Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536-0082, USA.
Priyanka
P
Ghosh
DoMin
D
Lee
Kyung Bo
KB
Kim
Audra L
AL
Stinchcomb
D000279:Administration, Cutaneous; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D004008:Diclofenac / Q000008:administration & dosage* / Q000145:classification*; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D009271:Naltrexone / Q000008:administration & dosage* / Q000737:chemistry*; D009339:Needles; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000502:physiology; D012995:Solubility; D013552:Swine
D003692:Delayed-Action Preparations; D004008:Diclofenac; D011092:Polyethylene Glycols; D009271:Naltrexone