Dosage form development, in vitro release kinetics, and in vitro-in vivo correlation for leuprolide released from an implantable multi-reservoir array.
OBJECTIVE
Implanted multi-reservoir arrays improve dosing control relative to osmotic pumps or polymer depots. The limited reservoir volume requires concentrated formulations. This report describes the development of a stable solid phase formulation of leuprolide acetate for chronic in vivo delivery from a multi-reservoir microchip and examines the correlation between in vitro release kinetics and serum pharmacokinetics.


METHODS
Concentrated formulations (>10% w/v) were prepared using small volume processing methods. Drug yield, release kinetics, and formulation stability were evaluated in vitro by HPLC. The correlation between in vitro and in vivo kinetic data was determined for a solid formulation by direct comparison of data sets and using absorption kinetics calculated from the Wagner-Nelson equation.


RESULTS
High yield and the control of release kinetics by altering peptide formulation or reservoir geometry were demonstrated. Lyophilized leuprolide in a soluble solid matrix exhibited reproducible release kinetics and was stable (>95% leuprolide monomer) after 6 months at 37 degrees C. A strong correlation was found between in vitro release kinetics and in vivo absorption by direct comparison of data sets and using the Wagner-Nelson absorption (slopes of 1.01 and 0.91; R(2) 0.99).


CONCLUSIONS
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.
Prescott
James H
JH
MicroCHIPS Inc, 6-B Preston Court, Bedford, MA, 01730 USA. jprescott@mchips.com
Krieger
Timothy J
TJ
Lipka
Sara
S
Staples
Mark A
MA
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004339:Drug Compounding; D004343:Drug Implants; D004355:Drug Stability; D004356:Drug Storage; D007700:Kinetics; D016729:Leuprolide / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D008954:Models, Biological; D008956:Models, Chemical; D011092:Polyethylene Glycols / Q000737:chemistry; D015203:Reproducibility of Results; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000295:instrumentation; D013696:Temperature
D018931:Antineoplastic Agents, Hormonal; D004343:Drug Implants; D011092:Polyethylene Glycols; D016729:Leuprolide