title: Baclofen-loaded microspheres: preparation and efficacy testing in a new rabbit model.
abstract: Intrathecal baclofen is the reference treatment for severe spasticity. This drug has to be injected chronically in the intrathecal space by implanted pumps which are very expensive, uncomfortable and sometimes lead to side effects. Previous work has been performed by our group to assess the feasibility of encapsulating baclofen into poly(lactide-co-glycolide) (PLGA) microspheres and injecting these preparations in the intrathecal space of rabbits. The aims of the present study were to improve the encapsulation process for industrial application (scale-up), and to set up an animal model to assess the duration of effect of the new formulations. Modifications included the replacement of methylene chloride by a less toxic solvent, ethyl acetate, and the use of high molecular weight polymers to extend the release rate of the drug. The temperature and organic solvent extraction rate were fully controlled during the whole manufacturing process. All these modifications resulted in high quality microsphere batches with a CV inferior to 5% for encapsulation efficiency and drug loading. Encapsulation efficiency and release patterns were dependent on the drug payload and the polymer used. A formulation displaying a sustained release of baclofen over 174 days and a moderate burst effect of 16% in the first day in vitro was evaluated in a new reliable model of baclofen activity based on electrophysiological measurement of H-reflex in the rabbit. The activity of a very low dose of baclofen microspheres in vivo was sustained over 35 days. Furthermore, the preparation was well tolerated. These newly developed preparations are a very promising approach for enhancing the efficacy and comfort of patients undergoing spasticity treatment.
authors.affiliation: Inserm U 646, Angers, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lagarce
authors.forename: Pascal
authors.initials: P
authors.lastname: Renaud
authors.forename: Nathalie
authors.initials: N
authors.lastname: Faisant
authors.forename: Guillaume
authors.initials: G
authors.lastname: Nicolas
authors.forename: Annie
authors.initials: A
authors.lastname: Cailleux
authors.forename: Joel
authors.initials: J
authors.lastname: Richard
authors.forename: Philippe
authors.initials: P
authors.lastname: Menei
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benoit
mesh_terms: D000818:Animals; D001418:Baclofen / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006181:H-Reflex / Q000187:drug effects / Q000502:physiology; D007278:Injections, Spinal; D008297:Male; D008863:Microspheres; D023421:Models, Animal; D011817:Rabbits
chemical_list: D001418:Baclofen