Methods of evaluating protein formulation stability and surfactant-stabilized insulin formulation derived therefrom

Abstract

Embodiments of the invention are directed to a method of estimating the physical stability of a protein formulation. A particular embodiment of the invention places the protein formulation under an agitational stress that causes the protein to aggregate at an accelerated rate. In one embodiment, the change in protein aggregation is monitored spectroscopically using Thioflavin-T. Embodiments of the invention then utilize a survival curve analysis to ascertain the relative physical stability of the different protein formulations under study. This method was used to develop novel surfactant-stabilized insulin formulations in a rapid, cost efficient manner, thus illustrating the utility of the inventive method to the discovery and development of pharmaceutical protein formulations.

1 . An aqueous insulin formulation comprising insulin, a buffer system, an isotonicity agent, a preservative, metal ions, and a non-ionic surfactant selected from at least a polysorbate, a poloxyethylene ether, a polyethylene glycol ether, and mixtures of these surfactants.  
     
     
         2 . The aqueous insulin formulation of  claim 1 , wherein the insulin is human insulin.  
     
     
         3 . The aqueous insulin formulation of  claim 2 , wherein the human insulin is a recombinant insulin.  
     
     
         4 . The aqueous insulin formulation, wherein the preservative is selected from at least phenol, m-cresol and mixture of these preservatives.  
     
     
         5 . An aqueous insulin formulation comprising insulin, a buffer system, an isotonicity agent, a preservative, metal ions and a non-ionic surfactant selected from at least a polysorbate, a poloxyethylene ether, a polyethylene glycol, and mixtures of these surfactants, wherein the insulin formulation exhibits a physical stability that is greater than or equal to the same insulin formulation containing the non-ionic surfactant Genapol PF-10.  
     
     
         6 . The aqueous insulin formulation of  claim 1 , wherein the insulin concentration is about 2 U/ml to about 1000 U/ml.  
     
     
         7 . The aqueous insulin formulation of  claim 6 , wherein the insulin concentration is about 400 U/ml.