Note: Descriptions are shown in the official language in which they were submitted.
lZ4~157
The present invention relates to a percutaneous
administration type pharmaceutical preparation in tape form
containing isosorbide dinitrate (ISDN) as an active ingredient
therein.
Isosorbide dinitrate (ISDN) and nitroglycerin (NG)
are known as effective medicines for angina pectoris. However,
neither of these is effective over a prolonged period of
application nor are they effective in suppressing or preventing
attacks of angina pectoris after an initial period of effect-
iveness. Therefore, a pharmaceutical preparation which would
supply ISDN gradually and at a constant rate over a long
period of time has been desired.
In an effort to overcome these deficiencies, a
percutaneous absorption type pharamaceutical preparation in
tape form containing ISDN or pentaerythritol tetranitrate
(PETN) has been proposed in U.S. Patent No. 4,420,470 wherein
the adhesive base material is composed of a copolymer contain-
ing alkyl acrylate or methacrylate in a concentration of at
least 50% by weight, a functional monomer in a concentration of
up to 20% by weight and a vinyl ester monomer in a concentra-
tion of up to 40~ by weight. However, such a percutaneous
absorption type pharmaceutical preparation in tape form has
the following three critical drawbacks:
Firstly, since such a pharmaceutical preparation is
administered via the skin having a tissue which serves to
prevent foreign substances from entering into the body, it is
difficult to administer an amount of active ingredients which
is sufficient to exert an immediate pharmaceutical effect.
Thus, a large-sized tape must be applied to the skin and/or an
absorption promoter must be incorporated into the adhesive
base material.
Secondly, this pharmaceutical preparation necessarily
has a side effect. Due to contact of the adhesive base layer
with the skin over a given period of time, the normal secretion,
metabolism, expansion and construction of the skin are prevented
and the skin suffers irritation at the edge portion of the tape and/or
. . _
~.
51S7
from the adhesive base layer thereof, resulting in a
number of red spots, and in extreme cases, incrustations
and/or edemata, on the skin,which can remain for several
days.
Thirdly, a part of the adhesive base mater~al
unavoidably remains on the skin when the tape i~ peeled
off.
Additionally, a part of the active ingredients
contained in the adhesive base material can penetrate
through the backing, and/or crystalize at the lnterface of
the adhesive base layer and the backing thereby resulting
in reduced pharmaceutical effect.
This invention was completely based on a
knowledge of the inventors that an adhesive base material
allowing a quick supply of ISDN to the skin should be
selected from adhesive materials in which ISDN can be
dissolved; skin irritation can be reduced by using
adhesive materials having excellent hydrophilic
propertles; and, for reduction of skin irritation,
adhesive materials containing polar monomers such as
acrylic acid, methacrylic acid, etc., should not be
employed for an adhesive base material, while adheqive
materials containing a monomer, N-vinyl-2-pyrrolidone
(VP), are desirable thereof.
2~ Accordingly, the invention provides a
percutaneous admlnistration type pharmaceutical
pr0paration in tape form comprising a flexlble backing,
whic~ non-permeable to the active ingredient, and an
adhesive base layer formed on said flexible backing; the
adhesive base layer consisting essentially of an adhesive
base material and an active ingredient compatible with
said adhesive base material, wherein the adhesive base
material is a copolymer containing 2-ethylhexyl acrylate
(EHA) in a concentration of 45 to 80 mole %, a
(meth)acrylate monomer in a concentration of 0 to 35 mole
%, which comprises one or more members selected f rom the
group consisting of propyl acrylate, butyl acrylate, hexyl
acrylate, 2-ethyl butyl acrylate, heptyl acylate, octyl
,,
lZ~S157
- 2a -
acrylate, nonyl acrylate, decyl methacrylate, and lauryl
methacrylate, and N-vinyl-2-pyrrolidone (VP) in a
concentration of 20 to 55 mole %, wlth the sum of the mole
% of EHA, (meth~acrylate and VP being 100, and with the
EHA/VP ratio in mole % being in the range of from 80/20 to
45/55, and the active ingredient is isosorbide denitrate
(ISDN) which is present in said adhesive base material in
a concentration of 10 to 30% by weight and in a
concentration of B0 to 100 iexclusive) % of the saturated
solubility concentration of ISDN in said adhesive base
material.
In a preferred embodiment, the adhesive ba~e
material compri~es a copolymer containing EHA in a
concentration of 55 mole~ or more and VP in a
concentration of 30 to 45
1~45~57
-- 3 --
mole%, and the concentration of ISDN in the adhesive base
material is 13~ by weight or more.
The adhesive base material may also contain a (meth)-
acrylate monomer, in a concentration of 35 mole~ or less,
which comprises one or more monomers selected from the group
consisting of propyl acrylate, butyl acrylate, hexyl acrylate,
2-ethyl butyl acrylate, heptyl acrylate, octyl acrylate,
nonyl acrylate, decyl methacrylate, and lauryl methacrylate.
The adhesive base material preferably contains the
(meth)acrylate monomer, if present, in a concentration of 15
mole% or less.
The above-mentioned adhesive base layer may be a
copolymer containing a multifunctional monomer in a concentra-
tion of 0.005 to 0.5~ by weight of the total amount of monomers
therein.
In a more preferred embodiment, the multifunctional
monomer is a di(meth)acrylate,;tri(meth)acrylate or tetra-
(meth)acrylate or a mixture of two or more thereof.
Thus, the invention described here~ makes possible
the objects of:
(a) providing a percutaneous administration type
pharmaceutical preparation in tape form,
which is excellent in the release of ISDN
dissolved in an adhesive base material at a
high concentration, whereby to permit an
effective administration of ISDN per unit
area thereof;
(b) providing a percutaneous administration type
pharmaceutical preparation in tape form, which
is significantly less irritative to the skin;
(c) providing a percutaneous administration type
pharmaceutical preparation in tape form,
which is excellent in both release and transfer
to the skin of the active ingredient thereby
exhibiting an immediate pharmaceutical effect
for angina pectoris, etc.;
l~S~S7
-- 4 --
(d) providing a percutaneous administration type
pharmaceutical preparation in tape form,
which can maintaln a high concentration of
ISDN in the blood per unit skin area, compared
wi-th conventional pharmaceutical preparations,
thereby exhibiting an excellent pharmaceutical
effect with a small application area to the
skin;
(e) providing a percutaneous administration type
pharmaceutical preparation in tape form,
which reduces unpleasant feeling on application
to the skin, since the pharmaceutical effect
can be exhibited with a minimized application
area to the skin;
(f) providing a percutaneous administration type
pharmaceutical preparation in tape form,
which can be applied to the skin by a simple
operation due to the minimized application
area; and
(g) providing a percutaneous administration type
pharmaceutical preparation to minimize red
spots on the skin due to a peculiar composition
of the adhesive base material.
For a better understanding of the invention, embodi-
ments will now be described, by way of example, with reference
to the accompanying drawings, in which:
Figure 1 is a graphical representation showing the
relationship between the application area of pharmaceutical
preparations in tape form and the concentration of ISDN in the
blood;
Figure 2 is a graphical representation showing the
relationship between the thickness of the adhesive base layer
of pharmaceutical preparatio~in tape form and the transfer
o~ ISDN to the skin; and
Figure 3 is a graphical representation showing the
relationship between the amount of IS~N per 10 cm2 of the
lZ~5157
-- 5 --
adhesive base layer of pharmaceu-tical preparations
in tape form and the concentration of ISDN in the blood.
N-vinyl-2-pyrolidone (VP) r the molecular weight of
which is 111, has the following structural formula:
CH2 = CH
/N\
H2C C=O
\CH2 - CH2
A VP homopolymer, which is water-soluble, meets
standard requirements for medical supplies.
It has been experimentally found by the inventors
that the above-mentioned monomer is copolymerizable with a
variety of acrylates and/or methacrylates and the resulting
copolymers can serve as an adhesive base material. The
desired copolymer comprises 2-ethylhexyl acrylate (EHA) and
N-vinyl-2-pyrrolidone (VP), satisfying the requirements for an
adhesive base material having properties such as adhesiveness,
solubility of ISDN, release of ISDN and reduced irritation.
More specifically, the copolymer contains EHA in a concentra-
tion of 45 mole% or more and VP in a concentration of 20 to
55 mole%. More preferably, it contains EHA in a concentration
of 55 mole% or more and VP in a concentration of 30 to 45
mole%. If the amount of VP is less than 20 mole%, ISDN will
not be effectively dissolved in the copolymer, i.e. the
adhesive base material. If the amount of VP is greater than
55 mole%, the adhesiveness of the adhesive base material will
be reduced.
Even though one or more other components, such as
(meth)acrylate (i.e. r methacrylate and/or acrylate) monomers
may be admixed in a concentration of 35 mole% or less, more
preferably, 15 mole% or less, with the composition of EHA of
45 mole% or more and VP of 20% or more (more preferably, EHA
of 55 mole% or more and VP of 30 mole% or more), the desired
properties and the abilities of the resulting adhesive base
12~5157
-- 6
material are maintained. For the maintenance of excellent
adhesiveness, a typical (meth)acrylate monomer for admixture
therewith is an alkyl (meth)acrylate, which is, for example,
propyl acrylate, butyl acrylate, hexyl acrylate, 2-ethyl
butyl acrylate, heptyl acrylate, octyl acrylate, nonyl
acrylate, decyl methacrylate, or lauryl methacrylate, but is
not limited thereto.
The ISDN contained in the adhesive is present in a
concentration of 10% by weight or more of the total weight of
the adhesive base material plus the weight of ISDN, and
preferably lO to 30% by weight, in a compatible state in the
adhesive base material having the above-mentioned composition.
The ISDN is more preferably in a concentration of 13 to 25%
by weight, based on the overall adhesive base material. It
should be understood that a concentration of lO to 30% by
weight of ISDN contained in the adhesive base material is
extremely high compared with a concentration of 8 parts by
weight (i.e., 7.4% by weight) of ISDN in the pharmaceutical
preparation disclosed in U.S. Patent No. 4,420,470, which was
discussed above.
When a material dispersed in a compatible state
into a matrix diffuses into or outside the matrix, its
diffusion rate is generally significantly higher than that of
a material existing in a powdered or crystalline state in the
matrix. Thus, to eliminate the conventional drawbacks, it is
essential that ISDN should exist within the adhesive base
material in a compatible state with a concentration which is
as close as possible to the saturated solubility concentration
thereof. The terminology "the saturated solubility concentra-
tion" used herein refers to an ISDN concentration high enoughsuch that the ISDN never crystallizes even though the adhesive
base material containing a certain amount of ISDN is allowed
to stand at room temperature for a long period of time. The
terminology "a compatible state" used herein refers to a
state in which ISDN exists in the saturated concentration or
lower within the adhesive base material.
,.. . .
lZ~5~ S7
According to this invention, although the saturated
concentration of ISDN in the adhesive base material depends
upon the composition of the adhesive base material, ISDN may
be contained in a slightly lower concentration than its
saturated solubility concentration, in each of the adhesive
base materials of various compositions. In light of the
adhesive base material compositions described above, such a
concentration of ISDN is in the range of 10~ by weight or
more, preferably 10 to 30% by weigh~. It is more preferably
in the range of 13 to 25% by weight of the base material.
For maintaining an excellent release level of ISDN, it is
generally preferred that the amount of ISDN to be added to
the base material is 80% or more of the satura-ted solubility
concentration of ISDN with respect to the base material. It
cannot be said that the base material which is best capable
of dissolving ISDN in a high concentration therein is also
most excellent in release of ISDN therefrom to the skin,
since there are unresolved questions with regard to the
determination of the distribution coefficient between the
base material and the skin. Moreover, there has not been
sufficient analysis of the phenomenon that the system varies
depending upon factors such as perspiration during application
of the tape to the skin. However, the base material according
to this invention has, in general, proven superior in transfer
of ISDN to the skin.
According to the present invention, a multi-
functional monomer is preferably added as a component of the
base material to copolymerize with the other monomer components,
thereby producing slight or extremely slight linkages among
the resulting polymers and resul-ting in increased internal
cohesive properties of the resulting base material, so that
none of the base material will remain on the skin when the
tape is removed, regardless of skin conditions or the amount
of perspiration on the skin. Furthermore, the use of such
a multifunctional monomer as a component of the base material
has no effect on the release of the active ingredient and
lZ~SlS~
-- 8
results in reduced irXitation of the resulting base material.
Examples of suitable multifunctional monomers are di~meth)-
acrylates obtained by reaction of (meth)acrylic acid with
polymethylene glycols such as hexamethylene glycol, octa-
methylene glycol, etc.; di(meth)acrylates obtained byreaction of (meth)acrylic acid with polyalkylene glycols such
as polyethylene glycol, polypropylene glycol, etc.; tri(meth~-
acrylates such as trimethylolpropane tri(meth)acry~ate,
glycerin tri~meth)acrylate, etc.; and tetra(meth)acrylates
10 such as pentaerythritol tetra(meth)acrylate etc. One or more
multifunctional monomers are added to the other monomers to
be copolymerized to form the base material, the added amount
preferably being in the range of 0.005 to 0.5% by weight of
the total amount of monomers to be copolymeriæed. If the
15 amount is less than 0.005~ by weight, the internal cohesive
properties due to linkages will not be effectively attained.
If the amount is above 0.5~ by weight, the resulting base
material will tend to gelatinize resulting in reduced diffu-
sion and/or release of ISDN.
The flexible backing used in this invention is non-
permeable to the active ingredient, i.e. ISDN. Examples of
suitable backing materials include a single film composed of
a polyester such as polyethylene terephthalate, etc., a
polyamide such as nylon 6, etc., or a polyurethane; a lamina-
25 ted film composed of a plurality of these single films; and
a laminated ~ilm composed of one or more of these single
films and a polyethylene (PE) film and/or an ethylene-vinyl
acetate copolymer (EVA) film.
In general, crystallization of chemical compounds
30 occurs at the interface between foreign substances and
the matrix containing the chemical compounds therein. In the
pharmaceutical preparation according to this invention,
although it appears that ISDN might crystallize at the inter-
face between the adhesive base layer and -the backing due to its
35 structure, such crystallization has not been observed with any
of the above-mentioned films when the amount of ISDN dissolved
lZ453 57
in the base material is in a concentration of between 80%
(inclusive) and 100% (exclusive) of the saturated solubility
concentration thereof. This phenomenon might be due to
properties of the base material resulting from the composition
as described above.
The percutaneous administration type pharmaceutical
preparation in tape form according to this invention may be
prepared as follows: -
Given amounts of EHA and VP, and, if necessary,
(meth)acrylate monomer(s) and/or multifunctional monomer(s)are admixed with ethyl acetate and/or other polymerization
solvents, followed by a radical polymerization reaction at
approximately 55C to 75C for 8 to 40 hours in a nitrogen
gaseous atmosphere, resulting in a polymer having a solid
content in an amount of 15 to 40% by weight. The viscosity of
thispolymer is in the range of l,000 to 100,000 cps at a
solid content of 25~ by weight, while the molecular weight
(average molecular weight calculated in terms of stylene by a
gel permeation chromatography) in in the range of lO0,000 to
l,000,000. The residual EHA and VP monomers in the polymer
amount to less than 2% by weight, respectively, based on the
total weight of solid.
As a polymerization initiator, azobis derivatives,
peroxides, etc. can be employed, but the process is not
limited thereto. Examples of azobis derivatives include
2, 2'-azobis isobutyronitrile (AIBN); 1, l'-azobis cyclohexane-
l-carbonitrile; and 2, 2'-azobis-2, 4-dimethyl-valeronitrile.
Examples of peroxides include benzoyl peroxide (BPO); lauroyl
peroxide (LPO); and di-tertiary bu-tyl peroxide.
An ISDN solution which is prepared by dissolving
ISDN in a solvent such as ethyl acetate is added to the
adhesive base material prepared in the manner described above,
resulting in a coating solution. The coating solution is then
applied to a given thickness, to a release paper or a backing
using a coating machine such as a direct coater or a reverse
coater, etc. and then dried at a temperature of 70C or less
lZ~51$7
-- 10 --
to form an adhesive base layer containing ISDN in a concen-
tration ranging from 10 to 30% by weight, the solvent being
in a concentration of 100 ppm or less and only a trace (0.1~
by weight or less) of residual monomers remaining. The base
5 layer has a ball tack value of 15 or more, and a backing or
a release paper is then laminated on the surface thereof, resulting in
the desired percutaneous a~minis-tration type pharmaceutical
preparation in tape form.
The following examples illustrate the invention.
10 Example 1
A separable flask was charged with 317.9 g (70
mole%) of EEIA, 82.1 g (30 mole~) of VP and 70.6 g of ethyl
acetate to form a monomer solution having a monomer concen-
tration of 85% by weight. The solution was heated at 60C
15 for 32 hours in a nitrogen a-tmosphere while adding dropwise
thereto lauroyl peroxide as a polymerization initiator and ethyl acetate
* as a polymerization solvent. Tb the resulting polymer, a certain amount
of an ethyl acetate solution of ISDN was added resulting in a coating
solution having solids (total ~so]ids of the polymP~r and th2
20 ISDN) content of 25% by weight and an ISDN solids content
of 12~ by weight. In the same manner as described above,
three further kinds of coating solution having a total
solids content of 25% by weight and ISDN solids contents of
14, 16 and 18~ by weight, respectively, were prepared. Each
25 of these solutions was coated on a release paper having a
thickness of 35 ~lm made of silicone-treated polyethylene
terephthalate (PET) and dried -to form on the release paper
an adhesive base layer having a thickness of 60~m, on which
a backing of PET having a thickness of 9 ~m was placed, re-
30 sulting in a pharmaceutical preparation in tape form.
Example 2
In the same manner as in Example 1, 215.2 g
(45 mole~) of EEIA, 129.7 g ~45 mole%) of VP, 55.1 g (10
mole%) of decyl methacrylate and 0.01~ by weight (40.0 mg~
35 of trimethlolpropane triacrylate were subjected to polymer-
ization. Using the resulting polymer, four coating solutions
having ISDN solids contents of 22, 24, 26 and 28~ by weight,
lZ~5~57
respectively, were prepared to obtain four different phar-
maceutical preparations.
Example 3
In the same manner as in Example 1, 302.0 g (65
mole%) of EHA, 98.0 g (35 mole%) of VP and 0.02% by weight
(80.0 mg) of hexamethyleneglycol aimethacrylate were used
to prepare four coating solutions having ISDN solids con-
tents of 14, 16, 18 and 20% by weight, respectively, result-
ing in four different pharmaceutical preparations.
Example 4
In the same manner as in Example 1, 261.9 g (55
mole~) o EHA, 71.8 g (25 mole%) of VP, 66.3 g (20 mole%)
of butyl acrylate and 0.01~ by weight (40.0 mg) of poly-
propylene glycol diacrylate were used to prepare Ifour coat-
ing solutions having ISDN solids contents of 10, 12, 14 and16% by weight, respec-tively, resulting in four different
pharmaceutical preparations.
Control 1
In the same manner as in Example 1, 400.0 g (100
mole%) of EH~ was used to prepare three coating solutions
having ISDN solids contents of 6, 8 and 10% by weight, re-
spectively, resulting in three different pharmaceutical
preparations.
Control 2
In the same manner as in Example 1, 188.7 g (35
mole~) of EHA and 211.3 g (65 mole%) of VP were used to pre-
pare four coating solutions having ISDN solids contents of
24, 28, 32 and 36% by weight, respectively, resulting in
four different pharmaceutical preparations.
Control 3
In the same manner as in Example 1, 93% by weight
(372.0 g) of EHA and 7% by weight (28.0 g) of acrylic acid
were used to prepare three coating solutions having ISDN
solids contents of 6, 8 and 10% by weight, respectively,
resulting in three different pharmaceutical preparations.
Experiment 1
The ISDN-saturated solubilities and the adhesive-
12f~5~57
nesses of the pharmaceutical preparations obtained above
were examlned, and the results are shown in Table l.
The .ISDN-saturatec1 solubi,1,ities were determined
as follows:
sy pee:Ling o~.~ the re].ease paper, the surface of
the adhesive base l.ayer was exposed and several needle-
sl1aped IS~N crysta].s were placed thereon. The surface was
then covered again by the re]ease paper, enclosed in an
aluminum laminated fi.1,m and malntained at room temperature
.1,0 for one month, after which the growth of ISDN crystals was
ob~erved. The symbol. "O" indicates that crystal. growth was
not ob.served, the symbo.1. "~" indicates that crystal growth
was i.nde~lr1it~, and the symbo~ "X" indicates that crystal
yrowth was defil1ite1.y observed. The ISDN-saturated sol-
l~ ubilities of each o~ the pharmaceutical preparations inExamp.1.es l to 4 and Controls l to 3 are given in parentheses
in Tabl.e 1..
The ad}-lesiveness with respect to each o.~ the
pharmaceutica]. preparations was examined just a.fter their
manu~acture by a ball tack method a-t room temperature. The
symbol.e "O" indlcates excel.lent adhesiveness and the symbol
"X" indicates an in.~erior adhesiveness.
~245~L57
Table 1
_ .
ISDN Solids Crystal
Adhesiveness
Content (wt~) Growth
Example 1 12 O (14) j 8
222- 8(26, 8
Example 2 2 6 ~ O
28 ~ O
_
Example 3 14 ~ 8 ~ 8
_ 20 I x o
_ 12 O (lO 8
Example 4 14 X O
16 x O
6 O (8) O
Control 1 10 X oo
.
Control 2 28 X (34) x
_ _
Conerol 3 10 L (~)
1~5~57
- 14 -
Table 1 ind.icates that the pharmaceutical pre-
paration of Control 2 was inEerior in adhesiveness.
Next, using the six different adhesive base ma-
terials described in Examples 1 to 4 and Control 1 and 3,
eighteen different pharmaceutical preparations as shown in
Table 2, having an ISDN concentration of 90% of the ISDN-
saturated solubilities which are given in parentheses in
Table 1, were prepared in the same manner as in Example 1.Three sample preparations in each Example and Control were
cut into squares, one of which had an area of lOcm2 with a
thickness of 60 ~m, another of which had a thickness of
60 ~m and contained ISDN of 10 mg therein, and the last of
which had an area of 10 cm2 and contained ISDN of 10 mg
therein.
~Z4~i~57
- 15 -
Table 2
. __
ISDN Thickness of I5DN
Composition Sample Concentra- Base Layer Area Content
No. tion (wt~)(~m) cm (mg)
_
1 ~ 1 60 10 i 7.6
Example 1 1 ~ 3 12.6 79 13.2 lg
. 2 ~ 1 60 10 14.0
Example 2 2 ~ 2 23.4 60 7.1 10
2 ~ 3 43 10 10
. .
3 - 1 60 10 9.2
Example 3 1 3 ~ 2315.3 6~ 10o 9 10
_
4 ~ 1 60 10 6.
Example 44 ~ 3 10.8 603 10 1O
5 ~ 1 60 10 4.3
5 - 2~ ~ 139 23.1 l~
6 - 1 60 10 4.3
5 - 2 ~ l39 l3.l l~
lZ~SlS7
- 16 -
Table 2 indicates that the required surface area
of each of the preparations according to this invention is
extremely small when compared wi-th that of the control pre-
parations when sample preparations-of the same ISDN content
and the same thickness of the base materials are prepared,
and that the amount o~ ISDN administered according to this
invention becomes extremely high when sample preparations of
the same area and the same thickness of the base layer are
compared to those of the control. Using these preparations,
10 the following Experiments 2 to 5 were carried out.
Experiment 2
Each of six different pharmaceutical preparations
(Sample Nos. 1-2, 2-2, 3-2, 4-2, 5-2 and 6-2) containing
ISDN of 10 mg was applied -to the back of a rabbit (Japanese
15 White sp.) on a portion where the hair had been removed.
After a predetermined period of time (i.e., 1, 4, 8 and 24
hours), a certain amountof blood was collected and subjected
to a determination oE the ISDN concentration therein. This
experiment was repeated three times. The results are shown
20 in Figure 1, indicating that the sample preparations accord-
ing to this invention are in approximately the same concen-
tration of ISDN in the blood as the control preparation
while each oE the pharmaceutical preparations of Examples
1-4 according to this invention has an area 1/2 to 1/3 the
25 control preparations of Controls 1 and 3, thereby permitting
a reduction of the application area and thus a simplified
application of the preparation.
Experiment 3
Each of the five pharmaceutical preparations
30 (Sample Nos. 1-3, 2-3, 3-3, 4-3 and 5-3) having an area of
10 cm2 and an ISDN content of 10 mg was applied to the
back and side of a rabbit lJapanese White sp.) on portions
where the hair had been removed. After a predetermined
period of time ~i.e., 2, 8 and 24 hours), each oF the
35 preparations was removed and subjected to an ISDN extrac-
tion treatment with methanol to extract ISDN, and then
measured by liquid chromatography. The determination
,~ :
~'~
~Z~ 57
- 17 -
values were subtracted from 10 mg of the initial ISDN con-
tents, resulting in the transfer values of ISDN to the skin.
The determination of the transfer of ISDN to the skin was re-
peated three times. The results are shown in Figure 2, in-
dicating that the transfer is approximately inversely pro-
portional to the thickness of the adhesive base layer and
that the preparations of Examples 1 to 4 having a thin
adhesive base layer are excellent in bioavailability.
Experiment 4
Each of the five pharmaceutical preparations (Sample Nos.
1-], 2-1, 3-1, 4-1 and 6-1), having an area of lOcm2 and a base layer
thickness of 60 ~m, and a lOcm2 peace of Blenderm ~ surgical tape were
applied to a rabbit in the same manner as in Experiment 3. After 24
hours, all of the tapes were removed to determine irritation
to the skin and the residual amount of the adhesive base
material. These procedures were repeated four times.
The irritation test was carried out by evaluating
the intensity of red spots on the skin JUSt after removal
of the tapes and again at 48 hours thereafter. The eval-
uation of marks is as follows: the mark zero (0) indicatesthat red spots were not observed at all; the mark 1 in-
dicates that traces of red spot were observed; the mark 2 in-
dicates that red spots were clearly observed, the mark 3 in-
! dicates that slightly cardinal red spots were observed; and
the mark 4 indicates that cardinal red spots were observed.In this experiment, neither incrustations nor edemata were
observed on the skin.
The total evaluation marks were averaged to rep-
resent the irritation indexes of each of the evaluated
tapes and are shown in Table 3.
Table 3
Tape Example Example Example Example Control Surgical
1 2 3 4 3 Tape
Index of
Irritation to 1.501.50 1.251.25 1.75 1.25
the skin
;, ~''
,; . .,~
1;2~51S7
- 18 -
Table 3 indicates that the pharmaceutical prepar-
ations according to this invention result in significantly
reduced irritation to the skin because their irritation in-
dexes are approximately equal to those of the control sur-
gical tape.
A test of the residual amount of adhesive wascarried out just after removal of the tapes. The evaluation
marks are as Eollows: the mark zero (0) indicates that the
residual amount was zero, the mark l indicates that the
residual amount was slight, the mark 2 indicates that
residual adhesive was observed on the skin corresponding to
the corners and/or the edges of the tape, and the mark 3
indicates that residual adhesive was observed on the skin
corresponding to a half or more of the area of the tape.
15The total evaluation marks were averaged to rep-
resent the residual adhesive indexes of each of the eval-
uated tapes and are shown in Table 4.
Table 4
20 TapeE ~ ple Example Example E~lple Control Surgical
1 2 3 4 3 Tape
Index of
Residual 0.75 0 0 0 0.50 0.50
25 Adhesive
Table 4 indicates -that the pharmaceutical pre-
parations according to this invention exhibit excellent ad-
hesiveness and reduced residual amounts of the adhesive, and
especially, the pharmaceutical preparations in Examples 2,
3 and 4, wherein a multi-functional monomer was used to pro-
duce slight or extremely slight linkages among the polymers,
which did not leave any adhesive on the skin at all.
Experiment 5
Each of the five pharmaceutical preparatior.s
(Sample Nos. 1-1, 2-l, 3-l, 4-1 and 6-l) (all having the
same thickness but varying in ISDN content) was applied
lZ~SlS7
to the back of a rabbit on a portion where the hair had been
removed. After a predetermined period of time (i.e., 1, 6
and 24 hours), the concentration of ISDN in the blood was
measured and the results of this are shown in Figure 3. The
determination was repeated three times.
Figure 3 shows that the pharmaceutical preparations
according to this invention are capable of affording an in-
creased concentration of ISDN in the blood compared with the
control pharmaceutical preparation when they have the same
area and thickness as the control.
It is understood that various other modifications
will be apparent to and can be readily made by those skilled
in the art without departing from the scope and spiri-t oE
this invention. Accordingly, it is not intendedlthat the
scope of the claims appended hereto be limited to the de-
scription as set forth herein, but rather that the claims
be construed as encompassing all the features oE patentable
novelty which reside in the present invention, including all
features which would be treated as equivalents thereof by
those skilled in the art to which this invention pertains.
, .
'I
