Compositions and methods for stabilizing liposomal drug formulations
The present invention is directed to liposomal compositions comprising a camptothecin, which are optimized to reduce camptothecin degradation and/or precipitation of camptothecin degradation products in the external medium. The invention further provides improved methods of formulating liposomal camptothecins, kits comprising liposome-encapsulated camptothecins, and methods of using the same to treat a variety of diseases and disorders, including cancer.
1 . A liposomal camptothecin formulation adapted for increased camptothecin stability, comprising:
(a) a camptothecin encapsulated in a liposome;
(b) a first solution exterior of said liposome wherein said first solution has a pH less than or equal to 4.5; and
(c) a second solution interior of said liposome.
2 . The formulation of claim 1 , wherein said second solution comprises MnSO 4 .
3 . The formulation of claim 1 , wherein said liposome comprises dihydrosphingomyelin and cholesterol.
4 . The formulation of claim 1 , wherein said formulation further comprises an anti-oxidant or free radical scavenger.
5 . The formulation of claim 1 wherein said formulation further comprises empty liposomes.
6 . The formulation of claim 1 , wherein said first solution comprises a citrate or tartrate buffer.
7 . The formulation of claim 1 , wherein said liposome comprises dihydrosphingomyelin and cholesterol, wherein said formulation further comprises an anti-oxidant or free radical scavenger, and wherein said second solution comprises MnSO 4 .
8 . A liposomal camptothecin formulation adapted for increased camptothecin stability, comprising:
(a) a camptothecin encapsulated in a liposome;
(b) a first solution exterior of said liposome;
(c) a second solution interior of said liposome; and
(d) an anti-oxidant or free radical scavenger.
9 . The formulation of claim 8 , wherein said first solution has a pH less than or equal to 4.5.
10 . The formulation of claim 8 , wherein said second solution comprises MnSO 4 .
11 . The formulation of claim 8 , wherein said liposome comprises dihydrosphingomyelin and cholesterol.
12 . (canceled)
13 . (canceled)
14 . The formulation of claim 8 , wherein said formulation further comprises empty liposomes.
15 . The formulation of claim 8 , wherein said first solution comprises a citrate or tartrate buffer.
16 . The formulation of claim 4 or 8 , wherein said anti-oxidant or free radical scavenger is ascorbic acid.
17 . The formulation of claim 16 , wherein the ascorbic acid is present at a concentration in the range of 1 mM to 100 mM.
18 . The formulation of claim 17 , wherein the concentration of the ascorbic acid is approximately 10 mM.
19 . The formulation of claim 4 or 8 , wherein said anti-oxidant or free radical scavenger is alpha-tocopherol.
20 . The formulation of claim 19 , wherein said alpha-tocopherol is present at a concentration in the range of 0.1 to 10 mole percent.
21 . The formulation of claim 20 , wherein said alpha-tocopherol is present at a concentration in the range of 0.4 to 3 mole percent.
22 . The formulation of claim 21 , wherein said alpha-tocopherol is present at a concentration of approximately 2 mole percent.
23 . The formulation of claim 1 or 8 , wherein said camptothecin is topotecan.
24 . The formulation of claim 23 , wherein said formulation is a unit dosage form of topotecan.
25 . The formulation of claim 24 , wherein said topotecan is present at a unit dosage form of about 0.01 mg/M 2 /dose to about 7.5 mg/M 2 /dose.
26 .- 32 . (canceled)
33 . A pharmaceutical composition adapted for intravenous administration of a liposome-encapsulated camptothecin, wherein said pharmaceutical composition comprises a formulation of claim 1 or 8 .
34 . (canceled)
35 . The formulation or pharmaceutical composition of claim 1 or 8 , wherein the first solution has a reduced oxygen content, as compared to the oxygen content under atmospheric conditions.
36 . A method for reducing the accumulation of camptothecin degradation products in a solution containing a camptothecin encapsulated in a liposome, comprising
formulating a camptothecin encapsulated in a liposome with a solution exterior of the liposome with a pH less than or equal to 4.5, and a solution interior of said liposome having the pH of the solution exterior of said liposomes at or below 4.5.
37 . The method of claim 36 , wherein said interior solution comprises MnSO 4 .
38 . The method of claim 36 , wherein said liposome comprises dihydrosphingomyelin and cholesterol.
39 . The method of claim 36 , wherein said solution or liposome further comprises an anti-oxidant.
40 . The method of claim 36 , further comprising empty liposomes in the solution.
41 .- 47 . (canceled)
48 . A kit comprising a liposome-encapsulated camptothecin for administration to a patient in need thereof, comprising:
(a) a vial comprising a solution containing a camptothecin encapsulated in a liposome, wherein said solution exterior of said liposome has a pH less than or equal to 4.5; and
(b) instructions for preparing and/or administering the liposome encapsulated camptothecin to a patient.
49 . The kit of claim 48 , wherein the interior of said liposome comprises MnSO 4 .
50 . The kit of claim 48 , wherein said solution or liposome comprises an antioxidant.
51 . The kit of claim 48 , wherein the solution containing a camptothecin encapsulated in a liposome further contains empty liposomes.
52 .- 62 . (canceled)
63 . A method of treating a cancer, comprising administering the pharmaceutical composition of claim 33 to a patient in need thereof, such that said cancer is treated.