Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Corticosteroid-containing Cream
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Preparations containing corticosteroids intended for
topical application are useful for the treatment of various
skin disorders. However, in order tbat the active ingredients
evidence their maximum effectiveness, they must be absorbed
through the skin. The horny layer, the stratum corneum, forms
a barrier which must be surmountea. Clearly, the tnerapeutic
effectiveness of the corticosteroids depends greatly on the
rate at which they are absorbed from the carrier base and at
which they diffuse through the barrier.
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One method of increasing the rate of transmission slightly
is by increasing the concentration of active ingredient in the
composition. However, this has important drawbacks in that
- there is a much greater likelihood of undesirable side effects
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~5 being experienced. Therefore, it is useful to adjust tne
corticosteroid concentration so that the optimum therapeutic
effect is achieved with a minimum concentration of active
ingredient~
This has been accomplished by dissolving the corticosteroid
'O in the base at a concentration wh;ch is close to saturation.
This has been achieved by the use or such materials as glycols,
low molecular weight alcohols, anà solubilizers~ Because of
the poor solubility of the corticosteroids, up to 6~% glycols
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must be used. In many cases, this causes skin irritations
which may require cessation of the treatment. In addition,
skin irritations resulting from even low concentrations of
these materials have also been reported.
In view of the foregoing problems, preference must be given
; to a base which contains the corticosteroid in suspended form.
Such bases are already known, bu~ tney contain wool fat, or
derivatives thereof, and are therefore prone to exhibiting
allergenic characteristics.
The effectiveness of a given corticosteroid depends on its
structure and its chemical and physical properties. If the
corticosteriod is contained in a base to be applied topically,
the properties of the base then become important factors in
determining the therapeutic effectiveness of the composition.
These properties of the base depend on the type of emulsifiers
~; and additives contained therein. It is not possible to
predict, at the present time, the manner in which an emulsion
system will act with a given corticosteroid. Therefore, one
cannot pre select a suitable base which will permit the steroid
to exhibit its maximum effectiveness.
It is among tbe objects of tne present invention to
increase the therapeutic effectiveness of the specific
corticosteroid known as fluocortolone by providing a suspension
base of a particular kind. As a result, a strong therapeutic
action is obtained with a relatively low concentration of
active ingredient. Thus, undesirable side effects are
minimized.
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Moreover, the new composition is at least equivalent in
effect to the pre-existing compositions, despite its reduced
fluocortolone content. In addition, superior skin tolerance is
obtained, due to the absence of allergenic substances such as
preservatives, wool fat, and glycol.
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In practicing the invention, there is provided a
,; corticosteroid-containing cream comprising
; 0.05 - 0.5 parts by weight fluocortolone
.~.. . . .
2.5 - 20 parts by weight fatty acid sorbitan esters and/or a
mixture of fatty acid-monoglycerides and fatty acid
diglycerides
`~ l - 5 parts by weight fatty acid monoglycerides
n,~ 1 - 10 parts by weight beeswax
5 - 25 parts by weight liquid paraffin
25- 75 parts by weight petroleum ~lelly
and water to 100 parts.
Another name for petroleum jelly is petrolatum.
With the foregoing composition, it is possible to obtain a
water in oil emulsion which contains fluocortolone suspended in
micronized form. The steroid itself, of course, is well known.
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As the fatty acid sorbitan esters, those with saturated or
unsaturated medium and higher fatty acids, especially paraffin
monocarboxylic acids are to be preferred. Especially preferred
are partial esters, or mixtures thereof, with l to 3 fatty acid
molecules per sorbitan molecule. The fatty acids desirably
have lO to 20 carbon atoms and, in particular, contain 12 to 18
carbon atoms. Lauric and oleic acids have been found
especially useful.
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The sorbitan esters can be used togetner with a mixture of
. fatty acid monoglycerides and fatty acid diglycerides. It is
also possible to use the sorbitan esters or the mixture of
! glycerides alone. Such glycerides, or mixtures thereof, can be
obtained by direct esterification of one mole of glycerine With
one to two moles of fatty acid. In addition, they can be
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' obtained by partial saponification of fats. Bot~ of these
methods generally produce a mixture of mono- and diglycerides
containing about 20% to about 80% by weight monoglyceride.
Preferred mixtures of fatty acid monoglycerides and fatty
acid diglycerides are mixtures of esters of higher, saturated
and unsaturated natural fatty acids, especially paraffin
monocarboxylic acids. These fatty acids desirably have 14 to
20 carbon atoms. Especially preferred are unsaturated fatty
acids with 16 to 20 carbon atoms. OLeic acid has been found
especially useful.
Furthermore, the compositions of the present invention
contain fatty acid monoglycerides. Preferred fatty acids are
higher, saturated and unsaturated natural fatty acids,
especially paraffin monocarboxylic acids which desirably have
; 14 to 20 carbon atoms. Especially preferred are saturated
fatty acids with 16 to 20 carbon atoms. Stearic acid has been
found especially useful.
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The beeswax can be white or yellow, and the paraffin can be
: a viscous liquid or a thin oil. The petroleum jelly is
. .advantageously white and, in a particularly preferred form, is
Ai of pharmaceutical grade; that is, free of skin irritating
components.
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In producing the compositions of the present invention, t~e
; components, with the exception of the water, are thoroughly
mixed ~ith each other and heated to 75C. Tbe water, in a
separate container, is brought to the same temperature. The
two are combined with stirring, and the emulsion which forms is
;- cooled to 30C. It can then be placed over a roller mill.
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The compositions of the invention are characterized by
surprisingly high therapeutic effectiveness, due to the special
composition of the suspension base. Since it contains no
allergenic or skin irritàting components (such as wool fat or
derivatives thereof, preservatives, or alcohols, such as
glycols), the unfavorable reaction problems of the prior art
are not found. The properties of the present composition are
particularly favorable if it is to be used under a protective
dressing (under occlusion).
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Under normal circumstances, inflammation or si~ilar skin
condi~ions which respond to anti-inflammatory agents are
treated by applying a cream or ointment containing 0.05% to
0 5% fluocortolone. The application is made several times
; 25 daily on the affected skin areas so that they are completely
~ covered. Most preferably, 0~2% fluocortolone is used.
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The surprising ef~ectiveness of the compositions of the
present invention, as well as the increased absorption of the
fluocortolone, is demonstrated in human pharmacological tests
on a substantial number of patients. The vasoconstriction
tests were carried out in accordarlce with the procedure of
McKenzie, which is generally accepted to demonstrate the
inflammation-inhibiting effect of topically applied
corticosteroids (A.W. McKenzie, and R.~. Atkinson: Arch.
Dermatolog. 89,741 (1964~). The investigations were carried
out on healthy individuals under double-blind conditions.
Test plasters having 100 mg each of the preparation to be
tested were applied to the back to the right and left of the
spine.The exposure time was 16 hours and tne results were tnen
evaluated after one half, two, four and eight hours. The
degree of skin paling was observed arld rated from 0 (no paling)
to 3 (considerable paling). The degree of skin paling is a
measure of the strength of the vasoconstrictive effect.
The numerical evaluation was achieved by calculating the
; areas under the curve obtained by plotting the average
vasoconstriction values against time, as is recognized in the
literature. For some ointment bases to which fluocortolone has
been added, we obtained the following exemplary area values:
% by weight
A. fatty acid mono-/-diglycerides 1.0
1,2-propylene glycol 1.0 area value. 10.2
white petroleum jelly 97.8
fluocortolone 0.2
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B. fatty acid triglycerides 45.0
. white petroleum jelly 54.8 area value: 8.9
fluocortolone 0~2
C. wool fat (lanolin) 20.0
. 5 fatty acid triglycerides 5.0
white petroleum jelly 35.0 area value: 11~2
, fluocortolone 0. 2
water 39.8
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D. fatty acid mono-/-diglycerides 2~0
fatty acid esters 5.0
liquid paraffin 19.4
white petroleum jelly 6.3 area value: 11.5
hard paraffin 6.3
sorbitol (70% aqueous solution) 10.0
glycerin 7.5
; fluocortolone 0~2
water 42.3
A standard ointment which contains 0. 25% fluocortolone and
0~25% fluocortolone capronate yields an area value of 15.9.
~ 20 This value is obtained with a total of 0.5~O active steroid
.~ present. The COmpQSitiOn of the present invention, on the
other hand, having a fluocortolone content of only 0~2%~ yields
an area value of 17 as follows:
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Cream according to the invention
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/O by weight
' mixture of oleic 10.0
` acid mono-/-diglycerides
- 5 stearic acid monoglyceride 3.0
` beeswax 5.0 area value: 17
liquid paraffin 7.0
white petroleum jelly 49.5
~ fluocortolone 0.2
; 10 water 25.3
The foregoing indicates clearly the greatly improved
effectiveness of the composition according to the present
invention. The new base increases the penetration of the
active fluocortolone as compared to known preparations
containing this same material. This increased effectiveness,
despite the lower fluocortolone content, is particularly
surprising, since increases in the area values are very
difficult to achieve in the upper range.
The following examples are intended to illustrate the
present invention:
Example 1
For the production of a highly effective cream, the
following components are mixed together and heated to 75C.
(All parts are by weight).
_g_
,;, 1 ~1L L`"~!L 6 ~
;
0.2 parts fluocortolone
parts oleic acid sorbitan ester
3 parts stearic acid monoglyceride
3 parts beeswax
- 5 14 parts liquid paraffin
48.5 parts white petroleum jelly
26.3 parts of water are heated separately to the same
temperature (75C). Subsequently, the two phases are combined
with each other under intensive stirring. An emulsion is
formed which is allowed to cool to 30C. This cream is
subsequently placed over a roller mill.
` Examples 2 and 3
In the same manner as described :in Example l, effective
creams are obtained from the following components. (All parts
are by weight):
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Example 2
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0.1 parts fluocortolone
2.5 parts a mixture of oleic acid mono- and diglycerides
i 5 0 parts oleic acid sorbitan ester
2.0 parts stearic acid monoglyceride
5.0 parts beeswax
17.5 parts liquid paraffin
27.5 parts white petroleum jelly
40.4 parts water
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Example 3
0.4 parts fluocortolone
8.4 parts lauric acid sorbitan ester
. 1.0 parts stearic acid monoglyceride
: 5 2.5 parts beeswax
6.0 parts liquid paraffin
24.0 parts white petroleum jelly
57.7 parts water.
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~hile only a limited number of specific embodiments of the
present invention have been expressl;y described, it is,
nonetheless, to be broadly construed and not to be limited
except by the character of the claims appended hereto.
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