Preparation Of Parecoxib Sodium Thermosensitive In-Situ Nasal Gel And Its Pharmacokinetics In Rats

Parecoxib Sodium（PCX）is a pro-drug of valdecoxib,which is a specific cyclooxygenase-2（COX-2）inhibitor,it is widely used in perioperative analgesia and cancer pain.The dosage form of PCX used in clinic is injection,which is usually administered by intravenous or intramuscular injection,but injection administration is invasive administration,which will bring certain pain and discomfort,and requires the assistance of others,so it is inconvenient to use and the patient’s compliance is poor.Nasal administration has the characteristics of quick absorption,high bioavailability and convenient administration,which is very suitable for emergency medicine.In situ nasal gel is a new nasal drug delivery formulation,which has the advantages of quick absorption,accurate dose,high bioavailability,convenient administration and sustained release and long duration.Based on the above analysis,this study intends to make PCX into a new type of preparation,a nasal thermosensitive in-situ gel.This study systematically researches PCX nasal thermosensitive in-situ gel through pre-prescription research,in vitro drug transnasal mucosa experiments,prescription composition and preparation process research,in vitro quality evaluation,in vivo pharmacokinetics and bioavailability research,and nasal mucosal toxicity evaluation.1.The pre-prescription study of PCX nasal thermosensitive in-situ gel was completed,including establishment of PCX content determination method,chemical stability of PCX solution,oil-water partition coefficient（P）,solubility.The chemical stability study of PCX solution showed that when pH<6,the chemical stability of PCX solution was poor,especially in the strong acid condition of pH=2.0,the degradation rate of PCX could reach 100%within24h,and when pH≥6,PCX hardly degrades and its solution has good chemical stability.The results of the oil-water partition coefficient determination showed that when pH<7.0,the P value of PCX was large,and decreasesd with the increase of pH,and the trend presented an inverted"S"shape.The solubility measurement results of PCX showed the solubility of PCX was low when the pH≤6,and the solubility increased gradually with the increase of pH.2.In vitro drug transnasal mucosa test of PCX was completed.The isolated sheep nasal mucosa was used to investigate the water-solubleβ-cyclodextrin（β-CD）penetration enhancement effects of DM-β-CD,HP-β-CD and SBE-β-CD on PCX,and the optimum concentration of the best penetration enhancer was screened at the same time.The results showed that 5%HP-β-CD had the best penetration enhancing effect,so it was used as the absorption and penetration enhancer of PCX nasal thermosensitive in-situ gel.3.The prescription screening and preparation process research of PCX nasal thermosensitive in-situ gel were completed.Taking the prescription dosage of Poloxam 407（F127）,Poloxam 188（F68）and hydroxypropyl methyl cellulose（HPMC）as factors,the gelation temperature and gelation time as indexes,and central composite design-response surface methodology（CCD-RSM）was used to screen the composition of blank gel prescription.Combined with the results of pre-prescription study,in vitro transnasal mucosa experiments and the quality standard of nasal gel,the optimal prescription of PCX nasal thermosensitive in-situ gel was determined as follows:2.5%PCX,5.0%HP-β-CD,20.88%F127,3.28%F68,0.28%HPMC,0.05%ethyl paraben and appropriate amount of water.4.The in vitro quality evaluation of thermosensitive in-situ gel for nasal use of PCX was completed,including appearance and pH,gelation temperature and gelation time,content of PCX and ethyl paraben,in vitro dissolution and release,effect of temperature and rotational speed on gel viscosity,expansion coefficient and water holding capacity of the preparation.The results showed that the appearance of the gel was clear and transparent,the pH was 7.4,the gelation temperature was 32.2℃,the gelation time was 48.2s,and the content of PCX and ethyl paraben were 95.0%～105.0%of the labelled amount.The in vitro dissolution test showed that the cumulative dissolution rate of the gel was 96.29%and the cumulative drug release rate was 84.76%at 80min,and the correlation coefficient was 0.9994,indicating that the drug release process in the gel was mainly affected by gel dissolution.The in vitro release test showed that PCX solution had a cumulative drug release of 81.9%within 3h,while the drug release rate of the gel was only 50.4%,and could reach 92.7%after 10h,indicating that the gel had an obvious sustained release effect.In addition,the gel had shear thinning phenomenonthe,expansion coefficient and water retention of PCX nasal thermosensitive in-situ gel were 2.78%and 97.81%respectively.5.The pharmacokinetics and bioavailability of PCX nasal thermosensitive in-situ gel in rats were studied.Firstly,a method for the determination of PCX in rat plasma was established.Then,with intramuscular injection of 0.5%PCX solution as a reference,the main pharmacokinetic parameters and relative bioavailability（F_r）of intranasal administration of5.0%PCX nasal thermosensitive in-situ gel were determined.The results showed that the main pharmacokinetic parameters of intranasal administration of PCX gel and intramuscular injection of PCX solution were as follows:T_maxwere 0.10h and 0.15h,C_maxwere14.86μg·mL^-1and 10.80μg·mL^-1,K_awere 21.18h^-1and 10.96h^-1,K_ewere 1.05h^-1and 1.60h^-1,AUC_0-∞were 10.65μg·h·mL^-1and 4.41μg·h·mL^-1respectively,the relative bioavailability F_rof PCX nasal thermosensitive in-situ gel was 241.50%,indicating that the absorption rate of PCX was faster and the bioavailability was significantly improved after intranasal administration.6.The nasal mucosal toxicity of PCX nasal thermosensitive in-situ gel was studied.In vitro and in vivo methods of toad upper jaw mucosal model were used to investigate the nasal mucosal toxicity of PCX nasal thermosensitive in-situ gel,blank thermosensitive gel and PCX solution respectively,using the morphology of upper jaw mucosa and lasting time of ciliary movement as indicators.The results showed that the above-mentioned tested substances had certain toxicity to the toad upper jaw mucosa,the effect of PCX solution on upper jaw mucosa was greater than PCX nasal thermosensitive in-situ gel,and thermosensitive blank gel had the least mucosal toxicity,but the toxicity was mild and reversible.