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

CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 10 / 505,861, which is the U.S. national stage of International Patent Application No. PCT / EP03 / 02004, filed on Feb. 27, 2003, and claims priority to European Patent Applications No. 0200476.6, filed Mar. 1, 2002, and No. 02023589.1, filed Oct. 23, 2002, all of which are incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]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 disea...

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 a long-acting β2-agonist and a corticosteroid as active ingredients in a solution of HFA propellant and a co-solvent. The formulation has a high fraction of superfine particles with a diameter equal or less than 1.1 microns, which can provide a significant amount of particles with a diameter equal or less than 0.1 microns. The formulation is highly efficient and can be used in combination with anticholinergic atropine-like derivatives for the treatment of COPD. The method of filling an aerosol inhaler with the formulation is also provided.

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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