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

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Abstract

Purpose

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.

Materials and 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°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; R2 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.

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Abbreviations

DMSO:

dimethylsulfoxide

IVIVC:

in vitro–in vivo correlation

PEG:

polyethylene glycol

PK:

pharmacokinetic

RSD:

relative standard deviation

SD:

standard deviation

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Acknowledgements

We would like to thank all members of the MicroCHIPS team that supported this work. Special recognition is given to David Brancazio, David Lanteigne, Christina Pelta, and Michael Shannon for their contributions.

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Authors and Affiliations

  1. MicroCHIPS, Inc., 6-B Preston Court, Bedford, Massachusetts, 01730, USA

    James H. Prescott, Timothy J. Krieger, Sara Lipka & Mark A. Staples

Authors
  1. James H. Prescott
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  2. Timothy J. Krieger
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  3. Sara Lipka
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  4. Mark A. Staples
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Correspondence to James H. Prescott.

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Prescott, J.H., Krieger, T.J., Lipka, S. et al. Dosage Form Development, in Vitro Release Kinetics, and in Vitro–in Vivo Correlation for Leuprolide Released from an Implantable Multi-reservoir Array. Pharm Res 24, 1252–1261 (2007). https://doi.org/10.1007/s11095-007-9243-2

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  • DOI: https://doi.org/10.1007/s11095-007-9243-2

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