In vitro and in vivo transdermal iontophoretic delivery of naloxone, an opioid antagonist

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Abstract

Aim

The feasibility of transdermal delivery of naloxone, an opioid antagonist, by anodal iontophoresis patches using Ag/AgCl electrodes was investigated.

Methods

To examine the effect of current strength, species variation and drug concentration on skin permeability of naloxone, in vitro skin permeation studies were performed using rat dorsal skin and porcine ear skin as the membrane. To determine in vivo transdermal absorption rate of naloxone, the iontophoretic patch system was applied to the dorsal skin of conscious rat with a constant current supply for 24 h.

Results

The in vitro steady-state skin permeation flux of naloxone current-proportionally (0–360 μA/cm2) increased without significant differences between these two different skin types. The in vitro delivery rate through the porcine skin was found to be independent of the concentration of naloxone hydrochloride dehydrate in the donor patch over the range from 1 to 10% (w/v). In the in vivo pharmacokinetic study, plasma concentrations of naloxone steadily increased and sustained steady-state levels from 4 h to 24 h after the initiation of current application. In vivo steady-state transdermal absorption rates at 90 and 180 μA/cm2 were 136 and 305 μg/h/cm2, respectively.

Conclusion

These results suggest that the transdermal delivery rates of naloxone by anodal iontophoresis are sufficient for the management of intoxication in opioid-overdosed patients.

Graphical abstract

Anodal iontophoresis provides sustainable and current-proportional plasma concentrations of naloxone, a short-acting opioid antagonist.

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Introduction

Naloxone is a non-specific, competitive opioid receptor antagonist used for the treatment of opioid-overdose-induced respiratory depression, for the detoxification in opioid-dependent patients (Clarke et al., 2005, van Dorp et al., 2007), and for avoiding opioid-anesthesia-induced respiratory depression in patients treated with high-dose opioid agonists (Johnstone et al., 1974, Takahashi et al., 2004). However, oral formulation is less suitable for naloxone because of its extremely low bioavailability (2%) due to high first-pass effect (Panchagnula et al., 2005, Shibata et al., 2002). The elimination half-life of naloxone in plasma is between 30 and 100 min (Fishman et al., 1973). Since the duration of action of most available opioids exceeds that of naloxone, repeated intravenous or intramuscular administration (0.8–2 mg boluses, repeated as necessary up to 10 mg) and continuous intravenous infusion (4–8 μg/kg/h) have been required to prevent recurrence of respiratory depression in both opioid-overdosed patients and post-operative patients treated with opioid anesthesia (Clarke et al., 2005, Johnstone et al., 1974, Lasagna, 1964, Takahashi et al., 2004, van Dorp et al., 2007).

Iontophoresis, an active transdermal drug delivery technology, non-invasively delivers hydrophilic charged molecules across the skin via application of a small electric current on the skin, enables precise control of drug delivery kinetics according to the modulation of the intensity and duration of current application (Batheja et al., 2006, Dixit et al., 2007, Nair et al., 1999). As results, transdermal iontophoretic drug delivery system offers the potential benefits of simplicity, efficacy and patient acceptance by maintaining a constant blood drug concentration for an extended period of time with acceptable inter-patient variations. Anodal iontophoresis is the method whereby a cationic drug is delivered across an epithelial barrier when placed under a positively charged delivery electrode (anode) from which it is repelled. A counter electrode completes the circuit by drawing physiological anions (i.e. Cl) from the body. Naloxone hydrochloride (Log P = 1.11 at pH 7.4, pKa1 = 7.09, pKa2 = 9.89) is a water-soluble drug and it exists as a cation in aqueous solution at pH 5–6. Hence, anodal iontophoresis is a desirable alternative administration route of naloxone for detoxication in opioid addiction and opioid anesthesia. However, to date there have been no reports regarding transdermal iontophoretic delivery of naloxone.

The aim of the present study is to evaluate the feasibility of transdermal iontophoretic delivery of naloxone using anodal iontophoretic patches in vitro and in vivo. To examine the effect of current strength, species variation and drug concentration on skin permeability of naloxone, in vitro skin permeation studies were performed using rat dorsal skin and porcine ear skin as the membrane. To determine in vivo transdermal absorption rate of naloxone, the iontophoretic patch system was applied to the dorsal skin of conscious rat with a constant current supply for 24 h, and the transdermal absorption rate was determined by a constrained numeric deconvolution method (Fiset et al., 1995, Park et al., 1998, Verotta, 1989).

Section snippets

Chemicals and animals

Naloxone hydrochloride dehydrate (Sigma–Aldrich, Inc., St. Louis, MO, USA) was dissolved in an aqueous solution with 3% (w/v) hydroxypropyl cellulose-H (HPC-H, Nippon Soda Co., Ltd., Tokyo, Japan) for iontophoretic experiments. Buspirone hydrochloride was purchased from LKT Laboratories, Inc. (St. Paul, MN, USA) for use as an internal standard in liquid chromatography tandem mass spectrometry (LC/MS/MS). High-performance liquid chromatography (HPLC) grade acetonitrile and ammonium acetate were

In vitro skin permeation study

Controlling plasma levels of naloxone is crucial in the medication of opioid-overdosed or opioid-dependent patients to avoid serious complications, because a rapid and remarkable elevation in blood levels of naloxone induced by high-dose administration and/or rapid intravenous infusion is supposed to cause catecholamine release and consequent pulmonary edema and cardiac arrhythmias (Clarke et al., 2005, van Dorp et al., 2007). One of benefits of transdermal iontophoresis is controlled drug

Conclusions

In an in vitro skin permeation study, the anodal iontophoretic patch system with constant current supply provided current-proportional transdermal delivery of naloxone with no significant difference between pig and rat skin. The in vitro skin permeation flux was found to be independent of the concentration of naloxone in the donor solution in the absence of competing ions. In an in vivo pharmacokinetic study, all of the systemic exposure, and the steady-state plasma concentration and

Acknowledgements

We would like to thank Mr. Y. Nomoto, Mr. M. Noguchi, Mr. M. Ito, Ms. M. Ishizaka, Mr. O. Yamaguchi, Ms. Y. Itsuzaki, Mr. M. Isshi and Mr. Nakamichi for their skill full technical support in the preparation of the iontophoretic patches, and in vitro and in vivo experiments. We would also acknowledge Dr. G. Smith for his scientific input on the preparation of the manuscript.

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