EP2029099A2

EP2029099A2 - Combination antihypertensive wafer

Info

Publication number: EP2029099A2
Application number: EP07725806A
Authority: EP
Inventors: Hans-Rainer Hoffmann; Reto BRÄNDLI; Frank Theobald
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2006-06-16
Filing date: 2007-06-04
Publication date: 2009-03-04
Also published as: DE102006027794A1; WO2007144082A2; JP2009539894A; CN101472557A; BRPI0711997A2; WO2007144082A3; CA2654211A1; US20100047322A1

Abstract

The present invention relates to a planar-shaped drug preparation that quickly dissolves or decomposes in an aqueous environment, for the application of active ingredient combinations for the treatment of hypertension, wherein the drug preparations contain at least two active ingredients that are suitable for the treatment of hypertension, and wherein the antihypertensive drug is selected from the group that encompasses beta receptor blockers, alpha receptor blockers, calcium antagonists, ACE inhibitors, AT1 antagonists, centrally acting antihypertensive drugs, direct vasodilators, and diuretics. The present invention also relates to the use of active ingredient combinations according to the invention for the production of an oral drug preparation for the treatment of high blood pressure, to a method for the therapeutic treatment of hypertension, and to a method for the production of a planar-shaped drug preparation.

Description

Antihypertensive combination wafer

The present invention relates to sheet-like dosage forms rapidly dissolving or decomposing in an aqueous environment for the application of combinations of active substances for the treatment of hypertension.

According to the High Pressure League, the ideal blood pressure is 120/80 mmHg. By contrast, hypertension (hypertension) is understood to mean a pathological increase in the pressure in the arteries to a systolic value of over 140 mmHg and a diastolic value above 90 mmHg.

Recent studies have shown that hypertension is a widespread disease in western countries, with 90% of those diagnosed with no cause of elevated blood pressure, suggesting primary or essential hypertension. Nevertheless, the development of hypertension is favored by several risk factors such as genetic predisposition, overweight, lack of exercise, stress or high salt intake. Primary hypertension is more often associated with other conditions such as obesity, type 2 diabetes, high blood lipid levels, and gout, which is referred to as metabolic syndrome.

In about 10% of patients, hypertension is a consequence of certain underlying diseases, such as narrowing of the renal arteries, chronic Changes in hormone balance, or medications. This form of hypertension is called secondary hypertension.

In Germany, between the ages of 25 and 74, more than 60 percent of men and 40 percent of women suffer from hypertension. From the age of 50, almost every second person in the population suffers from high blood pressure.

However, the constancy of blood pressure in a certain range is of crucial importance for the function of the body. If the blood pressure is too low, a deficiency supply of the organs with oxygen and nutrients can occur, whereby their function is restricted to the worst case after a complete organ failure the death can occur.

On the other hand, too high blood pressure often leads to atherosclerosis (arteriosclerosis), which can subsequently lead to apoplexy, myocardial infarction, heart failure, renal insufficiency and blindness.

If elevated blood pressure is not treated, the risk of secondary damage increases, but normalization of blood pressure can prevent it.

In addition, sudden high blood pressure increases can lead to a so-called hypertensive crisis, which is associated with severe respiratory distress and angina pectoris and is considered an urgent emergency requiring treatment. Although hypertension in the early stages usually shows little or no symptoms and the sufferers feel well, treatment is still urgently needed because of the serious potential long-term consequences.

Blood pressure is closely linked to the total amount of blood circulating in the blood vessels, which in turn correlates directly with the water balance of the body, which is regulated by the kidneys. Furthermore, the diameter of the blood vessels has an influence on the blood pressure, so that starting points of a therapy can be seen in these factors.

With only a slight increase in blood pressure, simple measures such as regular exercise, weight reduction, and a low-sodium diet can lower blood pressure.

If these measures do not lead to the desired success, a drug adjustment and treatment of hypertension is required, which requires a permanent and consistent intake of medication.

However, the studies mentioned above have also shown that only about 5% of patients suffering from hypertension are optimally supplied with medication.

Further, studies have shown that optimal adjustment of hypertension at an advanced stage can often only be achieved with a combination of two or more active agents, often from different groups of active ingredients. In the treatment of hypertension, a drug form is to be preferred, which on the one hand improves the compliance of patients and on the other hand allows for easy administration during the normal rhythm of life. The usual application of tablets has the disadvantage for many patients that this often water or the like is required for swallowing the tablets. This restricts mobility and is perceived as uncomfortable by many patients.

In addition, hypertensive emergencies require rapid, effective therapy. The dosage form should therefore be suitable for quickly releasing the active ingredients and ensuring rapid onset of action. Disintegration of the dosage form and release of the active ingredients should therefore already take place at the site of application, e.g. for oral dosage forms already in the oral cavity.

In addition, the dosage forms should be easy and directly administrable to even patients with strong

Shortness of breath and anxiety or even, for example, without awareness to facilitate the intake, or to allow the application by a third party.

The object of the present invention was therefore to provide a dosage form which allows the administration of combinations of active substances for the treatment of hypertension in such a way that a discrete, simple administration is possible without additional aids. Common administration forms for administering active substances in the treatment of hypertension are tablets, capsules or drops.

Although tablets or capsules can be taken easily, the onset of action is usually delayed and the active ingredients are subject to the "first-pass effect" on absorption via the gastrin tract tract, so that high initial concentrations of active ingredient in the tablet or capsule are required are.

In addition, liquid for swallowing the dosage form is usually needed, which is not always immediately available. Also, in a hypertensive crisis swallowing difficult or impossible, so that the application often proves problematic.

It has been found that this object is achieved by sheet-like administration forms of a hydrophilic polymer film which disintegrates in the oral cavity, the wafers containing at least two active substances which are suitable for the treatment of hypertension.

Also suitable as active ingredients are the free bases or else the therapeutically effective salts of the individual active compounds.

The combination of the active ingredients in the dosage form according to the invention makes it easier for the patient to take both active ingredients. The absorption of the active ingredients via the oral mucosa has the advantages over other peroral forms of administration, for example, that also patient patients with swallowing difficulties or patients refusing to take tablets may be given medications orally. In addition, the risk of medication errors is reduced because the patient only needs to take one drug for both drugs. Finally, the dosage forms according to the invention may also be inconspicuously packaged, so that their intake is also possible in the public eye analogous to that of a chewing gum or of the "fashionable" fashioned in recent times. This improves compliance and the success of therapy.

In particular, the combination of active substances in a dosage form for the treatment of hypertension, which antihypertensives of different classes of active ingredients can be combined, special advantages are achieved. Thus, e.g. a fast-acting, potent drug for the treatment of hypertensive emergencies, simplifying the administration of various means of emergency treatment.

Furthermore, active ingredients with different mechanisms of action may be present in a combination of active ingredients which act synergistically so that, as a result of the different physiological action for the treatment of hypertension, smaller amounts of the active ingredients can be dosed than would be the case with one-component compositions.

The administration of these drug combinations in areal dosage forms (wafers) allows not only a simple ingestion, but also an exact Ab-mood of the drug components with each other, so that

Misdosing by forgotten or double intake only of an active substance, and thus inadequate therapy of hypertension.

Another advantage of the transmucosal administration of drugs in some drugs is the circumvention of the gastrointestinal route and thus the avoidance of the "first pass" effect after oral administration, ie the metabolization of a significant portion of the drug during the first passage of the liver, so that high potency Since these agents do not suffer from drug losses via the first-pass effect, the dosage of the active ingredients can be correspondingly reduced, which also leads to a relief of the patient and an increase in well-being due to lower ADR.

Due to the simple and inexpensive production of the wafers, it is possible to provide a large number of medicaments with different active ingredient concentrations.

If the wafer is made of a laminate, then during production e.g. only the layer thickness of an active substance-containing layer or the concentration of the active ingredient can be changed. On the other hand, drugs with different

However, the active substance content but the same active ingredient ratio can be easily produced via different area blanks of the dosage form.

In addition, the wafers of the invention with the drug combinations due to their flat shape easily For example, in the wallet, and are immediately available on the go, easy to take and effective quickly, both in the therapy of hypertension as well as in a sudden onset of hypertensive emergency.

As water-soluble or swellable polymers for the hydrophilic water-soluble and / or swellable polymer film are suitable as the base polymer polymers from the group, the dextran, polysaccharides, including the starch and

Starch derivatives, cellulose derivatives, such as carboxymethylcellulose, ethylcellulose or propylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose (for example Walocel), methylcellulose, hydroxyethylcellulose and hydroxypropylethylcellulose, polyvinyl alcohols, polyethylene glycols, polyacrylic acids, polyacrylates , Polyvinylpyrrolidone, alginates, pectins, gelatin, alginic acid, collagen, chitosan, arabinogalactan, galactomannan, agar-agar, agarose, carrageenan natural gums, tragacanth, fumed silica, bentonite, and derivatives of the aforementioned hydrophilic polymers or combinations of two or more of these polymers. Alternatively, the polymer film may also be made from a polyvinyl alcohol-polyethylene glycol graft copolymer.

The polymer content of a dosage form according to the invention is preferably from 5 to 95% by weight, more preferably from 15 to 75% by weight, based on the dry weight of the dosage form. The pharmaceutical preparations according to the invention contain at least two active substances which are used for the treatment of hypertension, it being also possible in each case for at least one active substance to be present from all active ingredient groups.

The active substances are selected from the group of antihypertensive agents which include the beta-receptor blockers, alpha-adrenergic blockers, calcium antagonists, ACE inhibitors, AT1 antagonists, centrally acting antihypertensives, the direct vasodilators and the diuretics.

In a preferred embodiment, the pharmaceutical preparation contains at least two to five, preferably two to three, active ingredients. In the case of an active substance combination of two active substances, one of the active substances selected from the group of diuretics and the second active substance from the group of the beta-receptor blockers, the ACE inhibitor, the calcium antagonist or the ATi receptor antagonist is preferably selected.

In one preferred embodiment of the drug formulation containing three drugs from the group of antihypertensives, the first drug is preferably a diuretic and the second and third drugs of the combination are a beta-adrenergic blocker and a vasodilator, wherein the vasodilator is selected from the group and the second and third drugs are an ACE inhibitor and a calcium antagonist, or the second and third drugs are an antiparticle tonic and a vasodilator , In a further preferred embodiment, the pharmaceutical preparations contain at least one active substance which does not belong to the group of antihypertensives, for example a sedative. Alternatively, the pharmaceutical preparations may also contain a potassium salt to counterbalance the potassium loss caused by the diuretics.

The diuretics used in the pharmaceutical compositions of the present invention are selected from the group comprising xanthine derivatives, osmodiuretics, carbonic anhydrase inhibitors, thiazides, loop diuretics, potassium sparing diuretics, aldosterone antagonists, or cycloamindin derivatives. The active ingredients of the diuretics are selected from the group consisting of caffeine, theophylline, theobromine, mannitol, sorbitol, acetazolamide, hydrochlorothiazide, trichloromethiazide, buticide, bedroblumethiazide, bemetezide, mefruside, chlorthalidone, xipamide, clopamide, indapamide, furosemide, Azosemide, bumetanide, piretanide, torasemide, etazoline, ethacrynic acid, methylclothiazide, metozolone, polythiazide, spironolactone, potassium canrenoate, triameterene and amiloride, as well as pharmacologically acceptable salts and combinations of these agents.

The active ingredient content of the diuretic in the dosage form is between 0.1 mg to 50 mg, preferably between 0.5 mg to 20 mg, and more preferably between 2 mg to 10 mg per single dose.

The active ingredients of the invention used in

Receptor blockers are selected from the group consisting of allyl prenolol, oxprenolol, penbutolol, bupranolol, metipranolol, propranolol, nadolol, pindolol, mepindolol, carteolol, carazolol, timilol, sotalol, metoprolol, betaxolol, bisoprolol, atenolol, acebutolol, celiprolol and bopindolol, as well as pharmacologically acceptable salts and combinations of these agents ,

Bopindolol, bisoprolol and pindolol are preferably used as beta-receptor blockers.

The alpha-adrenergic blockers used in the invention contain active agents selected from the group comprising bunazosin, doxazosin, terazosin and urapidil, as well as pharmacologically acceptable salts and combinations of these agents.

The active ingredients of the ACE inhibitors are selected from the group comprising benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril and trandolapril, as well as pharmacologically acceptable salts and combinations of these agents.

Preference is given to using cilazapril, enalapril, benzapril, perindopril, spirapril and trandolapril as ACE inhibitors.

The calcium antagonists used in the pharmaceutical compositions of the present invention are selected from the group comprising calcium antagonists of the verapamil type, the diltiazem type and the dihydropyridines. The active ingredients of the calcium antagonists are selected from the group comprising diltiazem, gallopamil, verapamil, amlodipine, felodipine, isradipine, lacidipine, lercanidipine, Nicardipine, nifedipine, nilvadipine, nisoldipine and nitrendipine, as well as pharmacologically acceptable salts and combinations of these agents.

Felodipine, lacidipine, lercanidipn, amlodipine and nicardipine are preferably used as calcium antagonists.

The active ingredients of the ATi antagonists are selected from the group comprising candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan as well as pharmaceutically acceptable salts and combinations of these agents.

The antisympathotonics used in the pharmaceutical compositions of the present invention are selected from the group comprising clonidine and methyldopa, as well as pharmacologically acceptable salts and combinations of these drugs.

As direct vasodilators there are used active substances selected from the group comprising minoxidil and dihydrazazine as well as pharmacologically acceptable salts and combinations of these active substances.

To improve physicochemical properties, e.g. To reduce brittleness or embrittlement, moisturizers may be added to the film, e.g. Glycerol, propylene glycol, sorbitol, mannitol, polyethylene glycol, polyglycerol esters and the like.

In another embodiment, antioxidants may be added to the wafer to stabilize the film and the active ingredients be added, for example, vitamin C (ascorbic acid), ascorbyl palmitate, vitamin E (tocopherol acetate), hydroxybenzoic acid derivatives. Furthermore, acidic and basic ion exchangers can also be used as stabilizers.

In further embodiments, further ingredients such as dyes, pigments, flavors, natural and / or synthetic flavorings, sweeteners, buffering systems can be added to the film. In particular, flavorings and flavorings can mask the often poor taste or smell of the active ingredients and / or give the dosage form a pleasant taste, so that the willingness to take the medication by the patient is significantly improved.

The addition of buffering systems serves, on the one hand, to stabilize the film and the active ingredients against external influences and during storage, and on the other hand, it is possible to adjust the pH of the administration form to a physiologically acceptable pH, so that mucous membrane irritations are avoided , A buffer system can also improve the solubility of acidic or basic drugs in the matrix.

The administration forms according to the invention are thin, for example in the form of a wafer. The thickness of the dosage form is preferably 0.1 to 5 mm, more preferably 0.5 to 1 mm. The lower limit for the thickness of the dosage forms is about 50 μm. The area of the dosage form is between 0.09 cm ² and 12 cm ² , preferably between 1 cm ² and 8 cm ² , and particularly preferably between 3 cm ² and 6 cm ² .

In another embodiment, the wafers of the present invention include a disintegrant or wicking agent, e.g. a bicarbonate-acid mixture or an aerosil, which is activated by contact with liquid and accelerates the disintegration of the wafer after application and thus also the release of active ingredient.

In a preferred embodiment, the wafer is present as a foam, so that the Wirkstoffabgäbe due to the increased surface area is even faster. In this case, one or more of the active ingredients may also be present in liquid form in the cavities of the foam.

To improve the absorption of the active ingredients through the mucosa, permeation enhancers, e.g. Substances from the groups of fatty alcohols, fatty acids, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, fatty alcohol esters and fatty acid esters, in particular sorbitan monolaurate or esters of long-chain fatty acids with methyl, ethyl or isopropyl alcohol, or esters of fatty alcohols with acetic acid or lactic acid, or also substances such as DMSO ( Dimethylsulfoxide) and oleic diethanolamine. The proportion of these substances is 0.1 to 25 wt .-%, preferably from 1 to 10 wt .-%, each based on the total weight of the active ingredient matrix.

In addition, compounds containing the drug release may be included in the composition of the wafer delay (eg, microencapsulation), wherein in a preferred embodiment the wafer contains a liquid agent in microencapsulated form. The liquid active ingredient may be, for example, an alcoholic nitroglycerin solution.

In another embodiment, the wafer has mucoadhesive properties so that it adheres to the mucous membrane until it is completely dissolved.

In a preferred embodiment, at least one of the active ingredients is bound to an ion exchanger so that the hydrophilic polymer disintegrates rapidly in the oral cavity, but delays the release of the active agent first or at a changed pH, e.g. in the gastrointestinal tract. In this way, drugs with different mechanisms of action and absorption can be administered in one dosage form, i. At least one of the released active substances is either absorbed at the site of application, eg. Via the oral mucosa, or it is transported on and resorbed at another location.

The wafer can also be constructed as a laminate with different layers, wherein the active ingredients are contained in discrete layers, which are spatially separated from each other and differ in their construction. The active ingredients can be released at different sites of action or even delayed, if the disintegration time of the different layers of the wafer differs. Likewise, the active ingredients may be arranged in layers which disintegrate at different rates so that the entire preparation has a sustained-release effect.

In another embodiment, one of the outer layers may be mucoadhesive to promote adherence of the dosage form to the mucosa and to facilitate drug absorption through the mucosa through direct contact.

Decay in aqueous medium of the dosage form of the invention is preferably in the range of 1 second to 5 minutes, more preferably in the range of 5 seconds to 1 minute, and most preferably in the range of 10 seconds to 30 seconds.

The dosage forms according to the invention are advantageously suitable for the administration of medicaments in the oral cavity or for rectal, vaginal or intranasal administration. They can be used in human medicine as well as in veterinary medicine.

The present invention is further directed to the use of one of the active ingredient combination according to the invention for the preparation of an oral dosage form for the treatment of hypertension, wherein the dosage form is preferably formulated as a wafer.

Furthermore, the present invention is directed to a method for the therapeutic treatment of a hypertensive person, wherein the administration of a previously described active ingredient combination of antihypertensives by means of an orally administered Darreichungsfoπn carried out with transmucosal absorption.

Finally, the present invention is also directed to a process for the preparation of a sheet-like dosage form comprising the following steps:

- preparing a solution containing at least one polymer and at least two antihypertensive agents;

Spreading the solution on a coating base and

Solidifying the precipitated solution by drying and removal of the solvent.

Claims

claims

1. A surface-shaped, quickly disintegrating on contact with moisture, pharmaceutical preparation based on hydrophilic polymers for the treatment of hypertension, characterized in that the dosage form contains a Wirkstoffkombinati- on of at least two active substances which are suitable for the treatment of hypertension.

2. Pharmaceutical preparation according to claim 1, character- ized in that the active substances are selected from the

Group of antihypertensives comprising the beta-receptor blockers, alpha-receptor blockers, calcium antagonists, ACE inhibitors, AT3 antagonists, centrally acting antihypertensives, direct vasodilators and diuretics.

3. Pharmaceutical preparation according to one of the preceding claims, characterized in that one active ingredient from the group of the beta-receptor blocker and the second active ingredient from the group of diuretics is selected.

4. Pharmaceutical preparation according to one of the preceding claims, characterized in that one active ingredient from the group of ACE inhibitors and the second active ingredient is selected from the group of diuretics.

5. Pharmaceutical preparation according to one of the preceding claims, characterized in that one active ingredient from the group of calcium antagonists and the second active ingredient is selected from the group of diuretics.

6. Medicament preparation according to one of the preceding claims, characterized in that one active ingredient from the group of ATi receptor antagonists and the second active ingredient is selected from the group of diuretics.

7. Medicament preparation according to claim 1 or 2, characterized in that it consists of a combination of three active substances from the group of antihypertensives.

8. A pharmaceutical preparation according to claim 7, characterized in that one of the active ingredients is a beta-receptor blocker, the second active ingredient is a vasodilator and the third active ingredient is a diuretic, wherein the vasodilator is selected from the group consisting of the calcium antagonists, ACE inhibitors , Alphai receptor blockers and direct vasodilators.

9. Pharmaceutical preparation according to claim 7, characterized in that one of the active ingredients is an ACE inhibitor, the second active ingredient is a calcium antagonist and the third active ingredient is a diuretic.

10. A pharmaceutical preparation according to claim 7, characterized in that one of the active ingredients is an antisympathotonium, the second active ingredient is a vasodilator and the third active ingredient is a diuretic.

11. Pharmaceutical preparation according to one of the preceding claims, characterized in that the diuretic is selected from the group comprising xanthine derivatives, osmodiuretics, carbonic anhydrase inhibitors, thiazides, loop diuretics. ka, potassium-sparing diuretics, aldosterone antagonists or cycloamindin derivatives.

12. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredients of

Diuretics selected from the group consisting of caffeine, theophylline, theobromine, mannitol, sorbitol, acetazolamide, hydrochlorothiazide, trichloromethiazide, buticide, bedrofluoriazide, bemetezide, mefruside, chlorthalidone, xipamide, cocoamide, indapamide, furosemide, azosemide, Bumetanide, piretanide, torasemide, etozoline, etacrynic acid, methylclothiazide, metozolone, polythiazide, spironolactone, potassium canrenoate, triameterene and amiloride, as well as pharmacologically acceptable salts and combinations of these agents.

13. Medicament preparation according to one of the preceding claims, characterized in that the active substances of the beta-receptor blocker are selected from the group comprising alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, propanolol, nadolol, pindolol, mepindolol, carteolol, carazolol, Timolol, sotalol, metoprolol, betaxolol, bisoprolol, atenolol, acebutolol, celiprolol and bopindolol, as well as pharmacologically acceptable salts and combinations of these agents.

14. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredients of the alpha-receptor blocker are selected from the group comprising bunazosin, doxazosin, terazosin and urapidil and phaπna- ecologically acceptable salts and combinations of these agents.

15. Medicament preparation according to one of the preceding claims, characterized in that the active ingredients of the ACE inhibitors are selected from the group consisting of benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril and Trandolapril and pharmacologically acceptable salts and combinations of these agents.

16. Medicament preparation according to one of the preceding claims, characterized in that the calcium antagonists are selected from the group comprising calcium antagonists of the verapamil type, of the diltiazem type and the dihydropyridines.

17. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredients of the calcium antagonists are selected from the group consisting of diltiazem, gallopamil, verapamil, amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nisoldipine and nitrendipine and pharmacologically acceptable salts and combinations of these agents.

18. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredients of ATi antagonists are selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, Teisaidartan and valsartan and pharmacologically acceptable salts and combinations thereof Active ingredients.

19. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredients of the antisympathotonics are selected from the group comprising clonidine and methyldopa and pharmacologically acceptable salts and combinations of these active ingredients.

20. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredients of the direct vasodilators are selected from the group comprising minoxidil and dihydralazine as well as pharmacologically acceptable salts and combinations of these active substances.

21. Medicament preparation according to one of the preceding claims, characterized in that the hydrophilic polymer is selected from the group consisting of dextran, polysaccharides, including the starch and starch derivatives, cellulose derivatives, such as carboxymethylcellulose, ethyl or propylcellulose, hydroxypropylmethylcellulose , Hydroxypropylcellulose, sodium carboxymethylcellulose (eg Walocel), methylcellulose, hydroxyethylcellulose and hydroxypropylethylcellulose, polyvinyl alcohols, polyethylene glycols, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, alginates, pectins, gelatin, alginic acid, collagen, chitosan, arabinogalactan, Galactomannan, agar-agar, agarose, carrageenan natural gums, tragacanth, fumed silica, bentonite, as well as derivatives of the aforementioned hydrophilic polymers or combinations of two or more of these polymers.

22. Pharmaceutical preparation according to one of the preceding claims, characterized in that the polymer film a polyvinyl alcohol-polyethylene glycol graft copolymer.

23. Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation comprises a humectant selected from the group comprising glycerol, propylene glycol, sorbitol, mannitol, polyethylene glycol and polyglycerol ester contains.

24. Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation comprises an antioxidant selected from the group consisting of vitamin C (ascorbic acid), ascorbyl palmitate, vitamin E (tocopherol acetate), hydroxybenzoic acid derivatives.

25. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredient of the composition for taste masking is bound to an acidic or basic ion exchanger.

26. Medicament preparation according to one of the preceding claims, characterized in that the preparation contains dyes and / or pigments.

27. Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation contains natural and / or synthetic flavorings.

28. Medicament preparation according to one of the preceding claims, characterized in that the preparation contains a disintegrant or wicking agent.

29. Medicament preparation according to one of the preceding claims, characterized in that the pH of the preparation is adjusted via a buffer system.

30. Pharmaceutical preparation according to one of the preceding claims, characterized in that the hydrophilic polymer in less than 5 min, preferably in less than 3 min, more preferably in less than 1 min and more preferably in less than 30 s after application in the oral cavity decays.

31. Pharmaceutical preparation according to one of the preceding claims, characterized in that the hydrophilic polymer decomposes rapidly in the oral cavity, but the active substance remains bound to an ion exchanger which releases the active substance only in the gastrointestinal tract.

32. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredients are contained in discrete layers, which are spatially separated from each other and differ in their structure from each other.

33. Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation is present as a foam and at least one of the active ingredients is present in liquid form in the cavities of the foam.

34. Use of a dosage form according to one or more of claims 1 to 33 for rectal, vaginal or intra-nasal administration of pharmaceutical agents to humans or animals.

35. Use of a combination of active substances according to one of claims 3 to 11 for the preparation of an oral dosage form according to one of the preceding claims for the treatment of hypertension.

36. Use according to claim 35, characterized in that the drug is formulated as a wafer.

37. A method for the therapeutic treatment of a person suffering from hypertension, characterized in that the

Administration of a drug combination of antihypertensive agents according to claims 3 to 11 by means of an orally administered dosage form with transmucosal absorption.

38. A process for the production of a sheet-like dosage form according to one of claims 1 to 35, characterized in that it comprises the following steps:

- spreading the solution on a coating base; and

Solidifying the precipitated solution by drying and removal of the solvent.