Flux Across of Microneedle-treated Skin is Increased by Increasing Charge of Naltrexone and Naltrexol In Vitro
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The purpose of this investigation was to evaluate the in vitro microneedle (MN) enhanced percutaneous absorption of naltrexone hydrochloride salt (NTX·HCl) compared to naltrexone base (NTX) in hairless guinea pig skin (GP) and human abdominal skin. In a second set of experiments, permeability of the major active metabolite 6-β-naltrexol base (NTXOL) in the primarily unionized (unprotonated) form at pH 8.5 was compared to the ionized form (pH 4.5).
In vitro fluxes of NTX, NTX·HCl and ionized and unionized NTXOL were measured through microneedle treated or intact full thickness human and GP skin using a flow through diffusion apparatus. Solubility and diffusion samples were analyzed by HPLC.
Both GP and human skin show significant increases in flux when treated with 100 MN insertions as compared to intact full thickness skin when treated with NTX·HCl or ionized NTXOL (pH 4.5; p < 0.05). MN increased GP skin permeability for the hydrophilic HCL salt of NTX by tenfold and decreased lag time by tenfold too. Similar results were found using human skin, such that skin permeability to NTX·HCl was elevated to 7.0 × 10−5 cm/h. Permeability of the primarily unionized (unprotonated) form of NTXOL at pH 8.5 was increased by MN only threefold and lag time was only modestly reduced. However, MN treatment with the primarily ionized (protonated) form of NTXOL at pH 4.5 increased skin permeability fivefold and decreased lag time fourfold.
Enhancement was observed in vitro in both GP and human skin treated with MN compared to intact skin with the salt form of NTX and the ionized form of NTXOL. We conclude that transdermal flux can be optimized by using MN in combination with charged (protonated) drugs that have increased solubility in an aqueous patch reservoir and increased permeability through aqueous pathways created by MN in the skin.
KEY WORDSmicroneedle 6-β-naltrexol naltrexone protonation transdermal
We would like to thank Dr. Mark Allen at Georgia Tech for the use of his microfabrication facilities. This research was supported in part by NIH R01DA13425 and R01EB006369. Human skin was supplied by the National Cancer Institute (NCI) Cooperative Human Tissue Network (CHTN). HSG and MRP are members of the Center for Drug Design, Development and Delivery and the Institute for Bioengineering and Bioscience at Georgia Tech. MRP is the Emerson Lewis Faculty Fellow.
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