Studies On The Treatment Of Osteoarthritis With Lornoxicam Microspheres In Thermo-sensitive Gel

Osteoarthritis(OA)is one of the most common joint diseases,mainly caused by articular cartilage degeneration,articular cartilage proteoglycan biosynthesis abnormalities and degenerative lesions,affecting the quality of life of patients seriously.The current treatment methods are drug treatment and surgical treatment,which is expensive and poor compliance,the drug treatment is the mainly treatment method.The half-life of general preparation is short,in order to achieve effective plasma concentration we should administrate frequently and the patient's compliance is poor.Microspheres as a controlled release formulations can release the drugs slowly to achieve long-term purpose,to improve the efficacy of drugs and reduce drug side effects.Thermo-sensitive gel refers to the solution in the state after the solution,the use of polymer materials on the external temperature response phase transition from liquid to non-chemical cross-linked semi-solid gel formulations.Thermo-sensitive gel can be used for localized lesion site and have extended drug release cycle,lower dose and drug adverse reactions,simple process and so on.Lornoxicam is a nonsteroidal antiinflammatory drug,which can prevent the production of inflammatory mediators by inhibiting cyclooxygenase to inducible nitric oxide synthase,for the treatment of rheumatism,rheumatoid arthritis and bone in the clinical.In this study,Lnxc was selected as the model medicine to make the delayed-release and prolonged-action Lnxc microspheres.Preparation of Lnxc-PLGA-MS Thermo-sensitive gel for joint cavity injection with Chitosan and Sodium Glycerate Phosphate.The main methods and results were elaborated from the following four parts: The reappeared preparation and physicochemical properties of the Lnxc-PLGA-MS;The preparation and physicochemical properties of the Chitosan Thermo-sensitive gel with Lnxc-PLGA-MS.The in vitro evalution of the Chitosan Thermo-sensitive gel with Lnxc-PLGA-MS;The in vivo evalution of the ChitosanThermo-sensitive gel with Lnxc-PLGA-MS.1.The reappeared preparation and physicochemical properties of the Lnxc-PLGA-MSThe encapsulation efficiency of Lnxc was determined by the dissolution-ultracentrifugation method(W/O/W)and the methodology was inspected.The results showed that the free drug and Lnxc-PLGA-MS can be completely separated by the centrifugation-filtration method.The good linearity of the drug concentration was obtained within the range of 4.00~32.00 ?g/ml.The recovery and the RSDs(intra-day and inter-day)meet the requirement.The entrapment efficiency and particle size were used as the evaluation indexes to optimize the prescription and process,The Lnxc-PLGA-MS with the encapsulation efficiency of(81.53 ± 2.14)%and the particle size of(6.65 ± 0.06)?m was prepared.The results showed that the formulation of Lnxc-PLGA-MS prepared by the method was reasonable and the preparation process was stable.The dry microspheres were prepared by freeze-drying with 2% mannitol as scaffold.The formation of Lnxc-PLGA-MS was confirmed by DSC.2.The preparation and physicochemical properties of the Chitosan Thermo-sensitive gel with Lnxc-PLGA-MS.To prepare the Lornoxicam thermosensitive hydrogel in a material of chitosan and the formulation was optimized according to parameters of gelation temperature,gelation time as well as injectability.The results show that the thermosensitive hydrogel according to the Non-Newtonian fluids,and fluid at room temperature,gel phase transition had arisen at 37 temperature.3.The in vitro evalution of the Chitosan Thermo-sensitive gel with Lnxc-PLGA-MSIn this part,the method for the determination of Lnxc content in Lnxc-PLGA-MS was established.The results showed that the method had high recovery and good stability,and had good linearity in the range of 4 ~ 20 ?g / mL,can be used to accurately determine the amount of Lnxc in vitro release.The results showed that the cumulative release of drug solution achieved(42.21±0.46)% and(81.40±0.66)% at 1 h and 8 h,and of drug gel achieved(20.40%±0.35)% and(80.74±0.26)% at 1 h and 13 days.The effect of the in vitro sustained release isbetter.The vitro release behavior is consistent with Weibull equation,drug diffusion is the mian release mechanism,therefore,thermo-sensitive gel can be used for Lnxc-PLGA-MS ideal solvent.4.The in vivo evalution of the Chitosan Thermo-sensitive gel with Lnxc-PLGA-MS.In this part,the concentration of Lnxc in plasma,joint tissue and synovial fluid of rats was determined by HPLC.The results showed that the method had high specificity,good linearity,high precision and good recovery.The method meets the requirements for the determination of biological samples.After injection,the concentration of the drug group was higher than that the microspheres and the gel group,while the drug concentration of the microspheres group was slightly higher than that the gel group,especially in the first 8 hours.After injection of drug solution,the drug leakage through the joint cavity and quickly absorbed into the blood,making the plasma concentration of drugs higher;Which indicated that the microspheres and gels have a good sustained release effect,but the gel group have slower release effect and less adverse reactions than the microspheres group in the overall trend.