MXPA98010056A - Formulation and method for dealing with insufficienciacardiac, congest - Google Patents

Abstract

This invention provides a method for treating congestive heart failure comprising administering an effective amount of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine in a non-immediate, oral release formulation. or implant and non-immediate release formulations

Description

FORMULATION AND METHOD OF DEALING WITH CARDIAC, CONGESTIVE INSUFFICIENCY Reciprocal Reference This application is a continuation in part of the application Serial No. 08 / 659,463, filed on June 6, 1996.

Field of the Invention The present invention is in the fields of pharmacology and pharmaceutical chemistry and provides formulations and a method for using 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine for treatment of heart failure, congestive.

Background of the Invention Congestive heart failure (CHF) can be defined as an inability of the heart to satisfy the metabolic demands of the periphery with sufficient blood for adequate nutrition and waste removal. The term describes a complex of complicated symptoms that may include dyspnea, fatigue, pulmonary congestion, a REF .: 28875 enlarged heart and peripheral edema. CHF is the end result of long-term or serious cardiac or circulatory deficits. This is frequently caused by lasting hypertension, acute myocardial infarction, vascular disease, idiopathic cardiomyopathy and a wide variety of secondary attacks. The incidence of CHF is increasing and is the most frequent cause of hospitalization in patients over 65 years of age. First in the syndrome, both cardiac and peripheral regulatory mechanisms come into play to help counteract the primary insufficiency of the pump. For example, the speed of the heart increases, the volume of the left ventricle and the pressure can rise and the heart can dilate and / or suffer hypertrophy (currently called a remodeling process). In the periphery, the volume of blood increases, sodium and water are retained and an increase in reflexes in the activity of the sympathetic nervous system increases the arterial and venous tone and increases the contractility of the heart. Mainly as a result of the increased activity of the sympathetic nervous system, a panoply of neurohormones are elevated in the plasma including: norepinephrine, renin, neuropeptide Y (NPY), angiotensin II, aldosterone, vasopressin and factor atrial natriuretic. These compensatory changes act together to maintain the perfusion of vital beds such as the brain and heart. Although these potent mechanisms may have been originally involved to protect against acute loss of blood volume (eg, hemorrhage), in the state of chronic CHF, continuous activation of compensatory mechanisms (especially the sympathetic system) may act to Prevent cardiac function, efficient by making it harder for the heart to expel blood. Furthermore, does the appropriate elevation of peripheral neurohormones contribute to the exacerbation of many of the symptoms of CHF such as pulmonary and peripheral edema, hyponatremia and dilutional hypokalemia. The activation of neurohormonal systems in particular can contribute to the maintenance of a positive feedback cycle that can perpetuate the cycle leading to further decay in the patient's condition. For example, increased sympathetic tone can lead directly to an increase in heart rate, myoclonus necrosis, and hypertrophy leading to increased myocardial remodeling, increased wall tension, and diastolic dysfunction resulting in failure from the heart. The increased activity of the sympathetic nervous system also stimulates the release of epinephrine, norepinephrine and renin which in turn further increases the impedance to ventricular ejection and decreases blood flow to the kidneys. The latter acts as an additional stimulus for the activation of the renin-angiotensin system, and the cycle is perpetual. Clinically, it is now well appreciated that patients with CHF have increased sympathetic activation and elevations in plasma concentration of norepinephrine and reifin, and that excessive elevations of neurohormones are an important prognostic factor. The complexity of the syndrome has allowed numerous pharmacological interventions to be explored. These vary from drugs that directly stimulate the heart such as digitalis, ß-agonists and phosphodiesterase inhibitors to compounds that directly relax the peripheral vasculature such as nitrates, certain calcium channel blockers, oc blockers and direct acting vasodilators, such as as hydralazine. However, the best results to date in the treatment of CHF have been achieved with agents that in some way act to interrupt the feedback loop. positive referred above. The inhibition of neurhormonal activation, excessive seems to be particularly beneficial. In this way, ACE inhibitors have been useful adjuncts or helpers for therapy and are now recommended for almost all patients with this disorder. Recent tests of β-blockers are especially intriguing since it was thought for a long time that direct interference with the compensatory function of the sympathetic nervous system to stimulate contractility and maintain blood pressure could aggravate CHF. In fact, the judicious use of such agents has proven to be beneficial especially in cardiomyopathy as opposed to ischemic heart disease. In addition, certain ß-blockers such as bucindolol and carvedilol can also decrease plasma renin and norepinephrine. However, the best paradigm of drug therapy has improved survival only by approximately 10-15% and total morbidity and mortality in CHF remains depressing. In fact, the production of norepinephrine in the CNS and the periphery in patients with CHF from the New York Heart Association Class III and IV was still markedly elevated with optimal therapy of digitalis and ACE inhibitors.

Many clinicians are beginning to consider CHF as a neurohormonal disorder. Therefore, an agent acting through the CNS to interrupt the sympathetic impulse and attend neurohormonal stimulation to the diseased heart and periphery could favorably influence the morbidity and mortality of patients with CHF. Interestingly, this hypothesis has never been adequately analyzed. Clonidine was examined in a clinical trial, but only 13 patients were registered and the duration of treatment was relatively short (12 weeks), Giles et al., Angiology, 38, 537-548 (1987). However, courses were reported f--. orables including reductions in heart rate, increase in ejection fraction and improvement in functional status. Based on what is now known about the importance of local and systemic activation of the sympathetic nervous system in the pathophysiology of CHF, moxonidine has been suggested as a potentially beneficial therapeutic agent, Magiapane et al., FASEB, 9, 265 (1995), Michel et al., J. Cardiovasc. Pharmacol., 20, Supp. 4,524-530 (1992).

Elevated systolic and diastolic blood pressure are major risk factors for cardiovascular disorders such as myocardial infarction, coronary artery disease, and stroke. While it is well recognized that hypertension is particularly related to the risk of stroke, it is less appreciated that hypertension is also an important risk factor for coronary heart disease; equally important as elevated serum lipids. Hypertension is generally defined as an elevation of systolic and / or diastolic blood pressures to approximately 140/90 mm Hg and is the most common cardiovascular disease. In the United States alone, approximately 20-40 million people require treatment for hypertension. The currently available therapies include converting enzyme inhibitors, diuretics, vasodilators, beta blockers, central antisympathetic agents, and Ca ++ channel antagonists. Blood pressure is a function of vascular resistance, intravascular volume, cardiac output and the contractile state of blood vessels. Many physiological systems are involved in the regulation of intravascular volume homeostasis, mainly through the renal excretion of salt and water. Cardiac output is regulated by both cardiac, intrinsic and extrinsic factors and the sympathetic nervous systems. The contractile state of the blood vessels is determined by the intrinsic vascular factors, the sympathetic nervous system, the endothelial cell relaxation factors, the angiotensin renin system (RAS) and the fluid balance. The RAS is the main means by which the body controls the fluid, electrolyte balance and blood pressure. It is part of a complex homeostasis mechanism that involves a variety of hormones, enzymes, and autonomic signals. The final, physiological, key product of RAS is octapeptide Angiotensin II. The physiological activation of the RAS can be observed as a highly developed yet primitive system evolved to protect the body against sudden loss of blood volume or more gradual loss of sodium. In this way, Angiotensin II increases the perfusion pressure of the vital beds and promotes the readsorption of sodium and water. The last effects occur through the action of aldolesterone and vasopressin in the kidney.

The overactivity of the local RAS may be responsible for the final organ abnormalities associated with chronic hypertension. For example, Angiotensin II is known to be an important mediator of the development and differentiation of smooth muscle cells. In this way, Angiotensin II can mediate the proliferative, vascular response that accompanies the lesion to the vessel wall by mechanical means (ie angioplasty) or long-term elevated systemic pressure. As noted previously, Angiotensin II is an important regulator of glomerular function and the overactivity of RAS is undoubtedly an important factor in the development and progression of kidney diseases such as diabetic nephthy and hyperfiltration glomerulonephthies. The two enzymes, the queen and the enzyme that converts angiotensin (ACE), are mainly responsible for the generation of Angiotensin II and are widely distributed throughout the body. Although resin and prorenin are synthesized in juxtaglomerular cells (JG) of the kidney and are released into circulation, the most recent data strongly suggest a wider distribution. For example, renin and / or its mRNA are found in the brain, blood vessels, anterior pituitary, Adrenal cortex, kidney, ovary, uterus and heart. Renin is subject to inhibition of feedback by Angiotensin II as well as elevated glomerular pressures and an increase in sodium load. ACE is a dipeptidyl carboxypeptidase found primarily in association with the capillary lining of the lung. Similar to renin, it is also widely distributed, which is located in the blood vessels, heart, kidney, intestinal tract, and liver. AACE mediates the removal of the terminal dipeptide from Angiotensin I and also catalyzes the production of bradykinin. In the synthesis of Angiotensin II, ACE is not a factor that limits speed. In addition, it lacks specificity, requiring only a tripeptide sequence with a free carboxy group (since the intermediate amino acid is not proline). Consequently, a variety of endogenous peptides are substrates for the enzyme that includes enkephalins, substance P and Lys-bradykinin. The release of renin from juxtaglomerular cells (JG) in the kidney is inhibited by a direct action of Angiotensin II on JG cells. Angiotensin II also stimulates the secretion of aldosterone that increases the retention of sodium and increases the excretion of potassium in the kidney. With increased sodium retention, the intravascular volume increases and thus inhibits renin secretion. These feedback loops are divided into long (volume), short (Angiotensin II circulation), and ultra-short (Angiotensin II within JG cells). Many pharmacological interventions are activators or inactivators of renin secretion. Specifically, many drugs used in the treatment of high blood pressure directly or indirectly alter the secretion of renin. This effect may counteract or increase the effect of the medicine used to treat high blood pressure. Renin and angiotensinogen are also found in the walls of the vessel and in the brain. This has been termed as the extra renal renin-angiotensin (RAS) system. In this way, low levels of renin and the non-sensitivity or response to renin secretion to physiological stimuli in hypertensive patients can be obscured by the presence of an extravascular, very active renin system.

Agents that interfere with the angiotensin renin system have been used for 15 years to treat hypertension. The inhibitors of the enzyme that converts Angiotensin (ACE) clinically and therapeutically most successful were introduced into the commercial world about 14 years ago and have been a support in the treatment of mild hypertension to grav. These are used either as single agents or in combination with diuretics (which considering the physiology of the angiotensin renin system is rational). This is because the volume and depletion of salt tends to increase renin secretion (as a volume control), in this way the inhibition of the angiotensin system would lower the blood pressure even more. In 1991, moxonidine, a centrally acting antihypertensive agent, was approved in Germany. The search in the pharmacology of the receptor showed that moxonidine is a selective agonist in the imidazolinium receptors in the centrolateral medulla. The use of predominant alpha2-adrenoceptor agonists, such as clonidine, although useful, showed a high proportion of side effects, such as sedation, dry mouth, and other non-specific effects. These side effects are explained by a stimulation of the pre- and post-synaptic alpha2-adrenoceptors within the CNS. Additional investigations showed that drugs that act centrally similar to clonidine and moxonidine develop their antihypertensive action through binding to imidazoline receptors, while side effects are induced by action on alpha2-receptors. The differences between moxonidine and clonidine in clinical tolerability are explained by the greater selectivity of moxonidine for imidazoline receptors pref erably than alpha2-receptors. Having been approved in Germany since 1991, there is clearly extensive clinical experience with moxonidine administered in an immediate-release formulation. Moxonidine is almost completely absorbed from the gastrointestinal tract (absorption> 90%). The bioavailability is 88%, and the drug does not accumulate with repeated administration. Simultaneous food consumption does not have a significant effect on the absorption or bioavailability of moxonidine. The plasma half-life (t? / 2) is between 2 and 3 hours. The concentration in the plasma, maximum (Cmax) after the consumption of 0.2 mg of moxonidine is 1-3 ng / ml. The level in the plasma, maximum occurs in 30 - 180 minutes. The duration of the antihypertensive effect (up to 24 hours), in contrast to the plasma half-life, may be due to the slower clearance of moxonidine from its central sites of action (deep compartment). Moxonidine has low plasma protein binding of 7% and is eliminated over 60% without changing by the renal route. In patients with impaired renal function, the concentration in the peak plasma (Cmax), the half-life in the plasma and the area under the plasma concentration curve from 0 to 24 hours (AUC0-24) increase, but does not occur accumulation. Moxonidine has turned out to be a very well tolerated antihypertensive drug. As a typical side effect, dry mouth occurred in 2 - 15% of patients but usually improved with treatment progress. Other side effects similar to fatigue, headache and fading appeared in only a few patients. After acute administration, moxonidine decreased plasma levels of norepinephrine and epinephrine, and decreased plasma renin activity. Moxonidine has no influence on the circadian rhythm of blood pressure. The rebound phenomenon was not observed after cessation of treatment. Moxonodine is a well-tolerated antihypertensive agent alone and in combination with other antihypertensive drugs, such as diuretics, calcium antagonists and ACE inhibitors. It has been shown that moxonidine is a suitable medication for hypertensive impulses. It is neutral with respect to metabolic parameters and does not cause respiratory depression, which is important in the antihypertensive treatment of asthmatic patients. In clinical studies, 0.2 - 0.4 mg of moxonidine has been an effective daily dose range, with reductions in blood pressure4, between 10 and 20%. The antihypertensive efficacy of moxonidine was confirmed in open studies of up to 2 years as well as in comparative studies lasting up to 6 months. In one of the more recent studies, moxonidine was administered in doses of 0.2 mg once a day or 0.2 mg twice daily, while the decrease in baseline blood pressure was 27/19 or 29/15 mmHg , respectively. A similar blood pressure reduction of 27/16 mmHg was obtained in 49 patients after two years demonstrating that the antihypertensive effect of the dose does not diminish with time, that is, tolerance does not develop.

In 141 patients undergoing the 12-month treatment, where the dosage was individually triturated to obtain a target diastolic pressure of < 95 mmHg, the average blood pressure fell from 173/103 to 151/88 mmhg. Effectively treated 82 patients (58.2%) with 0.2 mg of moxonidine once a day, 53 patients (37.6%) needed 0.2 mg of moxonidine once a day, in addition: 1 patient 0.1 mg daily; 4 patients: 0.6 mg per day; 1 patient: 0.8 mg per day. Control of blood pressure occurred mainly within three weeks of the start of moxonidine therapy and was consistently maintained throughout the one-year study period. In a continuous observation study in 9295 hypertensive patients, moxonidine was an effective and safe hypertensive agent which improves the quality of life. After a treatment period of 12 weeks, the blood pressure decreased and the heart rate was reduced slightly by 3 beats / minute. The parameters of clinical laboratories remained unchanged, except for slight reductions in uric acid, glucose, triglyceride and cholesterol. Side effects were reported in 6.9% of patients. According to the results of the Framingham Heart Study, the hypertrophy of the ventricle left due to hypertension is the most common reason for CHF with poor prognosis. Desirably, an antihypertensive drug must induce the regression of myocardial hypertrophy, which often leads to heart failure. There is some evidence that therapeutic regimens, which lead to a decrease in growth factors, ie, norepinephrine and angiotensin II, induce regression of left ventricular hypertrophy. In a smaller study, the antihypertensive effect and the regression of left ventricular hypertrophy were evaluated in 20 hypertensive patients. After a 6-month therapy with moxonidine, the blood pressure was lowered and the thickness of the septal of the left ventricle was significantly reduced from 22.5 mm to 19.1 mm (average). Drugs, especially ACE inhibitors, used in the treatment of hypertension are increasingly important in the treatment of congestive heart failure. These drugs generally have peripheral sites of action and therefore cause counter-regulatory effects in the form of increased sympathetic activity or stimulation of the renin-angiotensin-aldosterone system.

The autoregulatory cardiovascular system counteracts the changes induced by the drug with the mechanisms of compensatory reflexes. Drugs that act centrally prevent compensatory counter-regulation, particularly the increase in sympathetic tone, which may play a role in the pathogenesis and maintenance of hypertensive organ disorders. In view of the increased sympathetic activity in the majority of hypertensive patients and in patients with congestive heart failure, it seems reasonable to control both indications with drugs that act centrally. Moxonidine reduces vascular, systemic resistance while increasing cardiac output in hypertensive patients. These hemodynamic changes can have beneficial effects in patients suffering from congestive, symptomatic heart failure. In a four-week open therapy study in patients with hypertension, essential or congestive heart failure, patients received 0.2 - 0.4 mg of moxonidine daily in the immediate-release formulation, commercially available as monotherapies or in addition to another medication . The blood pressure and the ejection fraction of the left ventricle were determined in rest and during exercise, after acute administration of 0.1 mg of moxonidine and after a treatment period of four weeks. Six patients with CHF were described as casuistic. In two patients, the ejection fraction worsened. One of them showed poor results after the acute administration of the drug and did not undergo chronic therapy. In two patients, the results basically did not change. One patient showed a clear improvement in acute administration and in chronic treatment as well. Another patient who also suffered from high blood pressure showed only a slight improvement in the ejection fraction of the left ventricle due to moxonidine therapy, but hypertension was well controlled so that the patient continued therapy with 0.2 mg b.i.d. moxonidine There was no uniform response to treatment with moxonidine in these patients. In the single dose study, moxonidine was administered as the immediate release formulation, commercially available to determine the effects on hemodynamics and hormones involved in hemodynamic regulation at rest and during exercise in patients suffering from congestive heart failure .

Ten patients, all suffering from congestive heart failure (NYHA class III) were included in an open-label study. Moxonidine was administered as an oral, individual dose of 0.4 mg. The hemodynamic and neurohumoral parameters at rest and during exercise were investigated before, as well as 1, 2 and 3 hours after drug consumption. The rates of pulmonary pressure and cardiac output were determined both at rest and during ergometric exercise by means of Swan-Ganz catheterization. A There were no relevant, clinical alterations in the right ventricular and pulmonary pressure indexes. The cardiac output and heart rate fell slightly while the volume of the apoplectic attack increased. We observed insignificant reductions, statistics on both systemic and pulmonary vascular resistance at rest and during exercise after consumption of moxonidine. In those normotensive patients, the blood pressure stopped in a time-dependent manner both at rest and in maximal exercise. With regard to neurohumoral effects, a decrease in plasma renin activity was observed, both at rest and during maximal exercise.

Severe decreases in plasma levels of norepinephrine at rest or during exercise have been observed, so only minor reductions in plasma epinephrine were recorded. There were also remarkable decreases in plasma levels of angiotensin II after consumption of moxonidine. No relevant changes of aldosterone and ANF were recorded in the plasma in this individual dose test. These findings indicate that moxonidine has no detrimental effects on hemodynamic parameters in patients with congestive heart failure. While the cardiac output and the volume of the stroke remain virtually unchanged, the pressure indexes tend to decrease. After an oral, acute administration of moxonidine, a neurohumoral counter-regulation has not been observed. In the evaluation of adverse cases and laboratory parameters, moxonidine was safe and well tolerated in patients with heart failure after a single dose of 0.4 mg. It has been unexpectedly discovered that the administration of the current commercial formulation (mediated release) of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine, moxonidine, produces a reduction of unacceptable oscillation in sympathetic activity in patients with CHF. A large, but transient reduction was observed 1-3 hours after dosing. Both the intensity and the short duration of the peak effect are undesirable. Clearly, the potential efficacy of moxonidine as a therapeutic agent for congestive heart failure will not be obtained unless the peak intensity can decrease and the duration of action can be extended without producing the problems inherent in a multiple dosing regimen. I do not know, I could have predicted in view of the cumulative clinical and laboratory experience with moxonidine in hypertension, as well as the limited experience in patients with congestive heart failure, that the administration of the present commercial formulation of moxonidine Patients with CHF would fail to produce a more sustained reduction in sympathetic activity.

Brief Description of the Invention The presently claimed invention provides a method for treating congestive heart failure which comprises administering to a mammal in need of such treatment an effective dose of moxonidine, or a pharmaceutically acceptable salt thereof, in a non-immediate release formulation. The invention also provides pharmaceutical formulations comprising an effective dose of moxonidine, or a pharmaceutically acceptable salt thereof, in association with one or more carriers, diluents or excipients to give the non-immediate release of the moxonidine. The present invention further provides a method and formulations to give a plasma elimination period, averaging from 6 to 16 hours. In addition, the present invention provides a method and formulations to give an average time to plasma concentration, maximum 2.5 to 5 hours.

Detailed Description of the Invention The compound 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine (moxonidine) is known and described in U.S. Patent No. 4,323,570 which is incorporated herein by reference in its entirety. The compound 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine is generally prepared as described in U.S. Patent No. 4,323,570. In Preferably, 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine is prepared as follows.

Azm • Cf HCl NH acetamidine hydrochloride, Diethyl malonate 4, 6-Dihydroxy-2-methylpyrimidine HjNOa, CH3COOH (smoking) -methyl-5- 4,6-Dichloro-2-methyl-5- nitropir imi dina , Raaßy-N ± -Amino-4,6-dichloro-2-methylpyrimidine N-Acetylimidazolin-2-one N- (1-Acetylimidazolin-2-ylidene) -4,6-dichloro-2-methyl-5-pyrimidinamine CH 3 OH .Cl 4-Chloro-N- (imidazolidin-2-c-Q-ylidene) -6-methoxy-2-methyl-O-C "H-, 0H 5-pyrimidinamine The N-acetylimidazolin-2-one is prepared by reacting acetic anhydride with 2-imidazolidone at room temperature. The reaction mixture is heated to between 80 ° C and 100 ° C for 90 minutes and then cooled from 10 ° C to about -10 ° C to give the N-acetylimidazolin-2-one. The first intermediate, 4,6-dihydroxy-2-methylpyridimidinamine, is synthesized by preparing sodium ethoxide in situ from sodium and anhydrous ethanol under a blanket of nitrogen. The acetamidine hydrochloride and diethyl malonate are added and the reaction mixture is heated to boiling for 2 to 5 hours to give 4,6-dihydroxy-2-methylpyrimidine. The second intermediate, 4,6-dihydroxy-2-methyl-5-nitropyrimidine, is then synthesized by slowly adding 4,6-dihydroxy-2-methylpyrimidine to a reaction mixture of fuming nitric acid in acetic acid. Once the addition of 4,6-dihydroxy-2-methylpyrimidine is completed, the reaction mixture stir for half an hour to 2 hours to give 4,6-dihydroxy-2-methyl-5-nitropyrimidine. After nitration, phosphorus oxychloride (P0C13) and 4,6-dihydroxy-2-methyl-5-nitropyrimidine are combined with stirring. To this mixture, the diethylaniline is added dropwise at a rate so that the temperature of the reaction mixture is kept below about 40 ° C. After the addition is complete, the reaction mixture is refluxed for one to three hours and then distilled under a vacuum to give the third intermediate, 4,6-dichloro-2-methyl-5-nitropyrimidine. The third intermediate, 4,6-dichloro-2-methyl-5-nitropyrimidine is hydrogenated over Raney-Ni as a 10% to 30% solution in toluene to give the corresponding compound, 4,6-dichloro-2-methyl- 5-aminopyrimidine, as a fourth intermediate or bradykinin. The fifth intermediate, N- (l-acetylimidazolin-2-ylidene) -4,6-dichloro-5-pyrimidinamine, is then prepared by combining phosphorus oxychloride, N-acetylimidazolin-2-one and 5-amino-4 , ß-dichloro-2-methylpyrimidine, and on heating to boiling for 2 to 4 hours, and then on cooling, with stirring at room temperature.

The final product, 4-chloro-N- (imidazolin-2-ylidene) -6-methoxy-2-methyl-5-pyrimidinamine, is synthesized by first preparing sodium methoxide in situ from anhydrous methanol and sodium. The fifth intermediate, N- (1-acetylimidazolin-2-ylidene) -4,6-dichloro-2-methyl-5-pyrimidinamine, is added and the reaction mixture is brought to a boil. From 15 minutes to 1 hour after the reaction mixture is boiled, in addition the sodium methoxide is added and the reaction mixture is boiled for 15 minutes at 1 hour to give -chloro-N- (imidazolin -2-ylidene) -6-methoxy-2-methyl-5-pyrimidinamine. The preparation of the various intermediates is carried out by standard techniques well known to those skilled in the art. The various reactants and reagents used in this synthesis are commercially available or readily prepared from commercially available material by standard methods well known to those skilled in the art. It will be appreciated that the compound of the present invention can be isolated per se or can be converted to an acid addition salt using conventional methods. As mentioned above, the invention includes pharmaceutically acceptable salts of moxonidine. The moxonidine can react with any of a number of non-toxic inorganic and organic acids, to form a pharmaceutically acceptable salt. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid , p-bromophenyl sulfonic acid ^ - carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Thus, examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulphonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, gamma- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as clohydric acid, brohydric acid and sulfuric acid. By the term "effective dose" is meant an amount of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine, or a pharmaceutically acceptable salt thereof, which will decrease or alleviate one or more symptoms or conditions associated with heart failure, congestive, hypertension or both. The term "treatment" as used herein, includes curative and prophylaxis of symptoms and named condition and improvement or elimination of the condition once it has been established. The "plasma elimination period" refers to a time required after the administration of an individual dose to reduce the amount of moxonidine in the plasma by 50 percent. Sometimes, the period of plasma removal will be referred to herein as t? / 2. The "time for maximum concentration in plasma" refers to the time required after administration of a single dose for moxonidine to achieve maximum concentration in the plasma. Unless stated otherwise, "average" when associated with the period of plasma removal and time for maximum concentration in plasma refers to the geometric average of the established values. The procedures for determining the plasma concentrations of moxonidine are described below. The compound of the present invention is an Ii-imidazoline ligand that demonstrates substantial selectivity for the Ii receptors on a2 adrenergic receptors. In the saturation binding experiments in the ventrolateral, bovine rostral (RVLM of bovine) marrow, moxonidine demonstrates a selectivity value (Ki sites at 2 in uM / Ki at sites l in uM) of greater than 20 and in preferred form greater than 30 X, where Ki is the inhibitory affinity constant. Of course, Ki is inversely proportional to the affinity, so that lower Ki values indicate greater affinity. In this way, the higher the selectivity value, the more selective the compound will be. In contrast, the selectivity value of clonidine in the RVLM of cattle is less than 4. See Ernsberger et al., J. Pharmacol. Exp. Ther., 264, 172-182 (1993) for details in the experimental protocol and results.

As used herein, the term "mammal" means the Mammalia class of higher vertebrates. The term "mammal" includes, but is not limited to, a human. The dose of the compound to be administered, in general, is from about 0.001 to about 5.0 mg / day; As usual, the daily dose can be administered in an individual bolus or in divided doses, depending on the judgment of the physician or physician in the case load. A more preferred range of doses is from about 0.01 to about 2.0 mg / day; other ranges of doses which may be preferred in cin circumstances are from about 0.005 to about 2.0 mg / day; from about 0.1 to about 2.0 mg / day; from about 0.05 to about 0.8 mg / day; and a particularly preferred range is from about 0.05 to about 2.0 mg / day. It will be understood that the dose for a given patient must always be adjusted by the judgment of the attending physician or physician, and that the dose is subject to modification based on the patient's size, the skinny or oily nature of the patient, the characteristics of the particular compound (free base or salt) selected, the severity of the patient's symptoms and psychological factors that may affect the physiological responses of the patient.

The pharmaceutical substances are substantially always formulated in pharmaceutical dosage forms, in order to provide an easily controllable dose of the drug, and to give the patient an elegant and easily manageable product. While it is possible to administer 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine directly, it is preferably employed in the form of a pharmaceutical formulation of sustained (non-immediate) release comprising one or more pharmaceutically acceptable carriers, diluents or excipients and the compound or a pharmaceutically acceptable salt thereof. Such formulations will contain, by weight, from about 0.01 percent to about 99 percent of the compound. In making the formulations of the present invention, the active ingredient will usually be mixed with at least one carrier, or diluted by at least one carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container using conventional techniques and methods for the preparation of pharmaceutical formulations. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient. In this way, the formulations may be in the form of tablets, granules, pills, powders, lozenges, sachets, seals, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium) and gelatin capsules soft or hard Examples of suitable carriers, diluents and excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, liquid paraffin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propyl-hydroxybenzoates, vegetable oils, such as olive oil, injectable organic esters such as ethyl oleate, talc, magnesium stearate, water and mineral oil. The formulations may also include wetting agents, lubricants, emulsifiers and suspending agents, preservatives, sweetening agents, perfume agents, stabilizing agents or flavoring agents. The formulations of the invention are formulated to provide for the non-immediate release of the active ingredient, by methods well known in the art. The formulations of the present invention are formulated for provide for the non-immediate release of the active ingredient for oral or implantable administration. In non-immediate release dosage forms, the release of the drug from its dosage form is the rate limiting step in the kinetic scheme of release-absorption-elimination. This is distinguished from the immediate release dosage forms where absorption of the drug through the biological membrane is a rate limiting step. Systems to provide non-immediate release have been divided into four categories: (1) delayed release; (2) sustained release; (3) site-specific release; and (4) receptor release. In general, delayed release systems are those that employ the intermediate, repeating dosing of a drug of one or more immediate release units incorporated in a single dose form. Examples of the delayed release systems include tablets and capsules of repeated action. and tablets with enteric coatings where synchronized release is achieved by a barrier coating. Sustained-release delivery systems include both controlled release and prolonged release. In general, sustained release systems include any drug delivery system that achieves a slow release of the drug over an extended period of time. When the system maintains relatively constant drug levels in the blood or target tissue, it is considered a controlled release system. Where the system extends the duration of action over that given by a conventional supply system, it is considered a prolonged release system. The "site-specific" and "receptor-specific" delivery systems refer to the targeting of a drug directly to a desired biological location. In the case of site-specific release, an objective is a particular organ or tissue. Analogously, in the case of receptor release, the target is the particular receptor for the drug within the particular organ or tissue. The forms of non-immediate, oral, typical release include diffusional systems and dissolution systems. In diffusional systems, the rate of release of the drug is determined by its diffusion through a polymer insoluble in water. In general, there are two types of diffusional devices, reservoir devices in which a drug core is surrounded by a polymeric membrane; and matrix devices in which the dissolved or dispersed drug is distributed substantially uniformly and throughout an inert polymer matrix. In current practice, many systems that use diffusion may also depend to some degree on dissolution to determine the rate of release. Common practices, used in deposit systems, include the microencapsulation of drug particles and the pressure coating of complete tablets or particles. Frequently, the particles coated by microencapsulation form a system where the drug is contained in the coating film as well as in the core of the microcapsule. The release of the drug typically includes a combination of dissolution and diffusion with the solution which is the process that controls the rate of release. The common material used as the barrier coating of the membrane, alone or in combination, are hardened gelatin, methyl and ethylcellulose, polyhydroxymethacrylate, hydroxypropylcellulose, polyvinyl acetate, and various waxes.

In matrix systems, three main types of materials are frequently used in the preparation of matrix systems that include insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices, which have been employed, include methyl acrylate-methyl methacrylate, poly-nyl chloride and polyethylene. Hydrophilic polymers include methyl cellulose, hydroxypropylmethylceulose and sodium carboxymethylcellulose. The fatty compounds include various waxes such as carnauba wax and glyceryl triesterate. The preparation of these matrix systems is by methods well known to those skilled in the art. These preparation methods generally comprise mixing the drug with the matrix material and compressing the mixture into tablets. With the wax matrices, the drug is generally dispersed in molten wax, which is then frozen, granulated and compressed into nuclei. As with other non-immediate systems, it is common for a portion of the drug to be immediately available as a first dose and the rest to be released in a sustained form. This is generally done in the matrix system by placing a first dose in a coating on the tablet. The coating can be applied by coating by pressure or by coating with conventional or air suspension vessels. Dissolution systems in general are products that have a decreased dissolution rate where the drug is highly soluble. The various approaches to achieve a low dissolution rate include preparing an appropriate salt or derivative of the active agent, by coating the drug with a slowly dissolving material or by incorporating the drug in a tablet with a slowly dissolving carrier. The encapsulated dissolution systems are prepared either by coating particles or drug granules with varying thicknesses of slowly soluble polymers or by microencapsulation. The most common method of microencapsulation is coacervation, which involves the addition of a hydrophilic substance to a colloidal dispersion. The hydrophilic substance, which operates as the coating material, is selected from a wide variety of natural and synthetic polymers including shellac, waxes, starches, cellulose acetate, phthalate or butyrate, polyvinylpyrrolidone, and polyvinyl chloride. After the coating material dissolves, the drug within the microcapsule is immediately available for dissolution and absorption. Thus, the release of the drug can be controlled by adjusting the thickness and dissolution rate of the coating. For example, the thickness can be varied from less than one μm to 200 μm by changing the amount of the coating material from about 3 to about 30 weight percent of the total weight. When using different thicknesses, typically three out of four, the active agent will be released at different predetermined times to give a delayed release affection. Of course, the coated particles can be compressed directly into tablets or placed in capsules. Matrix dissolution systems are prepared by compressing the drug with a polymer carrier that dissolves slowly in a tablet. In general, there are two methods for preparing drug-polymer particles, freezing and aqueous dispersion methods. In the freezing method, the drug is mixed with a polymer or wax material and either cooled or cooled and sieved or spray-frozen. In the aqueous dispersion method, the drug-polymer mixture is simply sprayed or placed in water and the resulting particles are collected. Osmotic systems are also available where osmotic pressure is used as a driving force to release a drug. Such Systems generally consist of a drug core surrounded by a semipermeable membrane that contains one or more orifices. The membrane allows the diffusion of water within the nucleus, but does not allow the release of the drug except through the holes. Examples of materials used as the semipermeable membrane include polyvinyl alcohol, polyurethane, cellulose acetate, ethylcellulose, and polyvinyl chloride. An additional system comprises ion exchange resins. These resins are crosslinked, water soluble polymers containing salt formation groups in repeat positions in the polymer chain. The active agent is bound to the resin by repeated exposure of the resin to the drug in a chromatographic column, or by prolonged contact of the resin with a solution of the drug. The release of the drug from the drug-resin complex depends on the ionic environment; which is the pH and the concentration of electrolytes within the gastrointestinal tract, as well as the specific properties of the resin. The drug molecules bound to the resin are released by changing with appropriately charged ions in the gastrointestinal tract followed by infusion of the free drug molecule out of the resin. In general, the speed of diffusion is controlled by the diffusion area, the union of the disfusional trajectories, and the degree of crosslinking in the resin. A further modification of the release rate can be given by coating the drug-resin complex. The most common types of dosage forms used for non-immediate, parenteral drug therapy are intramuscular injections, implants for subcutaneous tissues and various body cavities, and transdermal devices. In general, intramuscular injections involve the formation of a dissociable complex of one drug with another molecule. In this regard, the drug-molecule complex serves as a reservoir at the injection site for the release of the drug to the surrounding tissues. Examples of macromolecules include biological polymers such as antibodies and proteins or synthetic polymers such as polyvinylpyrrolidone, and polyethylene glycol. The complexes can also be formed between drugs and small molecules. When the drug molecule is large relative to the complex agent, the constant association will be greater and the complex more stable. Examples for the smaller molecules include zinc, optionally suspended in a gelatine solution or an oily solution. An alternative dosage form for an intramuscular injection is an aqueous suspension. By varying the viscosity and the particle size a stable suspension of the active ingredient can be given. Another common approach for the decreased dissolution rate is to decrease the saturation solubility of the drug. This is done through the formation of less soluble salts and prodrug derivatives and by using polymorphic crystal forms of the active ingredient. 4. Another approach is the use of oily solutions and oily suspensions. As will be appreciated by those skilled in the art, those drugs that have appreciable oil solubility and the desired splitting characteristics are more suitable for this approach. Examples of oils that can be used for intramuscular injection include sesame, olive, peanut, corn, almond, cottonseed and castor oil. With oil suspensions, the drug particles must first be dissolved in the oil phase and then split in the aqueous medium.

Emulsions comprising oil-in-water emulsions or water-in-oil emulsions can also be used. The implants comprise a polymeric barrier device for the drug which is inserted subcutaneously or into several body cavities. The polymeric material which is used, of course, it must be biocompatible and non-toxic and are typically selected from among hydrogels, silicones, polyethylenes, ethylene-vinyl acetate copolymers, and biodegradable polymers. 4 Hydrogels in general are a polymeric material that exhibits the ability to swell in water and retains more than 20 percent of that water within its structure, but which does not dissolve in water. Small molecular weight substances are capable of diffusion through hydrogels. A specific example of hydrogels includes polyhydroxyalkyl methacrylates, polyacrylamide and polymethacrylamide, polyvinylpyrrolidone, polyvinyl alcohol, and various polyelectrolyte complexes. Additional, implantable systems include subcutaneous devices and intravaginal devices. The percutaneous absorption of the drug, more commonly referred to as transdermal systems, in General includes the use of micro-membrane membranes as the barrier that controls the speed. Microporous membranes are films that vary in thickness with pore sizes ranging from several micrometers to a few angstroms. Examples of the material from which such membranes are made, include regenerated cellulose, nitrates / cellulose acetate, cellulose triacetate, polypropylene, polycarbonate and polytetrafluoroethylene. The barrier properties of these various films depends on the method of preparation, the medium with which the pores are filled, the pore diameter, percent porosity and tortuosity. An example of a transdermal system is described in U.S. Patent No. 4,201,211. Target delivery systems include nanoparticles and liposomes. Nanoparticles are examples of systems collectively known as colloidal drug delivery systems. Other membranes in this group include microcapsules, nanocapsules, macromolecular complexes, polymeric beds, microspheres and liposomes. In general, a nanoparticle is a particle containing dispersed drug with a diameter of 200-500 nm. The materials used in the preparation of the nanoparticles are sterilizable, non-toxic and biodegradable. Examples they include albumen, ethylcellulose, casein and gelatin. Typically, these are prepared by procedures similar to the microencapsulation coacervation method. Liposomes, in general, are phospholipids that when dispersed with aqueous media swell, hydrate and form two-layered, concentric, multilamellar vesicles with layers of aqueous media separating the bilayers from the lipids. Phospholipids can also form a variety of structures different from liposomes when they are dispersed in water depending on the molar ratio of lipid and water. In low ratios, the liposome is the preferred structure. The physical, real characteristics of liposomes depend on pH, ionic strength and the presence of divalent cations. These show low permeability to ionic substances and polar substances but at elevated temperatures they undergo a phase transition which alters their permeability. Polar drugs are trapped in the aqueous spaces and non-polar drugs bind to the bilayer of the vesicle lipid. Polar drugs are released when the bilayer is broken or by permeation, but nonpolar drugs remain afliate with the bilayer until it is disrupted by temperature or exposure to the drugs. lipoproteins. Of course, the liposome acts as the carrier or the active agent. Depending on the method of administration, the formulations of the present invention can be formulated as non-immediate (i.e. sustained) release tablets, capsules, injection solutions for parenteral use, gel, suspensions or elixirs for oral use or suppositories. Preferably, the compositions are formulated in a unit dose form, each dose containing an amount of active ingredient suitable to be given to a subject of 0.01 to 3.0 mg, more usually 0.05 to 2.0 mg, of the active ingredient. The term "unit dose form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired or prophylactic therapeutic effect, related to the desired daily or divided dose, in association with one or more suitable pharmaceutical carriers, diluents or excipients thereof to give sustained release of the active agent. With the sustained release formulation, the unit dosage form may contain from 0.01 to 5.0 mg of the active ingredient. A preferred formulation of the invention is a non-immediate, oral or implantable release formulation comprising 0.01 to 3.0 mg or 0.05 to 2.0 mg of active ingredient in conjunction with a pharmaceutically acceptable carrier therefor in a unit dosage form. A non-immediate release formulation, oral is more preferred. The non-immediate release formulations of the present invention should provide a prophylactic or therapeutic amount of moxonidine to a patient to achieve, and then maintain, an effective dose of the active agent with decreased undesirable effects. These formulations must achieve a more idealized spatial placement and the temporary supply of moxonidine, a particularly temporary supply. Of course, spatial placement refers to targeting a pharmaceutical agent for a specific organ or tissue while temporary delivery refers to controlling the rate of drug delivery. The non-immediate release formulations of the present invention should give one or more of the following advantages over known immediate release formulations: 1) minimize or eliminate problems of patient compliance; 2) use less total active agent; 3) minimize or eliminate local side effects; 4) Minimize or eliminate effects secondary systemic; 5) give less activity increase or reduction in activity of the active agent with chronic use; 6) minimize the accumulation of the active agent with chronic use; 7) improve the effectiveness in the treatment; 8) control of the condition more quickly; 9) reduce the fluctuation in the level of the drug giving an improved control of the condition; and 10) the economy. Of course, the obedience of the patient is a necessary and important component in the success of all the therapy of the self-administered drug. It is anticipated that the non-immediate release formulations of the present invention will give more constant levels of the drug. In healthy humans, a geometric average for time to maximum concentration in plasma (tmax) should be from 2.5 hours to approximately 5.0 hours, preferably 2.5 to 4.0 hours, with a plasma elimination duration, geometric average of approximately 6.0 hours at approximately 16.0 hours, preferably 7.0 -15.0 hours. In this way, the unit dose forms, of non-immediate release, described herein, are used, once or twice a day administration is contemplated.

Moxonidine is currently and commercially available in at least Germany and Austria as immediate release dosage tablets of 0.2, 0.3 and 0.4 mg as an antihypertensive agent. The complete formulation of the currently marketed 0.3 mg tablet is discussed below. For the 0.2 mg and 0.4 mg tablet, the amount of lactose is adjusted to accommodate the content of the higher or lower active ingredient.

FORMULATION - PRODUCT DESCRIPTION The film coated tablet, pale red of 105 mg containing 0.3 mg of moxonidine as an active ingredient. Active Ingredients [mg] Moxonidine 0.30 Other Ingredients Lactose 95,700 Povidone 0.700 Crospovidone 3.000 Magnesium Stearate 0.300 Hydroxypropyl Methylcellulose 2910 1,300 Ethylcellulose Acuosa 1,200 Polyethylene Glycol 6000 0.250 Talc 0.975 Red Ferric Oxide 0.025 Titanium Dioxide 1.250 The commercial, current formulations of moxonidine give an immediate, rapid release of the active agent having a geometric average tmax of 0.5 - 3.0 hours with a period of elimination of the plasma, geometric average of 2.0 - 3.5 hours. In order to more fully illustrate this invention, examples of the formulations believed to be useful with moxonidine are illustrated below. The examples are illustrative only and are not intended to limit the scope of the invention. Sustained release formulations which are believed to be useful for the present invention are described in U.S. Patent Nos. 4,140,755; 4,218,433; 4,389,393; 4,839,177; 4,865,849; 4,892,742; 4,933,186 and 5,422,123. The most preferred formulations are those described in U.S. Pat. No. 5, 422, 123.

Clinical Protocol and Results Data on the pharmacokinetics and pharmacodynamics of moxonidine have been obtained against placebo in patients with congestive heart failure. Changes in blood pressure, systolic, standing (SSBP) and changes in norepinephrine concentration in plasma (PNE) in moxonidine and placebo groups were used to evaluate the effects of moxonidine and to predict appropriate dosing strategies. Previous reports have suggested that administration of up to 0.6 mg of moxonidine to patients with essential hypertension (HTN) can produce significant reductions in blood pressure 24 hours after dosing, without an excessive incidence of hypertension. symptomatic The pharmacokinetics and pharmacodynamics in patients with CHF are compared to a previous report in patients with essential hypertension after a single dose of 0.25 mg (Kirch et al, J. Clin Pharmacol 30, 1088-1095 (1990)).

Protocol Study Design Summary Moxonidine was administered in a 2-phase, placebo-controlled, double-blind, randomized clinical trial in patients with Class II-III CHF, functional from the New York Heart Association (NYHA). Only patients receiving a stable dose of an ACE-angiotensin-converting enzyme inhibitor or those who failed ACE therapy were eligible. Patients could also be receptors for digitalis, diuretics and other drugs used as CHF therapy, with the condition that the dose be stable before starting the study. The study consisted of a selection period of individual anonymity, of 2 weeks, a double dose anonymity progesion period, of 4 weeks and a maintenance period of double anonymity, of 8 weeks. Patients were included in the study only if they met all of the following criteria: [1] Patients with CHF Class II-III, moderately severe, clinically stable, chronic, NYHA. [2] Men or women between the ages of 21 and 79 years. [3] Patients with left ventricular ejection fraction of 240%, 5 evaluated by radionucleotide angiocardiography, quantitative echocardiography, or angiocardiography within 1 month before study entry. [4] Patients who would be recipients or have previously failed in * ACE inhibitor therapy for CHF. Patients may be taking digitalis or diuretics or both. The doses of digitalis, diuretics, and other drugs used as CHF therapy would have been established for at least 2 weeks. Patients were excluded from the study for any of the following reasons: 20 [1] Myocardial infarction in the last 90 days. [2] Valvular or outflow tract obstruction, primary, hemodynamically significant (for example, mitral valve stenosis, valvular stenosis of the aortic, asymmetric septal hypertrophy, or malfunction of the prosthetic valve), severely reduced diastolic function, or congenital, complex heart disease. [3] Active myocarditis. [4] Syncopal episodes that are presumed to be life-threatening arrhythmias (asymptomatic cardiac arrhythmias, including non-sustained ventricular tag-ucardia, are not an exclusion criterion). [5] Probability of cardiac surgery, including transplant, in the near future. [6] Angina pectoris or unstable chest (defined as angina at rest) or stable, severe angina (more than two attacks per 20 days on average) despite treatment. [7] Systolic blood pressure 2 90 mg Hg (measured after 10 minutes of recline) or symptomatic hypotension. [8] Uncontrolled hypertension (blood pressure 25 systolic 3 180 mm Hg and pressure diastolic blood pressure 3 105 mm Hg) at the entrance, measured after 10 minutes of recline. [9] Advanced lung disease (FEVi / FVC 50 peak, expectoral flow velocity < 200 mL / sec. or FVC < 60% of predicted) or cor pulmonale. [10] Cerebrovascular disease (eg, cartotid artery stenosis, significant) that could be complicated or rendered potentially unstable by a reduction in blood pressure. [11] Collagen vascular disease different from rheumatoid arthritis (eg, systemic lupus erythematosus, polyarteritis nodosa, scleroderma). [12] Renal artery stenosis, significant, suspicious or severely reduced renal function (ie, creatinine 20> 160 μM / L). [13] Malignancies, except for surgically cured skin cancer, carcinoma in situ, or 5-year freedom from the disease after diagnosis of solid tumors.

[14] Requirement for immunosuppressive therapy (the use of steroids for non-life threatening diseases such as arthritis is not a exclusion). [15] Probability of an alleged participant who is non-adherent for reasons such as chronic alcoholism, lack of a fixed address, or drug addition.

[16] Liver disease, primary, significant. [17] Another disease or life-threatening condition such that the presumed participant is not realistically expected to complete the test. [18] Pregnant women or women of potential fertility who do not protect themselves from pregnancy by an acceptable method. 20 [19] Use of beta-blockers within the last 3 months. [20] Previous exposure to moxonidine within a month. [21] Concomitant use of other investigational drugs.

[22] Previous participation in this test. The exclusion criteria must be met at the entrance to the study and at Visit 3. (randomization). In addition, patients were excluded from the study if the following criteria were met in View 3 (randomization): [23] Unjustified lack of complacency with placebo medication between Visits 1 and 3 (<90% of prescribed medication). 4% The dose groups for the test were studied sequentially. Six groups of doses of moxonidine were evaluated. The dose groups were defined by a starting level of moxonidine and up to two increments of two.4 at 1-week intervals. The study drug was initially given on a once-a-day regimen. The periods of sequential study are defined as follows: • Selection (individual anonymity, 2 weeks): Evaluation of eligibility and compliance with placebo medication.

• Progress of the Dosage (double anonymity, 4 weeks): Administration of the first dose of the study drug followed by up to two dose increases in 1-week intervals. • Maintenance (double anonymity, 8 weeks): Two visits at 4-week intervals during which the dose of moxonidine was constant at the highest dose.

One week was defined as 5 to 9 days. For each individual patient, the progression of the study periods is illustrated in Table 1.

Table 1 Progression of the Study Period by Patient Study Period Variable Selection Progression of the dose Maintenance Study drug Placebo Placebo Placebo Moxonidine Moxonidine Step of the Dose 1, 2,3 3 Duration 2 Weeks 4 Weeks 8 Weeks Number of Visits 1, 2 3a, 4, 5b, 6a 7-, 8a, c 8-hour evaluation day (Study Day). b 4-hour evaluation day (Stage I only). c Visits 7 and 8 can be deleted during Stage I.

The visits 3, 6 and 8 are evaluation days of 8 hours (referred to as Study Days 1, 2 and 3), in which the daily dose of the study medication was stopped until the administration in the medical clinic, after which the patients were followed for up to 8 hours. During that time, psychological observations were made, adverse cases were removed and blood samples were taken for clinical laboratory measurements and neuroendocrine mediator assays and the concentration of the study drug. On Visits 4 and 5, patients received their dose of medication at the medical clinic and remained for observation in the clinic for 4 hours after the administration of the dose. During the study, the six moxonidine dose groups were studied sequentially, starting with Group Dose 1. For each dose group, 2 patients were randomly assigned for the medication in active study and one for placebo. It is assumed that three patients entered the study every week. The study ended when patients were randomly assigned to Group 6 Dosing of moxonidine or Visit 8 completed with placebo (the end of the period of maintenance of the dose), after which the patients were discontinued. The dosage size was progressively larger from the first to the sixth group. For each group, the starting dose was the smallest, with a maximum of two dose progression steps, subsequent at 1-week intervals.

Table 2 Moxonidine Dosage Steps in mg / day by Dosing Group Moxonidine Dosage Group Step of Dose 1 2 3 4 5 6 Home 1 0.1 0.1 0.1 0.1 0.2 0.2 Medium 2 0.1 0.2 0.2 0.3 0.3 0.4 Final 3 0.1 0.2 0.3 0.4 0.6 0.6 The dose sequence was presented in Table 3 Table 3 Moxonidine Dosage Sequence Dose Week Number Group 3 0 1 2 3 4 5 6 7 8 9 1 0.1 mg 0.1 mg 0.1 mgb 0.1mgc 2 0.1 mg 0.2mg 0.2mgb 0.2mgc 3 0.1mg 0.2mg 0.3mgb 0.3mg 4 0.1mg 0.3mg 0.4mgb 0.4mgc 5 0.2mg 0.3mg 0.6mg 0.6mgc 6 0.2mg 0.4mg 0.6mgb 0.6mgc a Two patients were randomly assigned to the active study drug and one to the placebo group. b Patients took the highest two for 2 weeks. c Patients were maintained for an additional 8 weeks at the highest dose of moxonidine for the dosing group.

Dosage and Administration Materials and Supplies Moxonidine tablets and placebo were provided to the hospital pharmacy and administered to patients in a sufficient number for each interval of visit. The 0.1 mg tablets of moxonidine and the placebo tablets were identical in appearance and were combined in appropriate proportions to ensure the desired dosages (including twice-daily dosing if required), ease of complacency, and maintenance of anonymity . The term "do s" in this protocol refers to the combination of the tablets of the study drug taken on an individual day. Current commercial formulations were used with the lactose content adjusted to accommodate the presence or the active ingredient's auserity as described above.

Selection Patients were given the first dose of placebo in the medical clinic and on Visits 1 and 2 they were given a sufficient supply of the placebo medication for dosing once a day. The drug under study should be taken once a day early in the morning as a single dose (6 tablets).

Progression of Dosage and Maintenance After randomization at Visit 3, each patient received a dose of moxonidine (0.1 or 0.2 mg) or placebo during Visit 3. The Visit 3 (Study Day 1) is one of the three days of evaluation of 8 hours during this protocol in which the study medication was taken in the medical clinic and the patient was followed for 8 hours for safety assessments and measurements of laboratory. In addition, on Visits 4 and 5, the dose of the medication was administered in the medical clinic and the patients were observed for four hours after the administration of the medicine dose. Visits 6 and 8 (Study Days 2 and 3) were also 8-hour evaluation days in which the daily dose was stopped for administration in the medical clinic, after which the patient was followed for up to 8 hours . On each of the 4-hour and 8-hour evaluation days, the patients did not take their daily medication until it was administered at the medical clinic. In each of Visits 3 through 7, patients were given sufficient moxonidine or placebo medication for administration of one per day until the next visit. The study drug or placebo was taken once a day early in the morning as an individual dose (6 tablets), unless the evidence of sympathetic hypotension justified the division of the dose, with the result that the regimen was twice a day. Measurements of efficacy include the following: • Concentrations in the plasma of neuroendocrine mediators (norepinephrine, N-terminal atrial natriuretic peptide). • Vital signs (systolic and diastolic blood pressure at rest and heart rate). • Reduction in diuretic dosing, prescribed. Blood was withdrawn for the analysis of the concentration in the plasma of the study drug at approximately 0, 0.5, 1, 1.5, 2, 4, 6 and 8 hours after the administration of the study drug in the three Study Days (Visitas 3, 6 and 8). The concentrations in the plasma were determined using an analytical method of gas chromatography / mass spectrometry. In general, aliquots of human plasma (1.0 ml) are enriched with 25.0 μl (10 pg / μl of internal working solution) of the internal standard (Clonidine, HCl). Each sample is extracted in ethyl acetate under basic conditions, the organic layer is removed, and the plasma is discarded. The samples are extracted again with 0.5 M HCl and the layer organic is discarded. The samples are then extracted into methylene chloride under basic conditions, the aqueous layer is discarded and the organic layer is taken to dryness under a stream of nitrogen. The dried sample residues are derivatized with 3,5-bis (trifluoromethyl) benzoyl chloride and evaporated again to dryness under nitrogen. The samples were reconstituted in 50 μl of acetonitrile, transferred to flasks on samplers, plastic, gas chromatography and injected (1 μl) into the GC / MS system.

Pharmacokinetics Unless stated otherwise, "average" affects a geometric average. The concentration profiles in the plasma-time of the first dose (Visit 3) of 0.1 mg of moxonidine in eight patients with CHF were prepared and evaluated. The absorption was rapid (average tmax: 0.75 hours), and the decrease in plasma concentration was fairly biphasic. The average oral clearance was 28.03 L / hr, and the average elimination period was 3.28 hours. The absorption of moxonidine was faster than that previously reported for patients with hypertension (average tmax: 1.07 hours). Oral clearance in patients with CHF was lower and the Mean life span was longer than in patients with hypertension (CL: 43.58 L / hr; tl / 2: 2.01 hours). Differences in clearance and mean lifespan between populations may have been due to differences in age and renal function (average age of CHF: 69 years; average age of HTN: 49 years) The most rapid absorption and the increased half-life of moxonidine may produce an elevation in Cmax in the population with CHF relative to patients with HTN at comparable doses. Despite the extrapolations based on Visit 3, plasma concentrations of moxonidine predict an insignificant accumulation of moxonidine after repeated administration to patients with CHF, even with a BID regimen. The predicted peak for all ratios for the BID dose is 20: 1. The above data demonstrated a temporal shift between the peak concentration of the drug in the plasma (1 hour) and maximum effect (4-6 hours) in patients with HTN. Also, the duration of the effect is much larger than predicted for the average life span in the plasma. Both observations suggest that the drug in the plasma slowly equilibrates with the site of effect in the CNS.

Pharmacodynamics Change in Blood Pressure, Systolic, Foot (SSBP) of the Baseline (T = 0) to 2 hr in Visit 3, Stage I Table 4 Blood, Systolic, Foot Pressure Patient Number Absolute Change Percent Change Placebo 101 -10 -8.3 107 -10 -10 201 25 21.7 205 10 7.7 301 20 15.4 303 5 5.0 Average 6.7 5.2 Moxonidine 0.1 mg 102 10 7.7 103 -60 -42.8 104 10 7.7 105 -10 -10 202 0 0 203 0 0 206 -10 -6.9 302 -15 -12 307 -5 -4.3 Average -8.9 -6.7 Table 4 shows the absolute changes and as a percentage of the baseline of the previous dose in the blood pressure, systolic, standing on Study Day 1 (visit 6). There were 6 patients who received placebo, and 9 who received moxonidine, 0.1 mg. The peak effect was in 2 hours after the administration of the drug. A course of SSBP increase was observed in the placebo group (mean 6.7 mm Hg). The change may have been due to the decrease in the effect of the morning dose of the ACE inhibitor taken before coming to the clinic. Compared to placebo, moxonidine produced a reduction in SSBP, the average deference being -15.6 mm Hg. (-11.9%). Consistent with previous data in hypertensive patients (HTN), a temporal shift was observed between the peak reduction in blood pressure and the peak plasma concentration of moxonidine. However, the time for the peak effect (3 hours) in patients with CHF was shorter than in patients with HTN (5 hours). Also, the duration of blood pressure reduction in patients with CHF was short, with an eight-hour return of the SSBP from the previous dose, after dosing. The short duration of action predicts insignificant accumulation of effect after dosing QD or BID, repeated.

Changes in Plasma Norepinephrine (PNE) Table 5 shows the absolute and percentage changes in plasma concentration of norepinephrine from the previous dose baseline to 2 hours after dosing (0.1 mg) in the norepinephrine groups. patients These values were obtained using normal clinical laboratory procedures.

Table 5 Change in Norepinephrine from Baseline (t = 0) to 2 hours in Visit 3, Stage I Norepinephrine Patient Number Change AIJ Change in Percent Placebo 101 40 6.7 107 144 40.9 201 48 23.5 205 104 15.1 301 40 10.6 303 -124 -16.8 Average 42.0 13.3 Moxonidine 0.1 mg 102 -62 -27.7 103 -168 -30.1 104 -142 -37.2 105 -360 -42.1 202 -92 -17.1 203 -6 -1.8 206 -50 -15.2 302 24 6.9 307 22 9.6 Average -92.7 -17.2 Moxonidine at 0.1 mg, produced a maximum reduction in the average PNE 2 hours after dosing at Visit 3. Two hours after dosing, the PNE was reduced by over 30% compared to placebo. The duration of the effect was short. The PNE in the moxonodine group returned to the baseline 4 hours after dosing. The effect of moxonidine on the PNE at Visits 3 and 6 in a representative subject showed that the patients did not respond to a dose of 0.1 mg at Visit 3, but responded strongly to alna dose of 0.3 mg at Visit 6. Without However, the PNE of the previous dose in Visit 6 was raised in relation to the baseline. Similarly, the baseline SNP of visit 6 was raised relative to the baseline SNP of Visit 3 in 5 of 8 patients who received moxonidine, but only 1 in 5 subjects who received placebo. The time for maximum reduction of PNE in patients with CHF (2 hours) was shorter than that reported for patients with HTN (6 hours). The short duration of effect in patients with CHF suggests that dosing QD and BID dosing of moxonidine will not sustain suppression of the PNE during a 24-hour interval. The PNE time course in a subject representative after 0.1 mg of moxonidine BID was almost superimposable with the time course after the administration of the first dose of 0.1 mg (Visit 3). The administration of the immediate release moxonidine 0.1-0.6 mg QD or 0.1-0.2 mg BID to patients with CHF failed to produce a sustained reduction in sympathetic activity during the dosing interval, although a large transient reduction was observed 1-3 hours after dosing in many subjects. Ideally, the dosing regimen should produce a "significant suppression of PNE through the following chronic dosing, without excessive reductions in blood pressure at the time of peak effect. These objectives could possibly be achieved with the formulation of immediate, commercial, current release by increasing the daily dose (beyond 0.6 mg / day) and reducing the dosage interval. However, a duration of 4-8 hours of effect after a dose of 0.1-0.6 mg suggests that the optimal dosage interval would be at least QID. However, the QID dosage may be impractical when patient compliance is a problem, and may even be associated with the high peak for all effect proportions. For example, the patient's noncompliance with a regimen of Multiple dosing can result in a failure to obtain the benefits of the active agent and can exacerbate the high peak for all proportions of the effect. Based on the foregoing, additional data are not disclosed herein, the administration of moxonidine by means of a non-immediate release formulation is required to provide a practical method to sustain sympathetic suppression while decreasing the peak for all proportions. Since sympathomatic hypotension can be precipitated by acute and transient reduction in sympathetic activity that is observed 1-3 hours after the administration of moxonidine, the side effect profile of moxonidine should also be improved by a non-release formulation. immediate The following examples will further illustrate the present invention.

Composition of the Formulas Example 1 The sustained release of the active compound is based on the principle of a hydrocolloid matrix. The matrix is formed by the hidoxypropyl methylcellulose, HPMC 2208 (15,000 mPas, at 2%, 20 ° C). A mixture of lactose and calcium phosphate was used as carrier. The release of the active compound was controlled by varying the relationships between these three components. The batch analysis tests showed a high sensitivity of the formula to variations in mixing time. The increased mixing times tend to lead to a non-uniform distribution of the lubricant which causes an insufficient hardness of the tablet.

Example 1 The Manufacturing Steps - mixing the inner powder in a planetary mixer; granulation; tray drying at 50 ° C overnight; dry milled when using an oscillation granulator, sieve-1 mm; addition of external powder and 30 minutes of drum mixing; Y compression Example 1 Analysis by Lots Example 2 Eyetablet (0.625 ma) Due to the therapeutic effect, delayed with the Example 1 (the data are not included), it was decided to combine a sustained release formulation with an initial dose. When the data were demonstrated (not included in the present), they were compared with the immediate release, normal moxonidine tablet, a decrease in blood pressure was observed, significant one hour after dosing. The "Eyetablet" is a special kind of pre-coated tablet: a biconvex, circular (6 mm diameter) battery is pressed into a circular "U" shaped liner in cross section and 9 mm in diameter, without the core which is completely covered. The coating contains the initial dose (0.1 mg) in an immediate release form. This disintegrates within 30-95 seconds due to a high content of decay enhancers (5% Crospovidone, 5% Corn Starch). The nucleus carries the sustained form (0.535 mg). A small amount of HPMC 2208 (max 5%), which is required for sustained release, was incorporated as a carrier inside the inner powder, facilitating the capture of a sufficient quantity of liquid for granulation. The tablets were coated for protection from moisture.

Example 2 The steps of Manufacturing Moxonidine-Eyetablet mixed of the inner powder in a planetary mixer; to. granulation; tray drying at 50 ° C overnight; dry milling using an oscillation granulator, sieve-0.75 mm; addition of external powder and 30 minutes of drum mixing (HPMC 20 minutes + magnesium stearate 10 minutes); compression; coating the cores with a 15% suspension by means of a spray gun (0.8 mm nozzle); mixing the incoming powder in a planetary mixer; granulation; tray drying at 50 ° C overnight; dry milled when using an oscillation granulator, sieve 0.75 mm.; addition of the interior powder and 30 minutes of drum mixing; compression; Y coating the cores with a 10% suspension by means of a spray gun (0.8 mm nozzle).

Example 2 Analysis by Lots Using procedures substantially similar to those described below for the Example 3-6, the formulations of Examples 3-1 to 3-5 were prepared and coated as described in 3-6, Example 3-1 Example 3-2 Example 3-3 Example 3-4 Example 3-5 Example 3-6 Example 3 The Steps of Mixed Manufacturing of the inner powder in a planetary mixer; granulation; tray drying at 50 ° C overnight; dry milled when using an oscillation granulator, sieve-1 mm; addition of external powder and 30 minutes of drum mixing; compression; Y Aqueous coating of the cores with a 12.5% suspension by means of a spray gun (0.8 mm nozzle).

Example 3-6 Analysis by Lots The formulations of Examples 1, 2 and 3-6 were evaluated in clinical studies, limited in patients with hypertension (data not included).

The formulation of Example 1 was supplemented to an immediate release tablet of 0.25 mg (Comp. Example A) in a study with eight hypertensive patients. The concentrations in the plasma were determined using the known GC / MS methodology. With the formulation of Example 1, the maximum concentration in the plasma was reached 2-3 hours after administration. The highest dose, compared to Example A, caused a 60% increase in the maximum concentration in the plasma (2.25 ± 1 ng). These kinetic data correspond to the increase in the blood pressure. Example 1 leads to a maximum greater than 50% decrease in systolic and diastolic blood pressure compared to Example A, which occurred 5-6 hours after administration. The period of action, defined as the period of time for which a decrease in diastolic blood pressure greater than or equal to 10 mm Hg was not significantly different for both formulations of Moxonidine. Also the degree of dryness of the mouth and fatigue were the same. Both formulations were well roasted. In a clinical study with four healthy volunteers the "Eyetablet" of Example 2 was compared to an immediate release tablet of 0.25 mg (Comparative Example A) with respect to kinetic behavior. The concentrations in the plasma were determined using the known GC / MS methodology. See for example Kirch et al., J. Clin. Pharmacol., 30, 1088-1095 (1990); Trenk et al., J. Clin. Pharmacol. , 27, 988-993 (1987); and Kirch et al., Clinical Pharmacokinetics, 15, 245-253 (1988). The "Eyetablet" caused a time period of 2.5 times of a blood level above 1 ng / ml compared to Example A, while the maximum concentration in the plasma remained almost constant. The onset of the effect was not substantially affected by the initial dose. Due to the small number of patients and the variability of the data, an evaluation of the period of the blood pressure lowering parameter is not considered appropriate. A study with two volunteers was carried out concerning the kinetic data only of the formulation of Example 3-6 which is subsequently reported along with the limited clinical kinetic data obtained as described above.

* The relative bioavailability was determined by calculating the theoretical AUC value of the same dose in a normal manner. The AUC value of the immediate release formulation = 100%.

By substantially following the procedures described in U.S. Patent No. 5,422,123, which is incorporated by reference herein, in its whole, Examples 4 (4-1 and 4-2), 5 and 6 were prepared as three-layered tablets. Example 4-1 Global Compositions Substance m / tablet Total weight of the tablet: 297.01 Diameter (mm): 8 Thickness (mm): 6.2 Example 4-2 Global Compositions Substance mg / tablet Total weight of the tablet: 297.0 Diameter (mm): 8 Thickness (mm): 6.2 Example 5 Global Composition Total weight of the tablet: 297. 02 Diameter (mm) Thickness (mm) 6. 2 Example 6 Global Compositions Substance mg / tablet (theoretical weight) Total weight of the tablet 297.02 Diameter (mm) Thickness (mm) 6.2 Example 6 Carrier Mixture Example 6 Active Mix In Vi ro Drug Release (Ph. Eur. 2nd Ed. V.5.4, Apparatus 2, 500 ml of water, 100 rpm, 37 ° C) The formulations of Examples 4-1, 4-2, 5 and 6 were evaluated in a limited clinical trial. The objectives of this study were (1) to provide data for the comparison of the bioavailability of four controlled release formulations, different from moxonidine after the administrations of individual doses and (2) analyze the dietary effect for one of the formulations in five additional subjects. The formulations, three dosages as tablets of 0.3 mg and one as 3 tablets with 0.1 mg each, were compared to a reference formulation, immediate release, commercialized (Comparative Example B) containing 0.2 mg of moxonidine per tablet.

Material and Methods The% formulations of Examples 4-1, 4-2 and 6 were used with 0.3 mg of moxonidine per tablet and the formulation of Example 5 contained 0.1 mg of moxonidine. The study was conducted in a 7-day, randomized, open-label elimination design consisting of 5 study periods with the administration of individual doses after an overnight fast. The first four study periods were carried out in a crossover design of four forms including the formulations of Comparative Example B, Example 6, Example 4-2 and Example 5. In the fifth period, the same subjects received the formulation of the Example 4-1 as single dose administration. The study population consisted of 10 subjects in fasting, healthy of any sex. The formulation of Example 6 was also analyzed in a parallel group of 5 additional subjects who were dosed after the high-fat breakfast of the United States Food and Drug Administration (FDA). During each study period, the subjects received an oral, individual dose with 240 ml of tap water at room temperature. For the quantification of moxonidine, 15 blood samples were collected at different times before and up to 12 hours for Comparative Example B and for 22 hours for the formulations of the present invention after dose administration. Plasma concentrations of moxonidine were determined using a GC-MS method with a limit of quantitation (LOQ) of 0.025 ng / ml described below. The aliquots of human plasma (1.0 ml) were enriched with 25.0 μl (10 pg / μl of internal working solution) of the internal standard (Clonidine, HCl). Each sample is extracted into ethyl acetate under basic conditions, the organic layer is removed, and the plasma is discarded. The samples are extracted again with 0.5 M HCl and the organic layer is discarded. The samples are then extracted into methylene chloride under basic conditions, the aqueous layer is discarded and the organic layer is taken dryness under a stream c nitrogen. The residues of the dry sample are derivatized with 3,5-bis (trifluoromethyl) benzoyl chloride and evaporated again to dryness under nitrogen. The samples are reconstructed in 50 μl of acetonitrile, transferred to plastic gas chromatography autosampler flasks and injected (1 μl) into the GC / MS system. The experimental data of the formulations were normalized to 0.3 mg of moxonidine, according to the true content shown in Table 1; the true content of the reference is assumed to be equal to the nominal content, ie 0.2 mg.

Table 1. Nominal and true content of moxonidine in the formulations. The true contents of the formulations were 94-109% of the nominal content.

The maximum concentration in the plasma (Craax) for each formulation was obtained from the series of data adjusted to the content. The area under the curve of concentration in the plasma against the time until the Last quantifiable concentration (AUC0-túitimo) was calculated using the linear, trapezoidal rule. The apparent (?) Elimination rate constant was calculated by linear regression of the terminal segment of the linear log-transformed concentration curve against time and was used to extrapolate the AUC to affinity (AUCo-oo). The leveling time t5o% cmax corresponds to the period of time during which the concentrations in the plasma are greater than 50% of the Cmax. The relative bioavailability of each of the formulations of the present invention to Comparative Formulation B was calculated in the following two forms representing an upper limit (Frel (1)) and a lower one (Frei (2)). 1 - rei (i) = AUCo-inf Example / AUCo-inf coprativo B 2. Ere? (2) = [AUCo-túltimo Ejmplo + (Ctúltimo E. ... pio / - ^ - comparative B)] / AUCo-inf Comparative Example B of AUCo-inf Comparative Example B was normalized to 0.3 mg to explain the dose differences. The point estimates and the confidence intervals of 90% for the relationships of the averages between the formulations of the invention were calculated based on the Cmax and AUC0-last log-transformed values, using ANOVA in pairs. The formulations of Example 6 and 5 are judged to be bioequivalent when the 90% confidence interval for log-transformed data ratios falls within 0.8 to 1.25.

Results and Discussion The curves of the concentration in the individual plasma were prepared against the time for the comparative formulation as well as the curves for the formulations of the invention. The concentrations in the plasma for a subject ^ * (in the treatment with Example 4-2) showed in exceptionally high values of 6 and 12 hours with corresponding high impact on the PK parameters and the average values. These two concentrations were excluded from the data set and PK analysis. The PK parameters are listed in Tables 2 and 3. The PK parameters for Comparative Example B found in this study (values given in parenthesis) were similar to those reported in the literature (1): Cmax 1.29 ± 0.32 (2.14 ± 0.4) ng / ml, tmax 0.74 ± 0.35 (average 0.5) h, AUC0-last 4.1 ± 1.9 (5.8 ± 0.2) ng h / ml, and t? -2 2.12 ± 0.58 (2.06 ± 0.10) h. All the formulations of the invention showed significantly lower Cmax values than the formulation of immediate release (Cmax 3.2 ± 0.4 ng / ml normalized dose) and a greater prolongation of plasma levels, consistent with its lower release in vitro. All the formulations of the invention produced very good relative bioavailability compared to the immediate release formulation. The variability within the subject observed for moxonidine in this study was generally lower for AUC than for Cmax. Half of the subjects showed a relatively large variability in Cmax. For the AUC, a4 * subject showed higher variability compared to the other subjects. When the test of the formulation of Example 6 in the fasted and fed state was performed in different subjects, the PK parameters are not directly comparable. However, these appeared to be in the same range with somewhat lower AUC values in the fed state. The concentration-time profiles of the formulations of Example 6 (0.3 mg) and Example 5 (0.1 mg given in 3 tablets) appeared to be superimposed suggesting a bioequivalence.

Table 2: Summary of PK parameters for fasting treatments. "Average" refers to geometric mean for Cmtx AUC and Frßl; average for tmax and tso% cmax- Sample size: 10.

Table 3: Summary of the PK parameters for the fed treatment. "Average" refers to the geometric average for Cmax and AUC; average for tmax. Sample size: 5 All four moxonidine formulations of the present invention that were analyzed against the reference formulation, immediate release, commercialized showed a leveling in the concentration profiles against time after the administrations of individual doses. All the formulations of the present invention also achieved a reduction of variability within the subject for Cmax and very good relative bioavailability. In addition, exceptionally little adverse effects were observed with all the formulations of the present invention. No statistically significant differences were observed between the formulations of Example 6, which contains 0.3 mg of moxonidine and Example 5 given as 3 tablets with 0.1 mg each. The formulation of Example 4-1 showed higher levels in the plasma and faster absorption than the formulations of Examples 4-2 and 6 and what results in a higher relative bioavailability.

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.

Having described the invention as above, the content of the following claims is claimed as property.

Claims (19)

1. A pharmaceutical formulation of non-immediate, oral or implant release, characterized in that it comprises an effective dose of moxonidine, or a pharmaceutically acceptable salt thereof, in association with one or more carriers, diluents or excipients to give the non-immediate release of the moxonidine

2. A formulation according to claim 1, characterized in that the non-immediate release gives a plasma elimination period, average of between 6 to 16 hours.

3. A formulation according to claim 2, characterized in that the period of elimination of plasma, average is between 7 to 15 hours.

4. A formulation according to claim 2, characterized in that the non-immediate release gives an average time for the maximum concentration in the plasma of between 2.5 to 5 hours.

5. A formulation according to claim 1, characterized in that the release is not Immediate gives a mean time for the maximum concentration in the plasma of more than 3 hours to 5 hours.

6. A formulation according to claim 5, characterized in that the average time for the maximum concentration in the plasma is between 3.5 to 4 hours.

7. The formulation according to claim 1, characterized in that the non-immediate release formulation is an oral dosage form.

8. The formulation according to claim 7, characterized in that a unit dose of the oral dosage form contains from about 0.01 mg to about 3.0 mg of moxonidine or a pharmaceutically acceptable salt thereof.

9. The formulation according to claim 7, characterized in that the oral dosage form is a delayed release system or a sustained release system.

10. The formulation according to claim 9, characterized in that the sustained release system is a controlled release system or a prolonged release system.

11. The formulation according to claim 7, characterized in that the oral dosage form is a diffusional system or a dissolution system, or a combination thereof.

12. The formulations? according to claim 11, characterized in that the diffusional system is a deposit system or a matrix system.

13. The formulation according to claim 12, characterized in that it comprises, by weight, 0-40% lactose; 0-85% calcium phosphate; 9-65% hydroxypropylmethylcellulose; and 0.05-1.5% moxonidine, or a pharmaceutically acceptable salt thereof, and optionally containing one or more diluents, excipients and carriers, with the proviso that at least one of lactose and calcium phosphate is present.

14. The formulation according to claim 13, characterized in that the. Oral dosage form is a tablet comprising a core disposed within a carrier vehicle wherein a) the core comprises, by weight, the core: 9-40% lactose; 0-40% calcium phosphate; 9-65% hydroxypropylmethylcellulose; 2-8% polyvinylpyrrolidone; 0.1-2% magnesium stearate; and 0.05-1.5% moxonidine, or a pharmaceutically acceptable salt thereof; and optionally containing one or more diluents, excipients and carriers; Y b) the barrier vehicle comprising, by weight of the barrier vehicle: 30-50% hydroxypropylmethylcellulose; 30-50% lactose; 2-8% polyvinylpyrrolidone; 0.1-2% magnesium stearate; Y 0-0.1% moxonidine or a pharmaceutically acceptable salt thereof; Y optionally containing one or more diluents, excipients and carriers; wherein the barrier vehicle partially covers the surface of the core.

15. A non-immediate, oral or implant release composition, characterized in that it is 4-chloro-5- (imidazolin-2-yl (amino) -6-methoxy-2-methylpyrimidine, or a pharmaceutically acceptable salt thereof, in association with one or more carriers, diluents or excipients, for use as a medicament.

16. A use according to claim 15, wherein the medicament is for the treatment of congestive heart failure.

17. A use according to claim 15, wherein the medicament is for the treatment of hypertension.

18. A use of 4-chloro-5- (imidazolin-2-yl (amino) -6-methoxy-2-methylpyrimidine, or a pharmaceutically acceptable salt thereof, for the preparation of a non-immediate, oral or of implant to treat heart failure, congestive.

19. A use of 4-chloro-5- (imidazolin-2-yl (amino) -6-methoxy-2-methylpyrimidine, or a pharmaceutically acceptable salt thereof, for the preparation of a measure of non-immediate, oral or of implant to treat hypertension.