SUSTAINED-RELEASE INTERLEUKIN-2 FOLLOWING INTRAMUSCULAR INJECTION IN RATS

A potential sustained-release recombinant interleukin-2 (rIL-2) formulation was evaluated following intramuscular (i.m.) injection in rats. Poloxamer 407 (Pluronic(R) F-127) is a block copolymer comprised of polyoxyethylene and polyoxypropylene segments which exhibits the property of reverse thermal gelation. Thus, an rIL-2/poloxamer 407 preparation was injected i.m. in rats as a viscous mobile solution with subsequent gelation in vivo. Resultant plasma rIL-2 concentration-time data indicated absorption rate-limited disposition of rIL-2 following i.m. injection. The mean values of the absorption rate constant (k(a)) were 0.64 +/- 0.073 and 0.21 +/- 0.019 h(-1) following i.m. injection of an rIL-2 aqueous solution and the rIL-2 gel formulation, respectively. The mean values of the elimination rate constant (k(elim)) were 1.76 +/- 0.22 and 1.21 +/- 0.079 h(-1) following administration of rIL-2 as an aqueous solution or gel formulation, respectively. The blood sampling time point at which the greatest plasma rIL-2 concentration (C-max) was observed was 2 h for rats injected i.m. with rIL-2 formulated in poloxamer 407 compared to 1 h for rats injected i.m. with an rIL-2 aqueous solution. The mean value of the C-max was significantly (p < 0.05) less in rats injected i.m. with the rIL-2 gel formulation (C-max = 12500 +/- 1450 pg/ml) compared to rats injected i.m. with an aqueous solution of rIL-2 (C-max = 19600 +/- 2650 pg/ml). The bioavailability of rIL-2 when injected i.m. as an rIL-2/poloxamer gel formulation relative to an i.m. injection of an rIL-2 aqueous solution was approx. 1.0. Cumulative amounts of rIL-2 recovered in the urine 48 h after an i.m. injection of either an rIL-2 aqueous solution or rIL-2 gel formulation were less than 1 percent of the administered dose. Since the rIL-2/poloxamer formulation evaluated in this study resulted in a decrease in the maximum blood concentration of rIL-2 achieved and an increase in the time required to reach a maximum blood concentration, without a reduction in the bioavailability of the protein, the rIL-2 gel formulation may represent an alternative, sustained-release mode of rIL-2 administration.