Abstract
Schizophrenia is a disorder characterized by cognitive impairment and psychotic symptoms that fluctuate over time and can only be mitigated with the chronic administration of antipsychotics. Here, we propose biodegradable microPlates made of PLGA for the sustained release of risperidone over several weeks. Two microPlate configurations – short: 20 × 20 × 10 μm; tall: 20 × 20 × 20 μm – are engineered and compared to conventional ~ 10 μm PLGA microspheres in terms of risperidone loading and release. Tall microPlates realize the slowest release documenting a 35% risperidone delivery at 100 days with a residual rate of 30 ng/ml. Short microPlates and microspheres present similar release profiles with over 50% of the loaded risperidone delivered within the first 40 days. Then, the therapeutic efficacy of one single intraperitoneal injection of risperidone microPlates is compared to the daily administration of free risperidone in heterozygous knockout mice for dysbindin-1, a clinically relevant mouse model of cognitive and psychiatric liability. In temporal order object recognition tasks, mice treated with risperidone microPlates outperform those receiving free risperidone up to 2, 4, 8, and 12 weeks of observation. This suggests that the sustained release of antipsychotics from one-time microPlate deposition can rescue cognitive impairment in dysbindin mice for up to several weeks. Overall, these results demonstrate that risperidone-loaded microPlates are a promising platform for improving cognitive symptoms associated to schizophrenia. Moreover, the long-term efficacy with one single administration could be of clinical relevance in terms of patient’s compliance and adherence to the treatment regimen.Graphical abstractSingle injection of long-acting risperidone-loaded µPL ameliorates the dysbindin-induced deficit in a clinically relevant mouse model of cognitive and psychiatric liability for up to 12 weeks
Highlights
Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting almost 1% of the population worldwide and representing a significant health care burden withOne method to increase patient’s adherence and compliance and reduce side effects relies on the use of long-acting injectable (LAI) formulations, which have shown huge improvements in preventing relapse, hospitalization, and mortality in schizophrenic patients [6]
Square 20 × 20 μm poly(lactic-co-glycolic acid) (PLGA) μPL loaded with RSP were fabricated using a template-based fabrication approach
The higher PLGA mass and thickness of the tall μPL led to a larger drug encapsulation and longer sustained release as compared to short μPL
Summary
Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting almost 1% of the population worldwide and representing a significant health care burden withOne method to increase patient’s adherence and compliance and reduce side effects relies on the use of long-acting injectable (LAI) formulations, which have shown huge improvements in preventing relapse, hospitalization, and mortality in schizophrenic patients [6]. RSP has been demonstrated to be effective in improving cognitive symptoms, which are key in the pathophysiology of schizophrenia [13, 14]. In this context, the first long-acting RSP (Risperdal ConstaTM) was approved by FDA in 2004 [15]. The first long-acting RSP (Risperdal ConstaTM) was approved by FDA in 2004 [15] This is an aqueous suspension of poly(lactic-co-glycolic acid) (PLGA) microspheres to be injected deep intramuscularly and showing a size of about 100 μm [16,17,18]. In 2018, FDA approved another RSPbased LAI formulation, named the RBP-7000 (PerserisTM), that would require only one subcutaneous injection every month [6, 15, 19]
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