Spray Dried Formulations for Inhalation-Meaningful Characterisation of Powder Properties

Spray drying as a particle engineering technique is of increasing interest in the field of inhalation and is already being utilised e.g., for the PulmoSphereTM products. As spray dried particles tend to agglomerate and are mechanically instable, low dose filling processes can be difficult. This study correlates powder flowability tests of spray dried formulations with filling processes with drum and dosator systems. Four pulmonary and four nasal powders with different characteristics in terms of shape, composition, and surface polarity were prepared and characterised for powder flowability according to Ph. Eur. and by powder rheometry. All formulations were filled with a manual drum TT and a dosator system. The classical flowability tests according to the Ph. Eur. showed a bad flow behaviour for hydrophilic pulmonary powders (x50 ~ 3 µm), whereas hydrophobic pulmonary particles and nasal particles (x50 ~ 25 µm) showed a better flowing behaviour. Powder rheometry supports this finding but can better differentiate flow behaviours

Preparation of Poly-Lactic-Co-Glycolic Acid Nanoparticles in a Dry Powder Formulation for Pulmonary Antigen Delivery

One of the key requirements for successful vaccination via the mucosa is particulate antigen uptake. Poly-lactic-co-glycolic acid (PLGA) particles were chosen as well-known model carriers and ovalbumin (OVA) as the model antigen. Aiming at application to the respiratory tract, which allows direct interaction of the formulation with the mucosal immune system, this work focuses on the feasibility of delivering the antigen in a nanoparticulate carrier within a powder capable of pulmonary delivery. Further requirements were adequate antigen encapsulation in order to use the characteristics of the particulate carrier for (tunable) antigen release, and capability of the production process for industrialisation (realisation in industry). For an effective particulate antigen uptake, nanoparticles with a size of around 300 nm were prepared. For this, two production methods for nanoparticles, solvent change precipitation and the double emulsion method, were evaluated with respect to antigen incorporation, transfer to a dry powder formulation, redispersion and antigen release characteristics. A spray drying step was included in the production procedure in order to obtain a respirable powder with an aerodynamic particle size of between 0.5 and 5 μm. The dried products were characterised for particle size, dispersibility and aerodynamic behaviour, as well as for immune response and cytotoxicity in cell culture models. It could be shown that the double emulsion method is suitable to prepare nanoparticles (270 nm) and to incorporate the antigen. By modifying the production method to prepare porous particles, it was possible to obtain an acceptable antigen release while maintaining an antigen load of about 10%. By the choice of polyvinyl alcohol as a stabiliser, nanoparticles could be dried and redispersed without further excipients and the production steps were capable of realisation in industry. Aerodynamic characteristics were good with a mass median aerodynamic diameter of 3.3 µm upon dispersion from a capsule-based inhaler

Nasal Powder Formulations: In-Vitro Characterisation of the Impact of Powders on Nasal Residence Time and Sensory Effects

Nasal drug delivery is still primarily associated with locally-effective drugs, but next-generation products utilising the benefits of nasal administration-such as easy access to a relatively permeable mucosa, the presence of immunocompetent cells, and a direct route to the brain-are under investigation. Nasal powders offer the potential to improve the drugs' effects by providing higher resistance against the mucociliary clearance, and thus prolonging the contact time of the drug with its target site. However, suitable and easy-to-use in-vitro setups tailored to the characterisation of this effect are missing. In this study, a selection of excipients for powder formulations were used to evaluate the applicability of different methods which investigate the influence on the contact time. The combination of the assessment of rheological properties, dynamic vapour sorption, and adhesiveness on agar-mucin plates was found to be a valuable predictive tool. For the additional assessment of the sensations associated with the close contact of powders and the mucosa, a slug mucosal irritation assay was conducted and adapted to powders. These methods are regarded as being especially useful for comparative screenings in early formulation development

In-Depth Comparison of Dry Particle Coating Processes Used in DPI Particle Engineering

High-shear mixer coatings as well as mechanofusion processes are used in the particle-engineering of dry powder inhalation carrier systems. The aim of coating the carrier particle is usually to decrease carrier-drug adhesion. This study comprises the in-depth comparison of two established dry particle coating options. Both processes were conducted with and without a model additive (magnesium stearate). In doing so, changes in the behaviour of the processed particles can be traced back to either the process or the additive. It can be stated that the coarse model carrier showed no significant changes when processed without additives. By coating the particles with magnesium stearate, the surface energy decreased significantly. This leads to a significant enhancement of the aerodynamic performance of the respective carrier-based blends. Comparing the engineered carriers with each other, the high-shear mixer coating shows significant benefits, namely, lower drug-carrier adhesion and the higher efficiency of the coating process

Development of High Dose Oseltamivir Phosphate Dry Powder for Inhalation Therapy in Viral Pneumonia

Oseltamivir phosphate (OP) is an antiviral drug available only as oral therapy for the treatment of influenza and as a potential treatment option when in combination with other medication in the fight against the corona virus disease (COVID-19) pneumonia. In this study, OP was formulated as a dry powder for inhalation, which allows drug targeting to the site of action and potentially reduces the dose, aiming a more efficient therapy. Binary formulations were based on micronized excipient particles acting like diluents, which were blended with the drug OP. Different excipient types, excipient ratios, and excipient size distributions were prepared and examined. To investigate the feasibility of delivering high doses of OP in a single dose, 1:1, 1:3, and 3:1 drug/diluent blending ratios have been prepared. Subsequently, the aerosolization performance was evaluated for all prepared formulations by cascade impaction using a novel medium-resistance capsule-based inhaler (UNI-Haler). Formulations with micronized trehalose showed relatively excellent aerosolization performance with highest fine-particle doses in comparison to examined lactose, mannitol, and glucose under similar conditions. Focusing on the trehalose-based dry-powder inhalers' (DPIs) formulations, a physicochemical characterization of extra micronized grade trehalose in relation to the achieved performance in dispersing OP was performed. Additionally, an early indication of inhaled OP safety on lung cells was noted by the viability MTT assay utilizing Calu-3 cells

Numerical investigation of screw design influence on screw feeding in a roller compactor

Roller compaction refers to a dry granulation process where fine particulate feed is fed to the counter rotating rolls of a roller compactor to form ribbons which are further milled to produce free flowing agglomerates. For the continuous production of ribbons, there needs to be an adequate supply of powder by the screw to the rolls without any interruptions. In general, screws used in roller compactors are designed to convey powders of all types (cohesive, bulky, compressible, etc.), whereby usage of different screw designs for different powder types may be avoided. However, using such single screw type roller compactors for poor flowing powders may be challenging. On the other hand, the selection of the right screw for a given powder can only be done based on a combination of prior experience and trial-and-error experimentation. Empirical correlations exist to predict the draw down rate of screw feeders depending on their design, however, these correlations assume that there is continuous supply of powder by the screw, which limits its application to free-flowing powders only. To address this, in this study numerical simulations are performed based on discrete element method (DEM) to investigate the impact of screw design on the powder supply to rolls for cohesive and poorly flowing powders. The geometry considered includes a hopper, horizontal feeding screw below the hopper, and two counter-rotating rolls at the end of the screw. Two different screw designs are investigated where the main difference between them is the pitch length. The influence of scraper speed is investigated. Additionally, the influence of material attribute such as cohesion is studied. For both designs, the simulation results calculated include the rate of powder supply by the screw, velocity of particles in the screw etc. The simulation results of powder supply rate are also compared with results obtained based on empirical correlation. Overall, this simulation approach helps in selecting appropriate screw design for the given cohesive powder

Pulmonary Application of Novel Antigen-Loaded Chitosan Nano-Particles Co-Administered with the Mucosal Adjuvant C-Di-AMP Resulted in Enhanced Immune Stimulation and Dose Sparing Capacity

The most successful medical intervention for preventing infectious diseases is still vaccination. This effective strategy has resulted in decreased mortality and extended life expectancy. However, there is still a critical need for novel vaccination strategies and vaccines. Antigen cargo delivery by nanoparticle-based carriers could promote superior protection against constantly emerging viruses and subsequent diseases. This should be sustained by the induction of vigorous cellular and humoral immunity, capable of acting both at the systemic and mucosal levels. Induction of antigen-specific responses at the portal of entry of pathogens is considered an important scientific challenge. Chitosan, which is widely regarded as a biodegradable, biocompatible and non-toxic material for functionalized nanocarriers, as well as having adjuvant activity, enables antigen administration via less-invasive mucosal routes such as sublingual or pulmonic application route. In this proof of principle study, we evaluate the efficacy of chitosan nanocarriers loaded with the model antigen Ovalbumin (OVA) co-administrated with the STING agonist bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) given by pulmonary route. Here, BALB/c mice were immunized with four doses of the formulation that stimulates enhanced antigen-specific IgG titers in sera. In addition, this vaccine formulation also promotes a strong Th1/Th17 response characterized by high secretion of IFN-γ, IL-2 and IL-17, as well as induction of CD8+ T cells. Furthermore, the novel formulation exhibited strong dose-sparing capacity, enabling a 90% reduction of the antigen concentration. Altogether, our results suggest that chitosan nanocarriers, in combination with the mucosal adjuvant c-di-AMP, are a promising technology platform for the development of innovative mucosal vaccines against respiratory pathogens (e.g., Influenza or RSV) or for therapeutic vaccines

Enhanced tenacity of mycobacterial aerosols from necrotic neutrophils

The tuberculosis agent Mycobacterium tuberculosis is primarily transmitted through air, but little is known about the tenacity of mycobacterium-containing aerosols derived from either suspensions or infected neutrophils. Analysis of mycobacterial aerosol particles generated from bacterial suspensions revealed an average aerodynamic diameter and mass density that may allow distant airborne transmission. The volume and mass of mycobacterial aerosol particles increased with elevated relative humidity. To more closely mimic aerosol formation that occurs in active TB patients, aerosols from mycobacterium-infected neutrophils were analysed. Mycobacterium-infected intact neutrophils showed a smaller particle size distribution and lower viability than free mycobacteria. In contrast, mycobacterium-infected necrotic neutrophils, predominant in M. tuberculosis infection, revealed particle sizes and viability rates similar to those found for free mycobacteria, but in addition, larger aggregates of viable mycobacteria were observed. Therefore, mycobacteria are shielded from environmental stresses in multibacillary aggregates generated from necrotic neutrophils, which allows improved tenacity but emphasizes short distance transmission between close contacts

Author Correction: Enhanced tenacity of mycobacterial aerosols from necrotic neutrophils

The original version of this Article contained errors within the affiliations section. Affiliation 4 was incorrectly given as ‘Leibniz Research Alliance INFECTIONS’21, Leipzig, Germany’. The correct affiliation is listed below: Leibniz Research Alliance INFECTIONS’21, Borstel, 23845, Germany Also, Affiliation 5 was incorrectly given as ‘German Center for Infection Research, TTU-TB, Borstel, 23845, Germany’. The correct affiliation is listed below: German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel, Germany. Finally, the original HTML version of this Article omitted an affiliation for G. Gabriel. The correct affiliations for G. Gabriel are listed below: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, 20251, Germany. Leibniz Research Alliance INFECTIONS’21, Borstel, 23845, Germany. German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel, Germany. These errors have now been corrected in the PDF and HTML versions of the Article

Characterisation of nasal devices for delivery of insulin to the brain and evaluation in humans using functional magnetic resonance imaging

This study aimed to characterise three nasal drug delivery devices to evaluate their propensity to deliver human insulin solutions to the nasal cavity for redistribution to the central nervous system. Brain delivery was evaluated using functional magnetic resonance imaging to measure regional cerebral blood flow. Intranasal insulin administration has been hypothesised to exploit nose-to-brain pathways and deliver drug directly to the brain tissue whilst limiting systemic exposure. Three nasal pump-actuator configurations were compared for delivery of 400 IU/mL insulin solution by measuring droplet size distribution, plume geometry, spray pattern and in vitro deposition in a nasal cast. The device with optimal spray properties for nose to brain delivery (spray angle between 30° and 45°; droplet size between 20 and 50 μm) also favoured high posterior-superior deposition in the nasal cast and was utilised in a pharmacological magnetic resonance imaging study. Functional magnetic resonance imaging in healthy male volunteers showed statistically significant decreases in regional cerebral blood flow within areas dense in insulin receptors (bilateral amygdala) in response to intranasally administered insulin (160 IU) compared to saline (control). These changes correspond to the expected effects of insulin in the brain and were achieved using a simple nasal spray device and solution formulation. We recommend that a thorough characterisation of nasal delivery devices and qualitative/quantitative assessment of the administered dose is reported in all studies of nose to brain delivery so that responses can be evaluated with respect to posology and comparison between studies is facilitated