Search

Purpose: To evaluate the efficiency of a new technique for delivering aerosols to intubated infants that employs a new Y-connector, access port administration of a dry powder, and excipient enhanced growth (EEG) formulation particles that change size in the airways., Methods: A previously developed CFD model combined with algebraic correlations were used to predict delivery system and lung deposition of typical nebulized droplets (MMAD = 4.9 μm) and EEG dry powder aerosols. The delivery system consisted of a Y-connector [commercial (CM); streamlined (SL); or streamlined with access port (SL-port)] attached to a 4-mm diameter endotracheal tube leading to the airways of a 6-month-old infant., Results: Compared to the CM device and nebulized aerosol, the EEG approach with an initial 0.9 μm aerosol combined with the SL and SL-port geometries reduced device depositional losses by factors of 3-fold and >10-fold, respectively. With EEG powder aerosols, the SL geometry provided the maximum tracheobronchial deposition fraction (55.7%), whereas the SL-port geometry provided the maximum alveolar (67.6%) and total lung (95.7%) deposition fractions, respectively., Conclusions: Provided the aerosol can be administered in the first portion of the inspiration cycle, the proposed new method can significantly improve the deposition of pharmaceutical aerosols in the lungs of intubated infants.

Purpose: The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques., Methods: An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations., Results: Significant improvement in the lung dose (3-4× increase) was observed using excipient enhanced growth (EEG) and enhanced condensational growth (ECG) delivery modes compared to control studies performed with a conventional size aerosol (~5 μm). This was due to reduced device retention and minimal deposition in the NMT airways. Increased condensational growth of the initially submicrometer particles was observed using the ECG mode and in the presence of hygroscopic excipients. CFD predictions for regional drug deposition and aerosol size increase were in good agreement with the observed experimental results., Conclusions: These controlled condensational growth techniques for the delivery of submicrometer aerosols were found to be highly efficient methods for delivering nasally-administered drugs to the lungs.

Background: Previous studies have characterized the size increase of combination submicrometer particles composed of a drug and hygroscopic excipient when exposed to typical airway thermodynamic conditions. The objective of this study was to determine the deposition and size increase characteristics of excipient enhanced growth (EEG) aerosols throughout the tracheobronchial (TB) airways and to evaluate the potential for targeted delivery., Methods: Submicrometer particles composed of a poorly water-soluble drug (insulin) and hygroscopic excipient (sodium chloride) were considered at drug:excipient mass ratios of 50:50 and 25:75. A previously validated computational fluid dynamics model was used to predict aerosol size increase and deposition in characteristic geometries of the mouth-throat (MT), upper TB airways through the third bifurcation (B3), and remaining TB airways through B15. Additional validation experiments were also performed for albuterol sulfate:mannitol particles. Both growth of combination particles and deposition are reported throughout the conducting airways for characteristic slow and deep (SD) and quick and deep (QD) inhalations., Results: For all EEG cases considered, MT deposition was less than 1% of the drug dose, which is at least one order of magnitude lower than with state-of-the-art and conventional inhalers. Final aerosol sizes exiting the TB region and entering the alveolar airways were all greater than 3 μm. For SD inhalation, deposition fractions of 20% were achieved in the lower TB region of B8-B15, which is a factor of 20-30×higher than conventional delivery devices. With QD inhalation, maximum alveolar delivery of 90% was observed., Conclusions: Increasing the dose delivered to the lower TB region by a factor of 20-30×or achieving 90% delivery to the alveolar airways was considered effective aerosol targeting compared with conventional devices. The trend of higher flow rates resulting in better alveolar delivery of aerosols is unique to EEG and may be used to design highly efficient dry powder inhalers.

Characteristic models of the upper conducting airways are needed to evaluate the performance of existing pharmaceutical inhalers and to develop new respiratory drug delivery strategies. Previous studies have focused on the development of characteristic mouth-throat (MT) geometries for orally inhaled products; however, characteristic upper tracheobronchial (TB) geometries are currently not available. In this study, a new characteristic model of the upper TB airways for an average adult male was developed based on an analysis of new and existing anatomical data. Validated computational fluid dynamics (CFD) simulations were used to evaluate the deposition of monodisperse and realistic polydisperse aerosols from multiple inhalers. Comparisons of deposition results between the new model and a simpler geometry were used to identify the effects of different anatomical features on aerosol deposition. The CFD simulations demonstrated a good match to regional pharmaceutical aerosol deposition from in vitro experiments in the same geometry. The deposition of both monodisperse and pharmaceutical aerosols was increased in the new TB geometry as a result of additional anatomical detail on a regional and highly localized basis. Tracheal features including an accurate coronal angle, asymmetry, and curvature produced a skewed laryngeal jet and significantly increased regional deposition. Branch curvature and realistic cross-sections increased deposition in the remainder of the TB model. A hexahedral mesh style was utilized to provide the best solution. In conclusion, a number of physiological features in the upper TB region were shown to influence deposition and should be included in a characteristic model of respiratory drug delivery.

The neoglycoproteins that consist of human serum albumin (HSA) modified with mannose 6-phosphate ([M6P]x-HSA) were synthesized, and they showed high binding property to hepatic stellate cells (HSC) by immunohistochemical analysis. In addition, an increased substitution (X) of 6-phosphated mannose (M6P) was associated with an increased accumulation in HSC. So the [M6P]x-HSA might be a carrier to deliver drugs to HSC. The antifibrotic drug, glycyrrhetin, was chosen to conjugate to M6P(26)-HSA. The result suggests there were 6 approximately 7 glycyrrhetin molecules having been conjugated to the carrier. Targeting glycyrrhetin to HSC might reduce its adverse affects and increase the efficacy.

The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn2+ ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn2+/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream H2O2 levels. Next, the released Mn2+ ions catalyzed H2O2 to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn2+/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn2+/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan. [ABSTRACT FROM AUTHOR]

Nasal delivery of lung targeted pharmaceutical aerosols is ideal for drugs that need to be administered during high flow nasal cannula (HFNC) gas delivery, but based on previous studies losses and variability through both the delivery system and nasal cavity are expected to be high. The objective of this study was to assess the variability in aerosol delivery through the nose to the lungs with a nasal cannula interface for conventional and excipient enhanced growth (EEG) delivery techniques. A database of nasal cavity computed tomography (CT) scans was collected and analyzed, from which four models were selected to represent a wide range of adult anatomies, quantified based on the nasal surface area-to-volume ratio ( SA/V ). Computational fluid dynamics (CFD) methods were validated with existing in vitro data and used to predict aerosol delivery through a streamlined nasal cannula and the four nasal models at a steady state flow rate of 30 L/min. Aerosols considered were solid particles for EEG delivery (initial 0.9 μm and 1.5 μm aerodynamic diameters) and conventional droplets (5 μm) for a control case. Use of the EEG approach was found to reduce depositional losses in the nasal cavity by an order of magnitude and substantially reduce variability. Specifically, for aerosol deposition efficiency in the four geometries, the 95% confidence intervals ( CI ) for 0.9 and 5 µm aerosols were 2.3–3.1% and 15.5–66.3%, respectively. Simulations showed that the use of EEG as opposed to conventional methods improved delivered dose of aerosols through the nasopharynx, expressed as penetration fraction ( PF ), by approximately a factor of four. Variability of PF , expressed by the coefficient of variation ( CV ), was reduced by a factor of four with EEG delivery compared with the control case. Penetration fraction correlated well with SA/V for larger aerosols, but smaller aerosols showed some dependence on nasopharyngeal exit hydraulic diameter. In conclusion, results indicated that the EEG technique not only improved lung aerosol delivery, but largely eliminated variability in both nasal depositional loss and lung PF in a newly developed set of nasal airway models. [ABSTRACT FROM AUTHOR]

Using the nasal route to deliver pharmaceutical aerosols to the lungs has a number of advantages, including coadministration during noninvasive ventilation. The objective of this study was to evaluate the growth and deposition characteristics of nasally administered aerosol throughout the conducting airways based on delivery with streamlined interfaces implementing two forms of controlled condensational growth technology. Characteristic conducting airways were considered including a nose-mouth-throat (NMT) geometry, complete upper tracheobronchial (TB) model through the third bifurcation (B3), and stochastic individual path (SIP) model to the terminal bronchioles (B15). Previously developed streamlined nasal cannula interfaces were used for the delivery of submicrometer particles using either enhanced condensational growth (ECG) or excipient enhanced growth (EEG) techniques. Computational fluid dynamics (CFD) simulations predicted aerosol transport, growth, and deposition for a control (4.7 μm) and three submicrometer condensational aerosols with budesonide as a model insoluble drug. Depositional losses with condensational aerosols in the cannula and NMT were less than 5% of the initial dose, which represents an order-of-magnitude reduction compared to the control. The condensational growth techniques increased the TB dose by a factor of 1.1–2.6×, delivered at least 70% of the dose to the alveolar region, and produced final aerosol sizes ≥2.5 μm. Compared to multiple commercial orally inhaled products, the nose-to-lung delivery approach increased dose to the biologically important lower TB region by factors as large as 35×. In conclusion, nose-to-lung delivery with streamlined nasal cannulas and condensational aerosols was highly efficient and targeted deposition to the lower TB and alveolar regions. Copyright 2014 American Association for Aerosol Research [ABSTRACT FROM AUTHOR]

In this study, a new computational fluid dynamics (CFD) modeling approach for pharmaceutical aerosols is further developed by evaluating the effects of turbulence, polydisperse aerosol size distribution, and multiple lung lobes on deposition in the mouth–throat (MT) and entire tracheobronchial (TB) airways. To evaluate a range of respiratory drug delivery conditions, a model dry powder inhaler (DPI; NovolizerTM) and a model spray soft-mist inhaler (SMI; RespimatTM) were considered. The respiratory geometry consisted of a previously developed characteristic MT and complete upper TB geometry through the third bifurcation (B3). More distal TB airways were simulated using stochastic individual path (SIP) models extending into each of the five lung lobes through bifurcation B15. Based on comparisons with new in vitro deposition data, results indicated that the low Reynolds number (LRN) k–ω turbulence model with near-wall corrections for anisotropic turbulence and velocity conditions accurately predicted deposited drug mass from both inhalers. Simulating the polydisperse aerosol size distribution had a large impact on overall deposited drug mass compared with a monodisperse approximation. However, a new equivalent mass median diameter (MMD), calculated as MMDeq = 1.25 × MMD, was shown to provide a good monodisperse estimate of the aerosol deposition from both inhalers considered in this study used with different inhalation flow conditions in the SIP models. Large variations in deposition were observed among the five lung lobes. However, deposition in the left lower lobe (scaled by a factor of 5) was found to be characteristic of total lobar deposition in the range of B4–B15 and allowed for the simulation of only one lobe. Implementing the approximations of an equivalent MMD and simulating deposition in one characteristic lung lobe increased the efficiency of the airway CFD simulations by over 25 times at the expense of a maximum 12% relative error compared with the more exact simulations. As an example of model utility, results indicated that the state-of-the-art SMI improved delivery efficiency of drug by a factor of 1.5 in the upper TB region and by over an order of magnitude in the lower TB airways compared with a commonly used high quality DPI. Copyright 2012 American Association for Aerosol Research [ABSTRACT FROM PUBLISHER]

Abstract: While a number of studies have considered the dynamics of ambient or environmental particles in the respiratory tract, far fewer have evaluated the transport and deposition of pharmaceutical aerosols from inhalers in the mouth-throat (MT) and tracheobronchial (TB) airways. The objective of this study was to develop a new stochastic individual path (SIP) modeling approach for simulating the MT and TB deposition of a pharmaceutical aerosol from a dry powder inhaler and to evaluate the effects of transient vs. steady state conditions and sampling of the airways. In the SIP approach, representative models of the MT and upper TB geometries are considered through the third respiratory bifurcation (B3; approximately lobar bronchi). Stochastic individual paths are then evaluated extending from B4 to the terminal bronchioles (B15) in which one branch of each bifurcation is continued and one is not. Three SIP geometries were considered extending into the lower right lung lobe through the end of the conducting airways. A commonly prescribed dry powder inhaler (DPI) was connected to the MT geometry and the deposition of drug mass from a realistic polydisperse pharmaceutical aerosol was evaluated. Predictions of deposited drug mass in the MT and upper TB geometries were found to be in good agreement with concurrent experimental results. Transient inhalation was shown to influence the deposition of particles in the MT and upper TB airways through B3, where the Womersley number is greater than 1. In contrast, transient conditions were found to have little influence on deposition in the TB region starting with B4, where steady state simulations provided a good representation of total, regional, bifurcation-averaged, and localized deposition. Furthermore, a single SIP model was shown to characterize both regional and highly localized deposition within a lung lobe assuming mean airway dimensions. The resulting SIP model provides a highly efficient method to simulate the regional and local deposition of pharmaceutical aerosols throughout the conducting airways. In comparison with performing fully transient simulations of all branches in the regions considered, the SIP modeling approach reduces computational effort by a factor of approximately 3×105 while predicting regional and local deposition values to within approximately 5%. [Copyright &y& Elsevier]

Background: Identifying possible drug-target interactions (DTIs) has become an important task in drug research and development. Although high-throughput screening is becoming available, experimental methods narrow down the validation space because of extremely high cost, low success rate, and time consumption. Therefore, various computational models have been exploited to infer DTI candidates. Methods: We introduced relevant databases and packages, mainly provided a comprehensive review of computational models for DTI identification, including network-based algorithms and machine learning-based methods. Specially, machine learning-based methods mainly include bipartite local model, matrix factorization, regularized least squares, and deep learning. Results: Although computational methods have obtained significant improvement in the process of DTI prediction, these models have their limitations. We discussed potential avenues for boosting DTI prediction accuracy as well as further directions. [ABSTRACT FROM AUTHOR]

[Display omitted] Depression is a serious psychiatric disorder with unsatisfactory outcomes due to difficulties in delivering therapeutic molecules from the periphery to the brain. Neuroinflammation plays a key role in neurobiology and the treatment of depression. Neutrophils can cross the blood–brain barrier (BBB) and infiltrate key brain regions related to the pathophysiology of depression during neuroinflammation. N-Acetyl Pro–Gly–Pro (PGP) peptides efficiently bind to CXCR2 receptors on the surface of neutrophils. The neuropeptide oxytocin demonstrated antidepressant properties in preclinical and clinical studies, but its inability to penetrate the BBB hampers its therapeutic applications. In this study, we established a novel drug delivery system based on neutrophil infiltration in key brain regions during neuroinflammation. PGP was used to modify oxytocin-loaded liposomes (PGP-OTL) as the target ligand. Systematic administration of PGP-OTL exhibited enhanced antidepressant properties resulting from elevated oxytocin concentrations, especially in the amygdala, a crucial depression-implicated brain region. Enhanced antidepressant effects of PGP-OTL, similar to the ones caused by central oxytocin infusion, were observed in behavioral measurement including forced swim and tail suspension tests. Our study demonstrated that PGP-OTL can "hitchhike" neutrophils and enhance delivery of therapeutics into the brain, thus providing the means for developing novel cell-liposome-based drug delivery strategies for depression therapy. [ABSTRACT FROM AUTHOR]