GB2068226A - Antiarrythmic sustained release disopyramide compositions - Google Patents

Abstract

Antiarrhythmic sustained release pharmaceutical compositions for oral administration comprise: (a) a-Ä2-Äbis-(1-methylethyl)aminoÜethylÜ- a-phenyl-2-pyridine acetamide or a pharmaceutically acceptable addition salt thereof with a mineral or organic acid, (b) an ester of glycerin and of a fatty acid containing from 10 to 22 carbon atoms, (c) an inert material having a solubility in water at ambient temperature of from 0.2 g to 3 g per millilitre.

Description

SPECIFICATION -Antiarrhythmic sustained release compositions The present invention relates to antiarrhythmic sustained release pharmaceutical compositions of which the active principle is a-[2-[bis( 1 -methyIethyI)aminoethyl]-a-phenyl-2-pyridine acetamide or a pharmaceutically acceptable acid addition salt thereof.

It is known that the absorption of medicinal substances by the body is of very variable duration and amount according to the route of administration. This absorption enables, in the most favourable cases, quick activity which can last for a few hours to be obtained.

In order to spread this activity over a period, various techniques are possible. Thus from a physical point of view it is possible to modify the shape of the particles of active principle, to coat the latter or to incorporate it in an appropriate substance. In addition, chemical techniques have been adopted such as the use of ion exchange resins or complexing.

In the field of antiarrhythmics, it is particularly useful to obtain products which exhibit good sustained release and of which the activity level is as constant as possible since the complaints to be treated generally require uninterrupted therapy over a long period.

We have now discovered a new sustained release form for the known antiarrhythmic disopyramide i.e. a-[2-[bis(1-methylethyl)amino]ethyl]-a-phenyl-2-pyridine acetamide and its acid addition salts, such as e.g. the phosphate, chloride, bromide, ethylene disulphonate, acetate or acid sulphate of sodium, which compounds are described in Special Medicament Patent No.

2,485 M.

Thus according to the present invention we provide antiarrhythmic sustained release pharma ceutical compositions comprising: (a) a-[2-[bis( 1 -methylethyl)amino]ethyl]-a-phenyl-2-pyridine acetamide or a pharmaceutically acceptable addition salt thereof with a mineral or organic acid, (b) an ester of glycerin and of a fatty acid containing from 10 to 22 carbon atoms, (c) an inert material having a solubility in water at ambient temperature of from 0.2 g to 3 g per millilitre.

The ester of glycerin and of a fatty acid can be a mono-, di-, or triester of glycerin and is formed with a fatty acid containing from 10 to 22 carbon atoms. Such esters include, for example, the mono-, di- and tristearates of glycerin, the mono-, di- and tripalmitates of glycerin, the di- and trilaurates of glycerin, the mono-, di- and tricaprates of glycerin and the mono-, di and trimyristates of glycerin: These esters can be used either alone or in admixture.

The inert materials of which the solubility in water at ambient temperature is from 0.2 g to 3 g per millilitre can be, for example, mineral salts such as sodium chloride or sugars such as e.g.

saccharose, lactose or glucose.

Among the pharmaceutical compositions which form the subject of the present invention, there may be mentioned especially those containing a-[2-[bis( 1 methylethyl)-amino]ethyl]-a phenyl-2-pyridine acetamide phosphate, preferably in an amount of 100 to 500 mg.

Also preferred are compositions containing 60% to 80% of a-[2-[bis(1-methylethyl)amino]e thyIa-phenyl-2-pyridine acetamide or a pharmaceutically acceptable acid addition salt thereof, 10% to 30% of an ester of glycerin and of a fatty acid containing from 10 to 22 carbon atoms, and 2% to 12% of an inert material having a solubility in water at ambient temperature of from 0.2 g to 3 g per millilitre.

In the compositions of the present invention the ester of glycerin and of a fatty acid containing from 10 to 22 carbon atoms is preferably glyceryl monostearate. As the inert material are preferably considered those having a solubility in water at ambient temperature of from 1.5 g to 2.5 g per millilitre and, in particular saccharose.

In the compositions of the present invention, it may also be advantageous to add to the three constituents defined above a binding agent such as polyvinyl pyrrolidone and a lubricant. The lubricant can, for example, be talc, stearic acid, zinc, calcium or aluminium stearates or preferably magnesium stearate. The binding agent and the lubricant can be added in the usual proportions, for example from 0.5% to 3% of each, and preferably from 0.5% to 1.5% of binding agent and from 2% to 3% of lubricant.

The compositions as defined above are endowed with remarkable sustained release antiar rhythmic properties. These properties are illustrated further on in the experimental portion.

Because of these properties, the compositions which form the subject of the present invention can be used in preventive treatment of rhythm disorders, arrhythmis relapses and paroxysmal tachycardia relapses or in the curative treatment of auricular or ventricular extrasystole and digitalic extrasystole and digitalic bigeminy.

The usual dose, which can be varied according to the product used, the subject treated and the complaint concerned can, for example, be from 100 mg to 500 mg of a-[2-[bis(1 methyIethyl)aminoethyl]-a-phenyl-2-pyridine acetamide phosphate per dose, by oral route in man, at the rate of one dose morning and evening.

The compositions of the invention may be prepared by mixing the various constituents according to techniques known per se.

The compositions can be presented in the pharmaceutical formulations currently used in human medicine such as, for example, plain or sugar-coated compressed tablets, gelatin capsules and granules which formulation may be prepared according to the usual methods.

Such formulations may include other excipients usually used in such pharmaceutical compositions, such as e.g. gum arabic, aluminium hydroxide, colloidal silica, starch and preservatives.

The following non-limiting Example serves to illustrate the invention.

Example: coated tablets Coated tablets were prepared according to the formulation: a-[2-[bis-( 1 -methylethyl)amino]ethyl] a-phenyl-2-pyridine acetamide phosphate (disopyramide phosphate) 322.5 mg glyceryl monostearate 90.0 mg castor sugar 30.0 mg polyvinyl pyrrolidone 5.0 mg magnesium stearate 12.5 mg coating (hydroxypropylmethyl cellulose, glucose, propylene glycol) 10.0 mg The a-[2-[bis-( 1 -methylethyl)amino]ethyl]-a-phenyl-2-pyridine acetamide, glyceryl monostearate and sugar are homogeneously mixed. The mixture obtained is fused at a temperature of about 65"C and the granules obtained are granulated through a sieve. The granulate thus obtained is moistened with an aqueous solution of polyvinyl pyrrolidone, dried and granulated again.The magnesium stearate is added to the granulate thus obtained and the resultant mixture is processed in a tabletting machine.

Coating is carried out by spraying with an aqueous solution of the hydroxypropylmethyl cellulose, glucose and propylene glycol with simultaneous drying.

Clinical study of the prolonged activity The plasma concentration of disopyramide in man was compared, as a function of time, after oral administration of 2 capsules each containing 100 mg of disopyramide and of 1 tablet as described in the Example containing disopyramide phosphate in an amount corresponding to 250 mg of disopyramide base.

The study was carried out on 6 subjects of male sex, 21 to 24 years old, with crossedadministration.

The plasma samples (10 ml each time) were taken at times 0 (just before administra tion)-0.5-1 -1.5-2-3-4-5-6-8-12-1 5-24-30-36-48 hours after administration. The analysis of the product was carried out by high pressure liquid chromatography, after extraction of the plasma using ethyl acetate.

So as to be able to compare directly the plasma concentrations obtained after the administration, given that different doses of disopyramide are contained in the gelatin capsules and in the compressed tablets, the concentrations were expressed in percentage of the dose administered per litre of plasma. The results obtained are as follows: (a) Timetables of maximum concentration: The maximum plasma concentration is reached over 2.58.hours for the gelatin capsule form and over 4.50 hours for the compressed tablet form.

(b) Amount of active principle attaining general circulation: The area included between the curve representing the plasma concentration of the product tested as a function of the time and the axis of the abscissae is calculated. Substantially identical results are obtained.

Gelatin capsules: 13.6% of the dose 1 -' h Compressed tablets: 13.2% of dose 1-' h 1 represents the plasma volume in litres h represents the time in hours.

(c) Latent period before the beginning of the action: Gelatin capsules: 0.34 h Compressed tablets: 0.29 h.

Conclusions: A significant delay in the resorption of the product in the compressed tablet form is thus shown as compared with the gelatin capsule form, given that the peak of maximum concentration is more retarded in the compressed tablet form.

In addition, the same total quantity of active principle attains general circulation in the compressed tablet and gelatin capsule forms. Finally, the active principle appears in the plasma at substantially identical times.

In the case of the compressed tablets, therefore, the medicaments is exhibiting sustained release.

Claims (14)

1. Antiarrhythmic sustained release pharmaceutical compositions comprising: (a) a-[2-[bis(1-methylethyl)amino]ethyl]-a-phenyl-2-pyridine acetamide or a pharmaceutically acceptable addition salt thereof with a mineral or organic acid, (b) An ester of glycerin and of fatty acid containing from 10 to 22 carbon atoms, (c) an inert material having a solubility in water at ambient temperature of from 0.2 g to 3 g per millilitre.

2. Compositions as claimed in claim 1 containing a-[2-[bis(1-methylethyl)amino]ethyl]-aphenyl-2-pyridine acetamide phosphate.

3. Compositions as claimed in claim 2 containing from 100 to 500 mg of a-[2-bis(1methylethyl)amino]ethyl]-a-phenyl-2-pyridine acetamide phosphate.

4. Compositions as claimed in any preceding claim comprising 60% to 80% of a-2-[bis(1- methylethyl)amino]-ethyl]-a-phenyl-2-pyridine acetamide or a pharmaceutically acceptable acid addition salt thereof, 10% to 30% of an ester of glycerin and of a fatty acid containing from 10 to 22 carbon atoms and 2% to 12% of an inert material having a solubility in water at ambient temperature of from 0.2 g and 3 g millilitre.

5. Compositions as claimed in any preceding claim wherein the ester of glycerin and of a fatty acid containing from 10 to 22 carbon atoms is glyceryl monostearate.

6. Compositions as claimed in any preceding claim wherein the inert material has a solubility in water at ambient temperature of from 1.5 g of 2.5 g per millilitre.

7. Compositions as claimed in claim 6 wherein the inert material is saccharose.

8. Compositions as claimed in any preceding claim additionally containing polyvinyl pyrrolidone and a lubricant.

9. Compositions as claimed in claim 8 containing from 0.5% to 1.5% of polyvinyl pyrrolidone and from 2% to 3% of lubricant.

1 0. Compositions as claimed in any preceding claim in the form of plain or coated tablets, gelatin capsules or granules.

11. Compositions as claimed in claim 1 substantially as herein described.

1 2. Compositions as claimed in claim 1 substantially as herein described in the Example.

1 3. A process for the preparation of compositions as claimed in claim 1 which comprises mixing the constituents (a), (b) and c) defined in claim 1.

14. Each and every novel methods, process, composition and product herein disclosed.