimethylol propane dimers.
  • Examples include isostearyl neopentanoate, palmityl neopentanoate, tetraoctylpentaerythritol and diisopropyl neopentanoate.
  • Amounts of this ester may suitably range from 1% to 90%, preferably from 20% to 75%, optimally from 30% to 50% by weight of the topical composition.
  • the C12 -C40 fatty glyceride ester alkoxylate preferably includes 4 to 20 moles alkylene oxide per mole of glyceride.
  • Preferred alkylene oxides are ethylene oxide and propylene oxide. Examples are PEG-6 caprylic/capric glyceride and PEG-8 caprylic/capric glyceride each of which are polyethylene glycol derivatives of a mixture of mono, di and triglycerides of caprylic and capric acids with a respective 6 and 8 moles of ethylene oxide. Amounts of this ester may suitably range from 1% to 90%, preferably from 5% to 50%, optimally from 10% to 20% by weight of the topical composition.
  • polyglycerol Cs -C22 mono or di-fatty acid ester examples include polyglycerol-3 beeswax, polyglycerol-4 cocoate, poly glycerol- 10 decalinoleate, poly glycerol- 10 decaoleate, polyglycerol-7 decastearate, polyglycerol-2 diisostearate, polyglycerol-3 diisostearate, polyglycerol-7 diisostearate, polyglycerol-2 dioleate, polyglycerol-3 dioleate, polyglycerol-6 dioleate, poly glycerol- 10 dioleate, polyglycerol-3 distearate, polyglycerol-6 distearate, poly glycerol- 10 distearate, poly glycerol- 10 heptaoleate, poly glycerol- 10 heptastearate, polyglycerol-6 hexaoleate, polyglycerol-2
  • polyglycerol-6 dioleate which is a diester of oleic acid and a glycerin polymer containing an average of 6 glycerin units. Amounts of this ester may range from 1% to 50%, preferably from 5% to 25%, optimally from 10% to 20% by weight of the topical composition.
  • Non-limiting examples include cetyl octanoate, lauryl pentanoate, palmityl palmitoate, isostearyl decanoate, oleyl heptanoate and combinations thereof. Amounts of this material may range from 1% to 50%, preferably from 5% to 30%, optimally from 10% to 20% by weight of the topical composition.
  • the ester base may range from about 30% to 95%, preferably from 40% to 80%, optimally from 50% to 70% by weight of the topical composition.
  • the topical compositions may further contain a solubiliser in the form of a glycerol C8-C22 mono fatty acid ester.
  • solubilisers include glycerol monoisostearate, glycerol monobehenate and glycerol monopalmitate.
  • the solubiliser may comprise about 0.1% to 20%, preferably from 0.5% to 10%, optimally from 1% to 5%, by mass of the topical composition.
  • the topical compositions may contain other carriers such as silicone oils.
  • the silicone oils may be cyclic or linear polydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5, silicon atoms, or polyalkyl siloxanes, polyalklyaryl siloxanes and polyether siloxane copolymers. Silicones may be present in amounts generally ranging from 1% to 50%, preferably from 2% to 25%, optimally between 10% and 20% by weight of the topical composition.
  • the topical compositions may also include additional ingredients typically found in cosmetic and skin care formulations such as cosmetic ingredients and pharmaceutical active ingredients.
  • topical compositions of the invention may include chalk, talc, fullers, earth, kaolin, starch, smectites clays, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate.
  • surfactants may be added including alkyl sulfates, such as Sodium Lauryl Sulfate, Sodium Laureth Sulfate, Sodium Coco-Sulfate and Sodium Trideceth Sulfate, betaines, such as cocobetaine, and carbohydrates, such as Lauryl Glucoside and Coco-Glucoside.
  • Other ingredients are colouring agents, opacifiers and perfumes. Amounts of these adjunct materials may conveniently range anywhere from 0.001% up to 20% by weight of the composition.
  • fragrance agents artificial and natural; e.g., gluconic acid, phenoxy ethanol, and triethanolamine
  • dyes and color ingredients e.g., Blue 1, Blue 1 Lake, Red 40, titanium dioxide, D&C blue no. 4, D&C green no. 5, D&C orange no. 4, D&C red no. 17, D&C red no. 33, D&C violet no. 2, D&C yellow no. 10, and D&C yellow no.
  • flavoring agents / aroma agents e.g., Stevia rebaudiana (sweetleaf) extract, and menthol
  • adsorbents e.g., adsorbents, lubricants, solvents, moisturizers (including, e.g., emollients, humectants, film formers, occlusive agents, and agents that affect the natural moisturization mechanisms of the skin), water-repellants, UV absorbers and/or reflectors (physical and chemical absorbers such as para-aminobenzoic acid (“PABA”) and corresponding PABA derivatives, titanium dioxide, zinc oxide, etc.), essential oils, vitamins (e.g., A, B, C, D, E, and K), trace metals (e.g., zinc, calcium and selenium), anti -irritants (e.g., steroids and non-steroidal anti-inflammatories), botanical extracts (e.g., Aloe vera, chamomile, cucumber extract, Gink
  • the topical compositions may also include fatty alcohols and fatty acids having from 10 to 20 carbon atoms. Especially preferred are such compounds as cetyl, myristyl, palmityl, isostearyl and stearyl alcohols and acids.
  • the topical compositions may further include a-hydroxy carboxylic acids. Suitable examples include: a-hydroxyethanoic acid, a-hydroxypropanoic acid, a-hydroxyhexanoic acid, a- hydroxyoctanoic acid, a-hydroxydecanoic acid, a-hydroxydodecanoic acid, a- hydroxytetradecanoic acid, a-hydroxyhexadecanoic acid, a-hydroxyoctadecanoic acid, a- hydroxyeicosanoic acid, a-hydroxydocosanoic acid, a-hydroxyhexacosanoic acid, and a- hydroxyoctacosanoic acid.
  • the a-hydroxy carboxylic acid may be in the acid form or in salt form.
  • Typical salts are the alkalimetal, ammonium and Ci -C30 ammonium salts, for example the sodium, potassium, triethanolammonium and ammonium salts form.
  • Typical salts are the alkalimetal, ammonium and C2 -C30 ammonium salts, for example the sodium, potassium, triethanolammonium and ammonium salts.
  • the a -hydroxy carboxylic acid will generally be present in a range from 0.001% to 20%, preferably from 0.01% to 15%, optimally from 0.5% to 10% by weight of the topical composition.
  • the topical composition may also include vitamins.
  • Examples include sources or derivatives of vitamin C, such as ascorbyl palmitate, ascorbyl glucoside, magnesium ascorbyl phosphate, ascorbyl lysostearate, vitamin A palmitate (retinyl palmitate) and vitamin E linoleate (tocopheryl linoleate).
  • sources or derivatives of vitamin C such as ascorbyl palmitate, ascorbyl glucoside, magnesium ascorbyl phosphate, ascorbyl lysostearate, vitamin A palmitate (retinyl palmitate) and vitamin E linoleate (tocopheryl linoleate).
  • vitamin C such as ascorbyl palmitate, ascorbyl glucoside, magnesium ascorbyl phosphate, ascorbyl lysostearate, vitamin A palmitate (retinyl palmitate) and vitamin E linoleate (tocopheryl linoleate).
  • Other esters of vitamin C, vitamin A and vitamin E may also be
  • the topical compositions may also include typical emulsifiers.
  • the emulsifiers may be nonionic, anionic, cationic or amphoteric in nature.
  • suitable emulsifiers include polyoxypropylene-polyoxyethylene ethers of cetyl alcohols and glycerol monoisostearate.
  • the emulsifiers may suitably range from 0.5% to 30%, preferably from 1% to 15%, optimally from 3% to 8% by weight of the topical composition.
  • the topical compositions may also include thickeners.
  • thickeners include cross-linked polyacrylate materials and gums such as xanthan, carrageenan, gelatine, karaya, pectin and locust beans gum.
  • the thickener may be present in amounts from about 0.1% to 20% by weight, preferably from 0.5% to 10% by weight, of the topical composition.
  • the topical compositions may also contain suitable preservatives.
  • suitable preservatives include alkyl esters of p-hydroxybenzoic acid, phenoxyethanol, hydantoin derivatives, proprionate salts, and a variety of quaternary ammonium compounds.
  • Preservatives will usually be employed in amounts ranging from 0.1% to 2% by weight of the topical composition.
  • the topical composition may also include substances such as p-anisic acid, sodium anisate, levulinic acid, sodium levulinate, sodium hydroxide, caprylyl glycol, 1,2-hexanediol, pentylene glycol, glyceryl caprylate, glyceryl caprate, ethylhexylglycerin, Undecylenamidopropyl-trimonium Methosulfate, propylene glycol, phenylpropanol, phenethyl alcohol, methylpropanediol, Dipropylene Glycol, or a combination thereof.
  • substances such as p-anisic acid, sodium anisate, levulinic acid, sodium levulinate, sodium hydroxide, caprylyl glycol, 1,2-hexanediol, pentylene glycol, glyceryl caprylate, glyceryl caprate, ethylhexylglycerin,
  • the present invention relates to a method for increasing the ceramide content of the stratum corneum, the method comprising topically administering a cosmetic composition of the present invention onto skin of an individual.
  • the present invention relates to a method of improving skin barrier function, the method comprising topically administering a cosmetic composition of the present invention onto skin of an individual. In some embodiments, the present invention relates to a method of increasing keratinocyte terminal differentiation in the epidermis, the method comprising topically administering a cosmetic composition of the present invention onto skin an individual.
  • the present invention relates to a method of upregulating enzymes in the epidermis associated with epidermal ceramide synthesis, the method comprising topically administering a cosmetic composition of the present invention onto skin of a subject.
  • the methods may in some embodiments be for improving skin complexion, improving skin radiance, improving skin tone, skin soothing, reducing premature skin ageing, wrinkle smoothing and/or supporting healthy look of skin.
  • the present invention relates to a method for non- pharmacological management of a skin disease, such as aphotic dermatitis, or condition associated with an impaired skin barrier function, such as increased transepidermal water loss (TEWL), dry skin, rough skin, irritated skin, the method comprising topically administering a composition comprising one or more compounds of formula I, in particular at least one said compound that has lactosyl or glycosyl residue in the position X of formula I, onto a skin of an individual.
  • a skin disease such as aphotic dermatitis
  • an impaired skin barrier function such as increased transepidermal water loss (TEWL)
  • TEWL transepidermal water loss
  • the invention related to non-pharmacological intervention for mitigation of a skin condition or a skin disease in an individual who has, or who is susceptible to developing an impaired skin barrier function, the method comprising topically administering a composition comprising one or more compounds of formula I, in particular at least one said compound that has lactosyl or glycosyl residue in the position X of formula I, onto a skin of said individual.
  • the individual who is susceptible to an impaired skin barrier function according to the invention is an individual has either heredity of impaired skin barrier function, or been exposed to hazardous envinromental factors.
  • the relevant hazardous environmental factors include, but not limited to, climatic conditions, such as UV light or chemical pollutants, such as polycyclic aromatic pollutants (PAH), particulate matter PM2.5, blue light, ozone or cigarette smoke.
  • climatic conditions such as UV light or chemical pollutants, such as polycyclic aromatic pollutants (PAH), particulate matter PM2.5, blue light, ozone or cigarette smoke.
  • PAH polycyclic aromatic pollutants
  • the invention in general relates to an individual who is a mammal, e.g. a domestic animal, like a dog or cat, or a human individual.
  • the individual is a human.
  • the human individual is an adult individual, i.e. a human of 20+ years old; in other preferred embodiments, the human individual may be a child or a teenager.
  • the later may be preferred, e.g., when compositions of the invention are intended for prophylactic treatment, such as non-pharmacological intervention for mitigation of a skin condition or a skin disease in an individual who has, or who is susceptible to developing an impaired skin barrier function.
  • glucosyl ceramide NS on the skin leads to an upregulation of ATP synthase subunit g, (mitochondrial), of ATP synthase subunit delta (mitochondrial), of cytochrome c oxidase subunit 6C, of NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 (mitochondrial), of NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8, of ATP-dependent zinc metallopro tease YME1L1, of NAD-dependent malic enzyme (mitochondrial) and of phosphomevalonate kinase.
  • lactosyl ceramide NS on the skin leads to an upregulation of ATP synthase subunit g, (mitochondrial), of ATP synthase subunit delta (mitochondrial), of cytochrome c oxidase subunit 6C, of cytochrome c oxidase subunit 2, of cytochrome c oxidase subunit NDUFA4, of cytochrome b-cl complex subunit 9, of ATP-dependent zinc metalloprotease YME1L1, of NAD-dependent malic enzyme (mitochondrial) and of phosphomevalonate kinase.
  • ATP synthase subunit g mitochondrial
  • ATP synthase subunit delta mitochondrial
  • cytochrome c oxidase subunit 6C of cytochrome c oxidase subunit 2C
  • cytochrome c oxidase subunit 2 of cytochrome c oxid
  • ATP is a versatile biochemical form of energy used to fuel metabolic processes. ATP is generated by the respiratory chain. During age and stress energy production is decreased and metabolism slowed down. Repair mechanisms are weakend and damage is accelerated. Activating the respiratory chain and therefore ATP generation keeps the metabolism high and provides energy for repair mechanisms, cells stay healthy & functional resulting in a healthy skin with a radiant complexion. Furthermore, an activated metabolism supports skin regeneration and helps to fight against signs of ageing.
  • ceramide NP ceramide NP
  • ceramide NG glucosyl ceramide
  • lactosyl ceramide or compositions comprising thereof may also be used for boosting energy of skin cells according to the invention.
  • Boosting energy of the skin cells refers to an improvement of overall metabolism and ATP-production and may also be referred to as skin vitalisation or skin energizing.
  • skin vitalisation or skin energizing.
  • Topical composition comprising one or more compounds of formula I
  • X is hydrogen or a glycosyl moiety, the carbon-carbon bond noted - is a double or a single bond,
  • R 1 is an alkyl chain having 10 - 20 carbon atoms
  • R 2 is hydrogen or a substituted or unsubstituted acyl having 16-34 carbon atoms
  • R 3 is hydrogen when the carbon-carbon bond noted - is a double or a single bond, and R 3 is -OH when the carbon-carbon bond noted - is a single bond,
  • R 4 is hydrogen when the carbon-carbon bond noted - is a double or a single bond, and R 4 is hydrogen or -OH when the carbon-carbon bond noted - is a double bond, said composition is characterized in that at least one of the one or more compounds of formula I has a lactosyl moiety or a glucosyl moiety in the position X.
  • Topical composition according to embodiment 1 or 2 wherein for one or more of the compounds of formula I, the stereochemical configuration is (2S,3R,4E) and the carbon-carbon bond noted - is a double bond.
  • Topical composition according to embodiment 1 or 2 wherein for one or more of the compounds of I, the stereochemical configuration is (2S,3S,4R) or (2S,3S), and the carbon-carbon bond noted - is a single bond.
  • Topical composition according to any one of embodiments 1 to 4, wherein for one or more of the compounds of formula I, R 1 is -C12H25 and/or R 2 is selected from hexadecanoyl, 2-hydroxyhexadecanoyl, octadecanoyl, 2-hydroxyoctadecanoyl, eicosanoyl, 2-hydroxyeicosanoyl, lignoceroyl, 2-hydroxytetracosanoyl, 30- (linoley loxy ) -triacontanoy 1.
  • a topical cosmetic composition comprising a composition according to any one of embodiments 1-12, for use in cosmetic treatment of skin of an individual, wherein said treatment improves the visual appearance of skin of said individual.
  • lactosyl ceramide for increasing the ceramide content of the stratum comeum, increasing keratinocyte terminal differentiation in the epidermis, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis, and/or improving skin barrier function in skin of an individual.
  • ceramide NP for increasing the ceramide content of the stratum comeum, increasing keratinocyte terminal differentiation in the epidermis, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis, and/or improving skin barrier function in skin of an individual.
  • ceramide NG for increasing the ceramide content of the stratum comeum, increasing keratinocyte terminal differentiation in the epidermis, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis, and/or improving skin barrier function in skin of an individual.
  • glucosyl ceramide for increasing the ceramide content of the stratum comeum, upregulating enzymes in the epidermis associated with epidermal ceramide synthesis, and/or improving skin barrier function in skin of an individual.
  • ceramide NS for increasing keratinocyte terminal differentiation in the epidermis and/or improving skin barrier function in skin of an individual.
  • a topical pharmaceutical composition comprising a composition according to embodiment 21, further comprising one or more compounds that are structurally different from a compound of formula I, and/or pharmaceutically active for treating of a skin disease or a pathological skin condition.
  • Method for non-pharmacological management of a skin condition associated with an impaired skin barrier function such as increased transepidermal water loss (TEWL), dry skin, rough skin, irritated skin, the method comprising topically administering a composition of any one of embodiments 1 to 13 onto a skin of an individual.
  • Method for non-pharmacological intervention for mitigation of a skin condition or a skin disease in an individual who has, or who is susceptible to developing an impaired skin barrier function the method comprising topically administering a composition of any one of embodiments 1 to 13 onto a skin of said individual. 26. Method according to embodiment 25, wherein the individual who is susceptible to an impaired skin barrier function has heredity of impaired skin barrier function, or been exposed to hazardous envinromental factors.
  • climatic conditions such as UV light or chemical pollutants, such as polycyclic aromatic pollutants (PAH), particulate matter PM2.5, blue light, ozone or cigarette smoke.
  • PAH polycyclic aromatic pollutants
  • Example 1 Topical compositions comprising ceramide blends
  • Example 2 Topical compositions comprising ceramide blends
  • Example 3 Human epidermal keratinocytes are obtained from a commercial vendor.
  • the cells are isolated from juvenile foreskin or from adult normal human tissue collected from various sites that include face, breast, abdomen, and thigh.
  • the cells are cultivated in a T25 flask using a commercial keratinocyte Growth Medium which is a serum-free medium and optimized for the in vitro cultivation of epidermal keratinocytes without feeder cells.
  • a commercial growth supplement and calcium is added to a final concentration of 1.2mM to induce differentiation.
  • the cells Upon reaching cell confluence, the cells are treated with either 200 ppm glucosylceramide or 200 ppm lactosylceramide, each dissolved in dimethyl sulfoxide (DMSO) for 1 week.
  • DMSO dimethyl sulfoxide
  • the cells are homogenised with 2mL chloroform: methanol (2:1), and transferred to a vial containing Phosphate Buffered Saline (PBS). The homogeniser is rinsed twice with solvent and all rinses are together. The organic phase is evaporated to dryness.
  • PBS Phosphate Buffered Saline
  • Ceramide levels produced by the keratinocytes are measured by a modified high-performance thin layer chromatography (HPTLC) method.
  • HPTLC high-performance thin layer chromatography
  • the dried residue is dissolved in 200pL chloroforrmmethanol (2:1).
  • Samples of 80pl and 20pL are then subjected to a HPTLC protocol in which the HPTLC plates are developed using a sequential development system: (1) dichloromethane:ethylacetate: acetone (80:16:4) to 85mm, (2) chloroforrmmethanohacetone (76:16:8) to 80mm, (3) hexane:chloroform:acetic acid: acetone: methanol (6:80:0.1:10:4) to 85mm.
  • the plates are stained with 3% copper acetate in 8% phosphoric acid and charred at 160°C for the quantitation of ceramides. Quantification is performed against known quantities of Ceramide NP by laser scanning densitometry. Each plate is scanned at 425nm and quantified using WinCATS software.
  • Gene expression is determined by isolating RNA samples from the keratinocytes using a Qiagen RNeasy kit with DNase I digestion. Reverse transcription is performed using a high- capacity cDNA kit. cDNA samples of 40ng are used for qPCR. Taqman gene expression assay is purchased commercially, and the qPCR reaction is performed using a fast amplifier. Data are normalized by reference genes, either polymerase (RNA) II polypeptide A (POLR2A) and ribosomal protein large, PO (RPLPO) of which expression does not change by the treatment. Relative gene expression is calculated by comparative CT method.
  • RNA polymerase II polypeptide A
  • RPLPO ribosomal protein large, PO
  • GABA b-glucocerebrosidase
  • Total ceramides in keratinocytes treated glucosylceramide or lactosylceramide are elevated compared to untreated keratinocytes.
  • the differentiation marker genes, involucrin and transglutaminase- 1 increase in expression. This response is also observed in additional genes of keratinocyte differentiation as SPRR1 and SPRR2.
  • the keratinocytes treated with glucosylceramide or lactosylceramide display reduced gene expression of inflammatory cytokines such as IL8 and TNF.
  • Example 4 Characterisation of effects of (glycosylated) ceramides and (glvco)sphingolipids as cosmetic active ingredients
  • RHE Reconstructed Human Epidermis
  • This system mimics the in vivo 3D structure of epidermal tissue as well as the conditions and processes that occur in normal epidermis.
  • RHE were cultured using the medium provided by the manufacturer until analysis.
  • RHE were maintained in survival for 24 hours, before RHE were topically treated with lipid in a base emulsion for 24h.
  • 3 RHE were treated with base emulsion alone and 3 more remained untreated as a control batch (Ctrl).
  • RHE were incubated under classical cell culture conditions (37°C, 5% C02).
  • Bioinformatics and statistical analysis Proteomic analysis returned a mean total of 34961 high-quality peptides corresponding to a mean 2422 identifiable and quantifiable RHE proteins among conditions. A summary of proteins differentially expressed within conditions is provided in Annexe 3. Proteins with a p-value ⁇ 0.05 in at least one of the concentrations tested for a lipid were considered significant and used for pairwise comparisons. Relevant proteins were classified by their biological processes and associated pathways using the publicly available gene ontology (GO) database provided by the Gene Ontology Consortium and Reactome. Interactome analysis was performed using Cytoscape combined with STRING.
  • GO gene ontology

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EP22726199.7A 2021-04-30 2022-04-29 Topische zusammensetzungen mit (glyco)sphingolipiden und/oder (glyco)ceramiden Pending EP4329718A1 (de)

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CH4702021 2021-04-30
PCT/PT2022/050018 WO2022231448A1 (en) 2021-04-30 2022-04-29 Topical compositions comprising (glyco)sphingolipids and/or (glyco)ceramides

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