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
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.