GB2286529A - Combination of class III and class II Antiarrhythmic drugs - Google Patents
Combination of class III and class II Antiarrhythmic drugs Download PDFInfo
- Publication number
- GB2286529A GB2286529A GB9413859A GB9413859A GB2286529A GB 2286529 A GB2286529 A GB 2286529A GB 9413859 A GB9413859 A GB 9413859A GB 9413859 A GB9413859 A GB 9413859A GB 2286529 A GB2286529 A GB 2286529A
- Authority
- GB
- United Kingdom
- Prior art keywords
- sotalol
- class
- antiarrhythmic drug
- combination product
- class iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A combination product of a class III Antiarrhythmic drug, especially (+)-Sotalol.HCl, and a class II Antiarrhythmic drug, e.g. (+/-)-Sotalol.HCl is useful for cardioprotective effects. The product may be in an oral dosage form in a weight ratio of approximately 9 parts +)-Sotalol to 1 part (+/-)-Sotalol.
Description
"Pharmaceutical Products*
The invention relates to pharmaceutical combination products, processes for their preparation and their use as medicaments.
As outlined, for example, in US 5,089,526 Antiarrhythmic drugs are commonly divided into four classes according to their electrophysical mode of action. The classifications are:
I Local Anaesthetic effect
II Beta-receptor blockage
III Prolongation of action potential duration IV Calcium antagonism.
Class I agents generally exert local anaesthetic activity directly at a cardiac cell membrane but have little or no action potential duration (APD).
Class II agents exert their effects through competitive inhibition of beta-adrenergic receptor sites thereby reducing sympathetic excitation of the heart. They generally have little or no effect on action potential duration (APD).
The characteristic of Class III agents is their ability to prevent or ameliorate arrhythmias by lengthening the action potential duration (APD).
US 5,089,526 describes (+)-Sotalol as a Class III
Antiarrhythmic drug as it lengthens the action potential duration of cardiac cells and is thereby useful in treating heart arrhythmias.
(+)-sotalol-Hcl may be represented by the formula:
According to the invention there is provided a combination product of a class III Antiarrhythmic drug with a class II
Antiarrhythmic drug.
In a particulary preferred embodiment of the invention the class III Antiarrhythmic drug comprises a pharmaceutically acceptable salt of (+)-Sotalol, especially (+)
Sotalol.HCl.
In an especially preferred arrangement the class II
Antiarrhythmic drug is selected from one or more of:
propranolol, oxprenolol, practolol, acebutolol,
pindolol, metindol, nadolol, labetalol, bisoprolol,
bunitrolol, tolamolol, formoterol, celiprolol,
bupranolol, (+)-Sotalol, (+)-Atenolol, (-)-Atenolol,
(+)-Metoprolol, (-)-Metoprolol, and pharmaceutically
acceptable salts, diastereoisomers as racemates or as
enantiomers or mixture of diastereoisomers thereof.
Typically the class II Antiarrhythmic drug comprises a pharmaceutically acceptable salt of (+) Sotalol, especially (+) Sotalol HCl.
Preferably the product is in oral dosage form, typically in a capsule or tablet form.
In one embodiment of the invention the weight ratio of the class III Antiarrhythmic drug to the class II
Antiarrhythmic drug is from 99:1 to 60:40.
In a preferred arrangement the class III Antiarrhythmic drug is (+)-Sotalol, the class II Antiarrhythmic drug is (+)-Sotalol, and the weight ratio is approximately 9:1.
The invention also provides in another aspect a pharmaceutical composition comprising (+)-Sotalol HCl and (+)-Sotalol HCl. In this case preferably the weight ratio of (+)-Sotalol HCl to (+)-Sotalol HC1 is approximately 9:1.
In a further aspect the invention provides a use of a composition comprising a class III Antiarrhythmic drug and a class II Antiarrhythmic drug for the manufacture of a medicament for cardioprotective effects including for the treatment or prevention of arrhythmias, in the setting of myocardial ischemia in the post infarcted heart and for the treatment of coronary heart disease.
The invention will be more clearly understood from the following description thereof given by way of example only.
The antiarrhythmic activity of the racemate Sotalol and especially of the enantiomeric pure (+)-Sotalol are documented in Arznein Forsch/Drug Res. 38 (I), Nr. 2 (1988) and in US Patent 3,341,584.
Antiarrhythmic drug therapy is the most common approach to arrhythmic suppression. The two usual indications for antiarrhythmic drugs are the relief of symptoms caused by arrhythmia with the potential of sudden cardiac death.
The antiarrhythmic efficiency of class III antiarrhythmic agent, Sotalol, has been related to its prolongation of the cardiac action potential duration (APD).
Control of cardiac arrhythmias by selectively lengthening repolarization has thereby been established as a growing concept in cardiac electrophysiology, and class III antiarrhythmic agents, amiodarone and sotalol, have been in clinical use since 1962 and 1974, respectively.
Racemic Sotalol, a class III antiarrhythmic agent with ss- adrenergic blocking activity, and its isomer (+)-Sotalol which exerts relatively little but sometimes desired ss- adrenergic blocking activity, have been shown to produce an equivalent prolongation of APD.
13-blockers are compounds which influence specific ss- adrenergic-receptors, which have to be blocked in the case of severe heart attacks. Such compounds as well as their activity are recorded in a large number of publications and patent applications.
Since the two groups of compounds act on different blood pressure-regulation systems, in combined use the effect of one definite and clearly described combination partner is raised by the other partner. In combined use this leads to a reduction in the dose of the combination partners, compared with single use as well as a reduction of adverse and undesired side reactions.
Thus the appearance of side effects known for the two classes of substance can be reduced or avoided if there is definite and very well defined combination of the two active compounds.
The following compounds or their physiologically acceptable salts can be considered as 13-blockers: Propranolol, oxprenolol, practolol, acebutolol,
pindolol, metindol, nadolol, labetalol, bisoprolol,
bunitrolol, tolamolol, formoterol, celiprolol,
bupranolol, (+)-Sotalol, (+)-Atenolol, (-)
Atenolol, (+)-Metoprolol, (-)-Metoprolol
In the compounds which possess several chiral atoms all possible diastereoisomers as racemates or as enantiomers, or mixture of various diastereoisomers can be considered.
Particularly preferred as ss-blockers are the following: (+)-Sotalol, (+)-Atenolol, (-)-Atenolol, (+)-Metoprolol, (-)-Metoprolol
The synthesis of pure (+)-sotalol is described in US
Patent Specification No. 5,089,526.
The separation of the racemate of the ss-blockers are very well described in the literature.
The invention also relates quite generally to products which contain: a) (+)-sotalol of the formula I or its physiologically
acceptable salts
and b) a ss-blocker or its physiologically acceptable salts
as a combination preparation for simultaneous, separate
or periodic regulated use in the treatment of
antiarrhythmias.
The pharmaceutical compositions can be prepared for example, by initially mixing the single components as powders, or by dissolving the single components in a suitable solvent such as, for example, a lower alcohol and then removing the solvent.
The ratio of the active agents in the combinations and compositions according to the invention is preferably 6099% by weight of (+)-sotalol to 40-18 by weight of ss- blocker.
As mentioned above the compositions and the definite combinations according to the invention can be used in drug therapy, particularly for cardioprotective effects.
It is very well known that cardioprotection plays an important part in the antiarrhythmic activity.
The described combinations may be useful in preventing life-threatening arrhythmias in the setting of myocardial ischemia in the post-infarcted heart as well as for the treatment of coronary heart disease.
The compositions and combinations according to the invention can be orally or parenterally administered in a corresponding pharmaceutical composition. For oral use, the active compounds are mixed with the additives usual for this purpose such as carriers, stabilizers or inert diluents, and converted by the usual methods into suitable forms for administration, such as tablets, dragees, cylindrical capsules, aqueous, alcoholic or oily suspensions or oily solutions.
An inert carrier e.g. gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, particularly maize starch, can be used. In this case, the composition can be formed both as dry or moist granules.
Vegetable and animal oils, such as sunflower oil or cod liver oil for example, can be considered as oily carriers or solvents.
For subcutaneous or i.v. administration, the active substances or their physiologically acceptable salts are brought into solution, suspension or emulsion, optionally with the usually employed substances such as solubilizers, emulsifiers or other auxiliaries.
As solvents for the active combinations and the corresponding physiologically acceptable salts can be considered e.g. water, physiologically salt solutions or alcohols, besides also sugar solutions or also a mixture of the various solvents mentioned.
The salts of the mentioned compounds that can be considered are those, depending on the basic nature of these compounds, with physiologically acceptable inorganic or organic acids such as e.g. HC1, HBr, H2SO4, maleic acid, fumaric acid, succinic acid, tartaric acid and citric acid.
The following example serves to illustrate the present invention, without restricting it thereto:
EXAMPLE 1
Preparation of an oral combination product from (+)
Sotalol and (*) Sotalol.
1000 tablets which contain 90 mg (+)-Sotalol.HCl and 10 mg of (+) Sotalol HCl are prepared as follows:
Dry granules
(+)-Sotalol HCl 90g
(+) Sotalol HCl lOg
maize starch 12.5g
microcrystalline cellulose 2g
magnesium stearate 1.5g
The two active agents are mixed and ground to granules.
Microcrystalline cellulose and magnesium stearate are mixed with the granules. The granules so obtained are compressed into 1000 tablets, each tablet containing 90 mg of + Sotalol and 10 mg of (+) Sotalol.
Example 2
Beta receptor blocking properties of mixtures of (+) and (+) Sotalol
Methods:
Experiments were carried out on isolated rat right atria suspended in an organ bath containing Krebs Hensleit solution at 310C. Contractions were measured using a Grass strain gauge, the signal from which was used to drive a cardiotachometer.
Isoprenaline dose response curves relating the concentration of isoprenaline to the increase in heart rate (HR) were obtained in the absence and presence of 4 mixtures of the isomers of sotalol:- (%D/L) 100/0, 95/5, 75/25, 50/50, at micromolar concentrations of 1.6, 6.4, 15, 64, and 160. The isoprenaline dose response curves were normalised and dose ratio shifts calculated (DR).
Schild plots relating log DR-1 to the concentration of sotalol were constructed and analysed by linear regression.
Results: (1) Control isoprenaline dose response curves.
In the absence of sotalol the baseline heart rate
was 175.1 +2.3 beats/min (mean + SEM). The
maximum HR brought about by isoprenaline was 316.9
i3.8 beats/min, and increase of 141.8+4.8 beats/min. The ED50 for this effect of
isoprenaline was 0.97 nano g/ml (95% C1 1.2-0.8).
(2) Effects of sotalol on baseline heart rate and
maximum response to isoprenaline.
Both 100%D and 50/50% D/L sotalol caused similar
reductions in the baseline and maximum heart rate
response to isoprenaline. Thus the actual change
in the heart rate in response to isoprenaline was
unaltered:
%DL Baseline HR Max HR IncreaseHR control 175.1i2.3 316.9i3.8 141.8+4.8
100/0 155.0+2.5 302.2+10.9 147.2+9.6
50/50 151.3i5.4 302.3+11.5 151.0+9.0 (3) Effects of sotalol on ED50 of isoprenaline dose
response curves.
Dose ratio shifts (DR-1) of isoprenaline dose
response curves brought about by mixtures of the
isomers of sotalol (%D/L) at the concentrations
indicated, (n) number of observations:
[sotalol] micromolar
1.6 6.4 16.0 64.0 160.0 %D/L 100/0 --- 6.2(1) 7.9(4) 15.5(1) 30.3(7)
95/5 --- 5.3(2) 19.6(2) --- 71.0(4)
75/25 2.4(1) 9.3(1) 10.9(1) 25.0(1) 23.0(4)
50/50 7.2(2) --- 21.0(5) --- 143.0(5)
Regression analysis of the Schild plot (logDR1/[sotalol]M) for each mixture gave slopes of less than unity, indicating effects of sotalol other than simple competitive inhibition of isoprenaline at the beta adrenceptor. The data for 100%D sotalol gave a slope of 0.56±0.05 (R=0.96) and for 50/50% D/L sotalol 0.69 ± 0.6 (R=0.96). Thus the slope of the 100%D was significantly less than that of 50/50%D/L. The slopes of the 95/5% and 75/25% D/L mixtures were intermediate between the above two values. The above differences in slope preclude statistical comparison of the elevations of the regression lines. However sufficient data is available at sotalol concentrations of 16 and 160 micromolar to allow the conclusion that, firstly the 100% D-isomer has significant beta-adrenoceptor antagonism and secondly that addition of increasing amounts of L-isomer increase the betaadrenoceptor antagonist effect.
These results show that the effects of the mixture of the isomers of sotalol on heart rate and the response of heart rate to isoprenaline cannot be explained by simple competitive inhibition of isoprenaline at the betaadrenoceptor, since the slopes of the Schild plots are significantly less than unity. Furthermore this reduction in slope is dependent upon the amount of D-isomer present in the mixture and indicates an action of the D-isomer which, despite having beta blocking activity, offsets the beta blocking effects of the L-isomer. Thus mixtures of the two isomers have pharmacological properties which cannot be predicted from the previously known pharmacology of each isomer (eg Singh et al 1987).
The treatment of cardiac arrhythmias in patients with ischaemic heart disease especially when accompanied by the signs and symptoms of heart failure presents a difficult clinical problem, since most anti-arrhythmic drugs, including beta blockers, depress cardiac contractility and may worsen heart failure. However treatment of heart failure with low dose beta-blockers is thought to cause up regulation of cardiac beta adrenoceptors and improve cardiac contractility. Thus a mixture of the isomers of sotalol in which the proportion of L-isomer (which is predominantly a beta blocking isomer) is significantly less than that of the D-isomer (predominantly an antiarrhythmic isomer) will be of use in the treatment of arrhythmias in patients with ischaemic heart disease and/or heart failure.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
Claims (17)
1. A combination pharmaceutical product or
pharmaceutical composition of a class III
Antiarrhythmic drug, especially (+)- Sotalol and
pharmaceutically acceptable salts thereof with a
class II Antiarrhythmic drug selected from one or
more of:
propranolol, oxprenolol, practolol, acebutolol,
pindolol, metindol, nadolol, labetalol,
bisoprolol, bunitrolol, tolamolol, formoterol,
celiprolol, bupranolol, (+)-Sotalol, ()-Atenolol, (-)-Atenolol, (i)-Metoprolol, (-)-Metoprolol, and
pharmaceutically acceptable salts,
diastereoisomers as racemates or as enantiomers or
mixture of diastereoisomers thereof.
2. A combination product as claimed in claim 1
wherein the class II Antiarrhythmic drug comprises ()Sotalol.HCl.
3. A combination product as claimed in any preceding
claim in an oral dosage form.
4. A combination product as claimed in any preceding
claim wherein the weight ratio of the class III
Antiarrhythmic drug to the class II Antiarrhythmic
drug is from 99:1 to 60:40.
5. A combination product as claimed in claim 4
wherein the class III Antiarrhythmic drug is (+)
Sotalol.
6. A combination product as claimed in claim 4 or 5
wherein the class II Antiarrhythmic drug is (*)- Sotalol.
7. A combination product as claimed in any of claims
4 to 6 wherein the weight ratio is approximately
9:1.
8. Use of a composition comprising a class III
Antiarrhythmic drug and a class II Antiarrhythmic
drug for the manufacture of a medicament for
cardioprotective effects including for the
treatment or prevention of arrhythmias, in the
setting of myocardial ischemia in the post
infarcted heart and for the treatment of coronary
heart disease.
9. Use as claimed in claim 8 wherein the class III
Antiarrhythmic drug comprises (+)-Sotalol or a
pharmaceutically acceptable salt thereof.
10. Use as claimed in claim 9 wherein the
Antiarrhythmic drug comprises (+)-Sotalol.HCl.
11. Use as claimed in claim 9 or 10 wherein the class
II Antiarrhythmic drug is selected from one or
more of:
propranolol, oxprenolol, practolol, acebutolol,
pindolol, metindol, nadolol, labetalol,
bisoprolol, bunitrolol, tolamolol, formoterol,
celiprolol, bupranolol, (+)-Sotalol, (+)-Atenolol,
(-)-Atenolol, (+)-Metoprolol, (-)-Metoprolol, and
pharmaceutically acceptable salts,
diastereoisomers as racemates or as enantiomers or
mixture of diastereoisomers thereof.
12. Use as claimed in claim 11 wherein the class II
Antiarrhythmic drug is ()Sotalol or a
pharmaceutically acceptable salt thereof.
13. Use as claimed in claim 12 wherein the class II
Antiarrhythmic drug is () Sotalol.HCl.
14. Use as claimed in any of claims 9 to 13 wherein
the weight ratio of the class III Antiarrhythmic
drug to the class II Antiarrhythmic drug is from
99:1 to 60:40.
15. Use as claimed in claim 14 wherein the class III
Antiarrhythmic drug is (+)-Sotalol, the class II
Antiarrhythmic drug is (+)-Sotalol, and the weight
ratio is approximately 9:1.
16. A combination product substantially as
hereinbefore described with reference to the
examples.
17. Use substantially as hereinbefore described with
reference to the examples.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE940146 | 1994-02-17 | ||
IES940272 IES940272A2 (en) | 1994-02-17 | 1994-03-29 | "Pharmaceutical Products" |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9413859D0 GB9413859D0 (en) | 1994-08-24 |
GB2286529A true GB2286529A (en) | 1995-08-23 |
GB2286529B GB2286529B (en) | 1998-02-18 |
Family
ID=26319692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9413859A Expired - Fee Related GB2286529B (en) | 1994-02-17 | 1994-07-08 | Combinations of class III antiarrhythmic drug (+)-Sotalol and class II antiarrhythmic drugs |
Country Status (3)
Country | Link |
---|---|
BE (1) | BE1006859A6 (en) |
GB (1) | GB2286529B (en) |
IE (1) | IES940272A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000045807A1 (en) * | 1999-02-05 | 2000-08-10 | Alangudi Sankaranarayanan | Pharmaceutical composition comprising a combination of dextro- and laevo- isomers of sotalol |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5089526A (en) * | 1983-05-23 | 1992-02-18 | Bristol-Myers Company | Antiarrhythmic class III process |
-
1994
- 1994-03-29 IE IES940272 patent/IES940272A2/en unknown
- 1994-07-08 GB GB9413859A patent/GB2286529B/en not_active Expired - Fee Related
- 1994-07-08 BE BE9400639A patent/BE1006859A6/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5089526A (en) * | 1983-05-23 | 1992-02-18 | Bristol-Myers Company | Antiarrhythmic class III process |
Non-Patent Citations (1)
Title |
---|
Chemical Abstracts 105:218636 & Cardiovasc. Res. 20(10), 705-9 (1988) * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000045807A1 (en) * | 1999-02-05 | 2000-08-10 | Alangudi Sankaranarayanan | Pharmaceutical composition comprising a combination of dextro- and laevo- isomers of sotalol |
US6281246B2 (en) | 1999-02-05 | 2001-08-28 | Torrent Pharmaceutical Ltd. | Pharmaceutical composition with sotalol combination and their use in treatment of cardiac ailments |
AU761521B2 (en) * | 1999-02-05 | 2003-06-05 | Torrent Pharmaceuticals Ltd | Pharmaceutical composition comprising a combination of dextro- and laevo- isomers of sotalol |
AU761521C (en) * | 1999-02-05 | 2004-01-22 | Torrent Pharmaceuticals Ltd | Pharmaceutical composition comprising a combination of dextro- and laevo- isomers of sotalol |
Also Published As
Publication number | Publication date |
---|---|
IES61567B2 (en) | 1994-11-16 |
GB2286529B (en) | 1998-02-18 |
BE1006859A6 (en) | 1995-01-10 |
GB9413859D0 (en) | 1994-08-24 |
IES940272A2 (en) | 1994-11-16 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20040708 |