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

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 syn...

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Bibliographic Details
Published in:	Pharmaceutical research Vol. 30; no. 1; pp. 247 - 256
Main Authors:	Ward, Brent B., Huang, Baohua, Desai, Ankur, Cheng, Xue-Min, Vartanian, Mark, Zong, Hong, Shi, Xiangyang, Thomas, Thommey P., Kotlyar, Alina E., Van Der Spek, Abraham, Leroueil, Pascale R., Baker, James R.
Format:	Journal Article
Language:	English
Published:	Boston Springer US 01-01-2013 Springer Springer Nature B.V
Subjects:	Analgesics Analgesics, Opioid - administration & dosage Analgesics, Opioid - chemistry Analgesics, Opioid - therapeutic use Animals Biochemistry Biological and medical sciences Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Delayed-Action Preparations - chemistry Dendrimers - chemistry General pharmacology Guinea Pigs Male Medical Law Medical sciences Morphine - administration & dosage Morphine - chemistry Morphine - therapeutic use Narcotics Pain - drug therapy Pain management Pharmaceutical sciences Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Pharmacology/Toxicology Pharmacy Prodrugs - administration & dosage Prodrugs - chemistry Prodrugs - therapeutic use Rats Rats, Sprague-Dawley Research Paper Solubility sustained release dendrimer pain control morphine Pharmaceutical technology Branched polymer Enzyme Controlled release form Opiates Morphine Esterases Prodrug Narcotic analgesic Analgesia In vivo Pain Dosage form Hydrolases Dendritic structure
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0724-8741 1573-904X
DOI:	10.1007/s11095-012-0869-3