Study On Aprepitant Solid Dispersions And Nanosuspensions

Aprepitant is a delayed antiemetic for antiemetics in cancer patients during chemotherapy.Aprepitant is a poorly soluble drug with a first-pass effect and a moderately potent P-gp substrate with low bioavailability.In this study,the preparation of aripipamide solid dispersion and nanosuspensions,improved the dissolution rate of aprepitant,and promote the transmembrane ability of aprepitant,increased the bioavailability of aprepitant,The mechanism of intermolecular hydrogen bonding between aprepitant and carrier was explained,and the mechanism of carboxymethyl chitosan promoting the absorption of aprepitant was explained.The solubility of aprepitant in different pH buffers and logP were determined.The solubility of aprepitant had pH dependence.With the decrease of pH,The solubility of picretine increased.Screening a series of water-soluble and enteric solid dispersion carrier,obtained with HPMCAS-MF and Soluplus^? as the best carrier.The optimum drug-to-drug ratio of these two materials was 1:4 and 1:5,respectively.The solid dispersions made of these two carriers can greatly improve the solubility and dissolution rate of aprepitant.The results of DSC,XRD and SEM showed that both solid dispersions could disperse the aprepitant into the solid dispersion in the amorphous state.It was found that the carbonyl and amino groups of aprepitant were detected by infrared spectroscopy With the carrier on the hydroxyl and carbonyl hydrogen bonding occurred between the role,respectively,to form a molecular solution.After the stability test,the experimental results show that the two kinds of solid dispersions have good stability,after a month storage,the two solid dispersions can be dissolved in 15min more than 85%.The mechanism of the formation of hydrogen bond between aprepitant and carrier was discussed by IR analysis.The carrier has better compatibility with aprepitant when the carrier contains both hydrogen bond acceptor and hydrogen bond donor.The preparation of aprepitant is nanosuspension and the stabilizer is HPC-SL,which only solves the dissolution of aprepitant and does not completely solve the transmembrane problem of aprepitant.Therefore,this study used a carrier material with the promotion of absorption as a stabilizer to prepare aprepitant nanosuspension,which can increase dissolution and increase transmembrane volume.Through the screening of a large number of carrier materials,it was found that the particle size of the nanosuspensions with carboxymethyl chitosan as the stabilizer was the smallest,and the particle size was determined by the grinding time,the grinding medium size,the concentration of the stabilizer and the operating mode of the ball mill.The particle size of tanamycin suspension was taken as the index,and the best prescription was obtained:the stabilizer concentration was 0.4%carboxymethyl chitosan aqueous solution,the grinding time was 8 h,the grinding medium diameter was 0.5 mm,the running mode was positive Reverse combination.And its curing method was investigated.The freeze-dried products were prepared and the stability of the nanoparticles was improved.For preparation of carboxymethyl chitosan as the carrier of nanosuspension on the DSC,XRD,TEM,dissolution and so on.The particle size of aprepitant nanosuspension was 193 ± 15.2 nm,and the Zeta potential was 66.2 ± 4.9 mV.The nanosuspension were found to be present in the suspension in the form of crystalline form,both lyophilized samples and suspensions were able to elute 85%in 5 min.Through infrared spectrum experiment,a group of the morpholine ring can interact with carrier of carbonyl group,which play a role of the stabilizer of carboxymethyl chitosan.The bioavailability of the above formulations was investigated.The area under the curve was:Aprepitant nanosuspensions>Soluplus-SDs>Emend^?>Soluplus-SDs>aprepitant>MF-SDs.The relative bioavailability of aprepitant nanosuspensions was 140.3%of the marketed preparations,whereas Soluplus-SDs were equivalent to the listed preparations.HPMCAS-MF solid dispersion has the lowest bioavailability.In vivo experiments show that carboxymethyl chitosan as a stabilizer of aprepitant nanosuspension,not only solved the problem of dissolution of aprepitant,but also to overcome its transmembrane problem has been a good absorption effect.In order to further investigate the effect of carboxymethyl chitosan as a carrier on the absorption of aprepitant nanosuspensions,we performed rat intestinal absorption and Caco-2 cell model in vitro.In the intestinal absorption study,found that aprepitant for the whole intestinal absorption of drugs,aprepitant nano-suspension can increase the absorption of aprepitant,the Papp value of 1.75 times the bulk drug.It was demonstrated that nanosuspensions can increase drug permeation because of the reduced action of P-glycoprotein and CYP3A4 enzymes on aprepitant.Carboxymethyl chitosan can open the small intestinal epithelial cells in close connection,which was the basis of its role in promoting absorption,this study by Caco-2 cell model test,and further explore the carboxymethyl chitosan and Soluplus^?to improve the mechanism of drug transmembrane transport.The transmembrane resistance was measured by measuring the transmembrane resistance and the amount of drug across the cell membrane.The effect of nanoparticle suspension of aprepitant on absorption was quantitatively investigated.There was no significant concentration-dependent effect of glycans on the uptake of aprepitant,with a 2.1-fold increase in the Papp value of the aprepitant nanosuspensions compared to Emend^?.It was also demonstrated that carboxymethyl chitosan and Soluplus^? had no significant cytotoxic effects.