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Organogels are excellent drug carrier for controlled release. Organogels based on amino acid derivatives has been widely used in the area of drug delivery. In this study, a series of the organogel system based on amino acid derivatives gelators was designed and prepared to investigate the structure-property correlation in organogels. To investigate the factors that influence the property of drug release, we varied the formulation in the organogels: gelator structure, gelator concentration, volume of antigelation solvent, and drug loading. Through the Box-Behnken tests, the optimum organogel formulation in vitro was obtained. The self-healing properties of the organogel have been utilised for injection of a model lipophilic risperidone in situ , and sustained release of the drug has been studied over about one week in vivo . In conclusion, the gelation ability of gelators could be adjusted by the gelator structure. Gel property is related with the whole composition of the formulation. As drug carrier, the drug release property of organogels is affected by multiple factors. Our investigation of the gel release property will play a theoretical guiding role in the application in the in situ drug delivery system.

The objective of the present study was to investigate the effect of molecular weight differences of poly (lactic-co-glycolic acid) (PLGA) on the in vitro release profile of risperidone microspheres. Four different PLGA molecular weights were investigated and all the microsphere formulations were prepared using the same manufacturing process. Physicochemical properties (particle size, drug loading, morphology and molecular weight) as well as in vitro degradation profiles of the prepared microspheres were investigated in addition to in vitro release testing. The in vitro release tests were performed using a previously developed flow through cell (USP apparatus 4) method. The particle size of the four prepared microsphere formulations varied, however there were no significant differences in the drug loading. Interestingly, the in vitro release profiles did not follow the molecular weight of the polymers used. Instead, the drug release appeared to be dependent on the glass transition temperature of the polymers as well as the porosity of the prepared formulations. The catalytic effect of risperidone (an amine drug) on PLGA during manufacturing and release testing, minimized the differences in the molecular weights of the four formulations, explaining the independence of the release profiles on PLGA molecular weight., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

The purpose of this study was to apply the phenomenon of liquid jet breakup to the preparation of sustained-release microspheres. The mechanisms of liquid jet breakup in different jet states were investigated and the single factor method was used to study the effect of each process parameter on the particle size and size distribution of microspheres. Meantime, the prepared microspheres were characterized by morphology, drug loading, encapsulation efficiency and in vitro release. The results indicated that the process of liquid jet breakup could have 5 different states. The laminar flow state dominated when the Reynolds number (Re) was low, and the prepared microspheres had larger particle sizes. When the Re was high, the turbulent state was dominant and the microspheres had smaller particle sizes. And during the transition state from the laminar flow to the turbulence, the microspheres had a wide particle size distribution. Different process parameters could affect the particle size and distribution of microspheres by changing the Re, surface tension coefficient and viscosity. The microspheres prepared by liquid jet breakup were smooth and round with the drug loading of 35% and the encapsulation efficiency of 88%. In addition, when the polymeric carrier materials were different, the microspheres could have various drug release models such as sustained release with a lag phase, sustained release with no lag phase, pulsed release and so on, which could be applied widespread in the future., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The present work was designed to explore the efficacy of neuroactive drug (risperidone) loaded chitosan lipid nanoparticle (RIS-CH-LNPs) to enhance the bioactivity in schizophrenia via the nasal route., Methods: The three-factor and three-level formulation by design approach was used for optimization and their effects were observed on (Y1) size in nm, (Y2) % drug loading, and (Y3) % drug release. The optimized formulation RIS-CH-LNPopt was further evaluated for its surface morphology, ex-vivo permeation study, in-vivo behavior study, and stability study. The developed RIS-CH-LNPs showed nanometric size range with high drug loading and prolonged drug release., Results: The optimized formulation (RIS-CH-LNPopt) has shown the particle size (132.7 nm), drug loading (7.6 %), drug release (80.7 %) and further ex-vivo permeation study showed 2.32 fold enhancement over RIS-SUS(suspension). In-vivo behavior studies showed that RIS-CH-LNPopt is able to show significant greater bioefficacy as compared to RIS-SUS [intranasal (i.n), intravenous (i.v)]. The pharmacokinetic and brain/plasma ratio of developed chitosan nanoparticle was higher at all time-points as compared to RIS-SUS either given by intranasal or intravenous route that proves the direct nose to brain transport pathway of the drug via nasal administration. The developed chitosan nanoparticle increases nose to brain drug delivery as compared to the dispersion of equivalent dose., Conclusion: The findings of this study substantiate the existence of a direct nose-to-brain delivery route for RIS-CH-LNPs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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) ( R 2  > 0.99). These studies exhibited a significance in the precise preparation of RIS-loaded PLGA microspheres.

The present study was designed to formulate and optimize transdermal risperidone soft lipid vesicles. The formulation optimized with phospholipid, safranal and ethanol were incorporated as permeation and absorption enhancers. The optimized risperidone soft lipid vesicle was further evaluated for skin irritation study, in-vivo pharmacokinetic study and locomotor activity. Three factor three level Box-Behnken design (BBD) was used to statistically optimize soft lipid vesicle using safranal (A), ethanol (B)and phospholipid (C) as independent variable, while their effect was observed for vesicle size (Y 1 ), entrapment efficiency (Y 2 ) and flux (Y 3 ). The optimized risperidone soft lipid vesicle (Ris-opt) showed nanometric vesicle size, high entrapment efficiency and marked enhancement in transdermal flux. The extent of absorption from Ris-opt was greater when compared to oral suspension with relative bioavailability of 177%. The histopathological evaluation revealed developed formulation did not showed skin irritation compared to standard irritant. The significant findings presented here encourage further studies with risperidone soft lipid vesicles for treatment of schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The objective of the present study was to determine whether an in vitro-in vivo correlation (IVIVC) can be established for polymeric microspheres that are equivalent in formulation composition but prepared with different manufacturing processes. Risperidone was chosen as a model therapeutic and poly(lactic-co-glycolic acid) (PLGA) with similar molecular weight as that used in the commercial product Risperdal® Consta® was used to prepare risperidone microspheres. Various manufacturing processes were investigated to produce the risperidone microspheres with similar drug loading (approx. 37%) but distinctly different physicochemical properties (e.g. porosity, particle size and particle size distribution). In vitro release of the risperidone microspheres was investigated using different release testing methods (such as sample-and-separate and USP apparatus 4). In vivo pharmacokinetic profiles of the risperidone microsphere formulations following intramuscular administration were determined using a rabbit model. Furthermore, the obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method and the calculated in vivo release was compared with the in vitro release of these microspheres. Level A IVIVCs were established and validated for the compositionally equivalent risperidone microspheres based on the in vitro release data obtained using USP apparatus 4. The developed IVIVCs demonstrated good predictability and were robust. These results showed that the developed USP apparatus 4 method was capable of discriminating PLGA microspheres that are equivalent in formulation composition but with manufacturing differences and predicting their in vivo performance in the investigated animal model., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: In the present study, a uniform ultra-small microsphere/sucrose acetate isobutyrate (SAIB) hybrid depot (m-SAIB depot) was designed to provide a long-term sustained release drug delivery system which not only reduced the burst release of an SAIB depot, but also eliminated the lag-time of PLGA microspheres., Methods: Risperidone loaded m-SAIB depot (Ris-m-SAIB depot) was characterized by in vitro drug release, pharmacokinetics, in vivo degradation and biocompatibility, in comparison with risperidone loaded SAIB depot (Ris-SAIB depot)., Results: Ris-m-SAIB depot showed a low burst release (0.64%) and a reduced in vitro drug release rate due to the encapsulation of most drug in microspheres. After intramuscular administration, the in vivo burst release of Ris-m-SAIB was significantly decreased, as reflected by the low Cmax/Cs(4-td) (approximately 30-fold reduction), in comparison with Ris-SAIB depot. From 4 to 78 days, Ris-m-SAIB depot showed a higher plasma drug level (1.55 ~ 16.30 ng/ml) with a steadier drug release profile compared with Ris-SAIB depot. Ris-m-SAIB depot degraded gradually with a degradation t1/2 of 54.6 days and exhibited good biocompatibility in vivo., Conclusion: These results demonstrate the potential application of a uniform ultra-small microsphere/SAIB hybrid depot for continuously delivering small drug molecules for long periods of time without burst release.

In the present study a series of biodegradable and biocompatible poly(ε-caprolactone)/poly(propylene glutarate) (PCL/PPGlu) polymer blends were investigated as controlled release carriers of Risperidone drug (RISP), appropriate for transdermal drug delivery. The PCL/PPGlu carriers were prepared in different weight ratios. Miscibility studies of blends were evaluated through differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Hydrolysis studies were performed at 37°C using a phosphate buffered saline solution. The prepared blends have been used for the preparation of RISP patches via solvent evaporation method, containing 5, 10 and 15wt% RISP. These formulations were characterized using FT-IR spectroscopy, DSC and WAXD in order to evaluate interactions taking place between polymer matrix and drug, as well as the dispersion and the physical state of the drug inside the polymer matrix. In vitro drug release studies were performed using as dissolution medium phosphate buffered saline simulating body fluids. It was found that in all cases controlled release formulations were obtained, while the RISP release varies due to the properties of the used polymer blend and the different levels of drug loading. Artificial Neural Networks (ANNs) were used for dissolution behaviour modelling showing increased correlation efficacy compared to Multi-Linear-Regression (MLR)., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In the present study, a risperidone loaded microsphere/sucrose acetate isobutyrate (SAIB) in situ forming complex depot was designed to reduce the burst release of SAIB in situ forming depot and to continuously release risperidone for a long-term period without lagime. The model drug risperidone (Ris) was first encapsulated into microspheres and then the Ris-microspheres were embedded into SAIB depot to reduce the amount of dissolved drug in the depot. The effects of different types of microsphere matrix, including chitosan and poly(lactide-coglycolide) (PLGA), matrix/Ris ratios in microspheres and morphology of microspheres on the drug release behavior of complex depot were investigated. In comparison with the Ris-loaded SAIB depot (Ris-SAIB), the complex depot containing chitosan microspheres (in which chitosan/Ris = 1 : 1, w/w) (Ris-Cm-SAIB) decreased the burst release from 12.16% to 5.80%. However, increased drug release rate after 4 days was observed in Ris-Cm-SAIB, which was caused by the high penetration of the medium to Ris-Cm-SAIB due to the hydrophilie of chitosan. By encapsulation of risperidone in PLGA microspheres, most drugs can be prevented from dissolving in the depot and meanwhile the hydrophobic PLGA can reduce the media penetration effect on the depot. The complex depot containing PLGA microspheres (in which PLGA/ drug=4 : 2, w/w) (Ris-Pm-SAIB) showed a significant effectiveness on reducing the burst release both in vitro and in vivo whereby only 0.64% drug was released on the first day in vitro and a low AUC0-4d value [(105.2± 24.4) ng.mL-1.d] was detected over the first 4 days in vivo. In addition, drug release from Ris-Pm-SAIB can be modified by varying the morphology of microspheres. The porous PLGA microspheres could be prepared by adding medium chain triglyceride (MCT) in the organic phase which served as pore agents during the preparation of PLGA microspheres. The complex depot containing porous PLGA microspheres (which were prepared by co-encapsulation of 20% MCT) (Ris-PPm-SAIB) exhibited a slightly increased AUC0-4d of (194.6±15.8) ng.mL-1d and high plasma concentration levels from 4 to 78 days [Cs(4-78d)=(7.8±1.2) ng.mL-1]. The plasma concentration on 78 day C78d was (9.0 2.5) ng.mL-1 which was higher than that of Ris-Pm-SAIB [C78d= (1.6 ± 0.6) ng.mL-1]. In comparison with Ris-Pm-SAIB, the AUC4-78d of Ris-PPm-SAIB increased from (379.0±114.3) ng.mL-1.d to (465.0 ±149.2) ng.mL-1.d, indicating sufficient drug release from the Ris-PPm-SAIB. These results demonstrate that the risperidone loaded porous PLGA microsphere/SAIB in situ forming complex depot could not only efficiently reduce the burst release of SAIB depot both in vitro and in vivo, but also release the drug sufficiently in vivo, and be capable to continuously release the drug for 78 days.

Determining thermal properties and morphology seems to be useful in the analysis of release and degradation processes form polymeric materials. Risperidone is available in the formulation of a long-acting injection based on poly(D,L-lactide-co-glycolide). Currently, alternative solutions are also offered, i.e., nano- and microparticles or implants, including copolymers of lactide and glycolide. The effect of risperidone content on the properties of poly(L-lactide-co-glycolide) matrices was determined. The study also involved an assessment of the changes during degradation. Risperidone free matrices and the matrices with risperidone were obtained by solvent casting. Thermal characteristics were tested by means of differential scanning calorimetry, and the morphology was evaluated using a scanning electron microscope. Risperidone did not change significantly semi-crystalline structure of poly(L-lactide-co-glycolide) matrices. The decrease in crystallization temperature and glass transition temperature during degradation was observed. Many pores and their deformation, the widening of pore area, cracks and slits because of degradation were observed. The analysis of thermal properties and morphology allowed us to explain degradation process. Matrices exhibited stable process of degradation, which may be advantageous for development of prolonged risperidone release systems.

Microspheres have been developed as drug carriers in controlled drug delivery systems for years. In our present study, near infrared spectroscopy (NIRS) is applied to analyze the particle size and drug loading rate in risperidone poly(d,l-lactide-co-glycolide) (PLGA) microspheres. Various batches of risperidone PLGA microspheres were designed and prepared successfully. The particle size and drug-loading rate of all the samples were determined by a laser diffraction particle size analyzer and high performance liquid chromatography (HPLC) system. Monte Carlo algorithm combined with partial least squares (MCPLS) method was applied to identify the outliers and choose the numbers of calibration set. Furthermore, a series of preprocessing methods were performed to remove signal noise in NIR spectra. Moving window PLS and radical basis function neural network (RBFNN) methods were employed to establish calibration model. Our data demonstrated that PLS-developed model was only suitable for drug loading analysis in risperidone PLGA microspheres. Comparatively, RBFNN-based predictive models possess better fitting quality, predictive effect, and stability for both drug loading rate and particle size analysis. The correlation coefficients of calibration set (Rc(2)) were 0.935 and 0.880, respectively. The performance of optimum RBFNN models was confirmed by independent verification test with 15 samples. Collectively, our method is successfully performed to monitor drug-loading rate and particle size during risperidone PLGA microspheres preparation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Polymeric microparticles have been used widely for sustained drug delivery. Current methods of microparticle production can be improved by making homogeneous particles in size and shape, increasing the drug loading, and controlling the initial burst release. In the current study, the hydrogel template method was used to produce homogeneous poly(lactide-co-glycolide) (PLGA) microparticles and to examine formulation and process-related parameters. Poly(vinyl alcohol) (PVA) was used to make hydrogel templates. The parameters examined include PVA molecular weight, type of PLGA (as characterized by lactide content, inherent viscosity), polymer concentration, drug concentration and composition of solvent system. Three model compounds studied were risperidone, methylprednisolone acetate and paclitaxel. The ability of the hydrogel template method to produce microparticles with good conformity to template was dependent on molecular weight of PVA and viscosity of the PLGA solution. Drug loading and encapsulation efficiency were found to be influenced by PLGA lactide content, polymer concentration and composition of the solvent system. The drug loading and encapsulation efficiency were 28.7% and 82% for risperidone, 31.5% and 90% for methylprednisolone acetate, and 32.2% and 92% for paclitaxel, respectively. For all three drugs, release was sustained for weeks, and the in vitro release profile of risperidone was comparable to that of microparticles prepared using the conventional emulsion method. The hydrogel template method provides a new approach of manipulating microparticles., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A solid lipid nanoparticles (SLN) formulation to improve the oral delivery of risperidone (RISP), a poorly water-soluble drug, was designed and tested. Initially, lipid-RISP solubility was screened to select the best lipid for SLN preparation. Compritol(®)-based formulations were chosen and their long-term stability was assessed over two years of storage (at 25 °C and 4 °C) by means of particle size, polydispersity index (PI), zeta potential (ZP) and encapsulation efficiency (EE) measurements. SLN shape was observed by transmission electron microscopy (TEM) at the beginning and end of the study. The oxidative potential (OP) of the SLN was measured and their biocompatibility with Caco-2 cells was evaluated using the (4,5-dimethylthiazol-2-yl)2,5-dyphenyl-tetrazolium bromide (MTT) assay. In vitro drug release and transport studies were performed to predict the in vivo release profile and to evaluate the drug delivery potential of the SLN formulations, respectively. The RISP-loaded SLN systems were stable and had high EE and similar shape to the placebo formulations before and after storage. Classical Fickian diffusion was identified as the release mechanism for RISP from the SLN formulation. Biocompatibility and dose-dependent RISP transport across Caco-2 cells were observed for the prepared SLN formulations. The viability of SLN as formulations for oral delivery of poorly water-soluble drugs such as RISP was illustrated., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The objective was to investigate the relationship between in vitro and in vivo release of commercial Risperdal(®) Consta(®) microspheres. A modified USP apparatus 4 method was used for accelerated and real-time in vitro release testing. The in vivo plasma profile (clinical data) reported for the product was deconvoluted for comparison with the in vitro release profiles. The in vivo profile differed from the real-time in vitro profile and was faster initially and then slower after approximately 30 days. This effect is considered to be due to differences in the in vivo conditions such as small interstitial volume, low pH and immune response. Accelerated in vitro release profiles obtained at temperatures (50°C and 54.5°C) above the microsphere glass transition temperature (Tg∼48°C) overlapped with the in vivo profile after time scaling. A linear in vitro-in vivo relationship was observed with correlation coefficients of 0.97 and 0.99 at 50°C and 54.5°C, respectively. The accelerated test performed below the Tg had a similar release profile to that of the real-time in vitro test. The accelerated tests performed above the Tg of the microspheres showed the potential to be used for in vivo performance prediction as well as for quality control purposes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). As new strategies to improve treatments efficiency are needed, we have studied cationic G4 PAMAM dendrimers' performance to act as efficient nanocarriers for this therapeutic drug. In this respect, we explored dendrimer-risperidone complexation dependence on solvent, temperature, pH and salt concentration, as well as in vitro cytotoxicity measured on L929 cell line and human red blood cells. The best dendrimer-risperidone incorporation was achieved when a mixture of 70:30 and 90:10 v/v chloroform:methanol was used, obtaining 17 and 32 risperidone molecules per dendrimer, respectively. No cytotoxicity on L929 cells was found when dendrimer concentration was below 3 × 10(-2) μM and risperidone concentration below 5.1 μM. Also, no significant hemolysis or morphological changes were observed on human red blood cells. Finally, attempting to obtain an efficient drug delivery system for risperidone, incorporation in G4 PAMAM dendrimers was optimized, improving drug solubility with low cytotoxicity., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Aim: The aim of this work was to develop extended-release risperidone nanoparticles for parenteral delivery (intravenous) and to reduce the dose-dependent extrapyramidal side effects of risperidone., Methods: Polymeric nanoparticles containing risperidone made of poly (epsilon-caprolactone) were designed by the nanoprecipitation method using polymeric stabilizers (poloxamers). The in vivo efficacy of prepared formulations and the risperidone solution was studied by administering them intravenously to apomorphine-treated mice. Extrapyramidal side effects of the risperidone and its formulations were also studied., Results: The particle size of the prepared nanoparticles ranged between 99 and 304 nm. Approximately 78-85% drug-encapsulation efficiency was achieved when risperidone was loaded at 1.7-4.1% by weight of the polymer. During in vivo studies, prepared risperidone-containing formulations showed a significant prolonged antipsychotic effect than that of risperidone solution, also having less extrapyramidal side effects., Conclusion: The prolonged effect of risperidone was obtained from the nanoparticles of risperidone administered by the intravenous route and this may improve the treatment of psychotic disorders by dose reduction.

The objective of this study was to develop sustained-release sucrose acetate isobutyrate (SAIB) in situ formulations of risperidone for parenteral delivery. The formulations 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 and the rate of risperidone release. The initial drug release could be increased by reducing the pH of the release medium and the release rate could be increased by an increase in drug loading. The burst release fell significantly from 20.0% to 3.5% following the inclusion of 10% (w/w) PLA in the formulations. In the case of this high viscosity depot system containing SAIB, anhydrous ethanol, PLA, and 25 mg/g risperidone, the in vivo biocompatible test results obtained support the use of SAIB as an injectable risperidone sustained-release formulation., ((c) 2007 Wiley-Liss, Inc.)

Aim: The aim of this work was to prepare poly(epsilon-caprolactone) nanoparticles of risperidone and to characterize them., Methods: Risperidone-loaded poly(epsilon-caprolactone) nanoparticles were prepared by the nanoprecipitation method using poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock polymeric stabilizer (PluronicF-68). The particles were characterized for particle size by photon correlation spectroscopy and transmission electron microscopy. The free dissolved drug in the nanosuspension was determined by the bulk equilibrium reverse dialysis bag technique. In vitro release studies were carried out using the dialysis bag diffusion technique., Results: The particle size of the prepared nanoparticles ranged from 90 to 300 nm. Nanoparticles of risperidone were obtained with high encapsulation efficiency (70-80%). The drug release from the risperidone nanoparticles was sustained in some batches for more than 24 h with 80% drug release, whereas release from risperidone in polyethylene glycol 400 solution showed release within 2 h., Conclusion: These studies suggest the feasibility of formulating risperidone-loaded poly(epsilon-caprolactone) nanoparticles for the treatment of psychotic disorders.