Baclofen-loaded microspheres in gel suspensions for intrathecal drug delivery: in vitro and in vivo evaluation.
Severe spasticity is a very disabling disorder treated by continuous baclofen intrathecal infusion which unfortunately remains an expensive and uncomfortable treatment. In order to address these issues, new sustained release formulations designed for intrathecal baclofen delivery were sought with the aim of minimising the burst effect of baclofen which can lead to toxicity. Baclofen was encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres which were then dispersed in chitosan thermosensitive gels, Pluronic PF-127 gels, carboxymethylcellulose solutions or Ringer lactate solution. The release rate was assessed in vitro using continuous flow cells and in vivo after intrathecal injection in goats: baclofen was quantified in cerebrospinal fluid (CSF) and plasma, and the associated pharmacological effect was evaluated. The results showed that the burst effect was reduced by at least a factor of 2 in vitro, after microsphere dispersion in viscous media. In vivo, PF-127 gel was found to be the best vehicle to reduce the burst effect by a factor of 10 in CSF, and by a factor of 2 in plasma. The toxic effect of baclofen due to the burst effect was reduced by the dispersion in PF127 gels. Therapeutic levels of baclofen in CSF were maintained during at least 1 month.
Lagarce
Frederic
F
Inserm U 646, Angers, France.
Faisant
Nathalie
N
Desfontis
Jean-Claude
JC
Marescaux
Laurent
L
Gautier
Freddy
F
Richard
Joel
J
Menei
Philippe
P
Benoit
Jean-Pierre
JP
D001418:Baclofen / Q000008:administration & dosage* / Q000737:chemistry; D005782:Gels; D007278:Injections, Spinal; D019344:Lactic Acid / Q000008:administration & dosage; D008863:Microspheres; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage; D012995:Solubility; D013535:Suspensions
D005782:Gels; D011108:Polymers; D013535:Suspensions; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D001418:Baclofen