Preparation Of Quetiapine Fumarate Long-acting Nanosuspensions For Injection And Its In Vitro And In Vivo Release Properties

BACKGROUND:Nanosuspension technology were refererd to a preparation process that used mechanical means to reduce the particle size of insoluble drugs,thereby increasing the bioavailability of drugs.There were two main categories:(1)Top-down method:medium grinding method and high-pressure homogenization method,which required high equipment and energy consumption.(2)Bottom-up method:Including a precipitation method and an emulsification method.This method required the use of an organic solvent for dissolving the drug.Therefore,there was a problem of residual solvent that could not be applied to the preparation of injections.Quetiapine fumarate(QF)was a water-insoluble,atypical antipsychotic drug,used to treat mania in schizophrenia and bipolar disorder.At present,there only had QF tablets in domestic,but had sustained release tablets and ordinary tablets in abroad.Quetiapine fumarate had a wide range of applications and low price,but its single dosage form,low bioavailability,and poor compliance with mental patients made the clinical use limited.Therefore,this study intended to prepare long-acting nanosuspension formulations of quetiapine fumarate for injection to improve its bioavailability and increased patient compliance,which had certain scientific value and market demand.OBJECTIVE:To prepare a long-acting quetiapine fumarate nanosuspension formulation with high bioavailability and suitable for intramuscular injection by media milling method,and to investigate the in vitro and in vivo release characteristics.Analysis of the clinical feasibility of the suspension formulations compared to commercially available tablets.METHOD:1.Based on the Chinese Pharmacopoeia(2015)(Ch.P.2015)and import standards,the physicochemical properties of quetiapine fumarate(QF)were studied and a method for the determination of in vitro dissolution was established.2.The wet media milling technique was used to prepare the nanoparticle preparations.The particle size was used as the index,and the L9(34)optimization process recipe was designed by combining the single factor experiment with the orthogonal experiment.3.Repeated preparation of three batches,reconstitution after lyophilization,and characterization of candidate nano formulations.4.In Vitro Experiments:Refer to ChP.2015,and determined the physical mixed preparation(direct physical mixing of QF and auxiliary materials)in a pH 6.8 phosphoric acid-sodium dihydrogen phosphate buffer solution at 50 rpm and a temperature of(37±0.5)℃,and in vitro released characteristics of candidate nanoformulations.5.In vivo experiments:SD rats were used as a model and intramuscular injections of physical mixture preparations and candidate nano preparations(average particle size of about 760 nm);intragastric administration of commercially available tablets,plasma concentrations were measured at different time points.RESULTS:1.A RP-HPLC method was established to determine the QF content.In the range of 0.50～10.0 μg/ml,the linear correlation was y=126.52x-6.9881 and R2=0.9999.The method had high resolution and high column efficiency.2.The optimal formulation was:Grinding medium(0.5mm:1mm:3mm=20:60:30)with 50 mg/ml QF,1%CMC-Na and 0.08%Tween-80 for 4 hours(every cycle,forward 10 min,stay 30 s,reverse 10 min)to obtain candidate preparations.(particle size about 760 nm).3.After reconstitution,the particle size,particle size distribution(PDI),Zeta potential and sedimentation ratio for candidate preparations were 766.9 nm,0.265,-35.89 mv,and 96.00%respectively.The DSC(drug in crystalline state)and morphology showed round spherical.4.In vitro:The cumulative release of the physical mixture preparation was approximately 89.4%at 150 min,and the cumulative release of the candidate nano formulation at 120 min was approximately 100%.5.In vivo:Comparing with the commercially available tablets,the peak time of the candidate nano formulations was delayed and there was no difference in the peak concentration,but the effective monitoring of the concentration time was prolonged and the area under the curve was significantly increased about 5 times,while the physical mixture formulation had not this phenomenon.CONCLUSION:Long-acting nanosuspensions of quetiapine fumarate were prepared by planetary media grinding milling.In vitro:The preparation was completely released and stable in properties.In vivo:Compared to oral formulations,nanosuspension formulations(particle size of about 760 nm)increased the bioavailability of QF with effective plasma concentrations for a period of up to 7 days.Therefore,the long-acting nano-suspension formulation could be used as a new candidate dosage form for increasing the bioavailability and compliance of quetiapine fumarate used in clinic in the future.