Release Of Risperidone Research Articles

Control of encapsulation efficiency and morphology of poly(lactide-co-glycolide) microparticles with a diafiltration-driven solvent extraction process

The removal of organic solvents during the preparation of biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microparticles by an O/W- solvent extraction/evaporation process was investigated and controlled by diafiltration. Emulsification and steady replacement of the aqueous phase were performed in parallel in a single-vessel setup. During the process, the solidification of the dispersed phase (drug:PLGA:solvent droplets) into microparticles was monitored with video-microscopy and focused beam reflectance measurement (FBRM) and the residual solvent content was analyzed with headspace gas chromatography (organic solvent) and coulometric Karl-Fischer titration (water). Microparticles containing dexamethasone or risperidone were characterized with regard to particle size, morphology, encapsulation efficiency and in-vitro release. Diafiltration-accelerated solvent extraction shortened the process time by accelerating solidification of dispersed phase but reduced the residual dichloromethane content only in combination with increased temperature. Increasing the diafiltration rate increased particle size, porosity, and the encapsulation efficiency of risperidone. The latter effect was particularly evident with increasing lipophilicity of PLGA. A slower and more uniform solidification of end-capped and increased lactide content PLGA grade was identified as the reason for an increased drug leaching. Accelerated solvent extraction by diafiltration did not affect the in-vitro release of risperidone from different PLGA grades. The initial burst release of dexamethasone was increased by diafiltration when encapsulated in concentrations above the percolation threshold. Both porosity and burst release could be reduced by increasing the process temperature during diafiltration. Residual water content was established as an indicator for porosity and correlated with the burst release of dexamethasone.

Accelerated removal of solvent residuals from PLGA microparticles by alcohol vapor-assisted fluidized bed drying

The removal of residual solvents from biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microparticles by fluidized bed drying was investigated. Microparticles were prepared by the O/W solvent extraction/evaporation method and the influence of various process and formulation parameters on the secondary drying was studied. PLGA microparticles and films were characterized for residual organic solvent and water content, recrystallisation, surface morphology, drug loading and in-vitro release of the drugs dexamethasone and risperidone. While alcohol-free fluidized bed drying decreased the residual dichloromethane content only from about 7 % (w/w) to 6.4 % (w/w) (18 °C) or 3.2 % (w/w) (35 °C) within 24 h, 140 mg/L methanol vapor in purge gas facilitated almost complete removal of dichloromethane or ethyl acetate from microparticles (0–0.11 % (w/w) after 6 h). By controlling the alcohol concentration and temperature of the purge gas, the alcohol absorption and complete removal was controlled. Risperidone increased the methanol absorption enhancing the plasticization. A high initial residual water content was identified to promote aggregation and was eliminated by starting fluidized bed drying without alcohol. Alcohol vapor-assisted fluidized bed drying accelerated microparticle manufacturing without affecting the redispersibility, the drug loading and the in-vitro release of risperidone and dexamethasone.

Reservoir-type intranasal implants for sustained release of risperidone: A potential alternative for long-term treatment of schizophrenia

To overcome the challenges of the blood-brain barrier for drug delivery to the central nervous system (CNS), intranasal implants were developed to improve the management of CNS conditions, such as schizophrenia. In the present work, we developed and characterised a drug-containing implant consisting of two parts: a core layer made from risperidone (RIS) and water-soluble polymers, including poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) (PEG), and a coating layer made of poly(caprolactone) (PCL) membrane. The obtained implants, where the core layer contained 75 % w/w risperidone, were characterised using several techniques: scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR). Moreover, the in vitro release profile of RIS was studied, showing that the PCL membrane could extend the release of RIS from 2 days up to 100 days. The in vitro release profile of the PCL-coated implant exhibited a linear release over the first 10 days, followed by a slower release rate that reached another linear phase up to 40 days. Subsequently, the drug release rates progressively slowed down. Finally, the results of in vitro biocompatibility studies indicated that the intranasal implants were biocompatible and non-cytotoxic. These findings suggest that the implants prepared in this work have the potential to provide long-acting drug delivery for targeting the brain.

Preparation and Characterization of Sustained Release Risperidone Loaded Eudragit Microparticles by Spray-Drying Technique

The goal of this work was to create novel risperidone-containing spray-dried microparticles using Eudragit® L100, a methacrylic polymer. Microparticles were designed with controlled release and enhanced in-vitro effects in mind and were meant to be taken orally. Spray-drying was used to create Eudragit® L100 microparticles loaded with risperidone. Risperidone-loaded Eudragit® L100 was successfully prepared to treat mental/mood disorders, according to an investigation into its physicochemical properties in-vitro. Spray-drying was an effective method for producing Eudragit® L100 microparticles loaded with risperidone. Formulations displayed a suitable drug entrapment percentage or nearly 89.94%. The mean diameter of the nearly spherical and spherical microparticles ranged from 30 to 50 μm, and they had a smooth surface. The distinctive peak of risperidone loaded with Eudragit L100 was visible in the fourier-transformed infrared (FTIR) spectra, indicating that the medication was fully encapsulated in the polymer. The dissolution rate of risperidone-loaded microparticles was slower than that of the pure medication. The use of spray-dried risperidone microparticles as a practical oral drug delivery method for more effective and regulated risperidone release is supported experimentally by our results.

Poly(Lactic Acid) Block Copolymers with Poly(Hexylene Succinate) as Microparticles for Long-Acting Injectables of Risperidone Drug.

In the present work, Risperidone microparticles from poly(lactic acid)/poly(hexylene succinate) (PLA-b-PHSu) block copolymers in different ratios, 95/05, 90/10 and 80/20 w/w, were examined as long-acting injectable formulations. Nuclear magnetic resonance (NMR) was used to verify the successful synthesis of copolymers. Enzymatic hydrolysis showed an increase in weight loss as the content of PHSu increased, while the cytotoxicity studies confirmed the biocompatibility of the copolymers. The polyesters were further used to encapsulate Risperidone by spray drying. The drug-loaded microparticles were studied by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and X-ray diffraction (XRD). SEM microphotographs confirmed that spherically shaped microparticles were prepared with sizes about 5–12 μm, while XRD and differential scanning calorimetry (DSC) studies evidenced that Risperidone was encapsulated in amorphous form. The drug loading and the entrapment efficiency of Risperidone were studied as well as the in vitro release from the prepared microparticles. As the content of PHSu increased, a higher release of Risperidone was observed, with PLA-b-PHSu 80/20 w/w succeeding to release 100% of RIS within 12 days. According to theoretical modeling, the kinetics of RIS release from PLA-b-PHSu microparticles is complex, governed by both diffusion and polymer erosion.

Development of intranasal implantable devices for schizophrenia treatment

In this work the preparation and characterisation of intranasal implants for the delivery of risperidone (RIS) is described. The aim of this work is to develop better therapies to treat chronic conditions affecting the brain such as schizophrenia. This type of systems combines the advantages of intranasal drug delivery with sustained drug release. The resulting implants were prepared using biodegradable materials, including poly(caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA). These polymers were combined with water-soluble compounds, such as poly(ethylene glycol) (PEG) 600, PEG 3000, and Tween® 80 using a solvent-casting method. The resulting implants contained RIS loadings ranging between 25 and 50 %. The obtained implants were characterised using a range of techniques including thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), X-ray diffraction (XRD), and Scanning Electron Microscopy (SEM). Moreover, in vitro RIS release was evaluated showing that the addition of water-soluble compounds exhibited significant faster release profiles compared to pristine PCL and PLGA-based implants. Interestingly, PCL-based implants containing 25 % of RIS and PLGA-based implants loaded with 50 % of RIS showed sustained drug release profiles up to 90 days. The former showed faster release rates over the first 28 days but after this period PLGA implants presented higher release rates. The permeability of RIS released from the implants through a model membrane simulating nasal mucosa was subsequently evaluated showing desirable permeation rate of around 2 mg/day. Finally, following in vitro biocompatibility studies, PCL and PLGA-based implants showed acceptable biocompatibility. These results suggested that the resulting implants displayed potential of providing prolonged drug release for brain-targeting drugs.

Evaluating Non-Conventional Chitosan Sources for Controlled Release of Risperidone.

In this work, two chitosan samples from cuttlebone and squid pen are produced and characterized. We studied the formation of thermoresponsive hydrogels with β-glycerol phosphate and found proper formulations that form the hydrogels at 37 °C. Gel formation depended on the chitosan source being possible to produce the thermoresponsive hydrogels at chitosan concentration of 1% with cuttlebone chitosan but 1.5% was needed for squid pen. For the first time, these non-commercial chitosan sources have been used in combination with β-glycerol phosphate to prepare risperidone formulations for controlled drug delivery. Three types of formulations for risperidone-controlled release have been developed, in-situ gelling formulations, hydrogels and xerogels. The release profiles show that in-situ gelling formulations and particularly hydrogels allow an extended control release of risperidone while xerogels are not appropriate formulations for this end since risperidone was completely released in 48 h.

Lipid-liquid crystals for 2 months controlled risperidone release: In-vitro evaluation and pharmacokinetics in rabbits

In this study, a drug delivery system based on lipid liquid crystal (LLC) was developed for the long-term delivery of risperidone to improve psychological treatment. Optimal LLC formulation was achieved based on maximum release after 60 days with different ratios of phosphatidylcholine (PC) to sorbitol monooleate (PC: SMO), tween grade 80 (w/w %), and tocopherol acetate (TA) (w/w %) using the Box-Behnken method. In vitro and ex vivo studies, pharmacokinetics, and histopathological examination in rabbits were conducted to compare the optimal LLC with Risperdal CONSTA®. The optimum formulation containing the PC to SMO ratio of 58.6%, tween 0.82% w/w, and TA 3.6% w/w was selected because it had the highest drug release percentage (100%) during about two months. Polarized optical microscopy (POM) revealed HII mesophase with a 2-dimensional structure. Cell culture also revealed moderate cytotoxicity for LLC-risperidone. Pharmacokinetic data displayed that the optimal LLC created a more consistent drug serum level within 60 days, and histopathology results demonstrated slight to moderate damage in rabbits’ organs. Furthermore, the accelerated stability test confirmed optimum stability for LLC and risperidone. This study confirmed the better pharmacokinetic potentials of SMO-based LLC systems compared with Risperdal CONSTA®, which would promote patient compliance and obviate the difficulties of additional oral therapy.

Long-lasting rescue of schizophrenia-relevant cognitive impairments via risperidone-loaded microPlates

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

Effect of polymer source variation on the properties and performance of risperidone microspheres

Owing to their inherent heterogeneity, determination of similarity of poly (lactic-co-glycolic acid) (PLGA) polymers is very challenging. The complexity in controlling PLGA characteristics has been recognized as an obstacle to the development of PLGA based long-acting complex drug products (such as microspheres). The objectives of the present study were: (1) to determine minor differences in the physicochemical characteristics (such as inherent viscosity, molecular weight (Mw), monomer ratio (L/G ratio), glass transition temperature (Tg), and blockiness) as well as in the hydrolytic degradation profiles of PLGAs from different sources; and (2) to investigate the impact of PLGAs from different sources on the properties and in vitro performance of risperidone microspheres. Four PLGA polymers were purchased from different sources with similar inherent viscosity and/or Mw, L/G ratio and end groups as per the manufacturers’ certificate of analysis (CoA). The physicochemical properties of these PLGAs were characterized using the same in-house methods and exhibited differences in inherent viscosity, Mw, blockiness and residue amount. Risperidone was chosen as the model drug and four microsphere formulations were prepared via the same solvent extraction/evaporation method using the PLGAs from different sources. The critical quality attributes of the microspheres (such as particle size, porosity and average pore diameter) and their in vitro release characteristics (burst effect and release rate) were shown to be different. A strong linear correlation was established between risperidone release and PLGA blockiness. This is the first time that such a correlation has been established, which promotes the potential need to further investigate the impact of PLGA blockiness on other PLGA based controlled release drug products.

Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo.

Schizophrenia, a psychiatric disorder, requires long-term treatment; however, large fluctuations in blood drug concentration increase the risk of adverse reactions. We prepared a long-term risperidone (RIS) implantation system that can stabilize RIS release and established in-vitro and in-vivo evaluation systems. Cumulative release, drug loading, and entrapment efficiency were used as evaluation indicators to evaluate the effects of different pore formers, polymer ratios, porogen concentrations, and oil–water ratios on a RIS implant (RIS-IM). We also built a mathematical model to identify the optimized formulation by stepwise regression. We also assessed the crystalline changes, residual solvents, solubility and stability after sterilization, in-vivo polymer degradation, pharmacokinetics, and tissue inflammation in the case of the optimized formulation. The surface of the optimized RIS microspheres was small and hollow with 134.4 ± 3.5 µm particle size, 1.60 SPAN, 46.7% ± 2.3% implant drug loading, and 93.4% entrapment efficiency. The in-vitro dissolution behavior of RIS-IM had zero-order kinetics and stable blood concentration; no lag time was released for over three months. Furthermore, the RIS-IM was not only non-irritating to tissues but also had good biocompatibility and product stability. Long-acting RIS-IMs with microspheres and film coatings can provide a new avenue for treating schizophrenia.

The PLGA Microspheres Synthesized by a Thermosensitive Hydrogel Emulsifier for Sustained Release of Risperidone

Risperidone is an important antipsychotic agent used for treatment of both acute and chronic schizophrenia. The drug has been effective in resolving the disease’s signs while keeping extrapyramidal side effects as low as possible. To achieve a sustained and gradual release of risperidone from PLGA microspheres, we utilized an emulsifying agent; PLGA-PEG-PLGA triblock (M-triblock), instead of PVA (M-PVA), applying ring-opening polymerization of the triblock via supercritical carbon dioxide (scCO2). PVA and PLGA-PEG-PLGA (as emulsifiers) were successfully employed to prepare risperidone-loaded PLGA microspheres. The scCO2 and microwave irradiation methods were used to construct PLGA-PEG-PLGA copolymers. The microspheres were subjected to various analyses to determine the particles’ sizes, morphological characteristics, and structure (via XRD) and in vitro drug release kinetics. Drug loading capacity and encapsulation percentage were also determined. The results showed a mean diameter of 43.34 ± 2.30 µm for M-PVA, and that of the M-triblock was 57.49 ± 1.21 µm. Risperidone encapsulation percentages were 72.8 ± 2.09 for M-PVAs and 73.4 ± 2.41 for the M-triblock. Particle size, risperidone distribution, and drug loading and encapsulation percentages were similar between M-PVAs and the M-triblock. In scanning electron microscopy (SEM), the morphology of the triblock emulsifier was more uniform than PVAs. The triblock emulsifier showed slower initial drug release than PVAs due to the precipitation of the triblock hydrogel around PLGA microspheres. Overall, the triblock used here can be a good alternative to PVA.

Morphological characterization of optimized risperidone-loaded in-situ gel forming implants with pharmacokinetic and behavioral assessments in rats

The present study aims to emphasize the enhanced efficacy of long acting in-situ gel forming implants (ISGFI) based on poly (lactic-co-glycolic acid) (PLGA) matrix to deliver anti-psychotic risperidone over extended time periods with reduced administration frequency. Schizophrenic patients show considerable difficulties in adherence and compliance to oral medications associated with negative outcomes including symptoms exacerbation and psychotic relapse. The studied optimized ISGFI formulation, comprised of 2.85:1 ratio of DMSO solvent:PLGA (type 75:25), was subjected to various characterization studies including morphological real-time changes, scanning electron microscopy and in-vitro drug release study. Pharmacokinetics and behavioral evaluations of anti-psychotic action of ISGFI systems were pursued on healthy and schizophrenia-induced rats respectively then compared to results of marketed microspheres. Morphological observations showed the immediate formation of whitish smooth ISGFI system owing to the rapid PLGA solidification after rapid DMSO dissipation into the external medium. Scanning electron microscopy confirmed the slow gradual biodegradation of the formed ISGFI. The optimized formulation assured its effectiveness to produce satisfactory initial burst and cumulative risperidone release and obviate costs of additional tablets needed during the commercial product use. Pharmacokinetic study manifested the effective performance of ISGFI to extend risperidone release for longer period (72 days) in comparison to the marketed formulations (48 days). Besides, optimized ISGFI were more effective in improving ketamine-induced schizophrenia-like symptoms in experimental rats, particularly in the first week of study period. Meanwhile, in-vitro, pharmacokinetic and pharmacodynamic evaluations had advocated the potential advantages of ISGFI systems for treating schizophrenia with improved adherence and compliance of patients.

Metod reverzne dijalize sa vrećicama za procenu in vitro oslobađanja lekovite supstance iz parenteralnih nanoemulzija - studija sa risperidonom

The present study describes the release pattern of risperidone, a poorly water-soluble psychopharmacological drug, from two parenteral nanoemulsions containing the mixture of medium-chain triglycerides and soybean oil as an oil phase, sodium oleate solution as an aqueous phase and lecithin alone or in combination with polysorbate 80 as emulsifiers/stabilizers. The nanoemulsions were prepared by hot high-pressure homogenization, and evaluated regarding physicochemical properties - a droplet size, polydispersity index, zeta potential, and viscosity, as well as biopharmaceutical performances - in vitro drug release by employing a reverse dialysis bag technique. Physicochemical characterization revealed a favorable mean droplet size (160-210 nm), narrow size distribution (<0.15), high surface charge (around -50 mV to -60 mV) and low apparent viscosity (4-6 mPa.s) of developed nanoemulsions, thus proving their suitability for parenteral administration of poorly water-soluble actives. The in vitro drug release study showed biphasic release profiles of risperidone, with significant differences between two investigated nanoemulsion formulations (differing only in the presence of polysorbate 80), indicating the influence of nanoemulsion matrix on drug release kinetics. However, the release of risperidone from investigated nanoemulsions was relatively rapid (more than 50% released within the first 5 min), suggesting their promising application in emergency situations. Furthermore, above 95% of the drug was released from both tested nanoemulsions within 180 min, while the kinetic release process could be described by Korsmeyer-Peppas model and supposed to be diffusion-controlled.Overall, it can be concluded that the reverse dialysis bag technique was the appropriate and enough discriminatory method to evaluate the in vitro release of risperidone from presented nanoemulsion systems.

Influence of drying processes on the structures, morphology and in vitro release profiles of risperidone-loaded PLGA microspheres

The purpose of this study was to investigate the influences of drying methods on the risperidone (RIS) release profiles of RIS-loaded PLGA microspheres. These microspheres were fabricated with an O/W emulsion solvent evaporation method. The wet microspheres were dried with freeze drying and vacuum drying methods. The microspheres were mono-dispersed spheres with an average diameter of 100 μm. Studies found that drying methods had great influence on the porosity, morphology, and release profiles of RIS-loaded PLGA microspheres. Specifically, the freeze-dried microspheres had higher porosity (78.46 ± 1.64%) than those vacuum-dried ones (52.45 ± 2.68%), and they showed higher RIS release rates (p < 0.05). In the accelerated release tests (45 °C), these microspheres dried under the pressures of 700 mmHg and 200 mmHg gave faster release rates than those ones dried under the pressure of 450 mmHg. Importantly, the accelerated release test (45 °C) had a high correlation with the real-time test (37 °C) (R2 > 0.99). These studies exhibited a significance in the precise preparation of RIS-loaded PLGA microspheres.

Preparation of New Risperidone Depot Microspheres Based on Novel Biocompatible Poly(Alkylene Adipate) Polyesters as Long-Acting Injectable Formulations

Risperidone (RIS)-loaded microspheres based on poly(alkylene adipate)s derived from dicarboxylic acids and different aliphatic diols were prepared by the oil in water emulsion and solvent evaporation method. Specifically, 3 polyesters, namely poly(ethylene adipate), poly(propylene adipate), and poly(butylene adipate), were prepared with the aid of a 2-stage melt-polycondensation method and characterized by gel permeation chromatography, proton nuclear magnetic resonance (1H NMR), differential scanning calorimetry, and X-ray diffraction analysis. Results showed that the molecular weight of the polyesters increased as the diol molecular weight increased, while all polymers were of semi-crystalline nature and the melting temperature was varying from 49.1°C to 51.8°C and 65.9°C for poly(propylene adipate), poly(ethylene adipate), and poly(butylene adipate), respectively. The particle size of the RIS-loaded microspheres varied from 10 to 100 μm depending on the polyester type and the drug loading, while X-ray diffraction analysis revealed amorphous active pharmaceutical ingredient in the cases of high drug-loaded microspheres. In vitro drug release studies along with scanning electron microscopy images of microspheres after the completion of dissolution process showed that in all cases RIS release was controlled by the glass transition temperature of polyesters and physical state of active pharmaceutical ingredients via diffusion.

Formulation of delivery systems with risperidone based on biodegradable terpolymers

Risperidone is applied in oral dosage formulations in the treatment of mental diseases. Current trends point toward parenteral delivery systems based on poly(lactide-co-glycolide), with wafers or rods being the more attractive option than the routinely used intramuscular suspension with microparticles. The aim of our work was to study the utility of solution casting and hot melt extrusion in the formulation of wafers and rods with risperidone based on terpolymers, namely poly(lactide-co-glycolide-co-trimethylene carbonate) and poly(lactide-co-glycolide-co-ε-caprolactone). Synthesis of the terpolymers was carried out by using a non-toxic zirconium initiator and a racemic (LL/DD) or optically active form of the lactide monomer. The delivery systems were analyzed by NMR, DSC, GPC, and SEM. The release profile was monitored by HPLC. Terpolymer chain microstructure, glass transition temperature, and morphology revealed unchanged values after formulation. Solution casting resulted in a drop in molecular weight to a smaller degree than hot melt extrusion. The presence of risperidone influenced another decrease in molecular weight. Both methods are adequate for the formulation of delivery systems based on terpolymers for prolonged release of risperidone. An adequate selection of monomer composition in terpolymers allows to control the release period. Risperidone was released in three phases, however, the burst effect was observed for poly(L-lactide-co-glycolide-co-ε-caprolactone).

An Accelerated Release Method of Risperidone Loaded PLGA Microspheres with Good IVIVC.

A long release period lasting several days or several weeks is always needed and thereby it is tedious and time consuming to screen formulations of such microspheres with so long release period and evaluate their release profiles in vitro with conventional long-term or "real-time" release method. So, an accelerated release testing of such system is necessary for formulation design as well as quality control purpose. The purpose of this study is to obtain an accelerated release method of risperidone loaded poly(lactic-co-glycolic acid) (PLGA) microspheres with good in vitro/in vivo correlation (IVIVC). Two formulations of risperidone loaded PLGA microspheres used for evaluating IVIVC were prepared by O/W method. The accelerated release condition was optimized by investigating the effect of pH, osmotic pressure, temperature and ethanol concentration on the release of risperidone from microspheres and the in vitro accelerated release profiles of risperidone from PLGA microspheres were obtained under this optimized accelerated release condition. The plasma concentration of risperidone were also detected after subcutaneous injection of risperidone loaded microspheres to rats. The in vivo cumulative absorption profiles were then calculated using Wagner-Nelson model, Loo- Riegelman model and numerical convolution model, respectively. The correlation between in vitro accelerated release and in vivo cumulative absorption were finally evaluated with Least Square Method. It was shown that temperature and ethanol concentration significantly affected the release of risperidone from the microspheres while pH and osmotic pressure of release media slightly affected the release behavior of risperidone. The in vitro release of risperidone from microspheres were finally undergone in PBS (pH7.0, 300mosm) with 20% (V/V) ethanol at 45°C. The sustained and complete release of risperidone was observed in both formulations under the accelerated release condition although these two release profiles were dissimilar. The correlation coefficients (R2) of IVIVC were all above 0.95 and the slopes were all between 0.9564 and 1.1868 in spite of fitted model and microsphere formulation. An in vitro accelerated release method of risperidone microspheres with good IVIVC was established in this paper and this accelerated release method was supposed to have great potential in both in vivo performance prediction and quality control for risperidone loaded PLGA microspheres.

Risperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation.

The aim of this study was to design and optimize risperidone (RIS) mucoadhesive buccal tablets for systemic delivery as an alternative route. Direct compression method was used for the preparation of buccal tablets, and screening studies were conducted with different polymers to determine their effects on tablet characteristics. Carbopol® (CP) and sodium alginate (SA) were selected as two polymer types for further optimization studies by applying response surface methodology. Tablet hardness (TH), ex vivo residence time (RT), and peak detachment force (DF) from buccal mucosa were selected as three important responses. Physicochemical compatibility of formulation excipients and RIS was evaluated by using Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) analysis. In vitro drug release profiles and release kinetics were investigated; swelling index and matrix erosion studies were conducted. Optimum formulation consisted of 16.4% CP and 20.3% SA, which provided 7.67±0.29 hour ex vivo RT, 45.52±4.85 N TH, and 2.12±0.17 N DF. FT-IR spectroscopy and DSC analysis revealed that there was no chemical interaction present between tablet ingredients. Cumulative RIS release of >90% was achieved after 8 hours of in vitro dissolution studies, which was supported by swelling and matrix erosion analysis. Mechanism of RIS release was fitted best to zero-order model, while release exponent (n) value of 0.77 demonstrated an anomalous (non-Fickian) release, indicating combined erosion and swelling mechanism. The results suggested that optimized buccal tablets of RIS would be a promising and alternative delivery system for the treatment of schizophrenia.

Preparation and characterization of silk fibroin hydrogel as injectable implants for sustained release of Risperidone

The principal objective of the present study is to achieve a depot formulation of Risperidone by gelation of silk fibroin (SF). For this purpose, hydrochloric acid (HCl)/acetone-based and methanol-based hydrogels were prepared with different drug/polymer ratios (1:3, 1:6, and 1:15). For all the drug-loaded methanol-based hydrogels, gel transition of SF solutions occurred immediately and the gelation time was 1 min, while the gelation time of HCL/acetone-based hydrogels was around 360 min. According to the results obtined from Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) spectra, solvent systems and Risperidone could induce β-sheet structure, but HCL/acetone system had the lowest effect on induction of β-sheets. The crystallinity was increased by increasing the amount of Risperidone, and drug to polymer ratio of 1:3 possessed the highest crystallinity. Thermogravimetric analysis (TGA) indicated that increasing the amount of drug in formulation increased the stability of hydrogels, and methanol-based hydrogel with a ratio of 1:3 had the most stable structure. The release rate of Risperidone from methanol-based hydrogel at ratio of 1:3 was lower than that for HCl/acetone-based one, and it decreased by increasing the amount of Risperidone. The release of Risperidone from methanol hydrogel at ratios 1:3 and 1:6 continued up to 25 d which is acceptable for depot form of Risperidone and shows that the extended release of Risperidone was achieved successfully. In conclusion, SF hydrogel with the ability to respond to the environmental stimuli is an excellent candidate for injectable implants for extended release of Risperidone.