Coupling the in vivo performance to the in vitro characterization of PLGA microparticles

Abstract

The main objective of the study was to determine if rodent housing conditions, specifically housing climate, could impact the in vivo performance of poly(lactide-co-glycolide) (PLGA) microspheres through temperature modification of the subcutaneous space. Vivitrol®, a once monthly naltrexone injectable suspension, was chosen as a model PLGA microparticle formulation for this study. Two lots of Vivitrol were used to ascertain any potential differences that may exist between the batches and if in vitro characterization techniques could delineate any variation(s). The pharmacokinetics of the naltrexone-PLGA microparticles were determined in the rodent model under two different housing climates (20 vs. 25 °C). The results demonstrate that such difference in housing temperature resulted in a change in subcutaneous temperature but actually within a narrow range (36.31-36.77 °C) and thus minimally influenced the in vivo performance of subcutaneously injected microparticles. The shake-flask method was used to characterize the in vitro release at 35, 36, and 37 °C and demonstrated significant differences in the in vitro release profiles across this range of temperatures. Minimal differences in the in vitro characterization of the two lots were found. While these results did not provide statistical significance, the local in vivo temperature may be a parameter that should be considered when evaluating microparticle performance. The IVIVCs demonstrate that in vitro release at 37 °C may not accurately represent the in vivo conditions (i.e., subcutaneous space in rodents), and in certain instances lower in vitro release temperatures may more accurately represent the in vivo microenvironment and provide better correlations. Future studies will determine the extent temperature and specifically co-housing, may have on the relative impact of the in vivo performance of injectable polymeric microparticles based upon the significant differences observed in the in vitro release profiles across the range of 35-37 °C.

Keywords: In vivo-in vitro correlation; Naltrexone; PLGA microparticles; Pharmacokinetics; Vivitrol.

Fig. 1.

Naltrexone in vitro release profiles at 35, 36, and 37 °C via sample and separate method.

Fig. 2.

Pharmacokinetic profile comparison of 1037T and 1052T in cold room (CR) and warm room (WR).

Fig. 3.

Subcutaneous temperature (T_SQ) profile comparison of 1037T and 1052T in cold (CR) and warm room (WR) (top), average of CR compared to WR (middle), and average temperatures of rodents housed in the cold room vs warm room (bottom).

Fig. 4.

IVIVC for Vivitrol lots 1037 T (left) and 1052 T (right).

Fig. 5.

Diffraction patterns of 1037T and 1052T.

Fig. 6.

Vivitrol morphology of two different lots, 1037T (left) and 1052T (right).

Fig. 7.

Vivitrol internal morphology of lot 1052T illustrating network structure and drug distribution. (Yellow arrows point to suspected crystalline naltrexone dispersed in PLGA matrix).