International Journal of Pharmaceutics 298 (2005) 68–79 Biopharmaceutics of intrathecal baclofen-loaded microparticles in a goat model Frederic Lagarce a,b , Nathalie Faisant a , Jean-Claude Desfontis c , Laurent Marescaux c , Freddy Gautier c , Delphine Holopherne c , Marie-Christine Rousselet d , Philippe Menei a,e , Jean-Pierre Benoit a,∗ a Inserm U 646, 10 rue A Boquel, 49100 Angers, France b Ethypharm SA, 194 Bureaux de la Colline, 92213 Saint Cloud, France c National Veterinary School of Nantes, Route de Gachet, 44000 Nantes, France d Department of Anatomo-Pathology, University Hospital, 4 rue Larrey, 49033 Angers Cedex 01, France e Department of Neurosurgery, University Hospital, 4 rue Larrey, 49033 Angers Cedex 01, France Received 22 November 2004; received in revised form 21 March 2005; accepted 25 March 2005 Available online 24 May 2005 Abstract The goal of this study was to develop a goat model allowing reliable pharmacokinetic (PK) studies of intrathecal baclofen (ITB) sustained release dosage forms using an implanted silicone catheter. ITB PK parameters (clearance, volume of distribution) following intrathecal bolus injection were determined for doses ranging from 100 to 560 g and a comparison to human data was made. Baclofen-loaded microparticles were then implanted in the intrathecal space of goats and the resulting baclofen levels were determined during 28 days. Finally, PK parameters were used to predict cerebrospinal fluid (CSF) baclofen rates from in vitro release profiles of baclofen-loaded microspheres. The catheter was well tolerated and did not interfere with behavioral testings. Baclofen CSF clearance (mean = 8.59 ± 2.43 ml/h) and volume of distribution (21.06 ± 13.32 ml) were not significantly affected by the increase of the dose (p > 0.05). In vivo, the baclofen levels in CSF were stabilized at 200 g/l after a period of 3 days. The predictive value of the in vitro release studies was good since the theoretical levels ranged between 128 and 257 g/l. In conclusion, a large animal model was developed and allowed the biopharmaceutic evaluation of baclofen microparticles injected via intrathecal route. © 2005 Elsevier B.V. All rights reserved. Keywords: Drug delivery; Baclofen; Pharmacokinetics; Goat; Microspheres; Sustained release dosage form ∗ Corresponding author. Tel.: +33 2 41 73 58 55; fax: +33 2 41 73 58 53. E-mail address: jean-pierre.benoit@univ-angers.fr (J.-P. Benoit). 1. Introduction Since almost 20 years, intrathecal baclofen (ITB) chronic injection, using implanted pumps and catheters, remains the reference conservative surgical 0378-5173/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2005.03.025