Preparation and Evaluation of Mucus-Penetrating Inhalable Microparticles of Tiotropium Bromide Containing Sodium Glycocholate.

This study aimed to prepare mucus-penetrating inhalable microparticles for dry powder inhalers and to evaluate their applicability in an asthma-induced rat model. Microparticles were prepared from water solutions containing tiotropium bromide, L-leucine, and sodium glycocholate (NaGc) as permeation enhancers using the spray drying method. Four formulations (SDL1, SDL2, SDL3, and SDL4) were used, depending on the various NaGc concentrations. Tiotropium microparticles were characterized by standard methods. Additionally, an asthma-induced rat model was used to confirm the effects of the formulations on lung function. Tiotropium microparticles with NaGc resulted in formulations with a more corrugated morphology and smaller particle size distribution than those without NaGc. SDL 1 had a rough surface with irregular morphology, and SDL 2, 3, and 4 had a corrugated morphology. All SDL formulations had an aerodynamic size of <3 µm. The microparticles with a corrugated morphology aerosolized better than SDL1 microparticles. The apparent permeability coefficient (Papp) values of SDL3 and SDL4 were significantly higher than those for raw tiotropium. In an in vivo study using an asthma-induced rat model, the specific airway resistance (Sraw), airway wall thickness, and mean alveolus size recovered to those of the negative control group in the SDL4 formulation.

Robust 3D Face Reconstruction Using One/Two Facial Images.

Being able to robustly reconstruct 3D faces from 2D images is a topic of pivotal importance for a variety of computer vision branches, such as face analysis and face recognition, whose applications are steadily growing. Unlike 2D facial images, 3D facial data are less affected by lighting conditions and pose. Recent advances in the computer vision field have enabled the use of convolutional neural networks (CNNs) for the production of 3D facial reconstructions from 2D facial images. This paper proposes a novel CNN-based method which targets 3D facial reconstruction from two facial images, one in front and one from the side, as are often available to law enforcement agencies (LEAs). The proposed CNN was trained on both synthetic and real facial data. We show that the proposed network was able to predict 3D faces in the MICC Florence dataset with greater accuracy than the current state-of-the-art. Moreover, a scheme for using the proposed network in cases where only one facial image is available is also presented. This is achieved by introducing an additional network whose task is to generate a rotated version of the original image, which in conjunction with the original facial image, make up the image pair used for reconstruction via the previous method.

Inhaled bosentan microparticles for the treatment of monocrotaline-induced pulmonary arterial hypertension in rats.

The conventional treatment of pulmonary arterial hypertension (PAH) with oral bosentan hydrate has limitations related to the lack of pulmonary selectivity. In this study, we verified the hypothesis of the feasibility of dry powder inhalation of bosentan as an alternative to oral bosentan hydrate for the treatment of PAH. Inhalable bosentan microparticles with the capability of delivery to the peripheral region of the lungs and enhanced bioavailability have been formulated for PAH. The bosentan microparticles were prepared by the co-spray-drying method with bosentan hydrate and mannitol at different weight ratios. The bosentan microparticles were then characterized for their physicochemical properties, in vitro dissolution behavior, and in vitro aerodynamic performance. The in vivo pharmacokinetics and pathological characteristics were evaluated in a monocrotaline-induced rat model of PAH after intratracheal powder administration of bosentan microparticles, in comparison to orally administered bosentan hydrate. The highest performance bosentan microparticles, named SDBM 1:1, had irregular and porous shape. These microparticles had not only the significantly highest aerosol performance (MMAD of 1.91 µm and FPF of 51.68%) in the formulations, but also significantly increased dissolution rate, compared with the raw bosentan hydrate. This treatment to the lungs was also safe, as evidenced by the cytotoxicity assay. Intratracheally administered SDBM 1:1 elicited a significantly higher Cmax and AUC0-t that were over 10 times higher, compared with those of the raw bosentan hydrate administered orally in the same dose. It also exhibited ameliorative effects on monocrotaline-induced pulmonary arterial remodeling, and right ventricular hypertrophy. The survival rate of the group administrated SDBM1:1 intratracheally was 0.92 at the end of study (Positive control and orally administrated groups were 0.58 and 0.38, respectively). In conclusion, SDBM 1:1 showed promising in vitro and in vivo results with the dry powder inhalation. The inhaled bosentan microparticles can be considered as a potential alternative to oral bosentan hydrate for the treatment of PAH.

The Effect of Particle Size and Surface Roughness of Spray-Dried Bosentan Microparticles on Aerodynamic Performance for Dry Powder Inhalation.

The purpose of this study was to prepare spray dried bosentan microparticles for dry powder inhaler and to characterize its physicochemical and aerodynamic properties. The microparticles were prepared from ethanol/water solutions containing bosentan using spray dryer. Three types of formulations (SD60, SD80, and SD100) depending on the various ethanol concentrations (60%, 80%, and 100%, respectively) were used. Bosentan microparticle formulations were characterized by scanning electron microscopy, powder X-ray diffraction, laser diffraction particle sizing, differential scanning calorimetry, Fourier-transform infrared spectroscopy, dissolution test, and in vitro aerodynamic performance using Andersen cascade impactor™ (ACI) system. In addition, particle image velocimetry (PIV) system was used for directly confirming the actual movement of the aerosolized particles. Bosentan microparticles resulted in formulations with various shapes, surface morphology, and particle size distributions. SD100 was a smooth surface with spherical morphology, SD80 was a rough surfaced with spherical morphology and SD60 was a rough surfaced with corrugated morphology. SD100, SD80, and SD60 showed significantly high drug release up to 1 h compared with raw bosentan. The aerodynamic size of SD80 and SD60 was 1.27 µm and SD100 was 6.95 µm. The microparticles with smaller particle size and a rough surface aerosolized better (%FPF: 63.07 ± 2.39 and 68.27 ± 8.99 for SD60 and SD80, respectively) than larger particle size and smooth surface microparticle (%FPF: 22.64 ± 11.50 for SD100).

Preparation and characterization of metformin hydrochloride controlled-release tablet using fatty acid coated granules.

Metformin hydrochloride (MFM) is often used as a controlled-release (CR) tablet to reduce dosing frequency. However, the MFM CR tablet contains significant amounts of excipients and the tablet size is also large. Dosing convenience and patient compliance can be increased by reducing the size of the CR tablets. The aim of this study was to prepare and evaluate the MFM controlled-release tablet (MFM-CRT) using two types of release modulators, inner and outer. The MFM-CRT was prepared by coating the MFM granules using a binder solution containing aluminum stearate (ALS) as the inner release-modulator, and polyethylene oxide (PEO) as the outer release-modulator. The dispersion stability of the binder solution was optimized by the dispersion analyzer. The MFM-CRT was evaluated for dissolution rate and tablet volume. Additionally, dissolution behavior and dissolution kinetics of the MFM-CRT were analyzed using micro-computed tomography (micro-CT). Although the optimal MFM-CRT showed no difference in the release rate as compared to the commercially available product of Glucophage® XR 500 mg (f2 value: 72), the length of the long axis was reduced by 6 mm and the weight was reduced by about 27%. We expect patient compliance to improve because of effective sustained release and volume reduction of MFM-CRT.

Physicochemical properties and drug-release mechanisms of dual-release bilayer tablet containing mirabegron and fesoterodine fumarate.

Introduction: In this study, a dual release bi-layer tablet containing Fesoterodine fumarate (Fst) 5 mg and Mirabegron (Mrb) 50 mg was prepared to investigate the different release behavior of each drug in bilayer tablet. The bilayer tablet was prepared based on monolayer-tablet formulation of each drug. Methods: The optimized bi-layer tablet showed an in vitro dissolution profile similar to commercial reference tablets Toviaz and Betmiga, based on a satisfactory similarity factor. Drug-release kinetics of each drug in the bilayer tablet were evaluated based on dissolution profiles. Drug-release behavior was evaluated by observing the surface of each layer by scanning electron microscopy and measuring the changes in weight and volume of the tablet during dissolution. Drug transfer between each layer was also investigated by Fourier -transform infrared spectroscopic imaging by observing the cross-section of the bilayer tablet cut vertically during dissolution. Results: The release of Fst was well suited for the Higuchi model, and the release of Mrb was well suited for the Hixson-crowell model. Compared with dissolution rate of each monolayer tablet, that of Fst in the bilayer tablet was slightly reduced (5%), but the dissolution rate of Mrb in bilayer tablet was dramatically decreased (20%). Also, a drug-release study confirmed that polymer swelling was dominant in Fst layer compared with polymer erosion, and degradation was dominant in MRB layer. Fourier-transform infrared imaging and 3-D image reconstruction showed that drug transfer in the bilayer tablet correlates with the results of drug-release behavior. Conclusion: These findings are expected to provide scientific insights in the development of a dual-release bilayer drug-delivery system for Fst and Mrb.

Spiral mouthpiece design in a dry powder inhaler to improve aerosolization.

This study presents the effect of a spiral mouthpiece design in a carrier-based dry powder inhalation on particle aerosol characteristics. Two kinds of mouthpieces, with spiral and non-spiral shaped flow channels, were fabricated by 3D-printing; particle image velocimetry and Anderson cascade impactor were performed to evaluate the drug aerosol characteristics. The obtained experimental results were in agreement with the simulation results of the computational fluid dynamics analysis. The spiral channel created a strong swirl motion of the air flow emitted from the mouthpiece exit, which produced angular momentum rather than the axial flow velocity in the forward direction. This is beneficial in terms of liberating the micronized drug particles from the carrier surface, and leads to more effective delivery of these drug particles to the peripheral target regions of the respiratory system. The spiral device could produce drug particles with significantly smaller mass median aerodynamic diameters and higher fine particle fraction than the non-spiral device.

The role of lactose carrier on the powder behavior and aerodynamic performance of bosentan microparticles for dry powder inhalation.

In this study, we prepared carrier-based formulations for dry powder inhalers by mixing bosentan microparticles with carrier, prepared in three separate types of lactose. Spray-dried, milled and sieved lactose resulted in formulations with various shapes, surface morphology and particle size distributions. In the spray-dried lactose, the micronized bosentan particles were trapped and strongly interlocked in the rugged surface of spray-dried lactose, whereas in the milled and sieved lactose they exhibited lower binding affinity onto the smooth surface of carrier. In all of the carrier-based formulations, the flow properties were improved compared with bosentan microparticles alone, in the following order spray-dried, sieved and milled lactose. The aerodynamic characteristics of each were evaluated by particle image velocimetry and Andersen cascade impactor™. Depending on the lactose carrier type, particle dispersion showed different flow characteristics. In the spray-dried lactose, the formulation was dispersed fast in the only frontal direction, while the milled and sieved lactose formulations formed a relatively slower S-shaped and fountain-shaped flow stream, respectively. In addition, milled and sieved lactose formulations showed that the drug particles were readily liberated from the lactose carrier, and demonstrated significantly higher aerosol performance than spray-dried lactose.