| The SAIB in situ forming systems consist of small amount of pharmaceutically acceptable organic solvent, high viscosity SAIB, active ingredient or/and additives. After mixing with small amounts of organic solvent, the high viscosity SAIB is formulated as a low viscosity solution. Upon injection, the organic solvent diffused out, while the water diffused in the SAIB/organic solvent system. As a result, a high viscosity depot was formed, from which the drug is released slowly.Risperidone is a second generation of atypical antipsychotic. It can be used to treat schizophrenia （including adolescent schizophrenia）, schizoaffective disorder, and the mixed and manic states associated with bipolar disorder. Compared with other traditional antipsychotic, it has advantages of improved therapeutical effect and lower extrapyramidal side effects.The risperidone-SAIB in situ forming depot has advantages of sustained-release profile, reduced administration frequency, improved bioavailability, steady plasma concentration level, reduced adverse effects and improved treatment compliance.At first, HPLC method was developed to determine the drug loading and in vitro release of risperidone-SAIB depot. The specificity, stability, and reproducibility of the method were good. The solubility of risperidone in different solvents and the stability were determined. The solubility in water was 0.22 mg/mL, while that in pH 7.4 PBS was only 0.39 mg/mL. Risperidone was sparingly soluble in ethanol and DMSO, but has a better solubility in NMP. Risperidone has a good stability in pH 7.4 PBS at 37℃, which provided a guarantee for the following in vitro release investigation.In this investigation, the effects of different factors on the in vitro release of SAIB depots were evaluated. To help further understand the release kinetics of risperidone from SAIB systems, a systematic assessment on the SAIB depot characteristics was carried out. Fixing the solvent concentration at 20%（w/w）, the cumulative release of drug after 1 d was 17.37% for EtOH,15.74% for NMP, and 4.95% for DMSO. The enhanced viscosity and intermolecular force, and the improved solidification rate of SAIB/DMSO solutions reduced the solvent diffusion rate and the burst drug release. By adding 10%（w/w） PLGA into SAIB/DMSO system, the viscosity and intermolecular force were enhanced. Upon contacting with water, a thicker shell was formed immediately at the interface, which reduced the mass transfer rate. For the SAIB/PLGA/DMSO （70/10/20, w/w/w）, the burst release of risperidone was 1.05%. During the first diffusion phase （0-34 day）, the release kinetics of risperidone most closely fitted zero-order release kinetics （r= 0.9924） with a slope of 0.72. The average percentage release was 0.72% per day. After 34 days, water diffused into the hydrophobic region of the depot along with the hydrolysis of PLGA. The visible collapsing depot structure of the SAIB/PLGA （70/10, w/w） mixture matrix depot took place along with the erosion of PLGA, which triggered the the fast drug release controlled by erosion process. The accumulative release was 66.82% on the 60th day.An UPLC-MS/MS method was developed to investigate the pharmacokinetic behavior of risperidone-loaded SAIB in situ forming depot system after i.m. administration in rats. The initial release in vivo decreased with increasing PLGA content. By increasing PLGA content from 0% to 10%（w/w）, the Cmax was significantly reduced from 728.8±121.8 to 280.3±98.5 ng/mL （p<0.01） and the AUC0-4d was decreased from 766.9±211.7 to 554.6±106.8 ng/mL-d （p<0.05）, while the AUC4-20d was markedly increased from 79.9±22.1 to 343.8±88.9 ng/mL-d （p<0.01）. The steady-state concentration （Cs） was defined as the average value of the plasma concentration from 4 to 20 day. The burst release of SAIB depot could be represented by Cmax/Cs. Cmax/Cs was reduced from 238.8±113.9 to 21.6±9.6 （p<0.01） by increasing PLGA from 0% to 10%. By inclusion of 10% PLGA, Cmax/Cmin （4-20 d）> used to evaluate steady degree of plasma concentration, was only 10.7±5.0. These results indicated that the SAIB/PLGA/DMSO （70/10/20, w/w/w） systems exhibited a lower burst release and a stable plasma concentration in vivo.To further reduce the burst release, a risperidone-loaded matix microsphere was prepared using particle size, burst release and drug loading as evaluation indexes. Different preparation methods, including conventional homogenization and membrane emulsification method, were employed to prepare microsperes. The results showed that microsphere, prepared by conventional homogenization method, had smooth surface and porous inner structure, with mean volume diameter of 18.95±18.88 μm, drug loading of 24.71% and burst release of 1.14%. However, the drug release rate markly increased from 2 to 14 days, and following with a slower release. After dispersing the microsphere into SAIB/EtOH system, the burst release was 1.88±0.07%, and the cumulative release was only 22.44% on day 60. By using membrane emulsification method through 10μm SPG, a uniform dispersion microsphere was obtained, which exhibited a smooth surface and dense inner structure, with mean volume diameter of 18.95±18.88μm, drug loading of 24.71% and burst release of 1.14%. The release kinetics of risperidone most closely fitted zero-order release kinetics （r= 0.9916） with a slope of 2.458. The average percentage release was 2.31% per day. The accumulative release was 69.39% on day 30. After encorporating into SAIB/EtOH system, the burst release was reduced to 0.64±0.10%, and the accumulative release was 19.89% on the 60th day. These results indicated that the drug release rate could be inhibited efficiently by incorporating risperidone-loaded matrix microsphere into SAIB depot.An UPLC-MS/MS method was employed to investigate the pharmacokinetic behavior of risperidone-loaded matrix microsphere-SAIB in situ forming depot system after i.m. administration in rats. Compared with microsphere-SAIB depot prepared by conventional homogenization method, the microsphere-SAIB depot prepared by membrane emulsification method through 10μm SPG exhibited a slower drug release behavior. The Cmax was significantly reduced from 186.6±104.2 to 73.9±30.6 ng/mL （p<0.05） and the AUC0-4d was decreased from 185.3±76.5 to 105.2±24.36 ng /mL-d （p<0.05）. After injection of 4 days, the drug release more steadily, resulting in a steady plasma concentration. The Cs from 4 to 54 days was 7.5±2.4 ng/mL, which was slight higher than that of the former depot （Cs=4.4±1.8 ng/mL）. The AUC478dwas increased from 238.2±101.1 to 379.0±114.3 ng/mL-d. It exhibited a lower burst release （Cmax/Cs=10.7±4.6） and a stable plasma concentration （Cmax/Cmin （4-s4 d）= 7.9） in vivo. Compared with the SAIB/PLGA/DMSO （70/10/20, w/w/w） system, the microsphere-SAIB depot revealed a lower plasma concentration and more prolonged release period. The Cmax was 4-fold lower than that of SAIB/PLGA/DMSO （70/10/20, w/w/w） system, while the AUCo-4days was 5-fold lower. The Cmax/Cs was reduced from 21.6±9.6 to 10.7±4.6 （p<0.05）. These results indicated that the burst release could be reduced efficiently by incorporating risperidone-loaded matrix microsphere into SAIB depot.The residue amount method was used to evaluate the in vivo drug release behavior and SAIB degradation behavior of risperidone-loaded matrix microsphere-SAIB in situ forming depot system. After i.m. administration in rats, the drug release rate has a good correlation relationship with diffusion-erosion model. The SAIB depot degraded slowly in vivo, following with first order kinetics. Meanwhile, the biocompatibility of risperidone-loaded matrix microsphere-SAIB in situ forming depot system was evaluated after i.m. administration to rats. The acute inflammation, chronic inflammation, fibrous tissue coating and microvascular proliferation at the injection sites was observed. The inflammation tissue was gradually replaced by fibrous tissue along with the degradation of SAIB. There was no sign of serious inflammation and necrosis during the experiment period. Thus, the risperidone-loaded matrix microsphere-SAIB in situ forming depot is biocompatible. |
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