Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine

Author(s)

de Araujo, Daniele Ribeiro ^[1] ; Saia Cereda, Cintia Maria ^[1] ; Brunetto, Glovanna Bruschini ^[1] ; Vomero, Viviane Urbini ^[2] ; Pierucci, Amauri ^[2] ; Santo Neto, Humberto ^[2] ; Rodrigues de Oliveira, Alexandre Leite ^[2] ; Fraceto, Leonardo Fernandes ^{[3, 1]} ; de Assuncao Braga, Angelica de Fatima ^[4] ; de Paula, Eneida ^[1]

Affiliation

^[1] State Univ Campinas UNICAMP, Inst Biol, Dept Biochem, BR-13083970 Campinas, SP - Brazil

^[2] State Univ Campinas UNICAMP, Inst Biol, Dept Anat, BR-13083970 Campinas, SP - Brazil

^[3] State Univ Sao Paulo UNESP, Dept Environm Engn, Sorocaba, SP - Brazil

^[4] State Univ Campinas UNICAMP, Fac Med, Dept Anesthesiol, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: Journal of Pharmacy and Pharmacology; v. 60, n. 11, p. 1449-1457, NOV 2008.
• Web of Science Citations: 30

Abstract

This study reports an investigation of the pharmacological activity, cytotoxicity, and local effects of a liposomal formulation of the novel local anaesthetic ropivacaine (RVC) compared with its plain solution. RVC was encapsulated into large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine, cholesterol and a-tocopherol (4:3:0.07, mole %). Particle size, partition coefficient determination and in-vitro release studies were used to characterize the encapsulation process. Cytotoxicity was evaluated by the tetrazolium reduction test using sciatic nerve Schwann cells in culture. Local anaesthetic activity was assessed by mouse sciatic and rat infraorbital nerve blockades. Histological analysis was performed to verify the myotoxic effects evoked by RVC formulations. Plain (RVCPLAIN) and liposomal RVC (RVCLUV) samples were tested at 0.125%, 0.25% and 0.5% concentrations. Vesicle size distribution showed liposomal populations of 370 and 130 nm (85 and 15%, respectively), without changes after RVC encapsulation. The partition coefficient value was 132 26 and in-vitro release assays revealed a decrease in RVC release rate (1.5 fold, P < 0.001) from liposomes. RVCLUV presented reduced cytotoxicity (P < 0.001) when compared with RVCPLAIN Treatment with RVCLUV increased the duration (P < 0.001) and intensity of the analgesic effects either on sciatic nerve blockade (1.4-1.6 fold) and infraorbital nerve blockade tests (1.5 fold), in relation to RVCPLAIN. Regarding histological analysis, no morphological tissue changes were detected in the area of injection and sparse inflammatory cells were observed in only one of the animals treated with RVCPLAIN or RVCLUV at 0.5%. Despite the differences between these preclinical studies and clinical conditions, we suggest RVCLUV as a potential new formulation, since RVC is a new and safe local anaesthetic agent. (AU)

• FAPESP's process: 06/00121-9 - New formulations for the controlled release of local anesthetics in dentistry: from development to clinical tests
• Grantee: Eneida de Paula
• Support Opportunities: Research Projects - Thematic Grants