U.S. patent application number 12/355367 was filed with the patent office on 2009-05-21 for use of flavonoids as immunomodulating or immuno-protective agents in cosmetic and dermatological preparations.
This patent application is currently assigned to Beiersdorf AG. Invention is credited to Ghita LANZENDORFER, Franz Stab, Sven Untiedt.
Application Number | 20090131340 12/355367 |
Document ID | / |
Family ID | 6535603 |
Filed Date | 2009-05-21 |
United States Patent
Application |
20090131340 |
Kind Code |
A1 |
LANZENDORFER; Ghita ; et
al. |
May 21, 2009 |
USE OF FLAVONOIDS AS IMMUNOMODULATING OR IMMUNO-PROTECTIVE AGENTS
IN COSMETIC AND DERMATOLOGICAL PREPARATIONS
Abstract
A method of treating or prophylactically treating
immunosuppression or allergic and inflammatory symptoms of skin
caused by UVB radiation which comprises applying to the skin a
cosmetic or dermatological composition which comprises one or more
flavonoids.
Inventors: |
LANZENDORFER; Ghita;
(Hamburg, DE) ; Stab; Franz; (Echem, DE) ;
Untiedt; Sven; (Hamburg, DE) |
Correspondence
Address: |
GREENBLUM & BERNSTEIN, P.L.C.
1950 ROLAND CLARKE PLACE
RESTON
VA
20191
US
|
Assignee: |
Beiersdorf AG
Hamburg
DE
|
Family ID: |
6535603 |
Appl. No.: |
12/355367 |
Filed: |
January 16, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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08849525 |
Aug 29, 1997 |
|
|
|
PCT/EP95/04908 |
Dec 12, 1995 |
|
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12355367 |
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Current U.S.
Class: |
514/27 ; 514/456;
514/458; 514/570; 514/685 |
Current CPC
Class: |
A61K 8/365 20130101;
A61P 43/00 20180101; A61K 2800/522 20130101; Y10T 428/193 20150115;
Y10S 514/859 20130101; Y10S 514/86 20130101; A61K 8/37 20130101;
A61K 45/06 20130101; A61P 29/00 20180101; A61P 37/08 20180101; A61K
8/36 20130101; A61K 8/361 20130101; A61K 31/19 20130101; A61Q 17/04
20130101; Y10S 514/858 20130101; Y10S 514/861 20130101; A61K 8/9789
20170801; A61Q 19/08 20130101; Y10S 514/864 20130101; A61Q 19/001
20130101; A61Q 19/00 20130101; A61K 31/192 20130101; A61K 8/602
20130101; A61Q 5/00 20130101; Y10S 514/863 20130101; A61K 8/498
20130101; A61P 17/00 20180101; A61K 31/70 20130101; Y10T 428/195
20150115; A61P 37/04 20180101; 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: |
514/27 ; 514/685;
514/570; 514/458; 514/456 |
International
Class: |
A61K 31/352 20060101
A61K031/352; A61K 31/12 20060101 A61K031/12; A61K 31/192 20060101
A61K031/192; A61K 8/49 20060101 A61K008/49; A61P 37/08 20060101
A61P037/08; A61P 29/00 20060101 A61P029/00; A61K 31/355 20060101
A61K031/355; A61K 31/7048 20060101 A61K031/7048 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 13, 1994 |
DE |
P 44 44 238.6 |
Claims
1. A method of treating or prophylactically treating
immunosuppression of skin cells induced by UVB radiation, wherein
the method comprises topically applying to skin of a person in need
thereof an effective amount therefor of a cosmetic or
dermatological composition comprising one or more compounds
selected from chalcones and glycosides thereof.
2. The method of claim 1, wherein immunosuppression is treated.
3. The method of claim 1, wherein the composition further comprises
one or more cinnamic acid derivatives.
4. The method of claim 1, wherein the composition further comprises
one or more antioxidants.
5. The method of claim 4, wherein the one or more antioxidants
comprise at least one of tocopherol and a derivative thereof.
6. The method of claim 1, wherein the composition further comprises
one or more of alpha-glucosylrutin, alpha-glucosylmyricitrin,
alpha-glucosylquercitrinin, alpha-glucosylquercitrin, rutin,
chrysin, kaempferol, myricetin, rhamnetin, apigenin, luteolin,
naringin, hesperidin, naringenin, hesperitin, morin, phloridzin,
diosmin, fisetin, vitexin, neohesperidin, flavone and
genistein.
7. The method of claim 1, wherein the composition comprises from
0.01% to 10% by weight of the one or more compounds, based on a
total weight of the composition.
8. The method of claim 7, wherein the composition comprises from
0.1% to 6% by weight of the one or more compounds.
9. The method of claim 1, wherein the cosmetic or dermatological
composition comprises an emulsion.
10. The method of claim 1, wherein the cosmetic or dermatological
composition comprises a gel.
11. A method for treating or prophylactically treating one or more
of allergic and inflammatory symptoms of skin caused by UVB
radiation, wherein the method comprises topically applying to the
skin a cosmetic or dermatological composition comprising one or
more compounds selected from alpha-glucosylrutin,
alpha-glucosylmyricitrin, alpha-glucosylquercitrinin,
alpha-glucosylquercitrin, quercetin, rutin, chrysin, kaempferol,
myricetin, rhamnetin, apigenin, luteolin, naringin, hesperidin,
naringenin, hesperitin, morin, phloridzin, diosmin, fisetin,
vitexin, neohesperidin, dihydrochalcone, flavone, genistein, and
chalcones and glycosides thereof.
12. The method of claim 11, wherein allergic symptoms are treated
or prophylactically treated.
13. The method of claim 11, wherein allergic symptoms are treated
or prophylactically treated.
14. The method of claim 11, wherein the composition further
comprises one or more antioxidants.
15. The method of claim 14, wherein the one or more antioxidants
comprise at least one of tocopherol and a derivative thereof.
16. The method of claim 11, wherein the composition comprises from
0.01% to 10% by weight of the one or more compounds, based on a
total weight of the composition.
17. The method of claim 16, wherein the composition comprises from
0.1% to 6% by weight of the one or more compounds.
18. The method of claim 11, wherein the cosmetic or dermatological
composition comprises an emulsion.
19. The method of claim 11, wherein the cosmetic or dermatological
composition comprises a gel.
20. The method of claim 11, wherein the one or more compounds
comprise alpha-glucosylrutin.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 08/849,525, the entire disclosure of which is
expressly incorporated by reference herein, which is a National
Stage of International Application PCT/EP95/04908, filed Dec. 12,
1995, which claims priority of German Patent Application No. 44 44
238.6, filed Dec. 13, 1994.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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.
[0004] 2. Discussion of Background Information
[0005] 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.
[0006] 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.
[0007] 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 phototoxic and photoallergic reactions. The damaging
influence of UVB radiation may be intensified by UVA radiation.
[0008] 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.
[0009] 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.
[0010] 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 defense 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
UVB. 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
defense and therefore their own destruction.
[0011] 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 defense of the skin. Effective defense reactions
against infectious organisms, such as, for example, Candida
albicans or herpes simplex virus, are furthermore absent.
[0012] 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
cell-cell contacts between epidermal keratinocytes and leukocytes,
such as, for example, T-lymphocytes and monocytes, are
regulated.
[0013] UVB-induced immunosuppression thus concerns a broad spectrum
of immunological dysfunctions which result in a reduction in the
defense reactions which normally proceed.
[0014] It is indeed customary to use absorbing agents, that is to
say the customary light protection substances, against the direct
action of ultraviolet radiation.
[0015] Derivatives of dibenzoylmethane, for example, are chiefly
used for protection against rays in the UVA range.
[0016] 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.
[0017] 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. 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
short-lived 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.
[0018] 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.
[0019] 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.
[0020] 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 [0021] a more effective prophylaxis against UVB
immuno-suppression can be achieved and [0022] the immune system
already damaged by UVB immuno-suppression can be strengthened
again.
[0023] The active compounds and formulations according to the
invention act in this way.
[0024] 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 immuno-suppression induced by UVB
radiation would achieve these objects.
[0025] 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.
[0026] 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 .alpha.-glucosylrutin, .alpha.-glucosylmyrictrin,
.alpha.-glucosylisoquercitrin and .alpha.-glucosylquercitrin.
Japanese Laid-Open Specification Hei-04-363,395 describes a process
for preventing decomposition of perfume constituents which is
distinguished, inter alia, by an addition of .alpha.-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 U.S. Pat.
Nos. 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.
[0027] However, no indication which could lead in the direction of
the present invention is to be found in these specifications.
[0028] The above objects are achieved according to the
invention.
[0029] 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.
[0030] Active compound combinations b), their use and formulations
which comprise these are preferred.
[0031] 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.
[0032] 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.
[0033] Topical formulations are preferred.
[0034] 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.
[0035] 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).
[0036] According to the invention, the flavonoids A) are preferably
chosen from the group consisting of substances of the generic
structural formulae
##STR00001##
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.
[0037] Further flavonoids according to the invention are
advantageously chosen from the group consisting of substances of
the following formulae:
##STR00002##
wherein Z.sub.1-Z.sub.5 have the abovementioned meanings and
Gly.sub.1, Gly.sub.2 and Gly.sub.3 are monoglycoside radicals.
[0038] Preferably, Gly.sub.1, Gly.sub.2 and Gly.sub.3 independently
of one another are chosen from the group consisting of hexosyl
radicals, in particular the rhamnosyl radicals and glucosyl
radicals. However, other hexosyl 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.
[0039] It is particularly advantageous in the context of the
present invention to choose the flavone glycoside or glycosides
from the group consisting of alpha-glucosylrutin,
alpha-glucosylmyrictrin, alpha-glucosylisoquercitrin and
alpha-glucosylquercitrin.
[0040] Compounds such as alpha-glycosylrutin,
alpha-glycosylhesperidin, alpha-glycosylnaringin,
alpha-mannosylrutin and alpha-rhamnosylrutin are furthermore
particularly preferred according to the invention.
[0041] It may also be advantageous to omit the above-mentioned
glycosidic radicals Gly.sub.1-3 and to use the unsubstituted
flavonoids (Gly.sub.1-3.dbd.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.
[0042] 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.
[0043] 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.
[0044] 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
##STR00003##
[0045] 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.
[0046] 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).
[0047] 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.
[0048] Cinnamic acid derivatives of the general formula
##STR00004##
and/or active amounts of cinnamic acid derivatives of the general
formula
##STR00005##
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.
[0049] The acids or salts thereof can be used, preferably the
physiologically tolerated salts, for example water-soluble salts
(sodium or potassium salts).
[0050] 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
##STR00006##
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.
[0051] 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.
[0052] Another derivative of cinnamic acid which is preferred
according to the invention is caffeic acid, which is distinguished
by the structure
##STR00007##
It is a widespread plant acid and is contained, for example, in
coffee, tobacco, poppy and dandelion.
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] Formulations with combinations b) which comprise
alpha-glucosylrutin and/or ferulic acid are particularly
preferred.
[0059] 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.
[0060] 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).
[0061] 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-ol). 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.
[0062] The tocopherol derivatives which are preferred according to
the invention are .alpha.-tocopherol and its esters, in particular
.alpha.-tocopheryl acetate. Esters of acids having 2-18, in
particular 2-8 C atoms are preferred.
[0063] 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.
[0064] 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), .alpha.-hydroxy-acids (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
.gamma.-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, trihydroxy-butyrophenone,
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
trans-stilbene 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).
[0065] 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.
[0066] 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.
[0067] 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).
[0068] 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.
[0069] 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).
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] If the cosmetic or dermatological formulation is a solution
or lotion, solvents which can be used are: [0078] water or aqueous
solutions; [0079] oils, such as triglycerides of capric or of
caprylic acid, or liquid triglycerides of natural origin [0080]
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 [0081] silicone oils, such as dimethylpolysiloxanes,
diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof
[0082] 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.
[0083] Mixtures of the abovementioned solvents are used in
particular. In the case of alcoholic solvents, water can be a
further constituent.
[0084] 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.
[0085] 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
poly-acrylate in the case of aqueous-alcoholic or alcoholic
gels.
[0086] 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 sub-stances mentioned.
[0087] 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.
[0088] 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).
[0089] 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.
[0090] The UVB filters can be oil-soluble or water-soluble.
Oil-soluble substances which may be mentioned are, for example:
[0091] 3-benzylidenecamphor derivatives, preferably
3-(4-methylbenzylidene)camphor and 3-benzylidenecamphor; [0092]
4-aminobenzoic acid derivatives, preferably 2-ethylhexyl
4-(dimethylamino)benzoate and amyl 4-(dimethylamino)benzoate;
[0093] esters of cinnamic acid, preferably 2-ethylhexyl
4-methoxycinnamate and isopentyl 4-methoxycinnamate; [0094] esters
of salicylic acid, preferably 2-ethylhexyl salicylate,
4-isopropylbenzyl salicylate and homomethyl salicylate; [0095]
derivatives of benzophenone, preferably
2-hydroxy-4-methoxybenzophenone,
2-hydroxy-4-methoxy-4'-methylbenzophenone and
2,2'-dihydroxy-4-methoxybenzophenone; [0096] esters of
benzalmalonic acid, preferably di(2-ethylhexyl)
4-methoxybenzalmalonate; and [0097]
2,4,6-trianilino-(p-carbo-2'-ethyl-1'-hexyloxy)-1,3,5-triazine.
[0098] Water-soluble substances which may be mentioned are, for
example: [0099] salts of 2-phenylbenzimidazole-5-sulphonic acid,
such as its sodium, potassium or its triethanolammonium salt, and
the sulphonic acid itself; [0100] sulphonic acid derivatives of
benzophenones, preferably
2-hydroxy-4-methoxybenzophenone-5-sulphonic acid and its salts; and
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] Advantageous formulations are furthermore obtained if the
active compounds according to the invention are combined with UVA
and UVB filters.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] The following examples are intended to illustrate the
present invention, without limiting it.
EXAMPLE 1
TABLE-US-00001 [0110] 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
EXAMPLE 2
TABLE-US-00002 [0111] 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
EXAMPLE 3
TABLE-US-00003 [0112] 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
EXAMPLE 4
TABLE-US-00004 [0113] 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
EXAMPLE 5
TABLE-US-00005 [0114] 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
EXAMPLE 6
TABLE-US-00006 [0115] 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
EXAMPLE 7
TABLE-US-00007 [0116] 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
EXAMPLE 8
TABLE-US-00008 [0117] 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
EXAMPLE 9
TABLE-US-00009 [0118] 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
EXAMPLE 10
TABLE-US-00010 [0119] 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
EXAMPLE 11
TABLE-US-00011 [0120] 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
EXAMPLE 12
TABLE-US-00012 [0121] 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 0.75 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
EXAMPLE 13
TABLE-US-00013 [0122] 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
EXAMPLE 14
TABLE-US-00014 [0123] 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
EXAMPLE 15
TABLE-US-00015 [0124] 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
EXAMPLE 16
TABLE-US-00016 [0125] 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
Evidence of the Action:
[0126] The advantageous properties of the present invention are to
be illustrated below with the aid of an experiment.
[0127] 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.
[0128] For this purpose, the test substances were added to the cell
cultures in various concentrations. A Phillips TL 20 W/12 lamp was
used as the source of irradiation.
[0129] 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.
[0130] 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.times.10.sup.5
stimulator cells treated with mitocytin (donor A) and
2.5.times.10.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).
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
Agents According to the Invention which were Tested in the
Experiment and are Active Against UVB Immunosuppression:
[0135] Chrysin, naringen, hesperidin, naringenin, hesperitin,
morin, phloridzin, diosmin, neohesperidin dihydrochalcone, flavone,
glucosylrutin and cinnamic acid derivatives of the general
formula
##STR00008##
and/or active amounts of cinnamic acid derivatives of the general
formula
##STR00009##
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.
Result:
[0136] 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.
LITERATURE ON THE METHOD USED
[0137] Blain, B. et al. (1964), Blood 23, p. 108 [0138] Meo, T. et
al. (1975), Transplant. Proc. 7, p. 127 [0139] Mommaas, A. M. et
al. (1990), J. Invest. Dermatol. 95, p. 313 [0140] Marinus, C. G.
et al. (1991), J. Invest. Dermatol. 97, p. 629
* * * * *