CA1127082A - Antianginal film and method of treating ischemic heart disease - Google Patents
Antianginal film and method of treating ischemic heart diseaseInfo
- Publication number
- CA1127082A CA1127082A CA324,996A CA324996A CA1127082A CA 1127082 A CA1127082 A CA 1127082A CA 324996 A CA324996 A CA 324996A CA 1127082 A CA1127082 A CA 1127082A
- Authority
- CA
- Canada
- Prior art keywords
- antianginal
- film
- acrylamide
- vinylpyrrolidone
- glycerol trinitrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
ABSTRACT OF THE DISCLOSURE
The antianginal film is a plate, 0.1 to 1.5 thick, consisting of a biologically soluble and resolvable carrier, which is a homopolymer of acrylamide or vinylpyrrolidone, or a copolymer thereof with acrylate, containing from 99 to 70 per cent by weight of acrylamide with vinylpyrrolidone and from 1 to 30 per cent by weight of acrylate having a molecular mass from 50,000 to 1,000,000, and the active principle having anti-anginal action, the components being taken in the following proportions, in per cent by weight:
active substance having antianginal action 3.0 - 30.0 biologically soluble and resolvable carrier 70.0 - 97.0 The film is useful for treating ischemic heart disease.
The antianginal film is a plate, 0.1 to 1.5 thick, consisting of a biologically soluble and resolvable carrier, which is a homopolymer of acrylamide or vinylpyrrolidone, or a copolymer thereof with acrylate, containing from 99 to 70 per cent by weight of acrylamide with vinylpyrrolidone and from 1 to 30 per cent by weight of acrylate having a molecular mass from 50,000 to 1,000,000, and the active principle having anti-anginal action, the components being taken in the following proportions, in per cent by weight:
active substance having antianginal action 3.0 - 30.0 biologically soluble and resolvable carrier 70.0 - 97.0 The film is useful for treating ischemic heart disease.
Description
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, 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 ... . ~ . . , .. , ~
~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 !
~ .. , . , . . , ,, ~, . . ... . .. . . . . . . .. . . ... . . .
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 ~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 . ~ .
,,, . . ~ ~,. .. . , ., . ... , . , , . . . .. .. , . , ., . ~. . . . , ~ .. . ... .. . ... . .
~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.
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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, 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 ... . ~ . . , .. , ~
~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 !
~ .. , . , . . , ,, ~, . . ... . .. . . . . . . .. . . ... . . .
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 ~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 . ~ .
,,, . . ~ ~,. .. . , ., . ... , . , , . . . .. .. , . , ., . ~. . . . , ~ .. . ... .. . ... . .
~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.
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~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 -... _ . , _ . ... _ . _ _ _ _ . , . , .. _ . _ . , _ . _ . , . , . . . .. ., ... _ . .. . , .. , _ . . . . .
. . . .
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-~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.
Table 7 Amount of the active substance (in %~ liberated in time lapses Antianginal (min.) preparation _ _ 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 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:
~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:
~,~
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.
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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 -... _ . , _ . ... _ . _ _ _ _ . , . , .. _ . _ . , _ . _ . , . , . . . .. ., ... _ . .. . , .. , _ . . . . .
. . . .
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-~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.
Table 7 Amount of the active substance (in %~ liberated in time lapses Antianginal (min.) preparation _ _ 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 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:
~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:
~,~
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.
Claims (5)
1. An antianginal film composition comprising a 0.1 to 1.5 mm thick plate consisting of a biologically soluble and resolvable polymer carrier selected from the group consisting of a homopolymer of acrylamide, and copolymers of acrylamide, vinylpyrrolidone and acrylates, containing from 99 to 70 per cent by weight of acrylamide with vinylpyrrolidone and from 1 to 30 per cent by weight of acrylates, having a molecular weight of from 50,000 to 1,000,000, and an active principle having antianginal action, the components being taken in the following proportions, in per cent by weight:
active substance having antianginal action 3.0 - 30.0 biologically soluble and resolvable carrier 70.0 - 97Ø
active substance having antianginal action 3.0 - 30.0 biologically soluble and resolvable carrier 70.0 - 97Ø
2. An antianginal film composition according to claim 1, which, in order to prolong its action, also contains a dis-persed solid fat melting at temperatures from 30 to 50°C, taken in the quantity of from 3 to 30 per cent by weight, calculated with respect to the sum of all other components.
3. An antianginal film composition according to claim 2, which contains a dispersed solid fat selected from the group consisting of cocoa butter, hydrogenized cotton-seed oil, glycerol laurate, and glycerol phthalate.
4. An antianginal film composition according to claim 1, which contains a polymer selected from the group consisting of a copolymer of acrylamide, vinylpyrrolidone, and ethylacrylate taken in the ratio of 0.6:0.2:0.2 respectively, a copolymer of acrylamide, vinylpyrrolidone and butyl acrylate, taken in the ratio of 1.0:0.5:0.3 respectively, and a copolymer of acryl-amide, vinylpyrrolidone, and ethylacrylate, taken in the ratio of 1:1:1, as the biologically soluble and resolvable polymer carrier.
5. An antianginal film composition according to claim 1, which contains a substance selected from the group consisting of glycerol trinitrate, pentaerythritol tetranitrate, and isosorbide dinitrate as the active principle.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SU782605039A SU806037A1 (en) | 1978-04-06 | 1978-04-06 | Antianginal agent |
| SU2,605,039 | 1978-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1127082A true CA1127082A (en) | 1982-07-06 |
Family
ID=20759951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA324,996A Expired CA1127082A (en) | 1978-04-06 | 1979-04-05 | Antianginal film and method of treating ischemic heart disease |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS6024763B2 (en) |
| CA (1) | CA1127082A (en) |
| DE (1) | DE2913752A1 (en) |
| FR (1) | FR2421610A1 (en) |
| GB (2) | GB2021610B (en) |
| SU (1) | SU806037A1 (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4291015A (en) * | 1979-08-14 | 1981-09-22 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing a vasodilator |
| IL61721A (en) * | 1980-12-16 | 1984-03-30 | Blank Izhak | Nitroglycerin preparations |
| JPS57116011A (en) * | 1981-01-08 | 1982-07-19 | Nitto Electric Ind Co Ltd | Pharmaceutical preparation |
| CA1218604A (en) * | 1981-07-08 | 1987-03-03 | Alec D. Keith | Trinitroglycerol sustained release vehicles and preparations therefrom |
| SU1011126A1 (en) * | 1981-07-14 | 1983-04-15 | Всесоюзный научно-исследовательский и испытательный институт медицинской техники | Method of treating diabetes mellitus |
| AU553343B2 (en) * | 1981-08-10 | 1986-07-10 | Advance Electrode Kabushikikaisya | Absorbent adhesive bandage with medicament release |
| US4482533A (en) * | 1982-01-11 | 1984-11-13 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing propranolol |
| ZA836627B (en) * | 1982-10-08 | 1984-05-30 | Verex Lab | Constant release rate solid oral dosage formulation of pharmaceutical compounds having a high degree of water solubility |
| FR2542998B1 (en) * | 1983-03-24 | 1986-01-31 | Rhone Poulenc Sante | NEW TRANSDERMAL FORM OF ISOSORBIDE DINITRATE |
| US4693887A (en) * | 1983-09-15 | 1987-09-15 | The Kendall Company | Microphase separated hydrogels for controlled release of bioactive materials |
| JPS6066759A (en) * | 1983-09-21 | 1985-04-16 | 日東電工株式会社 | Pharmaceutical preparation |
| JPS60148471A (en) * | 1983-12-27 | 1985-08-05 | マンヴイル サービス コーポレーション | Crown support type carrier |
| US5364628A (en) * | 1985-05-31 | 1994-11-15 | Sandoz Ltd. | Pharmaceutical compositions |
| JPS61280423A (en) * | 1985-06-05 | 1986-12-11 | Kiyuukiyuu Yakuhin Kogyo Kk | Mucosal application agent in oral cavity |
| US4764378A (en) * | 1986-02-10 | 1988-08-16 | Zetachron, Inc. | Buccal drug dosage form |
| DE3823395A1 (en) * | 1988-07-09 | 1990-03-15 | Holzapfel Boeving Partner Werb | Cloth impregnated with an active substance |
| EP0409383B1 (en) * | 1989-07-21 | 1994-04-06 | Izhak Blank | Estradiol compositions and methods for topical applications |
| US5232703A (en) * | 1989-07-21 | 1993-08-03 | Izhak Blank | Estradiol compositions and methods for topical application |
| US5204109A (en) * | 1989-12-28 | 1993-04-20 | Nitto Denko Corporation | Percutaneous gel preparation |
| EP1888025B1 (en) | 2005-06-08 | 2020-08-12 | Basf Corporation | Medicament carrier composition and method of forming a film therefrom |
| EP2887927B1 (en) * | 2012-08-23 | 2018-03-28 | Cardiolynx AG | Extended release compositions of an amino-c2-c6-alkyl nitrate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE859931C (en) * | 1944-05-24 | 1952-12-18 | Roehm & Haas G M B H | Galenic preparations |
| DE2301664C3 (en) * | 1973-01-13 | 1979-07-12 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Oral medicine containing nitroglycerin |
| JPS5138412A (en) * | 1974-09-24 | 1976-03-31 | Nippon Kayaku Kk | Kokoseizai no seiho |
| ZA765931B (en) * | 1975-10-10 | 1977-09-28 | Squibb & Sons Inc | Controlled release tablet |
| DE2634004B2 (en) * | 1976-07-29 | 1978-08-10 | Bernhard Dr. 8000 Muenchen Lippold | Process for accelerating the dissolution and improving the solubility of poorly soluble drugs intended for oral administration |
-
1978
- 1978-04-06 SU SU782605039A patent/SU806037A1/en active
-
1979
- 1979-04-05 CA CA324,996A patent/CA1127082A/en not_active Expired
- 1979-04-05 DE DE19792913752 patent/DE2913752A1/en not_active Ceased
- 1979-04-06 GB GB7912104A patent/GB2021610B/en not_active Expired
- 1979-04-06 GB GB8120761A patent/GB2078771B/en not_active Expired
- 1979-04-06 FR FR7908827A patent/FR2421610A1/en active Granted
- 1979-04-06 JP JP54041172A patent/JPS6024763B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2078771B (en) | 1983-03-09 |
| JPS54154511A (en) | 1979-12-05 |
| GB2021610A (en) | 1979-12-05 |
| GB2078771A (en) | 1982-01-13 |
| JPS6024763B2 (en) | 1985-06-14 |
| GB2021610B (en) | 1982-10-20 |
| FR2421610B1 (en) | 1982-11-12 |
| FR2421610A1 (en) | 1979-11-02 |
| DE2913752A1 (en) | 1979-12-20 |
| SU806037A1 (en) | 1981-02-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
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