Pressurised metered dose inhalers containing solutions of beta-2 agonists

Abstract

The present invention relates to a pharmaceutical formulation for use in the administration of 2(1H)-quinolinone derivatives long-acting β2-agonists by inhalation. In particular this invention relates to a chemically stable highly efficient TA 2005 HFA solution formulation to be administered by pressurised metered dose inhalers (pMDIs) characterized by a deep lung penetration. The invention also relates to methods for the preparation of said formulation and to its use in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

Description

BACKGROUND OF THE INVENTION [0001] Asthma is a disease which is becoming more prevalent and is the most common disease of childhood. It can be identified by recurrent wheeze and intermittent air flow limitation. Despite many advances in its understanding, said pathology remains a poorly understood and often poorly treated disease. Previously, contraction of airway smooth muscles has been regarded as the most important feature of asthma. Recently there has been a marked change in the way asthma is managed, stemming from the fact that asthma is recognized as a chronic inflammatory disease. Uncontrolled airway inflammation may lead to mucosal damage and structural changes giving irreversible narrowing of the airways and fibrosis of the lung tissue. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation. [0002] Another respiratory disease whose incidence is steadily increasing ...

AI Technical Summary

Benefits of technology

The present invention provides a pharmaceutical aerosol solution formulation that can be administered by pMDI, with a suitable shelf-life for pharmaceutical use. The formulation contains an active ingredient, a HFA propellant, and a co-solvent. The active ingredient is a 2(1H)-quinolinone derivative long-acting β2-agonist that is completely dissolved in the propellant-cosolvent system. The formulation provides a significant fraction of particles with a diameter equal or less than 1.1 microns, which are both extrafine particles and ultrafine particles. The formulation can also contain a corticosteroid as an additional active ingredient, which enhances the beneficial actions of the β2-agonist in patients with persistent asthma. The invention also provides a method of filling an aerosol inhaler with the composition of the invention. The technical effects of the invention include improved pharmaceutical aerosol solution formulations with improved shelf-life and optimal particle size for effective treatment of asthma and COPD.

Problems solved by technology

Despite many advances in its understanding, said pathology remains a poorly understood and often poorly treated disease.

Uncontrolled airway inflammation may lead to mucosal damage and structural changes giving irreversible narrowing of the airways and fibrosis of the lung tissue.

The first generation drugs such as salbutamol or fenoterol were characterized by a relatively short duration of action which has been considered as a disadvantage particularly for patients with nocturnal asthma.

Moreover, they have limited effects in COPD, since this disease involves ‘irreversible’ airways obstruction.

In fact, particles having aerodynamic diameters of greater than about 5 microns generally do not reach the lung since they tend to impact the back of the throat and are swallowed and possibly orally absorbed, while particles smaller than 1.5 (2.0) micron, i.e., about 0.5 to about 2 microns, capable of reaching the alveolar region, have been considered undesirable because they can be absorbed into the bloodstream and might enhance the undesired systemic effects of the drugs.

Furthermore, apart from ipratropium bromide, WO 94 / 13262 gives no guidance with respect to the amount of acid which has to be added in order to stabilise the medicaments without compromising the stability of the whole composition in the can.

As far as the role of water is concerned, it is only reported that humidity, in the case of certain active ingredients could be detrimental to the chemical stability during storage.

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