Lung deposition of budesonide inhaled via Turbuhaler: a comparison with terbutaline sulphate in normal subjects.

We wanted to evaluate whether lung deposition of budesonide and terbutaline sulphate differs, and to determine lung deposition of budesonide inhaled at different peak inspiratory flows, through Turbuhaler. Lung deposition of budesonide, a lipophilic substance, and of terbutaline sulphate, a hydrophilic substance, was therefore compared, after administration via an inspiratory flow-driven, multi-dose, powder inhaler (Turbuhaler, Astra Draco AB) to 10 healthy volunteers. The radionuclide 99mTc was used to label drug particles, and radioactivity, indicating drug deposition, was measured using a gamma camera. Budesonide was inhaled at a normal flow of 58 l.min-1 and at a slow flow of 36 l-min-1. At the faster flow, a mean +/- SD 27.7 +/- 9.5% of the metered dose was deposited in the lung and at the slower flow 14.8 +/- 3.3% was deposited (p < 0.001). Mean lung deposition of terbutaline sulphate inhaled at 57 l.min-1 was 27.0 +/- 7.7%. We conclude that inspiratory flow has an important effect on lung deposition, but water solubility appears to have no effect.

Nasal distribution of budesonide inhaled via a powder inhaler.

The distribution pattern of budesonide in the nasal passages and lungs was investigated in 10 healthy subjects after nasal inhalation. The subjects inhaled drug powder, radiolabelled with 99mTc, at maximum flow rate (46.3 +/- 6.8 l/min) and at 29.9 +/- 2.5 l/min via Turbuhaler. At both flows, the majority of the dose was deposited in the anterior part of the nasal cavity on a single, rather localized area, but some particles also penetrated more posteriorly into the main nasal passages and to the lungs. At maximum flow rate the nasal deposition was 65.2% (range 39.5-84.1%) and the lung deposition 4.7% (range 1.4-9.3%) of the metered dose, and at 30 l/min, the nasal deposition was 67.6% (range 49.7-81.6%) and the lung deposition was 4.2% (range 1.7-7.9%). A large fraction of the metered dose was deposited in the nasal adaptor of the inhaler during the administration (mean values 29 and 28%, for the two inhalation flows). Of the dose actually reaching the subject, 91 and 93% (mean values) was deposited in the nose. There were no statistically significant differences in distribution pattern between the two inhalation flows.

Pulmonary deposition of inhaled terbutaline: comparison of scanning gamma camera and urinary excretion methods.

Deposition from a multidose powder inhaler (Turbuhaler, Astra) delivering 500 micrograms of terbutaline sulfate per metered dose was compared by two techniques in a group of six healthy volunteers. The deposition of the radionuclide 99mTc, which was used to label terbutaline sulfate powder, was quantified by gamma camera (G-method). Simultaneously, the gastrointestinal absorption of swallowed drug was blocked with activated charcoal, and the amount of terbutaline in a urine sample, collected over a period of 48 h and corrected by a pharmacokinetic internal standard of intravenous deuterated terbutaline, was used as a measure of lung deposition (U-method). The mean (standard deviation) depositions in lung were 26.9 (3.8%) of the dose for the G-method and 21.1 (3.2)% of the dose for the U-method. Possible reasons for the differences between the two means are discussed. Both methods are suitable for assessing deposition from medical aerosol inhalers; the U-method requires access to gas chromatography-mass spectrometric equipment, and the G-method requires access to gamma camera facilities.

Deposition and clinical efficacy of terbutaline sulphate from Turbuhaler, a new multi-dose powder inhaler.

A radioaerosol technique has been developed in order to assess deposition patterns from a new metered dose powder inhaler (Turbuhaler, Astra Pharmaceuticals). The radionuclide Tc99m dissolved in chloroform was added to a spheronised formulation of micronised terbutaline sulphate and the chloroform was allowed to evaporate. Turbuhaler subsequently delivered 0.5 mg of treated drug per metered dose. In vitro tests with a multistage liquid impinger showed that the fractionation of the drug dose between different particle size bands was similar to the fractionation of radioactivity. In a group of ten asthmatic patients, a mean 14.2% (SEM 2.1) of the drug dose was deposited in the lungs, with 71.6% (3.0) of the dose in the oropharynx. Of the remainder, 13.7% (2.1) was deposited on the mouthpiece, and 0.5% (0.2) recovered from exhaled air. The radiolabel was present in both central and peripheral zones of the lungs. All patients bronchodilated; forced expiratory volume in one second (FEV1) increased from 1.40 (0.24) l to 1.77 (0.24) l (p less than 0.01) 20 min after inhalation. These results suggest that both the distribution of drug and the clinical effect of terbutaline sulphate delivered from Turbuhaler are similar to those from a pressurised metered dose inhaler (MDI).

A comparative distribution study of two procedures for administration of nose drops.

The intranasal distribution of nose drops has been studied in 12 healthy subjects, comparing an administration followed by two rapid inhalations through the nose, with an administration followed by turning the head to five positions. Insoluble particles of human serum albumin labelled with 99Tcm were suspended in the liquid before administration. A significantly larger area (p less than 0.05) in the nasal cavity was covered by the labelled nose drops when the subjects used the turning-the-head procedure. It appears that this procedure gave a larger passive distribution of the particles. The differences were about 10 to 15% between 3 and 45 min after administration. Some particles were rapidly transported into the pharynx. The retention of the particles at the initial site of deposition did not differ significantly between the two procedures and about 50% of the particles seemed to have penetrated to the ciliated region in the main nasal passages and were cleared. The results indicate that the procedure for administration of the nose drops influences the distribution in the nasal cavity, but the clinical relevance should be studied with respect to the efficacy of the active drug in patients.

Bronchodilatory therapy with nebuhaler: how important is the delay between firing the dose and inhaling?

Metered dose inhalers are sometimes used in conjunction with NebuhalerR, a 750 ml holding chamber, but the permissible delay time between actuating the aerosol into Nebuhaler and commencing inhalation is unknown. We have compared in 10 asthmatic patients the bronchodilator responses following inhalations of terbutaline sulphate from Nebuhaler after delays of 1, 5 and 30 seconds and following placebo inhalation. Terbutaline sulphate was administered as 2 puffs, each of 250 micrograms, separated by approximately 15 minutes. After each delay time, terbutaline produced increases in forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR) and maximum expiratory flow following exhalation of 75% of the forced vital capacity (V max25) significantly greater than those after placebo (P less than 0.01). Changes in PEFR did not vary significantly among the three delay times, but the increases in FEV1 and in V max25 were significantly reduced with 30 seconds' delay. It is concluded that the delay between actuation into Nebuhaler and commencing inhalation can be extended from 1 second to 5 seconds without significant loss of drug efficacy, and that further extension to 30 seconds causes only a small loss of bronchodilatation: hence the delay time is unlikely to be of major importance in clinical practice.

Deposition pattern of nasal sprays in man.

The intranasal distribution from an aqueous pump spray has been assessed in 13 normal subjects, using insoluble Teflon particles labelled with 99Tcm which were intended to simulate a suspension of drug particles. Three different combinations of metered volume and spray cone angle were compared. The main deposition of particles was in the anterior, non-ciliated, part of the nose, but some particles also penetrated more posteriorly into the main nasal passages and were cleared subsequently to the nasopharynx. No particles were detected in the lungs. With a single puff of 100 microliters volume, 46.5 +/- 4.4 (mean +/- SEM)% of the spray was retained in the anterior part of the nose after 30 minutes, but this was increased to 57.1 +/- 4.5% (P less than 0.05) with two puffs of 50 microliters. The latter were deposited over a significantly (P less than 0.05) smaller area in the nasal cavity. There was a trend towards lower particle retention and a greater area of deposition when the spray cone angle was decreased from 60 degrees to 35 degrees. These results indicate that the drug particles released from nasal pump sprays are distributed both to ciliated and non-ciliated zones, and that the choice of metered volume and possibly spray cone angle may play a role in determining the amount which penetrates to the main nasal passages.

Deposition pattern from a nasal pump spray.

The initial distribution and subsequent clearance of aerosol from a hand-operated nasal pump spray has been assessed from gamma camera scans in ten normal subjects, following labelling of placebo sprays with 99Tcm labelled Teflon particles (mean diameter 2 micron). Aerosol was concentrated chiefly in the anterior part of the nose, but the area of deposition varied between subjects. No particles reached the lungs. A mean 56% of the dose was retained at the initial site of deposition 30 minutes after administration, while the remaining 44% of the dose had cleared to the nasopharynx. The initial partitioning of nasal pump sprays between ciliated and non-ciliated zones is relevant both for effective topical therapy of the nasal cavity, and for possible systemic drug delivery by the intranasal route.

Improvement of pressurised aerosol deposition with Nebuhaler spacer device.

The effect on aerosol deposition from a pressurised metered dose inhaler of a 750 cm3 spacer device with a one way inhalation valve (Nebuhaler, Astra Pharmaceuticals) was assessed by means of an in vivo radiotracer technique. Nine patients with obstructive lung disease took part in the study. The pattern of deposition associated with use of a metered dose inhaler alone was compared with that achieved with the spacer used both for inhalation of single puffs of aerosol and for inhalation of four puffs actuated in rapid succession and then inhaled simultaneously. On each occasion there was a delay of 1 s between aerosol release and inhalation, simulating poor inhaler technique. With the metered dose inhaler alone, a mean (SEM) 8.7 (1.8)% of the dose reached the lungs and 80.9 (1.9)% was deposited in the oropharynx. With single puffs from the spacer 20.9 (1.6)% of the dose (p less than 0.01) reached the lungs, only 16.5 (2.3)% (p less than 0.01) was deposited in the oropharynx, and 55.8 (3.1)% was retained within the spacer itself. With four puffs from the spacer 15.2 (1.5)% reached the lungs (p = 0.02 compared with the metered dose inhaler alone, p less than 0.01 compared with single puffs from the spacer), 11.4 (1.2)% was deposited in the oropharynx, and 67.5 (1.8)% in the device itself. It is concluded that the spacer device gives lung deposition of metered dose aerosols comparable to or greater than a correctly used inhaler and oropharyngeal deposition is greatly reduced. The spacer should be used preferably for the inhalation of single puffs of aerosol but may also be used for the inhalation of up to four puffs actuated in rapid succession and then inhaled simultaneously.

Mode of inhalation for trained and untrained asthmatics using a pressurized aerosol.

A pressurized inhalation aerosol should be actuated at the beginning of a slow and deep inhalation, followed by a long pause of breathholding. In this study a registration was performed on the mode of inhalation. The flow-volume curve and the moment of actuation were obtained from an aerosol actuator provided with sensors, and the breathholding pause was measured. Data were obtained from 34 asthmatic patients, regularly trained to use the pressurized aerosol, and these data were compared with those from 44 untrained patients. When the subjects used a terbutaline sulfate aerosol in their usual fashion, most of the trained subjects succeeded well. Further improvements could possibly be made regarding the depth of inhalation and, after control with the recording device, regarding the flow rate at actuation. Most of the untrained subjects did not use a deep enough inhalation with respect to their vital capacity, and their breath-holding pause was very short. It only seems possible to improve these parameters by regular training. In order to reach optimal results the asthmatic patients must be regularly controlled and instructed regarding their use of a pressurized inhalation aerosol. A recording device is useful in demonstrating to each subject which parameter can be improved.

Different techniques of aerosol administration to the lower respiratory tract.

Nebulizers, pressurized aerosols and powder aerosols are often used by asthmatic patients in order to obtain an immediate, local effect from a low dose of a drug in the lower respiratory tract. However, the aerosol delivery systems are not ideal for oral inhalation as the availability to the lower respiratory tract is low, the device is not always easy to use in an acute situation, and the constituents in the dosage form may cause side effects. The aerosol delivery systems for clinical practice are described and their limitations are emphasized. It is suggested that controlled comparative studies be performed concerning various systems for oral inhalation.

Drug deposition of pressurized inhalation aerosols.

When a pressurized inhalation aerosol is used, a high loss of drug substance occurs in the upper respiratory tract. This is explained by the rather slow propellant evaporation after the initial aerosol generation, and by the high initial aerosol velocity. Indirect measurements can be performed with a view to obtaining an indication of the deposition pattern in subjects; but a radioactive technique must be used in order to obtain the complete deposition pattern in the body. The drug loss occurring when a person exhales seems to be low compared to the dose entering a subject.

The importance of particle size in response to inhaled bronchodilators.

The effect of 250 micrograms terbutaline sulphate of three different particle sizes from a metered dose inhaler was examined in ten non-asthmatic and ten asthmatic subjects. Particle size ranges were approximately less than five micrometers, five to ten micrometers and ten to fifteen micrometers. Responses to the less than five micrometers range were significantly greater than those to the larger sizes in both groups of subjects. In the asthmatic patients there was a suggestion that the difference between small and large particles was more marked for V50 than sGaw reflecting poorer penetration of large particles into smaller airways.

Deposition of pressurized suspension aerosols inhaled through extension devices.

Only a small fraction of the dose from a pressurized aerosol inhaler reaches the lung, because most is deposited on the upper airways by inertial impaction. We have investigated the effects on aerosol deposition of two spacer devices (a 10-cm tube and a 22-cm cone) by incorporating teflon particles (mass median aerodynamic diameter, 3.2 micrometer) labeled with 99mTc into pressurized canisters. Ten subjects with obstructive airway disease inhaled the aerosol in a controlled manner from a conventional actuator alone or in combination with the tube or the cone. Radioaerosol distribution was measured using a shadowshield whole body counter. Deposition on the conducting airways was significantly improved by both spacers, but alveolar deposition was unchanged. Initial oropharyngeal deposition was reduced by both spacers in all 10 patients. We conclude that the spacer devices may have a role to play in aerosol therapy by increasing drug availability to the lung, while at the same time decreasing unwanted drug deposition in the oropharynx.

Deposition of pressurised aerosols in the human respiratory tract.

Although the use of pressurised aerosol inhalers is widespread, little is known about the actual deposition of the aerosol in the respiratory tract, since this has previously been difficult to measure. We have incorporated Teflon particles (mean diameter 2 micrometer) with aerodynamic properties similar to those of bronchodilator drug crystals into pressurised aerosol canisters. Controlled inhalations by eight patients with obstructive airways disease showed that on average 8.8% of the dose was deposited in the lungs (3.0% in the alveoli and 5.8% on the conducting airways) and 80% in the mouth. These figures are in good agreement with previous indirect estimates of deposition based on metabolic studies. The remainder of the dose was either expired (1.0%) or deposited in the aerosol actuator (9.8%). This method should have wide application for measurement of deposition patterns under various conditions and for assessment of therapeutic effects.

Use of a special inhaler attachment in asthmatic children.

Asthmatics often find difficulties in using an aerosol inhaler correctly as they are unable to co-ordinate the release of a bolus of drug to coincide with an inspiratory effort. This is especially the case with children. The addition of a special attachment to an ordinary inhaler overcame this problem. Twelve asthmatic children produced significantly better PEFR measurements when 0.25 mg terbutaline sulphate was administered via an inhaler with the attachment than when an ordinary inhaler was used alone.