MXPA06000823A - Treatment and preventi0n of cardiovascular events - Google Patents

Abstract

A pharmaceutical dosage form for treating or preventing cardiovascular events comprises therapeutic amounts of:a ?-adrenergic receptor antagonist, a diuretic, or both;a cholesterol-lowering agent;an inhibitor of the renin-angiotensin system;and aspirin.

Description

TREATMENT AND PREVENTION OF CARDIOVASCULAR EVENTS FIELD OF THE INVENTION The invention relates to a treatment for patients who have an elevated risk of cardiovascular events and, more particularly, to a pharmaceutical composition for such treatment. which combines a β-adrenergic receptor blocking agent with a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin in a single-dose form, and a method for preparing the pharmaceutical composition. BACKGROUND OF THE INVENTION Cardiovascular diseases have been a leading cause of global morbidity and mortality, responsible for 16.6 million deaths in 2001. The majority (80%) of all deaths attributable to cardiovascular diseases (CVD for short). English) are in low and middle economy countries. For him In 2010, CVD is expected to become the leading cause of mortality in developed countries. There is now an impressive need for developing countries and others to define and implement preventive interventions for CVD. A considerable fraction of the world population has suffered serious cardiovascular events that put REF: 169111 danger to life, such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure, infarction, peripheral vascular disease and claudication. Risk factors associated with such life-threatening events include tobacco smoking, diabetes, elevated serum cholesterol, hypertension, systemic lupus erythematosus, previous attacks or heart attacks, hemodialysis, elevated homocysteine levels, obesity, sedentary life, reception of an organ transplant, and others. The risk of having a cardiovascular event is not restricted to those with hypertension or hypercholesterolemia, but continues to at least a blood pressure of 115/75 mm Hg and a total cholesterol level of 4.0 mmoles / 1 (approximately 155 mg / dl). However, only in the last few years have clinical trials confirmed the benefits of lowering blood pressure and cholesterol in high-risk patients who do not have a clinical diagnosis of hypertension or hypercholesterolemia. Here, the vast majority of adults and virtually all people with established vascular disease, can benefit from low blood pressure and cholesterol therapy, which may require the simultaneous administration of blood pressure lowering and cholesterol lowering agents. In the recent report of the World Health Organization-Wellcome Trust meeting, the authors highlighted the vast unmet needs in cardiovascular therapy and recommend the development of combination products for it. The number of individuals at high risk who can benefit from combination cardiovascular therapy producible in India and many other countries is substantial. In a combination product, each component causes a proportional risk reduction which is not affected by the presence or absence of the other medicines. The long-term benefits may be even greater, perhaps more than a total 75% reduction in total risk, since the risk is only partially invested in the first one to two years of blood pressure and cholesterol reduction treatment. Considering the above unfulfilled needs, it can be beneficial to have a therapy and effective and convenient formulations, which include preventive medicines of multiple cardiovascular disease that can effectively reduce the risk of cardiovascular events. In conventional therapy, patients at increased risk of cardiovascular events are often on multiple drug therapy, taking two or more different medications at the same time. Presenting multiple medications in a single composition promotes client compliance by avoiding the inconvenience of taking multiple doses of medicine in a single day, and reduce the chance of missed doses. U.S. Patent 6,235,311 to Ullah et al, discloses a pharmaceutical composition which is useful for lowering cholesterol and reducing the risk of myocardial infarction, the composition including a statin, such as pravastatin, lovastatin, simvastat ina, atorvastatin ina, cerivastat ina or fluvastatin, in combination with aspirin, in a way to minimize the chemical interactions between aspirin and statin, and to minimize the side effects of aspirin. Weissman et al. , in the Patents of the United States of North America No. 6,121,249 and 6,323,188 describe a method to reduce the incidence and severity of arterysclerosis, atherosclerotic central nervous system disease, claudication, coronary artery disease, disorders related to homocystin, hypertension, peripheral vascular disease, presenile dementia, and restenosis in humans by daily administration of an effective amount of a combination of acetylsalicylic acid (ASA), at least one antioxidant, a cyanocobalamin compound (Vitamin B12), a composed of folic acid, a pyridoxine compound (Vitamin B6) and a niacin compound. U.S. Patent 5,622,985 to Olukotun et al describes inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, also called "statins", particularly pravastatin, when used alone or with an inhibitor. of angiotensin-converting enzyme (ACE), decreases the risk of a second heart attack in a patient who has a substantially normal cholesterol level. US Pat. No. 6,576,256 to Liang et al discloses methods and compositions for reducing the risk of cardiovascular events in individuals who have an elevated cardiovascular risk, including individuals who have systemic lupus erythematosus. The methods comprise administering a combination of a cholesterol-lowering agent, such as a reduced HMG CoA inhibitor, an inhibitor of the regina-angiotensin system, such as an ACE inhibitor.; aspirin, and optionally one or more of Vitamin B6, vitamin B_2, and folic acid. Pharmaceutical formulations that combine all the active agents in the dosage unit form for single daily dosing are also provided. International Patent Publication WO 01/15674 of Aventis Pharma Deutschland GMBH relates to a combination of an angiotensin-renin system inhibitor, optionally an additional hypertensive agent, a cholesterol lowering agent, a diuretic, and an aspirin, which It can be administered to prevent cardiovascular events. The International Patent Publication WO 01/76632 by Wald and Law discloses a pharmaceutical formulation containing at least two agents that lower blood pressure, which have different modes of action, plus an active agent from at least two of: lipid regulating agents; platelet function alteration agents; and agents for decreasing serum homocysteine. It is desired in this document to provide at least some of the drugs in smaller amounts than their usual therapeutic doses. An article by N. J. Wald et al., "A Strategy to Reduce Cardiovascular Disease by More than 80%" British Medical Journal, vol. 326, p. 1419-1423, 2003, advocates the daily prophylactic treatment of people over 55 years of age, and anyone with existing cardiovascular disease, with a "Polipill" containing the following six drugs: a drug to lower cholesterol, such as either atorvastatin (10 mg) or simvastatin (40 mg), the combination of three drugs that lower blood pressure from different classes, such as thiazide, ß-blocker, and an ACE inhibitor (each in half the standard dose), folic acid (0.8 mg), and aspirin (75 mg). Finally, in accordance with the recommendations made by the World Health Organization to develop combination products for cardiovascular therapy and to prove their efficacy in high-risk individuals, it is highly desirable to develop a combination product using a variety of cardiovascular drugs including a β-adrenergic blocking agent, a diuretic, a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and optionally an anti-diabetes drug. SUMMARY OF THE INVENTION For patients with high cardiovascular risk, a convenient drug therapy prior to this invention was not available. According to the invention there is provided a combination of active agents of different categories which can be conveniently administered once a day to reduce a risk of cardiovascular event. The present invention provides a stable oral dosage form once a day containing a combination of a therapeutically effective dose of: a β-adrenergic receptor blocker, a diuretic, or both; a therapeutically effective dose reducing cholesterol agent; a therapeutically effective dose of an inhibitor of the renin-angiotensin system, a therapeutically effective dose of aspirin; and optionally at least one of vitamin B6, vitamin B12, and folic acid; and a method for treating a patient with elevated cardiovascular risk by administering the dosage form on a daily basis. In one aspect, the invention provides a pharmaceutical dosage form which comprises therapeutic amounts of: a β-adrenergic receptor antagonist, a diuretic, or both, a cholesterol-lowering agent; an inhibitor of the renin-angiotensin system; and aspirin. In another aspect, the invention provides a pharmaceutical dosage form which comprises therapeutic amounts of: a β-adrenergic receptor antagonist, a diuretic, or both; a cholesterol reducing agent; an inhibitor of the renin-angiotensin system; and aspirin, where the acid components are separated from basic components. In a further aspect, the invention provides a tablet which comprises two layers, wherein a first layer comprises simvastatin and aspirin, and a second layer comprises atenolol and lisinopril. In a still further aspect, the invention provides a tablet which comprises two layers, wherein the first layer comprises simvastatin and aspirin, and a second layer comprises hydrochlorothiazide and lisinopril. DETAILED DESCRIPTION OF THE INVENTION According to the present invention, there is provided a pharmaceutical composition which includes a β-adrenergic receptor blocker, a cholesterol lowering agent, an inhibitor of the renin-angiotensin system, and an aspirin, with? without a diuretic, which reduces the risk of cardiovascular event with minimal physical and chemical incompatibility, and gives reduced side effects normally associated with the use of such drugs.

When the terms "active agent", "pharmacologically active agent" and "drug" are used; it is understood that this includes the active molecule as well as pharmacologically active salts, esters, amides, prodrugs, metabolites, analogues, etc. pharmaceutically active. Many drug substances are formulated using such other forms, but only the active portion will be identified herein. The term "therapeutic amount" in connection with a drug indicates the amount of the drug contained in a daily dose, as is prescribed as usual by a primary indication that is within the scope of this invention. These quantities are suitably summarized for many drugs in the "BNF Recommended Dose" column of tables on pages 11-17 of the application WO 01/76632 (the data in the tables that are attributed to the March 2000 British National Formulary) and can also be found in other standard formulations and other prescription drug directors. For some drugs, the usual prescribed dose for an indication will vary somewhat from country to country. The β-adrenergic receptor antagonists block the action of the sympathetic nervous system and a portion of the involuntary nervous system. By blocking the action of these nerves, the heart rate is reduced and they are useful for treating the abnormally rapid rhythms of the heart. These drugs also reduce the strength of muscle contractions of the heart and lower blood pressure. By reducing the heart rate and the strength of muscle contraction, β-blockers reduce the demand for cardiac muscle oxygen. Useful β-adrenergic blocking agents are selected from a group which includes atenolol, betaxolol, acebutolol, bisoprolol, carteolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propanolol, sotanol and timolol. Atenolol is a currently preferred β-adrenergic blocking agent. This invention employs any effective cholesterol reducing agent or combination of such agents. Useful cholesterol reducing agents include HMG Coa reductase inhibitors, bile acid sequestrants, probucol and fibric acid agents. Also useful is the selective inhibitor of intestinal cholesterol absorption that has the adopted name "ezetimibe", and the chemical name 1- (4-fluorophenyl) -3 (R) - [3- (4-fluorophenyl) -3 (S) -hydroxypropyl] -4 (S) - (4-hydroxyphenyl) -2-azetidinone. Ezetimibe is particularly effective when it is administered together with a statin. HMG CoA reductase inhibitors are preferred. These agents are competitive inhibitors of HMg CoA reductase, the limiting step in the speed of cholesterol biosynthesis. They occupy a portion of the HMg Coa binding site, blocking the access of this substrate to the active site in the enzyme. Inhibitors of HMG CoA reductase include atorvastatin, cerivistatin, fluindostatin, fluvastatin, lovastatin, mevastatin, pravastatin, simvastatin and velostatin; the most preferred agents are lovastatin and pravastatin, particularly lovastatin. The renin-angiotensin system plays a major role in regulating blood pressure. Renin, an enzyme, works by acting on angiotensinogen to form the decapeptide angiotensin I. Angiotensin I is rapidly converted to the octapeptide angiotensin II by the angiotensin converting enzyme (ACE). Angiotensin II acts by numerous mechanisms to increase blood pressure, including increasing total peripheral resistance. The inhibitors of the renin-angiotensin system are classified as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor (ARB) antagonists. Examples of angiotensin-converting enzyme (ACE) inhibitors are captropril, cilazapril, delapril, enalapril, fentiapril, fosinopril, indolapril, lisinopril, perindopril, pivopril, quinapril, rRNApryl, espirapril, trandolapril, and zofenopril.; for use in this invention are captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril and trandolapril, and most preferred is enalapril. Useful angiotensin II receptor antagonists include losartan, iresartan, eprosartan, candesartan, valsartan, telmisartan, zolasartin and tasosartan. Losartan is preferred. In this invention, inhibitors of angiotensin converting enzymes (ACE) are more preferred over angiotensin II receptor antagonists. Cyclooxygenase inhibitors are useful in the present invention because of their ability to affect platelets: the cyclooxygenase inhibitor used and most widely studied is aspirin, which is shown to prevent myocardial infarction and strokes due to thrombosis, when administered in low daily doses over a long term to patients at risk of cardiovascular events. When enough aspirin is present in the circulatory system, the platelets that are formed have a damaged ability to aggregate over 7-10 whole days of half-life. Diuretics increase the rate of urine flow and sodium excretion and are used to adjust the volume and / or composition of body fluids in a variety of clinical situations, including hypertension, congestive heart failure, renal .falla, nephritic syndrome and cirrhosis. Diuretics can be selected from a variety of classes such as inhibitors of carbonic anhydrase, diuretics circuit, thiazides and related to thiazide diuretics, mild diuretic 1", and antagonists of mineralocorticoid receptors. In one embodiment of this invention thiazides and derivatives related to thiazides are preferred diuretics, including bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hidrofl? metazida, meticlotazida, polythiazide, triclormetazida, chlorthalidone, indapamide, metolazone, and quinethazone. currently, the most preferred diuretic is hydrochlorothiazide, which acts by blocking salt and fluid reabsorption in the kidneys, causing output increased urine (diuresis). it has been widely used also to treat mild hypertension. Furthermore, a combination product can include at least one antidiabetic agent, such as oral hipoglicérmicos agents metformin, the sulfonylurea drugs nclamide, tolbutamide, tolazamide, glyburide, glipizide and glimipiride and the thiazolidinedione, troglitazone, rosiglitazone and pioglitazone drugs. These generally act to improve the utilization of insulin by the cells, and (in some cases) stimulate the production of insulin by the pancreas or decrease the production of hepatic glucose. An anti-diabetic agent may be included in a product that is proposed for use by people who have diabetes mellitus not dependent on insulin. Elevated serum levels of homocysteine are highly correlated with atherosclerosis, heart disease, infarction, and peripheral vascular disease. Vitamin B6, vitamin B12 and folic acid act to lower the levels of ho cysteine and reduce the incidence of these disease states. Vitamin Be is included in amounts between approximately 2 mg and 2 grams. Vitamin B ^ will be included in amounts between approximately 3 μg and 2 mg. Folic acid will generally be included in amounts of up to about 5 mg, such as about 400 to 800 μg, about 500 μg to 2 pg, or about 1 g to 5 mg. It should be recognized that the aforementioned lists of drugs in their particular classes are not exhaustive, and that other drugs will also be useful in the invention. In general, it is desired to use drugs that can be dosed once a day, either due to their pharmacokinetic characteristics or due to their ability to be formulated in controlled release forms to facilitate patient compliance with the dosing regimen. According to one embodiment of the invention, various dosage forms that can effectively administer the drug combination include tablets, capsules and caplets (tablets), and may also comprise a plurality of granules, beads, powders, or pellets that may or may not be encapsulated. Various pharmaceutical compositions and preparation processes are indicated in a description that follows, wherein the terms "the combination" or "a combination" indicate combinations comprising therapeutically effective unit doses of the β-adrenergic receptor blocking agent, cholesterol-lowering agent, inhibitor of the reni system to angiotensin, aspirin and optionally one or more vitamins such as vitamin Bs, vitamin &; , folic acid or a combination thereof, a diuretic, and / or a hypoglycemic drug. Combining two or more active ingredients in a single dose form has critical considerations, due to the possibility of chemical interactions between the drug substances. Acidic active ingredients such as aspirin can react with basic drugs, and acidic ingredients such as aspirin can facilitate the degradation of acid-sensitive drugs including lovastatin and pravastatin. In the invention, such drug interactions are considered and the active interaction ingredients are physically separated using various methods given below. 1. Pressure coated tablets or multiple layer tablets In a combination where drugs such as aspirin and enalapril maleate are acidic drugs, and drugs such as atenolol and lovastatin are the basic drugs, the acidic and basic substances can be separated physically as two distinct or isolated layers in a compressed tablet, or in the core and cover of a pressure coated tablet. Hydrochlorothiazide, which is compatible with acid as well as basic drugs, has the flexibility of being placed in any layer. In a further embodiment of a multiple layer composition, at least one active ingredient may be enteric coated. In yet a further embodiment of a multiple layer composition, at least one active ingredient may be presented in a controlled release form. Another useful arrangement is to provide a combination in three or more segments physically isolated from a compressed tablet. The multi-layer tablet can be film coated. 2 . Tablets or Capsules comprising a plurality of beads, pellets or pellets All active ingredients that include the combination vitamins are formulated in pellets or pellets that are further coated with a protective coating, an enteric coating, or a film coating to avoid possible chemical interactions. The granulation and coating of the granules or beads is done using techniques well known to a person skilled in the art. At least one active ingredient can be presented in a controlled release form. Finally, these coated granules or beads are filled into hard or compressed gelatin capsules in the form of tablets. 3 . Capsules' comprising microtablets or mini-tablets of all active ingredients. Microtablets are prepared from individual components of a combination using well-known direct compression pharmaceutical procedures such as making tablets, dry granulation or wet granulation. All these individual microtablets are filled into hard gelatin capsules. A final dosage form may comprise one or more microtablets of each individual component. In addition, these microtablets can be film coated or enterically coated. 4. Capsule comprising one or more microtablets and powder, or one or more microtablets and granules or beads In order to avoid interactions between the drugs, some active ingredients of the combination can be formulated as microtablets and the other filled in capsules as a powder, granules or pearls. A microtableta can be film coated or enteric coated. At least one active constituent can be presented in a sustained release form. 5. Active ingredient distributed in the internal and external phase in tablets. In an attempt to divide the chemically incompatible components of the proposed combination, few interaction components are converted into granules or beads using pharmaceutical methods well known in the prior art. The prepared granules or beads (internal phase) are then mixed with the external phase comprising the remaining active ingredients and at least one pharmaceutically acceptable excipient. The mixture of this form comprises the internal and external phase which is compressed into tablets or molded into the tablets. In additional modalities included within this procedure, the granules or beads may be beads or granules of controlled release or immediate release, and may also be coated using an enteric polymer in an aqueous or non-aqueous system using methods and materials that are known in the art, if required. 6. Single dose unit which comprises a buffering agent All the ingredients of the combination are mixed and an adequate amount of one or more buffering agents is added to the mixture to minimize possible interactions. In the methods described above, the final coated dosage forms, particularly tablets, are films coated with 1-8%, more preferably 2-6% by weight of a polymer such as a cellulose ether, an acrylic such as a copolymer of methacrylate and methyl methacrylate or a vinyl such as polyvinyl alcohol. The aforementioned enteric coatings usually provide an accumulation of 5-15% by weight, on uncoated tablets or granules of enteric coating polymers such as shellac, a polymethacrylate, hydroxypropylmethylcellulose phthalate, polyvinyl acetaphthalate, and cellulose acetate phthalate. Many other coating substances, and techniques that are suitable for applying coatings to the particles, are known and can be used in the practice of this invention. The following examples are representative embodiments of the invention, and are not constructed to limit the scope of the invention as defined by the appended claims, but serve only to show how various procedures for developing a combination product are practically realized.

EXAMPLE 1 Dual-layer tablets weighing 360 mg are prepared using the following: To prepare the tablets, the components of the first layer are combined and mixed to achieve uniformity. Separately, the components of the second layer atenolol, lovastatin, hydrochlorothiazide, lactose, microcrystalline cellulose (such as AVICEL ™ PH 101 from FMC Corporation, Philadelphia, Pennsylvania USA) and iron oxide are sieved through a sieve and mixed for uniformity, then a solution of aqueous isopropanol containing povidone and butylated hydroxyanisole is used to granulate the dry mixture, which is then dried and ground and croscarmellose sodium, silicon dioxide, and zinc stearate are added and mixed. The mixture of the first layer and the mixture of the second layer are compressed sequentially in a mold to form bi-layer tablets, which are finally film coated.

EXAMPLE 2 A hard gelatin capsule is prepared which contains a microtablette, a mini-tablet, and a powder using the following: A microtablet coated with enalepril maleate film is prepared by mixing the first five ingredients listed, compressing to form a tablet, coating with a solution of hydroxypropylmethylcellulose, and drying. An enteric coated aspirin minitablet is prepared by mixing the first three listed ingredients, compressing to form a tablet, coating with an enteric polymer solution, and drying. A powder is prepared by mixing atenolol, lovastatin, hydroclortiazide and the listed excipients. Then, a hard gelatin capsule is filled with the microtablette and the mini-tablet and the powder to a size 0. EXAMPLE 3 Capsules containing a combination of cardiovascular drugs are prepared using the following: The lovastatin, atenolol, enalapril maleate, hydroclortiazide, aspirin, lactic acid and lactic acid are mixed uniformly and calcium carbonate and magnesium oxide are added to this mixture followed by additional mixing.

Magnesium stearate and silicon dioxide are added to the dry mixture and uniformly mixed, and a hard gelatin capsule is filled with the final powder. EXAMPLE 4 Tablets containing a combination of drugs are prepared using the following: To prepare the tablets, the first seven ingredients are added, then they are moistened and granulated, dried, and the following two ingredients are added and mixed to form a mixture of the first layer. A mixture of the second layer is prepared by dry granulating the first five ingredients of the second layer, the povidone, and the zinc dye and stearate moiety; then the granules, the rest of the dye and the zinc stearate, plus all the starch and sodium glycolate, are added and mixed. Finally, the first layer mixture is compressed into a dye, then the mixture of the second layer is added and compressed to form a two-layer tablet, the film is then film coated and dried. Alternatively, the mixture of the second layer has been prepared by wet granulation of the first five ingredients of the second layer, plus povidone; After drying and grinding, all the zinc stearate, tincture and sodium glycolate and starch are added and mixed.

EXAMPLE 5 Tablets containing a combination of drugs are prepared using the following: To prepare the tablets, the first ingredients are prepared as in example 4 above. The first six ingredients of the second layer, plus half of the zinc stearate and dye, are subjected to dry granulation, then the other half of the zinc stearate and dye, plus all the starch and sodium glycolate, are added, and they mix. Tableting is done as in Example 1, followed by film coating and drying. As in example 5, the first six ingredients of the second layer may alternatively be wet granulated, dried and milled, and then the three final ingredients are added and mixed. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (24)

2. Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical dosage form characterized in that it comprises therapeutic amounts of: a β-adrenergic receptor antagonist, a diuretic, or both; a cholesterol reducing agent; an inhibitor of the renin-angiotensin system, and aspirin. 2. The pharmaceutical dosage form according to claim 1, characterized in that it comprises a β-adrenergic receptor antagonist.
3. 3. The pharmaceutical dosage form according to claim 1, characterized in that it comprises a diuretic.
4. 4. The pharmaceutical dosage form according to claim 1, characterized in that the β-adrenergic receptor antagonist comprises atenolol.
5. 5. The pharmaceutical dosage form according to claim 1, characterized in that the cholesterol reducing agent comprises an inhibitor of HMG CoA reductase.
6. 6. The pharmaceutical dosage form according to claim 1, characterized in that the cholesterol reducing agent comprises lovastatin.
7. 7. The pharmaceutical dosage form according to claim 1, characterized in that the cholesterol reducing agent comprises simvastatin.
8. 8. The pharmaceutical dosage form according to claim 1, characterized in that the inhibitor of the renin-angiotensin system comprises an ACE inhibitor.
9. 9. The pharmaceutical dosage form according to claim 1, characterized in that the inhibitor of the renin-angiotensin system comprises enalapril.
10. 10. The pharmaceutical dosage form according to claim 1, characterized in that the inhibitor of the renin-angiotensin system comprises lisinopril.
11. 11. The pharmaceutical dosage form according to claim 1, characterized in that it further comprises an agent for lowering homocysteine levels.
12. 12. The pharmaceutical dosage form according to claim 1, characterized in that it also comprises folic acid.
13. 13. The pharmaceutical dosage form according to claim 1, characterized in that it also comprises a hypoglyceagent.
14. 14. The pharmaceutical dosage form according to claim 1, characterized in that it comprises atenolol, lovastatin, enalapril, aspirin, and hydrochlorothiazide.
15. 15. A pharmaceutical dosage form characterized in that it comprises therapeutic amounts of: a β-adrenergic receptor antagonist, a diuretic or both; a cholesterol reducing agent; an inhibitor of the renin-angiotensin system, and aspirin; wherein the acid components are separated from the basic components.
16. 16. The pharmaceutical dosage form according to claim 15, characterized in that it also comprises a diuretic.
17. 17. The pharmaceutical dosage form according to claim 15, characterized in that the acid components are presented in a layer of a multilayer tablet, and basic components are presented in another layer.
18. 18. The pharmaceutical dosage form according to claim 15, characterized in that the acidic components are presented in one of a core and a shell of a multiple compressed tablet, and the basic components are presented in the other of a core and shell.
19. 19. The pharmaceutical dosage form according to claim 15, characterized in that it comprises a mixture of acid component formed in a particle.
20. 20. The pharmaceutical dosage form according to claim 15, characterized in that it comprises a mixture of a basic component formed in a particle.
21. 21. The pharmaceutical dosage form according to claim 15, characterized in that it comprises a mixture of acidic component formed in a particle and a mixture of basic component formed in another particle.
22. 22. The pharmaceutical dosage form according to claim 15, characterized in that at least one mixture of acid component and a mixture of basic component is formed in a particle and coated with a polymer.
23. 23. A tablet characterized in that it comprises two layers, characterized in that a first layer comprises simvastatin and aspirin, and a second layer comprises atenolol and lisinopril.
24. 24. A tablet characterized in that it comprises two layers, characterized in that the first layer comprises simvastatin and aspirin, and a second layer comprises hydrochlorothiazide and lisinopril.