Aerosol formulation and clinical efficacy of bronchodilators

Abstract

This thesis subject is the improvement of the formulation of inhaled aerosols. It is well known that the formulation of inhaled drugs is not optimal: the major part of the mass delivered does not reach the lower airways. This phenomenon is due to the particle size of the inhaled particles, which is too large. Reduction of the size is the answer to this problem, but size reduction has its limits: too small particles do not deposit and are exhaled. The optimum between too large and too small is not known and has been the main object of this research project. The optimal particle size of a ß2-mimetic aerosol was determined in 8 stable asthmatics with a FEV1 of 72% of the predicted and it was shown that in these mild asthmatics the particle size of choice for a ß2-mimetic aerosol should be around 2.8 m m. Based on the distribution of the pulmonary receptors we expected that for parasympathicolytic aerosol a more central deposition pattern would be best. The latter being equivalent to a large optimal particle size. However, in mild asthmatics the optimal particle size for an ipratropium bromide aerosol also proved to be # 2.8 mm. Based deposition theories, we hypothesised that the optimal particle size of a 82-agonist or parasympathicolytic aerosol in patients with severe airflow obstruction had to be smaller, because these particles must pass obstructed airways. 7 stable patients with a mean FEV1 of 37.9% of predicted value inhaled three types of monodisperse salbutamol and ipratropium bromide aerosols, with particle sizes of 1.5 :m, 2.8 :m and 5 :m, respectively, and a placebo aerosol. Greater improvements in FEV1 were induced by the 2.8 :m aerosol than by the other particle sizes. The dilatations in the previous experiments were already clinically relevant at low dosages. To discover whether the bronchodilator effects of these low dosed monodisperse aerosols differed from those of standard dosages delivered by metered dose inhalers, we carried out a comparative trial. 10 stable outpatients, with a mean FEV1 of 58.1 % of predicted, inhaled a placebo aerosol, 8 µg of a 2.8 µm monodisperse ipratropium bromide aerosol and 40 µg from a metered dose inhaler plus spacer, followed by lung function measurements. We were able to show that the low dosed 2.8 µm aerosol proved to be equivalent to the higher dosed metered dose inhaler. Subsequently we compared the adverse effects of 160 µg fenoterol in the form of a 2.8 µm monodispers aerosol to those of 800 µg as a conventional metered dose inhaler aerosol. In twelve healthy volunteers changes in serum potassium, finger tremor, blood pressure, heart rate and specific airway conductance were measured before and 15 min after administration. Potassium levels decreased by 0.27 mmol/l after the monodispers aerosol, while the MDI lowered it by 0.67 mmol/l (p=0.001). Finger tremor also increased less. There was no significant specific airway conductance differences between the two actives. The overall conclusion of these experiments is that the best choice for a bronchodilator aerosol size are particles of 2.8 µm. When aerosols are composed of these particles, the dose of inhaled bronchodilators, relative to metered dose inhalers, can be reduces by 80%. This is accompanied by a major reduction in adverse effects.