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Sustained Analgesia Achieved Through Esterase-Activated Morphine Prodrugs Complexed with PAMAM Dendrimer

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ABSTRACT

Purpose

Design and evaluate the in vitro and in vivo efficacy of two extended release morphine formulations developed for IV administration by complexing esterase activated morphine prodrugs to surface-modified, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimer.

Methods

Prodrugs were synthesized, complexed with PAMAM dendrimer, characterized via ultra performance liquid chromatography (UPLC), nuclear magnatic resonance (NMR), and tested in vitro using rat plasma vs. saline control and in an in vivo rat and guinea pig pain model (modified Randall and Selitto test).

Results

We demonstrated that complexation with dendrimer allowed the solubilization of the prodrugs for in vivo applications without the need for salt, and that the structural design of the morphine prodrugs allowed the controlled release of morphine which extended the action of morphine-induced analgesia in an animal pain model from 2 h (control) to 6 h (Morphine Prodrug A).

Conclusion

The concept of complexing/solubilizing appropriately designed esterase-sensitive prodrugs with dendrimer to enhance the sustained release of these drugs may be a useful pharmacokinetic strategy for a range of therapeutics.

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Acknowledgments and Disclosures

This project has been funded in whole or in part with Federal funds from the Defense Advanced Research Projects Agency—DOD, under award W911NF-07-1-0437.

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Authors and Affiliations

  1. Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Brent B. Ward, Baohua Huang, Ankur Desai, Xue-Min Cheng, Mark Vartanian, Hong Zong, Xiangyang Shi, Thommey P. Thomas, Alina E. Kotlyar, Abraham Van Der Spek, Pascale R. Leroueil & James R. Baker Jr

  2. Oral and Maxillofacial Surgery, University of Michigan, TC-B1208, 1500 E. Medical Center Drive, Ann Arbor, Michigan, 48019, USA

    Brent B. Ward

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  1. Brent B. Ward
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  2. Baohua Huang
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  3. Ankur Desai
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Correspondence to Brent B. Ward.

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Ward, B.B., Huang, B., Desai, A. et al. Sustained Analgesia Achieved Through Esterase-Activated Morphine Prodrugs Complexed with PAMAM Dendrimer. Pharm Res 30, 247–256 (2013). https://doi.org/10.1007/s11095-012-0869-3

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  • DOI: https://doi.org/10.1007/s11095-012-0869-3

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