Title:  Insoluble compositions for controlling blood glucose

United States Patent:  6,531,448

Issued:  March 11, 2003

Inventors:  Brader; Mark Laurence (Indianapolis, IN)

Assignee:  Eli Lilly and Company (Indianapolis, IN)

Appl. No.:  217275

Filed:  December 21, 1998

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.

SUMMARY OF THE INVENTION

Accordingly, in its broadest aspect, the present invention provides insoluble compositions comprising a derivatized protein selected from the group consisting of insulin derivatives, insulin analog derivatives, and proinsulin derivatives, a protein selected from the group consisting of insulin, insulin analogs, and proinsulins, a complexing compound, a hexamer-stabilizing compound, and a divalent metal cation. The derivatized protein is either less soluble in an aqueous solvent than is the un-derivatized protein, is more lipophilic than un-derivatized insulin, or produces a complex with zinc and protamine that is less soluble than the corresponding complex with the un-derivatized protein. The insoluble compositions of the present invention may be in the form of amorphous precipitates, or more preferably, in the form of microcrystals. The microcrystals may be either rod-shaped or irregular in morphology. These insoluble compositions are useful for treating diabetes and hyperglycemia, and provide the advantages of having flatter and longer time action than NPH insulin. The insoluble compositions are mixable in a formulation with soluble protein or with soluble derivatized protein, or both. Furthermore, by varying the ratio between protein and derivatized protein, the extent of protraction of the time action can be finely controlled over a very great range of time-action, from that nearly the same as NPH insulin to much greater than that of NPH insulin.

More specifically, the present invention provides insoluble compositions of proteins and fatty acid-acylated proteins that are useful for treating diabetes and hyperglycemia. These compositions are comprised of fatty acid-acylated protein selected from the group consisting of fatty acid-acylated insulin, fatty acid-acylated insulin analog, and fatty acid-acylated proinsulin, protein selected from the group consisting of insulin, insulin analogs, and proinsulin, protamine, a phenolic preservative, and zinc. The present invention is distinct from previous fatty acid-acylated insulin technology in that the extension of time action of the present invention does not rely necessarily on albumin-binding, though albumin binding may further protract the time action of certain of the compositions of the present invention.

The invention provides a microcrystal comprising a protein selected from the group consisting of insulin, insulin analog, and proinsulin, a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analog, and derivatized proinsulin, a complexing compound a divalent metal cation, and a hexamer-stabilizing compound. The microcrystals of the present invention are useful for treating diabetes and for controlling blood glucose in a patient in need thereof.

The invention provides an amorphous precipitate comprising a protein selected from the group consisting of insulin, insulin analog, and proinsulin; a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analog, and derivatized proinsulin, a complexing compound a divalent metal cation, and a hexamer-stabilizing compound. The amorphous precipitates of the present invention are useful for treating diabetes and for controlling blood glucose in a patient in need thereof. They are also useful as intermediates in the formation of the microcrystals of the present invention.

The invention provides aqueous suspension formulations comprising an insoluble composition and an aqueous solvent. One such aqueous suspension formulation is comprised of a microcrystalline composition of the present invention and an aqueous solvent. Another such aqueous suspension formulation comprises an amorphous precipitate of the present invention and an aqueous solvent. The soluble, aqueous phase of the present suspension formulations may optionally be comprised of a protein, such as human insulin, or a soluble analog of human insulin, such as a monomeric insulin analog, that control blood glucose immediately following a meal, and may additionally or alternatively be comprised of a derivatized protein. The formulations of the present invention have superior pharmacodynamics compared with human insulin NPH, and their time-action can be purposefully selected over a wide range, from just slightly extended compared with human insulin NPH to very greatly extended compared with human insulin NPH.

The invention also provides processes for preparing hybrid hexamers, mixed hexamers, the amorphous precipitates, and the co-crystals of the present invention,

The invention provides a method of treating diabetes or hyperglycemia comprising, administering to a patient in need thereof a sufficient quantity of an insoluble composition of the present invention to regulate blood glucose levels in the patient.

The invention includes hybrid hexamer compositions comprising a protein selected from the group consisting of insulin, insulin analog, and proinsulin; a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analogs, and derivatized proinsulins, and zinc. The hybrid hexamers of the present invention are useful for treating diabetes and for controlling blood glucose in a patient in need thereof. They are also useful as intermediates in the formation of the insoluble compositions of the present invention, which are themselves useful for treating diabetes and for controlling blood glucose in a patient in need thereof. Hybrid hexamers are believed to be formed when a protein and a derivatized protein are first mixed together under conditions that strongly favor dissolution into lower states of aggregation than the hexameric state, and second, the conditions are changed to strongly favor the hexameric aggregation state.

The invention includes mixed hexamer compositions, comprised zinc hexamers of a protein selected from the group consisting of insulin, an insulin analog, or proinsulin and zinc hexamers of a derivatized protein selected from the group consisting of a derivatized insulin, derivatized insulin analog, or a derivatized proinsulin. The mixed hexamers of the present invention are useful for treating diabetes and for controlling blood glucose in a patient in need thereof. They are also useful as intermediates in the formation of the insoluble compositions of the present invention, which are themselves useful for treating diabetes and for controlling blood glucose in a patient in need thereof. Mixed hexamers are believed to be formed when a protein and a derivatized protein are first separately dissolved under conditions that favor the hexameric aggregation state, and then are mixed together under conditions that continue to strongly favor the hexameric aggregation state.

Claim 1 of 47 Claims

I 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 fatty acid-acylated insulin, fatty acid-acylated insulin analogs, and fatty acid acylated proinsulins;

c) a complexing compound;

d) a hexamer-stabilizing compound; and

e) a divalent metal cation.
 

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