Journal of Controlled Release 67 (2000) 1–8 www.elsevier.com / locate / jconrel Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis a b,c, d * K.C. Sung , Jia-You Fang , Oliver Yoa-Pu Hu a Department of Pharmacy, Chia Nan College of Pharmacy and Science, Tainan Hsien, Taiwan b Graduate Institute of Pharmaceutical Sciences, Taipei Medical College, 250 Wu-Hsing Street, Taipei, Taiwan c Research Center for Clinical Pharmacy, Taipei Municipal Wan Fang Hospital, Taipei, Taiwan d School of Pharmacy, National Defense Medical Center, Taipei, Taiwan Received 7 August 1999; accepted 12 November 1999 Abstract The in vitro transport of nalbuphine (NA) and its prodrugs across various skins was investigated in order to assess the effects of prodrug lipophilicity on passive as well as iontophoretic permeation. The passive diffusion of NA and its prodrugs increased with the drug lipophilicity. Iontophoresis significantly increased the transport of NA and its prodrugs; the enhancement ratio was highest for NA and decreased as the drug lipophilicity increased. Measurements using intact and stratum corneum (SC)-stripped skins showed that the SC was the major skin diffusion barrier for the passive permeation of NA and nalbuphine pivalate (NAP). The iontophoretic permeation of NA and NAP across intact and SC-stripped skins indicated that the SC layer was not rate-limiting for the permeation of NA, but remained the rate-limiting barrier for transdermal permeation of NAP. Permeation studies using SC-stripped and delipidized skins suggested that the intercellular pathway was the predominant route for the passive permeation of NA and NAP as well as the iontophoretic permeation of NAP across the SC. The relative rates of passive and iontophoretic permeation across Wistar rat skins demonstrated that a significant amount of NA may permeate skin via the appendageal routes, whereas NAP permeated predominantly through the lipid matrix.  2000 Elsevier Science B.V. All rights reserved. Keywords: Nalbuphine; Nalbuphine prodrug; Transdermal delivery; Iontophoresis 1. Introduction delivery via both passive diffusion and iontophoresis [3–6]. Several variables may affect the transdermal ion- Nalbuphine (NA) is a narcotic analgesic used in tophoretic permeation of drug molecules, including the treatment of both acute and chronic pain. It is a the physicochemical properties of the drug, the potent analgesic with relatively low side effects [7]. vehicle composition, electronic factors and the skin’s Due to its short elimination half-life and low oral barrier properties [1–4]. The lipophilicity of the drug bioavailibility [8], frequent injection is needed. In can have a significant influence on transdermal order to maintain the blood nalbuphine concentration and to improve the patient compliance and therapeu- tic effectiveness in pain management, a series of *Corresponding author. Fax: 1886-2-707-4804. E-mail address: fajy@ms9.tisnet.net.tw (J.-Y. Fang) nalbuphine prodrugs have been synthesized, includ- 0168-3659 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0168-3659(99)00269-2