MXPA06004933A - Combinations of at1-antagonists, amiloride or triamterine, and a diuretic - Google Patents

Abstract

The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising:(i) an AT1-receptor antagonist or a pharmaceutically acceptable salt thereof, and (ii) the diuretic amiloride or triameterine or a pharmaceutically acceptable salt thereof, and (iii) a further diuretic or a pharmaceutically acceptable salt thereof.

Description

COMBINATIONS OF ANTAGONISTS OF AT1, AMILORIDE OR TRIAMTERI N E Y U N DI U RÉTICO The invention relates to a combination, as a combined preparation or a pharmaceutical composition, respectively, comprising: (i.) An antagonism of the AT- receptor. , or a salt of it acceptable for pharmaceutical use; and (ii.) amiloride or triameterine, or a salt thereof acceptable for pharmaceutical use; and (iii.) a thiazide diuretic or a salt thereof, acceptable for pharmaceutical use. It is understood that the anonymiasis of the AT receiver. (also referred to as angiotensin receptor I I or ARB antagonists), are those active ingredients that bind to the ATj receptor subtype of the angiotensin receptor I I, but which do not result in receptor activation. As a consequence of the inhibition of the AT- receptor. For example, they can be used as ani-hypersensors, or for congestive heart failure. The anonymity class of the ATT receptacle includes compounds that have different stylistic aspects; Essentially those that are not pepíídicos are preferred. For example, it is possible to mention the compounds that are selected from the group consisting of Walloons (see EP 443983), Losarian (see EP253310), Candesarian (see 459136), Eprosarian (see EP403159), Rbesarian (see EP454511), Olmesarian ( see EP 503785), iasosaríán (see EP539086), íelmisaríán (see EP 522314), the compound with the designation E-1477 of the following formula: the compound with the designation SC-52458 of the following formula: and the compound with the designation of compound ZD-8731, of the following formula: or, in each case, a salt of them, acceptable for pharmaceutical use. They are favorite anilagonisías of the receiver of AT! those agencies that have been commercialized; and those that are most preferred are walruses, or a salt of it, acceptable for pharmaceutical use. A preferred salt of amiloride, acceptable for pharmaceutical use, is the hydrochloride. Amiloride hydrochloride is the component (ii) that is most preferred. < . A thiazide diuretic, for example, is selected from the group consisting of chloroiazide, hydrochloroxyzide, methyleclofiazide and chloroalide. The most preferred is hydrochloride. Preferred are combinations, such as combined preparations or pharmaceutical compositions, specifically, comprising: i.) An anonymysia of the TAI receptacle or a salt thereof, acceptable for pharmaceutic use; and ii.) amiloride or a salt thereof, acceptable for pharmaceutical use; and iii.) hydrochloride, or a salt thereof, acceptable for pharmaceutical use.

Preferred combinations are those combination preparations or pharmaceutical compositions, respectively, which comprise: i) valsaran or a salt thereof, acceptable for pharmaceutical use; and ii. ) chlorh id amiloride rale; and iii. ) hydrochloride. The publication of active agenis, identified by generic names or brand names, can be taken from the current edition of the standard "The Merck Index" or database, for example, from the Life Cycle Patenfs I nernaiional (for example, the IMS World publications). Your corresponding confiden is here incorporated by means of this reference. Any person with experience in mailary is fully trained to idenify the active agents and, based on these references, is trained in the same way to manufacture and test the indications and pharmaceutical properties in standard test models, in vitro and in vivo . It is also possible to use the corresponding active ingredients or their acceptable salt for pharmaceutical use, in the form of a solution, such as a hydraphine, or including other solvents used for chilling. The compounds that are to be combined can be presented as acceptable salts for pharmaceutical use. If you are compues, for example, they have at least one basic censor, they can form acid addition salts. The corresponding acid addition salts can also be formed, if desired, when additionally a basic ash is present. Compounds that have an acid g rupe (for example, COOH) can also form salts with bases. The diuretics amiloride or triameterine or, in each case, a salt of them acceptable for pharmaceutical use, block the Na + channels in the last disulfile and ducious collection cells, increasing the loss of sodium and chloride ions, at the same time as reduce the excretion of poiasio. It is known that the diuretics of iazide reduce the reabsorption of electrolytes from the renal lobules, thus increasing the excretion of sodium and chloride ions and, consequently, water. The excretion of poiasis was also increased by administering, for example, hydrochloride. The combination of amyloid, especially of its hydrochloride, or of triameterine, respectively, with an iazide diuretic, for example, hydrochloride, increased the excretion of sodium and chloride ions, at the same time as it diminishes the caliuremic effects. It is surprising that the experiential discovery that the combined administration of the combination of: i. ) an anonymity of the AT1 receptor; or a salt thereof acceptable for pharmaceutical use; and ii.) amiloride or a salt thereof acceptable for pharmaceutical use; and iii.) diuretic oxide, or an acceptable salt for pharmaceutical use, does not only cause a beneficial feperal effect, especially a poienciation, preferably a synergistic effect; It is also famous for its additional benefits, which come from combined irradiation, and other surprising beneficial effects, compared with a monotherapy that applies only one of the pharmaceutically useful compounds used in the combinations described here. In particular, it is surprising to find out from the experimental discovery that the combination of the present invention results not only in a beneficial effect, especially a promotion, preferably a synergistic effect, but also additional benefits that are the result of the invention. Combined, it is a surprising prolongation of effectiveness, a wider variety of fertility phenomena, and surprising beneficial effects on diseases and conditions such as those specified hereinafter. Additionally, it is a surprising effect of the combination of the present invention that a blood pressure is lowered further with a lower dose of each component of the ion therapy. -Better management of the poiasio and better homeosfasis. -Better proprioception of the myocardium, due to the hemodynamic effects of the freshers and the proiecfor efeccio of the valsary and the amyloid. In fact, they would control, by blocking the harmful actions of AT II on perfusion of the myocardium and by remodeling ischemia and necrosis after the myocardium, and the amiloride by blocking the Na + / H + exchanger that has a role in the myocardium. damage by ischemia-reperfusion, may protect the myocardium to a greater degree in repetitive ischemia and acute myocardial infarction. It can be demonstrated, by established test models, and especially by those test models that are described here, that the combination of therapeutic agents selected from the group consisting of (i) to (iii), results in further prevention. effecfive or, preferably, a more effective eradication of diseases such as those specified below. In particular, it can be demonstrated by means of tested test models, and especially the test models described here, that the combination of the present invention results in a more effective prevention or, preferably, a more effective treatment of the specified diseases. more ahead If it occurs simultaneously, it results not only in an additional incremental benefit, especially a synergistic synergistic effect, but also in additional benefits that are the result of the simul- ary situation, as a surprising prolongation of effectiveness, a wider variety of Ierapéuíico frafamienfo and surprising beneficial effects, for example, lower increment in weight, in diseases and conditions associated with diabetes mellitus, for various combinations such as those described here. In addition, for a human patient, especially elderly people, it is more convenient and easier to remember that two fableías should be done at the same time, for example, before a meal, which alternated in time, that is, in accordance with a more complicated tragic program. It is more preferable to admire both active ingredients as a fixed combination, that is, as a single ingredient, in all the cases described here. Taking a single table is still easier to handle than taking two tables at the same time. Addicionally, you can get the package with less effort. The term "synergistic synergy", as used herein, means that the effect obtained with the methods and compositions of the present invention is greater than the sum of the effects that are the result of methods and compositions comprising the active ingredients of the invention. it was inventionseparately. People who have experience in the field are fully trained to select a standard and standard animal test model to check the indications and beneficial effects that are indicated above and below. Pharmaceutic activities can be demonstrated when they are effected by administration of the representative class of ATi receptor antagonists or diuretics, respectively, or by the combination of the active agents used according to the present invention, for example, using pharmacological models correspond ieníes, known in the technical perinenie. The persons with experience in the maternity period, are fully trained to select a relevant animal test model, to check the therapeutic indications and the beneficial effects indicated in what comes and in what comes later. For example, beneficial effects on blood pressure can be demonstrated in the test model described in RL Webb and Coauiores, in J. Hypertension, 16: 843-852, 1998. Mefodos: The combination according to the present invention, which comprises the compound of formula (I) or a salt of it acceptable for pharmaceutical use, can be administered by various administration routes, but are tested, in this example, by using a conical infusion by means of osmoic bombs implanted subcutaneously. . Each agency can be tested in a wide variety of doses, to determine the optimum level of drug for each agency in the combination, to elicit maximum response. For these studies, it is preferred to use breeding groups that consist of at least six animals per group. Each study in which the effects of the experiment in combination are defined at the same time as the individual components are evaluated, is best done. While the effects of the drug can be observed with acute administration (such as 1 day), it is preferred to observe the responses in a chronic condition, as shown below, in which experiments were performed during a period of observation. from two to fres weeks. The long-term study is of sufficient duration to allow the development of the compensatory responses to occur and, therefore, the observed effect will more likely illuminate the real responses of the test system that represented sustained or persistent effects. The effects on blood pressure, illustrated further below, represented a synergistic, synergistic effect when the two agents are used in combination. Static analysis: Combination therapy can be compared with that of the monotherapy groups, by deducting the maximum change in blood pressure or the area under the curve (AUC, acronym for its designation in English: Area Under the Curve) to change the blood pressure with the time in each of the age groups. All values are represented as the group mean ± SEM. The essential meaning is obtained when p <; 0.05. The AUC values for each of the framerization groups can be compared explicitly using a one-way ANOVA, followed by the appropriate post-hoc analysis, for example, when performing a Tukey test. Resulados: Blood pressure can be reduced to a similar degree by using smaller doses of each of the components when given in combination, than when administering individual mono-therapies. An additional unexpected finding is that the blood pressure can be lowered to a greater degree with the combination than when the individual compound of formula (I) is administered, or a salt of it acceptable for pharmaceutical use, alone, at a dose beyond that. These beneficial effects, for example, can be demonstrated in the test model that is described by G. Jeremic and coauiores, in J. Cardiovasc. Pharmacol., 27: 347-354, 1996. For example, the valuable potential of the combination of the present invention for the prevention and the infarction of infarction to the myocardium (which includes the indication after the infarction to the myocardium to reread the advancement of the myocardium. congestive heart failure) can be found using the following model.

Study design In the study to be carried out, the permanent occlusion of the coronary artery (CAO, acronym for its designation in English: Coronary Aríery Occiusion) is used, as a model of acute infarction to the myocardium. Experiments are carried out with five groups of animals, characterized by the following aspects: • simulated animals • CAO + vehicle • CAO + valsaran (val) or a salt of it, acceptable for pharmaceutical use, • CAO + amiloride (ami) ) • CAO + hydrochlorothiazide (HCTZ), • CAO + valsartan or a salt of it acceptable for pharmaceutical use + amiloride + hydrochlorothiazide. During the study, the following variables were measured: • size of the infarction, • volume of the left ventricle chamber (LV, acronym for its English designation: Lefí Veníricle) • density of collagen iníersíicial and perivascular in myocardium of the available LV, • Conenido of blood COL-I and COL-III in available LV myocardium, mid-Western stain, • Cross-sectional area of cardiomyocytes and length in sections of the LV myocardium, • Renin and aldoserone concentrations in plasma, • Sodium concentration, poiasio and aldosferone in the urine, • Blood pressure in conscious animals, • Blood pressure in the LV and in the caróíida, in animals anesfesiados.

Methodology Size of the infarction: cross-sectional hisiological sections of six micras of thickness, of the left ventricle, with a blue color and are taken by means of a black and white video camera XC-77CE CCD (Sony). The resulting image is processed in a system for image analysis KS 300 (Cari Zeiss Vision) using a software developed specifically (Porzio and coauthors, 1995). A single operator, blinded to the process, defines interactively the limits of the intravenous circulatory system and the infarcted area is identified semiautomatically in each section, such as the area of ventricular function not included. The software calculates auyomically every component of the ventricular section defined as the chamber, the sepum, the infarcted area, the wall of the infariate LV, and the wall of the viable LV, a series of geometric parameters (Porzio and coauiores, 1995). Histology: The hearts are fixed in situ, by means of a perfusion with 4% formaldehyde, after deiodination in the diastole by means of an intravenous injection of 0.5 M KCl. After fixation, the left ventricle (LV) and the free wall of the right ventricle are weighed separately; The largest diameter of the LV is measured with a calibrator. Hisiological sections of the LV are finished with hemaxililin and eosin for qualitative examination and to quantify the cross-sectional area of cardiomyocytes, with a semiaufomatic ruin of image analysis. The deposition of infersficial collagen in the LV is evaluated in sections marked with Sirius red with a semiauimactic ruin of image analysis (Masson and coauíores, 1998). Collagen content in the LV of the available myocardium: The LV tissue is homogenized in the available myocardium; it was subjected to electrophoresis PAGE-SDS and electro-perforated on Ni-Cellellulose membrane. The spots are exposed to primary antibodies, i.e., collagen aniisers iipo I or iipo III rabbit-aniirrrafa (Chemicon). The primary antibodies are recognized by the secondary antibodies, conjugated with alkaline phosphatases (for collagen type I) or peroxidase (for collagen type III). Volume of the left ventricular chamber: The volume of the LV chamber is de-dialed in diastere-insized hearts (KCl) and fixed in formalin under a hydrostatic pressure equivalent to the dialysis pressure of the measured LV exile. A metric rod deníro of the VL would be inserted to measure the infernal length of the LV. The transverse diameters of the LV chamber are measured in two transversal sections of 1 mm thick, near the base and apex of the ventricle (Jeremic and coauthors, 1996). The volume of the chamber is computed from an equation that measures the transversal diameters and the infernal length. Left ventricular and systemic hemodynamics: A pressure transducer with micropunia (Millar SPC-320) connected to a recorder (Windograf, Gould Elecíronics) would be inserted from the right carotid artery to record the systolic and diasolic blood pressures. The pressure transducer is advanced within the LV to measure the systolic pressures of the LV (LVSP, acronym for its designation in English Lefí Ventricle Systolic Pressure) and the exfrema diaphragm pressures (LVEDP, acronym for its designation in English: Lefí Veníricle End- Diasolic Pressure), the first derivative of LV pressure during the time (+ dP / day) and cardiac rhythm. Noninvasive blood pressure: The systolic blood pressure and heart rate are measured by means of the fist in the tail (Lelica LE 5002) in conscious rages. Urine electrolyte hormones: The rats are individually housed in meiabolic cages and the 24-hour urine is collected in 1 mL of 6N HCl. The water intake is measured. The caycholamines of the urine are exluded in Bondeluí columns of C18 (Varian), separated by HPLC (analytical column Apex-ll, C18, 3 μm, 50x4.5 mm-, Jones Chromaiography) and quantified with an electrochemical deiecfor (Coufochem II , ESA) (Goldsfein and coaufores, 1981). Aldoserone in plasma and urine and angiotensin II in the plasma are deiodinated with specific radioimmunoassays (Aldoctk-2, DiaSorin and Angiotensin II, Nichols Diagnosis). Sodium and poiasis in the urine are measured by flame photometry.

Sample size There are 10 analyzable animals in each breeding group to deduce important biological differences. Only those areas with an infarct size of at least 10 percent in the LV section area, in the final analysis, are included. Endoihelial dysfunction has been recognized as a critical factor in vascular diseases. The endothelium plays a bimodal role, as the source of various hormones or subproducts with opposite effects: vasodilatation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombogenesis, production of antioxidants or oxidizing agents. Animals geneically predisposed to hyperfunction, with endothelial dysfunction, constitute a valid model to determine the efficacy of cardiovascular therapy. Endoihelial dysfunction is characterized, for example, by increased oxidant oxidation, which causes a decrease in nitric oxide; Increased factors involved in coagulation or fibrinolysis, such as the plasminogen activator inhibitor-1 (PAI-1), the isomeric factor (TF), the plasminogen activator of the iodide (ipa), the increased adhesion molecules, Factors such as ICAM and VCAM, the increased growth factors, such as bFGF, TGFb, PDG F, VEG F, are all factors that cause the cell to develop inflammation and fibrosis. The treatment, for example, the endophelial dysfunction, can be demonstrated by the following pharmacological test: Material and methods Male SH R rabies from 20 to 24 weeks of age, bought from RCC Ldí (Fullingsdorf, Switzerland) are manned in a controlled temperature and light space, with free access to rat feed (Nafag9331, Gossau, Switzerland) and to running water. The experiment is carried out in accordance with the guidelines of N I H and approved by the Office of the Caníón Veíerinario (Bew 1 61, Kaníonales Veíerináramí, Liesíal, Switzerland). All rabbits are irradiated with the syn- thesis inhibitor of NO L-NAME (Sigma Chemicals) administered in the drinking water (50 mg / L) for 12 weeks. The average daily dose of L-NAME calculated for the water consumed was 2.5 mg / kg / day (range 2.1 to 2.7). The rats can be divided into five groups: Group 1, conírol (n = 40); group 2, valsaran (val; n = 40); group 3, amiloride (ami; n = 30); group 4, hydrochloroiazide (HCTZ, n = 30); and group 5, a combination (val-ami-HCTZ (n = 30) .The drugs are administered in the drinking fluid.The doses to be used are selected from the work of Sweet and Coauiores (1987), Indicating the survival significantly increased in infarmed inflations to the scarred myocardium, the pressor efflux of Ang II can be reduced to 1 mg / kg obtained in normotensive conirol radicles, after frafinization with the compound of the formula (I), in the form of hemifumaraio (Gervais and coauiores, 1 999) Body weight is measured every week, systolic blood pressure and heart rate are recorded through pleismo with fist in the tail at three and two weeks before starting the procedure. This is done two weeks after the administration of the drug.The urine is collected during a period of 24 hours from the raisins in individual cages (meiabolics) the week before the treatment and at 4 and 1 2 weeks, to measure the volume and de-ermination of protein, creatinine, sodium and poiasium, using standard laboraire methods. At these same points of time, samples of blood from the rerio-orbital plexus (maximum 1 mL) are analyzed for creatinine, Na + and K +. Ten rats of each group are sacrificed at four weeks to collect the kidneys and hearts, for morphological analysis. The remaining rats are sacrificed at 12 weeks. The heart weight and the kidney weight are recorded. The sampling of terminal blood in EDTA at 5 percent at 4 weeks (morphometry study) and at 12 weeks (end of the study) for the determination of aldosterone by radioimmunoassay using an application equipment for aldosterone DPC count is carried out -RIA (Bühlmann, Switzerland).

Statistical analysis: All damages are expressed as the mean ± SEM. Statistical analysis is carried out using a one-way ANOVA, followed by a Duncan multi-rank test, and a Newman-Keuls test, for comparison between the different groups. The results with a probability value less than 0.05 are considered important.

RESULTS: Even at doses that do not reduce blood pressure, the administration of the combination of the present invention leads to significant improvements in survival rates. An improvement in the regression of arrosclerosis can be demonstrated without affecting serum lipid levels, for example, using the animal model that was described by H. Kano and co-authors in Biochemical and Biophysical Research Communications 259, 414-419 (1999). That the compounds or combinations according to the present invention can be used for the regression of an atherosclerosis induced by cholesterol diet, the test pattern described, for example, by C. Jiang and coauiores can be demonstrated. Br. J. Pharmacol. , (1991), 104, 1033-1037. Other benefits when applying the composition of the present invention are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dose; for example, that the doses not only need to be smaller, but that they are also applied less frequently, or that they can be used in order to decrease the incidence of colaferal effects. This is in accordance with the wishes and requests of the patients who are going to be treated.

Design of clinical programs A major design study is initiated in patients who are under impaired without prior or prior treatment, in order to select the dose or dose that is most appropriate for subsequent use. The positive result of the selected doses is based on the synergy for the decrease in blood pressure, the low incidence of collagenous effects and the better management of the poiasium, of the combination. This study includes 120 patients in each cell of the explored doses of monotherapy and / or mercantile combination of two of the components of the friple combination. In addition, a non-response test is conducted to show that the addition of an active schedule of the combination can result in additional blood pressure lowering and more low-level patients, without increasing colafferal effects. These studies show that this combination provides additional prophylaxis to the myocardium in patients with infarction to the myocardium, acute coronary syndrome, ischemic heart disease, myocardial revascularization in the acute phase, or chronic coronary occlusion. This assertion is supported by clinical studies that measure markers of ischemia and myocardial damage, such as Iroponine T and I, CPK MB, myobox, as well as markers of myocardial function, fal as ejection fraction, dimensions of the ventricle. left and confraciilty, measured by MRI, ultrasound, scintigraphy or other appropriate measurement of myocardial damage. Preferably the jointly effective effecive amounts of the active agents according to the combination of the present invention can be administered simul- taneously or sequentially in any order, separately or in a fixed combination. The pharmaceutical composition according to the present invention, which is described in the foregoing and further, may be employed for simul- anetional use or sequential use - < in any order, for separate use or as a fixed combination. Accordingly, the invention further relates to a method for preventing, delaying the progress of, or trafing a disease or condition, selected from the group consisting of: i) hyperintense, congestive heart failure, resenhosis after percutaneous transluminal angioplasty, and resenosis after coronary artery bypass surgery; ii.) arteriosclerosis, insulin resistance and syndrome X; diabeíes melliius íipo 2, obesity, nephropathy, hypophyroidism, survival to myocardial infarction (MI), coronary heart disease, hypertension in elderly patients, familial dyslipidemic hyperfunction, increased collagen formation, fibrosis and remodeling after hypertension (antiproliferative effect of the combination); all these diseases or conditions, associated with or without hyperintense; iii.) endoíelial dysfunction, with or without hyperintense; iv.) hyperlipidemia, hyperlipoproinemia, aerosol and hypercholesterolemia; v.) glaucoma; additionally: vi.) isolated hypertension (ISH, acronym for its designation in English Isolaíed Sysíolic Hyperience); v i i. Diabetic retinopathy; and viii.) peripheral vascular disease; which comprises administering to a warm-blooded animal, including humans, in need thereof, a jointly effective amount of a combination of the renin inhibitor of the formula (I), or a salt thereof acceptable for pharmaceutical use, with less a therapeutic agent comprising: i.) an anonymity of the receptacle of A ^ or a salt of it, acceptable for pharmaceutical use; and ii.) amiloride or a salt thereof, acceptable for pharmaceutical use; and iii.) diuretic or a salt thereof, acceptable for pharmaceutical use. Additionally, the present invention relates to the use of a combination comprising: i.) An anonyloxy of the ATY receptacle or a salt thereof, acceptable for pharmaceutical use; and ii.) amiloride, or a salt thereof, acceptable for pharmaceutical use; iii.) diuretic oily, or a salt thereof, acceptable for pharmaceutical use; for the manufacture of a medicament for the prevention of rearing in the advancement of, or for the eradication of, a disease or condition, selected from the group consisting of: (a) hypertension, congestive heart failure, restenosis after percutaneous transverse angioplasty, and restenosis after coronary artery bypass surgery; (b) arteriosclerosis, insulin resistance and syndrome X; diabetes mellitus type 2, obesity, nephropathy, survival to myocardial infarction (MI), coronary heart disease, hypertension in elderly patients, familial dyslipidemic hyper-tension, increased collagen formation, fibrosis and remodeling after hypertension ( antiproliferan effect of the combination); all these diseases or conditions, associated with or without hypertension; (c). endoíelial dysfunction, with or without hyperintense; (d). hyperlipidemia, hyperlipoproineinemia, aerosol and hypercholesterolemia; (and). glaucoma; additionally: (f). Isolated systole hyperlension; (g) diabéíica reíinopaíía; and (h). peripheral vascular disease. The invention further relates to a pharmaceutical composition for the prevention of the progression of the progression of a disease or condition, selected from the group consisting of: (a), hyper-tension, congestive heart failure, resenosis after of percutaneous transluminal angioplasty, and resenosis after coronary artery bypass surgery; (b) arteriosclerosis, insulin resistance and syndrome X; diabeides mellifus type 2, obesity, nephropathy, hypohyroidism, survival to myocardial infarction (MI), coronary heart disease, hyperfunction in elderly patients, familial dyslipidemic hyperintensity, increased collagen formation, fibrosis and remodeling after hyper-tension (antiproliferative effect of the combination); all diseases or conditions, associated with or without hypertension; (c). endothelial dysfunction, with or without hypertension; : (d). • hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolemia; (and). glaucoma; additionally: (f). isolated systolic hyperlension (ISH); (g) diabéfic reíinopaíía; and (h). peripheral vascular disease; which comprises i. ) an antagonism of the AT-i receptor or a salt thereof, acceptable for pharmaceutical use; and ii.) am iloride, or a salt thereof, acceptable for pharmaceutical use; and iii.) diuretic, or a salt thereof, acceptable for pharmaceutical use; and an acceptable portion for pharmaceutical use. Other benefits, when the composition of the present invention is applied, are that lower doses of the individual drugs which are to be combined according to the present invention can be used to reduce the dose, for example, that the necessary doses do not only they are often smaller, but they also apply less frequently, or they can be used in order to reduce the incidence of side effects. Esfo is in accordance with the wishes and requirements of the patients who will be evacuated. Preferably, effective conjunctive quantities can be administered from the therapeutic point of view of the active agents according to the combination of the present invention, in a simple or sequential manner, in any order, separately or in a fixed combination. The pharmaceutical composition according to the present invention, which is described in the foregoing and below, may be used for simultaneous use or for sequential use, in any order, for separate use or as a fixed combination. The present invention is a device for the prevention of, the retardation in the advancement of, the bringing about of a disease or condition in accordance with the present invention, comprising: a. ) an amount of valsartan or a salt of it acceptable for pharmaceutical use, in a first unit dose form; b.) a quantity of therapeutic agents (ii) and (iii) or, in each case, where appropriate, a salt thereof, acceptable for pharmaceutical use, in a second, etc. , unit dose form; and c. ) a container for first, second, and third forms, or forms. In a variation thereof, the present invention refers in a similar way to a "case of parts", for example, in the sense that the components which are to be combined in accordance with the present invention can be dosed independently, or mediated by the invention. the use of different fixed combinations, with different quantities of the components, that is to say, simultane- ously or at different points in time. The parts of the kit of parts can then be administered, for example, simultaneously, or they can be alternated chronologically; that is, at different time points and with equal or different time intervals, for any part of the parts case. Preferably, the time intervals are selected in such a way that the effect of the disease or condition brought about in the combined use of the paris is greater than the effect that would be obtained by using only one of the components. The invention further relates to a commercial package comprising the combination according to the present invention, together with instructions for simultaneous, separate or sequential use. These pharmaceutical preparations are for enteral administration, such as orally, and also rectally or parenterally, to homeothermal organisms, the preparations comprising the pharmacologically active compound, either alone or together with various customary pharmaceutical auxiliaries. For example, pharmaceutical preparations consist of about 0.1 per cent to 90 percent, preferably from about 1 percent to about 80 percent, of the active compound. Pharmaceutical preparations for enteral or parenteral administration and also for ocular administration are, for example, in unit dosage forms, such as coated tablets, tablets, capsules or suppositories, and also in amulets. These are prepared in a manner that is known per se, for example, using conventional mixing, granulating, coating, solubilizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, if desired, by granulating a mixture that has been obtained and, if required or needed, processing the mixture or granulate into containers or cores for blending. revesíida, after having added the auxiliary susfancias suitable. The dose of the active compound may depend on a variety of factors, such as the mode of admimisation, the species of the homeothermic organism, the age and / or the individual condition.

Preferred doses for the active ingredients of the pharmaceutical combination according to the present invention are effectively effective doses, especially those which can be obtained commercially. Normally, in the case of oral administration, an approximate daily dose of about 1 mg to about 360 mg is estimated, for example, for a patient with approximately 75 kg of weight. The dose of the active compound may depend on a variety of factors, such as the mode of administration, the homeophermic species, the age and / or the individual condition. The pharmaceutical preparation will be supplied in the form of a suitable dosage unit, for example, a capsule or a tablet, for oral irradiation. The valsartan will be supplied, as a representative of the anonymity class of the receiver of AT1 t in the form of a suitable dose unit, for example, a capsule or a shell, and comprising a therapeutically effective amount, for example, around 20 to about 320 mg of valsartan, which can be applied to patients. A suitable dosage unit form may comprise 40 mg, 80 mg, 160 mg or 320 mg per dosage unit form. The application of the active ingredient can occur several times a day, for example, with a daily dose of 20 mg or 40 mg of valsartan, which is increased by 80 mg daily, and additionally 160 mg daily has reached the 320 mg daily. It is preferable to apply valsartan twice a day with a dose of 80 mg or 160 mg, respectively, each. Corresponding doses can be added, for example, in the morning, at noon or at night. Administration is preferred twice a day. The hydrochloroiazide will be supplied in a suitable unit dosage form, for example, a capsule or tablet, and comprising a therapeutically effective amount, for example, from about 5 mg to about 50 mg, which can be applied to patients. The preferred doses per unit dosage form is 6.25 mg, 12.5 mg or 25 mg. The application of the active ingredient may occur several times a day. The doses of amiloride or of iridium, respectively, are those that are normally used for monotherapy; very preferable, in the lower scale of the prescribed doses. The application of the active ingredient may occur several times a day. A preferred dose per unit dosage form is 5 mg of amiloride hydrochloride. The combinations are preferred; in particular the pharmaceutical compositions comprising: (i) a dose of valsartan, selected from 40 mg, 80 mg, 160 mg and 320 mg of valsartan; (ii) 5 mg of amiloride hydrochloride, and (iii) a dose of hydrochlorothiazide selected from 12.5 and 25 mg of hydrochlorophiazide. Dosage unit forms or a single dose unit form are preferred, comprising: (i) a dose of selected valsartan of 40 mg, 80 mg, 160 mg, and 320 mg of valsartan; (ii) 5 mg of amiloride hydrochloride; and (iii) a dose of hydrochloride, selected from 12.5 and 25 mg of hydrochloride. Low-dose combinations are especially preferred. The following examples illustrate the invention described above; however, they are not intended to restrict the scope of this invention in any way. FORMULATION EXAMPLE 1 Tablets with film coating * Eliminated during the processing. The fableta revesfida with film is made, for example, in the following way: A mixture of valsara, microcrystalline cellulose, crospovidone, pareie of colloidal anhydrous silica / colloidal silicon dioxide / Aerosil 200, silicon dioxide and magnesium spherafer is premixed , in a diffusion mixer and then sieved through a sieving mill. The resulting mixture is premixed again in a diffusion mixer, compacted in a roller compactor and then heated to a stirred mill. The mixture of the colloidal anhydrous silica / colloidal silicon dioxide / Aerosil 200 is added to the mixture and the final mixing is effected in a diffusion mixer. The mixture is compressed in a rofatory hammer-forming machine, and the materials are checked with a film using pale red Diolack in a perforated tray.

FORMULATION EXAMPLE 2 Tablets coated with film The reversed table with film is made, for example, as described in formulation example 1.

FORMULATION EXAMPLE 3 Tablets coated with film * The composition of the coloring agent Opadry® coffee 00F16711 ** is tabulated later. Removed during the processing. Composition of the Opadry®: The film-coated table is prepared, for example, as described in formulation example 1.

FORMULATION EXAMPLE 4 Capsules The work is elaborated, for example, in the following way: Granulation / Drying Walkers and microcrystalline cellulose are granulated by spraying in a fluidized bed granulator, with a granulation solution consisting of povidone and sodium lauryl sulphate, dissolved in water purified. The obtained granulate is dried in a fluidized bed dryer.

Grinding / Mixing The dry granulate is ground together with the crospovidone and the magnesium stearate. The mass is then mixed in a mixer of the conical screw type, for approximately ten minutes.

Encapsulation The hard, empty gelatin capsules are filled with the granules to be mixed in bulk under conical conditions of moisture and moisture. The powder is removed from the filled capsules, inspected visually, checked for weight and left in quarters until the quality department considers them safe.

FORMULATION EXAMPLE 5 Capsules The formulation is made, for example, as described in formulation example 4.

FORMULATION EXAMPLE 6 Hard gelatin capsule EXAMPLES 7 TO 11

Claims (7)

1 .- A combination, such as a combined preparation or a pharmaceutical composition, respectively, characterized because it comprises: (i), an anonymity of the TA receiver. or a salt of it, acceptable for pharmaceutical use; and (ii). the diuretic am iloride or friameerine, or a salt thereof, acceptable for pharmaceutical use; and (iii). another diuretic, or a salt of it, acceptable for pharmaceutical use.

2. A combination according to claim 1, further characterized in that it comprises: (i), valsaran, or a salt thereof, acceptable for pharmaceutical use; and (ii). amiloride, or a salt thereof, acceptable for pharmaceutical use; and (iii). hydrochloride, or a salt thereof, acceptable for pharmaceutical use.

3. A combination according to claim 1, further characterized because it comprises: (i), valso, and (ii). hydrochloride of amlloride, and (iii). hydrochlorothiazide.

4. A pharmaceutical composition, characterized in that it comprises a combination according to any of claims 1 to 3.

5. - A pharmaceutical composition for the prevention of, the progress in the progression of a disease or condition selected from the group consisting of: a) hyperfensis, congestive heart failure, resenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; b.) arteriosclerosis, resistance to insulin and syndrome X, diabetes mellitus type 2, obesity, nephropathy, hypohyroidism, survival after myocardial infarction (MI), coronary heart disease, hypertension in the elderly, dyslipidemic hyperlipidemia family, increased collagen formation, fibrosis and remodeling after hypertension (aniproliferative effect of the combination); all diseases or conditions associated with or without hypertension; c.) endothelial dysfunction, with or without hypertension; d.) hyperlipidemia, hyperlipoproteinemia, aerosol and hypercholesterolemia; e.) glaucoma; additionally: f.) isolated syphilis hyperintense (ISH); g.) Diabetic retinopathy; and h.) peripheral vascular disease; comprising: (i.) an AT receptor antagonist, or a salt thereof acceptable for pharmaceutical use; and (ii.) the diuretic amiloride or friameferine, or a salt thereof acceptable for pharmaceutical use; and (iii.) another diuretic, or a salt thereof acceptable for pharmaceutical use; and (iv.) an assistant.

6. The use of a combination comprising: (i), an anonymity of the ATj receptacle, or a salt of it acceptable for pharmaceutical use; and (ii). the diuretic amiloride or triameryrene, or a salt thereof acceptable for pharmaceutical use; and (iii). another diuretic, or a salt thereof acceptable for pharmaceutical use; for the manufacture of a medicament for the prevention of, the retardation of the advance of, the travaze of a disease or condition, selected from the group consisting of: (a), hypertension, congestive heart failure, resenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, hypophyroidism, survival after myocardial infarction (MI), coronary heart disease, hypertension in the elderly, familial dyslipidemic hypertension, increase of collagen formation, fibrosis and remodeling after hypertension (antiproliferative effect of the combination); all these diseases or conditions associated with or without hypertension; (c). endothelial dysfunction with or without hypertension; (d). hyperlipidemia, hyperlipoproineinemia, atherosclerosis and hypercholesterolemia; (and). glaucoma; additionally: (f). isolated systolic hypertension (ISH); (g) Diabetic retinopathy; and (h). peripheral vascular disease.

7. A method for the prevention of, the delay in the advancement of, or the eradication of, a disease or condition selected from the group consisting of: (a), hypertension, congestive heart failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) arteriosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, hypoiricism, survival to myocardial infarction (MI), coronary heart disease, hypertension in the elderly, familial dyslipidemic hypertension, increased training of collagen, fibrosis and remodeling after hyperlension (anti-proliferative effect of the combination); all these diseases or conditions, associated with or without hypertension; (c). endothelial dysfunction with or without hypertension; (d). hyperlipidemia, hyperlipoproteinemia, arteriosclerosis and hypercholesterolemia; (and). glaucoma; additionally: (f). isolated systolic hypertension (ISH); (g) Diabetic retinopathy, and (h). peripheral vascular disease; characterized in that it comprises administering to a warm-blooded animal, including a human, which needs it, amounts which are effective from the therapeutic point of view, of the following: (i), an anonymysia of the AT receptor or a salt of it acceptable for pharmaceutical use; and (ii). the diuretic amiloride or Iriameterine, or a salt of it acceptable for pharmaceutical use; and (iii). other diuretic, or a salt of it acceptable for pharmaceutical use.