Insoluble compositions for controlling blood glucose
First Claim
1. An insoluble composition, comprising:
- a) a protein selected from the group consisting of insulin, insulin analog, and proinsulin;
b) a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analog, and derivatized proinsulin;
c) a complexing compound;
d) a hexamer-stabilizing compound; and
e) a divalent metal cation.
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Abstract
The present invention relates to insoluble compositions comprising a protein selected from the group consisting of insulin, insulin analogs, and proinsulins; a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analog, and derivatized proinsulin; a complexing compound; a hexamer-stabilizing compound; and a divalent metal cation. Formulations of the insoluble composition are suitable for both parenteral and non-parenteral delivery for treating hyperglycemia and diabetes. Microcrystal forms of the insoluble precipitate are pharmaceutically analogous to the neutral protamine Hagedorn (NPH) insulin crystal form. Surprisingly, it has been discovered that suspension formulations of such insoluble compositions possess unique and controllable dissolution properties that provide therapeutically advantageous glucodynamics compared with insulin NPH formulations.
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Citations
83 Claims
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1. An insoluble composition, comprising:
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a) a protein selected from the group consisting of insulin, insulin analog, and proinsulin;
b) a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analog, and derivatized proinsulin;
c) a complexing compound;
d) a hexamer-stabilizing compound; and
e) a divalent metal cation. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 73, 74, 75, 76, 77, 78, 79, 80, 81)
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71. A hybrid hexamer composition, comprising six monomers and zinc, wherein at least one monomer is selected from the group consisting of insulin, insulin analogs, and proinsulins, and at least one monomer is selected from the group consisting of derivatized insulin, derivatized insulin analogs, and derivatized proinsulins.
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72. A mixed hexamer composition, comprising zinc protein hexamers and zinc derivatized protein hexamers, wherein the zinc protein hexamers comprise zinc and a protein selected from the group consisting of insulin, insulin analogs, and proinsulins, and wherein the zinc derivatized protein hexamers comprise zinc and a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analogs, and derivatized proinsulins.
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82. A process for preparing hybrid hexamers, comprising dissolving a protein, a derivatized protein, a hexamer-stabilizing compound, and a divalent metal cation in an aqueous solvent having a pH that will permit the formation of hexamers.
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83. A process for preparing hybrid hexamers, comprising:
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a) dissolving a protein, a derivatized protein, a hexamer-stabilizing compound, and a divalent metal cation in an aqueous solvent having a pH that will not permit the formation of hexamers, and b) adjusting the pH to between about 6.8 and about 7.8.
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Specification