Note: Descriptions are shown in the official language in which they were submitted.
2 ~ 2 ~ 5 ~
Pharmaceutical and/or cosmetic composition and the use thereof
This invention relates to a pharmaceutical and/or cosmetic
composition with the characteristics of the generic part of claim -~
1 and the use of such a composition.
' ::
Pharmaceutical and/or cosmetic compositions for topical use are
known since a long time.
Besides the conventional ointments, creams, lotions, emulsions or
suspensions, which usually just act locally on the treated skin
area, other systems are known comprising a carrier material,
wherein the carrier material warrants the penetration of the
actlve ingredient contained in the carrier material into the skin `
or through the skin barrier.
DE PS 38 29 899, published on March 3, 1990, describes
pharmaceutical compositions of this kind, wherein the active
ingredients are phospholipid derivatives of the following formula
(I). ~
CU2 - ~ - ~ Z : ~ :
C~
C~
In the formula I R1 stands for hydrogen, a lower aliphatic alkyl
group with 1 to about 12 carbon atoms, an alkoxy group with about
6 to 30 carbon atoms, an alkylcarbonyloxy group with
about 6 to 30 carbon atoms, a furanosyl or pyranosyl group with 4
to about S0 carbon atoms, and in total up to 10 glycosidically
linked furanose and/or pyranose rings corresponding to the mono-, ~
di-, and oligosaccharides, R2 is an aliphatic alkyl group with ~ -
about 6 to 30 carbon atoms or an aliphatic alkylcarbonyl group
with about 6 to 30 carbon atoms, X stands for oxygen, sulfur or
the imino group, and R3 is the structure of an amino alcohol R4-
N(RsR6) in which R4 is an alkylene bridge group with 1 to about
12 carbon atoms optionally carrying a carboxyl group, and Rs and
2 2 ~
R6 independently of one another stand for hydrogen or lower alkyl
with 1 to 4 carbon atoms.
It is the object of the present invention to provide a novel
pharmaceutical and/or cosmetic composition for topical use,
which possesses a particularly high pharmaceutical and/or
cosmetic efficacy.
This object is solved by a pharmaceutical and/or cosmetic
preparation with the characteristic features of claim 1.
The inventive pharmaceutical and/or cosmetic composition which is
to be applied topically, comprises like the aforementioned
compositions according to the state of the art, at least a
carrier and at least one active ingredient, wherein the carrier
makes safe that the active ingredient does not remain locally on
the skin surface but penetrates into the skin or through the skin
barrier.
More specifically the inventive pharmaceutical and/or cosmetic
composition comprises linoleic acid and/or at least one linoleic
acid derivative as active ingredient.
The inventive pharmaceutical and/or cosmetic composition provides
several advantages.
Firstly said composition possesses a particularly high
pharmaceutical and/or cosmetic efficacy, especially in the
treatment of skin disorders and preferably in the treatment of
unclean or acnegenic skin, acne and accompanying disorders
related with acne.
This is due to the fact, that the active ingredient contained in
the inventive composition, i.e. linoleic acid and/or at least
said one linoleic acid derivative, rapidly penetrates into the
skin or through the skin barrier and therefore very soon after
the application of the inventive composition high concentrations
of the active ingredient are reached in the affected area.
The fact that the inventive composition is applied topically,
i.e. through the skin, leads to a particularly low frequency in -
side effects caused by the inventive composition. This is in
strong contrast to many known products which are administered by
for instance the oral route or by injection.
It could surprisingly be shown, that the active ingredient
linoleic acid and/or linoleic acid derivative contained in the
inventive pharmaceutical and/or cosmetic composition possesses a
high pharmaceutical and cosmetic efficacy, in particular when
said composition is being used for the therapy and or prophylaxis
of unclean or acnegenic skin, acne, pimples, pustules and/or
other accompanying disorders related with acne.
In this respect it could be observed, that already after a few
- ` 3 2~20~
topical treatments with the inventive composition an obvious
improvement was observed. The number of pimples, follicles,
pustules, efflorescences and comedones was reduced to such an
extent that already after a few days of treatment with the
inventive composition the skin became cleaner, softer and
smoother.
Also in acne, especially in severe and long-lasting acneiform
dermal disease, the treatment with the subject invention led to a
marked improvement and in most cases to a permanent healing of
the affected area. The treatment period necessary for such
improvement and healing was relatively short. Depending on the
grade of disorder in evident recovery and in the most cases a
permanent healing was noticed within a treatment period between 2
weeks and nearly 6 weeks, which cannot be achieved by
conventi~nal acne drugs.
Beyond this healing effect, the composition according to the
lnvention, gave the treated skin area a markedly smoother and
more elastic character, which gave the patients the impression of
a healthy skin.
In a first embodiment of the composition according to the
invention, t~e composition comprises liposomes as carrier. With
liposomes pursuant to the invention, unilamellar, oligolamellar
and multilamellar vesicles and fusioned bodies are being meant,
their formation being dependent upon the respective preparation
procedure. Said liposomes possess an empty inner space surrounded
by a membrane. Their diameter varies between 15 and 3500 nm,
especially between 100 nm and 300 nm.
In the same manner as biological cells, liposomes can store in
their vesicular inner space water-soluble compounds and/or
lipophilic substances in their membranes. In this respect, in
the subject invention the linoleic acid or the linoleic acid
derivative are, due to their lipophilicity, stored in the
liposomal membranes.
.
As liposome-forming compounds synthetic or natural polymers may
be used, like e.g. polyacrylates, polyesters, and/or polymeric
cellulose-derivatives.
In a preferred embodiment of the inventive composition the
liposomes are formed from at least one phospholipid.
Such phospholipids, which are preferably a mixture of
phospholipids, can be derived from natural sources like plant and
animal lecithins, from which by extraction and subsequent
purification according to known procedures such phospholipids
forming the liposomes may be obtained.
Preferably said phospholipids and said phospholipid mixtures are
isolated from eggs, oil seeds and oil fruits, like e.g. coconut,
2~2~
copra, palm kernels, groundnut, rape, sun flower, oil palms
and/or olives, and as mentioned before after the required
purification and concentration processed to liposomes.
In an especially preferred embodiment of the inventive
composition the liposomes are formed from at least one
phospholipid or a phospholipid mixture which has been isolated
according to known processes from a plant source, especially
sunflower or soybean. In this respect, such liposomes represent
vesicles as described above, the membrane of which consists of
phospholipids of plant origin, especially sunflower or soybean.
The composition according to the invention displays especially in
the case, when it comprises liposomes which are formed from
soybean phospholipids containing between 70 and 100 % by weight
1,2-diacylglycero-3-phosphocholine [(3-sn-phosphatidyl)choline,
soybean] an excellent pharmaceutical and/or cosmetic efficacy.
This is due to the fact that said liposomes, rich in 1,2-
diacylglycero-3-phosphocholine and therefore reproducibly formed,
have a large storage capacity for linoleic acid and/or linoleic
acid derivatives, and may therefore be loaded with linoleic acid
and/or the linoleic acid derivative in a reproducible manner.
Thls then warrants that on applying identical amounts of the
inventive composition on the skin, always identical amounts of
linoleic acid and/or linoleic acid derivative are applied and
through such a transport carrier are transferred into the skin or
through the skin barrier, which again guarantees the
reproducibility of the healing rate obtained with the composition
according to the subject invention. Therefore such an embodiment
of the inventive composition is especially preferred when the
composition according to the invention is being used for the
pharmaceutical or cosmetic treatment of unclean or acnegenic
skin, pimples, comedones, efflorescences, pustules, wheales as
well as acne and accompanying-disorders related with acne.
The proportion of the carrier contained in the subject
composition must be sufficiently high to warrant the free
transport of the composition into the skin or through the skin
barrier. Preferably said composition comprises between 5 and 50 %
by weight and especially between 15 and 30 % by weight carrier
and preferentially the above-mentioned phospholipid type carrier,
based on the overall composition.
In order to facili~ate at the topical application the uptake of
the subject composition through the skin, the subject composition
possesses a fluid or semi-solid consistency, and is preferably
formulated as a gel or as a fluid. Such a gel type or fluid
formulation can be obtained, when the inventive composition
comprises, besides the carrier and the active ingredient
(linoleic acid and/or a linoleic acid derivative), water and/or a
non-toxic solvent, especially a water-soluble alcohol. Especially
suited as a water-soluble alcohol are ethanol, 1-propanol and 2-
propanol and/or propylene glycol. Instead of water all aqueous
systems may be used according to the subject invention, like e.g.
purified water, distilled water, de-ionised water and aqueous
2 ~
salt solutions, preferably physiological sodium chloride
solutions or buffer solutions, preferably phosphate buffers.
In the previous paragraphs it has been shown, that the inventive
composition comprises linoleic acid and/or at least one linoleic
acid derivative. In this respect there are several basic
possibilities to provide the inventive composition with linoleic
acid or the at least said one linoleic acid derivative.
The first possibility is, that the active ingredient (linoleic
acid and/or the linoleic acid derivative) is physically
incorporated into the carrier. When for instance the above
described liposomes are used, and especially the phospholipid
liposomes, then the active ingredient is preferentially entrapped
in the membrane or in the phospholipid membrane respectively,
which surrounds the ball-like vesicles as an outer envelope. In
addition to this or instead of such an entrapment, there is the
further possibility that the active ingredient is contained in
the form of an aqueous dispersion inside the vesicles.
Instead of the aforementioned physical incorporation of linoleic
acid or the at least one linoleic acid derivative into the
carrier, the active ingredient (linoleic acid and/or the at least
one linoleic acid derivative) may, according to a second
possibility, be chemically incorporated into the carrier.
A third possibility of the inventive composition combines the
aforementioned first and second possibility, meaning that
according to this possibility the linoleic acid and/or the
linoleic acid derivative is incorporated physically and
chemically at the same time.
A further development of such a third possibility uses as carrier
a phospholipid. The linoleic acid and/or the at least one
linoleic acid derivative according to such a suitable embodiment
of the inventive composition being bound chemically and
physically to the phospholipid. Such a chemical bonding of the
linoleic acid and/or the linoleic acid derivative can be reached
by the acylation of the phospholipid carrier with the linoleic
acid and/or the linoleic acid derivative. Such an embodiment
excels by a particularly high pharmaceutical and/or cosmetic
efficacy.
It goes without saying, that such embodiments of the inventive
composition may be used, which comprise a phospholipid acylated
with linoleic acid and/or a linoleic acid derivative as active
ingredient, such an embodiment then comprising the active
ingredient (linoleic acid and/or the linoleic acid derivative),
taken from the viewpoint of the above three possibilities, only
in chemically-bound form.
In the preceding text passages it has been described, that the
carrier comprises a phospholipid or a phospholipid mixture. As
already mentioned, suitable material for such a carrier are
especially lecithins of plant and/or animal origin. The inventive
composition comprises especially 1,2-diacylglycero-3-
phosphocholine (3-sn-phosphatidylcholine) alone or in a mixture
with further phospholipids. Such further phospholipids which may
be present in the inventive composition as carrier, are
preferably 1,2-diacylglycero-3-phosphoethanolamine, 1,2-
diacylglycero-3-phosphoinositol, 1,2-diacylglycero-3-
phosphoserine, 1,2-diacylglycero-3-phosphoglycerol and 1,2-
diacylglycero-3-phosphate, all of them alone or together with
others.
In case the inventive composition comprises the aforementioned
phospholipid acylated with linoleic acid and/or the linoleic acid
derivative, then there is a possible differentiation between the
acylation with the linoleic acid and/or the linoleic acid
derivative in the 1-position of the phospholipid, the acylation
with the linoleic acid and/or the linoleic acid derivative in the
1- and the 2-position and the acylation with the linoleic acid -
and/or the linoleic acid derivative in the 2position. Accordingly
the subject composition comprises ~linoleoyl-3-phosphates, 1,2-
dilinoleoyl-3-phosphates and/or 21inoleoyl-3-phosphates of the
previous art.
An especially suitable embodiment of the inventive composition
comprises at least one phospholipid or phospholipid mixture
acylated with linoleic acid and/or a linoleic acid derivative of
the above kind, in which at least 60 % by weight of the acyl
groups are linoleic acid and/or linoleic acid derivative.
In an especially suitable and highly efficacious example of the
above described embodiment of the inventive composition, the `
composition comprises a phospholipid mixture which is
characterised by the following ratio of the acyl groups:
61-73 % by weight of the linoleic acid group,
10-14 % by weight of the palmitic acid group,
8-12 % by weight of the oleic acid group,
4-6 % by weight of the linolenic acid group,
3-5 % by weight of the stearic acid group and maximally
2 % by weight of other fatty acid groups.
For the treatment of acne and acneiform dermal disease, in
particular such examples of the previous advantageous embodiment
are suited, which comprise 15 to 30 % (based on the overall
preparatlon) of a phospholipid mixture, which contains 70 to 100
% (based on the phospholipid mixture) of 1,2diacylglycero-3-
phosphocholine. The acyl groups contained in said phospholipid
mixture are at least 60 % linoleic acid (linoleoyl-rest).
The rest of the acyl groups in the phospholipid mixture
(maxlmally 40 % of the total amount) contains in particular the
palmitlc acid group, the oleic acid group, the linolenic acid
group and/or the stearic acid group, preferably according to the
mass ratio as indicated before.
As it has been mentioned in one of the previous passages, the
inventive composition may contain for the phospholipid a
phospholipid mixture. Further phospholipids may be chosen from
the group existing of 1,2-diacylglycero-3-phosphate, 1,2-
diacylglycero-3-phosphoethanolamine, 1,2-diacylglycero-3-
phosphoserine, 1,2-diacylglycero-3-phosphoinositol and/or 1,2-
diacylglycero-3-phosphoglycerol. According to a preferred
embodiment the phospholipid mixture comprises up to 30 % of these
1,2-diacylglycerophosphate types, the further 70 % of the
phospholipid mixture being 1,2-diacylglycero-3-phosphocholine.
The percentage rates in this paragraph are based on the total
mass of the phospholipid mixture in the subject composition. As
it has been noted before, the overall composition contains a
share of 5 to 50 % of said phospholipid mixture as carrier
material.
. ~
According to another, likewise preferred embodiment, the
inventive composition contains for the phospholipid a 1,2-
diacylglycero-3-phosphocholine, wherein the 1-acyl group is
composed of a mixture of
45-61 % by weight linoleic acid groups,
19-26 % by weight palmitic acid groups,
8-12 ~ by weight of oleic acid groups,
4-6 % by weight of linolenic acid groups, -
6-9 % by weight stearic acid groups and/or
2 % by weight other fatty acid groups.
In order to guarantee, that such a preparation contains the
required amount of linoleic acid and/or the linoleic acid
derivative, it is possible to add a certain amount of linoleic
acid or the linoleic acid derivative, or according to a second
possibility the 2-position is taken by another linoleic acid
group. Most suitable are such 1,2-diacylglycero-3-
phosphocholines, in which the 1-acyl group is composed of a
mixture as lndicated above and in which the 2-acyl group being
composed of a mixture of
77-85 % by weight linoleic acid groups,
1-2 % by weight palmitic acid groups,
8-12 % by weight oleic acid groups,
4-6 % by weight linolenic acid groups,
0-1 % by weight stearic acid groups and/or
2 ~ by weight other fatty acid groups.
The concentration of linoleic acid and/or the at least one
linoleic acid derivative, which is contained in the inventive
composition as active ingredient bound by the carrier material in
chemically or physically form, may vary between 1 and 30 % by
weight, preferably between 3 and 18 % by weight. If the inventive
composition is used as a cosmetic preparation, such a preparation
contains linoleic acid and/or the linoleic acid derivative in
concentrations which vary between 1 and 8 % by weight, whereas on
the other hand respective pharmaceutical preparations
contain concentrations of active ingredient which vary more
specifically between 15 and 30% by weight. Such percentage
values for the concentration of linoleic acid or the at least one
8 2 ~
linoleic acid derivative are based on the overall preparation.
The composition pursuant to the invention possesses, as it was
stated before, preferentially a gel type or fluid consistency.
This means, that the inventive composition can be formulated into
preparations such as gels, solutions, lotions, ointments, creams,
sprays and/or aerosols. Conventional auxiliary materials such as
thickeners (CMC, Gabopol, alginates, xanthan) and dermatological
preservatives can be added. However, substances that stimulate
fat production, cover or even lubricate the skin should be
avoided. Furthermore, the preservative itself shall not
penetrate. Preferred preservatives to be added are water-soluble
alcohols, especially propylene glycol.
A particularly suitable embodiment of the inventive composition
has proved to be a liposomal gel that contains
between 30 and 93 % by weight water,
between 0 and 20 % by weight of the solvent as said above,
between 1 and 30 % by weight linoleic acid and/or the at
least one linoleic acid derivative, and
between 5 and 50 % by weight carrier, in particular the
aforementioned phospoholipids.
Such a gel type preparation contains preferably the already
mentioned alcohols as solvent, and has as a further advantage
that it is particularly simple to use.
A typical fluid liposomal form of administration pursuant to the
invention contains
between 69 and 94 % by weight water,
between b and 20 % by weight solvent,
between 1 and 30 % by weight linoleic acid and/or the at
least one linoleic acid derivative, and
between 5 and 30 % by weight carrier, in particular the
phospholipids as mentioned before.
In order to secure for the above fluid administration form
pursuant to the invention a long storability, it is advisable to
add a solvent to the preparation, in particular one or more of
the aforementioned alcohols. Only when such patients are to be
treated who show irritative skin reactions to solvents and in
particular to water-soluble alcohols, it is recommendable to use
the formulations which contain only water as fluid. The number of
such sensitive patients is however relatively small.
To guarantee the required sterility in such fluid formulations
pursuant to the invention which do not contain any organic
solvent and in particular no alcohols, such fluid formulations
are, according to a further embodiment, filled into air-tight
ampoules. The volume contained in such ampoules is sufficient for
a single application of the preparation.
2 ~
~ g
A further method of realization of the preparation according to
the invention, that is also preferred, involves a preparation
comprising a first component and a second component which is
packaged separatly fro~ it. In other words this form of
realization of the preparation according to the invention is
composed of two components stored separately from each other
whereby these two components are mixed with each other by the
user immediately before the preparation according to the
invention is employed. Hereby the first component contains a
solvent, at least one electrolyte and/or water, whereby the
solvent is chosen from the aforementioned solvents. Every
electrolyte used in the medical field can be used as electrolyte,
however the electrolyte is preferably a physiological saline
solution. In this form of realization of the method according to
the invention, the second component, which, as has already been
stated, is packaged separately from the first component, contains
the carrier material, the linoleic acid and/or the linoleic acid
derivative and a solvent of the aforementioned type, if required.
The addition of the solvent to the second component brings the
advantage that this adaptation of the preparation according to
the invention then takes the form of two liquid components that
are then very readily mixed with each other immediately before
use.
In order to adjust the necessary pH of the aforementioned
advantageous realization form of the preparation according to the
invention involving two components a further develepment of this
realization form involves addition of a suitable pH regulator to
one of the two components particularly the first component.
Whereby the regulator used is preferably an aqueous buffer system
or an appropriate base, whereby the pH of the mixed preparation
ready for use lies between 5.5 and 8, preferably between 6.5 and
7.5.
With respect to the concentrations of the aformentioned
particularly suitable form of the preparation according to the
invention in which the first and second components are mixed
immediately before application it should be said that the
concentrations in the first components are between
50 % by weight and 80 % by weight water and
between 0 % by weight and 20 % by weight solvent
and in the second component they are between
3 % by weight and 15 ~ by weight of the phospholipid carrier
material acylated with linoleic acid or at least one linoleic
acid derivative and
0 % by weight to 15 ~ by weight solvent.
A further development of this aformentioned realization form
involves the complete or partial replacement of the water (50 %
by weight to 80 % by weight) contained in the first component by
, ~., .
~ 1 0
an aqueous electrolyte solution and preferably by an aqueous
physiological sodium chloride solution (0.5 % by weight to 2.5 %
by weight sodium chloride). Further development containing
electrolyte is characterized by high sterility and a particularly `
long storage life.
Furthermore, the first component and/or the second component can
also contain normal additives, such as, for example, pH
regulators, buffer systems, emulsifiers and/or thickening agents.
As it has already been stated repeatedly, the subject composition
is in particular used for the prophylaxis and/or therapy of acne
and/or acneiform dermal disease. It was a surprising observation,
that the composition according to the invention when used in acne
or in acneiform dermal disease rapidly led to a complete healing
of such disorders, without any unpleasant or
disturbing side effects to be observed.
Acne in the context of this invention means all dermal
disorders, in which comedones, papules, pustules or
efflorescences develop, in particular disorders like Acne
catchecticorum, Acne necroticans, Acne varioliformis, Acne
picea, Acne vulgaris, Acne conglobata and Acne juvenilis.
The composition according to the invention can comprise in
addition conventional drugs for topical application, like e.g.
erythromycin, the salts of erythromycin or its derivatives,
tetracycline hydrochloride and/or retinoic acid (Tretinoin USP
XXI).
Suitable ratios of these conventional therapeutic agents are
for erythromycin 0,5 -4 ~ by weight,
for tetracycline 1-5 ~ by weight,
for azelaic acid 5-20 % by weight, and
for tretinoin 0,025 to 0,1 % by weight.
According to a further embodiment of the composition according to
the invention, the different ingredients of the composition are
packed separately. This can be achieved by mixing, directly prior
to use a first dry component, which contains the carrier and the
active ingredient, with a second component which consists of the
solvent as described above and/or water. The preparation of the
dry component may be achieved by pulverisation, granulation,
lyophilisation or any other appropriate known technology of the
combination of active ingredient and carrier.
It is evident that the dry component according to the description
in the previous paragraph can contain additionally any of the
previously listed therapeutic agents.
Suitable forms of administration are indicated in the subclaims.
The following examples further illustrate the invention.
For the preparation of the compositions according to the
following examples 1 to 6 different soybean phospholipids were
used. On the one hand a soybean phospholipid A was used
containing as main component 76 + 3 % by weight
phosphatidylcholine and a further 3 + 3 % by weight
lysophosphatidylcholine, on the other hand a soybean phospholipid
B was used, which contained the main component
phosphatidylcholine in an amount of 93 + 3 % by weight and again
3 + 3 % by weight of lysophosphatidylcholine.
Example 1 -
Soybean phospholipid A (330 kg) containing 100 kg linoleic acid
was taken up in a solvent mixture, consisting of 729 l purified
water and 257 l ethanol.
After homogenisation in vacuum at 300 mbar, the pH value of the
gel formed was adjusted to 6,5 + 1,5 by addition of sodium
hydroxide.
The transparent gel which was formed had a total content of free
and bound linoleic acid of 8,05 % by weight. The viscosity of the -
gel was 5000 + 3000 mPa.s.
The gel suited the purity requirements of the Category 2 of the
DAB 10 for final products.
Under appropriate storage conditions, meaning storage in airfree
envlronment and at 25 C, the gel was storable for at least 24
months.
Example 2
In a mixture of solvents, consisting of 12,793 g purified water
and 3,2000 g propylene glycol, an amount of 4 kg soybean :
phospholipid B, containing 1,4 kg bound linoleic acid, was added. -
After homogenisation a slightly transparent, soft gel appeared,
with a total content of free and bound linoleic acid of 7 % by
weight and a pH value of 6,5 + 1,5, this pH value being adjusted
by the addition of the necessary amount of sodium hydroxide. The
viscosity of the gel amounted to 3000 to 7000 mPa.s.
Example 3
A dispersion of 45 kg soybean phospholipid A containing 15,7 kg
linoleic acid in 400 l purified water was prepared. This
dispersion was stirred to homogeneity. After filtration the
dispersion was filled into ampoules.
This dispersion had a total content of free and bound linoleic
acid of approximately. 3,5 % and a pH value of 6 + 1, which was
based on the addition of a required amount of sodium hydroxide to
the dispersion.
The dispersion prepared according to this description was stable
r
'~ 12
:
for at least 24 months.
Example 4
In a mixture of solvents, consisting of 401,4 kg purified water
and 85 kg ethanol, an amount cf 50 kg phospholipid B containing
17,5 kg linoleic acid was dispersed. A turbid dispersion was
obtained in this manner, with a pH value of 6 + 1, this pH value
being adjusted by the addition of sodium hydroxide.
The total content of free and bound linoleic acid was 3,5 % by
weight.
Example 5
In a mixture of solvents, consisting of 401,4 kg purified water
and 85 kg 2-propanol, an amount of 50 kg phospholipid B
containing 17,5 kg linoleic acid was dispersed. A turbid
dlspersion was obtained in this manner, with a pH value of 6 + 1,
this pH value being adjusted by the addition of sodium hydroxide.
The total content of free and bound linoleic acid was 3,5 % by
weight.
Example 6
In a mixture of solvents, consisting of 12,793 g purified water
and 3,200~ g propylene glycol, an amount of 4 kg soybean
phospholipid B, containing 1,4 kg bound linoleic acid and
~ddtitional an additive of 400 g free linoleic acid, was added.
After homogenisation a slightly transparent, soft gel appeared,
with a total content of free and bound linoleic acid of 9 % by
weight and a pH value of 6,5 + 1,5, this pH value being adjusted
by the addition of the necessary amount of sodium hydroxide. The
viscosity of the gel amounted to 3000 to 7000 mPa.s.
To test the efficacy of the pharmaceutical compositions pursuant
to the invention, the preparations of Examples 3 and 6 were
investigated in 13 ~uvenile subjects. Besides their affected skin
which was characterised by the presence of pimples, comedones and
efflorescences, the subjects were in healthy condition.
The subjects were treated daily during a 8 week treatment period t,,
with the preparation. The content of an ampoule containing 5 ml
of composition according to Example 3 or 6 was applied by the
subjects themselves on the left side of the face and lightly `~ i~
rubbed in. As many of the preparation was applied, as could be
taken up by the skin. The right side of the face was left
untreated by all subjects during the whole txeatment period.
: .
Other active cosmetic or pharmaceutical treatment was not allowed `
during the test period.
At the beginning of the treatment, and 2,4 6 and 8 weeks after
' .::
~ 13 . ~
the beginning of the treatment the condition of the skin was :: .
evaluated. For this test the treated and non treated parts of the : :~
face were covered with a foil and a physician has marked the
comedomes and the efflorescences upon the foil (projection
slide).
The following table indicates the mean values for the number of
comedones and efflorescences. .
Table 1
Results of the treatment with the preparation produced according
to example 3.
Number of comedones
'
_ duration of treatment in weeks
Part of the face 0 2 4 6 8
left side 18,0 11,2 5,6 4,9 2,2 ~ ;~
right side 18,9 16,8 15,7 16,1 13,8
, ' ~ .~,'` ~ ',.",
Number of efflorescences `~
duration of treatment in weeks . : :
Dart of the face 0 2 4 _6 8
left side 15,2 7,1 3,2 2,4 1,1
right side 15,4 14,7 13,5 13,5 13,2
Table 2
Results of the treatment with the preparation produced according
to Example 6.
'. ',
number of comedones
duration of treatment in weeks : ;
: ~:
~art of the face 0 2 4 6 8
14 ~ :~ 2 ~
left side 19,0 12,2 5,9 4,2 1,2
:,
right side 19,9 17,2 16,3 16,8 15,8
~','
number of the efflorescences
duration of treatment in weeks :.
~,.,
part of the face 0 2 _ 4 6 8 ~ ~:
:
left side 15,7 6,3 2,2 1,8 1,0
right side 17,4 16,7 14,9 15,2 15,3
.,. ~
In none of the treated subjects any sign of adverse effects or ; :~-
the occurrence of skin irritation could be observed.
~., ~,'
Example 7 ~.
A mixture was prepared from 10 % by weight soybean phospholipids ~ "~
containing
80 % by weight 1,2-diacylglycero-3-phosphocholine,
,~ 15
8 % by weight 1,2-diacylglycero-3-phosphate,
4 % by weight 1,2-diacylglycero-3-phosphoethanolamine and
8 % by weight unspecified other phospholipids and
90 % by weight of a physiological saline solution (1 % by
weight sodium chloride in water).
The total acylgroup ratio of the phospholipids was
61-73 % by weight linoleic acid groups,
10-14 % by weight palmitic acid groups,
8-12 % by weight oleic acid groups,
4-6 % by weight linolenic acid groups,
3-5 % by weight stearic acid groups and
2 % by weight other fatty acid groups.
The product was a liposomal dispersion which was produced in
sterile form and contained therefore no preservatives at all. The
liposomal dispersion could be filtered and could be applied ~`
directly on the skin.
Example 8
A gel was made using the phospholipids described in example 7.
The gel contained 20 % by weight of the phospholipid according to
example 7, 16 % by weight ethanol and 64 % by weight water.
The product was a liposomal composition that could be applied
directly on the skin.
In each of the following examples 9 to 25 the phospholipid ` b~ ','':
mixture described in example 7 was used.
Example 9
A solution was made, containing ;
2 % by weight erythromycin,
16 % by weight phospholipid and
82 % by weight propylene glycol.
The solution could be applied directly on the skin.
Example 10
A solution was made, containing
2 % by weight erythromycin,
29 % by weight phospholipid,
16 % by weight ethanol and
62 % by weight propylene glycol.
This solution could be applied directly on the skin as well.
Example 11
An ointment was made, containing
2 % by weight erythromycin,
12 % by weight phospholipid and
86 % by weight cetylstearylalcohol.
16 2 ~
Example 12
An ointment was made, containing
2,5 % by weight erythromycin,
18 % by weight phospholipids,
20 % by weight propylene glycol and
59,5 % by weight cetylstearylalcohol.
Example 13
A gel was made, containing
4 % by weight erythromycin,
20 % by weight phospholipid,
16 % by weight ethanol and
60 % by weight water.
Example 14
A liposomal dispersion was made, containing
1 % by weight erythromycin,
10 % by weight phospholipid,
16 % by weight ethanol and ~,
73 % by weight water.
Erythromycin was placed in a flask and dissolved by shaking with
the solvent (ethanol, water) containing the phospholipids. A -
ready-made liposomal dispersion was formed which is to be
prepared just before its first use. It is intended for prompt use
and should be stored cold.
Example 15 ;
A ready-made liposomal dispersion was prepared as descri~ed in
Example 14, containing
1,2 % by weight erythromycin,
10 % by welght phospholipid,
20 % by weight propylene glycol and ~ -
68 % by weight water.
This liposomal dispersion had to be prepared directly before its
first use and was intended for prompt use.
Example 16
Two systems were separately prepared, which had to be combined
directly prior to the first use.
The first system contained
1,2 % by weight erythromycin and
:: .'
17 2~
20 % by weight ethanol,
whereas, the second system contained
5 % by weight phospholipid,
16 % by weight propylene glycol and
57,8 % by weight water.
Solutions 1 and 2 were combined just before the first use. A
ready-made liposomal dispersion was formed, which was intended
for prompt use.
Example 17
An ointment was made, containing
3 % by weight tetracycline hydrochloride,
16 % by weight propylene glycol and
57,8 % by weight water.
Example 18
An ointment was made, containing
2,5 % by weight
tetracyclinehydrochloride,
22,5 % by weight phospholipid, ;
25 % by weight anhydrous lanolin,
10 % by weight propylene glycol and
40 % by weight vaseline.
Example 19
A gel was made, containing
5 % by weight acelaic acid, ~ ~ -
20 % by weight phospholipid, `
16 % by weight propylene glycol and ~;
59 % by weight water.
Example 20
A gel was made, containing
15 % by weight acelaic acid,
20 % by weight phospholipid,
16 % by weight ethanol and
49 % by weight water.
Example 21
A cream was made, containing
10 % by weight az~laic acid,
20 % by weight phospholipid,
- 18
16 ~ by weight propylene glycol,
12 % by weight mono-, diglycerides and
42 % by weight water.
Example 22
A gel was made, containing
0,025 % by weight tretinoin,
20 % by weight phospholipid,
16 % by weight ethanol and
63,975 ~ by weight water.
Example 23
A gel was made, containing
0,05 % by weight tretinoin,
10 % by weight phospholipid,
16,7 % by weight ethanol, ~
2,2 % by weight xanthan and ~ `
71 % by weight water.
Example 24
A solution was made, containing
0,5 % by weight tretinoin,
10 % by weight phospholipid,
24 % by weight Macrocol 400,
17,95 % by weight ethanol and
48 % by weight propylene glycol.
Example 25 ~ ;
A cream was made, containing
0,05 % by weight tretinoin,
16 % by weight phospholipid,
24 % by weight cetylstearylalcohol,
22 % by weight propylene glycol and
37,95 % by weight water.
:: .
: :~
To test the efficacy of the compositions described above, a third
investigation on test persons was performed, in which the
liposomal dispersion of Example 7 was applied to the affected
test areas of 14 subjects twice daily for eight weeks.
The interpretation was done by marking the comedones and the
efflorescences on a projection slide, as was described for the
previous investigation.
Skln surface lipids were sampled by direct contact of the skln
,, , ,;, '. ~' '` . ' i ': "" :'" i . ' ' ' ~ ~
~ A ~ ;7~
19
with a mixture of n-hexane/isopropanol (3:2). The total linoleic
acid content of these samples was determined by gas
chromatography after conversion into the methyl ester.
The test results are given in table 3. The averages from 14
subjects are shown in figure 1 for the number of comedones and
efflorescences as well as the linoleic acid content of the skin
as function of the time of treatment. It is clear from the
graphic representation in figure 1 that the number of comedones
and efflorescences has declined by an average of about 50 % of
the initial value after only two weeks of treatment. After
treatment with the composition according to Example 7 for eight
weeks, an evidently further reduction occurred in the number of
comedones and efflorescences, associated with an increase of the
linoleic acid content of the skin surface.
In figure 2 the efficacy of various conventional acne agents is
shown, in the form of the percentage decline in the number of
comedones after 2 months.
Comparison of figures 1 and 2 shows clearly, that the treatment
with the liposomal dispersion according to Example 7 was even
more effective than isotretinoin, the most powerful acne agent up
to now. In contrast to isotretinoin, however, no side effects
have been observed in the studies up to now.
: .
Example 26
A composition was prepared using the soja phospholipid A
mentioned at the start, whereby the composition was characterized
by a first component packed in vessel 1 and a second component
packed in vessel 2.
The contents of vessel 1 were characterized by the following
components:
demineralized water 73.83 g
ethanol DAB 9 10 g
10 % sodium hydroxide 0.17 g.
Vessel 2 had the following contents:
phospholipid A 10 g
ethanol DAB 9 6 g
Example 27
A composition was also divided between 2 vessels. Whereby vessel
1 contained
demineralized water 73.83 g
isopropyl alcohol 10 g
10% sodium hydroxide 0.17 g
and vessel 2 had the following contents:
phospholipid A 10 g
isopropyl alcohol 6 g.
Example 28 :~
A further composition was prepared with vessel 1 containing ~ ~
1~ physiological saline solution 73.83 g . :
ethanol DAB 9 10 g
10% sodium hydroxide 0.17 g
and vessel 2 containing
phospholipid A 10 g
ethanol DAB 9 6 g .~
Example 29 ~ ~:
As in the aforementioned examples 2~ to 28 a composition prepared -;~
conslsting of 2 components, whereby vessel 1 contained ~ ~
1% physiological saline solution 73.83 g ~ '
isopropyl alcohol 10 g
10 % sodium hydroxide 0.17 g
Vessel 1 had the following contents~
phospholipid A 10 g
isopropyl alcohol 6 g
The components previously prepared in separate vessels in
examples 26 to 29 were mixed together by brief shaking (30 ~ -
seconds). ~his led to the formation from the components of
example 26 of a brownish liposomal gel with a mean lipo.~ome
diameter of 380 nm and a pH of 6.8, the components of example 27
also yielded a brownish, liposomal gel with a mean particle size
of 311 nm and a pH of 7.0, the components of example 28 yielded a
milky liposomal fluid with a mean particle size of 540 nm and a
pH of 6.6, and the components of example 29 yielded a yellowish
fluid liposomal preparation with a mean liposome particle size of
281 nm and a pH of 6.8.
n~
21
table 1
¦Subject No. Initially afler 2 weeks ~¦~ - ~ -:
I
_ C. Ef. L.S. C. Ef. L.S. C. Ef. L.S. C. Ef. L.S.
_ _ . _ _ _
1 28 19 G,64 23 8 1,62 16 7 3,49 12 6 3,57
32 4 0,34 15 2 1,45 11 2 1,94 11 0 2,97
_
3 6 10 0,40 4 4 4,45 1 7 1,21 0 5 2,90 : . ~
_ _ _ _ _
4 38 27 0,57 23 6 0,54 7 13 3,33 7 0 3,24
16 15 1,40 16 3 1 90 18 0 2,63 14 0 3,47 `~
_ _
6 0 33 1,30 0 19 2,13 0 11 2,80 0 3 3,40
_ _ _ _ __ _ .
7 35 25 1,94 22 7 3,22 19 1 6,28 17 0 4,59
_ _ _ ....
8 0 12 0,86 0 8 4,04 0 9 4,00 0 6 3,82
34 4 2,07 10 2 2,93 12 0 3,49 12 0 3,28
_ _ _ _ _
34 15 1,12 16 3 3,37 13 2 4,83 6 0 4,62
11 30 29 1,70 17 25 2,27 18 23 2,25 13 8 3,10
12 28 15 1,77 16 2 1,96 11 3 2,12 4 4 3,24
13 2 9 1,70 0 4 2,03 0 7 2,40 3 5 2,92
14 _ 8 0,57 6 0 1,20 4 0 1,79 0 0 3,14
C. = comedones
Ef.= efflorescence
L.S.= % linoleic acid in the eluate based on total fally acid content.
~'"~
