| Local anesthetics play an important role in pain management. Lidocaine is an amidelocal anesthetic with fast onset, good ability to permeate through mucosa, and broad rangeof safety. Effect can be achieved by the route of surface anesthesia, infiltration anesthesia,peripheral nerve blocks and epidural anesthesia. It is widely used in regional anesthesia,postoperative pain management, other acute and chronic pain therapy. However, its shortduration brought inconvenience to clinical use. Many trials have been made to prolong theaction of lidocaine. None of them got ideal effect. The present work was undertaken todevelop and characterize SLN as new drug carrier for lidocaine to prolong the anestheticeffect. The main work was as following:1） Methods for preparation of lidocaine loaded SLN were investigated. Theprescription and preparation parameter of lidocaine SLN was determined by monofactorialand orthogonal design. Lidocaine loaded SLN was prepared with monostearin (MS),glyceryl palmitostearate (GP) and stearic acid (SA) using high pressure homogenization.Poloxamer188was selected as surfactant. The particle sizes of lidocaine loaded SLN were143.0~388.4nm with polydispersity index0.286~0.445, zeta potential－17.5～－24.3mV. Transmission electronic microscopy（TEM） showed that the particles of lidocaineSLN were spherical or analogous spherical. Power X-ray diffraction (PXRD) showedamorphous state of lidocaine in the SLN.2）By adding different cryoprotectants to suspension of lidocaine SLN,6%trehalosewas selected as the cryoprotectant through the total scores including shape, appearance anddispersity after sample lyophylization.3）High Performance Liquid Chromatography (HPLC) was established to determinethe concentration of lidocaine. The mobile phase consisted of a methanol-0.5%ammoniumdihydrogen phosphate mixture at a ratio of75:25(v/v). This method had good repeatabilityand accuracy. The in vitro release by dialysis bag within48h showed that lidocainereleased from SLN was extended in both saline and pH7.4PBS as release medium. The extended release of lidocaine was observed with GP SLN. It was71.59%and69.01%insaline and pH7.4PBS, respectively. Then it was with MS SLN and SA SLN. Thecumulative release was77.14%、79.54%and86.78%、88.46%in saline and pH7.4PBS,respectively.4）The in vivo efficacy of lidocaine in different SLNs was evaluated in rats. From thetail withdrawal latency (TWL) and the maximum amplitude of motor unit action potential(MUAP), single injection of lidocaine SLNs suspension produced epidural sensory blockfor more than8h with MS SLN,12h with PR SLN and4h with SA SLN, while sameamount of lidocaine HCl in aqueous solution lasted only for less than2h; motor blockadelasted approximately2h for lidocaine SLNs with decreased intensity, while it was less than1h for lidocaine HCl.5）The preliminary toxicology in vitro and in vivo was assessed for GP SLN. The effecton viability using MTT colorimetry was evaluated by treatment of GP SLN, Lidocaine HCl,Blank SLN and control in human neuronal cells SH-SY5Y for1h,12h and24h. It wasfound that the suppression of cell viability was decreased for GP SLN and Blank SLNcompared with Lidocaine HCl in those periods of time. The in vivo efficacy andhistopathology of GP SLN was assessed by sciatic nerve block in rats. The sensory andmotor block of was longer than Lidocaine HCl, whereas Blank SLN had no detectableanesthetic effect. At1week after injection, the inflammatory in muscular and nerve tissuewas decreased for GP SLN and Blank SLN compared with Lidocaine HCl. At4weeks afterinjection, the inflammatory in muscular and nerve tissue was almost disappeared for GPSLN.In summary, SLN can be exploited as a promising new drug carrier for extending theaction of lidocaine used in epidural and peripheral anesthesia and analgesia. It provides analternative for multimodal analgesia in clinical settings. |
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