Research Paper

Pharmaceutical Research

, Volume 30, Issue 1, pp 247-256

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

  • Brent B. WardAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of MichiganOral and Maxillofacial Surgery, University of Michigan Email author 
  • , Baohua HuangAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
  • , Ankur DesaiAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
  • , Xue-Min ChengAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
  • , Mark VartanianAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
  • , Hong ZongAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
  • , Xiangyang ShiAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
  • , Thommey P. ThomasAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
  • , Alina E. KotlyarAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
    • , Abraham Van Der SpekAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
    • , Pascale R. LeroueilAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan
    • , James R. BakerJrAffiliated withMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan

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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.

KEY WORDS

dendrimer in vivo morphine pain control sustained release