Percutaneous absorption type pharmaceutical preparation of isosorbide dinitrate or pentaerythritol tetranitrate in pressure-sensitive laminate

A pharmaceutical preparation comprising a flexible backing and a base material provided thereon is described wherein the base material consists essentially of a polymer having a glass transition temperature of from -70.degree. C. to -10.degree. C. and exhibiting pressure-sensitivity at room temperature, and isosorbide dinitrate or pentaerythritol tetranitrate. This pharmaceutical preparation is applied to the skin, and permits the active ingredient to be absorbed through the skin into the body at a constant rate, and gradually over a long period of time.

FIELD OF THE INVENTION 
The present invention relates to a pharmaceutical preparation that is 
applied to the skin so that active ingredients are absorbed therethrough 
into the body (hereinafter the pharmaceutical preparation is referred to 
as "percutaneous absorption type pharmaceutical preparation"). More 
particularly, it is concerned with a percutaneous absorption type 
pharmaceutical preparation comprising a base material containing 
isosorbide dinitrate (ISDN) or pentaerythritol tetranitrate (PETN) which 
is effective to suppress or prevent attacks of angina pectoris. 
BACKGROUND OF THE INVENTION 
Nitroglycerin is known as a medicine for angina pectoris (i.e., a coronary 
vasodilator) and is used in an ointment form which can be sealed and 
stored. 
Recently, a pharmaceutical preparation in a tape form has been proposed, 
which comprises a backing and a pressure-sensitive adhesive layer with 
nitroglycerin incorporated thereinto on the backing. This type of 
pharmaceutical preparation, however, has not yet been put into practical 
use, since it cannot be stored due to the high volatility of the 
nitroglycerin, and the excessive percutaneous absorbability of 
nitroglycerin causes harmful side effects such as skin irritator. 
Isosorbide dinitrate (ISDN) and pentaerythritol tetranitrate (PETN) are 
known to be effective in the suppression or prevention of attacks of 
angina pectoris, and they are generally used in a tablet form. From a 
viewpoint of suppression or prevention, it is desirable that they are 
supplied into the body at a constant rate, and gradually over a long 
period of time. 
Various attempts, therefore, have been made to control the solubility 
characteristics of the tablet. However, since the absorbability of 
medicine varies depending on the pH in the stomach or intestines, the 
presence of contents, etc., it is generally impossible to supply the ISDN 
or PETN at a constant rate and gradually over a long period of time. 
SUMMARY OF THE INVENTION 
The principal object of the invention is to provide a percutaneous 
absorption type pharmaceutical preparation which permits supplying ISDN or 
PETN at a constant rate and gradually over a long period of time. 
It has now been found that this object can be attained by providing a base 
material comprising a polymer whose glass transition temperature (Tg) is 
adjusted to -70.degree. C. to -10.degree. C. and which is 
pressure-sensitive at room temperature and ISDN or PETN, coated on a 
flexible backing. 
The present invention, therefore, relates to a pharmaceutical preparation 
comprising a flexible backing and a base material provided on the backing, 
said base material comprising a polymer having a glass transition 
temperature (Tg) of from -70.degree. C. to -10.degree. C. and exhibiting 
pressure-sensitivity at room temperature, and isosorbide dinitrate (ISDN) 
or pentaerythritol tetranitrate (PETN). 
DETAILED DESCRIPTION OF THE INVENTION 
Polymers having a glass transition temperature (Tg) (measured using a 
differential scanning colorimeter) of less than -70.degree. C. are not 
suitable for use in the invention in that they reduce the shape retention 
properties of the base material and leave residues on the skin, and 
furthermore, in peeling the pharmaceutical preparation, they provide 
physical irritation to the skin. Also, polymers having a glass transition 
temperature (Tg) of more than -10.degree. C. are not suitable for use in 
the invention since they reduce the mobility of active ingredients in the 
polymeric substance, reducing the releasability thereof, and furthermore, 
reduce the adhesion of the pharmaceutical preparation to the skin. 
Moreover, when the glass transition temperature (Tg) is more than 
-10.degree. C., the dissolution and dispersion of the active ingredients 
in the polymer in the production of the base material become insufficient, 
and in some cases, a major portion of the active ingredient does not 
contribute to the treatment. 
The optimum glass transition temperature (Tg) is from -55.degree. C. to 
-25.degree. C. Polymers having a Tg of -70.degree. C. to -10.degree. C. 
and exhibiting pressure-sensitivity at room temperature can be selected, 
e.g., from synthetic resins and rubbers as set forth below: 
Synthetic resins include polyvinyl alkyl ethers, polyacrylates, 
polymethacrylates, polyurethanes, polyesters, polyamides, and 
ethylene-vinyl acetate copolymers. Rubbers include 
styrene-isoprene-styrene block copolymer rubber, styrene-butadiene rubber, 
polybutene rubber, polyisoprene rubber, butyl rubber, silicone rubber, and 
natural rubber. 
When these synthetic resins or rubbers per se do not have a glass 
transition temperature falling within the above-described range, they can 
be used in combination with other polymers, or alternatively, additives 
which are generally known can be added to adjust the glass transition 
temperature falling within the desired range. 
It has been found that acryl-based copolymers can meet the above-described 
requirements of adhesiveness, compatibility, solubility and releasability 
most surely and by a relatively simple procedure in the system in 
combination with ISDN or PETN. Preferred acryl-based copolymers contain at 
least 50% by weight of alkyl acrylate or alkyl methacrylate containing an 
average of at least 4 carbon atoms in the alkyl moiety. 
These acryl-based copolymers exhibit good adhesiveness to the skin and good 
solubility to active ingredients, and furthermore, less irritate the skin, 
and hold the active ingredients stably. 
The acryl-based copolymers as used herein include copolymers of alkyl 
acrylate or methacrylate and other copolymerizable functional monomers. 
These monomers are compounded in an amount of up to 20% by weight and 
preferably 0.5 to 15% by weight. By varying the amount of the monomer 
added, the cohesive properties of the resulting acryl-based copolymer can 
be changed, and therefore, the release rate or release amount of the 
active ingredient from the base material can be controlled. Also, it is 
possible to increase the hydrophilic properties of the acryl-based 
copolymer by selecting the type of the monomer. 
In addition, the acryl-based copolymers as used herein include copolymers 
of alkyl acrylate or methacrylate and other copolymerizable vinyl ester 
monomers. These monomers are compounded in an amount of up to 40% by 
weight, and preferably from 10 to 30% by weight. Acryl-based copolymers 
containing such vinyl ester monomers have a high solubility to the active 
ingredients. 
Thus, it can be understood that acryl-based copolymers composed of at least 
50% by weight of alkyl acrylate or methacrylate, from 0 to 20% by weight 
of functional monomer copolymerizable with the alkyl acrylate or 
methacrylate, and from 0 to 40% by weight of vinyl ester monomer 
copolymerizable with the alkyl acrylate or methacrylate are suitable to 
support therein ISDN or PETN. 
Alkyl acrylates and alkyl methacrylates which can be used include n-butyl 
acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, 
isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl 
acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, 
tridecyl acrylate, and tridecyl methacrylate. 
Functional monomers copolymerizable with the above alkyl acrylates or 
methacrylates which can be used include acrylic acid, methacrylic acid, 
itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, 
hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, 
dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, 
tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, 
methoxyethyl acrylate, methoxyethyl methacrylate, ethoxyethyl acrylate and 
ethoxyethyl methacrylate. 
Vinyl ester monomers copolymerizable with the above alkyl acrylates or 
methacrylates which can be used include vinyl acetate and vinyl 
propionate. 
The amount of the active ingredients added is generally from about 0.5 to 
20% by weight, and preferably from about 2 to 15% by weight, based on the 
total weight of the polymer (or copolymer) and the active ingredients, 
i.e., the weight of the base material, 
The thus-prepared base material is coated on a flexible backing, usually in 
a thickness of from 5 to 300 .mu.m. The base material can be coated on the 
backing entirely or partially, for example, in a striped, checked, wave, 
or other form as well as uniformly. 
In a preferred further embodiment of the pharmaceutical preparation of the 
invention, each base material containing two or more polymers having 
different glass transition temperature is coated on the backing one by one 
on one side thereof in a predetermined width, or is coated alternatively 
in a predetermined width, or is coated in an insular form. This modified 
pharmaceutical preparation has the advantage that since the polymers 
constituting the base material have different active ingredient-release 
rates due to the differences in the glass transition temperature, the 
total active ingredient-release period of the pharmaceutical preparation 
can be lengthened compared with pharmaceutical preparation having a base 
material in which a polymer having a single glass transition temperature 
is used. The effects obtained by coating the base material in such 
patterns can also be obtained by changing the coating thickness of the 
base material and/or the concentration of the active ingredient. 
Another preferred embodiment of the pharmaceutical preparation of the 
invention is to superpose a plurality of base material layers on the 
backing. In this modified pharmaceutical preparation, the concentration of 
the active ingredient in the base material layer is arranged so that it 
increases toward the backing, i.e., the concentration of the active 
ingredient in the lowermost layer is highest, and that in the uppermost 
layer is lowest, so that the active ingredient is supplied successively 
from lower layers to upper layers. This type of pharmaceutical preparation 
has the effect of preventing the percutaneous absorption of a large amount 
of active ingredient immediately after the application of the 
pharmaceutical preparation onto the skin. Thus, it can be understood that 
a pharmaceutical preparation having the same lamination structure as above 
with the exception that the gradient of concentration is reversed can be 
used as a pharmaceutical preparation producing an immediate effect, i.e., 
permitting the percutaneous absorption of the active ingredient in a short 
period of time. 
Any backing can be used in the invention so long as it has flexibility to 
the extent that when applied onto the skin, it does not produce a 
significant unpleasant feeling. 
Suitable examples of flexible backings which can be used include films or 
sheets of polyolefin, polyester, polyurethane, polyvinyl alcohol, 
polyvinylidene chloride, polyamide, ethylene-vinylacetate copolymer (EVA), 
ethylene-ethylacrylate copolymer (EEA), etc., metal-vapor deposited films 
or sheets thereof, rubber sheets or films, expanded synthetic resin sheets 
or films, unwoven fabrics, fabrics, knitted fabrics, paper, and foils. 
Those backings can be used individually or in the laminates thereof. 
Particularly, the use of a laminate having a copolymer such as EVA or EEA, 
e.g., a laminate of a polyester and EVA or a laminate of a polyester and 
EEA, provides the following advantage. When the base material is formed on 
the laminate (backing) such that the base material contacts the polymer of 
the laminate, if ISDN or PETN is blended in the base material in an amount 
more than the saturated solubility of the polymer, the copolymer layer 
adsorbs ISDN or PETN and crystallized product of the ISDN or PETN is not 
formed on the surface of base material, which does not result in lowering 
the adhesion of the pharmaceutical preparation to the skin. 
When backings having substantially no air permeability or moisture 
permeability are used, it is preferred to provide holes, slits, etc., by 
physical or chemical techniques since ISDN or PETN sometimes causes 
itching, etc., on the skin depending on the concentration thereof. 
In order to prevent the peeling-off of the pharmaceutical preparation and 
to reduce any unpleasant feeling, it is preferred to use backings which 
can stretch at least 10%, or which had been subjected to a 
stretch-contraction treatment. 
In a base material as described herein, there can also be incorporated 
fillers and absorption promotors, in order to better achieve the objects 
of keeping the shape retention properties of the base material, increasing 
the absorbability of the active ingredient through the skin into the body, 
and so forth. In addition, the base material may contain small amounts of 
additives such as a tackifier, a softening agent, and other chemicals such 
as an itching-preventing agent. 
Fillers which can be used include silica fine powder, titanium white, and 
calcium carbonate. Absorption promotors which can be used include alcohols 
such as propylene glycol, and diethylene glycol, salicylic acid, urea, 
allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, 
diisopropyl adipate, diethyl sebacate, ethyl laurate, methyl nicotinate 
and nicotinic acid. 
The amount of the filler added is 20% by weight or less based on the weight 
of the base material, and the amount of the absorption promotor added is 
30% by weight or less based on the weight of the base material.

The important feature of the pharmaceutical preparation of the invention 
that ISDN or PETN is supplied and absorbed at a constant rate and 
gradually over a long period of time will become apparent from the 
examples as set forth below. All parts are by weight. 
EXAMPLE 1 
______________________________________ 
parts 
______________________________________ 
Polyisoprene rubber 45 
Liquid paraffin 15 
Lanolin 5 
Aliphatic petroleum resin 
35 
______________________________________ 
This composition (Tg: -35.degree. C.) was melted at 120.degree. C. for 4 
hours in inert gas, and cooled to 73.degree. C. Then, 2 parts of ISDN was 
added thereto, and the mixture was thoroughly stirred to prepare a base 
material. The base material thus-prepared was flow-coated in a thickness 
of 100 .mu.m onto one surface of a foamed polyethylene sheet to obtain a 
pharmaceutical preparation. 
EXAMPLE 2 
______________________________________ 
parts 
______________________________________ 
Polyisobutylene rubber (viscosity- 
20 
average molecular weight: 1,200,000) 
Polyisobutylene rubber (viscosity- 
30 
average molecular weight: 35,000) 
Polybutene 20 
Wood rosin 30 
Toluene/ethyl acetate (2/1 by weight) 
250 
______________________________________ 
This composition (Tg: -40.degree. C.) was mixed by the method as described 
hereinafter to prepare a base material solution. The base material 
solution thus-prepared was coated on a releasing liner and dried to 
provide a coating film having a dry thickness of 100 .mu.m. The coating 
film then adhered to a soft polyvinyl chloride film to obtain a 
pharmaceutical preparation. 
Mixing Method 
Seven parts of PETN was dissolved in a mixed solvent of toluene and ethyl 
acetate, and polyisobutylene rubber was thoroughly dissolved therein. 
Then, the polybutene and wood rosin were added, and the resulting mixture 
was thoroughly stirred to prepare the base material solution. 
EXAMPLE 3 
A mixture of 50 parts of isooctyl acrylate and 50 parts of butyl acrylate 
was placed in a three-necked flask, and 25 parts of ethyl acetate was 
added thereto in an atmosphere of inert gas. They were polymerized at a 
temperature of 60.degree. to 64.degree. C. for 8 hours by the use of 0.3 
part of azobisisobutyronitrile as a polymerization initiator while adding 
dropwise ethyl acetate to obtain a solution of a copolymer (Tg: 
-51.degree. C.), having a solids content of 40% by weight and a viscosity 
of 410 poises (at 30.degree. C.). 
To 100 parts (as solids) of the solution was added 8 parts of ISDN, and the 
resulting mixture was stirred and coated on a releasing liner in a dry 
thickness of 50 .mu.m to form a coating film. The coating film 
thus-prepared then adhered to a polyethylene film to obtain a 
pharmaceutical preparation. 
EXAMPLE 4 
______________________________________ 
parts 
______________________________________ 
2-Ethylhexyl acrylate 
93 
Acrylic acid 7 
______________________________________ 
Using this composition, a pharmaceutical preparation was prepared by the 
same method as in Example 3 except that the backing was a laminate of 4 
.mu.m thick polyester and 5 .mu.m thick EVA. 
The thus-prepared copolymer (Tg: -55.degree. C.) solution had a solids 
content of 40% by weight and a viscosity of 805 poises. 
EXAMPLE 5 
______________________________________ 
parts 
______________________________________ 
2-Ethylhexyl acrylate 
74 
Acrylic acid 6 
Vinyl acetate 20 
______________________________________ 
Using this composition, a pharmaceutical preparation was prepared by the 
same method as in Example 3. 
The thus-prepared copolymer (Tg: -45.degree. C.) solution had a solids 
content of 37% by weight and a viscosity of 530 poises. 
EXAMPLE 6 
______________________________________ 
parts 
______________________________________ 
2-Ethylhexyl acrylate 
55 
Ethoxyethyl acrylate 
15 
Vinyl acetate 30 
______________________________________ 
Using this composition, a pharmaceutical preparation was prepared by the 
same method as in Example 3. 
The thus-prepared copolymer (Tg: -47.degree. C.) solution had a solids 
content of 63% by weight and a viscosity of 690 poises. In this example, 
as a backing, a polyester film was used. 
EXAMPLE 7 
The base material solutions prepared in Examples 4 and 5 were each coated 
on one side of a polyester film in a width of 40 mm and dried to prepare a 
pharmaceutical preparation having two base material layers, each having a 
thickness of 50 .mu.m. 
The pharmaceutical preparations prepared in Examples 1 to 7 were tested, 
and the results are shown in Tables 1 and 2. 
TABLE 1 
__________________________________________________________________________ 
Residual 
Content of 
Adhesion to Skin 
Active 
Example After 
Ingredient 
Mobility of Active Ingredient to Skin (hours) 
No. Initial 
8 Hours 
(%) 1/6 
2/6 
3/6 
4/6 
1 3 8 12 
24 
48 
__________________________________________________________________________ 
1 Good 
Fair 89 -- -- -- -- o o o o o o 
2 Good 
Fair 84 -- -- -- -- o o o o o -- 
3 Good 
Good 64 o o o o o o o o o -- 
4 Good 
Good 68 o o o o o o o o o o 
5 Good 
Good 85 -- -- -- o o o o o o o 
6 Good 
Good 73 -- -- o o o o o o o o 
7 Good 
Good 72 o o o o o o o o o o 
__________________________________________________________________________ 
Residual Content of Active Ingredient 
A pharmaceutical preparation sample (5 cm.times.5 cm) was adhered to the 
inside of the human upper arm, and after 18 hours, was peeled off. The 
sample thus-peeled was dissolved in 30 ml of ethyl acetate at 40.degree. 
C. for 26 hours while shaking. To the resulting solution was added ethyl 
acetate to make 50 ml. The thus-prepared solution was subjected to gas 
chromatographic quantitative determination. The residual content was 
determined with the initial amount of the active ingredient being taken as 
100%. 
Mobility of Active Ingredient to Skin 
A pharmaceutical preparation sample (5 cm.times.5 cm) was sticked to the 
inside of the upper arm. The symbol "o" indicates that the skin turned red 
or a feeling of flushing was caused, and the symbol "--" indicates that 
such phenomena did not occur. 
TABLE 2 
______________________________________ 
Concentration of Active Ingredient 
in Blood after Application of 
Pharmaceutical Preparation (ng/ml) 
Example for Predetermined Time (hrs) 
No. 0.5 1 3 8 24 48 
______________________________________ 
1 0 0 2.1 3.1 1.3 0.5 
2 0 0 3.8 7.1 4.1 0.7 
3 6.3 9.8 11.0 6.3 4.9 3.8 
4 7.3 10.1 10.9 5.4 5.8 2.4 
5 0 0.9 3.1 4.1 3.9 4.9 
6 0 1.1 6.7 7.3 6.1 3.1 
7 4.1 4.8 5.7 6.0 5.3 5.1 
______________________________________ 
Concentration of Active Ingredient in Blood 
A pharmaceutical preparation sample (2 cm.times.4 cm) was adhered to the 
back of a rabbit (weight: 2 kg) on an area where the hair had been 
removed. After a predetermined period of time, 3 ml of blood was 
collected, and the plasma was separated therefrom. The thus-separated 
plasma was 2 ml of n-hexane for extraction. The mixture was subjected to 
centrifugal separation, and then the extract was concentrated to 0.5 ml 
under an atmosphere of inert gas. Then, the concentrate was extracted with 
1 ml of acetonitrile. The acetonitrile layer thus-obtained was vaporized 
to dryness under inert gas, and the resulting residue was dissolved in 100 
.mu.l of benzene and was subjected to a gas chromatographic measurement. 
The sample of Example 7 in Tables 1 and 2 had the same area as in Examples 
1 to 6 but was designed so that the areas of the two base materials were 
equal. 
As can be seen from the above examples, the pharmaceutical preparation of 
the invention exhibits excellent adhesion to the skin and good 
releasability of the active ingredient. 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.