Research paper In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate Sonal R. Patel a,1 , Hui Zhong a , Ashutosh Sharma a , Yogeshvar N. Kalia b,c, * a Vyteris, Inc., Fair Lawn, NJ, USA b School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland c Centre Interuniversitaire de Recherche et d’Enseignement, ‘‘Pharmapeptides’’, Site d’Archamps, Archamps, France Received 18 July 2006; accepted in revised form 6 November 2006 Available online 14 November 2006 Abstract The objective was to evaluate the transdermal delivery of the 5-HT 1B/1D agonist, sumatriptan from an iontophoretic patch system, in vivo. Initial in vitro experiments were conducted to optimize formulation parameters prior to iontophoretic delivery in Yorkshire swine. It was found in vitro that increasing drug load in the patch from 9.7 to 39 mg had no statistically significant effect on cumulative delivery (cf. 305.6 ± 172.4 vs. 389.4 ± 80.4 lg cm 2 , respectively). However, for a given drug load (39 mg) increasing formulation pH from pH 4.7 to 6.8 significantly increased the cumulative amount of sumatriptan delivered across the skin (389.4 ± 80.4 vs. 652.4 ± 94.2 lg cm 2 ). A biphasic current profile comprising intensities of 1.8 mA from t =0 to t = 180 min and 0.8 mA from t = 181 min to t = 360 min was used for the in vivo experiments. Drug levels in the blood were 13.7 ± 4.5 and 53.6 ± 10.2 ng ml 1 at the 30 and 60 min time-points, rising to 90–100 ng ml 1 during the 90–180 min time-period. The in vivo results show that the pharma- cokinetics following transdermal iontophoretic delivery are comparable to those after oral, nasal or rectal administration, but do not match those upon subcutaneous injection. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Transdermal; Iontophoresis; Migraine; Sumatriptan; 5HT 1B/1D agonist; Non-invasive; In vivo 1. Introduction Sumatriptan is a selective serotonin 5-HT agonist at the 5-HT 1B and 5-HT 1D receptors (Fig. 1) used in the treat- ment of acute migraine episodes [1]. It was the first of the so-called ‘‘triptan’’ drugs which have had a significant impact on the treatment of acute attacks and it is available in several dosage forms including products for oral, nasal and rectal delivery [2]. However, patients cite limited effica- cy, slow onset and incomplete prevention of recurrence as major shortcomings of current therapies [3]. There is a con- sensus that subcutaneous injection of sumatriptan provides the most rapid response at the 30 min time-point (63%) and complete relief at the 2 h time-point (67%) (conventional endpoint for evaluating treatment efficacy) [3,4]. Yet, from the patient’s perspective, this is the least desirable modality of sumatriptan administration. In addition to the reluc- tance for self-injection, there are also reports of skin site reactions in more than 50% of patients [5]. Transdermal delivery offers a convenient alternative, par- ticularly where nausea prevents administration of an oral dosage form. In addition, sumatriptan has a relatively poor oral bioavailability (only 14%) and a relatively short half-life (T 1/2  2 h) [2]. However, based on the molecular properties of the weakly lipophilic sumatriptan base (log K o/w = 0.93 0939-6411/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2006.11.001 * Corresponding author. Laboratory of Medicinal Chemistry, School of Pharmaceutical Sciences, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland. Tel.: +33 450 31 50 24; fax: +33 450 95 28 32. E-mail address: yogi.kalia@pharm.unige.ch (Y.N. Kalia). 1 Present address: Forest Laboratories Inc., Harborside Financial Center Plaza V, Jersey City, NJ 07311, USA. www.elsevier.com/locate/ejpb European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 296–301