CA2111775A1

CA2111775A1 - Pharmaceutical and/or cosmetic preparation

Info

Publication number: CA2111775A1
Application number: CA002111775A
Authority: CA
Inventors: Miklos Ghyczy; Brigitte Nissen-Zoufal; Wolfgang Gehring
Original assignee: Miklos Ghyczy; Brigitte Nissen-Zoufal; Wolfgang Gehring; Rhone-Poulenc Rorer Gmbh
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1992-12-18
Filing date: 1993-12-17
Publication date: 1994-06-19
Also published as: JPH072676A; EP0606590A1

Abstract

ABSTRACT

A pharmaceutical and/or cosmetic agent is described, which comprises as active ingredient a mixture of N-acylalkanolamines and N-acylethanolamines besides the usual excipients.

Description

` ~ 211177~ :
.'~'. , Pharmaceutical and/or cosmetic preparation.

The present invention relates to a pharmaceutical and/or cosmetic preparation.

The use of N-acylethanolamines in products for the care of hair is known. A
publication of Goldemberg in J. Soc. Cosmet. Chem. 30 (1979) 415-427 describes for instance the use of acetyl-ethanolamines (MEA), to reduce eye irritation, caused by the tenside components in shampoos.
The oral use of N-oleoylphosphatidylethanolamines as a pharmaceutical preparation displays according to DE 27 56 866 Al a marked anti-atherosclerotic resp. Iipid-lowering activity, as could be proven in experimental animal models.

20 DE 36 06 664 Ai describes a plant protection preparation which besides a fungicide contains N-acylalkanolamine, the second active ingredient increasing the efficacy of the fungicide.

The aim of the present invention is to present a new pharmaceutical and/or cosmetic 25 preparation with a particularly high efficacy.

. .
This aim is reached with a pharmaceutical and/or cosmetic preparation with tlle characteristic features of claim 1.

.: .: . ~ . , .. . ~ .. ...... .. ~. - .

2 211177~
, The subject preparation according to the invention, which is suitable for pharmaceutical as well as cosmetic use, contains an active ingredient besides the usual excipients, consisting of a mixture of N-acylalkanolamines of the general formula I

s R2-CU-(CH2)n-NH~Rl whereby in the formula I
R1 represents the acyl moiety of a saturated CI-C 1 g-carboxylic acid and/or a o saturated C1-CIg-carboxylic acid derivative and/or the acyl moiety of an unsaturated C3-C I g-carboxylic acid and/or an unsaturatedC3-CIg-carboxylic acid derivative, R2 represents a hydroxy group and/or an ester group, however not a phosphoric acid ester, s R3 represents hydrogen and/or a Cl-C4-alkyl group and n is whole number between 0 and S, with N-acylethanolamines of the general formula Il, "~
Rs-O-CH 11 O

OH

s.,,.. ,.. ~, ..... ~ ,,. , j ,..... . . .. ... . . ..

3 ~11177~

whereby in the formula 11 R6 represents the acyl moiety of a saturated C I -C 1 g-carboxylic acid and/or a saturated Cl-CIg carboxylic acid derivative and/or me acyl moiety of an unsaturated C3-C Ig-carboxylic acid and/or an unsaturated C3-CIg-carboxylic acid derivative;
Rs represents hydrogen and/or the acyl group of a saturated and/or unsaturated C 16-C Ig-carboxylic acid and/or the acyl group of a saturated and/or unsaturated C16-CIg -carboxylic acid derivative; and R4 represents hydrogen andtor the acyl group of a saturated and/or unsaturated o C16-Clg-carboxylic acid and/or the acyl group of a saturated and/or unsaturated C16-CIg -carboxylic acid derivative.

Surprisingly it was observed, that the above mixture of active ingredients according to formula I and according to formula 11 provides excellent pharmaceutical and/or s cosmetic properties, which is illustrated by the fact that such preparations may be used with great success for the prevention of and in particular for the treatment of skin damage and/or skin diseases, like for instance skin burns, acne, insect bites, herpes infections, etc. A further advanta~e of the subject preparation is the fact, that the active ingredients they contain are harmless in toxicological respect in particular since the active ingredients represented by the forrnulas I and 11 are present in the human body anyway. Furthermore the above active ingredients can be dissolved in aqueous systems, or dispersions or suspensions can be made in water, so the preparation of a stable cosmetic or pharmaceutical preparation provides no particular problem. The active ingredients according to the forrnulas I and 11 are available, whereby the phosphoric acid esters according to the formula 11 are preferably isolated from natural products, in particular soybean phospholipids.

The concentration of the mixture of active ingredients according to the formulas I and Il in the subject pharmaceutical or cosmetic composition depends on the type of ::

' . .: . ' ' ., . ', :: . , ,':: ', . :.

4 ~11177~

disorder to be treated. Usually the concentration of the mixture of active inL~redients varies between 0,5 % by weight and 25 % by weight, preferably between 1 % by weight and 10 % by weight, relative to the total mass of the finished preparation.

s The mass ratio of N-acylalkanolamine (formula I) and N-acylethanolamine (formula 11) varies betweePI 55:45 and 80:20.

Particularly good qualities in respect to the prevention or treatment of the damage, irritations and diseases described in the specification, is provided by a specific o embodiment of the subject preparation comprising a N-acylalkanolarnine with a chemical structure according to the forrnula III. , ~ ~ -R2-CH-(CH2)n-NH-R

s In the formula Ill R1 represents the acyl moiety of acetic acid, propionic acid, lactic acid, palmitic ~ `
acid, stearic acid and/or oleic acid, ~:
20 R2 a hydroxy group, R3 hydrogen and/or a methyl group and n is 1 or 2.

Particularly suitable compounds according to the above formula 111, to be used single 2s or as mixtures with each other, are the following:

acetic acid-2-hydroxy-ethylamide, lauric acid-2-hydroxy~ethylamide, stearic acid-2-hydroxy-ethylamide, linoleic acid-2-hydroxy-ethylamide, palmitic acid-2-hydroxy-ethylamide, lauric acid-2-hydroxy-propylamide, linoleic acid-2-hydroxy-propylamide, ,~j: ,''' ,. :. ".: . ., ' . . : :

i ': : : ' : : ,. .

~11177~
.
oleic acid-2-hydroxy-propylamide, and the respective 2-hydroxy-ethylamide- and/ol 2-hydroxy-propylamide-derivatives, which contain as acyl groups the fatty acids from coconut oil and/or palm oil.

Another embodiment of the subject preparation, also providing a particularly high pharmaceutical efficacy, contains N-acylethanolamines with a chemical structure according to forrnula IV.
.

I

Rs-O-CH IV
11 , OH
In the formula IV
R4 and Rs, which may be identical or different, represent hydrogen and/or the acyl group of palmitic acid, stearic acid, linoleic acid, linolenic acid and/or oleic acid and : -20 R6 represents the acyl moiety of acetic acid, propionic acid, lactic acid, palmitic acid, stearic acid and/or oleic acid. ..

Preferably the above N-acylethanolamines according to forrnula IV are isolated from ;;
natural material, in particular plant lecithins, like e.g. soybean phospholipids.
2s Especially effective active ingredients are N-acetylphosphatidylethanolamine, N~
palmitylphosphatidylethanolamine and/or N-oleoylphosphatidylethanolamine, used as single compounds or as a tnixture with each other.

: . :

6 211177~
.

In particular when the subject preparation comprises an active ingredient, which exists of a combination of N-acetylphosphatidylethanolamine with N-acetylethanolamine, N-oleoylethanolamine, N-linoleoylethanolamine, N-acyl-2-hydroxypropylamine and/or N-acylethanolamine, the last two compounds containing fatty acids from coconut oil s and/or palm oil as acyl groups, such a preparation provides a particularly good prophylactic a~id/or therapeutic efficacy, in particular against the skin damage, the skin irritations and/or the skin diseases described in the present specification.

As has been stated before, the subject preparation can be prepared in every dosage o form, for instance as tablets, suppositories or as an infusion solution. Particularly suitable is a dosage form which allows a topical or local application. This means, that in this case the subject pharrnaceutical or cosmetic composition contains the usual excipients for topical application and preferably provides a fluid, half-solid or solid pharmaceutical form.
IS ~.
The fluid preparation can be prepared as drops, tinctures or sprays, containing the previously described mixture of active ingredients as a solution, a suspension or a dispersion.

20 For the preparation of a half solid dosage form gels, ointments, creams and foams can be selected, whereas for the solid preparations powders, granulates, pellets or micro .
capsules may be taken. If the pharrnaceutical or cosmetic preparation is used in a fluid dosage form, such solvents should be used, which do not cause any irritation of the skin. Such possibilities are water, alcohols with one hydroxy group, in particular 25 ethanol, isopropanol or n-propanol, alcohols, with more than one hydroxy groups, in particular glycerol and/or propanediol, polyglycoles in particular polyethylene glycol and/or Miglyol, glycerinformal, dimethyl isosorbite, natural and synthetic oils and/or esters.

,. . . .

.... . .. ... ..

7 21~ ~77~
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For the prodllction of the half solid preparations like the gels, the oinlments, the creams and the foams, besides the previously mentioned solvents, groundmass material like bentonite, veegum, guar flour and/or cellulose derivatives, in particular methyl cellulose and/or carboxy methyl cellulose may be used. Additional possible 5 groundmass materials are polymers fronn vinyl alcohol, vinyl pyrrolidone, alginates, pectines, polyàcrylates, solid and/or fluid polyethylene glycols, parrafines, fat alcohols, vaseline, waxes, fatty acids and/or esterified fatty esters.

To produce the so1id preparations, like the before-mentioned powders, granulates, o pellets or micro capsules, there is the possibility to use as an agglutinant for instance colloidal silicon dioxide, talcum, lactose, starch, sugar, cellulose derivatives, gelatine, metal oxides andlor metal salts. The concentration of the mixture of active ingredients and the mass ratio of the at least two active ingredients (formula I, formula III resp.
formula II, formula IV) may be varied according to the ranges which were mentioned 5 p~eviously.

Further possible components include preservatives, stabilisers, surfactants, emulsifiers, penetration enhancers, spreading agents and/or propellants.

20 According to a particularly suitable embodiment ~or the topical administration, the ~ -preparation contains phospholipids, in particular soybean phospholipids. Preferably such preparations are being used, which contain at least 80 % by weight phosphatidylcholine, the total ready to use cosmetic or pharmaceutical preparation ~ ~-providing a concentration of the phospholipid component between 1% by weight and ~ ~:
25 25 % by weight, preferably between 2 % by weight and 15 % by weight, this amount depending on the preparation itself and its intended use.

In particlllar it could be observed, that the active ingredient represented by the formula I especially when administered topically, may prevent light dennatosis, light sensitive ~, : : ., : :
. :.` .

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211177~
~ 8 dermatosis, for instance dermatitis solaris, actinic atrophy, cutis rhomboidalis nuchae, erythrosis interfollicularis colli, morbus Favre Racouchot, keratoses, cornu cutaneum,chilitis actiniae, estival prurigo, Mallorca acne, photo-toxic dermatosis, grass dermatitis, photo-allergic dermatitis, polymorphous light derrnatosis, hydroa s racciniformia, xeroderrna pigmentosum, lupus erythematous, rosacea-like derrnatitis, seborrheic eciema's and plane lichen, as well as the secondary phenomena connected with the various derrnatosis types, in particular dry skin, rough skin, redddening skin and skin wrinkling, as well as the early ageing of the skin, which makes the inventive preparation also particularly suitable for the use as a sun-protectant and in that respect o as a prophylactic preparation.
-~

Furthermore it could be shown surprisingly, that the inventive preparation is perfectly suited for the topical treatment of skin damage induced by light and/or heat, in : -particular also the previously mentioned skin damage, leading to a rapid healing.
:
When a pharmaceutical preparation comprising the active ingredient according to the ~.
formula 1, was used for the treatment of insect bites, like e.g. bites of bees, wasps, hornets, mites, ticks, sandfleas, hose-flies or gadflies, it could be shown, that soon ~
-after the administration of this preparation, a significant reduction of the symptoms of the insect bites was observed (redness, swelling resp. urtication for nation), whereas at ~ -the same time the pain or the itching caused by the insect bite is being reducedsubstantially.

Even in very sensitive patients no unwanted irritation or redness of the skin was observed after the topical use of the subject preparation.

If the subject pharmaceutical or cosmetic preparation is to be used as a sun-protectant, then it is recommendable, especially in those cases in which the preparation shall provide a high protective factor, to add, in addition to the at least one active ingredient, . . ~ . ., .. , .. , ,, -. ~ ~ , . , ; . , -9 ~111775 a substance which provides a light absorbant efficacy. For this purpose substances can be selected from the group of compounds consisting of, for instance derivatives of p-aminobenzoic acid, octyldimethyl-p-aminobenzoic acid, anthranilates, cinnamates,benzophenones and/or camphor derivatives, whereby however the concentration of such products in the final preparation may be substantially reduced compared with the conventional sun protectants. The final, preferred concentration is 50 to 70 % less than the concentration in the conventional sun protectants. The mixture of ingredients which is present in the inventive preparation, consisting of N-acylalkanolamines and N-acylethanolamines, apparently provides a synergistic interaction with the light~
o absorbing or light reflecting substances, making it possible to reduce their content in .
the preparation without a loss in light protectant factor The expression and/or in the present specification for the definition of R l, R2, R3, R4 and Rs was used to indicate that the respectively used N-acylalkanolamines (formula 1, formula 111) and the N-acylethanolamines (formula 11, formula IV) do not represent chemically uniform products. These compounds may represent mixtures, which contain a multitude of single products, which all differ from each other by the acyl group, the hydroxy group, the ester group and/or the meaning of R3.

Depending on the intended use the preparation may contain skin care additiolls or such ~ ~
components which increase the therapeutic efficacy. Such components may be selected :
from the group of local anaesthetics, antibiotics, antimycotics, antihistamines, steroids, UV-filters, vitamins, peptides, collagens, hyaluronic acids and/or plant extracts.

Advantageous embodiments of the subject preparation are defined in the dependent clalms.

, . , - ~ , .. . .. ...

`; 211177~
The subject preparation is filrther illustrated by the following examples.

Example 1.
A preparation I was produced, which comprised the following components:
phase A 55,00 g water, -14,00 g propylene glycol, 18,00 g phosphatidylcholhle ( at least 80% by weight soybean phosphatidylcholine), phase B 1,00 g N-acetylphosphatidylethanolamine, o 2,00 g N-acetylethanolamine and ;
10,00 jojoba oil.

Phase A was homogenised at 40 C in a rapidly turning mixer for 40 min until a clear .
gel had been formed. Phase B was added and mixing was continued until a clear s homogeneous gel had been formed.

Example 2.
A preparation 2 was produced from the following components: -phase A 52,00 g water, 14,00 g propylene glycol, 18,00 g phosphatidylcholine ( same as in Example 1), phase B 2,00 g N-acetylphosphatidylethanolamine, :
4,00 g N-acetylethanolamine and 10,00 gJojoba oil.
2s Phase A was homogenised at 40 C in a rapidly turning mixer for 40 min ulltil a clear gel had been formed. Phase B was added and mixing was continued until a clear homogeneous gel had been formed.

ll 211~77~
Example 3.
A third preparation contained the following components:
phase A 58,00 g water, 14,00 g propylene glycol, 18,00 g phosphatidylcholine, phase B 0,00 g N-acetylphosphatidylethanolamine, 0,00 g N-acetylethanolamine and 10,00 g jojoba oil.

o Phase A was homogenised at 40 C in a rapidly turning mixer for 40 min until a clear gel had been formed. Phase B was added and mixing was continued until a clear homogeneous gel had been formed. -The preparations I to 3 were investigated in 20 volunteers according to D~N 67 501 s (which evaluates the protection against erythema of externally applied sun protectants), to investigate their protection of the skin against the influence of sun ~ ~:
irradiation. -The investigation resulted in the following values~

preparation light protective factor (mean) :
8,7 2 9,S
3 2,1.
......... .

~ 12 211177~
:
To test the therapeutic anti-inflammatory efficacy of preparation I an investigation in 10 healthy volunteers was performed.

A local inflammatory response was provoked by the subcutaneous administration of5 histamine. The redness of the erythema was estimated with a Chromameter and the dermal perfusion according to a laser Doppler method.
Since, at a primary skin damage by light, histamine is being released from mast cells (leading to skin inflammations, as may be seen at sun-burn), the present method is highly relevant for the therapeutic efficacy against damage 'oy light. ;-The previously described test method represents a recognised investigational method and has been described in "Methods in Skin Research, 1985, pp 511 ff".

The course of the healing of the inflammation is depicted in the figures I and 2.
The two figures clearly illustrate, that the preparation I induces after 15 resp. 30 minutes a reduction in the redness and the hyperaemia compared to the preparation 3.

20 In a further test the destruction of dermally applied beta-carotene was estimated.
Beta-carotene represents one of the most important products for the protection of living tissue against damage by light.

On the lower arm of 10 volunteers 40 ul of beta-carotene solution ( 5 mg in 2,5 ml 2s hexane) on a precisely marked skin area.. After a period of 10 minutes the preparatiolls 2 and 3 were applied on the defined skin areas, the concentration in all preparations being 3 mg/cm2 ~ , '~ , ,. ! ' ' ' ' ' ' : ' ' ~ ' ' ' ' ' 13 ~11177~

The skin areas prepared according to the above description were illuminated after one hour with a Ultra-Vita-UVL lamp during 3 minutes at a distance of 50 cm.
Immediately thereafter the skin surface was extracted with I ml isopropanol for 1 minute.
s In the extraction fluid beta-carotene was estimated quantitatively by HPLC. :
A mixture of ~nethanol/hexane was used as eluent at a flow-rate of I ml/min using a -~
RP 18,3 11 4,6 x 75 mm (Ultrasphere Bechnan column).
At the outflow of the column a UV detector was positioned, analysing the fluid at 436 mn.
o The destruction of the beta-carotene due to the light irradiation is illustrated in the : ~ .:
following table.

preparation destruction (% of total amount) s 2 24 ~ .

20 In a case study in 10 volunteers, which had first and second degree burns, the efficacy of product 2 in comparison to product 3, was proven. The selected test area of 4 cm2 was marked and treated with product 2 or product 3. The time course of the healing showed without any doubt, that in the test areas treated with product 2 the duration until healing was shorter by 30 to 60 % as in the test areas treated with the product 3.

In a further case study the efficacy of the preparation 2 was investigated against insect bites.

In 4 volunteers, who had received 3 to 6 fly bites at arms or legs, a certain portion of the fly bites was treated with the preparation 2 and the other part witll the preparation 3.
In the fly bites treated with the preparation 2, a reduction in redness and diameter as s well as a disappearance of the itching sensation was observed as soon as 15 to 30 min after me application of the preparation.
On the other hand, the fly bites treated with the preparation 3 were 2 to 4 h after the beginning of the treatrnent still red and swollen and itched unpleasantly.

, .' . , : . ~ . ,

Claims

1. Pharmaceutical and/or cosmetic preparation, wherein said preparation comprises besides usual excipients, an active ingredient consisting of a mixture of N-acyl-alkanolamines of the general formula I

I

whereby in the formula I
R1 represents the acyl moiety of a saturated C1-C18-carboxylic acid and/or a saturated C1-C18-carboxylic acid derivative and/or the acyl moiety of an unsaturated C3-C18-carboxylic acid and/or an unsaturated C3-C18-carboxylic acid derivative;
R2 represents a hydroxy group and/or an ester group, however not a phosphoric acid ester, R3 represents hydrogen and/or a C1-C4-alkyl group and n represents a whole number between 0 and 5, with N-acylethanolamines of the general formula II, II

whereby in the formula 11 R6 represents the acyl moiety of a saturated C1-C18-carboxylic acid and/or a saturated C1-C18-carboxylic acid derivative and/or the acyl moiety of an unsaturated C3-C18-carboxylic acid and/or an unsaturated C3-C18-carboxylic acid derivative;
R5 represents hydrogen and/or the acyl group of a saturated and/or unsaturatedC16-C18-carboxylic acid and/or the acyl group of a saturated and/or unsaturated C16-C18-carboxylic acid derivative and R4 represents hydrogen and/or the acyl group of a saturated and/or unsaturatedC16-C18-carboxylic acid and/or the acyl group of a saturated and/or unsaturated C16-C18-carboxylic acid derivative.

2. The preparation according to claim 1, wherein said preparation comprises saidmixture of active ingredients at a concentration between 0,5% by weight and 25% by weight, preferably at a concentration between 1% by weight and 10% by weight, relative to the total mass of the finished preparation.

3. The preparation according to claims 1 or 2, wherein said preparation comprises said mixture of active ingredients at a mass ratio of N-acylalkanolamine to N-acylethanolamine between 55:45 and 80:20.

4. The preparation according to one of the preceding claims, wherein said N-acylalkanolamine provides a chemical structure, according to formula III, III

whereby in formula III
R1 represents the acyl group of acetic acid, propionic acid, lactic acid, palmitic acid, stearic acid and/or oleic acid, R2 represents a hydroxy group, R3 represents hydrogen and/or a methyl group and n is 1 or 2.

5. The preparation according to one of the preceding claims, wherein said N-acylethanolamine provides a chemical structure according me formula IV, IV

whereby in the formula IV
R4 and R5 are the same or different and represent the acyl moiety of palmitic acid, stearic acid, linoleic acid, linolenic acid and/or oleic acid; and R6 represents the acyl moiety of acetic acid, propionic acid, lactic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid and/or oleic acid.

6. The preparation according to one of the preceding claims, wherein the active ingredient comprises a mixture of N-acetylphosphatidylethanolamine with N-acelyl-ethanolamine, N-oleoylethanolamine, N-linoleoylethanolamine, N-acylethanolamine and/or N-acyl-2-hydroxypropylamine, the last two products containing the fatty acids from coconut oil and/or palm oil as acyl moieties.

7. The preparation according to one of the preceding claims, wherein the preparation provides a pharmaceutical form suitable for topical administration and comprises the usual excipients for this topical use.

8. Preparation according to claim 7, wherein the preparation comprises phospholipids, in particular soybean phospholipids as further component.

9. Use of the preparation according to one of the preceding claims for the prevention of skin damage induced by light, in particular induced by sun light.

10. Use of the preparation according to claims 1 to 8 for the treatment of skin damage induced by light and/or heat or by insect bites.