DRV liposomal bupivacaine: preparation, characterization, and in vivo evaluation in mice.
OBJECTIVE
To evaluate the dehydration-rehydration technique to prepare a formulation of liposomal bupivacaine, and to assess its analgesic efficacy.


METHODS
Bupivacaine hydrochloride (BUP) was encapsulated into dehydration-rehydration vesicles (DRV) of varying phospholipid (PL) compositions. Two bilayer-forming phospholipids were used, the "fluid" dimyristoyl-phosphatidylcholine and the "solid" distearoyl-phosphatidylcholine (DSPC), with 20 or 40 mol% cholesterol, in the presence of bupivacaine at a 1.28 or 0.64 BUP/PL mole ratio. After rehydration, drug/lipid ratios were determined. The formulation with the highest drug/lipid ratio (DSPC/cholesterol in an 8:2 mole ratio prepared in the presence of bupivacaine in a 1.28 BUP/PL mole ratio) was adjusted to a final bupivacaine concentration of 3.5% or 0.5%. The duration of skin analgesia after subcutaneous injection in mice produced by these formulations was compared with the conventional administration of a plain 0.5% solution of BUP. In addition, the concentration of residual bupivacaine at the injection site was followed for 96 h.


RESULTS
The relatively low organic solvent/aqueous phase and membrane/aqueous phase partition coefficients, together with liposomal trapped volume and BUP/PL mole ratio, indicated that most of the drug was encapsulated in the intraliposome aqueous phase of the DRV. The DSPC/cholesterol 8:2 mole ratio had the best drug encapsulation (BUP/PL = 0.36). Compared to plain BUP, these BUP-DRV produced significant prolongation of analgesia, which is explained by longer residence time of the drug at the site of injection.


CONCLUSIONS
Bupivacaine-DRV may have a role in achieving safe, effective, and prolonged analgesia in humans.
Grant
G J
GJ
Department of Anesthesiology, New York University School of Medicine, New York 10016, USA. gilbert.grant@med.nyu.edu
Barenholz
Y
Y
Piskoun
B
B
Bansinath
M
M
Turndorf
H
H
Bolotin
E M
EM
D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002021:Buffers; D002045:Bupivacaine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002214:Capsules; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004337:Drug Carriers; D004339:Drug Compounding; D007279:Injections, Subcutaneous; D008081:Liposomes; D008297:Male; D008567:Membranes, Artificial; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D010316:Particle Size; D012997:Solvents
D000779:Anesthetics, Local; D002021:Buffers; D002214:Capsules; D004337:Drug Carriers; D008081:Liposomes; D008567:Membranes, Artificial; D012997:Solvents; D002045:Bupivacaine