Long acting local anesthetic–polymer formulation to prolong the effect of analgesia ☆ Ariella Shikanov a , Abraham J. Domb a , Carolyn F. Weiniger b, ⁎ a School of Pharmacy, Hadassah Hebrew University Medical Schools, Ein Kerem, Jerusalem, POB 12000, Israel b Department of Anesthesiology, Hadassah Hebrew University Medical Schools, Ein Kerem, Jerusalem, POB 12000, Israel Received 22 May 2006; accepted 5 October 2006 Available online 20 October 2006 Abstract Prolonged postoperative analgesia cannot be achieved using single injections of local anesthetic solutions. The study objective was to evaluate the efficacy and toxicity of a new formulation of bupivacaine loaded in an injectable fatty acid based biodegradable polymer poly(sebacic-co-ricinoleic acid) for producing motor and sensory block when injected near the sciatic nerve. Bupivacaine was dissolved in poly(fatty ester-anhydride) paste and tested for drug release in vitro and in vivo after injection in mice. The efficacy and toxicity of the polymer–drug combination was determined by injecting the polymer formulation near the sciatic nerve of mice and measure the sensory and motor nerve blockade for 48 h, while monitoring the animal general health and the injection site. Seventy percent of the incorporated drug was released during 1 week in vitro. Single injection of 10% bupivacaine in the polymer caused motor and sensory block that lasted 30 h. Microscopic examination of the injection sites revealed only mild infiltration in three of eight examined tissues with no pathological findings for internal organs were found. In conclusion the polymer poly(sebacic-co-ricinoleic acid) is a safe carrier for prolonged activity of bupivacaine. © 2006 Elsevier B.V. All rights reserved. Keywords: Analgesia; Animal; Local anesthetic; Long-acting; Polymer–bupivacaine 1. Introduction Postoperative pain is a major problem for the healing process after surgery. Injection of local anesthetics is the most site- directed and effective analgesic modality for the management of postoperative pain. Local anesthetics reversibly block nerve conduction near their site of application or injection thus producing temporary loss of sensation over a specific area of the body [1]. Current clinical methods to prolong analgesia include multiple injections of short acting local anesthetic solutions but are time-consuming and demand expensive equipment and monitoring [2,3]. Application of local anesthetics via a catheter can produce neural blockade for days to weeks, however, catheters may become infected, blocked or migrate. This lack of efficient treatment for postoperative analgesia highlights the need for new therapeutic principles in this area [4]. The last decade has seen novel developments in this area [1,5,6]. Masters et al. [3] prepared a long-acting local anesthetic from biodegradable polyanhydride copolymers impregnated with local anesthetics. Liquid drug delivery systems such as liposomes are the most widely studied [7]. In this study we present a novel injectable drug delivery system for bupivacaine. The aim of this study was to determine whether a hydrophobic polymer based on fatty acids can prolong the release of bupivacaine in vivo. In addition the in vitro release was studied. 2. Materials and methods 2.1. Materials Poly(sebacic-co-ricinoleic acid)2:8 was synthesized as previously described [8]. The polymer having Mw = 4000 and Journal of Controlled Release 117 (2007) 97 – 103 www.elsevier.com/locate/jconrel ☆ Funding: This study was supported (in part) by grant no. 5868 from the Chief Scientist Office of the Ministry of Health, Israel and a grant from the Joint Research Fund of the Hebrew University and Hadassah Medical Organization, Jerusalem, Israel. ⁎ Corresponding author. Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Centre, Jerusalem, POB 12000, Israel. Tel.: +972 507 874059; fax: +972 8 971 4244. E-mail address: carolynfspencer@gmail.com (C.F. Weiniger). 0168-3659/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2006.10.014