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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]

Mucus is a selective barrier to particles and molecules, preventing penetration to the epithelial surface of mucosal tissues. Significant advances in transmucosal drug delivery have recently been made and have emphasized that an understanding of the basic structure, viscoelastic properties, and interactions of mucus is of great value in the design of efficient drug delivery systems. Mucins, the primary non-aqueous component of mucus, are polymers carrying a complex and heterogeneous structure with domains that undergo a variety of molecular interactions, such as hydrophilic/hydrophobic, hydrogen bonds and electrostatic interactions. These properties are directly relevant to the numerous mucin-associated diseases, as well as delivering drugs across the mucus barrier. Therefore, in this review we discuss regional differences in mucus composition, mucus physicochemical properties, such as pore size, viscoelasticity, pH, and ionic strength. These factors are also discussed with respect to changes in mucus properties as a function of disease state. Collectively, the review seeks to provide a state of the art roadmap for researchers who must contend with this critical barrier to drug delivery. [ABSTRACT FROM AUTHOR]

Abstract: Design of appropriate inhaled carriers with adequate aerodynamic properties, drug release, biodegradation and evasion of macrophage uptake is a major challenge for controlled release pulmonary drug delivery. In this study, PEG graft copolymerized onto N-phthaloyl chitosan (NPHCs) was synthesized then characterized using FTIR, EA, DSC and 2D-XRD. The resulting PEG-g-NPHCs copolymers were self-assembled into drug-loaded nanoparticles and encapsulated in respirable/swellable sodium alginate semi-IPN hydrogel microspheres as novel biodegradable carriers for controlled release pulmonary drug delivery. The developed nano-/microspheres carrier systems were formed via spray drying followed by ionotropic crosslinking in mild aqueous medium. The size of the developed self-assembled nanoparticles and the microspheres was measured using dynamic light scattering and laser diffraction, respectively. Morphology, moisture content, in vitro biodegradation and dynamic swelling studies were also investigated for the developed carriers. A model protein was entrapped and the in vitro release profiles were determined in PBS, pH 7.4 at 37°C. A dry powder aerosolization study was conducted using a Next Generation Impactor (NGI). The developed microspheres had suitable aerodynamic diameters (1.02–2.63μm) and an excellent fine particle fraction, FPF of 31.52%. The microspheres showed also a very fast initial swelling within the first 2min and started to enzymatically degrade within the first 2h. Moreover, the microspheres entrapped up 90% of the model drug and showed promising in vitro sustained release profiles as compared to the control formulation. [Copyright &y& Elsevier]

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]

In recent years, several new genome editing technologies have been developed. Of these the zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas9 RNA-guided endonuclease system are the most widely described. Each of these technologies utilizes restriction enzymes to introduce a DNA double stranded break at a targeted location with the guide of homologous binding proteins or RNA. Such targeting is viewed as a significant advancement compared to current gene therapy methods that lack such specificity. Proof-of-concept studies have been performed to treat multiple disorders, including in vivo experiments in mammals and even early phase human trials. Careful consideration and investigation of delivery strategies will be required so that the therapeutic potential for gene editing is achieved. In this review, the mechanisms of each of these gene editing technologies and evidence of therapeutic potential will be briefly described and a comprehensive list of past studies will be provided. The pharmaceutical approaches of each of these technologies are discussed along with the current delivery obstacles. The topics and information reviewed herein provide an outline of the groundbreaking research that is being performed, but also highlights the potential for progress yet to be made using these gene editing technologies. [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]

In this investigation, novel biodegradable physically crosslinked hydrogel microparticles were developed and evaluated in vitro as potential carriers for sustained pulmonary drug delivery. To facilitate sustained release in the lungs, aerosols must first navigate past efficient aerodynamic filtering to penetrate to the deep lung (requires small particle size) where they must then avoid rapid macrophage clearance (enhanced by large particle size). The strategy suggested in this study to solve this problem is to deliver drug-loaded hydrogel microparticles with aerodynamic characteristics allowing them to be respirable when dry but attain large swollen sizes once deposited on moist lung surfaces to reduce macrophage uptake rates. The microparticles are based on PEG graft copolymerized onto chitosan in combination with Pluronic® F-108 and were prepared via cryomilling. The synthesized polymers used in preparation of the microparticles were characterized using FTIR, EA, 2D-XRD, and differential scanning calorimetry (DSC). The microparticles size, morphology, moisture content, and biodegradation rates were investigated. Swelling studies and in vitro drug release profiles were determined. An aerosolization study was conducted and macrophage uptake rates were evaluated against controls. The microparticles showed a respirable fraction of approximately 15% when prepared as dry powders. Enzymatic degradation of microparticles started within the first hour and about 7–41% weights were remaining after 240 h. Microparticles showed sustained release up to 10 and 20 days in the presence and absence of lysozyme, respectively. Preliminary macrophage interaction studies indicate that the developed hydrogel microparticles significantly delayed phagocytosis and may have the potential for sustained drug delivery to the lung. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2343–2356, 2010 [ABSTRACT FROM AUTHOR]

Therapeutic delivery of drug and gene delivery systems have to traverse multiple biological barriers to achieve efficacy. Mucosal administration, such as pulmonary delivery in cystic fibrosis (CF) disease, remains a significant challenge due to concentrated viscoelastic mucus, which prevents drugs and particles from penetrating the mucus barrier. To address this problem, we used combinatorial peptide-presenting phage libraries and next-generation sequencing (NGS) to identify hydrophilic, net-neutral charged peptide coatings that enable penetration through human CF mucus ex vivo with ~600-fold better penetration than control, improve uptake into lung epithelial cells compared to uncoated or PEGylated-nanoparticles, and exhibit enhanced uniform distribution and retention in the mouse lung airways. These peptide coatings address multiple delivery barriers and effectively serve as excellent alternatives to standard PEG surface chemistries to achieve mucus penetration and address some of the challenges encountered using these chemistries. This biomolecule-based strategy can address multiple delivery barriers and hold promise to advance efficacy of therapeutics for diseases like CF. Unlabelled Image [ABSTRACT FROM AUTHOR]

The RNA interference (RNAi) constitutes a conservative mechanism in eukaryotic cells that induces silencing of target genes. In mammalians, the RNAi is triggered by siRNA (small interfering RNA) molecules. Due to its potential in silencing specific genes, the siRNA has been considered a potential alternative for the treatment of genetic and acquired diseases. However, the siRNA therapy has been limited by its low stability and rapid degradation in presence of nucleases, low cellular uptake, and immune response activation. In order to overcome these drawbacks, we propose the synthesis and characterization of non-viral delivery systems using chitosan derivatives to obtain siRNA complexes (polyplexes). The non-viral delivery systems synthesized included PEG-g-OCs (oligochitosan) and PEG-g-Cs (chitosan medium molecular weight). Both systems allowed the formation of siRNA polyplexes, increased the stability of siRNA in the presence of nucleases, enhanced cellular internalization, and showed low toxicity in the A549 cell line. Finally, the complexes obtained with the PEG-g-OCs system showed silencing activity in a GFP model in the cell line A549 in comparison with naked siRNA. [ABSTRACT FROM AUTHOR]

Abstract: This study involves the development and characterization of a series of sodium alginate-based pH-responsive hydrogel microspheres encapsulating poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The effect of the drying technique (air- or freeze-drying) on the size of the developed particles was determined. Swelling characteristics at different pH values, in vitro biodegradation and moisture contents of both air-dried and freeze-dried hydrogel particles were investigated. The effect of drying method on the morphology of the particles was also studied using SEM and AFM. Then, the developed alginate-PLGA particles were evaluated as potential carriers, through a new approach, to improve the dissolution, bioavailability and oral sustained release of silymarin, as a model of hydrophobic natural therapeutics. The used silymarin was isolated from the seeds of some native milk thistle (Silybum marianum) ecotypes of delta Egypt and was characterized with the aid of several analytical techniques including; 1H NMR, UV and FTIR. The obtained data showed a considerable effect of the alginate content and the drying method onto the characteristics of the prepared particles. Also, the results demonstrated that the developed alginate-based hydrogel microparticles encapsulating silymarin-loaded PLGA NPs can be used as biodegradable carriers that can confer sustained oral release of silymarin in addition to enhancing its overall dissolution and oral bioavailability. [Copyright &y& Elsevier]

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]