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

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.

Fig. 1

Microneedle array with 5 MN array for in vitro studies and 50 MN array for in vivo studies and applicator for 5 MN array(left panel), Yucatan miniature pig skin before treatment and following treatment with gentian violet for pore visualization (right panel).

Fig. 2

Structures of NTX/NTXol and DIC codrugs.

Fig. 3

Structures of intermediates for codrug synthesis. NMR data for intermediates are provided in Supplementary Material.

Fig. 4

Stability of NTX/DIC codrugs in 0.3 M acetate buffer pH 5.0. Data analyzed using pseudo first-order kinetics. n=3 for all codrugs.

Fig. 5

Flux of NTX/NTXol and skin concentration of parent drugs and codrugs. n≥3 for all studies. Flux of NTX from codrug I and codrug III are not significantly different (p>0.05) and they are higher than NTXol flux from codrug II and codrug IV (p<0.05). Skin concentration of NTX and codrug are not significantly different for I and III (p>0.05). Skin concentration of DIC is significantly different (p<0.05).

Fig. 6

Flux and skin concentration from codrug III and codrug III salt. n≥;3 for all studies. Flux of NTX was significantly higher (p<0.05). No significant difference in skin concentration except for codrug (p>0.05).