EP4153124A1

EP4153124A1 - Compositions and methods for providing skin care benefits

Info

Publication number: EP4153124A1
Application number: EP21726914.1A
Authority: EP
Inventors: Pamela GAMBA; Joanne Elizabeth HUNT; Alexander Gordon James; Barry Murphy; Emily Grace SMITH
Original assignee: Unilever Global IP Ltd; Unilever IP Holdings BV
Current assignee: Unilever Global IP Ltd; Unilever IP Holdings BV
Priority date: 2020-05-20
Filing date: 2021-05-19
Publication date: 2023-03-29
Also published as: WO2021234055A1

Abstract

The invention provides a composition for providing skin care benefits, such as reducing and/or preventing axillary malodour, by selectively supporting the growth of beneficial commensal S.epidermidis and/or C. acnes strains in the human cutaneous microbiome, the composition comprising at least one biotin binding compound and at least one precursor for biotin biosynthesis selected from pimelic acid, salts thereof or an anhydride thereof.

Description

COMPOSITIONS AND METHODS FOR PROVIDING SKIN CARE BENEFITS

Field of the Invention

The present invention relates to compositions and methods for providing skin care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human cutaneous microbiome.

Background of the Invention

Human skin harbours many diverse microorganisms, which colonize the stratum comeum of the epidermis and skin appendages such as sweat glands and hair follicles. The total of microorganisms in and on our skin is termed the cutaneous microbiota, and the skin microbiome is their collective genome.

Sequencing studies of diverse skin sites in healthy adults have shown that the composition of the skin microbiome is determined primarily by body site. Microbial colonization is differentially shaped by the physiological and topological variation of the skin, and varies systematically among different skin habitats, such as between dry, moist, and sebaceous skin.

The human axillae (underarms) are covered by squames, hair shafts and follicles, eccrine, apocrine and sebaceous glands. The axillary area represents a distinct ecological niche characterized by warm, moist and nutritionally rich conditions. Salts, proteins, squalene, sterols, sterol esters, wax esters, a wide range of lipids and fatty acids are secreted, thus sustaining one of the highest densities of microorganisms on the body surface.

The human cutaneous microbiome plays an important role in the generation of bodily malodour, particularly in the underarm (axilla) region. A primary causal molecule of axillary malodour has been identified as the thioalcohol 3-methyl-3-sulfanylhexan-1-ol (3M3SH). 3M3SH is derived from biotransformation of an odourless dipeptide precursor (Cys-Gly-3M3SH) by certain bacterial species found in the axilla.

Studies at the species level show that Staphylococcus hominis is positively associated with underarm malodour, whereas S. epidermidis and Cutibacterium acnes are anti-correlated. S. epideimidis colonizes predominantly the axillae, head, and nares. Studies have shown that metabolic products of S. epidermidis, including organic acids such as lactic acid, improve skin moisture retention, maintain a low acidic condition on the skin surface, and improve rough skin texture. S. epidermidis is also considered to supplement the barrier function of the epidermis and inhibit the colonization of skin pathogens such as S. aureus through factors such as nutrient competition, production of antimicrobial peptides (AMPs), immunomodulatory properties (inhibition of inflammatory cytokine production) and enhanced expression of tight junction proteins.

C. aeries is another major skin commensal that prevents colonization and invasion of pathogens, via the hydrolysis of triglycerides in sebum and release of fatty acids that are antimicrobial and contribute to an acidic pH of the skin surface.

The main intervention strategy used for the treatment of armpit malodours is the topical application of deodorants and antiperspirants. Deodorants reduce the bacterial counts in the axillae and add perfume to mask the malodour formation. Antiperspirants additionally block the eccrine sweat glands to reduce the moisture production.

Although there is no doubt that treatments such as deodorants and antiperspirants are effective, they may also deplete or eliminate beneficial commensal microbial strains such as S. epidermidis and Cutibacterium aeries. As noted above, these microbial strains are considered to play many important beneficial roles relating to skin health, skin appearance and skin function.

The present invention addresses this problem.

An objective of the present invention is to provide skin care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human cutaneous microbiome.

Summary of the Invention

The present invention provides a composition for providing skin care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human cutaneous microbiome, the composition comprising at least one biotin binding compound and at least one precursor for biotin biosynthesis selected from pimelic acid, salts thereof or an anhydride thereof. The invention also provides a method for providing skin care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human cutaneous microbiome, the method comprising the simultaneous or sequential administration to the skin of at least one biotin binding compound and at least one precursor for biotin biosynthesis selected from pimelic acid, salts thereof or an anhydride thereof.

The invention also provides the use of pimelic acid, salts thereof or an anhydride thereof, optionally in combination with at least one biotin binding compound, for providing skin care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human cutaneous microbiome.

Detailed Description and Preferred Embodiments

In the context of this invention “skin” is understood as the layers which comprise them, from the uppermost layer or stratum corneum to the lowermost layer or hypodermis, both inclusive. These layers are composed of different types of cells such as keratinocytes, fibroblasts, melanocytes, mastocytes, neurons and/or adipocytes, among others.

As used herein, “skin care" means regulating and/or improving cosmetic qualities of the skin. These qualities are subject to regulation and/or improvement both in healthy subjects as well as those which present diseases or disorders of the skin (such as psoriasis, lichen planus, folliculitis or atopic dermatitis).

Examples of skin care benefits in the context of this invention include reducing and/or preventing cutaneous, especially axillary, malodour; providing a smoother, more even texture; improving the elasticity or resiliency of the skin; improving the firmness of the skin; reducing the oily, shiny, and/or dull appearance of skin; improving the hydration status or moisturization of the skin, improving the appearance of fine lines and/or wrinkles; improving skin exfoliation or desquamation; plumping the skin; improving skin barrier properties; improving skin tone; reducing the appearance of redness or skin blotches and improving the brightness, radiancy, or translucency of skin.

A preferred method according to this invention is a method for reducing and/or preventing axillary malodour by selectively supporting the growth of commensal S.epidermidis and/or C.acnes strains in the human axillary microbiome, the method comprising the simultaneous or sequential administration to axillary skin of at least one biotin binding compound and at least one precursor for biotin biosynthesis as described above.

Advantageously, the compositions and methods of the invention are aimed at modulating natural interactions between beneficial commensal microbial strains in the human cutaneous microbiome (such as S. epidermidis and C. acnes) and other prominent members of the human cutaneous microbiome (such as S. hominis, S. haemolyticus and S. lugdunensis ). These microbes naturally compete for local resources and attachment to epithelial sites. Rather than generally reducing microbial load and diversity, the compositions and methods of the invention render an ecological change that favours selection of desirable over less desirable microbial strains.

Biotin binding compounds

The composition of the invention comprises, inter alia, at least one biotin binding compound.

As used herein, "biotin binding compound” denotes any compound which is capable of tightly but non-covalently binding to biotin (5-[(3aS,4S,6aR)-2-oxohexahydro-1 H-thieno[3,4-d]imidazol-4- yl]pentanoic acid).

Examples of biotin-binding compounds include biotin-binding proteins such as avidin-type molecules.

Avidin is a basic (pi c.10), homotetrameric glycoprotein (molecular weight 66-69 kDa) that contains terminal N-acetyl glucosamine and mannose residues. Each of the four subunits contains 128 amino acids and binds to biotin with high specificity and affinity (K_d of about 10 ¹⁵ M). Each subunit is composed of eight antiparallel b-strands that form a b-barrel, whose wide end binds to biotin. Avidin is originally derived from the eggs of birds, reptiles and amphibians.

The term "avidin-type molecule" as used herein encompasses native and recombinant forms of avidin as well as native and recombinant forms of avidin analogues such as streptavidin. Derived from Streptomyces avidinii, streptavidin is a c. 56 kDa non-glycosylated homotetrameric protein that binds to four biotins with a K_d of about 10 ¹⁵ M. Streptavidin has a tertiary/quatemary structure and amino acid arrangement similar to those of avidin and shows a moderate sequence homology level of c.30% sequence identity and 40% similarity with avidin. Streptavidin is non-glycosylated and has a slightly acidic pi of about 5-6. Neutravidin is another avidin analogue. It is the deglycosylated derivative of avidin and has a molecular weight of about 60 KDa. In the absence of the carbohydrate moieties, the pi of neutravidin is only slightly acidic (c.6.3). Bradavidin II is an avidin analogue that may be isolated from Bradyrhizobium japonicum, a nitrogen-fixing bacterium found in the root nodules of the soybean plant. Bradavidin II shows a moderate amino acid similarity with avidin (38%) and streptavidin (32%) but exhibits the same biotin binding affinity as avidin. Avidin analogues also include modified avidins prepared via covalent attachment to the available lysines of avidin. Examples include N-acyl avidins such as N-formyl, N-acetyl, N-phthalyl and N-succinyl avidin.

Preferred biotin-binding compounds for use in the invention are selected from native and recombinant forms of avidin.

Mixtures of any of the above described materials may also be used.

Precursor for biotin biosynthesis

The composition of the invention comprises, inter alia, at least one precursor for biotin biosynthesis selected from pimelic acid, salts thereof or an anhydride thereof.

Pimelic acid is a straight-chained, 7-carbon saturated a, w-dicarboxylic acid (lUPAC name heptanedioic acid).

Examples of salts of pimelic acid include alkali metal salts (such as sodium, potassium and lithium salts); divalent metal salts (such as calcium, magnesium and zinc salts); ammonium salts; C1-C4 substituted ammonium salts (such as methyl-, dimethyl-, and trimethyl ammonium salts) and C1-C4 alkanolamine salts (such as ethanolamine, diethanolamine and triethanolamine salts).

Preferred precursors for biotin biosynthesis for use in the invention are selected from pimelic acid, pimelic anhydride and mixtures thereof.

Product Forms

Compositions for use in the invention can take a variety of forms suitable for topical application. Examples of such forms include a solid or liquid soap, a lotion, a spray, a cream, a gel, an emulsion, a cleansing liquid or cleansing milk, a deodorant, an antiperspirant, an ointment, a hair treatment or a shampoo. References to a specific physical form of the composition (such as solid, liquid or gel) denote the form of the composition at 25 °C and 1.0 bar, unless specified otherwise.

One preferred type of composition for use in the invention is a deodorant composition for reducing or preventing cutaneous, especially axillary, malodour.

Compositions for use in the invention will generally contain from about 0.01% to about 10%, preferably from about 0.1 % to 1 % of the at least one biotin binding compound (by weight based on the total weight of the composition); and from about 0.01% to about 10%, preferably from about 0.1 % to 1 % of the at least one precursor for biotin biosynthesis selected from pimelic acid and/or salts thereof (by weight based on the total weight of the composition).

Compositions for use in the invention will generally include a cosmetically acceptable vehicle. The term “cosmetically acceptable” means that the vehicle is suitable for topical application to the skin, has good aesthetic properties, is compatible with the at least one biotin binding compound and the at least one precursor for biotin biosynthesis selected from pimelic acid and/or salts thereof and any other ingredients, and will not cause any safety or toxicity concerns.

The vehicle may comprise an aqueous phase, an oil phase, an alcohol, a silicone phase ora mixture thereof, and may be in the form of an emulsion. Emulsions can have a range of consistencies including thin lotions (which may also be suitable for spray or aerosol delivery), creamy lotions, light creams and heavy creams.

Exemplary emulsions include water-in-oil emulsions, oil-in-water emulsions, silicone-in-water emulsions, water-in-silicone emulsions, polyol-in-silicone emulsions, silicone-in-polyol emulsions, polyol-in-oil emulsions, oil-in-polyol emulsions, wax-in-water emulsions and water-oil-water triple emulsions. Preferred emulsions include oil-in-water emulsions and water-in-oil emulsions.

Compositions in the form of an emulsion, and suitable for use in the invention, typically have an oil phase containing at one or more cosmetically acceptable fatty materials which may be liquid or solid at room temperature (25°C).

Suitable cosmetically acceptable fatty materials include naturally derived oils (such as sunflower oil, borage oil, soybean oil, castor oil, olive oil and almond oil); esters of monoalcohols or of polyols with monocarboxylic or polycarboxylic acids, at least one of the alcohols and/or acids comprising at least one hydrocarbon-based chain containing at least 6 carbon atoms (such as octyl palmitate, isopropyl myristate, isopropyl palmitate, isopropyl isostearate, hexyl laurate, isohexyl laurate, isohexyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, dihexyldecyl adipate, lauryl lactate, myristyl lactate, cetyl lactate, oleyl stearate, oleyl oleate, oleyl myristate, lauryl acetate, cetyl propionate, isononyl isononanoate, propylene glycol dicaprate, diisopropyl adipate, dibutyl adipate, and oleyl adipate); ethers (such as dicapryl ether); fatty alcohols (such as cetyl alcohol, stearyl alcohol and behenyl alcohol); isoparaffins (such as isooctane, isododecane and isohexadecane); silicone oils (such as dimethicones, cyclic silicones, and polysiloxanes); and hydrocarbon oils (such as mineral oil, petrolatum and polyisobutene); fatty acids containing from 8 to 30 carbon atoms, (such as stearic acid, lauric acid, palmitic acid and oleic acid); vegetable fats (such as cocoa butter, coconut oil, palm oil and shea butter); petroleum-based, natural and synthetic waxes (such as lanolin wax, beeswax, camauba wax, candelilla wax, paraffin wax, lignite wax, microcrystalline waxes, ceresin, ozokerite, and polyethylene waxes); hydrogenated oils which are solid at 25° C (such as hydrogenated castor oil, hydrogenated jojoba oil, hydrogenated palm oil, hydrogenated tallow and hydrogenated coconut oil);and fatty esters that are solid at 25°C (such as C_20-40 alkyl stearate).

Compositions in the form of an emulsion, and suitable for use in the invention, typically have an aqueous phase, which may also include one or more organic liquids that are miscible with water at room temperature (25°C). Exemplary water-miscible organic liquids include monohydric and polyhydric alcohols and derivatives thereof such as C₂-C₆ alkanols (such as ethanol and isopropanol); C2-C10 glycols and polyols (such as glycerol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, caprylyl glycol, dipropylene glycol, and diethylene glycol); C3-C16 glycol ethers (such as mono-, di-, or tripropylene glycol (C1-C4) alkyl ethers and mono-, di-, or triethylene glycol (C1-C4) alkyl ethers) and polyethylene glycol having 2 to 12 oxyethylene units.

Compositions in the form of an emulsion, and suitable for use in the invention, generally include surface active ingredients, such as emulsifiers and solubilizers, to enable two or more immiscible components to be combined homogeneously and to help stabilize the composition. Emulsifiers that may be used to form O/Wor W/O emulsions include sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, PEG-20 sorbitan isostearate, polyglyceryl-3-diisostearate, polyglycerol esters of oleic/isostearic acid, polyglyceryl-6 hexaricinolate, polyglyceryl-4-oleate, polyglyceryl-4 oleate/PEG-8 propylene glycol cocoate, polyglyceryl-2 dipolyhydroxystearate, PEG- 30 dipolyhydroxystearate, oleamide DEA, TEA myristate, TEA stearate, magnesium stearate, sodium stearate, potassium laurate, potassium ricinoleate, sodium cocoate, sodium tallowate, potassium castorate, sodium oleate, cetyl phosphate, diethanolamine cetyl phosphate, potassium cetyl phosphate, sodium glyceryl oleate phosphate, dimethicone copolyol, cetyl dimethicone copolyol, octyldimethicone ethoxyglucoside copolyol, dimethicone copolyol crosspolymer and laurylmethicone copolyol.

Compositions for use in the invention may also be formulated in a single-phase carrier such as a hydrophobic or hydrophilic liquid. Suitable hydrophobic liquid carriers include liquid polyorganosiloxanes, mineral oils, hydrogenated polyisobutene, polydecene, paraffins and isoparaffins of at least 10 carbon atoms, aliphatic or aromatic ester oils (such as isopropyl myristate, lauryl myristate, isopropyl palmitate, diisopropyl sebecate, diisopropyl adipate and Ci₂to Ci ₅ alkyl benzoates), polyglycol ethers (such as polyglycol butanol ethers) and mixtures thereof. Suitable hydrophilic liquid carriers include water, monohydric or polyhydric aliphatic alcohols having 2 to 8, preferably 2 or 3 carbon atoms (such as ethanol and isopropanol, oligoglycol ethers having 2 to 5 repeat units (such as dipropylene glycol) and mixtures thereof.

Liquid form compositions for use in the invention may be thickened, for example using one or more water soluble or colloidally water soluble polymeric thickening agents. Suitable water soluble or colloidally water soluble polymeric thickening agents include hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyquatemium-10, carrageenan, guar gum, hydroxypropyl guar gum, xanthan gum, polyvinylalcohol, acrylic acid/ethyl acrylate copolymers, carboxyvinyl polymers, cross-linked polyacrylate polymers and polyacrylamide polymers.

Solid form compositions for use in the invention, such as gels and sticks, generally include one or more structurants, in an amount ranging from about 1 % to about 35% (by weight based on the total weight of the composition), depending upon the desired product consistency. Examples of structurants include fatty acid gelling agents selected from saturated fatty acids or hydroxyacids containing from about 8 to 30 carbon atoms and their salts, esters or amides (such as sodium and potassium stearate, 12-hydroxystearic acid, esters of 12-hydroxystearic acid and amides of 12- hydroxystearic acid); saturated, unsubstituted monohydric fatty alcohols containing from about 8 to 30 carbon atoms (such as cetyl alcohol, myristyl alcohol and stearyl alcohol); acyl amino acid derivatives such as N-lauroyl-L-glutamic acid di-n-butylamide; amide derivatives of di ortribasic carboxylic acids such as alkyl N,N' dialkylsuccinimide; inorganic particulate thickening agents selected from siliceous and alumino-siliceous materials (such as fumed silicas, bentonites, hectorites, colloidal magnesium aluminium silicates and organoclays such as stearalkonium bentonite, disteardimonium hectorite, quaternium 90-bentonite), quatemium-18 bentonite and quatemium-18 hectorite); and petroleum-based, natural and synthetic waxes (such as lanolin wax, beeswax, camaubawax, candelilla wax, castor wax, ontan wax, paraffin wax, lignite wax, microcrystalline waxes, ceresin, ozokerite, polymethylene and polyethylene waxes).

Combinations of any of the above described materials or product forms may also be used.

Compositions for use in the invention (as described above) may include additional skin care actives for improving the physical and/or aesthetic characteristics of the skin. Examples include vitamins, minerals and/or antioxidants, emollients, humectants, skin lightening agents, sunscreens, antiirritants, exfoliating agents, herbal extracts (such as pomegranate, white birch, green tea, chamomile and licorice extracts) and mixtures thereof.

Compositions for use in the invention (as described above) may include additional functional ingredients for improving the physical and/or aesthetic characteristics of the composition perse. Examples include inorganic pigments (such as titanium oxide, zirconium oxide, cerium oxide, zinc oxide, iron oxide, chromium oxide, manganese violet, ultramarine blue, chromium hydrate and ferric blue); organic pigments (such as carbon black and the organic lakes of barium, strontium, calcium or aluminium); pearlescent agents (such as mica coated with titanium oxide and/or iron oxide); dyes, preservatives (such as disodium EDTA, benzyl alcohol, methylparaben, phenoxyethanol, propylparaben, ethylparaben, butylparaben and isobutylparaben); pH adjusters and fragrances (such as essential oils, flower oils, natural extracts from resins, gums, balsams, beans, mosses and other plants, as well as synthetic aromatic materials).

Mixtures of any of the above described materials may also be used.

Packaging and Use

A composition for use in the invention (as described above) may be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a liquid composition can be packaged in a bottle or a roll-ball applicator, or in a container fitted with a pump suitable for finger operation, or in a propellant-driven aerosol device. Gel or cream compositions can be packaged in a non-deformable bottle or squeeze container, such as a tube or a lidded jar, or in an applicator having a dispensing head provided with at least one aperture through which the composition can be extruded under mild pressure. Solid compositions may be shaped into a stick form which may be elevated out of a dispensing package and directly applied to the desired area of skin.

The composition is suitably applied to the skin, preferably facial or axillary skin, at the rate of one or two applications per day. Generally, an amount corresponding to about 1 to 2 ml of the composition per application is applied uniformly over the area of treatment twice daily for a period of at least 7 (seven) days, more preferably at least 30 (thirty) days.

The invention will be further illustrated by the following, non-limiting Example.

EXAMPLE

Selected commensal bacterial strains were cultured on a solid chemically defined medium for 48 hours at 37°C in the presence of different additives, as follows:

It can be seen from the results that biotin is an essential cofactor supporting growth of both bacteria. When biotin is added to the medium, both species grow to form visible single colonies. When biotin is not added to the medium no bacterial growth is observed after incubation of the plates at 37°C for 48 hours. Similarly when biotin is added to the medium, but together with the biotin binder avidin, no bacterial growth is observed after incubation of the plates at 37°C for 48 hours.

It can also be seen from the results that pimelic acid is capable of replacing biotin as an essential cofactor supporting growth of S.epidermidis, but not in the case of S.hominis. Only S. epidermidis is able to grow in the presence of pimelic acid and absence of biotin. Similar results were obtained when pimelic anhydride was tested instead of pimelic acid.

It follows that pimelic acid (and/or pimelic anhydride) is capable of selectively supporting the growth of commensal S. epidermidis.

It also follows that pimelic acid (and/or pimelic anhydride) and a biotin binder (such as avidin) may be used to inhibit the growth of S. hominis while promoting the growth of S. epidermidis. S. hominis has been shown to be s one of the main causes of axillary malodour.

Claims

1. A composition for providing skin care benefits by selectively supporting the growth of beneficial commensal S.epidermidis and/or C.acnes strains in the human cutaneous microbiome, the composition comprising at least one biotin binding compound which is capable of tightly but non-covalently binding to biotin (5-[(3aS,4S,6aR)-2-oxohexahydro-1 H- thieno[3,4-d]imidazol-4-yl]pentanoic acid); and at least one precursor for biotin biosynthesis selected from pimelic acid, salts thereof or an anhydride thereof, , in which the biotin-binding compound is a biotin-binding protein selected from native and recombinant forms of avidin and native and recombinant forms of avidin analogues selected from streptavidin, bradavidin II, N-acyl avidins and mixtures thereof.

2. A composition according to claim 1 , in which the precursor for biotin biosynthesis is selected from pimelic acid, pimelic anhydride and mixtures thereof.

3 A method for providing skin care benefits by selectively supporting the growth of beneficial commensal S.epidermidis and/or C.acnes strains in the human cutaneous microbiome, the method comprising the simultaneous or sequential administration to the skin of at least one biotin binding compound as defined in claim 1 and at least one precursor for biotin biosynthesis selected from pimelic acid, salts thereof or an anhydride thereof.

4. A method according to claim 3, which is a method for reducing and/or preventing axillary malodour by selectively supporting the growth of commensal S.epidermidis and/or C.acnes strains in the human axillary microbiome.

5.. Method according to claim 4, in which the biotin-binding compound is selected from native and recombinant forms of avidin.

6. Method according to claim 4 or claim 5, in which the precursor for biotin biosynthesis is selected from pimelic acid, pimelic anhydride and mixtures thereof.

7. The use of pimelic acid, salts thereof or an anhydride thereof, n combination with at least one biotin binding compound as defined in claim 1 , for providing skin care benefits by selectively supporting the growth of beneficial commensal S.epideimidis and/or C.acnes strains in the human cutaneous microbiome.

8. Use according to claim 7, for reducing and/or preventing axillary malodour by selectively supporting the growth of commensal S.epidermidis and/or C.acnes strains in the human axillary microbiome.