Preparation Of Proanthocyanidin/Gelatin Non-covalent Bond Crosslinked Matrix And Its Application In Lidocaine Sustained Implants

Gelatin can be used for pharmaceutical applications due to its biodegradability,but it does not has ideal mechanical properties,the systems were susceptible to degradation in vivo,which limited its application.The objective of this study was to develop a novel gelatin material by using proanthocyanidin(PA)as a crosslinker.The PA/gelatin non-covalent bond crosslinked matrix can be used to control delivery of the hydrophobic drug lidocaine base for postoperative pain relief.Lidocaine implant prepared by loading lidocaine into the PA/gelatin non-covalent bond crosslinked matrix.Other polymers such as poloxamer P407,sodium hyaluronate and sodium alginate were adding to the PA/gelatin matrix to form a more stable network,which can increase the mechanical strength of the gelatin carrier.Swelling and drug release behavior were evaluated under two different release methods.Finally,in vitro release study was undertaken in agarose gel method mimicking physiological conditions at the implantation site.We applied the lidocaine implant around the rat sciatic nerve and evaluated the efficacy of rat sciatic nerve block,meanwhile the drug concentration in plasma was detective by established HPLC method.The best prescription composition: gelatin 540 mg,PA 60 mg,lidocaine 300 mg.The temperature was 50℃,the PA solution was slowly added to gelatin solution with stirring.Subsquently,300 mg of lidocaine powder was added to the PA/gelatin solution,stirred for 20 min.Then,the hot solutions were cooled at room temperature to a gel state.The matrixs were divided into several small pieces with a 10 mm diameter and placed at room temperature for 48 h.The matrixs were frozen at-20 °C then lyop Hilized in the freeze-drier at-45 °C for 20 h to obtain cylindrical porous matrixs.Scanning electronic microscope and polarizing microscope observation revealed that lidocaine was uniform Ly dispersed in the gelatin matrix.Polarizing microscope observation and XPRD analysis indicated that crystal lidocaine existed in the implants.In vitro release studies showed that the PA-crosslinked gelatin implant are more stable in PBS and exhibited prolonged release of lidocaine than noncrosslinked gelatin matrix.The PA-crosslinked lidocaine implant showed a sustained release over 72 h.In vivo pharmacokinetics showed low plasma drug concentration after sciatic nerve implantation in rats.The pharmacodynamics study showed prolonged duration of sensory blockade of sciatic nerve for 24 h.No obvious side effects and motor blockade happened in all of the tests in rats.The cell viability of L929 mouse fibroblast in the implant group was no significant reduction compared to the control group when the concentrations below 1000 μg/m L.