Semisolid composition for sensitive skin

Abstract

Disclosed is a semisolid composition suitable for topical administration to the skin of a subject, in particular a human subject having a sensitive skin. The composition is in the form of an o / w-type emulsion. It comprises a combination of beneficial agents, in particular a linear diarylheptanoid such as a curcuminoid, a beta-glucan, honey ferment, and / or a triglyceride oil having a high oleoyl content. The composition is further characterised in that its dispersed lipid phase represents a substantial weight fraction of the composition, and in that it exhibits a low emulsifier content.

Description

[0001] LSK24P01PC1

[0002] SEMISOLID COMPOSITION FOR SENSITIVE SKIN

[0003] Description

[0004] BACKGROUND

[0005] Sensitive skin is characterized by heightened reactions to environmental factors and topical products, often leading to discomfort, redness, and irritation. Advancements in skincare have led to the development of skin care products specifically formulated to address the needs of sensitive skin. Ingredients like ceramides have been proposed for restoring and maintaining the skin's natural barrier, preventing moisture loss and protecting against irritants.

[0006] Emollients such as shea butter are believed to attract and retain moisture, ensuring skin remains hydrated and supple. These ingredients are commonly found in moisturisers recommended for sensitive skin. Moreover, soothing agents such as colloidal oatmeal and aloe vera are believed to help reduce inflammation and soothe the irritated skin, providing relief from discomfort.

[0007] In spite of these efforts and achievements, there remains a need for further improvements in skin care for those subjects who have a sensitive skin.

[0008] SUMMARY OF THE INVENTION

[0009] Disclosed is a semisolid composition for topical administration to the skin of a subject which comprises at least two beneficial agents selected from a linear diarylheptanoid, a betaglucan, and / or a honey ferment. The composition is further characterised in that it is in the form of an o / w-type emulsion. As such, it comprises a dispersed lipophilic phase. The amount of the lipophilic phase is at least about 15 wt% relative to the total weight of the composition. Moreover, the composition is further characterised in that it comprises not more than about 3 wt.% of non-ionic emulsifiers.

[0010] In some preferred embodiments, the composition comprises at least one of each of said beneficial agents, i.e. at least one linear diarylheptanoid, at least one beta-glucan, and at least one honey ferment. In further preferred embodiments, the composition further comprises a triglyceride oil with a content of at least about 50 mol% of oleic acid residues.The subject is preferably a human subject, such as a human having a sensitive skin. Examples of human subjects having a sensitive skin may include, for example, human patients suffering from an atopic skin disease or condition, such as atopic dermatitis or atopic eczema.

[0011] A further aspect of the disclosure is a method for preparing a semisolid composition as described herein. The method comprises at least the following steps: (a) providing an aqueous phase comprising water, the beta-glucan, the honey ferment, and, if present, the water-soluble polymer or the combination of water-soluble polymers; (b) providing a lipophilic phase comprising the triglyceride oil and the linear diaiylheptanoid; (c) combining the aqueous phase and the lipophilic phase at a temperature in the range of 60°C to 95°C such as to form an emulsion; and (d) homogenising the emulsion under vacuum.

[0012] DETAILED DESCRIPTION OF THE INVENTION

[0013] In a first aspect, the present invention provides a semisolid composition for topical administration to the skin of a subject. The composition comprises at least two beneficial agents selected from a linear diaiylheptanoid, a beta-glucan, and / or a honey ferment. The composition is further characterised in that it is in the form of an o / w-type emulsion. It comprises a dispersed lipophilic phase, the amount of which is at least about 15 wt.% relative to the total weight of the composition. Moreover, the composition is further characterised in that it comprises not more than about 3 wt% of non-ionic emulsifiers, again based on the total weight of the semisolid composition.

[0014] As used herein, a semisolid composition is a composition showing the rheological properties which resemble, in part, the rheological behaviour of a viscous fluid and, also in part, that of an elastic solid. Macroscopically, a gel behaves like a solid upon the exertion of low shear force, and like a viscous fluid when the shear force exceeds a threshold which is defined as the yield point. Examples of semisolid materials include ointments, creams and viscoelastic hydrogels. According to the invention, the semisolid composition is in the form of an emulsion, and specifically in the form of an o / w-type emulsion. In this context, an emulsion is a system comprising at least two liquid or semisolid phases wherein one phase is finely dispersed in the other phase, the latter often being referred to as the continuous phase or coherent phase. In the fields of pharmaceuticals and cosmetic products, semisolid emulsion systems are typically referred to as creams. An o / w-type emulsion, such as an o / w-type cream, is a composition comprising a dispersed lipophilic or "oil" phase and a continuous hydrophilic or "water" phase. The dispersed phase exists in the form of small, homogeneously distributed liquid or semisolid droplets or particles. For the avoidance ofdoubt, an emulsion system does not exclude the present of a third or further phase which may be liquid or semisolid, such as in type w / o / w- or type o / w / o- emulsions or creams, or in the case of emulsions which further comprise dispersed solid particles. In other words, the dispersed phase may itself represent a liquid or semisolid suspension.

[0015] According to the present disclosure, the dispersed lipophilic phase of the composition amounts to at least about 15 wt.%, wherein the basis of the percentage is the total weight of the composition. In this context, the dispersed lipophilic phase should be understood as comprising all constituents of the composition which are dissolved or dispersed in the dispersed phase, and essentially excludes constituents that form the continuous hydrophilic phase. In this context, a constituent means any compound or material present in the composition, regardless of the function, i.e. including, without limitation, any beneficial agents, liquid carriers or solvents, or any excipients. In some further preferred embodiments, the amount of the dispersed lipophilic phase is at least about 20 wt.%, or in the range of about 20 wt.% to about 60 wt.%, or in the range of about 20 wt.% to about 50 wt%, such as about 20±5 wt.%, 25±5 wt.%, 30±5 wt.%, 35±5 wt.%, 40±5 wt.%, 45 wt.%, or 50±5 wt.%, respectively.

[0016] As mentioned, the composition comprises at least two beneficial agents. As used herein, a beneficial agent is a pharmaceutically or cosmetically active compound or material. A pharmaceutically active compound or material may also be referred to as active agent, therapeutic agent, active pharmaceutical ingredient (API), active principle, drug, bioactive agent, or the like, and describes a compound or material which is considered useful therapeutic purpose when administered to a subject. The therapeutic purpose may relate to the symptomatic or causative treatment of a disease, condition or symptom, as well as to the prevention, delay or reducing the risk of reoccurrence of a disease, condition or symptom. A cosmetically active compound or material is similar to a pharmaceutically active compound or material in that it may also have a biological effect for which it is considered useful for a therapeutic purpose. In addition, a cosmetically active compound or material may also have a desirable effect in terms of improving a desirable property, in particular relating to the appearance of a subject's body. It is noted that in many jurisdictions there is a regulatory difference between pharmaceutically active compounds or materials and cosmetically active compounds or materials. A precise distinction between the two regulatory categories based on technical or scientific facts may not always be possible, as evidenced by the fact that some active agents are regulated as cosmetic agents in some jurisdictions and as pharmaceutically active agents in other countries.As stated above, the semisolid composition comprises at least two beneficial agents selected from a linear diarylheptanoid, a beta-glucan, and / or a honey ferment. Diarylheptanoids, also referred to as diphenylheptanoids, are secondary plant metabolites. The molecules comprise two aryl groups (i.e. aromatic rings) linked together by a heptane chain. Exemplary linear diphenylheptanoids are curcuminoids, i.e. linear diphenylheptanoids found in turmeric (curcuma longa), such as curcumin, demethoxycurcumin, bisdemethoxycurcumin, and chemically modified versions thereof, such as tetrahydrodiferuloylmethane, also known as tetrahydrocurcumin, which have antioxidant activity. In some preferred embodiments, the linear diarylheptanoid is a curcuminoid. In further preferred embodiments, the linear diarylheptanoid is tetrahydrodiferuloylmethane. The amount or concentration of linear diarylheptanoid in the composition may, for example, be in the range of about 0.1 mg / g to about 10 mg / g, or preferably in the range of about 0.1 mg / g to about 1 mg / g, such as about 0.5 mg / g.

[0017] Beta-glucans, p-glucans, or as used herein, are polysaccharides based on p-D-glucose, and their chemically modified derivatives. Typically, p-glucans form linear backbones with 1-3 p-glycosidic bonds. In some embodiments, the p-glucan is selected from chemically modified p-glucans. In some further preferred embodiments, the p-glucan is carboxymethyl- p-glucan or a salt thereof, such as sodium carboxymethyl- p-glucan or magnesium carboxymethyl- p-glucan. The amount or concentration of the p-glucan in the composition may optionally, without limitation, be in the range of about 0.05 mg / g to about 10 mg / g, such as in the range of about 0.1 mg / g to about 0.5 mg / g, respectively.

[0018] In some embodiments, the composition comprises both a linear diarylheptanoid and a p-glucan; for example a curcuminoid such as tetrahydrodiferuloylmethane and a chemically modified p-glucan such as magnesium carboxymethyl-p-glucan. The weight ratio of tetrahydrodiferuloylmethane to magnesium carboxymethyl-p-glucan may, for example, be in the range from about 10 : 1 to about 1 : 10, or from about 5 : 1 to about 1 : 5, or even from about 2 : 1 to about 1 : 2, respectively.

[0019] Honey ferment, also referred to as fermented or partially fermented honey or honey ferment extract, is a product resulting from the biodegradation of honey as facilitated by microorganisms such as bacteria or yeasts. In some embodiments, the amount of honey ferment in the composition is from about 1 mg / g to about 100 mg / g, or from about 1 mg / g to about 50 mg / g, or from about 5 mg / g to about 30 mg / g, respectively. Also preferred are embodiments according to which the semisolid composition comprises, as beneficial agents,a curcuminoid such as tetrahydrodiferuloylmethane, in combination with a chemically modified p-glucan such as magnesium carboxymethyl-p-glucan, and a honey ferment.

[0020] As already mentioned, the semisolid composition is also characterised by a very low surfactant content. In particular, it contains not more than about 3 wt.% of non-ionic emulsifiers. In other words, even if the composition does comprise a non-ionic emulsifier or even a combination of two or more non-ionic emulsifiers, their total amount is not higher than about 3 wt.%, the percentage being based on the total weight of the composition. In further embodiment which are also preferred, the composition comprises not more than about 2.5 wt.% of non-ionic emulsifiers, or even not more than about 2 wt%, respectively.

[0021] Non-ionic emulsifiers are typically considered essential for stable creams, in particular creams having a substantial amount of dispersed lipid phase as preferred according to the present invention. As used herein, emulsifiers represent a subcategory of amphiphilic compounds referred to as surfactants. Their molecules comprise a hydrophilic portion and a lipophilic portion. Their key property is that they are able to stabilise emulsions. Non-ionic emulsifiers do not possess an ionic charge, in particular not at a relatively neutral pH, e.g. in the range from about pH 3 to about pH 10. Examples of non-ionic emulsifiers that are generally useful for stabilising semisolid emulsions include, for example, physiologically acceptable compounds from the groups of polysorbates, which are ethoxylated sorbitan esters with fatty acids, such as polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, or polysorbate 120; poloxamers, which are triblock copolymers comprising a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, such as poloxamer 407 or poloxamer 188; laureth-7, a polyethylene glycol ether of lauryl alcohol; alkyl polyglucoside; decyl glucoside; ceteareth-20; sorbitan oleate, also known as sorbitan monooleate; coco glucoside; PEG-40 hydrogenated castor oil; steareth-2; steareth-21; or cetyl alcohol.

[0022] In some specific embodiments, the composition is substantially free of particularly hydrophilic non-ionic emulsifiers, such as non-ionic emulsifiers characterised by an HLB value of about 18 or higher. Further preferred are embodiments in which the composition is substantially free of hydrophilic non-ionic emulsifiers having an HLB value of higher than 16, or higher than 14, 12, or 10, respectively. In a further embodiment, the composition is substantially free of hydrophilic non-ionic emulsifiers having an HLB value of about 8 or higher. The HLB value describes the hydrophilic-lipophilic balance of a surfactant, such as an emulsifier. According to the commonly used Griffin's method, the HLB value is expressed as20 times the molar mass of the hydrophilic molecule portion of the emulsifier divided by the total molar mass of the molecule, which results in a scale of 0 to 20. On this scale, an HLB value of 0 corresponds to an entirely lipophilic (or hydrophobic) molecule, whereas a value of 20 would correspond to an entirely hydrophilic (or lipophobic) emulsifier. Non-ionic emulsifiers that are normally considered as required or particularly useful for stabilising o / w-type emulsion systems such as creams typically have a high HLB value. The inventors have surprisingly found, however, that the beneficial agents specified herein can be incorporated into physically stable semisolid emulsion systems with substantial amounts of dispersed lipophilic phase, but with very small amounts of hydrophilic emulsifiers, or that are even substantially free of such compounds. In other embodiments, the composition is substantially free of polysorbates.

[0023] In some related embodiments, the composition comprises low amounts of a lipophilic nonionic emulsifier, such as a fatty alcohol having at least about 12 carbon atoms. For example, the composition may comprise from about 0.5 % to about 2 % of such compound by weight. In this context, and according to some some specific embodiments, the fatty alcohol is saturated. Also preferred are embodiments in which the fatty alcohol is a linear compound having at least 18 carbon atoms, such as, e.g., stearyl alcohol (1 -octadecanol), arachidyl alcohol (1-eicosanol), behenyl alcohol (1-docosanol), lignoceryl alcohol (1-tetracosanol), or combinations thereof. For example, the composition may comprise about 1 wt.% behenyl alcohol while being free of any more hydrophilic emulsifiers such as polysorbates.

[0024] A skilled person would understand that the functional terminology relating to such compounds is not always consistent; depending on the technical field and context, lipophilic non-ionic emulsifiers are also referred to as co-emulsifiers or emollients.

[0025] As used herein, the term "substantially free" means that the respective composition contains less than a functional amount of the optional ingredient, typically less than 1 % by weight, preferably less than 0.1 % or even 0.01 %, and also including zero percent by weight of the respective ingredient.

[0026] As mentioned, the composition for topical administration to the skin of a subject, which should be understood as meaning that the composition is technically, i.e. pharmaceutically or cosmetically, suitable for topical administration to the skin.

[0027] According to some of the preferred embodiments, the subject is a human subject Alternatively, the subject may also a non-human animal such as a pet or companion animal.The inventors have found that the composition disclosed herein is particularly suitable for sensitive skin, or for topical administration to the skin of a human subject having a sensitive skin. It was observed that the regular use of the composition over only a few days or weeks, human subjects affected by sensitive skin found that the status of the skin had improved significantly. In addition, the inventors found that the cream could support and care for the skin of patients undergoing radiation therapy, addressing the unique needs of compromised and sensitive skin. It is also highly effective for managing extremely dry and flaky skin, providing deep hydration and restoring the skin's natural moisture balance. Additionally, the cream soothes and calms irritated skin, helping to reduce redness and discomfort while promoting overall skin health and repair. Its gentle formulation makes it ideal for use on delicate or damaged skin, offering relief and protection in challenging conditions.

[0028] In this context, the expression "regular use" refers to a use over at least three consecutive days in which the composition is administered at least once a day. Particularly good results were observed after at least twice daily administration over a period of at least about 1 week. With respect to tolerability, the composition is also suitable for long-term use, such as twice or three time per day over periods of at least one month, three months, six months, or even more than one year.

[0029] Sensitive skin is a common condition affecting humans as well as non-human animals.

[0030] Patients suffering from an atopic skin disease or condition have a particularly sensitive skin. The expressions "atopic" and "atopy", as used herein, refer to an immunologic hypersensitivity that is mediated by an overproduction of immunoglobulin E in response to an exposure to a substantially non-toxic or harmless substance or material. Atopic skin reactions are part of the clinical manifestation of certain allergic diseases.

[0031] For example, patients suffering from atopic dermatitis, also referred to as atopic eczema, as well as dermatitis have been found to benefit considerably from the use of the composition disclosed herein. Symptoms of atopic dermatitis include redness, itching, swelling, blister formation, oozing or cracking of skin. Often, patients having atopic dermatitis cannot tolerate conventional skin care products, which may, for example, be associated with a hypersensitivity against certain components frequently used in such products.

[0032] Other skin diseases or conditions which may also be associated with sensitive skin include, without limitation, non-atopic forms of dermatitis such as contact dermatitis, stasis dermatitis and seborrhoeic dermatitis; non-atopic forms of eczema, scabies, psoriasis, lichen simplex, rosacea, urticaria, drug rashes, erythema multiforme, erythema nodosum, granuloma annulare, panniculitis, pyoderma gangrenosum, and Stevens-Johnson syndrome.Moreover, in some further preferred embodiments, the semisolid composition provided by the invention comprises a triglyceride oil as a further beneficial agent, in particular a triglyceride oil having a high content of oleic acid residues. More specifically, such preferred embodiments relate to compositions as otherwise described above, wherein at least the following beneficial agents are incorporated: a linear diarylheptanoid, a beta-glucan, a honey ferment, and a triglyceride oil having a content of at least about 50 mol% of oleic acid residues. In related embodiments, the linear diarylheptanoid is a curcuminoid such as tetrahydrodiferuloylmethane, the beta-glucan is a chemically modified beta-glucan such as carboxymethyl beta-glucan or the magnesium salt thereof.

[0033] As used herein, a content of at least about 50 mol% of oleic acid residues means that the respective triglyceride oil as a triglyceride composition in which at least half of the acyl groups (by number) attached to the glyceryl moieties represent oleoyl groups, also known as octadec-9-enoyl groups, (9Z)-octadecenoyl groups, or cis-9-octadecenoyl groups. Oleoyl groups are the acyl groups derived from oleic acid, also known as cis-9-octadecenoic acid, which is a monounsaturated fatty acid found in various native plant oils, but also in animal fats. High amounts of oleic acid residues, or oleoyl groups, are found in olive oil, canola oil, pecan oil, macadamia oil, and avocado oil, all of which often have a content of more than 50 mol% of oleic acid. There are also certain grades of sunflower oil that exhibit such high oleoyl content.

[0034] In some further embodiments, the triglyceride oil is olive oil, i.e. an oil extracted from the fruits of the olive tree, Olea europaea, in particular olive oil of high quality, such as virgin olive oil or extra virgin olive oil. In this context, olive oil produced by only mechanical means is called virgin oil, and extra virgin olive oil is virgin olive oil complying with certain chemical and organoleptic criteria.

[0035] The amount of the triglyceride oil in the composition may be selected taking into account the desired viscosity of the composition and the selection and amounts of other constituents. For example, and without limitation, the content of the triglyceride oil with high oleoyl content may be in the range of about 0.1 wt.% to about 10 wt.%, wherein 100 wt.% represent the total weight of the composition. In further preferred embodiments, the triglyceride oil is olive oil, and its content in the composition is in the range of about 0.5 wt.% to about 5 wt.%, or about 1 wt.% to about 3 wt.%, such as about 1 wt%, 2 wt.%, or 3 wt%, respectively. Also preferred are embodiments according to which the olive oil is the only triglyceride oil or, if another triglyceride oil is present, the predominant triglyceride oil in the composition. As used in this context, the predominant triglyceride oil means that the olive oil accounts for atleast about 50 wt.% of the total amount of triglyceride oils in the composition. In further embodiments, the olive oil accounts for at least about 75 wt% of the total amount of triglyceride oils in the composition.

[0036] The composition may comprise further constituents, for example one or more further beneficial agents or one or more excipients. In this context, excipients include any type of auxiliary agents, often also referred to as inactive ingredients, in particular compounds that are physiologically acceptable and typically used in pharmaceutical or cosmetic creams or emulsions.

[0037] Examples of potentially useful beneficial agents in view of the intended use of the composition on sensitive (e.g. atopic) skin include, without limitation, topical probiotics such as Streptococcus thermophilus, Vitreoscilla filiformis, Lactobacillus johnsonii, or Roseomonas mucosa; panthenol, also known as pantothenol, or nicotinamide, also known as niacinamide; ceramides to restore the skin's natural lipid barrier; allantoin for soothing and calming irritation; vitamin E as an antioxidant to combat oxidative stress; colloidal oatmeal to alleviate itching and provide a protective barrier; aloe vera extract for its moisturizing and anti-inflammatory properties; bisabolol for its skin-calming effects; and shea butter for its emollient and barrier-repairing properties. Additionally, omega-3 and omega-6 fatty acids, such as those found in evening primrose oil, borage oil, or linseed oil, may further enhance skin recovery and hydration.

[0038] Examples of potentially useful further ingredients which may - depending on the technical or regulatory perspective - be considered as beneficial agents or excipients, include, for example, moisturising agents, also known as humectants or skin conditioning agents, such as triethylene glycol, tripropylene glycol, propylene glycol, polypropylene glycols, glycerol, sorbitol, pentylene glycol, hexylene glycol, butylene glycol, urea, hyaluronic acid or salts thereof, or collagen. In some embodiments, the composition comprises at least one glycol, in particular selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, and combinations thereof. In some further embodiments, the composition comprises a combination of at least two of these glycols, and the total amount of glycols is in the range from about 1 wt.% to about 10 wt%. Also preferred are embodiments in which the composition comprises hyaluronic acid or a salts thereof, such as sodium hyaluronate, for example at an amount in the range of about 0.1 wt% to about 2 wt.%, or from about 0.1 wt% to about 1 wt%.

[0039] In this context, and as a skilled person will appreciate, it is noted that an ingredient may have more than one function in the composition. For example, hyaluronic acid or sodiumhyaluronate, if present, may function as moisturiser (or humectant or skin conditioning agents, respectively) and at the same time as thickening agent that also contributes to the physical stability of the emulsion system, for which it could be called a stabiliser, or an emulsion stabiliser.

[0040] Moreover, the composition may further comprise one or more buffering or pH-regulating agents, antioxidants, antistatic agents, colouring agents, perfumes, and / or abrasive agents, preferably in amounts as are typically used in topical pharmaceutical or cosmetic compositions.

[0041] In some further preferred embodiments, the composition comprises one or more thickeners, also known as viscosity enhancers, or thickening agents or viscosity enhancing agents. As mentioned above, it was found that the incorporation of hyaluronate is useful, and depending on the molecular mass of the selected grade of hyaluronate, this agent will not only have a moisturising effect, but also a viscosity-enhancing effect, which is particularly useful in the context of the invention as the composition has a low emulsifier content. In some embodiments, the composition comprises hyaluronic acid or a salt thereof, i.e. hyaluronate, and at least one further viscosity enhancer. Potentially useful viscosity enhancers include, without limitation, water-soluble polymers.

[0042] In an o / w-type emulsion system like the semisolid composition disclosed herein, the hydrophilic phase, also referred to as the water ("w") phase or aqueous phase, represents the continuous phase in which the inner phase is dispersed as evenly distributed, fine lipid droplets. Thickening the continuous hydrophilic phase be means of one or more water-soluble polymers will result in a physical stabilisation of the emulsion system. Potentially suitable water-soluble polymer include, in addition to hyaluronic acid or salts thereof, acrylic or methacrylic acid-based polymers, co-polymers and crosspolymers; polyvinyl alcohol; polyvinyl pyrrolidone; xanthan; hydrophilic cellulose ethers such as hydroxyethyl cellulose; or a combination of any of these. Accordingly, in some preferred embodiments, the semisolid composition comprises a continuous hydrophilic phase comprising a water-soluble polymer selected from acrylic or methacrylic acid-based polymers, co-polymers and crosspolymers, or salts thereof; hyaluronic acid or salts thereof; polyvinyl alcohol; polyvinyl pyrrolidone; xanthan; hydrophilic cellulose ethers such as hydroxyethyl cellulose; or a combination of any of these. Among the preferred combinations are combinations of a hyaluronic acid salt and at least one acrylic acid-based polymer, co-polymer or crosspolymer, or salt thereof, such as sodium acrylate, acrylates / vinyl isodecanoate crosspolymer, and / or sodium acryloyl dim ethyl taur ate copolymer. The total amount of water-soluble polymers in the continuoushydrophilic phase may, for example, be in the range of about 0.1 wt.% to about 5 wt.%, such as about 0.2 wt% to about 3 wt%, or about 0.3 wt.% to about 2 wt.%, respectively, wherein the percentage is based on the total weight of the composition (i.e. not only the hydrophilic phase).

[0043] Moreover, the dispersed lipid phase may contain further lipophilic constituents, such as one or more lipids, such as fats, oils, or waxes. Again, some of these ingredients may have more than function. For example, they may have a moisturising effect to the skin, even though they are not hydrophilic like some of the humectants mentioned above. Instead, the moisturising effect of lipophilic compounds is more typically brought about by an occlusive effect; These compounds form a lipophilic film on the skin by which the transepidermal water loss is decreased, leading to increased skin hydration. Such lipids, oils and waxes are also often called emollients, which means any substance that softens the skin by slowing evaporation of water.

[0044] As used herein, the term "lipids” is used for a broad spectrum of compounds and materials that are lipophilic and / or hydrophobic. Fats, oils, and waxes are examples of lipids. Fats are understood as triglyceride fats, i.e. solid or semisolid materials predominantly composed of triglycerides. Oils, as used herein, are liquid at room temperature and normal pressure, and cover both triglyceride oils and mineral oils. Waxes, in this context, include materials that are kneadable at 20 °C, solid to brittle-hard, have a coarse to fine crystalline structure, are translucent to opaque in colour but not glassy, melt above 40 °C without decomposing, are slightly viscous above the melting point, have a consistency and solubility that is strongly dependent on temperature and can be polished under slight pressure. Many natural waxes comprise large amounts of long-chain aliphatic hydrocarbons and esters of fatty acids and fatty alcohols or sterols.

[0045] Potentially useful fats, oils and waxes for formulating the dispersed lipophilic phase of the composition include, without limitation, plant oils, such as olive oil, as already described, sunflower oil, palm kernel oil, coconut oil, soybean oil, avocado oil, grape seed oil, argan oil, macadamia nut oil, or meadowfoam seed oil; so-called neutral oils composed of triglycerides with only saturated acyl groups. Natural waxes include, without limitation, beeswax, lanolin, carnauba wax, candelilla wax, jojoba seed oil, or hydrogenated jojoba oil. Mineral waxes and synthetic waxes include paraffin wax, ozokerite, polyethylene wax, or microcrystalline wax.

[0046] In some embodiments, the total amount of the lipids, i.e. fats, oils, waxes and the like in the composition may, for example, range from about 5 wt.% to about 30 wt.%, relative to the total weight of the composition. In other embodiments, the total amount of the lipids is in therange of about 5 wt.% to about 25 wt%, or about 5 wt.% to about 20 wt%, respectively. Typically, the lipids would represent the major part of the dispersed lipophilic phase by weight. In addition to the lipids, the dispersed lipophilic phase typically also comprises any ingredient or constituent of the composition which is not water-soluble or hydrophilic, such as lipophilic beneficial agents and lipophilic excipients. Examples of such lipophilic excipients include, without limitation, lipophilic antioxidants, such as tocopheryl acetate; lipophilic perfumes and colourants.

[0047] In some further preferred embodiments, the composition further comprises one or more phospholipids, wherein the amount of the phospholipid or, if more than one phospholipid is present, the total amount of phospholipids in the composition is at least about 0.5 wt%, relative to the total weight of the composition, such as from about 0.5 wt.% to about 3 wt.%. Moreover, according to these embodiments, the composition further comprises isostearyl isostearate, whose amount in the composition is selected to be sufficient to induce an orthorhombic phase of the phospholipid. For example, the weight ratio of the isostearyl isostearate to the phospholipid(s) may be in the range of about 1 : 1 to about 2 : 1. The inventors have found that the incorporation of phospholipid, in particular in the orthorhombic phase, substantially improves the properties of the composition in terms of viscosity and spreadability.

[0048] As used herein, a phospholipid is any member of a large class of fatlike, phosphorus-containing substances that play important structural and metabolic roles in living cells.

[0049] Phospholipids, along with sphingolipids, glycolipids, and lipoproteins, are called complex lipids, as distinguished from the simple lipids such as triglyceride oils or fats and waxes, and from other fat-soluble cell components, mostly isoprenoids and steroids. Phosphoglycerides, also known as glycerophospholipids, are an important subgroup of phospholipids, of which another prominent subgroup is represented by the phosphatidylcholines. In the context of the invention, the phospholipid, if present, is preferably selected from phosphatidylcholines. These compounds are composed of a choline head group and glycerophosphoric acid. The glycerophosphoric acid refers to a glyceryl ester with phosphoric acid and two fatty acids. Native phosphatidylcholines, which may for example be extracted from egg yolk or soybeans, often contain a variety of acyl groups, i.e. represent a mixture of phosphatidylcholines with various acyl groups and acyl group combinations. Such mixtures are often referred to as lecithin. In some preferred embodiments, the phospholipid(s) incorporated in the composition provided by this disclosure are a hydrogenated lecithin. The orthorhombic phase, as used herein, refers to one of the spacial arrangements which phospholipids formaggregates in which a lattice is formed that represents a rectangular prism with a rectangular base (a by b) and height (c), such that a, b, and c are distinct.

[0050] A further important constituent of the composition is water, as is implied by the fact that the composition is in the form of an o / w-type emulsion. In some preferred embodiments, the composition comprises a continuous phase whose predominant or major constituent is water, and in which other hydrophilic or water-soluble constituents are dissolved. In some embodiments, the composition comprises at least about 40 wt% water. Also preferred are embodiments in which the amount of water is in the range of about 40 wt.% to about 75 wt%, or about 45 wt.% to about 70 wt%, or about 50 wt.% to about 65 wt%, respectively.

[0051] In further preferred embodiments, the composition is further characterised by rheological properties which include a high zero-shear viscosity and / or a shear-thinning behaviour. As used herein, shear-thinning means that the viscosity of the composition decreases with increasing shear rates, which facilitates spreading on the skin. A zero-shear viscosity, in the context of this disclosure, refers to the viscosity of the composition when sheared at a minimal shear rate which is near zero, for example a shear rate, measured by rotation viscometry, of about 0.0001 1 / s or rpm. In some preferred embodiments, the zero-shear viscosity is at least 30,000 Pa»s, as measured by rotation viscometry at room temperature and 0.0001 rpm. Preferably, a plate-to-plate measuring system is used. In further embodiments, the composition exhibits a zero-shear viscosity in the range of at least about 40,000 Pa»s, for example in the range of about 40,000 Pa»s to about 60,000 Pa»s. Such high zero-shear viscosity is advantageous in terms of physical stability during transport and storage.

[0052] In another aspect, the invention is also related to the use of the semisolid composition disclosed herein in the treatment of a human subject suffering from an atopic skin condition. In a related aspect, the semisolid composition is used in the manufacture of a medicament for the treatment of a human subject suffering from an atopic skin condition.

[0053] A further aspect of the invention relates to a method of preparing a semisolid composition as described above. The method provides the steps of (a) providing an aqueous phase comprising water, the beta-glucan, and optionally a water-soluble polymer or a combination of water-soluble polymers; (b) providing a lipophilic phase comprising the triglyceride oil and the linear diarylheptanoid; (c) combining the aqueous phase and the lipophilic phase at a temperature in the range of 60°C to 95°C such as to form an emulsion; and (d) homogenising the emulsion under vacuum.Each of the steps (a) and (b) may optionally comprise two or more substeps. For example, Ingredients that are difficult to dissolve in water or in the respective lipophilic carrier may be added or combined at rather high temperatures followed by the homogenisation of the respective phase under high shear conditions, followed by the addition of ingredients that are somewhat more sensitive to shear and less stable at high temperatures.

[0054] For combining the aqueous phase and the lipophilic phase at a temperature in the range of 60°C to 95°C such as to form an emulsion during step (c) it may be useful to separately preheat each of the aqueous phase and the lipophilic phase to the target temperature within the specified range at which the emulsification is achieved.

[0055] For the avoidance of doubt, it may not be necessary to incorporate all constituents of the final semisolid composition in the two phases that are combined and emulsified in step (c). For example, constituents that are very temperature sensitive may be added to the emulsion after carrying out step (c), and optionally even after step (d). In other words, and according to some further preferred embodiments, the method comprises a further step (e) of adding one or more constituents of the composition to the emulsion as obtained in step (c) or step (d), under agitation of followed by agitation. In this context, agitation should be understood broadly such as to comprise stirring as well as homogenisation under high shear and / or high pressure.

[0056] Step (d) of homogenisation under vacuum requires that at least for a period of time during this step, homogenisation such as high shear homogenisation is carried out under lower than normal pressure. Optionally, the duration of the homogenisation activity is longer than the duration of the vacuum, or vice versa, as long as there is an overlap at which both conditions occur simultaneously. The vacuum may, for example, be adjusted to an absolute pressure of about 0.2 bar to about 0.8 bar, or in the range of about 0.3 bar to about 0.7 bar, such as about 0.3 bar, 0.4 bar, 0.5 bar, 0.6 bar, or 0.7 bar, respectively.

[0057] In a yet further aspect, the invention relates to a semisolid composition obtainable by the method specified herein-above.

[0058] EXAMPLES

[0059] Example 1

[0060] In an undervacuum homogenizer, an aqueous phase (approx. 50 kg) was prepared and homogenised at 75°C at 0.4 bar. The phase comprised water, 2.25 kg of pentylene glycol, 0.8 kg of hexylene glycol, 0.2 kg of sodium hyaluronate, and 0.3 kg of magnesium carboxymethylbeta-glucan. The constituents were combined at 75°C under stirring and homogenised at the same temperature using high-shear homogenisation (10 min at 1,200 rpm) at a pressure of 0.4 bar.

[0061] Separately, a lipophilic phase (approx. 22 kg) was prepared under stirring at 85 °C and normal pressure. The constituents were a combination of various triglyceride oils including native olive oil and natural waxes, partially hydrated (in total about 21 kg) in which a combination of polymers (sodium acrylate / sodium acryloyldimethyl taurate copolymer and acrylic acid / vinyl isodecanoate crosspolymer) (<1 kg) was dispersed, and a small amount of tetrahydrodiferuloylmethane (<0.5 kg). The constituents were combined at 85°C under stirring at normal pressure.

[0062] The aqueous phase and the lipophilic phase were then combined under stirring at 75°C, and emulsified into an o / w-type emulsion system at the same temperature. Subsequently, the emulsion was homogenised using high-shear homogenisation (3 min at 2,000 rpm) at a pressure of 0.5 bar, while maintaining the temperature of 75°C.

[0063] In further steps, the emulsion was cooled to about 35 °C, and additional constituents were added to the emulsion individually or as premixes. Where necessary, high-shear homogenisation at reduced pressure was used. The further constituents included, inter alia, honey ferment, honey extract, panthenol, niacinamide, isostearyl isostearate, various glycols, hydrogenated phosphatidylcholine, ascorbyl palmitate, tocopheryl acetate, and water. The final composition comprised not more than about 3 wt.% of non-ionic emulsifiers.

[0064] The rheological behaviour was characterised using rotation viscometry with a plate-to-plate measuring system. The testing was performed at room temperature (25°C) and in triplicates. In result, the composition showed a high zero-shear viscosity at a shear rate pf 0.0001 1 / s of 47,992 Pa*s with a relative standard deviation of 3.57%. Moreover, pronounced shear thinning was demonstrated: The viscosity at a shear rate of 1001 / s was 7.98 Pa*s with a relative standard deviation of 2.17%, and at 10001 / s, a viscosity of only 0.352 Pa*s with a relative standard deviation of 2.15% was found, indicating good physical stability and optimal spreading and usability. Preliminaiy stability testing demonstrated a high product stability.

[0065] Example 2

[0066] A further semisolid o / w-emulsion was prepared, comprising the beneficial agents honey ferment, tetrahydrodiferuloylmethane, and carboxymethyl beta-glucan. The oil phase of theemulsion which comprised olive oil represented about 20% of the total weight of the composition. The emulsion was formulated with 1 wt.% behenyl alcohol as a non-ionic emulsifier. Other non-ionic emulsifiers were absent Further constituents included the same as those mentioned in Example 1. Essentially the same manufacturing process was used as described in Example 1 At the final homogenisation step which was carried out at room temperature (about 25°C), the pH of the emulsion was adjusted to 5.3.

[0067] A slightly yellowish emulsion with very homogenous appearance was obtained. The emulsion was readily spreadable on skin without visible lumps or any phase separation behaviour.

[0068] The emulsion was inspected under an optical microscope in phase contrast mode and in bright-field mode with polarized light, using a 20x objective, resulting in 200x magnification. The composition appeared as a homogenous emulsion with fine, round droplets and evenly distributed liquid-crystalline structures.

[0069] The rheological properties were characterised as described in Example 1, and very similar viscosities were found, with a maximum viscosity of about 50,000 Pa*s at a shear rate of 0.0001 1 / s and a pronounced thinning with increasing shear rates.

[0070] Taking all properties in combination, the emulsion was considered to representan optimal topical formulation for the application to sensitive skin.

[0071] Example 3

[0072] In a further experiment, a composition similar to that of Example 2 was prepared, except that the behenyl alcohol was replaced by polysorbate 80 at the same relative amount, and except that the batch scale was 200 g. The polysorbate represents a conventional, hydrophilic non-ionic emulsifier as is typically considered essential for formulating a semisolid o / w-type emulsion.

[0073] The composition was characterised in the same manner as Examples 1 and 2. In result, it was found that the emulsion appeared macroscopically homogeneous and acceptable, even though some air bubbles were observed which break upon spreading.

[0074] Microscopically, the emulsion showed less liquid-crystalline structures than Examples 1 and 2; such structures were almost exclusively located at the edge of emulsion droplets. In terms of its rheological behaviour, the emulsion of Example 3 had a lower viscosity at all shearrates, with a zero-stress viscosity (at 0.0001 1 / 2) of about 14,500 Pa*s with a pronounced shear thinning behaviour. In practice, it would be perceived as a pourable emulsion.

[0075] Example 4 (Comparative)

[0076] A further semisolid o / w-emulsion was prepared having the same relative composition as Example 2, expect that the amount of behenyl alcohol was increased to 5% by weight. To keep the relative amounts of all other constituents constant, only the amount of water was slightly reduced to compensate the higher amount of behenyl alcohol. A batch of 200 g was manufactured in the same manner as in Example 3, and characterised as described.

[0077] In result, it was found that the resulting semisolid o / w-emulsion was macroscopically homogeneous, but under the microscope it displayed a coarse emulsion structure with irregular shaped droplets. It was expected that the physical stability would be insufficient for marketing purposes. Moreover, the formulation did not have a soft, pleasant texture and was not as easily spreadable as Examples 1 to 3. The rheological characterisation revealed that it was much more viscous, with a zero-stress viscosity above 80,000 Pa*s. In practice, the composition would not be considered as very suitable for being applied to highly sensitive skin.

Claims

Claims1. A semisolid composition for topical administration to the skin of a subject, the composition comprising at least two beneficial agents selected from:(a) a linear diaiylheptanoid,(b) a beta-glucan, and / or(c) a honey ferment;wherein the composition is in the form of an o / w-type emulsion having a dispersed lipophilic phase, wherein the amount of said lipophilic phase is at least about 15 wt.% relative to the total weight of the composition; andwherein the composition is further characterised in that it comprises not more than about 3 wt.% of non-ionic emulsifiers, relative to the total weight of the composition.

2. The semisolid composition according to claim 1, comprising the following beneficial agents:(a) a linear diaiylheptanoid,(b) a beta-glucan,(c) a honey ferment, and(d) a triglyceride oil having a content of at least about 50 mol% of oleic acid residues.

3. The semisolid composition according to claim 1 or 2, wherein the linear diarylheptanoid is a curcuminoid.

4. The semisolid composition according to claim 3, wherein the curcuminoid is tetrahydrodiferuloylmethane.

5. The semisolid composition according to any one of the preceding claims, wherein the beta-glucan is a derivatised beta-glucan or a salt thereof, and optionally a carboxymethyl beta-glucan or salt thereof.

6. The semisolid composition according to any one of the preceding claims, further comprising a phospholipid at an amount of at least about 0.5 wt.% relative to the total weight of the composition and isosteaiyl isostearate at a sufficient amount to induce an orthorhombic phase of the phospholipid.

7. The semisolid composition according to any one of the preceding claims, being substantially free of non-ionic emulsifiers having an HLB-value of about 8 or higher.

8. The semisolid composition according to any one of the preceding claims, being substantially free of polysorbates.

9. The semisolid composition according to any one of the preceding claims, comprising a continuous hydrophilic phase, said hydrophilic phase comprising a water-soluble polymer selected from acrylic or methacrylic acid-based polymers, co-polymers and crosspolymers; hyaluronic acid or salts thereof; polyvinyl alcohol; polyvinyl pyrrolidone; xanthan; hydrophilic cellulose ethers such as hydroxyethyl cellulose; or a combination of any of these.

10. The semisolid composition according to claim 9, wherein the amount of the water- soluble polymer or of the combination of water-soluble polymers is from about 0.3 to about 2.0 wt.%, relative to the total weight of the composition.

11. The semisolid composition according to any one of the preceding claims, characterised in that it exhibits a shear-thinning behaviour.

12. The semisolid composition according to any one of the preceding claims, having a zeroshear viscosity of at least 30,000 Pa»s, as measured by rotation viscometry at room temperature and 0.0001 rpm.

13. The semisolid composition according to any one of the preceding claims for use in the treatment of a human subject suffering from an atopic skin condition.

14. A method of preparing a semisolid composition according to any one of the preceding claims, comprising the steps of:(a) providing an aqueous phase comprising water, the beta-glucan, and optionally a water-soluble polymer or a combination of water-soluble polymers;(b) providing a lipophilic phase comprising the triglyceride oil and the linear diarylheptanoid;(c) combining the aqueous phase and the lipophilic phase at a temperature in the range of 60°C to 95°C such as to form an emulsion; and(d) homogenising the emulsion under vacuum.

15. A semisolid composition obtainable by the method of claim 14.