Dosage Form Development, in Vitro Release Kinetics, and in Vitro–in Vivo Correlation for Leuprolide Released from an Implantable Multi-reservoir Array

Abstract

Reproducible releases of a stable solid leuprolide formulation from a multi-reservoir microchip were achieved in vitro. Chronic pulsatile release was subsequently performed in vivo. Comparison of in vitro and in vivo data reveals that pharmacokinetics were controlled by the rate of release from the device.

Reservoir-based drug delivery systems utilizing microtechnology

“…The fully assembled devices included a drug filled array, microprocessor, implantable battery, and wireless antenna in a titanium housing that measured 4.5 × 5.5 × 1 cm 3 with a volume of ~ 30 ml. Initial studies with leuprolide formulated at 100 mg/ml and filled into 300 nl reservoirs showed good stability and an excellent in vitro-in vivo release rate correlation [98]. Similarly, an osteoporosis implant delivering pulsatile parathyroid hormone (PTH) was formulated at 500 mg/ml (~ 20 μg PTH/reservoir) and demonstrated good stability after 6 months at 37°C (Fig.…”

Long-term Stability and in vitro Release of hPTH(1–34) from a Multi-reservoir Array

“…In previous studies, a high leuprolide concentration formulation used in combination with a similar multi-reservoir device demonstrated very good in vitro-in vivo correlation, indicating that the rate limitation for delivery is the solubility and diffusion of the formulation from the reservoir (21). The rapid, pulsatile in vitro release data presented here for hPTH suggests similar (desirable) pharmacokinetics may be observed in vivo, but in vivo experiments have not yet been performed.…”

“…Each array contains 24 reservoirs with a volumetric capacity of 300 nL per reservoir (21). Individual reservoirs of the multi-reservoir array were filled with 200 nL of the concentrated hPTH(1-34) solution(s) using an automated dispensing apparatus.…”

“…Individual reservoirs of the multi-reservoir array were filled with 200 nL of the concentrated hPTH(1-34) solution(s) using an automated dispensing apparatus. The dispensing apparatus, which has been described previously, provides accurate and precise delivery of nanoliter volumes (21). After each reservoir array was filled, the contents were frozen and lyophilized, using the previously described lyophilization cycle.…”

“…In vitro release experiments were performed as described previously (21). Multi-reservoir arrays containing discrete doses of hPTH(1-34) were mounted in in vitro test devices and stored at 37˚C.…”