WO2020201377A1

WO2020201377A1 - Cream for treatment of skin injured by the sun

Info

Publication number: WO2020201377A1
Application number: PCT/EP2020/059296
Authority: WO
Inventors: Erin Worrall; Anna BORTKUN
Original assignee: Medica Clinical Nord Sverige Ab
Priority date: 2019-04-04
Filing date: 2020-04-01
Publication date: 2020-10-08

Abstract

The invention opertains to a cream, comprising as active ingredients: 0.5 - 7 % by weight of D,L-α-lipoic acid, 0.05-0.5 % by weight of coenzyme Q-10, 0.01-3 % by weight of acetyl-L-carnitine hydrochloride, 0.01 - 2% by weight of allantoin, and 0.1 - 10 % by weight of Aquaxyl and a method for preparing said cream.

Description

CREAM FOR TREATMENT OF SKIN INJURED BY THE SUN

Field of the Invention

This invention pertains to a cream for topical treatment of visibly

photodamaged skin caused by processes involving the influence of free radicals.

Background of the Invention

It is known that the first visible sign of the skin aging process is complexion’s dryness followed by decrease in elasticity. Gradually the skin becomes rough, dull and flaky. The appearing of deeper wrinkles can be observed. The further aging process leads to development of cherry hemangioma, seborrheic keratosis, actinic keratosis or pigmentary changes.

Changes observed with aging within epiderma consist of: thinning of epidermis caused by reduced proliferation of keratinocytes; thickening of stratum corneum due to proteinases dysfunction and disturbed desquamation process; reduction of the number of melanocytes resulting in weaker protection against UV light; decreasing the number of Langerhans cells leading to changed immunological response in aged skin; decreased sebum production resulting in dry skin, development of comedones and cysts as well as changed composition of hydrolipid barrier that becomes more sensitive to extrinsic factors (sunlight, temperature, mechanical trauma, pathogens).

The delamination of lamina densa and changes in structure of keratinocytes in stratum basale are the major causes of observed flattening of dermal-epidermal junction. The adherence of epidermis and dermis decreases in time.

Symptoms of aging process in dermis include: reduced size and number of fibroblast; decreased oxygen consumption and ATP concentration in extracellular matrix; the reduction in number of macrophages results in lack of collagenases and proteinases to cleave cross-linked collagen; less hyaluronic acid and dermatan sulphate in proteoglycan gel, making it less effective in water binding; structural changes in collagen lead to lose of elasticity; alterations of elastin fibers resulting in actinic elastoidosis.

The skin ageing process occurs through chronological aging (natural aging) and photoaging (premature ageing). The intrinsic/chronological aging results in thinning, loss of elasticity and general degradation of the skin. The extrinsic premature aging, photoaging, occurs in areas of habitual exposure to sunlight in form of elastosis, atrophy, wrinkling, vascular changes (erythema, telangiectasias), pigmentation changes (hyper- and hypo-pigmentation) or the development of seborrheic keratosis, actinic keratosis, comedones and cysts.

There are skin care products for prevention and treatment of skin aging, addressing different aspects of the aging process. The products designed for photoaged skin usually contain vitamin A, providing improved skin appearance and function, vitamins with well-known antioxidant potential, as vitamin E and C, and various active substances and peptides, targeting specific biochemical processes in the skin. The antioxidants should be considered as the most universal ingredients for prevention and treatment of photoaging: the negative impact of UV radiation and reactive oxygen species (ROS) is observed in various skin aging mechanisms, like glycation, DNA damage and mitochondrial deletions, ECM degradation, chronic inflammation, pigmentation changes, increased turnover time and disrupted barrier function, or accumulation of damaged proteins. The use of potential antioxidant as alpha lipoic acid (ALA) and/or Dihydrolipoic acid (DELLA) seems to be smart strategy regarding their functionality as free radical scavengers, regenerators for other antioxidants as vitamin C and E in skin, chelators for metals, and their role in repairing oxidized proteins.

Coenzyme Q-10, showing antioxidant efficacy, is found in epidermis in higher concentration than other antioxidants, suggesting its important role in protecting outmost layers of the skin from oxidative stress. Acetyl-L-camitine supports lipid oxidation in mitochondria, a process being less efficient with age. It has been demonstrated that topical application of a cream containing 5% ALA, 0,3% coenzyme Q10 (Q10) and 0,03% acetyl-L-carnitine (AC) was effective in reducing photo-induced changes in the skin (EP 1411889)

The existing solutions for prevention and treatment of skin aging caused by sunlight are affected by several problems:

Vitamin A, in its most active form, tretinoin (all-trans retinoic acid), is prohibited in cosmetics due to its teratogenic properties and strong side effects. The pure retinol is extremely sensitive to oxidation, making it difficult to keep the topical product active under shelf life. Undesirable side effects observed under retinol treatment are redness, dryness, skin flaking and sun-sensitivity. The retinol esters are more stable in time, but not as efficient as pure retinol in anti-aging treatments. Further, the use of vitamin A in products is restricted in several markets due to regulations (allowed concentrations at 0,3%), making it even more difficult to develop highly efficient product for prevention and treatment of photoageing. The active ingredients targeting defined aging mechanisms in the skin in for example peptides, are efficient, but cannot be considered as a universal solution for skin ageing due to their narrow specification.

Lipoic acid (ALA) has low aqueous solubility, is unstable under heat, low pH and light, and has an unpleasant sulfide-smell and an irritating taste. The physico-chemical properties of ALA make it difficult to formulate functional and esthetically accepted skin care product. However, minor side effects exist, especially in the initial phase of treatment, consisting of redness, rash and burning - yet these side effects are milder than any reaction to retinoids.

As such, there is a need for a skin cream for prevention and treatment of ageing skin, primarily caused by photoaging (i.e. sunlight), but with less risk of causing skin irritations, especially for persons with sensitive skin.

Summary of the Invention

Accordingly, the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing a cream, comprising as active ingredients: 0.5 - 7 % by weight of D,L-a- lipoic acid, 0.05-0.5 % by weight of coenzyme Q-10, 0.01-3 % by weight of acetyl-L- carnitine hydrochloride, 0.01 - 2% by weight of allantoin, and 0.1 - 10 % by weight of Aquaxyl.

Further is provided a method for preparing a cream, comprising the steps of; a) preparing an emulsion by mixing a water phase containing allantoin and Aquaxyl into an oil phase containing Q10 at 75-80°C; b) adding a solution of acetyl-L-carnitine hydrochloride to the emulsion from step a) at 70°C; c) adding a solution of D,L-a-lipoic acid in caprylic/capric triglycerides to the emulsion from step b) at 50-65°C; d) cooling down emulsion from step c) to 20 - 30°C.

The present invention has the advantage over the prior art that it provides a a facial cream with anti-ageing properties while being mild and non-irritant.

Brief Description of the Drawings

These and other aspects, features and advantages of which the invention is capable of will be apparent and elucidated from the following description of embodiments of the present invention, reference being made to the accompanying drawings, in which; Fig. l is a graph which shows a comparison of general efficacy for the

(existing) 5% ALA reference formulations and the 3% ALA (prototype) formulations of the invention, showing average results, based on points gained. The test objects evaluated several parameters while using the formulations by giving 1 to 5 points for each parameter,

Fig. 2 is a graph which shows a comparison of a dermatological patch test results for the (existing) 5% ALA reference formulation and the 1.6% and 3% ALA (improved) formulations of the invention, showing: Average Irritation Index (xav); erythema after 48h - average results,

Fig. 3 shows a comparison of the improvement of general skin condition for the existing ALA: 5% (QAL) formulation by clinical and photographic evaluation; and the 3 % ALA (QAL + allantoin + Aquaxyl) prototype formulation by instrumental evaluation; and 1,6% ALA (QAL + allantoin + Aquaxyl) prototype formulation by instrumental evaluation,

Fig. 4 shows the skin condition improvement for the 1,6 % ALA (QAL + allantoin + Aquaxyl) prototype formulation, measured as several parameters:

moisturizing effect, biomechanical parameter and size of wrinkles. Difference [%] between DO and D56, after regular use,

Fig. 5 shows the percentage of objects with positive effect from the 1,6 % ALA (QAL + allantoin + Aquaxyl) prototype formulation by measured parameter after 56 days of regular use [%],

Fig. 6 shows the skin condition improvement for the 3% ALA (QAL) reference formulation, measured as several parameters: moisturizing effect, biomechanical parameter and size of wrinkles. Difference [%] between DO and D56, after regular use,

Fig. 7 shows the percentage of objects with positive effect from the 3% ALA (QAL) reference formulation, by measured parameters after 56 days of regular application [%],

Fig. 8 shows images of skin texture for the 3% ALA (QAL) formulation before product application (DO) and after 56 days (D56) of regular application visualized with Visioline® VL 650, and

Fig. 9 shows images of skin texture for the 1,6% ALA (QAL) formulation before product application (DO) and after 56 days (D56) of regular application visualized with Visioline® VL 650.

Description of embodiments The concept of the invention is a composition and a method for preparing the composition for prevention and treatment of ageing skin, containing unique formulation of synergistic ingredients to obtain the good dermatological result. The current invention relates to lowered concentration of ALA in order to minimize potential irritational properties. A composition according to the invention also comprises allantoin and Aquaxyl in order to improve skin’s appearance and biomechanical properties. Despite the decrease of ALA content in the composition, which is making product less irritating and more aesthetically appealing, the results of the treatment are comparable to previously known compositions, due to two new components, allantoin and Aquaxyl, covering more skin aging manifestations than the previous composition.

Further, a method for treating skin is provided, comprising administering a topical composition according to the invention to the skin, containing alpha-lipoic acid, acetyl-L-carnitine, coenzyme Q10, allantoin and Aquaxyl (INCL Xylitylglucoside, Anhydroxylitol, Xylitol), or the dermatologically acceptable salts of any of these components in an amount effective to treat the skin. Treating skin comprises treating skin damage and the signs of aging of the skin. The skin damage can be due to intrinsic or extrinsic aging and includes, for example, wrinkles, sagging skin, decreased elasticity or dryness.

An alpha-lipoic acid is a part of the topical formulation used in the present invention. ALA is available as a racemate, and as D and L forms and R and S forms. Unless otherwise stated, ALA refers to all of these forms. ALA as used herein also includes the reduced form, dihydrolipoic acid (DHLA). Both forms of acid, reduced and oxidized, shows strong antioxidant properties: free radical scavengers, regenerators for other antioxidants as vitamin C and E in skin, chelators for metals, repairing agents for oxidized proteins.

Coenzyme Q-10, showing antioxidant efficacy, is found in epidermis in higher concentration than other antioxidants, suggesting its important role in protecting outmost layers of the skin from oxidative stress.

Acetyl-L-carnitine supports lipid oxidation in mitochondria, process being less efficient with age.

Allantoin is generally concerned as a soothing, softening and protecting ingredient in cosmetic formulations in a wide range of application, including skin care, toiletries and oral care products. The higher concentrations of allantoin (0,5 - 2%) supports natural regeneration of the skin by helping the skin to maintain its integrity: increases moisture retention by increasing comeocytes capacity to bin water; by loosening the intercellular kit or the desmosomes, that maintain the adhesion of comeocytes to each other, exfoliates dry and damaged cells and boosts the radiant appearance to the skin. In ageing skin, desquamation and regeneration processes are slowing down, resulting in dull, dry, flaky, rough complexion - condition that can be improved by allantoin presence promoting healthy skin, by stimulating epithelial growth and functioning as chemical debrider.

Aquaxyl is a ready-made combination of natural sugars, comprising

Xylitylglucoside, Anhydroxylitol and Xylitol. The mixture is developed and patented by Seppic France. The main function of Aquaxyl is being humectant, retaining and trapping molecules of free water in skin. It has been proven by the manufacturer that major improvement of skin condition can be observed, both visible on the surface and on tissue level due to Aquaxyl impact on water circulation and its reserves in skin.

Aquaxyl comprises 15-17% water, 3-20% Xylitol, 20-30% Anhydroxylitol, and 40-77% Xylitylglucoside (all % are wt%, ingredients are added to a total of 100%).

In order to make a composition with less irritant properties, formulations with a lower ALA concentration (<5% ALA) were evaluated in relation to the combination of ALA, Q10 and AC of patent EP 1411889. It was found that for lower ALA

concentrations, further active ingredients are required for efficacy in preventing and treating damaged skin to composition.

It was surprisingly found that allantoin and Aquaxyl, which are not generally considered as typical anti-aging ingredients and which provide different support to aging skin than ALA, Q10 and AC, resulted in improvement of skin conditions and function, both visual on skin surface and on tissue level.

As Allantoin and Aquaxyl are not antioxidants as ALA, it was surprising that the addition of Allantoin and Aquaxyl allowed for a lower ALA concentration while maintaining the efficacy of the formulation.

When formulations of 3% ALA or less were evaluated, the formulations had milder scent, brighter emulsion colour and less irritating properties. However, it was found that the combination of the five components of a cream according to the invention protected the skin by targeting different aging mechanisms, as mentioned above, and provided even better antiaging effect compared to the 5% ALA composition according to patent EP 1411889. A cream having only four of the components did not seem as promising during initial tests (i.e. when only Allantoin or Aquaxyl was added - data not shown), and was as such not pursued. Further, it was found that suitable preparation for optimal antiaging effect consist of: between 0,5 and 7% of alpha-lipoic acid (preferably 3%), between 0,05 and 0,5% of coenzyme Q10 (preferably 0,3%), between 0,01 and 3% of acetyl-L carnitine HC1 (preferably 0,03%), between 0,01 and 2% of allantoin (preferably 0,2%) and between 0,1 and 10% of Aquaxyl (preferably 3%).

In one embodiment, a cream, comprising as active ingredients:

0.5 - 7 % by weight of D,L-a-lipoic acid,

0.05-0.5 % by weight of coenzyme Q-10

0.01-3 % by weight of acetyl-L-carnitine hydrochloride,

0.01 - 2% by weight of allantoin,

and 0.1 - 10 % by weight of Aquaxyl, is provided.

In one embodiment, the cream comprises 0.5-4.0 % by weight of D,L-a-lipoic acid, 0.1-0.4 % by weight of coenzyme Q-10, 0.03-1.0 % by weight of acetyl-L- carnitine hydrochloride, 0.1 - 1.0 % by weight of allantoin, and 0.5 - 5 % by weight of Aquaxyl.

In one further embodiment, the Aquaxyl comprises 15-17% water, 3-20% Xylitol, 20-30% Anhydroxylitol, and 40-77% Xylitylglucoside.

The formulation of the invention improves the water balance in skin and improves desquamation to provide young, healthy appearance. As such, it was found that the moisturizing properties of the formulation of the invention reduces the need for additional moisturizing products, making daily skin care routine more convenient.

In one embodiment, the cream is for topical administration.

In one further embodiment, the cream is for dermal anti-aging treatment.

In one embodiment, the cream is for dermal treatment of visible sun injuries. Such sun injuries can be caused by processes involving the action of free radicals.

The cream of the invention is suitable for topical administration on areas exposed to the sun. Also, due to its non-irritant properties, it is very suitable for use on sensitive skin, such as in the face.

In one embodiment, the cream is a facial cream.

It was found that a 3% ALA composition had surprisingly good efficacy. This can be seen in figure 1 and 3, where in fact the 3% ALA solution of the invention preforms better than the 5% reference solution. Also, a 1,6% ALA composition for younger and more sensitive skin also showed very good properties. This was further confirmed by further tests of the 3% ALA solution, which are summarized in tables 3 to 5 and figures 3 to 7. These tests show a surprisingly good efficacy for the 3% ALA solution, even in comparison the 5% reference solution.

In one embodiment, the cream comprises: 1 - 4 % by weight of D,L-a4ipoic acid, preferably 1.6 - 3.0 % by weight of D,L-a-lipoic acid.

In one embodiment, the cream comprises: 0.1 - 0.3 % by weight of coenzyme

Q-10.

In one embodiment, the cream comprises 0.03-0.1 % by weight of acetyl-L- carnitine hydrochloride, such as 0.03 % by weight of acetyl-L-camitine hydrochloride.

In one embodiment, the cream comprises 0.1 - 0.5 % by weight of allantoin, preferably 0.15 - 0.25 % by weight of allantoin, such as 0.2 % by weight of allantoin.

In one embodiment, the cream comprises 2 - 4 % by weight of Aquaxyl, preferably 2.5 - 3.5 % by weight of Aquaxyl, such as 3.0 % by weight of Aquaxyl.

In one embodiment, the cream comprises: 1.6 - 3.0 % by weight of D,L-a- lipoic acid, 0.1 - 0.4 % by weight of coenzyme Q-10, 0.03 - 1.0 % by weight of acetyl- L-carnitine hydrochloride, 0.1 - 1.0 % by weight of allantoin, and 0.5 - 5 % by weight of Aquaxyl.

In one embodiment, the cream comprises: 1.6-3.0 % by weight of D,L-a-lipoic acid, 0.1-0.3 % by weight of coenzyme Q-10, 0.03 % by weight of acetyl-L-carnitine hydrochloride, 0.2 % by weight of allantoin, and 3.0 % by weight of Aquaxyl.

In one embodiment, the cream comprises: 1.6 or 3.0 % by weight of D,L-a- lipoic acid, 0.1 or 0.3 % by weight of coenzyme Q-10, 0.03 % by weight of acetyl-L- carnitine hydrochloride, 0.2 % by weight of allantoin, and 3.0 % by weight of Aquaxyl.

The cream of the invention is an oil-in-water emulsion, designed for efficient stabilization and delivery of active ingredients to the skin. The emulsion consists of raw materials providing proper consistency and pleasant application, emolliency, physico chemical and microbial stability. Care has been taken to ensure optimal occlusive properties of emulsion: too occlusive topical product increase risk of irritation, not enough occlusion decrease invention efficacy. Suitable supporting emulsions were evaluated, and two examples of supporting emulsions are shown below.

In one embodiment, the cream is an oil-in-water emulsion.

To improve stability and efficacy of ALA, which is known to be sensitive to oxidation when exposed to light and air, it is important to incorporate it into the formulation in a specific way. The preferred step while making the emulsion is dissolving ALA in a suitable amount of caprylic/capric triglyceride, under heating up to 50 to 65 degrees, preferably, 55 - 58°C. This step allows to keep ALA in an internal, dispersed phase of emulsion, protected from oxidizing factors and to prevent recrystallization of ALA in the emulsion, which would reduce its efficacy. The solution of ALA in caprylic/capric triglyceride, due to the triglyceride properties, can penetrate stratum corneum and deliver ALA more efficient to skin.

In one embodiment, a method for preparing a cream, comprising the steps of;

a) preparing an emulsion by mixing a water phase containing allantoin and Aquaxyl into an oil phase containing Q10 at 75-80°C; b) adding a solution of acetyl-L-carnitine hydrochloride to the emulsion from step a) at 70°C;

c) adding a solution of D,L-a-lipoic acid in caprylic/capric triglycerides to the emulsion from step b) at 50-60°C;

d) cooling down emulsion from step c) to 20 - 30°C.

In one embodiment, the solution of D,L-a-lipoic acid in caprylic/capric triglycerides is prepared by adding D,L-a-lipoic acid to a caprylic/capric triglyceride solution at 50 to 60 °C, such as 55-60 °C preferably 55 - 58°C.

The cream may include a supporting emulsion with other stabilizing and preserving ingredients.

A suitable supporting emulsion comprises: 20 - 80% of purified water

(preferably 59,46%), 1-20% caprylic/capric triglyceride (preferably 10%), 1 - 10%

Cl 5- 19 alkane from renewable sources (preferably 5,315%), 1 - 5% of shea butter ethyl esters (preferably 3%), 1 - 5% of cetearyl alcohol (preferably 2,6%), 1 - 5% of glycerin (preferably 2,6%), 1 - 5% of jojoba oil (preferably 2%), 1 - 5% of arachidyl alcohol (preferably 1,51%), 1 - 5% of glyceryl stearate (preferably 1,5%), 0,05 - 5% of shea butter (preferably 1,0%), 0,05 - 5% of octyldodecyl myristate (preferably 1,0%), 0,01 - 1% of behenyl alcohol (preferably 0,825%), 0,01 - 1% of sodium acrylate/sodium acryloyldimethyltaurate copolymer (preferably 0,525%), 0,01 - 1% of arachidyl glucoside (preferably 0,413%), 0,01 - 1% of cetearyl glucoside (preferably 0,4%), 0,01 - 1% of sodium hydroxide (preferably 0,372%), 0,01 - 1% of parfum (preferably 0,34%), 0,01 - 1% of lactic acid (preferably 0,324%), 0,01 - 1% of retinyl palmitate (preferably 0,25%), 0,01 - 1% of tocopherol (preferably 0,2%), 0,01 - 1% of ascorbyl palmitate (preferably 0,1%), 0,01 - 1% of xanthan gum (preferably 0,1%), 0,01 - 1% of propanediol (preferable 0,08%), 0,01 - 1% of sunflower oil (preferably 0,06%), 0,01 - 1% of citric acid (preferably 0,04%), 0,01 - 1% of polyglycerin-6 (preferable 0,028%), (preferable 0,008%). All % are wt%, and ingredients are added to a total of 100%.

In one embodiment, the cream of the invention comprises a supporting emulsion (cream base) which comprises one or several components selected from: 20 - 80% of purified water, 1-20% caprylic/capric triglyceride, 1 - 10% 05-19 alkane, 1 - 5% of shea butter ethyl esters, 1 - 5% of cetearyl alcohol, 1 - 5% of glycerin, 1 - 5% of jojoba oil, 1 - 5% of arachidyl alcohol, 1 - 5% of glyceryl stearate, 0,05 - 5% of shea butter, 0,05 - 5% of octyldodecyl myristate, 0,01 - 1% of behenyl alcohol, 0,01 - 1% of sodium acrylate/sodium acryloyldimethyltaurate copolymer, 0,01 - 1% of arachidyl glucoside, 0,01 - 1% of cetearyl glucoside, 0,01 - 1% of sodium hydroxide, 0,01 - 1% of parfum, 0,01 - 1% of lactic acid, 0,01 - 1% of retinyl palmitate, 0,01 - 1% of tocopherol, 0,01 - 1% of ascorbyl palmitate, 0,01 - 1% of xanthan gum, 0,01 - 1% of propanediol, 0,01 - 1% of sunflower oil, 0,01 - 1% of citric acid, 0,01 - 1% of polyglycerin-6, 0,01 - 1% of tartaric acid, 0,001 - 0,1% of gluconic acid. All % are wt%, and ingredients are added to a total of 100%.

Another suitable supporting emulsion comprises: 20 - 80% of purified water (preferably 59,30%), 1-20% caprylic/capric triglyceride (preferably 11%), 1 - 10% C15-19 alkane from renewable sources (preferably 3,315%), 1 - 5% of shea butter ethyl esters (preferably 4%), 1 - 5% of ethylhexyl stearate (preferably 4%), 1 - 5% of cetearyl alcohol (preferably 1,5%), 1 - 5% of glycerin (preferably 3,46%), 1 - 5% of arachidyl alcohol (preferably 2,2%), 1 - 5% of glyceryl stearate (preferably 1,5%), 0,05

- 5% of shea butter (preferably 1,5%), 1 - 5% of behenyl alcohol (preferably 1,2%),

0,01 - 1% of sodium acrylate/sodium acryloyldimethyltaurate copolymer (preferably 0,525%), 0,01 - 1% of arachidyl glucoside (preferably 0,60%), 0,01 - 1% of sodium hydroxide (preferably 0,245%), 0,01 - 1% of parfum (preferably 0,34%), 0,01 - 1% of lactic acid (preferably 0,324%), 0,01 - 1% of retinyl palmitate (preferably 0,12%), 0,01

- 1% of tocopherol (preferably 0,2%), 0,01 - 1% of ascorbyl palmitate (preferably 0,1%), 0,01 - 1% of propanediol (preferable 0,08%), 0,01 - 1% of sunflower oil (preferably 0,06%), 0,01 - 1% of citric acid (preferably 0,04%), 0,01 - 1% of polyglycerin-6 (preferable 0,028%), 0,01 - 1% of tartaric acid (preferable 0,016%), 0,001 - 0,1% of gluconic acid (preferable 0,008%). All % are wt%, and ingredients are added to a total of 100%.

In one embodiment, the cream of the invention comprises a supporting emulsion (cream base) which comprises one or several components selected from: 20 - 80% of purified water, 1-20% caprylic/capric triglyceride, 1 - 10% 05-19 alkane from renewable sources, 1 - 5% of shea butter ethyl esters, 1 - 5% of ethylhexyl stearate, 1 - 5% of cetearyl alcohol, 1 - 5% of glycerin, 1 - 5% of arachidyl alcohol, 1 - 5% of glyceryl stearate, 0,05 - 5% of shea butter, 1 - 5% of behenyl alcohol, 0,01 - 1% of sodium acrylate/sodium acryloyldimethyltaurate copolymer, 0,01 - 1% of arachidyl glucoside, 0,01 - 1% of sodium hydroxide, 0,01 - 1% of parfum, 0,01 - 1% of lactic acid, 0,01 - 1% of retinyl palmitate, 0,01 - 1% of tocopherol, 0,01 - 1% of ascorbyl palmitate, 0,01 - 1% of propanediol, 0,01 - 1% of sunflower oil, 0,01 - 1% of citric acid, 0,01 - 1% of polyglycerin-6, 0,01 - 1% of tartaric acid, 0,001 - 0,1% of gluconic acid. All % are wt%, and ingredients are added to a total of 100%.

A cream according to the invention comprises of ingredients of natural origin, is free from conventional preservatives and silicones. Cosmetic formulations considered as“natural” are generally more difficult to develop and stabilize, especially when they are rich in active components (increased risk of incompatibility, oxidation and deterioration).

Example 1 3 % ALA preparation

A prototype 3 % sample composition comprises: 3 % of alpha-lipoic acid,

0,3% of coenzyme Q10, 0,03% of acetyl-L carnitine HC1 0,2 % of allantoin and 3 % of Aquaxyl.

The supporting emulsion comprises: 59,46 % of purified water, 10% caprylic/capric triglyceride, 5,315% C15-19 alkane from renewable sources, 3% of shea butter ethyl esters, 2,6% of cetearyl alcohol, 2,6% of glycerin, 2% of jojoba oil, 1,51% of arachidyl alcohol, 1,5% of glyceryl stearate, 1,0% of shea butter, 1,0% of

octyldodecyl myristate, 0,825% of behenyl alcohol, 0,525% of sodium acrylate/sodium acryloyldimethyltaurate copolymer, 0,413% of arachidyl glucoside, 0,4% of cetearyl glucoside, 0,372% of sodium hydroxide, 0,34% of parfum, 0,324% of lactic acid, 0,25% of retinyl palmitate, 0,2% of tocopherol, 0,1% of ascorbyl palmitate, 0,1% of xanthan gum, 0,08% of propanediol, 0,06% of sunflower oil, 0,04% of citric acid, 0,028% of polyglycerin-6, 0,016% of tartaric acid, 0,008% of gluconic acid. All % are wt%, and ingredients are added to a total of 100%. All % are wt%, and ingredients are added to a total of 100%.

Example 2 1,6 % ALA preparation

A 1,6% sample composition for extra sensitive skin comprises: between 1,6 % of alpha- lipoic acid, between 0,1% of coenzyme Q10, between 0,03% of acetyl-L carnitine HC1, between 0,2% of allantoin and between 3% of Aquaxyl.

A supporting emulsion comprises: 59,30% of purified water, 11%

caprylic/capric triglyceride, 3,315% C15-19 alkane from renewable sources, 4% of shea butter ethyl esters, 4% of ethylhexyl stearate, 1,5% of cetearyl alcohol, 3,46% of glycerin, 2,2% of arachidyl alcohol, 1,5% of glyceryl stearate, 1,5% of shea butter,

1,2% of behenyl alcohol, 0,525% of sodium acrylate/sodium acryloyldimethyltaurate copolymer, 0,60% of arachidyl glucoside, 0,245% of sodium hydroxide, 0,34% of parfum, 0,324% of lactic acid, 0,12% of retinyl palmitate, 0,2% of tocopherol, 0,1% of ascorbyl palmitate, 0,08% of propanediol, 0,06% of sunflower oil, 0,04% of citric acid, 0,028% of polyglycerin-6, 0,016% of tartaric acid, 0,008% of gluconic acid. All % are wt%, and ingredients are added to a total of 100%.

Efficacy Trials

Comparative study:

The efficacy of two prototype formulations was tested and compared to efficacy of a formulation according to EP 1411889 (5 % ALA). The efficacy was evaluated in non-controlled user test: 25 Caucasian woman, age 40+, users of, applying test product twice a day on face under period of 6 weeks. After the test period objects were asked to evaluate the product within five categories: observed effect, scent, consistency, afterfeel, moisturising properties, and rating each category with 1 to 5 points, where 1 was the lowest, the least satisfying result and 5 was the best, the most satisfying result. Subjects were not trained within topical product evaluation.

Both prototype formulations contained same composition of active ingredients: ALA - 3%, Q10 - 0,3%, AC - 0,03%, allantoin - 0,2% and Aquaxyl - 3% and differed slightly in oil phase composition, without significance for result obtained.

Clinical study with instrumental measurement of effects:

The efficacy of the cream according to the invention in preventing and treating aging skin was also evaluated in a clinical study on 20 Caucasian women, age 40+, applying the product on face under 8 weeks (56 days) period, according to the following schedule: the first week - once every other day, the second week - once every day; the third to eighth week - twice a day (morning and evening). To obtain independent results, the following measurements were taken to control antiaging efficacy of invented formulation:

Corneometer CM 825 - measurement of skin moisturization before and after the product application

- Cutometer MPA 580 - measurement of biomechanical parameters

(firmness and elasticity) before and after the product application

Visioline VL 650 + 3D photo - measurement of length and depth of wrinkles before and after the product application with 3D photo.

Another cream was provided for younger, more sensitive skin, consisting of decreased concentrations of ALA, Q10 and acetyl-L-carnitine to minimize skin irritation risk. Even this formulation is an object of clinical test on 20 Caucasian woman, age 25+, using product under 8 weeks period.

Dermatological semi-open patch test:

Creams according to the invention were tested to assess their irritating potential and results were compared to analogical result obtained for all existing reference formulation.

The purpose of the study was to assess irritating and sensitizing properties (skin tolerance) of a cream according to the invention on a healthy adult skin. Patch skin tests according to Jadassohn-Bloch as modified by Rudzki were performed under the supervision of a dermatologist. The semi-occlusive test is the basic kind of test confirming contact allergy. The preparation was applied into a filter paper discs of 11 mm diameter, manufactured by SmartPractice and then fixed to the arm or interscapular area using sticking plaster. In a parallel time to objectify the results of the studies, two control samples were carried out: blind and with water. The patches were removed by dermatologist after 48h and the skin response was evaluated 15 min after removal. After further 24h and 48h from last verification, the skin response is again evaluated by dermatologist. Test subjects: 25 healthy volunteers with negative history of allergy, age 18+. None of the volunteers reported documented oversensitivity or a history of adverse reactions to individual ingredients of the tested product.

Table 1. Evaluation parameters of skin reaction

2^nd Comparative study:

The comparison of skin improvement provided by topical composition containing 5% ALA (QAL) vs. 3% ALA (QAL + allantoin + Aquaxyl) and 1,6% ALA (QAL + allantoin + Aquaqyl).

To compare efficacy of known cream composition (5% ALA) vs. efficacy data for 3% ALA composition of the present invention, the independent evaluation results were taken into account: 5% ALA, photographic evaluation; 5% ALA, clinical evaluation; 3% ALA, summaric results of instrumental tests (5 parameters measured), and 1,6% ALA, summaric results of instrumental tests (5 parameters measured).

Results of test of 5% ALA was previously presented (Beitner patent) in scale 1 - 5, as general efficacy: 1 = Worse; 2 = No change observed; 3 = Slight improvement; 4 = Medium improvement; 5 = Major improvement. The values for 5% ALA formulation were recalculated to be presented as a percentage share in the test group.

The values for 3% ALA formulation and 1,6% ALA formulation were summarized as follows: If one of 5 parameters per patient become improved, this represented a score of 1; if 2 parameters per patient become improved, this represented a score of 2, respectively, and so on up to 5 improved parameters per patient represented a score of 5. Results were summarized as an average, representing the test group.

2^nd Clinical study with instrumental measurement of effects:

The comparison of skin improvement provided by topical composition containing 1,6 and 3% ALA (QAL + allantoin + Aquaxyl). The instrumental tests were conducted by external laboratory. The aim of the study was confirmation/exclusion of the declared properties and efficacy of product using instrumental methods:

1. Skin moisturizing level - Corneometer CM 825. The aim of the study was to define the direct influence of the tested product on the skin moisture level. The comparison of results obtained with corneometer at the beginning of test (DO) and after 8 weeks application period.

2. Biomechanical skin parameter, elasticity and firmness - Cutometer MPA 580. The aim of the study was to define the direct influence of the tested product on biomechanical skin parameters, by measuring skin firmness and elasticity. The comparison of results obtained with cutometer at the beginning of test (DO) and after 8 weeks application period.

3. Wrinkles length and depth - Visioline VL 650. The aim of the study was to define the direct influence of the tested product on reduction of wrinkle length and depth. The comparison of results obtained with Visioline at the beginning of test (DO) and after 8 weeks application period. An example is shown in figures 8 and 9.

1,6% ALA (QAL + allantoin + Aquaxyl) - Instrumental test

The group of 20 female, age 27 - 66 (mean 53) was regularly using the tested product under study period of 56 days ± 2 days. 19 patients completed the study, 1 person resigned of personal reason; any side effects were observed. The patients were asked to follow the direction of use to avoid overreaction: during the first week - cream applied once every other day; the second week - once a day; from the third week to the end of test - twice a day, morning and evening. The patients were not allowed to use any other products of similar effect during test. In case of any side effects at the application site, patients were asked to immediately stop using the product and consult a specialist responsible for study. The measurements were taken before first product application, at the beginning of the test (DO) and after study period of 8 weeks of regular use (D56). The study was carried out in an air-conditioned room at the temp of 20 ±2°C and relative humidity 50±10%. The test results may be affected by such factors as: type and condition at the site of application and inter-individual genetic

characteristic.

3% ALA (QAL+ allantoin + Aquaxyl) - Instrumental test

The group of 20 female, age 42 - 71 (mean 57) was regularly using the tested product under study period of 56 days ± 2 days. 20 patients completed the study, any side effects were observed. The patients were asked to follow the direction of use to avoid overreaction: during the first week - cream applied once every other day; the second week - once a day; from the third week to the end of test - twice a day, morning and evening. The patients were not allowed to use any other products of similar effect during test. In case of any side effects at the application site, patients were asked to immediately stop using the product and consult a specialist responsible for study. The measurements were taken before first product application, at the beginning of the test (DO) and after study period of 8 weeks of regular use (D56). The study was carried out in an air-conditioned room at the temp of 20 ±2°C and relative humidity 50±10%.

Results

Comparative study:

The results obtained in the comparative study on 25 persons show that both prototype (3% ALA) formulations are well accepted by accustomed users and gained higher average results than existing formulation (5% ALA), which proves that changes made in original composition, despite reduction of ALA concentration, surprisingly improved product efficacy (Fig. 1). The existing formulation (5% ALA) was given 4,24 pts in average, while prototype A gained 4,41 pts and prototype B - 4,35 pts. The observed improvement of product efficacy should be considered as a result of addition of two actives: allantoin and Aquaxyl to existing formulation. Although the added components have moisturizing and calming properties, it was not expected that they would enhance the anti-ageing properties of the composition to such an extent.

In Fig. 1, a comparison of general efficacy of the formulations - average results, based on points gained. The test objects evaluated several parameters while using the formulation by giving 1 to 5 points for each parameter.

Dermatological semi-open patch test results:

The facial cream prototype solutions of 1.6 % and 3 % ALA of the invention was the subject of objective clinical test under dermatological control to assess its irritating and sensitizing properties, showing any skin reaction under 72h after application (96h examination was skipped due to 100% negative results). Similar tests were done for existing (5% ALA) formulation and some cases of erythema were observed 24h after application. The results a cream according to the invention is less prone to cause irritation and sensitization than the reference cream. Results in form of Average Irritation Index (x_av) are shown in table 2 and presented in Fig. 2.

Table 2. Calculated values of Average Irritation Index (xav).

In Fig. 2, it is shown that the cream according to the invention is less prone to cause irritation or sensitization than a composition comprising 5 % ALA, thus minimising the risk of adverse reactions. 2^nd Comparative study

Similar to the earlier comparative study, the 1,6% and 3% ALA formulations of the invention shows a surprisingly high skin improvement.

These results are summarized in tables 3 to 5 below, and visualized in figures 3, 8 and 9, which shows the improvement of the general skin condition for the formulation containing ALA: 5% (QAL) (clinical and photographic evaluation) and the 1,6 % and 3 % ALA (QAL + allantoin + Aquaxyl) formulation of the invention (instrumental evaluation). The images in figure 8 is an example of the 3% ALA formulation results. The images in figure 9 is an example of the 1,6% ALA formulation results.

Table 3. Summary of general skin condition improvement after test period.

Table 4. Calculation of percentage share of improvement grade for 5% ALA formulation.

Table 5. Calculation of percentage share of improvement grade for 1,6 % and 3% ALA (QAL + allantoin + aquaxyl) formulation.

2^nd Clinical study with instrumental measurement of effects:

Skin improvement provided by topical composition containing 1.6 % ALA (QAL + allantoin + Aquaxyl) and 3% ALA (QAL + allantoin + aquaxyl).

1.6% ALA (QAL + allantoin + Aquaxyl) - Instrumental test

1. The Skin moisturizing level test showed 6% improvement of skin moisturizing level, with 95% of subjects with positive effect. The test results prove that the tested cream moisturizes the skin.

2. The biomechanical skin parameter test showed 5% improvement of skin elasticity, with 84% of subjects with positive effect and 7% improvement of skin firmness, with 74% of subjects with positive effect. The test results prove that the cream improves skin elasticity and skin firmness.

3. The measurement of wrinkles length and depth test showed 9% reduction of wrinkles length, with 65% of subjects with positive effect and 4% reduction of wrinkles depth, with 71% of subjects with positive effect. The test results prove that the cream reduces wrinkles length and depth. The images of skin texture before test and after 8 weeks of regular application shows improvement in size of wrinkles as well as reduced skin roughness in test area.

The skin improvement for each test has been summarized in figure 4, and the percentage of objects with positive effect for each test have been summarized in figure 5.

3% ALA (QAL + allantoin + Aquaxyl) - Instrumental test

1. The Skin moisturizing level test showed 4% improvement of skin moisturizing level, with 90% of subjects with positive effect. The test results prove that the tested cream moisturizes the skin.

2. The biomechanical skin parameter test showed 4% improvement of skin elasticity, with 79% of subjects with positive effect and 7% improvement of skin firmness, with 89% of subjects with positive effect. The test results prove that the cream improves skin elasticity and skin firmness.

3. The measurement of wrinkles length and depth test showed 7% reduction of wrinkles length, with 67% of subjects with positive effect and 3% reduction of wrinkles depth, with 67% of subjects with positive effect. The test results prove that the cream reduces wrinkles length and depth. The images of skin texture before test and after 8 weeks of regular application shows improvement in size of wrinkles as well as reduced skin roughness in test area.

The skin improvement for each test has been summarized in figure 6, and the percentage of objects with positive effect for each test have been summarized in figure 7.

Although the present invention has been described above with reference to (a) specific embodiment(s), it is not intended to be limited to the specific form set forth herein. Rather, the invention is limited only by the accompanying claims and, other embodiments than the specific above are equally possible within the scope of these appended claims, e.g. different than those described above.

If not otherwise stated, all %-values are % by weight.

In the claims, the term "comprises/comprising" does not exclude the presence of other elements or steps. Furthermore, although individually listed, a plurality of means, elements or method steps may be implemented. Additionally, although individual features may be included in different claims, these may possibly

advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms "a", "an",“first”,“second” etc. do not preclude a plurality.

Claims

1. A cream, comprising as active ingredients:

0.5 - 7 % by weight of D,L-a-lipoic acid,

0.05-0.5 % by weight of coenzyme Q-10,

0.01-3 % by weight of acetyl-L-camitine hydrochloride,

0.01 - 2% by weight of allantoin,

and 0.1 - 10 % by weight of Aquaxyl.

2. The cream according to claim 1, wherein the cream is a oil-in-water emulsion.

3. The cream according to any of claims 1 to 2, wherein the cream is for topical administration.

4. The cream according to any of claims 1 to 3, wherein the cream is a facial cream.

5. The cream according to any of claims 1 to 4, wherein the cream is for dermal anti-aging treatment.

6. The cream according to any of claims 1 to 5, wherein the cream is for treatment of visible sun injuries on skin.

7. The cream according to any one of claims 1 to 6, comprising:

0.5-4.0 % by weight of D,L-a-lipoic acid,

0.1 -0.4 % by weight of coenzyme Q-10,

0.03-1.0 % by weight of acetyl-L-carnitine hydrochloride,

0.1 - 1.0 % by weight of allantoin, and

0.5 - 5 % by weight of Aquaxyl.

8. The cream according to any one of claims 1 to 6, comprising:

1.6-3.0 % by weight of D,L-a-lipoic acid,

0.1 -0.4 % by weight of coenzyme Q-10,

0.03-1.0 % by weight of acetyl-L-carnitine hydrochloride,

0.1 - 1.0 % by weight of allantoin, and

0.5 - 5 % by weight of Aquaxyl.

9. A method for preparing a cream according to any one of claims 1 to 8, comprising the steps of;

c) adding a solution of D,L-a-lipoic acid in caprylic/capric triglycerides to the emulsion from step b) at 50-65°C;

d) cooling down emulsion from step c) to 20 - 30°C.

10. The method according to claim 9, wherein solution of D,L-a-lipoic acid in caprylic/capric triglycerides is prepared by adding D,L-a-lipoic acid to a caprylic/capric triglyceride solution at 50 to 60 °C, preferably 55 - 58 °C.