HU183065B - Process for preparing a system containing polymeric matrix with prolonged release of glycerine-trinitrate - Google Patents

Abstract

The present invention relates to a method for producing a system comprising a polymeric matrix for release of a glycerol-rich nitrate. In the process according to the invention, 2 to 60% by weight of glycerol, 2 to 15% by weight of polyvinyl alcohol having a molecular weight of 100,000 to 150,000, polyvinylpyrrolidone 20 to 20,000 to 60,000 mol, and glycerol trinitrate are mixed and mixed. molded to the desired shape, preferably cast into a plate. FIG. 1 -1-

Description

The polymer matrix system consists of the following components: 2-60% by weight glycerol, 2-15% by weight polyvinyl alcohol 100,000-150,000 molecular weight, 2-10% by weight polyvinylpyrrolidone 20,000-60,000 molecular weight, and water. The water soluble polymer polyvinylpyrrolidone having hydration sites is not incompatible with the other components of the system of the invention and allows glycerol trinitrate to be released from the matrix continuously over a prolonged period.

German Patent Publication No. 27,449,493 discloses a carrier matrix consisting of a polypeptide such as hydrolyzed gelatin, dextran or alliginate and may optionally contain polyvinyl alcohol. The system containing these matrices is primarily for oral use and does not mention their sustained release.

Alza Corp. has made numerous attempts to produce matrices of a medical nature, but these are mainly theoretical and generally concern the preparation of silicone matrices.

It is a known fact that nitroglycerin is a systemic (living organism) active substance that can be used mainly in the treatment of certain heart diseases by the skin. For example, NITROL (KremersUrban, Milwaukee, Wisconsin, USA) and NITROBID (Marion, Kansas, USA) are creams containing 2% nitroglycerin in lanolin and applied to the patient's breast. However, they are effective only for a few hours.

Treatment with the system of the present invention achieves sustained release of the active ingredient over a much longer period, such as at least 24 hours.

Brief explanation of the drawings:

Figure 1 is a plan view of a bond that anchors the drug-containing polymer diffusion matrix of the invention to the skin.

Figure 2 is a cross-sectional view taken along line 2 - 2 'of Figure 1.

When used with the polymer matrix system of the invention, it is in a "dry" state. By "dry" we mean that the excess water used to make the matrix is not present or is present in a small amount in the matrix. As described in more detail below, the system is prepared by mixing glycerol trinitrate, glycerol, polyvinyl alcohol, polyvinylpyrrolidone and water, and pouring the resulting homogeneous mixture into sheets. It may be necessary to use excess water to pour the mixture well. The matrix is in the "wet" state immediately after casting. After pouring, allow excess water to evaporate. When essentially the excess water evaporates practically completely, the polymer matrix is in a "dry" state. During the evaporation of water, which

It takes 1-18 hours, the thickness of the diffusion matrix decreases, and a "shrunken" matrix is formed.

The " wet " matrix is from 2 to 60% by weight, and glycerol is preferably from 35 to 60% by weight. Preferably, the glycerol has a specific gravity of at most 1.23 g / ml.

Glycerol is required for the formation of an appropriate diffusion interface between the skin and the matrix, without which the sustained release of the active ingredient is not assured.

The "wet" matrix contains from 2% to 15% by weight, and preferably from 4% to 9% by weight, of polyvinyl alcohol. The molecular weight of the polyvinyl alcohol is between 100,000 and 150,000.

The molecular weight of the polyvinylpyrrolidone should be chosen so that the polymer is water soluble. This molecular weight should generally be between 20,000 and 60,000, and preferably between 35,000 and 50,000.

The remainder of the matrix is essentially water.

The "dry" polymer, in a so-called diffusion matrix (which permits diffusion of the active ingredient), contains glycerol in an amount of from about 55% by weight, preferably from 4% to 30% by weight, from 4% to 30% by weight, and preferably from 8% by weight. and from 18 to 18% by weight of polyvinyl alcohol, from 4 to 20% by weight, and preferably from 4 to 10% by weight, of a water soluble polymer containing hydration sites, namely polyvinylpyrrolidone and the remainder of water. Preferred molecular weight limits for polyvinyl alcohol and polyvinylpyrrolidone are the same for the "wet" and "dry" matrices.

The density of the "dry" matrix is 1.2 g / ml. Note that the weight ratio of glycerol to water in the "dry" matrix is about (0.6-1.8): 1, and preferably 1: 1. The "dry" matrix swells only slightly when immersed in water and is insoluble in water at room temperature. . However, when placed in boiling water, the matrix dissolves.

Glycerol trinitrate (finely divided) is dispersed in the diffusion matrix. After a relatively uniform release of the drug from the matrix over a prolonged period of time, typically 24 hours, the patient will benefit from the drug administered continuously over this period of time.

The amount of drug dispersed in the diffusion matrix will depend on the dose to be applied and the length of time the matrix will remain on the patient's skin. However, the amount of drug in the matrix should generally be greater than what is to be injected into the patient's body. If the diffusion matrix is to be used for 24 hours, the matrix must contain about ten times the drug. For example, if a patient is to receive approximately mg of glycerol trinitrate per 24 hours, the diffusion matrix should contain about 10 times that amount. Accordingly, preferably 40 to 60 mg are mixed in the diffusion matrix to ensure that mg is released from the matrix within 24 hours. Obviously, the amount of drug to be incorporated into the diffusion matrix is also influenced by factors such as the rate of drug release.

In a preferred embodiment of the process of the invention, glycerol trinitrate, also known as 1,2,3-propanetriol trinitrate, is used, and the drug is preferably added to the polymer matrix in admixture with lactose to reduce the explosive properties of glycerol trinitrate. In addition, in order to avoid the risk of explosion

The lactose mixture is added in a volume ratio of 183,065 to glycerol and water, at which ratio glycerol trinitrate does not escape from the system. Preferably, the lactose mixture contains 10% glycerol trinitrate and 90% β-lactose.

The preparation of the matrix containing glycerol trinitrate does not require the use of excess water. Thus, the preferred composition of this matrix is glycerol in an amount of 35 to 60% by weight, preferably 45 to 55% by weight, polyvinyl alcohol in an amount of 2 to 15% by weight, and preferably 4 to 9% by weight, 2 wt% to 10 wt% polyvinylpyrrolidone, preferably 2 wt% to 5 wt%, the rest being water. We have found that only a negligible amount of water evaporates from the "wet" matrix and therefore contains more glycerol. In this matrix mixture, the ratio by weight of glycerol to total polymer is generally greater than 1, and preferably (1.4-15): 1.

The amount of glycerol trinitrate to be used is based on the intention of delivering about 5 mg per 24 hours to the patient. The diffusion matrix of the present invention, which serves as a drug mediator and is intended to deliver 5 mg of active ingredient to a patient over a 24 hour period, should contain 40-60 mg of glycerol trinitrate. To achieve this goal, the concentration of glycerol trinitrate present in the matrix and the size of the skin surface covered by the diffusion matrix must be properly selected. In a preferred embodiment of the process according to the invention, the diffusion matrix contains between 0.1% and 4.0% by weight of glycerol trinitrate. Accordingly, a diffusion system containing glycerol trinitrate is prepared by providing The mixture is mixed with 20 mg of glycerol-trinitrate-lactose and the mixture is mechanically stirred until homogeneous. Preferably, this homogeneous mixture is poured into molds made of glass or stainless steel to provide layers of about 3 mm to about 4 mm in a further preferred embodiment of the process of the invention. The diffusion system is either pre-cast to the size to be used, or cut from sheets larger than necessary to the desired size. According to a further preferred embodiment of the method of the invention, square plates having a side length of 2.5-2.5 cm and a surface area of about 6.5 cm ² are prepared, and such plates are easily applied to the skin of patients.

The system comprising the diffusion matrix of the present invention can be best prepared by the following methods.

In a preferred embodiment of the invention, the matrix-containing system is prepared at atmospheric pressure. First, water and glycerol are mixed together. Since it has been found that such mixtures are not sufficiently stable in the alkaline pH range, the pH of the mixture is adjusted to neutral or slightly acidic, i.e. 6.5 to 7.0. In a preferred embodiment of the process of the invention, the pH of the mixture is adjusted to the desired value by addition of sodium citrate and citric acid.

Polyvinyl alcohol and polyvinylpyrrolidone are then added to the mixture of glycerol and water at room temperature with stirring. Then the mixture is heated to temperatures between about 90 C and about ⁴ to 95 ° C for the purpose of increasing the chain length of the polymers at atmospheric pressure and heated for approximately 1 hour at this temperature. If desired, the mixture may be maintained at this temperature for 48 hours prior to the addition of the active ingredient. In other words, the above mixture is stable for about 48 hours and can be heated for such time before the glycerol trinitrate is added. The mixture was then cooled to 80 ° C and stirred for an additional hour to remove bubbles. The drug is then added with vigorous stirring. Once the drug and polymer solution are homogeneous, the diffusion system containing the active ingredient can be poured into sheets.

According to another preferred embodiment of the process of the invention, the drug may be dissolved in a suitable solvent, such as glycerol or water. The solutions thus obtained can be stored without damage; after all at room temperature for a longer period of time.

According to another preferred embodiment of the process of the invention, glycerol and water are first mixed and the pH of the mixture is adjusted to the desired value by addition of an appropriate amount of sodium citrate and citric acid. Polyvinyl alcohol and polyvinylpyrrolidone are then added and the mixture is heated to about 120 ° C (about 2 atm absolute). Without mechanical stirring, approximately - Maintain this temperature through dust. According to a preferred embodiment of the process according to the invention, the mixture is heated in an autoclave. This variant is advantageous because no bubbles are introduced during autoclave heating. After heating, the mixture is brought to a temperature of about 20 ° C to about 80 ° C and mixed with the drug. After uniformly distributing the active ingredient in the liquid mixture, the drug-containing diffusion matrix is molded into sheets.

When using the methods described above, the active ingredient must be added to the mixture and thoroughly mixed while the polymer mixture is still in a liquid state. In addition, the mixture should be poured into plates within half an hour after the addition of the active ingredient. This is important to avoid sedimentation of the active ingredient. '

The temperature at which the active ingredient is added to the matrix solution depends on the stability of the active ingredient. Glycerol trinitrate begins to decompose at temperatures above about 50 ° C. Accordingly, the matrix solution is suitably cooled to 50 ° C and glycerol trinitrate is then added. The solution containing the active ingredient is then poured into molds, sheets. In addition, in the case of nitroglycerin, the pH of the finished mixture must be kept slightly acidic, i.e., between 6.5 and 7.0, since nitroglycerin is stable in this pH range.

183,065

Dimethylsulfoxide, decylmethylsulfoxide or other penetration enhancers may be added to facilitate penetration of the active ingredient into the skin.

If you want to extend the life of the diffusion matrix, you can add a spare active ingredient to the mixture. Local vasodilators may also be incorporated into the diffusion matrix to aid in the resolution of complaints caused by local circulatory dysfunctions, such as improving circulation in the limbs of elderly patients.

The drug delivery system of the present invention consists of two parts, a diffusion matrix containing the active ingredient and means for attaching the matrix to the patient's skin. The latter devices may take various forms, such as an adhesive layer similar to a conventional patch, which adheres the diffusion matrix to the skin of the patient to be treated. According to a preferred embodiment of the process according to the invention, such an adhesive layer may be a polyethylene or Mylar patch. In addition, an elastic band such as a rubber band, a scarf, or the like may be used. In this case, the diffusion matrix is applied directly to the patient's skin and secured with an elastic band. Generally, this method of attachment is used on the patient's arm or wrist. Further, an adhesive layer between the skin and the diffusion matrix can be used to allow the active ingredient to enter the skin.

The diffusion matrix containing the active ingredient is placed in a cavity lined with an inert material. Examples of inert lining materials include metal foil such as aluminum foil, polyolefins such as polyethylene or polypropylene, polyesters such as Mylart (polyethylene terephthalate), polyamides such as nylon, and the like. Alternatively, the diffusion matrix containing the active ingredient is poured into the cavity in the molten state and allowed to cool. An adhesive layer is applied under the cavity lining material. To exclude air, the adhesive layer and matrix are covered with a removable layer. Before using the diffusion matrix, the patient removes the release liner and places the matrix on the skin. The adhesive layer attaches the whole to the skin. After having a concentration gradient perpendicular to the plane defined by the surface of the matrix and the patient's skin, the drug can diffuse from the matrix into the patient's skin. Thus, the method of the present invention provides a system for continuously delivering a drug to the patient's skin through the skin over an extended period of time.

The structure of the packaging of the matrix according to the invention is illustrated in detail in Figures 1 and 2. As shown in the figures, the package has two main parts, the topsheet 12 and the bottom 10. The diffusion matrix containing the drug substance (e.g., glycerol trinitrate), numbered 14, is located in the cavity, designated by number 16, of the lower layer, designated 10. The diffusion matrix, when molten, can be poured into cavity # 16 and allowed to dry there. Alternatively, the molten polymer mixture, with or without active ingredient, may be poured into thin sheets and, after drying, cut into smaller pieces of suitable size. These smaller pieces are then placed in the cavity formed by the lower layer 10, designated by the number 16. The portion of the lower layer indicated by number 10 directly surrounding the matrix, indicated by number 18, is subjected to heat treatment, thereby adhering the matrix to the lower layer. The lower layer, denoted by 10, has a layered structure consisting of an outer layer of polyester (e.g., polyethylene terephthalate), denoted by number 20, a middle layer of a metal foil, such as aluminum foil, denoted by number 2, and the inner layer of 24. , ionomeric layer such as Surlyn. An adhesive layer, designated 26, is attached to the heat treated portion of the inner layer. Note that the adhesive layer does not cover the matrix.

Protect the matrix from contact with air by applying a topsheet sealing the matrix, designated 12. The topsheet, like the lower layer, consists of three layers, an outer layer of polyester, such as polyethylene terephthalate (28), a middle layer (30) of a metal foil, such as aluminum foil, and an inner ionomer (32). - such as Surlyn. The part of the inner layer that comes into contact with the adhesive part 26 of the lower layer 10, when assembled, is covered with a removable layer which allows the entire top layer to be easily removed.

The matrix is applied by first removing the topsheet and then adhering the exposed matrix to a suitable location on the patient's body, such as the arm or wrist, so that the active ingredient can diffuse into the patient's skin.

In a preferred embodiment of the process of the invention, the molten matrix is poured into the cavities of the lower portion, allowed to dry for a short time (e.g., about 10 minutes to about 1 hour) and then sealed by applying the topsheet to the lower layer.

The invention is further illustrated by the following non-limiting examples.

Example 1 One ml of glycerol and 45 ml of water, together with 1% sodium citrate by weight, were mixed and the pH was adjusted to 7 by addition of citric acid. Subsequently, the mixture is heated to 90 ° C, and 7 g of polyvinyl alcohol (hydrolyzed, molecular weight: 115,000) and 5 g of polyvinylpyrrolidone (molecular weight: 40,000) are added slowly while heating, but at least 70 ° C. The mixture was stirred at 90 ° C until dissolved. This may take about 10 minutes, but larger quantities may of course take longer. Then, 80 ml of the solution obtained above is mixed with 20 g of glycerol trinitrate-lactose mixture (10% glycerol trinitrate and 90% lactose) and

183,065 is mechanically stirred until homogeneous. The homogeneous mixture is then poured into glass or stainless steel molds to form a diffusion matrix system in the form of sheets of about 3 to 4 mm thick. These discs are then cut into square disks of about 2.5 cm in length, so that 1 to 1 such disks have a surface area of about 6.5 cm ² .

Example 2

948 g of 96% glycerol and 644 g of water are mixed and 27 g of thiodium citrate, 159 g (molecular weight 115,000) of polyvinyl alcohol and 93 g (molecular weight of 40,000) are dissolved at approximately 90 ° C. polyvinylpyrrolidone.

In another apparatus, 600 g of glycerol-trinitrate lactose (10% glycerol-trinitrate and 90% lactose) are dissolved in a mixture of 315 g of glycerol and 214 g of water at room temperature with stirring. After the polymers have dissolved, the glycerol trinitrate dispersion is added to the solution. The mixture was then stirred vigorously at 50 ° C to 55 ° C until a homogeneous mixture was obtained. During this time, the container is kept covered.

The finished homogeneous mixture is poured into flat molds made of glass or stainless steel. The diffusion matrix thus containing the drug is obtained in the form of sheets of about 3-4 mm thick. The plates are then cut into small plates having a side length of about 2.5 cm, i.e. about 6.5 cm ² .

Example 3

Male dogs are anesthetized with pentothalate sodium. Catheters are inserted into the femoral vein of both hind legs and into the abdominal aorta. Flow meters are attached to the femoral veins of both hind limbs. A polymeric matrix containing glycerol trinitrate prepared as described in Example 1 was placed on a carefully depilated skin surface in the middle of the left thigh of the animals, and left on it for 4 hours. We do not put matrix on the right hind foot, this foot is not treated. At 15, 30, 60, 120, 180, and 240 minutes after matrix insertion, 5 mL blood samples were collected via catheters from both femoral veins and the abdominal aorta. After blood collection, blood samples were cooled in ice, centrifuged at 0 ° C for 10 minutes, and 2 to 2 ml of plasma transferred to silanized (pre-treated with alkylated silicone oil) glass tubes. Each tube was charged with 5 ml of n-pentane and the glycine tri nitrate was extracted by gentle agitation at 0 ° C for 1 hour. The pentane solution was then poured into 5 ml Recti-Vial ™ vials and the solvent was almost completely removed. The residue was dissolved in 30 microliters of benzene, which also contained 2 nanograms of paranitroanisole as reference standard (reference substance). For quantitation, portions of this solution ranging from 1.0 microliters to 50.0 microliters are injected into an electron capture gas chromatograph (Hewlett-Packard 4610A gas chromatograph with ⁶³ Ni electron capture detector). The dimensions of the glass column are 1.2 mx 3 mm, 10% SE-30 filler, GASCHROM Q ™ with a mesh size of 0.15-0.12 mm. Column temperature: 140 ° C, sample input: 170 ° C, detector temperature: 220 ° C. A calibration curve for glycerol trinitrate is prepared using plasma samples containing a known amount of glycerol trinitrate.

The control experiment performed on the above rpod, the results of which are summarized in Table 1, clearly indicates that glycerol trinitrate is continuously absorbed from the matrix through the skin throughout the 4 hour observation period. In addition, the venous blood samples taken from the matrix-coated leg contain approximately a proportion of glycerol trinitrate to the surface of the skin-contacting matrix.

From the results of the above test, it is obvious that glycerol trinitrate is absorbed from the matrix and absorbed into the bloodstream.

The rate of absorption of glycerol trinitrate appears to be fairly constant between 30 and 240. minutes, as indicated by essentially unchanged arterial plasma levels of glycerol trinitrate.

Table 1

Matrix size (cm) 5 x 7.5 5 x 2.5 2.5 x 2.5 experiments 1. 2. -3. number nanograms glycerol blood samples trinitrate per ml of plasma

arterial, 15 minute 0.68 0.14 0.27 arterial, 30 minute 0.57 0.15 0.53 arterial, 60 minute 0.73 0.15 - arterial, 120 minute 0.85 0.49 0.36 arterial, 180 minute 1.29 0.68 0.50 arterial, 240 minute 1.26 0.21 0.30 Venous left thigh 15 minute 0.95 5.70 0.40 30 minute 0.51 8.30 0.32 60 minute 15.3 11.4 0.52 120 minute 26.9 7.63 0.75 180 minute 32.9 13.7 0.57 240 minute 32.0 5.55 0.23 Venous, right thigh 15 minute 0.44 9.18 0.09 (Control) 30 minute 0.61 21.6 0.15 60 minute 7.40 4.51 0.28 120 minute 2.33 13.0 0.42 180 minute 9.87 14.5 0.39 240 minute 13.9 4.10 0.23

183,065

Example 4 Five healthy male mongrel dogs were anesthetized with pentobarbital sodium. The catheter is inserted through the jugular vein into the right atrium, this ⁵ Christianity too, right heart blood samples halves. An arterial catheter is inserted into the right carotid artery for continuous measurement of arterial blood pressure. Both catheters are routed at the back of the neck. Then allowed to wake up the dogs and assayed 24 hours later, θ ^1, carried out in conscious starving condition holding harness supporting the animals. After the animals are accustomed to the laboratory environment, 20 ml of blood is drawn as a comparative sample from the right heart. Then, the right side of the chest ¹⁵ that deposits a carefully depilated skin area was a 2.5 x 2.5 cm, as in Example 1, a polymer matrix containing glycerol trinitrate piece. The matrix is fixed to the skin with a surgical patch. After application of the system 20 containing the polymer matrix, 5 ml blood samples were taken at the following times: 15 minutes, minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 7 hours, 8 hours, 9 hours. , 10 hours, 11 hours, 12 hours, 16 hours, 18 hours, 20 hours, 22 hours and 24 hours. The 25 animals are alert and unrestricted throughout the 24-hour sampling period. The animals show no symptoms which could be attributed to the dermal administration of glycerol trinitrate.

Immediately after blood collection, blood samples were gelled and centrifuged at 0 ° C for 10 minutes. Plasma samples are filled with 2 to 2 ml of plasma into a silanized glass tube (pre-treated with alkylated silicone oil). Each tube was charged with 5 ml of n-pentane and the glycerol trinitrate was extracted by gentle shaking at 0 ° C for 1 hour. The pentane solution was poured into 5 ml Recti-Vial vials and the solvent was almost completely removed. The residue was dissolved in 30 microliters of benzene containing 2 nanograms of para-nitroanisole as an external standard. For the determination of glycerol trinitrate, 1.0 to 5.0 microliters of this solution is subjected to electron capture detection.

injected into a working gas chromatograph (Hewlett-Packard 4610A gas chromatograph with 45 ⁶³ Ni electron capture detector). Glass column dimensions: 1.2 mx 3 mm, loading: 10% SE-30, support: GAS-Chrom Q ™ having a mesh size of 0.15-0.12 mesh. Column temperature: 140 ° C, sample input: 170 ° C, detector 50: 220 ° C. A glycerol trinitrate calibration curve is prepared using plasma samples containing a known amount of glycerol trinitrate.

Table 2 summarizes the glycerol trinitrate levels in canine plasma. ⁵⁵ The table gives the average value obtained from five dogs and a standard deviation of all time.

From the results shown in the table, it is evident that glycerol trinitrate is absorbed through the skin by a continuous and constant rate of 60 gels and that the average plasma level of glycerol trinitrate is 0.6 nanograms / ml. The data also show that the matrix is not depleted during the period under investigation, and indeed the rate of absorption of glycerol trinitrate has not even begun to decrease. Glycerol trinitrate blood levels are constant and do not decrease, even towards the end of the 24 hour observation period.

Table 2

Measurement time- of Nanograms glycerol trinitrate / ml. plasma 1. 2. 3. 4. 5. _Á ± kuuk kuuk kuuk, so tya tya tya tya ° rás 0.25 0.11 0.39 - 0.37 - 0.29 0.16 0.50 0.08 0.28 0.02 0.16 0.16 0.14 0.098 0.75 0.08 0.29 0.02 0.14 0.19 0.14 0.10 1.00 0.23 0.19 0.15 0.10 0.36 0.21 0.099 2.00 0.22 0.57 0.02 0.22 0.27 0.26 0.20 3.00 2.06 0.38 0.04 0.88 0.17 0.71 0.82 4.00 0.52 0.81 0.11 0.28 0.26 0.40 0.27 5.00 0.22 1.00 0.28 0.17 0.11 0.36 0.37 6.00 0.23 0.63 0.24 0.55 0.88 0.51 0.28 7.00 0.93 0.70 0.45 0.34 1.23 0.73 0.36 8.00 0.16 2.39 0.70 0.42 0.45 0.82 0.90 9.00 0.22 0.59 0.32 0.34 0.10 0.31 0.18 10.00 0.11 0.83 0.59 0.31 0.66 0.50 0.29 11.00 0.07 0.77 0.13 0.35 0.50 0.36 0.28 12.00 0.35 0.55 0.37 0.29 0.12 0.34 0.15 14.00 .0,04 0.39 0.18 0.17 0.20 0.20 0.13 '16, 00 0.07 0.41 0.28 0.57 0.32 0.38 0.17 18,00 0.26 1.17 0.32 0.29 0.39 0.49 0.39 20.00 0.34 0.41 0.52 0.33 0.24 0.31 0.11 22.00 0.20 1.11 0.66 - - 0.66 0.46 24.00 0.27 0.43 - - - 0.35 0.11

Patent claims

Claims (4)

A method of sustained release of glycerol trinitrate through the skin. for the preparation of a system comprising an absorbent polymer matrix, characterized in that:. 2 to 60% by weight of glycerol, 2 to 15% by weight of polyvinyl alcohol of 100,000 to 150,000 molar weight, 2 to 10% by weight of polyvinylpyrrolidone of 20,000 to 60,000 molar and optionally mixed with lactose - glycerol trinitrate. molding the mixture to the desired shape. 2. The process of claim 1, wherein glycerol and water are mixed, followed by dissolving the polyvinyl alcohol and polyvinylpyrrolidone at 90 ° C to 95 ° C with stirring. glycerol trinitrate, optionally in admixture with lactose, and the resulting mixture is poured into sheets. 3. The process of claim 1 wherein glycerol trinitrate is added after reducing the temperature of the mixture to 50-55 ° C. 4. A process according to any one of claims 1-3, wherein 35-60% glycerol, 4-9% polyvinyl alcohol and 2-5% polyvinylpyrrolidone are used.