Research On Poloxamer Thermosensitive In Situ Gel

The novel drug delivery system in situ gel system which is free flowing before being used can respond to environmental stimulus and form gel which can facilitate local drug delivery and a slow yet stable release of the drug incorporated. Thermosensitive in situ gel is flowing fluid at room temperature and can flood into the gaps between tissues after injection, but forms semisolid gel at the site of injection as a result of temperature increase.Triblock copolymer poly(ethylene oxide)–b-poly(propylene oxide)–b-poly(ethylene oxide) (PEO–PPO–PEO), known also as Pluronic? or poloxamers are nonionic surfactants. The family member F127 solution is thermosensitive upon heating. Our group had prepared thermosensitive in situ gel using F127 and F68, the influence of their ratios and concentrations on the properties of the gel was investigated.Dexamethasone sodium phosphate (DSP) was used as the model drug to investigate the erosion behavior of the gel and the drug release behavior from the gel. Meanwhile, residence time of the gel was studied in vivo, irritation of the gel on the tissue was also examined.Part 1 Preparation and Research on the Properties of the Poloxamer Gel Poloxamer thermosensitive in situ gel was prepared using Pluronic?F127和Pluronic?F68. The influence of ratios and concentrations of the two materials on gelation temperature, solution-gel transition temperature (Ts-g), mechanical strength as well as stable viscosity were investigated. Tube inverse method was used to test the gelation temperature. Rotation rheometer was used to measure sol-gel transition temperature, elastic modulus and stable viscosity. Results indicated that gelation temperature and Ts-g rose as F127 concentration increased, while viscosity and elastic modulus decreased accordingly. However increased F68 could lead to the opposite result. The poloxamer solution is Newtonian fluid with low viscosity when ambient temperature is below Ts-g but shows characteristics of pseudoplastic fluid with comparatively high viscosity when temperature rises near Ts-g..Part 2 Erosion and Drug Released Behavior of DSP Poloxamer Thermosensitive in situ Gel HPLC method was established to determine DSP released from the gel. Recovery, precision, stability all met the requirement of technology, and determination of DSP was not interfered by poloxamer. DSP standard curve is linear over the range of 1～100μg·ml-1, and the minimum detectable amount was 0.51ng. Gel erosion and DSP released were measured by membrane free method. The influence of F127 and F68 concentration on gel erosion and DSP released was also investigated. It was found that gel erosion and DSP released were linear correlative and both of them followed the zero-order kinetics. Increasing F127 concentration in the gel decreased gel erosion and DSP release time while increasing F68 concentration could lead to the opposite result. Part 3 Research on the Residence time of Poloxamer gel in vivo Female New Zealand rabbits were used as the model animals in the in vivo experiments. Poloxamer solution containing barium sulfate as a contrast medium was injected into oviduct on the experimental side through operation .Sterile physiologic saline used as the control agent was injected into oviduct on the other side. The rabbits were examined by digital radiography (DR) at designated time intervals after the operation to investigate the residence time of the gel. The gel still retained at the site 1 day after the operation while the physiologic saline disappeared. The amount of gel decreased with time and disappeared 7 days after the operation.Part 4 In vivo biocompatibility studies Oviduct of the New Zealand rabbit on experimental side was injected with poloxamer solutions while the one on the control side received an injection of sterile physiologic saline. The animals were sacrificed by air injection on 2 and 7 days after the operation. Oviducts were removed and examined carefully before made into slices and dyed with haematoxylin and eosin and then examined in light microscope. Inflammatory changes in the tissue were generally negligible. No signs of tissue damage or inflammatory cells such as lymphocyte, plasmocyte or mastocyte were seen. Inflammatory changes were also similar after the injection of physiologic saline. The result shows that F127/ F68 gel is biocompatible and does not cause noticeable damage to oviduct.Our group had prepared thermosensitive in situ gel using Pluronic?F127 and F68 as materials and DSP as the model drug. Influence of these two materials on the gel properties such as gelation temperature, sol-gel transition temperature, stable viscosity, mechanical strength was investigated. Methods to determine DSP released and gel dissolved in vitro were established, and it was found that DSP released and gel dissolved are linear correlative and both of them follow the zero-order kinetics. Drug releasing rate is mainly controlled by gel dissolving rate. It was confirmed by animal experiment that the gel was biocompatible and could retain 7 days in vivo. Our work has established new method for investigating thermosensitive in situ gel and its application in local drug delivery.