Stephen P. Newman

Effect of different modes of inhalation on drug delivery from a dry powder inhaler

Abstract Although the Spinhaler has been available for many years as a delivery device for sodium cromoglycate powder, the quantity of powder delivered to the lungs and the optimal mode of inhalation for this device have remained largely unknown. Lung deposition of 20 mg sodium cromoglycate powder (labelled with the radionuclide 99m Tc) from the Spinhaler has been measured in 10 healthy volunteers who inhaled by four carefully controlled inhalation modes, involving fast (120 l min −1 ) and slow (60 l min −1 ) peak inhaled flow rates, holding the head in the normal and tilted-back (60° to the horizontal) positions, and breath-holding pauses of 0 and 10 s. Inhalation at 60 l min −1 significantly ( P −1 . Among the inhalation modes tested, delivery to the lungs was optimised (mean 17.1% of the dose) when powder was inhaled at 120 l min −1 , with the head in the normal position, and with 10 s breath-holding.

Terbutaline sulphate Turbuhaler: effect of inhaled flow rate on drug deposition and efficacy

The deposition and efficacy of 0.5 mg terhutaline sulphate from Turbuhaler (Astra Pharmaceuticals). a multi-dose powder inhaler, have been measured simultaneously in 10 asthmatic subjects at two inhaled flow rates (fast, mean 57 l/min and slow, mean 28 l/min). At the fast flow rate, a mean (SEM) 16.8 (2.6)% of the dose was deposited in the lungs, compared with 9.1 (1.5)% of the dose at the slow flow rate (P < 0.01). At either flow rate, the majority of the dose was deposited in the oropharynx, and this quantity was significantly higher with slow inhalation (P < 0.01). There was a trend towards a reduced bronchodilator response at the lower flow rate, but this did not reach statistical significance. It is concluded that Turbuhaler works optimally at a fast inhaled flow rate, but functions adequately at a lower flow rate which some patients may find easier to attain.

Pharmacoscintigraphic Evaluation of Lung Deposition of Inhaled Zanamivir in Healthy Volunteers

ObjectiveThe objective of this study was to determine the sites of zanamivir deposition in the respiratory tract and the pharmacokinetics of zanamivir after oral inhalation from the Diskhaler™ device and from a prototype of a novel breath-activated device.DesignThis was a 2-period block-randomised study in which participants inhaled zanamivir from a Diskhaler™ and/or the prototype device on separate days.Study participants13 healthy volunteers (5 men and 8 women) aged 20 to 42 years (mean age 29 years) and weighing 54.0 to 94.0kg (mean bodyweight 69.2kg) entered the study.InterventionsParticipants were given dry powder zanamivir 10mg formulated with 99mTc from the Diskhaler™ or the prototype device on separate days. Scintigraphic images of the chest and oropharynx were recorded. Blood samples for determination of serum zanamivir and urine for excretion studies were taken up to 8 hours after drug administration. Safety was evaluated by monitoring lung function tests, adverse events and laboratory parameters.ResultsOrally inhaled zanamivir was well tolerated, as demonstrated by lung function tests. A mean of 13.2% (n = 11) of the 10mg dose from the Diskhaler™ was deposited in the bronchi and lungs. The deposition pattern varied between individuals, showing a preferentially central deposition pattern in some and a uniform distribution pattern in others. The major deposition site was the oropharynx (mean 77.6%), with a mean of 1.2% deposited on the trachea and a mean of 3.2% retained in the blister. Similar data were obtained with the prototype device. Inhalation of zanamivir gave a broad peak of systemic absorption with mean maximum serum concentrations of approximately 30 to 40 μg/L after 1.5 hours. The rate and extent of absorption were similar irrespective of inhalation device. Less than 5% of drug was excreted unchanged in urine within 8 hours of inhalation, confirming the low bioavailability of zanamivir after pulmonary delivery. A significant correlation existed between systemic exposure and peripheral lung deposition.ConclusionsThe local concentrations of zanamivir that result from oral inhalation via the Diskhaler™ are estimated to be > 10 μmol/L throughout the respiratory tract, well in excess of the concentrations observed to inhibit influenza virus neuraminidases by 50% (0.64 to 7.9 nmol/L). Similar deposition data were obtained with the Diskhaler™ and the prototype device, which was consequently not developed further. Pharmacoscintigraphy was confirmed as being a reliable technique for measuring zanamivir deposition in the respiratory tract.

Simple instructions for using pressurized aerosol bronchodilators

Although the manufacturers of pressurized aerosol bonchodilators issue instructions for using the inhalers, little or no experimental verification exists. Bronchodilatation has been measured after controlled inhalations of 500 μg terbutaline sulphate given in a systematic series of investigations to 8 patients with reversible airways obstruction at 2 different inhalation flow rates (25 1/min and 80 1/min), 3 different lung volumes (20%, 50% and 80% vital capacity) and followed by 2 different breath-holding pauses (4 and 10 seconds). The results indicate that patients may release the aerosol at any time during the course of a slow deep inhalation which should be followed by 10 seconds of breath-holding. This will ensure an optimal bronchodilator response.

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 <50mL to holding chambers with a volume of 750mL. 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.

In Vivo Lung Deposition of Hollow Porous Particles from a Pressurized Metered Dose Inhaler

AbstractPurpose: PulmoSphere™ particles are specifically engineered for delivery by the pulmonary route with a hollow and porous morphology, physical diameters < 5 μm, and low tap densities (circa 0.1 g.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 EvohalerTM, 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.

Lung deposition of 5 mg Intal from a pressurised metered dose inhaler assessed by radiotracer technique

Deposition from a pressurised metered dose inhaler (MDI) delivering 5 mg sodium cromoglycate (Intal 5, Fisons plc), has been measured by a Tc99m-labelling technique Ten healthy volunteers inhaled (i) from a standard MDI at 30 l/min, (11) from a 10 cm spacer tube (Aerotube) at 30 l/min, and (111) from the Aerotube at 100 l/min A mean (SE) 8.8(11) % of the dose was deposited in the lungs from the standard MDI, but this amount was not significantly changed either for slow inhalation (11.3(1.9) %) or fast inhalation (7.1(1.3) %) through the spacer Lung deposition was lower than that observed previously for other cantsters delivering smaller amounts of drug per metered dose Oropharyngeal deposition fell from a mean 79% with standard MDI to a mean 29% with the spacer (P < 0.05). It is concluded that a 10 cm tube spacer does not significantly enhance lung deposition of 5 mg Intal in subjects with good inhaler technique, but may reduce the incidence of orophdryngeal irritation, cough and unpleasant taste.

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.

Aerosol therapy in AIDS

Pneumocystis carinii pneumonia (PCP) is the most common presenting symptom in patients with the acquired immunodeficiency syndrome (AIDS). Clinical trials have shown that inhaled pentamidine, delivered by nebulizer, is an effective prophylaxis for PCP in high-risk patients, and can be used to treat mild to moderate episodes. Side effects are minor, in marked contrast to the parenteral route of administration. The choice of nebulizer system will determine both alveolar delivery of pentamidine and the incidence of cough related to deposition of droplets on large conducting airways. Radioaerosol studies have suggested that optimum nebulizer systems for inhaled pentamidine deliver the majority of the aerosol mass in droplets smaller than 2µm diameter, ideal for alveolar penetration.

Lung Mucociliary Transport in Man

The human lung has several defence mechanisms against all types of inhaled deposited material. The three main clearance mechanisms are (a) mucociliary transport, (b) cough and (c) alveolar clearance. In this article we review the various methods currently available for the objective measurement of the efficiency of the mucociliary clearance mechanism in vivo in man. We also summarize the effect of (a) physiological factors, (b) disease states, (c) therapeutic factors and (d) environmental pollutants on human lung mucociliary transport.