Viscosity of Suspensions of Strongly Bonded Spherical Particles of Nickel-Manganese-Cobalt Mixed Oxides (NMC) in Molten Poly(Ethylene Carbonate) for Batteries.

Ionically conductive polymers highly filled with active materials, such as metal oxides are increasingly studied for their potential use in all solid-state batteries. They offer the desirable processing ease of polymers for mass production despite interfacial issues that remain to be solved. In this study, it is shown that spherical particles of transition metal oxides can be introduced in co-polymers of alkene carbonate and ethylene oxide at loading close to the maximum packing fraction, without imparting the processability in the melt of the material. In particular, the viscosity does not show any yield stress and the increase of viscosity shows that the intrinsic viscosity of the filler does not match with the usual 2.5 value in the limit of the Einstein's equation. Conversely, rheological data show that the value is rather close to unity consistently with theoretical arguments that predicted that this scaling factor should be unity when particle rotation is precluded. In the present case, this behavior is attributed to strong bonding between polymer and filler that is proved by electronic microscopy and by dynamical mechanical spectroscopy showing a relaxation due to bound polymer.

Active Controlled and Tunable Coacervation Using Side-Chain Functional α-Helical Homopolypeptides.

We report the development of new side-chain amino acid-functionalized α-helical homopolypeptides that reversibly form coacervate phases in aqueous media. The designed multifunctional nature of the side-chains was found to provide a means to actively control coacervation via mild, biomimetic redox chemistry as well as allow response to physiologically relevant environmental changes in pH, temperature, and counterions. These homopolypeptides were found to possess properties that mimic many of those observed in natural coacervate forming intrinsically disordered proteins. Despite ordered α-helical conformations that are thought to disfavor coacervation, molecular dynamics simulations of a polypeptide model revealed a high degree of side-chain conformational disorder and hydration around the ordered backbone, which may explain the ability of these polypeptides to form coacervates. Overall, the modular design, uniform nature, and ordered chain conformations of these polypeptides were found to provide a well-defined platform for deconvolution of molecular elements that influence biopolymer coacervation and tuning of coacervate properties for downstream applications.

Development of Novel Bead Milling Technology with Less Metal Contamination by pH Optimization of the Suspension Medium.

To develop novel contamination-less bead milling technology without impairing grinding efficiency, we investigated the effect of the formulation properties on the grinding efficiency and the metal contamination generated during the grinding process. Among the various formulations tested, the combination of polyvinylpyrrolidone and sodium dodecyl sulfate was found to be suitable for efficiently pulverizing phenytoin. However, this stabilization system included a relatively strong acid, which raised the concern of possible corrosion of the zirconia beads. An evaluation of the process clearly demonstrated that acidic pH promoted bead dissolution, suggesting that this could be suppressed by controlling the pH of the suspension. Among the various pH values tested, the metal contamination generated during the grinding process could be significantly reduced in the optimized pH range without significant differences in the particle size of the phenytoin suspension after pulverization. In addition, the contamination reduction by pH optimization in the presence of physical contact among the beads was approximately 10-times larger than that without bead contact, suggesting that pH optimization could suppress not only bead dissolution but also the wear caused by bead collisions during the grinding process. These findings show that pH optimization is a simple but effective approach to reducing metal contamination during the grinding process.

Bevacizumab-Conjugated Quantum Dots: In Vitro Antiangiogenic Potential and Biosafety in Rat Retina.

Purpose: Disturbances that affect the inside of the eyeball tend to be highly harmful since they compromise the homeostasis of this organ. Alongside this, the eyeball has several anatomical barriers that prevent the entry of substances. This way, diseases that affect the retina are among those that present greater difficulty in the treatment. In many cases, abnormal proliferation of blood vessels (neovascularization) occurs from the lower layers of the retina. This process damages its structure physiologically and anatomically, causing the rapid and irreversible loss of visual capacity. This work aims to develop nanosuspensions of quantum dots (QDs) conjugated to bevacizumab. Methods: Two types of QDs were produced by aqueous route, stabilized with chitosan conjugated to bevacizumab. The antiangiogenic activity was evaluated in the chorioallantoic membrane model, in which results indicated discrete activity at the doses tested. Samples were assessed for their biosafety in animals, after intravitreal administration, by means of electroretinography (ERG), intraocular pressure (IOP) measurement, histological, morphometric, and immunohistochemical evaluation. Results: No significant alterations were detected in ERG that suggests damage to retinal function by the samples. No significant changes in IOP were also detected. The histological sections did not show signs of acute inflammation, although there was evidence of late retinal damage. The immunohistochemical analysis did not detect any apoptotic bodies. Conclusion: Preliminary results suggest that QDs present potential applicability in ocular therapy, and it is necessary to better characterize their in vivo behavior and to optimize their dosage.

Preparation of As4S4/Fe3O4 nanosuspensions and in-vitro verification of their anticancer activity.

Multifunctional nanoparticulate systems, especially those used in medicine, are currently of great interest. In this work, the in-vitro anticancer activity of As4S4/Fe3O4 composites dispersed in a water solution of Poloxamer 407 on breast MCF-7 and tongue SCC-25 cancer cells was verified. An increase in apoptotic cells as a consequence of higher caspase activities, a decrease in mitochondrial membrane potential and an accumulation of cells in the G2/M and subG0/G1 phases were detected after treatment with the As4S4/Fe3O4 nanosuspensions. The sterically stabilized nanosuspensions were characterized in relation to their particle size distribution, zeta potential and long-term stability properties. The interaction between the solid and liquid phases of the nanosuspensions was also studied using Fourier transform infrared spectroscopy.

Study on the stabilization mechanisms of wet-milled cepharanthine nanosuspensions using systematical characterization.

Objectives: Stability issues are inevitable problems that are encountered in nanosuspension (NS) technology developments and in the industrial application of pharmaceuticals. This study aims to assess the stability of wet-milled cepharanthine NSs and elucidate the stabilization mechanisms of different stabilizers.Methods: The aggregation state was examined via scanning electron microscopy, laser diffraction, and rheometry. The zeta potential, stabilizer adsorption, surface tension, and drug-stabilizer interactions were employed to elucidate the stabilization mechanisms.Results: The results suggest that croscarmellose sodium (CCS), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), or polyvinyl pyrrolidone VA64 (PVP VA64) alone was able to prevent nanoparticle aggregation for at least 30 days. Attempts to evaluate the stability mechanisms of different stabilization systems revealed that CCS improved the steric-kinetic stabilization of the NSs, attributed to its high viscosity, swelling capacity, and physical barrier effects. In contrast, the excellent physical stability of TPGS systems was mainly due to the reduced surface tension and higher crystallinity. PVP VA64 can adsorb onto the surfaces of nanoparticles and stabilize the NS via steric forces.Conclusion: This study demonstrated the complex effects of CCS, TPGS, and PVP VA64 on cepharanthine NS stability and presented an approach for the rational design of stable NSs.

Physiologically-Based Pharmacokinetic Model on the Oral Drug Absorption in Roux-en-Y Gastric Bypass Bariatric Patients: Amoxicillin Tablet and Suspension.

The potential of a physiologically-based pharmacokinetic (PBPK) model to predict oral amoxicillin bioavailability, by considering the physiological changes after "Roux-en-Y gastric bypass" (RYGB) surgery in bariatric patients, was evaluated. A middle-out approach for parameter estimations was undertaken using in vitro, in situ, and in vivo data. The observed versus predicted plasma concentrations and the model sensitivity of the simulated parameters of AUC0-inf and Cmax of amoxicillin (AMX) were used to confirm the reliability of the estimation. The model considers that a drug-transporter (Transp) in the initial segments of the normal intestine plays a significant role in the AMX absorption. A lower fraction absorbed (Fabs) was observed in RYGB patients (54.43% for suspension and 45.21% for tablets) compared to healthy subjects (77.48% capsule). Furthermore, the tablet formulation presented a lower dissolved fraction (Fd) and Fabs compared to the suspension formulation of AMX in RYGB patients (91.70% and 45.21% versus 99.92% and 54.43%, respectively). The AUC0-inf and Cmax were sensitive to changes in Rtintestine, PeffAMX, and Transp for both healthy and RYGB models. Additionally, AUC0-inf and Cmax were also sensitive to changes in the tlag parameter for tablet formulation in RYGB patients. The PBPK model showed a reduction in AMX bioavailability as a consequence of reduced intestinal length after RYGB surgery. Additionally, the difference in the predicted Fd and Fabs between suspension and tablet suggests that liquid formulations are preferable in postbariatric patients.

Intercalation of cationic peptides within Laponite layered clay minerals in aqueous suspensions: The effect of stoichiometry and charge distance matching.

Clays can be synthesised to have specific functional properties, which have been exploited in a range of industrial processes. A key characteristic of clay is the presence of a negatively charged surface, surrounded by an oppositely charged rim. Because of that, clays are able to sequester cationic compounds resulting in the formation of ordered layered structures, known as tactoids. Recent research has highlighted the possibility of utilising clay as a drug delivery compound for cationic peptides. Here, we investigate the process of intercalation by using the highly cationic peptide deca-arginine, and the synthetic clay Laponite, in aqueous suspensions with 2.5 wt% Laponite, and varying peptide concentrations. Small-angle X-ray scattering experiments show that tactoids are formed as a function of deca-arginine concentration in the dispersion, and for an excess of peptide, i.e. above a matched charge-ratio between the peptide and clay, the growth of the tactoids is limited, resulting in tactoidal dissolution. Zeta-potential measurements confirm that the observed dissolution is caused by overcharging of the platelets. By employing coarse-grained molecular dynamics simulations based on the continuum model, we are able to predict the tactoid formation, the growth, and the dissolution, in agreement with experimental results. We propose that the present simulation method can be a useful tool to tune peptide and clay characteristics to optimise and determine the extent of intercalation by cationic peptides of therapeutic interest.

Desonide nanoencapsulation with açai oil as oil core: Physicochemical characterization, photostability study and in vitro phototoxicity evaluation.

This study aimed to develop Eudragit® RL 100 nanocapsules loaded with desonide (DES) using açai oil (AO) or medium chain triglycerides (MCT) as oil core. Pre-formulation study showed that AO and MCT are suitable for nanocapsules preparation. The nanocapsules prepared with AO and MCT presented mean particle size around 165 and 131 nm, respectively; polydispersity index values <0.20, positive zeta potential values, drug content close to the theoretical value (0.25 mg mL-1), and DES encapsulation efficiency around 81%, regardless of the oil core (AO or MCT). Considering the photoinstability reported to DES, photodegradation studies were performed. The UV-A (365 nm) and UV-C (254 nm) photodegradation studies revealed less DES degradation when associated to the nanocapsules containing AO in comparison to those with MCT. The in vitro release study showed a biphasic release profile for both nanocapsule suspensions: an initial burst effect followed by a prolonged DES release. In addition, the formulations were considered non-phototoxic at 0.5 mg mL-1 when tested on 3 T3 murine fibroblasts and HaCaT human keratinocytes using the MTT and NRU viability assays. The irritant potential of the prepared nanocapsules and DES in free form were evaluated by HET-CAM method. All formulations were classified as slightly irritant, including the non-associate DES. In conclusion, the nanocapsule formulations developed in this study may be promising for therapeutic applications.

Development and evaluation of rapidly dissolving buccal films of naftopidil: in vitro and in vivo evaluation.

Objectives: Development and evaluation of rapidly dissolving film for intra-oral administration of naftopidil. Significance: Formulation of naftopidil in the form of rapidly dissolving buccal film can eliminate the dissolution problem of naftopidil and provide a greater chance for direct absorption into the systemic circulation bypassing the presystemic metabolism. This can improve the oral bioavailability. In addition, this film guarantees patient compliance and is suitable for geriatric patients. Methods: Rapidly dissolving film utilized hydroxypropyl methylcellulose E5 and polyvinylpyrrolidone K30 as the main components. The drug was loaded in pure form or after co-grinding with citric and/or tartaric acid. A solution of naftopidil in plurol oleique, labrasol, and tween 80 self-microemulsifying drug delivery systems (SMEDDS) was also loaded. The interactions of the drug with the excipients were monitored using thermal analysis, Fourier transform infrared spectroscopy, and X-ray diffraction. Naftopidil dissolution was monitored and selected films were used to assess the bioavailability after buccal administration to rabbit. Unprocessed drug suspension was administered orally and used as a reference. Results: Incorporation of naftopidil in the film developed a new crystalline structure. The crystallinity of drug was abolished in the presence of organic acids or SMEDDS. The rapidly dissolving films showed fast liberation of the drug irrespective to the composition. Those films enhanced the bioavailability of naftopidil compared to orally administered suspension with SMEDDS containing film being superior. Conclusion: The study introduced rapidly dissolving buccal film for enhanced dissolution and bioavailability of naftopidil.

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.

A carrier-free multiplexed gene editing system applicable for suspension cells.

Genetically engineered cells via CRISPR/Cas9 system can serve as powerful sources for cancer immunotherapeutic applications. Furthermore, multiple genetic alterations are necessary to overcome tumor-induced immune-suppressive mechanisms. However, one of the major obstacles is the technical difficulty with efficient multiple gene manipulation of suspension cells due to the low transfection efficacy. Herein, we established a carrier-free multiplexed gene editing platform in a simplified method, which can enhance the function of cytotoxic CD8+ T cells by modulating suspension cancer cells. Our multiple Cas9 ribonucleoproteins (RNPs) enable simultaneous disruption of two programmed cell death 1 (PD-1) ligands, functioning as negative regulators in the immune system, by accessing engineered Cas9 proteins with abilities of complexation and cellular penetration. In addition, combination with electroporation enhanced multiple gene editing efficacy, compared with that by treatment of multiple Cas9 RNPs alone. This procedure resulted in high gene editing at multiple loci of suspension cells. The treatment of multiple Cas9 RNPs targeting both ligands strongly improved Th1-type cytokine production of cytotoxic CD8+ T cells, resulting in synergistic cytotoxic effects against cancer. Simultaneous suppression of PD-L1 and PD-L2 on cancer cells via our developed editing system allows effective anti-tumor immunity. Furthermore, the treatment of multiple Cas9 RNPs targeting PD-L1, PD-L2, and TIM-3 had approximately 70-90% deletion efficacy. Thus, our multiplexed gene editing strategy endows potential clinical utilities in cancer immunotherapy.

Preparation and evaluation of etoposide-loaded lipid-based nanosuspensions for high-dose treatment of lymphoma.

Aim: High-dose administration of etoposide (VP16) was limited by its poor aqueous solubility and severe systemic toxicity on lymphoma therapy. Herein, a novel VP16-loaded lipid-based nanosuspensions (VP16-LNS) was developed for improving drug solubility, enhancing antitumor effect and reducing systemic toxicity. Materials & methods: VP16-LNS with soya lecithin and D-α-tocopheryl PEG 1000 succinate (TPGS) as stabilizers were prepared by nanoprecipitation method. Results: VP16-LNS exhibited uniform spherical morphology, small particle size and favorable colloidal stability. The concentration of VP16 in VP16-LNS was high enough (1017.67 µg/ml) for high-dose therapy on lymphoma. Moreover, VP16-LNS displayed long blood circulation time, selective intratumoral accumulation, remarkable antitumor effect and upregulated safety. Conclusion: VP16-LNS would be an efficient nanoformulation for clinical intravenous application against lymphoma.

Electro-demulsification of water-in-oil suspensions enhanced with implementing various additives.

A huge amount of various oily suspensions that frequently display properties of stable emulsions are produced per day in upstream and downstream petroleum industries. As this waste is considered potentially harmful to the environment, their management and disposal require particular attention. While current treatment processes, such as partial water removal via the separation of phases by centrifuging result in decreased waste volumes for disposal, a significant volume of water and oil remains trapped in the form of water-in-oil emulsion. Therefore, the electrokinetic method for oil-water separation came into consideration for the improvement of the quality and volume of separated products. This paper discusses the impacts of additives, namely, ferric chloride, alum, cationic polymer, clay, and a mixture of clay and cationic polymer on the electrokinetic treatment of suspensions. The tests were conducted at a lab scale using an array of steel electrodes and low voltage. The objective of this study was to observe the impact of voltage gradients on electro-demulsification, in conjunction with employing additives into the separation and recovery of water, light, and heavy oil. An optimal recovery of light oil by 28%-52% in addition to heavy oil and water in the presence of ferric chloride under a constant voltage gradient of 1 V/cm, was achieved. Furthermore, the same system revealed an excellent clarity of extracted water. The results from this study can be implemented at a larger scale in upstream and downstream petroleum industries.

Functionalized docetaxel-loaded lipid-based-nanosuspensions to enhance antitumor efficacy in vivo.

Purpose: To further enhance the antitumor efficacy through targeted delivery, DTX loaded lipid-based-nanosuspensions (DTX-LNS) were prepared and functionalized by PEGylation or NGR modification to develop DSPE-PEG2000 modified DTX-LNS (P-DTX-LNS) or DSPE-PEG2000-NGR modified DTX-LNS (N-DTX-LNS), respectively. Methods: Based on our previous work, functionalized DTX-LNS including P-DTX-LNS and N-DTX-LNS were prepared using thin-film hydration, and then characterized. Release behavior, stability in vitro, cytotoxicity and cellular uptake of functionalized LNS were observed. To demonstrate tumor targeting efficiency of functionalized DTX-LNS, in vivo real-time and ex vivo imaging study were conducted. Furthermore, therapeutic efficacy in vivo was evaluated in an H22-bearing mice model. Results: Functionalized DTX-LNS 100-110 nm in diameter were successfully prepared and exhibited good stability under various conditions. In vitro release studies demonstrated that DTX was released from functionalized DTX-LNS steadily and reached approximately 95% at 48 hrs. Functionalized DTX-LNS showed dose-dependent cytotoxicity and time-dependent internalization in human hepatocellular liver carcinoma cells (HepG2) cells. In vivo real-time and ex vivo imaging results indicated that tumor targeting efficiencies of P-DiR-LNS and N-DiR-LNS were 29.9% and 34.3%, respectively. Moreover, evaluations of in vivo antitumor efficacy indicated that functionalized DTX-LNS effectively inhibited tumor growth with low toxicity. Conclusion: The functionalized LNS exhibited suitable particle size, nearly spherical structure, enough drug loading and great potentials for large-scale production. The results in vitro and in vivo demonstrated that functionalized LNS could realize tumor targeting and antitumor efficacy. Consequently, functionalized DTX-LNS could be expected to be used for tumor targeting therapy.

A novel biostructure sorbent based on CysSB/MetSB@MWCNTs for separation of nickel and cobalt in biological samples by ultrasound assisted-dispersive ionic liquid-suspension solid phase micro extraction.

An efficient method based on CysSB/MetSB@MWCNTs as a novel bio structure material was used for determination/separation of nickel and cobalt (Ni and Co) in human samples by ultrasound assisted-dispersive ionic liquid-suspension solid phase micro extraction (USA-DIL-SSPME). In this procedure, CysSB/MetSB@MWCNTs suspended in 1-butyl-2,3-dimethylimidazolium hexafluorophosphate ([BDMIM][PF6]) and mixture dispersed to 10 mL of blood samples at optimized pH by injecting. Then, the Co/Ni (II) was extracted with CysSB/MetSB@MWCNTs without any ligands and settled down in conical tube by IL [Ni/Co→:SMWCNTs]. After back extraction of ions from remaining solution, the concentration of Co/Ni was determined by electro thermal atomic absorption spectrometry (ET-AAS). By optimizing, the linear range, detection limit and enrichment factor of CysSB @MWCNTs were obtained (0.1-3.4 µg L-1; 0.08-3.2 µg L-1), (0.028 µg L-1; 0.022 µg L-1) and (50.2; 48.7) for Ni and Co ions in human biological samples, respectively (RSD<5%). The adsorption capacity of CysSB@MWCNTs for Ni and Co ions was 226.7 mg g-1 and 193.3 mg g-1, respectively which was higher than MetSB@MWCNTs. The standard reference materials (NIST, SRM) and ICP-MS were used for validation of methodology.

Biologically safe colloidal suspensions of naked iron oxide nanoparticles for in situ antibiotic suppression.

A category of naked maghemite nanoparticles (γ-Fe2O3), named surface active maghemite nanoparticles (SAMNs), is characterized by biological safety, high water colloidal stability and a surface chemistry permitting the binding of ligands. In the present study, the interaction between SAMNs and an antibiotic displaying chelating properties (oxytetracycline, OxyTC) was extensively structurally and magnetically characterized. OxyTC emerged as an ideal probe for providing insights into the colloidal properties of SAMNs. At the same time, SAMNs turned out as an elective tool for water remediation from OxyTC. Therefore, a dilute colloidal suspension of SAMNs was used for the removal of OxyTC in large volume tanks where, to simulate a real in situ application, a population of zebrafish (Danio rerio) was introduced. Interestingly, SAMNs led to the complete removal of the drug without any sign of toxicity for the animal model. Moreover, OxyTC immobilized on SAMNs surface resulted safe for sensitive Escherichia coli bacteria strain. Thus, SAMNs were able to recover the drug and to suppress its antibiotic activity envisaging their feasibility as competitive option for water remediation from OxyTC in more nature related scenarios. The present contribution stimulates the use of novel smart colloidal materials to cope with complex environmental issues.

A novel oil-based suspension of a micro-environmental, pH-modifying solid dispersion for parenteral delivery: Formulation and stability evaluation.

The objective of this study was to evaluate a novel oil-based suspension as a potential parenteral drug delivery system for drugs with poor water solubility. Most of the new active pharmaceutical ingredients are weak acid or basic drugs with pH-dependent solubility. To limit this dependence, use of micro-environmental pH-modifying solid dispersions (micro pHm SD) has been proved to increase the bioavailability of these drugs. Toltrazuril (TOL), a weakly acidic drug with poor aqueous and pH-dependent solubility, was studied as a model drug. Recently, studies on TOL with focus on the parenteral injection are rarely to find in the literature. A novel parenteral oil-based TOL suspension was prepared containing TOL micro pHm SD (TSD) powders suspended in oil-based vehicles and the optimal formulation was screened. The stability of this formulation was assessed considering particle size distribution, settling volume ratio, redispersibility, thermal stability, and drug content. The optimized white oil-based TOL pHm SD suspension (W-TSDS) showed significant improved stability and shear-thinning behavior. In particular, fumed silica as suspending agent positively influenced the physical stability of the formulation. Furthermore, W-TSDS showed good injectability using 21 G needles and more rapid and sustained drug release compared to TSD powders in vitro. In the in vivo safety evaluation, W-TSDS showed good histocompatibility in rabbits injected subcutaneously or intramuscularly. We believe these findings provide an alternative choice of dosage form for the delivery of new active pharmaceutical ingredients.

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.

Chitosan-TPP nanoparticles stabilized by poloxamer for controlling the release and enhancing the bioavailability of doxazosin mesylate: in vitro, and in vivo evaluation.

Objective: Control the release and enhance the bioavailability of chitosan-doxazosin mesylate nanoparticles (DM-NPs). Significance: Improve DM bioavailability for the treatment of benign prostatic hyperplasia and hypertension. Methods: Plackett-Burman design was utilized to screen the variables affecting the quality of DM-NPs prepared by ionic gelation method. The investigated variables were initial drug load (X1), chitosan percentage (X2), tripolyphosphate sodium (TPP) percentage (X3), poloxamer percentage (X4), homogenization speed (X5), homogenization time (X6) and TPP addition rate (X7). The prepared DM-loaded NPs have been fully evaluated for particle size (Y1), Zeta potential (Y2), production yield (Y3), entrapment efficiency (Y4), loading capacity (Y5), initial burst (Y6), and cumulative drug release (Y7). Finally, DM pharmacokinetic has been investigated on healthy albino male rabbits by means of non-compartmental analysis. Results: The combination of variables showed variability of Y1, Y2, and Y3 equal to 122-710 nm, 3.49-23.63 mV, and 47.31-92.96%, respectively. While Y4 and Y5, reached 99.87%, and 8.53%, respectively. The prepared NPs revealed that X2, X3, and X4 are the variables that play the important role in controlling the release behavior of DM from the NPs. The in vivo pharmacokinetic results indicated the enhancement in bioavailability of DM by 7 folds compared to drug suspension and the mean residence time prolonged to 23.72 h compared to 4.7 h of drug suspension. Conclusion: The study proved that controlling the release of DM from NPs enhance its bioavailability and improve the compliance of patients with hypertension or benign prostatic hyperplasia.