Fine Particle Fraction: The Good and the Bad.

Fine particle fraction (FPF) is defined in general terms as the fraction or percentage of the drug mass contained in an aerosol cloud that may be small enough to enter the lungs and exert a clinical effect. An aerodynamic diameter of 5 μm represents the approximate border between "fine" and "coarse" particles, but there is no universally agreed upon definition of FPF in terms of an aerodynamic particle size range. FPF alone does not adequately describe a heterodisperse aerodynamic particle size distribution, and it needs to be combined with another measure or measures indicating the width of the distribution.

In vitro-in vivo correlations (IVIVCs) of deposition for drugs given by oral inhalation.

Conventional in vitro tests to assess the aerodynamic particle size distribution (APSD) from inhaler devices use simple right-angle inlets ("mouth-throats", MTs) to cascade impactors, and air is drawn through the system at a fixed flow for a fixed time. Since this arrangement differs substantially from both human oropharyngeal airway anatomy and the patterns of air flow when patients use inhalers, the ability of in vitro tests to predict in vivo deposition of pharmaceutical aerosols has been limited. MTs that mimic the human anatomy, coupled with simulated breathing patterns, have yielded estimates of lung dose from in vitro data that closely match those from in vivo gamma scintigraphic or pharmacokinetic studies.

Delivering drugs to the lungs: The history of repurposing in the treatment of respiratory diseases.

The repurposing of drug delivery by the pulmonary route has been applied to treatment and prophylaxis of an increasingly wide range of respiratory diseases. Repurposing has been most successful for the delivery of inhaled bronchodilators and corticosteroids in patients with asthma and chronic obstructive pulmonary disease (COPD). Repurposing utilizes the advantages that the pulmonary route offers in terms of more targeted delivery to the site of action, the use of smaller doses, and a lower incidence of side-effects.

Drug delivery to the lungs: challenges and opportunities.

Pulmonary drug delivery is relatively complex because the respiratory tract has evolved defense mechanisms to keep inhaled drug particles out of the lungs and to remove or inactivate them once deposited. In addition to these mechanical, chemical and immunological barriers, pulmonary drug delivery is adversely affected by the behavioral barriers of poor adherence and poor inhaler technique. Strategies to mitigate the effects of these barriers include use of inhaler devices and formulations that deliver drug to the lungs efficiently, appropriate inhaler technique and improved education of patients.

In vitro/in vivo comparisons in pulmonary drug delivery.

Establishing clear relationships between in vitro and in vivo data for inhaled drug products is an important goal. In vitro aerodynamic particle size distributions (APSDs) are expected to have some predictive power not only for drug deposition, but also for clinical effects. APSD data obtained by cascade impaction have been compared with lung deposition data measured in gamma scintigraphy studies.

Breath-synchronized plume-control inhaler for pulmonary delivery of fluticasone propionate.

A novel breath-synchronized, plume-control inhaler (Tempo inhaler) was developed to overcome limitations of a pressurized metered-dose inhaler. This report compared the Tempo inhaler and a commercial inhaler for fine particle distribution and lung deposition of fluticasone propionate. In vitro fine particle distribution was determined using the Andersen Cascade Impactor at inspiration rates of 28.

An in vitro study to assess facial and ocular deposition from Respimat Soft Mist inhaler.

Respimat Soft Mist() inhaler (SMI) is a novel multidose propellant-free inhaler device for delivery of inhaled drugs to patients with asthma and chronic obstructive pulmonary disease. In vitro studies have been undertaken to assess facial and ocular deposition from Respimat SMI in several potential misuse situations. A placebo aqueous drug formulation in Respimat SMI was radiolabeled by addition of (99m)Tc.

Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway.

A novel drug delivery platform has been developed that utilizes a naturally occurring receptor known as the neonatal Fc receptor (FcRn). The receptor is specific for the Fc fragment of IgG and is expressed in epithelial cells where it functions to transport immunoglobulins across these cell barriers. It has been shown that FcRn is expressed in both the upper and central airways in non-human primates as well as in humans.

Principles of metered-dose inhaler design.

The pressurized metered-dose inhaler (pMDI) was introduced to deliver asthma medications in a convenient and reliable multi-dose presentation. The key components of the pMDI device (propellants, formulation, metering valve, and actuator) all play roles in the formation of the spray, and in determining drug delivery to the lungs. Hence the opportunity exists to design a pMDI product by adjusting the formulation, metering-valve size, and actuator nozzle diameter in order to obtain the required spray characteristics and fine-particle dose.

Drug delivery to the nasal cavity: in vitro and in vivo assessment.

Drugs are given intranasally for both local and systemic applications, and the use of the intranasal route is predicted to rise dramatically in the next 10 years. Nasal drug delivery may be assessed by a variety of means, but high reliance is often placed upon in vitro testing methodology (emitted dose, droplet or particle size distribution, spray pattern, and plume geometry). Spray pattern and plume geometry define the shape of the expanding aerosol cloud, while droplet size determines the likelihood of deposition within the nasal cavity by inertial impaction.

Spacer devices for metered dose inhalers.

Spacer devices are attachments to the mouthpieces of pressurised metered dose inhalers (pMDIs), and range from tube spacers with a volume of <50 mL to holding chambers with a volume of 750 mL. Compared with a pMDI alone, spacers minimise coordination difficulties, reduce oropharyngeal deposition and often increase lung deposition. Spacers may not improve the clinical effect in patients able to use a pMDI properly, but may allow maintenance dosages of bronchodilators and corticosteroids to be reduced.

Dry powder inhalers for optimal drug delivery.

Dry powder inhalers (DPIs) have been available for delivering drugs to the lungs for over 30 years. In the last decade there has been a big increase in DPI development, resulting partly from recognised limitations in other types of inhaler device. Many companies are developing DPIs for asthma and chronic obstructive pulmonary disease (COPD) therapy, and there is increasing recognition of the potential role of DPI systems for other therapies, such as inhaled antibiotics and peptides/proteins.

Drug delivery to the lungs from dry powder inhalers.

When asthma is being treated, it is essential that sufficient drug is deposited at the site(s) where it is needed. In recent years, many dry powder inhalers have been developed by the pharmaceutical industry. Drug delivery to the lung from dry powder inhalers is dependent upon the patient's peak inhaled flow rate, and so it is very important to be able to assess the amount and location of drug delivered from different devices.

Radionuclide imaging technologies and their use in evaluating asthma drug deposition in the lungs.

Whole lung and regional lung deposition of inhaled asthma drugs in the lungs can be quantified using either two-dimensional or three-dimensional radionuclide imaging methods. The two-dimensional method of gamma scintigraphy has been the most widely used, and is currently considered the industry standard, but the three-dimensional methods (SPECT, single photon emission computed tomography; and PET, positron emission tomography) give superior regional lung deposition data and will undoubtedly be used more frequently in future. Recent developments in radionuclide imaging are described, including an improved algorithm for assessing regional lung deposition in gamma scintigraphy, and a patent-protected radiolabelling method (TechneCoat), applicable to both gamma scintigraphy and SPECT.

Deposition and effects of inhaled corticosteroids.

Inhaled corticosteroids are now recommended as maintenance therapy for all but the mildest cases of asthma, and may be delivered by a variety of devices and formulations. Drug delivery may be assessed by both in vitro and in vivo methods. Although drug deposition in the lungs is expected to predict clinical response, this relationship is often masked by the flat nature of corticosteroid dose-response curves.

Deposition and pharmacokinetics of budesonide from the Miat Monodose inhaler, a simple dry powder device.

Dry powder inhalers (DPIs) are used to deliver asthma drugs to patients, but lung deposition may depend upon the degree of inspiratory effort. The pulmonary deposition of the glucocorticosteroid budesonide (SMB-Galephar) has been assessed in 12 asthmatic patients when delivered by the Monodose inhaler (Miat, Milan, Italy); the Pulmicort Turbuhaler DPI (AstraZeneca, Lund, Sweden) was used as a comparator product. Patients inhaled from each device with maximal or sub-maximal inspiratory effort: Monodose inhaler 90 vs 45 l/min; Turbuhaler DPI 60 vs 30 l/min.

Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder.

Purpose: To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs).

Methods: Budesonide PulmoSphere (PSbud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 microg budesonide PulmoSphere inhaled from Eclipse DPI at target PIF of 25 L x min(-1) (PSbud25), and 50 L x min(-1) (PSbud50), and 800 microg of pelletized budesonide from Pulmicort Turbuhaler at 60 L x min(-1)(THbud60).

In vivo lung deposition of hollow porous particles from a pressurized metered dose inhaler.

Purpose: PulmoSphere particles are specifically engineered for delivery by the pulmonary route with a hollow and porous morphology, physical diameters < 5 microm, and low tap densities (circa 0.1 g x cm(-3)). Deposition of PulmoSphere particles in the human respiratory tract delivered by pressurized metered dose inhaler (pMDI) was compared with deposition of a conventional micronized drug pMDI formulation.