Note: Descriptions are shown in the official language in which they were submitted.
~L2~6~
The present invention relates to pharmaceutical
compositions useful in the treatment of acne which
compositions comprise L-cysteine or a pharmaceutically
acceptable salt thereof and propylene phenoxetol.
Anti-acne treatments axe well known but none are
sufficiently satisfactory as to obviat~ the need of a
further method of treatment. Known methods of treatment
by ultra-violet radiation, x-rays or surgery can cause
tissue to be destroyed or the sebaceous glands to atrophy;
conventional oestrogen therapy similarly atrophies the
sebaceous glands and may additionally be unacceptable to
female patients and may require a consi~erable time to
have an effect; and treatment with benzoyl peroxide can
cause local irritation. Clearly it would be desirable
lS to offer an alternative method of treating acneO
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The present inven~ion is based upon the discovery
that compositions containing L cysteine and propylene
phenoxetol may be used to treat acne without an
unacceptable level of undesirable side effects such as
the destruction of tissue to an unacceptable degree.
Accordingly, the present invention provides a
pharmaceutical composition useful in the treatment of
acne which composition comprises L-cysteine or a
pharmaceutically acceptable salt thereof and propylene
phenoxetol.
One of the considerable advantages of using
cysteine in the treatment of acne is that the medical
prac$itioner will be aware that it is a natural a~ino
aci*,~ so that confidence may be felt in that
unconventional and possibly irritant materials such as
thioglycolic acid can be avoided (U.S. Patent No.
4107330 discloses the topical applications of thioglycolic
acid in the treatment of acne). Organic sulfhydryl and
in particular N-acetyl cysteine have been applied to the
skin in order to reduce sebum production (see U.X. Patent
No. 1317773) but they were not shown to have any effect
on acne. L-cysteine has been used in the treatment of
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-- 3
eye diseases (see German Published Patent Application
No. 2441621) but that use is unrelated to the treatment
of acne.
Propylene phenoxetol, l-phenoxypropan-2-ol, has
been used in topical compositions for ~he treatment of
skin bacterial infections and skin fungal infections.
Its use, together with L-cysteine in the treatment of
acne has not been disclosed or suggested.
The usefulness of L-cysteine and propylene
phenoxetol in the treatment of acne is therefore
particularly surprisiny.
The L~cysteine and propylene phenoxetol are
normally applied in the form of a pharmaceutical
composition which comprises L-cysteine or a
pharmaceutically acceptable salt thereof and propylene
phenoxetol and a pharmaceutically acceptable carrier
therefor. The L-cysteine may have D-cysteine in
association therewith if desired but normally and
preferably L~cysteine is employed free of D-cysteine.
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Any convenient composition may be employed as
long as it is free of oxidising agents or other agents
incompatible with L-cysteine opropylene phenoxetol.
Compositions analogous to those of the aforementioned
patent documents may be employed if desired. However
it is preferred to employ a self-supporting aqueous gel.
~ ccordingly this invention provides a pharmaceutical
composition adapted for topical administration in the
form of a self-supporting aqueous gel containing
L-cysteine or a pharmaceutically acceptable salt thereof
and propylene phenoxetol.
Acceptable salts of cysteine include those with
topically acceptable metallic ions or nitrogenous bases
or topically acceptable acids. A particularly apt
salt is the hydrochloride. By a self-supporting gel
is meant a gel which when applied to an area of skin
remains in con~act with the area.
Most suitably the composition of this invention
will contain from 0.1 to 15% o~ L-cysteine or a
pharmaceutically acceptable salt thereof, more favourably
2.0 to 12% and preferably from 4 to 8~ (% terms when
used herein are expressed on a wt./wt. ~asis)~
1~60
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Most suitably the composition of this invention
will contain from 0.1 to 5% of propylene phenoxetol,
1-phenoxypropan-2-ol, more favourably 1 to 4%, and
preferably from 1.5 to 3~, for example 2%.
Optionally, ~hough not preferred, the composition
of this invention will contain preservative.
Preservatives which are most apt are those commonly
used in pharmaceutical compositions. Preferably the
preservative will he benzoic acid, in an amount of
10 0.01 to 0.5% preferably 0.05 to 0.2%.
Normally and preferably the composition will
contain a pharmaceutically acceptable gelling agent such
as cellulose derivatives or gums or starches or alginates
and polymers such as polyvinyl pyrrolidone or polyvinyl
alcohol or polyethoxy-polypropoxy glycol copolym~rs, but
a preferred gelling agent is a polyacrylic acid lightly
cross-linked with triallyl sucrose. Such polymers are
known as carboxyvinyl polymers of which the Carbopols
(Trade Mark) are one commercial embodiment. To form gels
these polymers must be neutralised~ Suitable
neutralising agents include solutions of alkali metal
or ammonium hydroxides and nitrogenous bases.
preferred neutraliser is a solution of sodium hydroxide.
2 ~
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Suitably the pharmaceutical compositions of the
present invention in the form of a gel will contain from
0.1 to 5% of gelling agent depending on the efficacy
of the agent, more suitably 0.5 to 4~ and preferably
5 l to 3%, for example 1.5%, 2% or 2.5~.
Normally and preferably the composition will
contain a humectant to prevent the gel drying in use.
Such humectants include alkylene glycols. A particularly
preferred humectant is propylene glycol~ This agent
has the added advantage in easing the dispersion of the
- gelling agent in the bulk of the water during preparation.
Suitably the composition may contain from 2 to lO~ of
humectant and preferably 3 to 7%.
Most suitably the pH of the composition will be
controlled to prevent oxidation of L-cysteine base to
cystine which occurs readily in solutions having a pH
value of greater than 8. The suitable range of pH value
is from ~ to 87 most suitably from 3 to 6 and preferably
~ to 6.
The pH value of a gel composition may also depend
upon the choice of gelling agent and the vi~cosity
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required for the final gel. Thus, if the pH value is
at the higher end of the range a hydroxyethyl cellulose
gelling agent may be used and for gels of lower pH
the preferred gelling agent is a polyacrylic acid ligh~ly
cross-linked by triallyl sucrose, when for example pH
values of 4 . 5 to 5.5 are employed.
The viscosity of the final gel were measured using
a Ferranti-Shirley cone and plate viscometer using the
following parameters,
4 cm cone
120 second sweep time
600g cm 1 torque spring
10 rpm speed
25~C temperature
,
The apparent viscosity at maximum sheer (10 r.p.m.
= 113.7 sec ) is suitably between 30 and 80 poise and is
preferably between 60 and 75 poise.
: ~ptionally the compositions of the present
invention may also contain other ingredients including
perfumes and inert fillers such as titanium dioxide to
provide a white rather than colourless gel.
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Normally and preferably the water used in ~he
composition will be freshly distilled water which has
been de-oxygenated by boiling and allowed to cool with
filtered 'inert' gas bubbling thr~ugh lt. By 'inert'
gas is meant a non-oxidising gas for cysteine, for example
carbon dioxide, particularly preferred is nitrogen. It
is also envisaged that any type of water for example
deonized water, may be used provided it i5 degassed to
remove oxygen and maintained thereafter under nitrogen.
L-cysteine and its salts are readily oxidised in aqueous
solutions by oxygen dissolved in the water, hence removal
of this oxygen and isolation of this solution from air,
avoids oxidation of L-~ysteine and its salts.
The particularly favoured form of the composition
of the present invention comprises from 2 to 12% of
L-cysteine hydrochloride, 1 to 4~ of propylene phenoxetol,
2 to 10% propylene glycol, 0.1 to 5% polyacrylic acid
cross-linked by triallyl sucrose, sodium hydroxide solution
to give a pH of 5O4 and sufficient water to adjust the
volume to lOQ~.
A preferred form of the composition of the present
invention comprises from 4 to 8% of L-cysteine, 1.5
60~
to 3% propylene phenoxetol, 5% propylene glycol, 1.5
polyacrylic acid lightly cross-linked with triallyl
sucrose, sodium hydroxide solution to adjust the pH of
5 4 and sufficient water to ad3ust the volume to 100%.
Typically the composition of the present
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invention will be packed into ~ ~ laquexed aluminium
tubes~
In a second aspect ~herefore the invention
provides a method of treating acne which comprises
applying top.ically to the affected areas an effective
amount of I,-cysteine or a, pharmaceutically acceptable
salt thereof and propylene phenoxetol. The composition
: will be applied topically to the affected area 2 times
daily or more frequently if required.
In severe cases it may be desirable to apply
the composition to the affected area up to 6 times a
day for example 2, 3, 4, 5 or 6 times daily. Generally
2, 3 or 4 applications daily are most convenient and
usually 2 or 3 applications will be made. In mild
cases a single application per day may be envisaged.
Generally, treatment will last for at least 7 days and
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may proceed for up to 14 to 23 days or even longer if a
physician considers it desirable.
In view of the susceptibility of cysteine to oxidation,
the skilled ~uorker will be aware that the compositions
employed will be free of agents that would oxidise the
cysteine.
Although propylene phenoxetol is the preferred anti-
bacterial agent in a less favoured aspect alternative anti-
bacterial agents may be employed. Thus in a broader aspect
the present invention provides a pharmaceutical composition
useful in the treatment of acne which composition comprises
L~cysteine or a pharmaceutically acceptable salt thereof and
an anti-bacterial agent.
Aptly the composition will contain from 0.1 to 15% of
I~cysteine or a pharmaceutically acceptable salt thereof.
Suitably the composition will contain from 0.2 -to 2.07o
L,cysteine or a pharmaceutically acceptable salt thereof,
more suitably will contain 0.25 to 1.5~o and preferably 0.3 to
0.5%, for exa~ple 0.35o, 0.4070 and 0.45/~ Of I,cysteine or a
20 pharmaceutically acceptable salt thereof. Preferably the
hydrochloride of L-cys-teine is employed.
The effectiveness of compositions containing such low
concentrations of L,cysteine with the antibacterial agent is
particularly surprising. Such concen-trations have the added
25 advantage of being particularly friendly towards the skin.
32
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Apt anti-bacterial agents are those which are compatible
with L,cysteine. Suitable anti-bacterial agents include
quaternary ammonium salts, for example ben~alkonium chloride
and propylene phenoxetol. m e preferred anti-bacterial agent
is propylene phenoxetol.
The following Examples are illustrative of the
invention.
Example 1
An aqueous gel was made containing:
L-cysteine 7.~/~ w/w 210g
Propylene phenoxetol 2.5% w/w 75g
Propylene glycol 4.5% w/w 135g
Carbopol 934P 2.0~o w/w 60g
Sodium hydroxide solution to adjust the p~ to 5.4
Distilled water to adjust the volume to 1007o w/w 2520g.
me freshly distilled water was boiled to remove
dissolved oxygen and allowed to cool with filtered nitrogen
bubbling through. Nitrogen was bubbled through the buIk
of the camposition for the entirety of the process including
the filling. The Carbopol 934P was dissolved in the water
by warming and stirring. Then the water was allowed to cool
to ambient tenmperature. l`he propylene phenoxetol was
dispersed in the propylene glycol and then added to the cool
water with stirring. The L-cysteine was then dissolved in the
solution and the p~I adjusted to pH 5.4 using sodium hydroxide
12
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solution. The weight of solution was adjusted to the weight
re~uired by addition of dea~ygenated water. The resultant
solution was mixed for a further 15 minutes under a nitrogen
blanket. The resultant clear product was transferred to a
tube filling apparatus under a blanket of nitrogen. The
product was filled in a conventional manner into araldite
lacquered aluminiun ~Ibes which have been flushed with nitrogen.
The tubes were sealed immediately.
The gel was dispensed from the tube as required.
Example 2
- An aqueous gel was made containing:
L,cysteine 8.070
Propylene phenoxetol 2. G7o
Propylene glycol 7.0%
C~rbopol 934P 1.25%
Titanium dioxide 0.25,~
Perfume 0.05%
Sodium hydroxide solution to adjust ~I to 5.2
Distilled water to adjust the weight to lOOYo.
The gel was formed and packed using the methods
described in Example 1. The titanium dioxide and perfume
were added along with the propylene phenoxetol after first
mixing with the propylene glycol.
,:
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Example 3
An aqueous gel was made containing:
Lrcysteine hydrochloride lO~o
Propylene phenoxetol 2
Propylene glycol 6~o
Carbopol 934P 2qo
Sodium hydroxide solution to adjust the pH to 4.5
Distilled water to adjust the weight to lOOg.
m e gel U~5 prepared and packaged in a si~ilar manner
to that described in ~xa~ple 1.
Exa~ple 4
-
An aqueous gel was prepared containing:
L,cysteine hydrochloride 0.45qO
Propylene pheno~etol 2.5~
Propylene glycol 6.0,~o
Carbopol 934P 1.5~
litanium dioxide 0.25%
Perf~une 0.06,~o
Sodium hydroxide solution to adjust the p~l to 5.6
Distilled water to adjust the weight to lOOg.
The gel was forned in a similar manner to that described
in Example 2.
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Example 5
An aqueous gel was prepared containing:
L,cysteine 0.35%
Propylene phenoxetol 2.0%
Propylene glycol 7.0%
Carbopol 93~P 1.25%
Perfume 0.0570
Sodium hydl-oxide solution to adjust the pH to 5.2
Distilled water to adjust the weight to lOOg.
m e gel was formed in a similar manner to that described
in Example 1.
A clinical trial was carried out on 20 human volunteers
suffering from acne. A gel having a formulation described in
Example 1 was applied to the effec,ed areas twice a day for 10 weeks.
These areas were inspected after 2, 4, 6, 8 and 10 weeks of
treatment. At the end bf 10 weeks the physician conducting the trial
concluded that the L-cysteine/propylene phenoxetol gel was an
efficacious treatment for acne.
