Preparation Of Celecoxib-loaded Nanoparticles And Tribology Study

ObjectiveOsteoarthritis(OA)is a refractory,progressive,and chronic joint disease characterized by degeneration,destruction,and bone hyperplasia of articular cartilage.One of the causes of osteoarthritis is the roughness or deformation of the cartilage,which is a vital hint to treat osteoarthritis.Nanoparticles have been widely used as an additive in the mechanical field,while it is not clear whether nanoparticles could alleviate joint friction through nanolubrication.The main purpose of this paper is to prepare nanoparticles using the nonsteroidal anti-inflammatory drug celecoxib as a model drug,which is prepared by nanoprecipitation,probe ultrasound,high pressure homogenization and dialysis.The particle size,zeta potential and drug loading capacity of the nanoparticles were used to evaluate the advantages and disadvantages of the four methods.The optimal method was used to prepare the nanoparticles with different materials,which was to investigate their friction properties and potential lubrication mechanisms.Additionally,release behavior of celecoxib was investigated by shaker.The project is going to develop a new formulation platform with both lubrication and anti-inflammation effect for early stage intervention of osteoarthritis.Methods(1)Nano-precipitation,probe ultrasound,high-pressure homogenization and dialysis were used to prepare drug-loaded PLGA nanoparticles,and the optimal method was selected to optimize the parameters.(2)PLGA,PLA,PLLA,PCL and PMMA celecoxibloaded nanoparticles were prepared by high pressure homogenization.(3)PBS containing 0.5%SDS and 0.1%HA worked as control group,0.5%(w/v)different materials loaded with nanoparticles were dissolved in 0.5%SDS and 0.1%HA in PBS for Mini-traction machine(MTM)test.(4)PBS containing 0.5%SDS and 0.22%HA worked as control group,0.5%(w/v)different materials loaded with nanoparticles were dissolved in 0.5%SDS and 0.22%HA in PBS solution for tribometer test.(5)0.1%nanoparticles were dissolved in PBS solution,and the lubrication mechanism was investigated by Quartz Crystal Microbalance(QCM)combined with Atomic Force Microscope(AFM).(6)Drug release were examined in a PBS buffer containing 0.22%SDS in a dialysis bag,which contains 1 mL of 0.22%HA.ResultsAll four methods could prepare drug-loaded nanoparticles.The average particle size and PDI of nanoparticles prepared by high pressure homogenization were 258.83 nm and 0.15,respectively.The average particle size and PDI of nanoparticles prepared by nanoprecipitation were 185.50 nm and 0.20,respectively.The average particle size and PDI of nanoparticles prepared by dialysis were 561.20 nm and 0.10,respectively.The average particle size and PDI of nanoparticles prepared by probe ultrasonication were 582.42 nm and 0.37,respectively.Drug loading capacity of nanoparticles was about 2.2%prepared by high-pressure homogenization,while the loading capacity of the rest of the methods were around 1%.Furthermore,the size of nanoparticles prepared by high pressure homogenization were small and evenly distributed,so high pressure homogenization method was selected.The prescription process of high-pressure homogenization was observed.As the concentration of celecoxib increased from 1 mg/mL to 2 mg/mL,the drug loading capacity could reach from 1.35%to 3.56%,but precipitation of drug appeared.The PVA concentration increased from 1%to 5%,and both the trend of particle size and the drug loading capacity increased first and then decreased.Increasing the oil-water volume ratio from 1:4 to 1:14,the loading capacity would reduce from 1.11%to 0.29%.The homogenization pressure increased from 100 bar to 800 bar,and the particle size decreased from 443.1 nm to 238.4 nm.The cycle of homogenizations did not significantly change the particle size.To sum up,the final parameters of optimal prescription were:celecoxib concentration was 1.5 mg/mL;PVA concentration was 2%(w/v);oil-water volume ratio was 1:4;the optimum process pressure was 800 bar followed by 3 cycles.The lyoprotectant has a significant effect on the particle size of nanoparticles,and the effect of different lyoprotectants varies a lot.The ratio of the particle size after lyophilization to before lyophilization was investigated to evaluate the effect of lyoprotectant.1%trehalose was 1.44,1%lactose was 1.27,1%maltose was 2.25,and 1%mannitol was 1.70.The effect of composite lyoprotectant to prevent the particle from being aggregated was not as good as a single lyoprotectant.Finally,the choice of lyoprotectant was 5%lactose with an only 20%increase in particle size.The nanoparticles were tested by MTM and Tribometer.The results show that the nanoparticles could reduce the friction coefficient.In MTM test,the nanoparticles of PMMA and PLA are better options to reduce friction,and the friction coefficient can be reduced by about 38.4%under low rolling speed(less than 10 mm/s).The nanoparticle friction coefficient of PCL decreased by about 33.8%,the lubrication effect of PLLA was relatively weak,and the friction coefficient decreased by about 23.1%.The tribometer test results show the same trend with 5%-7%reduction of friction coefficient.The QCM experimental results show that different materials have different adsorption capacities on the friction interface.The most adsorption of nanoparticles was PMMA,which was up to 0.937μg on the contact area.The self-assembled monolayers(SAM)after the QCM experiment were observed by AFM,and particles could be observed,which were adsorbed on the surface,indicating that the lubricating effect of the nanoparticles is related to the amount of adsorption of the particles.The addition of SDS to the release medium could increase the solubility of the celecoxib.When the concentration of SDS is 0.2%,the saturation solubility of celecoxib is about 3 μg/mL.When PLA and PCL were used as the nanocarrier,83.47%and 80.64%of celecoxib were released within 24 h and 120 h,respectively.However,when PLLA and PMMA were employed as the nanocarrier,95.38%and 46.13%of celecoxib were released up to more than a week,respectively.ConclusionFour kinds of methods of preparing nanoparticles were compared in this study,and high-pressure homogenization was selected to prepare particles with different materials.The reduction of friction coefficient could be explained by adsorption of nanoparticles on contact area.The non-steroidal anti-inflammatory drug celecoxib worked as a model drug,and sustained release of it could be up to 9 days.This subject successfully developed a new formulation platform with both lubrication and anti-inflammation effect for early stage intervention of osteoarthritis.