SUBCUTANEOUS FORMULATION AND METHODS FOR TREATING EDEMA REFRACTORY TO ORAL DIURETICS

1 . A method of treating edema in a subject, the method comprising administering subcutaneously an effective amount of a pharmaceutical composition to the subject comprising (i) an aqueous solution having a pH of between about 5 and about 9, (ii) between about 4 mg/ml and about 20 mg/mL arginine bumetanide salt, and (iii) one or more pharmaceutically acceptable excipients.

2 . The method of claim 1 , wherein the pharmaceutical composition comprises (i) an aqueous solution having between about 5 mg/mL and about 12 mg/mL arginine bumetanide salt, (ii) one or more pharmaceutically acceptable excipients, and (iii) wherein the aqueous solution has a pH of between about 6 and about 8.

3 . The method of claim 1 or 2 , wherein the pharmaceutical composition comprises a buffering agent.

4 . The method of claim 3 , wherein the aqueous solution is free of a buffering agent other than the buffer formed by bumetanide free acid combined with arginine.

5 . A method of treating edema in a subject, the method comprising administering subcutaneously an effective amount of a pharmaceutical composition to the subject comprising (i) an aqueous solution having a pH of between about 5 and about 9, (ii) between about 4 mg/mL and about 20 mg/mL potassium bumetanide salt, and (iii) one or more pharmaceutically acceptable excipients.

6 . The method of claim 5 , wherein the pharmaceutical composition comprises (i) an aqueous solution having between about 5 mg/mL and about 12 mg/mL potassium bumetanide salt, (ii) one or more pharmaceutically acceptable excipients, and (iii) wherein the aqueous solution has a pH of between about 6 and about 8.

7 . The method of claim 5 or 6 , wherein the pharmaceutical composition comprises a buffering agent.

8 . The method of claim 7 , wherein the aqueous solution is free of a buffering agent other than the buffer formed by bumetanide free acid combined with arginine potassium hydroxide.

9 . The method of any one of claims 1-8 , wherein the pharmaceutically acceptable excipients comprise a tonicity agent.

10 . The method of any one of claims 1-9 , wherein the aqueous solution has a pH of between about 6 and about 8.

11 . The method of any one of claims 1-10 , wherein the one or more pharmaceutically acceptable excipients comprises a sugar or sugar alcohol.

12 . The method of claim 11 , wherein the pharmaceutical composition comprises sucrose and/or mannitol.

13 . The method of any one of claims 1-12 , wherein the one or more pharmaceutically acceptable excipients comprises a preservative.

14 . The method of claim 13 , wherein the pharmaceutical composition comprises benzyl alcohol.

15 . The method of any one of claims 1-14 , wherein the pharmaceutical composition is administered in a dose volume of no more than 0.5 mL.

16 . The method of claim 15 , wherein the pharmaceutical composition is administered in a dose volume of between 25 μl to 250 μl.

17 . The method of any one of claims 1-16 , wherein pharmaceutical composition has a bioavailability of at least 90% upon administration to the subject.

18 . The method claim 17 , wherein the pharmaceutical composition has a bioavailability of at least 95% upon administration to the subject.

19 . The method of any one of claims 1-18 , wherein the edema is refractory to oral diuretics.

20 . The method of any one of claims 1-19 , wherein the subject has congestive heart failure.

21 . The method of any one of claims 1-20 , wherein the subject is suffering from edema in the lung.

22 . The method of any one of claims 1-21 , wherein the pharmaceutical composition is administered subcutaneously to the subject in an outpatient setting or the pharmaceutical composition is self-administered.

23 . The method of any one of claims 1-22 , wherein the subject has failed to achieve diuresis with oral diuretic therapy prior to the administering.

24 . The method of any one of claims 1-23 , wherein the subject is experiencing swelling of the legs, shortness of breath, difficulty breathing, or chest pain unresolved with oral diuretic therapy prior to the administering.

25 . The method of any one of claims 1-24 , wherein the subject is experiencing reduced intestinal motility prior to the administering.

26 . A pharmaceutical composition comprising an aqueous solution arginine bumetanide formulated for subcutaneous administration having a pH of between about 6 and about 8, between about 5 mg/mL and 12 mg/mL, and pharmaceutical excipients comprising a sugar or a sugar alcohol.

27 . The pharmaceutical composition of claim 25 , wherein the arginine bumetanide has a concentration of between about 8 mg/ml and about 10 mg/mL.

28 . A pharmaceutical composition comprising an aqueous solution potassium bumetanide formulated for subcutaneous administration having a pH of between about 6 and about 8, between about 5 mg/mL and 12 mg/mL, and pharmaceutical excipients comprising a sugar or a sugar alcohol.

29 . The pharmaceutical composition of claim 28 , wherein the potassium bumetanide has a concentration of between about 8 mg/ml and about 10 mg/mL.

30 . The pharmaceutical composition of any one of claims 26-29 , wherein the aqueous solution has a pH of about 6.5 to about 7.5.

31 . The pharmaceutical composition of any one of claims 26-30 , wherein the pharmaceutical composition comprises benzyl alcohol.

32 . The pharmaceutical composition of claim 31 , wherein the benzyl alcohol is in an amount of between about 0.2% (w/w) and about 1% (w/w).

33 . The pharmaceutical composition of claim 32 , wherein the benzyl alcohol is in an amount of about 0.5% (w/w).

34 . The pharmaceutical composition of any one of claims 26-33 , wherein the sugar alcohol is mannitol.

35 . The pharmaceutical composition of claim 34 , wherein the mannitol is in an amount of between about 2.0% (w/w) and about 5% (w/w).

36 . The pharmaceutical composition of claim 35 , wherein the mannitol is in an amount of about between about 2.5% (w/w) and about 4% (w/w).

37 . The pharmaceutical composition of any one of claims 26-36 , wherein the pharmaceutical composition comprises a buffer selected from citrate buffer and phosphate buffer.