Otamixaban formulations with improved stability

Abstract

The invention relates to a pharmaceutical composition comprising methyl (2R,3R)-2-{3-[amino(imino)methyl]benzyl}-3-{[4-(1-oxidopyridin-4-yl)benzoyl]amino}butanoate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable acidic reacting compound or to an aqueous solution or dispersion of the composition as well as a process for the preparation of the same, methods of using such compositions to treat subjects suffering from conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.

1 . An aqueous pharmaceutical composition for injection comprising
 a) from 0.1 mg/mL to 60 mg/mL methyl (2R,3R)-2-{3-[amino(imino) methyl]benzyl}-3-{[4-(1-oxidopyridin-4-yl)benzoyl]amino}butanoate and   b) from 1 mMol/L to 1000 mMol/L acidic reacting compound or its salt or a mixture thereof, said composition having   a pH from about pH 3 to about pH 5.0.   
     
     
         2 . The pharmaceutical composition according to  claim 1  wherein said acidic reacting compound is selected from the group consisting of citric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicyclic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, hyaluronic acid, acetyl salicylic acid or amino acids or mineral acids selected from the group consisting of hydrochloride acid or phosphoric acid or salts of said organic acids, amino acids and mineral acids or a mixture of one or more of said acidic reacting compounds. 
     
     
         3 . The pharmaceutical composition according to  claim 2  wherein said acidic reacting compound is selected from citric acid and sodium citrate or a mixture thereof. 
     
     
         4 . The aqueous pharmaceutical composition according to  claim 1  comprising from 1.0 mg/mL to 50 mg/mL methyl (2R,3R)-2-{3-[amino(imino) methyl]benzyl}-3-{[4-(1-oxidopyridin-4-yl)benzoyl]amino}butanoate and from 20 mMol to 25 mMol acidic reacting compound or its salt or a mixture thereof. 
     
     
         5 . An aqueous pharmaceutical composition according to  claim 4  comprising from 1.0 mg/mL to 5 mg/mL methyl (2R,3R)-2-{3-[amino(imino)methyl]benzyl}-3-{[4-(1-oxidopyridin-4-yl)benzoyl]amino}butanoate and
 from 20 mMol to 25 mMol acidic reacting compound or its salt or a mixture thereof. 
 
     
     
         6 . The pharmaceutical composition according to  claim 1  wherein the aqueous pharmaceutical composition posses a pH from about pH 3 to about pH 4.7 to an aqueous solution or dispersion of the pharmaceutical composition. 
     
     
         7 . The pharmaceutical composition according to  claim 6  wherein said acidic reacting compound creates a pH from about pH 3.7 to about pH 4.3. 
     
     
         8 . The pharmaceutical composition according to  claim 6  wherein said acidic reacting compound creates a pH from about pH 4.0 to about pH 4.2. 
     
     
         9 . The pharmaceutical composition according to  claim 1  containing a maximum impurity level of (2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl)benzoylamino]-butyric acid that does not exceed about 8.0% after long term storage. 
     
     
         10 . The pharmaceutical composition according to  claim 9  wherein said maximum impurity level is from 0.3% to 4.0%. 
     
     
         11 . The pharmaceutical composition according to  claim 1  containing a maximum impurity level of (2R,3R)-2-(3-Carbamoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl)benzoylamino]-butyric acid methyl ester that does not exceed about 5.0% after long term storage. 
     
     
         12 . The pharmaceutical composition according to  claim 11  wherein said maximum impurity level is from 0.7% to 4.5%. 
     
     
         13 . The pharmaceutical composition according to  claim 1  wherein said pharmaceutical composition is sterile. 
     
     
         14 . A method of treating acute myocardial infarction, non-ST elevation myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, intermittent claudication and restenosis in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition according to  claim 1 . 
     
     
         15 . The pharmaceutical composition according to  claim 9  wherein said maximum impurity level is from 0.4% to 1.8%. 
     
     
         16 . The pharmaceutical composition according to  claim 11  wherein said maximum impurity level is from 0.9% to 3.5%.