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

[0042] The formulations of the invention can also comprise a further active ingredient. In particular, the addition of a corticosteroid to a long-acting β2-agonist gives optimal control of asthma in most patients and relevant fixed combinations are increasingly used as a convenient controller in patients with persistent asthma. It has also been reported that each class of drug enhances the beneficial actions of the other. In fact, corticosteroids increase the expression of β2-receptors and protect them against down-regulation in response to long-acting β2-agonist exposure, whereas β2-agonist may enhance the anti-inflammatory actions of corticosteroids (Barnes P et al. Eur Respir J 2002, 19, 182-191).

[0043] Accordingly, another object of the present invention is to provide highly efficient formulations containing a 2(1H)-quinolinone derivative β2 agonist as active ingredient, further comprising a steroid. The high fraction of superfine particles of the formulation of the invention can allow both drugs to reach the small peripheral airways region in such a way as to better exercise their synergic effects in distal lung diseases. Moreover, in view of the aforementioned characteristics, it might be possible to develop formulations comprising fixed combinations of the β2 agonist and a steroid wherein the latter one could be present in a lower dose, by maintaining the same therapeutic effect.

[0044] A further aspect of the present invention is to provide highly efficient 2(1H)-quinolinone derivatives long-acting β2-agonist formulations in combination with an anticholinergic atropine-like derivative such as ipratropium bromide, oxitropium bromide and tiotropium bromide in order to provide a medicament particularly effective for the treatment of COPD.

[0052] In view of its technical feature of providing on actuation a fraction of particles with an aerodynamic diameter of less than 1.1 micron, of at least 30%, the formulation of the invention can be particularly effective for the treatment of asthma, COPD and, generally, of airway obstruction conditions wherein the pathology is associated with mucus hypersecretion which hinders the diffusion of the drug.

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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