Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-26
2004-05-04
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06730673
ABSTRACT:
TECHNICAL FIELD
The present invention relates to levosimendan solutions for pharmaceutical use, and particularly for intravenous administration. The solutions of the invention have enhanced stability and they are particularly useful as infusion or injection solutions or infusion concentrates. Levosimendan, or (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, is useful in the treatment of congestive heart failure.
BACKGROUND OF THE INVENTION
Levosimendan, which is the (-)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and methods for its preparation are described in EP 565546 B1 and WO 97/35841. 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. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. Transdermal compositions of levosimendan are described in WO 98/01111. Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients.
Administration of a drug by parenteral, e.g. intravenous, administration provides a number of advantages including the following:
an almost immediate response may be obtained by administering by intravenous injection or infusion a solution, usually aqueous, of the drug;
the therapeutic response may be more readily controlled by administering the drug parenterally, and
a drug can be administered parenterally to a patient when it cannot be administered orally because of the unconscious state of the patient, or because of inactivation or lack of absorption in the intestinal tract.
The manufacture of levosimendan solutions, and particularly solutions suitable for intravenous use, involves a number of problems which are caused by the sensitivity of levosimendan against chemical and physical influences. In solutions levosimendan is sensitive to chemical degradation which limits the shelf-life of solutions and may produce undesirable degradation products. Levosimendan is also poorly soluble in water and precipitates easily from aqueous solutions. The precipitation of intravenous solutions is extremely dangerous because particulate material may occlude the blood vessels. The solubility of levosimendan decreases further strongly when the pH is lowered from neutral, so that low pH would in principle seem unfavourable. Thus, there is a need for improved aqueous formulations of levosimendan which are chemically and physically stable under prolonged storage and suitable for intravenous administration.
SUMMARY OF THE INVENTION
It has now been found that the chemical stability of levosimendan solutions can be significantly improved if the pH of the solution is lowered from neutral to lower than 5, preferably to 4.5 or lower, most preferably to 3-4.2. Furthermore, it has been found that the precipitation of the active ingredient can be prevented in such chemically stable solutions.
Thus, in one aspect, the present invention provides a pharmaceutical aqueous solution with improved stability comprising
(a) levosimendan or a pharmaceutically acceptable salt thereof as an active ingredient, the pH-value of the solution being lower than 5, preferably about 4.5 or lower, most preferably from about 3 to about 4.2, and optionally
(b) a solubility enhancing agent.
In another aspect, the invention provides an aqueous intravenous infusion solution with improved stability comprising
(a) levosimendan or a pharmaceutically acceptable salt thereof as an active ingredient, the pH-value of the solution being lower than 5, preferably about 4.5 or lower, most preferably from about 3 to about 4.2; and optionally
(b) a solubility enhancing agent.
Still in another aspect the invention provides an intravenous infusion concentrate, particularly to be diluted with an aqueous vehicle before use, comprising
(a) levosimendan or a pharmaceutically acceptable salt thereof as an active ingredient;
(b) organic solvent comprising ethanol;
(c) a stability enhancing amount of a pharmaceutically acceptable organic acid having pKa in the range of from 2 to 4; and optionally
(d) a solubility enhancing agent.
DETAILED DESCRIPTION OF THE INVENTION
Levosimendan is crystalline powder at room temperature and has pKa of 6.26. At room temperature the solubility of levosimendan in phosphate buffer is 0.4 mg/ml (pH 7.4), 0.03 mg/ml (pH 6) and 0.02 mg/ml (pH 2). Thus, the water solubility of levosimendan decreases quite sharply when pH is lowered below neutral. However, it has been found that it is possible to prepare pharmaceutically acceptable aqueous solutions of levosimendan with pH lower than 5. Such solutions are chemically and physically stable over an extended period of time and, therefore, they are particularly suitable for pharmaceutical use.
In one aspect, the invention provides a pharmaceutical composition which comprises levosimendan or a pharmaceutically acceptable salt thereof as an active ingredient in an aqueous solution with pH lower than 5, preferably about 4.5 or lower, and most preferably from about 3 to about 4.2. The composition of the invention is particularly useful in various pharmaceutical applications in which levosimendan must be stored in the form of an aqueous solution for an extended period of time.
The therapeutically effective amount of levosimendan included in the composition of the invention depends e.g. on the administration route of the composition, the treatment procedure and the condition to be treated. In general, the amount of levosimendan in the composition is within the range of about 0.001-5 mg/ml. The daily dosage of levosimendan in man is within the range of about 0.1-50 mg, preferably about 0.2-20 mg, depending on the administration route, age, body weight and condition of the patient. Preferred peak plasma levels of levosimendan in steady state for the treatment of congestive heart failure are within the range of from about 1 to about 300 ng/ml, more preferably from about 10 to about 150 ng/ml, and especially from about 20 to about 60 ng/ml. Levosimendan can be administered intravenously with the infusion rate in the range of about 0.005-100 &mgr;g/kg/min, typically 0.01 to 10 &mgr;g/kg/min, more typically about 0.02 to 1 &mgr;g/kg/min. For the treatment of heart failure with continuous infusion the suitable rate is 0.05-0.4 &mgr;g/kg/min of levosimendan.
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.
The control of pH of the composition is essential to maintain the required stability of the active ingredient. Therefore, a suitable pharmaceutically acceptable acidic compound or buffer system in an amount effective to maintain the pH of the composition in the desired range, may be used. Preferred acidic compounds include pharmaceutically acceptable organic acids having pKa in the range of from about 2 to about 4. Such acids include 2-hydroxy alkanoic acids, such as citric acid, lactic acid, tartaric acid or malic acid. If a pharmaceutically acceptable buffer system is used, it is selected from a group of buffers that are effective to maintain pH below 5, preferably at 4.5 or lower, most preferably in the range of about 3-4.2, which buffers are well known in the art. Most preferably the buffer may be selected from citrate, acetate, phosphate and lactate buffers. The preparation of buffer systems is well known for one skilled in the art. In general, the acidic compound or buffer is used in an amount necessary to adjust the pH into the desired range. However, the amount used must be pharmaceutically acceptable.
The compositio
Bäckström Reijo
Granvik Päivi
Haikala Ritva
Pelttari Sirpa
Saukko Eva
Finnegan Henderson Farabow Garrett & Dunner LLP
Henley III Raymond
Orion Corporation
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