Aerosol drug delivery to the lungs during nasal high flow therapy: an in vitro study.

BACKGROUND: Aerosol delivery through a nasal high flow (NHF) system is attractive for clinicians as it allows for simultaneous administration of oxygen and inhalable drugs. However, delivering a fine particle fraction (FPF, particle wt. fraction < 5.0 µm) of drugs into the lungs has been very challenging, with highest value of only 8%. Here, we aim to develop an efficient nose-to-lung delivery system capable of delivering improved quantities (FPF > 16%) of dry powder aerosols to the lungs via an NHF system. METHODS: We evaluated the FPF of spray-dried mannitol with leucine with a next generation impactor connected to a nasopharyngeal outlet of an adult nasal airway replica. In addition, we investigated the influence of different dispersion (20-30 L/min) and inspiratory (20-40 L/min) flow rates, on FPF. RESULTS: We found an FPF of 32% with dispersion flow rate at 25 L/min and inspiratory flow rate at 40 L/min. The lowest FPF (21%) obtained was at the dispersion flow rate at 30 L/min and inspiratory flow rate at 30 L/min. A higher inspiratory flow rate was generally associated with a higher FPF. The nasal cannula accounted for most loss of aerosols. CONCLUSIONS: In conclusion, delivering a third of inhalable powder to the lungs is possible in vitro through an NHF system using a low dispersion airflow and a highly dispersible powder. Our results may lay the foundation for clinical evaluation of powder aerosol delivery to the lungs during NHF therapy in humans.

Proof-of-Principle Study in a Murine Lung Infection Model of Antipseudomonal Activity of Phage PEV20 in a Dry-Powder Formulation.

Bacteriophage therapy is a promising alternative treatment to antibiotics, as it has been documented to be efficacious against multidrug-resistant bacteria with minimal side effects. Several groups have demonstrated the efficacy of phage suspension in vivo to treat lung infections using intranasal delivery; however, phage dry-powder administration to the lungs has not yet been explored. Powder formulations provide potential advantages over a liquid formulation, including easy storage, transport, and administration. The purpose of this study was to assess the bactericidal activities of phage dry-powder formulations against multidrug-resistant (MDR) strain Pseudomonas aeruginosa FADDI-PA001 in a mouse lung infection model. Phage PEV20 spray dried with lactose and leucine produced an inhalable powder at a concentration of 2 × 107 PFU/mg. P. aeruginosa lung infection was established by intratracheal administration of the bacterial suspension to neutropenic mice. At 2 h after the bacterial challenge, the infected mice were treated with 2 mg of the phage powder using a dry-powder insufflator. At 24 h after the phage treatment, the bacterial load in the lungs was decreased by 5.3 log10 (P < 0.0005) in the phage-treated group compared with that in the nontreated group. Additionally, the phage concentration in the lungs was increased by 1 log10 at 24 h in the treated group. These results demonstrate the feasibility of a pulmonary delivery of phage PEV20 dry-powder formulation for the treatment of lung infection caused by antibiotic-resistant P. aeruginosa.

Additive Manufacturing of Prostheses Using Forest-Based Composites.

A custom-made prosthetic product is unique for each patient. Fossil-based thermoplastics are the dominant raw materials in both prosthetic and industrial applications; there is a general demand for reducing their use and replacing them with renewable, biobased materials. A transtibial prosthesis sets strict demands on mechanical strength, durability, reliability, etc., which depend on the biocomposite used and also the additive manufacturing (AM) process. The aim of this project was to develop systematic solutions for prosthetic products and services by combining biocomposites using forestry-based derivatives with AM techniques. Composite materials made of polypropylene (PP) reinforced with microfibrillated cellulose (MFC) were developed. The MFC contents (20, 30 and 40 wt%) were uniformly dispersed in the polymer PP matrix, and the MFC addition significantly enhanced the mechanical performance of the materials. With 30 wt% MFC, the tensile strength and Young´s modulus was about twice that of the PP when injection molding was performed. The composite material was successfully applied with an AM process, i.e., fused deposition modeling (FDM), and a transtibial prosthesis was created based on the end-user's data. A clinical trial of the prosthesis was conducted with successful outcomes in terms of wearing experience, appearance (color), and acceptance towards the materials and the technique. Given the layer-by-layer nature of AM processes, structural and process optimizations are needed to maximize the reinforcement effects of MFC to eliminate variations in the binding area between adjacent layers and to improve the adhesion between layers.

Studies of Radioaerosol Deposition in the Respiratory Tract.

Deposition of aerosols in the respiratory tract can be quantitatively and qualitatively studied by scintigraphy. The most commonly used radionuclide for this purpose is technetium-99m. The effects of various factors on particle deposition have been investigated by using radiolabeled aerosols in the past decade. Most of these studies were in vivo but some were in vitro or ex vivo. The factors examined include particle size, formulation, inhaler design, inhalation flowrate, body posture, and gravity. They have been shown to influence pulmonary deposition, nasal high flow nebulization, and intranasal delivery. A thorough understanding of the various factors is required for the advancement of respiratory-drug delivery. Scintigraphy is a powerful technique that can assist in this regard.

Storage stability of inhalable phage powders containing lactose at ambient conditions.

The aim of this study was to evaluate the storage stability of inhalable phage powders containing lactose and leucine as excipient. As an FDA-approved excipient for inhalation, lactose is preferred over other sugars. PEV phages active against antibiotic-resistant Pseudomonas aeruginosa was spray dried with lactose (55-90%) and leucine (45-10%). Produced powders were heat-sealed in an aluminium pouch at 15% relative humidity (RH) with subsequent storage at 20 °C/60% RH for 12 months. Lactose concentration in the powder positively influenced the phage stability over time. Formulation containing 90% lactose maintained the viability of PEV61 across the study, while ∼1.2 log10 titer reduction was observed in formulations with less lactose. PEV20 was more prone to inactivation (1.7 log10 titer loss at 12-month) when lactose concentration in the particle was below 80%. The fine particle fraction (% wt. particles <5 µm in aerosol) of phage powders was 52-61% and remained the same after 12-month storage. The results demonstrate that spray dried PEV phage powders containing lactose and leucine are biologically and physically stable over long-term storage at ambient temperature. Furthermore, these spray dried phage powders were shown to be non-toxic to lung alveolar macrophage and epithelial cells in vitro.

Crystal structure of aqua-(2-{[2-({2-[bis-(carboxyl-ato-κO-meth-yl)amino-κN]eth-yl}(carboxyl-ato-κO-meth-yl)amino-κN)eth-yl](carb-oxy-meth-yl)aza-niumyl}acetato)-gallium(III) trihydrate.

In the title GaIII complex compound with pentetic acid, [Ga(C14H20N3O10)(H2O)]·3H2O, the GaIII centre is bound in a slightly distorted octa-hedral coordination sphere by two amine N atoms, three carboxyl-ate O atoms and one water O atom. The complex mol-ecule exists as a zwitterion. In the crystal, the complexes are linked to each other via O-H⋯O and C-H⋯O hydrogen bonds, forming layers parallel to (001). Three uncoordinating water mol-ecules link the complex layers via O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds, forming a three-dimensional network.

Pulmonary drug delivery to older people.

Pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are common in older people. Treatment principles are well established in this group of patients; however, inadequate training and improper inhaler techniques often results in poor treatment outcomes. Healthcare professionals often do not have the required knowledge about the most common inhaler devices. Age-related conditions like cognitive ability and physical strength would also impact on the inhaler usage. Pharmacokinetics and pharmacodynamics may be affected by physiological changes, like impaired renal and hepatic functions and reduced lung functions. Adjusting and optimizing the inhaler device to the patient preferences, improvement of the drug formulation and inhalers, and using different adherence strategies might improve the treatment outcomes in elderly patients.

Phage therapy for respiratory infections.

A respiratory infection caused by antibiotic-resistant bacteria can be life-threatening. In recent years, there has been tremendous effort put towards therapeutic application of bacteriophages (phages) as an alternative or supplementary treatment option over conventional antibiotics. Phages are natural parasitic viruses of bacteria that can kill the bacterial host, including antibiotic-resistant bacteria. Inhaled phage therapy involves the development of stable phage formulations suitable for inhalation delivery followed by preclinical and clinical studies for assessment of efficacy, pharmacokinetics and safety. We presented an overview of recent advances in phage formulation for inhalation delivery and their efficacy in acute and chronic rodent respiratory infection models. We have reviewed and presented on the prospects of inhaled phage therapy as a complementary treatment option with current antibiotics and as a preventative means. Inhaled phage therapy has the potential to transform the prevention and treatment of bacterial respiratory infections, including those caused by antibiotic-resistant bacteria.