Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-12-19
2001-08-28
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06281246
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to an antiarrhythmic drug and particularly to a combination of d- and l-isomers of sotalol, being N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl] phenyl] methane sulfonamide, as a safer class III antiarrhythmic drug with reduced beta adrenergic blockade.
2. Description of the Related Art
Drug treatment of cardiac arrhythmias has undergone rapid changes during the last decade. Experimental studies have shown that drugs that act by delaying conduction, though are able to suppress ventricular arrhythmias, also increase the mortality particularly in patients with cardiac disease.
Cardiac Arrhythmia Suppression Trial (CAST) Investigators (New Engl J Med 1989; 321:407-412) and Cardiac Arrhythmia Suppression Trial II (CAST II) Investigators (New Engl J Med 1992; 327:227-33) have shown that drugs like flecainide, encainide and moricizine which act by blocking sodium channels cause increased mortality in patients who survived from acute myocardial infarction despite markedly suppressing premature ventricular contractions.
Coplen et al (Circulation 1990 Oct. 82(4):1106-16) have shown that even drugs like quinidine which has been used for so long in antiarrhythmic therapy increase the mortality in a variety of settings.
The Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE) study (Am J Cardiol 1993; 72:280-287) have further shown that, amiodarone, an antiarrhythmic agent which acts by increasing the duration of cardiac repolarization is better than those which act by blocking sodium channels.
The above disclosures emphasize the fact that suppression of arrhythmias does not necessarily decrease mortality and that the net effect on mortality is agent specific. In addition, the most important determinant of arrhythmia mortality is the nature and degree of ventricular dysfunction.
All these lead to dramatic changes in the choice of antiarrhythmic drugs for ventricular and supraventricular arrhythmias.
Thus, sotalol emerged as one of the drugs of choice for its beta blocking and antiarrhythmic activities, as it could reduce mortality by preventing ventricular fibrillation in patients with cardiac disease.
Jay W. Mason for the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Investigators (New Engl J Med 1993; 329:452-8) has shown that in patients with Ventricular Tachycardia (VT) and Ventricular Fibrillation (VF), sotalol a beta blocker with class III antiarrhythmic activity is better than six other class I antiarrhythmic compounds.
The results of the CAST and ESVEM trials have led to an increased interest in class III antiarrhythmic agents including sotalol (Callaghan et al, Am J. Cardiol, 1996; 78:(4A)(54-60).
Sotalol is being used as a equimolecular mixture of dextro- and laevo-isomer of the molecule. The isomers are equipotent in increasing the duration of repolarization and consequently the action potential duration and believed to be equally effective clinically as antiarrhythmic agent.
However, the laevo-isomer is a more potent beta blocker as compared to the dextro-isomer. As a result racemic sotalol with equal proportion of laevo- and dextro-isomers has more than required beta blocking activity which may compromise the cardiac function particularly in patients with structural heart disease.
In addition to the CAST trial a recent meta analysis of mortality data on 98000 survivors with myocardial infarction also found that class I agents were associated with increased mortality. Only class II and class III drugs were associated with decreased mortality. Unfortunately for a high percentage of these patients at risk, beta blockers are not tolerated or are contraindicated. The Survival With Oral d-Sotalol (SWORD) trial indicated that pure d-sotalol was also not of much benefit in patients with acute myocardial infraction (Am J. Cardiol 1995; 75:1023-1027).
U.S. Pat. No. 5,089,526 describes (+)-sotalol that is the dextro isomer as a class III antiarrhythmic drug capable of lengthening the action potential duration of cardiac cells and thus helpful in treatment of cardiac arrhythmias.
U K Patent 2,286,529 observes that the treatment of cardiac arrhythmias in patients with iscbaemic heart disease especially when accompanied by the signs and symptoms of heart failure presents a difficult problem, since most antiarrhythmic drugs including beta blockers, depress cardiac contractility and may worsen heart failure. In solving this problem this U K Patent finds that a mixture of the isomers of sotalol in which the proportion of l-isomer is significantly less than that of d-isomer will be of use in the treatment of arrhythmias in patients with ischaemic heart disease and/or heart failure. It further discloses a combination of 60 to 99 percentage of d-sotalol with 40 to 1 percentage of racemic or dl-sotalol which corresponds to 80 to 99.50 percentage of d-sotalol with 20 to 0.50 percentage of 1-sotalol as the most suitable range for this combination for treatment of heart patients.
SUMMARY OF THE INVENTION
The first objective of the present invention is to provide a safer class III antiarrhythmic drug with controlled beta adrenergic blockade.
The second objective of the present invention is to find out the safest ratio of d- and l-isomer in the combination drug of d- and l-sotalol which satisfies the above criteria.
The present invention provides for a safer antiarrhythmic drug with controlled beta adrenergic activity which comprises a combination of dextro- and laevo-rotatory isomers of sotalol being N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane sulfonamide, or their pharmaceutically acceptable salts as active ingredients, wherein the range of ratio of dextro- and laevo-isomer in said combination is from 1.5:1 to 3.5:1.
The invention also provides for pharmaceutical composition with the said combination of dextro- and laevo-isomers of sotalol as active ingredient, particularly oral and parenteral preparations containing such active ingredient.
The invention further provides for a method of treatment of cardiac ailments in mammals including human beings by administration of an optimally effective amount of the said combination of dextro and laevo rotatory isomers of sotalol.
DETAILED DESCRIPTION OF THE INVENTION
a. Preparation of Isomeric Mixture of Sotalol
Pure isomers of l-sotalol and d-sotalol were prepared from racemic sotalol as follows.
Racemic sotalol hydrochloride was converted into its base. Chiral separation was carried out by chiral chromatography and the isomers were reconverted back to their hydrochloride form.
In addition, using chemical method as described by Le Garrec (1987), enriched d-sotalol hydrochloride and l-sotalol hydrochloride were prepared using mandelic acid and subjected to conversion to the base form, chiral separation and reconversion to hydrochloride salt was carried out. The details of these procedures are given below:
i) Conversion of Sotalol Hydrochloride into Sotalol Base:
In 2 lit. round bottom flask, in 450 ml of water, (±) sotalol hydrochloride (200 g) was added under stirring at room temperature. Under stirring, a solution of 500 g of potassium carbonate in 300 ml of water was added. The stirring was continued for 48 hours. Solid material was separated to give 107 g of (±) sotalol.
ii) Resolution of Racemic Sotalol Base into its Enantiomers:
The solution containing racemic sotalol was chromatographed on a Chiralpak AD column containing 3,5-dimethoxyphenylcarbamoyl derivative. The mobile phase was a 82:18 mixture of n-hexane:absolute ethanol containing 0.2% of diethylamine (AR grade). Based on the method reported in Japanese Patent(JP-1-165569, 1989), the separation was standardised on an analytical Chiralpak AD column and then scaled up on a semipreparative Chiralpak AD column of 2×25 cm dimension. Racemic sotalol base (1.0 g) was dissolved in absolute ethanol (22 ml) by slightly warming to 45-50° C. An aliquot of 2 ml of the solut
Henley III Raymond
Sughrue Mion Zinn Macpeak & Seas, PLLC
Torrent Pharmaceutical Ltd.
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