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Claims for Patent: 7,687,516

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Claims for Patent: 7,687,516

Title:Alcohol free formulation of argatroban
Abstract: An aqueous formulation of argatroban and of related compounds is disclosed along with a reconstitutable formulation, each of which is substantially, if not totally alcohol free. The formulations are also substantially free, if not totally free, of mono-, di-, and oligo-saccharides. An especially preferred embodiment is a ready-to-administer 1 mg/ml injectable dosage form having argatroban, lactobionic acid, and methionine.
Inventor(s): Palepu; Nageswara R. (Southampton, PA)
Assignee: Eagle Pharmaceuticals, Inc. (Woodcliff Lake, NJ)
Application Number:11/973,485
Patent Claims: 1. A pharmaceutically acceptable formulation of argatroban of formula I or a pharmaceutically acceptable salt thereof, which is solubilized in aqueous solution at a concentration greater than that of argatroban in water alone, comprising (a) argatroban of formula I or a pharmaceutically acceptable salt thereof; (b) methionine; (c) lactobionic acid, pharmaceutically acceptable salts, and mixtures thereof; and (d) an optional buffer; wherein the formulation has a pH in excess of 8.5 ##STR00004##

2. The formulation of claim 1 which is (a) substantially free of ethanol or (b) substantially free of a mono-, di-, or oligo-saccharide and substantially free of a sugar alcohol.

3. The formulation of claim 1 in which said argatroban is present in a concentration equivalent to an amount (based on the argatroban moiety) selected from the group consisting of about 1 mg/ml, about 1.25 mg/ml, about 2 mg/ml, about 2.5 mg/ml or about 5 mg/ml.

4. The formulation of claim 1 wherein said buffer is at least one member selected from the group consisting of at least one of (1) a carboxylic acid, a hydroxy carboxylic acid, a dicarboxylic acid, with at least of its acid group pK.sub.as greater than 3.0, a salt thereof, or a mixture of said carboxylic acid and said salt thereof and (2) an alkali metal or ammonium carbonate, alkali metal or ammonium bicarbonate, or mixtures thereof.

5. The formulation of claim 1 wherein said buffer is an acetate buffer, an amino acid buffer, or alkali metal or ammonium carbonate/bicarbonate buffer.

6. The formulation of claim 1 wherein said methionine is present in aft amount of about 1 mg/ml to about 50 mg/ml.

7. The formulation of claim 1 packaged in a vial selected from 5 mg/vial to 500 mg/vial or in an IV infusion bag of a size selected from 25 ml/bag to about 500 ml/bag.

8. The argatroban formulation of claim 1 as a ready-to-administer aqueous solution comprising (a) argatroban or a pharmaceutically acceptable salt thereof in an amount of at least 0.75 mg/ml (based on the argatroban moiety); (b)(1) lactobionic acid or a pharmaceutically acceptable salt thereof in an amount (based on the non-salt form thereof) or a mixture of said lactobionic acid and lactobionic acid salt of at least 1.5 times the weight of the argatroban (based on the argatroban moiety) and/or (b)(2) an alkali metal or ammonium salt or mixture of alkali metal or ammonium salts of carbonic acid or mixture of lactobionic acid salts in an amount based on CO.sub.3 of at least 1.4 times the weight of the argatroban (based on the argatroban moiety); and (c) methionine or a pharmaceutically acceptable salt thereof in an amount (based on the non-salt form of methionine) of at least 1.5 times the weight of the argatroban (based on the argatroban moiety).

9. The formulation of claim 8 wherein said argatroban or pharmaceutically acceptable salt thereof is present in an amount of about 0.75 mg/ml to about 1.25 mg/ml based on the argatroban moiety.

10. The formulation of claim 8 wherein said lactobionic acid or pharmaceutically acceptable salt thereof is present (based on the non-salt form thereof) in an amount of not more than 2.5 times the weight of the argatroban (based on the argatroban moiety) or said alkali metal or ammonium salt or mixture of alkali metal or ammonium salts of carbonic acid is present in an amount based on CO.sub.3 of not more than 5.2 times the weight of the argatroban (based on the argatroban moiety).

11. The formulation of claim 8 wherein said methionine or pharmaceutically acceptable salt thereof is present (based on the non-salt form thereof) in an amount of not more than 2.5 times than weight of the argatroban (based on the argatroban moiety).

12. The formulation of claim 8 having a pH in excess of 8.6.

13. The formulation of claim 8 having a pH of about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, or about 9.2.

14. The formulation of claim 8 having (1) a weight ratio of argatroban or pharmaceutically acceptable salt thereof: lactobionic acid or pharmaceutically acceptable salt thereof: methionine or pharmaceutically acceptable salt thereof (each based on the respective non-salt forms) of about 0.75 to about 1.25: about 1.50 to about 2.50: about 1.50 to about 2.50 or (2) a weight ratio of argatroban or pharmaceutically acceptable salt thereof: alkali metal or ammonium salt or mixture of alkali metal or ammonium salts of carbonic acid (based on methionine or pharmaceutically acceptable salt thereof (each of the argatroban salt and amino acid salt based on the respective non-salt forms) of about 0.75 to about 1.25: about 1.4 to about 5.2: about 1.50 to about 2.50.

15. The formulation of claim 8 having (1) a weight ratio of argatroban or pharmaceutically acceptable salt thereof: lactobionic acid or pharmaceutically acceptable salt thereof methionine or pharmaceutically acceptable salt thereof (each based on the respective non-salt forms) of about 1: about 2: about 2 or (2) a weight ratio of argatroban or pharmaceutically acceptable salt thereof: alkali metal or ammonium salt or mixture of alkali metal or ammonium salts of carbonic acid (based on CO.sub.3) of about 1: about 1.9 to about 2.0: about 2 or (3) a weight ratio of argatroban or pharmaceutically acceptable salt thereof: alkali metal or ammonium salt or mixture of alkali metal or ammonium salts of carbonic acid (based on CO.sub.3) of about 1: about 4.1 to about 4.2: about 2.

16. A reconstitutable formulation of argatroban comprising (a) said argatroban or a salt thereof or mixtures thereof, (b) methionine or a salt thereof or mixtures thereof, (c) lactobionic acid or salt thereof or mixtures thereof, and (d) an alkali metal salt or ammonium salt of carbonic acid or mixtures thereof.

17. A method of reducing dosage administration errors in administering argatroban comprising providing a pharmaceutically acceptable concentrate formulation or a ready-to-administer formulation of argatroban as defined by the formulation of claim 1.

18. A method of treating thrombosis comprising administering to a patient having an argatroban treatable condition the composition of claim 1.

19. The method of claim 18 where said composition is in a ready-to-administer form.

20. The method of claim 18 where said composition is in the form of a concentrate and diluting said concentrate with an injectably suitable aqueous diluent to a suitable concentration for injection.

21. A method of treating an argatroban treatable condition comprising administering to a patient having an argatroban treatable condition a pharmaceutically acceptable formulation of argatroban of formula I or a pharmaceutically acceptable salt thereof, which is solubilized in aqueous solution, comprising (a) argatroban of formula I or a pharmaceutically acceptable salt thereof, (b) methionine; (c) lactobionic acid; (d) a buffer; and has a pH in excess of 8.5 ##STR00005##

22. The formulation of claim 1 which is (a) substantially free of ethanol and (b) substantially free of a mono-, di-, or oligo-saccharide and substantially free of a sugar alcohol.
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