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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]

Abstract: The objective of this study was to determine the effect of both carrier particle size and surface roughness on the aerosol performance of dry powder formulations. Two morphologically distinct grades of lactose, anhydrous (AN) and granulated (GR), were fractionated into 11 discreet sizes up to 300μm, and separately employed as carriers in 2% (w/w) budesonide blends. In vitro deposition studies were performed at 60Lmin−1 with an Aerolizer® DPI. It was found that large carriers can improve dispersion performance, although the effect is more pronounced with greater surface roughness. AN carriers exhibited minimal surface roughness and generally behaved as predicted from the literature, with the smaller carriers outperforming their larger counterparts. In contrast, GR carriers had a high degree of surface roughness, and the dispersion performance of larger carriers exceeded that of the smaller size fractions. Comparing the two lactose grades, AN carriers deposited a greater fraction of the total dose up to the 90–125μm size range, when they were surpassed in performance by the GR carriers. These results suggest that the mechanism of drug detachment varies with the physical properties of the carrier particle population, where surface roughness can alter the predominant detachment mechanism to favor larger carrier particle diameters. [ABSTRACT FROM AUTHOR]

Non-invasive delivery systems are desirable for routine administration of therapeutic protein and peptides. The large absorptive surface area of the lungs, thin alveolar epithelial barrier, and extensive vasculature makes the pulmonary route a promising option. For many years, drug delivery to the lungs has been achieved by nebulizers and metered dose inhalers. Two rapidly expanding fields of aerosol drug delivery are liquid-spray systems and dry-powder delivery systems. The selection of an aerosolization system for protein and peptide active compounds will be driven by several inter-related factors that include: physicochemical properties of the macromolecule, the principle of aerosolization of the device, and patient- and disease-related properties. Although novel liquid spray systems may have aerosol and delivery advantages over current inhalation aerosol technologies, rigorous scientific evaluation has not yet been performed due to the relatively recent introduction of these systems. Alternatively, dry-powder inhaler systems for protein and peptide therapeutics have undergone significantly more scientific evaluation. Dry-powder systems for protein and peptide therapeutics may have stability and sterility advantages. However, with currently used excipients and passive dispersion mechanisms, these devices are relatively inefficient. A convergence of improved particle manufacturing methods and technologies with active dispersion technologies may lead to more efficient delivery options. Alongside these delivery considerations, issues pertaining to economic viability, regulatory approval, and patient factors are equally important for selection of an appropriate delivery system. Thus, with our current understanding, there is no acceptable decision tree or algorithm that can be used to derive the most appropriate device technology for inhaled protein and peptide therapy. This review aims to provide guidance to select the best formulation alternative to deliver a candidate protein/peptide drug through the pulmonary route. [ABSTRACT FROM AUTHOR]

Abstract: Batch-to-batch variability, whereby distinct batches of dry powder inhaler formulations, though manufactured with identical components and specifications, may exhibit significant variations in aerosol performance, is a major obstacle to consistent and reproducible drug delivery for inhalation therapy. This variability may arise from processing or manufacturing effects that have yet to be investigated. This study focused on the potential effects of mild compression forces experienced during powder manufacture and transport (such as during the filling of, or storage in, a hopper) on the flowability and aerosol performance of a lactose-based dry powder inhaler formulation. Different grades of inhalation lactose were subjected to typical compression forces by either placing a weight of known mass on the sample or by using a Texture Analyzer to apply a constant force while measuring the distance of compaction. Powder flowability was evaluated with a rotating drum apparatus by imaging the avalanching of the powder over time. The average avalanche angle and avalanche time were used to determine the flowability of each sample, both before and after compression treatment. Aerosol performance of treated and untreated lactose/budesonide blends (2% (w/w)) was assessed in dispersion studies using a next generation impactor. At compression forces in excess of 5kPa, the flowability of milled lactose was decreased relative to the untreated sample. Compression of lactose prior to blending caused a decrease in in vitro aerosol dispersion performance. However, dispersion performance was unchanged when compression occurred subsequent to drug blending. In contrast, inhalation grade sieved lactose, differing from the milled grade with a lower concentration of lactose fines (<10μm) and larger overall particle sizes, exhibited no statistical differences in either flowability or dispersion performance across all experimental treatments. Thus, the compression of the lactose fines onto the surfaces of the larger lactose particles due to mild processing pressures is hypothesized to be the cause of these observed performance variations. It was shown that simulations of storage and transport in an industrial scale hopper can induce significant variations in formulation performance, and it is speculated that this could be a source of batch-to-batch variations. [Copyright &y& Elsevier]

[Display omitted] • Gelatin was used to develop a swellable matrix system for inhalable dry powder formulations to increase lung retention and control the release of drugs through ionic interactions. • A Box-Behnken approach was used to optimize aerodynamic performance by testing different combinations of SD process parameters. • Cromoglicate sodium (CS) and ipratropium bromide (IBr) microspheres were highly dispersible with a respirable fraction near 50% and a fine particle fraction near 60% • Only uncrosslinked CS and IBr microspheres increased their size by swelling after 5 min (ten and four times, respectively), which could allow for increased lung retention. • The formulations are produced with an accessible manufacturing process, a safe excipient that enhances particle dispersion, and has the potential to control the release of the drugs by a matrix-based approach. Controlled-release formulations for pulmonary delivery are highly desirable for treating chronic diseases such as COPD. However, a limited number of polymers are currently approved for inhalation. The study presents a promising strategy using gelatin as a matrix for inhalable dry powders, allowing the controlled release of ionic drugs. Ionized cromoglicate sodium (CS) and ipratropium bromide (IBr) interacted in solution with charged gelatin before spray drying (SD). Calcium carbonate was used as a crosslinker. The microspheres showed remarkable aerosol performance after optimizing the SD parameters and did not cause cytotoxicity in A549 cells. The microspheres were highly dispersible with ∼ 50–60% of respirable fraction and fine particle fraction 55–70%. Uncrosslinked microspheres increased their size from four to ten times by swelling after 5 min showing potential as a strategy to avoid macrophage clearance and prolong the therapeutic effect of the drug. Crosslinkers prevented particle swelling. Ionic interaction generated a moderate reduction of the drug release. Overall, this study provides a novel approach for developing DPI formulations for treating chronic respiratory diseases using a biopolymer approved by the FDA, potentially enhancing drug activity through controlled release and avoiding macrophage clearance. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The number of biologics in the therapeutic development pipeline is increasing including those delivered though inhalation (Morales, 2017; Fathe, 2016). Biologics comprise a broad variety of complex macromolecules with unique physicochemical characteristics. These distinctive characteristics control their pharmacological mechanisms of action, stability, and ultimately affect their processing, formulation, and delivery requirements. This review systematically covers crucial aspects of biologic powders formulations and dry powder inhalers which need to be taken into consideration to establish the drug loading and the payload to be delivered to reach the desired clinical dose. [ABSTRACT FROM AUTHOR]