Physical Stability of Insulin Formulations
The physical stability of insulin formulations is mediated by noncovalent aggregation of insulin. Hydrophobic forces typically drive the aggregation although electrostatics plays a subtle but important role. Aggregation typically leads to a loss in potency of the formulation, and therefore should be avoided. Extreme aggregation may lead to the formation of fibrils of insulin. The physical stability of insulin formulations is readily assessed by visual observation for macroscopic characteristics as well as by instrumental methods such as light and differential phase contrast microscopy. Various particle-sizing techniques also may be used to characterize microscopic phenomena.
In general, insulin solutions have good physical stability. Physical changes in soluble formula-tions may be manifested as color or clarity change or, in extreme situations, the formation of a precipitate. Insulin suspensions, such as NPH or Lente, are the most susceptible to changes in physical stability. These typically occur as a result of both elevated temperature and mechanical stress to the suspension. The increase in temperature favors hydrophobic interactions, while mechanical agitation serves to provide mixing and stress across interfacial boundaries. Nucleation of aggregation in suspensions can lead to conditions described as visible clumping of the suspension or “frosting” of the glass wall of the insulin vial by aggregates. In severe cases, resuspension may be nearly impossi-ble because of caking of the suspension in the vial. Temperatures above normal ambient (> 25LC) can accelerate the aggregation process, especially those at or above body temperature (37LC). Normal mechanical mixing of suspensions prior to administration is not deleterious to physical stability. However, vigorous shaking or mixing should be avoided. Consequently, this latter constraint has, in part, led to the observation that patients do not place enough effort into resuspension. Thus, proper emphasis must be placed on training the patient in resuspension of crystalline, amorphous, and pre-mixed formulations of insulin and insulin analogs. The necessity of rigorous resuspension may be the first sign of aggregation and should prompt a careful examination of the formulation to verify its suitability for use.
As with the chemical stability data, information regarding the physical
stability of the newer insulin analog formulations containing insulin lispro,
insulin aspart, insulin glulisine, insulin glargine, or insulin detemir, have
yet to be published. However, it is reasonable to assume that similar
constraints regarding extreme agitation and thermal excursions should be
avoided to minimize undesirable physicaltransformations such as precipitation,
aggregation, gelation, or fibrillation.