Liquid resistivity of pharmaceutical propellants using novel resistivity cell.

Metered-dose inhalers employ propellants to produce pharmaceutical aerosols for treating respiratory conditions like asthma. In the liquid phase, the DC volume resistivity of pharmaceutical propellants, including R134a, R152a, and R227ea, was studied at saturation pressures and room temperature (not vapour phase). These measurements are essential for industries like refrigerants. Aerosols from metered dose inhalers (MDIs) with these propellants become electrically charged, affecting medicament deposition in lung. The resistivity was measured using a novel concentric cylinder-type capacitance cell designed in-house. The resistivity for the propellants (R134a, R152a, and R227ea) was found to be 3.02 × 1010 Ωm, 2.37 × 109 Ωm and 1.31 × 1010 Ωm, respectively. The electrical resistivity data obtained was found to be at least two orders of magnitude higher than the limited data available in the literature. Challenges in the resistivity cell's development and performance are discussed, with a focus on various propellants and their mixtures with ethanol and moisture concentrations. The resistivity of propellant mixtures containing moisture concentrations ranging from 5 to 500 ppm and ethanol concentrations ranging between 1000 and 125,000 ppm was determined. The resistivity was tested across 10-min and 1-h periods and was performed in accordance with the contemporary IEC 60247 standard.

Materials analysis and image-based modelling of transmissibility and strain behaviour in approved face mask microstructures.

Comparisons are made between six different approved face masks concerning their particle transmissibility allied to mechanical properties. The latter involves material testing and stretch or strain behaviour under load. SEM and X-ray elemental analyses showed contrasting structures between random and ordered fibre orientations. These constitute the mask designs where transmissibility is to be minimised. Airflow velocity measurement enabled filtration to be measured between the different mask designs, from two to six layers of different fabrics in combination. SEM provided the fibre diameter and pore size of each mask layer, up to a maximum of six. Stretching each complete mask showed its elasticity and recovery behaviour on an energy basis. The energy conversion involved in mask straining involves areas enclosed within steady and cyclic load-extension plots. Thus, the work done in extending a mask and the energy recovered from its release identified a hysteresis associated with an irrecoverable permanent stretch to the mask fabric. Failure of individual layers, which occurred successively in extended stretch tests, appeared as a drop in a load-extension response. That change is associated with permanent damage to each mask and friction contact within the rearrangement of loose fibre weaves. Masks with the greatest number of layers reduced particle transmissibility. However, woven or ordered mask fabrics in two layers with different orientations provided comparable performance. Simulation of each mechanical response, velocity streamlining and fibre distribution within the mask layers are also presented.

Recent applications of electrical, centrifugal, and pressurised emerging technologies for fibrous structure engineering in drug delivery, regenerative medicine and theranostics.

Advancements in technology and material development in recent years has led to significant breakthroughs in the remit of fiber engineering. Conventional methods such as wet spinning, melt spinning, phase separation and template synthesis have been reported to develop fibrous structures for an array of applications. However, these methods have limitations with respect to processing conditions (e.g. high processing temperatures, shear stresses) and production (e.g. non-continuous fibers). The materials that can be processed using these methods are also limited, deterring their use in practical applications. Producing fibrous structures on a nanometer scale, in sync with the advancements in nanotechnology is another challenge met by these conventional methods. In this review we aim to present a brief overview of conventional methods of fiber fabrication and focus on the emerging fiber engineering techniques namely electrospinning, centrifugal spinning and pressurised gyration. This review will discuss the fundamental principles and factors governing each fabrication method and converge on the applications of the resulting spun fibers; specifically, in the drug delivery remit and in regenerative medicine.

Electrospinning/electrospraying coatings for metal microneedles: A design of experiments (DOE) and quality by design (QbD) approach.

The research presented here shows QbD implementation for the optimisation of the key process parameters in electrohydrodynamic atomisation (EHDA). Here, the electrosprayed nanoparticles and electrospun fibers consisting of a polymeric matrix and dye. Eight formulations were assessed consisting of 5% w/v of polycaprolactone (PCL) in dichloromethane (DCM) and 5% w/v polyvinylpyrrolidone (PVP) in ethanol. A full factorial DOE was used to assess the various parameters (applied voltage, deposition distance, flow rate). Further particle and fiber analysis using Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared Spectroscopy (FTIR), particle/fiber size distribution. In addition to this in vitro release studied were carried out using fluorescein and Rhodamine B as model dyes and in vitro permeation studies were applied. The results show a significant difference in the morphology of resultant structures as well as a more rapid release profile for the PVP particles and fibers in comparison to the sustained release profiles found with PCL. In vitro drug release studies showed 100% drug release after 7 days for PCL particles and showed 100% drug release within 120 min for PVP particles. The release kinetics and the permeation study showed that the MN successfully pierced the membrane and the electrospun MN coating released a large amount of the loaded drug within 6 h. This study has demonstrated the capability of these robust MNs to encapsulate a diverse range drugs within a polymeric matrix giving rise to the potential of developed personalised medical devices.

Application of mesoporous silica nanoparticles as drug delivery carriers for chemotherapeutic agents.

Recently, remarkable efforts have focused on research towards enhancing and delivering efficacious and advanced therapeutic agents. Even though this involves significant challenges, innovative techniques and materials have been explored to overcome these. The advantageous properties of mesoporous silica nanoparticles (MSNs), such as unique morphologies and geometries, makes then favorable for use for various drug delivery targeting purposes, particularly in cancer therapy. As we discuss here, MSNs have been utilized over the past few decades to improve the efficiency of anticancer drugs by enhancing their solubility to render them suitable for application, reducing adverse effects, and improving their anticancer cytotoxic efficiency.

Stable increased formulation atomization using a multi-tip nozzle device.

Electrohydrodynamic atomization (EHDA) is an emerging technique for the production of micron and nano-scaled particles. The process often involves Taylor cone enablement, which results in a fine spray yielding formulated droplets, which then undergo drying during deposition. In this work, novel multi-tip emitter (MTE) devices were designed, engineered and utilized for potential up-scaled EHDA, by comparison with a conventional single-needle system. To demonstrate this, the active ketoprofen (KETO) was formulated using polyvinylpyrrolidone (PVP) polymer as the matrix material. Here, PVP polymer (5% w/v) solution was prepared using ethanol and distilled water (80:20) as the vehicle. KETO was incorporated as 5% w/w of PVP. Physical properties of resulting solutions (viscosity, electrical conductivity, density and surface tension) were obtained. Formulations were electrosprayed through both single and novel MTEs under EHDA conditions at various flow rates (5-300 µl/min) and applied voltages (0-30 kV). The atomization process using MTEs and single nozzle was monitored at using various process parameters via a digital optical camera. Resulting particles were collected 200 mm below processing heads and were analyzed using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray diffraction (XRD) and scanning electron microscopy (SEM). Digital recordings confirmed stable MTE jetting at higher flow rates. Electron micrographs confirmed particle size variation arising due to nozzle head design and evidenced stable jetting derived greater near-uniform particles. DSC, XRD and TGA confirm KETO molecules were encapsulated and dispersed into PVP polymer particles. In conclusion, novel MTE devices enabled stable atomization even at higher flow rates when compared to conventional single-needle device. This indicates an exciting approach for scaling up (EHDA) in contrast to current efforts focusing on multiple-nozzle and pore-based processing outlets.

Facile Preparation of Drug-Loaded Tristearin Encapsulated Superparamagnetic Iron Oxide Nanoparticles Using Coaxial Electrospray Processing.

Naturally occurring polymers are promising biocompatible materials that have many applications for emerging therapies, drug delivery systems, and diagnostic agents. The handling and processing of such materials still constitutes a major challenge, which can limit the full exploitation of their properties. This study explores an ambient environment processing technique: coaxial electrospray (CO-ES) to encapsulate genistein (an isoflavonoid and model drug), superparamagnetic iron oxide nanoparticles (SPIONs, 10-15 nm), and a fluorophore (BODIPY) into a layered (triglyceride tristearin shell) particulate system, with a view to constructing a theranostic agent. Mode mapping of CO-ES led to an optimized atomization engineering window for stable jetting, leading to encapsulation of SPIONs within particles of diameter 0.65-1.2 µm and drug encapsulation efficiencies of around 92%. Electron microscopy was used to image the encapsulated SPIONs and confirm core-shell triglyceride encapsulation in addition to further physicochemical characterization (AFM, FTIR, DSC, and TGA). Cell viability assays (MTT, HeLa cells) were used to determine optimal SPION loaded particles (∼1 mg/mL), while in vitro release profile experiments (PBS, pH = 7.4) demonstrate a triphasic release profile. Further cell studies confirmed cell uptake and internalization at selected time points (t = 1, 2, and 4 h). The results suggest potential for using the CO-ES technique as an efficient way to encapsulate SPIONs together with sensitive drugs for the development of multimodal particles that have potential application for combined imaging and therapy.

Development and characterisation of cellulose based electrospun mats for buccal delivery of non-steroidal anti-inflammatory drug (NSAID).

In this study conventional electrospinning (ESp) was used to prepare a series of buccal films containing indomethacin (INDO, a nonsteroidal anti-inflammatory drug), Ethocel (10), hydroxypropylmethylcellulose (HPMC) and Tween® 80 at various concentrations. The films were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM), fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Drug release behaviour was assessed in vitro (buffer pH6.8). SEM revealed film morphology and mean fibre diameter was dependent on the process formulation. INDO was encapsulated in the amorphous state once electrospun as evidenced from DSC and XRD studies. The presence of other excipients within fibrous matrices was confirmed using FTIR and Raman spectroscopy. Loading and release of INDO from filamentous structures was influenced by formulation composition; indicating potential to 'fine-tune' dosage forms. Given that ESp is a one-step preparation method and operational at ambient conditions; an attractive route for engineering tailored film type dosage forms is presented. This is a valuable approach for optimizing dosage forms as needed in a single step for various age groups.

Pharmaceutical and biomaterial engineering via electrohydrodynamic atomization technologies.

Complex micro- and nano-structures enable crucial developments in the healthcare remit (e.g., pharmaceutical and biomaterial sciences). In recent times, several technologies have been developed and explored to address key healthcare challenges (e.g., advanced chemotherapy, biomedical diagnostics and tissue regeneration). Electrohydrodynamic atomization (EHDA) technologies are rapidly emerging as promising candidates to address these issues. The fundamental principle driving EHDA engineering relates to the action of an electric force (field) on flowing conducting medium (formulation) giving rise to a stable Taylor cone. Through careful optimization of process parameters, material properties and selection, nozzle and needle design, and collection substrate method, complex active micro- and nano-structures are engineered. This short review focuses on key selected recent and established advances in the field of pharmaceutical and biomaterial applications.

Formulation and evaluation of anti-rheumatic dexibuprofen transdermal patches: a quality-by-design approach.

Dexibuprofen (DXIBN) transdermal patches were formulated using various concentrations of selected polymeric excipients (matrix material; ethyl cellulose and polyvinylpyrrolidone, plasticizer (di-N-butyl phthalate), and a conventional permeation enhancer (almond oil)). Initial patch formulations were evaluated for their physiochemical properties (thickness, moisture uptake, final moisture content, and DXIBN content). Also, impact of patch components on resulting tensile strength and in vitro permeation were used to predict an optimal patch formulation using a quality-by-design (QbD) approach, which was subsequently evaluated and further compared with a commercial oral tablet dosage form for in vitro and in vivo release (rabbit model). Initially formulated patches demonstrated uniform thickness (0.44 ± 0.02 cm), relatively low moisture uptake (7.87 ± 1.11 w/w %), and highly acceptable drug loading values (100.0 ± 0.026%). The tensile strength of patches increased significantly with matrix polymer concentration and to a lesser degree with increase in plasticizer and permeation enhancer content, although these affected the permeation of DXIBN. Predicted properties (tensile strength and DXIBN steady-state flux) for the QbD-optimized formulation were in close agreement to experimental results. The QbD optimal patch formulation behavior differed significantly from the commercial tablet formulation in vivo. Such model-based predictions (QbD approach) will reduce cost and time in formulation development sciences.

Microneedle Coating Techniques for Transdermal Drug Delivery.

Drug administration via the transdermal route is an evolving field that provides an alternative to oral and parenteral routes of therapy. Several microneedle (MN) based approaches have been developed. Among these, coated MNs (typically where drug is deposited on MN tips) are a minimally invasive method to deliver drugs and vaccines through the skin. In this review, we describe several processes to coat MNs. These include dip coating, gas jet drying, spray coating, electrohydrodynamic atomisation (EHDA) based processes and piezoelectric inkjet printing. Examples of process mechanisms, conditions and tested formulations are provided. As these processes are independent techniques, modifications to facilitate MN coatings are elucidated. In summary, the outcomes and potential value for each technique provides opportunities to overcome formulation or dosage form limitations. While there are significant developments in solid degradable MNs, coated MNs (through the various techniques described) have potential to be utilized in personalized drug delivery via controlled deposition onto MN templates.

Hollow-layered nanoparticles for therapeutic delivery of peptide prepared using electrospraying.

The viability of single and coaxial electrospray techniques to encapsulate model peptide-angiotensin II into near mono-dispersed spherical, nanocarriers comprising N-octyl-O-sulphate chitosan and tristearin, respectively, was explored. The stability of peptide under controlled electric fields (during particle generation) was evaluated. Resulting nanocarriers were analysed using dynamic light scattering and electron microscopy. Cell toxicity assays were used to determine optimal peptide loading concentration (~1 mg/ml). A trout model was used to assess particle behaviour in vivo. A processing limit of 20 kV was determined. A range of electrosprayed nanoparticles were formed (between 100 and 300 nm) and these demonstrated encapsulation efficiencies of ~92 ± 1.8%. For the single needle process, particles were in matrix form and for the coaxial format particles demonstrated a clear core-shell encapsulation of peptide. The outcomes of in vitro experiments demonstrated triphasic activity. This included an initial slow activity period, followed by a rapid and finally a conventional diffusive phase. This was in contrast to results from in vivo cardiovascular activity in the trout model. The results are indicative of the substantial potential for single/coaxial electrospray techniques. The results also clearly indicate the need to investigate both in vitro and in vivo models for emerging drug delivery systems.

EHDA Spraying: A Multi-Material Nano-Engineering Route.

Electrohydrodynamic atomization (EHDA) enabling platform technologies have gathered significant momentum over the last two decades. Utilisation of the underpinning jetting process in tandem with desired materials (including polymers, ceramics, metals and even naturally occurring compounds such as peptides, DNA and cells) provides the basis for novel engineered therapies. Through EHDA processes, the generation of a variety of nano-meter and micro-meter scaled structures with control on surface and encapsulation features is attainable in a single step. While a host of adaptable EHDA techniques have evolved (e.g. printing and template patterning), there are two main processes that continue to dominate: electrospraying (ESy) and electrospinning (ESp). Although ESp has drawn considerable researcher interest for nanofibre applications, ESy is an important and timely process for nano- and micro-particle fabrication. Thus, an appropriate evaluation of ESy is vital. This short review focuses on key developments in the ESy field in relation to nanotechnologies with potential healthcare applications using metals, polymers and ceramics. An insight into the process of particle formation (during EHDA spraying or ESy), process parameters and materials specifications, is provided. Emerging biomedical and other healthcare research through nanotechnologies are highlighted.

Electrospun PVP-indomethacin constituents for transdermal dressings and drug delivery devices.

A method in layering dressings with a superficial active layer of sub-micrometer scaled fibrous structures is demonstrated. For this, polyvinylpyrolidone (PVP)-indomethacin (INDO) fibres (5% w/v PVP, 5% w/w indomethacin, using a 50:50 ethanol-methanol solvent system) were produced at different flow rates (50 µL/min and 100 µL/min) via a modified electrospinning device head (applied voltage varied between 15 ± 2 kV). We further assessed these structures for their morphological, physical and chemical properties using SEM, AFM, DSC, XRD, FTIR and HPLC-UV. The average diameter of the resulting 3D (ca. 500 nm in height) PVP-INDO fibres produced at 50 µL/min flow rate was 2.58 ± 0.30 µm, while an almost two-fold increase in the diameter was observed (5.22 ± 0.83 µm) when the flow rate was doubled. However, both of these diameters were appreciably smaller than the existing dressing fibres (ca. 30 µm), which were visible even when layered with the active spun fibres. Indomethacin was incorporated in the amorphous state. The encapsulation efficiency was 75% w/w, with complete drug release in 45 min. The advantages are the ease of fabrication and deposition onto any existing normal or functionalised dressing (retaining the original fabric functionality), elimination of topical product issues (application, storage and transport), rapid release of active and controlled loading of drug content (fibre layer).

Spatial and temporal evaluation of cell attachment to printed polycaprolactone microfibres.

Surface topography plays a crucial role in influencing cellular responses and has therefore been utilized in the development of numerous implantable devices. Whilst numerous studies have either investigated cell attachment or migration post-attachment, few have looked at the early-stages of this process temporally. The aim of this study was to evaluate the use of time-lapse microscopy to study the behaviour of fibroblasts cultured with polycaprolactone microfibres and to assess spatially and temporally the cell-structure interaction over a 24h period. Ordered polymeric structures were printed (predetermined) onto glass substrates using an electrohydrodynamic direct write process to produce fine (3-5 µm wide) structures. Fibroblast attachment and migration were characterized as a function of distance perpendicular from structures (∼17.3, 34.6 and 51.9 µm). The use of time-lapse microscopy revealed a gradual decrease in cell attachment as the distance from the microfibres was increased. The technique also revealed that some cells were attaching and detaching from the microfibre multiple times. Our findings demonstrate that time-lapse microscopy is a useful technique for evaluating early-stage cell-biomaterial interaction that is capable of recording important events that might otherwise be overlooked.