Cation complexes of insulin compund conjugates, formulation and uses thereof

• US 20060019874A1
• Filed: 07/19/2005
• Published: 01/26/2006
• Est. Priority Date: 07/19/2004
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: James, Kenneth D., Ferro, Michelle, Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Aggarwal, Diti, Malkar, Navdeep B., Puskas, Monica, Miller, Mark A.
• Granted Patent: US 7,875,700 B2
• Time in Patent Office: Days
• US Class Current: 514/6.200
• 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 complex comprising:

(a) an insulin compound conjugate comprising an insulin compound conjugated to a modifying moiety, and

(b) a cation,

where the insulin compound conjugate is complexed with the cation.

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

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

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

5. The complex of claim 3 where the insulin compound analog is a native proinsulin compound.

6. The complex of claim 3 where the insulin compound analog is an artificial proinsulin compound.

7. The complex of claim 3 where the insulin compound analog is a miniproinsulin compound comprising a C-peptide having 5 or less amino acids.

8. The complex of claim 3 where the insulin compound analog is a native proinsulin compound having a leader peptide which is cleavable or non-cleavable.

9. The complex of claim 3 where the insulin compound analog is an artificial proinsulin compound having a leader peptide which is cleavable or non-cleavable.

10. The complex of claim 3 where the insulin compound analog is a miniproinsulin compound comprising:

(a) a C-peptide having 5 or less amino acids;

(b) a leader peptide which is cleavable or non-cleavable.

11. The complex of claim 3 where the insulin compound analog is a pre-proinsulin compound comprising proinsulin compound and a leader peptide or carrier protein joined at the C-terminus or N-terminus of the proinsulin compound.

12. The complex of claim 3 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.

13. The complex of claim 3 where the insulin compound analog is an insulin compound comprising a leader peptide or a carrier protein.

14. The complex of claim 1 where the modifying moiety is selected to render the insulin compound conjugate more water soluble than a corresponding unconjugated insulin compound.

15. The complex of claim 1 where the modifying moiety is selected to render the insulin compound conjugate equally or more hydrophilic than a corresponding unconjugated insulin compound.

16. The complex of claim 1 where the modifying moiety is selected to render the insulin compound conjugate more amphiphilic than a corresponding unconjugated insulin compound.

17. The complex of claim 14 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.

18. The complex of claim 14 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.

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

20. The complex of claim 1 where:

(a) the modifying moiety is selected to render the insulin compound conjugate equally or more soluble than a corresponding unconjugated insulin compound; and

(b) the water solubility of the insulin compound conjugate is decreased by the addition of zinc.

21. The complex of claim 1 where:

(a) the modifying moiety is selected to render the insulin compound conjugate equally or more soluble than a corresponding unconjugated insulin compound;

(b) the water solubility of the insulin compound conjugate is decreased by the addition of zinc; and

(c) water solubility of the complex is greater than the water solubility of insulin compound.

22. The complex of claim 1 where:

(a) the insulin compound conjugate is an acylated insulin compound;

(b) the cation is zinc; and

(c) the water solubility of the insulin compound conjugate is decreased by the addition of the zinc.

23. The complex of claim 1 where:

(a) the insulin compound conjugate is an acylated insulin compound that is equally or more water soluble than a corresponding unconjugated insulin compound; and

(b) the cation is zinc; and

(c) the water solubility of the insulin compound conjugate is decreased by the addition of the zinc.

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

25. The complex of claim 1 where the relative lipophilicity of the insulin compound conjugate as compared to corrsesponding parent insulin compound (k_rel) is 1 or less than 1 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).

26. The complex of claim 25 wherein the relative lipophilicity is about 1 or less than 1.

27. The complex of claim 25 wherein:

(a) the insulin compound is human insulin, and

(b) the relative lipophilicity is less than 1.

28. The complex of claim 25 wherein the relative lipophilicity is less than 0.99, 0.98, 0.97, 0.96, 0.95, 0.94, 0.93, 0.92, 0.91, or 0.90.

29. The complex of claim 25 wherein the modifying moiety is not an alkyl moiety.

30. The complex of claim 25 wherein the modifying moiety is a carbon chain comprising oxy groups inserted therein.

31. The complex of claim 25 wherein the modifying moiety is a carbon chain having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbons, wherein the carbon chain comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10 oxy groups inserted therein.

32. The complex of claim 25 wherein the modifying moiety is a carbon chain having 5, 6, 7, 8, 9 or 10 carbons, wherein the carbon chain comprises 2, 3 or 4 oxy groups inserted therein.

33. The complex of claim 25 wherein the modifying moiety comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 polyalkalene glycol units.

34. The complex of claim 25 wherein the modifying moiety comprises 1, 2 or 3 polyethylene glycol units and 1, 2 or 3 polypropylene glycol units.

35. The complex of claim 25 wherein:

(a) the cation is zinc, and

(b) aqueous solubility of the insulin compound conjugate is decreased by addition of the zinc.

36. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is less than or equal to the solubility of the insulin compound conjugate.

37. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is greater than the solubility of the insulin compound conjugate.

38. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is greater than 5 times the solubility of the insulin compound conjugate.

39. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is from about 1/15 to 5 times the solubility of the insulin compound conjugate.

40. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is from about 1/10 to about 2 times the solubility of the insulin compound conjugate.

41. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is from about 1/10 to <

0 times the solubility of the insulin compound conjugate.

42. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is from greater than about 1/10 the solubility of the insulin compound conjugate at a pH of about 7.4 to substantially less than the solubility of the insulin compound conjugate at a pH of about 7.4.

43. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is from greater than about 1/10 the solubility of the insulin compound conjugate at a pH of about 7.4 to equal to or less than the solubility of the insulin compound conjugate at a pH of about 7.4.

44. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is substantially greater than the solubility of the insulin compound conjugate in solution at a pH of about 7.4.

45. The complex of claim 1 where the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is substantially less than the solubility of the insulin compound conjugate in solution at a pH of about 7.4.

46. The complex of claim 1 where:

(a) the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is substantially less than the solubility of the insulin compound conjugate in solution at a pH of about 7.4, and

(b) the cation-insulin compound conjugate remains soluble at greater than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 or 130 g/L in aqueous solution across a pH range from about 5 to about 8.5.

47. The complex of claim 1 where:

(a) the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is substantially less than the solubility of the insulin compound conjugate in solution at a pH of about 7.4, and

(b) the cation-insulin compound conjugate remains soluble at greater than about 1 g/L in aqueous solution across a pH range from 5.8 to about 8.5.

48. The complex of claim 1 where:

(a) the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is substantially less than the solubility of the insulin compound conjugate in solution at a pH of about 7.4, and

(b) the cation-insulin compound conjugate remains soluble at greater than about 1, 5, 10 or 20 g/L in aqueous solution across a pH range from 6.5 to about 8.

49. The complex of claim 1 where:

(a) the solubility of the cation-insulin compound conjugate complex at a pH of about 7.4 is substantially less than the solubility of the insulin compound conjugate in solution at a pH of about 7.4, and

(b) the cation-insulin compound conjugate remains soluble at greater than about 1, 5, 10 or 20 g/L in aqueous solution across a pH range from 6.9 to about 7.8.

50. The complex of claim 1 where:

(a) the complex is an R-type complex; and

(b) at a pH of about 7.4, the aqueous solubility of the complex is from about 10 to about 150 g/L. from about 20 to about 130 g/L, from about 30 to about 110 g/L, or from about 35 to about 60 g/L.

51. The complex of claim 1 where:

(a) the complex is an NPH-type complex; and

(b) at a pH of about 7.4, the aqueous solubility of the complex is from about 1 to about 150 g/L, from about 5 to about 120 g/L, or from about 10 to about 90 g/L.

52. The complex of claim 1 where:

(a) the complex is a T-type complex; and

(b) at a pH of about 7.4, the aqueous solubility of the complex is from about 30 to about 175 g/L, from about 50 to about 160 g/L, or from about 70 to about 150 g/L.

53. The complex of claim 1 where:

(a) the complex is an R-type Zn complex comprising protamine; and

(b) at a pH of about 7.4, the aqueous solubility of the complex is from about 10 to about 110 g/L, from about 20 to about 85 g/L, or from about 30 to about 70 g/L.

54. The complex of claim 1 where:

(a) the complex is a T-type Zn complex comprising protamine; and

(b) at a pH of about 7.4, the aqueous solubility of the complex is from about 10 to about 150 g/L, from about 20 to about 130 g/L, from about 30 to about 110 g/L, or from about 35 to about 60 g/L.

55. The complex of claim 1 where:

(a) the insulin compound conjugate is a monoconjugate; and

(b) the complex produces crystals in an aqueous solution at pH of about 4 to <

6.5, from about pH of about 4 to <

5.8, from about 4.2 to about 5.5.

56. The complex of claim 1 where:

(a) the insulin compound conjugate is a monoconjugate;

(b) the cation is zinc; and

(c) complex produces crystals in an aqueous solution at about 4.4 to about 5.2.

57. The complex of claim 1 where the insulin compound conjugate produces crystals in aqueous solution at a pH which is equal to the pI plus or minus 2.5.

58. The complex of claim 1 where:

(a) the modifying moiety comprises PAG and/or a PAG 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

(b) either the PAG component or the lipophilic component is coupled to the insulin compound.

59. The complex of claim 58 where the modifying moiety is coupled to one or more amino groups on the insulin compound.

60. The complex of claim 58 where a modifying moiety is coupled at the caboxy terminus of the A-chain and/or a modifying moiety is coupled at the caboxy terminus of the B-chain of the insulin compound.

61. The complex of claim 58 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.

62. The complex of claim 58 where a modifying moiety is coupled at an amino acid side chain functional group.

63. The complex of claim 58 where:

(a) the insulin compound comprises an amino group at A1, B1, and/or B29; and

(b) a single modifying moiety is coupled to a single amino group on the insulin compound at a position selected from the group consisting of A1, B1, and B29.

64. The complex of claim 58 where:

(a) the insulin compound comprises an amino group at B1, and/or B29,

(b) a first modifying moiety is coupled to an amino group at B1, and

(c) a second modifying moiety is coupled to an amino group at B29.

65. The complex of claim 58 where:

(a) the insulin compound comprises an amino group at B29, and

(b) a single modifying moiety is coupled to an amino group at B29.

66. The complex of claim 58 where a modifying moiety is coupled at a free amino group in the insulin compound to form a carbamate bond.

67. The complex of claim 58 where:

(a) the insulin compounds comprises a free hydroxyl group, and

(b) a modifying moiety is coupled to the free hydroxyl group to form a carboxyllic, ether, or carbonate bond.

68. The complex of claim 58 where:

(a) the insulin compounds comprises a free —

SH group, and

(b) a modifying moiety is coupled to the —

SH group to form a thioester, thioether, or sulfonate bond.

69. The complex of claim 1 where:

(a) the conjugated insulin compound molecule is acylated to the modifying moiety; and

(b) the modifying moiety does not consist of a fatty acid, an alkyl having more than 2 carbons, or an amino acid.

70. The complex of claim 1 where:

(a) the conjugated insulin compound molecule is acylated to the modifying moiety; and

(b) the modifying moiety does not does not comprise a fatty acid, an alkyl having more than 2 or 3 carbons, or an amino acid.

71. The complex of claim 1 where the cation component comprises a monovalent or multivalent metal cation.

72. The complex of claim 1 where the cation component comprises a monovalent metal cation selected from Na⁺, Li⁺, and K⁺.

73. The complex of claim 1 where the cation component comprises a divalent metal cation selected from the group consisting of Zn⁺⁺, Mn⁺⁺, Ca⁺⁺, Fe⁺⁺, Ni⁺⁺, Cu⁺⁺, Co⁺⁺ and Mg⁺⁺.

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

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

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

1 and about 1;

100, about 1;

2 and about 1;

12, or about 1;

2 and about 1;

7.

77. The complex of claim 1 where resistance of the complexed insulin compound conjugate to chymotrypsin degradation is greater than the chymotrypsin degradation of the corresponding uncomplexed insulin compound conjugate.

78. The complex of claim 1 where resistance of the complexed insulin compound conjugate to chymotrypsin degradation is greater than the chymotrypsin degradation of the corresponding complexed but unconjugated insulin compound.

79. The complex of claim 1 where the insulin compound conjugate consists of human insulin coupled at A1, B1and/or B29 to a modifying moiety having a structure:

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

81. The complex of claim 1 where the insulin compound conjugate consists of human insulin coupled at A1 and B29 to a modifying moiety having a structure:

82. The complex of claim 1 where the insulin compound conjugate consists of human insulin coupled at A1, B1 and/or B29 to a modifying moiety having a structure:

83. The complex of claim 1 where the modifying moiety has a formula:

84. The complex of claim 1 where the modifying moiety has a formula:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

101. The complex of claim 1 where the insulin compound conjugate is coupled at A1, B1 and/or B29 to a linear or branched PEG moiety having from 2 to 20 PEG subunits, from 2 to 15 PEG subunits, or from 2 to 10 PEG subunits.

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

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

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

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

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

107. The complex of claim 1 in a mixture having a pharmaceutically acceptable level of purity.

108. A composition comprising:

(a) the complex of claim 1;

and

(b) a second insulin compound conjugate or unconjugated insulin compound.

109. The composition of claim 108 where the complex of 108(a) and/or 108(b) is provided as a solid.

110. The composition of claim 108 where:

(a) one of the complexes of 108(a) and 108(b) is provided as a crystalline solid; and

(b) the other is provided as an amorphous solid.

111. The composition of claim 108 where the complex of 108(a) and/or 108(b) is provided as a crystalline solid.

112. The composition of claim 108 further comprising a third complex comprising:

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

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

113. The composition of claim 108 where the insulin compound conjugates of the complexes of 108(a) and 108(b) comprise different insulin compounds.

114. The composition of claim 108 where the complexes of 108(a) and 108(b) comprise different insulin compound conjugates.

115. The composition of claim 108 where:

(a) the complexes of 108(a) and 108(b) comprise different insulin compound conjugates, and

(b) the different insulin compound conjugates have different solubilities.

116. The composition of claim 108 where:

(a) the complexes of 108(a) and 108(b) comprise different insulin compound conjugates, and

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

117. The composition of claim 108 where:

(a) the complexes of 108(a) and 108(b) comprise different insulin compound conjugates, and

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

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

118. The composition of claim 108 where:

(a) the complexes of 108(a) and 108(b) comprise different insulin compound conjugates, and

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

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

119. The composition of claim 108 where:

(a) the complexes of 108(a) and 108(b) comprise different insulin compound conjugates, and

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

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

120. The composition of claim 108 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.

121. The composition of claim 108 where the composition is a co-crystal of HIM2 and insulin compound.

122. The composition of claim 108 where the composition is a co-crystal of HIM2 and IN105.

123. The composition of claim 108 where the composition is a co-crystal of IN105 and insulin compound.

124. The composition of claim 108 where the second active ingredient is insulin compound, and wherein co-crystallization with insulin compound reduces the solubility of the crystal relative to the solubility of a crystal of the insulin compound conjugate.

125. The composition of claim 108 where the second active ingredient is insulin compound, and wherein co-crystallization with insulin compound increases the solubility of the crystal relative to the solubility of a crystal of the insulin compound conjugate.

126. The composition of claim 108 where co-crystallization the insulin compound conjugate and the second active ingredient are selected to achieve a co-crystal having a desired therapeutic activity.

127. The composition of claim 108 where the composition is a co-crystal comprising:

(a) a rapid acting, rapid clearing, or highly potent insulin compound conjugate,

(b) a long-acting, slow clearing, or poorly potent insulin compound conjugate.

128. The composition of claim 108 where the composition is a co-crystal has a PK/PD profile suitable for post-prandial glucose control.

129. The composition of claim 108 where the composition is a co-crystal has a PK/PD profile suitable for overnight basal insulin compound control.

130. A composition comprising:

(a) the complex of claim 1;

and

(b) an unconjugated insulin compound.

131. The composition of claim 130 where the insulin compound is human insulin or lys-pro insulin compound.

132. The complex of claim 1 comprising two different insulin compound conjugates.

133. The complex of claim 1 comprising an insulin compound conjugate and an unconjugated insulin compound.

134. The complex of claim 1 comprising two different insulin compound conjugates comprising two different insulin compounds.

135. The complex of claim 1 comprising two different insulin compound conjugates.

136. The complex of claim 1 comprising an insulin compound conjugate and an unconjugated insulin compound.

137. The complex of claim 1 provided as a component of a hybrid co-crystal of two different insulin compound conjugates.

138. The complex of claim 1 provided as a component of a hybrid co-crystal of three different insulin compound conjugates.

139. The complex of claim 1 provided as a component of a hybrid co-crystal of a different insulin compound conjugates.

140. The complex of claim 1 comprising at least two different insulin compound conjugates.

141. The complex of claim 1 comprising a co-crystal of at least two different insulin compound conjugates.

142. The complex of claim 1 comprising one insulin compound conjugate and further comprising an unconjugated insulin compound.

143. The complex of claim 1 comprising comprising the insulin compound conjugate in a complex together with an unconjugated insulin compound.

144. The complex of claim 1 provided as a component of a co-crystal comprising two different hydrophilic insulin compound conjugates.

145. The complex of claim 1 provided as a component of a co-crystal comprising a hydrophilic insulin compound conjugate and a lipophilic insulin compound conjugate.

146. The complex of claim 1 provided as a component of a co-crystal comprising a hydrophilic insulin compound conjugate and an unconjugated insulin compound.

147. The complex of claim 1 provided as a component of a co-crystal comprising HIM2 crystallized together with an unconjugated insulin compound.

148. The complex of claim 1 provided as a component of a co-crystal comprising IN105 crystallized together with an unconjugated insulin compound.

149. The complex of claim 1 provided as a component of a co-crystal comprising HIM2 crystallized together with IN105.

150. The complex of claim 1 provided as a component of a co-crystal comprising HIM2 crystallized together with insulin compound and IN105.

151. A co-crystal comprising the complex of claim 1 and having a extended profile.

152. The complex of claim 1 further comprising a complexing agent.

153. The complex of claim 152 where the complexing agent is selected from the group consisting of protamines, surfen, globin proteins, spernine, spermidine albumin, amino acids, carboxyllic acids, polycationic polymer compounds, cationic polypeptides, polylysine, anionic polypeptides, nucleotides, and antisense.

154. The complex of claim 1 substantially devoid of protamine.

155. The complex of claim 1 in the form of a solid.

156. A composition comprising the complex of claim 155 in the form of a crystalline solid.

157. A composition comprising the complex of claim 155 in the form of rod shaped crystal.

158. A composition comprising the complex of claim 155 in the form of a crystal having irregular morphology.

159. A composition comprising the complex of claim 155 in the form of a crystals having an averege diameter ranging from about 0.5 to about 40 μ

m.

160. A composition comprising the complex of claim 155 in the form of crystals having a morphology as shown in FIG. 1, 2, 3, 4 or 5.

161. A composition comprising the complex of claim 155 in the form of a dry solid.

162. A composition comprising the complex of claim 155 in the form of a mixture of amorphous and crystalline solids.

163. A composition comprising the complex of claim 155 in the form of a substantially pure powder.

164. A composition comprising the complex of claim 155 in the form of a powder comprising a cation-insulin compound conjugate solid and one or more additional pharmaceutically acceptable components.

165. A composition comprising the complex of claim 155 as an undissolved component of a liquid.

166. A composition comprising the complex of claim 155 as a precipitate in a liquid.

167. A composition comprising the complex of claim 155 as a component of a suspension, emulsion or microemulsion.

168. The complex of claim 155 where in a dried state, the solid comprises:

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

(b) from about 0.05 to about 4% w/w Zn⁺⁺.

169. The complex of claim 155 where in a dried state, the solid comprises:

(a) greater than about 91% w/w insulin compound conjugate,

(b) from about 0.3 to about 4% w/w Zn<sup>−

+</sup>, and

(c) from about 0.2 to about 5% w/w phenol.

170. The complex of claim 155 where in a dried state, the solid comprises:

(a) greater than about 82% w/w insulin compound conjugate,

(b) from about 0.5 to about 4% w/w Zn⁺⁺, and

(c) from about 0.2 to about 14% w/w protamine.

171. The complex of claim 155 where in a dried state, the solid comprises:

(a) greater than about 71% w/w insulin compound conjugate,

(b) from about 0.5 to about 4% w/w Zn⁺⁺,

(c) from about 0.2 to about 14% w/w protamine, and

(d) from about 0.2 to about 15% w/w phenol.

172. The complex of claim 155 where in a dried state, the solid comprises:

(a) from about 0.1 to about 2% w/w Zn⁺⁺, and

(b) from about 0.08 to about 1% w/w phenol.

173. The complex of claim 155 where in a dried state, the solid comprises:

(a) from about 0.5 to about 1.3% w/w Zn⁺⁺,

(b) from about 0.1 to about 0.7% w/w phenol.

174. The complex of claim 155 where in a dried state, the solid comprises:

(a) from greater than or equal to 1 to about 3.5% w/w Zn⁺⁺, and

(b) from about 0.1 to about 3% w/w phenol.

175. The complex of claim 155 where in a dried state, the solid comprises:

(a) from greater than or equal to 1.3 to about 2.2% w/w Zn⁺⁺, and

(b) from about 0.4 to about 2% w/w phenol.

176. The complex of claim 155 where the solid is greater than about 90, 95, or 99% crystalline.

177. The complex of claim 155 where the solid is greater than about 90, 95, or 99% amorphous.

178. The complex of claim 155 where the solid comprises a mixture of amorphous solids and crystalline solids.

179. The complex of claim 155 where the solid comprises conjugated and unconjugated insulin compounds.

180. A pharmaceutical composition comprising the complex of claim 155.

181. The pharmaceutical composition of claim 180 where the complex comprises a solid present in a liquid.

182. The pharmaceutical composition of claim 181 where the solid is present in a buffer.

183. The pharmaceutical composition of claim 180 further comprising a stabilizing agent.

184. The pharmaceutical composition of claim 183 where the stabilizing agent is a phenolic compound.

185. The pharmaceutical composition of claim 183 where the stabilizing agent is selected from the group consisting of phenol, m-cresol and paraben.

188. A method of treatment comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a complex of claim 1.

189. The method of claim 188 where the subject is a diabetic.

190. The method of claim 188 where the composition is administered by a route selected from the group consisting of oral, oral ingestion, parenteral, buccal, sublingual, nasal, inhalation and transdermal.

191. The method of claim 188 where the composition is administered as a component of a pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, oral ingestion, parenteral, buccal, sublingual, nasal, inhalation and transdermal.

192. A pharmaceutical composition comprising the composition of claim 1 and a carrier.

193. The pharmaceutical composition of claim 192 formulated for administration by a route selected from the group consisting of oral, oral ingestion, parenteral, buccal, sublingual, nasal, inhalation and transdermal.

194. The pharmaceutical composition of claim 192 formulated in a form selected from the group consisting of solid dosage form, suspension, and film.

186. A method of making a cation-insulin compound conjugate complex, the method comprising combining in an aqueous solution an insulin compound conjugate and a cation.

187. The method of claim 186 where the aqueous solution comprises an organic solvent dissolved therein.