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. When determined using techniques specified in United States and European Pharmacopeias, FPF is measured by cascade impactors that have straight-sided ninety degree inlets through which air is drawn at a constant rate. It is not the purpose of in vitro tests to predict in vivo behavior, and FPF is primarily a measure of aerosol quality. Despite this, FPF broadly predicts the amount of drug from an inhaler device depositing in the lungs, but it systematically overestimates whole lung deposition and may not correctly predict the relative lung depositions for two inhalers of different types. The relationship between FPF and both drug pharmacokinetics and clinical response is incompletely understood at the present time, and more studies are needed to investigate these relationships. Modifications to impactor technologies, including inlets that mimic the human extrathoracic airways and the use of realistic breathing patterns, would be expected to improve the predictive power of in vitro tests for drug delivery in vivo.

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. However, different models of MTs do not always yield identical data, and selection of an anatomical MT and representative inhalation profiles remains challenging. Improved in vitro - in vivo correlations (IVIVCs) for inhaled drug products could permit increased reliance on in vitro data when developing new inhaled drug products, and could ultimately result in accelerated drug product development, together with reduced research and development spending.

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 28.3 and 45L/min. In vivo lung deposition was assessed in a randomized, two-arm, crossover study of (99m)Tc-radiolabeled fluticasone propionate in 12 healthy adult subjects, analyzed by gamma scintigraphy. In vitro: fine particle fractions at 28.3 and 45L/min were 88.6+/-3.6% and 89.2+/-3.0% (Tempo inhaler) versus 40.4+/-4.7% and 43.1+/-4.4% (commercial inhaler). In vivo: lung deposition was 41.5+/-9.8% (Tempo inhaler) versus 13.8+/-7.4% (commercial inhaler) and oropharyngeal deposition was 18.3+/-7.7% (Tempo inhaler) versus 76.8+/-7.1% (commercial inhaler). Variability of lung deposition was reduced from 55% (commercial inhaler) to 24% (Tempo inhaler) of the delivered dose. The Tempo inhaler produced significantly higher fine particle fraction values, reduced oropharyngeal deposition by 75%, and increased whole, central, intermediate, and peripheral lung delivery by more than 200%. Thus, the Tempo inhaler enhances efficient drug delivery to the lungs.

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. Success has been more variable for other drugs and treatment indications. Pulmonary delivery is now well established for delivery of inhaled antibiotics in cystic fibrosis (CF), and in the treatment of pulmonary arterial hypertension (PAH). Other inhaled treatments such as those for idiopathic pulmonary fibrosis (IPF), lung transplant rejection or tuberculosis may also become routine. Repurposing has progressed in parallel with the development of new drugs, inhaler devices and formulations.

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. Deposition was quantified by gamma camera on a removable facemask that was fitted over the head of a resuscitation mannequin. The eyes were simulated by adhesive plaster patches. When Respimat SMI was fired in three preselected positions away from the head, total face deposition (% ex-valve dose) averaged 7.3%, 7.8%, and 9.1%, and eye deposition averaged 0.6%, 0.1%, and 0.3%. When the inhaler was fired into a simulated exhalation, upper face deposition (mean 3.8%) and eye deposition (mean 0.1%) were also small. It is concluded that low deposition on the face, and especially in the eyes, is to be expected when Respimat SMI is fired accidentally outside the body, or is fired at the same time as the patient exhales. When Respimat SMI is misused in the ways described in this study, there is likely to be little potential for unwanted side effects resulting from ocular deposition.

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. Owing to the advantages offered by the pulmonary route, the challenges that the route poses are worth addressing, and if successfully addressed, the pulmonary route offers huge opportunities, often fulfilling unmet clinical needs.

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. Breath-actuated pMDIs, breath-coordinated pMDIs, spray-velocity modifiers, and spacer devices may be useful for patients who cannot use a conventional press-and-breathe pMDI correctly. Modern pMDI devices, which contain non-ozone-depleting propellants, should allow inhalation therapy via pMDI to extend well into the 21st century for a variety of treatment indications.

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. Pulmonary delivery of an erythropoietin- Fc fusion molecule (EpoFc) was previously demonstrated in non-human primates using this FcRn pathway. We have now conducted a phase I clinical study to test whether the FcRn pathway functioned similarly in man using human erythropoietin (Epo) fused to the Fc portion of human IgG1. The design was a three leg, non-randomized study conducted in healthy male volunteers with rising doses (3, 10, and 30 microg/kg) of the fusion protein targeted to the central lung regions. Using a target range of 10-30% vital capacity and 15 breaths per minute, approximately 70% of the lung-deposited dose of aerosolized EpoFc was delivered safely and effectively to the central lung regions. We showed dose-dependent concentrations of the fusion protein in the serum and an increase in circulating reticulocytes was evident in the highest dose group, thus demonstrating that large therapeutic molecules can be delivered to humans via the lung, with retention of biological activity, using the FcRn-mediated transport pathway.

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. Radionuclide imaging data on new inhaled asthma products provide a milestone assessment, and the data form a bridge between in vitro testing and a full clinical trials program, allowing the latter to be entered with increased confidence.

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. The effects of inhaled corticosteroids depend not only upon the pharmacology of the drug being administered, but also upon its delivery system, with more efficient devices not only improving therapeutic effect but also potentially increasing systemic adverse effects. Modern delivery systems that enhance drug targeting to the lungs make it possible to use lower dosages of inhaled corticosteroid, such that the clinical response is maintained but systemic exposure reduced.

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. Correct use of spacer devices is important, especially achieving control over electrostatic charge accumulation on the walls of plastic devices. In patients with severe acute asthma or severe chronic obstructive pulmonary disease, a pMDI plus large volume spacer may be a viable alternative to a nebuliser for delivering large bronchodilator doses. Although the addition of a spacer to every pMDI would not be justified, the use of large volume spacers has been recommended for any inhaled asthma drug in young children, and as a means of reducing systemic bioavailability of inhaled corticosteroids in adults and children alike.

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. Current FDA guidance recommends these methods as a means of documenting bioavailability (BA) and bioequivalence (BE) for topically acting solution formulations, because they can be performed reproducibly and are more discriminating among products. Nasal drug delivery in vivo may be determined by several radionuclide imaging methods: the two-dimensional imaging technique of gamma scintigraphy has been used most widely, but the three-dimensional method of positron emission tomography (PET) is being used increasingly often. In some situations a good in vitro/in vivo correlation (IVIVC) exists; for instance, negligible penetration into the lungs has been demonstrated in the case of nasal pump sprays delivering large droplets, while a clear difference may be shown in intranasal deposition between two aerosols with markedly different size distributions. However, recent studies have shown a poorer IVIVC for two similar nasal pump sprays, where significant differences in in vitro parameters were not reflected in differences in nasal deposition in vivo. It is suggested that radionuclide imaging data may have an important role to play as an adjunct to in vitro testing in BA and BE assessments and may provide a clearer understanding of the changes in in vitro parameters that are important for predicting differences in in vivo performance.

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. Optimised drug delivery may be achieved not only by improvements to devices, but also via more sophisticated formulations that disperse easily in the inhaled air-stream and which may often be delivered by relatively simple inhaler devices. DPIs could become the device category of choice for a wide range of inhaled therapies, involving both local and systemic drug delivery.

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. The formulations were radiolabelled with (99m)Tc, and deposition of budesonide was quantified by gamma scintigraphy. Mean (SD) whole lung deposition for the Monodose inhaler (% capsule dose), was independent of inspiratory effort (maximal: 21.4 (4.3)%; sub-maximal: 21.4 (7.5)%), while lung deposition for the Turbuhaler DPI (% metered dose) fell significantly with decreasing inspiratory effort (maximal: 25.1 (6.1)%; sub-maximal: 18.5 (6.5)%; P<0.05). The plasma concentrations of budesonide showed the same trends as the whole lung deposition data. The Monodose inhaler showed inspiratory effort-independent drug delivery characteristics, and could prove be a valuable low-cost alternative to more complex devices such as the Turbuhaler DPI. The Monodose inhaler may be especially useful in groups of patients unable to inhale maximally through DPIs, including young children and adult patients with severe respiratory impairment.

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. Whole-lung deposition correlated significantly with fine particle fraction (FPF) across a range of inhaler devices. FPF, defined in terms of aerosol <5.8 microm or <6.8 microm diameter, systematically overestimated lung deposition for virtually all inhalers. Lung deposition showed closer numerical equivalence to the percentage of the aerosol dose smaller than 3 microm diameter. Correlations exist between APSD data and whole-lung deposition, which may allow the greater use of APSD data for comparing inhaler devices. Agreement between in vitro and in vivo data may be improved by measuring APSD in ways that more closely mimic clinical use, including the use of impactor inlets that simulate the human upper airway anatomy. At the present time there are few published data that relate APSD to the clinical response of inhaled drugs in an unambiguous way.

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. Lung deposition has recently been assessed from a new dry powder inhaler, the Novolizer (ASTA Medica, now VIATRIS GmbH & Co. KG, subsidiary Sofotec GmbH & Co. KG, Frankfurt, Germany), using gamma scintigraphy. It was shown that the Novolizer deposited significantly more budesonide in the lungs than a Turbuhaler used either at similar inspiratory flow rates or with similar inspiratory effort. Equivalent clinical efficacy and safety profiles have also been shown in asthmatic patients treated with budesonide from each device.

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. METHODS: Nine healthy nonsmoking subjects (5 male, 4 female) completed a two-way crossover gamma scintigraphic study, assessing the lung and oropharyngeal depositions of albuterol sulfate, formulated as 99mTc-radiolabeled PulmoSphere particles or micronized particles (Ventolin Evohaler, GlaxoSmithKline, Ltd.) suspended in HFA-134a propellant. RESULTS: Mean (standard deviation) lung deposition, (% ex-valve dose) was doubled for the PulmoSphere formulation compared with Evohaler pMDI (28.5 (11.3) % vs. 14.5 (8.1) %, P < 0.01), whereas oropharyngeal deposition was reduced (42.6 (9.0) % vs. 72.0 (8.0) %, P < 0.01). Both PulmoSphere and Evohaler pMDIs gave uniform deposition patterns within the lungs. CONCLUSIONS: These data provided "proof of concept" in vivo for the PulmoSphere technology as a method of improving targeting of drugs to the lower respiratory tract from pMDIs, and suggested that the PulmoSphere technology may also be suitable for the delivery of systemically acting molecules absorbed via the lung.