SK5382000A3 - Pharmaceutical preparations - Google Patents

Abstract

The invention relates to new, in particular orally administered pharmaceutical preparations containing, as pharmaceutical agent, pentaerythritol tetranitrate (PETN) or its metabolites pentaerythritol trinitrate, pentaerythritol dinatrate and pentaerythrito mononitrate, in amounts which guarantee the patient a sufficient dosage with one administering (per day).

Description

Pharmaceutical preparations

Field of application of the invention

The invention relates to novel, in particular orally administrable, pharmaceutical preparations which contain, as the active substance, pentaerythrityltetranitrate (PETN) or its metabolites in such amounts as to guarantee a sufficient supply to the patient after a single dose (daily).

BACKGROUND OF THE INVENTION

Organic nitric esters, also referred to as organic nitrates, such as glycerol trinitrate (GTN) (Murrel, Lancet: 80, 113,151 (1879)), pentaerythrityltetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), Isosorbide 5-mononitrate (ISMN) (DE-OS-2221080, DE-OS-2751934, DE-OS-3028873, DE-PS-2903927, DE-OS-3102947, DE-OS-3124410, EP-A1-045076, EPAl -057847, EP-A1-059664, EP-A1-064194, EP-A1-067964, EP-A1143507, US-PS-3886186, US-PS-4065488, US-PS-4417065, US-PS4431829), isosorbide nitrate ( ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), propatyl nitrate (Medard, Mem. Poudres 35: 113 (1953)), trolnitrate (FR-PS 984523) or nicorandil (US-PS-4200640 ) and similar compounds are vasodilators that have been important for decades in the indication of angina or coronary heart disease (KHK) and find the widest therapeutic use (Nitrangin ®, Pentalong ®, Monolong ^® , and others).

Based on the pharmacokinetic properties as well as the route of administration (oral, sublingual, transdermal), nitrates distinguish acute and long-term. Acute nitrates such as glycerol trinitrate are used in the treatment of angina pectoris seizures or prior to exercise or in other situations that could experience induce angina pec2 toris seizures. They are therefore recommended for acute myocardial infarction, acute cardiac insufficiency, and catheter-induced coronary spasm in coronary angiography. Long-term nitrates are permitted for the prophylaxis and long-term treatment of angina pectoris; in acute attacks of angina and acute myocardial infarction, however, are contraindicated due to slow onset of action.

Organic nitrates are of high value in the medical treatment and prevention of various diseases that are not limited to heart and circulatory diseases. However, most of the prior art organic nitrates also have a number of serious therapeutic disadvantages. Thus, for example, so-called nitrate tolerance is observed, i.e. a reduction in the effect of nitrate at high dosages or when longer acting nitrates are applied. Side effects such as headache, dizziness, nausea, weakness, skin flushing as well as the risk of a stronger drop in blood pressure with reflective tachycardia (Mutschler, Arzneimittelwirkungen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart (1991)) are also documented. PETN, on the other hand, has a number of excellent properties as a drug substance, in particular little to no occurrence of the above-mentioned side effects, justifying the preferential use of this compound as a drug over other organic nitrates (Schriftenreihe Pentaerythrityltetranitrat, Dr. Dietrich Steinkopff Verlag, Darmstadt, 1994) ).

The active substance, PETN, is one of the oldest long-term nitrates used for the treatment of cardiovascular diseases. PETN is a typical representative of the substance group of so-called organic nitrates. Organic nitrates are prodrugs of which, in certain cell types of the body (particularly endothelial and vascular muscle cells), free radical nitric oxide, NO, is released by the enzyme bioactivation processes as its own active substance. In the vascular area, NO mainly mediates the relaxation of arteries and veins and is a major regulator of vasomotion, for example in coronary arteries. Organic long-term nitrates such as PETN therefore develop a corresponding vasodilating effect, which is meaningfully used to treat ischemic cardiovascular disorders. Their use appears to be particularly suitable from a pharmacological point of view, when there is a relative deficiency of NO caused by the disease.

In addition, specific activation of the enzyme, soluble dilute guanyl cyclase, found in smooth muscle cells and platelets, is of molecular pharmacological importance for PETN. This enzyme catalyzes the formation of cyclic guanosine monophosphate (cGMP), which is thought to be a mediator of vasorelaxation. In addition, it also has a beneficial effect on the pathologically increased tendency to thrombosis. PETN is characterized as a long-term nitrate with a separate pharmacological profile. This independence relates primarily to good tolerability with comparatively strong hemodynamic efficacy, marked venoselectivity, vascular protection and antiatherosclerotic properties, and pharmacokinetic behavior characterized by enterohepatic circulation.

Analysis and evaluation of pharmacokinetic data show that the pentaerythrityl dinitrate metabolite is largely responsible for the acute effect and the pentaerythrityl mononitrate metabolite for the long-term effect of PETN.

The galenic processing of organic nitrates into pharmaceutical preparations for the treatment of angina or ischemic heart disease is generally known. In particular, oral, parenteral, sublingual or transdermal applications in the form of tablets, dragees, capsules, solutions, sprays or patches are described for drugs with these indications (DD-A5-293492, DE-AS-2623800, DE-OS-3325652, DE- OS-3328094, DE-PS-4007705, DE-OS-4038203, JP-A 59/10513 (1982)).

In addition, a large number of drugs based on organic nitrates in exclusively retarded form with a longer lasting effect are known. These depot forms exhibit, in particular in the case of long-term drug therapy, significant advantages, such as achieving a relatively constant true image of the drug in the blood, thereby ensuring uniform efficacy and reducing side effects. The use of higher doses of nitrates for the administration of a single total daily dose of the drug makes retarding the drugs urgently needed from a therapeutic point of view. On the one hand, due to the occurring side effects strongly affecting the health of the patient, it is essential to prevent higher nitrate concentrations by safely controlling release. On the other hand, non-retarding administration of high doses of nitrate is prohibited in order to prevent a decrease in effect due to nitrate tolerance (Mutschler, Arzneimittelwirkungen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart (1991), p. 418n).

In the case of orally administrable forms of medicament, medicaments in retarded form can significantly reduce the necessary frequency of intake, preferably up to 1 dose per day, thereby substantially improving patient compliance and relieving both patients and physicians and healthcare professionals in outpatient and stationary settings. The formation of sustained-release controlled-release medicinal products is well known. The prolongation of the duration of action can be effected in principle by chemical means (by changing the drug substance), by pharmaceutical technology measures (by developing suitable dosage forms) or by utilizing physiological or pharmacological possibilities in the individual. Prolonging the effect of a drug substance by galenical measures is by far the most important given the diversity of implementation possibilities; these broad variants cover both drug forms (e.g. tablets, film-coated tablets and others) as well as retardation (coating, storage, matrix formation and others) and last but not least the necessary release-controlling retarding aids (e.g. cellulose derivatives, copolymers of acrylic acid, various plastic materials, fats, waxes, ion exchangers). Until now, a one-day dose of organic nitrates has been achieved solely by prolonging the release of the drug substance, i.e. one-day dose while avoiding both subtherapeutic and toxic plasma and tissue concentrations as well as maintaining optimal therapeutic tissue concentrations. ) achieved only by slowing the release of the active substance in a galenic manner. Such retarded formulations of this kind are generally difficult to prepare. Often, multi-stage technological methods must be used to guarantee specific galenic forms with the desired release profile over a longer period of time. In addition, the principal disadvantages of oral administration of delayed-release preparations, such as non-digestion, incomplete release of the drug, complications of non-compliance with dosing regimen, local irritation, efficacy problems in fat-rich diets, and other patient diseases (Sucker et al., Pharmazeutische Technologie) , 2nd Ed. (1991), 369n.). For some active substances, these measures may be neglected as long as the chemical properties of the substance (salt formation, prodrug formation) allow the duration of action to be prolonged. Until now, however, these pharmaceutical-technological measures have not been negligible in the above-mentioned organic nitrates.

Furthermore, in addition to the long-term known uses of nitrating agents, their use for the treatment and prevention of diseases that are caused by pathologically elevated concentrations of sulfur-containing amino acids in body fluids is described. These disease states, caused by congenital or inherited defects in the metabolism of these amino acids and which are characterized by elevated blood and urine concentrations of said amino acids (homocystinuria), are summarized under the name homocysteinemia (WO-A1-92 / 18002).

Other uses of the foregoing substances have recently been described as endotheloprotective agents (DE-A1-4410997), as agents against pathologically elevated intraocular pressure (WO-A1-95 / 13812), as agents against dysmenorrhea, dysfunctional uterine bleeding, premature pain and postpartum pain, respectively. by reducing uterine contractility (WO-A1-95 / 13802), as an anti-climacteric agent (WO-A1-95 / 1380) or as an erectile dysfunction agent (Merfort, Munch. Med. Wochenschr. 138 (1996), 504-). 507; Gomaa et al., Br Med J. 312 (1996), 1512-1515).

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel, especially orally administrable, pharmaceutical formulations which contain pentaerythrityltetranitrate, its metabolites pentaerythrityl trinitrate, pentaerythrityl dinitrate or pentaerythrityl mononitrate as active substances, which adequately medicate patients once a day.

The object of the invention is solved by pharmaceutical formulations comprising from more than 80 mg to 600 mg of pentaerythrityltetranitrate, pentaerythrityl trinitrate, pentaerythrityl dinitrate or pentaerythrityl mononitrate and conventional galenic excipients. In this connection, it is possible to vary the amount of drug substance over a wide range without loss of therapeutic efficacy and without the occurrence of particular side effects. Preferably, the ranges are 80 to 500 mg, 85 to 500 mg, 100 to 400 mg, 100 to 200 mg, 120 to 180 mg, in particular 150 mg. In this case, the proportion of active substance in the preparations can be up to 50% by weight, preferably 10 to 50% by weight. According to a further feature of the invention, the object is solved by the fact that the galenic auxiliaries used have no retarding effect or do not develop such a retarding effect, since they are used in amounts which are not retarding. For the purposes of the present invention, auxiliaries are understood to be substances which make it possible to place the active substances in the desired dosage forms of the preparations and are therefore suitable which achieve the desired dosage form and improve the known properties, in particular as regards the action of the active substances, its external availability, dosability and durability. Substances that find use as excipients must meet the following requirements: non-toxic, therapeutic indifference, physiological compatibility, sufficient stability and durability, compatibility with the active substance and others. For the purposes of use, preferably according to the invention, the auxiliaries are selected from the group of fillers, binders, glidants, mold separators, lubricants, disintegrants, humectants, adsorbents, retardants, jerks or tear agents, film formers, resorption accelerators, preservatives , stabilizers, emulsifiers, solubilizers, salts for affecting the osmotic pressure, buffers, dyes, fragrances, flavorings or sweeteners. The various adjuvants sometimes fulfill several functions at the same time. Depending on the specific task and each parameter of the substance, it is for the pharmaceutical practitioner to select suitable excipients also with a view to avoiding drug-excipient incompatibilities. Suitable pharmaceutical excipients include, but are not limited to: celluloses, cellulose derivatives, starches and starch-modified lactose, sorbitol, gelatin, PVP, phosphates, stearic acid and its salts, talk and silica. The medicaments are preferably prepared in liquid or solid form. Suitable solutions are, in particular, for the preparation of drops, injections, infusions, aerosol sprays or powder inhalations, suspensions, emulsions, syrups, tablets, film-coated tablets, dragees, capsules, coated tablets, powders, lozenges, implants, supositories, creams. , gels, ointments, patches or other transdermal systems. Surprisingly, it has now been found that to enhance the target within the meaning of the present invention, the auxiliaries used function exclusively as fillers, disintegrants, binders, flow regulators or glidants and lubricants, as well as non-release controlling agents. All the excipients themselves are indifferent to the drug. According to the invention, said pharmaceutical preparations are prepared in particular in a solid, orally administrable form. Powders, granules, coated tablets, tablets, film-coated tablets, capsules and dragees are particularly suitable for this purpose. The preparation of the galenical preparations is carried out according to conventional methods and rules known to the pharmaceutical expert, the choice of the technologies used and the galenic auxiliaries used being primarily determined by the drug substance to be treated and the desired resorption site. Of particular importance here are the questions of their physicochemical properties, the chosen form of application, the desired duration of action, the site of action, and the prevention of drug-excipient incompatibility. It is therefore up to the practitioner to select, in a substantially trivial manner, on the basis of known substance and process parameters, the form of the medicament, the excipient and the technology of preparation. The preparations according to the invention can advantageously be prepared on the basis of easy-to-use technologies in a known manner. In the preparation of pharmaceutical preparations, pentaerythrityltetranitrate, pentaerythrityl trinitrate, pentaerythrityldinitrate or pentaerythrityl mononitrate are obtained in a suitable mixture of excipients in defined amounts such that the finished pharmaceutical preparation contains from more than 80 mg to 600 mg of the drug substance homogeneously distributed in the system. The resulting powder mixtures can be compressed at a sufficiently high pressure, for example, on a rotary tablet press. In general, pressures of up to 50 kN, preferably 10-30 kN, are sufficient. Further, the powder blends are refillable on a machine for filling and capping hard gelatine capsules or filled into sachets. In addition, it is also useful to first compact said powder mixtures in a known manner, grind and homogenize, before further processing into tablets, gelatin capsules or sachets, respectively. According to a further feature of the invention, it is also advantageous to granulate the obtained powders with binder solutions after the drug substance has been introduced and after its homogeneous distribution in the excipient mixtures. The granules may then be filled into capsules or sachets or compressed into tablets. In addition, the prepared moldings may be coated in a suitable coating device to obtain film-coated tablets or dragees containing in the outer layer only excipients which do not exhibit or develop any retarding effect and are not understood as being retardant within the meaning of the present invention, which is resistant to gastric juices. Here, inter alia, the homogeneous distribution of the desired amounts of the active substance in the excipient mixture is sufficient to achieve the desired therapeutic objective and to achieve the desired task. Particularly simple filling into capsules, sachets, sachets, etc., or further processing into granules or tablets ensures the range of applications and the variety of shapes of the formulations of the invention with good bioavailability. A further modification of the invention is that each dosage form contains the total amount of drug substance per dosage unit inhomogeneously, especially in discrete amounts of particles. The pharmaceutical compositions of the invention may contain the drug substance individually or in combination with known cardiac and circulatory therapeutics, e.g. agents also useful as cardiac and circulatory therapeutics and further administered for clinical application. Also enrichment of the combination in spatially separated dosage forms is possible and is also included in the invention. Thus, the present invention opens - with the use of the disclosed pharmaceutical preparations - improved and substantially expanded therapeutic options for treating pathological situations such as cardiac and vascular diseases, in particular coronary heart disease, vascular stenosis and peripheral arterial bleeding disorders, hypertonia, microangiopathy, macroangiopathy in diabetes. mellitus, vascular and tissue stresses such as atherosclerosis, as well as resulting illnesses, further erectile dysfunctions, increased intraocular pressure, dysmenorrhea, dysfunctional uterine bleeding, uterine contractile dysfunction such as early onset pain, or incontinence pain .

The following examples are intended to illustrate the invention, its contents and embodiments, without limiting its scope.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

In a suitable mixer, 160 g of pentaerythryl tyltetranitrate (PETN), 300 g of lactose, 80 g of microcrystalline cellulose, 76 g of corn starch, 20 g of talc, 20 g of silica and 4 g of magnesium stearate are homogeneously mixed. The mixed material is compressed into tablets having a prescribed weight of 600 mg by a compression force of 10-30 kN.

Example 2

350 g of PETN, 100 g of lactose, 323 g of microcrystalline cellulose and 273 g of potato starch are mixed in a fluidized bed granulator, granulated with 1050 ml of 4% aqueous solution, then dried, sieved and mixed homogeneously with 60 g of talc, 20 g of magnesium stearate and 32 g silica. On a rotary tablet press, the granulate is compressed with a compression force of 10-30 kN to tablets having a prescribed weight of 1050 mg.

Example 3

In a suitable mixer, 900 g of lactose, 300 g of corn starch, 30 g of silica are mixed until homogeneous. The mixture is filled into sachets with 1530 mg fill weight.

Example 4

450 g PETN, 1350 g lactose, 300 g microcrystalline cellulose and 400 g potato starch are mixed in a fluidized bed granulator. 36 g of gelatin and 18 g of sorbitol dissolved in 350 g of water are injected into the mixture. The resulting granulate is dried and situated. 80 g of talc, 25 g of magnesium stearate and 41 g of silica are added to the crude granulate and mixed until homogeneous. On a rotary tablet press a compressor with a prescribed weight of 900 mg is prepared with a compression force of 10 30 kN.

Example 5

PETN and galenic excipients are mixed homogeneously in defined amounts. The blended material is processed into a compressed tablet press (Table 1).

Example 6

PENT and galenic excipients are mixed in defined amounts until homogeneity and then filled (A) into sachets and (B) into capsules (Table 2).

Example 7

PENT and galenic excipients are mixed in defined amounts. Compaction is then carried out. The compresses are homogenized on a sieve machine to a uniform size of 12 pounds. The screened material is filled (A) into sachets and (B) into capsules (Table 3).

Example 8

In the fluidized bed granulator, PENT and defined amounts of galenic excipients are mixed and then granulated with an aqueous binder solution. The dry granulate is screened and admixed with flow-controlling galenical agents, lubricants and glidants. Compresses (A) are prepared on a tablet press. The compresses thus prepared are (B) film-coated in a coating apparatus.

Example 9

Clinical trials of a daily dose of PETN greater than 80 mg show that the side effects that otherwise occur with nitrates, especially

(a) no typical nitrate headache is observed (Jähnchen et. al., Pentaerythrityltetranitrat-Strukturchemische, zellbiologische und klinische Perspektiven,

Dr. Dietrich Steinkopff Verlag, Darmstadt 1997)

(b) in addition, there is no attenuation (nitrate tolerance) under PETN and at doses higher than mg (Schneider, Pentaerythrityltetranitrat-Beiträge z Klinischen und Pharmakologischen Status, Dr. Dietrich Steinkopff Verlag, Darmstadt 1995).

The clinical research program includes other relevant parameters in the fields of use described above, such as

(c) reduction of angina attacks (Schneider, Pentaerythrityltetranitrat-Beiträge zum Klinischen und Pharmakologischen Status, Dr. Dietrich Steinkopff Verlag, Darmstadt 1995).

(d) reduction of the acute consumption of nitrates (Muschler, Pentaerythrityltetranitrat-Experimentelle und Klinische Befunde zu Coronaner Herzkrankheit und Herzinsuffizienz, Dr. Dietrich Steinkopff Verlag, Darmstadt 1996); and

(e) prolonging the increase in exercise tolerance ((Muschler,

Pentaerythrityltetranitrat-Experimentelle und Klinische

Befunde zu Koronaner Herzkrankheit und Herzinsuffizienz,

Dr. Dietrich Steinkopff Verlag, Darmstadt 1996).

With respect to these successful therapy criteria, there is no disadvantage with conventional multiple-daily dosing regimens when administered daily.

Example 10

In a comprehensive marginal study, treatment of angina pectoris with 150 mg PETN (analogously to Example 8, Table 4, c)) was compared once a day and with 50 mg PETN three times a day for a treatment period of 2 weeks. The efficacy and tolerability of 150 mg PETN in a one-day intake versus three-a-day intake and placebo have been demonstrated.

Table 1

Substances a) [mg] (b) [mg] (c) [mg] (d) [mg] PETN 85 160 300 200 lactose 100 300 200 0 cellulose 50 80 225 300 starch 100 76 150 100 Talk 0 20 5 0 oxide 40 20 15 20 silica stearate 0 4 0 10 magnesium Acid · 5 0 5 0 stearic prescribed 380 660 900 630 mass

Table 2 Substances (A) (B) a) [mg] (b) [mg] d) [mg] d) [Mg] PETN 600 500 100 200 lactose 300 0 60 200 cellulose 200 250 0 0 starch 250 250 60 0 Silicon dioxide 50 5 5 5 prescribed 1400 1005 225 405 mass Capsule size - - 1 0

Table 3

Substances (A) a) [mg] (B) (b) [mg] PETN 150 180 lactose 300 0 cellulose 300 500 starch 300 400 Prescribed weight 1050 1080

Table 4

Substances (A) (b) [mg] (c) [mg] (d) [mg] (B) (e) [mg] a) [Mg] PETN 100 125 150 100 120 cellulose 0 210 200 205 220 lactose 515 210 300 150 200 starch 15 226 250 200 200 gelatin 0 10 0 0 15 hydroxypropyl 0 0 0 15 0 cellulose sorbitol 0 5 0 0 10 Poly (l-vinyl-2- 0 0 25 0 0 pyrrolidone) Talk 15 21 5 10 15 stearate 5 7 0 0 5 magnesium Silicon dioxide 10 11 15 15 15

Table 4 - continued

Substances (A) (b) [mg] (c) [mg] (d) [mg] (B) (e) [mg] a) [Mg] acid 0 0 5 5 0 stearic prescribed 660 825 950 700 800 mass methyl hydroxy 0 0 0 0 4 propylcellulose Macrogol 4000 0 0 0 0 4

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Claims (36)

PATENT CLAIMS Pharmaceutical compositions, characterized in that: (a) contain, as the active substance, pentaerythityltetranitrate, pentaerythrityl trinitrate, pentaerythrityl dinitrate or pentaerythrityl mononitrate, (b) in an amount of more than 80 mg up to 600 mg as such (c) the usual galenic excipients. Pharmaceutical preparations according to claim 1, characterized in that the conventional galenic excipients do not have a retarding effect or do not cause a retarding effect. Pharmaceutical preparations according to claim 2, characterized in that the usual galenic excipients do not have a retarding effect. Pharmaceutical preparations according to claim 2, characterized in that the usual galenic auxiliaries are used in non-retarding amounts. Pharmaceutical preparations according to claims 1 to 4, characterized in that they contain the active substance in an amount of more than 80 mg to 500 mg. Pharmaceutical preparations according to claim 5, characterized in that they contain the active substance in an amount of from 85 to 500 mg. Pharmaceutical preparations according to claim 6, characterized in that they contain the active substance in an amount of from 100 to 400 mg. Pharmaceutical preparations according to claim 7, characterized in that they contain the active substance in an amount of from 100 to 200 mg. Pharmaceutical preparations according to claim 8, characterized in that they contain the active substance in an amount of from 120 to 180 mg. Pharmaceutical preparations according to claim 9, characterized in that they contain the active substance in an amount of 150 mg. Pharmaceutical preparations according to claims 1 to 10, characterized in that they contain the active substance in an amount of up to 50% by weight. Pharmaceutical preparations according to claim 11, characterized in that they contain the active substance in an amount of from 10 to 50% by weight. Pharmaceutical preparations according to claims 1 to 12, characterized in that they contain the drug substance dispersed homogeneously. 14. Pharmaceutical preparations according to claims 1 to 13, characterized in that they exist as solid oral preparations. Pharmaceutical preparations according to claim 14, characterized in that they are in the form of powders, granules, pellets, tablets, coated tablets, capsules and dragees. Pharmaceutical preparations according to claim 15, characterized in that they are in the form of tablets, film-coated tablets and dragees. Pharmaceutical preparations according to claim 16, characterized in that they are provided with a coating or film which is particularly resistant to gastric juice. A process for the preparation of pharmaceutical preparations, characterized in that the active substances pentaerythrityltetranitrate, pentaerythrityl trinitrate, pentaerythrityl dinitrate or pentaerythrityl mononitrate, (a) mixed in a defined quantity with the usual galenic excipients; (b) the mixtures obtained (i) are filled into capsules or sachets, (ii) are compacted, then ground and homogenized, (iii) granulated, then filled into capsules or sachets and also compressed into tablets or dragee cores by: (c) the pharmaceutical preparations contain from more than 80 mg to 600 mg of the active substance, and which: (d) if necessary, film-coated or coated. Method according to claim 18, characterized in that the compression into tablets or dragee cores is carried out by direct tableting. The method according to claims 18 and 19, characterized in that the compression into tablets or dragee cores is carried out at compression pressures up to 50 kN, in particular at 10 to 30 kN. Method according to claim 18, characterized in that the granulation is carried out with an aqueous binder solution. Use of pharmaceutical compositions according to claims 1 to 17 for the treatment and protection of human organ systems and vascular system. 23. Use of pharmaceutical preparations according to claim 22 for the protection of blood vessels and tissues. Use of the pharmaceutical compositions according to claim 22 for the treatment of cardiac, circulatory or cerebrovascular diseases. Use according to claim 24, characterized in that the heart or circulatory diseases are angina, ischemic heart disease, myocardial post-infarction or chronic cardiac insufficiency. Use according to claims 22 to 25 for once-daily administration. Use according to claims 22 to 26 for long-term treatment. Use according to claims 22 to 27, characterized in that the combination is carried out with other active substances used for the treatment of heart and circulatory diseases, in particular with those of the ACE-inhibitor class, antiatherosclerotics, antihypertensives, beta-blockers, hypocholesterolemics. , diuretics, calcium antagonists, coronary dilators, hypolipidemics, peripheral vasodilators, or platelet anti-aggregates. Use of pentaerythrityltetranitrate, pentaerythrityl trinitrate, pentaerythrityl dinitrate or pentaerythrityl mononitrate for the treatment of the human organ system and vascular system, characterized in that from more than 80 mg to 600 mg of the drug substance is administered and can be dispensed with without the use of galenic retardation principles. Use according to claim 29 for the protection of blood vessels and tissues. Use according to claim 29 for the treatment of cardiac, circulatory and cerebrovascular diseases. Use according to claim 31, characterized in that the heart or circulatory diseases are angina, ischemic heart disease, myocardial post-infarction or chronic cardiac insufficiency. Use according to claims 29 to 32, characterized in that the combination is carried out with other active substances used for the treatment of cardiovascular diseases, in particular those of the indication group ACE-inhibitors, antiatherosclerotics, antihypertensives, beta-blockers, hypocholesterolemics. , diuretics, calcium antagonists, coronary dilators, hypolipidemics, peripheral vasodilators, or platelet anti-aggregates. Use according to claims 29 to 33 for once-daily administration once a day. Use according to claims 29 to 34 for long-term treatment. A method of treating the human body using the pharmaceutical compositions of claims 1 to 17.