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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]

[Display omitted] Twin-screw extruders are useful in tuning certain product characteristics due to the ability to greatly modify screw profiles as well as operating parameters. However, their use has not yet been applied to dry powder inhalation. In this study the feasibility of using a twin-screw extruder to blend dry powders for inhalation was assessed. Micronized rifampicin (1%) was used as a model drug with lactose carrier (median size ∼ 44 µm) and 0.4% magnesium stearate as a multi-functional ternary agent. Blend performance was compared with low shear (Turbula®) batch mixing. Similar blend uniformity and aerosol performance was observed, indicating the twin-screw extruder successfully functions as a mixer for dry powders for inhalation. The ability to utilize the twin-screw extruder as a continuous mixer leads to new opportunities in the continuous manufacturing of powders for inhalation. [ABSTRACT FROM AUTHOR]

[Display omitted] The process of solids mixing is applied across a considerable range of industries. Pharmaceutical science is one of those industries that utilizes solids mixing extensively. Specifically, solids mixing as a key factor in the preparation of dry powder inhalers using the ordered mixing process will be discussed here. This review opens with a history of dry powder mixing theory, continues to ordered mixing in the preparation for dry powder inhalers, details key interparticulate interactions, explains formulation components for dry powder blends, and finally discusses different types of mixers used in the production of dry powder blends for inhalation. Lastly, the authors offer some suggestions for future work on this topic. [ABSTRACT FROM AUTHOR]

Monoclonal antibody (mAb) based therapies may provide a valuable new treatment modality for acute and chronic lung diseases, including asthma, respiratory infections, and lung cancer. Currently mAbs are delivered via systemic administration routes, but direct delivery to the lungs via the inhaled route could provide higher concentrations at the site of disease and reduced off-target effects. Though lyophilized mAbs may be reconstituted and delivered to the lungs using nebulizers, dry powder inhalers provide a more patient-friendly delivery method based upon their fast administration time and portability. However, particle engineering processes required to prepare respirable dried powders for DPI delivery involve multiple potential stressors for mAbs, which have not been fully explored. In this study, a systematic examination of various aspects of the particle engineering process (atomization, freezing, drying, and storage) was performed to further understand their impact on mAb structure and aggregation. Using anti-streptavidin IgG1 as a model mAb, atomization settings were optimized using a design of experiments approach to elucidate the relationship between feed flow rate, formulation solid content, and atomization airflow rate and protein structural changes and aggregation. The optimized atomization conditions were then applied to spray drying and spray freezing drying particle engineering processes to determine the effects of freezing and drying on IgG1 stability and aerosol performance of the powders. IgG1 was found to be particularly susceptible to degradation induced by the expansive air-ice interface generated by spray freeze drying and this process also produced powders that exhibited decreased storage stability. This study further delineates the design space for manufacturing of respirable biologic therapies and is intended to serve as a roadmap for future development work. [Display omitted] [ABSTRACT FROM AUTHOR]

A significant limitation of locally delivered treatments for chronic pulmonary infections is often the short residence time within the airways. Ciprofloxacin (CIP), for example, undergoes rapid absorption from the airway lumen. Previously, we demonstrated that the complexation of CIP with copper (CIP-Cu) reduces its apparent epithelial permeability and pulmonary absorption rate without affecting antimicrobial activity against Pseudomonas aeruginosa grown planktonically or as biofilms. This study aimed to evaluate the in vivo efficacy of CIP-Cu, prepared as a dry powder, in a chronic lung infection model. The powders were prepared by jet milling (CIP-HCl) and by spray drying (CIP-Cu). A bioluminescent strain of P. aeruginosa (PAO1::p16S lux) was used to prepare bacteria-loaded agar beads that were inoculated intratracheally to rats. The dynamics of the infection were monitored using luminometry. The bacteria/beads ratio was optimized to allow the highest luminescence signal and animal survival for 8 days. The efficacy of the treatment was evaluated by luminometry in addition to the end-point (Day 8) where colony counting was performed after lung harvesting. Luminescent P. aeruginosa entrapped in agar beads were useful to monitor the spatial development of the chronic lung infection in rats. The rats were treated with the dry powders in a nose-only inhalation exposure system (NOIES). CIP-Cu and CIP-HCl powders showed similar aerodynamic properties and comparable CIP lung deposition. However, treatment with CIP-Cu significantly (p < 0.01) reduced by 4-log the number of CFU of P. aeruginosa per lung in the chronic infection model, whereas CIP-HCl effect was not different from the untreated control group. [ABSTRACT FROM AUTHOR]

[Display omitted] Gene therapy and more recently, gene editing is attractive via pulmonary delivery for enhanced regional targeting. However, processing of sensitive therapeutics into dry powders for inhalation can be problematic due to relatively stressful spraying or milling steps. Thin-film freeze-drying (TFFD) has attracted attention with its promising application in the production of DPI formulations possessing respirable particle size range (1–5 µm) particularly for thermally or shear sensitive therapeutics. In this study, gene editing dry powder formulations containing PEGylated chitosan/CRISPR-Cas9 nanocomplexes were prepared by TFFD. To evaluate stability during processing, nanocomplex size, zeta potential and transfection efficiency of reconstituted formulations were evaluated, and six potential DPI formulations were identified and characterized in terms of geometric particle size, powder surface morphology, and crystallinity. It was found that two formulations containing 3% mannitol with or without leucine were identified as suitable for inhalation with a desired aerodynamic performance. The flow rate dependency and inhaler dependency of these two formulations were also evaluated at different flow rates (60 L/min and 45 L/min) and different inhaler devices (RS01 DPI and HandiHaler) using NGI testing. This study demonstrated that TFFD processing of CRISPR-Cas9 polymer nanocomplexes resulted in a suitable dry powder for inhalation. [ABSTRACT FROM AUTHOR]