Bio-Inspired Organic Synaptor with In Situ Ion-Doped Ultrathin Polyelectrolyte Containing Acetylcholine-Like Cation.

An ion-based synaptic transistor (synaptor) is designed to emulate a biological synapse using controlled ion movements. However, developing a solid-state electrolyte that can facilitate ion movement while achieving large-scale integration remains challenging. Here, a bio-inspired organic synaptor (BioSyn) with an in situ ion-doped polyelectrolyte (i-IDOPE) is demonstrated. At the molecular scale, a polyelectrolyte containing the tert-amine cation, inspired by the neurotransmitter acetylcholine is synthesized using initiated chemical vapor deposition (iCVD) with in situ doping, a one-step vapor-phase deposition used to fabricate solid-state electrolytes. This method results in an ultrathin, but highly uniform and conformal solid-state electrolyte layer compatible with large-scale integration, a form that is not previously attainable. At a synapse scale, synapse functionality is replicated, including short-term and long-term synaptic plasticity (STSP and LTSP), along with a transformation from STSP to LTSP regulated by pre-synaptic voltage spikes. On a system scale, a reflex in a peripheral nervous system is mimicked by mounting the BioSyns on various substrates such as rigid glass, flexible polyethylene naphthalate, and stretchable poly(styrene-ethylene-butylene-styrene) for a decentralized processing unit. Finally, a classification accuracy of 90.6% is achieved through semi-empirical simulations of MNIST pattern recognition, incorporating the measured LTSP characteristics from the BioSyns.

Formulation and Evaluation of a Self-Microemulsifying Drug Delivery System of Raloxifene with Improved Solubility and Oral Bioavailability.

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX.

Novel innovative computer-based test (Inno-CBT) item types for national licensing examinations for health care professionals.

BACKGROUND: An effective test mechanism to evaluate clinical knowledge and skills of the entry-level healthcare professionals is important for providing clinical competency and improving patient care. This study aimed to develop novel, innovative computer-based test (Inno-CBT) item types for application in the national examination of Korean healthcare professionals. METHODS: This exploratory study was conducted from May 2021 to March 2022 by a team of faculty members from pharmacy schools in South Korea. A literature search using PubMed, Google Scholar, RISS, Web of Science, and KoreaMed was performed. Forum presentations, media articles, and previous reports by the Korea Health Personnel Licensing Examination Institute (KHPLEI) were included. Workshops were held, information and ideas were collected and conceptualized, and item types were designed, drafted, and refined. By repeating this process, the Inno-CBT item types were finalized. RESULTS: Forty-one Inno-CBT item types with 28 subtypes were developed. New digital technologies, such as a reactive responsive media interface, an animation insertion, multimedia embedding, and network surfing, were utilized in these novel types. It was anticipated that these Inno-CBT item types would effectively measure abilities in healthcare knowledge, problem-solving skills, and professional behaviors. Some potential barriers to implementing the Inno-CBT item types include item difficulty, operational unfamiliarity, complexity in scoring protocols, and network security. CONCLUSIONS: A variety of styles of novel Inno-CBT item types were developed to evaluate the multifaceted and in-depth professional abilities required for healthcare professionals. Prior to implementing these item types in the national examination, item validation and technical support should be conducted.

Circulating small extracellular vesicles promote proliferation and migration of vascular smooth muscle cells via AXL and MerTK activation.

The proliferation and migration of vascular smooth muscle cells (VSMCs) after vascular injury lead to neointimal hyperplasia, thus aggravating vascular diseases. However, the molecular mechanisms underlying neointima formation are not fully elucidated. Extracellular vesicles (EVs) are mediators of various intercellular communications. The potential of EVs as regulators in cardiovascular diseases has raised significant interest. In the current study we investigated the role of circulating small extracellular vesicles (csEVs), the most abundant EVs (1010 EVs/mL serum) in VSMC functions. csEVs were prepared from bovine, porcine or rat serum. We showed that incubation with csEVs (0.5 × 1010-2 × 1010) dose-dependently enhanced the proliferation and migration of VSMCs via the membrane phosphatidylserine (PS). In rats with ligation of right carotid artery, we demonstrated that application of csEVs in the ligated vessels aggravated neointima formation via interaction of membrane PS with injury. Furthermore, incubation with csEVs markedly enhanced the phosphorylation of AXL and MerTK in VSMCs. Pretreatment with BSM777607 (pan-TAM inhibitor), bemcentinib (AXL inhibitor) or UNC2250 (MerTK inhibitor) blocked csEV-induced proliferation and migration of VSMCs. We revealed that csEV-activated AXL and MerTK shared the downstream signaling pathways of Akt, extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK) that mediated the effects of csEVs. We also found that csEVs increased the expression of AXL through activation of transcription factor YAP, which might constitute an AXL-positive feedback loop to amplify the signals. Finally, we demonstrated that dual inhibition of AXL/MerTK by ONO-7475 (0.1 µM) effectively hindered csEV-mediated proliferation and migration of VSMCs in ex vivo mouse aorta injury model. Based on these results, we propose an essential role for csEVs in proliferation and migration of VSMCs and highlight the feasibility of dual AXL/MerTK inhibitors in the treatment of vascular diseases.

Augmented Oral Bioavailability and Prokinetic Activity of Levosulpiride Delivered in Nanostructured Lipid Carriers.

The present study is aimed to develop and optimize levosulpiride-loaded nanostructured lipid carriers (LSP-NLCs) for improving oral bioavailability and prokinetic activity of LSP. LSP-NLCs were optimized with D-optimal mixture design using solid lipid, liquid lipid and surfactant concentrations as independent variables. The prepared LSP-NLCs were evaluated for physicochemical properties and solid-state characterization. The in vivo oral pharmacokinetics and prokinetic activity of LSP-NLCs were evaluated in rats. LSP-NLCs formulation was optimized at Precirol® ATO 5/Labrasol (80.55/19.45%, w/w) and Tween 80/Span 80 concentration of 5% (w/w) as a surfactant mixture. LSP-NLCs showed a spherical shape with a particle size of 152 nm, a polydispersity index of 0.230 and an entrapment efficiency of 88%. The DSC and PXRD analysis revealed conversion of crystalline LSP to amorphous state after loading into the lipid matrix. LSP-NLCs displayed a 3.42- and 4.38-flods increase in AUC and Cmax after oral administration compared to LSP dispersion. In addition, LSP-NLCs showed enhanced gastric emptying (61.4%), intestinal transit (63.0%), and fecal count (68.8) compared to LSP dispersion (39.7%, 38.0% and 51.0, respectively). Taken together, these results show improved oral bioavailability and prokinetic activity of LSP-NLCs and presents a promising strategy to improve therapeutic activity of LSP for efficient treatment of gastric diseases.

Controlled therapeutic delivery of CO from carbon monoxide-releasing molecules (CORMs).

Carbon monoxide (CO) has been regarded as a "silent killer" for its toxicity toward biological systems. However, a low concentration of endogenously produced CO has shown a number of therapeutic benefits such as anti-inflammatory, anti-proliferative, anti-apoptosis, and cytoprotective activities. Carbon monoxide-releasing molecules (CORMs) have been developed as alternatives to direct CO inhalation, which requires a specialized setting for strict dose control. CORMs are efficient CO donors, with central transition metals (such as ruthenium, iron, cobalt, and manganese) surrounded by CO as a ligand. CORMs can stably store and subsequently release their CO payload in the presence of certain triggers including solvent, light, temperature, and ligand substitution. However, CORMs require appropriate delivery strategies to improve short CO release half-life and target specificity. Herein, we highlighted the therapeutic potential of inhalation and CORMs-delivered CO. The applications of conjugate and nanocarrier systems for controlling CO release and improving therapeutic efficacy of CORMs are also described in detail. The review concludes with some of the hurdles that limit clinical translation of CORMs. Keeping in mind the tremendous potential and growing interest in CORMs, this review would be helpful for designing controlled CO release systems for clinical applications.

Synaptic Segmented Transistor with Improved Linearity by Schottky Junctions and Accelerated Speed by Double-Layered Nitride.

Neuromorphic devices have been extensively studied to overcome the limitations of a von Neumann system for artificial intelligence. A synaptic device is one of the most important components in the hardware integration for a neuromorphic system because a number of synaptic devices can be connected to a neuron with compactness as high as possible. Therefore, synaptic devices using silicon-based memory, which are advantageous for a high packing density and mass production due to matured fabrication technologies, have attracted considerable attention. In this study, a segmented transistor devoted to an artificial synapse is proposed for the first time to improve the linearity of the potentiation and depression (P/D). It is a complementary metal oxide semiconductor (CMOS)-compatible device that harnesses both non-ohmic Schottky junctions of the source and drain for improved weight linearity and double-layered nitride for enhanced speed. It shows three distinct and unique segments in drain current-gate voltage transfer characteristics induced by Schottky junctions. In addition, the different stoichiometries of SixNy for a double-layered nitride is utilized as a charge trap layer for boosting the operation speed. This work can bring the industry potentially one step closer to realizing the mass production of hardware-based synaptic devices in the future.

Formulation optimization, in vitro and in vivo evaluation of agomelatine-loaded nanostructured lipid carriers for augmented antidepressant effects.

The present study was intended to prepare and optimize agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) for augmented in vivo antidepressant potential. AGM-NLCs were optimized on several parameters including cumulative hydrophilic-lipophilic balance of surfactants, proportions of solid and liquid lipids, total amounts of drug and surfactants. AGM-NLCs were assessed for their physicochemical properties, in vitro AGM release and in vivo antidepressant effects in mice model. The optimized AGM-NLCs demonstrated spherical morphology with average particle size of 99.8 ± 2.6 nm, PDI of 0.142 ± 0.017, zeta potential of - 23.2 ± 1.2 mV and entrapment efficiency of 97.1 ± 2.1%. Thermal and crystallinity studies depict amorphous nature of AGM after its incorporation into NLCs. AGM-NLCs exhibit a sustained drug release profile after initial 2 h. Mice treated with AGM-NLCs exhibited reduced immobility time in behavioral analysis. Furthermore, cresyl violet staining demonstrated an improved neuronal morphology and survival in AGM-NLCs group. The concentrations and the expression of inflammatory markers (TNF-α and COX-2) in mice brain were significantly reduced by AGM-NLCs. Taken together, therapeutic effectiveness of AGM was markedly augmented in AGM-NLCs and thereby they could be promising nanocarriers for the effective delivery of antidepressants to brain.

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability.

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.

Enhanced neuroprotective and antidepressant activity of curcumin-loaded nanostructured lipid carriers in lipopolysaccharide-induced depression and anxiety rat model.

The present study aims to develop curcumin-loaded nanostructured lipid carriers (CUR-NLCs) and investigate their neuroprotective effects in lipopolysaccharide (LPS)-induced depression and anxiety model. Nanotemplate engineering technique was used to prepare CUR-NLCs with Compritol 888 ATO and oleic acid as solid and liquid lipid, respectively. Poloxamer 188, Tween 80 and Span 80 were used as stabilizing agents for solid-liquid lipid core. The physicochemical parameters of CUR-NLCs were determined followed by in vitro drug release and in vivo neuroprotective activity in rats. The optimized CUR-NLCs demonstrated nanometric particle size of 147.8 nm, surface charge of -32.8 mV and incorporation efficiency of 91.0%. CUR-NLCs showed initial rapid followed by a sustained drug release reaching up to 73% after 24 h. CUR-NLCs significantly elevated struggling time and decreased immobility time in forced swim and tail suspension tests. A substantial increase in time spent and number of entries into the light and open compartments was observed in light-dark box and elevated plus maze models. CUR-NLCs improved the tissue architecture and suppressed the expression of p-NF-κB, TNF-α and COX-2 in brain tissues from histological and immunohistochemical analysis. CUR-NLCs improved the neuroprotective effect of curcumin and can be used as a potential therapeutics for depression and anxiety.

Circulating Small Extracellular Vesicles Activate TYRO3 to Drive Cancer Metastasis and Chemoresistance.

Extracellular vesicles (EV) in the tumor microenvironment have emerged as crucial mediators that promote proliferation, metastasis, and chemoresistance. However, the role of circulating small EVs (csEV) in cancer progression remains poorly understood. In this study, we report that csEV facilitate cancer progression and determine its molecular mechanism. csEVs strongly promoted the migration of cancer cells via interaction with phosphatidylserine of csEVs. Among the three TAM receptors, TYRO3, AXL, and MerTK, TYRO3 mainly interacted with csEVs. csEV-mediated TYRO3 activation promoted migration and metastasis via the epithelial-mesenchymal transition and stimulation of RhoA in invasive cancer cells. Additionally, csEV-TYRO3 interaction induced YAP activation, which led to increased cell proliferation and chemoresistance. Combination treatment with gefitinib and KRCT-6j, a selective TYRO3 inhibitor, significantly reduced tumor volume in xenografts implanted with gefitinib-resistant non-small cell lung cancer cells. The results of this study show that TYRO3 activation by csEVs facilitates cancer cell migration and chemoresistance by activation of RhoA or YAP, indicating that the csEV/TYRO3 interaction may serve as a potential therapeutic target for aggressive cancers in the clinic. SIGNIFICANCE: These findings demonstrate that circulating extracellular vesicles are a novel driver in migration and survival of aggressive cancer cells via TYRO3 activation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3539/F1.large.jpg.

Triboelectric Nanogenerator: Structure, Mechanism, and Applications.

With the rapid development of the Internet of Things (IoT), the number of sensors utilized for the IoT is expected to exceed 200 billion by 2025. Thus, sustainable energy supplies without the recharging and replacement of the charge storage device have become increasingly important. Among various energy harvesters, the triboelectric nanogenerator (TENG) has attracted considerable attention due to its high instantaneous output power, broad selection of available materials, eco-friendly and inexpensive fabrication process, and various working modes customized for target applications. The TENG harvests electrical energy from wasted mechanical energy in the ambient environment. Three types of operational modes based on contact-separation, sliding, and freestanding are reviewed for two different configurations with a double-electrode and a single-electrode structure in the TENGs. Various charge transfer mechanisms to explain the operational principles of TENGs during triboelectrification are also reviewed for electron, ion, and material transfers. Thereafter, diverse methodologies to enhance the output power considering the energy harvesting efficiency and energy transferring efficiency are surveyed. Moreover, approaches involving not only energy harvesting by a TENG but also energy storage by a charge storage device are also reviewed. Finally, a variety of applications with TENGs are introduced. This review can help to advance TENGs for use in self-powered sensors, energy harvesters, and other systems. It can also contribute to assisting with more comprehensive and rational designs of TENGs for various applications.

CORM-2-entrapped ultradeformable liposomes ameliorate acute skin inflammation in an ear edema model via effective CO delivery.

The short release half-life of carbon monoxide (CO) is a major obstacle to the effective therapeutic use of carbon monoxide-releasing molecule-2 (CORM-2). The potential of CORM-2-entrapped ultradeformable liposomes (CORM-2-UDLs) to enhance the release half-life of CO and alleviate skin inflammation was investigated in the present study. CORM-2-UDLs were prepared by using soy phosphatidylcholine to form lipid bilayers and Tween 80 as an edge activator. The deformability of CORM-2-UDLs was measured and compared with that of conventional liposomes by passing formulations through a filter device at a constant pressure. The release profile of CO from CORM-2-UDLs was evaluated by myoglobin assay. In vitro and in vivo anti-inflammatory effects of CORM-2-UDLs were assessed in lipopolysaccharide-stimulated macrophages and TPA-induced ear edema model, respectively. The deformability of the optimized CORM-2-UDLs was 2.3 times higher than conventional liposomes. CORM-2-UDLs significantly prolonged the release half-life of CO from 30 s in a CORM-2 solution to 21.6 min. CORM-2-UDLs demonstrated in vitro anti-inflammatory activity by decreasing nitrite production and pro-inflammatory cytokine levels. Furthermore, CORM-2-UDLs successfully ameliorated skin inflammation by reducing ear edema, pathological scores, neutrophil accumulation, and inflammatory cytokines expression. The results demonstrate that CORM-2-UDLs could be used as promising therapeutics against acute skin inflammation.

Potential and Applications of Nanocarriers for Efficient Delivery of Biopharmaceuticals.

During the past two decades, the clinical use of biopharmaceutical products has markedly increased because of their obvious advantages over conventional small-molecule drug products. These advantages include better specificity, potency, targeting abilities, and reduced side effects. Despite the substantial clinical and commercial success, the macromolecular structure and intrinsic instability of biopharmaceuticals make their formulation and administration challenging and render parenteral delivery as the only viable option in most cases. The use of nanocarriers for efficient delivery of biopharmaceuticals is essential due to their practical benefits such as protecting from degradation in a hostile physiological environment, enhancing plasma half-life and retention time, facilitating absorption through the epithelium, providing site-specific delivery, and improving access to intracellular targets. In the current review, we highlight the clinical and commercial success of biopharmaceuticals and the overall applications and potential of nanocarriers in biopharmaceuticals delivery. Effective applications of nanocarriers for biopharmaceuticals delivery via invasive and noninvasive routes (oral, pulmonary, nasal, and skin) are presented here. The presented data undoubtedly demonstrate the great potential of combining nanocarriers with biopharmaceuticals to improve healthcare products in the future clinical landscape. In conclusion, nanocarriers are promising delivery tool for the hormones, cytokines, nucleic acids, vaccines, antibodies, enzymes, and gene- and cell-based therapeutics for the treatment of multiple pathological conditions.

Solid lipid nanoparticles-mediated enhanced antidepressant activity of duloxetine in lipopolysaccharide-induced depressive model.

The potential of duloxetine-loaded solid lipid nanoparticles (DLX-SLNs) for enhanced antidepressant activity was investigated in the current study. Nano-template engineering technology was successfully employed for the preparation of DLX-SLNs. In vivo forced swim and tail suspension tests were used to evaluate behavioral changes of rats in lipopolysaccharide-induced depression. The determination of brain-derived neurotropic factor (BDNF) in brain and plasma was carried out using enzyme-linked immunosorbent assay. The incorporation efficiency of optimized DLX-SLNs formulation was found to be 80 % with particle size of 114.5 nm, PDI of 0.29 and zeta potential of -18.2 mV. Powder X-ray diffractometry and differential scanning calorimetry demonstrated sufficient incorporation into lipid matrix and amorphous behavior of DLX. In vitro release profile of DLX-SLNs showed a sustained release achieving a cumulative amount of 52.97 % for 24 h. DLX-SLNs showed a significant decrease in immobility time in forced swim and tail suspension tests. DLX-SLNs increased BDNF levels in plasma and brain after 2 weeks. Immunohistochemistry results demonstrated significant reduction in the expression of tumor necrosis factor-α and cyclooxygenase enzyme-2 in brain. In conclusion, solid lipid nanoparticles can be utilized as a potential carrier for the delivery of antidepressant drugs into the brain.

CORM-2-Solid Lipid Nanoparticles Maintain Integrity of Blood-Spinal Cord Barrier After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is a devastating condition of the central nervous system that can lead to permanent motor and sensory deficits. Carbon monoxide-releasing molecule-2 (CORM-2) has been shown to have anti-inflammatory, anti-apoptotic, and angiogenic properties that may be useful for the treatment of SCI. However, it has a short carbon monoxide (CO) release half-life (approximately 1 min). To address this challenge, we developed a CORM-2-incorporated solid lipid nanoparticle (CORM-2-SLN) and evaluated its ameliorating effects for preventing blood-spinal cord barrier (BSCB) disruption and endothelial cell death following SCI. After a moderate compression injury of the spinal cord (compression with a 35-g impounder for 5 min), groups of rats were treated with a CORM-2-solution and CORM-2-SLNs at an equal dose of 10 mg/kg each via an intraperitoneal injection for 8 consecutive days. Behavior analysis was performed and animals were later sacrificed at different time points and evaluated for whether the CORM-2-SLNs prevented BSCB disruption and rescued endothelial cell damage following SCI. The CORM-2-SLN-treated group showed significantly diminished extravasation of Evans Blue dye with enhanced expression of tight junction proteins following SCI. Likewise, significantly diminished endothelial cell markers after SCI were optimally stabilized at 21 days. Additionally, lipopolysaccharide (LPS)-induced loss of tight junction integrity was significantly preserved after CORM-2-SLN treatment in human cerebral microvascular endothelial cell line (hCMEC/D3). Clinically, CORM-2-SLNs were associated with a significantly improved functional recovery, as compared with the CORM-2-solution. CORM-2-SLNs may help potentially to maintain BSCB integrity following SCI.

LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke.

Stroke is one of the commonest causes of death with limited treatment options. L-Carnosine has shown great promise as a neuroprotective agent in experimental stroke, but translation to the clinic is impeded by the large doses needed. We developed and evaluated the therapeutic potential of a novel delivery vehicle which encapsulated carnosine in lipoprotein receptor related protein-1 (LRP-1)-targeted functionalized polymersomes in experimental ischemic stroke. We found that following ischemic stroke, polymersomes encapsulating carnosine exhibited remarkable neuroprotective effects with a dose of carnosine 3 orders of magnitude lower than free carnosine. The LRP-1-targeted functionalization was essential for delivery of carnosine to the brain, as non-targeted carnosine polymersomes did not exhibit neuroprotection. Using Cy3 fluorescence in vivo imaging, we showed that unlike non-targeted carnosine polymersomes, LRP-1-targeted carriers accumulated in brain in a time dependent manner. Our findings suggest that these novel carriers have the ability to deliver neuroprotective cargo effectively to the brain.

Nanostructured lipid carriers-mediated brain delivery of carbamazepine for improved in vivo anticonvulsant and anxiolytic activity.

The limited brain delivery of carbamezapine (CBZ) presents a major hurdle in the successful epilepsy treatment. The potential of carbamezapine-loaded nanostructured lipid carriers (CBZ-NLCs) for improved brain delivery is investigated in the current study. CBZ-NLCs were prepared by using binary mixture of trilaurin and oleic acid as a lipid core stabilized with Poloxamer 188, Tween 80 and Span 80. CBZ-NLCs were evaluated for physicochemical properties, in vitro release, in vivo brain kinetics, anticonvulsant and anxiolytic activities. The optimized CBZ-NLCs demonstrated nanometric particle size (97.7 nm), surface charge of -22 mV and high drug incorporation (85%). CBZ-NLCs displayed biphasic release pattern with initial fast followed by sustained drug release. CBZ-NLCs significantly enhanced the AUC of CBZ (520.4 µg·h/mL) in brain compared with CBZ dispersion (244.9 µg·h/mL). In vivo anticonvulsant activity of CBZ-NLCs in PTZ-induced seizure model showed a significant increase in the onset time (143.0 sec) and reduction in duration (17.2 sec) of tonic-clonic seizures compared with CBZ dispersion (75.4 and 37.2 sec). The anxiolytic activity in light-dark box and elevated-plus maze models also demonstrated superiority of CBZ-NLCs to CBZ dispersion. From the results, CBZ-NLCs presents a promising strategy to improve brain delivery and therapeutic outcomes of CBZ in epilepsy.

Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs.

Approximately 40% of new chemical entities (NCEs), including anticancer drugs, have been reported as poorly water-soluble compounds. Anticancer drugs are classified into biologic drugs (monoclonal antibodies) and small molecule drugs (nonbiologic anticancer drugs) based on effectiveness and safety profile. Biologic drugs are administered by intravenous (IV) injection due to their large molecular weight, while small molecule drugs are preferentially administered by gastrointestinal route. Even though IV injection is the fastest route of administration and ensures complete bioavailability, this route of administration causes patient inconvenience to visit a hospital for anticancer treatments. In addition, IV administration can cause several side effects such as severe hypersensitivity, myelosuppression, neutropenia, and neurotoxicity. Oral administration is the preferred route for drug delivery due to several advantages such as low cost, pain avoidance, and safety. The main problem of NCEs is a limited aqueous solubility, resulting in poor absorption and low bioavailability. Therefore, improving oral bioavailability of poorly water-soluble drugs is a great challenge in the development of pharmaceutical dosage forms. Several methods such as solid dispersion, complexation, lipid-based systems, micronization, nanonization, and co-crystals were developed to improve the solubility of hydrophobic drugs. Recently, solid dispersion is one of the most widely used and successful techniques in formulation development. This review mainly discusses classification, methods for preparation of solid dispersions, and use of solid dispersion for improving solubility of poorly soluble anticancer drugs.