US20130040937A1

US20130040937A1 - Inhibitors for treating and preventing heart failure in felines

Info

Publication number: US20130040937A1
Application number: US13/584,657
Authority: US
Inventors: Balazs Albrecht; Martin Folger; Saskia Kley; Ingo Lang; Randolph Seidler
Original assignee: Boehringer Ingelheim Vetmedica GmbH
Current assignee: Boehringer Ingelheim Vetmedica GmbH
Priority date: 2011-08-12
Filing date: 2012-08-13
Publication date: 2013-02-14
Also published as: KR20140057604A; AU2012296938A1; CN103781468A; KR20140053307A; US20130084332A1; MX2014001556A; JP2014521714A; US20140227351A1; AR089646A1; MX2014001557A; EP2741736B1; JP2014521713A; BR112014003061A2; RU2014109074A; US9289390B2; EP2741735A1; EP3318247A1; CN103796638A; CA2843100A1; AR089645A1

Abstract

The present invention relates to an I_fblocker or a pharmaceutically acceptable salt thereof and methods of using the I_fblocker or a pharmaceutically acceptable salt thereof to treat and/or prevent heart failure (HF) in a feline patient. The invention also relates to improving the quality of life, improving the general health condition, as well as, prolonging the life expectancy in feline patients suffering from heart failure, specifically heart failure due to one or more of the following etiologies hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC).

Description

BACKGROUND OF THE INVENTION

A. Field of the Invention
The invention relates to veterinary medicine. In particular, the invention relates to inhibitors, or a pharmaceutically acceptable salt thereof, for the treatment of heart diseases, preferably heart failure (HF), in feline patients. It further relates to improving the quality of life, life expectency, and general health of felines suffering from heart failure, especially failure due to one or more of the following etiologies of hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC).
B. Description of the Related Art
Feline heart failure is predominantly caused by different cardiomyopathies. The most common feline cardiomyopathy (CMP) is hypertrophic cardiomyopathy (HCM), followed by restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC).
Typically cats with underlying cardiomyopathies remain clinically asymptomatic in the early stages of the disease until they are presented to the veterinarian because the disease has progressed and ventricular diastolic and/or systolic function is severely impaired resulting in heart failure.
Cats at this stage present either mild to moderate clinical symptoms with tachypnoea up to severe respiratory distress (dyspnoea) due to pulmonary oedema and/or pleural effusion requiring emergency treatment with oxygen therapy and intravenous diuretic and thoracocentesis in the case of pleural effusion.
Drugs that reduce heart rate should be of benefit; however, known heart rate-reducing drugs are nonspecific and have a range of actions on the cardiovascular and other systems, which both complicate the interpretation of the effects on heart rate and lead to undesired side effects.
Elevated heart rate, especially in pet animals, may be treated with bradycardic agents such as calcium (Ca⁺⁺) channel blockers, beta-receptor blockers, and other antiarrhythmic agents. Known Ca⁺⁺ channel blockers, which may be used for this purpose are diltiazem, verapamil, amlodipine, and nifedipine. Known beta-receptor blockers which may be used for this purpose are atenolol, bisoprolol, carvedilol, esmolol, sotalol, metoprolol, or propanolol.
Beta-receptor blockers and calcium channel blockers are the most frequently used drugs in preclinical feline CMP. However, the use of these drugs remains controversial since a beneficial effect on disease progression or survival has not been demonstrated with either drug. In addition, it has been shown that the left atrial systolic and global function was significantly decreased by atenolol.
Known other antiarrhythmic agents, which may be used for this puropose, are adenosine, amiodarone, atropine, digoxin, isoproterenol, lidocaine, tocainide, mexiletine, phenytoin, procainamide, propafenone, and quinidine, e.g. sulfonates gluconates. Calcium channel blockers, as well as, beta blockers can also be used as antiarrhythmic agents.
In addition, angiotensine-converting enzyme inhibitors (ACE inhibitors), positive inotropes and anti-thrombotic agents are often administered to cats with heart failure. ACE inhibitors are used to reduce the activity of the renin-angiotensin-aldosterone system. Known ACE inhibitors, which may be used for this purpose, are enalapril, ramipril, benzazepril, quinapril, perindopril, lisinopril, imidapril, zofenopril and trandolapril. Positive inotropes are used if the systolic function of the heart is decreased. Known positive inotropes, which may be used for this purpose, are pimobendan, dopamine, dobutamine, epinephrine, norepinephrine, isoprenaline, digoxin, digitalis alkaloids, and theophylline. Anti-thrombotic agents are administered in order to prevent the development of a thrombus or to dissolve it if it already exists. Known anti-thrombotic agents, which may be used for this purpose, are antiplatelet drugs, such as clopidogrel, aspirin; anticoagulants, such as heparin, warfarin, low molecular weight heparin, and thrombolytic drugs, such as streptokinase, tissue plasminogen activators.
So far known treatments in cats result in temporary relief of symptoms mainly with a diuretic drug to prevent further decompensation of the heart failure. However, all of these therapeutic regimens are only supportive in character and therefore limited.

SUMMARY OF THE INVENTION

The present invention provides methods and uses for the treatment of heart failure in feline patients, in particular cats. Further, the invention provides a means of improving the quality of life while reducing the risk of death in feline patients, such as cats, especially in those suffering from heart failure of any etiology.
The use of cilobradine or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment or prevention of heart failure is described in patent application EP 1 534 296 B1. Patent application EP 1 534 296 B1 is specifically incorporated herein by reference.
The present invention provides methods of treating one or more felines, preferably cats, that comprise administering a funny (If) current inhibitor or a pharmaceutically acceptable salt thereof to a feline at risk of heart failure or suffering from heart failure. A treated feline is expected to experience at least one improvement in health selected from the group consisting of reduced heart failure, prevented heart failure, improved quality of life, improved general health condition, and prolonged life expectency as compared to a similar feline at risk of heart failure or suffering from heart failure that has not received an I_fcurrent inhibitor. In particular, the present invention provides methods of treating felines suffering from heart failure due to hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC).
In the practice of the invention, preferred I_fcurrent inhibitors or pharmaceutically acceptable salts thereof include compounds selected from the group consisting of cilobradine, zatebradine, anilidine, ivabradine, and their respective pharmaceutically acceptable salts thereof. Cilobradine or its hydrochloric salt are more preferred compounds.
It is envisioned that I_fcurrent inhibitors or pharmaceutically acceptable salts thereof are administered either in an oral or parenteral form. The medicament containing the I_fcurrent inhibitors or pharmaceutically acceptable salt thereof may be in either a solid or a liquid formulation. In general, liquid formulations are preferred for cats due to their relative ease of adminstration. But, for other felines, a solid formulation, as described herein, may be desirable.
It will be understood by those of skill in the art that the dosage used may be tailored to the specific patient. Herein, preferred dosages include 0.01 to 2 mg per kg bodyweight per day. If the medicament is administered in a solid formulation then a preferred solid formulation comprises 0.001 to 0.2 mg of the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof per mg of the solid formulation. Alternatively, if the medicament is administered in a liquid formulation then a preferred liquid formulation comprises 0.1 to 20 mg of the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof per mg of the liquid formulation.
Administration of medicament comprising an I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof is preferably once or twice per day, and more preferably once per day. Preferably, the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof is administered in a daily dosage of 0.01 to 2 mg/kg bodyweight.
The invention also provides for the administration of combination therapy wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with at least one diuretic. Preferably, the diuretic is administered in a dosage of 0.5 to 10 mg/kg bodyweight once or twice daily. The diuretic may be administered simultaneously or sequentially, before or after, with the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof.
Methods of the invention also include administering a funny (I_f) current inhibitor or a pharmaceutically acceptable salt thereof (or medicament comprising a I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof) to a feline having heart failure selected from the group consisting of hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) such that the treated feline experiences at least one improvement in health selected from the group consisting of reduced heart failure, prevented heart failure, improved quality of life, improved general health condition, and prolonged life expectency as compared to a similar feline that has not received an I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1. The quality of life measured in cats over time. Cats treated with cilobradine are represented by solid black trapezes. Cats that received placebos are represented by open circles.

DETAILED DESCRIPTION

Herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a preparation” includes a plurality of such preparations. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs at the time of filing. The meaning and scope of terms should be clear; however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including”, as well as other forms such as “includes” and “included” is not limiting. All given ranges and values may vary by 1 to 5% unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term “about” was omitted from the description. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.
Cardiac pacemaker cells are key to the generation of pacemaker activity and the autonomic modulation of heart rate. They have the ability to spontaneously generate slow diastolic depolarisation that drives the membrane voltage away from the hyperpolarised level reached at the completion of one action potential towards the threshold level for initiating a subsequent action potential. The rhythmic action potentials thus generated propogate through the conducting systems of the heart and trigger myocardial contraction.
Pacemaker activity involves the interplay between several ionic currents that influence the spontaneous diastolic depolarisation of the sinoatrial node. The main source of depolarising current at this phase is the pacemaker or so-called “funny” (I_f) current. The pacemaker or funny I_fcurrent is a mixed potassium-sodium inward current that in cardiac pacemaker cells of the sinoatrial node activates upon membrane hyperpolarisation below a threshold of about −45 mV, and whose activation range encompasses the range of diastolic depolarisation (about −65 to −40 mV). Additionally, the I_fcurrent mediates control of cardiac rate by autonomic transmitters.
The present invention relates to a pacemaker or funny I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof for treating and/or preventing of heart diseases, preferably related to heart failure (HF) in feline patients, preferably cats. Furthermore, the invention relates to a pacemaker or funny I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof for improving quality of life, and/or improving general health condition, and/or prolonging life expectancy in feline patients, in particular cats, suffering from HF.
The term “heart failure” as used herein relates to a condition in which a problem with the structure or function of the heart impairs its ability to supply sufficient blood flow to meet the body's needs, in particular any contractile disorder or disease of the heart. Clinical manifestations are, as a rule, the results of changes to the heart's cellular and molecular components and to mediators that drive homeostatic control. Heart failure is caused by different diseases of the heart. There are several main indications with different etiology that may result in heart failure such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restricted cardiomyopathy (RCM), unspecified cardiomyopathy (UCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Preferably these cardiomyopathies are classified according to Kittleson (Kittleson, Textbook of veterinary internal medicine, Eds. Ettinger, Feldman, Elsevier Saunders, Philadelphia. 2005, 1082). Thus, according to a further aspect the present invention relates to a I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof for treating or preventing heart diseases, preferably HF due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC. Thus, the invention also relates a I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof for improving quality of life and/or improving general health condition and/or prolonging life expectancy in feline patients, preferably cats, suffering from HF due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC. The invention also relates to the management of heart failure in cats due to HCM, UCM, RCM, DCM, and/or ARVC.
The degree of heart disease in feline patients, preferably cats, in particular heart failure or heart failure due to HCM, UCM, RCM, DCM, ARVC, is as adopted by the International Small Animal Cardiac Health Council (ISACHC) classification scheme. For feline patients, in particular cats, heart failure is classified based on the result of history, physical examination, and further examinations such as echocardiographic examination, and if deemed necessary, thoracic radiographic examination. The classification scheme is as follows. Class IA comprises asymptomatic cats that show evidence of a heart murmur without clinical signs and without echocardiographic evidence of cardiac structural changes. Class IB comprises asymptomatic cats that show evidence of a heart murmur without clinical signs but with echocardiographic evidence of cardiac structural changes without enlargement of cardiac. Class II comprises cats with mild to moderate heart failure. Echocardiographic evidence of CMP and mild to moderate heart failure includes evidence of mild to moderate clinical symptoms for heart failure (i.e. shortening of breath/tachypnoea, mild respiratory distress/dyspnoea). Here, treatment (i.e. with a diuretic as defined herein, e.g. furosemide) is necessary to control clinical symptoms, but is possible at home.
Class IIIA comprises cats having advanced heart failure but outpatient therapy is possible. Echocardiographic evidence of CMP and advanced heart failure includes clinical signs that are immediately obvious, like respiratory distress (dyspnoea), or hypoperfusion at rest. Outpatient therapy is possible; hospitalization is not required. Class IIIB includes cats with advanced heart failure requiring hospitalization. Echocardiographic evidence of CMP shows advanced clinical signs of heart failure, which requires treatment at the hospital (i.e. iv (intravenous) furosemide, oxygen supplementation).
Thus, as an example the invention provides for treating a cat that belongs to class IIIA or IIIB with a composition of the invention such that the cat is improving in health or in symptoms enough for it to reach a better ISACHC class such as class II, or a class IA or a class IB, as compared to non-treated cats. The same is valid for treating a cat that belongs to the ISACHC scheme to belong to class II with a composition of the invention such that the cat is improving in health or in symptoms enough for it to be regraded as class IA or class IB, as compared to non-treated cats.
According to another aspect of the invention, cats suffering from heart disease can also be classified with a score of 1, 2 or 3 using a 4 point score adapted from the ISACHC. Here, a Score 1 means no clinical signs associated with heart disease are apparent but heart disease is detectable (e.g. auscultation, echocardiography and radiography). A Score 2 means that clinical signs of heart failure are evident and adversely affect the quality of life. Typical signs include dyspnea/tachypnea, pulmonary congestion, weakness/lethargy, anorexia, and exercise intolerance. A Score 3 means that clinical signs of advance heart failure are immediately obvious. These clinical signs could include respiratory distress, marked ascites/pulmonary congestion, profound exercise intolerance, or hypoperfusion at rest. A Score 4 identifies severe cases, which include moribundity, suffering from cardiogenic shock or acute posterior paresis/paralysis. Hospitalization is mandatory. Thus, as an example, a cat treated with a composition or method of the present invention and that belongs to score 3 or 4 would be expected to improve in health and/or in symptoms enough for it to reach a better ISACHC score such as score 2 or 3, respectively, as compared to non-treated cats.
The term “quality of life” as used herein also relates to a tendency of a better quality of life (QoL) when treated with a I_fcurrent inhibitor, in particular cilobradine, versus placebo treated patients. For the purpose of the present invention a cat's quality of life is assessed, in particular by owners and in general as described by Freeman et al. 2010 (Freeman L M, Rush J E, Oyama M A. Development and Evaluation of a Quality of Life Questionnaire for Cats with Cardiac Disease. J Vet Intern Med 2010; 24: 674). The change, in particular the improvement of the quality of life, is measured with the following grading system: 0 (not at all/none), 1 (very little/very few), 2 (little/few), 3 (moderately/some), 4 (much/many) and 5 (very much/a lot). The assessment further includes an evaluation of a development of and/or changes in breathing difficulties, tiredness/fatique, fainting/collapsing, eating habits, drinking habits, behaviour in general, behaviour regarding using a litter box, personality, and hospitalisation.
The cat's quality of life can also be assessed by the owner on a daily base. The change is measured with the following grading system: 1 (better), 2 (equal), 3 (worse). The assessment refers to the overall perception of the owner including all his/her impressions.
Thus, the method for improving the quality of life relates to an increase in one of the grading systems as described above. As an example the invention relates to improving quality of life in feline patients being grade 3 or 4 to grade 2 or 3, respectively, after the administration of the invention as described herein, as compared to non-treated cats.
The ease of administration also contributes to the quality of life of the animal in need of such treatment as the treatment can only be successful when it is possible to administer the pharmaceutical composition for the treatment of heart diseases to the feline, preferably a cat. An assessment of the ease of administration can be made. For example, whether the majority of the time it was mostly uncomplicated to give, difficult to give, or often not possible to give a pharmaceutical composition comprising a funny I_fcurrent inhibitor, in particular cilobradine, and other excipients and/or vehicles. In addition, the owner is asked if the medication was given in the majority of time with the application syringe directly into the mouth or with a small amount of food.
The demeanour of the feline, in particular a cat, is assessed by veterinarians, by evaluating how active, listless or depressed the feline acts. An assessment of the overall control of the heart disease is also included as poor, fair, good, or excellent.
The term “improving general health condition” as used herein relates to findings during clinical examination, results of the laboratory measurements, assessment of echocardiography, ECG, X-ray parameters, blood pressure measurement, dose of administered medication, as well as the cat's behavior. Thus, in order to evaluate the improvement of the general health condition of a feline patient, preferably at least two examinations have to be performed, in particular before and after administration as described herein. As an example, the general health condition of a feline patient is improved if the findings during clinical examination, results of the laboratory measurements, assessment of echocardiography, ECG, X-ray parameters, dose of administered medication, as well as, the cat's behavior show a beneficial effect of the administration of the invention as compared to non-treated cats.
The term “prolonging life expectancy” encompasses “long-term survival time” or “reducing cardiac mortality or morbidity”, which as used herein relates to the superiority of an I_fcurrent inhibitor, in particular cilobradine, as compared to a placebo or non-treatment in cats with heart failure, meaning that the cats have a longer life span, or improved quality of life, and/or general health following administration, preferably on a regular daily basis, of the described invention.
Cardiac mortality is defined to be an event when a spontaneous death occurs during the study period, where no other clinical cause could be identified despite the knowledge of the underlying cardiac disease. Cardiac morbidity is defined to be an event when a progression of the cardiac disease occurs that requires rescue therapy. Rescue therapy is given to a cat in the event of cardiac morbidity. Cardiac morbidity is defined to include progression of the cardiac disease with adjunct worsening of clinical symptoms (e.g. worsening of respiratory signs) when one of the following criteria is met: the cat requires diuretic treatment, preferably furosemide, with dosages above the upper dose limit of 10 mg/kg per day to control clinical symptoms (e.g. dyspnoea) of heart failure; the cat requires additional treatment, such as angiotensine-converting enzyme inhibitors, Ca-channel blockers, f3-receptor blockers, nitroglycerine, diuretics other than furosemide or other antiarrhythmic drugs because of worsening of clinical symptoms (e.g. dyspnoea, lethargy) and either worsening of echocardiographic examination parameters (e.g. significantly decreased FS, left atrium size enlargement) compared to baseline assessment or worsening of creatinine blood levels >440 μmol/L (>5.0 mg/dl) or development of clinically significant electrolyte imbalances (i.e. hypokaliaemia, hyponatriaemia); the cat develops a thromboembolic event; the cat develops more than two relapsing episodes of acute congestive heart failure (ISACHC class IIIB) requiring hospitalization necessitating oxygen therapy and/or intravenous (iv) diuretic medication; or the cat needs to have more than 2 repeated thoracocentesis. The assessment is based on the following hypothesis HO and HA: HO equates to no superiority of treatment with cilobradine as compared to placebo control; HA equates to superiority of treatment with cilobradine as compared to placebo control. As an example, the invention relates to prolonging life expectancy in feline patients, if the life span of the cat is prolonged in comparison to non-treated cats or if the assessment meets the requirements for the HA criterion as mentioned above, or a similar requirement.
“Funny I_fcurrent inhibitors”, also referred to as “I_fchannel blockers” or “I_fcurrent inhibitors” herein, relate to I_finhibitors including pharmaceutically acceptable salts thereof, which selectively block hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in cardiac conductive tissue, channels responsible for the transmembrane current known as I_f. It is through blockade of this current that I_fchannel blockers are assumed to produce their specific bradycardic effect. HCN channels are widely distributed in the nervous system and in the eye they mediate the current known as I_h. The effect of zatebradine and cilobradine on the I_hchannel has also been investigated (See Neuroscience, Vol. 59(2), pp. 363-373, 1994 for zatebradine, and British Journal of Pharmacology, Vol. 125, pp. 741-750, 1998 for cilobradine). The results have suggested that I_hcan also be blocked by these compounds. Since I_hhas been described in the different neurones of the visual signal processing system, the effect on I_hcurrent has been suggested to be an explanation for possible side-effects (visual disturbances) of some I_fblockers. Cilobradine in particular reduces the heart rate in the sinoatrial node of the heart by selective blockade of I_fchannels (“funny channels”) through a direct interaction with predominantly HCN4 channels. This blockage is potent and has a dosage and voltage dependency. Because of the high selectivity to the I_fcurrent, effects on vasomotor tone or myocardial contractility and lusitropy are not observed at therapeutically relevant doses in healthy cats. The negative chronotropic effect of cilobradine leads to a reduction of myocardial oxygen demand, prolongation of the diastolic interval, and increased stroke volume with a subsequent increase of myocardial oxygen supply.
Preferred I_fcurrent inhibitors include cilobradine, anilidine, zatebradine and ivabradine, more preferably cilobradine and zatebradine, and most preferred is cilobradine.
Cilobradine (3[(N(2(3,4 dimethoxy-phenyl)-ethyl)-piperidin-3 yl)-methyl]-(7,8 dimethoxy-1,3,4,5 tetrahydro-2H 3-benzazepin-2 one) and its hydrochloride salt, are disclosed for example in EP B 0 224 794 and its US counterpart U.S. Pat. No. 5,175,157, both of which are incorporated herein by reference. As already mentioned cilobradine is also known to have a favourable activity in the treatment or prevention of heart failure (see EP-B-1 534 296). Cilobradine, zatebradine and alinidine are also known to have a favourable activity in the treatment and induction of the regression of idiopathic hypertrophic cardiomyopathy (HCM), ischemic cardiomyopathy and valvular hypertrophic heart diseases (see WO 01/78699).
Anilidine [2 (N allyl-2,6 dichloro-anilino)-2 imidazolidine], is disclosed in U.S. Pat. No. 3,708,485, and ivabradine 3-[3-[[[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one and its hydrochloride salt, is disclosed in EP-B-534859, both of which are incorporated herein by reference.
Zatebradine [1(7,8 dimethoxy-1,3,4,5 tetrahydro-2H 3-benzazepin-2 on-3 yl)-3[N methyl-N (2(3,4-dimethoxy-phenyl)-ethyl)-propane], is disclosed in EP B 0 065 229 and its US counterpart U.S. Pat. No. 5,516,773, both of which are incorporated herein by reference. Zatebradine is known to have a favourable activity in the treatment of cardiac insufficiency (see EP B 0 471 388).
Ivabradine is especially known to have a favourable activity in the treatment of myocardial disorders (from EP-B-534859 or U.S. Pat. No. 5,296,482). The administration of ivabradine in cats with subclinical HCM is described by Riesem et al. (Riesen, Schober, Smith, Otoni, Xiaobai, Bonagura; AJVR, Vol.73, No. 2: Effects of ivabradine on heart rate and left ventricular function on healthy cats and cats with hypertrophic cardiomyopathy). Here, a significant heart rate reduction was observed in both healthy and subclinical HCM cats. The negative chronotropic effect showed dose-dependency in the healthy cats.
The term “patient” as used herein relates to feline patients, preferably cats, even more preferred domestic cats, in particular to felines suffering from heart failure, even more preferrably to cats suffering from heart failure. According to another embodiment of the invention the feline patients suffer from heart failure due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC.
Thus, according to the invention the funny I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine, is used for treating and/or preventing heart diseases, preferably heart failure (HF) in feline patients, preferably cats. Thus according to the invention the funny I_fcurrent inhibitors or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine, is used for treating and/or preventing heart diseases, preferably heart failure (HF) due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC in feline patients, preferably cats.
According to the invention the feline patient, preferably a cat, is additionally monitored with regard to its overall well-being and mortality. Administration of an I_f-channel blocker to a feline patient, in particular to cats, preferably results in not just the treatment and/or prevention of heart failure but also an improved quality of life and general health condition and a prolonged life expectancy.
Thus, the invention provides that the use of a funny current (I_f) inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine, improves the quality of life of feline patients, in particular cats, suffering from HF, in particular from HF due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC.
The invention provides that a funny current (I_f) inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine, also improves the general health condition of feline patients, in particular cats, preferably suffering from HF and/or HF due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC.
According to a further aspect of the invention, use of an I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine, prolongs the life expectancy of feline patients, in particular cats, preferably suffering from HF, especially HF due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC.
The term “effective amount” as used herein means an amount sufficient to achieve an alleviation of heart failure in a patient when a I_fcurrent inhibitor is administered at a dosage as described herein. The progress of the therapy can be monitored by standard cardiologic diagnosis, for example, by echocardiography, cardiac catheterization, or cardiac MRI, X-ray, ECG, cardiac biomarkers, or cardiac magnetic resonance imaging. The progress of the therapy can also be monitored by clinical symptoms as well as quality of life related parameters as defined above/herein. Furthermore the effective amount also gives the patient, preferably feline patients, more preferably cats, an improved quality of life and/or improved general health condition and/or prolonged life expectancy. This progress and improvement of well-being obtained by the therapy can be monitored by the pet owner, as well as, by a veterinarian.

Dosage

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the patient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the renal and hepatic function of the patient, and the effect desired.
A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disorder (e.g. heart failure). By way of general guidance, the dosage per administration of the active ingredient, preferably of a I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine, when used for the treatment and/or prevention of heart failure, will range from 0.01 mg/kg bodyweight to 1.0 mg/kg bodyweight per administration, preferably 0.02 to 0.8 mg/kg bodyweight, more preferably from 0.04 to 0.6 mg/kg bodyweight, even more preferably from 0.06 mg/kg to 0.4 mg/kg bodyweight or even 0.08 mg/kg to 0.3 mg/kg bodyweight, and most preferably from 0.1 mg/kg bodyweight to 0.3 mg/kg bodyweight or even 0.1 to 0.2 mg/kg bodyweight per administration. These dosages should be administered once or twice per day. The treatment is advisable in clinically apparent cases, both in acute as well as in chronic settings. The administration of the dosages preferably also results in one or more, preferably two or more, of the following conditions: an improved quality of life, improved general health condition and a prolonged life expectancy.
Thus the present invention relates to a use of a I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine for the preparation of a medicament/pharmaceutical composition for the treatment and/or prevention of a patient, preferably a feline patient, in particular a cat, suffering from heart failure. According to another aspect, the invention provides the use of a funny I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine for the preparation of a medicament/pharmaceutical composition for the treatment of a patient, preferably a feline patient, in particular a cat, suffering from heart failure due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC. This use preferably also results in one or more, preferably two or more of the following conditions: an improved quality of life, improved general health condition and a prolonged life expectancy in feline patients, in particular cats, suffering from heart failure, in particular heart failure due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC.
Preferably the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine is used for treating and/or preventing heart failure in a feline patient, in particular a cat, wherein the dosage to be administered is in the range from 0.01 to 2 mg/kg bodyweight per day, preferably in the range from 0.02 to 1.5 mg/kg bodyweight per day, more preferably in the range from 0.05 to 1 mg/kg bodyweight per day, even more preferably in the range from 0.07 to 0.7 mg/kg bodyweight per day, and most preferably in the range from 0.09 to 0.5 mg/kg bodyweight per day, and especially in the range or 0.1 to 0.3 mg/kg bodyweight per day or even 0.1 mg/kg to 0.2 mg/kg bodyweight per day.
Preferably the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, even more preferably cilobradine, is used for treating and/or preventing heart failure due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC in a feline patient, wherein the dosage to be administered is in the range from 0.01 to 2 mg/kg bodyweight per day, preferably in the range from 0.02 to 1.5 mg/kg bodyweight per day, more preferably in the range from 0.05 to 1 mg/kg bodyweight per day, even more preferably in the range from 0.07 to 0.7 mg/kg bodyweight per day, and most preferably in the range from 0.09 to 0.5 mg/kg bodyweight per day, or even in the range from 0.1 to 0.3 mg/kg bodyweight per day or even from 0.1 mg/kg to 0.2 mg/kg bodyweight per day.

Administration

The compounds of this invention can be administered in an oral dosage forms as tablets, capsules (each of which may include sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
According to the invention an I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine, is to be administered orally or parenterally.
The I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine, is administered once, twice, or three times per day, preferably once or twice, more preferably once per day.
The I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

Combined Use

Preferably, the I_fcurrent inhibitor, such as cilobradine, is administered in combination with a second active therapeutic agent. Preferably, the second active therapeutic agent is a diuretic. Preferably the diuretic is a loop diuretic, e.g. furosemide, bumetanide, ethacrynic acid or toresmide; or thiazide diuretic, e.g. chlorotiazide, hydrochlorothiazide, metolazone; or potassium-sparing diuretics, e.g. spironolactone, eplerenone, triamterene or amiloride. More preferably, the diuretic is furosemide and such potassium-sparing diuretic is spironolactone. The diuretic, in particular the loop diuretic, e.g. furosemide should be administered in a dose of 0.5 to 5 mg/kg once or twice daily. It may well be that the diuretic, e.g. furosemide, can be completely withdrawn once the patient has been stabilized.
Thus, according to a further aspect the present invention relates to the combined use of an I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine, with a diuretic, preferably a loop diuretic, e.g. furosemide, for the treatment of a feline patient, in particular a cat, suffering from heart failure. Preferably, the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine and adiuretic, in particular a loop diuretic, e.g. furosemide, are administered at the dosages described herein.
In a further aspect the present invention relates to a two phase combination therapy for the treatment of a patient suffering from heart failure comprising in the first phase the administration of an I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine in combination with a diuretic, in particular the loop diuretic, e.g. furosemide, and in the second phase the administration of the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine, without using loop diuretic, e.g. furosemide. Preferably, the I_fcurrent inhibitor, such as cilobradine, and a diuretic, in particular the loop diuretic, e.g. furosemide, are administered at the dosages described herein.
The present invention also relates to the combined use of a I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine, with one or two or more pharmaceutically active compounds selected from the group consisting of calcium channel blocker, a β-adrenoreceptor antagonists, positive inotropes, ACE inhibitors, anti-thrombotic agents and antiarrythmic agents, for the treatment and/or prevention of heart failure in a patient, preferably feline patient, more preferably a cat. In another aspect, the invention relates to an I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof, in particular cilobradine, zatebradine, anilidine or ivabradine, preferably cilobradine or zatebradine, more preferably cilobradine with one or two or more pharmaceutically active compounds selected from the group consisting of calcium channel blocker, a β-adrenoreceptor antagonists, positive inotropes, ACE inhibitors, antithrombotic agents and other antiarrythmic agents for the treatment and/or prevention of a patient, preferably feline patient, more preferably a cat, suffering from heart failure due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC. These described combined uses are also useful for one, two or more of the following conditions: improvement of the quality of life, improvement of general health condition, and a prolongation of life expectancy in feline patients, in particular cats, suffering from heart failure especially heart failure due to one or more of the following etiologies HCM, DCM, RCM, UCM and/or ARVC. Further, the invention relates to the management of heart failure in cats due to HCM, UCM, RCM, DCM, ARVC in conjunction with concomitant therapy such as administration of diuretics, in particular loop diuretics such as furosemide.
In a different aspect, one subject of the invention pertains to pharmaceutical compositions comprising cilobradine ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on), cilobradine hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride), zatebradine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline) for use in a method for the treatment of a heart disease in an animal, preferably a mammal, more preferably a predominantly carnivorous mammal, even more preferably feline, most preferably a cat.
In line with the aforesaid, cilobradine or cilobradine hydrochloride are preferred, more preferable is cilobradine hydrochloride, which is particularly preferred to use in multi-layered particles for the treatment of heart diseases, especially heart failure, in cats (felines), e.g. by incorporation into a respective medical formulation.
The use of liquid pharmaceutical compositions with a final concentration of the active ingredient of 0.5 to 5 mg/ml, preferaby 0.75 to 4 mg/ml, and more preferably 0.5 to 3 mg/ml is desired.
The invention provides the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof for use in methods as described herein, wherein the I_fcurrent inhibitor is selected from zatebradine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on, its enantiomer cilobradine ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on) or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline), or preferably cilobradine hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride).
Thus, the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof is provided for use in a method as described herein, wherein the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition in an overall liquid form, comprising the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof in a final concentration of 0.5 to 5 mg/ml, preferably 0.75 to 4 mg/ml, or more preferably in a final concentration 0.5 to 3 mg/ml.
The invention provides the use of a funny I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof for preparing a medicament, as described herein, wherein the funny I_fcurrent inhibitor is selected from zatebradine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on, its enantiomer cilobradine ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on) or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline), or more preferably cilobradine hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride).
The preparation of liquid formulations of the invention include the use of a funny I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof for preparing a medicament, as described herein, wherein the funny I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition in overall liquid form, comprising the funny I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof in a final concentration of 0.5 to 5 mg/ml, preferably 0.75 to 4 mg/ml, or more preferably 0.5 to 3 mg/ml.
The invention provides a method of treating or preventing heart failure and/or improving the quality of life and/or improving general health condition and/or prolonging life expectancy in a feline patient, preferably a cat, wherein the funny I_fcurrent inhibitor is selected from zatebradine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on, its enantiomer cilobradine ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on) or alinidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline), or more preferaebly cilobradine hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride).
Also provides is a method of treating or preventing heart failure and/or improving the quality of life and/or improving general health condition and/or prolonging life expectancy in a feline patient, preferably a cat, wherein the funny I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition in overall liquid form, comprising the funny I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof in a final concentration of 0.5 to 5 mg/ml, preferably 0.75 to 4 mg/ml, more preferably 0.5 to 3 mg/ml.
All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications, which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

Formulation of a Compound for the Treatment of a Heart Disease

This example provides the formulation of compound (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride in liquid form. For the production of multi-layered particles for incorporation into a liquid dosage form, a three-step process was applied that is summarized in Table 1.

TABLE 1

Flow chart for the production of multi-layered particles according to the
invention, comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-
piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-
3-benzazepin-2-on hydrochloride as active ingredient.

	starting
step	material	Coating	result

1	inert core	drug layering with	IR pellets
	particles	pharmaceutically active
		ingredient and HPMC/
		magnesium stearate
2	IR pellets	seal coating with PVP	SC (seal coated)
		K 30/Talc/colloidal
		siliciumdioxide	pellets
3	SC pellets	taste masking coating with	final multi-
		EC/HPMC/magnesium	layered particle
		stearate/colloidal
		siliciumdioxide

Step 1: Drug Layering

Microcrystalline cellulose particles with an average diameter of 100 μm were used as starting material and layered with active ingredient and binder, using water as the solvent. The layer material consisted of 66.6% (w/w) of the pharmaceutically active ingredient, 31.7% (w/w) HPMC (Pharmacoat® 606) and 1.7% (w/w) magnesium stearate, dispersed in purified water to yield approximately 19% solids in the spraying liquid. The resulting composition of the produced IR pellets is given in Table 2.

TABLE 2

Composition of IR pellets comprising (+)-3-[(N-(2-(3,4-dimethoxy-
phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-on hydrochloride.

	Component	Amount [% (w/w)]

	inert core particles (Cellets ® 100)	80.94
	pharmaceutically active ingredient	12.70
	HPMC (Pharmacoat ® 606)	6.04
	Magnesium stearate	0.32

Step 2: Seal Coating

The IR pellets produced in step 1 were further processed in the same apparatus by spraying the seal coating onto the IR pellets. The material for the seal coating was composed of PVP K 30 (commercially available by the provider BASF, Ludwigshafen, Germany, under the trade name Kollidon® 30/talc, at a weight-percent ratio of 75.4:22.5, dispersed in a 94:6 mixture (m/m) of acetone and ethanol. 0.5% (w/w) of a highly disperse (colloidal) silicium dioxide (Aerosil® 200, commercially available from Evonik) was added by an additional (intermediate step) to the seal coated material after the application of the PVP K 30/talc mixture and drying of the organic solvent. The total composition of the SC (seal coated) pellets yielded in this step (cilobradine seal coated pellets) is given in Table 3.

TABLE 3

Composition of SC pellets comprising (+)-3-[(N-(2-(3,4-dimethoxy-
phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-on hydrochloride.

	Component	Amount [% (w/w)]

	IR pellets comprising the	76.54
	pharmaceutically active ingredient
	PVP K 30 (Kollidon ® 30)	17.67
	Talc	5.29
	colloidal silicium dioxide (Aerosil ®	0.5
	200)

Step 3: Final Coating (Taste Masking Coating)

The SC pellets produced in step 2 were further processed in the same apparatus by spraying the final coating onto the SC pellets. The material for the final taste and/or odor masking coating was composed of EC/HPMC/magnesium stearate at a weight-percent ratio of 55.2:23.8:19.8 (the ratio of EC/HPMC in the film coating being about 70:30). For this purpose, EC, HPMC, and magnesium stearate were dispersed in a 1:1 mixture (v/v) of methanol and dichloromethane, and sprayed onto the SC pellets. The coating was applied to a thickness of 75% based on the initial amount of SC pellets. Like in step 2, 0.5% of the colloidal silica of Aerosil® 200 were added to the final product before sieving. The chosen EC was Ethocel® 45 cps STD Premium, commercially available from Dow Chemical, Schwalbach, Germany. The chosen HPMC for this layer was Methocel® E5 Premium LV, commercially available from Dow Chemical. Aerosil® 200 was provided by Evonik. The overall composition of the final multi-layered particles is given in Table 4.

TABLE 4

Composition of final multi-layered particles comprising (+)-3-[(N-(2-(3,4-
dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride.

	Component	Amount [% (w/w)]

	SC pellets comprising the	56.86
	pharmaceutically active ingredient
	EC	23.86
	HPMC	10.25
	Magnesium stearate	8.54
	colloidal silicium dioxide (Aerosil ®	0.5
	200)

Table 5 discloses the detailed overall composition of taste masked multi-layered particles comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride, as produced according to steps 1-3 of this example, along with the assumed physicochemical function of the respective material.

TABLE 5

Detailed composition of final multi-layered particles
comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-
piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-
2H-3-benzazepin-2-on hydrochloride

	Amount
Component	[% (w/w)]	Function

inert core particles (Cellets ® 100)	35.23	Carrier
pharmaceutically active ingredient	5.53	Drug layer
cilobradine (calculated as
hydrochloride)
HPMC	2.63
Polyvinylpyrrolidone K 30	10.05	Seal coating
Talc	3.01
Ethylcellulose	23.86	Final coating
HPMC	10.25	(taste masking)
Magnesium stearate	8.68
colloidal silicium dioxide	0.78	Reduction of
(Aerosil ® 200)		electrostatic charging
		in seal coating
		and final coating

Dissolution Experiments

The multi-layered particles produced in this example were tested with respect to their dissolution properties at two different pH values of 6.8 and 1.0. Measured values are the total percentage of released material after the respective time, normalized to the theoretical drug content. The result is given in Table 6.

TABLE 6

Drug release from multi-layered particles comprising (+)-3-[(N-(2-(3,4-
dimethoxyphenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride finally coated
with EC/HPMC 70:30 at pH 1 and pH 6.8 (mean, n ≧ 3).

Time [min]	% released at pH 1	% released at pH 6.8

0	0.0	0.0
5	19.4	7.2
10	25.6	9.4
30	53.4	16.7
45	72.9	23.2
60	87.2	30.9
90	103.4	48.3

According to these data, the dissolution from EC/HPMC coated pellets is delayed, thereby providing efficient taste and/or odor masking of the bitter drug (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on hydrochloride. This masking could be verified by acceptance tests with laboratory cats with the derived completely formulated liquid composition prepared as described below.
Usually, EC/HPMC films show a sustained release behaviour that is independent of pH. In this case, however, the product surprisingly showed a slower release at pH 6.8 which is favourable with regards to the invention, i.e. providing efficient taste masking in the oral cavity and a faster release in the acidic stomach. This behavior may be explained by the lipophilicity profile of the active substance cilobradine HCl, which is slightly more lipophilic at neutral pH values. This profile, together with the coating applied, may have led to a slower release.

Example 2

Preparation of a Liquid Pharmaceutical Composition

In order to prepare a liquid pharmaceutical composition, the final multi-layered particles comprising the active ingredient ciloradine prepared in the way explained above were incorporated into an oily liquid. This liquid consisted of a mixture of Medium chain triglycerides (Miglyol® 821, bought from Sasol, Hamburg, Germany), a hydrophilic colloidal silicium dioxide (Aerosil® 200, Evonik), a hydrophobic colloidal silicium dioxide (Aerosil ® R972, Evonik) and meat flavor, at the weight ratios listed in Table 7 below.

TABLE 7

Liquid pharmaceutical composition comprising multi-layered
particles comprising (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-
piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-on hydrochloride.

	Amount
Component	[% (w/w)]

medium chain triglycerides (Miglyol ® 821)	93.23
hydrophilic colloidal silicium dioxide (Aerosil ® 200)	4.44
hydrophobic colloidal silicium dioxide (Aerosil ® R972)	1.82
meat flavor	0.51

The multi-layered particles as produced according to step 3 were suspended in the mentioned liquid composition in an amount of about 3.8% (w/v), resulting in a concentration of 2 mg/ml of the pharmaceutically active ingredient (calculated as hydrochloride).
It has been found that the composition of the oily solvent, especially the mixture of hydrophilic and hydrophobic colloidal silica, ensures an appropriate viscosity behaviour of the suspension that remains more or less unchanged over the storage period. During storage, the suspension exhibits a high viscosity, preventing sedimentation of the suspended cilobradine pellets. If shaken, the viscosity of the suspension is transiently lowered so that it can easily be applied via a syringe-like oral dispenser.

Example 3

Treatment of Cats Suffering from HF Due to HCM

A blinded, controlled, randomised, efficacy field study was conducted with HCM cats receiving cilobradine (initial dose: 0.2 mg/kg po. twice daily) or a placebo (dose: 0.0 mg/kg po. twice daily) for 85 days. The dose of cilobradine could be adjusted during the study (dose range 0.1-0.5 mg/kg per-oral twice daily). The administration of furosemide was allowed in both groups. All cats were hospitalised in the first week of the study (study days 1-6), and they were allowed to go home afterwards (study days 7-85).
Cats with a diagnosis of HCM were included in the study. The diagnosis of HCM was established by using echocardiography showing global, regional or segmental thickness of the interventricular septum and/or left ventricular free-wall in diastole greater than 6 mm. Further inclusion criteria were: systolic blood pressure less than 170 mmHg; serum thyroxine (T4) was normal; and body weight was higher than 2 kg.
The owner provided a signed informed consent for the animal to enter the study. Cats that suffered from heart disease were scored using a 4 point score adapted from the ISACHC as follows:

Score 1: presence of heart disease associated with no clinical signs but detectable (e,g, auscultation, echocardiography and radiography);
Score 2: clinical signs of heart failure evident and adversely affect the quality of life. Typical signs include dyspnea/tachypnea, pulmonary congestion, weakness/lethargy, anorexia, exercise intolerance;
Score 3: clinical signs of advance heart failure immediately obvious. These clinical signs could have included respiratory distress, marked ascites/pulmonary congestion, profound exercise intolerance or hypoperfusion at rest; and
Score 4: severe cases: subject was moribund, suffered from cardiogenic shock or acute posterior paresis/paralysis. Hospitalization was mandatory.

Cats having one or more of the following criteria were excluded:

- a) The cat had received one or more of the following pretreatments: calcium channel blockers, e.g. diltiazem, angiotensin converting enzyme inhibitors, f3-blockers, acetylsalicylic acid, or digitales glycosides. (Cats pre-treated with furosemide alone were allowed to be included in either of the groups if they matched all inclusion criteria above.)
- b) Elevated serum T4 level;
- c) Elevated serum blood urea nitrogen (BUN) levels higher than 90 mg/dL or elevated serum creatinine levels higher than 3 mg/dL;
- d) Systolic arterial blood pressure greater than or equal to 170 mmHg;
- e) Dilated cardiomyopathy (DCM);
- f) Suffered from heart disease with a score of 4 (adapted ISACHC score) or with no documented episode of heart failure (score 2 or 3) within 30 days before enrollment;
- g) Fixed aortic stenosis;
- h) Were pregnant or lactating queens;
- i) Were nursing kittens;
- j) Body weight less than 2 kg; or
- k) Presence of sinus bradycardia (heart rate less than 120 bpm at consultation).

The cat's quality of life was assessed on a daily basis using the following grading system: 1 (better), 2 (equal), 3 (worse). As displayed in FIG. 1, the quality of life of the cat, which received cilobradine showed an almost continuous improvement (black trapeze). On the other hand, the quality of life of the cat, which received a placebo (open circle) became worse or did not change throughout the whole study period, see FIG. 1.
The heart rate of a cat receiving cilobradine was reduced throughout the study, whereas the heart rate of a cat receiving placebo increased (see Table 8). The reduction of the interventricular septal thickness in systole was considerably greater in the cat, which received cilobradine compared to the cat, which received a placebo (see Table 9).

TABLE 8

Heart rate (beats per minutes)

	SD 0	SD 7	SD 28	SD 56	SD 84

Cilobradine cat	152	120	144	124	210
Placebo cat	156	230	210	190	186

TABLE 9

Interventricular septal thickness in systole (mm)

	SD 0	SD 84

Cilobradine cat	11.7	7.5
Placebo cat	12.3	10.0

Furthermore, right heart enlargement was assessed by X-ray using the following scoring system: Score 1: normal size; Score 2: mild enlargement; Score 3: moderate enlargement; and Score 4: severe enlargement. Mild enlargement of the right side of the heart was observed using X-ray in the cat receiving a placebo at the end of the study. In contrast, the right side of the heart was normal in the cat receiving cilobradine throughout the study (see Table 10).

TABLE 10

Right heart enlargement (score)

	SD 0	SD 84

Cilobradine cat	1	1
Placebo cat	1	2

Example 4

Cilobradine showed a half-life of 10.1-13.9 h in healthy human, male subjects after once daily po. administration for 7 days (see Table 11 and Table 12). Cilobradine chloride salt was administered at a dose of 5, 10 and 20 mg per subject in the form of capsules. These doses are equal to 0.07, 0.14, and 0.28 mg/kg cilobradine chloride salt assuming a body weight of 70 kg. In contrast, cilobradine showed a half-life of 2.53-3.52 h in healthy cats after once daily po. administration for 4 days. Cilobradine hydrochloride was administered at a dose of 0.1 mg/kg and 0.3 mg/kg as a suspension. Interestingly, a dose dependent heart rate reduction was observed in both humans and cats over 9 h following the administration of the above mentioned cilobradine doses. There are some differences between cats and humans in terms of pharmacokinetics of cilobradine, which might be related to differences in absorption, metabolisation, distribution, or excretion. In summary, although similar pharmacodynamic features were observed in humans and cats, these were not in line with the observed different pharmacokinetic features between cats and humans.

TABLE 11

Human

Dose of cilobradine chloride salt (mg/subject)	5	10	20
Dose of cilobradine chloride salt (mg/kg)*	0.07	0.14	0.28
Half-life (h)	13.9	13.0	10.1

*assuming 70 kg body weight

TABLE 12

Cat

Dose of cilobradine hydrochloride (mg/kg)	0.1	0.3
Half-life (h)	3.52	2.53

Overall from the above described examples, it can be concluded that a cat suffering from heart failure, which has been treated with cilobradine show a clear improvement in its quality of life and its general health condition with very low administration dose, despite the fact that the half-life is significantly shorter in cats compared to humans.

Example 5

The pharmacodynamic profile of cilobradine hydrochloride was characterised at two dose levels administered by the oral route, once and twice daily, in the conscious cat. The study involved 2 groups of 3 male European Short Hair cats weighing between 4.15 kg and 4.75 kg on the day of the first treatment. Each cat was dosed with cilobradine hydrochloride once (sid) and twice (bid) daily successively at 0.1 or 0.3 mg/kg in a cross over-design. Each treatment was separated by an interval of 24 hours (sid) or 12 hours (bid). A washout period of 7 days was scheduled between the 2 dosing periods. Cats were previously instrumented with telemetric transmitters for heart rate measurements. Telemetric measurements were recorded for 15 seconds every 5 minutes at a sampling rate of 500 Hz on D-2, D-1, from D0 up to D9 and from D16 up to D25 except for D4 and D20 during blood sampling.
Under the experimental conditions adopted, cilobradine hydrochloride administered orally at the doses of 0.1 and 0.3 mg/kg per day, induced a dose-dependent bradycardia.
All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the following claims.

Claims

1. A method of treating a feline comprising administering a funny (I_f) current inhibitor or a pharmaceutically acceptable salt thereof to a feline at risk of heart failure or suffering from heart failure such that the treated feline experiences at least one improvement in health selected from the group consisting of reduced heart failure, prevented heart failure, improved quality of life, improved general health condition, and prolonged life expectency as compared to a similar feline at risk of heart failure or suffering from heart failure that has not received the I_fcurrent inhibitor.

2. The method of claim 1, wherein a feline suffers from or is at risk of heart failure due to hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC).

3. The method of claim 1, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of cilobradine, zatebradine, anilidine, ivabradine, and the respective pharmaceutically acceptable salts thereof.

4. The method of claim 1, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is administered in an oral or parenteral form.

5. The method of claim 1, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is administered in a dosage of 0.01 to 2 mg per kg bodyweight per day.

6. The method of claim 1, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is administered in a solid or liquid formulation.

7. The method of claim 6, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is a solid formulation comprising 0.001 to 0.2 mg of the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof per mg of the solid formulation.

8. The method of claim 6, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is a liquid formulation comprising 0.1 to 20 mg of the I_fcurrent inhibitor or the pharmaceutically acceptable salt thereof per mg of the liquid formulation.

9. The method of claim 1, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is administered in a daily dosage of 0.01 to 2 mg/kg bodyweight.

10. The method of claim 1, wherein the I_fcurrent inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with at least one diuretic.

11. The method of claim 10, wherein the diuretic is administered in a dosage of 0.5 to 10 mg/kg bodyweight once or twice daily.

12. A method of treating a feline comprising administering a funny (I_f) current inhibitor or a pharmaceutically acceptable salt thereof to a feline having heart failure selected from the group consisting of hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), unclassified cardiomyopathy (UCM), dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) such that the treated feline experiences at least one improvement in health selected from the group consisting of reduced heart failure, prevented heart failure, improved quality of life, improved general health condition, and prolonged life expectency as compared to a similar feline that has not received an I_fcurrent inhibitor.