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Optimization of Naltrexone Diclofenac Codrugs for Sustained Drug Delivery Across Microneedle-Treated Skin

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ABSTRACT

Purpose

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.

Conclusion

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.

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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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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536-0082, USA

    Priyanka Ghosh, DoMin Lee, Kyung Bo Kim & Audra L. Stinchcomb

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N. Pine St., Baltimore, Maryland, 21201, USA

    Priyanka Ghosh & Audra L. Stinchcomb

  3. AllTranz, Inc., Lexington, USA

    Audra L. Stinchcomb

Authors
  1. Priyanka Ghosh
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  2. DoMin Lee
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  3. Kyung Bo Kim
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  4. Audra L. Stinchcomb
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Corresponding author

Correspondence to Audra L. Stinchcomb.

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Ghosh, P., Lee, D., Kim, K.B. et al. Optimization of Naltrexone Diclofenac Codrugs for Sustained Drug Delivery Across Microneedle-Treated Skin. Pharm Res 31, 148–159 (2014). https://doi.org/10.1007/s11095-013-1147-8

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  • DOI: https://doi.org/10.1007/s11095-013-1147-8

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