Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
Creamy preparation containing _teroid_anl~ero~Ges~ f~ the
preparation thereof
The present invention relates to a novel creamy
preparation containing a steroid compound, which is
applicable to the skin.
It is well known that some steroid compoundsl such as
prednisolone, dexamethasone, cortisone, etc. have excel-
lent antiinflammatory activities and are usually used as
antiinflammatory agents in the form of ointments. However,
ointments feel sticky and unpleasant when appiied to the
skin, and furthermore, due to insufficient contact of the
lO steroid with the skin, the steroid is often insufficiently
absorbed by the skin. Moreover, the applied surface is
often rubbed by clothes, which results in loss of the
active ingdredient and also soiling of the clothes.
~esides, at high temperatures of 40C or higher, ointments
15 tend to become unstable.
In order to overcome these drawbacks of ointments, the
present inventors have attempted to prepare a more desir-
able substance for the topical application of steroid
- compounds, and provided a transparent, gelatinous prepa-ra-
20 tion which is prepared by mixing a solution of a steroid
compound in crotamiton with propylene glycol and adding
the resulting mixture to an aqueous solution of a carboxy- ;~
vinyl polymer and finally adding an organic amine to the
resulting mixture (cf. U.S. Patent 4,008,321~.
As a result of a further studying by the present
inventors, a creamy preparation of a steroid compound has
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now been developed which has greater stability and better
feeling in use.
According to one aspect of the present invention there
is provided a creamy preparation which comprises a stexoid
compound, a solvent selected f3-om crotamiton, propylene
glycol and mixtures thereof, a fluid oily substance, a
nonionic surfactant, and an aqueous solution of carboxy-
vinyl polymer, said preparation having been neutralized
with a basic substance and hav;ng a pH of 4 to 7 and a
10 viscosity of 10,000 to 100,000 centipoises at 20C, and
containing said fluid oily substance in an amount of 5 to
50 % by weight, said nonionic surfactant in an amount of
0.5 to S % by weight, and carboxyvinyl polymer in an
amount of 0.1 to 3.0 % by weight, based upon the total
15 weight of the preparation.
According to another aspect of the invention there is
provided a process for the preparation of a creamy pre-
paration of a steroid compound, which comprises dissolving
a steroid compound in a solvent selected from the group
20 consisting of crotamiton, propylene glycol and mixtures
thereof, adding thereto a fluid oily substance, a non-
ionic surfactant, a 1 to 10 % aqueous solution o~ car-
boxyviny] polymer, and then neutralizing the mixture with
a basic substance to give a creamy preparation having a pH
25 of 4 to 7 and a viscosity of 10,000 to 100,000 centipoises
and containing said fluid oily substance in an amount of 5
to 50 % by weight, said nonionic surfactant in an amount
of 0.5 to 5 ~ by weight, and carboxyviny] polymer in an
amount of 0.1 to 3.0 % by weight, based upon the total
30 weight of the preparation.
Preferably, the basic substance is water-soluble and
is added while heating the mixture at about 70 to 80C.
Examples of the steroids which may be contained in --
the creamy preparation include corticosteroids and esters
35 thereof, such as prednisolone, cortisone, triamcinolone,
bethamethasone, hydrocortisone, dexamithasone, methyl-
prednisolone, fluocinolone, fluorometholone, triamcinolone
acetonide, fluocinolone-acetonide, fluocinonide, clobetasol
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17-propionate, dexamethasone valerate, betamethasone
valerate, betamethasone acetate, betamethasone benzoate,
flumethasone, prednisolone acetate, hydrocortisone
valerate, dexamethasone valerate, betamethasone propion-
ate, betachloromethasone dipropionate, , or the like.The steroid compounds are incorporated into the creamy
preparation in an effective amount which varies depending
on the kind of steroid, but is usually in the range of
0.001 to 1 % by weight based on the total weight of the
10 preparation.
These steroids are usually insoluble in water, but are
easily soluble in crotamiton (i.e. N-crotonyl-N-ethyl-o-
toluidine). In the present invention, the steroids are
first dissolve~ in crotamiton or propylene glycol or a
15 mixture thereof. The steroids tend to be more soluble
in crotamiton than in propylene glycol, but although
crotamiton can be used alone, it is not preferable to
include more than 10 % by weight of this substance in
the creamy preparation. The propylene glycol may also
20 be used alone, but because of the lower solubility of
steroids in propylene glycol, it is usually used alone
only when the steroid compound has a comparatively high
solubility in propylene glycol, for instance, in the case
of dexamethasone.
~ccordingly, it is preferable in most cases to use a
mixture of crotamiton and propylene glycol. The dissolu-
tion of a steroid compound in a mixture of crotamiton and
propylene glycol may be carried out by first dissorbing
the steroid compound in either the crotamiton or the
30 propylene glycol and then adding the other one to the
solution. It is preferable to use a mixture of crota-
miton and propylene glycol also from the viewpoint that a "
mixture can give excellent emulsion stability and spread-
ability to the preparation. When propylene glyclol is
used in too Large an amount, the prepara'rion may produce
undesirable irritation to the skin, and hence, it should
be used in an amount of less than 20 % by weight. From
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the standpoint of solubility of steroids in the solvent,
the prevention of crystallization of steroids in the
preparation, and further emulsion stability, spread-
ability and the ~eeling of the preparation, crotamiton is
usually used in an amount of not more than 10 ~ by weight,
usually 0.5 to 10 % by weight, preferably 2 to 10 % by
weight, and propylene glycol is usually used in an amount
of less than 20 % by weight, i.e. ~rom 2 to less than 20 %
by weight, preferably 5 to 10 % by weight, based upon the
10 total weight of the preparation.
The fluid oily substances to be incorporated into the
creamy preparation include higher fatty alcohols, higher
fatty acids and higher fatty acid esters, oil~ hydro~
carbons, and mixtures thereof. Suitable examples of the
15 fluid oily substance are fatty alcohols having 8 to 18
carbon atoms, such as octyl alcohol, capryl alcohol, nonyl
alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol,
or stearly alcohol; monovalent or divalent fatty acids
having 8 to 1~ carbon atoms, such as lauric acid, myristic
20 acid, palmitic acid, oleic acid, linoleic acid, sebacic
acid, or stearic acid; alkyl esters of the fa~ty acids
as mentioned above wherein the alkyl moiety has 1 to
18 carbon atoms, such as isopropyl myristate, diethyl
sebacate, dibutyl sebacate, dioctyl sebacate, and mixtures
25 thereof.
The carboxyvinyl polymer is a hydrophilic vinyl
polymer with active carboxyl groups, which is prepared by
the polmerization of monomers comprising predominantly
acrylic acid [cf. Chem. & Eng. News, Vol. 36, page 64
(Sept. 29, 1958)i. A11 commercially available carboxy-
vinyl polymers can be used in the present invention.
Suitab]e examples are Carbopol 934, Carbopo] 940 and
Carbopol 941, which are trademarks of the products of
Goodrich Chemical Company. The carboxyvinyl polymer has
35 free carboxyl groups and their aqueous solution is thus
acidic. When the carboxyvinyl polymer is neutralized with
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a basic substance, a sticky gel is formed.
The basic substances to be used for the neutralization
of the carbo~yvinyl polymer include organic amines, such
as an alkylamine having 1 to 4 carbon atoms (e.g. methyl-
amine, ethylamine, or propylamine~, a dialkylamine havingl to 4 carbon atoms in each alkyl moiety (e.g. dimethyl-
amine, diethylamine, or dipropylamine), a trialkylamine
having l to 4 carbon atoms in each alkyl moiety te.g.
trimethylamine, triethylamine, or tripropylamine), an
lO alkanolamine having 1 to ~ carbon atoms in the a]kanol
moiety (e.g. methanolamine, ethanolamine, or propanol-
amine), a dialkanolamine having l to 4 carbon atoms in
each alkanol moiety (e.g. dimethanolamine, diethanol-
amine, dipropanolamine, or dibutanolamine), a trialkanol-
15 amine having l to 4 carbon at~ms in each alkanol moiety
(e.g. trimethanolamine, triethanolamine, tripropanolamine,or tributanolamine), and trimethylolaminomethane, and
also includes inorganic bases such as ammonia, an
aqueous solution of alkali metal hydroxides (e.g. sodium
20 hydroxi~e, or potassium hydroxide). All these basic
substances can give a gel having a similar viscosity when
they are used to neutralize the aqueous solution o car-
boxyvinyl polymer.
The nonionic surfactants to be incorporated into the
25 creamy preparation include sorbitan sesquioleate, sorbitan
trioleate, sorbitan monooleate, sorbitan monostearate,
sorbitan monolaurate, polyethy]ene glycol monostearate,
polyoxyethylene sorbitan monooleate, polyoxyethylene
sorbitan monolaurate, polyoxyethylene nonylphenyl ether,
30 polyoxyethylene cetyl ether, polyoxyethylene lauryl ether,
or mixtures thereof.
The creamy preparation of the present invention can be
prepared in the following manner.
A steroid compound is first dissolved in crotamitron
35 or polyethylene glycol or a mixture thereof (mixed ratio
of crotamiton : polyethylene glycol, 1 : lO to 5 : l by
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weight). A Eluid oily substance, a nonionic surfactant
and an aqueous solution o~ carboxyvinyl polymer are added
to the solution and a water-soluble basic substance is
added thereto with stirring, by which the carbox~vinyl
polymer is neutralized to give a viscous gel. The above
steps, i.e. the dissolution of the steroid compound in the
solvent and the mixing the ingredients, may be carried out
at room temperature but are preferably carried out at
about 70 to 80C.
Because of the action of the nonionic surfactant,
the oily phase of the mixture of a steroid compound and
a fluid oily substance,~and the aqueous phase of the
carboxyvinyl polymer solution become uniformly mixed to
give the desired creamy preparation. The creamy prepara-
15 tion thus obtained has a pH of 4 to 7, preEerably ~ to 5.5and a viscosity of 10,000 to 100,000 centipoises, prefer-
ably 30,000 to 80,000 centipoises, at 20C. The creamy
preparation contains 0.1 to 3.0 % by weight, preferably
0.5 to 1.2 ~ by weight, of the carboxyvinyl polymer based
20 upon the total weight of the preparation. The carboxy-
vinyl polymer is usually used in the form oE a 1 to 10 %
aqueous solution, preferably 2 to 4 ~ aqueous solution,
and after mixing the aqueous solution of the carboxyvinyl
polymer with the mixture of a steroid compound and other
ingredients, the content of the carboxyvinyl polymer in
the creamy preparation is regulated in the above range by
adding water thereto.
The pH of the preparation is regulated within the
range 4 to 7 by controlling the amount of the basic sub-
stance in the preparation. When the pH value is higherthan 7, i.e. when the preparation is alkaline, it tends to
be unstable, and on the other hand, when it is lower than
4, the preparation becomes too acidic and irritative to
the skin, and furthermore too large an amount of carboxy-
vinyl polymer is undesirably required for increasing theviscosity thereof.
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The f]uid oily substance is usually used in an amount
of 5 to 50 ~ by weight, preferably 10 to 20 % by weight,
based upon the total weight of the preparation, but when
crotamiton, which is also an oiLy substance, is used in
a large amount, the fluid oily substance is used in a
smaller amount. The nonionic surfactant is used in an
amount of 0.5 to 5 ~ by weight, preferably 1 to 2 % by
weight, based upon the total weight of the preparation.
The creamy prepara~ion of the present invention is a
10 uniform white cream and the viscosity thereof varies very
little from high temperature (e.g. ~0C) to low tempera-
ture (e.g. O~C), and also even when the preparation is
kept for a long period of time. Moreover, even when the
preparation is kept at a low temperature for a long period
15 of time, no crystallization of the steroid compound
appears. Accordingly, the creamy preparation is very
stable and does not have such drawbacks as seen in the
conventional ointments, such as melting or liquefaction
during summer time and hardening or solification during
20 winter time, and also separation of the oily phase and the
aqueous phase.
When the creamy preparation o~ the present invention
is applied to skin, it is contacted with salts, such as
sodium chloride, which are contained in a very smal]
25 amount in the perspiration or are present on the surface
of the skin and thereby the viscosity of the preparation
is rapidly decreased, and the preparation i9 liquefied and
shows good spreadability onto the skin. As a result, a
film of carboxyvinyl polymer is formed on the skin, which
30 promotes the absorption o~ the active ingredient ~steroid
compound) into the skin. Moreover, the film of carboxy-
vinyl polymer thus formed is readily dried when contacted
with air, and hence, the skin surface, to which the
preparation is applied, is not sticky but rather quite
smooth. Thus, the drawbacks of ointments such as soiling
of clothes and unpleasant feeling, can be eliminated.
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The creamy preparatlon of the present invention may
optionally incorporate other active ingredients, such as
antihistaminics, analgesics, and the like.
The creamy preparation of the present invention and
the method of preparation thereof are i]lustrated by the
following E~amples, but the present invention is not
limited thereto. In the Examples, the purified water was
prepared by purifying water with an ion exchange resin,
and the viscosity WAS measured at 20C by a C-type
10 viscosimeter (made by Tokyo Keilci Co., Ltd. ~apan).
Example l
Dexamethasone acetate (25 mg) was dissolved in
crotamiton (5 g) at about 70C, and isopropyl myristate
(lO g), propylene glycol (lO g), polyoxyethylene sorbitan
15 monolaurate (l g), a 4 % aqueous solution of a carboxy-
vinyl polymer (17 g), purified water (53 g) and a l %
aqueous solutlon of disodium edetate (1.2 g) were added
thereto. The mixture was heated to about 70 to 80C on
a water bath and a 2 % aqueous sodium hydroxide solution
(2 g) was added thereto with stirring, followed by the
addition of purified water until the total amount became
lO0 g. The mixture was thoroughly stirred and then cooled
to give a creamy preparation having a viscosity of 60,000
centipoises and a pH of 4.30.
Example 2
Fluocinonide (50 mg) was dissolved in crotamiton (7 g)
with warming, and liquid paraffin (lO g~, propylene glycol
(lO g), polyoxyethyelen lauryl ether (1 g), a 4 % aqueous
solution of carboxyvinyl polymer (20 g), purified water
(47 g) and a 1 % aqueous solution of disodium edetate
(1~2 g) were added thereto. The mixture was heated to
about 70 to 80C on a water bath, and a 2 ~ aqueous
solution of triethanolamine ~4.68 g) was added thereto
with stirring, followed by the addition of purified water
35 until the total amount became lO0 g. The mixture was
thoroughly stirred and then cooled to give a creamy
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preparation havlng a viscosity of 65,000 centipoises
and a pH of ~.47.
Example 3
Prednisolone (500 mg) was disso]ved in crotamiton
(10 g) with warming, and isopropyl myristate (lO g),
propylene glycol (10 g), polyoxyethylene sorbitan
monostearate (1.5 g), a ~ ~ aqueous solution of carboxy-
vinyl polymer (17 g), purified water (48 g) and a 1 ~
aqueous solution of ~isodium edetate (1.2 g) were added
10 thereto. The mixture was heated to about 70 to 80C on
a water bath and a 2 % aqueous solution oE trieth~lamine
(2.95 g) was added thereto with stirring followed by the
addition of purified water until the total amount became
lO0 g. The mixture was thoroughly stirred and then cooled
15 to give a creamy preparation having a viscosity of 54~,000
centipoises and a pH of 4.65.
Example 4
Dexamethasone (25 mg) was dissolved in propylene
glycol (20 g) with warming, and isopropyl myristate
~o (lO g), polyoxyethylene sorbitan (l.0 g), a 4 % aqueous
so~ution of carboxyvinyl polymer (13 9), purified water
(57 g) and a l ~ aqueous solution of disodium edetate
(1.2 9) were added thereto. The mixture was heated to
about 70 to 80C on a water bath and a 2 ~ aqueous solu-
25 tion of triethanolamine (5.2 9) was added thereto withstirring followed by the addition of purified water
until the total amount became lO0 9. The mixture was
thoroughly stirred and then cooled to give a creamy
preparation having a viscosity of 43,000 centipoises
30 and a pH of 4.80.
Example 5
Hydrocortisone (500 mg) was dissolved in crotamiton
(5 g) with warming, and liquid paraffin (lO g~, propylene
glycol (lO g), polyoxyethylene lauryl ether (1.5 g), a ~ %
35 aqueous solution of carboxyvinyl polymer (27 g), purified
water (38 g) and a 1 ~ aqueous solution of disodium
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edetate.(1.2 g) were added thereto with stirring. The
mixture was heated to about 70 to 80C on a water bath,
and a 2 % aqueous sodiurn hydroxide solution (lO g) was
added thereto with stirring followed by the addition of
purified water until the total amount became lO0 g. The
mixture was thoroughly stirred and then cooled to give a
creamy preparation having a viscosity of 35,000 centi-
poises and a pH of 5.30.
Examp].e 6
Triamcinolone acetonide (100 mg) was dissolved in
crotmiton (7 g) with warming, and isopropyl myristate
(10 g), propylene glycol (10 g), polyoxyethylene sorbitan
monolaurate (l g), a 4 ~ aqueous solution of carboxyvinyl
polymer (22 g), purified water (41 g) and a 1 ~ aqueous
15 solution of disodium edetate (1.2 g) were added thereto.
The mixture was heated to about 70 to 80C on a water bath
and a 2 ~ aqueous solution of triethylamine (6~5 g) was
added thereto with stirring followed by the addition of
purified water until the total amount became 100 g. The
20 mixture was thorough].y stirred and then cooled to give a
creamy preparation having a viscosity of 75,000 centi-
poises and a pH of 4.53.
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