Sustained analgesia achieved through esterase-activated morphine prodrugs complexed with PAMAM dendrimer.
OBJECTIVE
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).


CONCLUSIONS
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.
Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA. bward@umich.edu
Brent B
BB
Ward
Baohua
B
Huang
Ankur
A
Desai
Xue-Min
XM
Cheng
Mark
M
Vartanian
Hong
H
Zong
Xiangyang
X
Shi
Thommey P
TP
Thomas
Alina E
AE
Kotlyar
Abraham
A
Van Der Spek
Pascale R
PR
Leroueil
James R
JR
Baker
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry*; D006168:Guinea Pigs; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D050091:Dendrimers; C104700:PAMAM Starburst; D011355:Prodrugs; D009020:Morphine