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Delivery of drugs to the lungs via dry powder inhaler (DPI) is a promising approach for the treatment of both local pulmonary conditions and systemic diseases. Though DPIs are widely used for the pulmonary deposition of potent bronchodilators, anticholinergics, and corticosteroids, there is growing interest in the utilization of this delivery system for the administration of high drug doses to the lungs, as made evident by recent regulatory approvals for anti-microbial, anti-viral and osmotic agents. However, the formulation of high dose DPIs carries several challenges from both a physiological and physicochemical standpoint. This review describes the various formulation techniques utilized to overcome the barriers associated with the pulmonary delivery of high dose powders. [ABSTRACT FROM AUTHOR]

Twin-screw continuous mixing was used to prepare aerosol powders containing 1% budesonide, 0.3% magnesium stearate, and 98.7% α -lactose monohydrate. The effect of mixing configuration was studied using three screw profiles containing either a combing element, 30° forward kneading element, or a 60° forward kneading element. The impact of screw speed, feed rate, and multiple passes through the mixer on powder quality was investigated. The impact of specific energy on aerosol performance was dependent on the mixing configuration, and high energy input was detrimental to FPF for the 30° kneading element. Control of content uniformity was demonstrated by varying the mixing element in the screw profile. Passing the material through the mixer multiple times improved the aerosol performance. The robust and tunable nature of twin-screw mixing makes it a process well suited for continuous manufacturing of aerosol powders. [Display omitted] • The mixing process is robust above a critical specific throughput. • Excessive mixing shear can reduce aerosol performance due to press on forces. • More aggressive mixing elements in the screw profile improve content uniformity. • Aerosol performance improves with multiple passes through the mixer. • Increased mixing time reduces drug agglomerates to improve FPF. [ABSTRACT FROM AUTHOR]

The feasibility of twin-screw corotating extruder as a continuous process mixer to prepare dry powder inhalation (DPI) powders was investigated. Interactive mixtures of 1% micronized budesonide, 0.3% magnesium stearate and 98.7% alpha-lactose monohydrate were manufactured using a Leistritz Nano-16 extruder at various processing conditions. One set of GFM (grooved mixing) elements were included in the screw profile to provide distributive mixing of conveyed powders with the goal of resulting in a homogeneous mixture. Residence time in the twin-screw mixer was modelled to quantify mixing efficiency. Comparative powders were also prepared using either low or high-shear batch mixing to compare the effect of mixing methods on the properties of the budesonide dry powder inhalation formulation. Twin screw mixing results in homogeneous mixtures with aerosol performance comparable to that of high-shear batch mixing. Scanning electron microscopy confirmed that twin screw mixing produces particles with morphology like that of low and high-shear batch mixing. X-ray diffraction (XRD) analysis verified that there was no form change of the drug due to twin-screw processing. Statistical regression was used to probe the relationship between twin screw mixing process parameters such as screw speed and feed rate and aerosol performance. The twin screw mixing process was found to be robust, as no significant differences in aerosol performance were found for various processing parameters. [Display omitted] [ABSTRACT FROM AUTHOR]

There is currently no in vitro technique for assessing plume geometry of nasal sprays under airflow conditions. However, a majority of FDA approved nasal products recommend that patients inhale during actuation. Therefore, a reproducible in vitro test that measures plume angles under physiologically relevant inhalation flow rates would be useful. The purpose of this study was to adapt the recently described Plume Induction Port Evaluator (PIPE) apparatus for nasal sprays under flow and correlate these with nasal cast deposition patterns. Mass Median Plume Angles (MMPAs) of four nasal spray formulations with increasing viscosities were determined using the PIPE apparatus in the absence and presence of airflow. MMPAs were then correlated to drug deposition within 3D printed nasal casts using airflow. We evaluated different inhalation instructions obtained from the package insert of nasal products. MMPAs significantly reduced (narrower angles) when using flow for the three formulations with the lowest viscosities. An increase in the turbinate deposition was observed in the nasal casts when just one of the nostrils was closed during inhalation, except by the highest viscosity formulation. The turbinate deposition numerically correlated with changes in the plume angles observed using PIPE. [ABSTRACT FROM AUTHOR]

Abstract: Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections, including invasive pulmonary aspergillosis (IPA). IPA in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. In this study, particulate voriconazole (VRC) formulations were designed with suitable properties for inhalation using thin film freezing (TFF), a particle engineering process capable of producing low-density porous aggregate particles. Nanostructured amorphous morphology of VRC was less favorable in vitro and in vivo than microstructured crystalline morphology, despite being a poorly water-soluble compound. Using a Handihaler® dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K25 (1:3) had fine particle fractions of 37.8% and 32.4% and mass median aerodynamic diameters of 4.2 and 5.2μm, respectively. Single dose 24-h pharmacokinetic studies were conducted in ICR mice. AUC0–24h in the lung tissue and plasma was 452.6μgh/g wet lung weight and 38.4μgh/mL, respectively, following a 10mg/kg insufflated dose of TFF-VRC directly into the lungs of the mice, while AUC0–24h in the lung tissue and plasma was 232.1μgh/g wet lung weight and 18.6μgh/mL, respectively, following a 10mg/kg insufflated dose of TFF-VRC-PVP K25 (1:3). High concentrations of VRC in lung tissue coupled with clinically relevant plasma concentrations suggest that pulmonary delivery of microstructured crystalline VRC could potentially be a beneficial strategy for administration of VRC to patients with invasive pulmonary fungal infections. [Copyright &y& Elsevier]