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Formoterol superfine formulation

a technology of formoterol and superfine, applied in the direction of drug compositions, dispersed delivery, aerosol delivery, etc., can solve the problems of mucosal damage, fibrosis of lung tissue, and irreversible narrowing of airways and lung tissue,

Inactive Publication Date: 2005-07-14
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0032] Moreover, it has been found that the total systemic exposure corresponding to the fraction of drug absorbed through the lung plus the amount swallowed and absorbed through the gut is slightly inferior to that of the reference formulation, making the formulation of the invention potentially better tolerated.
[0054] 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.

Method used

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  • Formoterol superfine formulation
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Examples

Experimental program
Comparison scheme
Effect test

example 1

Superfine Formoterol HFA Formulation

[0090] A formulation was prepared with the composition as follows:

AmountsPer unitNominal doseComponents%μgFormoterol fumarate1.92mg0.019w / v12Anhydrous ethanol1416.7mg12w / w—HCl 1 M4.40mg*0.037w / w—HFA 134a (q.s.11808mg——to 10.09 ml)

*equivalent to 4.35 μl

[0091] The formulation (120 actuations / canister, overage of 40 actuations) was filled in standard aluminum canisters (two stage pressure filling) under pressure and fitted with a metering valve having a 63 μl metering chamber. Two actuators were used with orifice diameter of 0.30 and 0.42 mm. Results were obtained as a mean of 2 cans.

[0092] The aerodynamic particle size distribution was determined by ACI, according to the description on page 17 lines 4 to 12.

[0093] The delivery characteristics of the formulation are reported in Table 1 in comparison with the reference CFC formulation currently available on the market (Foradil). In particular the following parameters are reported: i) nominal dos...

example 2

Pharmacokinetics Study

[0095] The aim of the study was to evaluate the pharmacokinetics of formoterol in 6 healthy volunteers after single administration of the formoterol formulations of Example 1 at 120 μg dose (10 shots×12 μg / shot) in comparison with the marketed CFC formulation (Foradil). The experimental protocol is reported as follows:

[0096] Treatments [0097] Foradil CFC 120 μg. (10 shots×12 μg / shot): Reference formulation [0098] Formoterol / HFA orifice 0.42 mm 120 μg. (10 shots×12 μg / shot): Test formulation [0099] Formoterol / HFA orifice 0.30 mm 120 μg. (10 shots×12 μg / shot): Test formulation

[0100] The study was a single dose cross-over study; subjects received the drug at 8 a.m. The wash-out among different treatments was of at least 1 weeks. Patients were instructed to take 10 doses. Time 0 for each dose was defined as the time when the MDI is first actuated.

[0101] Bioanalysis

[0102] Assay of formoterol was carried out employing HPLC / MS validated method with a LOQ of 2 pg / ...

example 3

Effect of the Residual Humidity on the Formoterol Assay

[0110] The formulation of Example 1 filled in standard aluminum cans was stored in different conditions (25° C., 40° C.) and for different times (0, 3, 6 months).

[0111] The assay of formoterol was determined by HPLC while the water content was determined by Karl-Fischer method.

[0112] The results, reported in FIG. 2, show an inverse linear correlation between the assay of formoterol and the residual amount of water. The numbers between brackets refer to time and temperature condition, respectively. The formoterol assay for a residual humidity lower than 1500 ppm meets the requirements of the ICH guideline Q1A, whereas for a residual humidity higher than 1500 ppm, the assay decreases below 90%.

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Abstract

The present invention relates to a pharmaceutical formulation for use in the administration of a long-acting β2-agonist by inhalation. In particular this invention relates to a chemically stable highly efficient formoterol 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

FIELD OF THE INVENTION [0001] The present invention relates to a pharmaceutical formulation for use in the administration of a long-acting β2-agonist by inhalation. BACKGROUND OF THE INVENTION [0002] 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 lif...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/12A61K9/00A61K9/72A61K31/00A61K31/167A61K31/4704A61K31/485A61K45/06A61K47/06A61K47/10A61P11/00A61P11/06A61P11/08A61P11/16A61P43/00C07D215/26
CPCA61K9/008A61K31/4704A61K31/485A61K45/06A61K47/10A61K2300/00A61P11/00A61P11/06A61P11/08A61P11/16A61P43/00A61K9/00A61K9/12A61K31/167
Inventor DAVIES, REBECCA JAINEGANDERTON, DAVIDLEWIS, DAVID ANDREWMEAKIN, BRIAN JOHNCHURCH, TANYA KATHLEENBRAMBILLA, GAETANOFERRARIS, ALESSANDRA
Owner CHIESI FARM SPA
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