title: Poly(DL:lactic acid-castor oil) 3:7-bupivacaine formulation: reducing burst effect prolongs efficacy in vivo.
abstract: Prolonged analgesia may be achieved using a single injection of slow-release local anesthetic formulation. The study objective was to improve the efficacy of a previously reported formulation comprising 10% bupivacaine in poly(DL:lactic acid co castor oil) 3:7. The polymer was loaded with 15% bupivacaine and injected through a 22G needle close to the sciatic nerve of ICR mice. Sensory and motor nerve blockade were measured. The efficacy and toxicity of the polymer-drug combination were determined. Sixty percent of the incorporated bupivacaine was released during 1 week in vitro. During in vitro release no burst effect was seen, suggesting low toxicity of the formulation. Single injection of 0.1 mL of 15% polymer-bupivacaine formulation caused motor block that lasted 64 h and sensory block that lasted 96 h. The MTD of the polymer-drug formulation was established as 0.175 mL. Microscopic examination of the injection sites revealed reversible nerve inflammation and normal internal organs. The polymer poly(DL:lactic acid co castor oil) 3:7 is a safe carrier for prolonged activity of bupivacaine up to 96 h. The increase of drug load in the formulation reduces the drug release rates due to stronger polymer-drug interactions and higher overall hydrophobicity of the formulation.
authors.affiliation: Faculty of Medicine, Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Sokolsky-Papkov
authors.forename: Ludmila
authors.initials: L
authors.lastname: Golovanevski
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Domb
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Weiniger
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology*; D002368:Castor Oil / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004304:Dosage Forms; D005260:Female; D019344:Lactic Acid / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D011108:Polymers / Q000494:pharmacology; D012584:Sciatic Nerve / Q000187:drug effects* / Q000502:physiology; D017855:Transferases (Other Substituted Phosphate Groups)
chemical_list: D000779:Anesthetics, Local; D004304:Dosage Forms; D011108:Polymers; D019344:Lactic Acid; D002368:Castor Oil; D017855:Transferases (Other Substituted Phosphate Groups); C088138:undecaprenyl-phosphate galactosephosphotransferase; D002045:Bupivacaine