Search

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]

Objective To investigate influences of capsule fill weight, batch size, and storage conditions on in vitro aerodynamic performance of jet-milled ibuprofen (IBU) carrier-free, dry powder inhaler formulations. Materials and methods Milled and unmilled IBU samples were characterized thermally and spectroscopically. Physicochemical characterization was performed by quantifying specific surface area, density, and angle of repose. Performance testing was conducted on IBU formulations in combination with a high resistance Monodose RS01 using Next Generation Impactor. Results and discussion There were no detectable differences between IBU samples thermally and spectroscopically. The milled IBU sample exhibited improved powder flow in comparison with the unmilled sample. The milled IBU powders possessed surprisingly high in vitro aerodynamic performance with a fine particle fraction percentage between 67 and 85%, and a minimum respirable fraction percentage of 49%. The capsule fill weights, from 10 to 50 mg, and milling batch sizes did not significantly influence performance. The importance of powder conditioning following milling was illustrated as the storage duration and temperature negatively affected performance. Conclusion In vitro aerodynamic performance of IBU is independent of capsule fill weight and batch size; however, some period of powder conditioning is recommended to reduce variability in formulation performance. [ABSTRACT FROM AUTHOR]

Objective To crystallize diclofenac (DF) from diclofenac sodium (DFNa), to micronize DF and DFNa, and to evaluate in vitro aerodynamic performance of the jet-milled formulations Materials and methods From the acidic titration of aqueous DFNa, DF crystals were formed and were identified using thermal analysis, spectroscopy, and X-ray powder diffraction. Following the micronization of the DF and DFNa powders, the recovered samples were imaged, and their particle size distributions were evaluated. Samples before and after jet millings were characterized, and in vitro aerodynamic performance testing was performed on the DF sample before jet milling and the DF and DFNa samples following jet milling. Results and discussion Hollow needles of DF were precipitated. With similar particle size distributions, the jet-milled DFNa sample from the collection bag, and the DF sample from the cyclone were used for further characterization. Despite different deposition patterns in the Next Generation Impactor, the DF hollow needles had a comparable respirable fraction percentage to the jet-milled DF and DFNa particles. However, the jet-milled DF formulation had the best in vitro aerodynamic performance. Conclusions Hollow, crystalline needles of DF were formed and possessed promising aerosol performance in comparison with the jet-milled 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]

There are a multitude of formulation factors to consider when developing a pMDI. Evaluation of each of these variables has been performed over the years, but there has been an abundance of different approaches in the determination of the effects on device performance. Thus, although much is known about pMDI on the empirical level, a systematic approach has clearly been missing. With the ratification of the Montreal Protocol and the introduction of alternative propellant systems, the opportunity to establish relationships between different levels of testing, such as in vitro measurements and in vivo outcomes, and in vivo assessments and clinical outcomes, has arrived. This review outlines research efforts that have focused on the formulation of propellant-driven metered dose inhalers using alternative propellants. These formulation factors, including device characteristics, are reviewed with respect to the performance of MDIs. [Copyright &y& Elsevier]

[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]

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]

Abstract: The effect of device geometry and film characteristics on the performance of several passive flutter-induced dispersion DPI prototypes was investigated. Device resistance measurements indicated that the type of films, type of device geometry and specific device dimensions significantly affects the airflow resistance of the device. It was found that airflow resistance was positively correlated to the turbulence generated within the device. In addition, in vitro deposition studies indicated that the device geometry and film properties have a significant effect on aerosol dispersion performance. From these studies, selected prototypes were observed to have improved aerosolization performance without significant increases in device resistance. With further device design optimization, flutter induced dispersion DPI may be highly efficient mechanism for drug deaggregation and aerosolization. [ABSTRACT FROM AUTHOR]

The performance of dry powder aerosols for the delivery of drugs to the lungs has been studied extensively in the last decade. The focus for different research groups has been on aspects of the powder formulation, which relate to solid state, surface and interfacial chemistry, bulk properties (static and dynamic) and measures of performance. The nature of studies in this field, tend to be complex and correlations between specific properties and performance seem to be rare. Consequently, the adoption of formulation approaches that on a predictive basis lead to desirable performance has been an elusive goal but one that many agree is worth striving towards. The purpose of this paper is to initiate a discussion of the use of a variety of techniques to elucidate dry particle behavior that might guide the data collection process. If the many researchers in this field can agree on this, or an alternative, guide then a database can be constructed that would allow predictive models to be developed. This is the first of two papers that discuss static and dynamic methods of characterizing dry powder inhaler formulations. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1282–1301, 2007 [ABSTRACT FROM AUTHOR]

Characteristics of particles included in dry powder inhalers is extended from our previous report (in this journal) to include properties related to their dynamic performance. The performance of dry powder aerosols for pulmonary delivery is known to depend on fluidization and dispersion which reflects particle interactions in static powder beds. Since the solid state, surface/interfacial chemistry and static bulk properties were assessed previously, it remains to describe dynamic performance with a view to interpreting the integrated database. These studies result in complex data matrices from which correlations between specific properties and performance may be deduced. Lactose particles were characterized in terms of their dynamic flow, powder and aerosol electrostatics, and aerodynamic performance with respect to albuterol aerosol dispersion. There were clear correlations between flow properties and aerosol dispersion that would allow selection of lactose particles for formulation. Moreover, these properties can be related to data reported earlier on the morphological and surface properties of the carrier lactose particles. The proposed series of analytical approaches to the evaluation of powders for inclusion in aerosol products has merit and may be the basis for screening and ultimately predicting particle performance with a view to formulation optimization. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1302–1319, 2007 [ABSTRACT FROM AUTHOR]