A dose–response study of epidural liposomal bupivacaine in rabbits

• Published in: Journal of controlled release Vol. 60; no. 1; pp. 111 - 119
• Main Authors: Malinovsky, Jean-Marc, Le Corre, Pascal, Meunier, Jean-François, Chevanne, François, Pinaud, Michel, Leverge, Roger, Legros, Franz
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 28-06-1999; Elsevier
• Subjects: Anesthesia, Epidural; Anesthetic techniques: epidural; Anesthetics, Local - administration & dosage; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Bupivacaine - administration & dosage; Bupivacaine - chemistry; Bupivacaine - pharmacology; Dose-Response Relationship, Drug; Drug delivery system: liposomes; Drug Delivery Systems; Experimental anesthesia: rabbits; Female; General pharmacology; Hemodynamics - drug effects; Liposomes - chemistry; Local anesthetics: bupivacaine; Medical sciences; Neuropharmacology; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rabbits; Release kinetics; Anesthetic techniques: epidural; Experimental anesthesia: rabbits; Drug delivery system: liposomes; Local anesthetics: bupivacaine; Release kinetics; Encapsulation; Pharmaceutical technology; Rabbit; Liposome; Drug carrier; Lagomorpha; In vitro; Local anesthetic; Vertebrata; Mammalia; Bupivacaine; Animal; Dosage form; Active ingredient; Organic amide; Blood pressure; Intraarterial administration; Hemodynamics; Anilide; Release
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(99)00062-0

Liposomes are drug delivery systems used to prolong local effects of bupivacaine. We studied the relationships between motor and hemodynamic changes and epidural doses of plain bupivacaine (P) and liposomal bupivacaine (L) in rabbits equipped with chronical lumbar epidural and femoral arterial catheters. Liposomal (phosphatidylcholine–cholesterol) suspensions contained 20 mg
ml
−1 of lipid, and different doses of bupivacaine (Lipo 7.5=7.5-; Lipo 3.7=3.75-; Lipo 2.5=2.5-; Lipo 1.2=1.25-; and Lipo 0.7=0.65-mg of bupivacaine per ml). Forty rabbits were randomly assigned to five groups to receive epidural anesthesia (1 ml) as follows: Groups I to V received 0.65 to 7.5 mg of bupivacaine as P then as L. Release rate of bupivacaine from liposome was significantly slower using Lipo 3.7 than after Lipo 2.5 (
T
d was 3.9 h and 1.7 h respectively). Increasing the doses of L and P resulted in faster onset time for complete motor blockade and in a prolonged duration of motor effects. Liposomal formulation appears to be a powerful delivery system to prolong the motor effects of bupivacaine since
E
50 was lower and
E
max higher than after the use of plain solution (
E
50 4.49±1.81 mg and
E
max 152±40 min for P; and
E
50 2.61±0.23 mg and
E
max 202±9 min for L). Hemodynamic changes were linearly related to doses of bupivacaine injected. The best bupivacaine-to-lipid ratio to prolong motor effects using our model was 3.75 mg and 20.0 mg respectively (Lipo 3.7).