EA039250B1 - Use of pimobendan for the reduction of heart size and the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease - Google Patents

Abstract

The invention relates to the use of pimobendan in reducing the heart size and delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD), wherein the pimobendan treatment effects a reduction of the heart size of the already pathologically enlarged heart of the patient, wherein the pimobendan treatment effects a prolongation of the time of survival of the patient as compared to placebo treatment or non-pimobendan treatment, and wherein the patient is a mammal, preferably a human, a dog, a cat or a horse, more preferably a dog.

Description

The field of technology to which the invention belongs

The invention relates to medicine, in particular veterinary medicine. In particular, the invention relates to the use of pimobendan to reduce heart size and delay the onset of clinical symptoms in patients with asymptomatic (occult, preclinical) heart failure (HF) due to (myxomatous) mitral heart disease [(M)MVD], and/or chronic valvular disease heart disease (CVHD; also known as chronic valvular heart disease, CVD), and/or atrial and ventricular valve insufficiency (AVVI), and/or to slow the onset of clinical symptoms in patients with asymptomatic (latent, preclinical) HF due to (m) MVD and/or CVHD/CVD and/or AVVI and/or delayed onset of heart failure due to (myxomatous) mitral heart disease [(M)MVD] and/or chronic valvular heart disease (CVHD; also known as chronic valvular disease). heart apparatus, CVD), and/or atrial and ventricular valve insufficiency (AVVI).

Prerequisites for the creation of the invention

Heart failure is divided into different stages, which are defined by different classification systems, such as the functional classification systems of the International Small Animal Cardiac Health Council (ISACHC), the New York Heart Association (NYHA) and currently used classification according to the Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM), 2009.

Classification according to the International Council of Small Animal Cardiology (ISACHC) system

Class I: asymptomatic (also known as latent or preclinical)

Class IA: no evidence of compensation for underlying heart disease (no volume or pressure overload detected by radiography or echocardiography)

Class IB: clinical evidence of compensation for underlying heart disease (volume or pressure overload detected radiographically or echocardiographically)

Class II: Mild to moderate heart failure with clinical signs at rest or moderate exercise (needs treatment)

Class III: progressive heart failure; clinical signs of severe congestive heart failure

Class IIIa: possible home treatment

Class CV: hospitalization required

New York Heart Association (NYHA) Functional Classification System

Class I: Describes patients with asymptomatic heart disease (eg, chronic valvular heart disease (CVHD) is present, but there are no clinical signs even with exercise).

Class II: Describes patients with heart disease that causes clinical signs only with strenuous exercise.

Class III: Describes patients with heart disease that causes clinical signs with normal daily activities or little exercise.

Class IV: Describes patients with heart disease that causes clinical signs even at rest.

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The ACVIM system describes the four main stages of heart disease and heart failure

Stage A: Patients at high risk for developing heart disease but who currently do not have an identifiable structural heart disorder (eg, every Cavalierking Charles Spaniel without a heart murmur).

Stage B: Patients with structural heart disease (eg, typical mitral regurgitation murmur present) but never developed clinical signs due to heart failure (due to important clinical features for prognosis and treatment, the panel further breaks down Stage B into Stage B1 and IN 2).

Stage B1: Asymptomatic patients with no radiographic or echocardiographic evidence of cardiac remodeling in response to CVHD.

Stage B2: Asymptomatic patients who have hemodynamically significant valve regurgitation, as evidenced by radiographic or echocardiographic evidence of left-sided cardiac hypertrophy.

Stage C: Patients with present or past clinical signs of heart failure associated with structural heart disease.

Stage D: End-stage patients with clinical signs of CVHD heart failure who respond poorly to "standard therapy".

Cardiac pathology begins with ISACHC class I, NYHA class I, and ACVIM stage B2, in which there is a heart murmur or chamber enlargement but no clinical symptoms (ISACHC class I or asymptomatic/latent/preclinical). Clinical symptoms begin to appear as the disease progresses (ISACHC class II or III, NYHA class II, III or IV, ACVIM stages C and D).

Known progression of (M)MVD or CVHD/CVD or AVVI heart failure is associated with an increase in heart size. Cardiac remodeling due to morphological changes within the heart is generally regarded as a risk factor and is associated with worsening pathophysiological changes in the heart leading to heart failure. One of the objectives of the treatment of heart failure is to reduce the size of the heart and slow down the morphological changes in the heart.

A known pharmaceutically active compound for the treatment of heart failure is pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimilazol-5-yl]-5-methyl3(2H)pyridazinone) described in EP 0008391 and having the formula

Pimobendan is a well known compound for the treatment of congestive heart failure (CHF) arising, for example, from dilated cardiomyopathy (DCM) or mitral heart disease (MVD) in animals, especially dogs. Pimobendan is also approved as a medicinal product for human cardiovascular treatment in Japan.

Some publications describe the use of pimobendan for the treatment of heart failure in animals, such as, for example, the following individuals.

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WO 2005/092343 describes the use of PDE-III inhibitors, such as pimobendan, to reduce the size of the heart of a patient suffering from heart failure, but, however, without mentioning patients with asymptomatic (hidden, preclinical) heart failure due to mitral heart disease (MVD) .

Lombard et al. (Lombard CW et al., J Am Anim Hosp Assoc 2006, 42: 249-261) have described the clinical efficacy of pimobendan relative to benazepril in the treatment of clinically acquired atrioventricular valvular disease in dogs.

WO 2007/054514 refers to the use of PDE-III inhibitors such as pimobendan for the treatment of asymptomatic (also known as latent or preclinical) heart failure, however without mentioning patients with asymptomatic (occult, preclinical) heart failure due to mitral heart disease (MVD) .

Haggstrom J et al. (J Vet Intern Med 2008, 22: 1124-1135) described the effect of pimobendan or benazepril hydrochloride on survival time in dogs with clinical congestive heart failure caused by naturally occurring myxomatous mitral heart disease, but without mentioning patients with asymptomatic (hidden, preclinical) heart failure due to mitral heart disease (MVD).

Summerfield NJ et al. (Summerfield NJ et al., J Vet Intern Med 2012, 26: 1337-1349) described a clinical study on the efficacy of pimobendan in preventing congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (DCM). However, they did not indicate anything regarding patients with asymptomatic (hidden, preclinical) heart failure due to mitral heart disease (MVD).

Haggstrom J et al. (J Vet Intern Med 2013, 27: 1452-1462) described the short-term hemodynamic and neuroendocrine effects of pimobendan and benazepril in dogs with clinical myxomatous mitral heart disease and congestive heart failure. However, they did not indicate anything regarding patients with asymptomatic (hidden, preclinical) heart failure due to mitral heart disease (MVD).

The Internet website www.epictrial.com refers to the EPIC trial, a study to determine the effects of pimobendan in slowing the onset of clinical symptoms of congestive heart failure due to mitral heart disease (MVD). However, as of the priority date of this patent application, this trial is still ongoing and no research results have been made publicly available.

However, some other publications describe the adverse cardiac effects of pimobendan treatment, such as those presented below.

Schneider P et al. (Exp Toxic Pathol 1997, 49: 217-224) have described the relative cardiac toxicity of iv administered pimobendan to female beagles.

Tissier R et al. (Tissier R et al., Cardiovascular Toxicology 2005, 5(1): 43-51) disclosed adverse effects of increased mitral valve regurgitation and myocardial hypertrophy in two dogs on long-term (chronic) clinical therapy with pimobendan.

Amsallem E et al. (Cochrane Database Syst Rev 2005, 25: 1) found that phosphodiesterase inhibitors, such as pimobendan in particular, are associated with a substantial 17% increase in mortality in human patients and further significantly increase cardiac death. sudden death, arrhythmias and dizziness. The authors concluded that chronic use of phosphodiesterase inhibitors should be avoided in patients with heart failure.

Chetboul V et al. (Chetboul V et al., J Vet Intern Med 2007, 21: 742-753) reported the results of a prospective, controlled, blinded, and randomized study of the comparative cardiac adverse effects of pimobendan and benazepril monotherapy in dogs with mild degenerative asymptomatic mitral valve disease. hearts.

Ouellet M et al. (J Vet Intern Med 2009, 23: 258-263) described the effect of pimobendan on echocardiographic values in dogs with asymptomatic mitral heart disease. However, the study failed to identify favorable long-term changes in the severity of mitral regurgitation after adding pimobendan to ACE inhibitor treatment.

Thus, the object underlying the present invention is to provide a medical treatment that overcomes the problems of the prior art described above.

The essence of the invention

The present invention encompasses the use of pimobendan to reduce the size of the heart and slow the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral heart disease (MVD), preferably asymptomatic (occult, preclinical) congestive heart failure due to mitral heart disease ( MVD), more preferably asymptomatic (occult, preclinical) congestive heart failure due to myxomatous mitral heart disease (MMVD), where treatment with pimobendan results in a reduction in the size of the patient's already pathologically enlarged heart, and where treatment with pimobendan causes a prolongation of survival time

- 3,039,250 patients compared with placebo or no pimobendan treatment.

The advantages of the medical use(s) of pimobendan according to the present invention are as follows:

prolongation of the preclinical (also known as asymptomatic or latent) phase without clinical symptoms of congestive heart failure, slowing the onset (clinical symptoms) of congestive heart failure, improved survival time in treated patients compared to placebo treatment, improved quality of life in treated patients, decreased heart size in treated patients patients compared to baseline (i.e. before treatment), improvement in cardiac function/output in treated patients, reduction in sudden cardiac death/euthanasia of patients due to cardiac causes, reduced risk of congestive heart failure.

Any previously expressed concerns about the safety of the drug should be dispelled by the longer survival observed in the pimobendan group when all-cause mortality is analyzed. There is no difference between groups in the degree or type of potential side effects observed. This is despite the fact that dogs in the pimobendan group spent more time in the study and therefore were at risk of experiencing side effects for a longer time.

Detailed description of the invention

Before a more detailed description of the embodiments of the present invention, it should be noted that, as used in the description of the present invention and in the claims of the appended claims, the singular forms include the plural forms, unless the context specifically clears otherwise.

Unless specifically stated otherwise, all technical and scientific terms used in the present invention have the same meaning as generally understood by a person skilled in the art to which the claimed invention pertains. All of these ranges and values may range from 1% to 5%, unless specifically indicated otherwise, or otherwise known to a person skilled in the art, therefore, the term approximately is usually excluded from the description and claims. Although any methods and materials similar or equivalent to those described in the present invention may be used in the practice or testing of the present invention, the following describes the preferred methods, devices and materials. All publications referred to in the present invention are incorporated into this description by reference for the purposes of describing and disclosing substances, excipients, carriers and methodologies as described in the publications to be used in connection with the invention. Nothing contained herein should be construed as an admission that the invention provides the right to backdate such disclosure by prior invention.

The term patient, as used hereinafter and hereinafter, refers to an animal or individual suffering from (congestive) heart failure. The term patient encompasses mammals such as primates, including humans. In addition to primates, various other mammals can be treated according to the method of the present invention. For example, mammals such as, but not limited to, horses, dogs, cats, or equine, canine, feline species can be treated. Human, canine, feline, and equine patients are preferred. Human patients are female or male who suffer from heart failure. Typically, such individuals are children, young adults, adults or seniors between the ages of 6 and 80, preferably between 30 and 65 years of age. Most preferred are dogs.

The term heart failure, preferably congestive heart failure, as used hereinafter and hereinafter, refers to any disorder or disease of cardiac contractility. Clinical manifestations are usually the result of changes in the cellular and molecular components of the heart and in mediators that trigger homeostatic control. Heart failure, preferably congestive heart failure, is typically accompanied by an increase in heart size and deterioration in cardiac function.

The term reduction in heart size, as used earlier in the present invention and hereinafter, refers to a decrease in the size of a patient's heart, which is diagnosed using echocardiography and which can be determined in accordance with the radiographic methods proposed by James W. Buchanan et al. (Buchanan JW and et al., J Am Vet Med Assoc 1995, 206(2), 194-199) and is expressed as a relative measurement of heart size over the length of the thoracic vertebrae. Preferably, the relative heart size of said patient is reduced by at least 5%, preferably by at least 10%, 15%, 20%, 25%, or at least 30%, compared to baseline, i.e. before treatment with pimobendan, more preferably within 10-100 days, even more preferably within about 30-40 days, most preferably within about 35 days of treatment with pimobendan.

The term asymptomatic (occult, preclinical) (congestive) heart failure due to mitral heart disease (MVD), as used earlier in the present invention and hereinafter, refers to any contractile heart disorder or disease that is due to/is secondary to MVD - however, still without any clinical symptoms of (congestive) heart failure. In particular, it relates to heart failure ISACHC class I (class IA and/or class IB), NYHA class I and ACVIM stage B2.

The terms delay onset of clinical symptoms and prolongation of time to onset of clinical symptoms are used interchangeably earlier in the present invention and thereafter, and refer to the time period between diagnosing a patient's cardiac morphology until the onset of clinical symptoms of heart failure, preferably congestive heart failure, due to mitral heart disease (MVD) . In particular, they refer to the prolongation of time from still asymptomatic (latent, preclinical) heart failure ISACHC class I (class IA and/or class IB), NYHA class I and ACVIM stage B2 to symptomatic heart failure, preferably congestive heart failure, ISACHC class II and up to class III (class IIIA and/or class IIIB), NYHA class II, III and IV and ACVIM stages C and D.

For unambiguous interpretation throughout the present invention, the terms for medical indications mitral heart disease (MVD), myxomatous mitral heart disease (MMVD), chronic valvular heart disease (CVHD), chronic valvular heart disease (CVD) and atrial and ventricular valve insufficiency (AVVI ) are all used interchangeably. As for ISACHC class I (class IA and/or class IB), NYHA class I and ACVIM stage B2 heart failure, they are all synonymous with each other and have identical medical significance.

The term reduced risk of achieving congestive heart failure, as used hereinafter and hereinafter, refers to the relative risk of experiencing a clinical sign of heart failure, preferably congestive heart failure. Preferably, the relative risk is reduced by at least 5%, preferably by at least 10%, 15%, 20%, 25%, or at least 30%.

The term "effective amount" as used herein means an amount effective to achieve a reduction in heart size in patients with asymptomatic (occult, preclinical) heart failure (HF) due to mitral heart disease (MVD) and to achieve a slowing of the onset of clinical symptoms in patients with asymptomatic (hidden, preclinical) HF due to MVD, preferably congestive heart failure, in patients with asymptomatic (hidden, preclinical) HF due to MVD, when pimobendan is administered in unit dosage form.

In one aspect, the present invention relates to the use of pimobendan in accordance with the above and below in the present invention disclosed aspects and preferred embodiments, where asymptomatic (hidden, preclinical) heart failure due to mitral heart disease (MVD), preferably asymptomatic (hidden, preclinical) congestive heart failure due to mitral heart disease MVD, more preferably asymptomatic (occult, preclinical) congestive heart failure due to myxomatous mitral heart disease (MMVD) is ISACHC class I, preferably ISACHC class IA or class IB, more preferably ISACHC class IB, NYHA class I and ACVIM stage B2.

In another aspect, the present invention relates to the use of pimobendan in accordance with the above and below in the present invention disclosed aspects and preferred embodiments, where treatment with pimobendan leads to a decrease in the size of the heart of the already pathologically enlarged heart of the patient. In other words, such a patient suffers from asymptomatic (occult, preclinical) heart failure due to mitral heart disease (MVD) according to ISACHC class I (class IA and/or class IB), NYHA class I and ACVIM stage B2 and already has a pathologically enlarged heart ( as seen by echocardiography) but does not yet show any clinical symptoms of heart failure, preferably congestive heart failure.

In another aspect, the present invention relates to the use of pimobendan in accordance with the above and below in the present invention disclosed aspects and preferred embodiments, where treatment with pimobendan causes a prolongation of the survival time of the patient compared with placebo treatment or treatment without pimobendan. In this regard, treatment without the use of pimobendan refers to a comparative treatment, where the corresponding group of patients receives an active pharmaceutical ingredient other than pimobendan, instead of pimobendan or placebo. Preferably, such treatment with pimobendan causes a prolongation of the patient's survival time of at least 30 days, more preferably at least 2 months, even more preferably at least 3 months, even more preferably at least 4 months, even more preferably at least for at least 5 months, even more preferably at least

- 5 039250 at least 6 months, even more preferably at least 7 months, even more preferably at least 8 months, even more preferably at least 9 months, even more preferably at least 10 months, even more preferably at least 11 months, even more preferably at least 12 months, even more preferably at least 13 months, even more preferably at least 14 months, even more preferably at least 15 months compared to placebo treatment or treatment without pimobendan.

In another aspect, the present invention relates to the use of pimobendan in accordance with the above and below in the present invention disclosed aspects and preferred embodiments, where treatment with pimobendan causes a prolongation of the preclinical phase without the manifestation of clinical symptoms of congestive heart failure, causes a delay in the onset (clinical symptoms) of congestive heart failure insufficiency, increases survival time in treated patients compared to placebo treatment, improves quality of life in treated patients, results in a reduction in heart size in treated patients compared to baseline (i.e. before treatment), improves cardiac function/output in treated patients, reduces sudden cardiac death/euthanasia of patients due to cardiac causes and/or reduces the risk of congestive heart failure.

In another aspect, the present invention relates to the use of pimobendan in accordance with the above and below in the present invention disclosed aspects and preferred embodiments, where the patient is a mammal, preferably a human, dog, cat or horse, more preferably a dog.

The dosing regimen for pimobendan will, of course, vary depending on known factors such as pharmacodynamic characteristics and its method and route of administration; species, age, sex, health status, medical condition, and weight of the recipient; nature and severity of symptoms; type of concomitant treatment; frequency of treatment; route of administration, renal and hepatic function of the patient and the desired effect. The attending physician or veterinarian can determine and prescribe the effective amount of the drug needed to prevent, counteract, slow or stop the progression of the disorder.

As a basic guide, the daily oral dose of pimobendan, when used for the indicated effects, will be in the range of 0.2 to 0.6 mg/kg body weight SID, in particular 0.2 to 0.6 mg/kg body weight of pimobendan administered per day (EU) and 0.5 mg/kg body weight of pimobendan administered per day (US).

Preferably the daily dose of pimobendan is administered as two doses of 0.1 to 0.3 mg/kg body weight, preferably two doses of 0.1 to 0.3 mg/kg body weight every 12 hours (EU), more preferably two doses 0.25 mg/kg body weight every 12 hours (USA).

In yet another aspect, the present invention relates to the use of pimobendan in accordance with the disclosed aspects and preferred embodiments described above and below in the present invention, where pimobendan is administered at a daily dose of from 0.2 to 0.6 mg/kg body weight SID, in particular 0.2 to 0.6 mg/kg body weight of pimobendan administered per day (EU) and 0.5 mg/kg body weight of pimobendan administered per day (US).

Preferably the daily dose of pimobendan is administered as two doses of 0.1 to 0.3 mg/kg body weight, preferably two doses of 0.1 to 0.3 mg/kg body weight every 12 hours (EU), more preferably two doses 0.25 mg/kg body weight every 12 hours (USA).

According to another aspect of the present invention, pimobendan is administered in combination with at least one second active pharmaceutical ingredient (API). Such at least one second API may be selected from the group consisting of afterload reducers (arteriodilators) such as ACE inhibitors, preload reducers (venodilators) such as diuretics, platelet aggregation inhibitors, beta-blockers and angiotensin II antagonists, aldosterone antagonists, antiarrhythmic agents (if arrhythmias occur) and/or diuretics, especially where the ACE inhibitor may be selected from the group consisting of omapatrilat, MDL100240, alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, saralazine acetate, temocapril, trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilate and/or spirapril; and/or wherein the afterload reducer (arteriodilator) may be selected from the group consisting of hydralazine, calcium channel blockers diltiazem, verapamil, and amlodipine, nitroprusside, and phosphodiesterase inhibitors such as sildenafil; and/or wherein the beta-blocker may be selected from the group consisting of bisoprolol, carvedilol, metoprolol, propranolol, atenolol, esmolol, and/or timolol; and/or wherein the platelet aggregation inhibitor may be selected from the group consisting of aspirin, clopidogrel, factor Xa inhibitors, heparin, and low molecular weight heparins; and/or wherein the angiotensin II antagonist may be selected from the group consisting of saralazine acetate, candesartan, cilexetil, valsartan, candesartan, potassium losartan, eprosartan, irbesartan, tazosartan, sartan, and/or telmisartan; and/or wherein the aldosterone antagonist may be selected from the group consisting of spironolactone, triampterene, eplerenone, canrenone, potassium canrenone; and/or wherein the antiarrhythmic agents may be selected from the group consisting of amiodarone, betrylium, disopyramide, dofetilide, flecainide, ibutilide, mexiletin, tocainide, procainamide, lidocaine, propafenone, diltiazem, verapamil, digoxin, digitalis, quinidine and/or sotalol; and/or where the diuretic may be selected from the group consisting of furosemide, spironolactone, torasemide, bumetanide, ethacrynic acid, azosemide, muzolimin, pyretanide, tripamide, bendroflumethazide, chlorthiazide, hydrochlorothiazide, hydroflumethiazide, methiclothiazide, polythiazide, trichlormethiazide, chlorthialidon, methindolazone , quinetasone, etozolin, triamterene and/or amiloride; and/or wherein the preload reducer (venodilator) may be selected from the group consisting of nitroglycerin, nitroprusside, and isosorbide; and/or wherein the positive inotropic agents may be selected from the group consisting of dobutamine, digoxin, digitalis, dopamine, amrinone, and milrinone; and/or wherein the hyperpolarization-activated cyclic nucleotide-gated channel (HCN) blockers or negative chronotropic agents can be selected from the group consisting of cylobradine, ivabradine, and adenosine.

Preferably, pimobendan is co-administered with one or more APIs selected from the group consisting of one or more ACE inhibitors and one or more diuretics.

In yet another aspect, the present invention relates to the use of pimobendan in accordance with the previously disclosed aspects and preferred embodiments described hereinafter and hereinafter, wherein the pimobendan is administered before, during, or after the administration of one or more additional active pharmaceutical ingredients selected from the group consisting of ACE inhibitors, preferably benazepril; and diuretics, preferably furosemide. More preferably, pimobendan is administered simultaneously with benazepril and furosemide.

Pimobendan can be administered in oral dosage forms such as tablets, chewable tablets, gums, capsules (each including sustained release or timed release preparations), pills, powders, granules, elixirs, tinctures, suspensions, solutions, syrups and emulsions. It may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all such dosage forms are well known to those skilled in the art. It may be administered alone, but will usually be administered with a pharmaceutical carrier selected based on the given route of administration and standard pharmaceutical practice.

In another aspect, the present invention relates to the use of pimobendan in accordance with the above and below in the present invention disclosed aspects and preferred embodiments, where pimobendan is administered orally or parenterally, preferably orally, more preferably orally in the form of a tablet or capsule, most preferably orally in the form tablets.

Pimobendan can be administered in intranasal form by topical application of suitable intranasal vehicles or via transdermal routes using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage upon administration will, of course, be continuous rather than intermittent throughout the administration schedule.

Pimobendan is typically administered in admixture with suitable pharmaceutical diluents, excipients and/or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules, elixirs, syrups, etc., and consistent with generally accepted pharmaceutical practices.

For example, for oral administration in the form of a tablet or capsule, the active drug ingredient can be combined in an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol , sorbitol and others; for oral administration in liquid form, the oral drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and others. In addition, if desired or necessary, suitable binders, lubricants, disintegrators and coloring agents may also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sugars, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and others. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and others. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and others.

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Pimobendan can also be administered in the form of liposomal delivery systems such as small monolamellar vesicles, large monolamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

Pimobendan can also be administered in lipid coated form as part of a solid pharmaceutical preparation (see eg WO 2015/082389).

Pimobendan can also be associated with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, a pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide polylysine substituted with palmitoyl residues.

In addition, pimobendan can be associated with a class of biodegradable polymers suitable for controlled drug release, e.g. cross-linked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 to about 100 mg of the active ingredient per dosage unit.

In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.5-95% by weight, based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and others. Similar diluents may be used to prepare compressed tablets. Both tablets and capsules can be formulated as sustained release products to provide continuous drug release over a period of several hours. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from exposure to air, or enteric-coated for selective degradation in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring and flavoring agents to enhance patient acceptance.

In general, suitable carriers for parenteral solutions are water, a suitable oil, saline, aqueous dextrose (glucose) and appropriate sugar glycol solutions such as propylene glycol or polyethylene glycols. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffer substances. Antioxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. Additionally, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, the standard reference text in this field.

If two or more of the above second APIs are administered with pimobendan, then typically the amount of each component in a typical daily dose and typical dosage form may be reduced relative to the API dosage used when administered alone, taking into account the additive or synergistic effect of the API when administered in combination.

Especially if a single dosage unit is provided, then there is the potential for chemical interaction between the combined APIs. To this end, when pimobendan and at least one second API are combined in a single dosage unit, they are formulated such that, although the APIs are combined in a single dosage unit, physical contact between the APIs is minimized (i.e., reduced). For example, one API may be enteric coated. By enteric coating one of the APIs, it is not only possible to minimize contact between the combined APIs, but it is also possible to control the release of one of these components in the gastrointestinal tract so that one of these components is not released in the stomach, but instead is released in the intestine. . One of the APIs may also be coated with a material that provides sustained release through the gastrointestinal tract and also serves to minimize physical contact between the combined APIs.

In addition, the sustained release component may be additionally enteric-coated such that release of the component occurs only in the intestine. Yet another approach involves preparing a combination product in which one component is coated with a sustained release polymer and/or an enteric release polymer and the other component is also coated with a polymer such as low viscosity hydroxypropyl methylcellulose (HPMC) or other suitable materials. - 8 039250 fishing, known in this field, for additional separation of the active components. The polymer coating serves to form an additional barrier to prevent interaction with another component.

Examples

The following examples serve to further illustrate the present invention; but at the same time they should not be considered as limiting the scope of the invention disclosed in this document.

Example 1. Interim analysis data.

Previous studies have suggested that treatment with pimobendan significantly reduces mortality and morbidity in dogs with CHF. The potential benefit of pimobendan treatment in slowing the progression of asymptomatic (occult, preclinical) heart failure in dogs due to mitral heart disease (MVD) has not been shown to date.

Pimobendan is a benzimidazopyridazinone with an effective inotropic and vasodilating effect. Its combined effect of reducing preload and afterload, together with positive inotropic support, leads to a reduction in heart size and filling pressure in the hearts of dogs with latent heart failure due to mitral heart disease.

Administration of pimobendan to dogs suffering from asymptomatic (occult, preclinical) heart failure due to mitral heart disease (MVD) prolongs the time to onset of clinical signs of congestive heart failure by approximately 359 days (12.0 months) compared to placebo and increases survival time ( all-cause mortality) by approximately 168 days (5.6 months) compared with placebo. Therefore, treatment of dogs in the preclinical phase of heart failure results in improved disease outcome.

Example 2. Preliminary analysis of the results of the final study.

A preliminary endpoint analysis of a blinded, placebo-controlled study of 360 dogs showed that administration of pimobendan to dogs with MMVD and echocardiographically and radiographically confirmed cardiomegaly resulted in a prolongation of the preclinical period and was safe and well tolerated.

The median time to primary endpoint is 1228 days (95% CI 856 - ND) in the pimobendan group and 766 days (95% CI 667-875) in the placebo group (P = 0.038). The prolongation of the preclinical period by approximately 15 months represents a significant clinical advantage.

Overall survival, as defined by all-cause mortality, is also significantly greater in the pimobendan group compared to the placebo group (P=0.012), and this also represents a significant clinical benefit.

Pimobendan also caused a decrease in heart size compared to the placebo group when measured during the first 35 days of the study (P<0.0001).

The final results of the study were published during this time (Boswood A et al., J Vet Intern Med 2016, 30(6): 1765-1779).

Example 3. Reducing the size of the heart.

The sum of heart sizes over the length of the thoracic vertebrae, another measure of heart size, was obtained at regular intervals - every eight months - from those animals that remained in the study. There are various ways in which comparisons between groups can be made. The most commonly used route is to aggregate and compare the mean thoracic length heart size score in each group for the study period to obtain an area under the curve value, which is a single pooled statistic for each dog from which more than two were obtained. measurements [Matthews JN et al., BMJ 1990, 300(6719): 230-235]. This method has been used previously in veterinary research [Haggstrom J et al., J Vet Intern Med 2013, 27(6): 1441-1451].

If the average estimate of the size of the heart by the length of the thoracic vertebrae for both groups is calculated for the period during which the study is conducted, and compared between groups, the following results are obtained.

Thus, it can be concluded that the mean thoracic vertebral length heart size estimate for dogs remaining in the study, when averaged over the full duration of the study, is approximately 0.35 vertebrae lower for dogs treated with pimobendan (table). Thus, the echocardiographic results show an acute decrease in the size of the heart, which becomes noticeable after one month. Radiographic data indicate that differences in heart size continue to exist if heart size measurements are averaged over the period over which the study is performed.

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Group Mean Interquartile range P-value for comparison VHS placebo 11.90 11.38 -12.42 P = 0.0009 VHS Pimobendan 11.54 11.05 -12.16

Links.

(1) Amsallem E et al., Cochrane Database Syst Rev 2005, 25: 1 (2) Boswood A et al., J Vet Intern Med 2016, 30(6): 1765-1779 (3) Buchanan JW et al., J Am Vet Med Assoc 1995, 206(2), 194-199 (4) Chetboul V et al., J Vet Intern Med 2007, 21: 742-753 (5) EP 0 008 391 (6) Haggstrom J et al. , J Vet Intern Med 2008, 22: 1124-1135 (7) Haggstrom J et al., J Vet Intern Med 2013, 27(6): 1441-1451 (8) Haggstrom J et al., J Vet Intern Med 2013, 27: 1452-1462 (9) Lombard CW et al., J Am Anim Hosp Assoc 2006, 42: 249-261 (10) Matthews JN et al., BMJ 1990, 300(6719): 230-235 (11) Ouellet M et al., J Vet Intern Med 2009, 23: 258-263 (12) Schneider P et al., Exp Toxic Pathol 1997, 49: 217-224 (13) Summerfield NJ et al., J Vet Intern Med 2012, 26: 1337-1349 (14) Tissier R et al., Cardiovascular Toxicology 2005, 5(1): 43-51 (15) WO 2005/092343 (16) WO 2007/054514 (17) WO 2015/082389 (18) www.epictrial.com

Claims (12)

1. The use of pimobendan to reduce the size of the heart and slow the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure due to mitral heart disease (MVD), where treatment with pimobendan leads to a decrease in the size of the heart of the already pathologically enlarged heart of the patient and where treatment pimobendan resulted in a prolongation of patient survival compared to placebo or treatment without pimobendan. 2. Use according to claim 1, wherein the patient suffers from asymptomatic (hidden, preclinical) congestive heart failure due to mitral heart disease (MVD), preferably asymptomatic (hidden, preclinical) congestive heart failure due to myxomatous mitral heart disease (MMVD). 3. The use according to any one of claims 1, 2, where asymptomatic (hidden, preclinical) heart failure due to mitral heart disease (MVD), preferably asymptomatic (hidden, preclinical) congestive heart failure due to mitral heart disease (MVD), more preferably asymptomatic (hidden, preclinical) congestive heart failure due to myxomatous mitral heart disease (MMVD) is ISACHC grade I, preferably ISACHC grade IA or grade IB, more preferably ISACHC grade IB, NYHA grade I, and ACVIM grade B2. 4. The use according to any one of claims 1 to 3, wherein treatment with pimobendan results in a reduction in the size of the heart of an already pathologically enlarged patient's heart by at least 5%, more preferably by at least 10%, 15%, 20%, 25%, or at least 30% reduction from baseline, i.e. before starting treatment with pimobendan, preferably within 10-100 days, more preferably within about 30-40 days, most preferably within about 35 days of treatment with pimobendan. 5. The use according to any one of claims 1 to 4, wherein treatment with pimobendan causes a prolongation of patient survival compared to treatment with placebo or treatment without pimobendan by at least 30 days, more preferably at least 2 months, even more preferably - 10 039250 at least 3 months, even more preferably at least 4 months, even more preferably at least 5 months, even more preferably at least 6 months, even more preferably at least 7 months , even more preferably at least 8 months, even more preferably at least 9 months, even more preferably at least 10 months, even more preferably at least 11 months, even more preferably at least 12 months , even more preferably at least 13 months, even more preferably at least 14 months, even more preferably at least 15 months. 6. The use according to any one of claims 1 to 5, wherein treatment with pimobendan causes a prolongation of the preclinical phase without the manifestation of clinical symptoms of congestive heart failure, causes a delay in the onset (clinical symptoms) of congestive heart failure, increases the survival time of treated patients compared with placebo treatment, improves quality of life in treated patients, results in a reduction in heart size in treated patients compared to baseline (i.e. before treatment), improves cardiac function/output in treated patients, reduces sudden cardiac death/euthanasia in patients due to cardiac causes, and/or reduces risk of congestive heart failure. 7. Use according to any one of claims 1 to 6, wherein the patient is a mammal, preferably a human, dog, cat or horse, more preferably a dog. 8. Use according to any one of claims 1 to 7, wherein pimobendan is administered at a daily dose of 0.2 to 0.6 mg/kg body weight, preferably 0.5 mg/kg body weight. 9. Use according to claim 8, wherein the daily dose of pimobendan is administered as two doses of 0.1 to 0.3 mg/kg body weight, preferably two doses of 0.1 to 0.3 mg/kg body weight every 12 hours , more preferably two doses of 0.25 mg/kg body weight every 12 hours. 10. Use according to any one of claims 1 to 9, wherein the pimobendan is administered orally or parenterally, preferably orally, more preferably orally in tablet or capsule form, most preferably orally in tablet form. 11. Use according to any one of claims 1 to 10, where pimobendan is administered before, during or after the administration of one or more additional active pharmaceutical ingredients selected from the group including ACE inhibitors, preferably benazepril; and diuretics, preferably furosemide. 12. Use according to claim 11, wherein pimobendan is administered simultaneously with benazepril and/or furosemide, preferably benazepril and furosemide.