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.

Simvastatin (SV), a drug of the statin class currently used orally as anti- cholesterolemic, has been found not only to reduce cholesterol but also to have several other pharmacological actions that might be beneficial in airway inflammatory diseases. Currently, there is no inhalable formulation that could deliver SV to the lung. In this study a pressurised metered dose inhaler (pMDI) solution formulation of SV was manufactured, with ethanol as co-solvent, and its aerosol performance and physio- chemical properties investigated. A pMDI solution formulation containing SV and 6 %w/w ethanol was prepared. This formulation was assessed visually for SV solubility. Furthermore, the aerosols performance (using Andersen Cascade impactor at 28.3L/min) and active ingredient chemical stability up to 6 months at different storage temperatures, 4 and 25°C, was also evaluated. The physico-chemical properties of the SV solution pMDI were also characterised by differential scanning calorimetry (DSC), thermogravimetric analyses (TGA) and laser diffraction. The aerosol particles, determined using Scanning Electron Microscopy (SEM), presented smooth surface morphology and were spherical in shape. The aerosol produced had a fine particle fraction of 30.77 ± 2.44 % and a particle size distribution suitable for inhalation drug delivery. Furthermore, the short-term chemical stability showed the formulation to be stable at 4°C for up to 6 months while at 25°C, the formulation was stable up to 3 months. In this study a respirable and stable SV solution pMDI formulation for inhalation has been presented that could potentially used clinically as anti-inflammatory therapeutic for the treatment of several lung diseases.

A series of co-engineered macrolide-mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonisation, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital™ inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200 mg of 50:50 w/w AZ:mannitol had a 57.6% ± 7.6%  delivery efficiency with the fine particle fraction (≤ 6.8 µm)  of the emitted aerosol cloud being 80.4% ± 1.1%, with minimal throat deposition (5.3 ±0.9%) Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide-mannitol therapy may provide a means of treating bronchiectasis.

Recent murine studies found that rifapentine, dosed daily, at least halved tuberculosis treatment times compared to standard rifampicin and isoniazid-containing regimens. However, in humans, an inhalable form of rifapentine may be necessary to considerably shorten treatment duration due to physiological barriers associated with oral therapy. The current study compares two inhalable rifapentine dry powders – a novel pure crystalline form and an amorphous form – by a series of in vitro tests. The crystalline and amorphous powders had a mass median aerodynamic size of 1.68 ± 0.03 and 1.92 ± 0.01 µm, respectively, associated with a fine particle fraction of 83.2 ± 1.2 and 68.8 ± 2.1%, respectively. A quinone degradation product was identified in the amorphous powder stored for 1 month whilst the crystalline form remained chemically stable after storage at both 0% and 60% RH, 25 ᵒC, for at least 3 months. Rifapentine was well-tolerated by pulmonary tissue and macrophage cells up to approximately 50 µM. The accumulation of rifapentine within alveolar macrophage cells was significantly higher than for rifampicin, indicating enhanced delivery to infected macrophages. The novel inhalable crystalline form of rifapentine is suitable for targeted treatment of tuberculosis infection and may radically shorten treatment duration.

This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, while mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray dried samples, containing therapeutically relevant doses of SS and MA were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally the formulations were evaluated for their effects on cell viability and transport across an air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distribution and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10-6 and MA 10-3 M gave a significant increase in cilia beat frequency, while simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and ability to increase the ciliary beat frequency for improving the mucociliary clearance in patients suffering form hyper secretory diseases, whilst simultaneously acting on the underlying smooth muscle.

Purpose: The purpose of this study was to present a modified Andersen cascade impactor (ACI) as a platform to evaluate the deposition and subsequent transport of aerosol micropaticles across airway epithelial cells.
Methods: The impaction plate of an ACI was modified to accommodate up to eight Snapwells. Aerodynamic particle size distribution of the modified ACI was investigated with two commercially available formulations of Ventolin® (salbutamol sulphate) and QVAR® (beclomethasone dipropionate). Deposition and transport of these drug micropaticles across sub-bronchial epithelial Calu-3 cells were also studied.
Results: The modified ACI demonstrated reproducible deposition patterns of the commercially available pressurised metered dose inhalers compared to the standard ACI. Furthermore, the Calu-3 cells could be placed in different stages of the modified ACI. No significant effect was observed among the transport rate of different particle sizes deposited on Calu-3 cells within the range of 3.3 to 0.4 μm.
Conclusions:
The use of the cell compatible ACI to assess the fate of microparticles after deposition on the respiratory epithelia may allow for better understanding of deposited microparticles in vivo

Introduction: Tuberculosis remains rampant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of tuberculosis. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active tuberculosis infection. However, these results were not replicated in a subsequent human clinical trial.

Areas covered: This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Potential options for developing an inhalable form of rifapentine are also presented.

Expert opinion: Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of tuberculosis if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. Whilst the ultimate goal for global tuberculosis control is a vaccine, a short and effective treatment option is equally crucial.

The production of high quality graphical figures of scientific data is an important aspect of medical writing, since the significance of research findings can be lost to the audience if data is presented poorly or inaccurately. This review highlights the various requirements that a writer may encounter when preparing data in a graphical format for presentation and gives an overview of 15 graphing software packages that are available on a number of platforms.

The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurised metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried samples of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.