This review focuses on the development of micro- and nanotechnology-based drug delivery systems to target alveolar macrophages in association with intracellular infections, cancer and lung inflammation. Aspects of nanoparticle and micron-sized particle engineering through exploitation of particles’ physicochemical characteristics such as particle size, surface charge and geometry of particles will be discussed in this review. In addition, the application of nano carriers such as liposomes, polymeric nanoparticles and dendrimers will be included with respect to macrophage targeting.

The current study presents a new approach to tackle high dose lung delivery using a prototype multi-breath Orbital® DPI. One of the key device components is the ‘puck’ (aerosol sample chamber) with precision-engineered outlet orifice(s) that control the dosing rate. The influence of puck orifice geometry and hole number on the performance of mannitol aerosols were studied. Pucks with different orifice configurations were filled with 400 mg of spray-dried mannitol and tested in the Orbital® DPI prototype. The emitted dose and overall aerodynamic performance across a number of ‘breaths’ were studied using a MSLI. The aerosol performances of the individual actuations were investigated using in-line laser diffraction. The emptying rate of all pucks were linear between 20-80% cumulative drug released (R2 > 0.98) and the amount of formulation released per breath could be controlled such that the device was empty after 2 to 11 breath maneuvers. The puck-emptying rate linearly related to the orifice hole length (R2 > 0.95). Mass median aerodynamic diameters of the emitted aerosol ranged from 4.03 to 4.62 µm and FPF (≤ 6.4 µm) were 50-66%. Laser-diffraction suggested that the aerosol performance and emptying rates were not dependent on breath number, showing consistent size distribution profiles.

Background: Correct inhaler technique is vital in the management of asthma and chronic obstructive pulmonary disease. However inhaler misuse is ubiquitous, and patients seldom receive effective education on how to use inhalers. Prisoners may have additional contributing factors for inhaler misuse i.e. low health literacy and intellectual disability. Consequently health professionals within correctional service facilities have a unique opportunity, and arguably an even more critical role, in training of inmates in inhaler use.
Aim: To evaluate correctional services health professionals’ baseline inhaler techniques; to assess the impact of training on inhaler techniques; and to evaluate the impact of the training on service delivery to inmates.
Method: Nurses, working in a correctional services hospital complex were recruited. Their baseline inhaler technique (i.e. prior to training) was assessed, using inhaler technique checklists. An education intervention was then delivered, following which participants’ inhaler technique was reassessed.
Results: A total of 23 nurses participated in the study. At baseline, proportions demonstrating correct technique were 42%, 0% and 5% for metered dose inhalers, Turbuhaler and Accuhaler respectively. Following training, there was a statistically significant increase in proportion of participants demonstrating correct inhaler techniques [84% (p=0.008), 84% (p=0.000) and 90% (p=0.000)].
Conclusion: Nurses in correctional care are expected to check inmates’ inhaler technique as part of clinical care, but were unable to use inhalers correctly, and need training in this regard. Pharmacists are well placed to provide this training. 

Purpose:  This study investigated the effect of different active pharmaceutical ingredients (API) on aerosol electrostatic charges and aerosol performances for pressurised metered dose inhalers (pMDIs) using both insulating and conducting actuators.

Methods : Five solution-based pMDIs containing different API ingredients include beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FS), salbutamol base (SB) and ipratropium bromide (IPBr) were prepared using pressure filled technique. Actuator blocks made from nylon, polytetrafluoroethylene (PTFE) and aluminum were manufactured with 0.3 mm nominal orifice diameter and cone nozzle shape. Aerosol electrostatics for each pMDI formulation and actuator were evaluated using electrical low-pressure impactor (ELPI) and the drug depositions were analysed using high performance liquid chromatography (HPLC).

Results : All three actuator materials showed the same net charge trend across the five active drug ingredients, with BDP, BUD and FS showing positive net charges ranging from 134.78 ± 127.29 pC to 332.74 ± 86.74 pC for both nylon and PTFE actuators. While SB and IPBr having significantly negative net charges across all three different actuators, which correlates to the ionic functional groups presented in the drug molecule structures.

Conclusions:  The API present in a pMDI has a dominant effect on the electrostatic properties of the formulation, overcoming the charge effect arising from the actuator materials. The results have shown that the electrostatic charges for a solution-based pMDI could be related to the interactions of the chemical ingredients and change in the work function for the overall formulation.

The impact of a polyunsaturated fatty acid, arachidonic acid (AA), on membrane fluidity of epithelial cells and subsequent modulation of the drug transport was investigated. Membrane fluidity was assessed using molecular force microscopy. Calu-3 human bronchial epithelial cells were cultured on Transwell® inserts and the cell stiffness was assessed in the absence of fatty acids or in the presence of 30-μM AA. The morphology of the epithelial cells was distinctly different when AA was present, with the cell monolayer becoming more uniform. Furthermore the cell stiffness and variation in stiffness was lower in the presence of AA. In the fat-free medium, the median cell stiffness was 9.1kPa which dropped to 2.1kPa following exposure to AA. To further study this, transport of a common b2-agonist, salbutamol sulphate (SS) was measured in the presence of AA and in a fat free medium. The transport of SS was significantly higher when AA was present (0.61±0.09μg versus 0.11±0.003μg with and without AA respectively). It was evidenced that AA play a vital role in cell membrane fluidity and drug transport. This finding highlights the significance of the dietary fatty acids in transport and consequentially effectiveness of medications used to treat pulmonary diseases such as asthma.

Ventilator-associated pneumonia (VAP) remains a major burden to the healthcare system and intubated patients in intensive care units (ICU). In fact, VAP is responsible for at least 50% of prescribed antibiotics to patients who need mechanical ventilation. One of the factors contributing to VAP pathogenesis is believed to be rapid colonization of biofilm-forming pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus on the surface of inserted endotracheal tubes. These biofilms serve as a protective environment for bacterial colonies and provide enhanced resistance towards many antibiotics. This review presents and discusses an overview of current strategies to inhibit the colonization and formation of biofilm on endotracheal tubes, including antibiotic treatment, surface modification and antimicrobial agent incorporation onto endotracheal tube materials.

Purpose: The aim of this study was to assess the effects of low-dose clarithromycin, formulated as pressurised metered dose inhaler, following deposition on the Calu-3 respiratory epithelial cells.

Methods: Clarithromycin was deposited on the air-interface culture of Calu-3 cells using a modified Andersen cascade impactor. Transport of fluorescein-Na, production of mucus and interleukin-8 release from Calu-3 cells following stimulation with transforming growth factor-β and treatment with clarithromycin was investigated.

Results: The deposition of clarithromycin had significant effect on the permeability of fluorescein-Na, suggesting that the barrier integrity was improved following a short-term treatment with clarithromycin (apparent permeability values were reduced to 3.57×10-9 ± 2.32×10-9 cm.s-1, compared to 1.14×10-8 ± 4.30×10-8 cm.s-1 for control). Furthermore, the amount of mucus produced was significantly reduced during the course of clarithromycin treatment. The concentration of interleukin-8 secreted from Calu-3 cells following stimulation with transforming growth factor-β resulted in significantly lower level of interleukin-8 released from the cells pre-treated with clarithromycin (5.2 ± 0.5 ng.ml-1 clarithromycin treated vs. 7.7 ± 0.8 ng.ml-1 control, respectively).

Conclusions: Our data demonstrate that treatment with clarithromycin decreases the paracellular permeability of epithelial cells, mucus secretion and interleukin-8 release and therefore, inhaled clarithromycin holds potential as an anti-inflammatory therapy.

In mouse models of tuberculosis infection, oral rifapentine-based regimens have demonstrated superior efficacy compared to current treatment options. However, these results were not replicated in recent human clinical trials due to limited rifapentine access into pulmonary granulomas. A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations to rapidly treat infection. The pharmacokinetics of rifapentine in healthy mice was compared after intratracheal (IT) and intraperitoneal (IP) administration. Female BALB/c mice received rifapentine by IT or IP administration (20 mg/kg). Plasma, bronchoalveolar lavage (BAL) and tissue samples were harvested at each pre-specified time-point up to 24 hours and quantified. Concentration-time data were analysed using a mixed effects modelling approach to provide model-based estimates of area under the curve from time 0 to infinity (AUC0-∞). Whilst rifapentine was not detected in the BAL of mice dosed IP, IT delivery resulted in a maximum BAL fluid rifapentine concentration (25.2 ± 6.4 µg/mL) and an AUC0-∞ of 204.1 ± 67.8 mg/L.h. Between IT and IP delivery, the former had a considerably higher peak rifapentine lung concentration (321.3 ± 99.3 and 3.3 ± 1.2 µg/g, respectively) and AUC0-∞ (2614.4 ± 928.1 and 72.7 ± 24.9 mg/kg.h, respectively). The plasma AUC0-∞ after IT dry powder delivery (455.1 ± 132.4 mg/L.h) was approximately 4-fold smaller than the IP value (2010.1 ± 589.0 mg/L.h). Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity.

Solid lipid particles have been introduced since the early 1990s as an alternative drug carrier system to emulsions, liposomes and polymeric microparticles. This review presents an overview of the advantages and drawbacks of lipid particles, focusing on lipid microparticles (LMs), i.e. particles with dimensions in the micrometer range. Specific focus is on the role of the main excipients used for LMs formulations, lipids and surfactants, and their effect on LM properties. Furthermore, an update on preparation techniques and characterization methods are also presented. The interaction of LMs with biological systems will be also reviewed together with administration routes,with particular attention to most recent applications.

Purpose: To investigate the influence of different actuator nozzle designs on aerosol electrostatic charges and aerosol performances for pressurised metered dose inhalers (pMDIs).
Methods: Four actuator nozzle designs (flat, curved flat, cone and curved cone) were manufactured using insulating thermoplastics (PET and PTFE) and conducting metal (aluminium) materials. Aerosol electrostatic profiles of solution pMDI formulations containing propellant HFA 134a with different ethanol concentration and/or model drug beclomethasone dipropionate (BDP) were studied using a modified electrical low-pressure impactor (ELPI) for all actuator designs and materials. The mass of the deposited drug was analysed using high performance liquid chromatography (HPLC).
Results: Both curved nozzle designs for insulating PET and PTFE actuators significantly influenced aerosol electrostatics and aerosol performance compared to conducting aluminium actuator, where reversed charge polarity and higher throat deposition were observed with pMDI formulation containing BDP. Results are likely due to the changes in plume geometry caused by the curved edge nozzle designs and the bipolar charging nature of insulating materials.
Conclusions: This study demonstrated that actuator nozzle designs could significantly influence the electrostatic charges profiles and aerosol drug deposition pattern of pMDI aerosols, especially when using insulating thermoplastic materials where bipolar charging is more dominant.

Objectives: This study focuses on the development of an inhaled dry powder (DPI) formulation of simvastatin (SV), a common anti-cholesterol prodrug, which could potentially be used for its anti-inflammatory effects and its ability to reduce mucus production as therapy for respiratory diseases. Methods: Micronized SV samples were prepared by dry jet-milling. The long-term chemical stability and physico-chemical properties of the formulations were characterised in terms of particles size, morphology, thermal and moisture responses. Furthermore, in vitro aerosol depositions were performed. The formulation was evaluated for cell viability and its effect on cilia beat activity, using ciliated nasal epithelial cells in vitro. The formulation transport across an established air interface Calu-3 bronchial epithelial cells and its ability to reduce mucus secretion was also investigated. Results: The particle size of the SV formulation and its aerosol performance were appropriate for inhalation therapy. Moreover, the formulation was found to be non-toxic to pulmonary epithelia cells and cilia beat activity up to a concentration of 10-6 M. Transport studies revealed that SV has the ability to penetrate into airway epithelial cells and is converted into its active SVA metabolite. Single dose of SV DPI also decreased mucus production after 4 days of dosing. Conclusion: This therapy could potentially be used for the local treatment of diseases like chronic obstructive pulmonary disease or cystic fibrosis, where hyper mucus production and inflammation is present.

There are a multitude of formulation factors to consider when developing a solution-based pressurized metered dose inhaler (pMDI). Evaluation of these variables and their underpinning driving force has been performed over the years. Key components, including formulation composition and device design, play significant roles in determining the aerosol performance of these solution-based formulations. This review outlines research efforts that have focused on these essential governing factors, how the aerosol performance changes when these variables are modified and fundamental mechanisms affecting the delivery efficiency of such formulations.

Background: Respiratory disease is common in people with intellectual disability (ID). The inhaled route is preferred for medication administration in treating respiratory diseases including asthma. Cognitive, physical and sensory impairments of people with ID often necessitate assistance with medication taking; in supported accommodation this is provided by direct support professionals (DSPs). Method: A qualitative study design was used to explore DSPs experiences with asthma medication management. Data were collected via in-depth, semi-structured, face-to-face or telephone interviews. Results: Key findings included the complex balance of duties undertaken by DSPs, and a lack of consistency in asthma management processes across sites. Conclusions: This exploratory research suggests that DSPs are involved in asthma management and required to use clinical judgement, but are not provided with education and tools to manage asthma in, and foster correct inhaler use by, their clients. This highlights the need for tailored guidelines that integrate with NDIS principles. 

Previous studies have suggested that particle-particle impaction may influence aerosolisation properties in carrier-based dry powder inhalers, through transfer of kinetic energy from large carriers to surface-deposited active drug. The importance of particle-particle collision has yet to be compared against other mechanisms that could lead to drug liberation, such as particle-wall impaction and turbulence. In particular, particle-particle collisions are difficult to model in silico due to computational restrictions. This study investigated the effects of dry powder inhaler particle-particle collisions in vitro using an established carrier-drug model dry powder inhalation formulation. Spherical polystyrene beads of median size 82.80 µm were chosen as a model carrier as they were of uniform size, shape, surface area, density, porosity and hardness and thus eliminated potential variables that would have conflicted with the study. This model carrier was geometrically blended with micronised salbutamol sulphate (loaded blend). The correlation between the mass of loaded blend (5–40 mg) in the Rotahaler® DPI device and resulting fine particle fraction (FPF) was examined at a constant flow rate of 60 L.min-1. In a second experiment, the mass of loaded blend was kept constant and a variable amount of blank carrier particles were added to the Rotahaler® device to ascertain if additional “blank” carrier particles affected the final FPF. The efficiency of aerosolisation remained constant with varying amounts of blank carrier particles as determined by the fine particle fraction of the emitted dose (FPF-ED) and fine particle fraction of the loaded dose (FPF-LD). No statistical difference in FPF-ED and FPF-LD values were observed for increasing masses of blank carrier. In addition, no statistical difference in FPF-ED and FPF-LD between the two experiments was obtained. These observations suggest that particle-particle collisions are not a driving mechanism responsible for de-aggregation of drug from carrier-based systems.

Introduction: Natural compounds are emerging as effective agents for the treatment of malignant diseases. Curcumin (diferuloylmethane), the active constituent of turmeric extract, has gained significant interest as a plant-based compound with anti-cancer properties. Curcumin is physiologically very well tolerated, with negligible systemic toxicity observed even after high oral doses administration. Despite curcumin’s superior properties as an anti-cancer agent its applications are limited due to its low solubility and physico-chemical stability, rapid systemic clearance and low cellular uptake. 
Areas covered: This review focuses on the development of curcumin nano-particle formulation to improve its therapeutic index through enhanced cellular uptake, localization to targeted areas and improved bioavailability. The feasibility of nano-formulation in delivering curcumin and the limitations and challenges in designing and administrating the nano-sized curcumin particles are also covered in this review.  
Expert opinion: Nanotechnology is a promising tool to enhance efficacy and delivery of drugs. In this context, formulation of curcumin as of nano-sized particles could reduce the required therapeutic dosages and subsequently reduced its cell toxicity. These nanoparticles are capable to provide local delivery of curcumin targeted to specific areas and thereby preventing systemic clearance. In addition, using specific coating, better pharmacokinetic and internalization of nano-curcumin could be achieved. However, the potential toxicity of nano-carriers for curcumin delivery is an important issue, which should be taken into account in curcumin nano-formulation.

Biologics have become an increasingly important but also expensive part of the global medicinal cabinet. Generics of this class of drug, termed biosimilars, can relieve the financial burden on healthcare systems and improve patient accessibility. This mini-review covers the evolving international regulatory legislation for biosimilars, challenges for biosimilar development and expected developments. 

Crystalline Salbutamol sulphate (SS) is a common β2-agonist used in dry powder inhalers for the treatment of asthma. The solid-state characteristics of SS are import since they govern the stability and thus efficacy of the drug when incorporated into an inhalation medicine. Previous studies have investigated the thermal properties of SS and the complex array of thermal events have been attributed a mixture of melting and/or degradation mechanisms. In order to ascertain the exact thermal transformation processes that SS undergoes we utilised a combination of differential scanning calorimetry coupled with quadrupole mass spectrometry and thermogravimetric analysis coupled with Fourier transform infrared spectroscopy over the temperature range 25–500 °C. Based on the coupled thermal analysis data we proposed that SS undergoes a multi-step degradation mechanism in which the molecule dehydrates loosing water initially, followed by the break up of the secondary amine group and lastly formation of sulphur dioxide. When used in conjunction, the analytical techniques offered significant advantages over the use of thermal analysis alone, offering a better understanding of the transformations occurring to SS following heating.

Endotracheal intubation is commonly associated with hospital-acquired infections as the intubation device acts as reservoir for bacterial colonization in lungs. To reduce the incidence of bacterial colonization on the tubes, hydrogel coatings loaded with antimicrobial agents are gaining popularity. The aim of this study is to incorporate silver nanoparticles (AgNPs) into polyvinyl alcohol (PVA) to form stable hydrogels. Embedding AgNPs into PVA resulted in a decreased elongation at break and an increased tensile strength compared to PVA alone. Ag release profile varied as a function of the degree of hydrolysis of PVA: the higher degree of hydrolysis demonstrated a lower release rate. Fourier infrared transform spectroscopy demonstrated that AgNPs interacted exclusively with the –OH groups of PVA. AgNPs loaded PVA were non-toxic against human normal bronchial epithelial cells while effective against the attachment of Pseudomonas aeruginosa and Staphylococcus aureus with a greater effect on P. aeruginosa.

During the process of inhalable formulation drug development a deep knowledge of the physicochemical characteristics of the drug and formulation components and their relationship with the biological properties of the airways is necessary. 
For example, the solubility and lipophilicity of a drug may affect therapeutic efficacy by changing the residence time of the inhaled microparticles at the airways surface. Furthermore, the properties of aerosol drug particles, such as shape, size and density, as well as the diseases of the respiratory tract, delivery device and inhalation manoeuvre will have an impact on where these microparticles are deposited.

The airway epithelium is involved in the pathogenesis and treatment of several respiratory diseases. Epithelial cells are directly exposed to the environment and respond to xenobiotics such as medical therapies. In some cases the epithelial cells are the site of action for drug molecules or the drug molecules might need to be transported across the epithelium to arrive at the site of action (β2-agonists are transported across the epithelium to target underlying smooth muscle cells). The drug particles, which are deposited on the respiratory epithelia, have to interact with the mucus lining, dissolve and get transported through this layer. Despite advances in in vitro testing of respiratory epithelial permeability, there is little known about how and where drugs are absorbed at a cellular level and how long they reside in the lung. Therefore, pulmonary permeability assessment of drug particles, and the influence of formulation parameters on drug uptake at the epithelia, may provide insights that will allow formulations to be developed with optimised therapeutic outcomes.
This review focuses on the integration of these physicochemical characteristics with the biological factors to provide a better understanding of the fate of drug microparticles after deposition on the epithelial cells

Abstract - Purpose: Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient’s inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing.
Methods: Glycerol-containing and glycerol-free pMDI formulations with matched mass median aerodynamic diameters are investigated. High-speed schlieren imag- ing is used to extract time-resolved velocity, penetration and spreading angle mea- surements of the pMDI spray plume. The experimental data are used to validate the analytical model.
Results: The pMDI spray develops in a manner characteristic of a fully- developed steady turbulent jet, supporting the hypothesis. Equivalent glycerol- containing and non glycerol-containing formulations exhibit similar non-dimensional growth rates and follow a self-similar scaling behaviour over a range of physiolog- ically relevant co-flow rates.