Note: Descriptions are shown in the official language in which they were submitted.
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G o 1 d s c h m i d t AG, Essen
Use of 1,1-dioxoperhydro-1,2,4-thiadiazines
The invention relates to the use of 1,1-dioxoperhydro-
1,2,4-thiadiazines for the preparation of cosmetic or
pharmaceutical preparations which are effective against
bad skin and forms of acne.
Bad skin is essentially caused by increased activity of the
sebaceous glands and increased secretion of sebum
associated therewith. Acne is a skin disease characterized
by noninflamed and inflamed papules which can lead to the
formation of pustules, abscesses and scars. Causes are the
keratinization and blocking of hair follicles (formation of
comedones), increased sebum production and the production
of tissue-damaging enzymes by bacteria (Propionibacterium
acnes). Antibiotics, keratolytics and peroxides are used as
therapy.
Thus, for example, EP 0 536 360 A describes the topical
treatment of acne using the aminopenicillin and
cephalosporin classes of antibiotics. However, antibiotics
have the disadvantage that the controlled microorganisms,
for example bacteria, can become resistant thereto.
EP 0 639 068 A describes the treatment of acne using the
keratolytics salicylic acid and pantothenic acid.
Keratolytics soften or loosen keratinized layers of skin,
but have no effect on microorganisms which cause
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inflanunation. US 5 767 098 A describes the treatment of
acne by the topical application of a combination of an
antibiotic and a peroxide. However, substances such as
benzoyl peroxide are free-radical formers, which cause
oxidative stress of the skin and can therefore lead to
long-term damage. Although substances such as benzoyl
peroxide or retinoic acid are effective in reducing
pimples, they also cause irritations, sensitizations and
allergies, which manifest themselves as stinging, itching,
burning, flaking or reddening of the skin.
Taurolidine is a 1,1-dioxoperhydro-1,2,4-thiadiazine
derivative and a substance known for over 30 years (see
CH 482 713 A) and characterized by the general formula (I)
R'
I
~Nw
~2
~N
R
where, in the case of taurolidine ( I' ) , R1 - H and RZ is a
radical of the general formula (II)
R'
I
~N~
Ny H2
(II)
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It has hitherto been used exclusively in human medicine.
Thus, for example, EP 0 253 662 A describes the use of
taurolidine in the form of an aqueous solution for
parenteral administration during surgical interventions
against infections by bacteria or bacterial toxins.
WO 92/00743 describes a method for the treatment or
prophylaxis of tumors by administering an effective dose of
taurolidine and/or taunaltam. DE 35 33 612 A describes the
use of taurolidine as an anticoagulant. WO 94/03174
describes a dental composition comprising taurolidine for
the treatment of, for example, parodontitis.
The mode of action of taurolidine is presumably based on
the transfer of methylol groups to the hydroxyl or amino
groups positioned on toxins or on the murein of bacteria
cell walls. In solution, taurolidine (I') where R1 - H and
R2 - radical having the formula (II) is in equilibrium with
taurultam (I' ' ) where R1 and RZ - H and N-methyloltaurultam
(I' ' ' ) where Rl - H and R2 - -CH2-OH. With the transference
of the methylol groups to toxins or bacteria,
methyloltaurultam ( I " ' ) is converted into taurultam ( I " ) ,
which is in turn in equilibrium with methyloltaurinamide
(III)
R3H N-C H2-C H2-S 02- R°
(III)
where R3 - -CH20H and R4 - -NH2. The transference of methylol
groups results in the conversion of methyloltaurinamide to
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taurinamide (III') where R3 - H and R4 - -NH2. Taurinamide
(III') is transformed physiologically into taurine (III ")
where R3 - H and R4 - OH, a naturally occurring
aminosulfonic acid which is tolerated exceedingly well by
the body.
It is known from the literature that 1,1-dioxo-
perhydro-1,2,4-thiadiazines, in particular taurolidine
and the abovementioned metabolites, are effective
against various bacteria and fungi. For example,
Arzneim.-Forschung, 42 (II), 1992, 1157 - 1159
describes the in-vitro activity of taurolidine against
oral-pathogenic microorganisms. The investigation also
considers the anaerobic Propionibacterium acnes which,
apart from being found in inflamed areas in the gum, is
also found in inflammation foci in acne patients.
However, the appearance of Propionibacterium acnes in
acne patients and the inflammation caused as a result
are a consequence of acne, not a cause. On the
contrary, Propionibacterium acnes can also be found in
subjects not suffering from acne. The literature
reveals nothing about the use of taurolidine for
topical application to the skin for the purpose of
treating bad skin and acne.
The object of the present invention is therefore to provide
an active ingredient which counteracts the causes of bad
skin and acne, namely hyperkeratosis, excessive sebum
production and bacterial infection, but which does not have
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negative effects on the skin, such as, for example, skin
irritations, skin flaking or resistance by bacteria.
Surprisingly, we have now found that 1,1-dioxoperhydro-
1,2,4-thiadiazines of the general formula (I),
R'
I
~N~
02
~N
R
(i)
in particular taurolidine (I') where R1 - H and R2 - radical
having the formula (II)
R'
I
~N~
Ny H2
(II)
or taurultam ( I " ) where Rl and R'' - H are extremely
effective against bad skin and forms of acne, but, being
chemotherapeutics, do not have the disadvantaaes of
antibiotics, for example the development of resistances,
and, in addition, do not trigger irritations of any kind
upon topical application to the skin. The high
effectiveness against bad skin and acne which has been
found cannot be explained by the in-vitro activity of
taurolidine against Propionibacterium acnes alone, and was
therefore not to be expected.
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In a first embodiment, the invention provides for the use
of 1,1-dioxoperhydro-1,2,4-thiadiazines of the general
formula (I),
R'
I
~N~
~2
RAN
(I)
in which R1 and R2, which are identical or different, are
hydrogen atoms, alkyl radicals having 1 to 18 carbon atoms,
cycloalkyl radicals, aralkyl radicals or aromatic or
heterocyclic radicals each having 3 to 20 carbon atoms,
where the radicals R1 and Rz are optionally substituted, for
the preparation of cosmetic or pharmaceutical preparations
for the treatment of bad skin and acne. Corresponding
compounds, in particular compounds having substituted
radicals, are known from CH 48 27 13 A, to the entire
contents of which reference is made.
The invention further provides for the use of 1,1-dioxo-
perhydro-1,2,4-thiadiazines (I) in cosmetic or
pharmaceutical preparations for the treatment of bad skin
and acne, wherein, in the 1,1-dioxoperhydro-1,2,4-
thiadiazine (I), R1 and R2 are hydrogen atoms (taurultam
I "), or R1 is a hydrogen atom and R2 corresponds to a
radical of the formula (II) (taurolidine I').
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The concentration of 1,1-dioxoperhydro-1,2,4-thiadiazine
(I) including metabolites in the cosmetic or pharmaceutical
preparations is preferably 0.005 to 10.00 by weight,
preferably 0.01 - 5.0~ by weight, in each case based on the
total weight of the preparations.
According to an advantageous embodiment of the present
invention, 1,1-dioxoperhydro-1,2,4-thiadiazines (I) are
used with other agents effective against bad skin and acne
in cosmetic or pharmaceutical preparations. Particularly
suitable is a combination of 1,1-dioxoperhydro-1,2,4
thiadiazine (I) with a keratolytic, in particular salicylic
acid, lactic acid, glycolic acid, citric acid or malic
acid.
The preparations can be used in the form of liquid
compositions which can be applied using brushes or strips,
or by means of roll-on devices, as sticks and in the form
of W/O or O/W emulsions which can be applied from customary
bottles and containers, for example creams or lotions.
Furthermore, the preparations can advantageously be in the
form of face washes, tinctures or cleansing formulations.
Apart from water, customary carriers for the preparation of
the preparations which may be used are ethanol and
isopropanol, glycerol, propylene glycol, polyglycerol and
polyethylene glycol, fats or fat-like substances which are
beneficial to the skin, such as cetyl alcohol, cetearyl
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octanoate, decyl oleate and octyldodecanol, in the
quantitative ratios customary for such preparations, and
also thickeners, for example hydroxyethylcellulose or
hydroxypropylcellulose, salts of polyacrylic acid, poly-
vinylpyrrolidone, as well as, also in small amounts, cyclic
and chain-like silicone oils and organically modified
silicones.
Emulsifiers which have proven suitable for the preparation
of the preparations, which are advantageously to be applied
as liquid preparations to the desired areas of skin, and
which can be used in the preparations in a small amount,
for example 1 to 5~ by weight, based on the total
composition, are nonionogenic types, such as
polyoxyethylene fatty alcohol ethers, for example
cetostearyl alcohol polyethylene glycol ethers having 10,
or 25 added ethylene oxide units per molecule,
cetostearyl alcohol and sorbitan esters and sorbitan ester
ethylene oxide compounds (for example sorbitan monostearate
20 and polyoxyethylene sorbitan monostearate), glycerol and
polyglycerol esters, for example polyglycerol isostearate,
sugar esters, for example methylglucose dioleate or
cetearyl glucoside, polysiloxane-polyoxyethylene/oxy
propylene and polysiloxane-polyoxyethylene/oxypropylene
polycetyl copolymers.
In addition to said constituents, the preparations
according to the invention, the pH of which is preferably
adjusted to 3.5 to 9.0, in particular 4.0 to 6.5 for
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example using customary buffer mixtures, can be admixed
with perfume, dyes, antioxidants (for example a-tocopherol
and its derivatives or butylhydroxytoluene (BHT), 2,6-di-
tert-butyl-4-methylphenol) in amounts of from 0.01 to
0.03, based on the total composition), dispersion
auxiliaries, buffer mixtures or other customary cosmetic
raw materials.
The amounts of carriers to be used in each case can be
readily determined by the person skilled in the art by
simple exploratory experiments, depending on the type of
product in question.
The preparations according to the invention, apart from
specific preparations which are in each case noted
separately in the examples, are prepared in the customary
manner, in most cases by simply mixing with stirring, if
necessary with slight warming. For emulsions, the fatty
phase and the aqueous phase are, for example, prepared
separately, if necessary with warming, and are then
emulsified. Otherwise, the customary guidelines for
preparing pharmaceutical formulations are to be observed,
with which the person skilled in the art is familiar.
Advantageous working examples of the present invention are
given below.
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Examples:
Example 1:
Gel
~ by weight
Taurolidine 2.0
Hydroxyethylcellulose 2.0
Water 96.0
Taurolidine was dissolved in water, and the
hydroxyethylcellulose was incorporated. The resulting gel
was packed in aluminum tubes.
Example 2:
Wax stick
~ by weight
Hydrogenated castor oil 5.0
Beeswax 6.0
Hard paraffin
30.0
C12 to C15 alkyl benzoate 17.0
Taurolidine 0,9
Octyldodecanol 41.1
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The constituents were melted at about 75°C, mixed well and
poured into suitable molds.
Example 3:
Face wash
~ by weight
,_
Ethanol g,p
Taurolidine 2.0
Water 90.0
Example 4:
0/W Face cream
~ by weight
A Polyglyceryl-3 methylglucose3.0
distearate
Glyceryl stearate 2.g
Stearyl alcohol 1.2
Isocetyl palmitate
6.0
Ethylhexyl palmitate 6.0
Isopropyl palmitate 6.0
B Glycerol 3.0
Water 70.0
Taurolidine 2.0
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Phase A and phase B were heated separately to 70°C. Phase A
was added with stirring to phase B and then homogenized.
The mixture was cooled with gentle stirring.
Example 5:
W/O cream
~ by weight
A Cetyldimethicone copolyol 2.0
Polyglyceryl-4 isostearate 1.0
Mineral oil 12.0
Ethylhexyl stearate 5.0
Hydrogenated castor oil 0.8
Microcrystalline wax 1.2
B Sodium chloride 1.0
Taurolidine 1.5
Water 75,5
Phase A was heated to about 80°C, phase B was slowly
stirred in and then briefly homogenized. The mixture was
cooled to below 30°C with gentle stirring and homogenized
again.
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Example 6:
W/O/W Emulsion
_ ~ by weight
O Cetyldimethicone copolyol 2.0
Capryl/capric triglycerides 16.0
Salicylic acid 2.0
W1 Glycerol 1.0
Magnesium sulfate heptahydrate0.15
Taurolidine 1.0
Water 27.85
W2 Water 39.0
Propylene glycol 2.0
Caprylyl/capryl glucosides, 8.0
10~
Sodium hydroxide, 10~ q.s_
D Xanthan gum 0.1
Acrylate/C10-30 alkyl acrylate0.2
crosspolymer
Mineral oil 0,7
Phase W1 was added to phase O with stirring and then
homogenized. The components of phase W2 were mixed. A
dispersion was prepared from the components of phase D,
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added to W2 and briefly homogenized. The Wl/0 emulsion was
added to W2 in portions with stirring.
The surprisingly high effectiveness of 1,1-dioxoperhydro-
1,2,4-thiadiazines, in particular taurolidine, in the
treatment of bad skin and acne is demonstrated by way of
example by the following case descriptions.
Case 1:
Case 1 is an 18-year old girl with Acne simplex. For two
years she has been treated with customary substances
(benzoyl peroxide, aluminum oxide as peeling therapy), but
without success. She applied the gel from Example 1 twice
daily over a period of 3 months. After just two weeks a
positive development was found, evident from a reduction in
inflamed areas and infected pustules. After 3 months the
condition had fundamentally improved. No further treatment
with the taurolidine gel was necessary. No skin irritations
were observed throughout the entire treatment period.
Case 2:
Case 2 is a 34-year old man with severe acne and comedones
on the back. He was treated with the gel from Example 1 for
8 days. After just one day it was possible to observe a
decrease in infected areas. After three days the complaint
had already significantly improved. After one week no
further treatment was required.
