NZ751394B2 - Compositions that assist skin healing and/or maintain skin health - Google Patents

Abstract

The present invention relates to compositions that assist skin healing and/or maintain skin health. The invention also relates to methods for increasing collagen in the skin and methods for treating or preventing the development or recurrence of erythema. The compositions according to the present invention comprise disodium lauriminodipropionate tocopheryl phosphates and, preferably, one or more anti-irritants and one or more vitamins. vention comprise disodium lauriminodipropionate tocopheryl phosphates and, preferably, one or more anti-irritants and one or more vitamins.

Description

itions that assist skin healing and/or maintain skin health This application is a divisional of NZ 721641, all of which is hereby incorporated by reference in its entirety.

Field of the invention The present invention relates to compositions that assist skin healing and/or maintain skin health, such as increasing collagen in the skin and/or treatment or prevention of the development or recurrence of erythema. In on, the present invention relates to a method for assisting skin healing and/or maintaining skin health.

Background of the invention There are many causes of damage to the skin and many of these results in erythema.

Erythema is a skin condition characterised by abnormal redness of the skin. It is a medical condition that is more significant than the normal flushed cheeks and/or nose in the fair and sensitive skinned.

Erythema can occur in various skin conditions such as , psoriasis and rosacea.

It is a condition associated with inflammation of the skin and can be caused by external irritation of the skin, for example, by over exposure to the sun or contact with irritating substances such as plants (eg poison ivy), various als and some metals (eg nickel in jewellery). Erythema can also occur when the skin is damaged by piercing with an object or following an insect bite. This damage can be unintentional or an ed part of a procedure such as skin needling. Erythema may also occur following various medical and cosmetic procedures including laser ent, intense pulsed light (IPL) treatment and microdermabrasion. ma may occur in response to an ic reaction or an infection. It is a common side effect of radiotherapy treatment and can be a side effect of tion or an illness. As a final example, erythema may occur as a side effect of certain types of ing including vitamin A toxicity. Despite the numerous known causes of erythema, in a significant proportion of cases the cause of erythema is unknown.

Traditional treatments e otics such as doxycycline. Alternative oral treatments include vitamin A medications, such as isotretinoin, steroids and antifungal medications. These treatments have significant side effects, for example isotretinoin has [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by l [Annotation] l None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl teratogenic side-effects. Antibiotics, antifungals and steroids can be administered atopically but have limited efficacy and/or restrictions on use due to safety ns.

Other topical treatments include metronidazoie, azelaic acid, retinoic acid/retinaldehyde, and vitamin C.

There are also light therapies to treat erythema, particUlarIy erythema ated with rosacea and laser treatments involving the ablation of blood vessels. 1% hydrocortisone as a topical cream is one of the common short-term topical treatments for erythema. ' Therevare limitations to all ofrthe’current treatments either with y or toxicity. ma, particularly erythema associated with rosacea, can be a persistent and chronic condition involving repeated remission and exacerbation. Many of the treatments such as steroids or antibiotics are not appropriate for long term use. There is a need for a non-prescription, non-steroid product that effectively assists the skin to heal and, in particular, treats erythema. The minimisation of side-effects is particularly important because some conditions ated with ma, such as rosacea, often require lifelong symptomatic treatment. In addition. the subject’s skin may be so sensitive that many l products are irritating. If a treatment is not sufficiently mild, it can exacerbate rather than improve the symptoms. A better ent in these cases is one that is effective, mild and can be used long term.

W0 2002/74290 describes treatment of rosacea with a non-steroidal anti-inflammatory drug such as am, aspirin, ibufenac or naproxen in combination with nitroimidazole. ses compositions for treating rosacea containing chitosan, a chitosan derivative or a physiologically acceptable salt thereof and a short-medium chain oxylic acid amide. .25- Brimonidine was reported asouseful in the l treatment of erythema in WC of oxymetazoline for ‘ treatin2011/fi77, disclosed cream itionsmptoms of rosacea including erythema, and disclosed the, l treatment of rosacea with a combination of brimonidine and oxymetazoline.

[Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl sed the topical treatment of rosacea with berberine or'a biologically equivalent'analogue thereof. WO 2012/001053 disclosed treatment of rosacea with metronidazole esters.

' The ty of the dermis of the skin is collagen. The collagen both supports the skin structure and retains moisture. Collagen fibres in the skin are reduced by exposure to ultraviolet radiation. a dry environment andloxidation. The amount of collagen in the skin also reduces with age. Reduction of collagen is associated with reduced ence and ”elasticity in the skin. Increased collagen production improves skin healing in patients with erythema.‘ In addition, maintenance and/or increases in collagen levels in the skin assist to maintain skin function and appearance. Overtime, this may prevent aging or have an ing effect.

Retinoids are known to increase collagen production. r, they' have high photoreactivity and require protection from light for stable storage. Retinoids also have - significant incidence of e ons including photosensitisation of the skin, which makes skin more susceptible to sunburn. discloses the use of TGF-B and/or TGF—B degradation products in the induction of collagen in the skin. WO 2011/040363 discloses a composition 'for promoting en production comprising one or more. of D-aspartic acid, D-alanine and tives and/or salts thereof. describes a compoSition for promoting collagen productioncomprising one or more purine nucleic acid-related substances.

Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of tion that this prior art forms part of the common general knowledge in Australia or any Other jurisdiction or that this prior art could ‘25 reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.

[Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl ation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl Summary of the invention "The inventors of the present ion developed topical formulations intended as soothing ts for sensitive skin types, that is, to soothe sensitive but undamaged skin. The ations are intended to desensitise the skin by hydration and moisturisation. Surprisingly, the ors ered that the formulations of the invention have an additional and unexpected effect on healing damaged and inflamed Skin with erythema. In addition, the formulations of the invention have been found to increase the amount of en in the skin, which further s with skin healing. In addition, the increase in collagen may protect the skin from degradation due to aging ' and/or provide an anti-ageing benefit. in one aspect, the t invention provides a method of sing collagen in the skin‘of a subject comprising topical administration of a physiologically effective amount of a composition comprising disodium lauriminodipropionate tocopheryl phosphates. in an alternate aspect, the present invention provides a method of increasing collagen in the skin of a t comprising topical administration of a physiologically effective amount of a composition comprising hamemalis virginiana water. In a preferred embodiment, the subject is identified as likely to benefit from increased collagen in the skin. The benefit from the increased collagen may be improved healing following skin , the prevention or reduction of skin damage from exposure to ultraviolet radiation or during therapeutic or cosmetic procedures such as laser treatment, prevention of aging, maintenance of skin health, or ing. The increased production of collagen may occur in any skin cell type. It is‘particularly beneficial for'the increase in collagen to occur in fibroblasts. Where the increased production of collagen occurs in lasts it may also occur in other skin cell types.

A physiologically effective amount of disodium laurimin’Odipropionate eryl phosphates may be provided in the form of a topical formulation comprising 0.4 to 2% wlw disodium lauriminodipropionate eryl phosphates.

In a preferred embodiment, administration of the ition increases production of Collagal by about 10% or more, for example, when measured by fluorescent antibody binding. In a» preferred embodiment, administration of the composition increases [Annotation] tarranl None set by tarranl ation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl collagen III by about 20% or more and in a most preferred embodiment, administration of the composition increases collagen III by about 40%.

Further, in a preferred embodiment, administration of the composition increases production of collagen l by about 5% or more, for example, when measured by florescent antibody binding. In a particularly preferred embodiment, administration of the composition increases collagen l by about 15%. atively, the composition administered to the subject is a composition that if administered to human foreskin fibroblasts results in about a 40% increase in collagen Ill and/or about a 15% increase in collagen | after)r about 60 hours of incubation with the composition. '10 "In all alternative ments of the ion the subject can be a human subject.

In a second aspect, the present invention provides a method of treatment, prevention or prevention of recurrence of erythema comprising topical administration of a physiologically effective amount of a . composition comprising disodium lauriminodipropionate tocopheryl phosphates. in a preferred aspect, the method is a .method of ent. In one embodiment, the t is identified as having erythema.

In an alternate embodiment, the subjectis fied as being at risk of developing erythema. In another alternate embodiment, the subject is identified as being at risk of recurrence of erythema. The erythema may be caused by any of the known causes sed above. The cause of the erythema may be unknown. In one embodiment, the '20 treatment of the erythema is post laser skin ents, chemical peels, microdemiabrasion or skin needling. In another ment, the erythema treated is » assoCiated with rosacea, psoriasis or eczema. In another embodiment, the method is to prevent recurrence of rosacea. \ in a preferred embodiment, the administration of the composition reduced the Standard» \25 Scalar Rating for the erythema by 75% or more by 7 days after use. It is preferred if the Standard Scalar Rating is d by 80% or more by 7 days after use. In an ative red embodiment, the stration of the composition reduced the Standard Scalar fling for the erythema by 3.0 or more by 7 days after use. It is preferred if the [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] l MigrationNone set by tarranl ation] tarranl Unmarked set by tarranl Standard Scalar Rating is reduced by 3.3 or more by 7 days after use. The Standard Scalar Rating is explained below.

In an ative preferred embodiment, the administration of the composition resulted in a magenta to blue shift, ie a* as measured by a Minolta Spectrometer Model CM-2600, of -2.5 or a greater negative by 48 hours after use. it is preferred if the magenta to blue shift is -2.8 or a greater negative by 48 hours after use. In an alternative preferred embodiment, the magenta to blue shift is -4 or a greater negative by7 days after use. 'It is preferred if the magenta to blue shift is -4.6 or a greater ve by 7 days after use.

In an alternative red embodiment, the administration of the ition results in a AE. ie (AE) = «1(AL2 + Aa2 + Abz) as measured by a Minolta ometer, of 3.5 or more by 48 hours after use. It is preferred if the AE is 3.7 or more by 48 hours after use.

In an alternative red embodiment, the AE is 5 or more by 7 days after use. It is preferred if the AE~ is 5.7 or more by 7 days after use. in a preferred embodiment, the composition of the present invention comprises '15 disodium Iauriminodipropionate tooopheryl phosphates, at least one vitamin andrat least one anti-irritant. The anti-irritant can be an emollient, a vitamin, an antioxidant or a herbal extract. Vitamin E, liquid paraffin, aloe vera and avena sativa kernel extract are suitable. Avena sativa kernel extract is preferred. The at least one n is preferably nicotinamide. in a particularly red embodiment, the composition includes the two .20 vitamins nicotinamide and panthenol. - In. a particularly preferred ment, the composition of the present invention comprises disodium lauriminodipropionate tooopheryl phosphates, at least one vitamin, at least one anti-irritant and hamemalis iana water.

In one embodiment, the composition r includes menthol for a cooling effect. In a particularly preferred embodiment, the composition includes the anti-irritant avena sative kernel extract, the two vitamins nicotinamide and panthenol. and menthol.

[Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl ation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl The composition of the present invention optionally further includes one or more emulsifiers, emollients, ners, humectants. preservatives, body rs, pearlizing agents, bulking agents, pH adjusters, feel modifiers, colouring agents and/or fragrances.

The composition of the invention can be a cream, lotion or gel.

In one , the cOmposition of the invention comprises: a. disodium Iauriminodipropionate tocopheryl phosphate in an amount equivalent to 1 to 5 percent (wlw) of a 40% active composition; b. in combination with one or more of hamemalis virginiana water 0.5 to 10 percent (wlw); c. nicotinamide 0.5 to 5 percent (wlw); d. avena sativa kernel extract in an amount equivalent to 0.5 to 5 percent (wlw) of a 100 ppm solution; and e. menthol 0.01 to 0.1 percent (wlw).

Where the disodium inodipropionate tocopheryl ate in the above composition is in a form comprising 40% (wlw) active ingredient, that form is 1, 2, 3, 4 or percent (wlw) of the composition. More preferably, the disodium Iauriminodipropionate tecopheryl phosphate in the above composition is in a form comprising 40% active ingredient and that form is 3 percent (wlw) of the composition. Where the disodium Iauriminodipropionate tocopheryl phosphate is not in a form comprising 40% active, the active is preferably 1.2% (wlw) of the above composition.

The. avena sativa _kemel extract may be a 100 ppm solution. When in a 100 ppm on it is preferred that solution is 0.5 to 5 percent (wlw) of the composition and most preferred that the on is 1 percent (wlw) of the composition. Where the avena sativa ‘ kernel extract is in r form it is red that the active inthe extract is in an amount lent to the amounts stated above.

In one embodiment, the disOdium Iauriminodipropionate tocopheryl phosphate is in embocombifin with both the avena sativa kernel extract and the menthol. In an alternativent, the disodium, Iauriminodipropionate tocopheryl ate is in combination with both the avena sativa kernel extract and the nicotinamide. In an [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by l [Annotation] l Unmarked set by tarranl alternative embodiment, the disodium inodipropionate tocopheryl phosphate is in combination with both the avena sativa kernel extract and the hamemalis virginiana water. In a preferred embodiment, the disodium lauriminodipropionate tocopheryl phosphate is in combination with the avena sativa kernel extract, the menthol and the hamemalis virginiana water.

. In a preferred embodiment, the hamemalis virginiana water is in combination with all of the four ients listed in the paragraph directly above. In this embodiment, the - proportions are desirably: disodium lauriminodipropionate tocopheryl ates 3.00 percent (w/w) in the form of a 40% active composition; 'hamemalis virginiana water 3 t (w/w); avena sativa kernel extract in a 100 ppm on 1 percent (w/w); nicotinamide 1 percent (w/w); and menthol 0.03 percent (WM). '15 Alternatively. the proportions are desirably: um Iauriminodipropidnate tocopheryl phosphates 1.2 percent (wlw); hamemalis virginiana water 3 percent (w/w); avena sativa kernel extract in an amount equivalent to 1 percent (w/w) of a 100 ppm solution; ‘20 nicotinamide 1 percent (w/w); and menthol 0.031 percent (w/w).

In a prfired embodiment, the'composition consists essentially of: a. um lauriminodipropionate tocopheryl phosphates ‘1 .2 percent (w/w); [Annotation] tarranl None set by tarranl [Annotation] tarranl ionNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] l None set by tarranl ation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl b. hamemalis virginiana water 3 percent (w/w); c. avena sativa kernel extract in an amount equivalent to 1 percent (w/w) of a 100 ppm solution; d. nicotinamide 1 percent (w/w); e. menthol 0.03 percent (w/w); 'f. one or more humectants, emollients, ners, emulsifiers, preservatives, surfactants, pH adjusters, pearling, colouring or sent ; and g. waterq.s.. 1o In a further, aspect, the t invention provides the use of a physiologically effective amount of a composition comprising disodium lauriminodipropionate tocopheryl phOSphates in the preparation of a ment for increasing collagen in the skin of a subject. It is preferred, that the medicament is also for the topical treatment or prevention of thedevelopment or recurrence of erythema.

. In a further aspect. the present invention provides a composition comprising a physiologically ‘ effective amount of a , composition comprising disodium lauriminodipropionate tocopheryl phosphates when used to increase collagen in the skin .of’a subject. It is preferred, that the compositionxis also used in the topical treatment or prevention of the development or recurrence of erythema.

In a further aspect, the present invention provides the use of a composition comprising a' physiologically effective ' amount of a composition comprising disodium lauriminodipropionate tocopheryl phosphates for increasing collagen in the skin of a t. It is preferred, that the use is also for the l treatment or tion of the development or recurrence of erythema.

The ified composition may be presented in a container with a pump dispenser.

The amount sed from the pump can vary but is about 200 milligrams with a fixed % of active as described abOVe. One pump may supply a physiciogically effective amourm about 2.5 mg disodium lauriminodipropionate eryl phosphates for appli to the face. However, multiplepumps from the dispenser may also be [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl applied, for~ example, 2, 5 or 10 pumps to provide a physiologically effective dose to a greater area of skin or to increase the amount of product used on the same area of skin.

.Without wishing to be bound by theory or mode of action, it is-considered that the increase in the collagen in the skin in combination with the anti-inflammatory effect caused by-to’pical administration of the compositions of the ion causes the treatment or tion of the pment or recurrence of erythema.

Detailed description of the embodiments It will be understood that various terms employed in the specification, examples and claims have meanings that will be understood by one of ordinary skill in the art.

However, n terms are defined below.

As used , except where the context requires othewvise, the term "comprise" and variations of the term, such as "comprising are» not , comprises" and "comprised", intended to exclude further additives, components, integers or steps.

The term “composition" as used hout the specification is understood‘to mean a '15 Composition comprising a therapeutically effective amount‘of at least one therapeutic agent and at least one pharrnaceutically acceptable r, excipient,'diluent. additive or e consiStent with the intended form of topical administration and consistent with I if conventional pharmaceutical practices.

The term “disodium lauriminodipropionate eryl ates” as used throughout the specification is understood to mean a blend of tocopherol phosphates with disodium lauriminodipropionate having the International Nomenclature of Cosmetic Ingredients (INCI) name “disodium lauriminodipropionate tocopheryl phosphates”.

The term “hamemalis iniana water’" as used throughout the specification is understood to mean a witch hazel distillate, in particular, the witch hazel distillate having the lntemational Nomenclature of Cosmetic Ingredients (INCI) name Hamemalis Virginia (Witch Hazel) Water; ation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by l [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl The term “therapeutic agent” or simply “agent” or “active" as used hout the specification are understood to mean any substance that is intended for the diagnosis, cure, mitigation, ent, tion or modification of a state in a biological system.

The term “physiologically effective” as used throughout the specification relates to the amount or dose of an active agent or a ition thereof that will lead to the deSired physiological effect, in particular, the ion or treatment of ma, prevention of the development or recurrence of erythema or increase in en production in the skin. A physiologically effective amount will vary according to factors such as the, severity of the condition, age, gender, and skin type of a subject, and the y of the '10 substance to elicit a desired response in the subject.

The term “Cetereth-ZO" as used throughout the specification s to a polyethylene glycol ether of cetyl alcohol. Its synonyms include Ceteareth-20, Cetomacrogol 1000; PEG-20 cetyl ether; PEG-20 hexadecyl ether; polyethylene glycol 1000 cetyl ether; polyoxyethylene (20) cetyl ether.

The term “panthenol” as used throughout the specification es “dexpanthenol”.

The term “prevention” as used’throughout the specification means to inhibit, minimise, defer or delay the onset of a condition.

The composition according to the present invention comprises a physiologically ive amount of disodium Iauriminodipropionate tocopheryl ates. In * embodiment, the compositions according to the present invention comprise disodium lauriminodipropiOnate tocopheryl phosphates (40% active) in an amount of about 0.5 to percent (MW). in' a preferred embodiment, the compositions according to the present invention comprise um lauriminodipropionate tocopheryl phosphates (40% active) in an amount of about 1 to 5 percent (w/w) or comprise disodium Iauriminodipropionate tocopheryl phosphates active in an amount of about 0.5 to 2 percent (w/w). in a particularly preferred embodiment, the composition comprises about 3 percent (w/w) disodiqlauriminodiprOpionate tocopheryl phosphates (40% active) or 1.2 percent (wlw) acrve disodium Iauriminodipropionate.tocopheryl phosphates .

[Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl ed set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl The composition of the invention can be a cream, lotion or gel. In a red ment, the composition according to the present invention fUrther comprises at least one emulsifier. Emulsifiers suitable for use in pharmaceutical compositions are well known "to those of ordinary skill in the art and include, for example, polyoxyethylene tive of sorbitan monolaurate such as polysorbate 20, fatty alcohols such as cetearyl alcohol, ceteareth compounds, and emulsifying waxes. A preferred emulsifier is ceteareth-20, which is commercially available from Croda under the brand name Cetomacrogol 1000.

The amount of emulsifier added to the composition maybe y determined by one of ordinary skill in the art With a minimum of experimentation, and 'will depend upon factors known to those skilled in the art, such as the ties of the emulsifier and the desired properties of the ceutical composition.

According to one ment of the present invention, the composition may include at 4 least one additional “skin active agent". Skin active agents may afford an improvement 715 in the appearance. tone or texture of the skin, and may include, but are not limited to, sunscreens, anti-wrinkling or anti-aging agents, antioxidants, vitamins, depigmentating 'or skin lightening agents, rizing agents, emollients, metal ors, retinoids and retinoid derivatives, agents intended'to reduce skin irritation. and alpha-hydroxy acids.

It will be recognised that the inclusion of skin active agents in the composition according to the present invention will depend upon their physical, chemical and therapeutic compatibility with the other components of the composition. in one embodiment, the composition according to the present invention r comprises an effective amount of at least one sunscreen. Examples of sunscreens include, but are not d to, octyl methoxycinnamate, oxybenzone and butyl 'methoxydibenzoylmethane. Some such eens may- retain a more greasy feel but the composition still provides a suitable delivery vehicle for a therapeutic, such as mometasone furoate. In another embodiment the sunscreen is phenylbenzimidazol sulfoninid or disodium phenyl imidazole ulfonate or similar.

[Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by l [Annotation] tarranl Unmarked set by tarranl [Annotation] l None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl In one ment, the composition according to the present invention may include at least one additional rinkling or anti-aging agent. Examples of anti~wrinkling or anti- aging agents include, but are not limited to, retinoids (for example, retinoic acid, retinol, retinal, retinyl e, and retinyl palmitate), alpha hydroxy acids,\galactose' sugars (for example, melibiose and lactose), lipoic acid and dihydrolipoic acid, lactoferrin, ascorbic ‘acid, and ascorbic acid derivatives '(for example ascorbyl palmitate and ascorbyl polypeptide).

In another embodiment, the compositionaccording to'the present invention may include at least one antioxidant or a natural extract that contains antioxidants. idants may '10 be water or oil-soluble. Oil soluble antioxidants suitable for use in the composition of this invention include, but areynot limited to, tocopherols and tocopherol derivatives (for e, eryl acetate, alpha-tocopherol), tocotrienols and ubiquinone. Natural extracts containing idants suitable for use in the composition of this invention, include, but are not d to, extracts containing flavonoids, phenolic compounds, ,15 flavones, nes, isoflavonoids, mono-, di- and tri-terpenes, sterols and their derivatives. Examples of such natural extracts include grape seed, green tea, pine bark extracts and legume ts. idants may also ze skin irritation.

In another embodiment, the composition according to the present invention may include at least one agent intended to inhibit or minimise potential skin irritation, such as an emollient (e.g., liquid paraffin), a vitamin, an antioxidant (e.g., vitamin E) and a herbal extract (e.g. ”aloe vera or avena sativa kernel extract). Avena sativa kernel extract is a preferred [anti-irritant.

In another aspect according to the t invention, the composition comprises at least one other ent intended to improve the appearance, stability or consumer appeal of the composition; Such components include, but are not limited to: fragrances, emollients, preservatives, vitamins and vitamin derivatives, antioxidants, colours, humectants, plant extracts, surface active agents, and other ingredients to r soothe and protect the skin. ation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl Again, it will be recognised that the inclusion of other components intended to improve the appeal or stability of the composition according to the present invention will depend upon their physical, chemical and therapeutic compatibility with the other components of the composition. I According to the present invention the term ‘stability’ refers to a composition that does not present any significant macroscopic change of appearance or microsCopic change of appearance-(e9, precipitation of an ingredient) over time.

In one ment, the composition according to the t invention comprises at least one humectant. Examples of humectants include, but are not d to: glycerin, glycerol, sodium PCA, panthenol/dexpanthenol, sorbitol, propylene glycol, 1,3—butylene , polypropylene glycol, l, maititol, lactitoi, oat protein, oin, acetamine MEA and hylauronicacid.

In another embodiment, the composition according to the present invention may se at least one preservative. Examples of preservatives which may be used in the composition of this invention include, but are not limited to, sodium salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium te, sodium methyl hydroxybenzoate, sodium propyl ybenzoate, methyl para-hydroxybenzoate (i.e., methyl paraben), ethyl para-hydroxybenzoate, propyl para~hydroxybenzoate (i.e., propyl ,paraben) and butyl para-hydroxybenzoate. ' in another embodiment, the composition according to the present invention may comprise one or more ents. Parafflnum liquidum (liquid paraffin), etrasiloxane and cylclopentasiloxane (Dow, Cylcomethicone 345) are suitable emollients.

In another embodiment, the composition according to the present invention may comprise one or more thickeners. Xantham gum and aristoflex AVC ium acryloyldimethyI-taurateNP copolymer) are suitable thickeners. _ln anoB embodiment, the composition according to the present invention may - comprise one or more body builders such as cetearyl alcohol.

[Annotation] tarranl None set by l [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl ionNone set by tarranl [Annotation] tarranl Unmarked set by tarranl In another embodiment, the composition according to the present invention may comprise one .or more zing agents such as synthetic fluorophlogopite (and) titanium dioxide (and) tin oxide (Timiron Synwhite 40). in another embodiment, the composition according to the present invention may comprise one or more bulk agents such as water.

The formulations of the present invention are manufactured in a conventional manner by thoroughly mixing the ingredients at ambient or ed temperatures.

, Any ceutically acceptable acid may be employed to adjust the pH of the pharmaceutical composition of the present invention to a pH suitable for a topical 1O composition. The identity of such acids are known to those of ordinary skill in the art, and include, but are not limited to those described in the lntemational Cosmetic Ingredient Dictionary and ok 12m Edition, 2008, Volume'3, pp 3221-3222, Preferred acids are lactic acid, citric acid, hydrochloric acid and ic acid. A particularly preferred acid is citricvacid. .15 The examples that follow are intended to illustrate but in no way limit the present invention; Example 1 — ation of the composition A composition suitable for use in the methods of the present ion can be prepared- as follows: [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl ed set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl ,—0.10 Sodium PCA Cyclotetrasiloxane and cyclopentasiloxane Avena sativa kernel extract. 1.00 (100ppm solution) - . iis virginiana water Part F: Thickener Ammonium acryloyldimethyl- eNP copolymer —3-50 , Synthetic fluorophlogopite (and) titanium dioxide (and) tin oxide Disodium Iauriminodipropionate 3;00 tocopheryl phosphate (40% active) ' Methofi formulationi - [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl ation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl ation] tarranl Unmarked set by tarranl .1. Heat Part A water & citric acid to HBO-65°C 2. At 65 00 add Part-c and mix until dissolved 3. Add Part D with propeller mixing. Homogenise for 1 minute. 4. Cool batch to 50 °C with propeller mixing.- . Combine Part A Glycerin and-Dexpanthenol and add to batch 6. Add Part E & B with propeller . Homogenise for ‘30 seconds 7. Combine Part F Glycerin, Xanthan gum and. Synthetic fluorophlogopite (and) titanium - dioxide (and) tin oxide 8. Add ammonium'acryloyldimethyI—taurateNP copolymer then the rest of ‘Part F to the ‘10 Batch with propeller mixing 9. Cool batch to 45°C with propeller mixing.

. Add Part G with ler mixing 11. Homogenise for 2 minutes. .15 Example 2 - increase of collagen l and III in the skin Experimental protocol: 1. Human in ast (HFF) cells were seeded in a 96 well plate. 100p| of cells at 5X105 cells/ml was added per well in Dulbecco’s d eagle medium (DMEM) + % fetal calf serum (FCS) + penicillin omycin (penstrep). 2. .The cells were incubated at 37°C in 5% C02 overnight 3. After 24 hrs the cells were transferred serum free media‘(SFM) for 6 hrs 4. The cell replated with SFM plus in 200;” of the composition formulated in Example 1.

SFM alone was used as a control.

. The cells were left at confluence for 60 hrs to allow collagen to build up '6. Thulls were washed 3x with 100pl per well of phosphate buffered saline (PBS) 7. The cells were fixed and permeabilised in. ice cold MeOH (—20°C) [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl ation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl ation] tarranl Unmarked set by tarranl 8. The fixed cells were transferred to the r for 15 minutes 9. The fixed cells were aspirated and air dried briefly then washed 3x with 100pl per well of PBS and treated with Tween 20 (0.5%) in PBS for 10 minutes.

. The cells were blocked in 50pl per well PBS Tween + 3% normal goat serum (N68) and incubated in '50pl per well. primary antibody in PBS + 3% NGS. For the collagen l experiment the primary antibody was 1:200 Collagen l rabbit polyclonal antibody (Rockland - Cat# 600—401-103.05). For thecollagen III experiment the primary antibody was 1:200 Collagen Ill rabbit polyclonal antibody (Rockland - Cat# BOO—401405.05). 11. The cells were stored at room ature for 2 hours then washed 3x in 100pl per Well PBSand incubated in mm per well Alexa conjugated secondary antibody in PBS.

The antibody used was 1:200 Alexa 488 goat anti-rabbit 'lgG (lnvitrogen - Cat# A 11008). 12. The cells were stored at room ature for 1 hour then washed 3x in 100pl per well PBS and .100pl PBS was added to each well.

Analysis: Analysis was ted on an Olympus IX81 fluorescence microscope, with Olympus DP80 digital camera and CooILED light source. In both instances there was a 1.493 '20 second exposure and a 4x gain using the camera set to 0.6MP and with the light path split between the ocular and camera. Images were captured and ed using cellSens Dimension software us). Measurements are mean grey scale values of 14 bit images.

[Annotation] tarranl None set by tarranl [Annotation] tarranl ionNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl Table 1 - Collagen I —w_l-Cellstreated with exam . le 1 IEEIIIIIIIIIIIIIIIIIIIflfiflllllllliflZEIIIIIIIIIIIIIlifliilllllllllllllll E_——_ IZEJBIIIIIIIIIIIIIIIIIIIII3§§IIIIIIlEBEEIIIIIIIIIIIIIIflliiallllllllllllllllll IEEZIIIIIIIIIIIIIIIIIIlflilllllllIiIIEIIIIIIIIIIIIIIIEHEIIIIIIIIIIIIIIIII IJZEIIIIIIIIIIIIIIIIIIIliiflllllllIiflalllllllllllllllliiflllllllllllllllll IZEEIIIIIIIIIIIIIIIIIIIIZIIIIIIIIliEElIIIIIIIIIIIIIIIEEEIIIIIIIIIIIIIIIII lIHIiIIIIIIIIIIIIIIIIIIIIIEIBIIIIIIIliilllllllllllllllllilBlIIIIIIIIIIIIIIII 008 _—— . lNfliflIIMiIIIIIIIIIIIIIIHIIHIBEEIIIIiZBilIIIIIIIIIIIIIIIBEZIIIIIIIIIIIIIIIII ———— [SEMIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIZIIIIIIIIIIIIIIIIIEIIIIIIIIIIIIIIIIII —_——1 Mean OD percentage of- 100% ‘ SFM Mean OD , The results from Table‘ 1 are graphed in Figure 1. The graph shows a significant difference in the collagen I levels in cells treated with serum free medium ed with cells treated with the composition of example 1. The fluorescence for the cells treated with serum free medium was about 6,300, while the fluorescence for the cells treated ' with the composition of example 1was about 7,300. This ents a 15% increase in collagen l. 10A Table 2 — Collagen lll Cells treated with composition of exam . le 1 [Annotation] tarranl None set by tarranl [Annotation] tarranl ionNone set by tarranl [Annotation] tarranl Unmarked set by tarranl ation] tarranl None set by l [Annotation] tarranl MigrationNone set by tarranl [Annotation] l Unmarked set by tarranl , 2.0 Cells treated with composition of exam - le 1 797' 8122 ' - 10265 739125 7 7499.0 10275.8 e , Mean loo — blank 6759.9 9536.6 Est-I— 163.8 ' P Value v control 1.47E-08 ’ Mean OD 100% 141% ” percentage of SFM ‘ Mean OD , The results from Table 2 are graphed in Figure 2. The graph shows a significant difference in the collagen Ill levels in cells treated with serum free medium compared with cells treated with the composition of example 1’: The fluorescence for the cells treated with serum free ] was about 6,800. while the fluorescence for the cells treated with the composition of example 1 was about 9,500. This represents a 41% increase in collagen lll.

' Example 3 — reduction in erythema Experimental protocol: 1. The baseline assessment for each test participant was determined a day befOre exposure to the Solar tor at time = -1. 2. A Solar Simulator was used to induce mild erythema on 7 designated areas of the back of test subjects at time = 0. l ‘ 3. The composition of example 1 or a control of 1% hydrocortisone cream was topically applied to the irradiated skin immediately after irradiation and again 4-5 hours later. The {Composition or positive control was rubbed in Well upon each ation. There was also a negative control involving irradiation and assessment without topical application. 4. Test subjects returned for assessment at 24 hours (i=1), 2 days (i=2), 4 days (t=3) and 7 «fl (t=4).

[Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl ation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl ed set by l . ment involved visual assessment and scoring of the erythema. In addition, colorometric measurements were taken using a Minolta Spectrophotometer Model CM, 2600 and the L*a*t)* colour space values recorded. The L Value measures skin lightening, the a*b* values indicate change in tone against the background skin tone. _ Total colour change (AE) = \/(AL2 + Aa2 + Abz). Assessments at T=1 are compared with . , =2, T=3 and T=4 to quantify the improvement in colour over time. 6. Visual assessment g was madeaccording to the Standard Scalar Ratings: 0 = no erythema present 1 = minimal faint (light pink), uniform or spotty erythema 2 = mild erythema, pink uniform erythema covering most of contact site 3 = moderate erythema, pink/red erythema visibly. uniform in entire contact area » '4 = marked bright red erythema = severe deep red ma Results: '15 Table 5 - AE U-V only, negative control Positive control Composition of exam . le 1 Table 6 - magenta to blue shift (a* at the nt time point minus the initial a* D value) [Annotation] tarranl None set by l ation] tarranl ionNone set by tarranl [Annotation] tarranl Unmarked set by l [Annotation] tarranl None set by tarranl [Annotation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl _T=2 — T=1 T=3 — T=1 ‘ 1:4 ._ 1:1 control Positive control I1 - exam - lo 1 'Table 7 - Visual assessment scoring reduction0 UV only, 3.8 1.6 76.30 . negafive control ' ‘-----ucontrol Inn-nu-ofexam- le 1 ltwill be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text. All of these different combinations constitute various alternative aspects of the invention.

Claims (24)

1. Use of a physiologically effective amount of a composition comprising disodium lauriminodipropionate tocopheryl phosphate, avena sativa kernel extract, nicotinamide, hamemalis virginiana water, and menthol in the preparation of a medicament formulated for the topical treatment, tion or tion of recurrence of ma caused by external irritation of the skin of a subject, wherein the al irritation of the skin is selected from over exposure to the sun and contact with an irritating substance.

2. The use of claim 1, n the irritating nce is a plant or a metal.

3. The use according to claim 1 or claim 2, wherein the use reduces the Standard Scalar Rating for the erythema by either (i) 77% or more; or (ii) 3.0 or more after 7 days.

4. The use according to any one of claims 1-3, wherein the use results in (i) a magenta to blue shift (a*) of -2.5 or a greater negative; and/or (ii) a ΔE of 3.5 or more by 48 hours after use as ed by a Minolta Spectrometer; or the method results in (i) a magenta to blue shift of -4 or a greater negative and/or (ii) a ΔE of 5 or more by 7 days after use as measured by a Minolta Spectrometer.

5. The use according to any one of claims 1-4, wherein the medicament is for the maintenance of skin health.

6. The use according to any one of claims 1-5, wherein the medicament also increases the collagen in the skin of the subject.

7. The use according to claim 6, wherein the increased collagen comprises increased production of collagen in fibroblasts in the skin. 1003244951

8. The use according to claim 6 or claim 7, wherein the use increases production of collagen III by about 10% or more and/or increases production of collagen I by about 5% or more.

9. The use according to claim 8, wherein the use increases production of collagen III by about 40% and/or increases production of collagen I by about 15%.

10. The use according to any one of claims 1-9, wherein the composition is a cream, lotion or gel.

11. The use ing to any one of claims 1-10, wherein the ition further es the vitamin panthenol or dexpanthenol.

12. The use according to any one of claims 1-11, n the composition is an emulsion.

13. The use of any one of claims 1-12, wherein the composition further includes one or more emulsifiers, ents, thickeners, ants, preservatives, body builders, bulking agents, pH adjusters, and/or feel modifiers.

14. The use according to claim 13, wherein the composition further comprises at least one emulsifier selected from the group ting of polyoxyethylene derivative of sorbitan monolaurate such as polysorbate 20, fatty alcohols such as cetearyl alcohol, ceteareth compounds, and emulsifying waxes.

15. The use according to claim 14, wherein the emulsifier is ceteareth-20.

16. The use according to any one of claims 1-15, wherein the disodium lauriminodipropionate tocopheryl phosphate is in a form comprising 40% active ingredient and that form is 3 % (w/w) of the composition.

17. The use according to any one of claims 1-16, wherein the disodium lauriminodipropionate tocopheryl ate active is 1.2% (w/w) of the composition. 1003244951

18. The use according to any one of claims 1-17, wherein the ition comprises: a. hamemalis virginiana water 0.5 to 10 % (w/w); b. disodium lauriminodipropionate tocopheryl phosphate in an amount equivalent to 1 to 5 % (w/w) of a 40% active composition; c. nicotinamide 0.5 to 5 % (w/w); d. avena sativa kernel extract in an amount equivalent to 0.5 to 5 % (w/w) of a 100 ppm solution; and e. l 0.01 to 0.1 % (w/w).

19. The use according to claim 18, wherein the composition comprises: a. disodium lauriminodipropionate tocopheryl phosphates 1.2 % (w/w); b. hamemalis iana water 3 % (w/w); c. avena sativa kernel extract in an amount equivalent to 1 % (w/w) of a 100 ppm solution; d. nicotinamide 1 % (w/w); and e. menthol 0.03 % (w/w).

20. The use according to claim 19, wherein the composition consists ially a. disodium lauriminodipropionate tocopheryl phosphates in an amount equivalent to 1.2 percent (w/w); b. hamemalis virginiana water 3 percent (w/w); c. avena sativa kernel extract in an amount equivalent to 1 percent (w/w) of a 100 ppm solution; d. namide 1 percent (w/w); e. menthol 0.03 percent (w/w); f. one or more humectants, emollients, thickeners, emulsifiers, preservatives; surfactants, pH ers and pearling, colouring or scent agents; and g. water q.s. 1003244951

21. The use according to any one of claims 1-20, wherein the physiologically effective amount is about 2.5mg disodium lauriminodipropionate tocopheryl phosphate applied to the face.

22. The use according to any one of claims 1-21, wherein the composition is in a container with a pump dispenser.

23. The use according to claim 22, wherein the pump dispenses about 200 milligrams.

24. The use according to claim 22 or claim 23, n one pump supplies about 2.5 mg disodium lauriminodipropionate eryl phosphates. 1003244951 [Annotation] tarranl None set by tarranl [Annotation] l MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl [Annotation] tarranl None set by tarranl ation] tarranl MigrationNone set by tarranl [Annotation] tarranl Unmarked set by tarranl