EA043968B1 - PHARMACEUTICAL COMPOSITION FOR PREVENTION AND/OR TREATMENT OF SKIN DISORDERS, COMPOSITION BASED ON ITS AND THEIR APPLICATION - Google Patents

Description

Field of technology to which the invention relates

The present invention is directed to a new composition containing a synergistic combination of vitamin D or its precursor, 7-dehydrocholesterol (7-DHC), and a mixture of hyaluronic acid with a low molecular weight of 4 to 50 kDa and hyaluronic acid with a higher molecular weight of not more than 200,000 kDa, encapsulated in a colloidal lipid-based carrier system (preferably lipid-based vesicles such as liposomes, niosomes, transferosomes), and formulations based thereon for topical use, as well as their use in the prevention and/or treatment of inflamed skin disorders skin, eczema, rosacea, atopic dermatitis, psoriasis, photodamage, skin atrophy, skin dyspigmentation, photodermatitis, telangiectasia, rosacea and actinic keratosis.

State of the art

Skin disorders according to ICD-10 (International Classification of Diseases, Version 2016) include (a) a group of conditions in which the skin becomes inflamed, blistered and crusty, thick and scaly (including eczema, which causes burning and itching that occurs over a long period of time), (b) any type of skin inflammation, (c) an inflammatory process affecting the skin (with signs of red rash, itching and blistering), such as contact dermatitis, atopic dermatitis, seborrheic dermatitis and psoriasis, and (d) pruritic papulovesicular dermatitis, which occurs in response to many endogenous and exogenous agents. Photodamage to the skin (according to ICD-10 version 2016) is described as a skin disorder caused by ultraviolet A (UVA) and ultraviolet B (UVB) rays with the following main symptoms: skin atrophy, skin dyspigmentation (spots/dots), photodermatitis (erythema: inflamed, reddened skin), telangiectasia (rosacea) and actinic keratosis. UVB radiation with a wavelength of 280-315 nm provides the energy needed by the skin to produce vitamin D3, but is also a major mutagen that penetrates the epidermal layer of the skin, leading to DNA mutations that can lead to skin cancer (non-melanoma skin cancer (NMSC) and melanoma). Such mutations may be clinically associated with specific signs of photodamage, such as increased elastin and collagen defects leading to skin atrophy. UVA rays with a wavelength of 315-400 nm are able to penetrate deeper into the skin compared to UVB rays and thus can damage both the epidermal and dermal layers. With constant exposure to UVA radiation, the size of the dermis layer will decrease, causing skin atrophy. Potential damage includes dilated or destroyed blood vessels causing telangiectasia (rosacea) or indirect damage to cellular DNA and skin barrier lipids and proteins through the formation of reactive oxygen species (ROS), which are cytotoxic.

Exposure to both UVA and UVB radiation can also lead to inflammation and vasodilation, which clinically manifests as telangiectasia (rosacea) and photodermatitis (erythema leading to inflammation and redness of the skin), dyspigmentation (spots/dots) and other skin disorders [see, for example, 1, 2, 3].

Inflamed skin tissue contains high concentrations of reactive oxygen species (ROS), such as nitric oxide. Nitric oxide (NO) additionally reacts with oxygen (O₂) with the formation of peroxy-nitrite (ONOO^-). Peroxynitrite and its decomposition products as a result of reaction with CO2 (NO2 and CO3^-) are extremely cytotoxic as a result of the oxidation of lipids, proteins and DNA in the epidermis.

Various approaches have been proposed to prevent skin inflammation such as photodamage and its effects, including the use of vitamins such as vitamin D3 and its derivatives and precursors, and hyaluronic acid, etc.

Vitamin D is a group of fat-soluble vitamins, with vitamin D3 (or cholecalciferol) and vitamin D2 (or ergocalciferol) being the most important members for humans. Typically, vitamin D3 is obtained by photolysis of 7-dehydrocholesterol (or 7-DHC, which is predominantly found in the spinal cord and basal layer of the upper layer of skin at approximately 25-50 μg/cm ² ) using UVB radiation [see e.g. 4 -7, fig. 1] to produce a provitamin D3 precursor, which is then thermally isomerized to produce vitamin D3. It is known that the formation of vitamin D3 in the skin decreases significantly during aging (no more than 75 wt.% at the age of 70 years). Vitamin D3 and its precursors and derivatives are very biologically active. For example, the 7-DHC precursor has the ability to bind reactive oxygen species, which is NO, and thus avoids excessive formation of cytotoxic peroxynitrite in the upper parts of the skin, preventing the intractable problem (vicious cycle) of skin inflammation with cellular damage to the skin [Fig. 2, 3]. Vitamin D3 is involved in many processes, including bone mineralization, bone growth and bone remodeling, modulation of cell growth, neuromuscular and immune functions, and others. It has also been suggested that certain vitamin D3 analogues (e.g., 25-hydroxyvitamin-D3 or calcidiol, 1,25-dihydroxyvitamin-D3 or calcitriol, calcipotriol; see e.g. 8, 9, 10,

- 1 043968 fig. 3) can be used for topical application to treat skin conditions including psoriasis [see, for example, 11, 12, 13, 14]. In addition, recent studies using genetically modified mice that exhibit altered mineral homeostasis due to high vitamin D3 activity have shown signs of premature aging that include growth retardation, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, and generalized skin and organ atrophy. These and other data suggest that serum calcidiol may be associated with an increased risk of chronic diseases associated with aging, including cancer. Vitamin D is also involved in the restoration of the skin barrier [see, for example, 15, fig. 2], supporting immune defense against microorganisms and protecting healthy microflora [see, for example, 16], vitamin D3 also reduces inflammation, maintaining skin condition, and is involved in wound healing [see, for example. 17-20] and protecting the skin from photodamage [see, for example, 21-25, Fig. 2, 3].

It is suggested that widespread local production of vitamin D in the skin, accompanied by skin darkening, is the most important mechanism for protecting the skin from photodamage [see, for example, 26].

Hyaluronic acid (HA) is a linear polysaccharide with repeating disaccharide units, consisting of glucuronic acid and N-acetylglucosamine, and is one of the main substances in the matrix in which cells and fibrous matrix constituents such as collagen and elastin are embedded [see , for example, 27, 28, fig. 2]. NA has an extremely high capacity to bind water [see, for example, 29] and contributes significantly to the maintenance of extracellular space and control of tissue hydration, acting as a humectant [see, for example, 30]. It is known that cross-linking of ND polymer chains turns the ND solution into a gel. The crosslinker molecules link the individual chains of the HA polymer, forming a network that appears macroscopically as a gel mass. It is assumed that NA plays a key role in tissue regeneration [see, for example, 31, 32, fig. 2].

However, despite the presence of numerous skin treatment compositions that are offered on the market, there is still a high need for compositions with which the common symptoms of skin inflammation, especially photodamage, can be prevented and/or treated, namely the affected skin and, even more, prevent more effectively skin damage caused by exposure to solar radiation, especially UV radiation.

The present inventors have discovered that vitamin D3 or a derivative or precursor thereof, preferably a precursor such as 7-dehydrocholesterol (7-DHC) or a derivative thereof, can be formulated in combination with HA as a stabilized colloid. This colloidal carrier system exhibits a synergistic effect in the treatment and prevention of inflamed skin, especially photodamage of the skin, such as skin atrophy, skin dyspigmentation (spots/dots), photodermatitis (erythema: inflamed and reddened skin), telangiectasia (rosacea) and prevention of UV exposure -radiation to avoid the formation of skin erythema and actinic keratosis [Fig. 2].

Thus, the present inventors provide a new composition comprising vitamin D3 or its precursor such as 7-DHC, and HA, optionally in combination with additional excipients, encapsulated in a lipid-based colloidal carrier system (preferably lipid-based vesicles, such as liposomes, niosomes, transferosomes) to ensure penetration and localized delivery of stabilized vitamin D3 or its precursor such as 7-DHC to the upper layers of the skin.

The two active substances combined for topical application are able to act synergistically directly in the upper layers of the skin on the main disorders of inflamed skin, especially photodamage, in particular the symptom according to ICD-10 caused by exposure to solar radiation and especially exposure to UV radiation in against unprotected and damaged areas of the skin. Thus, with the new composition according to the present invention, the disadvantages of the prior art can be overcome. The additional seven excipients will act synergistically with the two active ingredients to provide optimal effectiveness for the prevention and/or treatment of the described skin conditions. The described composition (and compositions based on it) will provide a new approach for the prevention and/or treatment of most disorders of inflamed skin damaged by exposure to solar radiation and especially UV radiation of the skin [Fig. 2, 3].

Brief description of the invention

In a first aspect, the present invention is directed to a new composition (also referred to as a composition according to the present invention) containing a synergistic combination of at least one of vitamin D3 or its precursor, such as 7-DHC, and a mixture of hyaluronic acid with a low molecular weight of 4 to 50 kDa and hyaluronic acid with a higher molecular weight of not more than 200,000 kDa, encapsulated in a lipid-based colloidal carrier system (to ensure optimal skin penetration and stabilization of vitamin D3 or its precursor), and suitable formulations based thereon. By encapsulation in the oil (or lipid) phase, vitamin D3 or its precursor (7-DHC) is stabilized and unwanted reactions (such as oxidation or other degradation reactions) are eliminated. A lipid-based colloidal carrier system ensures that vitamin D3 (and inactive vitamin D3 precursors such as 7-DHC) penetrates the upper layers of the skin where they exert their activity (after being converted to the active form of vitamin D3 upon exposure to UVA and UVB radiation ).

In a preferred embodiment, vitamin D3 is a vitamin D3 precursor, such as 7-DHC, and the composition of the present invention contains a vitamin D precursor, such as 7-DHC, in combination with a mixture of low molecular weight hyaluronic acid from 4 to 50 kDa and hyaluronic acid acids with a higher molecular weight of not more than 200,000 kDa, encapsulated in a lipid-based colloidal carrier system. Vitamin D (and in particular a vitamin D3 precursor such as 7-DHC) is preferably present in the colloidal carrier system at a final concentration of 0.01 to 0.5 wt%.

In other embodiments, the composition further comprises one or more, preferably 1, 2, 3, 4, 5, 6, 7, additional components selected from vitamin A, at least one of vitamin B, vitamin C and vitamin E. Preferably the composition further contains one or more, most preferably all, of (i) retinyl palmitate (vitamin A), (ii) riboflavin (vitamin B2), (iii) nicotinamide (vitamin B3), (iv) dexpanthenol (provitamin B5), (v) folic acid (vitamin B9), (vi) L-ascorbic acid (vitamin C) and (vii) tocopherol acetate (vitamin E).

In another specific embodiment, the lipid-based colloidal carrier system is a liposomal carrier system (preferably a lipid-based vesicle, e.g., liposome, niosome, transferosome) consisting of at least one phospholipid and at least one fatty acid. Preferably, the lipid-based colloidal carrier system contains, for example, one or more of lecithin, linolenic acid, linoleic acid, phosphatidylcholine and caprylic/capric triglyceride.

In a preferred embodiment, a lipid-based colloidal carrier (e.g., a lipid-based vesicle such as a liposome, niosome, transferosome) contains a synergistic combination of 7-DHC and HA in combination with two lipophilic agents: retinyl palmitate (vitamin A), tocopherol acetate (vitamin E), and five hydrophilic agents: riboflavin (vitamin B2), nicotinamide (vitamin B3), dexpanthenol (provitamin B5), folic acid (vitamin B9), L-ascorbic acid (vitamin C).

Lipophilic agents are encapsulated in a bilayer or multilamellar system, while hydrophilic agents are encapsulated in the aqueous phase. Thus, in one embodiment, the composition of the present invention is prepared by (i) encapsulating vitamin D3 (and in particular a vitamin D3 precursor such as 7-DHC) in the oil (or lipid) phase of a lipid-based colloidal carrier system at values corresponding to room temperature, and (ii) separate preparation of ND in the aqueous phase. The compositions are prepared by emulsifying an aqueous phase into an oil (or lipid) phase (by mixing or spontaneous combination at room temperature). Preferably the particles will have a diameter of 10500 nm, more preferably 10-300 nm, most preferably 20-150 nm.

In a further aspect, the composition of the present invention is in the form of various formulations suitable for topical, transdermal and mucosal administration. Such topical formulations contain the pharmaceutical composition of the present invention as well as additional auxiliary agents such as buffers, preservatives and the like. Typical formulations include hydrogels, lyogels, hydrolotions, lipolotions, creams, ointments, and the like.

In a further aspect, the present invention is directed to the use of the composition of the present invention (and topical formulations based thereon) in the prevention and/or treatment of skin conditions, inflamed skin, eczema, rosacea, atopic dermatitis, psoriasis, photodamage, skin atrophy, dyspigmentation skin, photodermatitis, telangiectasia, rosacea and actinic keratosis.

Brief description of graphic materials

Fig. 1: Sufficient concentrations of the inactive 7-DHC precursor are transported in the form of a lipid-based colloid according to the present invention to the upper layers of the skin, where it is converted to active vitamin D3 upon exposure to UVA and UVB radiation.

Fig. 2: 7-DHC in the oil (or lipid) phase and hyaluronic acid (HA) in the aqueous phase are included in a colloidal carrier system that allows penetration into the upper layers of the skin. By activating and synthesizing vitamin D3 from 7-DHC, the pathway of skin damage from UVA/UVB sunlight can be blocked. Inactive 7-DHC is protected from oxidative processes by encapsulation in the carrier system and, in addition, is activated only in the targeted upper layers of the skin, having a potent effect in eliminating cytotoxic ROS in the form of peroxy-nitrites formed as a result of nitrate oxidation processes. This function of absorbing NO produced in excess allows you to protect the skin from damage caused by UVA/UVB.

- 3 043968

Fig. 3: 7-DHC pathway for strong anti-inflammatory activity in the upper layers of the skin after activation to vitamin D3.

Detailed description

In a first aspect, the present invention is directed to a new composition, hereinafter also referred to as a composition according to the present invention, containing a synergistic combination of at least one of vitamin D3 or its precursor, such as 7-dehydrocholesterol (7-DHC), and a mixture of low-grade hyaluronic acid. molecular weight from 4 to 50 kDa and hyaluronic acid with a higher molecular weight of not more than 200,000 kDa, encapsulated in a lipid-based colloidal carrier system (preferably lipid-based vesicles such as liposomes, niosomes, transferosomes) and suitable formulations based thereon for local use. All definitions and embodiments set forth hereinafter apply to the compositions (and topical formulations) of the present invention and their routes of use (unless otherwise indicated). The term topical application as used herein refers to application to any part of the skin and mucous membranes, including the mucous membranes of the eyes. The term photodamage as used in this document refers to the ICD-10 2016 definition and is described as a skin disorder caused by sun exposure and UVA and UVB radiation. The term synergistic when used in relation to the compositions of the present invention means that the therapeutic effect of the combination of agents is greater than the sum of the effects of the individual agents in the combination.

The term vitamin D as used herein refers to any of the forms with antirachitic activity known in the art that are suitable for use in food, for example, vitamin D1, vitamin _D2 , vitamin D3, vitamin D4, vitamin _D5 , vitamin D6 and vitamin D ₇ . Preferred is vitamin D3 as used herein, which refers to vitamin D3 as well as a vitamin D3 precursor such as 7-DHC (provitamin D3) or a derivative thereof, or a vitamin D3 derivative such as 25-hydroxyvitamin D3 or 1a, 25dihydroxyvitamin D3, including 1a-hydroxyvitamin D3, which activates the vitamin D receptor or which can be metabolized in humans to a compound that activates the vitamin D receptor. 7-DHC is preferred. Vitamin D, preferably vitamin D3 and its precursor 7-DHC, is used at a concentration of 10,000-50,000 IU and 0.01-4 wt.%. The preferred concentration is from 0.01 to 3 wt.%, more preferably from 0.01 to 0.75 wt.%, most preferably from 0.01 to 0.5 wt.%, based on the total weight of the composition in accordance with the present invention.

The term hyaluronic acid (also known as hyaluronan, hyaluronate or HA), as used herein, refers to a non-sulfated glycosaminoglycan consisting of repeating disaccharide units of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) linked to each other by alternating beta-1 ,4 and beta-1,3 glycosidic bonds. The term hyaluronic acid or HA as used herein refers to HA or salts of HA, such as sodium, potassium, magnesium and calcium salts, among others. The term hyaluronic acid or HA includes both natural and synthetic formulas and combinations of such natural and synthetic formulas, including their salt forms. NA and its fractions with different molecular sizes and its corresponding salts have been used as drugs, especially in the treatment of arthropathies, as an adjuvant and/or replacement agent for natural organs and tissues, especially in ophthalmology and cosmetic surgery, and as agents for cosmetic drugs. NA-based products have also been developed for use in orthopedics, rheumatology and dermatology. High molecular weight (MW) fractions of HA, characterized by an average MW of about 1 to about 1.5 MDa, are widely known to provide excellent moisturizing properties in cosmetic compositions such as lotions and creams. It was noted that HA fractions with very low MW have a greater ability to penetrate the skin barrier. In preferred embodiments, a cross-linking agent (eg, 1,4-butanediol diglycidyl ether (BDDE), etc.) can be used to link the HA polymer chains to each other, converting liquid HA solutions into gels. Thus, in a particular embodiment, the HA is in the form of a gel obtained by cross-linking the polymer chains of HA (via the primary hydroxyl group (-CH2OH) and/or secondary hydroxyl groups (-CHOH) in the HA monomer unit), wherein the cross-linked HA has a low molecular weight has a high ability to retain water in the skin. HA for use in the present invention is preferably characterized by a low MW, for example from 4 to 50 kDa, in combination with a higher MW of not more than 200,000 kDa. Typically, HA is used at a concentration of 0.01 to 8 wt% (or 80 mg/ml), preferably 0.01 to 5 wt% (or 50 mg/ml), more preferably 0.01 to 4 wt.% (or 40 mg/ml), most preferably from 0.01 to 3 wt.% (or 30 mg/ml). The most preferred total concentration of HA is 3 wt.%, preferably as a mixture of HA with the lowest molecular weight of 4-5 kDa, HA with a low to medium molecular weight or an average molecular weight of 40-50 kDa and HA with a high molecular weight of 50,000- 200,000 kDa (wt.%). Preferably the ratio of HA with the lowest molecular weight is 4-5

- 4 043968 kDa to HA with an average molecular weight of 40-50 kDa to HA with a high MW of 50000-200000 kDa (1-10) is: (0.1-2):(0.1-2), preferably (2- 6):(0.5-1.5):(0.5-1.5), most preferably about 4:about 1:about 1 (or approximately equal to the wt.% of medium and high MW HA). Thus, most preferred is a 3 wt% HA mixture containing 2 wt% low molecular weight 4-5 kDa HA, 0.5 wt% low to medium molecular weight HA, or 40-50 kDa low molecular weight HA. and 0.5 wt.% HA with a high molecular weight of 50000200000 kDa.

Together with vitamin D, such as vitamin D3, such as 7-DHC, HA is characterized by a synergistic effect regarding the hydration of the epidermis and also regarding the immunoprotective effect [see, for example, 33, 34, 35, 36 fig. 2, 3]. HA, together with vitamin D3 such as 7-DHC, has a synergistic physicochemical mechanism of action on photodamaged skin.

Thus, in a preferred embodiment, the composition according to the present invention contains 7-DHC in the oil phase in the colloidal carrier system and HA as an active substance in the aqueous phase of the colloidal carrier system. The two phases are prepared separately and then combined to form a lipid-based colloidal carrier system.

In addition, 7-DHC has also been found to serve as an additional activator of additional components (hereinafter also referred to as excipients) that are particularly effective in preventing and/or treating photodamage. In particular, it has been found that with compositions further containing one or more components selected from vitamin A (preferably retinyl palmitate), at least one of vitamin B, vitamin C (preferably L-ascorbic acid) and vitamin E (preferably acetate tocopherol), effective prevention and/or treatment of photodamage is achieved [see. fig. 1, 2, 3].

Thus, in specific embodiments, the composition of the present invention further comprises one or more, preferably 1, 2, 3, 4, 5, 6 or 7, additional components selected from vitamin A (preferably retinyl palmitate), at least one of vitamin B, vitamin C (preferably L-ascorbic acid) and vitamin E (preferably tocopherol acetate).

The term vitamin A as used herein refers to retinol, retinal, retinoic acid and several pro-vitamin A carotenoids (most preferably beta-carotene), preferably the base form retinyl palmitate. Vitamin A and, in particular, retinyl palmitate absorb light in the short wavelength UVA range, providing a photoprotective effect on the skin. Retinyl palmitate has been found to have an additive effect together with 7-DHC on short-wave UVA absorption, inhibiting NF-κB expression, and therefore acts against UV-induced skin inflammation [see e.g. 36 , 37]. Retinyl palmitate diffuses into the skin, where it is partially hydrolyzed to retinol, penetrates the stratum corneum, epidermis and dermis, and acts as a UV filter, absorbing UV radiation in the range of 300-350 nm, thereby supporting the action of the compositions according to the present invention. Typically, retinyl palmitate is used at a concentration of 0.01 to 2 wt%, preferably 0.01 to 0.5 wt%, more preferably 0.01 to 0.2 wt%, most preferably 0.01 up to 0.1 wt.%.

The term vitamin B as used herein refers to a class of water-soluble, chemically diverse vitamins including thiamine (B1), riboflavin (B2), niacin (NI), pantothenic acid (B5), pyridoxine (B6), folate (B7) and various cobalamins (B12). In one embodiment, the term vitamin B as used herein refers to riboflavin (B2). Typically, riboflavin is used at a concentration of 0.01 to 2 wt%, preferably 0.01 to 0.2 wt%, more preferably 0.01 to 0.1 wt%, most preferably 0.01 up to 0.05 wt.% of the total weight of the composition in accordance with the present invention. In another embodiment, the term vitamin B as used herein refers to nicotinamide. Nicotinamide, or nicotinic acid amide (B3), is a hydrophilic endogenous substance that can act as an antioxidant, can improve epidermal barrier function, reduce skin hyperpigmentation, reduce skin atrophy, reduce redness/mottling, and improve skin elasticity [54, 55]. Nicotinamide exhibits a synergistic effect with NA in restoring the structural and functional integrity of the epidermal barrier function and as an epidermal moisturizer [Fig. 2]. Nicotinamide controls NFKB-mediated transcription of signaling molecules by inhibiting nuclear poly(ADP-ribose) polymerase-1 (PARP-1). Additionally, nicotinamide will have additional effects on NFKB-mediated transcription with 7DHC and vitamin A (particularly retinyl palmitate) [see, for example, 38, 40]. Typically, nicotinamide (vitamin B3) is used at a concentration of 0.5 to 5 wt%, preferably no more than 4 wt%, more preferably no more than 3 wt%, most preferably 3 wt%, based on the total weight of the composition according to with the present invention.

In another embodiment, the term vitamin B as used herein refers to

- 5 043968 refers to dexpanthenol (provitamin B5). When applied topically, dexpanthenol acts as a humectant and its activity may be based on the hygroscopic properties of dexpanthenol. Dexpanthenol additionally exhibits a protective effect against skin irritation [see, for example, 39]. Dexpanthenol significantly accelerates the healing process of wounds in children after tonsillectomy [see, for example, 36]. Typically, dexpanthenol (vitamin B5) is used at a concentration of 0.5 to 5 wt%, preferably 3 wt%, more preferably 2.5 wt%, most preferably 1 wt% of the total weight of the composition according to the present invention.

In a further embodiment, the term vitamin B as used herein refers to folic acid (B9). Folic acid is necessary for DNA synthesis, repair and methylation, in particular for nucleotide biosynthesis and homocysteine remethylation. Folic acid is essential for the production of cellular DNA, RNA and is known for its use in preventing neural tube defects (NTDs) and serious birth defects and in treating anemia caused by folate deficiency. Folic acid has also been shown, in combination with creatine, to significantly accelerate the regeneration of the epidermal layer of the skin in vitro and in vivo [see, for example, 41] and thus may contribute to a synergistic effect together with 7-DHC, covering UV-induced cellular damage and inflammation [fig. 2]. Typically, folic acid (vitamin B9) is used at a concentration of 0.01 to 0.2 wt%, preferably 0.07 wt%, more preferably 0.05 wt%, most preferably 0.02 wt% of total weight of the composition in accordance with the present invention.

The term vitamin C as used herein refers to L-ascorbic acid, which is used as a supplement to treat and prevent scurvy and skin erythema [see, for example, 42, 43]. Scurvy causes brown spots on the skin, loose gum tissue, and bleeding from all mucous membranes. L-ascorbic acid functions as an electron donor for various important enzymes in the skin, which are required for the hydroxylation of proline and lysine in collagen synthesis [see, for example, 44, 45, 46] and the synthesis of carnitine, which is important for the transport of fatty acids into mitochondria for the formation of ATP in skin cells [see, for example, 47, 48]. Ascorbate also functions as an antioxidant, protecting against oxidative stress [see e.g. 49] and is a potent reducing agent capable of rapidly scavenging a range of reactive oxygen species (ROS) and thus may promote synergistic effects with 7DHC. Typically, L-ascorbic acid is used at a concentration of 0.1 to 10% by weight, preferably up to 5% by weight, more preferably 2% by weight, most preferably 3% by weight, based on the total weight of the composition according to the present invention.

The term vitamin E as used herein refers to compounds known as tocopherols and tocotrienols, preferably tocopherol acetate. Tocopherol acetate can penetrate the skin to living cells, where approximately 5 wt.% is converted into free tocopherol. Tocopherol acetate has antioxidant activity and acts as a peroxide radical scavenger, inhibiting the formation of damaging free radicals in tissue [see, e.g., 50] and thus may promote synergistic effects with 7-DHC. Typically, tocopherol acetate is used at a concentration of 0.1 wt% to 5 wt%, preferably 0.1 to 5 wt%, more preferably 0.1 to 3 wt%, most preferably 0.1 up to 2 wt.% of the total weight of the composition in accordance with the present invention.

Thus, in preferred embodiments, the composition of the present invention containing 7-DHC and HA further contains one or more components selected from retinyl palmitate, riboflavin, nicotinamide, dexpanthenol, folic acid, L-ascorbic acid and tocopherol acetate, encapsulated in a colloidal system - lipid-based carrier. In specific embodiments, the composition of the present invention contains 7-DHC and HA, as well as a combination of the following:

a) retinyl palmitate and riboflavin, or retinyl palmitate and nicotinamide, or retinyl palmitate and dexpanthenol, or retinyl palmitate and folic acid, or retinyl palmitate and L-ascorbic acid, or retinyl palmitate and tocopherol acetate;

b) riboflavin and nicotinamide, or riboflavin and dexpanthenol, or riboflavin and (v) folic acid, or riboflavin and L-ascorbic acid, or riboflavin and tocopherol acetate;

c) nicotinamide and dexpanthenol, or nicotinamide and folic acid, or nicotinamide and L-ascorbic acid, or nicotinamide and tocopherol acetate (vitamin E);

d) dexpanthenol and folic acid, or dexpanthenol and L-ascorbic acid, or dexpanthenol and tocopherol acetate;

f) folic acid and L-ascorbic acid or folic acid and tocopherol acetate;

f) L-ascorbic acid and tocopherol acetate.

Most preferably, the compositions (and topical formulations) of the present invention containing 7-DHC and HA further contain retinyl palmitate, riboflavin, nicotinamide, dexpanthenol, folic acid, L-ascorbic acid and tocopherol acetate components encapsulated in a colloidal system - lipid-based carrier. The most preferred concentrations and concentration ranges are described as follows in the table

1.

Table 1

Active ingredients* Concentration range, weight % Preferred concentration, wt. % CAS No. 7-DHC 0.01-5 0.15 434-16-2 ON 0.01-5 3 (or 30 mg/ml) 9004-61-9 Retinyl palmitate 0.01-0.5 0.500 79-81-2 Riboflavin 0.01-0.2 0.100 83-88-5 Nicotinamide 0.5-4 4000 98-92-0 Dexpanthenol 0.5-2.5 2500 81-13-0 Folic acid 0.01-0.2 0.050 59-30-3 L-ascorbic acid 0.1-10 3000 50-81-7 Tocopherol acetate 0.1-5 2000 7695-91-2

* Active ingredients included in the colloidal carrier system according to the present invention (typically: water: >50 wt.%, for example 50-75 wt.%; carrier system - 10 wt.%; additional ingredient in the form of oil , preservatives, buffers, filters - 5-25 wt.%).

The term lipid-based colloidal carrier system (system) (or colloid) as used herein refers to commonly known particulate carrier systems, preferably spherical vesicles having at least one lipid bilayer. Typical colloidal carriers include liposomes, niosomes, transferosomes, micelles, nanoparticles, microemulsions and others, preferably liposomes, niosomes, transferosomes, most preferably liposomes. Depending on its size and the number of bilayers, the lipid-based colloidal carrier system is presented in the form of: (a) multilamellar vesicles (MLV), (b) large unilamellar vesicles (LUV), (c) small unilamellar vesicles (SUV), (d ) multivesicular vesicles (MW), oligolamellar vesicles (OLV). The preferred particle size is in the range of 10-500 nm, preferably from 10 to 300 nm, more preferably 20-150 nm.

In specific embodiments, the colloids are based on natural and/or synthetic phospholipids and typically comprise 10% by weight of the composition. Typically, useful phospholipids include fatty acids with phosphate-containing polar ends that are hydrophilic and thus water soluble, and hydrophobic ends that are fat soluble, linked together by a glycerol molecule (eg, glycerophospholipids) or sphingosine molecules (for example, phosphosphingolipids).

In some embodiments, the phospholipids used in the colloidal carrier system include one or more of phosphatidylcholine, lysophosphatidylcholine, hydrogenated phospholipids, and unsaturated phospholipids. Examples of glycerophospholipids include phosphatidic acid (phosphatidate) (PA), phosphatidylethanolamine (cephalin) (PE), phosphatidylcholine (lecithin) (PC), phosphatidylserine (PS) and phosphoinositides, which further include phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol tri-phosphate (PIP3). Examples of phosphosphingolipids include ceramide phosphorylcholine (sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol. The colloidal carrier system of the present invention may further contain fatty acids, for example, omega-3, omega-6 and omega-9 fatty acids. Preferred examples used in the present invention are lecithin, sphingomyelin, phosphatidylcholine, linoleic acid, linolenic acid, caprylic acid, capric acid, white lupine seed oil, squalene, imidazolidinyl urea and sodium ascorbyl phosphate. A preferred embodiment of the lipid-based colloidal carrier system is shown in Table 1. 2.

table 2

Ingredients (INCI) Concentration range, weight. % Quantity, weight. % CAS No. Phosphatidylcholine 0-2-80 40.00 8002-43-5 Sphingomyelin 0-2-80 20.00 85187-10-6 Linolenic acid 0-5-50 10.00 463-40-1 Linoleic acid 0-5-50 10.00 60-33-3 Caprylic triglyceride 0.2-40 10.00 73398-61-5 Capric triglyceride 0.2-40 10.00 65381-09-1 Total amount: 100.00

In a further embodiment, the colloidal carrier system may also include polycarbonate, polyvinylpyrrolidone (PVP), also polyvidone or povidone-based membranes, preferably copovidone with an MW of 10-500 nm. Copovidone will be used as a film-forming agent and binder, as well as a carrier system.

For use in the present invention, lipophilic agents will be encapsulated in the bilayer system, while hydrophilic agents will be encapsulated in the aqueous phase of the system. Thus, the vitamin D precursor (e.g., 7-DHC or its derivative) and phospholipid(s) and

- 7 043968 optional additional lipophilic agents (eg retinyl palmitate and tocopherol acetate) are directly incorporated into the oil phase of the colloidal carrier system at room temperature. In a separate step, HA and optional additional hydrophilic agents (eg, riboflavin, nicotinamide, dexpanthenol, folic acid, L-ascorbic acid) are mixed together separately in an aqueous solution. An aqueous solution containing HA and optional additional hydrophilic agents is mixed with an oil phase containing a vitamin D precursor (such as 7-DHC or a derivative thereof). After emulsification of the two phases, the hydrophilic components (HA and additional hydrophilic agents) of the compositions are present in the aqueous parts, while the lipophilic components of the compositions have already been incorporated in the first stage into the phospholipid bilayers of the particles.

Thus, in most preferred embodiments, the lipid-based colloidal carrier system (preferably lipid-based vesicles such as liposomes, niosomes, trans-pherosomes) consists of lecithin, linolenic acid, linoleic acid, phosphatidylcholine and caprylic/capric triglyceride, to which is added with vitamin D3 components, such as 7-DHC or a derivative thereof, and HA, and optionally at least one, preferably 1, 2, 3, 4, 5, 6 or 7, retinyl palmitate, riboflavin components , nicotinamide, dexpanthenol, folic acid, L-ascorbic acid and tocopherol acetate. Using the same uniquely loaded and stable carrier system, the synergistic compositions according to the present invention will penetrate into the upper layers of the skin to provide action directly at the desired site.

Depending on the nature and type of application, the compositions of the present invention may further contain one or more of pharmaceutically acceptable additives, excipients, excipients commonly used in formulations used for application to the skin and/or mucous membranes.

Typical additives include, for example, an appropriate UV filter system or one or more UVA/B radiation protectants to prevent photodamage and protect against UVA and UVB solar radiation exposure, such as trans-urocanic acid, a breakdown product of filaggrin, butylmethoxydibenzoylmethane Neo Heliopan 357, Eusolex 9020, Parsol 1789, methylenebis-benzotriazolyltetramethylbutylphenol (nano), Tinosorb M, ethylhexyltriazone Uvinul T 150, bis-ethylhexyloxyphenolmethoxyphenyltriazine Tinosorb S, ethylhexylmethoxycinnamate Uvinul MC 80, Parsol MCX, Neo Heliopan AV 4, etc. UV filter(s) are included with active ingredients and excipients to prevent skin erythema and actinic keratosis or other forms of non-melanoma skin cancer (NMSC).

Typical excipients include, for example, surfactants, emulsifying agents, emollients, thickening agents, conditioning preservatives, buffering agents, humectants, flavoring agents, and the like. Thus, the carrier system may further contain one or more surfactants. The term surfactant refers to a material that reduces the surface tension of a liquid and the interfacial tension between two liquids, allowing them to spread more easily. Surfactants contain a hydrophilic head, which is attracted to water molecules, and a hydrophobic tail, which repels water while being attracted to oil and grease in dirt. These counteracting forces weaken the adhesion of dirt and trap it in water, allowing it to be removed from surfaces such as human skin, textiles and other hard surfaces when surfactants dissolve in water. Examples of suitable surfactants include, but are not limited to, nonionic, ionic (both anionic and cationic), or zwitterionic (or amphoteric, where the surfactant head contains two oppositely charged groups) surfactants. Examples of anionic surfactants include, but are not limited to, those based on sulfate, sulfonate or carboxylate anions, such as perfluorooctanoate (PFOA or PFO), alkyl benzene sulfonate, soaps, fatty acid salts or alkyl sulfate salts such as perfluorooctane sulfonate (PFOS), sodium dodecyl sulfate (SDS) ), ammonium lauryl sulfate or sodium laureth sulfate (SLES). Examples of cationic surfactants include, but are not limited to, those based on quaternary ammonium cations such as or alkyltrimethylammonium, including cetyltrimethylammonium bromide (CTAB) or hexadecyltrimethylammonium bromide, cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC) ) or benzethonium chloride (BZT). Examples of zwitterionic surfactants include, but are not limited to, dodecyl betaine, cocamimidopropyl betaine, or cocoamphoglycinate. Examples of nonionic surfactants include, but are not limited to, alkyl poly(ethylene oxide), alkyl phenol poly(ethylene oxide), poly(ethylene oxide) copolymers, poly(propylene oxide) (commercially referred to as poloxamers or poloxamines), alkyl polyglucosides including octyl glucoside and decyl maltoside, fatty alcohols including cetyl alcohol and oleyl alcohol, cocamide MEA, cocamide DEA or polysorbates including Tween 20, Tween 80 or dodecyldimethylamine oxide. Preferably, the surfactant is foaming and skin-friendly, including polysorbates such as polysorbate 20 or 40, cocoglucoside, lauryl glucoside, decyl glucoside, lauryl sulfates such as ammonium, sodium, magnesium, MEA, triethylamine (TEA) ) or MIPA lauryl sulfate, cocamidopropyl betaine or sodium alkyl sulfosuccinates.

In specific embodiments, the surfactant is at least one polysorbate, for example polysorbate 10-150, which is a nonionic surfactant widely used as adjuvants and emulsifiers. Preferably, the polysorbate is a polysorbate-type surfactant formed by ethoxylation of sorbitol prior to the addition of lauric acid as Scattics, PS20 as Alkest TW 20 and Tween 20. Polysorbates are effective in stabilizing the colloidal carrier, and in the presence of liquid lipids with different C-chains fatty acids with a less organized crystalline structure may provide better loading capacity for accommodating the active substance. The effect of polysorbate will be to stabilize the carrier system due to the physicochemical properties of the formulated nanoparticles. The colloidal carrier system is stabilized with a polysorbate such as polysorbate 20 or polysorbate 80. Polysorbate will be used as the best dispersant for the liposomal carrier system. The small size and superior particle surface to volume ratio will increase the loading efficiency and bioavailability of the active substance, making the liposomal carrier system a more effective delivery system.

In other specific embodiments, the surfactant is polyvinylpyrrolidone (PVP), which is known to either prevent sedimentation or reduce the resulting particle size of active ingredients or excipients with highly pH-dependent water solubility. A PVP-like poloxamer/copovidone will be used to stabilize the particles in the liposomal formulation. It is assumed that dissolution efficiency is higher in the presence of polyvinylpyrrolidone (PVP) and increases with increasing polymer concentration. PVP is typically used to stabilize and increase the efficacy and bioavailability of the liposomal carrier system.

Thus, in specific embodiments, the carrier system may further comprise polycarbonate, polyvinylpyrrolidone (PVP), polyvidone, povidone-based membranes, povidone, copovidone, hypromellose and Eudragit EPO, preferably copovidone with an MW of 10-500 nm.

The amount of surfactant in the compositions of the present invention ranges from 0.5 to 10% by weight of the total weight of the composition of the present invention.

The term emollient refers to a product that softens and soothes the skin to correct dryness and flaking of the skin, lubricate the skin's surface, promote moisture retention in the skin, and alter product textures. Examples of suitable emollients for topical use include, but are not limited to, octylhydroxystearate, lanolin, caprylic/capric triglyceride, cetyl palmitate, octyldodecanol, cetyl alcohol, isopropyl isostearate, glyceryl dilaurate, isopropyl myristate, palm alcohol, dimethicone, squalane, inca inchi seed oil, shea butter, cocoate sucrose or mixtures thereof. Preferably, the emollients are selected from the group consisting of dimethicone, squalane, inca inchi seed oil, shea butter, caprylic/capric triglyceride, octyldodecanol, or mixtures thereof. The amount of emollient in the compositions of the present invention ranges from 10 to 30% by weight of the total weight of the composition of the present invention.

The term humectant refers to a hygroscopic agent that attracts water molecules from the environment through either absorption or adsorption, preventing moisture loss from the skin. Examples of suitable humectants for topical use include, but are not limited to, glycerin, diglycerin, ethylhexylglycerin, glucose, honey, lactic acid, polyethylene glycol, propylene glycol, sorbitol, sucrose, or trehalose. Preferably, the humectant is selected from the group consisting of glycerin, diglycerin, ethylhexylglycerin, and mixtures thereof. The amount of humectants in the compositions according to the present invention is 0.5-15 wt.%, preferably 0.5-10 wt.%, based on the total weight of the composition according to the present invention.

The term thickener or thickener or viscosity enhancer, as used interchangeably herein, refers to a material that increases its viscosity without significantly modifying its other properties. Examples of suitable viscosity enhancers include, but are not limited to, cellulose or derivatives thereof, for example, hydroxypropyl methylcellulose, polyethylene glycol, microcrystalline cellulose, cetearyl alcohol, alginates, branched polysaccharides, colloidal silica, xanthan gum, carbomer, or polyacrylates. Preferably, the viscosity enhancer is selected from the group consisting of microcrystalline cellulose, cetearyl alcohol, cellulose, xanthan gum and carbomer. The amount of viscosity enhancing agents in the compositions of the present invention ranges from 0.5 to 15% by weight, preferably 0.5 to 10% by weight, of the total weight of the composition of the present invention.

The term emulsifying agent or emulsifier as used in this document interchanges

- 9 043968 variable, refers to a material that reduces surface tension, promoting the formation of homogeneous mixtures of immiscible liquids by changing interfacial tension. An emulsifier stabilizes the emulsion, increasing its kinetic stability. Examples of suitable emulsifiers include, but are not limited to, glyceryl trioleate, glyceryl oleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene monostearate, glycerol monooleate, sucrose distearate, polyethylene glycol monostearate, octylphenoxypoly(ethyleneoxy)ethanol, deacylerin penta-isostearate, sorbitan sesquioleate , hydroxylated lanolin, lecithin, lanolin, triglyceryl diisostearate, simple polyoxyethylene olein ether, calcium stearoyl-2-lactylate, sodium lauroyl lactylate, sodium stearoyl lactylate, cetearyl glucoside, methyl glucoside sesquistearate, sorbitan monopalmitate, methoxypolyethylene glycol-22/dodecyl glycol copolymer, polyethylene glycol-45/dodecyl glycol copolymer, distea polyethylene glycol 400 and glyceryl stearate, polyglyceryl-3 esters and candelyl/ jojoba/rice bran, cetyl phosphate, potassium cetyl phosphate or mixtures thereof. Preferably, the emulsifier is selected from the group consisting of glyceryl oleate, lecithin, sodium lauroyl lactylate, sodium stearoyl lactylate, glyceryl stearate, polyglyceryl-3 esters and candelilla/jojoba/rice bran and mixtures thereof. The amount of emulsifier in the compositions of the present invention is from 0.5 to 15% by weight, preferably from 0.5 to 10% by weight, based on the total weight of the composition according to the present invention.

The term pH adjusting agent or buffering agent refers to acids or bases that can be used to adjust the pH of the final product to the desired level without affecting the stability of the solution. Examples of suitable pH adjusting agents for topical use include, but are not limited to, acetic acid, lactic acid, citric acid, gluconic acid, ethanolamine, formic acid, oxalic acid, tartaric acid, potassium hydroxide, sodium hydroxide, triethanolamine, and mixtures thereof. Preferably, the pH adjusting agents are selected from the group consisting of triethanolamine, sodium hydroxide, lactic acid and citric acid. The amount of pH adjusting agent in the compositions of the present invention is from 0.01 to 1 wt.% based on the total weight of the composition of the present invention.

The term conditioning preservative refers to a compound that has a moisturizing function, more particularly to a compound that affects the barrier function to maintain the stratum corneum in a hydrated state, such as ceramides, sphingoid-based compounds, lecithins, glycosphingolipids, phospholipids, cholesterol and its derivatives, phytosterols (stingmasterol, β-sitosterol or campesterol), essential fatty acids, 1,2-diacylglycerol, 4chromanone, pentacyclic triterpenes, petrolatum and lanolin; or a compound that directly increases the water content in the stratum corneum of the epidermis, such as trehalose and its derivatives, glycerol, pentanediol, pidolates, serine, xylitol, peroxyethanol, sodium lactate, glyceryl polyacrylate, ectoine and its derivatives, chitosan, oligo- and polysaccharides, cyclic carbonates, Nlauroylpyrrolidonecarboxylic acid and N-aaa-benzoyl-L-arginine. The amount of such compounds in the compositions of the present invention is from 0.001 to 30% by weight, preferably from 0.01 to 20% by weight, based on the total weight of the composition according to the present invention.

The term flavoring agent refers to any fragrance or flavoring agent that is capable of producing a pleasant odor. The flavoring agent contained in the compositions of the present invention may be derived from natural or synthetic fragrances and flavoring agents and mixtures thereof. Examples of naturally occurring fragrances and fragrances include extracts of flowers (lily, lavender, rose, jasmine, ylang-ylang), stems and leaves (patchouli, geranium, vernonia), fruit (coriander, anise, cumin, juniper), fruit peel (bergamot , lemon, orange), roots (angelica, celery, cardamom, iris, calamus), wood (pine, sandalwood, buckout, rose cedar), herbs and grains (tarragon wormwood, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), gums and balms (galbanum, gum, benzoin, myrrh, incense, opopanax).

Preferably, the amount of flavoring agents is from 1 to 30 wt.% by weight, more preferably from 2 to 25 wt.% by weight, relative to the total weight of the composition. The preferred composition is shown in table. 3.

- 10 043968

Table 3

Ingredients (INCI) without active substances and phospholipids of the carrier system Quantity, weight. % Function CAS No. Distilled water 56.79 Solvent 7732-18-5 Isopropyl myristate 1.0 Emollient with emulsifying properties 110-27-0 Palmitoyl tripeptide-5 1.0 Emollient with emulsifying properties 623172-56-5 95 Palmitic acid 1.0 Emollient with emulsifying properties 57-10-3 G licerin 3.0 Emollient with emulsifying properties 56-81-5 White lupine seed oil 2.0 Emollient with emulsifying properties 545-47-1 Palmitoyl pentapeptide 1.0 Emollient with emulsifying properties 214047-00-4 Cetearyl alcohol 1.0 Emollient with emulsifying properties 67762-27- 0/8005-44-5 Polidocanol 3.0 Emollient with emulsifying properties 3055-99-0 Squalene 1.0 Emollient with emulsifying properties 111-02-4 Hydroxypalmitoylsphinganine 1.0 Emollient with emulsifying properties 190249-36-6 Imidazo lidinylurea 2.0 Humidifier 39236-46-9 Sweet almond oil 5.0 Preservative with conditioning effect 8007-690/90320-37-9 Pyridoxine hydrochloride 1.0 Preservative with conditioning effect 58-56-0 Sodium ascorbyl phosphate 2.0 Preservative with conditioning effect 66170-10-3 Phenoxyethanol/Peroxyethanol 1.0 Preservative with conditioning effect 122-99-6 Green tea polyphenols 1.0 Preservative with conditioning effect 84650-60-2 Sodium citrate 1.0 Buffer agent 68-04-2 Glyceryl stearate PEG-5 1.0 Surface-active substance 51158-08-8 138860-92-1 Stearic acid 1.0 Surface-active substance 57-11-44 Trans-urocanic acid, which is a breakdown product of filaggrin 1.0 UV filter 104-98-3-3465- 72-3 Butylmethoxydibenzoylmethane 4.8 UV filter 70356-09-1 Methylenebis- benzotriazolyltetramethylbutylphenol (nano) 3.5 UV filter 103597-45-1 Ethylhexyltriazone 2.0 UV filter 88122-99-0 Bis- ethylhexyloxyphenolmethoxyphenyltriazine 0.8 UV filter 187393-00-6 Ethylhexylmethoxycinnamate 0.1 UV filter 5466-77-3 Octyldodecanol 1.0 Flavoring agent 5333-42-6 Geranium oil 0.002 Flavoring agent 84650-10-2 Bitter orange oil 0.002 Flavoring agent 8008-57-9 Lemon oil 0.002 Flavoring agent 8008-56- 8/84929-31-7 Rosewood oil 0.004 Flavoring agent 83863-32-5 Total amount: 100.00

The lipid-based colloidal carrier system (e.g., lipid-based vesicles such as liposomes, niosomes, transferosomes) can be prepared using any known technique (for the preparation of carrier systems in a general context, see, e.g., Liposomes, eds Angel Catala, pub. InTech, 2017 (ISBN 978-953-51-3580-7), or of liposomal carriers see e.g. Liposomes, Methods and Protocols, Springer Protocols, eds. D'Souza, Gerard G.M., 2017). For example, a colloid can be formed using any conventional technique for preparing multilamellar lipid vesicles (MLVs), that is, by placing lipophilic vitamin D3 or its precursor with one or more lipids in a suitable vessel, dissolving the lipids in an organic solvent such as chloroform, and evaporating organic solvent to obtain a lipid film. In the next step, hydration of the lipid film is achieved by adding an aqueous solution containing hydrophilic components, including hyaluronic acid. Typically, the resulting lipid suspension is shaken or vortexed to obtain the final composition

- 11 043968 in accordance with the present invention. Alternatively, techniques used to produce large unilamellar lipid vesicles (LUVs), such as reverse phase evaporation, injection methods, and detergent dilution, can be used to form liposomes. A review of these and other methods for preparing lipid vesicles can be found in Liposome Technology, Volume I, Gregory Gregoriadis Ed., CRC Press, Boca Raton, Fla., (1984), which is incorporated herein by reference. For example, lipid-containing particles may be in the form of steroidal lipid vesicles, stable plurilamellar lipid vesicles (SPLVs), monophasic vesicles (MPVs), or lipid matrix carriers (LMCs). In the case of MLV, liposomes can optionally be subjected to multiple (five or more) freeze-thaw cycles to increase their entrapment volumes and entrapment efficiency and to provide more uniform interlamellar solute distribution.

In one embodiment, liposomes are prepared, for example, by hot homogenization under pressure to obtain high incorporation efficiency (EE). The effectiveness of inclusion will give the percentage of the active substance that is successfully captured/adsorbed in the nanoparticles and will be transferred to the deeper layers of the skin. The main problem in the use of nanostructured lipid carriers (NLCs) as carriers for a hydrophilic active substance is the limited loading capacity (LC) and incorporation efficiency (EE) of the NLC for such molecules, with the EE in wt.% equal to [(added active substance - free unentrapped active substance)/added active substance] * 100 (thus, as an example, wt.% EE 5 wt.% means that 5 wt.% active substance is captured in the carrier system).

The temperature of the phase transition from the gel form to crystalline two-dimensional network states with lower mobility in the liquid crystal structure. The phase transition temperature of these lipids depends on the end group, chain lengths and the level of saturation of the fatty acid esters. The temperature will range from -20 to 60°C and can be determined using thermoanalytical methods. The mobility of lipophilic agents embedded in the liquid crystalline phase increases, and they can change position within the lipid layers, but not leave the lipid layers [46].

The physical structure of the multilamellar layered system will be created by the interaction between phospholipids and the aqueous environment during high pressure homogenization and dehydration of dry lipids. Using this method, multilamellar vesicles (MLVs) are formed. Polycarbonate membranes with a size of 10-500 nm will be used for liposome extrusion. Homogenization and size will be determined by the filter pore diameter and the number of extrusion stages. The goal will be to achieve maximum switching efficiency.

The use of this carrier system provides unique physicochemical properties such as ultra-small size (small particles in the size range of 1-100 nm), large surface area to mass ratio and high reactivity, which differ from bulk material with the same composition. These properties are used to overcome skin penetration limitations for large molecular sizes and encapsulate lipophilic and hydrophilic substances as needed to pass through the skin barrier.

In a further aspect, the present invention is directed to suitable formulations based on the compositions of the present invention for topical or transdermal use.

The compositions of the present invention can be used in various types of topical or transdermal applications and may be in solid, liquid or semi-solid form. Thus, suitable formulations include, but are not limited to, emulsions (e.g., oil and/or silicone in water emulsions, water in oil and/or silicone emulsions, water/oil/water or water/silicone/water emulsions, and oil/water emulsions). water/oil or silicone/water/silicone emulsions), microemulsions, aqueous dispersions, oils, milks, balms, foams, aqueous or oily lotions, aqueous or oily gels, creams, solutions, aqueous-alcoholic solutions, aqueous glycol solutions, hydrogels , serums, ointments, mousses, pastes, sprays and aerosols, and also provides for the inclusion of compositions according to the present invention in any transdermal patches. In a typical transdermal therapeutic system, such as a patch or pad, the compositions of the present invention (with or without at least one adjuvant) are optionally included in combination with penetration enhancers and/or crystallization inhibitors. Thus, in certain embodiments, the compositions are in the form of a cream, gel, or lotion; in other specific embodiments, the compositions are in the form of a transdermal therapeutic system, such as a patch or pad.

In an additional aspect, the present invention is directed to the use of the composition (and compositions based thereon) according to the present invention in the prevention and/or treatment of symptoms of photodamage to the skin, in particular, in the prevention and/or treatment of skin atrophy, skin dyspigmentation (spots/dots), photodermatitis (erythema: skin inflammation and redness), telangiectasia, (rosacea) and prevention of actinic keratosis, as well as protecting the skin from solar radiation, UVA and UVB radiation.

- 12 043968

Thus, the present invention provides a method of preventing and/or treating photodamage to the skin in a subject, comprising administering a composition (and topical compositions thereof) according to the present invention to the subject in an amount effective to stop the process of photodamage, i.e. to inhibit reactive oxygen species ROS, 0-2 peroxide and nitric oxide (NO) and hence the accumulation of cytotoxic peroxynitrite (ONOO-).

The compositions (or formulations based thereon) can be administered either at regular intervals as needed (eg, once, twice or several times per day) or in a substantially continuous manner (eg, through a transdermal patch).

The following examples are exemplary examples to illustrate the present invention without limiting the scope of the present invention.

Examples

Methods and materials.

The dried phospholipids were dispersed at room temperature in an aqueous solution with spontaneous formation of spherical colloids. 7-DHC, 98.7% pure (HPLC; area %), was liquefied at 140 to 150°C. Propylene glycol was added to 7-DHC in a liquid state and the resulting mixture was mixed with phospholipid-based colloids with vigorous stirring at room temperature to form colloids of 20-150 nm in size with the addition of 7-DHC in the oil phase of the colloids. HA (2% low molecular weight, 4 kDa, 96.8% purity, 0.5 wt% average molecular weight, 48.3 kDa, 97.3% purity and 0.5 wt% high molecular weight 1.78x106 Yes, purity grade for eye drops 100%) was dispersed/dissolved with stirring in water and added separately with stirring at room temperature. The HA mixtures were added to phospholipid-based colloids already loaded with 7-DHC and stirred for 20 min at room temperature to obtain a spontaneously formed homogeneous hydrogel. Microscopic analysis revealed spherical particles with a size of 20-150 nm. The hydrogel was macroscopic and stable by HPLC analysis, showing the same concentration of added 7-DHC over 6 months.

For the lipid phase, 98.7% purity (HPLC; area %) 7-DHC was used (liquidated at temperatures between 140 and 150°C). Propylene glycol was used as an organic solvent for 7-DHGC and phospholipids.

For the aqueous phase, ND was used (in the form of a mixture of 2% low molecular weight, 4 kDa, 96.8% purity, 0.5 wt.% average molecular weight, 48.3 kDa, 97.3% purity and 0.5 wt.% with a high molecular weight of 1.78x106 Yes degree of purity for eye drops 100%).

Stirring for 20 min at room temperature resulted in the spontaneous formation of a homogeneous hydrogel. Microscopic analysis revealed spherical particles with a size of 20-150 nm.

Stability studies showed high stability (>98%) over 6 months and a constant DHC content of 1.5% by HPLC analysis.

Example 1. Cream system without UV filter.

Table 4

Ingredients (INCI) Quantity, weight. % CAS No. 7-DHC 0.15 434-16-2 ON 3 9004-61-9 Retinyl palmitate 0.5 79-81-2 Skin conditioning Riboflavin OD 83-88-5 Nicotinamide 4.0 98-92-0 Dexpanthenol 2.5 81-13-0 Folic acid 0.05 59-30-3 L-ascorbic acid 3.0 50-81-7 Tocopherol acetate 2.0 7695-91-2 Distilled water 46,196 7732-18-5 Solvent Glyceryl stearate PEG-5 1.0 51158-08-8 138860-92-1 Surface-active substance Stearic acid 1.0 57-11-44 Emollient with emulsifying properties Isopropyl myristate 1.0 110-27-0

- 13 043968

Palmitic acid 1.0 57-10-3 White lupine seed oil 2.0 545-47-1 Palmitoyl pentapeptide 1.0 214047-00-4 Sweet almond oil 5.0 8007-69-0/90320-37-9 Squalene 1.0 111-02-4 Polidocanol 3.0 3055-99-0 Hydroxypalmitoylsphinganine 1.0 190249-36-6 Pyridoxine HCL 5.0 8007-69-0/90320-37-9 Preservative with conditioning effect Sodium ascorbyl phosphate 2.0 66170-10-3 Sodium citrate 1.0 6132-04-3 Buffer Lecithin 2 8002-43-5 Composition of the encapsulating carrier* Sphingomyelin 2 85187-10-6 Linolenic acid 1 463-40-1 Linoleic acid 1 60-33-3 Phosphatidylcholine 3 26853-31-6 Caprylic triglyceride 1 73398-61-5 Octyldodecanol 1.0 5333-42-6 Flavoring agent Bitter orange oil 0.002 8008-57-9 Lemon oil 0.002 8008-56-8/84929-31-7 VP/eicosene copolymer 2.5 28211-18-9 Film former Total amount: 100

Example 2. Gel system without UV filter.

Table 5

Ingredients (INCI) Quantity, weight. % Function CAS No. 7-DHC 0.15 Active Ingredient - ROS Binder 434-16-2 ON 3 Active ingredient - humectant 9004-61-9 Retinyl palmitate 0.5 Skin conditioning 79-81-2 Riboflavin OD Skin conditioning 83-88-5 Nicotinamide 4.0 Skin conditioning 98-92-0 Dexpanthenol 2.5 Skin conditioning 81-13-0 Folic acid 0.05 Skin conditioning 59-30-3 L-ascorbic acid 3.0 Skin conditioning 50-81-7 Tocopherol acetate 2.0 Skin conditioning 7695-91-2 Distilled water 65.77 Solvent 7732-18-5 Stearic acid 1.0 Surface-active substance 57-11-44 Isopropyl myristate 1,o Emollient with emulsifying properties 110-27-0 Palmitic acid 1.0 Emollient with emulsifying properties 57-10-3 Cetearyl alcohol 1.0 Emollient with emulsifying properties 67762-27-0/8005-44-5 Polidocanol 2.0 Emollient with emulsifying properties 3055-99-0 Sodium citrate 1.0 Buffer agent 6132-04-3 Lecithin 1 Composition of the encapsulating 8002-43-5 carrier* Sphingomyelin 2 Composition of the encapsulating carrier* 85187-10-6 Linolenic acid 1 Composition of the encapsulating carrier* 463-40-1 Linoleic acid 1 Composition of the encapsulating carrier* 60-33-3 Phosphatidylcholine 2.0 Composition of the encapsulating carrier* 26853-31-6 Caprylic triglyceride 1 Composition of the encapsulating carrier* 73398-61-5 Capric triglyceride 1 Composition of the encapsulating carrier* 65381-09-1 Triethanolamine 0.08 pH adjusting agent 102-71-6 Peroxyethanol 3 Preservative 95684-29-0 Total amount: 100

- 14 043968

Example 3. Serum system without UV filter.

Table 6

Ingredients (INCI) Quantity, weight. % Function CAS No. 7-DHC 0.15 Active ingredient binder ROS 434-16-2 ON 3 Active ingredient humectant 9004-61-9 Dexpanthenol 2.5 Skin conditioning 81-13-0 Folic acid 0.05 Skin conditioning 59-30-3 Tocopherol acetate 2.0 Skin conditioning 7695-91-2 Distilled water 70.3 Solvent 7732-18-5 Glyceryl stearate PEG-5 1.0 Surface-active substance 51158-08-8 138860-92-1 Stearic acid 1.0 Surface-active substance 57-11-44 Isopropyl myristate 1.0 Emollient with emulsifying properties 110-27-0 Palmitic acid 1.0 Emollient with emulsifying properties 57-10-3 Palmitoyl pentapeptide 1.0 Emollient with emulsifying properties 214047-00-4 Polidocanol 2.0 Emollient with emulsifying properties 3055-99-0 Hydroxypalmitoylsphinganine 1.0 Emollient with emulsifying properties 190249-36-6 Sodium citrate 1.0 Buffer agent 6132-04-3 Lecithin 1 Composition of the encapsulating carrier* 8002-43-5 Sphingomyelin 2 The composition of the encapsulating 85187-10-6 th carrier* Linolenic acid 1 Composition of the encapsulating carrier* 463-40-1 Linoleic acid 1 Composition of the encapsulating carrier* 60-33-3 Phosphatidylcholine 3 Composition of the encapsulating carrier* 26853-31-6 Caprylic triglyceride 1 Composition of the encapsulating carrier* 73398-61-5 Capric triglyceride 1 Composition of the encapsulating carrier* 65381-09-1 Peroxyethanol 3 Preservative 95684-29-0 Total amount: 100

Example 4. System for application to the face with a UV filter.

- 15 043968

Table 7

Ingredients (INCI) Quantity, weight. % Function CAS No. 7-DHC 0.15 Active Ingredient - ROS Binder 434-16-2 ON 3 Active ingredient - humectant 9004-61-9 Distilled water 55.15 Solvent 7732-18-5 Glyceryl stearate PEG-5 1.0 Surface-active substance 51158-08-8 138860-92-1 Stearic acid 1.0 Surface-active substance 57-11-44 Isopropyl myristate 1.0 Emollient with emulsifying properties 110-27-0 Palmitic acid 1.0 Emollient with emulsifying properties 57-10-3 Pyridoxine HCL 5.0 Preservative with conditioning effect 8007-69- 0/90320-37-9 Sodium ascorbyl phosphate 2.0 Preservative with conditioning effect 66170-10-3 Polidocanol 3.0 Emollient with emulsifying properties 3055-99-0 Hydroxypalmitoylsphinganine 1.0 Emollient with emulsifying properties 190249-36-6 Sodium citrate 1.0 Buffer agent 6132-04-3 Lecithin 1 Composition of the encapsulating carrier* 8002-43-5 Sphingomyelin 2 Composition of the encapsulating carrier* 85187-10-6 Linolenic acid 1 Composition of the encapsulating carrier* 463-40-1 Linoleic acid 1 Composition of the encapsulating carrier* 60-33-3 Phosphatidylcholine 3 Composition of the encapsulating carrier* 26853-31-6 Caprylic triglyceride 1 Composition of the encapsulating carrier* 73398-61-5 Capric triglyceride 1 Composition of the encapsulating carrier* 65381-09-1 VP/eicosene copolymer 2.5 Film former 28211-18-9 Trans-urocanic acid, which is a breakdown product of filaggrin 1 UV filter 104-98-3- 3465-72-3 Butylmethoxydibenzoylmethane Neo Heliopan 357, Eusolex9020, Parsol 1789 3.8 UV filter 70356-09-1 Methylenebis- benzotriazolyltetramethylbutylphenol (nano) Tinosorb Μ 2.5 UV filter 103597-45-1 Egilhexyltriazone Uvinul T 150 2.0 UV filter 88122-99-0 Bis- ethylhexyloxyphenolmethoxyphenyltriazine Tinosorb S 0.8 UV filter 187393-00-6 Egilhexylmethoxycinnamate Uvinul MS 80, Parsol MSKh, Neo Heliopan AV 4 0.1 UV filter 5466-77-3 Peroxyethanol 3 Preservative 95684-29-0 Total amount: 100,000

Example 5. System for application to the body with a UV filter.

- 16 043968

Table 8

Ingredients (INCI) Quantity, weight. % Function CAS No. 7-DHC 0.15 Active ingredient binder ROS 434-16-2 ON THE* 3 Active ingredient humectant 9004-61-9 Retinyl palmitate 0.2 Skin conditioning 79-81-2 Riboflavin OD Skin conditioning 83-88-5 Nicotinamide 2.0 Skin conditioning 98-92-0 Dexpanthenol 2.5 Skin conditioning 81-13-0 Folic acid 0.05 Skin conditioning 59-30-3 L-ascorbic acid 2.0 Skin conditioning 50-81-7 Tocopherol acetate 1.0 Skin conditioning 7695-91-2 Distilled water 56,263 Solvent 7732-18-5 Stearic acid 1.0 Surface-active substance 57-11-44 Pyridoxine HCL 3.0 Preservative with conditioning effect 8007-690/90320-37-9 Sodium ascorbyl phosphate 2.0 Preservative with conditioning effect 66170-10-3 Polidocanol 3.0 Emollient with emulsifying properties 3055-99-0 Sodium citrate 1.0 Buffer agent 6132-04-3 Lecithin 1 Composition of the encapsulating carrier* 8002-43-5 Sphingomyelin 2 Composition of the encapsulating carrier* 85187-10-6 Linolenic acid 1 Composition of the encapsulating carrier* 463-40-1 Linoleic acid 1 Composition of the encapsulating carrier* 60-33-3 Phosphatidylcholine 3 Composition of the encapsulating carrier* 26853-31-6 Caprylic triglyceride 1 Composition of the encapsulating carrier* 73398-61-5 Capric triglyceride 1 Composition of the encapsulating carrier* 65381-09-1 VP/eicosene copolymer 2.5 Film former 28211-18-9 Trisodium ethylenediamine disuccinate, trisodium ethylenediamine disuccinate solution, NatrlquestE30 3) 0.037 Chelating agent 20846-91- 7/178949-82-1 Trans-urocanic acid, which is a breakdown product of filaggrin 1 UV filter 104-98-3- 3465-72-3 Butylmethoxydibenzoylmethane Neo Heliopan 357, Eusolex 9020, Parsol 1789 3.8 UV filter 70356-09-1 Methylenebis- benzotriazolyltetramethylbutylphenol (nano) Tinosorb Μ 2.5 UV filter 103597-45-1 Egilhexyltriazone Uvinul T 150 2.0 UV filter 88122-99-0 Bis- ethylhexyloxyphenolmethoxyphenyltriazine Tinosorb S 0.8 UV filter 187393-00-6 Egilhexylmethoxycinnamate Uvinul MS 80, Parsol MSKh, Neo Heliopan AV 4 0.1 UV filter 5466-77-3 Total amount: 100,000

- 17 043968

List of references

1. Gary J. Fisher, Ph.D., Zeng Quan Wang, Ph.D., Subhash C. Datta, Ph.D James Varani, Ph.D., Sewonkang, M.D., And John J. Voorhees, M.D. Pathophysiology Of Premature Skin Aging Induced by Ultraviolet Light The New England Journal Of Medicine December 11, 2016

2. Wound Repair and Regeneration. 15 (5): 708-17 September 2007.

3. American Academy of Dermatology, Aging Skin Net, “Causes of Aging Skin.”

4. Matthias Wacker and Michael F. Holick Sunlight and Vitamin D A global perspective for health DermatoEndocrinology 5:1, 51-108; January/February/March2013.

5. Holick MF Vitamin D deficiency. N.Engl. J. Med. 357 (3): 266-81 July 2007.

6. Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Current Opinion in Endocrinology, Diabetes and Obesity. 9 (1): 87-98 February 2002.

7. Holick MF Sunlight and Vitamin D. Journal of General Internal Medicine. 17 (9): 733-735 September 2002.

8. Meghan Russell Assessing the Relationship between Vitamin D3 and Stratum Comeum Hydration for the Treatment of Xerotic Skin Nutrients 2012, 4, 1213-1218.

9. Abramovits W. Calcitriol 3 microg/g ointment: an effective and safe addition to the armamentarium in topical psoriasis therapy. J Drugs Dermatol. 2009;8(8 Suppl):s 17-22.

10. Gerritsen MJ, Van De Kerkhof PC, Langner A. Long-term safety of topical calcitriol 3 microg g(-l) ointment. Br J Dermatol. 2001;144 Suppl 58:17-19.

11. Meghan Russell Assessing the Relationship between Vitamin D3 and Stratum Comeum Hydration for the Treatment of Xerotic Skin Johnson and Johnson Skin Research Center, CPPW, Johnson & Johnson Consumer Companies, Inc., Skillman, NJ 08558, USA Nutrients 2012, 4, 1213 -1218

12. Rizova E, Corroller M. Topical calcitriol—studies on local tolerance and systemic safety. Br J Dermatol. 2001;144 Suppl 58:3-10.

13. Mason AR, Mason J, Cork M, Dooley G, Edwards G. Topical treatments for chronic plaque psoriasis. Cochrane Database SystRev. 2009(2):CD005028.

14. Murphy G, Reich K. In touch with psoriasis: topical treatments and current guidelines. J Eur Acad Dermatol Venereol. 2011;25 Suppl 4:3-8.

15. vY. Oda, Y. Uchida, S. Moradian, D. Crumrine, P.M. Elias, D.D. Bikie. Vitamin D receptor and coactivators SRC 2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. J Invest Dermatol, 129 (2009), pp. 1367-1378

16. Jurgen Schauber, Richard L. Gallo, Antimicrobial peptides and the skin immune defense system, Journal of Allergy and Clinical Immunology, Volume 122, Issue 2, August 2008, Pages 261-266, ISSN 0091-6749

17. Burkiewicz CJ, Guadagnin FA, Skare TL, do Nascimento MM, Servin SC, de Souza GD. Vitamin D and skin repair: a prospective, double-blind and placebo controlled study in the healing of leg ulcers. Rev Col Bras Circ. 2012 Sep-Oct;39(5):401-7.

18. Schauber J, Dorschner RA, Coda AB, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007;117:803-11.

19. Zasloff M. Sunlight, vitamin D, and the innate immune defenses of the human skin. J Invest Dermatol. 2005;125:xvi-xvii.

- 18 043968

20. J.D. Heilbom, M.F. Nilsson, G. Kratz, G. Weber, O. Sorensen, N. Borregaard, et al. The cathelicidin antimicrobial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium J Invest Dermatol, 120 (2003), pp. 379-389.

21. De Haes P, Garmyn M, Verstuyf A et al. Two 14-epi analogues of 1,25-dihydroxyvitamin D3 protect human keratinocytes against the effects of UVB. Arch Dermatol Res 2004:12:527-534

22. De Haes P, Garmyn M, Carmeliet G et al. Molecular pathways are involved in the anti-apoptotic effect of 1,25dihydroxyvitamin D3 in primary human keratinocytes. J Cell Biochem 2004:93:951-967.

23. De Haes P, Garmyn M, Degreef H, Vantieghem K, Bouillon R, Segaert S. 1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes. J Cell Biochem 2003:89:663-673.

24. Wong G, Gupta R, Dixon K M et al. 1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway. J Steroid Biochem Mol Biol 2004:89-90:567-570.

25. De Haes P, Garmyn M, Verstuyf A et al. 1,25-Dihydroxyvitamin D3 and analogues protect primary human keratinocytes against UVB-induced DNA damage. J Photochem Photobiol B 2005: 78: 141-148

26. Reichrath, Jorg. Vitamin D and the skin: an ancient friend, revisited. Experimental dermatology, 2007, 16. Jg., Nr. 7, pp. 618-625

27. Kielty CM, Whittaker SP, Grant ME, Shuttleworth CA. Type AT collagen microfibrils: evidence for a structural association with hyaluronan. J Cell Biol. 1992;118:979-90

28. Baccarani-Contri M, Vincenzi D, Cicchetti F, Mori G, Pasquali-Ronchetti I. Immunocytochemical localization of proteoglycans within normal elastin fibers. Eur J Cell Biol. 1990; 53:305-12

29. Cleland RL, Wang JL. Ionic polysaccharides. 3.Dilute solution properties of hyaluronic acid fractions. Biopolymers. 1970;9:799-810

30. Bhattacharya J, Cruz T, Bhattacha-rya S, Bray BA. Hyaluronan affects extravascular water in the lungs of unanesthetized rabbits. J Appl Physiol. 1989;66:2595-9

31. Weindl G, Schaller M, Schafer-Korting M, Korting HC. Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects. Skin Pharmacol Physiol. 2004; 17:20713

32. Turino GM. The lung parenchyma—a dynamic matrix. (J. Bums Amberson lecture). Am Rev Respir Dis. 1985; 132:1324-34

33. Robert A. Greenwald And Wai W. Moy Effect Of Oxygen-Derived Free Radicals On Hyaluronic Acid Arthritis And Rheumatism, Vol. 23, No. 4 (April 1980)

- 19 043968

34. Eleni Papakonstantinou, Michael Roth and George Karakiulakis Hyaluronic acid A key molecule in skin aging. Dermato-endocrinology 4:3, 253-258; July-December 2012.

35. Foschi DI, Castoldi L, Radaelli E, Abelli P, Calderini G, Rastrelli A, Mariscotti C, Marazzi M, Trabucchi E. Hyaluronic acid prevents oxygen free-radical damage to granulation tissue: a study in rats. Int J Tissue React. 1990;12(6):333-9.

36. Celebi SI, Tepe C, Yelken K, Celik O. Efficacy of dexpanthenol for pediatric post-tonsillectomy pain and wound healing. Ann Otol Rhinol Laryngol. 2013 Jul;122(7):464-7.

37. Siddharth Mukherjee, Abhijit Date, Vandana Patravale, Hans Christian Korting, Alexander Roeder, Gunther Weindl Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety Clinical Interventions in Aging 2006:1(4) 327-348.

38. Wohlrab JI, Kreft D. Niacinamide - mechanisms of action and its topical use in dermatology. Skin Pharmacol Physiol. 2014;27(6):311-5.

39. Biro KI, Thaci D, Ochsendorf FR, Kaufmann R, Boehncke WH. Efficacy of dexpanthenol in skin protection against irritation: a double-blind, placebo-controlled study. Contact Dermatitis. 2003 Aug;49(2):80-4.

40. Julia Steitz, Jurgen Bruck, Julia Lenz, Steffi Buchs, Thomas Tilting. Peripheral CD8+ T Cell Tolerance Against Melanocytic Self-Antigens in the Skin Is Regulated in Two Steps by CD4+ T Cells and Local Inflammation: Implications for the Pathophysiology of Vitiligo. Journal of Investigative Dermatology Volume 124, Issue 1, January 2005, Pages 144-150.

41. Knott Al, Koop U, Mielke H, Reuschlein K, Peters N, Muhr GM, Lenz H, Wensorra U, Jaspers S, Kolbe L, Raschke T, Stab F, Wenck H, Gallinat S. A novel treatment option for photoaged skin. J Cosmet Dermatol. 2008 Mar;7(l): 15-22.

42. The American Society of Health-System Pharmacists. Retrieved December 8, 2016.

43. WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 496. ISBN 9789241547659. Retrieved 8 December 2016.

44. Prockop DJ, Kivirikko KI (1995). Collagens: molecular biology, diseases, and potentials for therapy. Annu. Rev. Biochem. 64: 403-34.

45. Peterkofsky V (December 1991). Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in skin. Am. J. Clin. Nutr. 54 (6 Suppl): 1135S-1 MOS.

46. Kivirikko KI, Myllyla R (1985). Post-translational processing of procollagens. Annals of the New York Academy of Sciences. 460: 187-201.

-

Claims (14)

47. Rebouche CJ (December 1991). Ascorbic acid and carnitine biosynthesis. Am. J. Clin. Nutr. 54 (6 Suppl): 1147S-1152S.PMID 1962562. 48. Dunn WA, Rettura G, Seifter E, Englard S (September 1984). Carnitine biosynthesis from gammabutyrobetaine and from exogenous protein-bound 6-N-trimethyl-L-lysine by the perfused guinea pig liver. Effect of ascorbate deficiency on the in situ activity of gamma-butyrobetaine hydroxylase (PDF). J Biol. Chem. 259(17):10764-70. PMID 6432788. 49. Padayatty SJ, Katz A, Wang Y, Eek P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK, Levine M (February 2003). Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr. 22 (1): 18-35. doi:10.1080/07315724.2003.10719272. PMID 12569111. Archived from the original on July 21, 2010. 50. Traber MG, Stevens JF; Stevens (2011). Free Radical Biology and Medicine - Vitamins C and E: Beneficial effects from a mechanistic perspective. Free Radical Biology and Medicine. 51 (5): 1000-13 2011. CLAIM 1. A composition for the prevention and/or treatment of skin disorders, containing at least one vitamin D3 or its precursor, which is 7-dehydrocholesterol (7-DHC), and a mixture of hyaluronic acid with a low molecular weight from 4 to 50 kDa and hyaluronic acids with a higher molecular weight of not more than 200,000 kDa, encapsulated in a lipid-based colloidal carrier system. 2. The composition according to claim 1, containing a precursor of vitamin D3, which is 7-DHC. 3. The composition according to claim 1 or 2, where the lipid-based colloidal carrier system includes liposomes, niosomes, transferosomes, micelles, nanoparticles, microemulsions. 4. The composition according to any of the previous claims, further containing one or more additional components selected from vitamin A, at least one of vitamin B, vitamin C and vitamin E. 5. The composition according to claim 4, wherein at least one vitamin B is riboflavin (vitamin B2), nicotinamide (vitamin B3), dexpanthenol (provitamin B5) and/or folic acid (vitamin B9). 6. The composition according to claim 1, additionally containing (i) retinyl palmitate (vitamin A), (ii) riboflavin (vitamin B2), (iii) nicotinamide (vitamin B3), (iv) dexpanthenol (provitamin B5), (v) folic acid acid (vitamin B9), (vi) L-ascorbic acid (vitamin C) and (vii) tocopherol acetate (vitamin E). 7. The composition according to any of the previous paragraphs, additionally containing at least one UV filter. 8. The composition according to any of the previous paragraphs, further containing at least one excipient selected from surfactants, emulsifying agents, emollients, thickening agents, conditioning preservatives, buffering agents, humectants, flavoring agents. 9. The composition of claim 8, wherein the surfactant is polycarbonate, polyvinylpyrrolidone (PVP), polyvidone, povidone membranes, povidone, copovidone, hypromellose or Eudragit EPO. 10. The composition of claim 8, wherein the surfactant is polysorbate 10150. 11. The composition according to any of the preceding claims, wherein the lipid-based colloidal carrier system consists of one or more components selected from phospholipids, lecithin, sphingomyelin, linolenic acid, linoleic acid, phosphatidylcholine and caprylic/capric triglyceride. 12. A topical composition containing a composition according to any one of claims 1 to 11, in solid, liquid or semi-solid form. 13. Composition for topical use according to claim 12, containing a composition according to any of claims 1 to 11, in the form of emulsions, microemulsions, aqueous dispersions, oils, milks, balms, foams, aqueous or oily lotions, aqueous or oily gels, creams, solutions, hydroalcoholic solutions, water-glycol solutions, hydrogels, serums, ointments, mousses, pastes, sprays or aerosols or transdermal patches. 14. Use of a composition according to any one of claims 1 to 11 in the prevention and/or treatment of skin disorders, inflamed skin, eczema, rosacea, atopic dermatitis, psoriasis, photodamage, skin atrophy, skin dyspigmentation, photodermatitis, telangiectasia, rosacea and actinic keratin -