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Last Updated: March 28, 2024

Claims for Patent: 8,491,880


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Summary for Patent: 8,491,880
Title:Pharmaceutical formulations of biodegradable biocompatible camptothecin-polymer conjugates
Abstract: A camptothecin/polymer dual phase drug release system is described that is stable in both liquid and lyophilized states. The polymer contains acetals and/or ketals.
Inventor(s): Rolke; James (Beverly, MA), Petter; Russell C. (Stow, MA), Yin; Mao (Nedham, MA), Yurkovetskiy; Aleksandr (Littleton, MA), Liu; Gui (Lexington, MA), Farhan; Emile (Dedham, MA)
Assignee: Mersana Therapeutics, Inc. (Cambridge, MA)
Application Number:12/635,027
Patent Claims:1. A pharmaceutical composition suitable for intravenous administration comprising a compound of formula (I): ##STR00022## wherein one of R.sub.1 is H or ##STR00023## and the other is ##STR00024## one of R.sub.2 is H or ##STR00025## and the other is ##STR00026## CPT is camptothecin; n is 32-3320; m is 0-833; k is 1-216; wherein k, m, and n are selected so that about 1% to about 15% of the compound by weight is camptothecin; a stabilizing agent; one or more buffers; and a surfactant; wherein the molecular weight of the compound is from about 10 kD to about 500 kD, and the pharmaceutical composition has a pH of about 4.0 to 5.2.

2. The pharmaceutical composition of claim 1, wherein about 4% to about 7% of the compound by weight is camptothecin.

3. The pharmaceutical composition of claim 2, wherein about 5% to about 6% of the compound by weight is camptothecin.

4. The pharmaceutical composition of claim 2, wherein about 6% of the compound by weight is camptothecin.

5. The pharmaceutical composition of claim 1, wherein the stabilizing agent is selected from the group consisting of sorbitol, mannitol, sucrose, lactose, glucose, xylitol, maltose, hydroxypropyl-.beta.-cyclodextrin, lactitol, dextrose, glycerin, and maltitol.

6. The pharmaceutical composition of claim 5, wherein the stabilizing agent is sorbitol.

7. The pharmaceutical composition of claim 6, wherein the sorbitol is present at a concentration of about 1 mg/mL to about 500 mg/mL.

8. The pharmaceutical composition of claim 5, wherein the stabilizing agent is mannitol.

9. The pharmaceutical composition of claim 8, wherein the mannitol is present at a concentration of between about 1 mg/mL to about 500 mg/mL.

10. The pharmaceutical composition of claim 8, wherein the mannitol is present at a concentration of between about 1 mg/mL to about 200 mg/mL.

11. The pharmaceutical composition of claim 8, wherein the mannitol is present at a concentration of between about 1 mg/mL to about 25 mg/mL.

12. The pharmaceutical composition of claim 8, wherein the mannitol is present at a concentration of about 10.3 mg/mL.

13. The pharmaceutical composition of claim 8, wherein the mannitol is present at a concentration of about 20.3 mg/mL.

14. The pharmaceutical composition of claim 1, wherein the one or more buffers is selected from the group consisting of sodium citrate, ascorbate, succinate, lactate, citric acid, boric acid, borax, hydrochloric acid, disodium hydrogen phosphate, acetic acid, formic acid, glycine, bicarbonate, tartaric acid, Tris-glycine, Tris-NaCl, Tris-ethylenediamine tetraacetic acid ("EDTA"), Tris-borate-EDTA, Tris-acteate-EDTA ("TAE") buffer and Tris-buffered saline, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid ("HEPES"), 3-(N-morpholino)propanesulfonic acid ("MOPS"), piperazine-1,4-bis(2-ethanesulfonic acid) ("PIPES"), 2-(N-morpholino)ethanesulfonic acid ("MES"), phosphate buffered saline ("PBS"), saline-sodium citrate ("SSC"), saline-tris-EDTA ("STE"), and tris-magnesium.

15. The pharmaceutical composition of claim 14, wherein the one or more buffers includes sodium citrate.

16. The pharmaceutical composition of claim 14, wherein the one or more buffers includes sodium citrate and citric acid.

17. The pharmaceutical composition of claim 1, wherein the surfactant is selected from the group consisting of Polysorbate 80, Polysorbate 20, Poloxamer 407, Solutol HS 15, Poloxamer 188, sodium lauryl sulphate, ether sulphates, sulphated oils, cetrimide BP, benzalkonium chloride, lecithin, cetromacrogel 1000 BPC, and alkali metal soaps of the formula RCOOX where R=C10-C20 alkyl group, and X=sodium, potassium, or ammonium.

18. The pharmaceutical composition of claim 17, wherein the surfactant is Polysorbate 80.

19. The pharmaceutical composition of claim 18, wherein the Polysorbate 80 is present at a concentration of between about 0.1 mg/mL to about 10 mg/mL.

20. The pharmaceutical composition of claim 19, wherein the Polysorbate 80 is present at a concentration of between about 0.1 mg/mL and about 4.5 mg/mL.

21. The pharmaceutical composition of claim 20, wherein the Polysorbate 80 is present at a concentration of about 0.1 mg/mL to about 1.0 mg/mL.

22. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a storage stable aqueous solution.

23. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a highly storage stable aqueous solution.

24. The pharmaceutical composition of claim 1, wherein the composition is a lyophilized cake suitable for intravenous administration after reconstitution.

25. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is storage stable and the pH of the pharmaceutical composition is about 4.2 to about 4.8.

26. The pharmaceutical composition of claim 25, wherein about 4% to about 7% of the compound by weight is camptothecin.

27. The pharmaceutical composition of claim 25, wherein about 5% to about 6% of the compound by weight is camptothecin.

28. The pharmaceutical composition of claim 25, wherein about 6% of the compound by weight is camptothecin.

29. The pharmaceutical composition of claim 25, wherein the one or more buffers are selected from the group consisting of sodium citrate, ascorbate, succinate, lactate, citric acid, boric acid, borax, hydrochloric acid, disodium hydrogen phosphate, acetic acid, formic acid, glycine, bicarbonate, tartaric acid, Tris-glycine, Tric-NaCl, Tris-ethylenediamine tetraacetic acid, ("EDTA"), Tris-borate-EDTA, Tris-acteate-EDTA ("TAE") buffer and Tris-buffered saline, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid ("HEPES"), 3-(N-morpholino)propanesulfonic acid ("MOPS"), piperazine-1,4-bis(2-ethanesulfonic acid) ("PIPES"), 2-(N-morpholino)ethanesulfonic acid ("MES"), phosphate buffered saline ("PBS"), saline-sodium citrate ("SSC"), saline-tris-EDTA ("STE"), and tris-magnesium.

30. The pharmaceutical composition of claim 29, wherein the one or more buffers includes sodium citrate.

31. The pharmaceutical composition of claim 29, wherein the buffer one or more buffers sodium citrate and citric acid.

32. The pharmaceutical composition of claim 25, wherein the stabilizing agent is selected from the group consisting of sorbitol, mannitol, sucrose, lactose, glucose, xylitol, maltose, hydroxypropyl-.beta.-cyclodextrin, lactitol, dextrose, glycerin, and maltitol.

33. The pharmaceutical composition of claim 32, wherein the stabilizing agent is sorbitol.

34. The pharmaceutical composition of claim 33, wherein the concentration of sorbitol is about 1 mg/mL to about 500 mg/mL.

35. The pharmaceutical composition of claim 32, wherein the stabilizing agent is mannitol.

36. The pharmaceutical composition of claim 35, wherein the concentration of mannitol is about 1 mg/mL to about 500 mg/mL.

37. The pharmaceutical composition of claim 35, wherein the concentration of mannitol is about 1 mg/mL to about 200 mg/mL.

38. The pharmaceutical composition of claim 35, wherein the concentration of mannitol is about 1 mg/mL to about 25 mg/mL.

39. The pharmaceutical composition of claim 35, wherein the concentration of mannitol is about 10.3 mg/mL.

40. The pharmaceutical composition of claim 35, wherein the concentration of mannitol is about 20.3 mg/mL.

41. The pharmaceutical composition of claim 25, wherein the surfactant is selected from the group consisting of Polysorbate 80, Polysorbate 20, Poloxamer 407, Solutol HS 15, Poloxamer 188, sodium lauryl sulphate, ether sulphates, sulphated oils, cetrimide BP, benzalkonium chloride, lecithin, cetromacrogel 1000 BPC, and alkali metal soaps of the formula RCOOX where R=C10-C20 alkyl group, and X=sodium, potassium, or ammonium.

42. The pharmaceutical composition of claim 41, wherein the surfactant is Polysorbate 80.

43. The pharmaceutical composition of claim 42, wherein the concentration of Polysorbate 80 is between about 0.1 mg/mL to about 10 mg/mL.

44. The pharmaceutical composition of claim 42, wherein the concentration of Polysorbate 80 is between about 0.1 mg/mL and about 4.5 mg/mL.

45. The pharmaceutical composition of claim 42, wherein the concentration of Polysorbate 80 is about 0.1 mg/mL to about 1.0 mg/mL.

46. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is highly storage stable.

47. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is suitable for lyophilization and reconstitution.

48. The pharmaceutical composition of claim 47, wherein about 4% to about 7% of the compound by weight is camptothecin.

49. The pharmaceutical composition of claim 47, wherein about 5% to about 6% of the compound by weight is camptothecin.

50. The pharmaceutical composition of claim 47, wherein about 6% of the compound by weight is camptothecin.

51. The pharmaceutical composition of claim 47, wherein the stabilizing agent is selected from the group consisting of sorbitol, mannitol, sucrose, lactose, glucose, xylitol, maltose, hydroxypropyl-.beta.-cyclodextrin, lactitol, dextrose, glycerin, and maltitol.

52. The pharmaceutical composition of claim 51, wherein the stabilizing agent is sorbitol.

53. The pharmaceutical composition of claim 52, wherein the sorbitol is present at a concentration of between about 1 mg/mL and about 500 mg/mL.

54. The pharmaceutical composition of claim 51, wherein the stabilizing agent is mannitol.

55. The pharmaceutical composition of claim 54, wherein mannitol is present in the pharmaceutical composition at a concentration of between about 1 mg/mL to about 500 mg/mL.

56. The pharmaceutical composition of claim 54, wherein mannitol is present in the pharmaceutical composition at a concentration of between about 1 mg/mL to about 200 mg/mL.

57. The pharmaceutical composition of claim 54, wherein mannitol is present in the pharmaceutical composition at a concentration of between about 1 mg/mL to about 25 mg/mL.

58. The pharmaceutical composition of claim 54, wherein mannitol is present in the pharmaceutical composition at a concentration of about 10.3 mg/mL.

59. The pharmaceutical composition of claim 54, wherein mannitol is present in the pharmaceutical composition at a concentration of about 20.3 mg/mL.

60. The pharmaceutical composition of claim 47, wherein the one or more buffers is selected from the group consisting of sodium citrate, ascorbate, succinate, lactate, citric acid, boric acid, borax, hydrochloric acid, disodium hydrogen phosphate, acetic acid, formic acid, glycine, bicarbonate, tartaric acid, Tris-glycine, Tris-NaCl, Tris-ethylenediamine tetraacetic acid ("EDTA"), Tris-borate-EDTA, Tris-acteate-EDTA ("TAE") buffer and Tris-buffered saline, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid ("HEPES"), 3-(N-morpholino)propanesulfonic acid ("MOPS"), piperazine-1,4-bis(2-ethanesulfonic acid) ("PIPES"), 2-(N-morpholino)ethanesulfonic acid ("MES"), phosphate buffered saline ("PBS"), saline-sodium citrate ("SSC"), saline-tris-EDTA ("STE"), and tris-magnesium.

61. The pharmaceutical composition of claim 60, wherein the one or more buffers includes sodium citrate.

62. The pharmaceutical composition of claim 60, wherein the one or more buffers includes sodium citrate and citric acid.

63. The pharmaceutical composition of claim 47, wherein the surfactant is selected from the group consisting of Polysorbate 80, Polysorbate 20, Poloxamer 407, Solutol HS 15, Poloxamer 188, sodium lauryl sulphate, ether sulphates, sulphated oils, cetrimide BP, benzalkonium chloride, lecithin, cetromacrogel 1000 BPC, and alkali metal soaps of the formula RCOOX where R=C10-C20 alkyl group, and X=sodium, potassium, or ammonium.

64. The pharmaceutical composition of claim 63, wherein the surfactant is Polysorbate 80.

65. The pharmaceutical composition of claim 64, wherein the concentration of Polysorbate 80 is from about 0.1 mg/mL to about 10 mg/mL.

66. The pharmaceutical composition of claim 65, wherein the concentration of Polysorbate 80 is from about 0.1 mg/mL and about 4.5 mg/mL.

67. The pharmaceutical composition of claim 65, wherein the concentration of Polysorbate 80 is about 0.1 mg/mL to about 1.0 mg/mL.

68. The pharmaceutical composition of claim 47, wherein the pharmaceutical composition is storage stable.

69. The pharmaceutical composition of claim 47, wherein the pharmaceutical composition is highly storage stable.

70. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of an injectable solution and is prepared using a liquid to reconstitute a lyophilized cake comprising the compound of formula (I).

71. The pharmaceutical composition of claim 70, wherein about 4% to about 7% by weight of the compound is CPT.

72. The pharmaceutical composition of claim 71, wherein about 5% to about 6% by weight of the compound is CPT.

73. The pharmaceutical composition of claim 71, wherein about 6% by weight of the compound is CPT.

74. The pharmaceutical composition of claim 70, wherein the stabilizing agent is selected from the group consisting of sorbitol, mannitol, sucrose, lactose, glucose, xylitol, maltose, hydroxypropyl-.beta.-cyclodextrin, lactitol, dextrose, glycerin, and maltitol.

75. The pharmaceutical composition of claim 74, wherein the stabilizing agent is sorbitol.

76. The pharmaceutical composition of claim 75, wherein the concentration of sorbitol is about 1 mg/mL to about 500 mg/mL.

77. The pharmaceutical composition of claim 70, wherein the stabilizing agent is mannitol.

78. The pharmaceutical composition of claim 77, wherein the concentration of mannitol is between about 1 mg/mL to about 500 mg/mL.

79. The pharmaceutical composition of claim 77, wherein the concentration of mannitol is between about 1 mg/mL to about 200 mg/mL.

80. The pharmaceutical composition of claim 77, wherein the concentration of mannitol is between about 1 mg/mL to about 25 mg/mL.

81. The pharmaceutical composition of claim 77, wherein the concentration of mannitol is about 10.3 mg/mL.

82. The pharmaceutical composition of claim 77, wherein the concentration of mannitol is about 20.3 mg/mL.

83. The pharmaceutical composition of claim 70, wherein the surfactant is selected from the group consisting of Polysorbate 80, Polysorbate 20, Poloxamer 407, Solutol HS 15, Poloxamer 188, sodium lauryl sulphate, ether sulphates, sulphated oils, cetrimide BP, benzalkonium chloride, lecithin, cetromacrogel 1000 BPC, and alkali metal soaps of the formula RCOOX where R=C10-C20 alkyl group, and X=sodium, potassium, or ammonium.

84. The pharmaceutical composition of claim 83, wherein the surfactant is Polysorbate 80.

85. The pharmaceutical composition of claim 84, wherein the concentration of Polysorbate 80 is about 0.1 mg/mL to about 10 mg/mL.

86. The pharmaceutical composition of claim 85, wherein the concentration of Polysorbate 80 is from about 0.1 mg/mL and about 4.5 mg/mL.

87. The pharmaceutical composition of claim 85, wherein the concentration of Polysorbate 80 is about 0.1 mg/mL to about 1.0 mg/mL.

88. The pharmaceutical composition of claim 70, wherein the pH of the injectable solution is about 4.2 to about 4.8.

89. The pharmaceutical composition of claim 70, wherein the one or more buffers is selected from the group consisting of sodium citrate, ascorbate, succinate, lactate, citric acid, boric acid, borax, hydrochloric acid, disodium hydrogen phosphate, acetic acid, formic acid, glycine, bicarbonate, tartaric acid, Tris-glycine, Tris-NaCl, Tris-ethylenediamine tetraacetic acid ("EDTA"), Tris-borate-EDTA, Tris-acteate-EDTA ("TAE") buffer and Tris-buffered saline, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid ("HEPES"), 3-(N-morpholino)propanesulfonic acid ("MOPS"), piperazine-1,4-bis(2-ethanesulfonic acid) ("PIPES"), 2-(N-morpholino)ethanesulfonic acid ("MES"), phosphate buffered saline ("PBS"), saline-sodium citrate ("SSC"), saline-tris-EDTA ("STE"), and tris-magnesium.

90. The pharmaceutical composition of claim 89, wherein the one or buffers includes sodium citrate.

91. The pharmaceutical composition of claim 89, wherein the one or more buffers includes sodium citrate and citric acid.

92. The pharmaceutical composition of claim 70, wherein the liquid is sterile water.

93. The pharmaceutical composition of claim 70, wherein the liquid is 0.9% Normal saline.

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