Studies On The Injectable Risperidone-SAIB In Situ Depot System

Risperidone, one of the newer high-potency antipsychotic agents, is an effective drug for the treatment of positive as well as negative symptoms of schizophrenia and it has a limited ability to cause causing extrapyramidal side effects at therapeutically effective doses.The sucrose acetate isobutyrate (SAIB) system is a biodegradable material for developing an injectable sustained-release in situ depot using a polymer-free solution consisting of a small amount of organic solvent, the active ingredient and SAIB. SAIB with high viscosity does not dissolve in water. However, the solution viscosity of SAIB is significantly degraded by adding small amount of solvent, and it can be easily injected in vivo, then form in situ depot by solvent exchange.In this study, the development of an effective injectable risperidone-SAIB in situ depot with limited adverse effects and with excellent treatment compliance would make an important contribution to the long-term management of schizophrenia.HPLC method was developed for the assay of risperidone. The solubility and oil/water partition coefficient of risperidone in different pH was determined. The solubility of risperidone in water was 0.13 mg/mL, but was affected by pH. The LogP was 2.02, showed that it was highly lipophilic. The use of the SAIB/solvent system was able to improve the solubility of risperidone to a degree which depended on the composition of the solvent systems. Risperidone showed its well stability by the results of the experiments in high temperature and humidity studies, but did not stable in light studies. The content of risperidone in PBS was 97.14% by 37℃after 5 days.The rheological properties of SAIB/solvent system was studied, and it was similar to Newtonian fluid. The factors such as the type of solvent, concentration, additive, drug and temperature had effect on the rheological properties. Ethanol was a suitable solvent compared with Ethyl lactate and N-methylpyrrolidone (NMP). The solution viscosity of SAIB was reduced from 1.29 to 0.11 Pa.s with only increasing the content of Ethanol from 10% to 20%. Polylactic acid (PLA) and risperidone could increase the intermolecular force and viscosity. The solution viscosity reduced significantly by steping up the temperature. It is easy to inject for 20% solvent in SAIB system. The particle size distribution of risperidone was controlled by spray dried. 93.5% of the powders was below 100μm, and the mean size was 44.77±30.20μm. The risperidone-SAIB in situ depot contained SAIB, solvent (anhydrous ethanol, ethyl lactate or N-methyl-2-pyrrolidone), and additives such as polylactic acid (PLA). In-vitro release profiles of risperidone from the SAIB formulations, which followed the Higuchii square root law, were obtained. An increase in SAIB content from 75% to 85% resulted in a reduction in the initial burst from 30.7 to 15.6% for SAIB/EtOH system. The initial drug release could be increased by reducing the pH of the release medium, but the release in later stage was not effected. The release rate could be increased by an increase in drug loading and the slow dissolution of the suspended drug. The presence of PLA probably altered the initial release of risperidone by forming a diffusional membrane around the depot after contact with the aqueous buffer. The drug release profiles followed the Higuchii square root law from 0 to 31 day. In the later stage, the drug release rate was uniformity and close to zero from 9 to 31 day. The burst release fell from 20.0% to 10.8% following the inclusion of 1% (w/w) PLA in the formulations, the average percentage release was 1.7% for every day from 9 to 13 day, and the accumulative release was 75.0% on Day 31. When the concentration of PLA was increased to 10% (w/w), the burst release was significantly reduced, the average percentage release was 1.2% for every day from 9 to 13 day, and the accumulative release was 43.4% on Day 31.The in vivo pharmacokinetic behavior of risperidone and 9-OH-risperidone were studied utilizing UPLC-MS/MS method. The pharmacokinetic study of risperidone after intravenous administration in rats Was performed. The pharmacokinetic parameters were studied according to non- compartment model. The result showed that PLA is effective in reducing the burst effect. After a 12.5 mg/kg IM injection of a 25 mg/g risperidone-SAIB in situ depot, the C_max was markedly reduced from 944.1±80.2 to 330.4±33.6 ng/mL by increasing PLA from 1% to 10% (w/w), the T_max were prolonged from 2 to 4.3±2.0 h, and the area under the curve from day 0 to 2 (AUC_0-2day) was reduced significantly from 16294.8±3946.4 to 7025.3±1979.2 ng·hour/mL (P＜0.05). The steady-state concentration (C_s) was the average value of the plasma concentration from 9 to 21 day, and the C_max/C_s was significantly reduced due to the increased PLA from 415.8 to 11.3. For the risperidone-SAIB in situ depot including 10% PLA, the high release rates over a short period allowed therapeutic plasma concentrations to be achieved in the initial stages after activation, and sustained release of the drug led to a stable plasma concentration. Non-linear pharmacokinetic was found for the SAIB in situ depot after IM administration. For the high drug loading, the suspended particles acted as a drug reservoir, continuously dissolving to replenish what was being lost and it led to a stable plasma concentration in later stage.Microdialysis technique was used to determine the concentration of risperidone in muscle after IM administration of risperidone solution and SAIB in situ depot.For injection of risperidone solution, the concentration decreased rapidly, and fell below detectability after 4 days. However, for the in situ depot, C_max was 1176.0 ng/mL, T_max Was 0.083 h, AUC_0-25day was 57289.3 ng-hour/mL. The results showed that the measured muscle microdialysis concentrations of risperidone, corrected for recovery were comparable to the drug active moiety levels in plasma concentrations, and the dependablity equation was y=3.085x—41.29, r = 0.9964. The percentage of release in vivo was plotted against the cumulative release percent in vitro to obtain a correlation relationship, and the dependablity equation was y=0.371x—4.14, r =0.9708.The biocompatibility of risperidone-SAIB in situ depot were evaluated in rats after IM injection. It was observed that acute inflammation, chronic inflammation and at the injection sites. It was because that injection or implantation of a biomaterial resulted in a foreign body response, and it was most often in the case of a biodegradable material. However, the foreign body reaction was gradually reduced by SAIB degradation, and no signs of serious inflammation and necrosis were evident. Therefore, these preliminary findings suggest that SAIB formulations are biocompatible and tolerated.