Prominently selective fluorescence approach with distinctive biopharmaceutical utility for analysis of lurasidone in human plasma and urine: Application to in vitro dissolution and content uniformity testing.

A relevant approach based on the attractive inherited merits of fluorescence spectroscopy has been established for quantitative estimation of a newly approved second-generation atypical antipsychotic lurasidone (LUR) in its raw materials and pharmaceutical dosage forms. This study brings to light the strong native fluorescence of LUR at 400 nm in water after excitation at 316 nm. Different experimental parameters that may compromise the fluorescence of the drug were carefully investigated and optimized. A linear response was established between the relative fluorescence intensity and concentration over the concentration range of 50-650 ng/mL with excellent correlation (r = 0.9998). The validity of the method was evidenced in accordance with International Council for Harmonization guidelines, with minimal detection and quantification limits of 2.88 and 8.73 ng/mL, respectively. The method was effectively applied for the estimation of LUR in spiked human plasma and urine samples with acceptable recoveries. The biopharmaceutical significance of the method was heightened by its successful applications for both content uniformity and in vitro dissolution testing. Three different tools accredited the greenness character of the presented study. Eco-friendliness, effortlessness, and cost effectiveness are crucial hallmarks of our study. The presented study demonstrates potential applicability in quality control laboratories with limited resources.

Exploitation of erythrosine B as a fluorometric marker for lurasidone determination through electrostatic attraction; application to content uniformity test.

A recently developed antipsychotic drug, lurasidone, was determined using a simple, sensitive, and eco-friendly spectrofluorimetric approach. The suggested approach was based on the quantifiable quenching impact of lurasidone on the inherent fluorescence of erythrosine B in an acidic environment employing a Teorell-Stenhagen buffer (pH 4). Following excitation at 530 nm, the quenching of erythrosine B fluorescence was monitored at 552 nm. The system variables were systematically optimized to enhance the formation of the lurasidone-erythrosine B ion pair for analytical purposes. A linear calibration graph was built in the range of 20-600 ng mL-1 with 0.9998 as a coefficient of correlation. The quantitation and detection limits were 13.5 and 4.5 ng/mL, respectively. The analytical validity of the designed approach was assessed with respect to International Council on Harmonization (ICH) guiding principles. The proposed methodology was employed with high recoveries for assessing lurasidone in bulk powder and its therapeutic tablet dosage form. Additionally, the uniformity of tablet formulations was tested using the developed approach. Finally, the established approach was assessed for its greenness using various tools.

Long Acting Ionically Paired Pamoate-based Suspension of Lurasidone: An exploration of Size Effects on in vitro Dissolution and in vivo Pharmacokinetic Behaviors.

Latuda® is an oral tablet approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. However, the clinical efficacy of Latuda® is compromised by patient noncompliance due to frequent daily administration, especially for patients experiencing severe schizophrenia, whose medication is often needed for several months to years. Hence, developing a long-acting injectable formulation of lurasidone is urgently needed. Herein, a poorly water-soluble lurasidone pamoate (LP) salt was synthesized via the facile ion pair-based salt formation technology. The solubility of LP was decreased by 233 folds compared with that of lurasidone hydrochloride (LH). Furthermore, suspensions of LH and LP with three different particle sizes, including 400 nm small-sized nanocrystals (SNCs), 4 µm medium-sized microcrystals (MMCs), and 15 µm large-sized microcrystals (LMCs) were prepared and characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The in vitro release results showed that particle sizes had great effects on the sustained release of LH, where large-sized particles exhibited superior sustained release than the smaller ones. Besides, LP suspensions exhibited better sustained release than LH suspensions at the same size scale. Moreover, the pharmacokinetics showed that LP LMCs produced an extended in vivo intramuscularly injectable profile for up to 45 days, which was 10 days longer than that of the LH LMCs. Our findings demonstrated that particle size had appreciable impacts on drug sustained release and provided valuable knowledge for the rational design of optimized micronized suspensions for long-acting injectables.

Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride.

As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited a much lower dissolution than that of its stable crystalline form arising from its gelation during the dissolution process. In the current study, a supramolecular coamorphous system of LH with l-cysteine hydrochloride (CYS) was prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. Surprisingly, in comparison to crystalline and amorphous LH, such a coamorphous system dramatically enhanced solubility (at least ∼50-fold in the physiological pH range) and dissolution (∼1200-fold) of LH, and exhibited superior physical stability under long-term storage condition. More importantly, the coamorphous system was able to eliminate gelation of amorphous LH during dissolution. In order to further explore the mechanism of such improvement, the internal interactions of the coamorphous system in the solid state and in aqueous solution were investigated. Fourier transform infrared spectroscopy, Raman spectroscopy, and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in the benzisothiazole ring of LH and the NH3+ group of CYS after coamorphization. A fluorescence quenching test with a Stern-Volmer plot and density functional theory modeling, phase-solubility study, and NMR test in D2O indicated that ground-state complexation occurred between LH and CYS in aqueous solution, which contributed to the solubility and dissolution enhancement of LH. The current study offers a promising strategy to overcome poor solubility/dissolution and be able to eliminate gelation of amorphous materials by coamorphization and complexation.

Chemical puzzles in the search for new, flexible derivatives of lurasidone as antipsychotic drugs.

In the pharmacotherapy of schizophrenia, there is a lack of effective drugs, and currently used agents cause a large number of side effects. The D2, 5-HT1A, 5-HT2A receptors are among the most important receptor targets in the treatment of schizophrenia, but antagonism at 5-HT6 and 5-HT7 receptors may bring about additional improvement of cognitive functions. However, doubt exists regarding the importance of 5-HT7R in the pharmacotherapy. In 2010, lurasidone (with high affinity for D2, D3, 5-HT1A, 5-HT2A, 5-HT7 receptors) was approved for the treatment of schizophrenia. Due to the efficacy of the mentioned drug and doubts related to the role of 5-HT7R, we decided to obtain compounds with an activity profile similar to that of lurasidone, but with the reduced affinity for 5-HT7R and increased affinity for 5-HT6R. For this purpose, we chose aflexible hexyl derivative of lurasidone (2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 1a) as a hit structure. After molecular modeling, we modified it, in the area of the arylpiperazine and imide group, using the moieties found in other known CNS drugs. We received the compounds in accordance with the previously developed method of ecological synthesis in the microwave radiation field. Among the obtained compounds, N-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)naphthalene-sulfonamides 1v and 1w were distinguished as multifunctional ligands showing increased affinity for 5-HT6R, and 2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 1i - a multifunctional ligand showing moderate affinity for 5-HT6R and threefold lower for 5-HT7R. In the paper, we discuss some of the observed dependencies regarding 5-HT6/5-HT7R affinity using molecular docking methods.

Stable solid dispersion of lurasidone hydrochloride with augmented physicochemical properties for the treatment of schizophrenia and bipolar disorder.

Crystalline solid dispersion of lurasidone hydrochloride (LH) was made with various polar and non-polar small molecules to overcome the poor aqueous solubility issue. LH-Glutathione (GSH) solid dispersion in 1:1 ratio was prepared by co-grinding method and characterized by using differential scanning calorimetry (DSC), powder X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. GSH acts as antioxidant and reported for anti-schizophrenic activity may provide synergistic action with LH or reduce the side effects. LH in LH-GSH solid dispersion (SD) has shown improvement in solubility by 7.9 folds than plain drug which translated in terms of improved dissolution rate by two-folds. The in vitro dissolution results showed maximum dissolution rate with LH-GSH SD (97.85 ± 2.40%) compared to plain drug (50.5 ± 3.02%) at 15 min (t15 min, %) and thus, satisfying criteria of immediate release dosage form. DSC and FTIR data confirmed the stability of LH-GSH SD for 3 months at accelerated stability condition (40 ± 2°C and 75 ± 5% RH). The prepared LH-GSH SD can be used as a tool to target dual problems that is, enhanced physicochemical properties along with possible management of disorder which could be due to synergism with co-administered GSH. This approach is thought to be efficiently providing the relief to the psychological patients.

Brain targeted delivery of lurasidone HCl via nasal administration of mucoadhesive nanoemulsion formulation for the potential management of schizophrenia.

This investigation aimed to design, develop, and optimize intranasal nanoemulsion for brain targeted delivery of lurasidone hydrochloride for the management and treatment of schizophrenia. The design of experiment supported optimization of high-pressure homogenization (HPH) process was executed for the manufacturing of lurasidone loaded nanoemulsion. The nanoemulsion comprising of lurasidone hydrochloride (10 mg/mL), 20% Oilmix, 25% surfactant and, 55% aqueous phase (w/w) was processed with HPH at optimized conditions to get droplet size in the nano range. The droplet size of optimized nanoemulsion was found to be 48.07 ± 3.29 nm with a polydispersity index of 0.31 ± 0.01. The optimized translucent nanoemulsion (% transmittance of 88.56 ± 2.47) was found to be non-toxic to sheep nasal mucosa and stable for six months. The results of ex vivo diffusion study revealed the improvement in drug diffused by mucoadhesive nanoemulsion (MLNE) (1.41 × 10-4 ± 1.11 × 10-5 cm2/min) as compared to the solution (1.15 × 10-4 ± 1.35 × 10-5 cm2/min). The results of pharmacodynamic studies in mice uncover the highest inhibition of compulsive behavior (64.63%) and spontaneous locomotor activity (60.87%) shown by MLNE. This may be due to increased bioavailability in a brain, and possibly confirms the potential of nanoemulsion in targeting the brain through nasal route in the treatment of schizophrenia.

Effects of Temperature and Ionic Strength of Dissolution Medium on the Gelation of Amorphous Lurasidone Hydrochloride.

PURPOSE: Amorphous lurasidone hydrochloride (LH) showed decreased dissolution behavior in comparison to crystalline LH owing to gelation during dissolution as reported in our previous study. The current study aims to investigate external factors including temperature and ionic strength on the gelation and hence the dissolution of amorphous LH. METHODS: Dissolution tests of amorphous LH were performed under different temperatures and buffer ionic strengths. The formed gels were characterized by rheology study, texture analysis, PLM, SEM, DSC, XRPD and FTIR. RESULTS: With the increase of temperature and ionic strength of medium, the dissolution of amorphous LH decreased, while the strength, hardness and adhesiveness of in situ formed gel enhanced. Amorphous LH converted into its crystalline state during dissolution and the crystallization rate was affected by medium conditions. With medium temperature increasing from 30°C to 45°C, the gel microstructure changed from interconnecting fibrillar network to spherical particle aggregate. On the other hand, the formed spherulitic gel aggregate exhibited increased particle size when increasing the ionic strength of medium. CONCLUSIONS: With increase of temperature and ionic strength, the gel strength of in situ formed gel from amorphous LH enhanced with more compact microstructure, subsequently leading to decreased dissolution profiles.

Fabrication of solid lipid nanoparticles of lurasidone HCl for oral delivery: optimization, in vitro characterization, cell line studies and in vivo efficacy in schizophrenia.

Objective: The aim of the present investigation was to investigate the efficacy of solid lipid nanoparticles (SLNs) to enhance the absorption and bioavailability of lurasidone hydrochloride (LH) following oral administration. Methods: The LH loaded SLNs (LH-SLNs) were prepared by high pressure homogenization (HPH) method, optimized using box Behnken design and evaluated for particle size (PS), entrapment efficiency (EE), morphology, FTIR, DSC, XRD, in vitro release, ex vivo permeation, transport studies across Caco-2 cell line and in vivo pharmacokinetic and pharmacodynamic studies. Results: The LH-SLNs had PS of 139.8 ± 5.5 nm, EE of 79.10 ± 2.50% and zeta potential of -30.8 ± 3.5 mV. TEM images showed that LH-SLNs had a uniform size distribution and spherical shape. The in vitro release from LH-SLNs followed the Higuchi model. The ex vivo permeability study demonstrated enhanced drug permeation from LH-SLNs (>90%) through rat intestine as compared to LH-suspension. The SLNs were found to be taken up by energy dependent, endocytic mechanism which was mediated by clathrin/caveolae-mediated endocytosis across Caco-2 cell line. The pharmacokinetic results showed that oral bioavailability of LH was improved over 5.16-fold after incorporation into SLNs as compared to LH-suspension. The pharmacodynamic study proved the antipsychotic potential of LH-SLNs in the treatment of schizophrenia. Conclusion: It was concluded that oral administration of LH-SLNs in rats improved the bioavailability of LH via lymphatic uptake along with improved therapeutic effect in MK-801 induced schizophrenia model in rats.

Solid dispersion adsorbate technique for improved dissolution and flow properties of lurasidone hydrochloride: characterization using 32 factorial design.

The aim of the present study was to improve the dissolution and flow properties of lurasidone hydrochloride (LH) by solid dispersion adsorbate (SDA) technique. Solid dispersions (SDs) of LH were prepared by fusion method using Poloxamer P188. The melt dispersion was adsorbed onto the porous carrier Florite (calcium silicate). A 32 factorial design was employed to quantify the effect of two independent variables, namely ratio of carrier (Poloxamer 188) and LH in SD and ratio of adsorbent (Florite) to SD. SDA granules of LH were studied for flow properties and characterized using differential scanning calorimetry, scanning electron microscopy, and X-ray diffraction. Tablets of optimized composition of SDA granules (equivalent to 20 mg of drug) and plain tablets were prepared by direct compression method. The dissolution studies were carried out in Mcllvaine buffer (pH 3.8) as per USFDA guidelines and characterized for parameters such as percent dissolution efficiency, t50, and Q30. Tablets prepared from SDA granules showed almost four-fold increase in cumulative percentage drug release as compared to tablets prepared from plain LH. The value of dissolution efficiency was enhanced from 49.60% for plain tablets to 94.15% for SDA tablets. SDA granules did not show any change in drug release and X-ray diffraction pattern after storage at 40 °C/75% of RH for 3 months, which confirms that Florite prevented conversion of drug from amorphous form to crystalline form improving physical stability of the amorphous state of LH.

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state.

OBJECTIVE: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs). METHODS: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control. RESULTS: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5 min. Pharmacokinetic study showed that the AUC(0-∞) and Cmax for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption. CONCLUSION: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.

Design, Optimization, and Evaluation of Lurasidone Hydrochloride Nanocrystals.

The present investigation was carried out to design, optimize, and evaluate lurasidone hydrochloride nanocrystals for improving its solubility and dissolution characteristics. Nanocrystals were prepared by media milling technique using zirconium oxide beads with 0.1 mm diameter. Various stabilizers, viz. poloxamer 188, PVP K30, SLS, HPMC E15, and PVP S 630 D, were evaluated to stabilize the nanocrystals. The Pareto chart obtained through Plackett-Burman screening design revealed that HPMC E 15 showed the highest standardized effect (p value <0.05) on percent dissolution efficiency at 2 min. In subsequent studies, a 3(2) factorial design was employed to quantify the effect of two independent variables, namely amount of stabilizer and milling time on predetermined response variables mean particle size, saturation solubility, and percent dissolution efficiency at 2 min. Statistical analysis of the factorial design revealed that all predetermined response variables were significantly dependent (p value <0.05) on the independent variables. The observed response of the optimized batch prepared as per the desirability function was in close agreement with predicted response, and mathematical model generated was validated. The optimized batch was lyophilized, and X-ray powder diffraction studies indicated that there was no substantial change in crystallinity of the drug. The optimized formulation showed mean particle size of 228 nm and released almost all the drug within first 5 min. Since the crystallinity of the drug is maintained, improvement in saturation solubility and dissolution efficiency could be attributed to decrease in mean particle size of the drug.

Specific surface area of mannitol rather than particle size dominant the dissolution rate of poorly water-soluble drug tablets: A study of binary mixture.

The dissolution behavior of tablets, particularly those containing poorly water-soluble drugs, is a critical factor in determining their absorption and therapeutic efficacy. Traditionally, the particle size of excipients has been considered a key property affecting tablet dissolution. However, lurasidone hydrochloride (LH) tablets prepared by similar particle size mannitol, namely M200 (D90 = 209.68 ± 1.42 µm) and 160C (D90 = 195.38 ± 6.87 µm), exhibiting significant differences in their dissolution behavior. In order to find the fundamental influential factors of mannitol influencing the dissolution of LH tablets, the properties (particle size, water content, true density, bulk density, tapped density, specific surface area, circularity, surface free energy, mechanical properties and flowability) of five grades mannitol including M200 and 160C were investigated. Principal component analysis (PCA) was used to establish a relationship between mannitol properties and the dissolution behavior of LH. The results demonstrated that specific surface area (SSA) emerged as the key property influencing the dissolution of LH tablets. Moreover, our investigation based on the percolation theory provided further insights that the SSA of mannitol influences the probability of LH-LH bonding and LH infinite cluster formation, resulting in the different percolation threshold states, then led to different dissolution behaviors. Importantly, it is worth noting that these findings do not invalidate previous conclusions, as reducing particle size generally increases SSA, thereby affecting the percolation threshold and dissolution behavior of LH. Instead, this study provides a deeper understanding of the underlying role played by excipient SSA in the dissolution of drug tablets. This study provides valuable guidance for the development of novel excipients aimed at improving drug dissolution functionality.

Development of LC-MS/MS method for quantification of Lurasidone using volumetric absorptive microsampling (VAMS); a comparative study between dried blood and plasma samples.

The ecological impact of biological, chemical, and analytical research practices, including toxic reagents and biohazardous waste, has led to the development of alternative sampling and extraction techniques for bioanalysis. Microsampling (sample volume < 50 µL) aligns with the 3Rs principle, allowing multiple sampling points from the same animal at different time points and improving animal welfare. A bioanalytical method was developed to investigate factors related to bioanalytical challenges and the implementation of microsampling techniques. An LC-MS/MS method for Volumetric Absorptive Microsampling (VAMS), 20 µL, was developed for quantifying Lurasidone using a liquid-liquid extraction technique. The method uses a C18, Phenomenex column for chromatographic separation and a mobile phase composition of Methanol, Acetonitrile, and Water with 0.1 % HFBA. The method was validated over a concentration range of 5.0 to 1200.0 ng/mL and achieved acceptable precision and accuracy. The recovery for analyte from VAMS was approximately 40% at four different concentrations and is consistent (%CV < 15), with no significant differences among HCT levels. The matrix factor ranged between 85.00 and 115.00 %, showing no substantial issues with reduced or enhanced signal. The stability data showed no significant degradation of LUR in VAMS samples when stored at room temperature for 15 days. The newly established method for Lurasidone confirmed the use of VAMS sampling method and its analysis on LC-MS/MS. Further, the data obtained from microsampling techniques was compared with conventional (plasma) technique, as proof-of-concept, and it confirms the agreement between the two methods. The study supports the advantages of microsampling in protecting the environment and animals while maintaining scientific judgement.

Contrasting the pharmacokinetic performance and gut microbiota effects of an amorphous solid dispersion and lipid nanoemulsion for a poorly water-soluble anti-psychotic.

Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable âˆ¼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a 'gut neutral' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota - an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.

Effect of sodium lauryl sulfate-mediated gelation on the suppressed dissolution of crystalline lurasidone hydrochloride and a strategy to mitigate the gelation.

In dissolution test, the surfactant sodium lauryl sulfate (SLS) is usually added to increase the dissolution of insoluble drugs and achieve the sink condition. However, the current study found that 0.1 % SLS would significantly decrease the dissolution of crystalline lurasidone hydrochloride (LH, a BCS Ⅱ drug). The aim of this study was to clarify the mechanism of this unexpected phenomenon and explore a strategy for mitigating the negative effect of SLS on the dissolution of LH. Sample characterizations (such as PLM, DSC, PXRD, IR and NMR) confirmed that the insoluble single-phase amorphous LH-SLS complex (with a single Tg at 35.2 °C) formed during dissolution in 0.1 % SLS aqueous solution via electrostatic interaction, tetrel bond interaction, and hydrophobic effect. Due to the plasticization effect of water, the transition of amorphous LH-SLS from its glassy state to viscous supercooled liquid state led to the gel formation, and suppressd the dissolution of LH. Meanwhile, the solubility curve of LH in SLS aqueous solution at various concentrations exhibited an unusual V-shaped feature, with the CMC value of SLS serving as the inflection point, since the gel degree was attenuated due to the micelle solubilization of SLS. Additionally, an innovative strategy was developed to alleviate the inhibiting effect of SLS on LH dissolution based on the potential competitive interactions. This study not only enriches the internal mechanism of surfactant-inhibited drug dissolution but also informs an effective strategy to mitigate the gelation.

Exploring micellar-based polymeric systems for effective nose-to-brain drug delivery as potential neurotherapeutics.

Non-invasive nose-to-brain delivery presents a competitive strategy for effective drug targeting. This strategy can potentially evade the blood-brain barrier (BBB) depending on the pathway the drug and/or drug/micelle composite travels, thereby allowing direct drug delivery to the brain. This delivery strategy was employed for lurasidone, a clinically USFDA-approved neurotherapeutic molecule in bipolar disorders and schizophrenia treatments. The aim of this study was to develop mixed polymeric micelles of lurasidone HCl (LH) for targeted brain delivery via intranasal route. Lurasidone HCl-loaded mixed micelles (LHMM) were prepared by solvent evaporation method and optimized by 32 factorial design to quantify the effects of excipients on micelle size and entrapment efficiency. Fourier transform infrared spectroscopy helped in scrutinizing drug-excipient interactions whereas transmission electron microscopy images showed particle size and shape. Further, LHMM and LHMM hydrogel were evaluated for in vitro diffusion, histopathology, ex vivo permeation, in vivo pharmacokinetics and stability studies. Optimized LHMM exhibited 175 nm particle size and 97.8% entrapment efficiency with improved in vitro drug diffusion (81%). LHMM hydrogel showed 79% ex vivo drug permeation without any significant signs of nasociliary toxicity to sheep nasal mucosa. Single dose in vivo pharmacokinetic studies showed improved therapeutic concentration of drug in the brain post intranasal administration with 9.5 ± 0.21 µg/mL Cmax and T1/2 of 19.1 ± 0.08 h as compared to pure drug. LHMM, when administered by intranasal route, demonstrated significant increase in the drug targeting efficiency as well as potential (%DTE and %DTP) of drug as compared to pure lurasidone. Thus, nanosized mixed micelles were useful in effective brain delivery of lurasidone HCl via intranasal route. Graphical abstract.

Self microemulsifying drug delivery system of lurasidone hydrochloride for enhanced oral bioavailability by lymphatic targeting: In vitro, Caco-2 cell line and in vivo evaluation.

The global aim of this research was to develop and evaluate self-microemulsifying drug delivery system (SMEDDS) to improve oral bioavailability of Lurasidone Hydrochloride (LH). A chylomicron flow blocking approach was used to evaluate lymphatic drug transport. The developed LH-SMEDDS was composed of Capmul MCM C8 (oil), Cremophor EL (surfactant) and Transcutol HP (co-surfactant). Highest microemulsifying area was obtained at 3:1 ratio (surfactant:cosurfactant) and mean globule size was found to be 49.22 ±â€¯1.60 nm. More than 98% drug release was obtained with LH-SMEDDS in phosphate buffer pH 6.8. Confocal microscopy and flow cytometry studies revealed higher fluorescence indicating deeper penetration across Caco-2 cells with Coumarin-6 SMEDDS as compared to Coumarin-6 solution. Mean Fluorescence Intensity (MFI) with Coumarin-6 loaded SMEDDS was increased 25.57 times with respect to Coumarin-6 solution. The permeability across Caco-2 cells was enhanced 3 times with LH-SMEDDS as compared to LH-suspension. Furthermore, Area Under Curve with LH-SMEDDS was found to be 2.92 times higher than that of LH suspension indicating improved bioavailability after formulating SMEDDS. Lymphatic transport in oral absorption of LH-SMEDDS was proved via lymphatic uptake study. All the findings suggest the effectiveness of lipid-based formulation i.e. SMEDDS of LH to augment the oral bioavailability via intestinal lymphatic pathway.

Charge-assisted bond N+H mediates the gelation of amorphous lurasidone hydrochloride during dissolution.

Lurasidone hydrochloride (LH), the hydrochloride form of lurasidone with a charge-assisted bond N+H, is an atypical antipsychotropic agent for the treatment of schizophrenia. As a BCS class II drug, LH has a low oral bioavailability mainly due to its poor water solubility and low dissolution. In order to improve its solubility, amorphization of LH was performed and characterized. Unexpectedly, the dissolution rate of amorphous LH was much lower than that of crystalline LH. In addition, the amorphous LH powders quickly aggregated when contacting the dissolution media (water, 37°C), and formed a sticky gel adhering on the paddle. The follow-up polarized light microscope, XRPD, DSC, and FTIR analysis found that amorphous LH transformed to crystalline LH during dissolution. On the other hand, no such gelation phenomenon of amorphous lurasidone was observed under the same dissolution condition. However, the gel would reform when dropping concentrated hydrochloric acid slowly into the bottom of the medium during the dissolution of amorphous lurasidone, and XRPD/DSC/FTIR results indicated that the regenerated gel was consisted of crystalline LH, suggesting that the charge-assisted bond N+H in the structure of LH mediated the gel formation of amorphous LH during its dissolution process.

Phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) as a dual solubilization approach for development of formulation with diminished food effect: Fast/fed in vivo pharmacokinetics study in human.

The novel self- nanoemulsifying self-nanosuspension (SNESNS) combines the advantages of two efficient solubilization technologies; the nanoemulsion and the nanosuspension. The aim of this study is to test the efficiency of phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) formulation as a powerful tool to diminish the food effect on bioavailability of lurasidone hydrochloride as BCS Class II model drug. Phospholipid was incorporated into SNESNS to increase the solubilization power of the in-situ formed nanoemulsion and facilitate the dispersion of the in-situ formed nanosized drug particles. P-SNESNS was evaluated for particle size, Polydispersity index, in vitro dissolution and transmission electron microscopy (TEM). The drug amount dissolved after water dilution of LSD p-SNESNS was ~2 folds that dissolved after dilution of non-phospholipid SNESNS. The self-nanosuspension obtained by aqueous dilution of p-SNESNS kept the cubic morphology of LSD macroparticles. The high in vitro dissolution of LSD in the non-sink dissolution media (water and Phosphate buffer pH6.8) indicated that the p-SNESNS formulation had successfully increased the drug solubility irrespective of pH of the medium. The pharmacokinetics parameters of LSD p-SNESNS in humans were the same in both the fasted and fed states and were similar to those of LSD capsules in the fed state. Our results propose that p-SNESNS could be promising to increase patient compliance and drug efficiency of BCS class II antipsychotics by diminishing the food effect on their oral absorption and preventing the necessity to administer them with food.