Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTIONS
CORTICOSTEROID-CONTAINING OINTMENTS
I~ACKOROi3ND OF THE INVENTION
1) Field of the Inventions
The present invention relates to corticosteroid-
containing ointments, and more specifically to cortico-
steroid-containing ointments which contain deprodone
propionate as an effective ingredient, can exhibit its ef-
facts to the maximum extent and over a prolonged period of
time, du not have skin irritation, and are physicochemically
stable.
2) Description of the Related Art:
Corticosteroids have heretofore been employed widely
as remedial agents in the field of dermatology because they
exhibit even in a small amount strung therapeutic effects
for inflammatory and allergic skin diseases and have fast-
acting property compared with other medicaments.
When a corticosteroid is used as an external prepara-
Lion for a localised disease in the field of dermatology, it
is often applied in the form of an ointment since an oint-
ment has excellent protective and anti-inflammatory action
for the skin and gives very little irritation or contact
dermatitis to the skin.
The corneum in the surface of the skin however in-
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herently functions as a barrier in order to prevent pene-
tration of foreign substances from the outside into the
body. This has led to the problem that sufficient per-
cutaneous absorption cannot be achieved with an ointment
containing a steroid ingredient simply mixed in a base which
has conventionally been employed in external preparations.
To improve this problem, various percutaneaus absorp-
tion promoters such as 1-dodecylazacyclaheptan-2-one,
dimethylsulfoxide and dimethylformamide have been used in
recent years. These promoters are however not considered
sufficient in safety and feeling of use.
Tt is also practiced to use a corticosteroid having
strong effects so as to tentativel;t improve the percutaneous
absorption or to increase the concaantration of a cortico-
steroid so as to increase the therapeutic effects. These
methods are however accompanied by the problem of side ef-
fects because the influence to the whole body or a part
thereof increases in proportion to the effects and con-
centration of the corticosteroid.
2p It has therefore been desired to develop a cortico-
steroid-containing ointment which has high curative effects
and which gives less side effects to the whole body or a
part thereof and has higher safety.
It is however to be noted that the curative effects of
an ointment significantly vary depending on the kind of its
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base and the like even when the ointment contains the same
effective ingredient at the same concentration and an oint-
ment having excellent curative effects and little side ef-
fects can be obtained for the first time when its effective
ingredient and its base match well in physicochemical
properties.
SUMMARY OF THE INVENTION
Under such circumstances, the present inventors have
carried out an extensive investigation on the relationship
between individual corticosteroids and bases. As a result,
it has been found that addition of deprodone propionate
represented by a formula, which is to be described
hereinafter, to a specific base can provide an ointment
which allows deprodone propionate to exhibit its effects to
the maximum extent and over a prolonged period of time, doss
not have side effects such as skin irritation, and is
physicochemically stable, leading to the completion of the
present invention.
In one aspect of the present invention, there is thus
provided an ointment comprising the following ingredients
(a) and (b):
(a) 0.05--1 wt.% of deprodone propionate; and
(b) 89-99.95 wt.% of a base foraned of white petrolatum
and a liquid hydrocarbon.
The use of white petrolatum as one of components of a
base, i.e., component (b) in the present invention makes it
possible to cover 'the skin with an oily film without side
effects such as irritation and contact dermatitis to the
skin. Therefore, white petrolatum prevents transpiration of
water from the skin and permits a sort of ODT (occlusive
dressing technique), and further can promote the per-
cutaneous absorption of the medicinal ingredient. In addi-
tion, the use of the liquid hydrocarbon significantly im-
proves the spreadability onto the skin, thereby improving
the feeling of use, increasing the retention of the medi-
cinal ingredient on the skin and enhancing the curative ef-
fects.
The feeling of use can be improved further by the use
of a polyhydric alcohol in the present invention.
Corticosteroid-containing ointments according to the
present invention remain physicochemically stable even when
stored over a long period of time, have substantially no
skin irritation and side effects, and exhibit superb cura-
five effects.
HRIEF DESCRIPTION OF THE DRAWING
FIG. 1 diagrammatically illustrates the results of a
vasoconstriction test of the ointments of Examples 1-3 and
Comparative Examples 1-5.
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DETATLED DESCRIPL'ION OF THE INVENTION
.AND PREFERRED EMBODIMENTS
Deprodone propionate, ingredient (a) in the present
invention, is a compound which is obtained by esterifying
with propionic acid the 17-position of the prednisolone
skeleton and deoxidating its 21-position and has the struc-
tore represented by the following formula:
CH3
I
C=O
HO -.OCOCH2CH3
O ~
Ingredient (a) is added in an amount of 0.05-1 wt.%
(hereinafter indicated merely by '°%"), preferably 0.1-0.5%,
both based on the whale composition.
fPhe base, ingredient (b), is composed of white
petrolatum and a liquid hydrocarbon. Illustrative.of the
liquid hydrocarbon include light liquid paraffin, liquid
paraffin and squalane.
In the present invention, white petrolatum can amount
preferably~to 7~:-98.95% of the base, with 85-95% being par-
ticularly preferred. The liquid hydrocarbon can account
preferably for 1-15%, especially 5-10% of the base. In-
gredient (b) is added in an amount of 89-99.95% based on the
whole composition.
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_
It is pxeferred to add a polyhydric alcohol
[ingredient (c)] further to the ointment of the present in-
vention.
Examples of the polyhydr:ic alcohol as ingredient tc)
include glycerin, sorbitol, sorbitan and glycols. Among
these, it is preferred to use either one of propylene
glycol, 1,3-butylene glycol and polyethylene glycols having
an average molecular weight of 200°5,000.
Ingredient (c) can be added in an amount of 1.-10~,
preferably 2-6°s based on the whole composition.
It is also preferred to add a stabilizer in the pres-
ent invention. For example, butylhydroxyanisole, dibutyl-
hydroxytoluene (BHT) or the like can be employed.
The present invention will haareinafter be described in
further detail by the following examples, comparative exam-
pies and tests.
Example 2
Heprodone propionate 0.3 g
Light liquid paraffin S g
BHT 0.02 g
White petrolatum Sufficient to produce 5.00 g
BHT was melted in light l3c~uid paraffin at 5o-60°C,
followed by the dispersion of deprodone propionate. The
resultant dispersion was added to white petrolatum which had
been heated and melted at 65-'75°C in advance. After the
.,
mixture thus prepared was stirred, it was filtered and then
stirred until it became homogeneous. The mixture was cooled
to prepare an ointment.
Example 2
Depradone propionate 0.3 g
Light liquid paraffin 5 g
Propylene glycol 5 g
BHT 0.02 g
White petrolatum Sufficient to produce 100 g
l0 An ointment was prepared in a similar manner to Exam-
ple 1.
Example 3
Depradone propionate 0.3 g
Light liquid paraffin 5 g
~,5 1,3-butylene glycol 5 g
0.02 g
BHT
White petrolatum Sufficient to produce 100 g
An ointment was prepared in a similar manner to Exam-
ple 1.
20 Comparative Example l
Deprodone propionate 0.3 g
White petrolatum Sufficient to produce 100 g
Depradone propionate was added to white petrolatum
which had been heated and melted at 65-75°C in advance.
25 After the mixture thus prepared was stirred and filtered, it
_ g
was stirred until it became homogeneous. The mixture was
cooled to room temperature to prepare an ointment,
Comparative Example 2
Deproa~one propionate 0.3 g
Propylene glycol ~0 g
BHT 0,01 g
White petrolatum Sufficient to produce 100 g
Deprodone propionate and BHT were added to propylene
glycol. The resultant mixture was added to white petrolatum
which had been heated and melted at 65-75°C in aduance.
After the mixture thus prepared was stirred and filtered, it
was stirred until it became homogeneous, The mixture was
cooled to room temperature to prepare an ointment.
Comparative Example 3
Deprodone propionate 0.3 g
Propylene glycol 10 g
BHT 0.02 g
Gelled hydrocarbon Sufficient to produce 100 g
Deprodone propionate and BHT were added to propylene
glycol. The resultant mixture was heated and melted at 50-
60°C to prepare a trituration and stock, melt. Gelled
hydrocarbon was added little by little to the melt, whereby
gelled hydrocarbon was mixed and dispersed in the melt. An
ointment was prepared accordingly.
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Comparative Example 4
Deprodone propionate 0.3 g
Ethanol 35 g
Carboxyvinyl polymer 1 g
Triethanolamine 0~8 g
BHT 0.01 g
Purified water Sufficient 'to produce 100 g
Deprodone propianate and BIiT were dissolved in ethanol
in advance. An aqueous solution of carboxyvinyl polymer,
said solution having been prepared beforehand as a tritura°
tion and stock solution, was added to the ethanol solution,
followed by neutralization with triethanolamine. The
resultant mixture was diluted with purified water to give
the final weight of 100 g, whereby an ointment was prepared.
Comparative Example 5
Deprodone propionate 0.3 g
Propylene glycol '~.2 g
Concentrated glycerin 17.7 g
Sorbitol 3.1 g
Light liquid paraffin 61.0 g
Solid paraffin 3.2 g
Propylene glycol monostearate 0.5 g
Sucrose fatty acid ester 5 g
Methyl parahydroxybenzoate 0.1 g
Propyl parahydroxybenzoate o.1 g
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HHT 0.02 g
Purified water Sufficient to produce 100 g
Propylene glycol monostearate, sucrose fatty acid
ester, methyl parahydroxybenzoate, propyl parahydroxyben-
zoate and BHT were added under heat and stirring to con-
centrated glycerin and propylene glycol, followed by the
further addition of deprodone propionate. Light liquid
paraffin and solid paraffin were added further gradually un-
der stirring. Purified water was then added. After the
resultant mixture was stirred, it was caoled to prepare an
ointment.
Test 1
With respect to the ointments obtained in Examples 1-3
and Comparative Examples 1-5, respE:ctively, a vasocanstric-
Lion test was conducted on the normal human skin in an open
system in accordance with the following testing method.
(Testing method)
An adhesive plaster (30 mm wide, 1"7 cm long, about
1 mm thick) through which holes having an internal diameter
of 10 mm were formed was adhered to a lower middle back area
of a volunteer. Each test ointment was applied for 2 hours
in two of the holes at a rate of 30 mg per hole. After the
two-hour period, the test ointments were removed. After 2,
4, 6, 8, 10 and 12 hours from the removal of the test oint-
meets, the degrees or the presence or absence of skin pale-
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- 11
ness due to vasoconstriction were determined. Two points
were given when marked paleness was observed, one point when
apparent paleness was observed, 0.5 point when slight pale-
ness was observed, and 0 point when no paleness was ob-
served. Average of scores on 30 volunteers were determined.
The results are diagrammatically shown in FIG. 1.
In the above test, the ointments of Examples 1.-3 in
which white petrolatum was used as a base and light liquid
paraffin was employed in combination with white petrolatum
,0 optionally along with one or more of propylene glycol, 1,3-
butylene glycol and polyethylene glycol had high averages as
shown in FIG. 1. It is hence envisaged that the effects of
deprodone propionate were long-lastang.
Tn addition, bases prepared in accordance with the
same formulations as Examples 1-3 and Comparative Examples
1-5 except for the omission of deparodone propionate were ap-
plied to lower middle back areas o:E 30 normal volunteers at
two spots per base and volunteer. After 48 hours, the ir°
ritation of each base was observed. As is shown in Table 1,
irritation (slight erythema) was observed with,respect to
the bases of Comparative Examples 4 and 5, but similar ir-
ritation was practically unobserved with respect to the
bases of Examples ~.-3.
Regarding physicochemical stability, the ointments of
the examples were superior, as shown in Table 2, in dis-
colorationr bleeding and the stability of deprodone
propionate to those of the comparative examples although the
former ointments developed some bleeding at 45'C.
Table 1 irritation Test of Bases
Sample Percent positive
Example 1 0/60
Example 2 0/60
Example 3 ~ 1/60
Comparative Example 0/60
1
Comparative Example 2/60
2
Comparative Example 2/60
3
Comparative Example 7/60
4
Comparative Example 4/60
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