Simultaneous Transdermal Delivery of Buprenorphine Hydrochloride and Naltrexone Hydrochloride by Iontophoresis

Abstract

The opioids buprenorphine hydrochloride (BUP) and naltrexone hydrochloride (NTX) show promise as a combination treatment for addiction, but no means of delivering the two compounds in one medicine currently exist. In this paper, we report sufficient input rates of both these drugs from one iontophoretic transdermal drug delivery system. Experiments were performed using dermatomed pig skin mounted in glass side-bi-side cells. BUP and NTX were iontophoretically delivered together from the anode using direct constant current from Ag/AgCl electrodes. The transdermal drug fluxes and the masses of drugs in both the stratum corneum and the underlying epidermis/dermis were measured. The apparent electroosmotic flow was quantified using a neutral marker (acetaminophen). The effects of donor composition (drug concentration/molar fraction and pH), current density and profile, and the choice of receptor solution were assessed. Iontophoresis dramatically increased the flux of both drugs compared to passive control values. Target fluxes (calculated from literature clearance values and required therapeutic plasma concentrations) were greatly exceeded for NTX and were met for BUP. The latter accumulated in the skin and suppressed electroosmotic flow, inhibiting both its own flux and that of NTX. NTX, in turn, negatively influenced the flux of BUP via co-ion competition. Lowering current density by increasing the delivery area resulted in increased electroosmotic flow but did not significantly affect current-normalized drug fluxes. Delivering the drugs from both electrodes and reversing the polarity for every 2 h did not increase the flux of either compound. In summary, during iontophoresis, BUP and NTX inhibited each other’s flux by two distinct mechanisms. While the more complex behavior of BUP complicates the optimization of this drug combination, iontophoresis nevertheless appears to be a feasible approach for the controlled codelivery of NTX and BUP through the skin.

Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula

“…The skin permeation rate was measured using a horizontal diffusion cell (PermeGear). 21 , 22 All test compounds were dissolved in 3.84 mM isopropyl myristate. We used the β2 adrenergic receptor agonist tulobuterol as a percutaneous positive control.…”

A Snapshot of Transdermal and Topical Drug Delivery Research in Canada

“…By passing an electrical current through the skin, this technique serves to enhance skin permeability, as well as allow positively charged compounds to be transported into the skin by the resulting electric field. Though various groups are developing iontophoresis-based transdermal delivery methods for both small molecule- and peptide-based drugs [100,101], the topic is seemingly not undergoing active research within Canada.…”

Electrically controlled transdermal delivery of naproxen and indomethacin from porous cis‐1,4‐polyisoprene matrix

“…An electric current (typically <0.5 mA/cm 2 ) is applied on the skin to drive the charged molecule by the electrophoresis force, along with the resulting electroosmotic flow from ions in the solvent 3 . Recent study on the iontophoresis drug delivery have clearly demonstrated the effectiveness and the advantages of this technique 4‐12 …”