| Paliperidone is the first-line drug for atypical antipsychotics and has a good therapeutic effect on both negative and positive symptoms of schizophrenia,and is not easily produced extrapyramidal reactions.Due to the large individual differences in the use of paliperidone,the bioavailability is low.Therefore,our laboratory combines the advantages of prodrugs to synthesize various paliperidone ester derivatives.We finally select Isoperidone for further formulation studies.Liposomes can entrappe in fat-soluble and water-soluble drugs,and is an ideal drug carrier.However,liposomes are prone to aggregation and sedimentation during storage and transportation.Therefore,proliposome can improve the above-mentioned disadvantages.In this study,soybean phospholipids,cholesterol and polyethyleneimine polymers modified by lolinyl chloride(PEI-LA)were used as membrane materials.After the Isoperidone was loaded,the carrier mannitol was added for freeze-drying to prepare positively charged oral cations prosliposomal(Isoperidone proliposomes,P-Iso)P-Iso improves the solubility of Isoperidone and enhances the oral bioavailability of Isoperidone by enhancing its adsorption with small intestinal epithelial cells.This study includes the following:1.Establishment the analysis method of P-Iso in vitro.In this study,high-performance liquid chromatography(HPLC)was used for the quantitative analysis of Isoperidone and a series of methodological validation was performed.The method validation shows that the RSD value of this method is less than 1.50%,and the specificity is good and meets the relevant requirements.Therefore,the HPLC method can be used for the determination and quality control of drug content in P-Iso.This study also established a method for the determination of the entrapment efficiency of iso-butyl ketone liposomes reconstituted with P-Iso by ultrafiltration centrifugation.The results of the recovery rate showed that the recoveries of the method were in the range of 99.52% to 106.80%,and RSD values.All less than 3.00%,can effectively separate the free drug from the suspension obtained by reconstitution of the lyophilized product.2.Preparation and formulation optimization of P-Iso.In this study,liposome preparation method using ethanol injection method,adding the carrier and freeze-dried to prepare P-Iso.With the entrapment efficiency as the index of inspection,single factor experiments were performed to select the three most significant factors: lipid-to-drug ratio,phospholipid-to-cholesterol ratio,and phospholipid-to-PEI-LA ratio for response surface optimization experiments.The final optimization result was SPC:drug=9.65,SPC:chol=5.04,SPC:PEI-LA=21.49.The verification test showed that the encapsulation efficiency of P-Iso was 53.78% and the predicted value was 53.99%.The prediction result of the model was accurate and reliable.The particle size measured by the laser particle size analyzer was 241.4±6.4 nm,the PDI value was 0.268±0.025,the zeta potential was 12.7±2.1 mV,and the encapsulation efficiency was 50.45%±0.42%.2.Quality evaluation of P-Iso.In this study,the particle size and potential of P-Iso prepared by the optimal formulation were evaluated.P-Iso is a colorless,odorless,white powder with good porosity.FE-SEM observation of the morphology showed that the reconstituted liposomes were spherical and had a particle size of about 200 nm.In vitro release experiments showed that P-Iso had a sustained release effect in both artificial gastric juice(pH 6.8)and artificial intestinal fluid(pH 6.8).Differential scanning calorimetry(DSC)analysis showed that the drug and membrane materials(SPC,etc.)and mannitol in P-Iso were not simply physically mixed,and other interactions between Isoperidone and other excipients were generated.4.Establishment biological sample analysis method of P-Iso and pharmacokinetics study.In this study,an accurate and sensitive UPLC-MS/MS method for determination of paliperidone in plasma of Beagle dogs was established.The method validation results show that the method is of good specificity and the intra-day and inter-day accuracy is 3.40%.At 8.57%,the recovery of the test sample was 84.13%~89.15%.It can be used in vivo pharmacokinetic study of Beagle dogs after oral administration of P-Iso.The pharmacokinetic characteristics of the oral administration of isobutyricin and P-Iso were compared.The Cmax,Tmax,AUC0 –∞,and MRT0 –∞ of P-Iso were compared with those of the direct oral drug substance.With an increase,the relative bioavailability was 2.46,indicating that the prepared liposomes have the effect of prolonging the action time with the gastrointestinal tract and increasing the oral bioavailability of Isoperidone.In summary,the surface of the liposomes reconstituted in this study was positively charged,and the lyophilized product had better porosity,and the entrapment efficiency,particle size,and potential of ipidone ketone liposome before and after freeze-drying.Little change.The results of animal experiments show that its oral bioavailability is significantly higher than that of raw materials. |
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