Preparation,Characterization And Biological Activity Evaluation Of Three Antipsychotics Solid Dispersions

Oral drug delivery remains the simplest and easiest administration route,and solid oral dosages forms have many advantages over other types of oral dosage forms,such as the greater stability,smaller bulk,accurate dosage and easy production.The low bioavailability of the drug after oral administration is related to its low solubility and low dissolution rate.The solid dispersions（SDs）are simple and effective formulation technology,and has been widely used in improving the solubility and bioavailability of poorly water-soluble drugs.DP-VPA is a phospholipid prodrug of valproic acid,which has been highly recommended as an adjunct to antipsychotics for the treatment of schizophrenia.Meanwhile,phospholipids are considered as promising excipients in solid dispersions for improving the solubility and bioavailability of poorly water-soluble drugs.Aripiprazole（ARI）,ziprasidone hydrochloride（ZIP·HCl）,and olanzapine（OLA）are poorly water-soluble and widely administered antipsychotics.Therefore,in this study,ARI,ZIP·HCl or OLA and DP-VPA were prepared into SDs,and the solubility test and biological activity evaluation were carried out.The prepared SDs may enhance the drugs’solubility,bioavailability and exert synergistic anti-schizophrenic effects.In this study,the SDs of ARI,ZIP·HCl or OLA containing DP-VPA-C₁₈(DV₁₈)were prepared by the solvent evaporation methods and characterized by PXRD,DSC and FTIR techniques.The solubility of ARI,ZIP·HCl or OLA in the prepared SDs was significantly improved in different media（p H 1.2,p H 4.5,p H 6.8 and H₂O）.And in addition to the SDs of OLA,the increased dissolution of drug was positively correlated with the increased DV₁₈content in SDs（p H 6.8）.Pharmacodynamic studies in mice showed those SDs also exhibited synergistic antipsychotic effects in reversing apomorphine-induced climbing behavior and reversing ditazepine-induced hyperactivity behavior.Furthermore,the optimal drug ratios between ARI,ZIP·HCl or OLA and DV₁₈were determined as 1:10（SD-ARI 10）,1:8（SD-ZIP 8）and 1:20（SD-OLA 20）,respectively.The oral bioavailability of SD-ARI 10 or SD-ZIP 8 was significantly improved when compared to the pure drugs,and the relative bioavailability was 1.17 and1.67-fold,respectively.This research showed that DP-VPA,as a carrier drug,could improve the pharmacokinetics and pharmacodynamics of antipsychotics drug solid dispersions.And it is a promising solid dispersion carrier with market potential.