CA2290702C - Topical compositions and methods for reducing ageing processes of skin and treating pathological lesions of skin - Google Patents

Abstract

The invention provides a topical composition and a method for reducing ageing processes of skin and/or treating pathological lesions of skin. The composition comprises a hydroximic acid derivative of formula I

Description

TOPICAL COMPOSITIONS AND METHODS FOR REDUCING AGEING
PROCESSES OF SKIN AND TREATING PATHOLOGICAL LESIONS
OF SKIN
The invention refers to a topical composition and a method for reducing the ageing processes of skin and/or treating the pathological lesions of skin.
More specifically the invention - refers to a topical composition comprising a hydroximic acid derivative of the formula i I R i R -A- i -N-O-CHZ-CH-CHZ- \ I

wherein Rl represents a hydrogen atom or a Cl_s alkyl group, RZ stands for a hydrogen atom, a Cl_5 alkyl group, a C~z cycloalkyl group or a phenyl group optionally substituted by a hydroxy or a phenyl group, or Rl and R2 together with the nitrogen atom they are attached to form a 5 to 8 membered ring optionally containing one or more further nitrogen or oxygen atoms) and said ring can be condensed with a benzene zing, R3 means a hydrogen atom, a phenyl group, a aaphthyl group or a pyridyl group wherein said groups can be substituted by one or more halo atoms) or Cl.~ alkoxy group(s), is a hydroxy group, X stands for an amino group, R forms with B a chemical bond, A is a group of the formula Ra R5 -(CH)m (CH)~-[Or -(CHz)p 1 b wherein R4 represents a hydrogen atom, RS stands for a hydrogen atom, m has a value of 0, 1 or 2, n has a value of 0, 1 or 2, p is an integer from 0 to 4, or a physiologically acceptable acid addition salt thereof as the active ingredient.
The human skin is a natural target of light radiation having several known pleasant and unpleasant effects such as sunburn and carcinogenesis. Due to the ultraviolet radiation free radicals (for example hydroxy radicals or nascent oxygen) form in the skin. Such free radicals can injure the DNA and contribute to the ageing of the skin.
A well-known theory of the ageing process of skin is based on the deteriorating effect of free radicals. In addition to the effect of ultraviolet radiation, free radicals may also form in biochemical processes. Thus, due to e.g. inflammation, hypoxia or reactive hyperaemia, free radicals of oxygen origin such as superoxide anion, 2a perhydroxy or hydroxy radical, hydrogen peroxide etc. may form.
Free radicals having powerful oxidizing effect can injure the membrane by oxidizing the unsaturated fatty acid components of the membrane (peroxidization of lipids) on the one hand, and reactive aldehydes are formed during the oxidization on the other hand. In the injury of membrane, the increased intake of calcium leads to cell death, and pathological processes are started due to the presence of the reactive aldehydes:
- injury of DNA, mutation in both the cell nucleus and mitochondrium;
- change in the properties of the interstitial proteins (i. e.
elastin) owing to formation of crosslinks.
It is known that the elastic structures of collagen proteins and elastin contain a lot of water. It is characteristic of the interstitial proteins that they are rich in lysine. The reactive aldehydes such as malondialdehyde give condensation reaction with the side chains containing amino groups to yield crosslinks. Thus, the originally elastic structure becomes rigid and hydrophobic. During the above process, at first lipofuscin ceroids, then age pigments are formed.
The natural protective mechanisms against ultraviolet radiation include bronzing due to the formation of melanin, DNA
repair mechanism etc. The deficiency of a protective mechanism such as the damage of the DNA repair and consequently the loss of the correction of the DNA injuries caused by the ultraviolet rays leads to the early ageing of skin or perhaps to a disease called xeroderma pigmentosum that can be accompanied by the development of a malignant tumor. Sunburn spots caused by bronzing in the early childhood are healed leaving an extended scar.
In addition to spinocellular carcinoma, various malignant tumors (e.g. melanoma, cerato-acanthoma, basalioma, sarcoma) can develop.

Thus, it is of great significance if the ageing processes of skin could be influenced and the pathological lesions could be treated.
The hydroximic acid derivatives of the formula I
are known. HU-P No. 177 578 and its equivalent US-P
No. 4,308,399 describe hydroximic acid derivatives within the compounds of the formula I suitable for the treatment of diabetic angiopathy.
HU-P No. 207 988 and its equivalent EP No. 417 210 also describe hydroximic acid halides having a selective beta-blocking effect, thus, being suitable for the treatment of diabetic angiopathy.
HU-P Application No. 2385/92 published under No. T/66350 describes further hydroximic acid derivatives.
These known compounds can be used in the treatment of vascular deformations, mainly in the therapy of diabetes mellitus.
The invention provides a composition suitable for reducing the ageing processes of skin and/or treating the pathological lesions of skin. More particularly, the composition comprises a hydroximic acid derivative of the formula I or a physiologically acceptable acid addition salt thereof as the active ingredient. Uses of the composition for reducing ageing processes of skin or treating pathological lesions of skin, as well as commercial packages comprising the compositions for such uses, are also provided by the invention.
Under the pathological lesions of skin for which the composition of the invention is suitable, especially the followings are meant:

4a -dry skin;
-actinic keratosis, aktinic prurigo (Lopez-Gonzalez's disease);
-polymorphic light exanthema;

:', - toxic photopathy;
- photo-allergy;
- p~trpura senilis;
- solar atrophy of skin;
- pnberal strias (stria migrans);
- e~astoma di~'usuno. (old skin);
- X-ray dermatitis;
- gouty polychondritis;
- decubitus (bedsore). .
in the ~de<saiption and Claims, under the term "composition"
a topical composition is meant which is suitable in the first place for local (topical) treatment, and is applied to the skin surface in a conventional manner.
The composition of the invention comprises a hydroximic acid derivative of the formula I or a physiologally acceptable acid addition salt thereof as the active ingredient in admixture with one or more conventional carriers) of topical compositions.
In the specification and Claims a Cl_5 alkyl group is, for example, a methyl, ethyl, n propyl, isopropyl, n-butyl or n-pentyl group, preferably a methyl or an ethyl group.
A C,~~ cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl group, preferably a cyclopentyl or a cyclohexyl group.
A 5 to 8 membered ring containing one or more heteroatom(s) can be, for example, a pyrrole, pyrazole, imidazole, oxazole, pyridine, pyridazine, pyrimidine, piperazine, morpholine, indole, quinoline etc. ring.
A halo atom is, for example, a fluoro, chloro, bromo or iodo atom, preferalby a chloro or a bromo atom.

The physiologically acceptable acid addition salts of the compounds of the formula I are the acid addition salts formed with physiologically acceptable inorganic acids such as hydrochloric acid, sulfuric acid etc. or with physiologically acceptable organic acids such as acetic acid, fumaric acid, lactic acid etc.
A preferred subgroup of the compounds of the formula I
consists of the hydroximic acid derivatives of the formula Ra Rs I
R3-(CH)g,-(CH)"-C-X R
~I
N-O-CHI- iH-CHI-N\ II
Y R'' wherein R~, R2, R3, R4, Rs, m and n are as stated in relation to formula I, X represents an amino group, Y means a hydroxy group.
Especially preferred compounds of the formula II are those wherein RI and R' together with the nitrogen atom they are attached to form a piperidino group, R3 stands for a pyridyl group, m and n have a value of 0, X is as defined above. Of these compounds, preferred species are as follows:
O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (Compound "B").
The compounds of the formula I can be prepared by the processes known from HU-P No. 177 578.
The composition of the invention contains, in general, 0.1 to 30 % by mass, suitably 2 to 10 % by mass, preferably 4 to 5 % by mass of a hydroximic acid derivative of the formula I or a __._._.__ _ ._... __~..__ _.

physiologically acceptable acid addition salt thezeof as the active ingredient and conventional carriers) of the topical compositions.
The compositions of the invention can be conventional topical formulations suitable for the local treatment of the skin surface. Preferred formulations are creams, body emulsions, sun-emulsions, skin treatment foanps, sprays, skin regenerating ampouls etr.
The compositions of the invention may contain, in addition to the active ingredient the conv~tional carriers of cosmetic compositions generally in an amount of 70 to 99.9 % by mass.
Suitable carriers are, for example, one- or two basic alcohols having a saturated or an unsaturated carbon chain such as cetyl alcohol, stearyl alcohol, cetyl-stearyl alcohol, oleyl alcohol, lauryl alcohol, ethylene glycol, propylene glycol, glycerol; natural fats and oils such as olive oil, avocado oil, wheat-germ oilo, maize-germ oil, lanolin, cocoa butter; higher hydrocarbons such as vaseline oil, vaseline; bee-wax; cellulose derivatives; emulgators such as sodium lauryl sulfate, fatty acid or oleic acid esters of sorbitan, fatty acid or oleic acid esters of polyethylene glycol)s, sorbitan ethers of fatty alcohols or oleic alcohols, polyethylene glycol) ethers of fatty alcohols or oleic alcohols, glycerides of fatty acids; vitamins, herb extracts such as camomile extract; preservatives such as methyl, p-hydroxy benzoate, chlorohexidine gluconate; light protecting factors etc.
The compositions of the invention are prepared by blending the ingredients thereof, in a manner known per se. In case of compositions based on a waterloil or oil/water emulsion, in general, the ingredients of the fatty phase and those of the aqueous phase are g separately admixed, then the two phases are blended using a fatty phase of elevated temperature, if required. The active ingredient of the formula I is added, preferably in an aqueous solution, to the fatty phase or to the mixture of the other ingredients.
The skin ageing inhibition effect of the compounds of the formula I was examined on guinea-pigs. The skin surface of 8 guinea-pigs was depilated, then, on both sides of the animals 1 cm2 areas were irradiated by LJV-B light of 100 mJ/cm2 intensity. After the irradiation one side of the animals was covered with the cream of Example 1 comprising 4 % by mass of the test compound as the active ingredient. The other side of each animal was covered with a mixture of cosmetic carriers comprising no active ingredient (i.e. a cream corresponding to that of Example 1 was used, however, said cream contained water instead of the active ingredient, too). Thus, as a matter of fact, an internal control was used in the experiment.
In case of 4 animals the treatment with the cream was performed immediately after the irradiation, then the treatment was repeated daily for a week (group I). In case of the other 4 animals the skin surface irradiated was treated with the cream of the invention and the control cream, respectively, only 24 hours after the irradiation (group II).
In case of animals of group I a minimal erythema could be observed on the skin surface irradiated and treated with the composition of the invention ?4 and 48 hours after the irradiation.
On the skin surface used as control an area without epithelium could be noticed, and this state subsisted during the 7 days of observation. From the 4th day no difference could be detected between the skin surface irradiated and treated with the composition of the invention and the surrounding skin area.
In case of animals of group II, on the treated area as well as on the control area, skin injuries (vesicula, bulla) could be observed, then an area without epithelium developped. On the 7th day after the irradiation the area treated with the composition of the invention was epithelized.
On the basis of the above examination it can be established that the skin surface is protected from the damaging effects of the LTV-B light by the composition of the invention and the compound of the formula I, respectively. If the skin surface is treated with the composition of the invention immediately after the irradiation, only a weak injury of the epithelium is experienced, at the most.
Skin injuries developped by LJV-B radiation are healed owing to the treatment with the composition of the invention in a shorter time than without treatment. The compound of the formula I
exerts an epithelizing effect.
Thus, a further embodiment of the invention consists of a method for reducing the ageing processes of skin and/or treating the pathological lesions of skin, said method comprising treating the affected skin surface with a cosmetically effective non-toxic amount of a hydroximic acid derivative of the formula I or a physiologically acceptable acid addition salt thereof.
Suitably, the skin surface is treated with a cosmetic composition comprising 0.1 to 30 % by mass of a hydroximic acid derivative of the formula I or a physiologically acceptable acid addition salt thereof.
_ _ _._._. _ ._.. , 1~
Preferably, the skin surface is treated with O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime or a physiologically acceptable acid addition salt thereof.
The invention is further elucidated by means of the following Examples.
Eacample 1 Cream (oil/water) The cream consists of the following ingredients:
compound of the formula 4.0 % by mass I

cetylstearyl alcohol 7.5 % by mass stearic acid 9.0 % by mass glycerol monostearate 2.0 % by mass sodium lauryl sulfate 0.5 % by mass methyl p-hydroxybenzoate 0.1 % by mass distilled water 76.9 % by mass 100.0 % by mass The lipophilic ingredients (cetylstearyl) alcohol, stearyc acid and glycerol monostearate) are melted on a water-bath. The sodium lauryl sulfate and methyl p-hydroxy-benzoate are dissolved in about 38 ml of distilled water at 60 to 65 °C, the pH of the solution is adjusted by the addition of diluted aqueous sodium hydroxide solution to a value of 9 to 10, then the aqueous solution is admixed to the mixture of the lipophilic ingredients, and the emulsion obtained is stirred until cold. The active ingredient is dissolved in the remaining water and the solution is admixed to the cooled cream.

Example Z

Cream (water/oil) The cream consists of the following ingredients:

compound of the formula I 5.0 % by mass cetylstearyl alcohol 10.0 % by mass white wax 10.0 % by mass neutral oil 3 5. 0 % by mass Imwitor~~ 780 K (partial glycerides of vegetable fatty acids) ~.0 % by mass methyl p-hydroxybenzoate 0.1 % by mass distilled water 34.9 % by mass - 100.0 % by mass "~ The ingredients are blended the method described using in Example 1.

Example 3 Cream (water/oil) The cream consists of the following ingredients:

compound of the formula I 5.0 % by mass cetylstearyl alcohol 1.5 % by mass white wax 1.5 % by mass lanalcol 2.5 % by mass cholesterol 1.0 % by mass white vaseline 43.5 % by mass sodium tetraborate 2.0 % by mass methyl p-hydroxybenzoate 0.1 % by mass distilled water 42.9 % by mass 100.0 % by mass CA 02290702 1999-12-O1~

The ingredients are blended using the method described in Example 1.

Example 4 Moisturizing cream for night The cream consisting of the following ingredients is prepared using the method described in Example 1:

compound "B" 5.0 % by mass cetyl alcohol 5.0 % by mass lanolin (anhydrous) 5.0 % by mass cocoa-butter 5.0 % by mass vaseline 5.0 % by mass vaseline oil 5.0 % by mass isopropyl miristate 1.0 % by mass isopropyl palmitate 1.0 % by mass wheat-germ oil 10.0 % by mass evening primrose oil 5.0 % by mass vitamin A 0.03 % by mass vitamine E 0.05 % by mass glycerol 5.0 % by mass propylene glycol 5.0 % by mass methyl p-hydroxybenzoate 0.2 % by mass perfume 0.1 % by mass water, demineralized 42.62 % b,~ass 100.00 % by mass Example 5 Moisturizing cream for day The cream consisting of the following ingredients is prepared by the method described in Example 1.

compound "B" 5.0 % by mass cetyl alcohol S.0 % by mass lanolin (anhydrous) 5.0 % by mass vaseline 5.0 % by mass vaseline oil 5.0 % by mass isopropyl miristate 1.0 % by mass isopropyl palmitate 1.0 % by mass borage oil 4.0 % by mass peanut oil 11.0 % by mass vitamin A 0.03 % by mass vitamin E 0.05 % by mass glycerol 5.0 % by mass propylene glycol 5.0 % by mass methyl p-hydroxybenzoate 0.2 % by mass perfume 0.1 % by mass water, demineralized 47.62 % by mass 100.00 % by mass Example 6 Body milk The body milk consisting of the following ingredients is prepared by the method described in Example 1.

compound "B" 4.0 % by mass stearic acid monoglyceride 2.0 % by mass cetylstearyl alcohol 2.0 % by mass peanut oil 5.0 % by mass vaseline oil 3.0 % by mass polyoxyethylene cetylstearyl alcohol (degree of polymerization: 20) 2.0 % by mass glycerol 4.0 % by mass methyl p-hydroxybenzoate 0.2 % by mass propyl p-hydroxybenzoate 0.1 % by mass butylhydroxytoluene 0.01 % by mass water, demineralized 77.69 % by mass 100.00 % by mass

Claims (7)

CLAIMS:

1. Use of a composition, comprising a hydroximic acid derivative of the general formula:

wherein:
R1 represents a hydrogen atom or a C1-5 alkyl group;
R2 represents a hydrogen atom, a C1-5 alkyl group, a C5-7 cycloalkyl group or a phenyl group optionally substituted by a hydroxy or a phenyl group; or R1 and R2 together with the nitrogen atom they are attached to from a 5 to 8 membered ring optionally containing one or more further nitrogen or oxygen atom(s) and said ring optionally can be condensed with a benzene ring;

R3 represents a hydrogen atom, a phenyl group, a naphthyl group or a pyridyl group wherein said groups optionally can be substituted by one or more halo atom(s) or C1-4 alkoxy group(s); and A represents -(CH2)p-, wherein p is an integer of from 0 to 4;

or a physiologically acceptable acid addition salt thereof;

in admixture with a carrier suitable for topical application to skin, for reducing ageing processes of skin or treating pathological lesions of skin.

2. A use according to claim 1, comprising a hydroxyimic acid derivative of the general formula I, wherein R1 and R2 together with the nitrogen atom they are attached to form a piperidino group, and R3 and A are as defined in claim 1, or a physiologically acceptable acid addition salt thereof.

3. A use according to claim 1 or 2, wherein the hydroxyimic acid derivative of general formula I is O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime or a physiologically acceptable acid addition salt thereof.

4. A use according to any one of claims 1 to 3 of a composition comprising 0.1 to 30% by mass of the hydroxyimic acid derivative of general formula I.

5. A composition for topical application to skin for reducing ageing processes of skin or treating pathological lesions of skin, comprising a hydroximic acid derivative of the formula I, as defined in claim 1, 2 or 3, or a physiologically acceptable acid addition salt thereof, as active ingredient, in admixture with a carrier suitable for topical application to skin.

6. The composition of claim 5, comprising 0.1 to 30%
by mass of the active ingredient.

7. A commercial package, comprising a composition of claim 5 or 6, and associated therewith instructions for the use of the composition for reducing skin ageing processes or treating pathological skin lesions.