Iodothyronine compositions

• US 20040087483A1
• Filed: 05/02/2002
• Published: 05/06/2004
• Est. Priority Date: 08/22/2000
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: New River Pharmaceuticals Inc. (Shire plc)
• Inventors: Piccariello, Thomas, Moncrief, James Scott, Olon, Lawrence Peter, Goldstein, Alex Saunders, Boerth, Nancy Johnston
• Granted Patent: US 7,163,918 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT

Abstract

The present invention relates to compositions comprising an active agent. More specifically, the invention relates to active agent compositions that include a peptide carrier and an active agent covalently attached to at least one of the N-terminus, the C-terminus, a side chain of the peptide carrier, and/or interspersed within the peptide chain; methods for protecting and administering active agents; and methods for treating thyroid disorders.

Claims

1. A composition comprising:

a carrier peptide that comprises at least one iodothyronine active agent, with the proviso that no more than four active agents are contiguously bonded.

2. The composition of claim 1, wherein said iodothyronine active agent is T3.

3. The composition of claim 1, wherein said iodothyronine active agent is T4.

4. The composition of claim 1, comprising both T3 and T4 active agent.

5. The composition of claim 1, comprising T3-Glu-Glu.

6. The composition of claim 1, comprising T4-Glu-Glu.

7. The composition of claim 1, comprising T3-Ser-Ser.

8. The composition of claim 1, comprising T3-PolySer.

9. The composition of claim 1, comprising T4-Ser-Ser.

10. The composition of claim 1, comprising T3-Lys.

11. The composition of claim 1, comprising T4-Lys.

12. The composition of claim 1, wherein said active agent is covalently interspersed in said carrier peptide.

13. The composition of claim 1, wherein said carrier peptide is an amino acid or an oligopeptide.

14. The composition of claim 1, further comprising said carrier peptide covalently attached to a fatty acid.

15. The composition of claim 1, wherein said carrier peptide is covalently attached to PEG.

16. The composition of claim 1, wherein said carrier peptide is covalently attached to cyclodextrin.

17. The composition of claim 1, wherein said carrier peptide is noncovalently associated with cyclodextrin.

18. The composition of claim 1, wherein said polymer formulations afford sustained release of the active agent.

19. The composition of claim 1, wherein said carrier peptide enhances absorption.

20. The composition of claim 1, wherein said active agent is covalently attached to said carrier peptide at said carrier peptide'"'"'s N-terminus, C-terminus, at least one side chain, or a combination thereof.

21. The composition of claim 20, wherein said active agent is covalently attached to the N-terminus of said carrier peptide.

22. The composition of claim 20, wherein said active agent is covalently attached to the C-terminus of said carrier peptide.

23. The composition of claim 20, wherein said active agent is covalently attached to at least one side chain of said carrier peptide.

24. The composition of claim 1, wherein said carrier peptide is a homopolymer or a heteropolymer.

25. The composition of claim 24, wherein said carrier peptide is a homopolymer comprising naturally occurring amino acids.

26. The composition of claim 24, wherein said carrier peptide is a homopolymer comprising synthetic amino acid.

27. The composition of claim 24, wherein said carrier peptide is a heteropolymer comprising two or more naturally occurring amino acids.

28. The composition of claim 24, wherein said carrier peptide is a heteropolymer comprising two or more synthetic amino acids.

29. The composition of claim 24, wherein said carrier peptide is a heteropolymer comprising one or more naturally occurring amino acids and one or more synthetic amino acids.

30. The composition of claim 1, wherein said composition further comprises at least one adjuvant attached to said carrier peptide.

31. The composition of claim 30, wherein said adjuvant enhances absorption.

32. The composition of claim 30, wherein said adjuvant enhances bioadhesive properties.

33. The composition of claim 32, wherein said bioadhesive property of said adjuvant imparts sustained release pharmacokinetics of the active agents in the alimentary tract.

34. The composition of claim 33, wherein said adjuvant targets delivery of the active agent/peptide conjugates to specific locations in the alimentary tract, specific cells in the systemic circulation or to specific enzymes in the intestinal lumen or brush border membrane.

35. The composition of claim 30, wherein said adjuvant is a fatty acid.

36. The composition of claim 30, wherein said adjuvant is cyclodextrin.

37. The composition of claim 30, wherein said adjuvant is PEG.

38. The composition of claim 30, wherein said adjuvant is the peptide itself.

39. The composition of claim 1, which is formulated to enhance the solubility of the active agent in aqueous or organic solvents.

40. The composition of claim 39, wherein said enhanced solubility allows even dispersion in polymer formulations.

70. A method of treating a thyroid hormone disorder comprising administering the composition of claim 1.

41. A composition comprising a carrier peptide and at least one iodothyronine active agent, wherein the combined number of carrier peptide and iodothyronine active agent residues is less than five.

42. A capped active agent composition comprising:

a carrier peptide; and

at least one iodothyronine active agent covalently bonded to the N-terminus or C-terminus of said carrier peptide;

wherein said composition comprises less than five active agents.

43. A side chain active agent composition comprising:

a carrier peptide; and

at least one iodothyronine active agent covalently bonded to at least one side chain of said carrier peptide.

44. An interspersed active agent composition comprising:

a carrier peptide; and

at least one iodothyronine active agent bonded at both its N-terminus and C-terminus to said carrier peptide or another iodothyronine active agent;

wherein said composition comprises less than five active agents contiguously bonded.

45. A T3/T4 composition prepared by process comprising the steps of:

(a) forming the N-carboxyanhydride (NCA) of one or more amino acids

(b) forming the NCA of a T3 and a T4 iodothyronine active agent,

(c) adding an initiator to promote formation of dimers, oligomers or polymers of T3, T4 or both T3 and T4.

46. The composition of claim 45 wherein step (b) incorporate both thyroid hormones, T4 and T3 in a desired ratio.

47. The composition of claim 45, wherein said forming steps are carried out so as to form an interspersed and side chain attached iodothyronine active agent/carrier peptide complex.

48. The composition of claim 45, wherein the initiator is a suitably protected amino acid, and where the process further comprises the step of deprotecting.

49. The composition of claim 45, further comprising the step of incorporating an adjuvant into the active agent/carrier peptide composition.

50. The composition of claim 45, wherein the initiator is the iodothyronine active agent, T4 or T3.

51. The composition of claim 45, wherein the amino acid-NCA, T4-NCA, T3-NCA, and initiator are present in a ratio of about 110.5:

7.5;

1;

7.4.

52. The composition prepared by a process comprising the steps of:

(a) dissolving an N-carboxyanhydride (NCA) of an amino acid and at least one of T3-NCA and T4-NCA in a solvent to form a reaction mixture;

(b) adding an initiator to said reaction mixture;

(c) forming a precipitate comprising a T3, T4 or T3/T4 product.

53. The composition of claim 52, wherein said solvent comprises at least one of DMF and THF.

54. The composition of claim 52, wherein said initiator is triethylamine.

55. The composition of claim 52, wherein said process further comprising the steps of purifying said precipitate by a process comprising:

(a) collecting, washing and resuspending said precipitate in heated water;

(b) cooling said precipitate;

(c) filtering said precipitate; and

(d) drying said precipitate to obtain said final product.

56. The composition of claim 52, wherein said amino acid is one of the 20 naturally occurring amino acids.

57. The composition of claim 56, wherein said amino acid is Glu.

58. The composition of claim 52, wherein said amino acid is a synthetic amino acid.

59. The composition of claim 52, wherein T4-NCA but not T3 NCA is dissolved.

60. The composition of claim 52, wherein T3-NCA but not T4-NCA is dissolved.

61. The composition of claim 52, wherein both T3-NCA and T4 NCA are dissolved.

62. The composition of claim 52, wherein said solvent is dimethylacetamide, N-methylpyrrolidone, chloroform, dichloromethane, carbon tetrachloride, trichloroethane, dimethyl sulfoxide, dioxane, diethylether, dimethoxyethane, ethyl acetate, benzene, pentane, hexane, cyclohexane, toluene or anisole.

63. The composition of claim 62, wherein said initiator is monosodium glutamate, glutamic acid, γ

-t-butyl glutamic acid, diethylamine, ethylamine, butylamine, pyrrolidine, pyridine or piperidine.

64. The composition of claim 52, wherein said precipitating solvent is methanol, ethanol, propanol, methoxyethanol, pentanol, chloroform, dichloromethane, carbon tetrachloride, trichloroethane, diethylether, dimethoxyethane, ethyl acetate, benzene, pentane, hexane, pentanol, cyclohexane, toluene, anisole, ethylene glycol, or propylene glycol.

65. The composition of claim 52, wherein said purification includes ultrafiltration, size exclusion chromatography, ion exchange chromatography or reverse phase high performance liquid chromatography.

66. A composition comprising:

T3, T4, or mixture thereof covalently attached to a fatty acid.

67. A composition comprising:

T3, T4, or mixture thereof covalently attached to PEG.

68. A composition comprising:

T3, T4, or mixture thereof covalently attached to a cyclodextrin.

69. A composition comprising:

T3, T4, or mixture thereof noncovalently associated with cyclodextrin.

71. A method of treating thyroid hormone disorders, said method comprising administering to a patient an iodothyronine active composition comprising:

a carrier peptide; and

at least one iodothyronine active agent covalently interspersed within said carrier peptide or covalently attached to an N-terminus, a C-terminus, at least one side chain of said carrier peptide, or a combination thereof;

wherein no more than four active agents are contiguously interspersed within the carrier peptide.

72. A method of administering an iodothyronine active composition to a patient,

said composition comprising:

a carrier peptide; and

at least one iodothyronine active agent, wherein no more than four active agents are contiguously bonded.