A new beclomethasone dipropionate multidose powder inhaler in the treatment of bronchial asthma.

The clinical efficacy, tolerability and acceptability of a new multidose powder inhaler (MDPI) containing beclomethasone dipropionate (BDP) were compared with those of a BDP aerosol administered with a large volume spacer (MDI-spacer) among adult asthmatics currently receiving from 500 to 1,000 microgram/day of an inhaled corticosteroid. During the study, the dosage of BDP from both devices was 400 microgram twice daily. Ninety-one patients were randomized to the MDPI group and 42 to the MDI-spacer group. The trial was performed as an open, randomized, parallel group multicenter study. The duration of the treatment period was 12 weeks, and the study was preceded by a 2-week run-in period. During the run-in period, the mean morning peak expiratory flow (PEF) was 487 and 466 1/min in the MDPI and MDI-spacer groups, respectively. After the 12-week treatment, the morning PEF was 491 1/min in the MDPI group and 463 1/min in the MDI-spacer group. The evening values were 500 and 479 1/min during the run-in period and 496 and 476 1/min after the 12-week treatment, respectively. Asthma symptom scores and the use of rescue medication were low in both groups, indicating good efficacy of the preparations tested. The median dose of histamine required to decrease forced expiratory volume in 1 s by 15% increased during the study from 800 to 1,098 microgram in the MDPI group and from 795 to 960 microgram in the MDI-spacer group. The most frequent adverse events in both groups were hoarseness and sore throat. There were no statistically significant differences between the treatment groups in serum cortisol values or in the number of patients with thrush. Seventy-two percent of the patients regarded the MDPI easier to use while 95% considered it more portable. Over 80% of the patients felt that the MDPI was also easier to clean and as easy or easier to learn to use than the MDI-spacer. To conclude, the novel powder inhaler is well tolerated and at least equally effective as the conventional MDI-spacer combination in the treatment of asthma with BDP. However, in everyday use, patients clearly favored the powder inhaler.

Pulmonary deposition and clinical response of 99mTc-labelled salbutamol delivered from a novel multiple dose powder inhaler.

Pulmonary deposition of 99mTc-labelled sulbutamol was determined after delivery from a novel multiple dose powder inhaler (Easyhaler). The clinical efficacy of the inhalation powder, evaluated simultaneously with gamma camera detection, was compared with that obtained after drug delivery from a metered dose inhaler-spacer combination. The study was performed as an open, non-randomized cross-over trial. A single dose of radiolabelled inhalation powder was inhaled on the first and the inhalation aerosol, as control, on the second study day. Sulbutamol sulphate was labelled with 99mtechnetium, and the inhalation powder was formulated by mixing radioactive drug particles with carrier material. Aerodynamic properties of the radiolabelled inhalation powder were similar to those of the unlabelled salbutamol powder. Delivered dose from the breath-actuated powder inhaler was adjusted to be equal to two puffs from a conventional aerosol actuator with a short plastic mouthpiece. Twelve non-smoking asthmatic patients participated in the trial. The mean pulmonary deposition of 24% was obtained after drug delivery from Easyhaler powder inhaler. Clinical efficacy of the medications was similar in terms of area under the FEV1 curve, maximum FEV1 and the improvement ratio. Thus it can be suggested that powder delivery from Easyhaler powder inhaler and the aerosol delivery through the spacer are equally effective.

In vitro deposition and clinical efficacy of two sodium cromoglycate inhalation powders.

In this study, the in vitro deposition as well as the clinical efficacy of two dry powder inhalation preparations containing 20 mg of disodium cromoglycate were evaluated. The preparations were Blacil and Lomudal administered either with I.S.F. or Spinmatic powder inhalers, respectively. The in vitro inhalation study was performed using the cascade impacted method. During the in vitro test, similar fractions of the drug doses were retained in both inhalation devices. A remarkably larger proportion of the pelletized drug powder from the Lomudal preparation was deposited in the imitated upper airway than from the Blacil preparation consisting of the mixture of micronized disodium cromoglycate particles and lactose as a carrier. On the other hand, a larger fraction of the drug dose was deposited in the imitated lung area after the administration of the Blacil preparation than from Lomudal. The clinical study was performed as an exercise test in sixteen asthmatic patients. The preparations tested were statistically equally effective. The decrease in all the values of the pulmonary function parameters (PEF, FEV1) was, however, smaller after the administration of disodium cromoglycate from Blacil than from Lomudal preparation. According to the results of this study, the cascade impaction test seems to be valuable for predicting the efficacy of inhalation powders.

Physical properties and clinical efficacy of two sodium cromoglycate inhalation aerosol preparations.

In this study, the particle size distribution and the droplet characteristics of the delivered aerosol cloud were first determined for two disodium cromoglycate inhalation aerosol preparations obtained from different manufacturers. In addition, the in vitro deposition properties and the clinical efficacy of these preparations were compared. The evaluation of the in vitro deposition was performed using a cascade impactor. The clinical efficacy was monitored by measuring the peak expiratory flow (PEF) values after the exercise test in fifteen asthmatic patients. The particle size and the spray characteristics of these two inhalation aerosol preparations were similar; the results of the in vitro test confirmed their similar physical properties. Both disodium cromoglycate preparations clearly alleviated the bronchoconstriction after the exercise test. According to the results of the clinical trial, supported by the laboratory scale studies, both disodium cromoglycate aerosols are of equal value in asthma inhalation therapy.

In vitro inhalation behaviour and therapeutical response of salbutamol particles administered from two metered dose aerosols.

In this study the particle size, as well as the in vitro deposition and the immediate bronchodilating effect on asthmatic patients, of two salbutamol inhalation aerosol preparations (Ventoline, Glaxo, UK, and salbutamol inhalation aerosol, Orion Pharmaceutica, Finland) were compared. The in vitro deposition study was performed using the modified Sierra Andersen cascade impactor. The bronchodilating effect of inhaled aerosol doses were monitored by measuring peak expiratory flow (PEF) values. In the clinical study, the pulse and blood pressure of the patients, as well as the side effects, were also recorded. Due to the anatomy and physiology of human lungs, the accepted optimum size for inhaled drug particles is under 5 microns, and preferably under 2 microns. Over 95% of the drug particles in both aerosol preparations were under 5 microns. 30% of the salbutamol particles in the Ventoline inhalation aerosol were under 2 microns, whereas in Orion salbutamol aerosol 14% of the drug particles were under 2 microns. Respectively 23% of Ventoline and 19% of the Orion salbutamol preparation penetrated into the therapeutically most significant imitated alveolar stages of the modified cascade impactor. Both salbutamol aerosols showed a clear clinical efficacy in the bronchodilating test. In addition, no significant differences existed in the bronchodilating effect of these inhalation aerosols. In conclusion, although there seemed to be a slight difference in the particle size distribution and in the in vitro inhalation behaviour, this variation did not have any effect on the clinical response.

Removal of inhaled 99mTc-labelled particles of disodium cromoglycate from the lungs.

Disodium cromoglycate particles were labelled with 99mTc by spray-drying technique. The in vitro dissolution profile as well as the leakage of radioactivity from the drug particles were determined using a through-flow cell method. The radioactive drug particles were mixed with a lactose carrier and inhaled from a dry powder device by five healthy volunteers. The removal of the inhaled drug particles from the lungs was evaluated by a gamma camera. A close relationship between the dissolution of the drug as such and the leakage of radioactivity was noted. Gamma scintigraphy indicated a biphasic exponential removal of radioactivity from the lung region. The slow component with the halftime of about 55 min was mainly due to the dissolution of drug particles in the lungs. The halftime of the fast component describing mucociliary clearance was less than 10 min. This process was the dominating one for the removal of the drug from the lungs. The experiment thus showed that the main fraction of the inhaled dose was deposited in the tracheobronchial region. Accordingly, only a small portion of the dose initially deposited in the lung can be absorbed and induce a therapeutic effect.

Effects of inspirease holding chamber on the deposition of metered dose inhalation aerosols.

A modified cascade impaction method as well as a radiotracer technique has been used to assess the effects of the 700 ml collapsible holding chamber (InspirEase) on the in vitro and in vivo deposition of inhaled metered dose aerosols. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the InspirEase-device was evaluated with the modified cascade impactor which method imitated the human respiratory tract. For the in vivo study the disodium cromoglycate particles were labelled with pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of gamma camera. InspirEase increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper passages and mouth clearly decreased. Thus using the InspirEase holding chamber not only a better lung penetration of the inhaled drug particles can be achieved but also the local side effects would be decreased.

Nasal distribution of radioactive drug administered using two dosage forms.

The deposition patterns of 99mtechnetium labelled disodium cromoglycate particles administered either from a metered dose aerosol with a conventional nasal adaptor or from a dry powder nasal inhaler were studied using gamma camera. Disodium cromoglycate particles were firstly labelled with 99mTc using the spray drying technique. Both the metered dose aerosol and the dry powder dosage form were formulated using these radioactive drug particles. Seven healthy volunteers inhaled either three aerosol doses or one dry powder dose unit into one nostril. The drug dose reaching nasal cavity after administration from these two dosage forms was about the same. The deposition patterns as well as the changes in distribution due to the mucociliary transport were monitored by a gamma camera equipped with a low energy all purpose collimator. Initially drug doses deposited in a wider area of the nasal cavity when disodium cromoglycate particles were administered as a dry powder dosage form. In addition, retention index (%) which illustrates the movements of drug particles by mucociliary transport from the initial area of application seemed to be slightly higher for a metered dose aerosol than for a dry powder dosage form. At the end of the 30 minutes measuring period the area of the mucosal layer covered by radioactive drug particles was clearly wider for the dry powder dosage form than for the metered dose aerosol. Thus it is well possible to administer drug particles effectively into the nasal cavity as a dry powder dosage form.

Effect of the new spacer-device on the deposition of the inhaled metered dose aerosol.

The effect of the new spacer-device on the in vitro and in vivo deposition of inhaled drug particles was studied. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the new pear-shaped spacer-device was evaluated with the modified cascade impactor method. For the in vivo study the disodium cromoglycate particles were labelled with a pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of a gamma camera. The new spacer-device increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper airways and mouth clearly decreased. Thus using the new spacer-device evaluated in this study the local side effects would be decreased.

In vivo evaluation of the new multiple dose powder inhaler and the Rotahaler using the gamma scintigraphy.

Deposition of 99mTc-labelled particles of disodium cromoglycate in the respiratory tract was evaluated after inhalation from two dry powder inhalers. The inhalers tested were a new multiple dose powder device (Chiesi Farmaceutici) and the Rotahaler powder device (Glaxo). Fractional deposition in the whole lung area, the upper respiratory passages and the stomach, as well as in the inhaler, was measured using a gamma camera. Ten healthy volunteers participated in the inhalation test. The mean, whole lung deposition of the inhaled disodium cromoglycate particles was about 9 per cent of the dose for the both devices. The deposition patterns of the inhaled drug doses in the lung area given by the devices were, however, clearly different. The Chiesi powder inhaler was more efficient in dispersing the drug particles into the therapeutically important alveolar regions of the lungs. The fraction of the dose retained in the inhaler was significantly higher for the Rotahaler than for the Chiesi powder device. On the other hand, the deposition in the upper passages was somewhat larger for the Chiesi device than for the Rotahaler. According to the deposition results of this study, a new multiple dose powder inhaler can be useful in inhalation therapy.