FR2471784A1 - EXTENDED ACTION ANTIARRHYTHMIC DRUGS WITH THE ACTIVE INGREDIENT AS A / 2- / BIS (1-METHYLETHYL) AMINO / ETHYL / -A-PHENYL-2-PYRIDINE ACETAMIDE OR SALTS THEREOF, AND THE PROCESS FOR THE PREPARATION OF THESE MEDICAMENTS AND COMPOSITIONS INCLUDING THEM - Google Patents

Abstract

NEW LONG-ACTING ANTIARRHYTHMIC DRUGS CONTAINING: A. A-2-BIS (1-METHYLETHYL) AMINOETHYL-A-PHENYL-2-PYRIDINEACETAMIDE OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE SALTS. B. AN ESTER OF GLYCEROL AND A C10-C22 FATTY ACID. C. AN INERT CHARGE WHOSE SOLUBILITY IN WATER AT ROOM TEMPERATURE IS BETWEEN 0.2G AND 3G PER MILLILITER. PREPARATION PROCESS AND COMPOSITIONS CONTAINING THEM.

Description

The present invention, to the realization of which participated

  Messrs. BLOOR John Robert, HAYES Geoffrey and SER Jacques are concerned with new long-acting anti-arrhythmic drugs, as well as the process for the preparation of these new drugs and the compositions for their use. It is known that the absorption of drug substances by the organism is of long duration. and of very variable importance according to the routes of administration.

  in the most favorable cases to obtain a

  pide, and which may last a few hours. To spread out in time this activity is resorted to various artifices; From a physical point of view, it is thus possible to modify the size of the active ingredient particles, to coat the latter or to incorporate it into a suitable substance. Chemical devices have been devised, such as the use of carbon dioxide resins. Furthermore, in the field of antiarrhythmic drugs, it is

  It is particularly useful to obtain products that

  dually and the action is as constant as possible, since the condition to be treated most often requires uninterrupted therapy for a long time. The deanderese has discovered a new delayed form of a known untiarytbmic drug, namely the 2-bis (1-methylethyl) amino-ethyl-ophenyl-2-pyridine acetamide and its salts, such as phosphate, chloride, bromide,

  ethylene disulfonate, acetate or acidic sulfate of

  The present invention thus relates to novel long-acting antiarrhythmic drugs, characterized by the fact that they contain:

  a) α- [2- [bis (1-methylethyl) amino] ethyl] m: phenyl-2-py-

  ridine acetamide or one of its addition salts with a-

  inorganic or organic pharmaceutically acceptable acids, b) an ester of glycerol and a fatty acid containing from 22 to 22 carbon atoms, c) an inert filler whose solubility in water at temp =

  ambient temperature is between 0.2 g and 3 g per millili-

  be. The ester of glycerol and a fatty acid can be a mono-, di- or triester of glyceryl, formed with fatty acids containing from 10 to 22 carbon atoms; mention may be made, for example, of mono-, di-, or glyceryl tristearate,

  mono-, di-, or glyceryl tripalmitate, the di- or tri-

  glyceryl spleen, mono-, di-, or glyceryl tricaprate or mono-, di-, or glyceryl trimyristate. These esters

  can be used alone or mixed.

  Inert fillers whose solubility in water at

  ambient temperature is between 0.2 g and 3 g

  liter may be, for example, inorganic salts, such as sodium chloride, or sugars, such as sucrose,

lactose or glucose.

  Among the medicinal products which are the subject of the present invention, the medicaments are particularly selected, characterized in that they contain α- [2- [bis (1-methylethyl) amino] ethyl] -1-phenyl-2-pyridineacetamide phosphate. also retains particular characterized drugs

  in that they contain about 60% to 80% of a- / 2- / bis (1-

  methylethyl) amino / ethyl / α-phenyl-2-pyridineacetamide, 10% by weight of an ester of glycerol and a fatty acid containing from 22 to 22 carbon atoms, and 2% to 12% of an inert filler whose solubility in water at room temperature is

  between 0.2 g and 3 g per milliliter.

  Among the medicaments which are the subject of the present invention, those which are characterized in that the ezter of glycerol and of a fatty acid containing from 10 to 22 atoms are particularly selected.

  of carbon is glyceryl monostearate.

  We also retain those characterized in that the char-

  Inert gel has solubility in water at room temperature of between 1.5 g and 2.5 g per milliliter; among these, the medicaments characterized in that the charge is preferred.

  inert is sucrose.

  In the context of the present invention, it has also been found that it could be advantageous to add to the three components

  defined above, a binding agent such as polyvinyl pyrrolidone

lidone and a lubricant.

  The present invention thus also relates to the medicaments as defined above, characterized in that

247 1784

  that they contain, in addition, polyvinyl pyrrolidone and

a lubricant.

  The lubricant may be, for example, talc, stearic acid, zinc, calcium or aluminum stearates, but magnesium stearate is preferred. The binder 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% binder, and from 2% to 3% of lubricant. The drugs as defined above, are endowed with remarkable antiarrhythmic prolonged properties. These

  properties are illustrated later in the experimental section.

  Experimental. Because of these properties, the drugs, object of

  the present invention can be used in the treatment

  prevention of rhythm disturbances, relapses of

  rhythm, relapses. of paroxysmal tachycardia, or in the curative treatment of atrial extrasystolias

  ventricular organs, extrasystole and bigemianism di-

gitaliques.

  The usual dose, variable according to the product used, the subject treated and the affection in question may be, for example, from 100 mg to 500 mg of α- / 2-bis (1-methylethyl) amino / ethyl phosphate. -a-phenyl-2-pyridineacetamide taken by route

  oral in men, one dose taken morning and evening.

  The subject of the invention is also a process for the preparation of medicaments, as defined above, characterized

  in that one mixes, according to the known techniques in them-

  same, the different constituents, as defined above-

above.

  Finally, the subject of the invention is the pharmaceutical compositions

  which close at least one medicinal product, such as

  written above. These compositions are intended for the oral route. These pharmaceutical compositions may occur

  in the pharmaceutical forms commonly used in

  such as, for example, tablets, tablets,

  single or coated tablets, capsules, granules; they

  are prepared according to the usual methods.

  When carrying out the pharmaceutical compositions, as defined above, it is possible to add excipients conventionally used in these pharmaceutical compositions, such as talc, gum arabic, aluminum hydroxide.

  colloidal silica, lactose, starch, stearic acid

  magnesium stearate, preservatives. He will be given now; without limitation, a

  example of implementation of the invention.

  EXAMPLE: Coated Tablets Coated tablets having the formula:

  α- / 2-bis (1-methylethyl) amino / ethyl-α-phenol phosphate

  nyl-2-pyridineacetamide (phosphatedediaopyramide) 322.5 mg - glyceryl monostearate ................... 90.0 mg - powdered sugar ....... ..........

  .......... 30.0 mg - polyvinyl pyrrolidone ....................... 5.0 mg magnesium stearate ... ................... 12,5 mg - coating (hydroxypropylmethylcellulose, glucose, propyleneglycol) ................. ..DTD: .. 10.0 mg homogeneously mixed α- / 2-bis (1-methylethyl) amino-ethyl-α-phenyl-2-pyridineacetamide phosphate, glyceryl monostearate and sugar, The melting mixture is brought to a temperature of about 65.degree. C., the resulting granules are sieved through a sieve, the said granules are wetted with a dry polyvinylpyrrolidone solution, and the caliber is again calibrated, the magnesium stearate is added and the mixture is then passed through. ..DTD: compression machine.

  The coating is carried out by spraying an aqueous solution of a mixture of hydroxypropylmethyl cellulose,

  glucose and propylene glycol, and simultaneous drying.

  Clinical study of the delayed activity In man, the plasma concentrations of disopyramide were compared with oral doses of 2 capsules at 100 mg of disopyramide and 1 tablet of disopyramide of disopyramide, as a function of time. example

  corresponding to 250 mg of disopyramide base.

  The study covered 6 male subjects aged 21

  at age 24, in cross administration.

  Plasma samples (10 ml each time) were

  performed at time O (just before administration) -0.5-

  -1-1.5-2-3-4-5-6-8-12-15-24-30-36-48 hours after administration

  tration. The dosage of the product is carried out by chromatogra-

  liquid high pressure, after extraction of plasma from

using ethyl acetate.

  In order to be able to directly compare the plasma concentrations obtained after administration given that different doses of disopyramide are contained in the capsules and in the tablets, the concentrations were

  expressed as a percentage of the dose administered per

be plasma.

  The results obtained are as follows: a) Maximum concentration schedules The maximum plasma concentration is reached in 2.53 hours in the capsule form and in 4.50 hours for the tablet form. B) Quantit of active ingredient reaching the general circulation

  The area between the curve represented by

  the plasmatic concentration of the test product

  function of time and the detection of asse-

  0 sensibly similar results o Capsules 13.6% of the dose 1lo h Tablets g 1.2 o of the dose 1l0o h 1 Represents the plasma volume in liters h represents the time in hours c) TemD "latency before the start of the action Capsules @ D0 4 h Tablets 0.29 hr Conclusions It is thus possible to note a significant delay in the resorption of the product in the compressed fo0-e compared to the capsule form, since the maximum concentration peak is later in the form. compriméo

  Moreover, the same total amount of principle

  tif reaches the general circulation in the forms

  me and capsule. Finally, the active ingredient appears in the plasma

  In the case of tablets, we are dealing well with long-acting medications.

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Claims (9)

R E V E N D I C A T I 0 N S   1. - New anti-arrhythmic drugs with   lined, characterized in that they contain:   a) α- / 2- bis (1-methylethyl) amino / ethyl / α-phenyl-2-py   ridineacetamide or one of its addition salts with pharmaceutically acceptable mineral or organic acids; b) an ester of glycerol and a fatty acid containing from 22 to 22 carbon atoms,   (c) an inert filler, the solubility of which in water at   ambient temperature is between 0.2 g and 3 g liter.   2. - Drugs according to claim 1, characterized   in that they contain the α- / 2- bis (1-methyl) phosphate   ethyl) amino / ethyl / -a-phenyl-2-pyridineacétamide.   3. - Drugs according to claim 1 or 2, characterized   in that they contain about 60% to 80% of a- / 2-   / Bis (l-methylethyl) amino / ethyl / -a-phenyl-2-pyridineacétami-   from 10% to 30% of an ester of glycerol and a fatty acid containing 10 to 22 carbon atoms, and 2% to 12%   an inert filler whose solubility in water   ambient temperature is between 0.2 g and 5 g liter.   4. - Drugs according to any one of the claims   I to 3, characterized in that the ester of glycerol and a fatty acid containing from 10 to 22 carbon atoms is the glyceryl monostearate.   5. - Drugs according to any one of the claims   1 to 4, characterized in that the inert filler solubilizes   in water at room temperature between 1.5 g and 2.5 g per milliliter.   6. - Drugs according to claim 5, characterized in   that the inert filler consists of sucrose.   7. - Drugs according to any one of the claims   1 to 6, characterized in that they contain in addition to the poly- vinyl pyrrolidone and a lubricant.   8. - Process for the preparation of medicaments, as defined   according to one of claims 1 to 7, characterized   in that the various constituents, as defined, are mixed according to techniques known per se in themselves. in these claims.   9. - Pharmaceutical compositions, characterized in that they contain at least one of the drugs, such as   defined in any one of claims 1 to 7.