Note: Descriptions are shown in the official language in which they were submitted.
9479
SPECIFICATION
1. TITLE OF THE INVENTION
Gel preparations for external application
2. BACKGROUND OF THE INV~N'1'ION
~ield of the invention
The present invention relates to gel preparations for
external application cont~;n;ng diclofenac sodium as active
ingredient and having good stability and nice feeling on use.
Description of the Prior Art
Diclofenac sodium is a derivative of phenylacetic acid
represented by the formula:
Cl CH2COONa
NH
Cl
which is a non-steroid drug soluble in water and alcohols
having excellent antiinflammatory and analgetic effects.
For the present, it is used only in the form of oral prepara-
tions or suppositories and shows excellent antiinflammatory
and analgetic effects. However, side effects such as stomach
and intestines trouble, liver trouble and kidney trouble,
are at issue, especially in the case of the oral administra-
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~ZC}`9479
tion. Therefore, antiinflammatory and analgetic preparationswhich are absorbed cutaneously without showing such side
effects are desired.
In this regard, a gel preparation for external applica-
tion containing indomethacin, a non-steroid drug, is known t
Japanese Patent Laid-open No. Sho 53(1978)-81616). In this
preparation, however, there is a question of stability and
there is a defect that its yellow color due to the color of
indomethacin itself soils clothes as it is applied on the
skin. Thus, the inventor of the present invention has found
preparations for external applicaiton which consist of a
solution comprising another non-steroid compound having anti-
inflammatory and analgetic effects, at least one of peppermint
oil and salicylic acid ester in an amount sufficient to
dissolve the non-steroid compound and a base for external appli-
cation (Japanese Patent Application No. Sho 56(1981~-128032).
However, any and every compound having antiinflammatory and
analgetic effects, which may be used in.such preparations,
is limited to water-insoluble one.
3. SUMMARY OF THE lN~:NlION
The present invention provides gel preparations for
external application characterized by being prepared from
diclofenac sodium as the active ingredient, water, lower
alkanols and glycols as medium, a carboxyvinyl polymer as
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12~9~79
gelating agent and a weak basic substance as neutralizing
agent. The gel preparations for external application of
this invention have good stability and nice feeling on use
and show excellent antiinflammatory and analgetic effects
by cutaneous absorption.
4. BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph showing changes with the lapse of
time in the amount of diclofenac sodium contained in the
preparation of Example 1 of the present invention, and Figs.
2 to 4 are graphs showing changes with the lapse of time in
the amount of diclofenac sodium contained in the preparations
of Referential Examples 1 to 3, respectively.
5. DESCRIPTION OF THE PREFERRED EMBODIMENTS
The content of diclofenac soidium, the active ingredient,
in the gel preparation of the present invention is usually
0.3 to 3.0 % by weight, preferably, 0.5 to 2.0 % by weight of
the preparation.
As the medium for the active ingredient, water, lower
alkanols and glycols are used.
It is possible to prepare a stable gel preparation of
diclofenac sodium using as medium a combination af water
and iower alkanols or a combination of water and glycols.
However, when water and a lower alkanol are used, absorption
~2ns47s
of the active in~redient diclofenac sodium is not good,
because the preparation gets dry so easily that diclofenac
sodium crystallizes out on the surface of the skin. On the
other hand, when water and a glycol are used as medium, it
is necessary to use the glycol in an amount of at least 30 %
or more, in consideration of irritation which may be caused
by pH on the skin. Nevertheless, if a glycol is used for the gel
preparation in an amount of 30% or more,the preparation does not
get dry well as applied on the skin~. Moreover, the irritation on
the skin by the glycol remains still as a problem.
Therefore, it is re~uired to use a combination of water,
lower alkanols and glycols.
The medium in the preparation of the present invention
is used in such amount as is sufficient at least to dissolve
the active ingredient and as constitutes the whole prepara-
tion together with the gelating agent, the neutralizing agent,
the active ingredient, etc.
The ratio by weight of water to organic solvents in
the medium is, for example, from 8:2 to 4:6. It is preferred
that water is 80 % by weight or less, lower alkanols are 60
% by weight or less and glycols are 40 % by weight or less
- of the medium. As a preferable mixing ratio by weight for
the medium use in the present invention, there can be mention-
ed a ratio of water: lower alkanols: glycols of approximately
60 : 30 : 10.
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As the lower alkanols, there can be mentioned methanol,
ethanol, propanol, iso-propanol butanol and the like. Among
these, ethanol and iso-propanol are preferred.
As the glycols, ethylene glycol, propylene glycol and
1,3-butylene glycol are mentioned. The preferred among these
are propylene ~lycol and 1,3-butylene glycol.
The most preferable combination for the medium of the
above three solvents is water: ethanol: propylene glycol or
water: ethanol: 1,3-butylene glycol.
Carboxyvinyl polymers used as the gelating agent are
hydrophilic polymers obtained by polymerization of acrylic
acid as the main component. It is desirable to use a commer-
cial product. As commercially available products, there can
be mentioned Hiviswako 103, Hiviswako 104, and Hiviswako 105
r~ ~ra~ o f
~ 15 ~ Wakojunyakukogyo K.K. in Japan, Carbopol 934, Carbopol
~'d)~7ark'~ 0 ~
940 and Carbopol 941 ~K~ Goodrich Chemical Co. in U.S.A.,
and the like.
~ In the preparations of the present invention, weak
basic substances are used as the neutralizing agent in such
amount as enables to adjust the preparations almost neutral,
that is, at a pH of 6 - 8, preferably, a pH of 6.5 - 7.5.
An amount of, for example, 0.1 - 5 ~ by weight of the
preparation would suffice to atta}n the purpose.
As the weak basic substances, aliphatic amines are
preferred. The aliphatic amines include primary, secondary
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~Z(~9~'79
and tertiary alkanolamine and primary, secondary and tertiary
alkylamines. As concrete examples of the alkanolamines, there
can be mentioned monoethanolamine, diethanolamine,diisopr~nol~m;n~,
triethanolamine, triisopropanolamine, etc. As t~e alkylamines are
mentioned dimethylamine, diethylamine, trimethylamine, trie-
thylamine and the like. Especially preferred among these
are triethanolamine and diisopropanolamine. To use such weak
kasic substance as the neutralizing agent is one of the
characteristic features of the present invention. It is
proved that to use a strong base such as sodium hydroxide as
the neutralizing agent is improper. Comparing carboxyvinyl
polymers with diclofenac in the form of free acid, the acidity
of the former is stronger than that of the latter. However,
carboxyvinyl polymers are by themselves weak acids. Accordingly,
when a strong base such as sodium hydroxide is used as the
neutralizing agent, the pH value increases to about 9.
Although it is possible to prepare gel preparations of diclofenac
sodium using a gelating agent under such condition, the strong
basicity increased to a pH value of about 9 is undesirable
for the preparations for external application because it causes
irritation on the skin. On the other hand, when gel preparations
of diclofenac sodium are prepared without neutralizing the
carkoxyvinyl polymer with sodium hydroxide, the free acid of
diclofenac is formed in the resulting gel ~reparations since
the sodium ion of diclofenac sodium combines with said carboxy-
12G~94~9
vinyl polymer having an acidity stronger than diclofenac evenif the polymer were under the pH condition of about 7. Although
diclofenac in the form of sodium salt is stable, diclofenac
itself is hardly soluble and loses stability in the preparations
with the lapse ol time.
Further, to the gel preparation of the present invention,
at least one of r~rrPrm;nt oil, Q-menthol, methyl salicylate, ethyl
salicylate and glycol monosalicylate may be added, if desired.
Peppermint oil and Q-menthol give cool feeling to the skin, and
salicylic acid derivatives accelerate cutaneous absorption of
the active ingredient. They are applied as an inductive
stimulant in the case of pain complaints and increase the
analgetic effects. These auxiliary agents are added to the
gel preparations usually in an amount of 0.5 to 5 % by weight.
Although there is no limitation on the method of
preparing the gel preparation of the present invention, they
can be prepared, for example, according to the following
methods: Diclofenac sodium is dissolved in a lower alkanol.
To the solution obtained are added an aqueous solution of a
carboxyvinyl polymer and glycol, while stirring. Then, a
nP~ltr~ ;ng agent is added further to the solution, while
stirring, in such amount as adjusts the pH of the resulting
gel preparat~on at about 6 8. Thus, the gel preparation
of the present invention is obtained. The gel preparation of
the present invention can be prepared also by adding an aqueous
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94~9
solution of a carboxyvinyl polymer to a solution obtained by
dissolving diclofenac sodium in a mlxture of a lower alkanol
and a glycol, while stirring, and then adding a neutralizing
agent to the resulting solution while stirring.
To the gel preparation of the present invention, those
applicable in the art, such as aromatic agent, antiseptic
agent, coloring agent, etc., may be added in a small amount,
besides the salicylic acid esters as mentioned above, if so
desired. However, good preparations are obtained usually
without necessity for adding such additives.
The gel preparation of the present invention thus obtained
have good stability. They do not show any change in the viscosity
even at high temparatures and any crystallization at low
temperatures. Moreover, they adhere well to the skin and
spread very well. Eurther, they do not give sticky feeling
and they get dry easily.
In the following, the present invention is illustrated
by giving Examples of the preparations of the present invention
and Referential Examples of preparations having a similar
composition and a low pH value. However, the invention shall
not be limited to these Examples.
Example 1
~iclofenac sodium (lg) was dissolved in 95% ethanol
(30g) which stirring. On the other hand, propylene glycol
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lZ~.Y9479
(lOg), 4% aqueous solution (25g) of a carboxyvinyl polymer
Carbopol 940 and purified water (20g) were mixed uniformly
by stirring, and triethanolamine (1.5g) was added to the
mixture while continuing the stirring. To the gel base thus
prepared, the alcoholic solution of diclofenac sodium pre-
viously prepared was added and the whole was adjusted to 100g
by further adding purified water. After stirring well, a gel
preparation having a viscosity of 20,000 centipoise and a pH
of 7.15 was obtained.
Example 2
Diclofenac sodium (o.5g) was dissolved in 95% ethanol
(25g) while stirring. On the other hand, 1,3-butylene glycol
(20g), 4% a~ueous solution (~5g) of Carbopol 940 and purifed
water (20g) were mixed uniformly by stirring, and triethanol-
amine (1.5g) was added to the mixture while continuing the
stirring. To the gel base thus prepared, the alcoholic
solution of diclofenac sodium previously prepared was added
and the whole was adjusted to 100g by further adding purified
water. After stirring well, a gel preparation having a viscosity
of 22,000 centipoise and a pH of 7.15 was obtained.
Example 3
Diclofenac sodium (3.0g) and l-menthol (0.5g) were
dissolved in 95~ ethanol (40g) by stirring. On the other
lZ(~9479
hand, propylene glycol (lOg), 4% aqueous solution (25g) of
Carbopol 940 and purified water (15g) were mixed uniformly by
stirring, and diisopropanolamine (3.0g) was added to the mixture
while continuing the stirring. To the gel base thus prepared,
the alcoholic solution of diclofenac sodium previously
prepared was added and the whole was adjusted to lOOg by
further adding purified water. After stirring well, a gel
preparation having a viscosity of 17,000 centipoise and a pH
of 7.20 was obtained.
Referential Example 1
Diclofenac sodium (l.Og) and peppermint oil (3.0g) were
diSsolved in 95% ethanol (40g) by stirring. Separately, 3%
solution (20g) of Carbopol 940 in propylene glycol, 4%
aqueous solution (25g) of Carbopol 940, citric acid (0.3g)
and purified water (8.0g) were mixed uniformly by stirring,
and triethanolamine (0.05g) was added to the mixture while
continuing the stirring. To the gel base thus prepared, the
alcoholic solution of ~ f~.n~ sodium and peppermint oil prepared
previously was added and the whole was adjusted to lOOg by
further addition of purified water. After stirring well, a
gel preparation having a viscosity of 22,000 centipoise and
a pH of 5.2 was obtained.
Referential Example 2
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~2(~9479
~iclcfenac sodium (l.Og) was dissolved in 95% ethanol (40g)
by stirring. Separately, 3% solution (20g) of Carbopol 940
in propylene glycol, 4% aqueous solution (25g) of Carbopol
940 and purified water (lOg) were mixed uniformly by stirring,
and triethanolamine (0.05g) was added to the mixture while
continuing the stirring. To the gel base thus prepared, the
alcoholic solution of diclofenac sodium prepared previously
was added and the whole was adjusted to lOOg by further addition
of purified water. After stirring well, a gel preparation
having a viscosity of 23,000 centipoise and a pH of 5.4 was
obtained.
Referential Example 3
Diclofenac sodium (l.Og) was dissolved in 95% ethanol
(20g) by stirring. Separately, 3% solution (40g) of Carbopol
940 in propylene glycol, 4% aqueous solution (lOg) of Carbopol
940 and purified water (25g) were mixed uniformly by stirring,
and triethanolamine (0.8g) was added to the mixture while
continuing the stirring. To the gel base thus prepared, the
alcoholic solution of diclofenac sodium previously prepared
was added and the whole was adjusted to lOOg by further adding
purified water. After stirring well, a gel preparation having
a viscosity of 21,000 centipoise and a pH of 5.8 was obtained.
Next, comparison between the gel preparations of the
lZ~}9479
above Examples and the gel preparation of the Referential
Examples was effected with regard to the stability of diclo-
fenac sodium with the lapse of time. More precisely, the
content of diclophenac sodium in each preparation was measured
just after the preparation was obtained and after the lapse
of a preseribed time, according to the method of analysis as
described hereinafter. The changes with the lapse of time in
the content of diclofenac sodium in the preparation of Example
1 are shown in Fig. 1, and those of the preparations of Referential
Examples 1 to 3 are shown in Figs. 2 to 4, respectively (
abscissa: days elapsed, ordinate: percentages of the active
ingredient contained in the preparation, taking that just after
the preparation is obtained as the 100~).
It is apparent from these Figures that the preparation
of Example 1 is significantly high in the stability with the
lapse of time, as compared with the preparations of the
Refersntial Examples.
The measurement of the content of diclofenac sodium in
the above gel preparation was effected by extracting diclofenac
sodium with ethanol, isolating diclofenac sodium from the
extract by high-speed liquid chromatography (column: Lichrosorb
A ~a ~ r~)
Pl8, developing agent: methanol/water/acetic acid - 600 :
400 : 5, room temperature), and determining the ultraviolet
absorbance (254 nm).
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