Title of Invention

"A MEDICAL PRODUCT COMPRISING A THROMB LYTIC AGENT AND LEVOSIMENDAN AS A COMBINED PREPARATION"

Abstract A combination therapy for the treatment of acute myocardial infarction comprises administering a combination of a thrombolytic agent and levosimendan or a pharmaceutically acceptable salt thereof to a patient. The combination synergistically reduces mortality of patients with acute myocardial infarction. (FIG. - Nil)
Full Text "A MEDICAL PRODUCT COMPRISING A "THROMBOLYTIC AGENT AND
LEVOSIMENDAN AS A COMBINED PREPARATION"
Technical field
The invention relates to a medical product comprising,
a thrombolytic agent and levosimendan or a pharmaceutically
acceptable salt thereof ?as a combined preparation.
Background of the invention
Myocardial infarction is an important complication of coronary artery disease
and usually results from a critical reduction in coronary blood flow secondary to
coronary thrombosis. Intravenous thrombolytic agent therapy has been widely used to
restore flow to the occluded coronary artery. A thrombolytic agent is a medicament
capable of lysing the fibrin-platelet thrombus, and thereby permitting; blood to again
flow through the affected blood vessel. Such agents include streptokinase, urokinase,
prourokmase, reteplase, alteplase and itissue-type plasminogen activator (t-PA). The
mortality of patients with acute myocardial infarction even if treated with
thrombolytic agents remains high.
Levosimendan, which is the (-)-enaatiomer of [[4-(l,4,5,6-tetrahydro-4-
methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and the method for
its preparation is described in EP 565546 B1. Levosimendan is potent in the
treatment of heart failure and has significant calcium dependent binding to troponin.
Levosimendan is represented by the formula:
The hemodynamic effects of levosimendan in man are described in Sundberg,
S. et al., Am. J. Cardiol., 1995; 75:1061-1066 and in Lilleberg, J. et al., J.
Cardiovasc. Pharmacol., 26(Suppl.1), S63-S69,1995. Pharmacokinetics of
levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J.
Cardiovasc. Pharmacol., 26(Suppl.l), S57-S62,1995. The use of levosimendan in the
treatment of myocardial ischemia is described in WO 93/21921. The use of
levosimendan in the treatment of pulmonary hypertension is described in WO
99/66912. The use of levosimendan in the treatment or prevention of coronary graft
vasospasm in described in WO 01/ 00211. Levosimendan solutions suitable for
intravenous use have been described in WO 01/19334. Clinical studies have
confirmed the beneficial effects of levosimendan in congestive heart failure patients.
Summary of the invention
It has now been found that administration of a thrombolytic agent together
with levosimendan has a beneficial synergistic effect on the mortality of patients
treated for myocardial infarction. Therefore, the combination is particularly useful for
the treatment of acute myocardial infarction.
Thus, in one aspect the present invention provides a method for the treatment
of acute myocardial infarction, which comprises the simultaneous, separate or
sequential administration of an effective amount of a thrombolytic agent and
levosimendan or a pharmaceutically acceptable salt thereof to a patient in need
thereof.
In another aspect the present invention provides a method for the treatment of
acute myocardial infarction, said method comprising administering to a patient in
need thereof a thrombolytic agent in combination with levosimendan or a
pharmaceutically acceptable salt thereof.
hi another aspect the present invention provides a method for reducing
mortality of patients with acute myocardial infarction, which comprises the
simultaneous, separate or sequential administration of an effective amount of a
thrombolytic agent and levosimendan or a pharmaceutically acceptable salt thereof to
a patient in need thereof.
In another aspect the invention provides a method for reducing mortality of
patients with acute myocardial infarction, which comprises administering to a patient
in need thereof a thrombolytic agent in combination with levosimendan or a
pharmaceutically acceptable salt thereof.
In another aspect the invention provides a medical product comprising,
separately or together, as active ingredients a thrombolytic agent and levosimendan
or a pharmaceutically acceptable salt thereof as a combined preparation.
In another aspect invention provides a pharmaceutical composition
comprising as active ingredients a thrombolytic agent and levosimendan or a
pharmaceutically acceptable salt thereof.
In another aspect the invention provides the use of a thrombolytic agent and
levosimendan or a pharmaceutically acceptable salt thereof as active ingredients in
the manufacture of a combined preparation for simultaneous, separate or sequential
administration.
In still another aspect the invention provides use of a thrombolytic agent and
levosimendan or a pharmaceutically acceptable salt thereof as active ingredients in
the manufacture of a medicament for reducing mortality of patients with myocardial
infarction.
Detailed description of the invention
The method of the invention relates to a combination therapy for more
effective treatment of acute myocardial infarction. The present method provides a
treatment, which improves the overall clinical outcome of patients treated with a
thrombolytic agent by administering levosimendan in combination with a
thrombolytic agent. In particular, the combination treatment of the invention is able
to synergistically reduce mortality of acute myocardial infarction patients.
The terms "treatment" or "treating" as used herein refers to reduction in
severity or frequency of symptoms and/or their underlying cause, improving the
clinical outcome of a patient, prevention of the occurrence of the symptoms and/or
their underlying cause, and improvement or remediation of damage.
The term "acute myocardial infarction" is defined as immediate or sudden
(not chronic) infarction of the heart muscle, i.e. an insufficiency of arterial blood
flow as a result of occlusion of a coronary artery due to at least partial blockage of
the artery by an embolus or thrombus. As used herein, "thrombus" or "embolus" refer
to a blood clot within the blood vessel. "At least partial" blockage of the artery means
that the artery contains an embolus or thrombus, which reduces the cross sectional
area of the artery.
The term "thrombolytic agent" is meant to refer to any agent effective in
helping to dissolving or breaking up an occluding thrombus. A thrombolytic agent
may be selected from those thrombolytic agents, which are known in the art. These
include, but are not limited to, streptokinase, urokinase, prourokinase, alteplase,
reteplase, anistreplase and tissue plasminogen activator (t-PA) and biologically active
variants thereof. A combination of two or several thrombolytic agents may be also
used.
The active ingredients are preferably administered concurrently as soon as
possible, preferably within six hours, after the onset of symptoms of an acute
myocardial infarction. If it is desired to avoid other medication during the
thrombolytic therapy, which may be given e.g. as an intravenous bolus or infusion,
levosimendan may be administered sequentially after the administration of the
thrombolytic agent.
While it is preferred to administer levosimendan during or immediately after
the thrombolytic therapy, it has been found that the synergistic effect of the
combination is still obtained, if levosimendan administration is started not later than
five days, preferably not later than three days, more preferably not later than 48
hours, from the thrombolytic therapy or, preferably, from the onset of symptoms of
an acute myocardial infarction.
If desired, levosimendan administration may also be given before the
thrombolytic therapy. However, in general, thrombolytic therapy should be started as
soon as possible once the condition of a blocked artery has been diagnosed. .
Therefore, it is preferred that, in case of sequential administration, the treatment
method according to the invention comprises a first step of administering an effective
amount of a thrombolytic agent and a second step of administering an effective
amount of levosimendan, wherein the time period between the two treatments is not
more than five days, preferably not more than three days, more preferably not more
than 48 hours.
The administration routes of the active ingredients include, but are not limited
to, enteral, e.g. oral or rectal, or parenteral, e.g. intravenous, intramuscular,
intraperitoneal or transdermal. In the treatment of myocardial infarction, the active
ingredients are preferably administered parenterally, intravenous route being
particularly preferred. Single or multiple dosages may be given. Preferably, the active
agents are administered via continuous infusion.
Preferably, the method comprises administering to a patient an amount of the
combination, which is synergistically effective in reducing mortality of patients with
myocardial infarction.
Levosimendan may be administered intravenously using an infusion rate
which is from about 0.05 to 0.4 µg/kg/min. For an intravenous bolus a suitable dose
is in the range from about 5 to 30 µg/kg. In the treatment of patients with acute
myocardial infarction an intravenous bolus followed by continuous infusion may be
needed.
Levosimedan may be administered orally to man in daily dose ranging from
about 0.1 to 8 mg given once a day or divided into several doses a day, depending on
the age, body weight and condition of the patient. The effective amount of
levosimendan to be administered to a subject depends upon the condition to be
treated, the route of administration, age, weight and the condition of the patient.
Preferred thrombolytic agents include streptokinase, urokinase, prourokinase,
alteplase, reteplase, anistreplase and tissue plasminogen activator (t-PA) and
biologically active variants thereof as well as any combinations thereof. The
thrombolytic agent may be administered using the conventional dosage ranges for
these agents, for example a daily dosage used when the agent is administered in
thrombolytic therapy as a monotherapy. The range will, of course, vary depending on
the thrombolytic agent employed. Examples of normal dosage ranges are as follows:
urokinase - 500,000 to 6,250,000 units/patient; streptokinase -140,000 to 2,500,000
units/patient; prourokinase - 5,000 to 100,000 units/patient; anistreplase - 10 to 100
units/patient; t-PA - 0.5 to 2.0 mg/kg body weight.
Thrombolytic therapy is typically given as an intravenous bolus alone or
followed by intravenous infusion or as an infusion alone. The infusion is normally
administered over a time ranging from less than one hour to about 12 hours, typically
from about 1 to 3 hours. For example, the thrombolytic therapy may comprise
administration of up to 10 % of the total dose as bolus injection over 1 to 5 minutes
and the remaining 90 % then as a constant infusion during the next hour.
When the symptoms have been alleviated to the desired level, treatment can
be stopped.
The combination may be supplemented with one or more other active
ingredients, e.g. anticoagulants, or surgical methods such as angioplasty.
The active ingredients can be formulated into pharmaceutical dosage forms
suitable for the treatment according to the present invention using the principles
known in the art. They are given to a patient as such or preferably in combination
with suitable pharmaceutical excipients in the form of tablets, granules, capsules,
suppositories, emulsions, suspensions or solutions whereby the contents of the active
compound in the formulation is from about 0.5 to 100 % per weight. Choosing
suitable ingredients for the composition is a routine for those of ordinary skill in the
art. It is evident that suitable carriers, solvents, gel forming ingredients, dispersion
forming ingredients, antioxidants, colours, sweeteners, wetting compounds, release
controlling components and other ingredients normally used in this field of
technology may be also used.
The active ingredients may be formulated in the same pharmaceutical
formulation. Preferably, such pharmaceutical composition of thrombolytic agent and
levosimendan is adapted to intravenous administration. Such compositions may be
prepared for storage by mixing these compounds with optional pharmaceutically
acceptable carriers, excipients or stabilizers, e.g. into the form of infusion
concentrates or aqueous solutions, or powders adapted to be reconstituted with sterile
water or aqueous infusion vehicles for infusion.
Alternatively, the active ingredients are formulated as separate pharmaceutical
dosage forms. The combination of the two pharmaceutical dosage forms may be
packaged as a single medical product or kit for use in the method of the invention,
optionally together with a package insert instructing to the correct use of the medical
product.
Formulations suitable for intravenous administration such as injection or
infusion formulation, comprise sterile isotonic solutions of the active ingredient and
vehicle, preferably aqueous solutions. Typically an intravenous infusion solution of
levosimendan comprises from about 0.01 to 0.1 mg/ml of levosimendan. Levosimen-
dan composition as stored before use is preferably an infusion concentrate product,
which can be reconstituted with sterile water or aqueous infusion vehicle for
infusion. Levosimendan solutions suitable for use in the present invention are
described e.g. in WO 01/19334.
For oral administration of levosimendan in tablet form, suitable carriers and
excipients include e.g. lactose, corn starch, magnesium stearate, calcium phosphate
and talc. For oral administration in capsule form, useful carriers and excipients
include e.g. lactose, corn starch, magnesium stearate and talc. For controlled release
oral compositions release controlling components can be used. Typical release
controlling components include hydrophilic gel forming polymers such as
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl celluloses,
alginic acid or a mixture thereof; vegetable fats and oils including vegetable solid oils
such as hydrogenated soybean oil, hardened castor oil or castor seed oil (sold under
trade name Cutina HR), cotton seed oil (sold under the trade names Sterotex or
Lubritab) or a mixture thereof; fatty acid esters such as triglycerides of saturated fatty
acids or their mixtures e.g. glyceryl tristearates, glyceryl tripalmitates, glyceryl
trimyristates, glyceryl tribehenates (sold under the trade name Compritol) and
glyceryl palmitostearic acid ester.
Tablets can be prepared by mixing levosimendan with the carriers and
excipients and compressing the powdery mixture into tablets. Capsules can be
prepared by mixing levosimendan with the carriers and excipients and placing the
powdery mixture in capsules, e.g. hard gelatin capsules. Typically a tablet or a
capsule comprises from about 0.1 to 8 mg, more typically 0.2 to 5 mg, of
levosimendan.
Thrombolytic agent compositions as used in clinical practice comprises
generally water as a carrier and pharmaceutical adjuvants known in the art, i.e.
isotonizing agents; acid, base or buffer substances to adjust the pH of the solution;
and stabilizing agents for the thrombolytic agent. Said thrombolytic agent
composition as stored before use is preferably a sterile lyophilized product, which
can be reconstituted with sterile water for injection.
The concentration of the thrombolytic agent in the composition depends on
the nature of the thrombolytic agent. For example, tissue plasminogen activator may
be present in an amount from 20 mg to 100 mg per dosage form. The concentration
of tissue plasminogen activator in a lyophilized product is typically in the range of
from 1.5 to 2 % (w/w). As pH adjusting agents, phosphoric acid and optionally
sodium hydroxide may be used, so that upon reconstitution with sterile water for
injection, a pH of about 7.3 is reached. As stabilizing agent for the thrombolytic
agent, an ammo acid may be used, for example I^arginine in the case of tissue
plasminogen activator. The stabilizing agent makes up the bulk of the lyophilized
thrombolytic agent, typically from about 70 % to about 80 % (w/w).
Examples of preferred products according to the present invention are those
wherein the thrombolytic preparation and levosimendan solution are miscible and,
when mixed, form a stable formulation for up to eight hours at room temperature.
The two formulations can then be stored together, but in separate containers such as
vials, prefilled syringes and the like, and mixed immediately before use. A preferred
container comprises the thrombolytic preparation (a) and the levosimendan solution
(b) separately in a two-chamber container including means to mix both liquids. The
two-chamber container is ideally a pre-filled, two-chamber syringe with bypass or
similar means (e.g. a breakable seal) allowing mixing of the two separate solutions
prior to administration, and which is further adapted for use with infusion devices.
Alternatively, the separate containers may be adapted to allow administration
of the thrombolytic preparation and the levosimendan solution sequentially, e.g. such
that levosimendan solution can be administered immediately after thrombolytic
administration or e.g. after one hour from the administration of the thrombolytic
agent.
Salts of levosimendan may be prepared by known methods. Pharmaceutically
acceptable salts are useful as active medicaments, however, preferred salts are the
salts with alkali or alkaline earth metals.
Pharmaceutical examples.
Example 1. Concentrate solution for intravenous infusion
(a) levosimendan 2.5 mg/ml
(b)KollidonPF12 10 mg/ml
(c) citric acid 2 mg/ml
(d) dehydrated ethanol ad 1 ml (785 mg)
The concentrate solution was prepared by dissolving citric acid, Kollidon PF121 and
levosimendan to dehydrated ethanol in the sterilized preparation vessel under stirring.
The resulting bulk solution was filtered through a sterile filter (0.22 µm). The sterile
filtered bulk solution was then aseptically filled into 8 ml and 10 ml injection vials (with
5 ml and 10 ml filling volumes) and closed with rubber closures.
The concentrate solution for intravenous infusion is diluted with an aqueous
vehicle before use. Typically the concentrate solution is diluted with aqueous isotonic
vehicles, such as 5 % glucose solution or 0.9 % NaCl solution so as to obtain an
aqueous intravenous solution, wherein the amount of levosimendan is generally
within the range of about 0.001 -1.0 mg/ml, preferably about 0.01 - 0.1 mg/ml.
Example 2. t-PA composition in lyophilized state
(a) t-PA 2.0 % (w/w)
(b) phosphoric acid 20 % (w/w)
(c) L-arginine 78 % (w/w)
The ingredients were mixed, lyophilized and sterilized using standard
methods. The lyophilized product comprising 20, 50 or 100 mg t-PA per dosage form
(vial) is reconstituted with sterile water for injection, for example to solution having
concentration of 1 mg/ml.
Example 3. Oral levosimendan composition
Hard gelatin capsule size 3
Levosimendan 2.0 mg
Lactose 198 mg
The pharmaceutical preparation in the form of a capsule was prepared by
mixing levosimendan with lactose and placing the powdery mixture in hard gelatin
capsule.
Experiments
Effect of the combination on the mortality of the patients with acute myocardial
infarction
Patients who had suffered from acute myocardial infarction within five days received
placebo or a 6-hour infusion of levosimendan using a bolus of 6,12 or 24 µg/kg and
subsequent infusion of 0.1, 0.2 or 0.4 µg/kg/min. Patients were divided according to
whether they had received thrombolytic therapy or not. The 180 day mortality was
measured. The results are shown in Table 1. It can be seen that the combination
provided synergistic reduction in the mortality of patients with acute myocardial
infarction.
TABLE 1. The mortality of patients with acute myocardial infarction receiving
levosimendan, a thrombolytic agent or a combination thereof.
We claim :
1. A medical product comprising, separately or together, as active ingredients
a thrombolytic agent and levosimendan or a pharmaceutically acceptable salt
thereof as a combined preparation.
2. A pharmaceutical composition comprising as active ingredients a
thrombolytic agent and levosimendan or a pharmaceutically acceptable salt
thereof.
3. The composition, as claimed in claim 2, wherein the said composition is
useful as a medicament for reducing mortality of patients with acute myocardial
infarction.
The present invention relates to a medical product comprising,
separately or together, as active ingredients a thrombolytic agent and levosimendan
or a pharmaceutically acceptable salt thereof as a combined preparation. The
combination synergistically reduces mortality of patients with acute myocardial
infarction.

Documents:

1023-kolnp-2004-granted-abstract.pdf

1023-kolnp-2004-granted-assignment.pdf

1023-kolnp-2004-granted-claims.pdf

1023-kolnp-2004-granted-correspondence.pdf

1023-kolnp-2004-granted-description (complete).pdf

1023-kolnp-2004-granted-examination report.pdf

1023-kolnp-2004-granted-form 1.pdf

1023-kolnp-2004-granted-form 18.pdf

1023-kolnp-2004-granted-form 3.pdf

1023-kolnp-2004-granted-form 5.pdf

1023-kolnp-2004-granted-gpa.pdf

1023-kolnp-2004-granted-letter patent.pdf

1023-kolnp-2004-granted-reply to examination report.pdf

1023-kolnp-2004-granted-specification.pdf


Patent Number 215525
Indian Patent Application Number 01023/KOLNP/2004
PG Journal Number 09/2008
Publication Date 29-Feb-2008
Grant Date 27-Feb-2008
Date of Filing 19-Jul-2004
Name of Patentee ORION CORPORATION
Applicant Address ORIONINTIE 1, FIN-02200 ESPOO FINLAND
Inventors:
# Inventor's Name Inventor's Address
1 PODER PENTTI KUUNSIRPPI 2 B 58, FIN-02210 ESPOO FINLAND
PCT International Classification Number A61K31/50
PCT International Application Number PCT/FI03/00078
PCT International Filing date 2003-01-31
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 20020197 2002-02-01 Finland