Study On Iloperidone Sustained-release Micropheres

Iloperdone is a new atypical antipsychotics. In2009, Iloperdone wasapproved by the Food and Drug Administration(FDA) for sale in the Unitedstates, which was used for treatment of schizophrenia. Not only iloperdoneis effective in treating the positive symptoms of schizophrenia, but also itcan improve the negative symptoms of schizophrenia, while can reduceextrapyramidal syndrome. It has clinical value with significant effect andlesser adverse effect. Currently, Iloperdone (Fanapt) was supplied as atablet defined for oral administration（there is no other formulations in themarket）, patients need long-term medication and specially care. Injectablesustained-release microspheres have many advantages, such as to reduceadministration frequency, high bioavailability, no first-pass effect, stableplasma concentration and to enhance the patient compliance, etc. Usingbiodegradable polylactic-co-glycolic acid (PLGA) as microspheres carrierwith better biocompatibility and readily biodegradable absorption in vivo,which attracted more and more attention from scholars. Therefore, usingPLGA as microspheres carrier, iloperidone made injectablesustained-release microspheres, by intramuscular administration, the designed time of drug release was one month, with the purpose of reducingadministration frequency, maintaining steady-state plasma concentrationsand enhancing the patient compliance, which has important clinicalsignificance for treatment of schizophrenia.The equilibrium solubility and oil-water partition coefficient ofiloperidone were investigated firstly, the results showed that iloperidonewas a kind of lipophilic drug. Therefore, iloperidone was selected as themodel drug, iloperidone sustained-release microspheres were prepared byan O/W emulsion-solvent evaporation method. The encapsulationefficiency (EE) and the drug loading (DL) were assessed by Ultravioletspectrophotometry(UV). The in vitro release of iloperidone from thesustained-release microspheres was evaluated by dynamic membranedialysis method, which lay the foundation for prescription screening andprocess optimization of iloperidone sustained-release microspheres.Iloperidone sustained-release microspheres were prepared by an O/Wemulsion-solvent evaporation method. According to the results of singlefactor experiments, PLGA concentration, the mass ratio of iloperidone andPLGA, the volume ratio of organic and aqueous phase, PVA concentrationand speed of mechanical stirring were the main influence factors. On thebasis of single factor experiments, the optimal formulation selected byorthogonal design that was evaluated by EE、DL and burst release, Theoptimized preparation conditions were as follows: PLGA concentration was 80g·L-1, PVA concentration was1%, speed of mechanical stirring was10000rpm, the volume ratio of organic and aqueous phase was1:30, themass ratio of iloperidone and PLGA was1:5.The physico-chemical characteristics of iloperidone was evaluated.Iloperidone sustained-release microspheres were dried using freeze-dryingmethod that were loose and white powder. The results of scanningelectronic microscopy(SEM) showed that iloperidone sustained-releasemicrospheres was a spherical and smooth surface; The size of iloperidonesustained-release microspheres was determined by Zetasizer Nano ZS90that was21.94μm; The moisure of iloperidone sustained-releasemicrospheres was﹤2.0%, which met the requirements; The pH ofiloperidone sustained-release microspheres were in the range of4to9inthree solvent, which met the requirements of physiological conditions andwas suitable for intramuscular administration; The EE of iloperidonesustained-release microspheres were above80%, which met therequirements of the Chinese Pharmacopoeia.The in vitro releasing conditions of microspheres was investigated,determined pH7.4phosphate buffer solution (with1%Tween80and0.02%sodium azide) as releasing media. We established a fast-releasingmethod, the results showed that the fast-releasing method in the conditionof65℃and200rpm was similar to the sustained-releasing method(r=0.9913), so it was reasonable that using fast-releasing method substituted sustained-releasing method to study the in vitro release behaviorof iloperidone from the sustained-release microspheres. The behavior ofiloperidone sustained-release microspheres in releasing media was fittingthe Higuchi model. The mechanic of drug release was synergistic actionabout diffusion with skeleton dissolution. The results of the in vitro releaseof iloperidone showed that the cumulative release percentage of iloperidonesustained-release microspheres within30day was above86%, it wasindicated that the homemade iloperidone microspheres had obvioussustained-release effect, which met the requirements of sustained-releasemicrospheres and achieved the desired results.The stability of iloperidone sustained-release microspheres wasevaluated, the results showed that high moisture and high temperatureaffected the properties of the iloperidone sustained-release microspheres.The iloperidone sustained-release microspheres could be kept stable at25℃for6month without any signifiant changes, it was illustrated that thequality of iloperidone sustained-release microspheres was stable, itsformulation and process met the requirements of production and storage.The preliminary pharmacokinetics iloperidone sustained-releasemicrospheres was studied, The results indicated that iloperidonemicrospheres in rabbit can slowly release drug around30day, whichachieved the desired results. The correlations of in vitro and in vivo wereevaluated, the release showed a good correlation for iloperidone sustained-release microspheres.