Development of a Codrug Approach for Sustained Drug Delivery Across Microneedle-Treated Skin

Microneedle (MN) enhanced transdermal drug delivery enables the transport of a host of molecules that cannot be delivered across the skin by passive diffusion alone. However, the skin being a self-regenerating organ heals itself and thus prevents delivery of molecules through micropores for a 7-day...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2013-05, Vol.102 (5), p.1458-1467
Main Authors: Ghosh, Priyanka, Pinninti, Raghotham R., Hammell, Dana C., Paudel, Kalpana S., Stinchcomb, Audra L.
Format: Article
Language:English
Subjects:
Administration, Cutaneous
Animals
codrug
cyclooxygenase inhibitor
Cyclooxygenase Inhibitors - metabolism
Diclofenac - metabolism
Drug Delivery Systems - methods
Guinea Pigs
metabolism
microneedle
naltrexone
Naltrexone - administration & dosage
Naltrexone - blood
Naltrexone - pharmacokinetics
Narcotic Antagonists - administration & dosage
Narcotic Antagonists - blood
Narcotic Antagonists - pharmacokinetics
Needles
permeability
pore closure
preformulation
Skin - drug effects
Skin - metabolism
Skin Absorption - drug effects
stability
Swine
transdermal
Transdermal Patch
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Summary:Microneedle (MN) enhanced transdermal drug delivery enables the transport of a host of molecules that cannot be delivered across the skin by passive diffusion alone. However, the skin being a self-regenerating organ heals itself and thus prevents delivery of molecules through micropores for a 7-day time period, the ideal transdermal delivery goal. Hence, it is necessary to employ a second drug molecule, a cyclooxygenase inhibitor to enhance pore lifetime by decreasing local subclinical inflammatory response following MN treatment. A codrug approach using a 3-O-ester codrug of the model drug naltrexone (NTX) with diclofenac (DIC), a cyclooxygenase inhibitor, was tested in vitro as well as in vivo to look at stability, bioconversion and permeation. The results indicated that the approach could be useful for transdermal drug delivery of NTX from a single patch for a week, but stability and solubility optimization will be required for the codrug before it can deliver significant levels of NTX into the plasma. The skin concentration of DIC was high enough to keep the pores open in vivo in a hairless guinea pig model as demonstrated by day seven pore visualization studies.
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.23469