Hugh D. C. Smyth

Influence of size and surface roughness of large lactose carrier particles in dry powder inhaler formulations

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.

Biodegradable nano-micro carrier systems for sustained pulmonary drug delivery: (I) Self-assembled nanoparticles encapsulated in respirable/swellable semi-IPN microspheres

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 degrees C. A dry powder aerosolization study was conducted using a Next Generation Impactor (NGI). The developed microspheres had suitable aerodynamic diameters (1.02-2.63 microm) and an excellent fine particle fraction, FPF of 31.52%. The microspheres showed also a very fast initial swelling within the first 2 min 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.

Controlled Release Pulmonary Administration of Curcumin Using Swellable Biocompatible Microparticles

This study involves a promising approach to achieve sustained pulmonary drug delivery. Dry powder particulate carriers were engineered to allow simultaneous aerosol lung delivery, evasion of macrophage uptake, and sustained drug release through a controlled polymeric architecture. Chitosan grafted with PEG was synthesized and characterized (FTIR, EA, DSC and 2D-XRD). Then, a series of respirable amphiphilic hydrogel microparticles were developed via spray drying of curcumin-loaded PLGA nanoparticles with chitosan-grafted-PEG or chitosan. The nanoparticles and microparticles were fully characterized using an array of physicochemical analytical methods including particle size, surface morphology, dynamic swelling, density, moisture content and biodegradation rates. The PLGA nanoparticles and the hydrogel microspheres encapsulating the curcumin-loaded PLGA nanoparticles showed average size of 221-243 nm and 3.1-3.9 μm, respectively. The developed carriers attained high swelling within a few minutes and showed low moisture content as dry powders (0.9-1.8%), desirable biodegradation rates, high drug loading (up to 97%), and good sustained release. An aerosolization study was conducted using a next generation impactor, and promising aerosolization characteristics were shown. In vitro macrophage uptake studies, cytotoxicity and in vitro TNF-α assays were performed for the investigated particles. These assays revealed promising biointeractions for the respirable/swellable nano-micro particles developed in this study as potential carriers for sustained pulmonary drug delivery.

Swellable microparticles as carriers for sustained pulmonary drug delivery

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(R) 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.

3D Printing technologies for drug delivery: a review

Abstract With the FDA approval of the first 3D printed tablet, Spritam®, there is now precedence set for the utilization of 3D printing for the preparation of drug delivery systems. The capabilities for dispensing low volumes with accuracy, precise spatial control and layer-by-layer assembly allow for the preparation of complex compositions and geometries. The high degree of flexibility and control with 3D printing enables the preparation of dosage forms with multiple active pharmaceutical ingredients with complex and tailored release profiles. A unique opportunity for this technology for the preparation of personalized doses to address individual patient needs. This review will highlight the 3D printing technologies being utilized for the fabrication of drug delivery systems, as well as the formulation and processing parameters for consideration. This article will also summarize the range of dosage forms that have been prepared using these technologies, specifically over the last 10 years.

Dry Powder Inhaler Device Influence on Carrier Particle Performance

Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer® and Handihaler® through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer®, reflecting the improved performance observed in vitro. Collisions within the Handihaler®, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.

Poly(ethylene glycol)―carboxymethyl chitosan-based pH-responsive hydrogels: photo-induced synthesis, characterization, swelling, and in vitro evaluation as potential drug carriers

In this study, carboxymethyl chitosan was prepared, characterized, and then photo-induced graft copolymerized with poly(ethylene glycol) under a nitrogen atmosphere in aqueous solution using 2,2-dimethoxy-2-phenyl acetophenone (DMPA) as the photo-initiator. The grafting copolymerization process was confirmed and the resulting copolymers were characterized using differential scanning calorimetry (DSC), FTIR spectroscopy, 2D-X ray diffraction, and elemental analysis. The kinetics of the grafting reactions was also studied. Under the applied experimental conditions, the optimum grafting values were obtained at: CMCs=0.2 g, PEGA=249 mM, DMPA=10.4 mM at a 2 h reaction time. Some of the resulting copolymers were selected and used in the presence of methylene bisacrylamide (MBA) as a crosslinking agent to develop pH-responsive hydrogel matrices. The swelling characteristics and the in vitro release profiles of 5-fluorouracil (5-FU), as a model drug, from the hydrogels were investigated. The results revealed that the hydrogel matrices developed in this study can be customized to act as good candidates in drug delivery systems.

Magnetically Responsive Nanoparticles for Drug Delivery Applications Using Low Magnetic Field Strengths

The purpose of this study is to investigate the potential of magnetic nanoparticles for enhancing drug delivery using a low oscillating magnetic field (OMF) strength. We investigated the ability of magnetic nanoparticles to cause disruption of a viscous biopolymer barrier to drug delivery and the potential to induce triggered release of drug conjugated to the surfaces of these particles. Various magnetic nanoparticles were screened for thermal response under a 295-kHz OMF with an amplitude of 3.1 kA/m. Based on thermal activity of particles screened, we selected the nanoparticles that displayed desired characteristics for evaluation in a simplified model of an extracellular barrier to drug delivery, using lambda DNA/HindIII. Results indicate that nanoparticles could be used to induce DNA breakage to enhance local diffusion of drugs, despite low temperatures of heating. Additional studies showed increased diffusion of quantum dots in this model by single-particle tracking methods. Bimane was conjugated to the surface of magnetic nanoparticles. Fluorescence and transmission electron microscope images of the conjugated nanoparticles indicated little change in the overall appearance of the nanoparticles. A release study showed greater drug release using OMF, while maintaining low bulk heating of the samples (T=30degC). This study indicates that lower magnetic field strengths may be successfully utilized for drug delivery applications as a method for drug delivery transport enhancement and drug release switches.

Disruption of the mucus barrier by topically applied exogenous particles

The mucus barrier is well established as a formidable barrier to exogenous substances and forms the first line of defense for mucosal surfaces. Drugs and particle systems are known to be significantly hindered via a variety of interactions with mucus, and some efforts have been reported that can mitigate these interactions. We investigated topically applied particulate systems (nano and micro) for their potential to interact with mucus and influence on the diffusion of model drugs across the mucus barrier. Functionalized polystyrene nanoparticles and microparticles and diesel particulate matter were topically applied to established in vitro mucus models. Particle treated mucus was then assessed, compared to controls, for drug permeation rates. The average permeation rate of drugs increased 2-fold following the application of particles to mucus compared to permeation of the same drug through mucus alone. In some cases permeation enhancement of small model drugs was over 5 times that of controls. Assessment of particle physicochemical properties also indicated that significant interactions occurred between mucus and the particles as determined by zeta potential changes and size changes. Collectively this work supports the hypothesis that topically applied particles interact with the mucus barrier causing disruption of this barrier allowing for increased drug permeation. These findings have implications for improved drug delivery and enhanced environmental exposure to exogenous substances.

Prediction of dry powder inhaler formulation performance from surface energetics and blending dynamics.

The purpose of these studies was to investigate the ability of surface energy measurements and rates of mixing in dry powder inhaler (DPI) formulations to predict aerosol dispersion performance. Two lactose carrier systems comprising either spray-dried or milled particles were developed such that they had identical physical characteristics except for surface morphology and surface energies avoiding confounding variables common in other studies. Surface energy measurements confirmed significant differences between the powder systems. Spray-dried lactose had a higher surface entropy (0.20 vs. 0.13 mJ/m2K) and surface enthalpy (103.2 vs. 79.2 mJ/m2) compared with milled lactose. Mixing rates of budesonide or fluorescein were assessed dynamically, and significant differences in blending were observed between lactose systems for both drugs. Surface energies of the lactose carriers were inversely proportional to dispersion performance. In addition, the root mean square (RMS) of blending rates correlated positively with aerosol dispersion performance. Both techniques have potential utility in routine screening of DPI formulations.