HK1053979A - Use of bradycardiac substances in the treatment of myocardial diseases associated with hypertrophy and novel medicament combinations - Google Patents

Description

Bradycardia for treating hypertrophic cardiomyopathy and novel pharmaceutical compositions

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Use of bradycardia substances for treating elevated heart rate, especially Ca⁺⁺Channel blockers such as diltiazem and verapamil, or beta-receptor blockers such as atenolol, bisoprolol, carvedilol, metoprolol or propranolol, and i_fChannel blockers such as chalcone (zatebradine) [1- (7, 8-dimethoxy-1, 3, 4, 5-tetrahydro-2H-3-phenylaza  -2-on-3-yl) -3- [ N-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) propane](see EP-B-0065229), 3- [ (N- (2- (3, 4-dimethoxy-phenyl) -ethyl)) -piperidin-3-yl) -methyl]- (7, 8-dimethoxy-1, 3, 4, 5-tetrahydro-2H-3-phenylaza  -2-one) (see EP-B-0224794) and its enantiomer cilobradine (+) -3- [ (N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -piperidin-3- (S) -yl) -methyl-l-y-lmethylamine](7, 8-dimethoxy-1, 3, 4, 5-tetrahydro-2H-3-phenylaza  -2-one]Or allylnidine [2- (N-allyl-2, 6-dichloroanilino) -2-imidazolidine, see also U.S. Pat. No.3,708,485]Furthermore, it is known that petradine also has a suitable effect on the treatment of cardiac insufficiency (see EP-B-0471388).

However, such bradycardia substances are also known, in particular the above-mentioned compounds, in which i_fChannel blockers such as chalcone, cilobradine or allylic pyridine, of which cilobradine is particularly preferred, are advantageous for symptomatic treatment of hypertrophic cardiomyopathy, particularly for treatment of primary Hypertrophic Cardiomyopathy (HCM) such as residual hypertrophy of the myocardium after myocardial infarction, ischemic cardiomyopathy, hypertrophy of valve defects and hypertrophy of the myocardium with toxic or iatrogenic effects.

It has now surprisingly been found that bradycardia substances, in which i_fChannel blockers such as chalcone, ciclopirox or allylidine, in particular ciclopirox, are preferred, which not only have a suitable therapeutic effect on the clinical symptoms of hypertrophic cardiomyopathy, but also even lead to regression of these severe heart diseases.

The invention relates to a substance which slows the heart, in particular to a novel application of the compound, wherein i_fChannel blockers such as chalcone bradine, cilobradine or allylidine, especially cilobradine, are preferred, which lead to regression of hypertrophic cardiomyopathy, particularly suitable for the treatment of primary hypertrophic cardiomyopathy in humans and domestic animals.

In order to achieve the above-mentioned effects of the invention, it is appropriate to use the bradycardia substance in the literature in the doses given for the individual bradycardia substances used for the treatment of elevated heart rates. For example, one dose of cilobradine, orally administered, is 0.1 to 0.5mg/kg, preferably 0.2 to 0.4mg/kg, 1 to 3 times a day, 0.2 to 1mg/kg, 2 times a day for chalcone and 0.5 to 5mg/kg, 2 times a day for allylic pyridine.

The invention relates to a new application of bradycardia substance, which adopts i_fThe channel blocker cilobradine was studied as an example using the following method:

cats with severe hypertrophic cardiomyopathy (heart rate about 200 beats/min), using ST-enhanced electrocardiograms as myocardial ischemia signals, increased creatine kinase activity in blood and in ultrasound images, with greater compression of the ventricular wall with reduced ventricular volume and sputum content, were shown to be using_fThe clinical symptoms were greatly improved (pain was eliminated, electrocardiogram was normal, normal physiological activity image was restored) after treatment with a channel blocker such as cilobradine (0.3mg/kg oral, 2 times a day).

After 1 year and approximately 2 years of treatment, studies have surprisingly shown that myocardial hypertrophy subsides and symptoms remain improved.

The corresponding diseases in humans were studied using feline hypertrophic cardiomyopathy as a model (Kittleson et al, Circulation 91, 3172-3180 (1999)).

By i_fThe channel blocker cilobradine not only results in an improvement of symptoms, but also a regression of the disease.

The invention also relates to pharmaceutical compositions containing at least one bradycardia substance, in particular one of the above-mentioned compounds, preferably i_fChannel blockers, and at least one substance acting on the heart, for example a cardiac glycoside such as methacin or digitoxin; vasodilators such as nitroglycerin; ACE inhibitors such as captopril or enalapril; angiotensin-II antagonists such as losartan or temisiartan, which are also suitable for the treatment of hypertrophic cardiomyopathy, in particular primary Hypertrophic Cardiomyopathy (HCM), by combining them with a substance which slows down the heart rate.

In order to achieve the effect of the invention, generally a single bradycardia substance known from the literature is used in the doses used for treating heart rate elevations, as well as doses used for substances known from the literature acting on the heart.

For this purpose, the bradycardia substances, either alone or in combination with other compounds acting on the heart, are formulated with one or more customary inert carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or lipid substances, for example stearin, or suitable mixtures thereof, to give customary pharmaceutical preparations, for example plain tablets, sugar-coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.

Thus, for example, a composition formed from cilobradine and a cardiac compound will generally contain from 0.1 to 0.5mg/kg, preferably from 0.2 to 0.4mg/kg, of cilobradine per oral administration, plus from 0.01 to 1mg of methyl digoxin, 1 to 2 times per day; 0.01 to 1mg digoxin, 1 time per day; 0.1 to 2mg of nitroglycerin, 2 to 3 times per day; 10 to 100mg of captopril, 1 to 2 times per day; 2 to 20mg of enalapril, 1 time per day; 10 to 200mg of loxaden, 2 times a day; or 20 to 80mg of over-honey sanda 1 time per day.

As in pharmaceutical compositions_fThe partner of the channel blocker additionally acts on a separate biological system, and i_fChannel blockers inhibit reflex increases in heart rate, which may occur when combined with the above-mentioned mixing partners, which have a synergistic effect.

The invention is illustrated by the following examples, without being restricted thereto.

Example 1 capsule composition containing 1.25mg of cilobradine: 1 the capsule contains:

lactose monohydrate 82.75mg

Method for preparing 55.3mg corn starch

The active substance, lactose monohydrate and corn starch were mixed and filled into size 4 capsules.

Example 2 capsules containing 10mg of cilobradine. Consists of the following components: 1 the capsule contains:

lactose monohydrate 77.6mg

Method for preparing 51.7mg corn starch

The active substance, lactose monohydrate and corn starch were mixed and filled into size 4 capsules.

Example 3

Tablet composition containing 7.5mg cilobradine: 1A tablet contains:

active substance 7.5mg

Corn starch 59.5mg

Lactose 48.0mg

Polyvinylpyrrolidone 4.0mg

Magnesium stearate 1.0mg

Method for producing 120.0mg in total

The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed and moistened with water. The wet mixture was forced through a 1.5 mesh screen and dried at 45 ℃. The dried granules were passed through a 1.0 mesh screen and mixed with magnesium stearate. The final blend was compressed into tablets using a tablet press equipped with slotted 7mm diameter punches to form tablets.

The weight of each tablet is as follows: 120mg of

Example 4 sugar coated tablet containing 5mg cilobradine tablet 1 the tablet core contained:

active substance 5.0mg

Corn starch 41.5mg

Lactose 30.0mg

Polyvinylpyrrolidone 3.0mg

Magnesium stearate 0.5mg

Method for producing 80.0mg in total

Mixing active substance, corn starch, lactose and polyvinylpyrrolidone, and wetting with water. The wet material was forced through a 1.0mm fine sieve and dried at 45 c, and then the granules were passed through the same sieve. After mixing with magnesium stearate, convex tablet cores with a diameter of 6mm are compressed by means of a tablet press. The cores thus produced are coated in a known manner with a coating liquid which contains predominantly sucrose and talc. The final sugar coated tablet is polished with wax.

Sugar-coated tablet weight: 130mg of

Example 5 ampoule 1 containing 5mg of cilobradine contains:

active substance 5.0mg

Sorbitol 50.0mg

Method for preparing 2.0mg water for injection

The active substance is dissolved in water for injection in a suitable mixing vessel, and the solution is made isotonic with sorbitol.

After filtration through the membrane filter, the solution was poured into washed and sterilized ampoules under nitrogen and autoclaved for 20 minutes in a steam flow.

Example 6 suppository 1 containing 10mg of cilobradine the suppository contains:

active substance 0.010g

Hard fats (e.g., Witepsol H19 and W45) 1.690g

Method for producing 1.700g in total

Melting the hard fat. The milled active was homogeneously dispersed in the melt at 38 ℃. Cooled to 35 c and poured into slightly cooled suppository molds.

Example 7 drops containing 10mg of cilobradine 100ml of solution contain:

active substance 0.2g

Hydroxyethyl cellulose 0.15g

Tartaric acid 0.1g

Sorbitol solution, 70% dry weight 30.0g

Glycerol 10.0g

Benzoic acid 0.15g

Method for preparing distilled water with volume of 100ml

Distilled water was heated to 70 ℃. Hydroxyethyl cellulose, benzoic acid and tartaric acid were dissolved therein under stirring. The solution was cooled to room temperature and glycerol and sorbitol solution were added with stirring. The active was added at room temperature and the mixture was stirred to complete dissolution. Then, vacuum was applied with stirring to remove air from the syrup.

Claims (8)

1. A pharmaceutical composition for treating hypertrophic cardiomyopathy comprises bradycardia material and optional material acting on heart.

2. Pharmaceutical composition according to claim 1, characterized in that Ca is used⁺⁺Channel blockers, beta-blockers or i_fChannel blockers act as bradycardia substances.

3. A pharmaceutical composition according to claim 1, characterized in that,using i_fChannel blockers act as bradycardia substances.

4. Pharmaceutical composition according to claim 3, characterized in that as i, there is used chalcone (zatebradine), ciclobradine (cilobradine) or allylidine_fA channel blocker.

5. Pharmaceutical composition according to claim 3, characterized in that cilobradine is used as i_fA channel blocker.

6. Pharmaceutical compositions according to claims 1 to 5, characterized in that they additionally contain, as a further cardioactive compound, a cardiac glycoside, a vasodilator, an ACE-inhibitor or an angiotensin-II antagonist.

7. Use of an active substance as claimed in claims 1 to 6 for the treatment of hypertrophic cardiomyopathy.

8. Use of an active substance as claimed in claims 1 to 6 for the preparation of a pharmaceutical composition for the treatment of hypertrophic cardiomyopathy.