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Claims for Patent: 6,803,046

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Claims for Patent: 6,803,046

Title: Sincalide formulations
Abstract:The invention features sincalide formulations that include an effective amount of sincalide, a bulking agent/tonicity adjuster, a stabilizer, a surfactant, a chelator, and a buffer. The invention also features kits and methods for preparing improved sincalide formulations, as well as methods for treating, preventing, and diagnosing gall bladder-related disorders using sincalide formulations.
Inventor(s): Metcalfe; Edmund C. (Hillsborough, NJ), Monteferrante; Jo Anna (Raritan Township, NJ), Newborn; Margaret (Hamilton Township, NJ), Ropiak; Irene (Lawrenceville, NJ), Schramm; Ernst (North Brunswick, NJ), White; Gregory W. (Monmouth Junction, NJ), Zodda; Julius P. (Mercerville, NJ)
Assignee: Bracco International B.V. (Amsterdam, NL)
Application Number:10/222,540
Patent Claims: 1. A stabilized, physiologically acceptable formulation of sincalide comprising: (a) an effective amount of sincalide, (b) at least one stabilizer, (c) a surfactant/solubilizer (d) a chelator, (e) a bulking agent/tonicity adjuster, and (f) a buffer.

2. The formulation of claim 1 having a pH from 6.0 to 8.0.

3. The formulation of claim 1, wherein said buffer is selected from the group consisting of phosphoric acid, phosphate, citric acid, citrate, sulfosalicylate, acetic acid, acetate, methyl boronic acid, boronate, disodium succinate hexahydrate, one or more amino acids, lactic acid, lactate, maleic acid, maleate, potassium chloride, benzoic acid, sodium benzoate, carbonic acid, carbonate, bicarbonate, boric acid, borate, sodium chloride, succinic acid, succinate, tartaric acid, tartrate, tris-(hydroxymethyl)aminomethane, and biological buffers.

4. The formulation of claim 1, wherein said buffer is a phosphate buffer.

5. The formulation of claim 4, wherein said buffer is dibasic potassium phosphate.

6. The formulation of claim 1, wherein said surfactant/solubilizer is selected from the group consisting of anionic surfactants, pluronics, poloxamers, SDS, Triton-100, polysorbates, propylene glycol, PEG and similar compounds, Brij58 9poly(oxyethylene)20 cetyl ether, cremophor EL, cetyl trimethylammonium bromide (CTAB), dimethylacetamide (DMA), NP 40 (Nonidet P-40), and N-methyl-2-pyrrolidone (Pharmasolve), and amino acids.

7. The formulation of claim 1, wherein said surfactant is a nonionic surfactant.

8. The formulation of claim 7, wherein said nonionic surfactant is a polysorbate.

9. The formulation of claim 7, wherein said nonionic surfactant is polysorbate 20 or polysorbate 80.

10. The formulation of claim 1, wherein said stabilizer is selected from the group consisting of antioxidants and amino acids.

11. The formulation of claim 10, wherein said stabilizer is an antioxidant.

12. The formulation of claim 11, wherein said stabilizer is sodium metabisulfite.

13. The formulation of claim 1, wherein said formulation comprises a plurality of stabilizers.

14. The formulation of claim 13, wherein said stabilizers comprise L-arginine monohydrochloride, L-methionine, L-lysine monohydrochloride, and sodium metabisulfite.

15. The formulation of claim 1, wherein said bulking agent/tonicity adjuster is selected from the group consisting of mannitol, amino acids, lactose, potassium chloride, sodium chloride, maltose, sucrose, PEG's, trehalose, raffinose, dextrose, cyclodextrins, dextran, galacturonic acid, Ficoll, and polyvinylpyrrolidone (PVP).

16. The formulation of claim 15, wherein said bulking agent/tonicity adjuster is D-mannitol.

17. The formulation of claim 1, wherein said chelator is pentetic acid (DTPA).

18. The formulation of claim 17, wherein said chelator is pentetic acid, said surfactant is polysorbate 20, said buffer is dibasic potassium phosphate, and said bulking agent/tonicity adjuster is D-mannitol.

19. The formulation of claim 1, wherein said formulation is suitable for parenteral administration.

20. A stabilized, physiologically acceptable formulation of sincalide comprising: (a) about 0.0008-0.0012 mg/mL sincalide, (b) about 20 to 50 mg/mL mannitol, (c) about 2 to 7 mg/mL arginine, (d) about 0.2 to 1 mg/mL methionine, (e) about 2 to 30 mg/mL lysine, (f) about 0.002 to 0.012 mg/mL sodium metabisulfite, (g) about 0.000001 to 0.003 mg/mL polysorbate 20, (h) about 0.1 to 3 mg/mL pentetic acid (DTPA), and (i) about 1.1 to 1.8 mg/mL dibasic potassium phosphate.

21. A method for making a stabilized formulation of sincalide, said method comprising the step of mixing: (a) at least one stabilizer, (b) a surfactant/solubilizer, (c) a chelator, (d) a bulking agent/tonicity adjuster, (e) a buffer (f) an aqueous solution, and (g) sincalide.

22. The method of claim 21, wherein said formulation has a pH from 6.0 to 8.0.

23. The method of claim 21, wherein said buffer is selected from the group consisting of phosphoric acid, phosphate, citric acid, citrate, sulfosalicylate, acetic acid, acetate, methyl boronic acid, boronate, disodium succinate hexahydrate, one or more amino acids, lactic acid, lactate, maleic acid, maleate, potassium chloride, benzoic acid, sodium benzoate, carbonic acid, carbonate, bicarbonate, boric acid, borate, sodium chloride, succinic acid, succinate, tartaric acid, taitrate, tris-(hydroxymethyl)aminomethane, and biological buffers.

24. The method of claim 21, wherein said buffer is a phosphate buffer.

25. The method of claim 24, wherein said buffer is dibasic potassium phosphate.

26. The method of claim 21, wherein said surfactant/solubilizer is selected from the group consisting of anionic surfactants, pluronics, poloxamers, SDS, Triton-100, polysorbates, propylene glycol, PEG and similar compounds, Brij58 9poly(oxyethylene)20 cetyl ether, cremophor EL, cetyl trimethylammonium bromide (CTAB), dimethylacetamide (DMA), NP 40 (Nonidet P-40), and N-methyl-2-pyrrolidone (Pharmasolve),and amino acids.

27. The method of claim 21, wherein said surfactant is a nonionic surfactant.

28. The method of claim 27, wherein said nonionic surfactant is a polysorbate.

29. The method of claim 28, wherein said nonionic surfactant is polysorbate 20 or polysorbate 80.

30. The method of claim 21, wherein said stabilizer is selected from the group consisting of antioxidants and amino acids.

31. The method of claim 30, wherein said stabilizer is an antioxidant.

32. The method of claim 30, wherein said stabilizer is sodium metabisulfite.

33. The method of claim 21, wherein said method further comprises mixing a plurality of stabilizers.

34. The method of claim 33, wherein said stabilizers comprise L-arginine monohydrochloride, L-methionine, L-lysine monohydrochloride, and sodium metabisulfite.

35. The method of claim 21, wherein said bulking agent/tonicity adjuster is selected from the group consisting of mannitol, amino acids, lactose, potassium chloride, sodium chloride, maltose, sucrose, PEG's, trehalose, raffinose, dextrose, cyclodextrins, dextran, galacturonic acid, Ficoll, and polyvinylpyrrolidone (PVP).

36. The method of claim 35, wherein said bulking agent/tonicity adjuster is D-Mannitol.

37. The method of claim 21, wherein said chelator is pentetic acid (DTPA).

38. The method of claim 37, wherein said chelator is pentetic acid, said surfactant is polysorbate 20, said buffer is dibasic potassium phosphate, and said bulking agent/tonicity adjuster is D-mannitol.

39. The method of claim 21, wherein said formulation comprises about 0.0008 to 0.0012 mg/mL sincalide; about 20 to 50 mg/mL mannitol, about 2 to 7 mg/mL arginine; about 0.2 to 1 mg/mL methionine; about 2 to 30 mg/mL lysine; about 0.002 to 0.012 mg/mL sodium metabisulfite; about 0.000001 to 0.003 mg/mL polysorbate 20, about 0.1 to 3.0 mg/mL pentetic acid (DTPA); and about 1.1 to 1.8 mg/mL dibasic potassium phosphate.

40. A kit, comprising: (i) a powder mixture comprising (a) sincalide, (b) at least one stabilizer, (c) a surfactant, (d) a chelator, (e) a bulking agent/tonicity adjuster, and (f) a buffer; (ii) a container to hold said powder mixture; and (iii) optionally, a physiologically acceptable fluid.

41. The kit of claim 40, wherein said buffer is selected from the group consisting of phosphoric acid, phosphate, citric acid, citrate, sulfosalicylate, acetic acid, acetate, methyl boronic acid, boronate, disodium succinate hexahydrate, one or more amino acids, lactic acid, lactate, maleic acid, maleate, potassium chloride, benzoic acid, sodium benzoate, carbonic acid, carbonate, bicarbonate, boric acid, borate, sodium chloride, succinic acid, succinate, tartaric acid, tartrate, tris-(hydroxymethyl)aminomethane, and biological buffers.

42. The kit of claim 40, wherein said buffer is a phosphate buffer.

43. The kit of claim 40, wherein said buffer is dibasic potassium phosphate.

44. The kit of claim 40, wherein said surfactant is selected from the group consisting of anionic surfactants, pluronics, poloxamers, SDS, Triton-100, polysorbates, propylene glycol, PEG and similar compounds, Brij58 9poly(oxyethylene)20 cetyl ether, cremophor EL, cetyl trimethylammonium bromide (CTAB), dimethylacetamide (DMA), NP 40 (Nonidet P-40), and N-methyl-2-pyrrolidone (Pharmasolve),and amino acids.

45. The kit of claim 40, wherein said surfactant is a nonionic surfactant.

46. The kit of claim 45, wherein said nonionic surfactant is a polysorbate.

47. The kit of claim 46, wherein said nonionic surfactant is polysorbate 20 or polysorbate 80.

48. The kit of claim 40, wherein said stabilizer is selected from the group consisting of antioxidants and amino acids.

49. The kit of claim 48, wherein said stabilizer is an antioxidant.

50. The kit of claim 49, wherein said stabilizer is sodium metabisulfite.

51. The kit of claim 40, wherein said powder mixture comprises a plurality of stabilizers.

52. The kit of claim 51, wherein said stabilizers comprise L-arginine monohydrochloride, L-methionine, L-lysine monohydrochloride, and sodium metabisulfite.

53. The kit of claim 40, wherein said bulking agent/tonicity adjuster is selected from the group consisting of mannitol, amino acids, lactose, potassium chloride, sodium chloride, maltose, sucrose, PEG's, trehalose, raffinose, dextrose, cyclodextrins, dextran, galacturonic acid, Ficoll, and polyvinylpyrrolidone (PVP).

54. The kit of claim 40, wherein said chelator is pentetic acid (DTPA).

55. The kit of claim 40, wherein said container is a vial.

56. A method for treating or preventing a medical condition associated with total parenteral nutrition (TPN), said method comprising administering to a patient receiving TPN an effective amount of a sincalide formulation, said formulation comprising: (a) sincalide, (b) at least one stabilizer, (c) a surfactant, (d) a chelator, (e) a bulking agent/tonicity adjuster, and (f) a buffer.

57. The method of claim 56, wherein said medical condition is TPN-associated cholestatis.

58. The method of claim 56, wherein said formulation is administered by injection.

59. The method of claim 56, wherein said formulation has a pH from 6.0 to 8.0.

60. The method of claim 56, wherein said buffer is selected from the group consisting of phosphoric acid, phosphate, citric acid, citrate, sulfosalicylate, acetic acid, acetate, methyl boronic acid, boronate, disodium succinate hexahydrate, one or more amino acids, lactic acid, lactate, maleic acid, maleate, potassium chloride, benzoic acid, sodium benzoate, carbonic acid, carbonate, bicarbonate, boric acid, borate, sodium chloride, succinic acid, succinate, tartaric acid, tartrate, tris-(hydroxymethyl)aminomethane, and biological buffers.

61. The method of claim 56, wherein said buffer is a phosphate buffer.

62. The method of claim 61, wherein said buffer is dibasic potassium phosphate.

63. The method of claim 56, wherein said surfactant is selected from the group consisting of anionic-surfactants, pluronics, poloxamers, SDS, Triton-100, polysorbates, propylene glycol, PEG and similar compounds, Brij58 9poly(oxyethylene)20 cetyl ether, cremophor EL, cetyl trimethylammonium bromide (CTAB), dimethylacetamide (DMA), NP 40 (Nonidet P-40), and N-methyl-2-pyrrolidone (Pharmasolve),and amino acids.

64. The method of claim 56, wherein said surfactant is a nonionic surfactant.

65. The method of claim 64, wherein said nonionic surfactant is a polysorbate.

66. The method of claim 65, wherein said nonionic surfactant is polysorbate 20 or polysorbate 80.

67. The method of claim 56, wherein said stabilizer is selected from the group consisting of antioxidants and amino acids.

68. The method of claim 67, wherein said stabilizer is an antioxidant.

69. The method of claim 68, wherein said stabilizer is sodium metabisulfite.

70. The method of claim 56, wherein said method comprises mixing a plurality of stabilizers.

71. The method of claim 69, wherein said stabilizers comprise L-arginine monohydrochloride, L-methionine, L-lysine monohydrochloride, and sodium metabisulfite.

72. The method of claim 56, wherein said bulking agent/tonicity adjuster is selected from the group consisting of mannitol, amino acids, lactose, potassium chloride, sodium chloride, maltose, sucrose, PEG's, trehalose, raffinose, dextrose, cyclodextrins, dextran, galacturonic acid, Ficoll, and polyvinylpyrrolidone (PVP).

73. The method of claim 72, wherein said bulking agent/tonicity adjuster is D-mannitol.

74. The method of claim 56 wherein said chelator is pentetic acid (DTPA).

75. The method of claim 74 wherein said chelator is pentetic acid, said surfactant is polysorbate 20, said buffer is dibasic potassium phosphate, and said bulking agent/tonicity adjuster is D-mannitol.

76. The method of claim 56, wherein said formulation comprises about 0.0008 to 0.0012 mg/mL sincalide; about 20 to 50 mg/mL D-mannitol, about 2 to 7 mg/mL L-arginine; about 0.2 to 1 mg/mL L-methionine; about 2 to 30 mg/mL L-lysine; about 0.002 to 0.012 mg/mL sodium metabisulfite; about 0.000001 to 0.003 mg/mL polysorbate 20, about 0.1 to 3 mg/mL pentetic acid (DTPA); and about 1.1 to 1.8 mg/mL dibasic potassium phosphate.

77. A method for imaging the hepatobiliary system of a subject, said method comprising: (a) administering a hepatobiliary imaging agent to said subject; (b) before or after step (a), administering to a subject a sincalide formulation comprising: (i) sincalide, (ii) at least one stabilizer, (iii) a surfactant, (iv) a chelator, (v) a bulking agent/tonicity adjuster, and (vi) a buffer; and (c) detecting said imaging agent in said subject with a detection device.

78. The method of claim 77, wherein said sincalide formulation is administered by injection.

79. The method of claim 77, wherein said sincalide formulation is administered to said subject before administration of said hepatobiliary imaging agent.

80. The method of claim 77, wherein said sincalide formulation is administered to said subject after administration of said hepatobiliary imagining agent.

81. The method of claim 77, wherein said hepatobiliary imaging agent is a .sup.99m Tc-IDA (Iminodiacetic acid) analog.

82. The method of claim 77, wherein said hepatobiliary imaging agent is .sup.99m Tc-mebrofenin.

83. The method of claim 77, wherein said method further comprises, after administration of said sincalide formulation, measuring said the gallbladder ejection fraction (GBEF) of said subject.

84. The method of claim 77, wherein said detection device scans the body of said subject for radioactivity.

85. The method of claim 84, wherein said detection device is a gamma camera.

86. The method of claim 77, wherein said formulation has a pH from 6.0 to 8.0.

87. The method of claim 77, wherein said buffer is selected from the group consisting of phosphoric acid, phosphate, citric acid, citrate, sulfosalicylate, acetic acid, acetate, methyl boronic acid, boronate, disodium succinate hexahydrate, one or more amino acids, lactic acid, lactate, maleic acid, maleate, potassium chloride, benzoic acid, sodium benzoate, carbonic acid, carbonate, bicarbonate, boric acid, borate, sodium chloride, succinic acid, succinate, tartaric acid, tartrate, tris-(hydroxymethyl)aminomethane, and biological buffers.

88. The method of claim 77, wherein said buffer is a phosphate buffer.

89. The method of claim 88, wherein said buffer is dibasic potassium phosphate.

90. The method of claim 77, wherein said surfactant is selected from the group consisting of anionic surfactants, pluronics, poloxamers, SDS, Triton-100, polysorbates, propylene glycol, PEG and similar compounds, Brij58 9poly(oxyethylene)20 cetyl ether, cremophor EL, cetyl trimethylammonium bromide (CTAB), dimethylacetamide (DMA), NP 40 (Nonidet P-40), and N-methyl-2-pyrrolidone (Pharmasolve) and amino acids.

91. The method of claim 77, wherein said surfactant is a nonionic surfactant.

92. The method of claim 91, wherein said nonionic surfactant is a polysorbate.

93. The method of claim 92, wherein said nonionic surfactant is polysorbate 20 or polysorbate 80.

94. The method of claim 77, wherein said stabilizer is selected from the group consisting of antioxidants and amino acids.

95. The method of claim 94, wherein said stabilizer is an antioxidant.

96. The method of claim 95, wherein said stabilizer is sodium metabisulfite.

97. The method of claim 77, wherein said method comprises mixing a plurality of stabilizers.

98. The method of claim 97, wherein said stabilizers comprise L-arginine monohydrochloride, L-methionine, L-lysine monohydrochloride, and sodium metabisulfite.

99. The method of claim 77, wherein said bulking agent/tonicity adjuster is selected from the group consisting of mannitol, amino acids, lactose, potassium chloride, sodium chloride, maltose, sucrose, PEG's, trehalose, raffinose, dextrose, cyclodextrins, dextran, galacturonic acid, Ficoll, and polyvinylpyrrolidone (PVP).

100. The method of claim 77, wherein said bulking agent/tonicity adjuster is D-mannitol.

101. The method of claim 77, wherein said chelator is pentetic acid (DTPA).

102. The method of claim 101, wherein said chelator is pentetic acid, said surfactant is polysorbate 20, said buffer is dibasic potassium phosphate, and said bulking agent/tonicity adjuster is D-mannitol.

103. The method of claim 77, wherein said formulation comprises about 0.0008 to 0.0012 mg/mL sincalide; about 20 to 50 mg/mL D-mannitol, about 2 to 7 mg/mL L-arginine; about 0.2 to 1 mg/mL L-methionine; about 2 to 30 mg/mL L-lysine; about,0.002 to 0.012 mg/mL Sodium metabisulfite; about 0.000001 to 0.003 mg/mL polysorbate 20; about 0.1 to 3 mg/mL pentetic acid (DTPA); and about 1.1 to 1.8 mg/mL dibasic potassium phosphate.

104. A method for imaging the hepatobiliary system of a subject, said method comprising: a) administering to a subject a sincalide formulation comprising: (i) sincalide, (ii) at least one stabilizer, (iii) a surfactant, (iv) a chelator, (v) a bulking agent/tonicity adjuster, and (vi) a buffer; and b) scanning the subject using a diagnostic imaging modality.

105. The method of claim 104 wherein said imaging modality is selected from the group consisting of magnetic resonance imaging, scintigraphic imaging and ultrasound imaging.

106. A stabilized, physiologically acceptable formulation of sincalide comprising: (a) about 0.001 mg/mL sincalide; (b) about 34 mg/mL D-mannitol; (c) about 6 mg/mL L-arginine; (d) about 0.8 mg/mL L-methionine; (e) about 3 mg/mL L-lysine; (f) about 0.008 mg/mL sodium metabisulfite; (g) less than about 0.01 mg/mL polysorbate 20; (h) about 0.4 mg/mL pentetic acid; and (i) about 1.8 mg/mL dibasic potassium phosphate.

107. The kit of claim 40 comprising: a) about 0.005 mg sincalide; b) about 100 to 250 mg mannitol; c) about 0.000005 to 0.015 mg polysorbate 20; d) about 2 mg pentetic acid (DTPA); e) about 0.01 to 0.06 mg sodium metabisulfite; f) about 5.4 to 12 mg potassium phosphate (dibasic); g) about 1 to 5 mg methionine; h) about 10 to 60 mg lysine; and i) about 10 to 35 mg arginine.

108. A kit comprising: a) about 0.005 mg sincalide; b) about 170 mg D-mannitol; c) less than about 0.01 mg polysorbate 20; d) about 2 mg DTPA; e) about 0.04 mg sodium metabisulfite; f) about 9 mg potassium phosphate (dibasic); g) about 4 mg L-methionine; h) about 15 mg L-lysine monohydrochloride; and i) about 30 mg L-arginine monohydrochloride.
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