Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-03
2002-12-10
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S821000
Reexamination Certificate
active
06492382
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to dried preparations containing a class III antiarrhythmic compound in the form of a crystalline or amorphous salt or any combination thereof, where the counterion is selected from pharmaceutically acceptable water-soluble organic or inorganic acids. The present invention also relates to frozen preparations containing a class III antiarrhythmic compound in the form of a salt solution, where the counterion is selected from pharmaceutically acceptable water-soluble organic or inorganic acids. Preferred preparations contain a salt of the compound 3,7-diazabicyclo[3.3.1]-nonane-3-carboxylic acid, 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-1,1-dimethylethyl ester (hereinafter Compound A). Further aspects of the present invention include salts of Compound A per se, processes for preparing the preparations, as well as use of the preparations for prophylaxis and/or treatment of cardiac arrhytmia.
BACKGROUND OF THE INVENTION
Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation.
Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).
In the treatment of cardiac arrhythmias, the negative outcome in some clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with drugs, acting primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval of the ECG. Class III antiarrhythmic drugs may be defined as drugs which prolong the action potential duration (which can be caused by a block of outward K
+
currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to induce a unique form of proarrhythmia known as torsades de pointes, which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs.
Most antiarrhythmic drugs (including class III antiarrhythmic drugs) have a duration of action of between 3 and 12 hours. For example, the selective class III antiarrhythmic drug ibutilide (Pharmacia & Upjohn) has a half-life of elimination, which averages at around 6 hours when the drug is administered intravenously to a human patient.
In the minimisation of the side effects (including torsades de pointes) associated with anti-arrhythmic drugs, compounds which are effective, yet short acting, when administered intravenously, are expected to be of benefit. Accordingly, compounds which have a duration of action which is relatively short (hereinafter referred to as “short acting compounds”) may be expected to have clinical advantages when used in the acute conversion of arrhythmias, including reduced monitoring and hospitalisation time.
The class III antiarrhythmic compounds of the present invention, including Compound A, are such short acting compounds useful in the prophylaxis and treatment of cardiac arrhythmias. Their properties and the preparation thereof are described in International Patent Application WO 99/31100 that is hereby incorporated by reference.
Compound A is poorly soluble in water and unstable in water solutions. Compound A can thus not be readily formulated as a ready-for-use aqueous solution.
The physico-chemical properties of the class III antiarrhythmic compounds of the present invention, including Compound A (which is a weak base), such as low water solubility and decomposition in water solution, especially at a low pH, provide difficulties in formulating pharmaceutical preparations containing these compounds which are stable during storage and easy to administer, e.g. parenterally in a suitable volume.
In addition of being unphysiologically low, the pH of the acidic solution makes the active substance decompose and thus the storage stability of the solution will be insufficient.
Thus, an objective of the present invention is to provide pharmaceutical preparations containing certain class III antiarrhythmic compounds having good storage stability.
A further objective of the invention is to provide a parenteral pharmaceutical preparation of Compound A having good storage stability and which can be easily administered as a solution to mammals.
A still further objective of the invention is to provide a method of preparing such a parenteral pharmaceutical preparation.
SUMMARY OF THE INVENTION
One aspect of the invention relates to a dried pharmaceutical preparation for preparation of a solution ex tempore comprising a class III antiarrhythmic compound of the general formula
wherein
R represents linear, branched, cyclic or acyclic C
1-6
alkyl, in the form of a crystalline or amorphous salt or any combination thereof, wherein the counterion is selected from an acid which is a pharmaceutically acceptable water-soluble organic or inorganic acid.
Another aspect of the invention relates to a frozen, aqueous pharmaceutical preparation comprising a class III antiarrhythmic compound of the general formula
wherein
R represents linear, branched, cyclic or acyclic C
1-6
alkyl, in the form of a salt solution, wherein the counterion is selected from an acid which is a pharmaceutically acceptable water-soluble organic or inorganic acid.
Yet another aspect of the invention relates to a process for the preparation of a dried or frozen pharmaceutical preparation containing the class III antiarrhythmic compound of the invention, comprising dissolving the class III antiarrhythmic compound in the acid and water, optionally adjusting the pH with an alkalising agent and drying or freezing, respectively, the resulting solution.
Still another aspect of the invention relates to a salt of the compound 3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid, 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-1,1-dimethylethyl ester, a salt of the compound 3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid, 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-1,1-dimethylethyl ester or any mixture thereof, wherein the counterion is selected from an acid which is a pharmaceutically acceptable water-soluble organic or inorganic acid, suitably tartaric acid.
A further aspect of the invention relates to use of a salt or salt solution of a class III antiarrhythmic compound according to the invention in the manufacture of a dried or frozen pharmaceutical preparation for the prophylaxis and/or treatment of cardiac arrhythmia.
A still further aspect of the invention relates to a method for the prophylaxis and/or treatment of cardiac arrhythmia, especially atrial and ventricular arrhythmia, wherein a pharmaceutical preparation according to the present invention is administered to a mammal in the need of such prophylaxis and/or treatment after reconstitution and optional dilution or thawing and optional dilution.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that the solubility of the active substance and the storage stability of a pharmaceutical preparation, of a class III antiarrhythmic compound of the present invention, especially parenteral preparations of Compound A, can be considerably improved by dissolving the active substance in water together with a water-soluble organic or inorganic acid, and by optionally adjusting the pH to a p
Björe Annika
Granath Anna-Karin
Krass Frederick
White & Case LLP
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