Folke Morén

Drug deposition of pressurized inhalation aerosols I. Influence of actuator tube design

Abstract The droplet size from a pressurized aerosol is dependent on time for evaporation of the propellants or distance from the actuator orifice. In order to investigate the influence of the evaporation of the propellants five tubes of various lengths and diameters were attached to a conventional inhalation aerosol actuator using Bricanyl, terbutaline sulphate, as a model. Nine healthy volunteers inhaled eight doses in each test from the conventional actuator alone or combined with the various tubes. The firing of dose was coordinated with the inhalation and for three selected designs the inhalation was voluntarily delayed for 5 sec after the firing. The drug deposited in the actuator, tube and mouth was analyzed spectrophotometrically. It was found that the deposition of drug in the mouth could be reduced significantly by attaching an additional tube to the actuator. The total loss of drug substance in the actuator, tube and mouth could also be reduced significantly indicating the possibility of increasing the availability of drug to the airways. When the inhalation was voluntarily delayed for 5 sec the total loss of terbutaline sulphate in actuator, tube and mouth increased compared to the corresponding tests with coordinated inhalation.

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.

The nasal distribution of metered does inhalers

The intranasal distribution of aerosol from a metered dose inhaler has been assessed using a radiotracer technique. Inhalers were prepared by adding 99Tcm-labelled Teflon particles (simulating the drug particles) to chlorofluorocarbon propellants, and scans of the head (and chest) taken with a gamma camera. Ten healthy subjects (age range 19-29 years) each performed two radioaerosol studies with the inhaler held in two different ways: either in a single position (vial pointing upwards) or in two positions (vial pointing upwards and then tilted by 30 degrees in the sagittal plane). The vast majority of the dose (82.5 +/- 2.8 (mean +/- SEM) per cent and 80.7 +/- 3.1 per cent respectively for one-position and two-position studies) was deposited on a single localized area in the anterior one-third of the nose, the initial distribution pattern being identical for each study. No significant radioaerosol was detected in the lungs. Only 18.0 +/- 4.7 per cent and 15.4 +/- 4.1 per cent of the dose had been removed by mucociliary action after 30 minutes, and it is probable that the remainder had not penetrated initially beyond the vestibule. Since the deposition pattern was highly localized and more than half the dose probably failed to reach the turbinates it is possible that the overall effect of nasal MDIs is suboptimal for the treatment of generalized nasal disorders.

Fraction of dose exhaled after administration of pressurized inhalation aerosols

Abstract After the administration of a pressurized inhalation aerosol, a fraction of the dose will be lost with the exhaled air. In the present study suspension aerosols containing a freely water-soluble drug, terbutaline sulphate, and a practically insoluble drug, budesonide, were administered to 10 healthy subjects. The air flow rate, the tidal volume, and the moment of actuation were registered for each of the inhaled doses. The exhalation was performed without any breath-holding pause. The drug in the exhaled air was collected on a membrane filter and in an absorbing solution. The fraction of the dose lost with the exhaled air was less than 1% for both drugs. Differences in air flow rate and tidal volume did not affect the results. A particle growth due to moisture absorption did not appear to be important for the total drug deposition in the respiratory tract

Drug deposition of pressurized inhalation aerosols II. Influence of vapour pressure and metered volume

Abstract The influence of vapour pressure and metered dose volume on drug deposition was tested using terbutaline sulphate pressurized aerosols with the conventional Bricanyl actuator and an attached tube. In each test the nine healthy volunteers inhaled eight doses at 1 min intervals coordinated with the dose firing. The amount of drug deposited in actuator, tube and mouth was determined spectrophotometrically. It was found that the increase in vapour pressure from 374 kPa to 502 kPa resulted in a significantly higher deposition of drug in the actuator but in a significantly lower deposition in the tube, in the mouth and for the net total loss in actuator, tube and mouth. An increase in metering volume from 25 or 50 μl to 100 μl resulted in a significantly higher deposition of drug in the actuator, in the tube and for the net total loss in actuator, tube and mouth. In order to obtain a high availability of drug to the airways the metering volume of the pressurized aerosol should be low and the vapour pressure high.

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.

In vitro dose sampling from pressurized inhalation aerosols investigaton of procedures in BPC and NF

Abstract In the British Pharmaceutical Codex and National Formulary, pressurized inhalation aerosols are assayed with regard to the dose available to the patient. The tests involve a correction for loss of drug substance in the inhalation device. In the present study, the in vitro procedures were investigated for appropriate sampling. A high drug retention was found in the valve stem. This retention decreased at short intervals between actuations. Drug retention in the actuator increased when the recipient volume of air was small and the air flow rate was low. The results indicate that sampling from pressurized inhalation aerosols should be made into the air at a fixed interval between actuations. It is also recommended that the flow rate is increased compared with the National Formulary monographs.

Investigation of assay procedures for pressurized inhalation aerosols

Abstract In compendial procedures the concentration in pressurized inhalation aerosols is determined after actuation into a reception liquid contained in a pressure tube or after actuation under the surface of a reception liquid contained in a beaker. In the present study, the recovery of these sampling procedures was investigated and compared with a determination based on the total drug content in the same aerosol units. The sampling procedure involving actuation into a pressure tube was found to be incomplete mainly because of drug retention in the valve stem. The results indicate that a correction should be made for the valve stem retention. Actuation under the surface of chloroform resulted in a low recovery, as some drug substance was probably lost into the air.