Stabilization of insulin through ligand binding interations
First Claim
1. A composition comprising insulin hexamers, said hexamers having a T3 R3 or R6 conformation, said conformation stabilized by at least one ligand having a dissociation constant KD of less than about 5 mM, said ligand being selected from the group consisting of aliphatic carboxylic acids or their salts comprising aliphatic acids of at least 5 to 12 carbon atoms and aromatic carboxylic acids or their salts, wherein the aromatic carboxylic acids or their salts comprise at least one aromatic ring selected from the group consisting of phenyl, naphthyl, pyrrolyl imidazolyl, indolyl and 4-oxo-1.4-pyranyl and wherein the aliphatic carboxylic acids or aromatic carboxylic acids can be substituted with hydroxylate anion, thiolate anion, hydroxy, methoxy, amino, alkyl, nitro, or amido groups.
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Abstract
Insulin formulations containing ligands for the insulin hexamer which bind several orders of magnitude more tightly to the hexamer than chlorine ion or acetate ion. These ligands are aliphatic and aromatic carboxylates having a dissociation constant (KD) of less than about 5 mM, and preferably less than about 1 mM. The increased tightness of binding conveys additional stability to the insulin hexamers, improving their usefulness in slow release and fast acting formulations (for example, for the treatment of diabetics).
21 Citations
6 Claims
- 1. A composition comprising insulin hexamers, said hexamers having a T3 R3 or R6 conformation, said conformation stabilized by at least one ligand having a dissociation constant KD of less than about 5 mM, said ligand being selected from the group consisting of aliphatic carboxylic acids or their salts comprising aliphatic acids of at least 5 to 12 carbon atoms and aromatic carboxylic acids or their salts, wherein the aromatic carboxylic acids or their salts comprise at least one aromatic ring selected from the group consisting of phenyl, naphthyl, pyrrolyl imidazolyl, indolyl and 4-oxo-1.4-pyranyl and wherein the aliphatic carboxylic acids or aromatic carboxylic acids can be substituted with hydroxylate anion, thiolate anion, hydroxy, methoxy, amino, alkyl, nitro, or amido groups.
Specification