Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep.
Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine-polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 microg epinephrine, with the addition of 150 microg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53+/-0.53 l/min and the mean elimination half-life was 120.5+/-73.1 min. Following brachial plexus nerve injection, bupivacaine C(max) were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8+/-1.0 h (bupivacaine alone) compared to 24.6+/-1.2 h following microsphere administration.
Le Corre
Pascal
P
Laboratoire de Pharmacie Galénique, Biopharmacie et Pharmacie Clinique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 35043 Rennes Cedex, France. pascal.le-corre@univ-rennes1.fr
Estèbe
Jean Pierre
JP
Clément
Rozenn
R
Du Plessis
Laure
L
Chevanne
François
F
Ecoffey
Claude
C
Le Verge
Roger
R
D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001702:Biopharmaceutics; D001835:Body Weight; D001917:Brachial Plexus / Q000502:physiology*; D002045:Bupivacaine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D005079:Excipients; D005260:Female; D006207:Half-Life; D007262:Infusions, Intravenous; D007267:Injections; D019344:Lactic Acid; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D012756:Sheep; D012995:Solubility
D000779:Anesthetics, Local; D005079:Excipients; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002045:Bupivacaine