Desirable Route Research Articles

ORAL INSULIN DELIVERY: AN OVERVIEW

Oral insulin is an exciting space of research and development within the field of diabetology. The oral route is taken into account to be the foremost convenient and desired route of drug delivery, particularly, when repeated or routine administration is necessary. Diabetes mellitus is a serious pathologic condition that is to blame for major healthcare problems. Insulin replacement therapy has been employed in the clinical management of diabetes mellitus for over 90 years. So, the development of oral insulin remains an ultimate goal to both enhance ease of use and to produce therapeutic benefits rooted in its direct delivery to the portal vein and liver. This brief review covers the importance, novel approaches of oral insulin delivery as well as challenges, market status and future perspectives of oral insulin products.

Breath Hold Facilitates Targeted Deposition of Aerosolized Droplets in a 3D Printed Bifurcating Airway Tree.

The lungs have long been considered a desired route for drug delivery but, there is still a lack of strategies to rationally target delivery sites especially in the presence of heterogeneous airway disease. Furthermore, no standardized system has been proposed to rapidly test different ventilation strategies and how they alter the overall and regional deposition pattern in the airways. In this study, a 3D printed symmetric bifurcating tree model mimicking part of the human airway tree was developed that can be used to quantify the regional deposition patterns of different delivery methodologies. The model is constructed in a novel way that allows for repeated measurements of regional deposition using reusable parts. During ventilation, nebulized ~3-micron-sized fluid droplets were delivered into the model. Regional delivery, quantified by precision weighing individual airways, was highly reproducible. A successful strategy to control regional deposition was achieved by combining an inspiratory wave form with a "breath hold" pause after each inspiration. Specifically, the second generation of the tree was successfully targeted, and deposition was increased by up to four times in generation 2 when compared to a ventilation without the breath hold (p < 0.0001). Breath hold was also demonstrated to facilitate deposition into blocked regions of the model, which mimic airway closure during an asthma that receive no flow during inhalation. Additionally, visualization experiments demonstrated that in the absence of fluid flow, the deposition of 3-micron water droplets is dominated by gravity, which, to our knowledge, has not been confirmed under standard laboratory conditions.

G‐C3N4/TiO2 Composite Film in the Fabrication of a Photocatalytic Air‐Purifying Pavements

The fabrication of a photocatalytic air‐purifying pavement with a facile loading route, long depolluting period, and excellent deNOx activity under weak solar irradiation is essential for ambient air purification. Herein, a promising methodology is developed relying on the exploitation of a graphitic carbon nitride/TiO2 (g‐C3N4/TiO2) composite hydrosol at room temperature. The TiO2 hydrosol can act as a source of photocatalyst and dispersant for g‐C3N4 during loading. The photoinduced hydrophilicity, adhesive force, and regeneration tests in the laboratory show the long‐term deNOx application potential of g‐C3N4/TiO2 coatings. Field studies indicate that the NO removal rate is 70.7% of g‐C3N4/TiO2‐coated pavement in the morning (07:00–10:00) and afternoon (17:00–19:00), at which times solar radiation is weakest. The deNOx efficiency is influenced by solar irradiation and traffic volume. The latter exerts a more significant influence on deNOx efficiency than the former. A desirable route in fabricating a photocatalytic air‐purifying pavement is provided and offers a promising photocatalyst suitable for outdoor environmental remediation.

Bi/Bi2O3 nanoparticles supported on N-doped reduced graphene oxide for highly efficient CO2 electroreduction to formate

Electrocatalytic CO2 reduction (CO2ER) into formate is a desirable route to achieve efficient transformation of CO2 to value-added chemicals, however, it still suffers from limited catalytic activity and poor selectivity. Herein, we develop a hybrid electrocatalyst composed of bismuth and bismuth oxide nanoparticles (NPs) supported on nitrogen-doped reduced graphene oxide (Bi/Bi2O3/NrGO) nanosheets prepared by a combined hydrothermal with calcination treatment. Thanks to the combination of undercoordinated sites and strong synergistic effect between Bi and Bi2O3, Bi/Bi2O3/NrGO-700 hybrid displays a promoted CO2ER catalytic performance and selectivity for formate production, as featured by a small onset potential of -0.5 V, a high current density of -18 mA/cm2, the maximum Faradaic efficiency of 85% at -0.9 V, and a low Tafel slope of 166 mV/dec. Experimental results reveal that the higher CO2ER performance of Bi/Bi2O3/NrGO-700 than that of Bi NPs supported on NrGO (Bi/NrGO) can be due to the partial reduction of Bi2O3 NPs into Bi, which significantly increases undercoordinated active sites on Bi NPs surface, thus boosting its CO2ER performance. Furthermore, a two-electrode device with Ir/C anode and Bi/Bi2O3/NrGO-700 cathode could be integrated with two alkaline batteries or a planar solar cell to achieve highly active water splitting and CO2ER.

A Miracle Metal@Zeolite for Selective Conversion of Syngas to Ethanol

Direct catalytic conversion of syngas provides a desirable route for ethanol manufacture; however, it still suffers from poor ethanol selectivity and insufficient catalyst durability. In this issue of Chem, Wang et al. design a catalyst with a metal@zeolite core-shell structure, enabling remarkably high ethanol production from syngas with long-term stability.

Smart Navigation via Strategic Communications in a Mixed Autonomous Paradigm

This paper investigates the optimal information design for a system to minimize congestion cost in the presence of both autonomous vehicles (AVs) and human-driven vehicles (HVs). We incorporate asymmetric information between AVs and HVs in a routing game where there are two routes available and one of them has a state-dependent congestion cost. AVs are informed of the state and make choices as a fleet while HVs rely on information provided by the system and make self-interested choices. The system designs information in a Bayesian persuasion manner aiming to mitigate HVs' selfish routing such that traffic congestion cost is minimized. We show that the penetration of AVs can mitigate HVs' overcrowding problem and the first-best can be achieved when the fleet size of AVs reaches a high level. We find that it is optimal for the system to randomize in providing traffic information rather than to provide perfect information to HVs. When the information distortion is mild, HVs overcrowd the more desirable route as in the complete information benchmark. When the information distortion is strong enough, their behaviors are flipped and overcrowd the less desirable route. Interestingly, our research sheds light on the interaction of AV platooning and information provision. Finally, credibility constraint limits the social planner's persuasion power in navigating HVs away from overcrowding the more desirable route. When the fraction of AVs is high enough, the first-best can be achieved through the synergy of AV platooning and information provision.

Unified Contamination-Aware Routing Method Considering Realistic Washing Capacity Constraint in Digital Microfluidic Biochips

To fully utilize the dynamic reconfigurability of digital microfluidic biochips, most of electrodes would be shared by different droplets. Thus, contaminations caused by liquid residues among droplets are inevitable which lead to lethal errors in bioassays. To remove the contaminations, washing operations are introduced as an essential step to ensure the correctness of bioassay. However, existing works have oversimplified assumptions on the washing droplet's behavior and constraints which cannot clean all contaminations with erroneous outcomes. Moreover, straightforward integration of washing operations with droplet routing may increase the execution time of a bioassay which is not feasible for timing-critical bioassay. To effectively remove contaminations and minimize the execution time of a bioassay, this article proposes a unified contamination-aware routing method, which addresses the above issues simultaneously. Firstly, we present a top-down scheme to generate candidates of routing paths, then construct a shortest-path model to select desirable routing solution for all subproblems. With a decision diagram of droplets, we further propose an integer linear programming (ILP) formulation to compact the execution time. Finally, contamination removal by washing droplets with realistic washing capacity is considered for all subproblems. Tested on real-life benchmarks, our proposed method can significantly reduce 72% contamination spots and save 11% execution time.

Facile synthesis of a CuMnOx catalyst based on a mechanochemical redox process for efficient and stable CO oxidation

Low-temperature catalytic combustion of CO is a desirable route for CO removal. We reported the sythesis of highly active CuMnOx catalyst by a mechanochemical redox process.

Exploring Multicompartment Plug Flow–Based Model Approach in Biopharmaceutics: Impact of Stomach Setting and the Estimation of the Fraction Absorbed of Orally Administered Basic Drugs

There has been an increasing interest in accurate prediction of human pharmacokinetics of drug candidates to reduce cost and increase productivity during research and development. Modeling efforts have primarily focused on predicting drug absorption after oral administration because it is the most desired route for small molecule drug delivery. Despite significant progress in the field, the fraction of dose absorbed (Fa) is still considered to be a challenging parameter to predict. In recent years, compartment and transit models have become increasingly popular because of their effectiveness. A multicompartment plug flow–based model in which the stomach is assigned as a single compartment has been built. However, this model was found to be less accurate in estimating stomach solubilization of basic drugs under certain conditions and leads to false-negative results. Therefore, a modified multicompartment approach was developed by dividing the stomach into 4 compartments allowing the model to better mimic the physiological conditions. This approach was found to be more precise in estimating Fa for basic drugs compared to the previous approach. Based on this finding, it is believed the aforementioned approach should also be applicable to all compartmental-based models when similar issues are encountered.

Metal-Organic Gel-Derived Multimetal Oxides as Effective Electrocatalysts for the Oxygen Evolution Reaction.

Exploring efficient and durable catalysts derived from earth-abundant and cost-effective materials is a highly desirable route to overcome the sluggish anodic oxygen evolution reaction (OER). A series of multinary metal-organic gels (MOGs) with various and alterable metal element compositions are prepared by straightforward mixing of metal ions with ligand 4,4',4''-[(1,3,5-triazine-2,4,6-triyl)tris(azanediyl)]tribenzoic acid (H3 TATAB) in solution at room temperature. Spinel-type metal oxides with excellent electrocatalytic OER performance were then obtained through calcination of the as-synthesized MOGs. In electrochemical testing, the trimetallic oxide CoFeNi-O-1 (derived from the MOG with a Co/Fe/Ni molar ratio of 5:1:4) exhibits remarkable catalytic activity with a low overpotential of 244 mV at a current density of 10 mA cm-2 and a small Tafel slope of 55.4 mV dec-1 in alkaline electrolyte, outperforming most recently reported electrocatalysts. This work not only provides a promising OER catalyst and enriches the application of MOGs in the catalytic field, but also offers a facile new route to acquiring multicomponent metal oxides with high electrocatalytic activity.

Chitosan based thermosensitive injectable hydrogels for controlled delivery of loxoprofen: development, characterization and in-vivo evaluation.

Oral drug delivery is natural, most acceptable and desirable route for nearly all drugs, but many drugs like NSAIDs when delivered by this route cause gastrointestinal irritation, gastric bleeding, ulcers, and many undesirable effects which limits their usage by oral delivery. Moreover, it is almost impossible to control the release of a drug in a targeted location in body. We developed thermo-responsive chitosan-co-poly(N-isopropyl-acrylamide) injectable hydrogel as an alternative for the gastro-protective and controlled delivery of loxoprofen sodium as a model drug. A free radical polymerization technique was used to synthesize thermo-responsive hydrogel by cross-linking chitosan HCl with NIPAAM using glutaraldehyde as cross-linker. Confirmation of crosslinked hydrogel structure was done by Fourier transform infrared spectra (FTIR). The thermal stability of hydrogel was confirmed through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The scanning electron microscopy (SEM) was performed to evaluate the structural morphology of cross-linked hydrogel. To evaluate the rheological behavior of hydrogel with increasing temperature, rheological study was performed. Swelling and in vitro drug release studies were carried out under various temperature and pH conditions. The swelling study revealed that maximum swelling was observed at low pH (pH 1.2) and low temperature (25 °C) compared to the high range of pH and temperature and it resulted in quick release of the drug. The high range of pH (7.4) and temperature (37 °C) however caused controlled release of the drug. The in vivo evaluation of the developed hydrogel in rabbits demonstrated the controlled release behavior of fabricated system.

Increased growth rate and productivity following stable depletion of miR-7 in a mAb producing CHO cell line causes an increase in proteins associated with the Akt pathway and ribosome biogenesis

Cell line engineering using microRNAs represents a desirable route for improving the efficiency of recombinant protein production by CHO cells. In this study we generated stable CHO DP12 cells expressing a miR-7 sponge transcript which sequesters miR-7 from its endogenous targets. Depletion of miR-7 results in a 65% increase in cell growth and >3-fold increase in yield of secreted IgG protein. Quantitative labelfree LC-MS/MS proteomic profiling was carried out to identify the targets of miR-7 and understand the functional drivers of the improved CHO cell phenotypes. Subcellular enrichment and total proteome analysis identified more than 3000 proteins per fraction resulting in over 5000 unique proteins identified per timepoint analysed. Early stage culture analysis identified 117 proteins overexpressed in miR-7 depleted cells. A subset of these proteins are involved in the Akt pathway which could be the underlying route for cell density improvement and may be exploited more specifically in the future. Late stage culture identified 160 proteins overexpressed in miR-7 depleted cells with some of these involved in ribosome biogenesis which may be causing the increased productivity through improved translational efficiency. This is the first in-depth proteomic profiling of the IgG producing CHO DP12 cell line stably depleted of miR-7. SignificanceChinese hamster ovary (CHO) cells are the mammalian cell expression system of choice for production of recombinant therapeutic proteins. There is much research ongoing to characterise CHO cell factories through the application of systems biology approaches that will enable a fundamental understanding of CHO cell physiology, and as a result, a better knowledge and understanding of recombinant protein production. This study profiles the proteomic effects of microRNA-7 depletion on the IgG producing CHO DP12 cell line. This is one of the very few studies that attempts to identify the functioning proteins driving improved CHO cell phenotypes resulting from microRNA manipulation. Using subcellular enrichment and total proteome analysis we identified over 5000 unique proteins in miR-7 depleted CHO cells. This work has identified a cohort of proteins involved in the Akt pathway and ribosome biogenesis. These proteins may drive improved CHO cell phenotypes and are of great interest for future work.

Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium.

Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic-acid-based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal and dose-dependent control of encoded protein expression. Inhaled delivery of IVT-mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g-1 of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE-mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT-mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium.

Ultrafine Ni(OH)2 nanoneedles on N-doped 3D rivet graphene film for high-performance asymmetric supercapacitor

Integrating nanometer-sized active materials into free-standing conductive porous substrates is a highly desirable route to obtain high-performance energy storage devices. Herein, we designed and fabricated a free-standing N-doped 3D rivet graphene (N-3DRG) film with lightweight and bicontinuous 3D porous structures using chemical vapor deposition (CVD). Then, dense lawn-like ultrafine Ni(OH)2 nanoneedles were deposited onto the outer and inner surfaces of N-3DRG via a hydrothermal process. The N-3DRG film shows excellent conductivity and high specific surface area, which can facilitate the rapid transfer of electrons and provide more surface area for the deposition of active materials. The ultrafine nanometer-sized morphology of the Ni(OH)2 nanoneedles exposes more active sites to the electrolyte, which significantly accelerates mass transfer and improves the reaction kinetics. Owing to the distinct structural advantages, the Ni(OH)2/N-3DRG electrode exhibits a high specific capacity of 256.1 mAh g−1 (based on the total mass of the electrode). Furthermore, the as-fabricated Ni(OH)2/N-3DRG-based asymmetric supercapacitor achieves a rather high energy density of 50.8 Wh kg−1 at an average power density of 452 W kg−1 and excellent cycle stability.

Enhanced transdermal lymphatic delivery of doxorubicin via hyaluronic acid based transfersomes/microneedle complex for tumor metastasis therapy

Tumor-draining lymph nodes (TDLN) are major metastatic sites for many solid tumor to support tumor progression and metastasis. Lymphatic delivery is regarded as a desirable route to promote adoptive immune response via vaccination, or to achieve efficient chemotherapy for tumor metastasis. In this study, a novel dissolving microneedle was fabricated using hyaluronic acid, integrated with transfersome (T) to break the limit of transdermal cargo transit. In virtue of the insertion capacity of microneedle and the lymphatic delivering ability of transfersomes, such transfersome/microneedles complex (T/MNs) was expected to enhance lymphatic delivery. The results revealed that the microneedles were able to efficiently insert into rat skin and release the doxorubicin loaded transfersome (DOX-T) in dermis via self-dissolution. DOX-T would maintain their multilayer structure as released from dissolved microneedles. DOX-T/MN could significantly promote accumulation of DOX in lymph nodes compared to epidermal diffusion, and increased its transdermal bioavailability in plasma. The results not only are promising for chemo-therapy of tumor through lymphatic drug delivery, especially for killing the metastasized tumor cells appeared in draining lymph nodes, they also provide an efficient strategy for tumor immune-therapy using transdermal administration.

Geographical access to GPs and modes of cancer diagnosis in England: a cross-sectional study

Poor geographical access to health services and routes to a cancer diagnosis such as emergency presentations have previously been associated with worse cancer outcomes. However, the extent to which access to GPs determines the route that patients take to obtain a cancer diagnosis is unknown. We used a linked dataset of cancer registry and hospital records of patients with a cancer diagnosis between 2006 and 2010 across eight different cancer sites. Primary outcomes were defined as 'desirable routes to diagnosis' [screen-detected and 2-week wait (TWW) referrals] and 'less desirable routes' [emergency presentations and death certificate only (DCO)]. All other routes (GP referral, inpatient elective and other outpatient) were specified as the reference category. Geographical access was measured as travel time in minutes from patients to their GP, and multinomial logistic regression was used to estimate relative risk ratios (RRR). Longer travel was associated with increased risk of diagnosis via emergency and DCO, but decreased risk of diagnosis via screening and TWW. Patients travelling over 30 minutes had the highest risk of a DCO diagnosis, which was statistically significant for breast, colorectal, lung, prostate, stomach and ovarian cancers (compared with patients with travel times ≤10 minutes: RRR 5.89, 7.02, 2.30, 4.75, 10.41; P < 0.01 and 3.51, P < 0.05). Poor access to GPs may discourage early engagement with health services, decreasing the likelihood of screening uptake and increasing the likelihood of emergency presentations. Extra effort is needed to promote early diagnosis in more distant patients.

Recent Advances in Catalytic Asymmetric Synthesis of Tertiary Alcohols via Nucleophilic Addition to Ketones

AbstractChiral tertiary alcohols are an important class of organic compounds which have found wide applications in both academia and industry. Therefore, various synthetic strategies towards these compounds have already been developed. Among them, the catalytic asymmetric addition of carbon nucleophiles to ketones is the most desirable route owing to its straightforwardness as well as its economic, efficient and versatile advantages. This review summarizes and discusses the recent achievements in this field classified according to the reaction types. Special attention is paid to the mechanisms, advantages and limitations of each reaction. In addition, the applications of these catalytic processes in the synthesis of related natural products, pharmaceuticals or their analogues are briefly discussed as well.magnified image

Fractal Model of Transdermal Drug Delivery

Skin, separating the vital organs of a human body, is a desirable route for drug delivery. However, the intact skin is normally permeable only for drug molecules with a low molecular weight. The stratum corneum (SC), being the outermost layer of the skin and the epidermis being the second – more permeable – layer of the skin, play an essential function in transdermal drug delivery. Physical and chemical methods of skin poration are used to enhance transdermal drug delivery. Each poration leads to an irregular system of pores which are connected with a system of micro-capillaries passing through the epidermis. Both the systems by their irregularity form a fractal porous matrix. Drugs administrated by this matrix can be either suspensions and solutions or creams and gels, therefore they have to be modelled as non-Newtonian fluids. To analyse the fluid flow through the porous matrix the model of the epidermis is assumed as gobbet-andmortar with the tortuous mortar of variable thickness and after transition from the mortar to the tube one considered classical and fractal capillary flows of selected non-Newtonian fluids. Fractal expressions for the flow rate, velocity and permeability of fluids flow in a porous matrix are derived based on the fractal properties of the epidermis and capillary model. Each parameter in the proposed expressions does not contain any empirical constant and has a clear physical meaning and the proposed fractal models relate the flow properties of considered fluids with the structural parameters of the epidermis as a porous medium. The presented analytical expressions will help understand some of the physical principles of transdermal drug delivery.

APPLICATION OF LIQUISOLID TECHNOLOGY TO ENHANCE THE DISSOLUTION OF CEFIXIME FROM ITS ORAL CAPSULES

Objective: Oral drug delivery is the most desired route for drug administration for its well-known features. Therefore, many attempts were implemented to improve the poor solubility of many active ingredients in order to enhance their dissolution and absorption via the oral route. From these, the liquisolid system is a very promising technology for enhancing solubility and bioavailability of poorly soluble drugs.Methods: In this research, oral capsules of cefixime were prepared by liquisolid technique after mixing different concentrations of the drug with propylene glycol (non-volatile solvent), followed by their addition to different proportions of microcrystalline cellulose and aerosil i.e. different carrier: coating (R-value). The liquisolid capsules were evaluated for In vitro disintegration and dissolution in addition to content uniformity and weight variations. Furthermore, solubility studies, scanning electron microscope (SEM) were performed to the optimum formula. Finally, the release profile of the optimum formula was compared with the marketed cefixime capsules.Results: Liquisolid formula (F3) with 70% cefixime and R-value equals 10 was selected as the optimum formula having higher % release in 45 min (99.5%±0.53) compared to other formulas with faster release rate in the first 20 min than marketed capsules. It had an acceptable disintegration time (25 min±0.76), content uniformity (197.6±0.92) and weight variation (698.04±0.16). Results of solubility study, SEM assured enhancement in solubility and dispersibility of the drug.Conclusion: This research proved that liquisolid system is a promising technology in improving the solubility and dissolution of cefixime from its capsules and hence it may improve its absorption and oral bioavailability.

Studying alternative approaches for placement of cuffed hemodialysis catheters in hemodialysis patients with bilateral internal jugular vein occlusion.

Internal jugular vein occlusion often makes necessary the use of less desirable routes as external jugular, subclavian, and femoral vein approaches in addition to inferior vena cava approaches. This a prospective cross-sectional follow-up study of the alternative approaches for placement of cuffed hemodialysis catheters in end-stage renal disease patients with bilateral internal jugular vein occlusion from the interventional nephrology point of view. The study was conducted on 134 end-stage renal disease patients who were referred for insertion of a challenging hemodialysis catheter due to bilateral internal jugular vein occlusion. Ultrasound Doppler guided catheter insertion was used as a routine practice in addition to fluoroscopy or post insertion X-ray to localize catheter tip position and exclude complications. Follow-up of patients was conducted until the end of the study or catheter removal. The most highly prevalent alternative approach is the trans-external iliac vein inferior vena cava approach (43.28%) followed by external jugular vein approach (14.93%), innominate vein approach (10.18%), internal jugular vein collaterals by interventional radiology (7.46%), femoral vein approach (7.46%), transhepatic approach (5.97%), subclavian vein approach (5.22%), and finally the retrograde femoral vein approach (1.49%). End-stage renal disease patients maintained on regular hemodialysis who have bilateral internal jugular vein obstruction and non-functioning arteriovenous fistula/graft is a daily scenario in nephrology practice. Our study showed that there is a variety of approaches for the insertion of cuffed hemodialysis catheters other than occluded internal jugular veins. Interventional nephrologists have a major role in solving the problem of poor hemodialysis vascular access. These alternative approaches can conserve the anatomically limited number of percutaneous access sites in each patient.