bigel

Abstract

A bigel comprises an oleogel at between 40 and 80 wt% of the bigel and a hydrogel at between 20 and 60 wt% of the bigel. The oleogel comprises at least one vegetable oil at 70-98 wt% of the oleogel, at least one wax at 1-30 wt% of the oleogel, and at least one oil-soluble skin conditioning agent at 0.1-10 wt% of the oleogel. The hydrogel comprises water at 60-90 wt% of the hydrogel, at least one water-soluble vitamin at 1-20 wt% of the hydrogel, at least one humectant at 10-30 wt% of the hydrogel, at least one viscosity controlling agent at 0.1-10 wt% by weight of the hydrogel, and optionally at least one pH adjusting agent. The bigel can be used to improve the status of skin suffering from or marred by dryness, red dots, itching, eczema, and / or inflammation.

Description

[0001] BIGEL

[0002] TECHNICAL FIELD

[0003] The present invention relates to bigels in the form of mixtures of a hydrogel and an oleogel, and in particular to bigels having beneficial properties when applied to the skin of human subject.

[0004] BACKGROUND

[0005] There are numerous known ways to formulate topical compositions for pharmaceutical and / or cosmetic uses, each of which has their own advantages and disadvantages.

[0006] For example, some pharmaceutical and cosmetic ingredients are only sparingly soluble in water and, therefore, are optimally formulated in an oily composition rather than an aqueous composition. Oily gels, i.e., so-called oleogels, can be made by gelling an oil to combine the relatively solid consistency of a gel with the total transparency of an oil. However, oleogels generally have the drawback of feeling greasy and unpleasant, on account of the presence of the oily compound. This unpleasant feel very often discourages users, particularly in the case of dermatological and cosmetic applications.

[0007] One approach to overcome such disadvantages of oleogels is to include an oily phase as part of an emulsion. An emulsion can be defined as a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is known as the discontinuous phase or internal phase, and the dispersion medium is the continuous or external phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or an aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. However, emulsions are generally unstable, hence emulsifying agents must be added in order to form a stable emulsion.

[0008] Another approach is to produce a mixture of an oleogel and an aqueous gel, i.e., a so-called hydrogel, in the form of a bigel. Such a bigel is a biphasic semisolid system that combines the hydrophilic properties of the hydrogel with the hydrophobic properties of the oleogel. EP 1 083 880 B1 discloses a stable gel mixture having a substantially uniform appearance and comprising at least one oleogel and at least one aqueous gel. The oleogel comprises at least one oily agent gelled with at least one cellulose polymer. US 2011 / 0158920 A1 discloses a method for producing a bigel by providing an oleogel comprising at least one oily agent gelled with at least one cellulose polymer and providing an aqueous gel comprising at least one component whose viscosity is pH dependent, such as a carbomer. The method alsocomprises mixing the oleogel and the aqueous gel together to form a bigel and subsequently adjusting the viscosity of the bigel under high flow and low shear stirring to obtain a bigel of a desired viscosity.

[0009] KR 101723183 B1 discloses a method for manufacturing skin temperature sensitive hydro oil gel. The method comprises a) adding purified water, a nonionic gel polymer and carrageenan, heating and stirring the materials and preparing a first mixture; b) adding coconut oil and / or jojoba oil, and beeswax, heating and stirring the same, and obtaining a second mixture; c) inputting the second mixture in the step b) in a manufacturing tank, stirring the same and obtaining a third mixture; d) adding polyhydric alcohol to the third mixture, stirring the same and preparing a fourth step, and cooling and defoaming the same; e) transferring the fourth mixture in a sol state in the step d) to a coating machine; f) coating the fourth mixture transferred to the coating machine in the step e); g) molding the fourth mixture coated in the step f) in a desired shape and manufacturing oil gel; and h) packaging the oil gel in the step g).

[0010] There is still a need for bigels having beneficial properties when applied to the skin of a human subject.

[0011] SUMMARY

[0012] It is general objective to provide a bigel having beneficial properties when applied to the skin of a human subject.

[0013] This and other objectives are met by embodiments disclosed herein.

[0014] The invention is defined by the independent claims. Further embodiments of the invention are defined by the dependent claims.

[0015] An aspect of the invention relates to a bigel comprising an oleogel at between 40 and 80 % by weight of the bigel and a hydrogel at between 20 and 60 % by weight of the bigel. The oleogel comprises at least one vegetable oil at between 70 and 98 % by weight of the oleogel, at least one wax at between 1 and 30 % by weight of the oleogel, and at least one oil-soluble skin conditioning agent at between 0.1 and 10 % by weight of the oleogel. The hydrogel comprises water at between 60 and 90 % by weight of the hydrogel, at least one water-soluble vitamin at between 1 and 20 % by weight of the hydrogel, at least one humectant at between 10 and 30 % by weight of the hydrogel, at least one viscosity controlling agent at between 0.1 and 10 % by weight of the hydrogel, and optionally at least one pH adjusting agent.Further aspects of the invention relates to a bigel according to above for use as a medicament, for use in treatment of a skin condition selected from the group consisting of dry skin, itching skin, eczema, burnt skin, cracked skin, red skin, rosacea, skin irritation, psoriasis, skin inflammation and petechia, and cosmetic use of the bigel according to above.

[0016] Another aspect of the invention relates to a method for producing a bigel according to above. The method comprises mixing the at least one vegetable oil and the at least one wax at a temperature above room temperature, and optionally allowing the mixture between the at least one vegetable oil and the at least one wax to cool to a temperature equal to or below 65°C. The method also comprises mixing the at least one oil-soluble skin conditioning agent into the optionally cooled mixture between the at least one vegetable oil and the at least one wax to form the oleogel, and optionally cooling the oleogel to room temperature. The method further comprises mixing the at least one viscosity controlling agent and water, mixing the at least one water-soluble vitamin and the at least one humectant into the mixture between the at least one viscosity controlling agent and water, preferably at room temperature, to form the hydrogel, and optionally adjusting pH of the hydrogel by addition of the at least one pH adjusting agent. The method further comprises mixing the oleogel and the hydrogel, preferably at room temperature, to form the bigel.

[0017] The bigel is a stable formulation that can easily be applied to the skin of a human subject. The bigel generally has a non-greasy feel when applied to the skin and is easily spread onto the skin surface. The bigel also has anti-inflammatory effect as seen in suppressing anti-inflammatory cytokines, in particular in response to ultraviolet (UV) exposure. The bigel is compatible with human skin and is regarded as being not irritant. The bigel further has soothing effect on skin discomforts induced by capsaicin and SLS. In particular, the bigel significantly reduced skin redness (erythema), transdermal water lass (TEWL), burning and itching induced by capsaicin or SLS. The bigel was additionally shown to increase skin hydration and decrease skin dryness (desquamation). The beneficial properties of the bigel when applied to the skin of a human subject mean that the bigel can be used to improve the status of skin suffering from or marred by dryness, red dots, itching, eczema, and / or inflammation.

[0018] BRIEF DESCRIPTION OF THE DRAWING

[0019] The embodiments, together with further objects and advantages thereof, may best be understood by making reference to the following description taken together with the accompanying drawings, in which:

[0020] Fig. 1 is a flow chart illustrating a method of producing a bigel according to an embodiment.Fig. 2 is a diagram illustrating surface percentage positive to tumor necrosis factor-alpha (TNF-a) immunostaining in the epidermis on day 5.

[0021] Fig. 3 is a diagram illustrating release of interleukin-1 alpha (IL-1oc) from epidermis into culture medium on day 5.

[0022] Fig. 4 illustrates mean skin redness values of the treated area and the untreated area (treated only with capsaicin), compared with inter-group analysis (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0023] Fig. 5 illustrates median value of burning in the treated area and the untreated area (treated only with capsaicin), compared with inter-group analysis (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0024] Fig. 6 illustrates median value of itching in the treated area and the untreated area (treated only with capsaicin), compared with inter-group analysis (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0025] Fig. 7 illustrates mean erythema values of the treated area and the untreated area (treated only with SLS), compared with inter-group analysis (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0026] Fig. 8 illustrates mean TEWL values of the treated area and the untreated area (treated only with SLS), compared with inter-group analysis (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****))

[0027] Fig. 9 illustrates mean hydration values, expressed in A.U., with intra-group analysis (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0028] Fig. 10 illustrates mean TEWL values, expressed in g / m2 / h, with intra-group analysis (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).Fig. 11 illustrates median values of the clinical evaluation of erythema (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0029] Fig. 12 illustrates median values of the clinical evaluation of skin dryness / desquamation (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0030] Fig. 13 illustrates median values of the subjective evaluation of itching sensation (P values, >0.05 (ns), <0.05 (*), <0.01 (**), <0.001 (***), <0.0001 (****)).

[0031] DETAILED DESCRIPTION

[0032] The invention relates to a bigel in the form of a mixture of a hydrogel and an oleogel to form a biphasic semisolid system that combines the hydrophilic properties of the hydrogel with the hydrophobic properties of the oleogel.

[0033] The bigel of the invention is a stable formulation that can easily be applied to the skin of a human subject. The bigel generally has a non-greasy feel when applied to the skin and is easily spread onto the skin surface. The bigel also has anti-inflammatory effect as seen in suppressing anti-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-a) and interleukin 1 alpha (IL-1 a), in particular in response to UV exposure. The bigel is compatible with human skin and is regarded as being not irritant. The bigel further has soothing effect on skin discomforts induced by capsaicin and SLS. In particular, the bigel significantly reduced skin redness (erythema), transdermal water lass (TEWL), burning and itching induced by capsaicin or SLS. The bigel was additionally shown to increase skin hydration and decrease skin dryness (desquamation). The beneficial properties of the bigel when applied to the skin of a human subject mean that the bigel can be used to improve the status of skin suffering from or marred by dryness, red dots, itching, eczema, and / or inflammation.

[0034] An aspect of the invention relates to a bigel comprising an olegol at between 40 and 80 % by weight (wt%) of the bigel and a hydrogel at between 20 and 60 wt% of the bigel. The oleogel comprises at least one vegetable oil at between 70 and 90 wt% of the oleogel, at least one wax at between 1 and 30 wt% of the oleogel and at least one oil-soluble conditioning agent at between 0.1 and 10 wt% of the oleogel. The hydrogel comprises water at between 60 and 90 wt% of the hydrogel, at least one water-soluble vitamin at between 1 and 20 wt% of the hydrogel, at least one humectant at between 10 and 30 wt% ofthe hydrogel, and at least one viscosity controlling agent at between 0.1 and 10 wt%ofthe hydrogel. The hydrogel may optionally also comprise at least one pH adjusting agent.

[0035] Reference to an interval herein, such as from X up to Y or between X and Y, encompasses the full range between X and Y, including the end points of the interval, i.e., X and Y, unless specified otherwise.

[0036] The bigel is a biphasic gel system in the form of a mixture of two phases, a hydrophilic phase, i.e., the hydrogel, and a lipophilic phase, i.e., the oleogel. These two phases are combined in specific ratios (weight ratio between hydrogel : oleogel selected between 1 : 1.33 and 1 : 4) to create the bigel as a semi-solid formulation.

[0037] The oleogel of the bigel comprises at least one vegetable oil. The at least one vegetable oil of the oleogel provides skin conditioning effect to the bigel.

[0038] The oleogel comprises the at least one vegetable oil at between 70 and 98 wt% of the oleogel. In a preferred embodiment, the oleogel comprises the at least one vegetable oil at between 75 and 95 wt% of the oleogel, preferably at between 80 and 95 wt% of the oleogel, and more preferably at between 85 and 95 wt% of the oleogel. In a particular embodiment, the oleogel comprises the at least one vegetable oil at between 87.5 and 92.5 wt% of the oleogel. Hence, the oleogel comprises the at least one vegetable oil as a main ingredient or ingredients.

[0039] In an embodiment, the oleogel comprises a single vegetable oil. In another embodiment, the oleogel comprises a mixture or combination of multiple, i.e., at least two, vegetable oils.

[0040] In an embodiment, the at least one vegetable oil is selected from the group consisting of jojoba oil, sunflower oil, baobad oil, olive oil, canola oil, coconut oil, flaxseed oil, oat oil, and any combination thereof. In a preferred embodiment, the at least one vegetable oil is selected from the group consisting of jojoba oil, sunflower oil, baobad oil, and any combination thereof.

[0041] In a particular embodiment, the oleogel comprises a mixture or a combination of jojoba oil, sunflower oil, and baobad oil. For instance, the oleogel comprises jojoba oil at between 30 and 40 wt% of the oleogel, preferably at between 32.5 and 37.5 wt% of the oleogel, the sunflower oil at between 40 and 50 wt% of the oleogel, preferably at between 42.5 and 47.5 wt% of the oleogel and baobad oil at between 5 and 15 wt% of the oleogel, preferably at between 7.5 and 12.5 wt% of the oleogel.Jojoba oil is an excellent emollient, helping to hydrate and soften the skin by mimicking the natural oils (sebum) produced by the skin. It is non-comedogenic and rich in antioxidants, including vitamin E, which protect the skin from oxidative stress and premature aging. Jojoba oil further helps soothe irritated skin and reduces redness, making it ideal for sensitive or inflamed skin. Jojoba oil is resistant to oxidation, which thereby extends the shelf-life of the bigel.

[0042] Jojoba oil is an oil produced from the seeds of the jojoba plant (Simmondsia chinensis). It typically has a fatty acid profile of 0-3 wt% of palmitic acid, 0-1 wt% of palmitoleic acid, 5-15 wt% of oleic acid, 65-80 wt% of gadoleic acid, 0-1 wt% of behenic acid, 10-22 wt % of erucic acid and 0-3.5 wt% of nervonic acid and where the wt% is of the weight of all fatty acids in jojoba oil. The corresponding wax ester composition is typically 0-2 % C36, 5-10 wt% C38, 26-37 wt% C40, 44-56 wt% C42, 8-13 wt% C44 and 0-3 wt% C46. An example of jojoba oil that could be used in the bigel is presented in Example 1.

[0043] Sunflower oil is rich in antioxidants, including vitamin E, which protects the skin from oxidative stress and premature aging. It provides essential fatty acids, such as linoleic acid, which maintains the skin barrier and keep the skin moisturized. Sunflower oil is non-comedogenic, soothing, and antibacterial.

[0044] Sunflower oil is the non-volatile oil pressed from the seeds of the sunflower (Helianthus annuus). Sunflower oil is mainly a triglyceride comprises palmitic acid , typically about 5%, stearic acid, typically about 6%, oleic acid, typically about 30%, and linoleic acid typically about 59%. An example of sunflower oil that could be used in the bigel is presented in Example 1.

[0045] Baobad oil is rich in omega fatty acids and deeply hydrates the skin and helps prevent water loss, making it ideal for dry skin applications. Baobad oil supports the skin’s natural barrier, promoting healing and protecting against environmental stressors. It has soothing properties, which can reduce redness and irritation, making a bigel containing baobad oil suitable for sensitive or inflamed skin. Baobad oil is rich in vitamins A, D, E and F, which nourishes the skin, improves elasticity and combat signs of aging.

[0046] Baobad oil is a natural, plant-derived oil extracted primarily from the seeds of the baobab tree (Adansonia digitata). Baobab oil is rich in essential fatty acids including oleic acid (30-40 wt%), linoleic acid (20-35 wt%), palmitic acid (18-30 wt%), and stearic acid (2-7 wt%). An example of baobad oil that could be used in the bigel is presented in Example 1.The oleogel of the bigel comprises at least one wax. The at least one wax of the oleogel modifies the viscosity of the bigel by acting as thickening agent to increase the viscosity of the oleogel and thereby of the bigel. The at least one wax further improves film formation by creating a protective layer on the skin, which helps lock in moisture and shields the skin against environmental factors.

[0047] The oleogel comprises the at least one wax at between 1 and 30 wt% of the oleogel. In a preferred embodiment, the oleogel comprises the at least one wax at between 2.5 and 25 wt% of the oleogel, preferably at between 2.5 and 20 wt% of the oleogel, more preferably at between 2.5 and 15 wt% of the oleogel, and most preferably at between 5 and 12.5 wt% of the oleogel.

[0048] In an embodiment, the oleogel comprises a single wax. In another embodiment, the oleogel comprises multiple waxes.

[0049] In an embodiment, the at least one wax is selected from the group consisting of candelilla wax, jojoba wax, carnauba wax, soy way, beeswax, rapeseed wax, rose wax, and any combination thereof. In a preferred embodiment, the oleogel comprises candelilla wax.

[0050] In a particular embodiment, the oleogel comprises candelilla wax at between 5 and 12.5 wt% of the oleogel.

[0051] Candelilla wax has several beneficial properties for the bigel including forming a semi-occlusive barrier on the skin, reducing transepidermal water loss and locking in moisture. Compared to other waxes, candelilla wax feels less greasy, making it ideal for lightweight skin formulations. It is non-comedogenic and provides a protective layer that shields the skin from environmental irritants and pollutants. Candelilla wax further acts as a stabilizing agent enhancing the stability and texture of the bigel.

[0052] Candelilla wax is a wax derived from the leaves of the small candelilla shrub Euphorbia antisyphilitica. With a melting point of 68.5-72.5 °C, candelilla wax consists of mainly hydrocarbons (about 50 wt%, chains with 29-33 carbons), esters of higher molecular weight (20-29 wt%), free acids (7-9 wt%), and resins (12-14 wt%, mainly triterpenoid esters). An example of candelilla wax that could be used in the bigel is presented in Example 1.The oleogel of the bigel comprises the at least one oil-soluble skin conditioning agent. In an embodiment, the oleogel comprises one oil-soluble skin conditioning agent. In another embodiment, the oleogel comprises multiple oil-soluble skin conditioning agents.

[0053] The oleogel of the bigel comprises at least one oil-soluble skin conditioning agent at between 0.1 and 10 wt% of the oleogel. In an embodiment, the oleogel comprises the at least one oil-soluble skin conditioning agent at between 0.25 and 7.5 wt% of the oleogel, preferably at between 0.5 and 5 wt% of the oleogel, more preferably at between 0.75 and 2.5 wt% of the oleogel, and most preferably at between 1 and 2 wt% of the oleogel.

[0054] In an embodiment, the at least one oil-soluble skin conditioning ingredient is selected from the group consisting of at least one ceramide, at least one oil-soluble vitamin, glycerin, squalane, cholesterol, at least one fatty acid, and any combination thereof.

[0055] Ceramides act as skin conditioning agents reinforcing the skin’s natural barrier, helping to prevent water loss and protecting against environmental aggressors. Ceramides are also excellent at retaining moisture, keeping the skin hydrated and plump. They further enhance the skin’s resilience, reducing sensitivity and irritation. By improving hydration and skin elasticity, ceramides can minimize the appearance of fine lines and wrinkles.

[0056] Glycerin, also referred to as glycerol or propane-1, 2, 3-triol, is a humectant, provides skin barrier support and improves the skin texture by smoothening and softening the skin. It is non-comedogenic and soothes irritated and sensitive skin, reducing redness and discomfort.

[0057] Squalane mimics the skin’s natural oils, delivering lightweight yet long-lasting moisture. It helps fortify the skin’s natural lipid barrier, reducing water loss and protecting against irritants. It absorbs quickly into the skin without leaving a greasy residue and is non-comedogenic. Squalane has antioxidant properties and soothing effects to the skin.

[0058] Cholesterol has barrier repair and maintenance effects, rebuilding and maintaining the skin’s natural barrier, preventing moisture loss and protecting against environmental damage. It works synergistically with ceramides and fatty acids to retain water in the skin, and contributes to skin flexibility and resilience.Fatty acids may be included in the oleogel to restore and maintain the skins natural lipid barrier, which prevents moisture loss and protects against environmental damage. Fatty acids help lock in moisture, keeping the skin soft, smooth and hydrated. Fatty acids enhance the skin’s lipid content, they improve elasticity and resilience, reducing dryness and roughness. Fatty acids can calm inflammation and irritation, making them suitable for sensitive or compromised skin. Fatty acids also have emollient effects.

[0059] Illustrative, but non-limiting, examples of fatty acids that can be included in the oleogel include linoleic acid, oleic acid, stearic acid, and any combination thereof.

[0060] In an embodiment, the at least one oil-soluble skin conditioning ingredient is selected from the group consisting of at least one ceramide, at least one oil-soluble vitamin, and any combination thereof. In a preferred embodiment, the oleogel comprises a combination of at least one ceramide and at least one oil-soluble vitamin.

[0061] In an embodiment, the oleogel comprises at least one ceramide at between 0.25 and 7.5 wt% of the oleogel, preferably at between 0.5 and 5 wt% of the oleogel, more preferably at between 0.75 and 2.5 wt% of the oleogel, and most preferably at about 1 wt% of the oleogel.

[0062] In an embodiment, the at least one ceramide is selected from the group consisting of ceramide 1, ceramide 2, ceramide 3, ceramide 6-I I, ceramide 9, a sphingolipid, and any combination thereof.

[0063] Ceramide 1, also referred to as ceramide EOP and [30-oxo-30-[[(2S,3S,4 / ?)-1 ,3,4-trihydroxyoctadecan-2-yl]amino]triacontyl] (9Z,12Z)-octadeca-9,12-dienoate, has the general molecular formula CeeFhzNOe. Ceramide 2, also referred to as ceramide NG and A / -[(2S,3 / ?)-1,3-dihydroxyoctadecan-2-yl]octadecanamide, has the general molecular formula C36H73NO3. Ceramide 3, also referred to as ceramide NP and (Z)- / V-[(2S,3S,4 / ?)-1,3,4-trihydroxyoctadecan-2-yl]octadec-9-enamide, has the general molecular formula C36H71NO . Ceramide 6-II, also referred to as ceramide AP and 2-hydroxy- / V-[(2S,3S,4R)-1 ,3,4-trihydroxyoctadecan-2-yl]octadecanamide, has the general molecular formula C36H73NO5. Ceramide 9, also referred to as ceramide EOS and [30-[[(E,2S,3R)-1,3-dihydroxyoctadec-4-en-2-yl]amino]-30-oxotriacontyl] (9Z,12Z)-octadeca-9,12-dienoate, has the general molecular formula C66H125NO5.Illustrative, but non-limiting, examples of sphingolipids that can be used as ceramides in the oleogel include phytosphingosine, tetraacetylphytosphingosine, sphingosine, sphingosine, glycosphingolipids, and any combination thereof.

[0064] Phytosphingosine, also referred to as (2S,3S,4 / ?)-2-aminooctadecane-1,3,4-triol, has the general molecular formula C18H39NO3. Tetraacetylphytosphingosine, also referred to as [(2S,3S,4R)-2-acetamido-3,4-diacetyloxyoctadecyl] acetate, has the general molecular formula C26H 7NO7. Sphingosine, also referred to as (E,2S,3 / ?)-2-aminooctadec-4-ene-1,3-diol, has the general molecular formula C18H37NO2. Sphinganine, also referred to as (2S,3 / ?)-2-aminooctadecane-1 ,3-diol, has the general molecular formula C18H39NO2. Glycosphingolipids are a subtype of glycolips containing the amino alcohol sphingosine.

[0065] In an embodiment, the at least one ceramide is selected from the group consisting of ceramide 1, ceramide 3, ceramide 6-II, ceramide 9, a sphingolipid, and any combination thereof, such as a combination of ceramide 1, ceramide 3, ceramide 6-II, ceramide 9, and at least one sphingolipid, preferably phytosphingosine, tetraacetylphytosphingosine, glycosphingolipids, and any combination thereof.

[0066] In an embodiment, the oleogel comprises at least one oil-soluble vitamin at between 0.025 and 1 wt% of the oleogel, preferably at between 0.05 and 0.75 wt% of the oleogel, more preferably at between 0.075 and 0.5 wt% of the oleogel, and most preferably at between 0.075 and 0.25 wt% of the oleogel, such as at about 0.1 wt% of the oleogel.

[0067] In an embodiment, the at least one oil-soluble vitamin is selected from the group consisting of vitamin A, vitamin E, and any combination thereof. In a particular embodiment, the oil-soluble vitamin is vitamin E.

[0068] Vitamin A, preferably in the form of retinoids, such as retinol or retinyl esters, promotes cell turnover, improving skin texture and reducing the appearance of wrinkles and fine lines. It stimulates collagen production, enhancing skin firmness and elasticity.

[0069] Vitamin E, such as in the form of one or more tocopherols and / or one or more tocotrienols, have antioxidant effect, neutralizing free radicals and protecting the skin from damage caused by UV rays and environmental pollutants. It reinforces the skin’s lipid barrier to lock in hydration and prevents dryness. Vitamin E also reduces inflammation and calms irritated or sensitive skin.The hydrogel of the bigel comprises at least one water-soluble vitamin. The at least one water-soluble vitamin of the hydrogel acts as skin-conditioning humectant to the bigel. In an embodiment, the hydrogel comprises one water-soluble vitamin. In another embodiment, the hydrogel comprises multiple water-soluble vitamins.

[0070] The hydrogel comprises the at least one water-soluble vitamin at between 1 and 20 wt% of the hydrogel. In a preferred embodiment, the hydrogel comprises the at least one water-soluble vitamin at between 2.5 and 17.5 wt% of the hydrogel, preferably at between 5 and 15 wt% of the hydrogel, more preferably at between 7.5 and 12.5 wt% of the hydrogel, and most preferably at about 10 wt% of the hydrogel.

[0071] In an embodiment, the at least one water-soluble vitamin is selected from the group consisting of vitamin B3, vitamin B5, vitamin C, and any combination thereof. In a preferred embodiment, the hydrogel comprises a combination of vitamin B3, vitamin B5 and vitamin C.

[0072] Vitamin B3, also known as niacin and can be in the form of nicotinic acid, nicotinamide and / or nicotinamide riboside, strengthens the protective lipid barrier of the skin, reducing water loss and enhancing hydration. It also helps soothing and calming inflammation. Vitamin B3 further acts as antioxidant providing protection from free radicals and pollutants, induces keratin production, keeping the skin firm and healthy, and improves skin elasticity and smooths fine lines and wrinkles.

[0073] In an embodiment, the hydrogel comprises vitamin B3 at between 2 and 6 wt%of the hydrogel, preferably at between 3 and 5 wt% of the hydrogel, and more preferably at about 4 wt% of the hydrogel.

[0074] Vitamin B5, also known as pantothenic acid, acts as a humectant, attracting and retaining moisture to keep the skin hydrated, and strengthens the skin’s natural barrier, thereby reducing water loss and protection against irritants. Vitamin B5 reduces redness, irritation and discomfort, and promotes skin regeneration. If further improves skin texture and has anti-inflammatory effect.

[0075] In an embodiment, the hydrogel comprises vitamin B5 at between 1 and 5 wt%of the hydrogel, preferably at between 2 and 4 wt% of the hydrogel, and more preferably at about 3 wt% of the hydrogel.

[0076] Vitamin C, also known as ascorbic acid and ascorbate, has antioxidant effects, neutralizing free radicals and protecting the skin from environmental damage caused by UV rays and pollution. It also stimulatescollagen synthesis, improving skin elasticity, and has anti-inflammatory effect and promotes repair of damage caused by UV exposure.

[0077] In an embodiment, the hydrogel comprises vitamin C at between 0.5 and 4 wt% of the hydrogel, preferably at between 1 and 3 wt% of the hydrogel and more preferably at about 2 wt% of the hydrogel.

[0078] The hydrogel of the bigel comprises at least one humectant. In an embodiment, the hydrogel comprises one humectant. In another embodiment, the hydrogel comprises multiple humectants.

[0079] The hydrogel comprises the at least one humectant at between 10 and 30 wt% of the hydrogel. In a preferred embodiment, the hydrogel comprises the at least one humectant at between 10 and 20 wt% of the hydrogel, preferably at between 12.5 and 17.5 wt% of the hydrogel, and more preferably at between 14 and 15 wt% of the hydrogel.

[0080] In an embodiment, the at least one humectant is selected from the group consisting of glycerin, urea, hyaluronic acid, propylene glycol, sorbitol, and any combination thereof. In a preferred embodiment, the at least one humectant is selected from the group consisting of glycerin, urea, hyaluronic acid, and any combination thereof. In a particular embodiment, the hydrogel comprises a combination of glycerin, urea, and hyaluronic acid.

[0081] In an embodiment, the hydrogel comprises glycerin at between 5 and 15 wt% of the hydrogel, preferably at between 7.5 and 12.5 wt% of the hydrogel, and more preferably at about 10 wt% of the hydrogel.

[0082] Urea is a powerful humectant, drawing water to the skin and keeping it deeply hydrated. Urea also enhances the skin’s natural barrier function, reducing water loss and protecting against irritants. It further calms irritation and inflammation.

[0083] In an embodiment, the hydrogel comprises urea at between 2 and 6 wt% of the hydrogel, preferably at between 3 and 5 wt% of the hydrogel, and more preferably at about 4 wt% of the hydrogel.

[0084] Hyaluronic acid is a powerful humectant, attracting and retaining water to keep the skin moisture. It boosts the skin’s elasticity and smoothness, and calms and reduces irritation.In an embodiment, the hydrogel comprises hyaluronic acid at between 0.01 and 1.5 wt% of the hydrogel, preferably at between 0.025 and 1.25 wt% of the hydrogel, and more preferably at between 0.05 and 1 wt% of the hydrogel.

[0085] The hydrogel of the bigel comprises at least one viscosity controlling agent. In an embodiment, the hydrogel comprises one viscosity controlling agent. In another embodiment, the hydrogel comprises multiple viscosity controlling agents. The at least one viscosity controlling agent is preferably included to modulate the viscosity of the bigel, preferably increase the viscosity of the bigel, i.e., act as a thickening agent.

[0086] The hydrogel comprises the at least one viscosity controlling agent at between 0.1 and 10 wt% of the hydrogel. In an embodiment, the hydrogel comprises the at least one viscosity controlling agent at between 0.5 and 7.5 wt% of the hydrogel, preferably at between 1 and 5 wt% of the hydrogel, and more preferably at between 1.5 and 2.5 wt% of the hydrogel.

[0087] In an embodiment, the at least one viscosity controlling agent is selected from the group consisting of carbomer (polyfacrylic acid), PAA), xantan gum, hydroxyethyl cellulose, guar gum, bentonite, cetyl alcohol, and any combination thereof. In a preferred embodiment, the hydrogel comprises hydroxyethyl cellulose.

[0088] Hydroxyethyl cellulose not only acts as a thickening agent but also improves stability of the bigel by preventing separation of the bigel ingredients. It also provides a smooth, protective layer on the skin, improving hydration. Hydroxyethyl cellulose further enhances spreadability, improving easy application of the bigel on the skin.

[0089] The hydrogel of the bigel comprises water at between 60 and 90 wt% of the hydrogel. In an embodiment, the hydrogel comprises water at between 70 and 80 wt% of the hydrogel, preferably at between 72.5 and 77.5 wt% of the hydrogel, and more preferably at between 74 and 75 wt% of the hydrogel.

[0090] The bigel preferably has a slightly acidic pH, i.e., a pH below 7. The pH of the bigel can be adjusted by addition of at least one pH adjusting agent to the hydrogel. In such an embodiment, the hydrogel comprises the at least one pH adjusting agent at an amount to adjust pH of the bigel at between 3.5 and 6.5, preferably at between 4 and 6.5, more preferably at between 4.5 and 6.5, and most preferably between 5 and 6, such as about 5.5.Illustrative, but non-limiting, examples of pH adjusting agents that could be included in the hydrogel include hydrochloric acid (HCI), citric acid, lactic acid, gluconlactone, phosphoric acid, and any combination thereof. In an embodiment, the hydrogel comprises HCI as pH adjusting agent. In another embodiment, the hydrogel comprises citric acid as pH adjusting agent.

[0091] The bigel of the invention is very stable both during its shelf-life and upon application onto the skin. The stability of the bigel may, in an embodiment, be further enhanced by inclusion of at least one emulsifier that can be included to lower the surface tension between the oleogel and the hydrogel. The at least one emulsifier thereby promotes an efficient mixing of the oleogel and the hydrogel into a bigel and reduces the risk of the bigel separating into a lipophilic phase (oleogel) and hydrophilic phase (hydrogel) during storage and / or application.

[0092] Illustrative, but non-limiting, examples of an emulsifier that could be used include glyceryl stearate, cetearyl alcohol, polysorbate 20, polysorbate 80, lecithins, sodium stearoyl lactylate, sorbitan monooleate, PEG-40 hydrogenated castor oil, methyl glucose sesquistearate, PEG methyl glucose sesquistearate, such as PEG-20 methyl glucose sesquistearate, and any combination thereof.

[0093] The at least one emulsifier could be included in the oleogel, such as for methyl glucose sesquistearate, or in the hydrogel, such as for PEG-20 methyl glucose sesquistearat. It is also possible to include at least one emulsifier in the oleogel and at least one emulsifier in the hydrogel.

[0094] The at least one emulsifier can be included at up to 5 wt% of the bigel, preferably at up to 4 wt% of the bigel, and more preferably at up to 3 wt% of the bigel. For instance, the at least one emulsifier can be included at between 0.1 and 5 wt% of the bigel, preferably at between 0.25 and 4 wt% of the bigel, more preferably at between 0.5 and 3 wt% of the bigel, and most preferably at between 1 and 3 wt%, preferably at between 1.5 and 2.5 wt% of the bigel.

[0095] The bigel comprises the hydrogel at between 20 and 60 wt% of the bigel, and the oleogel at between 40 and 80 wt% of the bigel. In a preferred embodiment, the bigel comprises the hydrogel at between 25 and 60 wt% of the bigel and the oleogel at between 40 and 75 wt% of the bigel, preferably the bigel comprises the hydrogel at between 30 and 60 wt% of the bigel and the oleogel at between 40 and 70 wt% of the bigel, more preferably the bigel comprises the hydrogel at between 35 and 60 wt% of the bigel and theoleogel at between 40 and 65 wt% of the bigel, and most preferably the bigel comprises the hydrogel at between 40 and 60 wt% of the bigel and the oleogel at between 40 and 60 wt% of the bigel.

[0096] In another embodiment, the bigel comprises the hydrogel at between 25 and 50 wt% of the bigel, and the oleogel at between 50 and 75 wt% of the bigel. In a preferred embodiment, the bigel comprises the hydrogel at 50 wt% of the bigel and the oleogel at 50 wt% of the bigel.

[0097] The bigel of the invention has anti-inflammatory effects and protects the skin from UV-induced stress as seen in a reduction in inflammatory cytokines induced by UV-irradiation, including TNF-a and IL-1 a. The bigel is compatible with human skin and is regarded as being not irritant. The bigel further has soothing effect on skin discomforts induced by capsaicin and SLS. In particular, the bigel significantly reduced skin redness (erythema), transdermal water lass (TEWL), burning and itching induced by capsaicin or SLS. The bigel was additionally shown to increase skin hydration and decrease skin dryness (desquamation).

[0098] The bigel can thereby be used in treatment of various skin conditions including dry skin, itching skin, eczema, burnt skin, cracked skin, red skin, rosacea, skin irritation, psoriasis, skin inflammation and petechia.

[0099] An aspect of the invention therefore relates to a bigel according to the embodiment for use in treatment of a skin condition selected from the group consisting of dry skin, itching skin, eczema, burnt skin, cracked skin, red skin, rosacea, skin irritation, psoriasis, skin inflammation and petechia. A related aspect of the invention defines use of a bigel according to the embodiment for the manufacture of a medicament for treatment of a skin condition selected from the group consisting of dry skin, itching skin, eczema, burnt skin, cracked skin, red skin, rosacea, skin irritation, psoriasis, skin inflammation and petechia.

[0100] Treating or treatment as used herein and is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results could include, for instance, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized state of disease, i.e., prevent worsening, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission.

[0101] Treating as used herein also encompass preventing a skin condition. Preventing or prophylaxis as used herein and is well understood in the art, means an approach in which a risk of developing a skin conditionis reduced or prevented, including prolonging or delaying development of the skin condition. For instance, a subject predisposed to develop a skin condition, such as due to genetic or hereditary predisposition, could benefit for administration of the bigel to prevent, reduce the risk of, delaying and / or slowing development of the skin condition.

[0102] The bigel of the invention can thereby be used as a medicament.

[0103] The bigel of the invention also has beneficial cosmetic properties to the skin including moisturizing and soothing the skin. The bigel can thereby be for cosmetic use.

[0104] The bigel is applied to and spread onto the skin where a treatment or cosmetic effect is desired. The bigel can be applied in any suitable amount as desired by the subject but typically ranges from 0.5 to 5 mg / cm2, preferably between 0.5 and 2.5 mg / cm2, more preferably between 0.5 and 2 mg / cm2, such as about 0.5 mg / cm2, 0.75 mg / cm2, 1 mg / cm2, 1.25 mg / cm2, 1.5 mg / cm2, 1.75 mg / cm2, or 2 mg / cm2.

[0105] A method of treating a skin condition includes topically applying the bigel onto a skin of a subject suffering from a skin condition. The bigel is preferably applied at the above presented amounts to an affected area of the skin of the subject to thereby treat the skin condition.

[0106] The skin condition is preferably selected from the group consisting of dry skin, itching skin, eczema, burnt skin, cracked skin, red skin, rosacea, skin irritation, psoriasis, skin inflammation and petechia.

[0107] The bigel of the invention can be produced according to various embodiments. One such embodiment is shown in Fig. 1. In this embodiment, the oleogel is produced in steps S1 to S3 and the hydrogel is produced in steps S4 and S6. The oleogel and the hydrogel are then mixed in step S7 to produce the bigel.

[0108] The method comprises mixing, in step S1 , the at least one vegetable oil and the at least one wax at a temperature above room temperature. This step S1 is preferably performed at a temperature selected within an interval of from 40 up to 80°C. If the mixing in step S1 is performed at an elevated temperature above 65°C then the method may optionally comprise allowing the mixture between the at least one vegetable oil and the at least one wax to cool to a temperature equal to or below 65°C. A next step S2 comprises mixing the at least one oil-soluble skin conditioning agent into the optionally cooled mixturebetween the at least one vegetable oil and the at least one wax to form the oleogel. The method optionally comprise cooling the oleogel to room temperature in step S3, preferably while stirring.

[0109] The method also comprises mixing, in step S4, the at least one viscosity controlling agent and water. The mixing in step S4 is preferably performed at room temperature. A next step S5 comprises mixing the at least one water-soluble vitamin and the at least one humectant into the mixture between the at least one viscosity controlling agent and water to form the hydrogel. The mixing in step S5 is preferably performed at room temperature. The method optionally comprises adjusting pH of the hydrogel by addition of the at least one pH adjusting agent in step S6.

[0110] The oleogel produced in steps S1-S3 and the hydrogel produced in steps S4-S6 are then mixed in step S7 to form the bigel. The mixing in step S7 is preferably performed at room temperature.

[0111] If the bigel comprises at least one emulsifier, then the emulsifier(s) can be included in the oleogel and / or in the hydrogel. In the former case, i.e., included in the oleogel, then the emulsifier could be added at step S1 , in between step S1 and S2, or at step S2. In the latter case, i.e., included in the hydrogel, then the emulsifier is preferably added between step S4 and S5. In such a case, the mixture between water and the at least one viscosity controlling agent is preferably heated to an elevated temperature above room temperature, such as within an interval of from 40 up to 60°C, such as about 50°C, prior to or following addition of the at least one emulsifier. The mixture is then preferably mixed at the elevated temperature until the at least one emulsifier has been dissolved. The mixture is then preferably allowed to cool to temperature, preferably while stirring.

[0112] The mixing performed in steps S1-S5, and S7 can be performed using any mixing equipment including, but not limited to, an overhead stirrer or a disperser homogenizer.

[0113] EXAMPLES

[0114] EXAMPLE 1

[0115] The bigels of Examples 1 to 5 were produced according to the manufacturing process outlined in Fig. 1.

[0116] In this manufacturing process, the oleogel was produced in steps S1-S3 and the hydrogel was produced in steps S4-S6. In more detail, the vegetable oils Gojoba oil, sunflower oil and baobad oil) and candelilla wax were mixed at an elevated temperature of 75°C for 10 minutes using an overhead (OH) stirrer(Heidolph RZR 2102) at 1200 rpm. The oil and wax mixture was then allowed to cool to about 65°C followed by addition of ceramide and vitamin E and mixing at 60°C for 10 minutes using the OH stirrer at 1200 rpm. The oleogel was then further mixed while cooling to room temperature (RT, 20-23.5°C).

[0117] The hydrogel was produced by mixing water and hydroxyethyl cellulose (HEC) at RT for 20 minutes using the OH stirrer at 1000 rpm. Urea, vitamins B3 and B5, and glycerin were added to the aqueous HEC solution while mixing at RT for 10 minutes using the OH stirrer. Vitamin C was then added while mixing with the OH stirrer at RT for 10 minutes and the pH of the hydrogel was adjusted by addition of hydrochloric acid (HOI) or citric acid.

[0118] The bigel was then produced by mixing of the oleogel and the hydrogel in step S7 at RT with the OH stirrer for 10 minutes or using a disperser homogenizer (T 25 ULTRA-TURRAX®, I KA, Germany) for 5 minutes. The bigel had a pH of 5.5.

[0119] The following ingredients were used in the following Examples:

[0120] Jojoba oil Jojoba Oil, Henry Lamotte Oils GmbH

[0121] Sunflower oil Sunflower Oil, Henry Lamotte Oils GmbH

[0122] Baobad oil Baobad Oil, Bionord

[0123] Candelilla wax KahlWax 2039L Candelilla, Bionord

[0124] Ceramide DS-CERAmix-V™, Croda Nordica AB

[0125] Vitamin E DL-Alpha-Tocopherol Care, BASF

[0126] Hydroxyethyl cellulose Natrosol™ 250 HX Pharm, Vendico Chemical AB

[0127] Hyaluronic acid HyaPoly® Sodium Hyaluronate CLMW, Silvaco A / S

[0128] Glycerin Mascerol-refined glycerin 99.5 %, Caldic Denmark A / S

[0129] Urea Urea, crystalline pure, Procudan A / S

[0130] Vitamin C Ascorbic acid fine granular, CosTech Chemicals ApS

[0131] Vitamin B5 D-Pantenol, Vendico Chemical AB

[0132] Vitamin B3 Niacinamide, Jubilant Life Sciences NV

[0133] Water Demineralized water, Persano Group A / S

[0134] Citric acid Citric acid monohydrate, Bodotex

[0135] Methyl glucose Glucate™ SS, Lubrizol

[0136] sesquistearateEXAMPLE 2

[0137] The bigel of Example 2 was produced as described in Example 1 and consists of, in percentage by weight of the bigel:

[0138] Oleogel (50 % by weight of the bigel)

[0139] Jojoba oil 17.5 % (35 % by weight of the oleogel)

[0140] Sunflower oil 21.95 % (43.9 % by weight of the oleogel)

[0141] Baobad oil 5 % (10 % by weight of the oleogel)

[0142] Candelilla wax 5 % (10 % by weight of the oleogel)

[0143] Ceramide 0.5 % (1 % by weight of the oleogel)

[0144] Vitamin E 0.05 % (0.1 % by weight of the oleogel)

[0145] Hydrogel (50 % by weight of the bigel)

[0146] Hydroxyethyl cellulose 1 % (2 % by weight of the hydrogel)

[0147] Hyaluronic acid 0.05 % (0.1 % by weight of the hydrogel)

[0148] Glycerin 5 % (10 % by weight of the hydrogel)

[0149] Urea 2 % (4 % by weight of the hydrogel)

[0150] Vitamin C 1 % (2 % by weight of the hydrogel)

[0151] Vitamin B5 1.5 % (3 % by weight of the hydrogel)

[0152] Vitamin B3 2 % (4 % by weight of the hydrogel)

[0153] Water 37.45 % (74.9 % by weight of the hydrogel)

[0154] The bigel was produced by mixing the oleogel and the hydrogel using the OH stirrer.

[0155] EXAMPLE 3

[0156] The bigel of Example 3 was produced as described in Example 1 and consists of, in percentage by weight of the bigel:

[0157] Oleogel (25 % by weight of the bigel)

[0158] Jojoba oil 8.75 % (35 % by weight of the oleogel)

[0159] Sunflower oil 10.975 % (43.9 % by weight of the oleogel)

[0160] Baobad oil 2.5 % (10 % by weight of the oleogel)

[0161] Candelilla wax 2.5 % (10 % by weight of the oleogel)Ceramide 0.25 % (1 % by weight of the oleogel)

[0162] Vitamin E 0.025 % (0.1 % by weight of the oleogel)

[0163] Hydrogel (75 % by weight of the bigel)

[0164] Hydroxyethyl cellulose 1.5 % (2 % by weight of the hydrogel)

[0165] Hyaluronic acid 0.56 % (0.75 % by weight of the hydrogel)

[0166] Glycerin 7.5 % (10 % by weight of the hydrogel)

[0167] Urea 3 % (4 % by weight of the hydrogel)

[0168] Vitamin C 1.5 % (2 % by weight of the hydrogel)

[0169] Vitamin B5 2.25 % (3 % by weight of the hydrogel)

[0170] Vitamin B3 3 % (4 % by weight of the hydrogel)

[0171] Water 55.69 % (74.25 % by weight of the hydrogel)

[0172] The bigel was produced by mixing the oleogel and the hydrogel using the OH stirrer. The same ingredients were used to produce a bigel by mixing the oleogel and the hydrogel using the disperser homogenizer.

[0173] EXAMPLE 4

[0174] The bigel of Example 4 was produced as described in Example 1 and consists of, in percentage by weight of the bigel:

[0175] Oleogel (50 % by weight of the bigel)

[0176] Jojoba oil 18 % (36 % by weight of the oleogel)

[0177] Sunflower oil 22.7 % (45.4 % by weight of the oleogel)

[0178] Baobad oil 5 % (10 % by weight of the oleogel)

[0179] Candelilla wax 3.75 % (7.5 % by weight of the oleogel)

[0180] Ceramide 0.5 % (1 % by weight of the oleogel)

[0181] Vitamin E 0.05 % (0.1 % by weight of the oleogel)

[0182] Hydrogel (50 % by weight of the bigel)

[0183] Hydroxyethyl cellulose 1 % (2 % by weight of the hydrogel)

[0184] Hyaluronic acid 0.05 % (0.1 % by weight of the hydrogel)

[0185] Glycerin 5 % (10 % by weight of the hydrogel)

[0186] Urea 2 % (4 % by weight of the hydrogel)Vitamin C 1 % (2 % by weight of the hydrogel)

[0187] Vitamin B5 1.5 % (3 % by weight of the hydrogel)

[0188] Vitamin B3 2 % (4 % by weight of the hydrogel)

[0189] Water 37.45 % (74.9 % by weight of the hydrogel)

[0190] The bigel was produced by mixing the oleogel and the hydrogel using the OH stirrer. The same ingredients were used to produce a bigel by mixing the oleogel and the hydrogel using the disperser homogenizer.

[0191] EXAMPLE 5

[0192] The bigel of Example 5 was produced as described in Example 1 and consists of, in percentage by weight of the bigel:

[0193] Oleogel (50 % by weight of the bigel)

[0194] Jojoba oil 18 % (36 % by weight of the oleogel)

[0195] Sunflower oil 22.7 % (45.4 % by weight of the oleogel)

[0196] Baobad oil 5 % (10 % by weight of the oleogel)

[0197] Candelilla wax 3.75 % (7.5 % by weight of the oleogel)

[0198] Ceramide 0.5 % (1 % by weight of the oleogel)

[0199] Vitamin E 0.05 % (0.1 % by weight of the oleogel)

[0200] Hydrogel (50 % by weight of the bigel)

[0201] Hydroxyethyl cellulose 1.1 % (2.2 % by weight of the hydrogel)

[0202] Hyaluronic acid 0.05 % (0.1 % by weight of the hydrogel)

[0203] Glycerin 5 % (10 % by weight of the hydrogel)

[0204] Urea 2 % (4 % by weight of the hydrogel)

[0205] Vitamin C 1 % (2 % by weight of the hydrogel)

[0206] Vitamin B5 1.5 % (3 % by weight of the hydrogel)

[0207] Vitamin B3 2 % (4 % by weight of the hydrogel)

[0208] Water 37.35 % (74.7 % by weight of the hydrogel)

[0209] The bigel was produced by mixing the oleogel and the hydrogel using the OH stirrer.

[0210] EXAMPLE 6This example evaluated the anti-inflammatory effects of the bigel according to Example 4 on human skin explants ex vivo.

[0211] Materials and Methods

[0212] 19 human skin explants of an average diameter of 11±1 mm were prepared on an abdoplasty coming from a 46-year-old woman with a phototype II according to Fitzpatrick skin color classification. The skin explants were kept in survival in BEM culture medium (BIO-EC’s Explants Medium) at 37°C in a humid, 5 % CO2 atmosphere, in the dark.

[0213] Bigel application

[0214] The bigel was applied topically on the basis of 2 L per explant of 1 cm2(«2 mg / cm2) and spread using a small spatula on day 0 (DO), D1 and on D4 (before UV exposure). The control explants did not receive any treatment except the renewal of culture medium. The culture medium was half renewed (1 ml per well) on D1 and entirely (2 ml per well) on D4.

[0215] Table 1 - skin explant

[0216] Batch Conditions No. of explants Sampling time CO Tissue control 3 DO c Non-treated control 4 D5 T Treated with bigel 4 D5 c-uv UVA 4 MED + UVB 4 MED 4 D5 T-UV Treated with bigel + UVA 4 MED + UVB 4 MED 4 D5

[0217]

[0218] UV irradiations

[0219] On D4, the culture media of all the batches was replaced by 1 mL Hank’s balanced saline solution (HBSS) per explant. The explant batches were irradiated using a UV simulator Vibert Lourmat RMX 3W with a dose of 18 J / cm2of UV-A corresponding to 4 minimal erythemal dose (MED) and a dose of 0.6 J / cm2of UV-B corresponding to 4 MED. The unirradiated explant batches were kept in HBSS in the dark. At the end of the irradiation, all the explants were put back in 2 mL of fresh BEM culture medium.

[0220] Sampling

[0221] On DO, the 3 explants from the batch CO were collected and cut in two parts. Half was fixed in buffered formalin solution and half was frozen at-80°C. On D5, 24 hours after the end of the irradiation, 3 explantsfrom the concerned batches were collected and treated in the same way than in DO. The culture media (2 mL) of each sample was collected on day 5 and stored at -20°C for further analysis

[0222] Histological processing

[0223] After fixation for 24 hours in buffered formalin, the samples were dehydrated and impregnated in paraffin using a Leica PEARL dehydration automat. The samples were embedded using a Leica EG 1160 embedding station. 5 pm thick sections were made using a Leica RM 2125 Minot-type microtome, and the sections were mounted on Superfrost® histological glass slides. The microscopical observations were performed using a Leica DMLB, an Olympus BX43 or BX63 microscope. Pictures were digitized with a numeric DP Olympus camera with CellSens storing software.

[0224] Cell viability

[0225] The cell viability of the epidermal and dermal structures was assessed by microscopical observation of formalin-fixed paraffin embedded (FFPE) skin sections after Masson’s trichrome staining, Goldner variant. The staining was assessed microscopical observation.

[0226] TNF-a

[0227] TNF-a immunostaining was performed on frozen skin sections with a polyclonal anti-TNF-a antibody (R&D system, ref. AF-410-NA) diluted at 1:50 in phosphate buffered saline - bovine serum albumin 0.3 % (PBS-BSA 0.3%) and incubated over night at room temperature and revealed by Alexa Fluor 488 (Lifetechnologies, ref. A11078). The nuclei were counterstained with propidium iodide. The immunostaining was semi-quantified by image analysis using the software cellSens (Olympus). Nine images were analyzed per batch.

[0228] Dosage oflL-1a

[0229] I L-1 oc dosage was performed with human I L-1 oc ELISA kit (Cayman, ref. 583301). According to provider’s guidelines, the culture medium and the I L-1 a standard were incubated with acetylcholinesterase (AChE) Fab’ conjugate binding IL-1 oc in wells which contained coated IL-1 a antibody, overnight at 4°C. After well plate washing, the reaction was revealed with a solution containing AChE substrate. Absorbance at 412 nm was measured using the M200Pro Tecan microplate reader and Magellan? software. IL-1 a assay was performed on culture BEM media collected for all batches, except TO. The concentration of I L-1 a was expressed in pg / mL.Image analysis method

[0230] The image analysis was performed on all the images of each batch, according to the following method using CellSens software:

[0231] • determination of the region of interest (ROI) in the immunostained images, i.e., the epidermis, resulting in an ROI mask;

[0232] • detection of immunostaining by selecting the pixels corresponding to the immunostaining by thresholding, resulting in an immunostaining mask;

[0233] • selection of the immunostaining in the ROI by combination of the ROI mask and the immunostaining mask; and

[0234] • measurement of the surface of the epidermis, measurement of the surface of the immunostaining in the epidermis and calculation of the percentage of surface of the epidermis covered by the immunostaining staining.

[0235] Stained surfaces comparisons

[0236] The stained surface percentage (Surf%) for the treatment was compared to the untreated condition, i.e., C vs. T. The same comparison is made for the exposed batches, i.e., C-UV vs. T-UV.

[0237] Statistical analysis

[0238] Statistical analysis was performed using classical Student t-test. The tests were carried out in bilateral mode on two samples of supposedly different variances (heteroscedastic).

[0239] # significant with p<0.1 (90%)

[0240] * significant with p<0.05 (95%)

[0241] ** significant with p<0.01 (99%)

[0242] ns non-significant

[0243] Results

[0244] Cell viability

[0245] The results of the cell viability tests are presented in Table 2.

[0246] Table 2 - cell viability

[0247] Cell viability

[0248] Batch

[0249] Epidermis Dermis

[0250] CO G G

[0251]

[0252] c FG G T FG G

[0253] C-UV SA G

[0254] T-UV SA G

[0255]

[0256] G: good; FG: fairly good; SA: sligh tly altered

[0257] On DO, the cell viability was good in the epidermis and in the papillary dermis for the batch CO.

[0258] On D5, the cell viability was fairly good in the epidermis and good in the papillary dermis for both the control batch C and the treated batch T. There were no differences in cell viability between the treated and the non-treated explant batches at D5 (C vs. T). The UV irradiations induced slight epidermal alterations compared to the non-irradiated batches at D5 (C vs. C-UV; T vs. T-UV). There were no differences in cell viability between the treated and the non-treated explant batches following UV irradiation at D5 (C-UV vs. T-UV).

[0259] TNF-a

[0260] Fig. 2 illustrates the surface percentage positive to TNF-a immunostaining in epidermis on D5 for the non-irradiated explant batches (C, T) and the UV-irradiated explant batches (C-UV, T-UV). There was no significant difference in TNF-a staining between untreated control (C) and bigel treated (T) explant batches when not exposed to any irradiation. UV irradiation induced a significant increase of TNF-a immunostaining in the epidermis as compared to non-irradiated explant batches (C-UV vs. C). Treatment of the explant batches of the bigel prior to UV-irradiation significantly reduced TNF-a immunostaining with 39 % (p<0.01) (T-UV vs. C-UV).

[0261] IL-1 a

[0262] Fig. 3 illustrates the release of IL-1 a into the culture medium from the explant batches on D5 for the nonirradiated explant batches (C, T) and the UV-irradiated explant batches (C-UV, T-UV). There was a slight increase in IL-1 a for the bigel treated explant batches (T) as compared to non-treated explant batches (C) when not exposed to any irradiation. UV irradiation induced a significant increase of IL-1 a release as compared to non-irradiated explant batches (C-UV vs. C). Treatment of the explant batches of the bigel prior to UV-irradiation reduced IL-1 a release with 28 % (T-UV vs. C-UV: 94.3±28.6 pg / mL vs. 130.8±90.9 pg / mL).The conclusions from this example were that the bigel was well tolerated by the human skin explants ex vivo and that the bigel induced a significant decrease ofTNF-a synthesis and a decrease in I L-1 oc release upon UV-A and UV-B exposure. The results thereby indicate that the bigel had anti-inflammatory effects on the skin explants.

[0263] EXAMPLE 7

[0264] The bigel of Example 7 consists of, in percentage by weight of the bigel:

[0265] Oleogel (50 % by weight of the bigel)

[0266] Jojoba oil 18 % (36 % by weight of the oleogel)

[0267] Sunflower oil 22.7 % (45.4 % by weight of the oleogel)

[0268] Baobad oil 5 % (10 % by weight of the oleogel)

[0269] Candelilla wax 3.75 % (7.5 % by weight of the oleogel)

[0270] Ceramide 0.5 % (1 % by weight of the oleogel)

[0271] Vitamin E 0.05 % (0.1 % by weight of the oleogel)

[0272] Hydrogel (50 % by weight of the bigel)

[0273] Hydroxyethyl cellulose 1 % (2 % by weight of the hydrogel)

[0274] Hyaluronic acid 0.05 % (0.1 % by weight of the hydrogel)

[0275] Glycerin 5 % (10 % by weight of the hydrogel)

[0276] Urea 2 % (4 % by weight of the hydrogel)

[0277] Vitamin C 1 % (2 % by weight of the hydrogel)

[0278] Vitamin B5 1.5 % (3 % by weight of the hydrogel)

[0279] Vitamin B3 2 % (4 % by weight of the hydrogel)

[0280] Methyl glucose 2 % (4 % by weight of the hydrogel)

[0281] sesquistearate

[0282] Water 35.45 % (70.9 % by weight of the hydrogel)

[0283] The bigel of Example 7 was produced as described in Example 1 but with the following differences. The mixture between water and HEC was heated to 50°C while stirring with the OH stirrer and methyl glucose sesquistearate was added to the mixture. Once methyl glucose sesquistearate had dissolved the heating was stopped allowing the mixture to cool to room temperature while stirring with the OH stirrer. The continued process as disclosed in Example 1 was followed for the production of the hydrogel.The bigel was produced by mixing the oleogel and the hydrogel using the OH stirrer.

[0284] EXAMPLE 8

[0285] This example evaluated the compatibility with human skin (irritant potential) under normal conditions of use and reasonably foreseeable misuse conditions of the bigel according to Example 4.

[0286] Materials and Methods

[0287] The bigel was used in a single application by a closed patch epicutaneous assay, on the healthy skin of the back, in 20 volunteers, males orfemales, of age between 18 and 65 years.

[0288] The bigel was left in contact with the skin for 48 hours (model Curatest® F, adhesive strips for patch test, Lohmann and Rauscher International GMBH and Co., Rengsdorf, Germany) in sufficient amount to fill one 1 cm2test disk (approximately 0.07-0.1 ml). The assessment was made by comparison with a "negative control” in the form of an empty patch.

[0289] A positive control consisting of an internal sample with known irritative potential was also inserted monthly. Fifteen minutes and 24 hours after patch removal the skin reactions were evaluated according to defined parameters (erythema, desquamation, oedema and vesicles).

[0290] At each observational time (15 min and 24 h after patch removal) the application area was carefully examined by two evaluators, separately, for the parameters reported in Table 3. Each parameter was scored with values ranging from 0 to 3 to express increasing severity of the observed reactions. Any other undesirable local reaction and subjective effect were also observed and registered.

[0291] Table 3 - Evaluation scale for skin reactions

[0292] Erythema Oedema Dryness / Desquamation Vesicles Score None None No signs None 0

[0293] Slight oedema

[0294] Dryness with light Very small

[0295] Slight erythema, (edges of area

[0296] desquamation (smooth vesicles (barely 1 hardly noticeable well defined by

[0297] skin) visible)

[0298] definite raising)

[0299]

[0300] Clearly visible,

[0301] Moderate

[0302] Moderate and small vesicles

[0303] oedema (raised Moderate desquamation 2 uniform redness (well-defined

[0304] ca 1 mm)

[0305] contours)

[0306] Severe and Severe oedema

[0307] uniform redness (raised >1 mm

[0308] Large, well- (with / without and extending Severe desquamation 3

[0309] defined vesicles

[0310] wounds and / or beyond area of

[0311] eschar) exposure)

[0312]

[0313] Scores assigned by both evaluators, for erythema, desquamation, oedema and vesicle were registered for each volunteer. They were cumulatively considered. This allowed extrapolation of the Mean Irritation Index (Mil). By comparing the results obtained by each evaluator, the bigel was classified on the basis of the highest average irritation index, according to the ranges of values indicated in Table 4.

[0314] Table 4 - Product classification based on Mil

[0315] Mil Class

[0316] < 0.4 Not irritant 0.5 < Mil < 1.9 Slight irritant 2.0 < Mil < 4.9 Moderate irritant 5.0 < 8.0 Strongly irritant

[0317]

[0318] Results were interpreted according to ISO 10993-23:2021 - “Biological evaluation of medical devices — Part 23: Tests for irritation” which applies a 0.4 cut-off for positive outcomes. The effect of modest reactivity, which is often observed due to the exaggerated exposure conditions of this test, did not influence the final interpretation. The Mil scores were rounded up to the first decimal place.

[0319] Results

[0320] The results of the Mil evaluation are presented in Table 5.

[0321] Table 5 - Mil evaluation

[0322] Product Concentration MH at 15 min MH at 24 h Bigel Pure 0 0.1 Control Empty 0 0

[0323]

[0324] The bigel was accordingly classified as not irritant.

[0325] EXAMPLE 9

[0326] This example evaluated the soothing effect of the bigel according to Example 4 on skin discomforts induced by capsaicin.

[0327] Materials and Methods

[0328] In order to evaluate the soothing effect of the bigel, a stinging test with a solution of capsaicin was carried out on both nasolabial folds to induce an itching or stinging sensation.

[0329] The following parameters were evaluated:

[0330] Skin redness on picture acquired by Antera® 3D, at TO (when the discomfort was at its maximum peak, generally after 2 / 3 minutes from the application of capsaicin), before the product application, at T5 min, T10 min and T15 min after the bigel application;

[0331] Clinical evaluation of skin redness on picture acquired by Visia® - 7 Canfield (red filter) on Likert scale (1-5) at TO (when the discomfort was at its maximum peak, generally after 2 / 3 minutes from the application of capsaicin), before the product application, at T5 min, T10 min and T15 min after the product application; and

[0332] Subjective evaluation of the perceived burning and itching sensation in the treated area and control area by VAS (Visual Analog Score) from 0 (no discomfort) to 10 (very strong discomfort) at TO (when the discomfort was at its maximum peak, generally after 2 / 3 minutes from the application of capsaicin) before the product application, at T1 min, T2 min, T3 min, T4 min, T5 min, T10 min and T15 min after the product application.

[0333] The study was carried out on 20 volunteers between the ages of 18 and 65 years, of both sexes, who were found to be sensitive to the capsaicin stinging test.

[0334] The soothing efficacy of the bigel was evaluated by applying capsaicin to the nasolabial folds. Following application to one side of the face, the bigel was applied:

[0335] 10 subjects applied 2 mg / cm2of the test product on the treated area; and

[0336] 10 subjects applied 1 mg / cm2of the test product on the treated area.

[0337] The contralateral side of the face was used as a control area.In order to evaluate the soothing effect of the test product, a stinging test with a solution of 0.1 % capsaicin was carried out on both nasolabial folds to induce itching and / or burning sensation.

[0338] Subsequently, after the onset of symptoms, the two skin areas were treated as follows, according to a previously defined randomization scheme:

[0339] 1 area was treated with the bigel (10 subjects with 2 mg / cm2and 10 subjects with 1 mg / cm2); 1 area was left untreated as negative control.

[0340] The treatment has been carried out for about 15 minutes for each volunteer.

[0341] The selection of volunteers was based on the stinging test, in which capsaicin was first dissolved in 95% ethanol and then prepared in five dilution steps between 3.16 x 10-3% and 3.16 x 10-5% in 10% ethanol. Volunteers’ nasolabial folds were first cleaned with 10 % ethanol to let them get use to the feeling. Then the most diluted preparation of capsaicin was topically applied on one side with a cotton swab (17 ± 2 pl) together with 10% ethanol in the other fold, as control. If the volunteer did not feel a difference between the two sides within 3 min the next concentration was applied. The detection threshold was set to the concentration when volunteers identified a difference between capsaicin and ethanol, and the sensation was experienced for more than 30 s. The side for application of capsaicin and ethanol was changed between each step and volunteers did not know on what side capsaicin was applied. Those who tested positive were then recruited, and before each measurement, each volunteer was allowed to relax for about 10 minutes in an air-conditioned room to avoid abnormal samples due to excessive sweating, stress, or particular external conditions.

[0342] The assessment of red skin redness using Antera® 3D is one of the most advanced applications of dermatological imaging technology. Red areas are typically associated with increased superficial vascularisation, capillary dilation (telangiectasia), inflammation, or reactive hyperaemia. Accurate understanding of the nature, intensity, and distribution of these manifestations is essential for both differential diagnosis and clinical monitoring. This is the average concentration of hemoglobin per unit area relative to the selected area. Antera® 3D camera uses multispectral photometry, a technology that analyses light reflection at different wavelengths to determine the chromatic composition of the skin. In particular, the red component of the skin is mainly determined by the presence of hemoglobin in the superficial blood vessels. Through spectral analysis, Antera® 3D is able to selectively isolate and quantifythe light absorption associated with hemoglobin, generating a detailed hemoglobin map of the examined area.

[0343] The measurement of skin redness was performed using the Visia® - 7 Canfield, which rotates smoothly around the subject to easily photograph left, right, and frontal facial views. The multi-point positioning system and live image overlay facilitate the acquisition of perfectly recorded images to document progress over time. The VISIA® - 7 Canfield uses RBX® technology to analyze skin color variations, allowing it to detect and quantify redness as well as other skin characteristics based on their color and intensity.

[0344] Feature counting provides a count of the number of discrete instances of the assessed feature, regardless of the size or intensity of each instance. Feature counting can be used to monitor treatment progress when it is desired to reduce the number of discrete instances of a particular feature. The parameter of redness was assessed by feature counting.

[0345] To assess the perception of burning and itching sensations, each volunteer was asked to indicate at TO (after capsaicin application), and after 1 (T1 min), 2 (T2 min), 3 (T3 min), 4 (T4 min), 5 (T5 min), 10 (T10 min) and 15 (T15 min) minutes after application of the bigel, the burning and itching sensation using a score from 0 (no discomfort) to 10 (very strong discomfort) on a VAS scale.

[0346] Results

[0347] Fig. 4 illustrates mean skin redness values of the treated area and the untreated area (treated only with capsaicin), compared with inter-group analysis. Redness increased significantly at T5, T10 and T15 minutes on the untreated side. There were no significant increase in redness at T5, T10, or T15 minutes on the treated side. Further, compared to the untreated area, there was significant differences at T10 and T15 minutes in the treated area.

[0348] According to clinical evaluations, the bigel did not exacerbate skin redness after 5, 10, or 15 minutes of use. Instead, the untreated area showed a significant increase in skin redness at both 10 and 15 minutes.

[0349] Fig. 5 illustrates median value of burning in the treated area and the untreated area (treated only with capsaicin), compared with inter-group analysis.According to subjective evaluation about burning, the treated area (both with 2 mg / cm2and 1 mg / cm2) showed a statistically significant reduction at Timm (just after the bigel application) at T5, T10 and T15 minutes after the bigel application. There was also a statistically significant difference between the treated area and the untreated area at Timm (just after the bigel application), T1, T2, T3, T4 and T15 minutes after the bigel application.

[0350] Fig. 6 illustrates median value of itching in the treated area and the untreated area (treated only with capsaicin), compared with inter-group analysis.

[0351] According to subjective evaluation about itching, the treated area (both with 2 mg / cm2and 1 mg / cm2) showed a statistically significant reduction at T15 minutes after the product application. There was also a statistically significant difference between the treated area and the untreated area at Timm (just after the bigel application), T1, T2, T3, T4, T5 and T10 minutes after the bigel application.

[0352] EXAMPLE 10

[0353] This example evaluated the soothing effect of the bigel according to Example 4 on skin discomforts induced in laboratory under controlled conditions through chemical stress (SLS).

[0354] Materials and Methods

[0355] The soothing efficacy of the product was evaluated by applying 2 patches soaked in a 2% solution of SLS (sodium lauryl sulfate) to the inner surface of the forearm and kept in contact with the skin for 24 hours. After removal of the plaster, the two areas were treated as follows:

[0356] 1 area was treated with the bigel (10 subjects with 2 mg / cm2and 10 subjects with 1 mg / cm2); 1 area was left untreated as negative control.

[0357] The following parameters were evaluated:

[0358] Skin redness (Erythema index) by means of a measuring instrument capable of determining the skin hemoglobin content (erythema) of the skin, Mexameter® MX18, at basal Tb (before SLS patch application), at TO (after SLS patch removal), T15 min, T30 min and T2 h after the bigel application;

[0359] TEWL, by means of the Tewameter® TM300 instrument capable of measuring transepidermal water loss (TEWL) at basal Tb (before SLS patch application), at TO (after SLS patch removal), T15 min, T30 min and T2 h after the bigel application;

[0360] Instrumental images of skin redness were acquired with Antera® 3D at basal Tb (before SLS patch application), at TO (after SLS patch removal), T15 min, T30 min and T2 h after the bigel application.The study was carried out on 20 volunteers between the ages of 18 and 65 years, of both sexes, who were found to be sensitive to the capsaicin stinging test.

[0361] In order to assess the soothing effect of the bigel, a measurement was taken using Mexameter® prior to application of the patch in order to determine the basal skin hemoglobin content (erythema index) and a TEWL measurement. After removal of the patch, the erythema and TEWL values were measured again in all areas (TO). Immediately after the measurement, one area was treated with the bigel (10 subjects with 2 mg / cm2and 10 subjects with 1 mg / cm2) and one area remained untreated as a negative control. The same parameters (erythema index and TEWL) were measured 15, 30 minutes and 2 hours after application of the bigel.

[0362] Before each measurement, each volunteer was allowed to relax for approximately 10 minutes in an airconditioned room to avoid anomalous sampling due to excessive sweating or stress or peculiar external conditions.

[0363] The measurement of the skin erythema value E through Mexameter® MX18 is based on the principle of light absorption / reflection by the skin. The special probe of the Mexameter® MX18 emits light at three different wavelengths while a detector simultaneously measures the light reflected by the skin. The relative positions of the source and the detector ensures that only diffused and scattered light is measured. Since the quantity of emitted light is defined, the quantity of light absorbed by the skin can be calculated. As mentioned, for the measurement of erythema three different wavelengths are used; the first one corresponds to the spectral absorption peak of hemoglobin, whereas the other two were chosen to avoid influences of other colorimetric pigments (e.g., bilirubin). The results of measurements are shown on a digital display on a scale from 0 to 999 and expressed with the parameter E (erythema). The probe is very sensitive as compared with visual observation and shows a wide scale of values of erythema (0-999), which allows to accurately monitor extremely little variations in the color of interest.

[0364] The measurement of TEWL using Tewameter® TM300 (Courage-Khazaka GmbH, Germany) is an internationally accepted standard method of measurement. The measurement of water evaporation is based on the principle of diffusion in an open chamber. The measurement method with the open chamber is the only method to evaluate the TEWL continuously. The instrument is an evaporimeter that measures the water vapor released from a surface, through Fick's law:m / dt=-D x A x dp / dx

[0365] wherein A = surface (m2), m = water transported (g), t = time (hours), D = diffusion constant (0.0877 g / m (h (mm Hg)), p = atmospheric vapor pressure (mm Hg), x = distance between the skin surface and the measurement point (m).

[0366] The diffusion law dm / dt shows the amount of water transported by cm2in a unit time (hours); TEWL values are measured in g / h / m2. The degree of water vapor diffusion is directly dependent on the relative environmental humidity, on the integrity of the skin barrier, on temperature, and in reverse, on the thickness of stratum corneum.

[0367] Results

[0368] Fig. 7 illustrates mean erythema values of the treated area and the untreated area, compared with intergroup analysis. There was a reduction in erythema in the treated area of -5.7% after 15 minutes, -6.9% after 30 minutes, -12.2% after 2 hours following application of the bigel, compared to the values measured after removal of the patch with SLS (TO). The reduction in erythema was statistically significant.

[0369] Fig. 8 illustrates mean TEWL values of the treated area and the untreated area, compared with intergroup analysis. There was a reduction in TEWL in the treated area of -16.4% after 15 minutes, -16.0% after 30 minutes and -22.2% after 2 hours following application of the bigel, compared to the values measured after removal of the patch with SLS (TO). The reduction in TEWL was statistically significant.

[0370] EXAMPLE 11

[0371] This example evaluated the soothing effect of the bigel according to Example 4 against skin discomforts typical of sensitive, dry and reactive skin under normal condition of use in 20 healthy volunteers.

[0372] Materials and Methods

[0373] The following parameters were analyzed:

[0374] Corneometric analysis of skin hydration using Corneometer® CM825, before application (TO) and after 7 and 14 days (T7d and T14d), following bigel use.

[0375] Analysis of transepidermal water loss (TEWL) using Tewameter® TM300, before application (TO) and after 7 and 14 days (T7d and T14d), following bigel use.Clinical evaluation of skin erythema, dryness / desquamation using a 0-3 scale (absent - evident), before application (TO) and after 7 and 14 days (T7d and T14d), following bigel use.

[0376] Subjective evaluation of itching sensation using a VAS (Visual Analogue Scale), ranging from 0 (no discomfort) to 10 (very strong discomfort), before application (TO) and after 7 and 14 days (T7d and T14d), following bigel use.

[0377] Additionally, 24 hours after the first bigel application and at the end of the study, volunteers completed a self-assessment questionnaire to express their opinion on organoleptic characteristics, pleasantness and efficacy of the product.

[0378] The study was carried out on 20 healthy male and female volunteers, aged between 18 and 65 years, with sensitive, dry, and reactive skin, presenting discomforts typical of this skin type (such as a tendency to redness, skin tightness, and itching).

[0379] The study was conducted under standard environmental conditions at each measurement time point, monitoring and maintaining constant environmental temperature and humidity. The test was carried out on the body. The analysis of skin hydration and TWEL were performed on the tibial area. The treatment lasted 14 consecutive days for each volunteer.

[0380] The bigel was applied to the body. Half of the test panel used the product once a day, and the other half used it twice a day. Before each measurement, each volunteer was allowed to relax for approximately 10 minutes in a climate-controlled room to avoid anomalous sampling due to excessive sweating or stress.

[0381] The measurement of skin hydration using the Corneometer® CM825 (Courage-Khazaka GmbH, Germany) is a widely accepted and recognized technology in evidence-based biomedical research. This method is based on determining the capacitance of the superficial stratum corneum. Similar to other biophysical skin parameters, this measurement depends on various environmental physical factors, such as humidity and temperature, which must be strictly controlled. The ideal measurement conditions are 20 °C and 50% relative humidity. The Corneometer® CM825 measures the capacitance of the epidermis, which is proportional to its water content, at a depth of approximately 15 pm. This method relies on the difference in relative electric permittivity between water (= 81) and most other substances (< 7). The Corneometer® probe (49 mm2surface area) is positioned vertically on the test area of the skin. The measurement of capacitance lasts one second. Each measurement is performed in triplicate, and themean value is recorded. Values are expressed by the instrument in arbitrary units ranging from 0 to 120. The accuracy of the measurements is ± 3%.

[0382] The measurement of transepidermal water loss (TEWL) using Tewameter® TM300 (Courage-Khazaka GmbH, Germany) was performed as described in Example 10.

[0383] The clinical evaluation of skin erythema, and dryness / desquamation was performed before application (TO), after 7 and 14 days (T7d and T14d) of bigel use. The parameters were assessed using a 0-3 scale (0- absent, 1 - slight, 2 -moderate, 3 -evident) to express the different levels of visibility of the observed condition.

[0384] The subjective evaluation of itching sensation was performed before application (TO), after 7 and 14 days (T7d and T14d) of bigel use. The parameter was assessed using a VAS, ranging from 0 (no discomfort) to 10 (very strong discomfort): each volunteer was asked to indicate the intensity of the perceived discomfort at the different analysis time points.

[0385] Results

[0386] Fig. 9 illustrates mean hydration values, expressed in A.U., with intra-group analysis. There was an increase in skin hydration by 16.0 % after 7 days and by 19.4% after 14 days of bigel use. These variations were statistically significant compared to TO.

[0387] Fig. 10 illustrates mean TEWL values, expressed in g / m2 / h, with intra-group analysis. There was a decrease in TEWL by -19.3 % after 7 days and by -23.5 % after 14 days of bigel use. These variations were statistically significant compared to TO.

[0388] Fig. 11 illustrates median values of the clinical evaluation of erythema. There was a decrease in skin erythema, from a median value of slight to a median value of absent after 7 and 14 days of bigel use. These improvements were statistically significant compared to TO. Specifically, an improvement in skin erythema was observed in 94% of subjects after 7 days and in 100% of subjects after 14 days.

[0389] Fig. 12 illustrates median values of the clinical evaluation of skin dryness / desquamation. There was a decrease in skin dryness / desquamation, from a median value of moderate to a median value of slight after 7 days and to a median value of absent after 14 days of bigel use. These improvements werestatistically significant compared to TO. Specifically, an improvement in skin dryness / desquamation was observed in 90% of subjects after 7 days and in 100% of subjects after 14 days.

[0390] Fig. 13 illustrates median values of the subjective evaluation of itching sensation. There was a decrease in itching sensation, from a median value of 5 to a median value of 3 after 7 days, and to a median value of 1 after 14 days of bigel use. These improvements were statistically significant compared to TO. Specifically, an improvement in skin dryness / desquamation was observed in 100% of subjects after 7 and 14 days.

[0391] Tables 6 and 7 summarize the ratings given by the test subjects on the bigel.

[0392] Table 6 - Questionnaire

[0393] Strongly Neither agree Strongly Agree Disagree

[0394] agree nor disagree disagree Bigel reduces skin dryness 80% 20% 0% 0% 0% Bigel reduces skin itching feeling 60% 40% 0% 0% 0% Bigel reduces skin redness 50% 37.5% 12.5% 0% 0% Bigel is suitable for sensitive and

[0395] 70% 30% 0% 0% 0% reactive skin

[0396] Bigel is easy to apply 70% 30% 0% 0% 0% Bigel is not sticky and absorbs quickly 50% 40% 10% 0% 0%

[0397]

[0398] Table 7 - Questionnaire

[0399] Yes No Have you experienced any adverse reactions caused by the bigel? 0% 100% Would you recommend this product to a friend? 100% 0%

[0400]

[0401] The embodiments described above are to be understood as a few illustrative examples of the present invention. It will be understood by those skilled in the art that various modifications, combinations and changes may be made to the embodiments without departing from the scope of the present invention. In particular, different part solutions in the different embodiments can be combined in other configurations, where technically possible.

Claims

CLAIMS1. A bigel comprising:an oleogel at between 40 and 80 % by weight of the bigel; anda hydrogel at between 20 and 60 % by weight of the bigel, whereinthe oleogel comprises:at least one vegetable oil at between 70 and 98 % by weight of the oleogel; at least one wax at between 1 and 30 % by weight of the oleogel; andat least one oil-soluble skin conditioning agent at between 0.1 and 10 % by weight of the oleogel; andthe hydrogel comprises:water at between 60 and 90 % by weight of the hydrogel;at least one water-soluble vitamin at between 1 and 20 % by weight of the hydrogel; at least one humectant at between 10 and 30 % by weight of the hydrogel; at least one viscosity controlling agent at between 0.1 and 10 % by weight of the hydrogel; andoptionally at least one pH adjusting agent.

2. The bigel according to claim 1, wherein the oleogel comprises the at least one vegetable oil at between 75 and 95 wt% % by weight of the oleogel, preferably at between 80 and 95 % by weight of the oleogel, more preferably at between 85 and 95 % by weight of the oleogel, and most preferably at between 87.5 and 92.5 % by weight of the oleogel.

3. The bigel according to claim 1 or 2, wherein the oleogel comprises the at least one wax at between 2.5 and 25 % by weight of the oleogel, preferably at between 2.5 and 20 % by weight of the oleogel, more preferably at between 2.5 and 15 % by weight of the oleogel, and most preferably at between 5 and 12.5 % by weight of the oleogel.

4. The bigel according to any one of claims 1 to 3, wherein the at least one vegetable oil is selected from the group consisting of jojoba oil, sunflower oil, baobad oil, olive oil, canola oil, coconut oil, flaxseed oil, oat oil, and any combination thereof, preferably selected from the group consisting of jojoba oil, sunflower oil, baobad oil, and any combination thereof, and more preferably a combination of jojoba oil, sunflower oil, and baobad oil.

5. The bigel according to claim 4, wherein the oleogel comprises jojoba oil at between 30 and 40 % by weight of the oleogel, preferably at between 32.5 and 37.5 % by weight of the oleogel.

6. The bigel according to claim 4 or 5, wherein the oleogel comprises sunflower oil at between 40 and 50 % by weight of the oleogel, preferably at between 42.5 and 47.5 % by weight of the oleogel.

7. The bigel according to any one of claims 4 to 6, wherein the oleogel comprises baobad oil at between 5 and 15 % by weight of the oleogel, preferably at between 7.5 and 12.5 % by weight of the oleogel.

8. The bigel according to any one of claims 1 to 7, wherein the at least one wax is selected from the group consisting of candelilla wax, jojoba wax, carnauba wax, soy way, beeswax, rapeseed wax, rose was, and any combination thereof, preferably candelilla wax.

9. The bigel according to claim 8, wherein the oleogel comprises candelilla wax at between 5 and 12.5 % by weight of the oleogel.

10. The bigel according to any one of claims 1 to 9, wherein the oleogel comprises the at least one oilsoluble skin conditioning agent at between 0.25 and 7.5 % by weight of the oleogel, preferably at between 0.5 and 5 % by weight of the oleogel, more preferably at between 0.75 and 2.5 % by weight of the oleogel, and most preferably at between 1 and 2 wt% % by weight of the oleogel.

11. The bigel according to any one of claims 1 to 10, wherein the at least one oil-soluble skin conditioning ingredient is selected from the group consisting of at least one ceramide, at least one oilsoluble vitamin, glycerin, squalane, cholesterol, at least one fatty acid, and any combination thereof, preferably selected from the group consisting of at least one ceramide, at least one oil-soluble vitamin, and any combination thereof, and more preferably a combination of at least one ceramide and at least one oil-soluble vitamin.

12. The bigel according to claim 11 , wherein the oleogel comprises at least one ceramide at between 0.25 and 7.5 % by weight of the oleogel, preferably at between 0.5 and 5 % by weight of the oleogel, more preferably at between 0.75 and 2.5 % by weight of the oleogel, and most preferably at about 1 % by weight of the oleogel.

13. The bigel according to claim 11 or 12, wherein the at least one ceramide is selected from the group consisting of ceramide 1, ceramide 2, ceramide 3, ceramide 6-II, ceramide 9, a sphingolipid, and any combination thereof.

14. The bigel according to any one of claims 11 to 13, wherein the oleogel comprises at least one oilsoluble vitamin at between 0.025 and 1 % by weight of the oleogel, preferably at between 0.05 and 0.75 % by weight of the oleogel, more preferably at between 0.075 and 0.5 % by weight of the oleogel, and most preferably at between 0.075 and 0.25 % by weight of the oleogel, such as at about 0.1 % by weight of the oleogel.

15. The bigel according to any one of claims 11 to 14, wherein the at least one oil-soluble vitamin is selected from the group consisting of vitamin A, vitamin E, and any combination thereof, preferably vitamin E.

16. The bigel according to any one of claims 1 to 15, wherein the hydrogel comprises the at least one water-soluble vitamin at between 2.5 and 17.5 % by weight of the hydrogel, preferably at between 5 and 15 % by weight of the hydrogel, more preferably at between 7.5 and 12.5 % by weight of the hydrogel, and most preferably at about 10 % by weight of the hydrogel.

17. The bigel according to any one of claims 1 to 16, wherein the at least one water-soluble vitamin is selected from the group consisting of vitamin B3, vitamin B5, vitamin C, and any combination thereof, preferably a combination of vitamin B3, vitamin B5 and vitamin C.

18. The bigel according to claim 17, wherein the hydrogel comprises vitamin B3 at between 2 and 6 % of weight of the hydrogel, preferably at between 3 and 5 % of weight of the hydrogel, and more preferably at about 4 % of weight of the hydrogel.

19. The bigel according to claim 17 to 18, wherein the hydrogel comprises vitamin B5 at between 1 and 5 % of weight of the hydrogel, preferably at between 2 and 4 % by weight of the hydrogel, and more preferably at about 3 % of weight of the hydrogel.

20. The bigel according to any one of claims 17 to 19, wherein the hydrogel comprises vitamin C at between 0.5 and 4 %of weight of the hydrogel, preferably at between 1 and 3 % by weight of the hydrogel, and more preferably at about 2 % of weight of the hydrogel.

21. The bigel according to any one of claims 1 to 20, wherein the at least one humectant is selected from the group consisting of glycerin, urea, hyaluronic acid, propylene glycol, sorbitol, and any combination thereof, preferably selected from the group consisting of glycerin, urea, hyaluronic acid, and any combination thereof, and more preferably a combination of glycerin, urea, and hyaluronic acid.

22. The bigel according to claim 21, wherein the hydrogel comprises glycerin at between 5 and 15 % of weight of the hydrogel, preferably at between 7.5 and 12.5 % of weight of the hydrogel, and more preferably at about 10 % of weight of the hydrogel23. The bigel according to claim 21 or 22, wherein the hydrogel comprises urea at between 2 and 6 % of weight of the hydrogel, preferably at between 3 and 5 % of weight of the hydrogel, and more preferably at about 4 wt% of weight of the hydrogel.

24. The bigel according to any one of claims 21 to 23, wherein the hydrogel comprises hyaluronic acid at between 0.01 and 1.5 % of weight of the hydrogel, preferably at between 0.025 and 1.25 % of weight of the hydrogel, and more preferably at between 0.05 and 1 % of weight of the hydrogel.

25. The bigel according to any one of claims 1 to 24, wherein the at least one viscosity controlling agent is selected from the group consisting of carbomer, xantan gum, hydroxyethyl cellulose, guar gum, bentonite, cetyl alcohol, and any combination thereof, preferably hydroxyethyl cellulose.

26. The bigel according to any one of claims 1 to 25, wherein the hydrogel comprises the at least one viscosity controlling agent at between 0.5 and 7.5 % of weight of the hydrogel, preferably at between 1 and 5 % of weight of the hydrogel, and more preferably at between 1.5 and 2.5 % of weight of the hydrogel.

27. The bigel according to any one of claims 1 to 26, wherein the hydrogel comprises water at between 70 and 80 % by weight of the hydrogel, preferably at between 72.5 and 77.5 % by weight of the hydrogel, and more preferably at methyl glucose sesquistearate between 74 and 75 % by weight of the hydrogel.

28. The bigel according to any one of claims 1 to 27, wherein the hydrogel comprises the at least one pH adjusting agent at an amount to adjust pH of the bigel to between 3.5 and 6.5, preferably between 5 and 6, and more preferably to about 5.5.

29. The bigel according to any one of claims 1 to 28, wherein the at least one pH adjusting agent is selected from the group consisting of hydrochloric acid (HCI), citric acid, lactic acid, gluconlactone, phosphoric acid, and any combination thereof, preferably HCI or citric acid.

30. The bigel according to any one of claims 1 to 29, wherein the bigel comprises an emulsifier up to 5 % by weight of the bigel, preferably up to 4 % by weight of the bigel, more preferably up to 3 % by weight of the bigel, and most preferably at between 1.5 and 2.5 % by weight of the bigel, preferably wherein the emulsifier is selected from the group consisting of polyethylene glycol (PEG) methyl glucose sesquistearate, methyl glucose sesquistearate, and any combination thereof.

31. The bigel according to any one of claims 1 to 30, wherein the bigel comprises:the hydrogel at between 25 and 50 % by weight of the bigel, preferably at 50 % by weight of the bigel; andthe oleogel at between 50 and 75 % by weight of the bigel, preferably at 50 % by weight of the bigel.

32. A bigel according to any one of claims 1 to 31 for use as a medicament.

33. A bigel according to any one of claims 1 to 31 for use in treatment of a skin condition selected from the group consisting of dry skin, itching skin, eczema, burnt skin, cracked skin, red skin, rosacea, skin irritation, psoriasis, skin inflammation and petechia.

34. Cosmetic use of a bigel according to any one of claims 1 to 31.

35. A method for producing a bigel according to any one of claims 1 to 31 , the method comprising:mixing the at least one vegetable oil and the at least one wax at a temperature above room temperature, preferably selected within an interval of from 40 up to 80°;optionally allowing the mixture between the at least one vegetable oil and the at least one wax to cool to a temperature equal to or below 65°C;mixing the at least one oil-soluble skin conditioning agent into the optionally cooled mixture between the at least one vegetable oil and the at least one wax to form the oleogel;optionally cooling the oleogel to room temperature;mixing the at least one viscosity controlling agent and water, preferably at room temperature; mixing the at least one water-soluble vitamin and the at least one humectant into the mixture between the at least one viscosity controlling agent and water, preferably at room temperature, to form the hydrogel;optionally adjusting pH of the hydrogel by addition of the at least one pH adjusting agent; and mixing the oleogel and the hydrogel, preferably at room temperature, to form the bigel.

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