Note: Descriptions are shown in the official language in which they were submitted.
CA 02244679 1998-07-22
TRANILAST-CONTAINING PREPARATION FOR EXTERNAL APPLICATION
AND METHOD OF PRODUCING THE SAME
FIELD OF THE INVENTION
The present invention relates to a preparation for
external application containing tranilast as an active
ingredient, more specifically to a preparation for topical
application giving good transdermal absorbability of the active
ingredient in the preparation due to improvement of the base
and capable of sufficiently keeping an effective drug
concentration in the skin tissue after application, which
preparation is directed to treat keloid having little skin
irritation, hypertrophic scar, psoriasis, palmoplantar
pustulosis, prurigo nodularis including urticaria perstans,
allergic dermatitis (e.g., atopic dermatitis, contact
dermatitis, dutaneous pruritus, sting of an insect, priurigo
simplex acuta, etc.), the other eczema and dermatitis
including progressive palmoplantar keratoderma and lichen
symplex chronicus.
BACKGROUND OF THE INVENTION
An antiallergic drug, tranilast, has been commercially
available as a therapeutic agent for allergic diseases. It
has also been reported to show excellent pharmaceutical
effect on keloid and hypertrophic scar (Kiyoshi Ichikawa et
al., Oyo Yakuri (Pharmacometrics) 43(5), 401 (1992), Haruo
Suzawa et al., Nichi Yakuri-shi (Folio Pharmacol Japan) 99, 231
(1992)). Tranilast has been used in the dosage form for oral
administration such as capsules, tablets, dry syrup, fine
granules, and the like. However, the drug orally taken is
absorbed from the digestive tract through portal vein to liver
where the drug is metabolized to give a so-called first passing
effect. Thereafter, a part of the drug is transferred to local
sites and its biological availability is decreased.
Accordingly, it is necessary to administer a relatively large
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amount of the drug so as to maintain the effective drug
concentration in blood, which increases manifestation of side
effects. Further, preparations for external application directly
applied to local sites of skin, particularly patches, have been
considered favorable for the treatment of keloids, hypertrophic
scar, and allergic dermatitis so that it is necessary to
maintain an effective drug dosage sufficiently in the skin.
Attention has been paid to patches as preparations for
topical application as well as a new route for applying
systemic drugs as transdermal drug delivery system (TDS). In
other words, in TDS, a drug absorbed from its preparation
through epidermis is taken into blood stream via subcutaneous
capillary vessels while a portion of the drug is transferred
directly to local skin tissues without being taken into blood
stream. Aiming at such a topical application effect, a number
of patches utilizing non-steroid anti-inflammatory drug
systems (NSAIDS) have been already developed and commercially
available.
Further, subcutaneous application by patches is
effective as the controlled release method of drugs by which
effects of drugs can be prolonged and the concentration of
drugs in blood can be controlled. Thus, it is possible to
suppress manifestation of side effects.
However, skin inherently has a property to defend the
inside of body from foreign substances that may invade from
TM
the outside. Keratolytic agents such as Azone are sometimes
used as a base in order to increase transdermal absorption of
a drug. Such agents give high skin irritation and thus may
possibly cause side effects such as an eruption on the skin.
Transdermal absorbability depends on characteristics of the
molecule, which extremely limits formulation of the drugs
that can give effective transdermal absorption.
Tranilast is sparingly soluble in water. Among organic
solvents, it is hardly soluble in methanol, ethanol, ethyl
acetate, while it is soluble in dimethyl formamide, pyridine,
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dioxane, and acetone though these solvents are not suitable
for the base of preparations for external application. The
drug can be solved to some extent in a kind of fatty acid and
its ester, animal and vegetable oils and fats, terpene
compounds, and alcohols, but the solubility is not sufficient
and the drug cannot be dispersed well in the preparations. This
affects transdermal absorbability of tranilast and the
solubility of the drug makes it difficult to formulate the drug
into a patch.
As a preparation containing tranilast for external
application, a patch containing tranilast has been developed,
which contains a kind of fatty acid and alcohols as
absorption aids to improve cutaneous absorbability (Japanese
Patent Application Laid-Open No. Hei 4-99719). However, this
patch requires a large amount of absorption aids, such as
fatty acid ester or alcohols, which might possibly cause skin
irritation.
A tranilast-containing ointment has also been developed,
which contains a basic aqueous solution as an absorption aid
(Japanese Patent Application Laid-Open No. Hei 6-128153).
This preparation for external application has basic pH due to
the basic aqueous solution contained as an absorption aid.
The basic substance itself might possibly cause skin
irritation. Thus, there are problems that make it difficult
to put the preparations into practical use.
SUMMARY OF THE INVENTION
An object of the present invention is to solve the above
-described problems in the prior art to achieve the practical
use of the preparation for external application containing
tranilast as an active ingredient, which has good transdermal
absorbability of the active ingredient in the preparation,
sufficiently keeps a drug concentration effective in the skin
tissues, and shows little skin irritation.
The earlier report (Toyomi Waseda, The Japanese Journal
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of Dermatology, 99 (11), 1159 (1989)) describes that the
effective concentration of tranilast in the skin tissue for
treatment of keloid patients is about 8 to 10 g/g when it is
orally administered in a dose of 300 mg/day in three divided
doses for three days. Another earlier report (Yasuo Goto et al.,
Kiso to Rinsho (The Clinical Report), 25(15), 69 (1991))
discloses that in the experiment using rat carrageenan-induced
granulation tissue model a dose-dependent inhibitory effect was
observed when tranilast was orally administered in a dose of 50,
100, and 200 mg/kg for consecutive 14 days and the drug
concentration in the skin tissue one hour after the final
administration was 4.2 0.4, 10.3 0.9, and 23.17 1.7 g/g,
respectively. Consequently, the tranilast concentration in the
skin tissue after its application to the skin should desirably
be comparable to or higher than the values as described above.
Keloid, hypertrophic scar, and allergic dermatitis are
diseases giving some appearance on the skin surface that is
not only apparently ugly but also sometimes accompanied by
strong itchiness or pain as subjective symptoms. Accordingly,
it is preferable that preparations for external application
to be directly applied to the diseased part should not
produce irritation by contact and the base in the preparation
does not cause skin irritation. Particularly, patches are
preferably elastic and do not have undue strong adhesiveness
so that little resistance occur when they are detached. In
this connection, a cataplasm containing water or a soft type of
plasters is desired.
The present invention provides a preparation for
external application and a method of producing it to achieve
the above object, which preparation contains an aqueous base
comprising tranilast, its salt, or a mixture thereof as an
active ingredient, in which the aqueous base comprises a
dissolution medium, a dispersant, an absorption aid, an
adhesive, and/or a form-keeping agent, and water, the active
ingredient is dissolved in the dissolution medium, and dispersed
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in the aqueous base by means of the dispersant. The present
invention provides such a preparation for external application
comprising tranilast and a patch for external application which
comprises a support having the preparation for external
application coated thereon.
Further, the present invention relates to a method of
producing a preparation for external application containing
tranilast, which comprises dissolving an active ingredient
selected from tranilast, its salt, or a mixture thereof in a
dissolution medium, adding thereto a dispersant, and
mixing the solution with an aqueous base comprising an
absorption aid, an adhesive, and/or a form-keeping agent, and
water, and to a method of producing a patch for external
application which comprises coating the above preparation for
external application on a support.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a permeation/diffusion cell used in the
test for skin permeation rate of the drug in the preparation
of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Tranilast, which is the active ingredient of the
preparation for external application of the present
invention, is N-(3,4-dimethoxycinnamoyl)-anthranilic acid
represented by the following formula or salt thereof:
CHg 4 HOOC
cH3o H=cH-cONx b
The content of tranilast in the preparation is preferably 0.05
to 5 wt%. If the content of the active ingredient is too low,
its pharmacological effect is insufficient. If it is too
high, it does not show additional merit and, thus, is
CA 02244679 1998-07-22
economically disadvantageous.
In the preparation for external application of the
present invention, the dissolution medium to solve tranilast
therein is selected from oily substances including fatty
acids and derivatives thereof, animal and vegetable oils and
fats, terpene compounds, alcohols, crotamiton,
N-methyl-2-pyrrolidone, and triethanolamine.
The fatty acids and derivatives thereof that can be used
as the dissolution medium are monocarboxylic acids or esters
thereof having 3 to 30 carbon atoms. The fatty acids include
octadecanoic acid, oleic acid, and linoleic acid. The fatty
acid esters include glycerol monocaprate, tetradecyl
tetradecanoate, hexadecyl hexadecanoate, oleyl oleate, and
isopropyl myristate. Further, fatty acid alkali metal salts
are exemplified by fatty acid sodium salts.
The animal and vegetable oils and fats include almond
oil, olive oil, camellia oil, persic oil, peppermint oil, soy
bean oil, sesami oil, mink oil, cottenseed oil, corn oil,
safflower oil, coconut oil, eucalyptus oil, castor bean oil,
hydrogenated castor bean oil, soybean lecithin, and the like.
The terpene compounds include menthol, menthone, limonene,
pinene, piperidone, terpinene, terpinolene, terpinol, and
carveol. The alcohols are non-aqueous alcohols, such as benzyl
alcohol, and octanols.
Further, examples of organic solvents that can be used
as the dissolution medium other than those described above
include crotamiton, N-methyl-2-pyrrolidone, triethanolamine,
and the like.
Among the above oily substances, preferable examples are
oleic acid, linoleic acid, glycerol monocaprate, oleyl oleate,
castor bean oil, hydrogenated castor bean oil, soybean oil,
soybean lecithin, 1-menthol, menthone, limonene, benzyl
alcohol, crotamiton, N-methyl-2-pyrrolidone, and
triethanolamine. Particularly, crotamiton and
N-methyl-2-pyrrolidone are most preferable because they do
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not only dissolve tranilast but also enhance its transdermal
absorption. The dissolution medium may be used alone or in
combination of two or more thereof. Its total content is
preferably 2 to 5 wt%.
When a solution obtained by solving tranilast in the
dissolution medium is mixed with the aqueous base comprising
an absorption aid, an adhesive, and/or a form-keeping agent,
and water upon production of the preparation for external
application, tranilast must be uniformly dispersed in the
final preparation. Since tranilast is extremely sparingly
soluble in water as described above, it is not solved in part
when mixed with the aqueous base and gives poor
dispersibility . If the drug is not sufficiently dispersed in
the preparation, its amount to be released is lowered, which
results in a decrease in the amount transdermally absorbed.
According to the present invention, the preparation with
good dispersibility can be produced by dissolving tranilast
dissolved in the dissolution medium, adding the dispersion
medium thereto, mixing the solution well to allow the
dispersion medium to retain at least a part of, preferably
substantially all amount of, tranilast, and kneading it with
the aqueous base. The dispersion medium to be used is
pharmaceutically acceptable solid powder, particularly
inorganic solid powder, having ability to retain tranilast
dissolved in the dissolution medium. Preferable examples of
the dispersion medium are silicon dioxides such as silicon
dioxide hydrate or soft silicic acid anhydride, and silicates
such as magnesium silicate hydrate or aluminum silicate hydrate,
with silicon dioxide hydrate (white carbon) being most
preferred.
Namely, a preparation with good dispersibility can be
prepared by dissolving tranilast in the dissolution medium,
adding white carbon to the solution, mixing it thoroughly to
allow tranilast to be adsorbed, and mixing the resulting
dispersion with the aqueous base.
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The ratio of the amount of the dispersion medium to the
total amount of tranilast and the dissolution medium is 1/3 to
1/5.
The absorption aid for enhancing absorption of tranilast
from the preparation into the skin tissue is selected from fatty
acids and derivatives thereof that are used as a base in
preparations for external application, animal and vegetable oils
and fats, terpene compounds, alcohols, crotamiton, and
N-methyl-2-pyrrolidone. Preferable examples thereof include
oleic acid, 1-menthol, ethanol, propylene glycol, butanediol,
1,2,6-hexanetriol, benzyl alcohol, crotamiton, and
N-methyl-2-pyrrolidone. These may be used alone or in
combination of two or more thereof. Propylene glycol,
butanediol, or N-methyl-2-pyrrolidone is most preferably
used. These compounds can be added to the preparation in an
amount of 0.5 to 10 wt%, preferably 2 to 5 wt%, to keep the
sufficient drug concentration in the skin tissue after its
application without causing skin irritation.
The pH value is another factor that enhances absorption
of tranilast into the skin tissue. Tranilast is absorbed well
into the skin at the pH range from the neutral region to the
weak acidic region. Preferable pH range is 3.5 to 7.5 taking
account of skin irritation of the preparation and
form-keeping ability Citric acid and tartaric acid can be
used to adjust the pH of the preparation.
The patch for external application is required not to
cause contact irritation on the diseased part, to keep the
form of the preparation, and to retain adhesiveness
sufficiently, because the preparation is directly applied on
the diseased part exposed on the skin surface. As the patch
that satisfies the above requirements, aqueous types are
preferably used though non-aqueous soft type plasters can
also be used.
Water-soluble polymers to be used as the adhesives
and/or the form-keeping agent includes polyacrylic acid and
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its derivatives, acrylate copolymer and its emulsion,
cellulose derivative and its derivative, gum arabic, gelatin,
casein, polyvinyl alcohol, polyethylene glycol, polyvinyl
alcohol, polyethylene glycol, polyvinyl pyrrolidone, methyl
vinyl ether/maleic anhydride copolymer and its emulsion, and
naturally-occurring polysaccharides. These compounds may be
used alone or in combination of two or more thereof . Its
total amount to be added to the preparation ranges from 5 to
15 wt%. Preferably, polyacrylic acid and its derivatives, and
acrylate copolymer and its emulsion are used. In the case of
using sodium polyacrylate, it is possible to use as an
aluminum compound capable of crosslinking activated alumina,
synthetic aluminum silicate, aluminum hydroxide, and the like.
Examples of fat-soluble polymers that can be used as the
adhesive and/or the form-keeping agent include natural rubber,
isoprene rubber, polyisobutyrene rubber, styrene-butadiene
rubber, styrene-isoprene-styrene block copolymer,
styrene-butadiene-styrene block copolymer, silicone, rosin,
polybutene, lanolin, petrolatum, plastibase, beeswax, and solid
paraffin.
Polyhydric alcohols that can be used as the adhesive
and/or the form-keeping agent include glycerol, polyethylene
glycol, ethylene glycol, and D-sorbitol. These can be used alone
or in combination of two or more thereof. The total amount to be
added is preferably 5 to 40 wt%.
Using the above-described adhesive and/or form-keeping
agent, it is possible to provide the tranilast-containing
patch for external application that can keep adhesiveness,
its form, and flexibility for a long time, with causing
little skin irritation.
Further, if desired, it is possible to use a nonionic
surface active agent or an inonic surface active agent, the
other additives for medicines, for example, polyacrylic acid
metal salt, bentonite, titanium oxide, and the like, in a
necessary amount.
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According to the present invention, the thus-prepared
preparation for external application containing tranilast is
spread on the support fabric such as flannel, nonwoven
fabric, or the like and a film for peeling such as
polyethylene, polypropylene, polyester, or the like on the
exposed surface of the opposite side of the support fabric.
The resulting products can be brought to market as a
preparation for external application.
It is also possible to use the preparation for external
application of the present invention as ointment or cream to be
directly applied on the diseased part as it is without spreading
on the support.
In the preparation for external application containing
tranilast according to the present invention, tranila.st,
which is sparingly soluble in water, is dissolved in the
dissolution medium and dispersed in the aqueous base with
being retained by the dispersion medium. Thus, tranilast is
uniformly dispersed in the aqueous base. Because of this, the
active ingredient is easily released to provide high skin
absorbability, its effective concentration in the skin tissue
after its application is sufficiently maintained with little
skin irritation. -
Description of Preferred Embodiment
The following Examples will demonstrate the present
invention in more detail, but are not construed to limit the
scope of the present invention.
EXAMPLE 1
Three g of tranilast was dissolved in a mixed solution
of 20 g of crotamiton and 10 g of ethanol by gradually
heating to 60 to 70 C . After adding 7 g of white carbon
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thereto, the mixture was thoroughly mixed and ethanol was
removed under reduced pressure. Then, 5 g of 1-menthol and
2.5 g of titanium oxide were added thereto and the mixture
was mixed to prepare a tranilast solution. Separately, 25 g
of tartaric acid was dissolved in 552 ml of water followed by
adding 50 g of sodium polyacrylate, 60 g of polyacrylate
starch, and 250 g of glycerol. The resulting mixture was
mixed well to prepare an aqueous base mixture.
The tranilast solution, the aqueous base mixture, 0.5 g
of dry aluminum hydroxide gel, and 25 g of methyl
acrylate/2-ethylhexyl acrylate copolymer resin emulsion were
uniformly kneaded to obtain 0.3% tranilast-containing
preparation for external application. The pH of the preparation
was 5.2.
EXAMPLE 2
Three g of tranilast was dissolved in a mixed solution
of 20 g of crotamiton and 25 g of N-methyl-2-pyrrolidone.
After adding 7 g of white carbon thereto and mixing the
solution well, ethanol was removed under reduced pressure.
Then, 5 g of 1-menthol and 2.5 g of titanium oxide were added
and mixed to prepare a tranilast solution. Separately, 25 g
of tartaric acid in 527 ml of water was mixed well with 50 g
of sodium polyacrylate, 60 g of starch acrylate, and 250 g of
glycerol to prepare an aqueous base mixture.
The tranilast solution, the aqueous base mixture, 0.5 g
of dry aluminum hydroxide gel, and 25 g of methyl acrylate-2-
ethylhexyl acrylate copolymer resin emulsion were kneaded
uniformly to obtain 0.3% tranilast preparation for external
application. The pH of the preparation was 5.2.
EXAMPLE 3
In the same composition containing tranilast and the
base for external application as described in Example 1, 50 g
of butanediol was added to the aqueous base mixture and
glycerol was used in an amount of 200 g in place of 250 g to
obtain 5% butanediol-containing tranilast preparation for
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external application.
EXAMPLE 4
In the same composition containing tranilast and the
base for external application as described in Example 3,
propylene glycol was used in place of butanediol to obtain 5%
propylene glycol-containing tranilast preparation for
external application.
EXAMPLE 5
In the same composition containing the base for external
application as described in Example 1, 1% tranilast preparations
for external application each having the pH of 4.3, 5.4,
6.3, and 7.4 were obtained using 10 g of tranilast, tartaric
acid in an amount varied as shown in the following table, and
various sodium polyacrylate (50 g) as shown in the following
table.
Tartaric acid Sodium polyacrylate pH
(g) (Showa Denko k.k)
"Example 5-1 50 Viscomate NP-700 4.3
Example 5-2 20 Viscomate NP-700 5.4
Example 5-3 10 Viscomate NP-600 6.3
Example 5-4 0 Viscomate F480SS 7.4
[Performance Evaluation Test]
TEST EXAMPLE 1
Using the preparations of Examples 5-1 through 5-4,
influences of pH on penetrability of the drug into the skin was
evaluated by the in vitro test with the penetration rate as an
index.
In this test, penetration/diffusion cell shown in
Fig. 1 was used.
The rat abdominal skin was interposed in the fixing
device 1, a patch having the test preparation spread on the
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support was attached to the fixing device 2 so as to contact the
preparation for external application with the rat abdominal
skin on the fixing device 2. In order to prevent air from
entering the container 3, 5.18 ml of Tyrode's solution was
added thereto. The penetration/diffusion cell was placed in
the incubator maintained at 37 C , Tyrode's solution 5 was
stirred with the stirring bar 4 and a 0.5 ml portion of
Tyrode's solution was sampled at each point of time within 1
to 7 hours. The drug concentration in the sampled solution
was measured to calculate the penetration rate of the drug in
the test preparation for external application into the rat
abdominal skin: The drug concentration was measured by
HPLC. The results are shown in Table 1.
Conditions for HPLC
Column: CAPCELLPAK C18 (SG120), 4.6 mm x 150 mm
Mobile phase:
50 mM ammonium acetate buffer(pH 6.0)/acetonitrile
= 750/250 (0 to 10.5 min)
-- 375/625 (10.5 to 15 min)
-~ 750/250 (15 to 20 min)
Column temperature . 40 C
Flow rate . 1.0 ml/min
Detection wavelength: 320 nm for tranilast
254 nm for internal standard
substance (ethyl p-
hydroxybenzoate)
Retention time: 5 min for tranilast,
min for internal standard substance
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Table 1: Influences of pH on transdermal absorption of the
preparation for external application
Amount penetrated Penetration rate*1
(,u g/cmz ) n=3
pH of Base 1 hr 3hr 5 hr 7 hr 24 hr (5 to 24 hr)
4.3 0.00 0.02 0.15 0.40 4.21 0.22 0.02
5.4 0.00 0.03 0.10 0.40 3.79 0.20 0.03
6.3 0.00 0.00 0.12 0.35 2.93 0.15 0.03
7.4 0.00 0.00 0.04 0.11 0.17 0.06 0.02
*1: tL g/cm2 /hr S.E.
TEST EXAMPLE 2
In the same manner as in Examples 3 and 4, the
preparations were prepared so as to make each of the amount of
the absorption aid, propylene glycol and butanediol, 2%, 5%, and
and 10% and make the amount of N-methyl-2- pyrrolidone 2.5%. The
resulting preparations were respectively spread on the support
to give patches. Using the resulting patches, skin
absorbability of the skin absorption aids, that is, propylene
glycol, butanediol, and N-methyl-2-pyrrolidone, was evaluated
by measuring the penetration rate of tranilast and the amount
of tranilast accumulated in the skin. The results are shown in
Table 2. The skin penetration rate was determined in accordance
with the method as described in Test Example 1. The drug
concentration in the skin was determined as described below.
Abdominal body hair of Wistar-Imamichi male rats (200 g)
was cut with a hair clipper or a shaver under anesthesia with
ether and the preparation was applied to the abdominals skin
(3 x 3 cm). Eight hours after application of the preparation,
the rats were sacrificed and the stratum corneum was removed
thoroughly, by stripping with cellophane adhesive tape on the
skin at the middle of the part where the preparation was
applied. After removing fat, capillary vessels, and the like in
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dermis, a part of the dermis was taken out by punching with a
puncher(o 1.0 cm) and cut into thin strips. Then, the thin
strips of the skin section were mixed with 2 ml of methanol,
1 ml of an ethanol solution of ethyl p-hydroxybenzoate (internal
standard substance) (10 g/ml), and 0.5 ml of 50 mM ammonium
acetate buffer (pH 6.0). The resulting mixture was homogenized
well by microhomogenization and centrifuged at 15,000 rpm for
min.. The resulting supernatant was applied to HPLC. The same
conditions for HPLC as in Test Example 1 were followed.
Table 2: Effect of skin absorption aid on transdermal absorption
of tranilast
Absorption aid
Penetration rate Drug concentration
( g/cm2/h) in skin (g g/g)
- 0.22 0.01 26.01 1.29
2% propylene glycol 0.38 0.07 44.93 -~- 4.66
5% propylene glycol 0.33 0.07 45.92 8.71
10% propylene glycol 0.68 t 0.10 35.24 0.69
2% butanediol 0.50 0.13 36.04 5.08
5% butanediol 0.64 0.18 49.74 -~- 7.19
10% butanediol 0.83 0.07 33.08 0.92
2.5% N-methyl-2-pyrrolidone 0.68 f 0.10 53.23 10.88
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