EP4153123A1 - Compositions and methods for providing scalp care benefits - Google Patents

Abstract

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

Description

COMPOSITIONS AND METHODS FOR PROVIDING SCALP CARE BENEFITS

Field of the Invention

The present invention relates to compositions and methods for providing scalp care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human scalp 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 scalp is part of the integumentary protecting system of the human head, and represents a distinct ecological niche in which relatively high follicular density, large numbers of sweat and sebaceous glands and high relative humidity create a unique environment for microbial colonization. Maturation of the stratum comeum generates a steady supply of amino acids, sweat glands secrete minerals and sebaceous glands provide sebum, which act together to provide a favourable, nutrient-rich environment.

Dandruff is a benign but aesthetically unpleasant cosmetic scalp complaint. Up to half the global population will suffer from the condition at some point during their lifetime. Dandruff is generally characterized by the presence of excessive flakes on the scalp and in the hair and is often accompanied by itch. The condition tends to develop post-puberty and is restricted to the scalp with the presence of terminal hair.

The main intervention strategy used for the treatment of dandruff is the topical application of antifungal agents such as zinc pyrithione and climbazole which are normally delivered from a shampoo. These antifungal agents remove (or at least reduce the level of) Malassezia spp. from the scalp. Although there is no doubt that treatments such as zinc pyrithione and climbazole are effective antifungal agents, they do not directly address the perturbations in the scalp microbio e that are thought to play a significant role in dandruff formation. The abundance of S. epidermidis and C. acnes has been observed to be decreased on dandruff scalps (compared with non-dandruff scalps), whereas the levels of S. capitis show a concomitant and significant increase. Dandruff has also been associated with changes in the proportion between fungal and bacterial populations. For example, the ratio of Malassezia nastricta to C. acnes has been observed to be significantly higher on dandruff scalps.

The present invention addresses this problem.

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

Summary of the Invention

The present invention provides a composition for providing scalp care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human scalp 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 scalp care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human scalp microbiome, the method comprising the simultaneous or sequential administration 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 to the surface of the scalp.

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 scalp care benefits by selectively supporting the growth of beneficial commensal microbial strains in the human scalp microbiome.

Detailed Description and Preferred Embodiments

In the context of this invention “scalp” is understood as the layers which comprise it, 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, “scalp care" means regulating or improving cosmetic qualities of the scalp. These qualities are subject to regulation or improvement both in healthy subjects as well as those which present with scalp diseases or disorders (such as psoriasis, lichen planus, folliculitis or atopic dermatitis).

Examples of scalp care benefits in the context of this invention include reducing or preventing cosmetic signs of dandruff such as dryness, scaling or flaking.

A preferred method according to this invention is a method for reducing or preventing cosmetic signs of dandruff such as dryness, scaling or flaking, by selectively supporting the growth of commensal Staphylococcus epidermidis and/or Cutibacterium acnes strains in the human scalp microbiome, the method comprising the simultaneous or sequential administration to the surface of the scalp of at least one biotin binding compound and at least one precursor for biotin biosynthesis as described above.

Cutibacterium spp. (predominantly C. acnes) and Staphylococcus spp. (predominantly S. epidermidis), are the most abundant bacteria found in scalp swabs of non-dandruff individuals, comprising approximately 90% of the total gene sequences.

C. acnes is a 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.

Similarly, metabolic products of S. epidermidis, including organic acids, have been shown to 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 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.

Advantageously, the compositions and methods of this invention are aimed at modulating natural interactions between beneficial commensal microbial strains and other prominent members of the human scalp microbiome. 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 microbial strains (specifically S. epideimidis and/or C.acnes) over less desirable microbial strains (specifically S. capitis and/or M. resthcta).

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.

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 or a 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.

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 sebacate, 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.

Preferred types of composition for use in the invention include shampoos, oils and lotions, which are intended for topical application to the hair and scalp.

Shampoo compositions for use in the invention are generally aqueous (i.e. they have water or an aqueous solution as their major component), and will suitably comprise from 50 to 98%, preferably from 60 to 90% water (by weight based on the total weight of the composition).

Shampoo compositions for use in the invention will typically comprise one or anionic surfactants such as sodium oleyl succinate, ammonium lauryl sulfosuccinate, ammonium lauryl sulphate, sodium dodecylbenzene sulphonate, triethanolamine dodecylbenzene sulfonate, sodium cocoyl isethionate, sodium lauryl isethionate, sodium N-lauryl sarcosinate, sodium lauryl sulfate, sodium lauryl ether sulfate (n) EO, (where n ranges from 1 to 3), ammonium lauryl sulfate and ammonium lauryl ether sulfate (n) EO, (where n ranges from 1 to 3) .

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

The total amount of anionic surfactant in shampoo compositions for use in the invention generally ranges from 5 to 30%, preferably from 8 to 20% (by weight based on the total weight of the composition).

Shampoo compositions for use in the invention may also include co-surfactants such as nonionic surfactants, which can be included in an amount ranging from 0.5 to 8%, preferably from 2 to 5%

(by weight based on the total weight of the composition) and/or amphoteric or zwitterionic surfactants, which can be included in an amount ranging from 0.5 to 8%, preferably from 1 to 4%

(by weight based on the total weight of the composition). Representative nonionic surfactants include alkanolamides such as cocamide monoethanolamide and cocamide monoisopropanolamide; alkyl polyglucosides such as cocoglucoside and lauryl glucoside; and acyl glucamides such as cocoyl methyl glucamide.

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

Shampoo compositions for use in the invention may also include one or more cationic polymers, which can be included in an amount ranging from 0.01 to 5%, preferably from 0.05 to 2% (by weight based on the total weight of the composition). Representative cationic polymers include cationic polysaccharide polymers such as cationic cellulose derivatives and cationic guar gum derivatives such as guar hydroxypropyltrimethylammonium chloride.

Shampoo compositions for use in the invention may also include one or more suspending agents, which can be included in an amount ranging from 0.05 to 5%, preferably from 0.1 to 3% (by weight based on the total weight of the composition). Representative suspending agents include polyacrylic acids, cross-linked polymers of acrylic acid, copolymers of acrylic acid with a hydrophobic monomer, copolymers of carboxylic acid-containing monomers and acrylic esters, cross-linked copolymers of acrylic acid and acrylate esters, heteropolysaccharide gums and crystalline long chain acyl derivatives such as ethylene glycol distearate. Hair oils and lotions 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). Lotions are typically aqueous emulsions having an aqueous phase in addition to the oil phase.

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 C20-40 alkyl stearate).

The aqueous phase of lotions for use in the invention 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.

Lotions for use in the invention may also 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.

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 actives for improving the physical and/or aesthetic characteristics of the scalp and/or the hair. Examples include amino acids, vitamins, minerals and/or antioxidants, emollients, humectants, sunscreens, anti-irritants, exfoliating agents, botanical 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 tube, 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.

The composition is suitably applied to the hair and scalp and massaged into the surface of the scalp. Generally, an amount corresponding to about 1 to 15 ml of the composition per application is applied uniformly over the area of treatment daily or at least once a week over a time interval of at least 7 (seven) days, more preferably at least 30 (thirty) days.

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

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, all 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 and Cutibacterium acnes , but not in the case of S. capitis. Only S. epidermidis and Cutibacterium acnes are 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 C.acnes and 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. capitis while promoting the growth of C. acnes and S.epidermidis. S. capitis has been shown to be highly enriched on scalps that are classified as being affected by dandruff.

In-silico modelling studies indicate that Malassezia restricta growth may be inhibited in a similar way to S. capitis when biotin is replaced by pimelic acid as described above. The ratio of Malassezia restricta to C. acnes has been observed to be significantly higher on dandruff scalps.

Claims

1. A composition for providing scalp care benefits by selectively supporting the growth of beneficial commensal S.epidermidis and/or C.acnes strains in the human scalp 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 scalp care benefits by selectively supporting the growth of beneficial commensal S.epidermidis and/or C.acnes strains in the human scalp microbiome, the method comprising the simultaneous or sequential administration 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 to the surface of the scalp.

4. A method according to claim 3, which is a method for reducing or preventing cosmetic signs of dandruff by selectively supporting the growth of commensal Staphylococcus epidermidis and/or Cutibacterium acnes strains in the human scalp 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, in combination with at least one biotin binding compound as defined in claim 1 , for providing scalp care benefits by selectively supporting the growth of beneficial commensal S.epideimidis and/or C.acnes\ strains in the human scalp microbiome.

8. Use according to claim 8, for reducing or preventing cosmetic signs of dandruff by selectively supporting the growth of commensal Staphylococcus epidermidis and/or

Cutibacterium acnes strains in the human scalp microbiome.