Note: Descriptions are shown in the official language in which they were submitted.
` ~ 211177~ :
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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.
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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
R3 -
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,
CH2-O-R4
"~
Rs-O-CH 11
O
CH2-O-P-O-CH2-CH2-NH-R6
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
R3
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,
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~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.
.
CH2-O-R4
I
Rs-O-CH IV
11 ,
CH2-0-P-O-CH2-CH2-NH-R6
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.
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`; 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
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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 ~ .
3 100
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.
14 211 1775
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.
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