Note: Descriptions are shown in the official language in which they were submitted.
82
This invention relates to pharmacy, and more
particularly it relates to a new medicinal form, a medicinal
film having antianginal action, and the method of treating
ischemic heart disease. Said antianginal films are used in
cardiology to treat ischemic heart disease.
Known in the prior art are antianginal preparation~
used to arrest attacks of stenocardia containiny active sub-
stances such as glycerol trinitrate, isosorbide dinitrate,
pentaerythrityl tetranitrate, and others.
In addition to said active substances these medicinal
preparations contain an inert carrier which is resolved in
liquid media of the body. For example, used in the prior art
are granules of glycerol trinitrate containing sug~r, starch,
and other substances as fillin~ materials (Soviet State
Pharmacopoeia, 10th edition).
A disadvantage of the known medicinal preparations
containing readily soluble substances, such as sugar~ as a
filling material, is their low stability in storage and lack
of prolonged action.
Also known in the prior art are also tablets of
glycerol trinitrate, prepared by the microcapsulation method
(Sustak, Nitrong) wherein the microcapsules perform the func-
tion of the carrier material~ which is derivatives of cellulose,
such as methyl cellulose, ethyl cellulose, acetyl cellulose,
cellulose acetophthalate, etc. (see U.S. Patent No. 665,2g7).
Medicinal preparations enclosed in microcapsules
start exerting their medicinal action at delayed (to 60 minutes)
terms, and this makes it impossible to use them for rapid
arresting of stenocardia attacks.
~nother disadvantage of capsuled preparations is the
relative complexity of their manufacture.
Known widely in the prior art are antianginal pre-
' ''~"' ' '' .
27Q~32
parations manufactured in the form of tablets and dragées.
These also include multi-coated pills, containing synthetic
polymers, such as polyvinyl alcohol, and a copolymer of
polyvinyl alcohol and vinyl acetate, as resolvable carrier
material. Synthetic polymers are used to coat tablets or
granules so that the rate of liberation of the active
principle could be controlled - (French Patent No~ 2,326,933,
U.S. Patent No. 4,0129498).
Also known in the prior art are antianginal prepara-
tions in the form of chewing gum containing the active principle
and various additives. The base material used in these pre-
parations are polyacrylate polymers - (U.S. Patent No.
3,594,~70~.
The disadvantage of the known medicinal preparations
in the form of tablets pressed with powdered synthetic poly-
mers, and also enclosed in coats of such polymers, is that they
can be improperly administered (especially by children who can
chew them be~ore swallowing) and hence produce undesirable side
effects due to rapid uncontrolled absorption into the body.
The method o~ treating with such medicinal prepara-
tions involves the patient swallowing the medicine (peroral
adrninistration), or placing it under the tongue until it fully
resolves (sublingual administration) or chewing the gum to
ensure gradual administration of the medicine with saliva. In
all these administration methods, the active principle pene-
trates the alimentary tract where it is dissolved, absorbed
through the mucosa, and delivered first to the liver and then
to the blood circulating system (Petkov, V., "~ledicine 3 Body,
Pharmacological Effect", Medicina i Fizkultura1 Sofia~ 1974)o
The general pharmacological disadvantage inherent
in all known medicinal antianginal preparations and methods
of manufacturing thereof is that when the preparations enter
~L~27~2
the alimentary tract J and later the liver, the liberated
active substance is partially inactivated by the enzymatic
systems in the body. The degree of inactivation o~ the
preparations depends on specific characteristics of the
living body and its physiological stat~, wh.ich, in general,
makes it impossible to dose the medicinal preparation in-
dividually so as to ensure its optirnum effect.
The main object of this invention is to provide a
novel medicinal form, viz., a medicinal film having anti-
anginal action, characterized by prolonged action J improved
accuracy of dosage of the active substance, and stability in
storage.
The specific object of the invention is to provide
a novel medicinal form, namely, antianginal film, which can
be used as a medicinal preparation characterized by prolonged
action, increased accuracy of dosage of the active principle,
and stability in storage.
Said object has been attained by providing an anti-
anginal film composition, according to the invention, compris-
ing a 0.1 to 1.5 mm thick plate consisting of a biologically
soluble and resolvable carrier, namely J a homopolymer of
acrylamide or a copolymer of acrylamide J vinylpyrrolidone and
acrylates, containing from 99 to 70 percent by weight of
acrylamide with vinylpyrrolidone, and from 1 to 30 percent
by weight of an acrylate having a molecular weight of 50,000
to 1,000~000, and an active substance having antianginal action,
said components being taken in the ~ollowing propor~ions, in
percent by weight:
active substance having antianginal action 3.0 - 30.0
biologically soluble and resolvable carrier 70.0 - 97Ø
In order to prolong its action, the medicinal film
also contains dispersed solid fat melting from 30 to 50C,
8Z
taken in the quantity of from 3 to 30 percent by weight with
respect to the weight of all other components.
It is recommended that the antianginal film contain
cocoa butter, hydrogenized cotton-seed oil, glyce~ol laurate
or phthalate, as the dispersed solid fat.
The proposed film contains a copolymer of acrylamide,
vinylpyrrolidone, and ethyl acrylate, taken in the ratio of
0.5:0.2:0.2 respectively, or a copolymer of acrylamide,
vinylpyrrolidone, and butyl acrylate, taken in the ratio of
1.0:0.5:0.3 respectively, or a copolymer of equal quantities
of acrylamide, vinylpyrrolidone and ethyl acrylate 9 as a
biologically soluble and resolvable carrier polymer.
The proposed medicinal film preferably contains
glycerol trinitrate, isosorbide dinitrate, or pentaerythritol
tetranitrate as the active principle.
The selection of the biologically soluhle and
resolvable carrier from homopolymers of acrylamide and
vinylpyrrolidone and their copolymers with acrylates taken
in the specified ratios, depends, according to the invention,
on the ability of said polymers to dissolve in liquid media
of the body, their harmlessness, and ability to form labile
complex bonds with the active principle of the preparation.
Solid fats incorporated in the proposed medicinal film,
regulate its hydrophobic properties to control the rate of
liberation of the active principle from the swollen medicinal
film.
The proposed antianginal film can be taken in
capsules or be applied to the mouth mucosa. The latter
method of administration is a novel method and has not been
described in the literature. It makes it possible to treat
ischemic heart disease by individual doses.
According to the invention, the method of treating
-- 4 --
... . ~ . . , .. , ~
~Z7(~g~Z
ischemic heart disease with the proposed antianginal ~ilm by
individual doses, consists in that a film of a biologically
soluble and resolvable carrier polymer containing no active
principle of antianginal action, is first applied to a chosen
site of the mouth mucosa of the patient, and the time o~
resolution of the film is determined. This time characterize~
the possible time during which the active substance will pass
to the body. Next a film is selected containing that amount
of the active principle which should be given to the patient
during the time of resolution. Finally, said film containing
the required amount of the antianginal preparation is applied
(once or repeatedly) to the chosen site of the mouth mucosa
of the patient to ensure continuous and optimal therapeutic
effect during the entire period of dissolution of said film.
The main advantage of the proposed method of treat-
ing ischemic heart disease is that the active principle is
delivered directly into the systemic blood flow bypassing
the liver, the preparation intake being uniform in the course
of a prolonged period of time.
Antianginal films were tried in a clinic. The
clinical trials had the following objects: (1) to carry out
comparative studies of pharmacodynamics of the antianginal
film containing glycerol trinitrate and the known preparation
Sustak as the active substance, both preparations being given
per ~s; (2) to study the pharmacodynamics of the proposed
antianginal film, containing glycerol trinitrate, by applying
it to the mouth mucosa, and tablets of glycerol trinitrate
given sublingually.
The pharmacodynamic effects were assessed by the
central and peripheral hemodynamic indices, and also by the
changes in tolerance to physical exercise. Earlier we had
established the correlation (r = 0.~1 + 0.06, p < 0.001)
. .
~Z7~Z
between the dynamics (under the effect of nitrates) of the
peripheral and central blood circulation indices and the
results of the ECG-monitoring with controlled physical load.
This helped us judge the efficacy of the proposed medicinal
film containing glycerol trinitrate by studyin~ analogous
hemodynamic parameters.
The proposed medicinal film containing glycerol
trinitrate was studied on twenty-three male patients between
the ages of 37 to 62 (average age 48) with ischemic heart
disease manifested in strain stenocardia, with 1 to 15 attacks
a day, seven patients had myocardial infarction in the past
~with ECG records). The clinical manifestations of the disease
averaged from 5 months to 12 years. Twenty-one patients were
tested by bicycle ergometry: twelve of them showed low toler-
ance for physical load, medium tolerance was in five and high
in four patients. me mean load in the test group was 421.4
kg-m/min, the work done was 2260 kg-m. Thirteen patients were
examined by coronary angiography. Four patients had three
main branches of the coronary arteries affected, two branches
2Q were affected in one patient, and one branch in four patients,
no local stenoses of the coronary vessels were found in the
remaining three patients. m ree patients had initial signs
of cardiac insufficiency. Patients with marked arterial
hypertension were not studied.
The following study methods were used: finger
impedance plethysmography (FIP), impedance cardiography,
ECG-monitoring with controlled physical load, and bicycle
ergometry.
FIP was used to assess the peripheral vascular
action of the medicinal film containing glycerol trinitrate
by the size of the first negative wave "b" on the first
derivative of plethysmogram curve (b). This value was
-- 6 --
!
~ .. , . , . . , ,, ~, . . ... . .. . . . . . . .. . . ... . . .
7~Z
expressed in 10 Ohm/sec.
Impedance-cardiography was used to determine the
stroke volume of the hea~t, from which the stroke index
(ml/sq.m) was determined.
ECG-monitoring with controlled physical load was
used to study the dyna~ics of the depression of the ST segment
under standard physical loads during many hours of ECG-
monitoring with a portable monitor with subse~uent computer
analysis of the electrocardiogram. ~t one-hour intervals,
the patient was given by the doctor a specially selected
standard physical load and the action of the proposed medicinal
film containing glycerol trinitrate was assessed by the decrease
in the depression of the ST segment ~as compared with the
initial one).
The index of ST(D) segment standard depression,
characterizing the change in the depression per pulse increment
unit was used to assess the efficacy of the proposed medicinal
film.
During the bicycle ergometry, we increased the con-
tinuous load in steps, beginning with 150 kg-m/min for three
minutes, with subsequent 100 percent increase in the load.
ECG was taken with 12 standard leads; the arterial pressure
and the respiration rate were measured at the second minute
of each load step. The load continued (in the absence of
contraindications) until horizontal or down-sloping depression
of the segment ST to less than 1 mm was attained or until
attack of angina pectoris developed. The following indices
were analyzed: intensity of the load and the volume of the work
done, pulse rate and arterial pressure at the start and at
the peak load: time of continuous work on the bicycle ergo-
meter until signs of myocardial ischemia developed.
Drug therapy was suspended ~4 hours before the tests
7~8~2
(except glycerol trinitrate for sublingual administration
to arrest angina pectoris attacks). The initial indices of
FIP, the impedance cardiographic indices and arterial press-
ure wère recorded in 2-3 hours after a light breakfast.
During ECG-monltoring tests, each patient was given a
specially selected starting physical load.
On the first-day of the studies, all patients were
tested fo~ sensitivity to nitrates by sublingual doses of
0.5 mg of glycerol trinitrate in tablets. Patients who showed
low tolerance for nitrates were later yiven Sustak, (6.4 mg
of glycerol trinitrate) or tablets of glycerol trinitrate
~6.0 mg)~ while patients with high tolerance for nitrates
were given Sustak (12.8 mg) or glycerol trinitrate tablets
(9.0 mg). The dose of the proposed medicinal film containing
glycerol trinitrate for application to the mouth mucosa was
determined depending on the time of resolution of the carrier-
without the active principle (glycerol trinitrate). To
determine individual doses of the medicinal film containing
glycerol trinitrate, the doctor applied the polymer carrier
(without the active principle) to the mouth mucosa, for
example in the region of the upper gum a~ove the canines or
pre-molars, and determined the time during which the film
fully resolved. ~ext he chose the medicinal film containing
the required amount of glycerol trinitrate which would ensure
continuous and optimal therapeutic effect during the time of
full resolution of the film.
Approximate calculation: 0.3 - 0.5 mg of glycerol
trinitrate per each 30 minutes of film resolution. The
selected type of the medicinal film containing the correspond-
ing dose of glycerol trinitrate, namely, 1 mg (for 60-~0
minutes of resolution), or 7 mg (for 2-3 houx resolution);
or 3 mg ~to 5 hours of film resolution) can then be practiced
;
.
l~Z7~82
by the patient himself, who applies the film to the gum
mucosa on the same or the opposite side.
Each pharmacodynamic study was continued from 6 to
7 hours. The hemodynamic indices were recorded at one-hour
intervals at standard conditions. In complex studies with
ECG-monitoring, the physical load followed the recording of
the hemodynamic indices.
Bicycle ergometry was carried out by the double
blind method during two days, in 1.5 hour intervals after
applying the film carrier or the film containing glycerol
trinitrate onto the gum. The standard conditions of imposing
dosed physical loads were observed during the tests.
On the days of studies, food and physical activity
of patients were strictly controlled.
The results of studies were treated statistically
by the Student's method.
Comparative pharmacodynamic studies-of Sustak
(6.4 and 12.8 mg) and of the medicinal film containing glycerol
trinitrate in capsules for peroral administration (6.0 and 9.0
mg) were carried out on ten patients. The materials pertain-
ing to one patient were excluded from statistic analyses
because of technical artefact of ~IP. Tables 1 and 2, which
follow below, give the hemodynamic indices obtained in the
course of studies after taking one dose of Sustak or the
medicinal film containing glycerol trinitrate in capsules.
The group of patients who were given 12.8 mg of Sustak and
9~0 mg of glycerol trinitrate in capsules in the proposed
medicinal film, contained only persons with low sensitivity
to glycerol trinitrate. The mean hemodynamic effect of this
preparation in the selected group of patients only insignii-
cantly differed from the similar effect in the group of
patients who were given smaller doses (6.4 and 6~0 mg res-
~Z7~8~
pectively). ~e effects di~fered insignificantly in both
magnitude and duration.
Systolic arterial pressure (SAP) was lower compared
with the initial level and remained so for three hours after
taking Sustak (7.2 + 1.7 percent maximum), and for two hours
after taking the medicinal film containing glycerol trinitrate
(8.3 + 3.4 percent maximum), but the lowered S~P was not
statistically proven.
The stroke index, according to impedance cardio-
graphy, decreased distinctly in the course of the first few
minutes after administrations of Sustak and remained so for
4-5 hours. The proposed medicinal film containing glycerol
trinitrate in capsules decreased the stroke index only after
30 minutes and this effect persisted for four hours. The
delayed action probably depended on the time of the capsule
dissolution in the alimentary tract. The maximum decrease in
the stroke index was more significant after the administration
of the m~dicinal film containing glycerol trinitrate (27O4
+ 3.2 in 60 minutes) compared with the corresponding magnitude
attained after the administration of Sustak (24.7 + 5.6 in 30
minutes).
The amplitude of the wave "b", according to FIP,
increased to the maxim~un extent in the first 10-30 minutes
after the administration of Sustak and the initial level was
restored in 6 hours. With the proposed medicinal film contain-
ing glycerol trinitrate the maximum changes were observed in
longer lapses of time (in 2-3 hours) and the initial indices
were restored in shorter time (by the fifth hour).
In the drawings which illustrate the invention,
FIGS. 1 and 2 are curves showing hemodynamic indices
obtained for said studies.
Fig. 1 illustrates pharmacodynamics of Sustak (6.4
-- 10 ~
, _
~27~
mg) and the medicinal film containing glycerol trinitrate
~6.0 mg), taken per os, according to impedance-cardiography
and finger impedance ethysmography TIP. Mean data are
presented. Plotted against the axis of ordinates is
SI% - variations in the stroke index, in percent oE t~e
starting value (figures to the left of the axis), ~b x 10 ~
ohm/sec - the change in the value of the first negative wave
"b" on the curve of the first FIP derivative, with respect
to the initial value, expressed in ohm/sec with the scale
factor 10 2 introduced for the sake of convenience of cal-
culations (figures to the right of the axis). Plotted
against the axis of abscissas is time (t) in hours. Circles
and triangles are used for the proposed medicinal film con-
taining glycerol trinitrate and shaded circles and triangles
for Sustak~
Fig. 2 shows pharmacodynamics of Sustak (12.8 mg)
and the proposed medicinal film containing glycerol tri-
nitrate (9 mg), taken per os, according to impedance cardio-
graphy and FIP. Mean data are given. Symbols and designations
used in the figure are the same as in Fig. 1.
The comparison shows that the hemodynamic effect
of the proposed medicinal film containing glycerol trinitrate
is similar to that of Sustak.
The pulse rate and the diastolic pressure did not
significantly change except for two cases where tachycardia
developed during the first 15 minutes after the administration
of Sustak.
Side effects were o~served in five patients after
the administration of Sustak (diæziness in two and headache
in three) and only in three patients (headache) after the
administration of the proposed medicinal film containing
glycerol trinitrate~
~Z7~
Pharmacodynamics of the proposed medicinal film
containing glycerol trinitrate applied to the mouth mucosa
and of glycerol trinitrate in tablets, given sublingually,
were studied. The investigations showe~ that the time of
resolution of the carrier film (without glycerol trinitrate)
varies significantly in different persons: from 30 minutes
to 6~5 hours, and in some cases even to 10 hours. It follows
therefore that one and the same medicinal film containing,
for example, 2 mg, will cause grave side effects from over-
dosage (hypertension, collapse, etc.) in persons in whomthe time of full resolution of the film is 30 - 45 minutes,
while the same film will give an insufficient dose to patients
in whom the film will resolve only in six and more hours, the
adequate dose of the preparation being given only to patients
in whom the film will resolve in 2-3 hours.
Pharmacodynamic studies of the proposed medicinal
film containing glycerol trinitrate in doses of 1, 2 and 3
mg~ (depending on the time of resolution of the film witho~t
glycerol trinitrate) were carried on 17 patients with ischemic
heart disease with angina pectoris. The film was applied to
the mouth mucosa. Glycerol trinitrate preparations did not
produce any response in one patient who was therefore removed
from further analysis. The results of the studies are given
in Tables 3 and 4 which follow hereinafter.
The proposed medicinal film containing 1 mg of
glycerol trinitrate was given to 9 patients in whom the film
resolved in 1.5 to 2.5 hours. Systolic arterial pressure
diminished, compared with the initial level, in the course
of 15 minutes following sublingual administration of
glycerol trinitrate (maximum by 8.3 + 2.2 percent at the
fifth minute) and in the course of two hours with applying
the film on the mouth mucosa (maximum by 7.9 + 1.6 percent
12 -
~Z~08Z
at the 90th minute). The changes in the systolic arterial
pressure were however not reliably proven statistically.
The stroke index decreased after sublingual use
of glycerol trinitrate in tablets in the course of 20 rninutes
(maximum by 40.3 - 2.9 percent by the fifth minute) and in
the course of three hours with the application of the
medicinal film to the mouth mucosa (maximum by 34.9 + 4.1
percent by the 60th minute).
The a-mplitude of the wave "b" in the FIP increased
to its maximum in the course of the first five minutes follow-
ing sublingual use of glycerol trinitrate in tablets and
restored to the initial level in thirty minutes. When the
proposed film was applied to the mouth mucosa, the amplitude
of the wave "b" increased immediately and returned to the
initial level in three hours.
Thus, the medicinal film containing glycerol
trinitrate produced a marked effect on the hemodynamics in
the first minutes after its application to the mouth mucosa,
and the effect persisted for about three hours. The inten-
sity of the hemodynamic effect of the medicinal film wassimilar to that of glycerol trinitrate tablets given sub-
lingually, but the intense effect persisted -for much longer
periods with the proposed medicinal film.
Medicinal film containing 2 mg of glycerol tri-
nitrate was given to 7 patients in whom the mean resolution
time of the film carrier (without glycerol trinitrate) was
from 2.5 to 4 hours. The stroke index, wave l'bl' in FIP were
proven to change and the indices were close to the data
obtained with the dose of 1.0 mg. There were no reliable
proofs of changes in the systolic arterial pressure. In
two cases the hemodynamic effect was observed for four hours
which fully coincided with the time of resolution of the
- 13 -
. ~ .
,,, . . ~ ~,. .. . , ., . ... , . , , . . . .. .. , . , ., . ~. . . . , ~ .. . ... .. . ... . .
~27~8;2
corresponding film without glycerol trinitrate in these
patients~
The results of said studies are given in Figs.
3 and 4.
Fig. 3 shows the pharmacodynamics of ylycerol
trinitrate in tablets (0.5 mg) given sublingually and the
proposed medicinal film containing glycerol trinitrate
~2 mg) when applied to the mouth mucosa (according to
impedance cardiography and FIP data). Mean data are given.
The designations and symbols used in the figure are the
same as in Fig. 1.
Fig. 4 shows pharmacodynamics of glycerol trinitrate
tablets (0.5 mg) given sublingually and of the proposed
medicinal film containing 1 mg of glycerol trinitrate when
applied to the mouth mucosa (impedance cardiography and FIP
data). Mean data are given~ The symbols and designations are
the same as in Fig. 1.
ECG-monitoring with controlled physical load was
carried out as follows. Dynamics o~ depression of the ST
~0 segment was studied in ten patients to whom controlled
physical loads were given after giving placebos (6 patients)
and the proposed film containing 2 mg of glycerol trinitrate
(8 patients). The data obtained indicate that after apply-
ing the medicinal film containing glycerol trinitrate to
the mouth mucosa, the ST segment depression (~ ~/0) was
reliably proven to decrease in the course of three hours
with application of equal loads, the maximum effect being
attained at the 30-~Oth minute. The ST segment depression
variations in patients to whom placebos had been given did
not exceed 4 percent. The results of the tests are given
in Table 5 and Fig. 5.
Fig. 5 shows the dynamics of the ST segment
~7~
depression under standard phy~ical loads after application
of the proposed medicinal film containing glycerol trinitrate
to the mouth mucosa (2 mg), according to ECG-monitoring.
Mean data are given.
Plotted against the axis of ordinates is the change
in the ST segment depression (~ ~/O) after applicat~on of t~e
film without glycerol trinitrate (placebo), designated by a
curve with dots; or after applying the medicinal film con-
taining glycerol trinitrate to the mouth mucosa (designated
by a curve with dots in circles). Time (t) in minutes,
after the administration of the preparation, is plotted
against the axis of abscissas.
Tolerance for physical load with bicycle ergometer
was tested in eleven patients to whom a placebo was given
after 1 or 2 mg of the medicinal film containing glycerol
trinitrate. Mean results of the bicycle ergometric test
given in Table 6 show the increasing tolerance for physical
load and increasing activity in patients to whom the true
preparation was given. In two cases we failed to complete the
predetermined work because of general fatigue although the
patients were given the true preparation, and the test was
discontinued with patients to whom the place~o was given
~although the load was lessened) because signs of myocardial
ischemia developed.
The studies carried out showed the efficacy of the
proposed medicinal film containing gl~cerol trinitrate both
given Per os and glued to the mouth mucosa to patients with
ischemic heart disease. Comparative pharmacological studies
of the medicinal film containing glycerol trinitrate for
peroral use and of Sustak showed that both preparations produce
similar effects on the studied hemodynamic parameters: stroke
index, systolic arterial pressure 9 and peripheral vasodilationO
~27~8Z
Objective hemodynamic measurements showed that the medicinal
film containing glycerol trinitrate, given per os, produces
a specific pharmacodynamic effect in the course of 4-4.~
hours (like Sustak). When considering mean data, important
information concerning individual response to the therapy
should also be included. For example, the indices were
quite varied after the administration of 12.8 mg of Sustak,
which was associated with individual response of patients
to the preparation. More uniform results were obtained with
the proposed film containing glycerol trinitrate applied to
the mouth mucosa of the patients. The direct uptake of
glycerol trinitrate by the body, bypassing the liver, ensures
a pronounced pharmacodynamic effect which manifests practically
instantaneously and persists for 2.5 - 4 hours. This method of
administration of the active principle has the following
advantages: a reliable and pronounced hemodynamic effect is
attained with markedly lower doses of the active substance
patients do not complain of any inconveniences and well
tolerate this medicinal form, a great advantage of the new
form is that it is possible to control the uptake of glycerol
trinitrate whenever necessary, it is easy to discontinue the
uptake of the preparation by removing the unresolved film in
cases where it becomes necessary, or, on the contrary, it is
easy to renew the therapy, the therapeutic effect being
attained practically instantaneously.
- 16 -
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- 27 --
-~
~27~8;~
The high efficacy o~ the proposed medicinal form
has been proven by the data of the test with physical loads
which showed considerable improvement of tolerance for loa~
and increased activity of patients with the medicinal ~ilm
attached to the mouth mucosa~
Hernodynamic data well agree with the results of
ECG-monitoring under repeated standard physical loads, which
objectively proves efficacy of the proposed film containing
glycerol trinitrate.
Side effects, which develop during the treatment
with the proposed film containing glycerol trinitrate, are
insignificant. Slight pricking at the site of a,pplication
of the film was reported by 11 patients in the course of the
first 10-30 minutes, after which these sensations subside.
Nine patients had dizziness, the same as with the use of
glycerol trinitrate tablets for sublingual administration.
Individu~l doses of medicinal films containing other
active principles, e.g. isosorbide dinitrate, pentaerythritol
tetranitrate, etc., can also be given for application to the
mouth mucosa.
The method of individual dosage ensures not only a
more prolonged e~fect of the preparation tin the course of a
few hours) but also prevents side effects 9 such as headache,
dizziness, postural hypotonia, or nausea. It is known that
like glycerol trinitrate, isosorbide dinitrate taken per os
in the form of tablets is rapidly metabolized in the liver by
the enzymatic'mechanism, i.e. its biological assimilability
with the administration per os is low and differs significantly
in various patients. If isosorbide dinitrate is used in the
medicinal film as the active substance, it enters the blood
circulating system from the mouth mucosa bypassing the liver.
When ,pentaerythritol tetranitrate tablets are taken
-
- 28
... _ . , _ . ... _ . _ _ _ _ . , . , .. _ . _ . , _ . _ . , . , . . . .. ., ... _ . .. . , .. , _ . . . . .
. . . .
z
per os, the major part of the active principle gets into the
blood circulating system in inactivated form because of its
metabolism in the liver.
The method of individual doses of the medicinal
film containing pentaerythritol tetranitrate ensures the
delivery of the active substance into the systemic blood
circulation bypassing the liver. It considerably prolongs
the hemodynamic effect (in the course of several hours) and
prevents side effects, such as headache, noise in the ears,
dizziness, posturai hypertension, diarrhea.
~n important advantage of the proposed medicinal
film possessing antianginal action is its high adhesion in
the swollen state to the mouth mucosa, which makes it possible
to attach it to a chosen site of the mucosa where it remains
fixed until fully resolved to ensure uniform delivery of the
active substance directly into the mucosa and further into
the blood circulation system bypassing the gastrointestinal
tract to rule out uncontrolled partial inactivation of the
active principle.
In contrast to the known carriers, polymer carriexs
of the proposed medicinal film, on contact with aqueous
solutions ensure marXedly more uniform delivery of the
active substance into the body which decreases, or even
completely removes side effects, such as headache, or sharp
changes in the blood pressure which are otherwise observed
with the known antianginal preparations. me uniform libera-
tion of the active principle, for example, of glycerol
trinitrate, from the medicinal film is illustrated in Table
7 which is given kelow (the data are given in comparison with
the known tablets of glycerol trinitrate).
The mPthod of preparing the antianginal film accord-
ing to the invention is as follows: Solutions of a biological-
- 29 -
~lZ7~8~
ly resolvable soluble polymer carrier and the active substance
are prepared in standard mixers. The solvents should be com-
patible, or a single solvent should be used to dissolve the
active substance and the polymer carrier. ~he solutions are
then put together at the required ratio of the components,
air is removed from the solutions in vacuum at room temperatu~e
and a film, 0.1 to 1.5 mm thick, is cast on an inert surface
by using standard casting equipment. The film is dried at
temperatures to 40C until the residual amount of the solvent
does not exceed 10 percent by weight, and circular plates of
the required size are pressed out mechanically. If the
medicinal film should contain dispersed fat, it is introduced
into the solution containing the active substance and the
biologically soluble and resolvable polymer carrier, and the
mixture is stirred mechanically, by ultrasound, or by any
other known method to ensure uniform distribution of fat in
the mixture.
Thus prepared antianginal medicinal films having
prolonged action and improved accuracy of dosage, can be
stored for periods of time that considerably exceed expiration
time of other medicinal forms such as dragées, tablets,
granules, etc.
- 30 -
Table 7
Amount of the active substance
(in %~ liberated in time lapses
Antianginal (min.)
preparation _ _
2 5 10 30 60
Glycerol trinitrate
tablets 40 70 100 - -
Medicinal film of poly-
acrylamide containing
glycerol trinitrate20 3S 60 80100 t
Medicinal film of co-
polymer of acrylamide,
vinylpyrrolidone and
ethyl acrylate (1~
containing glycerol
trinitrate 25 40 60 75100
- 31 -
For a better understanding of the invention, the
following examples of its practical embodiment are given by
way of illustration.
Example 1
Antianginal film, having the following composition,
in percent by weight, is prepared:
glycerol trinitrate 3
polyacrylamide (molecular
mass, 970 7 000) 97
A solution of glycerol trinitrate in ethyl alcohol,
having a concentration of 1 percent by weight, and polyacryl-
amide solution in water, having a concentration of 10 percent,
is prepared in glass vessels. Next 970 g of polyacrylamide
solution are placed in a vessel provided with a stirrer and
30 g of glycerol trinitrate solution are added. Stirring is
continued for 30 minutes at 80-100 rpm. The solution is then
placed in a vacuum cabinet and air is removed from the solution
at 10 mm Hg for 2-3 hours at room temperature. The solution
is now cast onto a polished metal plate in a 4-5 mm thick layer.
The plate is placed in a heated cabinet and kept there for 24
hours at a temperature of 20C, then for 1~ hours at a tempera-
ture of 30C, and finally for 12 hours at 40C. The obtained
medicinal film, 0.5 mm thick, is kept at room temperature for
24 hours, and round discs, 7 mm in diameter,are stamped out
mechanically. Each disc contains about 0.5 mg of glycerol
trinitrate.
Example 2
Antianginal film containing the following components,
in perc~nt by weight, is prepared:
glycerol trinitrate 30
copolymer of acrylamide,
N-vinylpyrrolidone, and ethyl-
acrylate (1:1:1; mol. weight, 80,000~ 70
- ~ 32 -
~70~
The components are dissolved in an aqueous alcohol
mixture (75:25) to obtain 10-20 percent solutions. The
medicinal film is then prepared by the procedure described
in Example 1.
Example 3
Antianginal film having the following cornposition,
in percent by weight, is prepared:
glycerol trinitrate 10
copolymer of acrylamide,
N-vinylpyrrolidone and butyl-
acrylate (1:0.S:0.3, mol.weight,
80,000~ 9O
The components are subsequently dissolved in an
aqueous-alcohol mixture (75:25) to obtain 10-20 percent
solutions. The further procedure is the same as described
in Example 1.
Example 4
Antianginal film having the following composition,
in percent by weight, is prepared:
glycerol trinitrate 3
copolymer of acrylamide,
N-vinylpyrrolidone and ethyl-
acrylate ~0.6:0.2:0.2, mol. wto, 97
50,000)
cocoa butter 3 (with respect
to the other
components)
The components are subsequently dissolved and dispersed in an
aqueous-alcohol mixture (75:25) to obtain 10-20 percent
solutions and dispersions of the components. The dispersion
is prepared by mechanical stirring. The further procedure
is the same as described in Example 1.
Example 5
Antianginal film, having the following composition9
in percent by weight, is prepared:
- 33 -
~lZ7~3~
glycerol trinitrate . S
copolymer of acrylamide,
~-vinylpyrrolidone, and
ethylacrylate (0.6:0.2:0.2,
mol. wt., 500,000) 95
cocoa butter 30 (with respect
to all okher
components)
The further procedure for preparing the film is the
same as described in Example 4~
Example 6
Antianginal film, having the following composition,
in percent by weight, is prepared:
glycerol trinitrate 5
copolymer of acrylamide,
~-vinylpyrrolidone, and
ethylacrylate (0.6:0.2:0.2,
mol. weight, 500,000) 95
hydrogenized cotton-seed oil 10 (with respect
to all other
components)
The method of preparing the film is described in
Example 4.
Example 7
Antianginal film, having the following composition,
in percent by weight, is prepared:
pentaerythritol tetranitrate 20
copolymer of acrylamide,
. N-vinylpyrrolidone and ethyl-
acrylate (0.6:0.2:0.2 mol.
wt., 500,000) 80 :
cocoa butter 10 (with respect
to all other
components)
The procedure for preparing said medicinal film is
the same as described in Example 4.
Exam~le 8
Antianginal film, having the following composition,
in percent by weight, is prepared:
- 34 -
~,~
Q~
isosorbide dinitrate 20
copolymer of acrylamide,
N-vinylpyrrolidone and
ethylacrylate (0.6:0.2:0.2;
mol. wt., 500,000) 80
The components are subsequently dissolved in an
aqueous-alcohol mixture (50:50) to obtain 15-20 percent
solutions of the components. The further procedure is the
same as described in Example l.
Example 9
Antianginal film having the following composition,
in percent by weight, is prepared:
pentaerythritol tetranitrate 20
copolymer of acrylamide,
~-vinylpyrrolidone and
ethyl acrylamide (0.6:0.2:0.2;
mol. wt. 500,000) 80
cocoa butter 10 (with res-
pect to all
other com-
ponents)
The method is the same as described in Example 4
Example lO
Antianginal film, having the following composition,
in percent by weight, is prepared:
glycerol trinitrate 5
copolymer of acrylamide,
~-~inylpyrrolidone and ethyl-
acrylate (0.6:0.2:0~2, mol.
wt., 500,000) 95
glycerol phthalate 10 (with respect
to all other
components)
The method for preparing the medicinal film is the
same as described in Example 4.
