Research Of Condition-activated Drug Delivery System Of Risperidone

Research of Condition-activated Drug Delivery System of RisperidoneRisperidone is one of the members of the atypical neuroleptic drugs and a candidate as a clinically applicable neuroprotective drug.It is widely used in the treatment of schizophrenia and bipolar disorder.In addition to its superior efficacy profile relative to conventional neuroleptic agents for acute treatment of psychotics symptoms,it is also considered to be more effective for improving long-term outcome in schizophrenia.However,current delivery methods for risperidone are far from ideal. Conventional oral administration has some drawbacks such as poor oral bioavailability,short plasma half life and widely fluctuating blood concentrations, which have indicated the need for a sustained drug delivery system.Two condition-activated drug delivery systems of risperidone were developed.One is non-solvent activated sustained release drug delivery system,the other is temperature and non-solvent activated sustained release drug delivery system.In the former system,we focused on risperidone PLGA depot(PD) and risperidone solid-PLGA depot(SPD).In the latter system,risperidone Poloxamer-solid lipid-PLGA depot (FSPD) was prepared and tested in vivo.In the preformulation study,the HPLC method for analysing risperidone was established firstly and the influence of benzyl benzoate(BB),benzyl alcohol(BA), glyceryl monosterate(GT) on the solubility of risperidone in saline was determined. Method of risperidone release in vitro was also established.The solubility results showed BB,BA and GT increase risperidone solubility a little.The sink condition was maintained with enough medium and frequent replacement of fresh saline during the in vitro release experiment.In the study of PD in vitro,the PD was prepared with PLGA and biocompatible organic solvents.The basic concept of this kind drug carrier can be interpreted briefly as follow:it contains a polymer that does not dissolve in the bath side liquid and polymer solvent that is fully or partially miscible with the bath side liquid.Upon injection into aqueous environment,the solvent diffuses into aqueous surrounding and water penetrates into the polymer matrix.Liquid-liquid demixing is a necessary process that is responsible for decreasing PLGA solubility and result in an "in situ implant".This depot solution is usually injected intramuscularly or subcutaneously. Drug dissolved in the polymer solution released in a controlled fasion.The in vitro study result showed the concentrations of PLGA and kinds of solvents would influnce the release of risperidone.In the study of SPD in vitro,,a combination of PLGA,solid-lipids and solvents mixtures(BB and BA) was in non-solvent activated drug delivery system.The in vitro drug release from SPD was investigated as a function of the concentration and type of solid lipids,the concentration and molecular weight of PLGA and the proportion of solvents components.The solid lipids and PLGA solidified upon contact with the release medium.The exist of solid lipid would reduce drug initail release dramatically. The drug release rate from SPD decreased with increasing the concentration of solid lipids and PLGA as well as PLGA molecular weight.The typies of solid lipids and PLGA also affected the drug release.In vivo study,the SPD was compared with PD without solid-lipid on pharmacokinetics and degradation behavior.Risperidone concentration in the plasma was analyzed by HPLC and the area under curve(AUC),main resistance time(MRT) were caculated.Bioavailability of risperidone was obtained by comparing AUC data of PD and SPD with AUC data from risperidone solution administrated intravenously. An extended-release profile and significantly reduced burst effect resulted when solid lipid was added.The MRTs of PD and SPD are 32.605±50h and 86.86±13.71h respectively,and the abosulte bioavailabilities of PD and SPD are 63.3±10.1%and 87.77±4.57%.It is evident from this study that PD and SPD is suitable for developing prolong-release injectable implant delivery systems for risperidone. On the base of non-solvent activated sustained release drug delivery systems,a noval temperature and non-solvent activated drug delivery system was developed.PLGA BB/BA was used as oil phase and F127 was used as water phase,which were mixed in to be a O/W emulsion.It can be activated by bodily temperature and fluids to a sustained release depot.The MRT and the abosulte bioavailability of it are 105.35±10.91h and 84.84±27.6%.The condition-activated risperidone sustained release drug delivery systems have outstanding performance in controlling drug release as well as high bioavailability. Besides,its preparation is simple and low-cost.The condition-activated sustained release drug carriers are potential to be developed into a new product.