EP0818997A1

EP0818997A1 - Compositions including amiodarone and betaxolol

Info

Publication number: EP0818997A1
Application number: EP96902328A
Authority: EP
Inventors: Soorianarain Baligagoo
Original assignee: Individual
Current assignee: Individual
Priority date: 1996-02-02
Filing date: 1996-02-02
Publication date: 1998-01-21
Also published as: WO1997027850A1

Abstract

Novel pharmaceutical compositions for use in the field of organic chemistry and particularly that of therapeutic chemistry are disclosed. The compositions consist of a beta blocker selected from the group which consists of betaxolol and salts thereof and combined with amiodarone in limited doses so that a synergistic effect is achieved. Said compositions are useful for treating heart diseases.

Description

COMPOSITIONS COMPRISING AMIODARONE AND BETAXOLOL

The present invention relates to the field of organic chemistry and more particularly to that of therapeutic chemistry.

More particularly, it relates to new cardioprotective drugs which have a low incidence of side effects.

It specifically relates to new pharmaceutical compositions formed from a combination of a specific beta-blocking agent and amiodarone in low doses so as to avoid or limit the occurrence of annoying side effects.

It is known, in fact, that beta-blocking agents have significant anti-arrhythmic and anti-ischόmic activity, at the usual doses, but they have the drawback of triggering significant side effects. Amiodarone, for its part, is an effective antiarrhythmic agent but whose sensitive side effects considerably limit its use. In general, the combination of a beta-blocker and amiodarone is contraindicated and this mention appears in all official dictionaries {cf. VIDAL).

STATE OF THE ART

Angina disease is the result of a mismatch between the heart's oxygen supply and the heart's oxygen requirements. Current angina pectoris drugs have remarkable efficacy, but it is not always possible with these drugs to prevent both exertional pain and exertional arrhythmias without inducing undesirable side effects. Reducing arrhythmias during exercise is important because such arrhythmias can lead to death. The objective of the invention is the creation of a very effective angina pectoris drug also possessing a certain anti-arrhythmic activity but devoid of certain side effects such as disorders of sexual function.

These disorders are common in young adults following the use of beta-blocker drugs. Other drugs cause headaches so intense that they stop the medication. Still other beta-blockers induce peripheral disorders, fatigue or depression EXPERIENCE

Studies have been done with several chemical agents in combination, to define the synergies allowing to obtain increased clinical effects on the symptoms while reducing the side effects usually observed with combinations of drugs when used separately at the normal dose. .

Following prolonged and intense research activity, the Applicant has found that there is a synergy between a certain beta-blocker and amiodarone at low doses, and therefore that it is possible to envisage such a combination in pharmaceutical compositions, provided that the dose of each of these active ingredients is low.

Indeed, the beta-blocking agent selected and amiodarone paradoxically, manifest a synergistic action at these doses, which makes it possible to eliminate any side effect. In particular, the daily dose of amiodarone thus administered is low enough so that the side effects which it possibly causes are considerably reduced.

The product alone containing the lower dose of amiodarone was designed from the quality of life scale focused on your relationship between pain and exertion. The development of this scale allowed the determination of the optimal dose. In fact, the pharmaceutical compositions according to the invention significantly shift the curve of the symptoms to the left. This displacement is greater than that observed with a nitro derivative and with a calcium antagonist.

The invention therefore consists of new pharmaceutical compositions combining amiodarone at low doses and a blocking agent chosen from the group consisting of betaxolol and its addition salts at low doses, in combination or in mixture with an excipient or a inert non-toxic, pharmaceutically acceptable vehicle.

The invention therefore relates to new pharmaceutical compositions formed from a combination based on Amiodarone and a beta-blocker, characterized in that the beta-blocker is chosen from the group consisting of betaxolol and its salts. addition with a therapeutically compatible mineral or organic acid.

Among the betaxolol salts. more specifically, the hydrochloride effectively used in the form of a pharmaceutical specialty. In addition, nitrate, phosphates, acetate, propionate, citrates, tartrates, malates, gluconates or glucose 1-phosphate find equivalent use. According to the invention, the pharmaceutical compositions contain from 25 mg to 400 mg per unit dose of Amiodarone and more particularly from 50 mg to 100 mg.

The dose of betaxolol or one of its salts ranges from 2.5 mg to 75 mg per unit dose and preferably from 5 mg to 25 mg per dose. It can be lowered for intravenous administration at a dose as low as 0.5 mg.

Most preferably, the pharmaceutical compositions contain 100 mg of amiodarone and 10 mg of betaxolol or one of its salts with a therapeutically compatible mineral or organic acid.

Depending on the case, it is possible to use as beta-blocking agent according to the invention, the racemic molecule or a split molecule, optically active. In general, the optically active forms of beta-blocking agents exhibit the same level of activity as the racemic molecule, but on the other hand, their activity is purer, that is to say that their administration leads to fewer side effects. .

The pharmaceutical compositions according to the invention are intended essentially for oral administration. However, parenteral or rectal administration may be considered. The most suitable forms for these routes of administration are ampoules, multidose vials, auto-injectable syringes, lyophilisates to be reconstituted with a solvent for use, bare or coated tablets, dragees, capsules, soft capsules, pills, granules, powders flavored or not, sweetened or not, suppositories or rectal capsules.

The appropriate inert excipient is chosen from those which are suitable for oral or rectal administration such as starches, celluloses, alkyl ceilubse, carboxymethy! cellulose, lactose, calcium carbonate, calcium phosphate, magnesium phosphate, magnesium carbonate, alumina, silica, calcium silicate, magnesium silicate or talc.

Dispersing agents, disintegrating agents, release agents, binding agents or compression agents can be added thereto.

For suppositories, cocoa butter or semi-synthetic triglycerides or polyethylene glycol stearates are used. As vehicle, sugar syrup, distilled water, physiological serums, lipid emulsions or even dispersions of surfactants, nonionic agents, and generally isotonic preparations are preferably used.

The invention also relates to a process for obtaining the pharmaceutical compositions defined above.

The pharmaceutical forms according to the invention are prepared according to the usual methods of manufacture in the pharmaceutical field.

The following examples illustrate the invention without however limiting it:

EXAMPLE I

Betaxolol and amiodarone tablets

Betaxolol 40 g

Amiodarone 100 g

Wheat starch 35 g

Calcium carbonate 30 g Calcium sulfate 15 g

Hydroxy ethylcβllulose 5 g

Povidone excipient 15 g

Magnesium stearate 25 g per 1000 tablets with an average weight of 0.26 g

EXAMPLE II

Betaxolol and amiodarone tablets

Betaxolol 30 g Amiodarone 80 g

Wheat starch 60 g

Corn starch 30 g

Micro crystalline cellulose 20 g

Povidone excipient 15 g Magnesium stearate 25 g per 1000 tablets with an average weight of 0.26 g

EXAMPLE ill

Betaxolol and amiodarone capsules

Betaxolol 50 g

Amiodarone 50 g

Lactose 100 g

Copolymer of ethylene oxide and propylene oxide sold under the brand PLURONIC F18 .... 10 g

Colloidal silica 10 g per 1000 finished capsules at an average weight of 0.20 g EXAMPLE IV

Amiodarone and betaxolol capsules

Amiodarone 50 g

Betaxolol 30 g

Lactose 100 g

Micro crystalline cellulose 20 g

Talc 10 g per 1000 finished capsules at an average weight of 0.20 g

EXAMPLE V

Betaxolol and amiodarone tablets

Amiodarone 100 g Betaxolol 40 g

Ethylcellutose 20 g

Calcium carbonate 100 g

Sodium crosslinked carboxymethylcellulosθ 20 g Talc 10 g per 1000 finished tablets at an average weight of 0.29 g

EXAMPLE VI

One tablet containing: Amiodarone 100 mg

Betaxolol 5 mg

Excipients required for a finished tablet with an average weight of 0.220 g

EXAMPLE SEEN A tablet containing:

Amiodarone 50 mg

Betaxolol 4 mg

Excipients required for a finished tablet with an average weight of 0.220 g

EXAMPLE VIII

One tablet containing:

Amiodarone 75 mg

Betaxolol 5 mg

Excipients required for a finished tablet with an average weight of 0.220 g.

This product could be given in a single dose to the most sensitive patients and in two daily doses to other patients. EXAMPLE IX

A sachet containing:

Amiodarone 400 mg

Betaxolol 5 mg

Lactose 100 mg

This product can be administered as a loading dose in the presence of severe tachycardia such as, for example, Bouveret tachycardia or a severe angina attack with ventricular extrasystoles and tachycardia.

After using 3 to 6 tablets, as a loading dose, the doctor can administer the ideal product as maintenance treatment with a daily dose of Amiodarone of 150 mg and a dose of Betaxolol of 10 mg.

Intravenous use

The optimal product according to the invention used in the emergency treatment of acute myocardial infarction, acute ventricular tachycardia, multiple ventricular extrasystoles and tachycardia in the presence of ischemic heart disease is an intravenous form containing 0.5 mg betaxolol and 25 mg amiodarone intended to be administered within 1 to 2 minutes and which may be repeated if the tachycardia persists or until the expected results are obtained.

Case 5

A double-compartment or double-piston syringe or a set containing two micro-syringes containing in one compartment: piston or betaxolol syringe 0.5 mg, and in the other: 25 mg of amiodarone.

Case 6

A syringe containing in a mixture with appropriate excipients and stabilizers: amiodarone 25 mg and betaxolol 0.5 mg.

EXAMPLE X Amiodarone hydrochloride solution for injection 100 g

Betaxolol hydrochloride 60 g

Mannitol 40 g

Citrate buffer for pH 6 20 g

Purified water qs 2000 ml for 1000 vials of 2 ml. EXAMPLE XI Suspension for injection

Amiodarone 100 g

5 Betaxolol 60 g

Phosphate buffer pH 7.8 40 g

Ethylene diamino tetraacetic acid 10 g methyl p-hydroxy benzoate 0.15 g

Distilled water qs 2000 ml i o for 1000 vials of 2 ml

STUDY OF THE EFFECTIVENESS OF THE INVENTED PRODUCT

Orally administered: The effects of the new drug were compared orally to the effects of three known drugs according to the study protocols illustrated in Schemes 1, 2 and 3:

DIAGRAM 1: comparison to amiodarone

0 DIAGRAM 2: comparison to betaxolol

DIAGRAM 3: comparison to isosorbidβ dinitrate

The results demonstrate a clear superiority of the new drug compared to the 5 three products mentioned above at the 5th medical visit on the efficacy parameters. The new drug has fewer side effects than amiodarone and betaxolol taken alone, according to the attached table.

In two cases, where there were multiple ventricular extrasystoles on exertion with 0 sensations of loss of consciousness on exertion, the medicament according to the invention completely eliminated the ventricular extrasystoles on exertion and the sensation of unconsciousness then that no other known drug was able to eliminate the symptoms and the ventricular extrasystoles (figure 1 and figure 2).

5 These two cases are summarized below:

Case 1

He is a 43-year-old director who complained of chest pain and whose father died suddenly, at 57, of cardiac arrest. The ECG 0 showed numerous ventricular extrasystoles at rest with, upon exertion, one ventricular extrasystole for every four beats. The use of the drug. according to the invention, has resulted in a complete disappearance of the ventricular extrasystoles at rest and during exertion, without any side effect.

Case n ° 2 It is a young woman of 40 years, executive, who presented a pain in the chest with the effort, radiating to the back and the left arm. The electrocardiogram showed, upon exertion, numerous ventricular extrasystoles, including doublets and triplets at a heart rate of 126. The use of the product sebn the invention has completely disappear symptoms and the ventricular extrasystoles 'effort. The risk of sudden death can be considered to have been considerably reduced. There was no side effect.

In three cases where the anginal disease was not controlled by any drug with satisfaction (in 2 cases, the drugs led to a complete loss of the function of sexual erection), the drug sebn the inventbn effectively controlled the anginal disease with a quality of life considered by the patient to be normal, the effort pains having completely disappeared and there was no side effect.

Study of antianginal effects and side effects

CAPTION: The product according to the invention is exceptionally effective on two major parameters of angina pectoris (number of angina pains and duration of painless walking). These differences are statistically significant. The product according to the invention has no major side effects.

Claims

1. New pharmaceutical compositions containing a beta-blocking agent and ambdarone, characterized in that, as beta-blocking agent, betaxolol or one of its addition salts present at low doses is used to cause an effect synergistic.

2. New pharmaceutical compositions according to claim 1 ° in which the betaxolol is in racemic form or in split form.

3. New pharmaceutical compositions according to claim 1 or claim 2 "in which the amount of betaxobl ranges from 2.5 mg to 75 mg per unit dose.

4. New pharmaceutical compositions according to the claim 1 ° in which the amount of betaxobl ranges from 5 mg to 25 mg per unit dose.

5. New pharmaceutical compositions according to one of claims 1 to 4 ^e in which the amiodarone is present in amounts ranging from 25 to 400 mg per unit dose.

6. New pharmaceutical compositbns sebn claim 5 ^e in which the amount of amiodarone échebnne from 50 mg to 100 mg per unit dosage.

7. New pharmaceutical compositions according to one of the claims 1 to 6 ° in which the two active ingredients are added or mixed with an excipient or an inert non-toxic, pharmaceutically acceptable vehicle.

8. A process for the preparation of pharmaceutical compositions according to one of the claims 1 to 7 ° in which the amiodarone and the beta-blocker chosen from the group formed by betaxobl and one of its salts, are mixed or added, pharmaceutically -acceptable, an excipient or an inert, non-toxic, pharmac ^β utically-acceptable vehicle.