Protein-surface interactions in drug delivery systems

The successful, long-term delivery of therapeutic proteins via continuous infusion depends on the maintenance of biological activity in the delivery device environment. The efficacy of a recombinant-based biologic therapy program may be greatly impaired due to the interactions between the therapeutic protein and the drug delivery device surfaces. Activity losses can occur by several mechanisms including direct removal by irreversible adsorption; reversible, denaturing adsorption; surface-mediated aggregation phenomena and chemical instability.; In this work, we have addressed the surface-related activity losses associated with the delivery of commercial formulations of interleukin-2 (IL-2) with a portable pump and a silicone rubber catheter tubing at 37{dollar}spcirc{dollar}C. We monitored both the concentration and biological activity of delivered IL-2 over a 24 hour period under actual clinical infusion conditions. We found rapid, tenfold losses in delivered IL-2 activity. Irreversible adsorption to the catheter tubing could only account for a portion of these losses; the balance of these losses were attributed to transient surface interaction phenomena. Corroborating evidence for reversible, denaturing adsorption on the catheter tubing was obtained from an analysis of the structure of delivered IL-2 via circular dichroism (CD) and fluorescence spectroscopy and an analysis of the amount and structure of adsorbed IL-2 via Fourier transform infrared (FTIR) spectroscopy. The experimental results were used to formulate a simple mechanistic model for IL-2 adsorption.; However, much of protein formulation design is directed towards the minimization of adsorptive protein losses and protein aggregation rather than the maintenance of biological activity upon delivery. Commonly applied strategies for interface-related protein stabilization has traditionally relied either on the surface passivation with excipients, such as human serum albumin (hSA), and surfactants, such as sodium dodecyl sulfate and Tween-20, or on the stabilization of the native protein structure in the solution phase by excipient-mediated excluded volume phenomena.; We investigated strategies for mitigating the biological activity losses by examining the interactions between IL-2 and such excipients that are currently employed in commercial formulations to combat surface adsorption phenomena. These excipients include representative members of the ionic, non-ionic and polymeric surfactant groups. After we examined the effect of these cosolvents on the stability of IL-2 in solution at elevated temperatures, we assessed their effectiveness in mitigating surface-induced denaturation phenomena and in preserving the activity of IL-2 during pump-based continuous infusion. Our results indicated that both ionic (SDS) and non-ionic surfactants (Tween-20) can effectively stabilize IL-2 during delivery. In contrast, polymeric surfactants (Pluronics) destabilize IL-2 and reduce the active delivery profile. Further, polyethylene glycol (PEG), under binding as well as excluded volume conditions, was found to diminish the biological activity of delivered IL-2.