WO1998033476A1

WO1998033476A1 - Skin preparation

Info

Publication number: WO1998033476A1
Application number: PCT/NO1998/000036
Authority: WO
Inventors: Gunnar Volden
Original assignee: Gunnar Volden
Priority date: 1997-02-04
Filing date: 1998-02-02
Publication date: 1998-08-06
Also published as: NO970503L; AU6006898A; NO970503D0; NO304009B1

Abstract

Skin preparation containing gamma-linolenic acid and optionallylinoleic acid, and also retinol or a derivative thereof.

Description

SKIN PREPARATION

This invention relates to a skin preparation for patients/persons with moderately to very dry skin. This includes those who have atopic eczema, minor degrees of ichthyoses, eczema craquele, elderly people with dry skin and others with dry skin.

GENERAL PURPOSE

Dry skin itches and is troublesome, and everybody with dry skin has a predisposition to different skin diseases. The most common cause of irritative contact eczema is dry, cracked skin. Moderately to very dry skin is characterized by a "dusty" appearance with scaling and cracking of the skin resulting in small to larger fissures. The skin barrier is defect so that external agents will easily penetrate into living cells in the skin and cause diseases. A feature of defect skin barrier function is increased transepidermal water loss from the skin. It is therefore very important to restore the lost barrier function to the greatest possible extent in order to prevent skin diseases as much as possible.

THE STATE OF ART There are many moisturizing creams, but no one which is really effective and at the same time pleasant to use. The moisturizing creams on the market, are characterized in that they either act for a short time, from minutes up to a few hours, whereafter the skin is as dry as before, or they contain so much fat that they are sticky and unacceptable to use. The result is that the cream must be applied several times daily to achieve the desired effect, and for fatty creams the result is that they will soil clothes, linen, objects which are to be handled etc.. Thus, in both cases the user-friendliness is so poor that very many abstain from applying any cream.

The purpose of the invention is to temporarily restore the lost barrier function in order to reduce the number of applications of the moisturizing cream to once daily. Further, the moisturizing cream should have a consistency which makes it pleasant to use. The combination of effect and user-friendliness is the key word.

A normal and good skin barrier function depends on a normal content and metabolism of essential fatty acids. Essential fatty acids are vital for integrity, maturation and function of keratinocytes. They comprise the lipids that maintain epidermal barrier function, and they contribute to the control of epidermal hyperplasia and to cellular immunoregulation. There are two families of essential fatty acids, the n-6 which are supplied from linoleic acid in food, and the n-3 from alpha-linolenic acid (it is uncertain whether the latter is essential). There is no established syndrome of n-3 deficiency. The n-6 essential fatty acids must be converted into their long-chain polyunsaturated metabolites before they perform their biological function.

The addition of gamma linolenic acid to skin creams restores a normal content of metabolites of essential fatty acids in patients with dry skin. In order to obtain an optimum effect both gamma linolenic acid and linoleic acid are added to skin creams. After application of the cream the dry, cracked skin feels soft and flexible. However, relatively frequent application of cream is required.

Linoleic acid is converted to gamma-linolenic acid by means of the enzyme delta-6-desaturase. This is an absolutely essential step in the body synthesis of prostaglandins and leukot enes which are of decisive physiological importance. If this reaction does not take place, there will be a deficiency in metabolites, and diseases may be the result.

Chemical structure C18: 2 n-6

Linoleic acid H3C

Metabolism

C 18:2 n-6 (linoleic acid)

C 18:3 n-6 (gamma-linolenic acid)

4-

prostaglandins and leukothenes

Epidermis lacks delta-6-desaturase, which, however, is found in the blood.

Metabolites of essential fatty acids are therefore primarily accumulated in the blood, and epidermis is supplied with linoleic and gamma-linolenic acid separately from the blood. Ordinary fat in food such as vegetable oils and animal fat does not contain gamma-linolenic acid. The delta-6-desaturation reaction is sensitive. The ability to convert linoleic acid to gamma-linolenic acid in a person decreases with age, diabetes mellitus, alcohol consumption, stress which liberates catecholamines, diets rich in sugar and saturated fat. A defect function of delta-6-desaturase has been found in persons with atopic eczema, and reduced function has been found in elderly people, so that linoleic acid will not or only to a minor extent be converted to gamma-linolenic acid. The deficiency in essential fatty acids and lacking conversion of linoleic acid lead to thin hair, scaly, rough epidermis which results in dermatitis, fragile superficial capillaries which easily crack and give rise to bleeding, reduced wound healing, increased transepidermal water loss, itching and skin infections.

It has been assumed that linoleic acid on the skin is ineffective since the human epidermis does not contain delta-6-desaturase, and in practice it has been demonstrated that linoleic acid has a limited effect on dry skin. Topical treatment with prostaglandin E₂ and the precursor which is aracidonic acid, improve scaling in dry skin, but does not restore the defect barrier function.

It has now been found that by adding retinol or a derivative thereof it is

5 possible to obtain a highly improved effect of gamma-linolenic acid and optionally linoleic acid. Thus, according to the invention there is provided a skin preparation containing gamma-linolenic acid and optionally also linoleic acid, and the preparation is characterized in that it also contains retinol or a derivative thereof, in particular an ester thereof, preferably retinol palmitate. The preparation may o suitably be in the form of an ointment or a cream, but it may also be more liquid, such as a lotion or a liniment.

Vitamin A (retinol) and its metabolites such as retinoic acid serve as physiological regulators of growth and differentiation of many cell types. Retinol is a precursor for the synthesis of retinoic acid. Animal cells cannot themselves s synthesise retinol. The molecule is generated by oxidative breakdown of carotenoids, in particular beta-carotene. Most of the available information indicates that retinoic acid and other biologically active retinoides are synthesised in target cells by metabolism of retinol. Biologically active retinol metabolites in the skin are all trans-retinoic acid, 13-cis-retinoic acid, 3,4-didehydroretinoic acid o and possibly also retinoyl glucuronide.

The keratinization (hornification) in the superficial parts of the skin is strongly influenced by retinoic acid. Vitamin A in itself is essentially inactive for the keratinization. It is not until after it has been converted to retinoic acid that it has an effect. At very low retinoic acid concentrations the horn layer becomes ₅ much thicker and harder and cracks, and the skin is dry and often with inflammation and/or infection. Too high retinoic acid concentration leads to thinning of the epidermis, drying of the skin and inflammation. A loss of skin barrier function is obtained both with too low and too high retinoic acid concentrations. o Retinol palmitate with added polysorbate penetrates into the epidermis and is here converted to retinoic acid. It is well known that the retinoic acid itself, also at relatively low concentrations, may induce irritative dermatitis with erythema. However, retinol palmitate which is preferably used according to the invention, will not cause irritation of the skin.

In order to examine the effect of linoleic acid and gamma-linolenic acid borage oil (contains 33-43% of linoleic acid and 20-28 % of gamma-linolenic acid), was used alone or together with retinol palmitate in 3 half-side double-blind studies carried out on patients with a very dry skin.

In study number I five patients were treated two times daily with cream base on one half of the body and the same containing borage oil on the other.

The side which had been treated with borage oil had a statistically significantly better softening and moisture retaining effect, while the barrier function was not significantly better.

In study number II five patients were treated two times daily with cream base on one half of the body and the same containing 0,2% retinol palmitate on the other. There was a statistically significantly better barrier function on the side treated with retinol palmitate and somewhat better softening effect (not significant).

In study number III six patients were treated once daily with cream base containing borage oil on one side and the same with retinol palmitate in addition on the other. Both softening and moisture retaining effect and the barrier function were statistically significantly better on the side treated with borage oil and retinol palmitate. The softening and moisture retaining effect was equally good on the side treated with borage oil two times daily in study I as the side which had been treated with borage oil and retinol palmitate once daily in study number III. The barrier function was equally good on the side treated with retinol palmitate two times daily in study number II as the one which had been treated with borage oil and retinol palmitate once daily in study number III.

Conclusion:

The combination of linoleic acid and gamma-linolenic acid with retinol palmitate has a superior effect compared with each of them alone. The combination provides a better softening and moisture retaining effect. The combination has a more long-lasting effect so that application once daily gives just as good softening and moisture retaining effect, and just as good barrier function as each of them alone two times daily.

According to the invention it is only necessary to use the skin cream once daily in order to make the skin soft and flexible. The cream has a consistency which makes it pleasant to use. This is a clear improvement compared with existing creams which have to be applied several times per day, or creams which are so fat that they are not cosmetically acceptable. The use of the new preparation inhibits the development of skin diseases.

It is known that skin exposure to sun/ultraviolet radiation or environment poisons is detrimental for the skin and may give rise to skin diseases, ageing of the skin and in some cases also skin cancer. It is known that these insults result in the formation of free oxygen radicals and these are the factors which are the real cause for the damages. The skin is the organ which is most exposed to free oxygen radicals due to the contact with oxygen and other detrimental substances from the environment.

Among other effects free oxygen radicals damage essential fatty acids and the genetic material (DNA) and this is the reason for the ageing of the skin, development of diseases and possibly skin cancer. Antioxidants inhibit these damages. The skin preparations according to the invention may advantageously contain such antioxidants and other per se known additives as mentioned above. Vitamin E (alpha-tocopherol acetate) is an effective antioxidant which prevent the formation of free oxygen radicals and thereby inhibits skin diseases and skin cancer, and also protects the skin against ageing. Vitamin E protects in particular essential fatty acids and lipids in the skin. The most important lipids which serve to keep the skin soft, are protected by adding vitamin E.

Liposomes are very small fatty beads which consist of the most important lipids in normal skin. They consist of several types of lipids, where the most important ones are phospholipids and ceramides. Liposomes themselves have a water retaining ability, and in addition they contribute to restore the protection in the outermost layer of the skin in people with dry and cracked skin.

Ginseng is an important health plant which has been used as a pharmaceutical in the far East for several thousand years against several diseases and other troubles. Ginseng has a refreshing and strengthening effect. Several scientists in the west have confirmed the effect of ginseng in double blind tests. The active substances in the ginseng root are called "ginsenosides".

Ginseng in creams supplies nutrient and energy to the skin so that the skin feels soft, fresh and supple. The reason for this is partly the effect of ginsenosides, but also that ginseng increases the effect of gamma-linolenic acid and increases the production of basic substance (glycosaminoglycanes), DNA and proteins.

Q₁₀ (coenzyme Q₁₀=Ubiquinone 50) is the body's own natural substance which converts the nutrients into energy in the cells of the body. Most of the Q₁₀ is synthesised within the cells and very little is supplied as food. In addition to providing energy Q₁₀ is an important antioxidant which neutralises free oxygen radicals and thereby prevents diseases and retards the ageing process. The amount of Q₁₀ in the body decreases with age and diseases, while the need for Q₁₀ increases. Vitamin E and Q₁₀ have a synergistic effect, so that vitamin E increases the effect of Q₁₀, while Q₁₀ increases the effect of vitamin E. Together this means that they have more than double effect.

As indicated all the above mentioned additives may advantageously be incorporated in the compositions according to the inventions.

Typical process with typical components and amounts.

Components Weight %

Magnesium aluminium silicate 0,2-2,0

Carbomer 0,1-1 ,0

Water (deionised)

This mixture is homogenised for about 20 min. to a homogeneous mixture, and to this mixture the following components are added:

Glycerol 1-5

Lactic acid 1-6

NaOH 0,1-1

Magnesium sulphate heptahydrate 0,1-1 ,0

Methylparaben 0,1-0,4

Propylparaben 0,1-0,4 and the resulting mixture is heated to about 70°C.

A mixture of:

Cetylalcohol 1-6

Stearic acid 0,5-4

Vaselinum album 1-10

Paraffinum liquidum 1-10 dimeticon (silicone) 0,5-10

Polysorbate 60 1-3

Polysorbate 80 1-3

Borage oil 0,5-20 is heated to about 70°C and mixed with the above mixture and homogenised to a cream or lotion.

At 30-40°C the following components are added:

Vitamin A-palmitate (retinol palmitate) 0,01-10

Vitamin E-acetate (alfa-tocopherol acetate) 0,05-10

Liposomes 0,5-10

The last 3 ingredients are homogenised into the products. This is an ordinary basis for all the products. In addition some products contain special substances which provide special properties, and these are urea, camphor, menthol, zinc oxide, iron(lll)oxide, methyl salicylate, EDTA, ginseng extract, coenzyme Q₁₀ (Ubiquinone 50 or Q₁₀).

Claims

P a t e n t c l a i m s

1. Skin preparation containing gamma-linolenic acid and optionally linoleic acid, characterized in that the preparation also contains retinol or a derivative thereof.

2. Skin preparation according to claim 1 , characterized in that it contains retinoic acid or an ester thereof.

3. Skin preparation according to any of claims 1 and 2, characterized in that it contains retinol palmitate.

4. Skin preparation according to any of claims 1-3, characterized in that it is in the form of an ointment, a cream, a lotion or a liniment.

5. Skin preparation according to claim 3, characterized in that it contains 0.01-10 weight% of retinol palmitate.

6. Skin preparation according to claims 1-5, characterized in that it contains 0.5-20 weight% of borage oil.

7. Skin preparation according to any of claims 1-6, characterized in that it contains one or more antioxidants.

8. Skin preparation according to claim 7, characterized in that it contains 0.05-10 weight% of vitamin E-acetate and/or coenzyme Q₁₀.