Note: Descriptions are shown in the official language in which they were submitted.
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P A T E N T A N W A L T E Hans-~urgen Fell~e
Patent Attorney
FELKE & WALTER Wolf-Jiirgen Walter
Patent Attorney
EUROPEAN PATENT ATTORNEYS Am Stadtpar
D-1156 n
Telep : (00372)5590981
efax~ (00372)5592508
00765
Preparation for topical use
The invention relates to a cosmetic or
dermatological composition having light protection
properties in a special application form, in which
fluorocarbon-containing asymmetric lamellar phospholipid
aggregates function as carriers of melanin.
It is known that short-wave W light (UV/A, W/B;
UV/C, wavelength ranges from 400 to 200 nm) can have a
damaging effect on the skin and is a significant factor
for premature skin ageing. In extreme form, the action
can consist in a cytogenetic change in individual skin
cells and lead to the formation of skin carcinomas
(melanomas). These hazards have continuously increased
due to environmentally related factors (ozone hole) with
an increased W burden. In order to overcome this fact,
it is customary, by means of special cosmetics and
dermatological agents, to protect the exposed skin tissue
by the use of special W light protection filters. The
active compound of these compositions is based on the
following principles:
1. Absorption of W light by the use of W-active
organic compounds
2. Scattering of W light by finely dispersed tita
nium dioxide or other micropigments
The efficacy of these systems, which can be
detected simply by recording their W absorption maxima
in the wavelength range 250-400 nm or by scattering
curves, is evident. The problem, however, is the biologi-
cal acceptability of the substances, in particular the
possible chemical substance alterations under the
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influence of energy-rich radiation.
A further critical point is the depth of penetra-
tion of the W filter into the skin when it is used as a
constituent of a cosmetic or dermatological agent. The
suitable site of action is the region between the horny
layer and basal layer. In order to meet these demands,
testing for one year is necessary, as has been previously
prescribed for pharmacological active compounds. Accor-
ding to their intended use and their individual efficacy,
the W filters are applied topically in a suitable medium
in a wide concentration range between 1 and 10 %.
Thus, e.g., DE-A-3242385 (Zabotto) describes a
cosmetic composition which, in addition to other active
compounds, contains 1.5 % Parsol Ultra (Givaudan) for the
reduction of skin ageing due to the action of light.
Melanin, which also occurs in human and animal
cells, the melanocytes, is known as a natural light
protection active compound in higher organisms. Melanin
is a brown to black-coloured polymeric pigment of the
vertebrates, which is formed, inter alia, from the amino
acid tyrosine and pigments both skin, hair and iris. The
melanin formed in the melanocytes of the skin migrates
into the basal layer of the epidermis and there releases
the pigment into the epidermal cells. Since melanin, as
a polymeric substance, hardly dissolves, the previous
attempts to bring this substance to its site of action by
means of topical applications are to be regarded as not
thoroughly successful.
The invention has set the object of making
possible topical use of melanin at its site of action.
According to the invention, a preparation for
topical use having light protection properties is
characterised in that it contains melanin which is
dissolved or dispersed in one or more lipophilic fluoro-
carbons which are present as asymmetric lamellar
phospholipid aggregates in an aqueous system together
with a phospholipid, with a particle size of the aggre-
gates in the range from 200 to 3000 nm.
The naturally obtained (e. g. from Sepia
~.~ 389' 5
~- _
officinalis) or synthetically produced (oxidation of
tyrosine, e.g. with HzOz) melanin is present, dissolved or
suspended by the fluorocarbon, encapsulated in the core
of the asymmetric lamellar phospholipid aggregates. The
structural arrangement in the lamellar aggregates is
fundamentally different from that of aqueous liposomes
(vesicles). The hydrophobic nature of the fluorocarbon
calls for a reversal in the polarity of the phospholipid
molecule such that the lipophilic fatty acid radicals
interact with the fluorocarbon in the core of the aggre-
gate by dispersive forces. In this arrangement, further
phospholipid bilayer films are constructed to give asym-
metric lamellar globular aggregates according to spec-
ified conditions.
The novel asymmetric structure was confirmed by
Sip-NMR investigations and spectroscopic investigations.
The exceptional stability of the aggregates results from
their lamellar structure and from the corresponding
surface charge .
A plurality of fluorocarbons can be employed,
e.g. aliphatic straight-chain and branched fluoroalkanes,
mono- or bicyclic and optionally fluoroalkyl-substituted
fluorocycloalkanes, perfluorinated aliphatic or bicyclic
amines, bis(perfluoroalkyl)ethenes, perfluoropolyethers
and mixtures thereof. Particularly preferred fluoro-
carbons are those such as perfluorodecalin, F-butyltetra-
hydrofuran, perfluorotributylamine, perfluorooctyl
bromide, bis-fluoro(butyl)ethene or bis-fluoro(hexyl)-
ethene or C6-C9-perf luoroalkanes . The amount of f luoro-
carbons here is in the range from 20 to 100 o w/v,
preferably in the range from 40 to 100 a. A particularly
preferred range is that from 70 to 100 a w/v.
It was possible to determine the dependence of
the penetration rate and the depth of penetration on the
particle size of the aggregates experimentally by separ
ate investigations using labelled encapsulated fluoro-
carbons. According to these experiments, smaller par-
ticles migrate more rapidly and more deeply into the skin
tissue than larger particles. The choice of fluorocarbons
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or their mixtures according to their lipid solubility
(represented by their critical solubility temperature CST
in n-hexane) allows, as a further important criterion,
the regulation of the residence time in the tissue.
While, e.g. perfluorotributylamine (F-TBA, CST 59°C)~
having a high CST value and poor lipid solubility has a
relatively high residence time, in contrast to this
perfluorodecalin (PFD, CST 22°C) but also F-butyltetra-
hydrofuran, F-hexane and others are released
correspondingly more rapidly from the tissue. With the
aid of fluorocarbon mixtures, systems with desired CST
values, i.e. lipid and membrane solubilities, can be
prepared specifically with respect to the intended use.
The content of the fluorocarbons in the lamellar.
aggregates can vary between 1 and 100 ~S w/v according to
the intended use. Suitable fluorocarbons are in
particular:
aliphatic straight-chain and branched alkanes having 6 to
12 carbon atoms, e.g. perfluorohexane, perfluorooctane,
perfluorononane;
mono- or bicyclic cycloalkanes, which are optionally
F-alkyl-substituted, e.g. perfluoromethylcyclohexane,
perfluorodecalin;
aliphatic tertiary amines, N-containing polycycles, e.g.
perfluorotripopylamine [sic), perfluorotributylamine,
F-cyclohexylmethylmorpholine;
perfluoroethers, such as aliphatic ethers, F-alkylfurans,
bicyclic and substituted bicyclic ethers having two or
three oxygen atoms in the molecule, e.g. perfluorodihexyl
ether, perfluorobutyltetrahydrofuran, perfluoropoly-
ethers;
perfluoroalkyl halides, e.g. perfluorooctyl bromide,
perfluorohexyl bromide, perfluorooctyl chloride;
Bis-F(alkyl)ethenes, e.g. bis-F(butyl)ethene,
bis-F(hexyl)ethene.
The term "fluorocarbons" used here is understood
as meaning perfluorinated or highly fluorinated carbon
compounds or mixtures which are able to transport gases
such as OZ and CO2. Partially fluorinated hydrocarbon
~1~~9'~~
_ 5 _
compounds within the context of this invention are those
in which most of the hydrogen atoms are replaced by
fluorine atoms, e.g. the bis-F(alkyl)ethenes which, as
far as can be detected, are chemically and biologically
inert and thus non-toxic. This is usually achieved when
approximately up to 90 % of the hydrogen atoms are
replaced by fluorine atoms. Preferred fluorocarbons
within the context of the present invention are those in
which at least 95 % of the hydrogen atoms are replaced,
more preferably 98 % and most preferably 100 %.
Suitable phospholipids are naturally occurring
phospholipids such as Soya or egg lecithin, and also
lecithins (phospholipids) which can be prepared syntheti-
cally and which overall are known as being skin-com-
patible and good for the skin. Because of the
advantageous action on the stability of the asymmetric
lamellar aggregates, phospholipid mixtures having a
content from 10 to 99 %, preferably 30 to 99 %, in
particular 60 to 90 % of phosphatidylcholine in addition
to other naturally occurring accompanying products are
preferably used. The phospholipid content in the topical
formulation varies between 0.5 and 20 %, preferably 10 to
20 %.
The particle sizes of the aggregates, and the
phospholipids are selected such that a penetration into
deeper layers of the skin, e.g. into the epidermis or the
dermal region does not take place and the light protec
tion filter according to the invention thus reaches its
site of action after it has penetrated the horny layer.
The particle sizes are in the range from 200 to 3000 nm,
preferably in the range from 250 to 1000 nm.
The invention also relates to a process for the
production of preparations for topical use, which is
characterised in that melanin is dissolved or dispersed
in one or more fluorocarbons and this dispersion is
converted by homogenisation with a phospholipid in an
aqueous system into' asymmetric lamellar phospholipid
aggregates containing the fluorocarbons and melanin,
having particle sizes between 200 and 3000 nm.
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The solubility of the polymeric melanin can be
increased by addition of lipophilic substances to the
fluorocarbon as solubilisers. Suitable lipophilic sub-
stances are native oils, triglycerides or aliphatic
alkanes, selected from the group consisting of olive oil,
soya bean oil, sunflower oil, pentane, heptane, nonane,
decane or mixtures thereof.
The homogenisation can be effected by customary
processes, e.g. using a high-speed stirrer (12,000 to
15,000 rpm), by ultrasound or by means of pressure
homogenisation such that the particle size is ensured.
The invention will be illustrated in greater
detail below by means of examples. In the associated
drawings
Fig. 1 is a diagram of the critical solubility tempera-
tures (CST) of perfluorocarbon mixtures in n-hexane using
perfluorodecalin as a starting point
Fig. 2 is a diagram of the critical solubility tempera
tures of perfluorocarbon mixtures in n-hexane using
F-octylbromide as a starting point.
Some selected fluorocarbons and their OZ solubi-
lity, their vapour pressure and their critical solubility
temperature are shown in Table 1. Starting from these
values, the desired characteristics for the penetration
of the skin with the aid of the composition according to
the invention can be selected for mixtures of fluoro-
carbons.
Table 1
Fluorocarbon Oz solubility Vapour CST
[m] [sic] of Pressure
Oz~100 ml of Fc] P37e~
[mm Hg]
Perfluorooctyl
bromide 50 14 -24.5
Perfluorodecalin 40 12.5 22
bis-F(butyl)ethene ~ 50 12.6 22.5
F-cyclohexylmethyl-
morpholine 42 4 38.5
F-tripropylamine 45 18.5 43
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F-dihexyl ether 45 2 59
F-tributylamine 40 1 59
Perfluorodecalin-F-
tributylamine 1:1 40 7 42
Perfluorobutyl-
tetrahydrofuran 52 51 29
F-methylcyclohexane 57 180 8.2
F-hexane 58 414 20
Example 1
A 10 % strength aqueous phospholipid solution of
soya lecithin and containing 40 a phosphatidylcholine was
mixed with cooling in an ultrasonic disintegrator with a
fluorocarbon mixture composed of perfluorodecalin (90 %)
and F-dibutylmethylamine (10 %) and melanin. The asym-
metric lamellar phospholipid aggregates obtained in this
process had a mean particle size of approximately 240 nm
and contained the melanin.
The aggregates prepared in this manner were incorporated
into the following processing forms of light protection
agents according to customary processes.
Example 2 Emulsion (body lotion)
Polyacrylic acid 0.30
TEA 0.30 %
p-Methylhydroxybenzoate 0.20
p-Propylhydroxybenzoate 0.10 %
Imidazolidinylurea 0.20 %
Na EDTA 0.06 %
Cetyl/stearyl alcohol, 1.00 %
Stearic acid 1.00 %
Isopropyl myristate/palmitate 3.00
Liquid paraffin 4.00 %
Jojoba oil 2.00 %
Melanin/phospholipid aggregates 10.00
Perfume oil 1.00
Demineralised water q~s~
_ g _
Example 6 sic] Emulsion (cream)
Polyacrylic acid 0.30
Propylene glycol 5.00
TEA 0.30
Emulsifier 1 6.00 %
Emulsifier 2 4.50 %
Aloe vera 2.00
Rice husk oil 1.50 %
Cetyl/stearyl alcohol 1.00
Jojoba oil 1.50 %
p-Methylhydroxybenzoate 0.20
p-Propylhydroxybenzoate 0.10 %
Imidazolidinylurea 0.20 %
Melanin/phospholipid aggregates 20.00
Perfume oil 1.00
Demineralised water q.s.
ExamQle 4 Lotion
Emulsifier system
consisting of water, 34.00
stabilisers, polyglycerol esters,
polyoxyethylene esters, isopropyl
palmitate
Glycerol 5.00
2 MgS04 . 7H20 0 . 5 0
5
Melanin/phospholipid aggregates 6.00 %
p-Methylhydroxybenzoate 0.20 %
p-Propylhydroxybenzoate 0.10
Imidazolidinylurea 0.30
Perfume oil 1.00
Demineralised water q~s~
Example 5 Eyeshadow compressed with licrht
protection
factor
Talc 40.00
Mg carbonate , 1.50 %
Mg stearate 2.50 %
Kaolin 2.20
Colorants 15.80 %
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Pearl lustre pigments 21.50 a
Perfume oil 1.50
Silk protein 5.00
Emulsion as processing means
Emulsifier 4.50
Silicone oil, volatile 2.50 0
Melanin/phospholipid aggregates 4.50 0
Preservative 0.30
Demineralised water q.s.
