Cation complexes of insulin compound conjugates, formulation and uses thereof

• US 7,875,700 B2
• Filed: 07/19/2005
• Issued: 01/25/2011
• Est. Priority Date: 07/19/2004
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: James, Kenneth D., Ferro, Michelle, Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Aggarwal, Diti, Malkar, Navdeep B., Puskas, Monica, Miller, Mark A.
• Primary Examiner(s): Lukton; David
• Application Number:
  US11/184,668
• Publication Number:
  US 20060019874A1
• Time in Patent Office: 2,016 Days
• Field of Search: 514 2- 4, 530/303, 530/345, 530/304
• US Class Current: 530/304
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 33/30 Zinc; Compounds thereof
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/69 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The invention provides a complex including a cation and an insulin compound conjugate. The insulin compound conjugate includes insulin compound, such as human insulin or an analog thereof, conjugated to a modifying moiety, such as a polyethylene glycol moiety. The invention also includes solids and pharmaceutical compositions including such complexes, methods of making such complexes, and methods of using such complexes in the treatment of insulin compound deficiencies and other ailments. Further, the invention includes novel insulin compound conjugates and modifying moieties for use in making novel insulin compound conjugates. The invention also includes fatty acid compositions for administration of pharmaceutical agents, such as the novel insulin compound conjugates, and/or the cation-insulin compound conjugate complexes of the invention.

Claims

1. A solid complex comprising:

an insulin compound conjugate comprising an insulin compound conjugated to a modifying moiety, wherein the modifying moiety comprises from 2 to 10 PEG subunits (OCH₂—

CH₂) forming a PEG component coupled to a lipophilic component, where the lipophilic component is selected from the group consisting of alkyls, fatty acids and linear or branched lipids, and either the PEG component or the lipophilic component is coupled to the insulin compound at the B29 amino acid residue; and

a cation, wherein the cation is a divalent cation selected from the group consisting of Zn⁺⁺, Mn⁺⁺, Ca⁺⁺, Fe⁺⁺, Ni⁺⁺, Cu⁺⁺, Co⁺⁺ and Mg⁺⁺;

where the insulin compound conjugate is complexed with the cation, and wherein the solid complex is a crystalline solid or a rod shaped crystal.

2. The complex of claim 1 where the insulin compound conjugate comprises an insulin compound analog.

3. The complex of claim 2 where the insulin compound analog is human insulin with Lys²⁸ and Pro²⁹.

4. The complex of claim 2 where the insulin compound analog is a native proinsulin compound.

5. The complex of claim 2 where the insulin compound analog is an artificial proinsulin compound.

6. The complex of claim 2 where the insulin compound analog is a miniproinsulin compound comprising a C-peptide having 5 or less amino acids.

7. The complex of claim 2 where the insulin compound analog is a native proinsulin compound having a leader peptide which is cleavable or non-cleavable.

8. The complex of claim 2 where the insulin compound analog is an artificial proinsulin compound having a leader peptide which is cleavable or non-cleavable.

9. The complex of claim 2 where the insulin compound analog is a miniproinsulin compound comprising:

a C-peptide having 5 or less amino acids;

a leader peptide which is cleavable or non-cleavable.

10. The complex of claim 2 where the insulin compound analog is a pre-proinsulin compound comprising proinsulin compound and a leader peptide or a carrier protein joined at the C-terminus or N-terminus of the proinsulin compound.

11. The complex of claim 2 where the insulin compound analog is a single chain insulin compound precursor comprising insulin compound A-chain-B-chain, where the A chain and/or B chain may be truncated at the point of attachment to the other by 1, 2 or 3 amino acids.

12. The complex of claim 2 where the insulin compound analog is an insulin compound comprising a leader peptide or a carrier protein.

17. The complex of claim 1 where the water solubility of the insulin compound conjugate is decreased by the addition of zinc.

18. The complex of claim 1 where the relative lipophilicity of the insulin compound conjugate relative to the corresponding parent insulin compound is 1 or less than 1.

19. The complex of claim 18, wherein:

(a) k_rel=(t_conjugate−

t₀)/(t_human−

t₀);

(b) relative lipophilicity is measured on an LiChroSorb RP18 (5 μ

m, 250×

4 mm) high performance liquid chromatography column by isocratic elution at 40°

C.

(c) the following mixtures are used as eluents;

(i) 0.1M sodium phosphate buffer at pH 7.3 containing 10% acetonitrile, and

(ii) 50% acetonitrile in water;

(d) void time (t₀) is identified by injecting 0.1 mM sodium nitrate;

(e) retention time for human insulin is adjusted to at least 2t₀ by varying the ratio between the mixtures of (c)(i) and (c)(ii).

20. The complex of claim 1 where the modifying moiety is coupled to one or more amino groups on the insulin compound.

21. The complex of claim 1 where a modifying moiety is coupled at the carboxy terminus of the A-chain and/or a modifying moiety is coupled at the carboxy terminus of the B-chain of the insulin compound.

22. The complex of claim 1 where a modifying moiety is coupled at the N-terminus of a leader peptide which is coupled to the B-chain of the insulin compound.

23. The complex of claim 1 where the cation comprises Zn⁺⁺.

24. The complex of claim 1 where the cation is greater than about 90, 95, 99, or 99.9% Zn⁺⁺.

25. The complex of claim 1 where molar ratio of insulin compound conjugate to cation is between about 1:

1 and about 1;

100, about 1;

2 and about 1;

12, or about 1;

2 and about 1;

7.

28. The complex of claim 1 where the insulin compound conjugate consists of human insulin coupled at B29 to a modifying moiety having a structure:

31. The complex of claim 1 where the modifying moiety has a structure:

32. The complex of claim 1 where the modifying moiety has a structure:

33. The complex of claim 1 where the modifying moiety has a structure:

34. The complex of claim 1 where the modifying moiety has a structure:

35. The complex of claim 1 where the modifying moiety has a structure:

36. The complex of claim 1 where the modifying moiety has a structure:

37. The complex of claim 1 where the modifying moiety has a structure:

38. The complex of claim 1 where the modifying moiety has a structure:

39. The complex of claim 1 where the modifying moiety has a structure:

40. The complex of claim 1 where the modifying moiety has a structure:

41. The complex of claim 1 where the modifying moiety has a structure:

42. The complex of claim 1 where the modifying moiety has a structure:

43. The complex of claim 1 where the modifying moiety has a structure:

44. The complex of claim 1 where the modifying moiety has a structure:

45. The complex of claim 1 where the modifying moiety has a structure:

46. A complex mixture comprising the complex of claim 1.

47. A solid mixture comprising the complex of claim 1.

48. A hybrid complex comprising the complex of claim 1.

49. A co-crystal comprising the complex of claim 1.

50. A composition comprising the complex of claim 1 wherein the composition is provided as a lyophilized powder.

52. A composition comprising:

a first complex according to the complex of claim 1; and

a second complex selected from a group consisting of a conjugated insulin compound or unconjugated insulin compound.

53. The composition of claim 52 where the first complex and second complex is provided as a solid.

54. The composition of claim 52 where:

the second complex is provided as an amorphous solid.

55. The composition of claim 52 where the complex of where the first complex and second complex is provided as a crystalline solid.

56. The composition of claim 52 further comprising a third complex comprising:

an insulin compound conjugate comprising an insulin compound coupled to a third modifying moiety, and

a cation component, where the insulin compound conjugate is complexed with the cation.

57. The composition of claim 52 where the first complex and second complex comprise different insulin compounds.

58. The composition of claim 52 where:

the first complex and second complex comprise different insulin compound conjugates, and

one of the complexes comprises a lipophilic insulin compound conjugate and the other of the complexes comprises a hydrophilic insulin compound conjugate.

59. The composition of claim 52 where:

the first complex and second complex comprise different insulin compound conjugates, and

one of the complexes has a circulation half-life of from about 1 to about 4 hours; and

the other of the complexes has a circulation half-life that is greater than the circulation half-life of the first complex.

60. The composition of claim 52 where:

the first complex and second complex comprise different insulin compound conjugates, and

one of the complexes has a rapid-acting profile; and

the other of the complexes has a medium-to-long acting profile.

61. The composition of claim 52 where:

the first complex and second complex comprise different insulin compound conjugates, and

one of the complexes has profile suitable for basal insulin compound control; and

the other of the complexes has a profile suitable for post-prandial glucose control.

62. The composition of claim 52 where the composition is a crystal exhibiting one or more of the following characteristics:

substantially homogenous dissolution, a single in vivo dissolution curve, and/or a single peak pharmacodynamic profile.

63. The composition of claim 52 where the composition is a co-crystal of HIM2 and insulin compound.

64. The composition of claim 52 where the composition is a co-crystal of HIM2 and IN105.

65. The composition of claim 52 where the composition is a co-crystal of IN105 and insulin compound.

66. The composition of claim 52 where the composition is a co-crystal which has a PK/PD profile suitable for post-prandial glucose control.

67. The composition of claim 52 where the composition is a co-crystal which has a PK/PD profile suitable for overnight basal insulin compound control.

68. A composition comprising the complex of claim 1 in the form of a crystalline solid having irregular morphology.

69. A composition comprising the complex of claim 1 in the form of a crystalline solid having an average diameter ranging from about 0.5 to about 40 μ

m.

70. A composition comprising the complex of claim 1 and one or more additional pharmaceutically acceptable components.

75. A pharmaceutical composition comprising the complex of claim 1 and a pharmaceutically acceptable carrier.

76. The pharmaceutical composition of claim 75 further comprising a stabilizing agent.

77. The pharmaceutical composition of claim 76 where the stabilizing agent is a phenolic compound.

78. The pharmaceutical composition of claim 76 where the stabilizing agent is selected from the group consisting of phenol, m-cresol and paraben.

79. A method of treating diabetes comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a complex of claim 1.

80. The method of claim 79 where the composition is administered orally.

81. The complex of claim 1, wherein the complex is an R-type complex, an NPH-type complex, a T-type complex, an R-type Zn complex, or T-type Zn complex.

82. The complex of claim 81, wherein the R-type Zn complex or T-type Zn complex further comprises protamine.

13. A solid complex comprising:

an insulin compound conjugate comprising an insulin compound conjugated to a modifying moiety, wherein the modifying moiety comprises (OCH₂—

CH₂) PEG subunits forming a PEG component coupled to a lipophilic component, where the lipophilic component is selected from the group consisting of alkyls, fatty acids and linear or branched lipids, and either the PEG component or the lipophilic component is coupled to the insulin compound at the B29 amino acid residue; and

a cation, wherein the cation is a divalent cation selected from the group consisting of Zn⁺⁺, Mn⁺⁺, Ca⁺⁺, Fe⁺⁺, Ni⁺⁺, Cu⁺⁺, Co⁺⁺ and Mg⁺⁺;

where the insulin compound conjugate is complexed with the cation,

where the modifying moiety is selected to render the insulin compound conjugate more water soluble than a corresponding unconjugated insulin compound, and wherein the solid complex is a crystalline solid or a rod shaped crystal.

14. The complex of claim 13 where the modifying moiety is selected to render the insulin compound conjugate more amphiphilic than a corresponding unconjugated insulin compound.

15. The complex of claim 13 where the modifying moiety is selected to render the insulin compound conjugate at least 1.05, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 times more soluble than a corresponding unconjugated insulin compound in an aqueous solution at a pH of about 7.4.

16. The complex of claim 13 where the modifying moiety is selected to render an insulin compound conjugate having a solubility that exceeds about 1 g/L, 2 g/L, 3 g/L, 4 g/L, 5 g/L, 10 g/L, 15 g/L, 20 g/L, 25 g/L, 50 g/L, 75 g/L, 100 g/L, 125 g/L, or 150 g/L at a pH ranging from about 4 to about 8.

26. The complex of claim 13 where resistance of the complexed insulin compound conjugate to chymotrypsin degradation is greater than the chymotrypsin degradation of a corresponding uncomplexed insulin compound conjugate.

27. The complex of claim 13 where resistance of the complexed insulin compound conjugate to chymotrypsin degradation is greater than the chymotrypsin degradation of a corresponding complexed but unconjugated insulin compound.

29. The complex of claim 13 where the modifying moiety has a formula:

30. The complex of claim 13 where the modifying moiety has a formula:

51. The complex of claim 13 in a mixture having a pharmaceutically acceptable level of purity.

71. The complex of claim 13 where in a dried state, the solid comprises:

greater than about 96% w/w insulin compound conjugate, and

from about 0.05 to about 4% w/w Zn⁺⁺.

72. The complex of claim 13 where in a dried state, the solid comprises:

greater than about 91% w/w insulin compound conjugate,

from about 0.3 to about 4% w/w Zn⁺⁺, and further comprises

from about 0.2 to about 5% w/w phenol.

73. The complex of claim 13 where in a dried state, the solid comprises:

from about 0.1 to about 2% w/w Zn⁺⁺, and further comprises

from about 0.08 to about 1% w/w phenol.

74. The complex of claim 13 where the solid is greater than about 90, 95, or 99% crystalline.