GB2078771A

GB2078771A - Drug carrier

Info

Publication number: GB2078771A
Application number: GB8120761A
Authority: GB
Original assignee: V KARDIOLOG NAUCH TS AKAD MEDI; VNI I ISPYTATEL I MEDITSIN TEC
Current assignee: V KARDIOLOG NAUCH TS AKAD MEDI; VNI I ISPYTATEL I MEDITSIN TEC
Priority date: 1978-04-06
Filing date: 1979-04-06
Publication date: 1982-01-13
Also published as: JPS54154511A; FR2421610A1; GB2021610A; CA1127082A; GB2078771B; GB2021610B; SU806037A1; FR2421610B1; JPS6024763B2; DE2913752A1

Abstract

A soluble carrier, which may be combined with an active ingredient to produce a pharmaceutical composition, in the form of a plate of thickness 0.1 to 1.5 mm, is made from a homopolymer of acrylamide or a copolymer of acrylamide with vinylpyrrolidone or a copolymer of these two and an acrylate. The carrier has a molecular weight of from 50,000 to 1,000,000.

Description

1

SPECIFICATION Drug Carrier

GB 2 078 771 A 1 This invention relates to pharmacy, and more particularly it relates to a drug carrier. In a preferred aspect the invention relates to a medicinal film which, when combined with an active ingredient, has antianginal action. Such an antianginal film may be used in cardiology to treat ischemic heart disease. 5 Use of antianginal preparations containing active ingredients such as glycerol trinitrate, isosorbide dinitrate, pentaerythritol tetranitrate is known.

In addition to these active ingredients such medicinal preparations contain an inert carrier which on administration is dissolved in the liquid media of the body. For example, granules of glycerol trinitrate containing sugar, starch, and other substances as filling materials have been used. See Soviet 10 State Pharmacopoeia, 1 Oth edition.

A disadvantage of known medicinal preparations containing re-adily soluble substances, such as sugar, as filling material, is their low stability in storage and their lack of prolonged action.

Also known are tablets of glycerol trinitrate, prepared by the microcapsulation method (Sustak, Nitrong) in which microcapsules act as the carrier material. Hence a derivative of cellulose, such as methyl cellulose, ethyl cellulose, acetyl cellulose and cellulose acetophthalate, can be used. See USA Patent No. 665,297.

Medicinal preparations enclosed in microcapsules are not active immediately they are administered-there may be a delay of up to 60 minutes-and this makes it impossible to use them for rapid arresting of stenocardia attacks.

Another disadvantage of capsuled preparations is the relative complexity of their manufacture.

Antianginal preparations manufactured in the form of tablets and dragees are also known. These include multi-coated pills, containing synthetic polymers, such as polyvinyl alcohol, and a copolymer of polyvinyl alcohol and vinyl acetate, as dissolvable carrier material. Synthetic polymers are used to coat tablets or granules so that the rate of liberation of the active principle can be controlled, see French 25 Patent No. 2,326,933 and US Patent No. 4,012,498.

Furthermore, antianginal preparations in the form of chesing gum containing the active principle and various additives are known. The base materials used in these preparations are polyacrylate polymers as disclosed in US Patent No. 3,594,470.

Furthermore, antianginal preparations in the form of chewing gum containing the active principle 30 and various additives are known. The base materials used in these preparaiions are polyacrylate polymers as disclosed in US Patent No. 3,594,470.

The disadvantage of known medicinal preparations when in the form of tablets pressed with powdered synthetic polymers, and also enclosed in coats of such polymers, is that they can be administered incorrectly, especially by children who may chew them before swallowing. This produces 35 undesirable side effects due to rapid uncontrolled administration into the body.

A suitable method of treatment with such medicinal preparations consists in a patient swallowing the medicine (peroral administration), placing it under the tongue until it fully dissolves (sublingual administration), or chewing a gum containing the medicine to ensure gradual administration with saliva. In all of these methods, the active principle penetrates into the alimentary tract where it is 40 dissolved, absorbed through the mucosa, and delivered first to the liver and then to the blood circulating system (Petkov, V., 'Wedicine, Body, Pharmacological Effect," Medicina i Fizkultura, Sofia, 1974).

The general pharmacological disadvantage inherent in all known medicinal antianginal preparations is that when the preparations enter the alimentary tract, and later the liver, the liberated 45 active ingredient is partly inactivated by the enzyme systems in the body. This is due to the way these preparations are made. The degree of inactivation depends on specific characteristics of the living body and on its physiological state, which in general make it impossible to predict the dose which will give best results.

We have now devised a novel medicinal film. This film, when activated, has prolonged action, 50 improved accuracy of dosage, and stability in storage.

Thus, the present invention consists in a plate or film of thickness 0. 1 to 1.5 mm for use as a drug carrier. It is made of soluble polymeric material comprising either: a homopolymer of acrylamide; a copolymer of acrylamide and vinylpyrrolidone, or a copolymer of acrylamide and vinylpyrrolidone (70 to 99% by weight together) and an acrylate (1 to 30% by weight); the molecular weight of the material being from 50,000 to 1,000,000.

The drug carrier can be used for instance to prepare an antianginal composition. In order to determine the correct dosage of such an antianginal composition for a particular patient one can administer to the patient a sample of the carrier and note the time required for the carrier to dissolve.

An active composition is then prepared by combining with a similar sample of carrier sufficient active 60 ingredients for the period of time over which the carrier took to dissolve.

The active compositions made from the drug carrier of the invention preferably comprises from 3 to 30% by weight of active ingredient and from 70 to 97% by weight of carrier. Furthermore, we prefer that these two components are the only components of the carrier.

2 GB 2 078 771 A 2_ Although various polymeric materials may be used as the carrier of the invention, there are three systems that we particularly prefer; firstly, a copolymer of 0.6 parts of acrylamide, about 0.2 parts of vinylpyryolidone, and about 0.2 parts of ethyl acrylate; secondly, a copolymer of 1.0 part of acrylamide, about 0.5 parts of vinylpyrrolidone, and about 0,3 parts of butyl acrylate; and, thirdly, a copolymer of 5 equal parts of acrylamide, vinylpyrrolidone and ethyl acrylate.

The nature of the biologically soluble carrier and the particular ratios of the monomers it contains will be chosen with regards to the ability of the polymers to dissolve in the liquid media of the body, their harmlessness, and their ability to form labile complex bonds with a suitable active ingredient. Solids fats incorporated in the proposed medicinal film or other form of composition, regulate its hydrophobic properties and thereby control the rate of liberation of the active ingredient from the swollen medicinal film.

For an antianginal composition, glycerol trinitrate, isosorbide dinitrate, or pentaerythritol tetranitrate is preferred as the active ingredient.

In order to prolong the action of the antianginal composition a solid fat may be dispersed throughout it. Suitable fats are those that melt between 30 and 501 C, and the preferred amount is from 15 3 to 30% by weight based on the weight of the composition excluding fat. Specific examples of the fats are cocoa butter, hydrogenized cotton-seel oil, glycerol laurate and glycerol phthalate, One of these or a mixture of two or more may be used.

The proposed antianginal film can be taken in capsules or be applied to the mouth mucosa. This latter method of administration is a novel method and has not been described in the literature. It makes 20 it possible to treat ischemic heart disease by individual doses.

A method of treating ischemic heat disease with the proposed antianginal film by individual doses can be carried out as follows. A film of a biologically soluble carrier polymer containing no active antianginal ingredient is first applied to a chosen site of the mouth mucosa of the patient, and the time of resolution of the film is determined. This time gives the time during which active substances can pass into the body. Next, a film is prepared containing that amount of the active principle which should be given to the patient during the time of resolution. Finally, the film containing the required amount of the antianginal preparation is applied (once or repeatedly) to the chosen site of the mouth moscosa of the patient. This ensures continuous and optimal thereapeutic effect during the entire period of dissolution of the film.

The main advantage of this method of treating ischemic heart disease is that the active principle is delivered directly into the systemic blood flow bypassing the liver, ensuring uniform absorption over a long period of time.

Antianginal films were tried in clinic for the following reasons: firstly, to carry out comparative studies of pharmacodynamics of an antianginal film administered per os and containing as active ingredient glycerol trinitrate and the known preparation Sustak; and, secondly, to compare the pharmacodynamics of the proposed antianginal film containing glycerol trinitrate by applying it to the mouth mucosa, and of tablets of glycerol trinitrate given sublingually.

The pharmacodynamic effects were assessed by central and peripheral, hemodynamic indides, and also by changes in tolerance to physical exercise. Earlier we had established a correlation, r-_0.81 +0.06; p<0.001, for the effect of nitrates between the dynamics of peripheral and central blood circulation indices and the results of ECG-monitoring with a controlled physical load. This helped us Judge the efficacy of the proposed medicinal film containing glycerol trinitrate by studying analogous hemo-dynamic parameters.

The proposed medicinal film containing glycerol trinitrate was studied on 23 male patients aged 45 from 37 to 62 (average age, 48) with ischemic heat disease rilanifested in strain stenocardia, with 1 to attacks a day; seven patients had myocardial infarction in the past and had ECG records. The clinical manifestations of the disease averaged from five months to 12 years. Twenty-one patients were tested by bicycle ergometry: 12 of them showed low tolerance for physical load, 5 showed medium tolerance, 4 showed high tolerance. The mean load in the test group was 421.4 kg/m/min, and the work done 50 was 2260 kg-m. Thirteen patients were examined by coronary angiography. Four patients had three main branches of the coronary arteries affected, one patient had two branches affected, and four patients had one branch affected. No local stenosis of the coronary vessels was found in the remaining three patients. Three patients had the 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 piethysmogram curve (b).

This value was expressed in 10-1 Ohm/see.

I mpedance-cardiography was used to determine the stroke volume of the heart, from which the stroke index (mi/sq.m) was determined.

ECG monitoring with controlled physical load was used to study the dynamics of the depression of the ST segment under standard physical loads. This ECG monitoring was carried out over many hours with a portable monitor, and this resulting electrocardiogram was subsequently analysed with a65 3 GB 2 078 771 A 3 4 1-5 computer. At one-hour intervals the patient was given by a doctor a specially selected standard physical load, and the action of the proposed medicinal film containing glycerol trinitrate was assessed by a comparison of the decrease in the depression of the ST segment compared with the initial reading.

The index of ST(D) segment standard depression characterizes the change in the depression per 5 pulse increment unit, and this was used to assess the efficiency of the proposed medicinal film.

During bicycle erogemetry, we increased the continuous load in steps, beginning with 150 kgm/min for three minutes, followed by 100 per cent increases 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 contra indications) until horizontal or down- sloping depression of the ST segment to less than 1 mm was attained or until attack of angina pectoris 10 developed. The following indices were analyzed: intensity of the load and the volume of the work done; pulse rate and arterial pressure at initial and at peak loads: duration of continuous work on the bicycle ergometer until signs of myocardial ischernia developed.

Drug therapy, other than sublingual administration of glycerol trinitrate to arrest attacks of angina pectoris was suspended 24 hours before the tests. The initial indices of FIP, the impedance cardiographic indices and arterial pressure were recorded in 2-3 hours after a light breakfast. During ECG monitoring tests, each patient was given specially selected starting physical load.

At the first day of the studies, all patients were tested for sensitivity to nitrates by sublingual administration of tablets containing 0.5 mg of glycerol trinitrate. Patients who showed low tolerance for nitrate were later given low doses of Sustak (6.4 mg of glycerol trinitrate) or of tablets of glycerol 20 trinitrate (6.0 mg), while patients with high tolerance for nitrates were given higher doses of Sustak (12.8 mg) or of glycerol trinitrate tablets (9.0 mg). The dose of the proposed medicinal film containing glycerol trinitrate for application to the mouth muscosa was determined depending on the time of resolution of the carrier in the absence of the active principle, glycerol trinitrate. To determine individual doses of the medicinal film containing glycerol trinitrate, a doctor applied the polymer carrier 25 (without the active principle) to the mouth mucosa, for example in the region of the upper gum above the canines or premolars, and determined the time during which the film fully resolved. Next he chose a medicinal film containing the required amount of glycerol trinitrate which would ensure continuous and optimal thereapeutic effect during the time required for full resolution of the film.

Approximate calculations shows that 0.3-0.5 mg of glycerol trinitrate are required for each 30 30 minutes of film resolution. The selected medicinal film containing the corresponding dose of glycerol trinitrate, viz. 1 mg for 60-90 minutes of resolution, 2 mg for 2-3 hours resolution, or 3 mg for up to 6 hours of resolution, can then be administered by the patients himself, by applying the film to the gum mucos on the same or the opposite side.

Each pharmacodynamic study was continued for from 6 to 7 hours. The hemodynamic indices 35 were recorded at one-hour intervals in 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 over two days, in 1.5 hours after applying the film-carrier or the film containing glycerol trinitrate onto the gum. Standard conditions for imposing dosed physical loads were observed during the tests.

On the days of studies, food and physical activity of patients were strictly controlled, and the results of the studies were treated statisitically 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 results from one of the patients were not analysed statistically because of a technical artefact of FIP. Tables 1 and 2 give the hemodynamic indices obtained in the course of studies after taking one dose of Sustak or of the medicinal film containing glycerol trinitrate in capsules. The patients who were given 12.8 mg of Sustak and 9.0 mg of glycerol trinitrate in capsules in the proposed medicinal film all had low sensitivity to glycerol trinitrate. The mean hemodynamic effect of this preparation in this group of patients differed only insignificantly from a similar effect in a 50 group of patients who were given smaller doses (6.4 and 6.0 mg respectively). The effects differed significantly in both magnitude and duration.

Systolic arterial pressure (SAP) was lower than the initial level and remained so for three hours after taking Sustak (7.2+1.7 per cent maximum), and for two hours after taking the medicinal film containing glycerol trinitrate (8.3+3.4 per cent maximum). This has not, however, been proved 55 statistically.

The stroke index, according to impedance cardiography, 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 trinitate in capsules decreased the stroke index only after 30 minutes, and this effect persisted for four hours. The delayed action way probably due to the time required for the capsule to dissolve in the alimentary tract. The maximum decrease in the stroke index was more significant after administration of the medicinal film containing glycerol trinitrate (27.4+3.2 in 60 minutes) compared with a corresponding magnitude attained after the administration of Sustak (24.7+ 5.6 in 30 minutes).

4 GB 2 078 771 A 4 Table 1

First Group of 4 patients Dynamics of systolic arterial pressure (SAP), stroke index (SI), amplitude of wave "b" in FIP after administration of Sustak (6.4 mg) and New film containing glycerol trinitrate (6 mg) per os.

Mean Deviation from Initial Level 5 Initial value Time after administration, min 10 30 60 Sustak, SAP 129.2 -4.7 2.7 -7.2+1.7 -4.6+2.2 -8.2+11.4 Si 26.8 -16.3 9.6 -18.2+9.4 -24.7+5.61) -20.0+5.2 "b" 16.2 8.0 7.3 15.0 10.2 19.0 13.0 16.0 9.0 New Film SAP 128.7 -3.0 1.0 -1.5 1.9 -8.3+3.4 -3.4+3.6 SI 29.0 -7.5 7.6 -0.5 5.2 -10.5+9.0 -10.0+3.1 "b" 12.5 12.5 7.6 8.7+3.8 10.0+5.0 14.0+2.4xl Table 1 cont

180 240 300 360 420 480 -5.0 2.1 -7.0 1.9 -4.7 3.2 -2.1+4.0 -1.2+2.8 +0.9+1.7 +6.0+2.0 -22.7+4.3x -18.2+8.6 -17. 2+4.6 -1 7+3.4 2. -4.7+3.0 +3.7+2.2 +14.0+1.0 20.0 11.4 15.0 2.Oxx) 12.5+3.2x) 13.0+2.8x) 9.0+5.2 -1.6 1.7 -5.0+0 4.7+2.5 -4.4+3.3 -3.7+5.5 -0.9+1.5 +2.2 9.8 +1.5+3.5 -7.0 -21.7+2.8x) -22.5+2.9x') -12.7+3.5 -2.0+3.6 -4.3 4.7 +0.7+3.8 +4.0 24 5.1 x) 26.0+11.5 29.0+9.0 6.0+5.1 5.0+0 2.5 2.5 5.0 Deviations in -b- are given in Ohm/see; the other values are in per cent; x),<0.05; xx),<0.01 Table 2

Second group of Five patients Dynamics of systolic arterial pressure (SAP), stroke index (SO, and amplitude of wave "b" in FIP after peroral administration of Sustak (12.8 mg) and new film containing 9 mg of glycerol trinitrate.

Mean Deviation from Initial Level Initial indices Time After Administration, in Min 30 20 30 60 Second group Sustak, SAP 122.0 -6.9+4.1 -7.3+4.1 -4.4+4.7 -4.8+2.5 (n=5) SI 31.4 -1 2.6+4.4xl -16.4+5.1 x) -15.6+5.7 -22.8 2.8xl -b- 19.5 23.0+7.8 32.0+12.4 21.0+9.7 15.0+6.8 New Film SAP 120.6 0 1.3 -1.0 1.9 -3.0+1.4 -7.0+2.5 - SI 31.8 -8.6 5.7 -9.4+4.6 -1 6.8 4.5x; -27.4+3.2xl -b- 16.0 2.5+3.2 8.0 3.4 18.0 5.4x) 18.0+6.Ox Table 2 cont

180 240 300 360 420 480 3.8 5.1 -4.1+4.0 -1.8+2.8 -0.8 2.3 +8.2+2.6 +13.7+3.5 9.2 4.7 -17.5 4.31) -11.4+5.6 +3.3 3.8 +5.4+7.8 +8.6+5.0 +7.0 5.0 9.7 24.0 10.2 13.6+6.6 10.0 6.9 -1.1 3.7 -3.6+5.9 0+5.0 -5.1+3.1 -5.0 2.2 -1.3+4.4 +2.4+2.2 +3.8+2.1 +5.3+2.7 +16.0 -25.0 1.6xxx) -23.0+1.91 -16. 6+2.1 xxl -8.4+2.7 -3.2+3.4 -2.0 2.2 +10.0 13.0+2.0x) 18.0+4.4x) 10.0+2.2x) 18.0 5.1x) 4.0+3.7 5.0+5.0 0 Deviations in -b- are given in Oh.m/sec; the other values are in per cent; xp<0.05; Mp<0.01; xxx),<0.001 GB 2 078 771 A 5 t is The amplitude of the wave "b", according to FIP, increased to the maximum extent in the first 10-30 minutes after the administration of Sustak, and the initial level was restored within 6 hours. With the proposed medicinal film containing glycerol trinitrate, the maximum changes were observed over longer periods of time (2-3 hours), and the initial values were restored within a shorter time (by 5 the fifth hour).

Hemodynamic indices obtained by these experiments are given in Figures 1 and 2 of the accompanying drawings. Figure 1 illustrates pharmacodynamics of Sustak (6.4 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 along the ordinate and shown to the left of the axis is A S%-variations in the stroke index, in per cent of the starting value. On the 10 right of the ordinate is Abx 10-2 ohm/sec-the change with respect to the initial value in the value of the first negative wave "b" on the curve of the first FIP derivative, expressed in ohm/sec with the scale factor 10-2 introduced for the sake of convenience of calculations.

Time (t) is plotted along the abscissa. Open circles and triangles are used for the proposed medicinal film containing glycerol trinitrate, and shaded circles and triangles for Sustak.

Figure 2 shows pharmacodynamics of Sustak (12.8 mg) and the proposed medicinal film containing glycerol trinitrate (9 mg), taken per os, according to impedance cardiography and FIP. As before, mean data are given. Symbols and designations used in the figure are the same as in Figure 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 in two cases where tachycardia developed during the first 15 minutes after the administration of Sustak.

Side effects were observed in five patients after the administration of Sustak (dizzines in two and headaches in three), but only in three patients (all three had headaches) after administration of the proposed medicinal film containing glycerol trinitrate.

Pharmacodynamics of the proposed medicinal film containing glycerol trinitrate applied to the mouth mucosa, and of tablets of glycerol trinitrate given sublingually were studied. The investigations showed 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 30 effects from overdosage (for example hypotension and collapse) in persons in whom the time of full resolution of the film is, say, 30-45 minutes, while the same film will give insufficient dose to patients in whom the film will resolve only after say, six or more hours. This dose would be ideal for patients in whom the film will resolve in 2-3 hours.

Pharmacodynamic studies of the proposed medicinal film containing glycerol trinitrate in doses of 35 1,2 and 3 mg, (as determined by the time of resolution of the film without glycerol trinitrate) were carried out on 17 patients with ischernic heart disease with angina pectoris. The film was applied to mouth mucosa. Glycerol trinitrate preparations did not produce any response in one patient, who was not therefore analysed further. The results of the studies are given in Tables 3 and 4.

The proposed medicinal film containing 1 mg of glycerol trinitrate was given to 9 patients in 40 whom the film resolved in 1.5 to 2.5 hours. Systolic arterial pressure diminished, compared with the initial level, within 15 minutes of sublingual administration of the glycerol trinitrate (maximum by 8.3 2.2 per cent at the fifth minute), and within two hours of applying the film on mouth mucosa (maximum by 7.9+1.6 per cent at the 90th minute). The changes in the systolic arterial pressure were not however reliably proved statistically.

Table 3

Nine patients were each given a film containing 1 mg of glycerol trinitrate (Group 1), and seven patients were each given a film containing 2 mg (Group 2).

Dynamics of systolic arterial pressure (SAP), Stroke index (SI), and amplitude of wave "b" after application of film to mouth mucosa.

Mean Deviation from Initial Level Initial indices in minutes 2 5 10 30 Group 1 SAP 134.3 -2.7+0.6 -2.8_+0.7 -4.2+1.3 -7.3 0.8 S1 28.8 -25. 0 5.5xx -27.8+4.lxxx 32.2+3.5xxx -33.6 3.1-- "b" 14.2 13.1 4.Ox 20.3+4.6xx 1 5.3 2.Oxxx 24.2+4.811x Group 2 SAP 125.3 -3.1 1.2 6.2+1.3 -5.0+3.8 -5.9+1.0 SI 27.9 -21.0 1.5xxx -23.2 3.8xx -23.4+2.8xxx -28.3+6.1 xx "b" 0.15 28.9+6.Oxx 28.3 4.4 31.4+4.3x--- 213.6+4_.4xxx 6 GB 2 078 771 A 6 Table 3 cont Mean Deviation from Initial Level in minutes 90 120 150 180 210 240 -7.8 1.6 -7.9+1.6 -3.8+0.8 -0.5+1.0 -0.3+1.2 +1.0+2.0 +2.2+1.6 -34.9+4.111' -25.4+5.Oxx -23.3+4.6xx -14.2+6.7 -14.3+6.1 +3.2+1.8 +1.0 4. 4 22.2+5.9'x 20.0+7.6x 20.6+7.Oxx 7.5 2.8 5.0 2.4 0_+1.4 1.5 4.1 -5.4 1.6 -6.0 1.5 -5.4+1.2 -5.1+1.9 -0.6+0.8 +2.6+1.7 +2.6+1.8 -28.0 5.6xx -27.0+6.2x -26. 4+7.Ox -1 9.4+3.9x -12.3+4.4 -3.7+5.2 -3.4+5. 6 29.3+3.Oxxx 25.5 7.3x 25.8+8.1x 11.0+ 1.0xxx 7.1+2.6 0+2.9 2.0+2.0 Deviations in 'U' are given in Ohm/sec the others are in percent; x),<0.05; xx),<0.01; xxx),<0.001 Table 4 Dynamics of systolic arterial pressure (SAP), stroke index (SI), and wave "b" amplitude in TRP after sublingual administration of tablet containing 0.05 mg of glycerol trinitrate. There were 15 9 patients in Group 1 and 7 patients in Group 2.

Mean Deviation from Initial Level Initial indices Time after Administration Min 2 5 10 Group 1 Tablets of SAP 130.8 -7.1+1.5 -8.3 2.2 -4.2+1.6 glycerol trinitrate Si 28.8 -34.3+4.6"x -40.3+2.9'xx -33.8+4.3xxx 0.5 mg "b" 18.6 21.0 5.8x 34.0+8.2xx 24.0 5.9xx Group 2 SAP 129.3 -8.7+2.6 -9.6+2.1 -7.9+1.8 SI 30.5 -26.3 5.61x -29.6+5.4xx -28.4+5.7xx "b" 16.0 20.0 5.3x 28.0 5.4xx 22.0+4.3xx Table 4 cont

20 30 40 50 60 -2.7+1.7 +0.8+2.1 +0.4+1.1 +2.1+1.1 +2.3+0.2 +3.0+1.0 -20.0+3.9xx -12.0+4.0 -3.1_ 2.0 +3.7_ 2.4 +1.014.2 -2.3_ 5.0 18.0+4.6xx 10.0+3.Ox 0+3.0 0 1.7 0+2.06 0 5.0 -3.5+3.3 -6.1+3.4 -3.7+4.1 +0.6 3.3 -1.7+2.7 -2+0 16.1+7.7 - 16.1 +3.9x -6.0 3.9 +0.3+3.5 +2.2 3.9 +4.7+5.9 11.0+5.5 12.0+3.5x 5+2.5 2.0+0.9 0+1.6 0+1.7 Deviations in "b" are given in Ohm/sec; the others are given in per cent; X)p<0-05; xx)p<0.0 1; XMp<0.001 35 The stroke index decreased after sublingual use of glycerol trinitrate in tablet form within 20 minutes (maximum by 40.3 2.9 per cent by the fifth minute), and within three hours of the application of the medicinal film to mouth mucosa (maximum 34.9+4.1 per cent by the 60th minute).

The amplitude of the wave -b- in FIP increased to its maximum within five minutes following sublingual use of glycerol trinitrate in tablet form and it returned to its initial level after thirty minutes. 40 When the proposed film was applied to mouth mucosa, the amplitude of the wave -bincreased immediately and returned to its initial level after three hours.

Thus, medicinal film containing glycerol trinitrate had a marked effect on the hemodynamics in the first minutes after its application to mouth mucosa, and the effect persisted for about three hours.

The intensity of the hemodynamic effect of the medicinal film was similar to that of glycerol trinitrate 45 tablets given sublingually, but the intense effect persisted for much longer periods within the proposed medicinal film.

Medicinal film containing 2 mg of glycerol trinitrate 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 and wave -b- in FIP changed, and the values obtained were close to those obtained were close to J 7 GB 2 078 771 A 7 those obtained with a dose of 1.0 mg. There was no reliable proof 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 corresponding film without glycerol trinitrate for these patients.

The results of these studies are given in Figures 3 and 4 of the accompanying drawings.

Figure 3 compares the pharmacodynamics of glycerol trinitrate in tablets (0.5 mg) given sublingually and of the proposed medicinal film containing glycerol trinitrate (2 mg) applied to mouth mucosa (according to impedancecardiagraphy and FIP data). Mean data are given. The designations and symbols used in the figure are the same as in Figure 1.

Figure 4 compares the pharmacodynamics of glycerol trinitrate tablets (0. 5 mg) given sublingually and of the proposed medicinal film containing 1 mg of glycerol trinitrate applied to the 10 mouth mucosa (impedance cardiography and FIP data). Mean data are given. The symbols and designations are the same as in Figure 1.

ECG monitoring with a controlled physical load was carried out as follows. The dynamics of depression of the ST segment was studied in ten patients subjected to controlled physical loads. Firstly, t5 6 patients were given placebos, and the proposed film containing 2 mg of glycerol trinitrate was given to 8 patients. The data obtained reliably proves that after applying the medicinal film containing glycerol trinitrate to mouth mucosa, the ST segment depression (AD%) decreases during the course of three hours with application of equal loads, the maximum effect being attained at the 30-60th minute The ST segment depression variations in patients to whom a placebo had been given did not exceed 4 percent. The results of the tests are given in Table 5 and Figure 5.

Figure 5 shows the dynamics of the ST segment depression under standard physical loads after application of the proposed medicinal film containing glycerol trinitrate to mouth mucosa (2 mg), according to ECG monitoring. The values are mean values.

Plotted along the ordinate is the change in the ST segment depression (AD%). The curve marked with dots shows the change after application of a film without glycerol trinitrate (placebo) and the curve marked with circles shows the change after applying a medicinal film containing glycerol trinitrate to mouth mucosa. Time (t) in minutes, after the administration of the preparation is plotted along the abscissa.

Table 5

Pharmacodynamics of medicinal film containing glycerol trinitrate when applied to mouth 30 mucosa (mean data of ECG monitoring) (8 patients) compared to effect of placebos (6 patients).

Time After Administration Min Placebo 0 30 - - Pmax (st/min) 88.5+3.2 94.0+3.5 35 STmax (mm) 1.3+0.3 1.2+0.1 D (U) 4.2 0.9 3.3 0.5 6 AD (%) 3.6+5.6 0 New Film Pmax (st/min) 101.8+3.3 100.1+2.6 ST ax (mm) 1.9+0.31 0.6 0.22 40 D (U) 6.6 0.97 2.1+0.70 AD (%) 0 -70+7.2xxx Table 5 cont

120 180 240 300 90.5+4.2 86.6+4.6 87.8+3.9 86.6+3.4 90.5+4.6 45 1.2+0.1 1.2+0.2 1.3 0.2 1.3 0.2 1.2+0.2 3.6 0.6 4.7+1.1 4.2+1.1 4.2+0.9 3.6+0.6 -1.0+3.8 0.1+3.0 -0.4+3.4 2.8+3.0 -1.4+4.2 95.1+2.4 95.5+2.1 97.4+3.6 99.5+3.8 107.2+6.3 so 0.4 _0.13 0.7+_0.17 1.0+0.3 1.6+_0.35 2.0+0.2 so 1.9+0.65 2.7+0.7 3.6+1.00 5.7 1.3 5.8 + 0. 9 -74.0 6.8xx -62.7+7.91xx -52.6 11.2xx -19.7+7.1 -4.5+7.8 P,,x is the maximum pulse rate under load. STmax is the maximum depression depth of segment ST under load.

D X),<0.0 1; xx),.0.00 1. 55 8 GB 2 078 771 A 8 Tolerance to physical load produced using a bicycle ergometer was tested in eleven patients to each of whom of placebo was given after administration of 1 or 2 mg of the medicinal film containing glycerol trinitrate. Mean results of this test are given in Table 6, which shows 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 5 were given the true preparation. Also, the test was discontinued on patients to whom a placebo was given (although the load was lessened) who developed signs of myocardial ischernia.

The studies carried out showed the efficacy of the proposed medicinal film containing glycerol trinitrate, both when given per os and when glued to mouth mucosa of patients with ischernic heart disease. Comparative pharmacological studies of the medicinal film containing glycerol trinitrate for 10 peroral use and of Sustak showed that both preparations produce a similar effect on those hemodynamic parameters that were studied, viz stroke index, systolic arterial pressure, and peripheral vasodilation. Objective hemodynamic measurements showed that the medicinal film containing glycerol trinitrate, given per os, produced a specific pharmacodynamic effect in the course of 4-4.5 hours (like Sustak). When considering mean data, important information concerning individual responses to the therapy should also be considered. For example, the results were quite varied after the administration of 12.8 mg of Sustak, and this was considered to be due to individual response to patients to the preparation. More uniform results were obtained with the proposed film containing glycerol trinitrate when applied to mouth mucosa of the patients. The direct uptake of glycerol trinitrate by the body, bypassing the liver, ensures a pronounced pharmacodynamic effect which occurs practically 20 instantaneously and lasts 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 substances; patients do not complain of any inconveniences and happily tolerate this medicinal form; it is possible to control the uptake of glycerol trinitrate whenever necessary (this is particularly important); it is easy to discontinue the uptake of the preparation by removing the unresolved film if necessary; and it is easy to renew the therapy, the therapeutic effect being attained practically instantaneously.

Table 6

Comparison of ECG data taken under controlled physical load on bicycle ergometer, after giving placebo and medicinal film containing 1 or 2 mg of glycerol trinitrate (applied to mouth mucosa) (11 patients).

Mean load Load intensity Time of continuous work, kg/m, kg/min. min Placobo 2154 100395.4 6.6 New Film 4425 240 600.0 10.4 35 Table 6 cont

Heartbeat rate Arterial pressure initial load initial load 72.3 119.8 126/78 167/97 82.5 131.0 115/78 160/91 Criteria for discontinuation of test AP+fatigue+ST 11 0 9 2 AP means of angina pectoris ST is segment ST depressions >1 mm; The high efficancy of the proposed medicinal form has been proved by the data from the test with physical loads. This data demonstrated considerable improvement in tolerance to load and also 45 increased activity of patients with the medicinal film attached to mouth mucosa.

Hemodynamic data agree well with the results of ECG monitoring under repeated standard physical loads, and this objectively proves efficiency of the proposed film containing glycerol trinitrate.

Any side effects which may develop during treatment with the proposed film are insignificant.

Slight pricking at the site of application of the film was reported by 11 patients in the course of the first 50 10-30 minutes, after which these sensations subsided. Nine patients felt dizzy, the same number as with the use of glycerol trinitrate tablets for sublingual administration.

Individual doses of medicinal films containing other active principles, e. g. isosorbide dinitrate and pentaerythritol tetranitrate, can be applied to mouth mucosa.

J 1 9 GB 2 078 771 A 9 1 15 The method of individual dosage ensures not only a prolonged effect (such as over a few hours) but also prevents side effects, such as headache, dizziness, postural hypotonia, and nausea. It is known that, like glycerol trinitrate, isosorbide dinitrate taken per os in the form of tablets is rapidly enzymatically metabolized in the liver i.e. its biological assimilability if administered per os is low and differs significantly from one patient to another. If isosorbide dinitrate is used in a medicinal film as the active substance. it enters the blood circulating system from mouth mucosa, bypassing the liver.

Similarly when pentaerythritol tetranitrate tablets are taken per os, the major part of the active ingredient enters the blood circulating system in inactivated form because of its metabolism in the liver.

The method of individual dosage of a medicinal film containing pentaerythritol tetranitrate 10 ensures delivery of the active ingredient into the systemic blood circulation by a route which bypasses the liver; this considerably prolongs the hemodynamic effect (to several hours) and prevents side effects, such as headache, noise in the ears, dizziness, postural hypotension and, diarrhoea.

An important advantage of the proposed medicinal film possessing antianginal action is its high adhesion in the swollen state to mouth mucosa. This makes it possible to attach the film to a chosen site of the mucose where it remains fixed until fully resolved, thus ensuring uniform delivery of the active ingredient directly into the mucosa and then into the blood circulation system, avoiding the gastrointestinal tract that would cause partial inactivation of the drug.

In contrast to known carriers, the proposed polymeric medicinal film, on contact with aqueous solutions, ensures markedly more uniform delivery of the active ingredient 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 known antianginal preparations. This uniform liberation of the active ingredient, for example glycerol trinitrate, from a medicinal film is illustrated in Table 7, where a comparison is made with known tablets of glycerol trinitrate.

Tabile 7 25 Antianginal Preparation Amount of active ingredient (in%) liberated after indicated number of minutes.

2 5 10 60 Glycerol trinitrate 40 70 100 30 tablets

Medicinal film of poly acrylamide containing glycerol trinitrate 20 35 60 80 100 Medicinal film of 35 copolymer of acrylamide, vi nylpyrrol i done and ethyl acrylate (1 AA) contain ing glycerol trinitrate 25 40 60 75 100 A method of preparing an antianginal film of the invention is as follows. Solutions of a biologically 40 resolvable soluble polymer carrier and of an active ingredient are prepared in standard mixers. The solvents should be compatible, or a single solvent should be used to dissolve the active substance and the polymer carrier. The solutions are then put together at the required ratio of the components and air is removed from the solutions under vacuum at room temperature. A film, 0. 1 to 1.5 mm thick, is then cast on an inert surface using standard casting equipment. The film is dried at a temperature up to 4011C, until the residual amount of solvent does not exceed 10 per cent by weight. Finally, circular plates of the required size are pressed out mechanically. If the medicinal film is to contain dispersed fat, it may be introduced into the solution containing the active ingredient and the biologically soluble and resolvable polymer carrier, and this mixture is stirred mechanically, by ultrasound, or by any other known method 50 to ensure uniform distribution of fat in the mixture.

Antianginal medicinal films prepared in this way have prolonged action and improved accuracy of dosage, and they can be stored for considerably longer than other medicinal forms such as dragees, tables and granules.

The invention is further illustrated by the following Examples.

GB 2 078 771 A 10 Example 1

An antianginal film was prepared having the following composition in per cent by weight.

glycerol trinitrate 3 polyacrylamide (molecular mass, 970,000) 97 5 Solutions of glycerol trinitrate in ethyl alcohol (1 per cent by weight) and polyacrylamide in water (10 per cent) were prepared in glass vessels. Next, 970 g of polyacrylamide solution were placed in a vessel provided with a stirrer and 30 g of glycerol trinitrate solution were added. Stirring was continued for 30 minutes at 80-100 rpm. The solution was then placed in a vacuum cabinet and air was removed from the solution at 10 mm Hg for 2-3 hours at room temperature. The solution was then 10 cast onto a polished metal plate in a 4-5 mm thick layer. The plate was placed in a heated cabinet and kept there for 24 hours at a temperature of 200C, then for 12 hours at a temperature of 301C, and finally for 12 hours at 401C. The resulting medicinal film, 0.5 mm thick, was kept at room temperature for 24 hours, and round discs, 7 mm in diameters, were stamped out mechanically. Each disc contained about 0.5 mg of glycerol trinitrate.

1,5 Example 2

An antianginal film was prepared containing the following components, in per cent by weight.

glycerol trinitrate 30 copolymer of acrylamide, N-vinylpyrrolidone, and ethylacrylate 20 (1: 1: 1; mol. weight, 80,000) 70 The components were dissolved in an aqueous-alcohol mixture (7:;25) to obtain a 10-20 per cent solution. The medicinal film was then prepared by the procedure described in Example 1.

Example 3

An antianginal film was prepared having the following composition, in per cent by weight. 25 glycerol trinitrate 10 copolymer of acrylamide, N-vinylpyrrolidone and buty] acrylate (1:0.5:0.3; mol. wt.

80,000) 90 30 The components were dissolved in an aqueous alcohol mixture (75:25) to obtain a 10-20 per cent solution. The remaining procedure was the same as described in Example 1.

Example 4

An antianginal film was prepared having the following composition, in per cent by weight.

glycerol trinitrate 3 35 copolymer of acrylamide, N-vinylpyrrolidone and ethylacrylate (0.6:0.2:0.2; mol.wt. 50,000) 97 cocoa butter 3 (with respect to the other components). 40 These components were dissolved and dispersed in an aqueous-alcohol mixture (75:25) to obtain a 10-20 per cent solution and dispersion of the components. The dispersion was prepared by mechanical stirring. The remaining procedure was the same as described in Example 1.

Example 5

An antianginal film was prepared having the following composition in percent by weight. 45 glycerol trinitrate copolymer of acrylamide, N-vinyl pyrrolidone, and ethylacrylate (0.6:0. 2:0.2 mol.wt., 500,000) i cocoa butter (with respect to all other components).

The remaining procedure for preparing the film was the same as described in Example 4.

11 GB 2 078 771 A 11 Example 6

Example 7

An antianginai film was prepared having the following composition, in per cent by weight.

glycerol trinitrate copolymer of acrylamide N-vinyl pyrrolidone, and ethyl acrylate (0.6:0. 2:0.2 mol.wt. 500,000) hydrogenized cotton-seed oil (with respect to all other components).

The method of preparing the film was the same as described in Example 4.

4 - An antianginal film was prepared having the following composition, in per cent by weight.

' Pentaerythritol tetranitrate copolymer of acrylamide, N-vinylpyrrolidone and ethyl acrylate (0.6:0.2:0. 2; mol.wt. 500,000) cocoa butter (with respect to all other components).

The procedure for preparing the medicinal film was the same as described in Example 4.

Example 8

isosorbide dinitrate copolymer of acrylamide, N-vinylpyrrolidone and ethylacrylate (0.6:0.2:0. 2 mol.wt. 500,000) The components were dissolved in an aqueous-alcohol mixture (50:50) to obtain a 15-20 per cent solution. The remaining procedure was the same as described in Example 1.

Exa nle 9 An antianginal film was prepared having the following composition, in per cent by the weight. 30 14 pentaerythritol tetranitrate copolymer of acrylamide, N-viny]pyrrolidone and ethyl acrylamide (0.6:0.2:0.2; mol.wt. 500,000) cocoa butter The method was the same as described in Example 4. Examnle 10 (with respect to all other components).

An antianginal film was prepared having the following composition, in per cent by weight. 40 glycerol trinitrate copolymer of acrylamide, N-vinyipyrrolidone and ethyl acrylate (0.6:0.2:0. 2 mol.wt. 500,000) glycerol phthalate (with respect to all other components).

The method of preparing the medicinal film was the same as described in Example 4.

GB 2 078 771 A

Claims

1. A drug carrier in the form of a plate of film of thickness 0.1 to 1.5 mm of soluble polymeric material, comprising either: a homopolymer of acrylamide; a copolymer of acrylamide and vinyl pyrrol idone; or a copolymer of acrylamide and vinyl pyrrol Wone (70 to 99% by weight together) and an acrylate (1 to 30% by weight) the molecular weight of this material being from 50,000 to 1,000,000.

2. A drug carrier according to claim 1, in which the material is a copolymer of 0.6 parts of acrylamide, about 0.2 parts of vinylpyrrolidone and about 0.2 parts of ethylacrylate.

3. A drug carrier according to claim 1, in which the material is a copolymer of 1.0 part of 10 acrylamide, about 0.5 parts of vinylpyrrolidone and about 0.3 parts of butyl acrylate.

4. A composition according to claim 1, in which the material is a copolymer of 1 part of acrylamide, about 1 part of vinylpyrrolidone and about 1 part of ethyl acrylate.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1982. Published by the Patent Office. 25 Southampton Buildings. London, WC2A lAY, from which copies may be obtained.

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