Optimization of Naltrexone Diclofenac Codrugs for Sustained Drug Delivery Across Microneedle-Treated Skin
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The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone.
Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship.
The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement.
The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.
KEY WORDScodrugs drug delivery microneedle stability transdermal
ACKNOWLEDGMENTS AND DISCLOSURES
We would like to acknowledge Dr. Mark Prausnitz and Dr. Vladimir Zarnitsyn at the Georgia Institute of Technology for their expert advice and assistance with the MN arrays. This work was funded by NIH grant R01DA13425 and R42DA32191. Additional funding sources included the University of Kentucky Center for Drug Abuse Research Translation (CDART.)
Audra L. Stinchcomb is a significant shareholder in and Chief Scientific Officer of AllTranz Inc., a specialty pharmaceutical company involved in the development of transdermal formulations for MN delivery.
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