U.S. patent application number 08/849525 was filed with the patent office on 2002-10-03 for use of flavonoids as immunomodulating or immuno-protective agents in cosmetic and dermatological preparations.
Invention is credited to LANZENDORFER, GHITA, STAB, FRANZ, UNTIEDT, SVEN.
Application Number | 20020142012 08/849525 |
Document ID | / |
Family ID | 6535603 |
Filed Date | 2002-10-03 |
United States Patent
Application |
20020142012 |
Kind Code |
A1 |
LANZENDORFER, GHITA ; et
al. |
October 3, 2002 |
USE OF FLAVONOIDS AS IMMUNOMODULATING OR IMMUNO-PROTECTIVE AGENTS
IN COSMETIC AND DERMATOLOGICAL PREPARATIONS
Abstract
The invention relates to the use of cosmetic and dermatological
formulations having a) a content of a compound or several compounds
from the group consisting of flavonoids or having b) a content of
an active compound combination comprising a compound or several
compounds chosen from the group consisting of flavonoids in
combination with a compound or several compounds chosen from the
group consisting of cinnamic acid derivatives and c) if appropriate
an additional content of a compound or several compounds from the
group consisting of antioxidants for treatment or prophylactic
treatment of the immunosuppression induced by UVB radiation, in
particular for treatment or prophylactic treatment of inflammatory,
allergic or autoimmune-reactive symptoms, and for protecting cells
which participate in the immune response of the skin.
Inventors: |
LANZENDORFER, GHITA;
(HAMBURG, DE) ; STAB, FRANZ; (ECHEM, DE) ;
UNTIEDT, SVEN; (HAMBURG, DE) |
Correspondence
Address: |
NORRIS, MCLAUGHLIN & MARCUS, P.A.
220 EAST 42ND STREET
30TH FLOOR
NEW YORK
NY
10017
US
|
Family ID: |
6535603 |
Appl. No.: |
08/849525 |
Filed: |
August 29, 1997 |
PCT Filed: |
December 12, 1995 |
PCT NO: |
PCT/EP95/04908 |
Current U.S.
Class: |
424/401 ; 424/64;
424/70.1; 514/30; 514/532; 514/559; 514/570 |
Current CPC
Class: |
A61K 8/36 20130101; A61K
8/9789 20170801; A61K 31/192 20130101; A61Q 19/00 20130101; A61Q
19/001 20130101; Y10T 428/193 20150115; A61K 31/19 20130101; A61K
8/602 20130101; A61K 45/06 20130101; A61Q 5/00 20130101; Y10S
514/864 20130101; A61P 37/08 20180101; A61K 8/37 20130101; A61K
31/70 20130101; A61P 29/00 20180101; Y10S 514/858 20130101; A61K
8/365 20130101; Y10S 514/859 20130101; Y10S 514/86 20130101; Y10T
428/195 20150115; A61P 17/00 20180101; A61P 37/04 20180101; A61Q
19/08 20130101; Y10S 514/861 20130101; A61P 43/00 20180101; A61K
2800/522 20130101; Y10S 514/863 20130101; A61K 8/361 20130101; A61K
8/498 20130101; A61Q 17/04 20130101; A61K 31/19 20130101; A61K
2300/00 20130101; A61K 31/192 20130101; A61K 2300/00 20130101; A61K
31/70 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/401 ; 424/64;
424/70.1; 514/30; 514/532; 514/559; 514/570 |
International
Class: |
A61K 031/70; A61K
007/025; A61K 007/06; A61K 006/00; A61K 007/00; A61K 031/235; A61K
031/20; A61K 031/19 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 13, 1994 |
DE |
P 44 44 238.6 |
Claims
1. Use of cosmetic and dermatological formulations having a) a
content of a compound or several compounds from the group
consisting of flavonoids or having b) a content of an active
compound combination comprising a compound or several compounds
chosen from the group consisting of flavonoids in combination with
a compound or several compounds chosen from the group consisting of
cinnamic acid derivatives and c) if appropriate an additional
content of a compound or several compounds from the group
consisting of antioxidants for treatment or prophylactic treatment
of the immunosuppression induced by UVB radiation, in particular
for treatment or prophylactic treatment of inflammatory, allergic
or autoimmune-reactive symptoms, and for protecting cells which
participate in the immune response of the skin.
2. Use according to claim 1, characterized in that the flavonoids
are chosen from the group consisting of alpha-glucosylrutin,
alpha-glucosylmyrictrin, alphaglucosylisoquercitrinin and
alpha-glucosylquercitrin, quercitin, rutin, chrysin, kaempferol,
myricetin, rhamnetin, apigenin, luteolin, naringin, hesperidin,
naringenin, hesperitin, morin, phloridzin, diosmin, fisetin,
vitexin, neohesperidin dihydrochalcone, flavone, glucosylrutin and
genistein.
3. Use according to claim 1, characterized in that the formulations
comprise combination b).
4. Use according to claim 1, characterized in that the formulations
comprise one or more hydroxycinnamic acids.
5. Use according to claim 1, characterized in that cinnamic acid
derivatives of the formula 10and/or active amounts of cinnamic acid
derivatives of the general formula 11wherein the groups X, Y and R
independently of one another can be chosen from the group
consisting of H and branched or unbranched alkyl having 1-18 C
atoms, are used.
6. Formulations according to claim 1, characterized in that they
comprise caffeic acid and/or ferulic acid.
7. Use according to claim 1, characterized in that formulations
with combinations b) comprise alpha-glucosylrutin and/or ferulic
acid.
8. A method for the treatment of immunosuppresion of the skin cells
induced by UVB radiation and for protecting the cells which
participate in the immune response of the skin, said method
comprising applying an effective amount of a cosmetic or
dermatological formulation comprising: a) one or more flavonoids;
b) one or more cinnamic acid derivatives; and c) optionally an
antioxidant to said skin.
9. The method according to claim 8, wherein the flavonoid is
selected from the group consisting of alpha-glucosylrutin,
alpha-glucosylmyrictrin, alpha-glucosylisoquercitrinin and
alpha-glucosylquercitrin, quercitin, rutin, chrysin, kaempferol,
myricetin, rhamnetin, apigenin, luteolin, naringin, hesperidin,
naringenin, hesperitin, morin, phloridzin, diosmin, fisetin,
vitexin, neohesperidin dihydrochalocone, flavone, glucosylrutin and
genistein.
10. The method according to claim 8, wherein the formulation
comprises one or more flavonoids and one or more cinnamic acid
derivatives.
11. The method according to claim 8, wherein the formulation
comprises one or more cinnamic acid derivatives wherein the
cinnamic acid derivative is a hydroxycinnamic acid.
12. The method according to claim 8, wherein the formulation
comprises one or more cinnamic acid derivatives wherein the
cinnamic acid derivative is of the formula 12and/or of the formula
13wherein the groups X, Y and R independently of one another are H
or branched or unbranched alkyl having 1-18 C atoms.
13. The method according to claim 8, wherein the symptom of the
immunosuppression is inflammation, allergy or an
autoimmune-reactive symptom.
14. A cosmetic or dermatological formulation which comprises an
effective amount of: a) one or more flavonoids; b) optionally one
or more cinnamic acid derivatives; c) optionally an oxidant; and d)
alpha-glucosylatine and/or ferulic acid.
Description
[0001] The present invention relates to active compounds and
formulations comprising such active compounds for cosmetic or
dermatological treatment and/or prophylaxis of inflammatory,
allergic or autoimmune-reactive symptoms, and protecting cells
which participate in the immune response of the skin.
[0002] As a barrier organ in the human organism, the skin,
especially the epidermis, is particularly subjected to external
effects. According to current scientific understanding, the skin
represents an immunological organ which, as an immunocompetent
peripheral compartment, plays its own role in inductive, effective
and regulatory immune processes of the total organism.
[0003] Light occupies an important position among the physical
environmental influences. The damaging effect of the ultraviolet
component of solar radiation on the skin is generally known. While
rays having a wavelength below 290 nm (the so-called UVC range) are
absorbed by the ozone layer in the earth's atmosphere, rays in the
range between 290 and 320 nm, the so-called UVB range, cause
erythema, simple sunburn or even burns of greater or lesser
severity. The narrower range around 308 nm is stated as a maximum
for the erythema activity of sunlight.
[0004] Ultraviolet light from the wavelength range between about
320 and 400 nm (UVA range) can also cause secondary damage to the
skin. It has thus been proved that UVA radiation also leads to
damage to the elastic and collagenic fibres of connective tissue,
which causes the skin to age prematurely (so-called photoageing),
and that it is to be regarded as a cause of numerous phototoxic
toxic and photoallergic reactions. The damaging influence of UVB
radiation may be intensified by UVA radiation.
[0005] UVB radiation is of particular interest in the development
of topical sunscreen compositions, since the action spectrum for
the acutely inflammatory processes (sunburn) and chronic damage
(photoageing) is located here.
[0006] In addition to these effects, a serious change in the
intraepidermal immunological situation may furthermore occur under
the action of UVB, this being called UVB-induced immunosuppression.
Under certain circumstances, depending on the dose of radiation,
far-reaching changes in the immunological processes of the skin
with both local and systemic effects are possible consequences
here.
[0007] Immunosuppression generally is the suppression or
attenuation of the reactivity of the immune system. UVB-induced
immunosuppression can be classified into local and systemic
effects. In the end, it includes a large number of the most diverse
aspects, all of which comprise reduction of the normal
immunological defence mechanisms of the skin. The increased tumour
growth was thus already related to the immunosuppressive action of
UVB light very early on using the model of mice irradiated with
UVE. This UVB-induced immunosuppresion is nowadays discussed as the
mechanism by means of which UVB-induced neoplastic cells, which are
in themselves highly immunogenic, withdraw from immunological
defence and therefore their own destruction.
[0008] There is furthermore a marked decrease in contact
hypersensitivity reaction in the case of UVB irradiation compared
with some agents which sensitize the skin. The reason for this
could lie in a drastic reduction in the number of epidermal
Langerhans cells and/or a change in their morphology and
functionality. However, Langerhans cells are the afferent arm of
the immunological defence of the skin. Effective defence reactions
against infectious organisms, such as, for example, Candida
albicans or herpes simplex virus, are furthermore absent.
[0009] Finally, the expression of "intercellular adhesion
molecule-1" on epidermal keratinocytes is suppressed as a
consequence of a dermatologically relevant UVB exposure. This
glycoprotein on the cell surface (also called ICAM-1) is one of the
most important cellular communication structures, via which direct
cellcell contacts between epidermal keratinocytes and leukocytes,
such as, for example, T-lymphocytes and monocytes, are
regulated.
[0010] UVB-induced immunosuppression thus concerns a broad spectrum
of immunological dysfunctions which result in a reduction in the
defence reactions which normally proceed.
[0011] It is indeed customary to use absorbing agents, that is to
say the customary light protection substances, against the direct
action of ultraviolet radiation.
[0012] Derivatives of dibenzoylmethane, for example, are chiefly
used for protection against rays in the UVA range.
[0013] Many compounds are known for protection against UVB
radiation, these chiefly being derivatives of 3-benzylidenecamphor,
of 4-aminobenzoic acid, of cinnammic acid, of salicylic acid, of
benzophenone and also of 2-phenylbenzimidazole.
[0014] It was furthermore also known to employ free radical
collectors as agents which act against photo-oxidative symptoms in
the skin induced by UV radiation.
[0015] As is known, such photochemical reaction products are
chiefly free-radical compounds, for example hydroxyl radicals or
superoxide radical anions. Undefined free-radical photo products
which are formed in the skin itself can also show uncontrolled
secondary reactions because of their high reactivity. However,
singlet oxygen, a non-radical excited state of the oxygen molecule,
may also occur under UV irradiation, as may shortlived epoxides and
many other reactive oxygen species. Singlet oxygen, for example, is
distinguished from the triplet oxygen normally present
(free-radical ground state) by an increased reactivity.
Nevertheless, excited, reactive (free-radical) triplet states of
the oxygen molecule also exist.
[0016] It has thus already been proposed to employ vitamin E or
vitamin E esters, substances of known antioxidative action, in
light protection formulations. However, the background was always
UV protection by absorption of light or protection against
photo-oxidative processes. Furthermore, the activity of vitamin E
from topical vehicles was weak. A high dosage also provided no
remedy, since a more prooxidative action was achieved, especially
with vitamin E.
[0017] Combinations of 2,4-O-furfurylidenesorbitol, thiols and
vitamin E, which are mentioned in PCT/DE93/00773, for intensifying
the endogenous immune system of the skin have also fallen short of
expectations.
[0018] The object of the present invention was therefore, and this
object is achieved according to the invention, to provide active
compounds and formulations comprising such active compounds, with
the aid of which
[0019] a more effective prophylaxis against UVB immuno-suppression
can be achieved and
[0020] the immune system already damaged by UVB immuno-suppression
can be strengthened again.
[0021] The active compounds and formulations according to the
invention act in this way.
[0022] It was surprising and not to be foreseen by the expert that
the cosmetic or dermatological formulations for treatment and/or
prophylaxis of the immunosuppression induced by UVB radiation,
characterized by a therapeutically or cosmetically active content
of the substance specified below, and the use of cosmetically or
dermatologically acceptable substances specified below for cosmetic
or dermatological treatment and/or prophylaxis of the
immunosuppression induced by UVB radiation would achieve these
objects.
[0023] The substances according to the invention chosen from the
group consisting of flavonoids and their glucosides, from the group
of cinnamic acid derivatives and from the group of tocopherols and
their derivatives are particularly advantageous.
[0024] Japanese Laid-Open Specification Hei-06-138,941 indeed
describes oral formulations having a content of water-soluble
glucosides, which can be chosen, for example, from the group
consisting of a-glucosylrutin, u-glucosylmyrictrin,
a-glucosylisoquercitrin and a-glucosylquercitrin. Japanese
Laid-Open Specification Hei-04-10 363,395 describes a process for
preventing decomposition of perfume constituents which is
distinguished, inter alia, by an addition of a-glucosylrutin to the
corresponding formulations. European Laid-Open Specification 586
303 and European Laid-Open Specification 595 694 furthermore
describe the use of flavonoids as antioxidants or light protection
substances in cosmetics. It is furthermore known from US-A
4,144,325 and 4,248,861 and from numerous other documents to employ
vitamin E in cosmetic and dermatological light protection
formulations. However, the use according to the invention of
vitamin E and its derivatives for cosmetic or dermatological
prophylaxis of the immunosuppression induced by UVB radiation was
not made obvious by the prior art.
[0025] However, no indication which could lead in the direction of
the present invention is to be found in these specifications.
[0026] The above objects are achieved according to the
invention.
[0027] The invention relates to the use of cosmetic and
dermatological formulations having
[0028] a) a content of a compound or several compounds from the
group consisting of flavonoids or having
[0029] b) a content of an active compound combination comprising a
compound or several compounds chosen from the group consisting of
flavonoids in combination with a compound or several compounds
chosen from the group consisting of cinnamic acid derivatives
and
[0030] c) if appropriate an additional content of a compound or
several compounds from the group consisting of antioxidants for
treatment or prophylactic treatment of the immunosuppression
induced by UVB radiation, in particular for treatment or
prophylactic treatment of inflammatory, allergic or
autoimmune-reactive symptoms, and for protecting cells which
participate in the immune response of the skin.
[0031] Active compound combinations b) , their use and formulations
which comprise these are preferred.
[0032] The invention also relates to the use of the active compound
according to the invention for the purposes mentioned and their use
as immunomodulating or immunoprotective active compounds, in
particular in cosmetic and dermatological formulations.
[0033] The active compounds and formulations according to the
invention are used for protection of immunocompetent cells, such as
Langerhans cells, and for protection of cell constituents.
[0034] Topical formulations are preferred.
[0035] Preferred flavonoids according to the invention are, for
example, hydroxylated flavones, flavanones, isoflavones or
chalcones, and in each case also glycosides thereof, as well as
these non-hydroxylated base structures and parent substances.
[0036] The flavonoids according to the invention are also
designated A) below, the cinnamic acid derivatives according to the
invention are designated B) and the antioxidants according to the
invention are also designated C).
[0037] According to the invention, the flavonoids A) are preferably
chosen from the group consisting of substances of the generic
structural formulae 1
[0038] wherein Z.sub.1-Z.sub.5 independently of one another are
chosen from the group consisting of H, OH and O-alkyl, wherein the
alkyl groups can be branched and unbranched and can contain 1-10 C
atoms, and wherein Gly is chosen from the group consisting of mono-
and oligoglycoside radicals, or can also be H. Preferred glycoside
radicals are those mentioned below for Gly.sub.1-Gly.sub.3 .
[0039] Further flavonoids according to the invention are
advantageously chosen from the group consisting of substances of
the following formulae: 2
[0040] wherein Z.sub.1-Z.sub.5 have the abovementioned meanings and
Gly.sub.1, Gly.sub.2 and Gly.sub.3 are monlglycoside radicals. for
example allosyl, altrosyl, apiosyl, arabinosyl, biosidyl,
galactosyl, gulosyl, glucoronidyl, idosyl, mannosyl, talosyl and
xylosyl, are also advantageously to be used, where appropriate. It
may also be advantageous according to the invention to use pentosyl
radicals.
[0041] It is particularly advantageous in the context of the
present invention to choose the flavone glycoside or glycosides
from the group consisting of alpha-glucosyl-rutin,
alpha-glucosylmyrictrin, alpha-glucosylisoquer-citrin and
alpha-glucosylquercitrin.
[0042] Compounds such as alpha-glycosylrutin,
alpha-glycosylhesperidin, alpha-glycosylnaringin,
alpha-manno-sylrutin and alpha-rhamnosylrutin are furthermore
particularly preferred according to the invention.
[0043] It may also be advantageous to omit the abovementioned
glycosidic radicals Gly-.sub.3 and to use the unsubstituted
flavonoids (Gly-.sub.3 =H), such as, for example, quercitin. It may
also be of advantage to use flavonoids in which the glucoside
radical is bonded to C7, C4', C3' or C5' via phenolic OH
functions.
[0044] It may furthermore be advantageous to use flavonoids in
which the phenolic OH function on C9 is present in the free form
(so-called chalcones) . It is particularly advantageous to use
neohesperidin dihydrochalcone from this group.
[0045] It is advantageous in the context of the present invention
to choose the flavonoid or flavonoids from the group consisting of
quercitin, rutin, chrysin, kaempferol, myricetin, rhamnetin,
apigenin, luteolin, naringin, hesperidin, naringenin, hesperitin,
morin, phloridzin, diosmin, fisetin, vitexin, neohesperidin
dihydrochalcone, flavone, glycosylrutin and genistein.
[0046] The flavonoids which are particularly preferred according to
the invention are chrysin, naringin, hesperidin, naringenin,
hesperetin, morin, phloridzin, diosmin, neohesperidin
dihydrochalcone, flavone and, in particular, alpha-glucosylrutin of
the formula 3
[0047] It can furthermore be advantageous in the context of the
invention to use commercially available flavonoid-containing plant
extracts. These can be aqueous-alcoholic or aqueous-glycolic
extracts and dry extracts obtained by the customary methods.
[0048] The following extracts have proved to be particularly
advantageous: citrous fruit peel or kernel extract (for example
Citricidal/Synthapharm) , soya extract (for example
Phytodermin/Chem. Laboratorium Dr. Kurt Richter GmbH), Sophora
japonica extract (for example Sophorine/Solabia), Scotch thistle
extract (for example Psoralen Silymarin/Mani GmbH Chemische
Produkte), cat's-foot blossom extract, spinach extract and a mixed
plant extract of passion flower, blackcurrant and vine leaves (AE
Complex/Solabia).
[0049] Suitable cinnamic acid derivatives are, for example,
hydroxycinnamic acids and derivatives thereof, it being possible
for the derivatives to be, for example, those defined below.
[0050] Cinnamic acid derivatives of the general formula 4
[0051] and/or active amounts of cinnamic acid derivatives of the
general formula 5
[0052] wherein the groups X, Y and R independently of one another
can be chosen from the group consisting of H and branched or
unbranched alkyl having 1-18 C atoms, can be used according to the
invention.
[0053] The acids or salts thereof can be used, preferably the
physiologically tolerated salts, for example water-soluble salts
(sodium or potassium salts).
[0054] Ferulic acid is regarded as a particularly advantageous
cinnamic acid derivative in the context of the present invention.
Ferulic acid (4-hydroxy-3-methoxy-cinnamic acid, caffeic acid
3-methyl ether) is characterized by the structural formula 6
[0055] It is widespread in plants and occurs, for example, in beet
crops, cereals and the latex of the umbelliferous plants Ferula
asafoetida and Ferula nartex, which give it its name. The E form is
a colourless crystalline solid under normal conditions, and the Z
form is in the form of a yellowish oil under normal conditions.
[0056] In the context of the present invention, it is preferable to
use E-ferulic acid. However, it is also advantageous, where
appropriate, to employ Z-ferulic acid or any desired mixtures of E-
and Z-ferulic acid.
[0057] Another derivative of cinnamic acid which is preferred
according to the invention is caffeic acid, which is distinguished
by the structure 7
[0058] It is a widespread plant acid and is contained, for example,
in coffee, tobacco, poppy and dandelion.
[0059] It is also advantageous, where appropriate, to use plant
extracts with a content of cinnamic acid derivatives according to
the invention, in particular ferulic acid and/or caffeic acid.
[0060] The term "derivatives of caffeic acid or ferulic acid" is to
be understood as meaning their cosmetically or pharmacologically
acceptable esters, salts and base adducts, in particular those such
as are described above for the cinnamic acid derivatives.
[0061] Preferred combinations according to the invention are
combinations of one or more substances from the group consisting of
the abovementioned flavonoids or combinations of one or more
representatives of the flavonoids with a derivative of cinnamic
acid, or also the combination with several cinnamic acid
derivatives.
[0062] Combinations of flavonoids, flavone glucosides or
flavonoid-containing plant extracts with ferulic acid and the
combination of synthetically modified, in particular glycosylated
flavonoids, such as alpha-glycosylrutin, with cinnamic acid
derivatives are particularly preferred according to the
invention.
[0063] The weight ratio of the cinnamic acid derivatives to the
flavonoid or flavonoids is advantageously 25:1 to 1:25, preferably
5:1 to 1:5, particularly preferably about 2:1 to 1:2.
[0064] Formulations with combinations b) which comprise
alpha-glucosylrutin and/or ferulic acid are particularly
preferred.
[0065] The compounds of group A or those of the combination of
active compounds A) and B) can be present as the sole active
compounds in the formulations according to the invention.
[0066] However, in addition to active compounds A) or the
combination of A) and B), the formulations according to the
invention can also additionally and preferably have a content of an
antioxidant or several antioxidants C).
[0067] The antioxidants C) according to the invention can
advantageously be chosen from the group consisting of tocopherols
and derivatives thereof. The tocopherols, also called vitamin E,
are derived from the parent substance tocol
(2-methyl-2-(4,8,12-trimethyltridecyl)-chroman-6-o- l). The
configuration 2R,4`R,8`R is attributed to .alpha.-tocopherol, which
occurs naturally the most frequently and is the most important. It
is occasionally also called RRR-.alpha.-tocopherol.
[0068] The tocopherol derivatives which are preferred according to
the invention are a-tocopherol and its esters, in particular
a-tocopheryl acetate. Esters of acids having 2-18, in particular
2-8 C atoms are preferred.
[0069] If vitamin E and/or derivatives thereof are the antioxidant
or antioxidants, it is advantageous to choose the particular
concentrations thereof from the range from 0.001 to 10% by weight,
based on the total weight of the formulation.
[0070] It is furthermore advantageous to use antioxidants C) from
the group consisting of amino acids (for example glycine,
histidine, tyrosine and tryptophan) and derivatives thereof,
imidazoles (for example urocanic acid) and derivatives thereof,
peptides, such as D,L-carnosine, D-carnosine, L-carnosine and
derivatives thereof (for example anserine), carotenoids, carotenes
(for example .alpha.-carotene, .beta.-carotene and lycopene) and
derivatives thereof, chlorogenic acid and derivatives thereof,
liponic acid and derivatives thereof (for example dihydroliponic
acid), aurothioglucose, propyl-thiouracil, thioredoxin and
glutathione, and furthermore (metal)chelators (for example
.alpha.-hydroxy-fatty acids, palmitic acid, phytic acid and
lactoferrin), a-hydroxyacids (for example citric acid, lactic acid
and malic acid), humic acid, bile acid, bile extracts, bilirubin,
biliverdin, EDTA, EGTA and derivatives thereof, unsaturated fatty
acids and derivatives thereof (for example y-linolenic acid,
linoleic acid and oleic acid), folic acid and derivatives thereof,
ubiquinone and ubiquinol and derivatives thereof, vitamin C and
derivatives (for example ascorbyl palmitate, Mg ascorbyl phosphate
and ascorbyl acetate), vitamin A and derivatives (vitamin A
palmitate) and coniferyl benzoate of benzoin resin,
butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiac resin
acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid
and derivatives thereof, mannose and derivatives thereof, mannose
and derivatives thereof, sesame oil, sesamolin, zinc
and.derivatives thereof (for example ZnO and ZnSO.sub.4), selenium
and derivatives thereof (for example selenium methionine),
stilbenes and derivatives thereof (for example stilbene oxide and
transstilbene oxide) and the derivatives of these active compounds
mentioned which are suitable according to the invention (salts,
esters, ethers, sugars, nucleotides, nucleosides, peptides and
lipids).
[0071] The amount of the abovementioned antioxidants C) (one or
more compounds) in the formulations is preferably 0.001 to 30% by
weight, particularly preferably 0.05-20% by weight, in particular
1-10 by weight, based on the total weight of the formulation.
[0072] The cosmetic and/or dermatological formulations according to
the invention can have the customary composition and can be used
for prophylaxis and/or for treatment of the skin in the context of
a dermatological treatment or prophylaxis and/or treatment in the
context of cosmetics. However, they can also be used in make-up
products of decorative cosmetics.
[0073] The cosmetic and dermatological formulations according to
the invention preferably comprise 0.001% by weight to 30% by
weight, preferably 0.01% by weight to 10% by weight, but in
particular 0.1% by weight to 6% by weight, based on the total
weight, of one or more substances A) according to the invention or
of the combination of A) and B).
[0074] It is advantageous according to the invention to use
combinations of several antioxidants, in particular if at least one
of the components is chosen from the group consisting of flavonoids
and glucosides thereof and cinnamic acid derivatives.
[0075] It is particularly advantageous to use combinations of at
least one compound from the flavonoids A) or derivatives thereof,
at least one compound from the cinnamic acid derivatives B) and
vitamin E or its derivatives C).
[0076] It is particularly advantageous to use combinations of
synthetically modified, for example glycosylated flavonoids or
derivatives thereof, ferulic acid and vitamin E or its derivatives.
It is also particularly advantageous to use combinations of
naturally occurring flavonoids or derivatives thereof, cinnamic
acid and derivatives thereof and vitamin E or its derivatives.
[0077] The weight content of active compounds from the group
consisting of flavonoids and derivatives thereof and the group
consisting of cinnamic acid and its derivatives can be varied in a
wide range of ratios in the combinations. The weight ratio of the
active compounds is preferably 20:1 to 1:20, in particular 10:1 to
1:10, particularly preferably 2:1 to 1:2.
[0078] The weight content of active compounds from the group
consisting of flavonoids and derivatives thereof and the group
consisting of tocopherol and its derivatives can likewise be varied
within a wide range of ratios in the combinations. The weight ratio
of the active compounds is preferably 20:1 to 1:20, in particular
10:1 to 1:10, particularly preferably 2:1 to 1:2.
[0079] If combinations of active compounds of the group consisting
of flavonoids and derivatives thereof and the group consisting of
cinnamic acid and its derivatives with the group consisting of
tocopherol and its derivatives are used, the weight ratios can
preferably be varied within the following limits: 20:1 to 1:20, in
particular 10:1 to 1:10, particularly preferably 2:1 to 1:2.
[0080] For cosmetic or dermatological treatment and/or prophylaxis
of the immunosuppression induced by UVB radiation, for protection
of the immunocompetent cells, such as Langerhans cells, and for
protection of cell constituents, the formulations according to the
invention, preferably combinations of flavonoids and derivatives
thereof, cinnamic acid and derivatives thereof and vitamin E and
derivatives thereof, are applied to the skin in a sufficient amount
in the manner customary for cosmetics or dermatological agents.
[0081] Cosmetic formulations according to the invention for
protection of the skin can be in various forms, such as are usually
employed, for example, for this type of formulation. They can thus
be, for example, a solution, an emulsion of the water-in-oil (W/o)
type or of the oil-in-water (O/W) type, or a multiple emulsion, for
example of the water-in-oil-in-water (W/O/W) type, a gel, a
hydrodispersion, an anhydrous ointment, a solid stick or also an
aerosol.
[0082] The cosmetic formulations according to the invention can
comprise cosmetic auxiliaries such as are usually used in such
formulations, for example UV/A and UV/B filters, preservatives,
bactericides, perfumes, agents for preventing foaming, dyestuffs,
pigments which have a colouring action, thickeners, surface-active
substances, emulsifiers, softening substances, humidifying and/or
humectant substances, fats, oils, waxes or other customary
constituents of a cosmetic formulation, such as alcohols, polyols,
polymers, foam stabilizers, electrolytes, organic solvents or
silicone derivatives.
[0083] If the cosmetic or dermatological formulation is a solution
or lotion, solvents which can be used are:
[0084] water or aqueous solutions;
[0085] oils, such as triglycerides of capric or of caprylic acid,
or liquid triglycerides of natural origin
[0086] fats, waxes and other natural and synthetic fatty
substances, preferably esters of fatty acids with alcohols of low C
number, for example with isopropanol, propylene glycol or glycerol,
or esters of fatty alcohols with alkanoic acids of low C number or
with fatty acids
[0087] silicone oils, such as dimethylpolysiloxanes,
diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms
thereof
[0088] alcohols, diols or polyols of low C number and ethers
thereof, preferably ethanol, isopropanol, propylene glycol,
glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl
ether, propylene glycol monomethyl, monoethyl or monobutyl ether,
diethylene glycol monomethyl or monoethyl ether and analogous
products.
[0089] Mixtures of the abovementioned solvents are used in
particular. In the case of alcoholic solvents, water can be a
further constituent.
[0090] Emulsions according to the invention, for example in the
form of a sunscreen cream, a sunscreen lotion or a sunscreen milk,
are advantageous and comprise, for example, the fats, oils, waxes
and other fatty substances mentioned, as well as water and an
emulsifier such as is usually used for such a type of
formulation.
[0091] Gels according to the invention usually comprise alcohols of
low C number, for example ethanol, isopropanol, 1,2-propanediol,
glycerol and water, or an above-mentioned oil, in the presence of a
thickener, which is preferably silicon dioxide or an aluminium
silicate in the case of oily-alcohol gels and is preferably a
polyacrylate in the case of aqueous-alcoholic or alcoholic
gels.
[0092] Anhydrous cosmetic and dermatological formulations, such as
ointments or skin oils, according to the invention are advantageous
and comprise, for example, the fats, oils, silicone oils, waxes and
other fatty substances mentioned.
[0093] Solid sticks according to the invention comprise, for
example, naturally occurring or synthetic waxes, fatty alcohols or
fatty acid esters. Lip care sticks are preferred.
[0094] Suitable propellants for cosmetic or dermatological
formulations according to the invention which can be sprayed from
aerosol containers are the customary known readily volatile,
liquefied propellants, for example hydrocarbons (propane, butane
and isobutane), which can be employed by themselves or as a mixture
with one another. Compressed air can also advantageously be used.
The expert of course knows that there are propellant gases which
are non-toxic per se and which would be suitable in principle for
the present invention, but which should nevertheless be omitted
because of an unacceptable action on the environment or other
concomitant circumstances, in particular fluorohydrocarbons and
fluorochlorohydrocarbons (CFCs).
[0095] The formulations according to the invention can furthermore
preferably comprise substances which absorb UV radiation in the UVB
range, the total amount of the filter substances being, for
example, 0.1% by weight to 30% by weight, preferably 0.5 to 10% by
weight, in particular 1 to 6% by weight, based on the total weight
of the formulation, in order to provide cosmetic formulations which
protect the skin from the entire range of ultraviolet radiation.
They can also be used as sunscreen agents.
[0096] The UVB filters can be oil-soluble or water-soluble.
Oil-soluble substances which may be mentioned are, for example:
[0097] 3-benzylidenecamphor derivatives, preferably
3-(4-methylbenzylidene) camphor and 3-benzylidenecamphor;
[0098] 4-aminobenzoic acid derivatives, preferably 2-ethylhexyl
4-(dimethylamino)benzoate and amyl 4-(dimethylamino)benzoate;
[0099] esters of cinnamic acid, preferably 2-ethylhexyl
4-methoxycinnamate and isopentyl 4-methoxycinnamate;
[0100] esters of salicylic acid, preferably 2-ethylhexyl
salicylate, 4-isopropylbenzyl salicylate and homomenthyl
salicylate;
[0101] derivatives of benzophenone, preferably
2-hydroxy-4-methoxybenzophe- none,
2-hydroxy-4-methoxy-4'-methylbenzophenone and
2,2'-dihydroxy-4-methoxybenzophenone;
[0102] esters of benzalmalonic acid, preferably di(2-ethylhexyl)
4-methoxybenzalmalonate; and
[0103]
2,4,6-trianilino-(p-carbo-2'-ethyl-l'-hexyloxy)-1,3,5-triazine.
[0104] Water-soluble substances which may be mentioned are, for
example:
[0105] salts of 2-phenylbenzimidazole-5-sulphonic acid, such as its
sodium, potassium or its triethanolammonium salt, and the sulphonic
acid itself;
[0106] sulphonic acid derivatives of benzophenones, preferably
2-hydroxy-4-methoxybenzophenone-5-sulphonic acid and its salts;
and
[0107] sulphonic acid derivatives of 3-benzylidenecamphor, such as,
for example, 4-(2-oxo-3-bornylidenemethyl)-benzenesulphonic acid,
2-methyl-5-(2-oxo-3-bornylidenemethyl) -benzenesulphonic acid and
its salts.
[0108] The list of UVB filters mentioned, which can be used in
combination with the active compounds according to the invention,
is not of course intended to be limiting.
[0109] The invention also relates to the combination of one or more
active compounds according to the invention with one or more UVB
filters, and cosmetic or dermatological formulations according to
the invention which also comprise one or more UVB filters.
[0110] It may also be advantageous to combine one or more active
compounds according to the invention with UVA filters which have
usually been contained to date in cosmetic and/or dermatological
formulations. These substances are preferably derivatives of
dibenzoylmethane, in particular 1- (4'-tert-butylphenyl) -3- (4,
-methoxyphenyl) propane-1,3-dione and
1-phenyl-3-(4'-isopropylphenyl) propane-1,3-dione. The invention
also relates to these combinations and formulations which comprise
these combinations. The amounts used for the UVB combination can be
employed.
[0111] Advantageous formulations are furthermore obtained if the
active compounds according to the invention are combined with UVA
and UVB filters.
[0112] Cosmetic formulations comprising active compounds according
to the invention can also comprise inorganic pigments which are
usually used in cosmetics for protecting the skin from UV rays.
These are oxides of titanium, zinc, iron, zirconium, silicon,
manganese, aluminium and cerium and mixtures thereof, as well as
modifications in which the oxides are the active agents. The
pigments are particularly preferably those based on titanium
dioxide.
[0113] The invention also relates to these combinations of UVA
filters and/or UVB filters and pigment and to formulations which
comprise this combination. The amounts mentioned for the above
combinations can be used.
[0114] Unless stated otherwise, all the amounts data, contents and
percentage contents are based on the weight and the total amount or
on the total weight of the formulations.
[0115] The following examples are intended to illustrate the
present invention, without limiting it.
[0116] Example 1
1 W/O cream % by weight Paraffin oil 10.00 Petrolatum 4.00 Wool wax
alcohol 1.00 PEG 7-hydrogenated castor oil 3.00 Aluminium stearate
0.40 Diosmin 0.50 Ferulic acid 0.50 Glycerol 2.00 Water,
preservative and perfume to 100.00
[0117] Example 2
2 W/O cream % by weight Paraffin oil 20.00 Petrolatum 4.00 Glucose
sesquiisostearate 2.00 Aluminium stearate 0.40
.alpha.-Glucosylrutin 1.00 Caffeic acid 0.50 Vitamin E acetate 1.00
Glycerol 5.00 Water, preservative and perfume to 100.00
[0118] Example 3
3 O/W lotion % by weight Paraffin oil 8.00 Isopropyl palmitate 3.00
Petrolatum 4.00 Cetearyl alcohol 2.00 PEG 40-castor oil 0.50 Sodium
cetearyl sulphate 0.50 Sodium carbomer 0.40 Ferulic acid 0.50
Phloridzin 0.20 Glycerol 3.00 .alpha.-Tocopherol 0.20 Octyl
methoxycinnamate 5.00 Butylmethoxydibenzoylmethane 1.00 Water,
preservative and perfume to 100.00
[0119] Example 4
4 O/W cream % by weight Paraffin oil 7.00 Avocado oil 4.00 Glyceryl
monostearate 2.00 Sodium stearate 1.00 Ferulic acid 0.50 Sophora
japonica extract 0.80 (Sophorine/Solabia) Sodium phytate 1.00
Titanium dioxide 1.00 Sodium lactate 3.00 Glycerol 3.00 Water,
preservative and perfume to 100.00
[0120] Example 5
5 Lip care stick % by weight Hydrogenated castor oil 4.00 Ceresin
8.00 Beeswax 4.00 Carnauba wax 2.00 Petrolatum 40.00
.alpha.-Glycosylrutin 0.10 .beta.-Carotene 0.10 Caffeic acid 0.30
Paraffin oil, pigments and dyestuffs to 100.00
[0121] Example 6
6 Lip care stick % by weight Isopropyl lanolate 10.00 Acetylated
lanolin 4.00 Beeswax, bleached 9.00 Carnauba wax 4.00 Petrolatum
40.00 Morin 0.10 Tocopheryl acetate 0.10 Ferulic acid 0.10 Paraffin
oil, pigments and dyestuffs to 100.00
[0122] Example 7
7 Liposome-containing gel % by weight Lecithin 6.00 Shea butter
3.00 Ferulic acid 0.50 Neohesperidin dihydrochalcone 0.10
Tocopherol 0.20 Biotin 0.08 Sodium citrate 0.50 Glycine 0.20 Urea
0.20 Sodium PCA 0.50 Hydrolysed collagen 2.00 Xanthan gum 1.40
Sorbitol 3.00 Water, preservative and perfume to 100.00
[0123] Example 8
8 Gel % by weight Carbopol 934 P 2.00 Triethanolamine 3.00 Ferulic
acid 0.50 Hesperitin 0.10 Tocopherol acetate 0.20 Polyoxyethylene
sorbitan fatty acid ester 0.50 (Tween 20) Glycerol 2.00 Sodium PCA
0.50 Hydrolysed collagen 2.00 Water, preservative and perfume to
100.00
[0124] Example 11
9 Sunscreen emulsion % by weight Cyclomethicone 2.00 Cetearyl
alcohol + 2.50 PEG 40-hydrogenated castor oil + Sodium cetearyl
sulphate Glyceryl lanolate 1.00 Caprylic acid/capric acid
triglyceride 0.10 Laurylmethicone copolyol 2.00 Octyl stearate 3.00
Castor oil 4.00 Glycerol 3.00 Acrylamide/sodium acrylate copolymer
0.30 Hydroxypropylmethylcellulose 0.30 Octyl methoxycinnamate 5.00
Butyl-methoxy-dibenzoylmethane 0.50 Sophora japonica extract 0.70
(Sophorine/Solabia) Tocopheryl acetate 1.00 Na.sub.3HEDTA 1.50
Perfume, preservative, dyestuffs as desired H.sub.2O, completely
desalinated to 100.00
[0125] Example 12
10 Sunscreen emulsion % by weight Cyclomethicone 2.00 Cetearyl
alcohol + 2.50 PEG 40-hydrogenated castor oil + Sodium cetearyl
sulphate Glyceryl lanolate 1.00 Caprylic acid/capric acid
triglyceride 0.10 Laurylmethicone copolyol 2.00 Octyl stearate 3.00
Castor oil 4.00 Glycerol 3.00 Acrylamide/sodium acrylate copolymer
0.30 Hydroxypropylmethylcellulose 0.30
[0126] Example 9
11 Sunscreen emulsion % by weight Cyclomethicone 2.00
Cetyldimethicone copolyol 0.20 PEG 22-dodecyl copolymer 3.00
Paraffin oil (DAB 9) 2.00 Caprylic acid/capric acid triglyceride
5.80 Octylmethoxycinnamate 5.80 Butyl-methoxy-dibenzoylmethane 4.00
Hesperidin 0.50 Tocopheryl acetate 0.50 ZnSO.sub.4 0.70
Na.sub.4EDTA 0.30 Perfume, preservative, dyestuffs as desired
H.sub.2O, completely desalinated to 100.00
[0127] Example 10
12 Sunscreen emulsion % by weight Cyclomethicone 2.00
Cetyldimethicone copolyol 0.20 PEG 22-dodecyl copolymer 3.00
Paraffin oil (DAB 9) 2.00 Caprylic acid/capric acid triglyceride
5.80 Octyl methoxycinnamate 5.80 Butyl-methoxy-dibenzoylmethane
4.00 Naringin 0.25 Ferulic acid 0.50 Tocopherol 0.50 ZnSO.sub.4
0.70 Na.sub.4EDTA 0.30 Perfume, preservative, dyestuffs as desired
H.sub.2O, completely desalinated to 100.00 Octyl methoxycinnamate
5.00 Butyl-methoxy-dibenzoylmethane 0.75 Extract of passion flower,
blackcurrant 2.50 and grape leaves (AE Complex/Solabia) Ferulic
acid 0.30 Na.sub.3HEDTA 1.50 Perfume, preservative, dyestuffs as
desired H.sub.2O, completely desalinated to 100.00
[0128] Example 13
13 Massage cream % by weight Stearyl alcohol 2.00 Petrolatum 4.00
Dimethicone 2.00 Isopropyl palmitate 6.00 Cetearyl alcohol 4.00 PEG
40-hydrogenated castor oil 2.00 Tocopherol 0.50 Scotch thistle
extract 0.30 (Pronalen Silymarin/Mani GmbH) Glycerol 3.00 Water,
preservative and perfume to 100.00
[0129] Example 14
14 Hair lotion % by weight Ethanol 40.00 Diisopropyl adipate 0.10
Perfume 0.10 PEG 40-hydrogenated castor oil 0.20 Naringenin 0.10
Tocopheryl acetate 0.10 Dyestuff, preservative as desired Water to
100.00
[0130] Example 15
15 Hair lotion % by weight Isopropyl alcohol 45.00 Cat's-foot
blossom extract (Helicrysum) 1.00 Propylene glycol 0.50 Perfume,
dyestuff, preservative as desired Water to 100
[0131] Example 16
16 Spray formulation % by weight Naringenin 0.10 Tocopherol 0.10
Ferulic acid 0.05 Ethanol 28.20 Perfume as desired Propane/butane
25/75 to 100
[0132] Evidence of the action:
[0133] The advantageous properties of the present invention are to
be illustrated below with the aid of an experiment.
[0134] The UVB mixed lymphocyte reaction method (UVB-MLR) was used
as the model for the immunosuppressing action of UVB radiation. The
UVB-MLR is a method of analyzing the effects of test substances on
UVB-induced suppression of a cellular immune response. It is a
modification of the MLR, an immunological in vitro standard method
which serves as a measure of the activation and functionalization
of the T-lymphocyte system.
[0135] For this purpose, the test substances were added to the cell
cultures in various concentrations. A Phillips TL 20W/12 lamp was
used as the source of irradiation.
[0136] 7.5 mJ UVB/cm.sup.2, 15 mJ UVB/cm.sup.2 and 30 mJ
UVB/cm.sup.2 were employed as the irradiation dose.
[0137] Mononuclear cells from the peripheral blood of two healthy
human donors are purifed by means of density gradient
centrifugation and cultured together in microtitre plates. The
individual culture here is composed of 3.0 x 105 stimulator cells
treated with mitocytin (donor A) and 2.5 x .sup.5 responder cells
(donor B) (incubation at 37.degree. C., 7.5% of CO.sub.2, 10% of
FCS (foetal calf serum) in RPMI 1640 medium).
[0138] In a "one way" MLR, the stimulator cells are arrested
physiologically by the treatment with mitocytin, so that only they
act as a cellular antigen for the responder cells, proliferation of
which is determined via the incorporation of .sup.3H-thymidine. The
responder cells are no longer recognized as an antigen by the
stimulator cells.
[0139] The incorporation of .sup.3H-thymidine is analyzed after
separation of all the cells, that is to say stimulator and
responder cells. The amount of .sup.3H-thymidine incorporated
correlates with the ability to give an immune response; the less
.sup.3H-thymidine incorporated, the greater the UVB
immunosuppression.
[0140] In order now to determine the influence of UV light on cell
proliferation (responder cells), the stimulator cells are
irradiated with the corresponding UVB dose before their incubation
with the responder cells. In corresponding parallel batches, the
corresponding test substance is present in the culture medium
during the irradiation.
[0141] Comparisons of the proliferation of the responder cells
which can be achieved in the absence and presence of test
substances after co-culture with the stimulator cells allow
conclusions to be drawn on immunoprotective properties of these
substances at the level of UVB-induced immunosuppression.
[0142] Agents according to the invention which were tested in the
experiment and are active against UVB immunosuppression:
[0143] Chrysin, naringen, hesperidin, naringenin, hesperitin,
morin, phloridzin, diosmin, neohesperidin dihydrochalcone, flavone,
glucosylrutin and cinnamic acid derivatives of the general formula
8
[0144] and/or active amounts of cinnamic acid derivatives of the
general formula 9
[0145] wherein the groups X, Y and R independently of one another
can be chosen from the group consisting of H and branched or
unbranched alkyl having 1-18 C atoms, were used as the test
substance.
[0146] Result:
[0147] A significant immunoprotective action was to be observed for
all the abovementioned agents according to the invention which were
tested and are active against UVB immunosuppression, and for all
the three UVB dose values.
[0148] Literature on the method used: Blain, B. et al. (1964),
Blood 23, p. 108 Meo, T. et al. (1975), Transplant. Proc. 7, p. 127
Mommaas, A.M. et al. (1990), J. Invest. Dermatol. 95, p. 313
Marinus, C.G. et al. (1991), J. Invest. Dermatol. 97, p. 629
* * * * *