Personalizing aerosol medicine: development of delivery systems tailored to the individual.

Inhalation of drugs for therapeutic effects is not a recent innovation as illicit drugs have been 'smoked' for millennia. Nicotine delivery 'devices' in convenient packaged cartons of cigarettes are simple to use, inexpensive per dose and accessible to people of most ages and lung function, but of course their use leads to increased cancer, emphysema, heart disease and other medical and societal problems. In contrast, many inhalation pharmaceutical medical devices are expensive, nonportable, inconvenient, and/or are used improperly thus leading to poor therapeutic benefit.

Method to introduce mannitol powder to intubated patients to improve sputum clearance.

Background: Poor sputum clearance is a common problem encountered in intubated patients, which may cause airway obstruction, hypoxaemia, and increased risk of lower respiratory tract infection. This may result in longer intensive care unit (ICU) stay or even death. Dry powder mannitol has been shown to improve sputum clearance, and thus we developed a system to deliver it to intubated patients.

Nano spray drying: a novel method for preparing protein nanoparticles for protein therapy.

There has been an increasing interest in the development of protein nanotherapeutics for diseases such as cancer, diabetes and asthma. Spray drying with prior micro mixing is commonly used to obtain these powders. However, the separation and collection of protein nanoparticles with conventional spray dryer setups has been known to be extremely challenging due to its typical low collection efficiency for fine particles less than 2μm.

Impact angles as an alternative way to improve aerosolisation of powders for inhalation?

This study aims to investigate the role of impact angles on the de-agglomeration performance of powders for inhalation. Agglomerates of a model drug mannitol were impacted at customized impaction throats containing two angles (15-75 degrees and 45-45 degrees) or a single angle (15 degrees, 45 degrees and 90 degrees) using various air flow rates. The mass fraction of fine particles <5microm in the aerosol (FPF(Loaded)) was measured by a liquid impinger coupled to a laser diffractometer.

Electrostatic charge characteristics of jet nebulized aerosols.

Background: Liquid droplets can be spontaneously charged in the absence of applied electric fields by spraying. It has been shown by computational simulation that charges may influence particle deposition in the airways. The electrostatic properties of jet nebulized aerosols and their potential effects on lung deposition have hardly been studied.

Particle aerosolisation and break-up in dry powder inhalers 1: evaluation and modelling of venturi effects for agglomerated systems.

Purpose: This study utilized a combination of computational fluid dynamics (CFD) and standardized entrainment tubes to investigate the influence of turbulence on the break-up and aerosol performance of a model inhalation formulation.

Methods: Agglomerates (642.8 mum mean diameter) containing 3.

Co-spray-dried mannitol-ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease.

The aim of this study was to assess the potential of delivering a combination therapy, containing mannitol (a sugar alcohol with osmotic characteristics), and ciprofloxacin hydrochloride (an antibacterial fluoroquinolone), as a dry powder inhaler (DPI) formulation for inhalation. Single and combination powders were produced by spray drying ciprofloxacin and mannitol, from aqueous solution, at different ratios and under controlled conditions, as to obtain similar particle size distributions. Each formulation was characterised using laser diffraction, scanning electron microscopy, differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and colloidal force microscopy.

The contribution of different formulation components on the aerosol charge in carrier-based dry powder inhaler systems.

Purpose: To measure aerosol performance of a lactose carrier/salbutamol sulphate powder blend and identify contributions of non-formulation and formulation components on the resulting aerosol charge.

Methods: A 67.5:1 (%w/w) blend of 63-90 microm lactose with salbutamol sulphate, and lactose alone (with and without the blending process), was dispersed from a Cyclohaler into the electrical Next Generation Impactor at 30, 60 and 90 L/min.

Can low-dose combination products for inhalation be formulated in single crystalline particles?

This study aims to produce and test the performance of novel crystalline respirable particles containing two low-dose active ingredients and mannitol. This technique overcomes the usual requirement of blending with lactose carriers in formulating combination inhalation products. Ternary powders were produced by co-spray drying solutions containing an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and mannitol as a crystalline excipient.

A novel method for the production of crystalline micronised particles.

The aim of this study was to develop a method for converting an amorphous drug to a crystalline form to enhance its stability and inhalation performance. Spray-dried amorphous salbutamol sulphate powder was conditioned with supercritical carbon dioxide (scCO(2)) modified with menthol. The effect of menthol concentration, pressure, temperature and time on the characteristics of the resulting salbutamol sulphate powder was investigated.

Electrostatics of pharmaceutical inhalation aerosols.

Objectives: This review focuses on the key findings and developments in the rapidly expanding research area of pharmaceutical aerosol electrostatics.

Key Findings: Data from limited in-vivo and computational studies suggest that charges may potentially affect particle deposition in the airways. Charging occurs naturally in the absence of electric fields through triboelectrification, that is contact or friction for solids and flowing or spraying for liquids.

Does electrostatic charge affect powder aerosolisation?

To study if electrostatic charge initially present in mannitol powder plays a role in the generation of aerosols, mannitol was unipolarly charged to varying magnitudes by tumbling the powder inside containers of different materials. The resulting charge in the powder was consistent with predictions from the triboelectric charging theories, based on the work function values from literature and electron transfer tendencies from measurement of contact angle. The latter generated a parameter, gamma(-)/gamma+, which is a measure of the electron-donating capacity relative to the electron-accepting tendency of material.

Pharmacopeial methodologies for determining aerodynamic mass distributions of ultra-high dose inhaler medicines.

Three different impactor methodologies, the Andersen cascade impactor (ACI), next-generation impactor (NGI) and multistage-liquid impinger (MSLI) were studied to determine their performance when testing ultra-high dose dry powder formulations. Cumulative doses of spray-dried mannitol (Aridol) were delivered to each impactor at a flow rate of 60Lmin(-1) (up to a max dose of 800mg delivering 20 sequential 40mg capsules). In general, total drug collected in both the ACI and NGI falls below the range 85-115% of label claim criteria recommended by the United States of America Food and Drug Administration (FDA) at nominal mannitol doses exceeding 20mg and 200mg, respectively.

The influence of flow rate on the aerosol deposition profile and electrostatic charge of single and combination metered dose inhalers.

Purpose: The capability of the electrostatic next generation impactor (eNGI) has been investigated as a tool capable of measuring the electrostatic charge of single (Flixotide; containing fluticasone propionate (FP)) and combination (Seretide; FP and salmeterol xinafoate (SX)) pressurised metered dose inhalers (pMDIs) at different flow rates.

Methods: Aerosol mass distributions were investigated at 30, 60 and 90 l.min(-1) and simultaneous charge measurements recorded.

Controlled release antibiotics for dry powder lung delivery.

Introduction: Two controlled release (CR) antibiotics intended for inhalation therapy were evaluated.

Material And Methods: Ciprofloxacin and doxycycline (both hydrochlorides) were selected as model drugs. Microparticles containing 90:10 ratio of polyvinyl alcohol (PVA) and single antibiotics or combinations were obtained via spray drying.

Measuring charge and mass distributions in dry powder inhalers using the electrical Next Generation Impactor (eNGI).

The electrical Next Generation Impactor (eNGI) was assessed against the electrical low-pressure impactor (ELPI) and next generation impactor (NGI) for its capability to characterise particle size and electrostatic charge properties of dry powder inhaler (DPI) formulations. Following assessment, the relationship between inhalational air flow rate and drug powder charge was explored using the eNGI. At a vacuum flow rate of 30L/min, doses of Pulmicort (budesonide 400 microg) and Bricanyl (terbutaline 500 microg) were dispersed into the ELPI, NGI and eNGI, from which particle size profiles and charge profiles were ascertained.

Recent advances in controlled release pulmonary therapy.

Delivering therapeutic agents to the airways maximizes their concentration in lung tissue, decreasing systemic exposure or facilitating systemic absorption as desired. Many formulations exist for the treatment of respiratory illnesses however, no controlled release inhalation formulation exists to-date. This review is an update of the current advances in controlled release inhalation formulations and evaluation.

Preparation and evaluation of controlled release microparticles for respiratory protein therapy.

A series of microparticle formulations, designed for controlled release pulmonary therapy, were evaluated in terms of their physical properties, aerosol performance, lung epithelial cell toxicity, and controlled release profile. A protein, bovine serum albumin (BSA) was chosen as a model macromolecule active ingredient which was coprocessed, using spray drying, with varying concentrations of the release modifier, polyvinyl alcohol (PVA). The spray dried microparticles were tested for their physico-chemical characteristics (e.

Introduction of the electrical next generation impactor (eNGI) and investigation of its capabilities for the study of pressurized metered dose inhalers.

Purpose: To introduce the design of the electrical next generation impactor (eNGI), and validate its proposed function as a method of electrostatic characterization for pressurized metered dose inhaler (pMDI) formulations.

Methods: Flixotide (fluticasone propionate), ventolin (salbutamol sulphate), and qvar (beclomethasone dipropionate) were used as model pMDIs in this study. At an airflow rate of 30 l/min, five individual actuations of each pMDI were introduced into the electrical low-pressure impactor (ELPI), Next Generation Impactor (NGI), and the eNGI.

Lactose composite carriers for respiratory delivery.

Purpose: Lactose dry powder inhaler (DPI) carriers, constructed of smaller sub units (composite carriers), were evaluated to assess their potential for minimising drug-carrier adhesion, variability in drug-carrier forces and influence on drug aerosol performance from carrier-drug blends.

Methods: Lactose carrier particles were prepared by fusing sub units of lactose (either 2, 6 or 10 microm) in saturated lactose slurry. The resultant composite particles, as well as supplied lactose, were sieve fractioned to obtain a 63-90 microm carriers.

Scanning white-light interferometry as a novel technique to quantify the surface roughness of micron-sized particles for inhalation.

A novel approach of measuring the surface roughness of spherical and flat micron-sized drug particles using scanning white-light interferometry was applied to investigate the surface morphology of micron-sized active pharmaceutical ingredients (APIs) and excipient particles used for inhalation aerosols. Bovine serum albumin (BSA) and alpha-lactose monohydrate particles were chosen as model API and excipient particles, respectively. Both BSA and lactose particles were prepared with different degrees of surface corrugation using either controlled spray drying (four samples of BSA) or decantation (two samples of lactose).

What is the role of particle morphology in pharmaceutical powder aerosols?

Background: The aerosol performance of a powder for inhalation drug delivery is controlled by a number of physicochemical properties of the formulation, including particle size, density and morphology.

Objective: The role of particle morphology in powder inhalers will be reviewed.

Methods: Original research publications in the literature about the contribution of particle morphology to the aerosol performance of pharmaceutical powders have been selected, including both the lactose carriers and the drugs.

Micro-particle corrugation, adhesion and inhalation aerosol efficiency.

Atomic force microscopy (AFM) was used to evaluate the particle adhesion and surface morphology of engineered particles for dry powder inhaler (DPI) respiratory therapy to gain a greater understanding of interparticle forces and the aerosolisation process. A series of spherical model drug particles of bovine serum albumin (BSA) was prepared with different degrees of surface corrugation. The particles were evaluated in terms of particle size (laser diffraction) and microscopic morphology (scanning electron microscopy).

Dissolution kinetic behavior of drug nanoparticles and their conformity to the diffusion model.

Advances in nanomedicine are expected to escalate in the coming years, particularly related to the availability and delivery of optimum dosage. It is crucial that the dissolution behavior of such novel dosage forms be adequately scrutinized to maximize their therapeutic benefits. In this work, the dissolution behavior of irregularly shaped nanoparticles was analyzed using a modified negative-two-thirds-root diffusion model (with shape factor, sigma, incorporated into the equation to describe shape evolution).