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Claims for Patent: 7,589,106

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Claims for Patent: 7,589,106

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. (South Hampton, PA)
Assignee: Eagle Pharmaceuticals, Inc. (Woodcliff Lake, NJ)
Application Number:11/904,067
Patent Claims: 1. A pharmaceutically acceptable formulation of the compound of formula I or a pharmaceutically acceptable salt thereof, which is solubilized in an aqueous solution, said formulation comprising (a) argatroban of formula I or a pharmaceutically acceptable salt thereof ##STR00002## (b) methionine, pharmaceutically acceptable salts thereof, and mixtures thereof; (c) a member selected from the group consisting of one or more non-amino acid pH adjusting organic acids, organic bases, inorganic acids or inorganic bases, or salts thereof and mixtures thereof; and (d) a member selected from the group consisting of lactobionic acid and pharmaceutically acceptable salts thereof, which formulation is substantially free of ethanol and substantially free of a sugar alcohol and has a pH in excess of 8.5.

2. 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.

3. The formulation of claim 1 wherein said member (e) is at least one member selected from the group consisting of (1) a carboxylic acid, a hydroxy carboxylic acid, a dicarboxylic acid, with at least one of its acid group pKa(s) 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.

4. The formulation of claim 1 wherein said member (c) comprises an acetate anion or a carbonate or bicarbonate anion.

5. The formulation of claim 1 wherein said amino acid is present in an amount of about 1 mg/ml to about 50 mg/ml.

6. The formulation of claim 1 wherein said member (c) comprises at least one of an acetate anion, a carbonate anion or a bicarbonate anion, wherein said carbonate and bicarbonate anion are present at least in part from an alkali metal or ammonium carbonate, alkali metal or ammonium bicarbonate, or carbonic acid, and said acetate ion is present at least in part from an acetic acid salt or acetic acid.

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 argatroban or a pharmaceutically acceptable salt thereof in an amount of at least 0.75 mg/ml (based on the argatroban moiety); lactobionie 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 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 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 CO.sub.3): 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): methionine or pharmaceutically acceptable salt thereof (each of the argatroban salt and methionine salt based on the respective non-salt forms) of about 1: about 4.1 about 4.2.

16. A reconstitutable formulation of argatroban comprising (a) said argatroban or a salt thereof or mixtures thereof, and (b)methionine, pharmaceutically acceptable salts thereof, and mixtures thereof; (c) a member selected from the group consisting of one or more non-amino acid pH adjusting organic acids or organic base or salts thereof and mixtures thereof; and (d) a member selected from the group consisting of lactobionic acid; which reconstitutable formulation is substantially free of a mono-, di-, or oligosaccharide and substantially free of a sugar alcohol.

17. A method of treating thrombosis comprising administering to a patient having thrombosis the composition of claim 1.

18. The method of claim 17 where said composition is in a ready-to-administer form.

19. The method of claim 17 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.

20. The formulation of claim 1 further comprising an osmolality adjuster.

21. The formulation of claim 1, further comprising a pH adjuster.

22. A pharmaceutically acceptable argatroban formulation, which is solubilized in aqueous solution, said formulation comprising (a) argatroban of formula I or a pharmaceutically acceptable salt thereof ##STR00003## (b) methionine, pharmaceutically acceptable salts thereon and mixtures thereof; (c) a member selected from the group consisting of one or more non-amino acid pH adjusting organic acids or organic base or salts thereof and mixtures thereof; and (d) a member selected from the group consisting of lactobionic acid, which formulation is substantially free of ethanol and substantially free of a sugar alcohol and has a pH in excess of 8.5.

23. The formulation of claim 22, further comprising a pH adjuster other than those materials selected from said member (b), sald member (c) and said member (d) of said claim 22.
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