Note: Descriptions are shown in the official language in which they were submitted.
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SPECIFICATION
PERCUTANEOUSLY ABSORBABLE PATCH
[Technical Field]
This invention relates to a percutaneously
absorbable preparation-containing patch suitable for
persistently releasing estrogen and luteal hormone as
medicinal ingredients from the preparation.
[Background Art]
Estradiol contained in estrogen is secreted
from the ovary of a woman during her reproducible
period of time. Thus, women who are at the menopause
or thereabouts become lacking in estradiol whereupon
they suffer from their menopausal disorder, irregular
menstruation or the like. Remedies for these symptoms
are now taken by the use of orally administrable
preparations, but these preparations are rapidly
metabolized by digestive canals such as stomachs and
intestines and also by livers to be made inactive.
Thus, in order to obtain sufficient medicinal
efficacy, a large dose of estradiol must be
administered. The use of such a high dose is very
likely to cause adverse side effects and the like.
Accordingly, the use of estradiol in
combination with luteal hormone, which, through
percutaneous administration, can reduce the metabolism
of estradiol and permits the estradiol to reach blood
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and, at the same time, inhibits the side effects of
the estradiol per se, has been studied in the art.
For example, Japanese Pat. Appln. Laid-Open
Gazette No. 342532/92 discloses a percutaneously
absorbable preparation which comprises estradiol and
luteal hormones as active ingredients and a tackifier
composed mainly of an acrylic tackifier consisting of
2-ethylhexyl acrylate and N-vinyl-2-pyrrolidone. The
acrylic tackifier, however, has poor capability of
releasing drugs and has strong irritation to the skin,
thereby rendering said preparation unsuitable for
continuous administration for a long period of time.
Japanese Patent Gazette No. 51623/94 discloses a
method wherein estradiol and norethisterone acetate as
active ingredients are dissolved in a gel comprising
hydroxypropyl cellulose and ethanol, this is then
formed to a reservoir type, and the release of the
active ingredients is regulated with the aid of a
permeant regulating membrane. Ethanol, however, has
ZO strong irritation to the skin and causes side effects
such as rubefaction at preparation-applied sites very
frequently.
The percutaneously absorbable patches
containing a preparation under various studies as
mentioned above are low in biological utility since
the active ingredients contained therein can be used
only to a limited extent. In addition, the tackifier
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per se or the addition of absorption accelerators such
as ethanol will raise a problem of skin irritation
since the preparation is attempted to be
percutaneously administered.
[Summary of the Invention]
In view of the above disadvantages, the
inventors of this invention have made intensive
studies with a view to providing percutaneously
absorbable patch containing a preparation, which has
1) a simple structure,
2) improved biological utility, and
3) reduced skin irritation thus
completing this invention.
Thus, the percutaneously absorbable
preparation-containing patch of this invention
comprises: (1) a base comprising as essential
ingredients a (A - B) n - A based elastoner (elastic
polymer) (wherein A is substantially a monovinyl-
substituted aromatic compound polymer block, B is
substantially a conjugated diolefin copolymer block
and n is an integer of 3 - 7), crotamiton and a
softening agent; and (2) at least two hormones as
active ingredients.
According to this invention, at least two
hormones are contained as the active ingredients.
Estrogen and luteal hormone are usually used as the
two active ingredients.
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Examples of the estrogen are estradiol,
estrone, estriol, equilin, equilenin and derivatives
thereof. Among them, estradiol is usually used in the
percutaneously absorbable preparation contained in the
patch according to this invention.
The luteal hormone is suitably selected from
the group consisting of progesterone,
hydroxyprogesterone caproate, medroxyprogesterone
acetate, dydrogesterone, chlormadinone acetate,
ethisterone, dimethisterone, norethisterone,
norethisterone acetate, norethisterone enanthate,
ethynodial acetate, megestrol acetate and
allylestrenol.
The content of the estrogen exemplified by
the estradiol is 0.01 to 10% by weight, preferably
0.05 to 5% by weight, more preferably 0.1 to 1% by
weight, based on the total amount of the
pharmaceutical preparation. Although the content of
the luteal hormone varies depending upon the kind
thereof, it is usually 0.01 to 10% by weight,
preferably 0.05 to 5% by weight, more preferably 0.1
to 1% by weight, based on the total amount of the
pharmaceutical preparation. The content of the luteal
hormone is preferably 1 to 5 times (weight ratio) that
of estrogen exemplified by estradiol.
In this invention, the (A - B) n - A based
elastomers usable as the base are those which are
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commercially easily available and include a styrene-
butadiene-styrene block copolymer (trade name:
Califlex TR-1101 produced by Shell Chemical Corp.), a
styrene-isoprene-styrene block copolymer (trade name:
Califlex TR-1107 and Califlex TR-1111 produced by
Shell Chemical Corp.), a styrene-isoprene-styrene
block copolymer (trade name: JSR 5000 and JSR 5100
produced by Nippon Synthetic Rubber Co.) and a
styrene-isoprene-styrene block copolymer (trade name:
Quintack 342-1 produced by Nippon Zeon Co.) with the
styrene-isoprene-styrene block copolymer being
particularly preferred. The use of the (A - B) n - A
type elastomers as the base for the preparations will
greatly enhance the releasability of the estrogen
exemplified by estradiol and the luteal hormone as
well as the biological utilizability thereof.
Crotamiton used in this invention markedly
improves the preparations in solubility of both the
estrogen exemplified by estradiol and the luteal
hormone contained in the preparations, in
releasability of these active ingredients from the
preparations, and in percutaneous absorption of these
active ingredients and the like. Further, crotamiton
has never been incorporated as a solubilizer and
absorption accelerator for the estrogen (exemplified
by estradiol) and the luteal hormone into the (A - B)
n - A based elastomer supported preparation before the
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accomplishment of this invention and there is found no
literature which suggests such incorporation of
crotamiton as mentioned above.
Examples of softening agents used in this
invention include liquid paraffin, polybutene, castor
oil, cotton seed oil, palm oil, coconut oil, and
process oil.
The use of the base containing as the
essential components the (A - B) n - A type elastomer,
the crotamiton, and the softening agent will enhance
the biological utilizability of said hormones and will
reduce rubefaction and rash which are otherwise caused
by medicinal irritation to the skin.
The preferable contents of the (A - B) n - A
based elastic polymer, the crotamiton, and the
softening agent in the percutaneously absorbable
preparation contained in the patch according to this
invention are as follows.
The total content of the essential
ingredients consisting of the (A - B) n - A based
elastomer and the crotamiton, is preferably 20 to 99%
by weight, more preferably 30 to 60% by weight based
on the total amount of the preparation. For the
content of each ingredient, the content of the (A - B)
n - A based elastomer is preferably 5 to 50% by
weight, more preferably 10 to 20% by weight, based on
the total amount of the preparation, the content of
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the crotamiton is preferably 1 - 20% by weight, more
preferably 3 to 10% by weight, based on the total
amount of the preparation, and the content of the
softening agent is preferably 10 to 70% by weight,
more preferably 20 to 65% by weight, based on the
total amount of the preparation. The combination of
the ingredients having the above respective contents
is best for attaining the effect of this invention.
The percutaneously absorbable preparation
contained in the patch of this invention may contain
conventional additives in addition to the above
essential ingredients. Specific examples of the
conventional additives are synthetic rubbers, such as
polyisobutyrene; tackifiers, such as saturated
alicyclic hydrocarbon resins (for example, Arcon P-100
(trade name)), rosin esters (for example, KE-311
(trade name), KE-100 (trade name), or Super Ester S-
100 (trade name)), alicyclic hydrocarbons (for
example, Escorez 5300 (trade name)), terpene
hydrogenated resins (for example, Clearon P-105 (trade
name)), and hydrogenated rosin esters (for example,
Foral 105 (trade name)); and super absorbent polymers,
such as Sumikagel SP-520 (trade name), Aquakeep 4SH
(trade name), Arasorb 800F (trade name), Sunwet lM-
300MPS (trade name), and Sunwet lM-lOOOMPS (trade
name), and inorganic fillers, such as zinc
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calcium carbonate, titanium dioxide, and silica. They
may be added in a suitable amount.
The content of the tackifier is 0 to 40% by
weight based on the total amount of the preparation
and, when the maintenance of satisfactory tackiness is
required, is 5 to 40% by weight based on the total
amount of the preparation. Although the above content
suffices for attaining the purposes, it is more
preferably 10 to 30% by weight. The content of the
water-absorptive polymer is 0 to 15% by weight based
on the total amount of the preparation and, when
optionally added to the preparation, is preferably 0.1
to 10% by weight, more preferably 0.5 to 5% by weight.
The support for the preparation of this
invention is preferably one having no influence on the
release of the drug and, in addition, superior
flexibility and is preferably selected from a film or
woven fabric of polyester, polypropylene, polyethylene
or the like and an aluminum foil, or a flexible
composite material comprising a laminate of these
plastic films or woven fabrics.
The dosage form of the percutaneously
absorbable preparation contained in the patch of this
invention is preferably a plaster, particularly
preferably an anhydrous plaster.
A general process for producing the
percutaneously absorbable preparation-containing patch
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of this invention will be described hereunder. All
ingredients of a base except for crotamiton are heat
melted and then incorporated with active ingredients
and crotamiton to obtain a preparation which is then
spread over a support, covered with a liner and then
cut into a desired shape to produce preparation-
containing patches. Alternatively, the preparation
may be once applied over a film which has been treated
to be made releasable, after which the preparation-
applied film was pressed against a suitable support totransfer the spread preparation thereto, and suitably
cut thereby producing preparation-containing patches.
Further, it is also possible to use a method which
comprises dissolving all the ingredients in an organic
solvent such as hexane, toluene or ethyl acetate,
spreading the solution on a support, removing the
organic solvent to produce a preparation, covering the
preparation with a liner and then cutting the
preparation-coated support into a predetermined shape
to produce preparation-coated patches, or a method
which comprises once spreading the above solution over
a film which has been treated to be made releasable,
removing the organic solvent, transfering the
resulting preparation to a suitable support by
pressing it against the support thereby to produce
preparation-attached patches.
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The percutaneously absorbable preparation-attached
patches of this invention thus prepared can enhance
the release of the estrogen exemplified by estradiol
and the luteal hormone as active ingredients, improve
the biological utilizability of these active
ingredients and, at the same time, have the effect of
markedly relieving the skin irritation in case of
continuous administration and long-term
administration.
[Brief Description of the Drawings]
Fig. 1 shows data on estradiol in a
percutaneous permeation test 1 on hairless mice. In
the same Fig., the abscissa represents the
preparation-applied time (hr), the ordinate the amount
of the percutaneous permeation (llg/cm2), O data on
estradiol of Example 2, O data on estradiol of
Reference Example 1 and ~ data on estradiol of
Reference Example 2.
Fig. 2 shows data on norethisterone acetate
in a percutaneous permeation test 1 on hairless mice.
In the same Fig., the abscissa represents the
preparation-applied time (hr), the ordinate the amount
of the percutaneous permeation (lg/cm2), ~ data on
norethisterone acetate of Example 2, O data on
norethisterone acetate of Reference Example 1 and
data on norethisterone acetate of Reference Example 2.
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Fig. 3 shows data on estradiol in a
percutaneous permeation test 2 on hairless mice. In
the same Fig., the abscissa represents the
preparation-applied time (hr), the ordinate the amount
of the percutaneous permeation (~Ig/cm2), 0 data on
estradiol of Example 23, ~ data on estradiol of
Example 17, ~ data on estradiol of Example 15 and -
data on estradiol of Comparative Example 1.
Fig. 4 shows data on norethisterone acetate
in a percutaneous permeation test 2 on hairless mice.
In the same Fig., the abscissa represents the
preparation-applied time (hr), the ordinate the amount
of the percutaneous permeation (llg/cm2), 0 data on
norethisterone acetate of Example 23, O data on
norethisterone acetate of Example 17, ~ data on
norethisterone acetate of Example 15 and ~ data on
norethisterone acetate of Comparative Example 1.
Fig. 5 shows data on estradiol in a test for
measuring the active ingredients concentration in the
blood of rabbits. In the same Fig., the abscissa
represents the preparation applied time (hr), the
ordinate t~e estradiol concentration in the blood
(ng/ml), O data on estradiol of Example 23, O data
on estradiol of Example 17, ~ data on estradiol of
Example 15 and ~ data on estradiol of Comparative
Example 1.
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Fig. 6 shows data on norethisterone acetate
in a test for measuring the active ingredients
concentration in the blood of rabbits. In the same
Fig., the abscissa represents the preparation-applied
time (hr), the ordinate the norethisterone acetate
concentration in the blood (ng/ml), 0 data on
norethisterone acetate of Example 23,. 0 data on
norethisterone acetate of Example 17, ~ dat~ on
norethisterone acetate of Example 15 and ~ data on
norethisterone acetate of comparative Example 1.
[Prefereed Embodiments of the Invention]
This invention will be described in more
detail refering to the following Examples, Test
Examples and the like. In Examples, Comparative
15 Examples and Reference Examples, all the numerical
values are in % by weight.
Example 1
Styrene-isoprene-styrene 37.00
block copolymer (trade name:
Califlex TR-1107)
Liquid paraffin 61.78
Butylhydroxytoluene O.Z0
Crotamiton 1.00
Estradiol 0.01
Norethisterone acetate 0.01
Using the above ingredients, a preparation
was prepared, spread on a support and cut into a
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desired size, in accordance with the above general
production process to produce a patch containing a
percutaneously absorbable preparation of a
estradiol/norethisterone acetate mixture type.
Example 2
Styrene-isoprene-styrene block copolymer
(Trade name- Califlex TR-1107) 35.00
Liquid paraffin 57.00
Crotamiton 5.00
Estradiol 0.50
Norethisterone acetate 2.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Example 3
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 28.00
Liquid paraffin 27.00
Crotamiton 20.00
Super absorbent polymer
(Trade name: Sumikagel SP-520) 5.00
Estradiol 10.00
Norethisterone acetate 10.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
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- 14 -
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Example 4
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 35.00
Liquid paraffin 56.00
Crotamiton 5.00
Super absorbent polymer
(Trade name: Aquakeep 4SH)1.00
Estradiol 0.50
Norethisterone 2.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
mixture type.
Example 5
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 20.00
Liquid paraffin 53.00
Crotamiton 3.00
Super absorbent polymer
(Trade name: Aquakeep 4SH)20.00
Estradiol 1.00
Norethisterone 3.00
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The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
mixture type.
Example 6
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 35.00
Liquid paraffin 52.00
Crotamiton 5.00
Super absorbent polymer
(Trade name: Arasorb 800F)5.00
Estradiol 0.50
Norethisterone 2.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
mixture type.
ExamPle 7
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 35.00
Liquid paraffin 52.00
Crotamiton 4.00
Super absorbent polymer
(Trade name: Arasorb S-lOOF)5.00
Estradiol 1.00
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Norethisterone 3.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
mixture type.
Example 8
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 35.00
Liquid paraffin 53.00
Crotamiton 5.00
Super absorbent polymer
(Trade name: Sunwet IM-300MPS) 5.00
Estradiol 0.50
Medroxyprogesterone acetate 1.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an
estradiol/medroxyprogesterone acetate mixture type.
Example 9
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 35.00
Liquid paraffin 53.00
Crotamiton 5-00
Super absorbent polymer
(Trade name: Sunwet IM-lOOOMPS) 5.00
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Estradiol 0.50
Medroxyprogesterone acetate 1.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an
estradiol/medroxyprogesterone acetate mixture type.
Example 10
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 40.00
Polyisobutylene 5.00
Liquid paraffin 37.70
Butylhydroxytoluene 0.30
Crotamiton 5.00
Tackifier (alicyclic saturated hydrocarbon resin)
(Trade name: Arcon P-100) 10.00
Estradiol 0.50
Medroxyprogesterone acetate 1.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an
estradiol/medroxyprogesterone acetate mixture type.
Example 11
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 5.00
Polyisobutylene 10.00
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Liquid paraffin 40.00
Crotamiton 6.00
Tackifier (alicyclic saturated hydrocarbon resin)
(Trade name: Arcon P-100) 35.00
Estradiol 1.00
Medroxyprogesterone acetate 3.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an
estradiol/medroxyprogesterone acetate mixture type.
Example 12
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 50.00
Liquid paraffin 26.00
Butylhydroxytoluene 0.50
Crotamiton 5.00
Super absorbent polymer
(Trade name: Arasorb S-lOOF)2.00
Tackifier (alicyclic saturated hydrocarbon resin)
(Trade name: Arcon P-100) 12.50
Estradiol 1.00
Progesterone 3.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
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absorbable preparation of an estradiol/progesterone
mixture type.
Example 13
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 27.00
Liquid paraffin 41.00
Crotamiton 3.00
Tackifier (rosin ester)
(Trade name: KE-311) 25.00
Estradiol 1.00
Progesterone 3.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/progesterone
mixture type.
Example 14
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 50.00
Polyisobutylene 2.00
Liquid paraffin 30.80
Butylhydroxytoluene 0.20
Crotamiton 5.00
Tackifier (hydrogenated alicyclic hydrocarbon)
(Trade name: Escorez 5300) 10.00
Estradiol 0.50
Progesterone 1.50
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The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/progesterone
mixture type.
Example 15
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 20 . 00
Liquid paraffin 33.00
Crotamiton 5.00
Tackifier (alicyclic saturated hydrocarbon resin)
(Trade name: P-100) 36.00
Estradiol 1.00
Norethisterone acetate 5.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Example 16
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 29 . 50
Liquid paraffin 30.00
Crotamiton 7.50
Super absorbent polymer
(Trade name: Sunwet IM-lOOOMPS) 10.00
Tackifier (hydrogenated alicyclic hydrocarbon)
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(Trade name: Escorez 5300)20.00
Estradiol 0. 50
Norethisterone acetate 2.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Example 17
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 22.50
Liquid paraffin 39.50
Crotamiton 10.00
Tackifier (alicyclic saturated hydrocarbon resin)
(Trade name: P-100) 25.00
Estradiol 0. 50
Norethisterone acetate 2. 50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Example 18
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 5.00
Liquid paraffin 60.00
Crotamiton 3.00
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Tackifier (rosin ester)
(Trade name: Super Ester S-100) 30.00
Estradiol 1.00
Norethisterone 1.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
mixture type.
Example 19
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 27.00
Liquid paraffin 40.00
Crotamiton 5.00
Tackifier (alicyclic saturated hydrocarbon resin)
(Trade name: Arcon P-100) 25.00
Estradiol 1.00
Norethisterone 2.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
mixture type.
Example 20
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 34.50
Liquid paraffin 42.50
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Crotamiton 5.00
Tackifier (hydrogenated rosin ester)
(Trade name: Foral 105) 15.00
Estradiol 0.50
Medroxyprogesterone acetate 2. 50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an
estradiol/medroxyprogesterone acetate mixture type.
Example 21
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 34 . 50
Liquid paraffin 34. 00
Polyisobutylene 8.00
Crotamiton 3 . 00
Super absorbent polymer
(Trade name: Arasorb 800F)3 . 00
Tackifier (terpene hydrogenated resin)
(Trade name: Clearon P-105) 15.00
Estradiol 0.50
Medroxyprogesterone acetate 2 . 00
The procedure of Example 1 was followed
-except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an
estradiol/medroxyprogesterone acetate mixture type.
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- 24 -
Example 22
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 25.00
Liquid paraffin 40.00
Crotamiton 4.00
Tackifier (hydrogenated alicyclic hydrocarbon
resin)
(Trade name: Escorez 5300) 25.00
Estradiol 1.00
Progesterone 5.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/progesterone
mixture type.
Example 23
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 22.50
Polyisobutylene 5.00
Liquid paraffin 36.50
Crotamiton 5.00
Super absorbent polymer
(Trade name: Arasorb S-lOOF)3.00
Tackifier (rosin ester)
(Trade name: KE-311) 25.00
Estradiol 0.50
Norethisterone acetate 2.50
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The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Example 24
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1111) 34.50
Liquid paraffin 40.50
Crotamiton 3.00
Super absorbent polymer
(Trade name: Arasorb S-lOOF)3.00
Tackifier (rosin ester)
(Trade name: KE-311) 15.00
Estradiol 1.00
Norethisterone acetate 3.00
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Example 25
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 25.00
Polyisobutylene 5.00
Liquid paraffin 41.90
Tackifier (rosin ester)
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(Trade name: KE-311) 25.00
Crotamiton 0.10
Estradiol 0. 50
Norethisterone acetate 2.50
The procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Comparative Example 1
Styrene-isoprene-styrene block copolymer
(Trade name: Califlex TR-1107) 25.00
Polyisobutylene 5.00
Liquid paraffin 42.00
Tackifier (rosin ester)
(Trade name: KE-311) 25.00
Estradiol 0. 50
Norethisterone acetate 2.50
The Procedure of Example 1 was followed
except that the above ingredients were used, thereby
to produce a patch containing a percutaneously
absorbable preparation of an estradiol/norethisterone
acetate mixture type.
Reference Example 1
Acryl resin-based solvent-type pressure sensitive
adhesive
(Trade name: NISSETSU PE-300, solid content 40%)
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92 . 00
(solid content)
Crotamiton 5.00
Estradiol 0.50
Norethisterone acetate 2 . 50
The procedure of Example 1 was followed
except that the above ingredients were mixed together
to form a mixture which was applied to a backing
material (such as a support or liner) in such a manner
that the thickness of the thus applied mixture on the
backing material was the same as those in the Examples
after the solvent of the former has been evaporated.
The dried mixture attached to the backing material was
cut into pieces of a desired size to prepare a patch
containing a percutaneously absorbable preparation of
a estradiol/norethisterone acetate mixture type.
Reference Example 2
Silicon adhesive
(Trade name: Silascon 355 Medical Adhesive,
solid content 18.5%) 92 . 00
(solid content)
Crotamiton 5.00
Estradiol 0.50
Norethisterone acetate2 . 50
The procedure of Reference Example 1 was
followed except that the above ingredients were used,
thereby to produce a patch containing a percutaneously
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absorbable preparation of a estradiolinorethisterone
acetate mixture type.
Experiment 1
(Percutaneous permeation test 1 on hairless mice)
Percutaneous permeation tests were made on
hairless mice using the patches obtained in Example 2
and Reference Examples 1 - 2, respectively.
The results are shown in Figs. 1 and 2. As is seen
from the result, the patch of Example 2 clearly
exhibits excellent release of estradiol and nor-
ethisterone acetate as compared with those of
Reference Examples 1 - 2. This is because the
preparation of the present invention contains the (A -
B) n - A based elastomer, crotamiton and the softening
agent as the base component.
Experiment 2
(Percutaneous permeation test 2 on hairless mice)
Using each of the patches of Examples 15, 17 and
23 as well as the patch of Comparative Example 1, a
percutaneous permeation test was made on hairless mice
with the results being shown in Figs. 3 and 4.
As is shown in the result, the patches of Examples
15, 17 and 23 clearly indicate excellent release of
estradiol as compared with that of Comparative Example
1. This is because the preparation of the present
invention contains crotamiton.
Experiment 3
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(Test for measuring the concentration of the
medicinal ingredient in the blood of rabbits)
Using each of the patches of Examples 15, 17 and
23 as well as the patches of Comparative Example 1,
measurements for concentration of the active
ingredient in the blood of rabbits were made. Nippon
white-colored hares were depilated at their back and
then the concentrations of estradiol and
norethisterone acetate were measured with the lapse of
time with the results being shown in Figs. 5 and 6.
As is indicated in the results, the preparations
of Examples 15, 17 and 23 are excellent in the rise of
concentration of the medicinal ingredients in blood,
the amount of the ingredients released and durability
as compared with that of Comparative Example 1.
[Utilizability in the Industrial Field]
As mentioned above, the percutaneously absorbable
preparation-containing patch of this invention
comprising as essential ingredients the (A - B) n - A
based elastomer, crotamiton and the softening agent as
well as two hormones, especially an estrogen
exemplified by the estradiol and a luteal hormone, as
an medicinal ingredient are most suitable for release
of the medicinal ingredient therefrom, exhibit
sufficient medicinal efficacy without causing
rubefaction, rashes and the like when used.
