Research On Ophthalmic Thermosensitive In Situ Gels Of Diclofenac Sodium

As one non-steroidal anti-inflammatory drug, regular diclofenac sodium (DS) drops were used to cure the ophthalmic postoperative noninfectious inflammations. However, its regular drops ofen have several disadvantages, such as short residence time, low bioavailablity. The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliance to be developed, however, the applications of numerous pharmaceutical methods are limited simultaneously, which presents great challenge in designing ophthalmic dosage forms.Ophthalmic thermosensitive in situ ge1s refer to the polymer solutions can be administrated as liquid, which undergo a phase transition to semisolid gel upon exposure to physiological temperature. So it has the combined advantages of drops and gel, and could be used to prolong the retention time and improve bioavailablity. But this drug delivery system still was hampered because of its low bioadhesive force and quick erosion rates. So sodium hyaluronate (SH) was used as bioadhesive polymers to improve its characteristic.In this thesis, DS was selected as a model drug. A thermosensitive gel was developed using P407, P188 and SH. A series of relative studies were carried out.Part 1 Preparation of DS poloxamer gelsThe formulation was optimized using central composite design- response surface methodology (CCD-RSM). The effects of P407 and P188 were evaluated. Response variables selected in the research were the gelation temperatures before and after simulated tear fluid (STF) dilution. Quadratic models were used to estimate the relationship between the poloxamer concentrations and gelation temperatures, and to delineate RSM and overlay contour plots in order to select the optimal formulation. Four optimal formulations were prepared according to the optimized area predicted by quadratic model and evaluated. The observed values agreed well with model predicted values. Quadratic models between the poloxamer concentrations and gelation temperatures and the optimized formulation containing 21%P407/5%P188 were obtained.Part 2 Rheological properties and physicochemical properties of DS poloxamer gelsThe influence of concentrations of SH, STF, shear ratios, temperature and time on solution-gel transition (Ts-g), elastic modulus, viscosity modulus as well as shear viscosity were investigated by rotation rheometer. Results indicated that Ts-g rose as STF diluted, while viscosity and elastic modulus decreased accordingly. However increased SH 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.Bioadhesive force-measuring device was used to evaluate the bioadhesive force and cloud points were observed. The results showed that the cloud points of DS poloxamer gels decreased with SH concentration in gel increased, while bioadhesive forces rose accordingly.Part 3 Erosion and drug release behavior of DS poloxamer gelsErosion of the gels and release of DS from the gels were investigated by membrane-free method and HPLC, and the following factors were included for comparison including the release area, shaking frequency, concentration of SH, and STF. The erosion and the drug release rate were increased with the rise of release area and shaking frequency and decreased with the addition of SH in gels. The release rate became faster after STF dilution. Drug release was controlled by the erosion of the gel.Part 4 Residence time of DS poloxamer gels and in vivo biocom- patibility studiesFluorescein sodium was selected as the marker to monitor the corneal residence time by slit-lamp microscope. The results showed that the DS poloxamer gels could prolong drug residence time of fluorescein sodium marker significantly on the surface of eye and the retentive effect was superior to the DS eye drops.Rabbit ocular irritation experiments were performed. The results suggested that the DS ophthalmic thermosensitive in situ gel was biocom- patible and nonirritant.RSM plus CCD was successfully used to optimize the formulation of thermosensitive in situ gels of DS. The rheological properties, erosion rates and DS release raes of DS poloxamer ge1s were evaluated systemly.The study in vivo showed that the residence time of the gel was improved a lot and there was no ocular irritation or damage for DS poloxamer ge1s. The formulations showed great potential for using as an ophthalmic sustained drug delivery system.