WO2010010141A1

WO2010010141A1 - Pramipexole for treating cardiomyopathy

Info

Publication number: WO2010010141A1
Application number: PCT/EP2009/059473
Authority: WO
Inventors: Juergen Reess
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2008-07-25
Filing date: 2009-07-23
Publication date: 2010-01-28

Abstract

The invention relates to a novel use of pramipexole for the treatment of cardiomyopathy. The invention is related to the use of pramipexole or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cardiomyopathy, particularly dilated cardiomyopathy, preferably postpartum or peripartum cardiomyopathy, and a method of treatment thereof.

Description

PRAMIPEXOLE FOR TREATING CARDIOMYOPATHY

Field of the Invention

The invention relates to a novel use of pramipexole. The invention is related to the use of pramipexole for the preparation of a medicament for the treatment of cardiomyopathy, particularly postpartum or peripartum cardiomyopathy and a method of treatment thereof.

Background Art

Pramipexole is chemically designated as (65)-N6-propyl-4,5,6,7-tetrahydro-l,3- benzothiazole-2,6-diamine (IUPAC) and has the molecular formula C10H17N3S and a relative molecular mass of 211.324. The chemical formula (formula 1) is as follows:

formula 1

The salt form commonly used is pramipexole dihydrochloride monohydrate (molecular formula C10H21CI2N3OS; relative molecular mass 302.27). Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs in the range of 296°C to 301⁰C, with decomposition. The substance is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane. Pramipexole is a chiral compound with one chiral centre. Pramipexole is classified as a known non-ergoline dopamine D₂ receptor agonist. It is pharmacologically unique in that it is a full agonist and has receptor selectivity for the dopamine receptors, with particularly high affinity for the D3 receptor subtype. Pramipexole (trade names Mirapex® and Sifrol®) or pharmaceutically acceptable salts thereof has a known medication primarily indicated for treating Parkinson's disease and restless legs syndrome (RLS). It is also sometimes used off- label as a treatment for cluster headache. The pure (S)- or (-)-enantiomer is the pharmaceutically active substance of particular interest within the context of this invention. Cardiomyopathy, a disease that primarily affects the muscle of the heart, is a deterioration of the mechanical and/or electrical function of the myocardium (heart muscle) for any reason. Different cardiomyopathies have different causes, and affect the heart in different ways. There exists a variety of causes which has quite often genetic reasons. The disease is usually related with the risk of arrhythmia and/or sudden cardiac death.

Treatment depends on the type of cardiomyopathy, but may include medication, implanted pacemakers, defibrillators, or ventricular assist devices (LVADs), or ablation. The goal of treatment is often symptom relief, and some patients may eventually require a heart transplant. Treatment of cardiomyopathy and other heart diseases using alternative methods such as stem cell therapy is commercially available but is not supported by convincing evidence.

It is therefore an object of the present invention to provide an improved treatment for cardiomyopathy or related conditions, which may be tailor-made for each individual patient in need thereof.

Summary of the Invention

The present invention is directed the use of pramipexole or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment and/or prevention of cardiomyopathy, particularly dilated cardiomyopathy, particularly preferred postpartum cardiomyopathy or peripartum cardiomyopathy.

Description of the Invention

The present invention is based on a novel therapeutic strategy of treating cardiomyopathy, a concept of the application of pramipexole.

Pramipexole has been developed for symptomatic treatment of Parkinson's disease and the restless legs syndrome and a complete dataset of pharmacokinetic and pharmacodynamic data are available. In a novel study it was shown that female mice with a cardiomyocyte-specific deletion of STAT3 develop postpartum cardiomyopathy (PPCM). In these mice, cardiac cathepsin D expression and activity was enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. On the contrary, a cleavage product of prolactin does not occur in a healthy heart. As a result, treatment with pramipexole which decreases the prolactin level or may act as an inhibitior of prolactin secretion, and thus probably intervenes into the pathomechanism of cardiomyopathy, will ameliorate the symptoms and finally support the cure of cardiomyopathy. Therefore, the use of pramipexole in order to treat cardiomyopathy represents a novel therapeutic strategy. Consequently, the dopamine agonist pramipexole will have a benefit on cardiomyopathy treatment and will alleviate the symptoms, prevent the progression of the disease and will finally support the cure of the disease.

Thus, the inventors established the present invention to use the dopamine receptor agonist pramipexole for the treatment of cardiomyopathy.

There exist several types to categorize cardiomyopathy, e.g. into extrinsic and intrinsic types of cardiomyopathy. However, in March 2006, the American Heart Association (AHA) has proposed an updated definition and classification which will be used in the present description. Within this classification cardiomyopathies are categorized into primary and secondary cardiomyopathies, the primary cardiomyopathies are sub-divided into congenital, acquired and mixed forms.

Exemplary congenital primary cardiomyopathies include, but are not limited to hypertrophic cardiomyopathy, arrhythmo genie right ventricular cardiomyopathy, left ventricular hypertrophy (LVH), glycogen storage diseases, conduction defect syndromes (lenegre syndrome), mitochondrial myopathies, ionic channel defects, long QT syndrome (LQTS), Brugada syndrome, short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Asian SUNDS ("sudden unexplained nocturnal death syndrome").

Mixed (congenital and acquired) primary cardiomyopathies include but are not limited to dilated cardiomyopathy and restrictive cardiomyopathy. Acquired primary cardiomyopathies include but are not limited to myocarditis, takotsubo cardiomyopathy, cardiomyopathy in pregnancy, and tachycardia induced cardiomyopathy.

Secondary cardiomyopathies include but are not limited to conditions associated with infiltration (amyloidosis, hurler syndrome), storage diseases (glycogen storage disease), toxic substances (cardiotoxicity), endomyocardial disorders (endomyocardial fibrosis), endocrine diseases, cardiofacial syndromes, inflammatory/granulomatous disorders neuromuscular/neurologic disorders, cardiofarciale syndrome, malnutrition, autoimmune /connective tissue diseases, electrolyte disorders or following a cancer therapy.

Since the novel use of pramipexole is for the treatment of cardiomyopathy in all forms mentioned within this description, some types of cardiomyopathies will be described in detail in for illustration without meant to be limiting.

Hypertrophic cardiomyopathy (HCM or HOCM) is a genetic disorder caused by various mutations in genes encoding sarcomeric proteins. In HCM the heart muscle is thickened (hypertrophied), which can obstruct blood flow and prevent the heart from functioning properly. HCM can be defined as obstructive or non-obstructive. The obstructive variant of HCM, hypertrophic obstructive cardiomyopathy (HOCM), has also historically been known as idiopathic hypertrophic subaortic stenosis (IHSS) and asymmetric septal hypertrophy (ASH). Another, non-obstructive variant of HCM is apical hypertrophic cardiomyopathy. It is most famous as a leading cause of sudden cardiac death in young athletes. The incidence of HCM is about 0.2% to 0.5% of the general population.

The clinical course of HCM is variable. Many patients are asymptomatic or mildly symptomatic. The symptoms of HCM include dyspnea (shortness of breath), chest pain (sometimes known as angina), uncomfortable awareness of the heart beat (palpitations), lightheadedness, fatigue, fainting (called syncope) and sudden cardiac death. Often, symptoms mimic those of congestive heart failure (particularly activity intolerance & dyspnea), but it must be noted that treatment is very different.

The first medication that is routinely used for treatment of HCM are beta-blockers such as metoprolol, atenolol, bisoprolol, propranolol. Alternately a calcium channel blocker such as verapamil may be substituted for beta-blockade. Most patients' symptoms may be managed medically without needing to resort to interventions such as surgical septal myectomy, alcohol septal ablation or pacing. In cases that are refractory to all other forms of treatment, cardiac transplantation is an option.

HCM is also the most common heart disease in cats (feline hypertrophic cardiomyopathy).

Arrhythmogenic right ventricular cardiomyopathy (ARVC) also known as arrhythmo genie right ventricular dysplasia (ARVD) is a type of nonischemic cardiomyopathy which arises from an electrical disturbance of the heart in which heart muscle is replaced by fibrous scar tissue. The right ventricle is generally most affected.

Left ventricular hypertrophy (LVH) is the thickening of the myocardium (muscle) of the left ventricle of the heart. While ventricular hypertrophy occurs naturally as a reaction to aerobic exercise and strength training, it is most frequently referred to as a pathological reaction to cardiovascular disease, or high blood pressure. The principal method to diagnose LVH is echocardiography, during which the thickness of the muscle of the heart can be measured. The electrocardiogram (ECG) often shows signs of increased voltage from the heart in individuals with LVH, so this is often used as a screening test to determine who should undergo further testing with an echocardiogram.

A further type of congenital primary cardiomyopathy is the glycogen storage disease also known as glycogenosis or dextrinosis is any one of several inborn errors of metabolism that result from enzyme defects that affect the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types.

Another type of congenital primary cardiomyopathy is catecholaminergic polymorphic ventricular tachycardia (CPVT) an inherited heart rhythm disorder caused by a mutation in voltage gated ion channels and resulting in arrhythmias. CPVT is usually treated with beta blockers, verapamil or an ICD (implantable cardiac defibrillator).

The preferred use of pramipexole according to the present invention is directed to dilated cardiomyopathy. Dilated cardiomyopathy (DCM) also known as congestive cardiomyopathy is the most common form and one of the leading indications for heart transplantation. In DCM the heart especially the left ventricle is enlarged and the pumping function is diminished. The decreased heart function can affect the lungs, liver, and other body systems. It occurs more frequently in men than in women, and is most common between the ages of 20 and 60 years. About one in three cases of congestive heart failure (CHF) is due to dilated cardiomyopathy. Although no cause is apparent in many cases, dilated cardiomyopathy is probably the end result of damage to the myocardium produced by a variety of toxic, metabolic, or infectious agents. It may be the late sequel of acute viral myocarditis, possibly mediated through an immunologic mechanism. Autoimmune mechanisms are also suggested as a cause for dilated cardiomyopathy. A reversible form of dilated cardiomyopathy may be found with alcohol abuse, pregnancy, thyroid disease, stimulant use, and chronic uncontrolled tachycardia. Many cases of dilated cardiomyopathy are described as "idiopathic" meaning that the cause is unknown.

Patients suffering DCM are given the standard therapy for heart failure, typically including salt restriction, angiotensin-converting enzyme (ACE) inhibitors, diuretics, digitalis, and anticoagulants as well as alternative treatments including food supplements Coenzyme QlO, L-Carnitine, Taurine and D-Ribose. Atrificial pacemakers and implantable cardioverter- defibrillators may be used. In patients with advanced disease who are refractory to medical therapy, cardiac transplantation may be considered.

Dilated cardiomyopathy is also known in dogs and cats.

Due to the above-mentioned mechanism of action, the dopamine agonist pramipexole may be used for the treatment of dilated cardiomyopathy, will alleviate the symptoms, prevent the progression of the disease and will finally support the cure of the disease.

Restrictive cardiomyopathy (RCM) - a further mixed primary cardiomyopathy - is an uncommon cardiomyopathy. The walls of the ventricles are stiff, but may not be thickened, and resist the normal filling of the heart with blood. A rare form of restrictive cardiomyopathy is the obliverative cardiomyopathy, wherein the myocardium in the apices of the left and right ventricles becomes thickened and fibrotic, causing a decrease in the volumes of the ventricles and a type of restrictive cardiomyopathy. A form of an acquired primary cardiomyopathy is myocarditis which is an inflammation of the myocardium, the muscular part of the heart. It is generally due to viral or bacterial infection. It may present with chest pain, rapid signs of heart failure, or sudden death.

Takotsubo cardiomyopathy, a further acquired primary cardiomyopathy type, also known as transient apical ballooning, stress-induced cardiomyopathy and simply stress cardiomyopathy, is a type of non-ischemic cardiomyopathy in which there is a sudden temporary weakening of the myocardium.

Tachycardia induced cardiomyopathy, also known as chronotropic cardiomyopathy and tachycardio myopathy, is a weakening of the myocardium that is due to prolonged periods of a fast heart rate. It is likely dependent on a number of unknown factors.

A particularly preferred use according to the present invention is directed to cardiomyopathy developed in or in association with pregnancy. Such a disease is particularly peripartum cardiomyopathy also known as postpartum cardiomyopathy (also abbreviated as "PPCM"), a form of dilated cardiomyopathy that is defined as a deterioration in cardiac function presenting typically between the last month of pregnancy and up to five months postpartum. The cause of PPCM is unknown. Therefore, PPCM is a diagnosis of exclusion, wherein patients have no prior history of heart disease and there are no other causes of heart failure. Echocardiogram is used to both diagnose and monitor the effectiveness of treatment for PPCM. It is estimated that the incidence of PPCM is between 1 in 3000 to 4000 live births. Some studies assert that PPCM may be slightly more prevalent among older women who have had higher numbers of liveborn children and among women of older and younger extremes of childbearing age. However, a quarter to a third of PPCM patients are young women who have given birth for the first time.

As with other forms of dilated cardiomyopathy, PPCM involves a decrease of the left ventricular ejection fraction (EF) with associated congestive heart failure and an increased risk of atrial and ventricular arrhythmias and even sudden cardiac death. While the use of tocolytic agents or the development of pre-eclempsia may contribute to the worsening of heart failure, they do not cause PPCM; many women have developed PPCM who neither received tocolytics nor had pre-eclempsia. In short, PPCM can occur in any pregnancy. Currently, researchers are investigating cardiotropic viruses, autoimmune dysfunction, and genetics as possible components that contribute to or cause the development ofPPCM.

Symptoms usually include one or more of the following: orthopnea (difficulty breathing while lying flat), dyspnea (shortness of breath on exertion), pitting edema (swelling), cough, frequent night-time urination, excessive weight gain during the last month of pregnancy (two to four or more pounds per week), palpitations (sensation of racing heart-rate, skipping beats, long pauses between beats, or fluttering), and chest pain. The shortness of breath is often described by PPCM patients as the inability to take a deep or full breath or to get enough air into the lungs.

Unfortunately, patients and clinicians sometimes dismiss early symptoms because they appear to be typical of normal pregnancy, i.e. PPCM is difficult to recognize. Yet, early detection and treatment are critically important to the patient with PPCM. Delays in diagnosis and treatment of PPCM are associated with increased morbidity and mortality.

Known treatment for PPCM is similar to treatment for congestive heart failure. Conventional heart failure treatment includes the use of diuretics, beta blockers, and angiotensin- converting enzyme inhibitors (ACE-I) after delivery or hydralzine/nitrates before delivery. ACE-I may be replaced by angiotensin receptor blockers (ARB), if not well tolerated by the patient. Treatment with bromocriptine, an inhibitior of prolactin secretion, prevents the development of PPCM. Sometimes implantation of a left ventricular assist device or even heart transplant also becomes necessary. Most PPCM patients improve with treatment.

Therefore, pramipexole may also be used for the treatment of PPCM, will alleviate the symptoms, prevent the progression of the disease and will finally support the cure of the disease. Pramipexole may be used in the treatment of any cardiomyopathy due to its ability to decrease the prolactin level or inhibit the prolactin secretion, and is therefore assumed to directly interfere with the initiating and causing events of cardiomyopathies. According to the present invention it is therefore provided a novel use of pramipexole for the treatment of cardiomyopathy, particularly dilated cardiomyopathy, particularly preferred peripartum cardiomyopathy or postpartum cardiomyopathy (PPCM).

Women that develop cardiomyopathy after first pregnancy have an increasing risk to worsen the condition after a second pregnancy such that a heart transplant will be necessary. Therefore, pramipexole may also be used in patients of increased risk for developing a cardiomyopathy, patients susceptible to worsen the disease conditions and/or for prevention.

Pramipexole may be easily formulated in the usual pharmaceutical forms, preferably oral pharmaceutical forms such as tablets, capsules, suspensions, liquid form and the like. The usual methods of pharmaceutical scientists are applicable. It may usefully be administered, if there is any reason to do so in a particular circumstance, in other pharmaceutical forms, such as, but not limited to, injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will substantially always be preferred, however, to administer the anti-inflammatory agent as a tablet or capsule and such pharmaceutical forms are recommended.

It is considered that pramipexole or a pharmaceutically acceptable salt thereof is effective in the treatment of the indications as outlined above, while providing a benefecial safety profile, in particular, but not necessarily limited to, pleuropulmonal fibrosis, retroperitoneal fibrosis and fibrotic valvular heart disease and the like - for example if compared with bromocriptine.

The effective amount or dose of pramipexole, in particular in form of a pharmaceutically acceptable salt such as the dihydrochloride monohydrate, for treating cardiomyopathy is in the range from about 0.1 mg/day to about 10 mg/day. The preferred adult dose is in the range from about 0.2 to about 6 mg/day, and a more highly preferred adult dose is from about 0.4 to about 5 mg/day. The optimum dose for each patient must be set by the physician in charge of the case, taking into account the patient's size, other medications which the patient requires, severity and course of the cardiomyopathy or condition and all of the other circumstances of the patient.

The term "effective amount" of an active substance as used in the present invention means an amount sufficient to achieve the desired therapeutic effect such as to alleviate or eliminate the symptoms of the cardiomyopathy in a patient.

As used herein, the term "treatment" means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the cardiomyopathy in a patient.

The expression "cardiomyopathy" comprises any type of cardiomyopathy.

Pramipexole is available in the market as an immediate release formulation, known under the brand names Sifrol^® (Germany) or Mirapex^® (USA). Within the present context it also may be recommendable to apply pramipexole in an extended release form, a suitable one of which is disclosed in WO 2006/015942 or WO 2006/015943, each of which is hereby incorporated by reference (for each patent application the disclosure of the whole document).

An extended release tablet according to WO 2006/015942 and applicable in the context of the present invention is characterised in that the extended release formulation comprises pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least one water swelling polymer, preferably other than pregelatinized starch. The matrix preferably comprises at least two water swelling polymers preferably other than pregelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer. The anionic polymer preferably is selected from the group of optionally crosslinked acrylic acid polymers, methacrylic acid polymers, alginates and carboxymethylcellulose. The anionic polymer is an optionally crosslinked acrylic acid polymer, wherein the content of the optionally crosslinked acrylic acid polymer in the matrix is from about 0.25 wt.-% to about 25 wt.-%, and preferably from about 0.5 wt.-% to about 15 wt.-%, and preferably from about 1 wt.-% to about 10 wt.- %. Optionally, at least one of the at least two polymers is a substantially neutral polymer, preferably other than pregelatinized starch. Preferably, the substantially neutral polymer is selected from hydroxypropyl cellulose and hydroxypropylmethyl cellulose. More preferably the substantially neutral polymer is hydroxypropyl methylcellulose, and wherein the content of hydroxypropyl methylcellulose in the matrix is from about 10 wt.-% to about 75 wt.-%, and preferably from about 25 wt.-% to about 65 wt.-%.

Further excipients include, but are not limited to magnesium stearate, microcrystalline cellulose, lactose, silicon dioxide, starch, preferably corn starch.

In one embodiment the matrix comprises about:

(a) pramipexole or a salt thereof 0.05 to 5 wt.-% (b) anionic water swelling polymer(s) 0.25 to 25 wt.-%

(c) neutral water swelling polymer(s) 10 to 75 wt.-%

(d) further excipients ad 100 wt.-% with preferably the pramipexole being in form of its hydrochloride monohydrate, the anionic water selling polymer (b) preferably being an acrylic acid polymer, preferably from the carbomer group, more preferably carbopol 941 , the neutral water swelling polymer (c) preferably being hydroxypropylmethylcellulose and the further pharmaceutical acceptable excipients being selected from the group of magnesium stearate, silicon dioxide, corn starch, lactose, microcrystalline cellulose.

In one embodiment the matrix comprises

(a) at least one water swelling polymer other than pregelatinized starch and optionally excipients, the resulting tablet providing a pH-independent in vitro release characteristic in the range from pH 1 to 7.5, or

(b) at least one water swelling anionic polymer and optionally excipients, the resulting tablet providing a pH-dependent release characteristic with a preferably faster release characteristic in the range of pH < 4.5, and a slower and further on pH-independent release characteristic in the range from pH 4.5 to 7.5.

Such an extended release tablet may have a non- functional coating. Preferably, such tablet is for a once daily application.

An extended release pellet formulation according to WO 2006/015943 and applicable in the context of the invention is characterised in that it comprises an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof, and at least one release- modifying excipient. Preferably, the active ingredient is embedded within a matrix formed by the at least one release-modifying excipient, which is preferably selected from the group of lipids, waxes, and water-insoluble polymers. Preferably, it comprises a core and a coating, wherein at least one release-modifying excipient is incorporated in the coating and optionally the active ingredient is incorporated in the core. Such a coating may comprise at least a first layer and a second layer surrounding the first layer, wherein the first layer comprises the active ingredient, and wherein the second layer comprises at least one release-modifying excipient, preferably selected from ethylcellulose, cellulose acetate, polyvinylacetate, polyacrylates, polymethacrylates, and ammonio methacrylate copolymer. The second layer further may comprise at least one water-soluble excipient, preferably selected from hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and polyethylene glycol. The second layer may further comprise an enteric coating polymer, preferably selected from methacrylic acid copolymers type A and B.

In one embodiment, the second layer comprises from about 10 to about 85 wt.-% of the enteric coating polymer and from about 15 to about 75 wt.-% of the water-insoluble polymer. The core may comprise a saccharide, such as saccharose, starch, cellulose and a cellulose derivative, preferably microcrystalline cellulose.

In one embodiment, the extended release pellet formulation comprises an inert pellet core; a first layer being an active ingredient layer comprising pramipexole or a pharmaceutically acceptable salt thereof and optionally one or more wet binders and further excipients; and - a second layer provided on the first layer, the second layer being an extended release coating comprising

(a) at least one water-insoluble polymer and optionally a pore former, the resulting pellet having a pH-independent in vitro release characteristic or (b) a mixture of a pH-dependent enteric-coating polymer and a pH- independently water swelling polymer, the resulting pellet having a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8 and a more accelerated release above pH 7.3.

The inert pellet core may comprise polysaccharides, cellulose, a cellulose derivative, starch and/or waxes. The inert pellet core further may comprise saccharose and/or microcrystalline cellulose, preferably microcrystalline cellulose.

Such an extended release pellet formulation using active pellets containing pramipexole or a pharmaceutically acceptable salt thereof may be prepared by wet or melt extrusion or melt granulation instead of pellets prepared by drug substance layering onto inert pellet cores.

The water- insoluble polymer of the extended release pellets may be selected from the group consisting of ethylcellulose, cellulose acetate, polyvinylacetate, polyacrylates and derivatives, such as quaternary ammonium substituted acrylic polymer, preferably ammonio methacrylate copolymer, type B, and ethylcellulose, most preferably ethylcellulose.

The pH-dependent enteric-coating polymer may be an anionic carboxylic acrylic polymer, preferably a partly methyl esterifϊed methacrylic acid polymer, soluble above a pH value of 5.5, preferably above a pH value of 7.0.

The pH-independently water swelling polymer also may be a quaternary ammonium substituted acrylic polymer, preferably having an ammonium substitution of about 5 to about 10 % by weight.

The pH-dependent enteric-coating polymer may be present in an amount of 10 to 85 % by weight of the coating and the pH-independently water swelling polymer is present in an amount of 15 to 75 % by weight of the coating.

The extended release coating may additionally contain a pore-forming component. The pore-forming component may be selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and polyethylen glycol, preferably selected hydroxypropylcellulose from the Klucel series.

The extended release pellet formulation containing an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof may be prepared by wet or melt extrusion or melt granulation using excipients achieving extended release without a further diffusion membrane.

The pellets may be applied in form of a capsule, which comprises a sufficient number of pellets to provide a daily dose administered at one time.

To the extent that any pharmaceutically active compound is disclosed or claimed in the present invention, it is expressly intended that all active metabolites which are produced in vzVo are included, and it is expressly intended that all enantiomers, diastereomers or tautomers are included, if the compound is capable of occurring in its enantiomeric, diastereomeric or tautomeric form and if not indicated otherwise. Obviously, the isomer which is pharmacologically most effective and most free from side effects is preferred.

Pramipexole may be administered in form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" means a salt of pramipexole which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically-acceptable acid addition salts and pharmaceutically-acceptable base addition salts. Lists of suitable salts are found in, e. g. , S. M. Birget al, J. Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

Pramipexole may be used in form of a salt which may be prepared from pharmaceutically acceptable acids. When selecting the most preferred salt, or to clarify whether a salt or the neutral compound is used, properties such as bioavailability, ease of manufacture, workability and shelf life are taken into consideration, inter alia. Suitable pharmaceutically acceptable acids include acetic acid, benzenesulphonic acid (besylate), benzoic acid, p- bromophenylsulphonic acid, camphorsulphonic acid, carbonic acid, citric acid, ethanesulphonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid (mesylate), mucinic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p- toluenesulphonic acid and the like. Examples of pharmaceutically acceptable salts include, without being restricted thereto, acetate, benzoate, hydroxybutyrate, bisulphate, bisulphite, bromide, butyne-l,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-l,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulphonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, naphthalene- 1-sulphonate, naphthalene-2-sulphonate, oxalate, phenylbutyrate, phenylproprionate, phosphate, phthalate, phenylacetate, propanesulphonate, propiolate, propionate, pyrophosphate, pyrosulphate, sebacate, suberate, succinate, sulphate, sulphite, sulphonate, tartrate, xylenesulphonate and the like.

In the context of the present invention pramipexole is the (-) enantiomer (65)-N6-propyl- 4,5,6,7-tetrahydro-l,3-benzothiazole-2,6-diamine and the pharmaceutically acceptable salts thereof.

However, the (+) enantiomer thereof, (6i?)-N6-propyl-4,5,6,7-tetrahydro-l,3-benzothiazole- 2,6-diamine and the pharmaceutically acceptable salts thereof may be employed in the present invention instead or in addition to pramipexole as well.

In any case, the preferred active ingredient of the present invention is pramipexole, i.e. the (-) enantiomer (65)-N6-propyl-4,5,6,7-tetrahydro-l,3-benzothiazole-2,6-diamine and the pharmaceutically acceptable salts thereof.

In the following the invention shall be illustrated in form of exemplary formulations. However, the present invention is not limited to the described formulations, but other dosage forms and additives are possible. Formulation Examples of pramipexole

a.) immediate release formulations:

Tablet comprising 0.125 mg pramipexole-dihydrochloride-monohydrate, or 0.25 mg thereof, or 0.5 mg thereof, or 1 mg thereof in combination with mannitol, corn starch, highly dispersed silicon dioxide, povidon, magnesium stearate. This formulation is known in the market as Sifrol^® or Mirapex^® (immediate release formulation).

b.) extended release formulations:

ba. pramipexole extended release tablets ba.l

ba.2

ha.6

ba.9

ba.10

ba.ll

For any of the above mentioned examples the weight relations between the ingredients may vary within the range outlined in the description, in particular the amount of pramipexole, pramipexole dichloride monohydrate respectively, may vary, preferably between 0.01 and 7 mg, more preferably between 0.5 and 5 mg.

General scope of the composition:

(a) pramipexole or a salt thereof 0.05 to 5 wt.-%

(b) anionic water swelling polymer(s) 0.25 to 25 wt.-%

(c) neutral water swelling polymer(s) 10 to 75 wt.-%

(d) further pharmaceutically acceptable excipients ad l00 wt.-%

bb. pramipexole extended release capsules bb.l

* removed during processing, does not appear in the final product

bb.2

removed during processing, does not appear in the final product bb.3

* removed during processing, does not appear in the final product bb.4

* removed during processing, does not appear in the final product bb.5

* removed during processing, does not appear in the final product bb.6

bb.7

Pellets prepared by melt extrusion with hydrophilic excipients

In order to achieve adequate content uniformity, 9 g polyethylene glycol 6000 (PEG) is mixed with 1 g of pramipexole. Then this mixture is mixed with 50 g PEG 6000 and 40 g poloxamer 188. The mixture is extruded in a twin screw extruder at 54°C, diameter of dye is 0.7 mm using a face cut granulator to achieve pieces of about 1 mm. These are rounded in a spheronizer at 400 rpm and 41⁰C. The pellets are sieved, the fraction of 0.8 - 1.1 mm is used for retardation as described in the previous examples.

Examples for melt extrusion:

bb.8

Pellets prepared by melt extrusion

In order to achieve adequate content uniformity, 9 g stearyl alcohol is mixed with 1 g of pramipexole. Then this mixture is mixed with 90 g stearyl alcohol. The mixture is extruded in a twin screw extruder at 51⁰C, diameter of dye is 0.7 mm using a face cut granulator to achieve pieces of about 1 mm. These are rounded in a spheronizer at 400 rpm and 41°C. The pellets are sieved, the fraction of 0.8 - 1.1 mm is used for retardation as described in the previous examples. The following table provides some further examples of melt extrusion.

Examples for melt extrusion:

bb.9

Extended release pellets prepared by wet extrusion

In order to achieve adequate content uniformity, 9 g microcrystalline cellulose is mixed with 1 g of pramipexole. Then this mixture is mixed with 60 g microcrystalline cellulose and 30 g carbomer 97 IP. The mixture is extruded in a twin screw extruder with an adequate amount of water (or binder solution), diameter of dye is 0.7 mm. The resulting extrudates are rounded in a spheronizer at 400 rpm. After drying, pellets are sieved, the fraction of 0.8 - 1.1 mm is filled into capsules.

bb.lO

Extended release pellets prepared by melt extrusion

In order to achieve adequate content uniformity, 9 g hydrogenated castor oil is mixed with 1 g of pramipexole. Then this mixture is mixed with 60 g hydrogenated castor oil and 30 g carnauba wax. The mixture is extruded in a twin screw extruder with an adequate amount of water (or binder solution), diameter of dye is 0.7 mm. The resulting extrudates are rounded in a spheronizer at 400 rpm. Pellets are sieved, the fraction of 0.8 - 1.1 mm is filled into capsules.

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Extended release pellets prepared by hot melt granulation/melt pelletization

In this process agglomeration of active ingredient with excipients is promoted by the addition of low melting point, lipophilic binders, such as waxes, fats, fatty acids, fatty acid alcohols, and more water soluble polymers, such as poloxamers or polyethylene glycols. The binder is usually added to the other components as a powder. The binder is liquefied by heat generated either by friction during the mixing phase or by a heating jacket. Excipients suitable are e.g. lactose, microcrystalline cellulose, and dibasic calcium phosphate. After melting and granulation of the mass, the resulting mass is either cooled down, screened and processed into tablets together with further excipients or, spheronized into pellets, which can be coated in addition, and filled into capsules.

For any of the above mentioned examples the weight relations between the ingredients may vary within the range outlined in the description, in particular the amount of pramipexole, pramipexole dichloride monohydrate respectively, may vary within the formulation of one capsule, preferably between 0.01 and 7 mg, more preferably between 0.5 and 5 mg.

Claims

1. Use of the active ingredient pramipexole, (65)-N6-propyl-4,5,6,7-tetrahydro-l,3- benzothiazole-2,6-diamine, or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of cardiomyopathy.

2. The use according to claim 1, characterised in that the cardiomyopathy is a dilated cardiomyopathy.

3. The use according to claim 1 or 2, characterised in that the patient is a female patient.

4. The use according to any one of claims 1 to 3, characterised in that the female patient is a mammalian patient, particularly a human.

5. The use according to any one of claims 1 to 4, characterised in that the cardiomyopathy is developed in or in association with pregnancy.

6. The use according to any one of claims 1 to 5, characterised in that the cardiomyopathy is postpartum cardiomyopathy or peripartum cardiomyopathy

(PPCM).

7. The use according to any one of claims 1 to 6, characterised in that the pharmaceutical composition is for oral administration.

8. The use according to any one of claims 1 to 7, characterised in that the active ingredient is present in an immediate release formulation or an extended release formulation.

9. The use according to any of claims 1 to 8, characterised in that the active ingredient is present in an extended release formulation.

10. The use according to claim 9, characterised in that the extended release formulation is an extended release tablet formulation or an extended release pellet formulation.

11. The use according to any one of claims 9 or 10, characterised in that the extended release tablet formulation comprises pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising

(a) at least one water swelling polymer other than pregelatinized starch and optionally excipients, the resulting tablet providing a pH-independent in vitro release characteristic in the range from pH 1 to 7.5 or (b) at least one water swelling anionic polymer and optionally excipients, the resulting tablet providing a pH-dependent release characteristic with a faster release characteristic in the range of pH < 4.5, and a slower and further on pH- independent release characteristic in the range from pH 4.5 to 7.5.

12. The use according to any one of claims 9 or 10, characterised in that the extended release tablet formulation comprises pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising:

(a) pramipexole or a salt thereof 0.05 to 5 wt.-%

(b) anionic water swelling polymer(s) 0.25 to 25 wt.-% (c) neutral water swelling polymer(s) 10 to 75 wt.-%

(d) further pharmaceutically acceptable excipients ad 100 wt.-% with preferably the pramipexole being in form of its hydrochloride monohydrate, the anionic water selling polymer (b) preferably being an acrylic acid polymer, preferably from the carbomer group, more preferably carbopol 941, the neutral water swelling polymer (c) preferably being hydroxypropylmethylcellulose and the further pharmaceutical acceptable excipients being preferably selected from the group of magnesium stearate, silicon dioxide, corn starch, lactose, microcrystalline cellulose.

13. The use according to any one of claims 9 or 10, characterised in that the extended release pellet formulation comprises an inert pellet core; a first layer being an active ingredient layer comprising pramipexole or a pharmaceutically acceptable salt thereof and optionally one or more wet binders and further excipients; and a second layer provided on the first layer, the second layer being an extended release coating comprising

(a) at least one water-insoluble polymer and optionally a pore former, the resulting pellet having a pH-independent in vitro release characteristic or

(b) a mixture of a pH-dependent enteric-coating polymer and a pH- independently water swelling polymer, the resulting pellet having a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8 and a more accelerated release above pH 7.3.