HK1079425B - Formoterol superfine formulation - Google Patents

Description

Formoterol superfine preparation

Technical Field

The present invention relates to a method for administering long-acting beta by inhalation₂-an agonist agent.

Background

Asthma is an increasingly common disease and is the most common disease in children. It can be diagnosed by recurrent wheezing and intermittent limitation of ventilation. Although much progress has been made in understanding the condition, it is poorly understood and is often a disease with poor therapeutic efficacy. Previously, contraction of airway smooth muscle was considered to be the most important feature of asthma. There has recently been a significant change in the treatment of asthma, based on the fact that asthma is considered to be a chronic inflammatory disease. Uncontrolled airway inflammation can lead to mucosal damage and structural changes, resulting in irreversible narrowing of the airway and fibrosis of the lung tissue. Treatment is therefore aimed at controlling symptoms so that normal life can be achieved, while providing a basis for treating this underlying inflammation.

Another respiratory disease whose incidence is steadily increasing worldwide is Chronic Obstructive Pulmonary Disease (COPD). Most patients with COPD have lung disease by smoking. It will rise to the fifth most prevalent disease by 2020 throughout the world, according to the trend of smoking (LeckieM et al Exp Opin Invest Drugs 2000, 9, 3-23).

Chronic Obstructive Pulmonary Disease (COPD) is defined as a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema.

Chronic bronchitis is characterized by excessive secretion of bronchial mucus, whereas emphysema refers to abnormal and permanent enlargement of the air space distal to the terminal bronchioles, with wall destruction and no significant fibrosis (American torac Society). Each condition is treated as a specific disease.

Chronic obstructive bronchiolitis is an obstruction of the peripheral airways due to inflammation of the bronchioles.

β₂Adrenoreceptor agonists have been the first line of treatment for asthma for many years due to their bronchodilatory effect. Previous studies have also shown that β₂Agonists have potent anti-inflammatory properties, as represented by, for example, inhibition of proinflammatory cytokine release.

First generation drugs such as salbutamol or fenoterol are characterized by short duration of action, which has been considered particularly disadvantageous for patients suffering from nocturnal asthma. Moreover, they have limited effectiveness in COPD, since this disease involves "irreversible" airway obstruction. Thus developing longer-acting beta₂Agonists such as formoterol, salmeterol and TA 2005 have announced a major and new development trend for the treatment of asthma. According to some authors, long-acting beta₂Agonists (LABAs) may have acute anti-inflammatory activity in vivo (Johnson M Clin Exp Allergy 1992, 22, 177-181; Stelmach I et al Ann Allergy Asthma Immunol 2002, 89, 67-73). These drugs are a new treatment option of interest for patients with Chronic Obstructive Pulmonary Disease (COPD) because they show significant effects in improving lung function and controlling symptoms.

β₂Adrenergic agonists are also capable of promoting clearance of alveolar fluid in several animals as well as in vitro in the lungs of rats and humans. In view of these findings, β -adrenergic agonist treatment has been proposed as a possible treatment to accelerate the elimination of pulmonary edema in patients with acute pulmonary edema (Sacuma T et al AmJ Respir Crit Care Med 1997, 155, 506-. By beta₂Agonist therapy may also increase surfactant secretion and may produce an anti-inflammatory effect, thus facilitating restoration of pulmonary vascular permeability (Ware L et al New Eng. J Med 2000, 342, 1334-1349).

Drugs intended for the treatment of lung diseases such as asthma and COPD are currently administered by pulmonary delivery by inhalation of an aerosol relying on the mouth and throat so that the drug can reach the lungs. They may be administered in aqueous or hydroalcoholic formulations by nebulizer, by dry powder inhalers, or as dry powders in halogenated hydrocarbon propellants. These propellant-based systems require suitable pressurized metered dose inhalers (pMDIs) that release a metered amount of drug with each actuation. The relevant preparations may be in the form of solutions or suspensions. Solution formulations do not present problems of physical stability of the suspended particles relative to suspensions and therefore can ensure higher dose uniformity and reproducibility. As far as the types of propellants are concerned, hydrofluoroalkanes [ (HFAs), also known as hydrogen-fluorine-carbon (HFCs) ] will be indispensable propellants such as chlorofluorocarbons (also known as Freons or CFCs) which have been the preferred propellant aerosols for pharmaceutical use for many years, and their use in the destruction of the ozone layer has been suggested to be discontinued. In particular, 1, 1, 1, 2-tetrafluoroethane (HFA134a) and 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA227) are known to be the best candidates for non-CFC propellants and a number of pharmaceutical aerosol formulations employing such HFA propellant systems have been disclosed.

In developing therapeutic aerosols, the aerodynamic particle size of the inhaled particles is the most important variable in defining the location of droplet or particle deposition in the lungs of a patient; in short, it will determine whether drug targeting was successful or failed. See, P.Byron, "Aerosol Formulation, Generation, and Delivery Using nonmeasured Systems," respiratory drug Delivery, 144-.

Thus, one prerequisite for the development of therapeutic aerosols is a preferred particle size.

When the formulation is in the form of a suspension, the particle size of the cloud is determined by the particle size of the suspended drug, defined by the milling/micronization process. When the formulation is in solution, there is no volume distribution of suspended drug particles, and a much finer cloud of droplets is produced, defined primarily by the concentration of drug in solution.

Solid particles and/or droplets in an aerosol formulation can be characterized by their mass median aerodynamic diameter (MMAD, around which the total aerodynamic diameter is equally distributed).

Deposition of particles in the lung depends primarily on three physical mechanisms:

i) collision, function of particle inertia;

ii) gravity induced sedimentation; and

iii) diffusion resulting from Brownian motion of fine submicron (< 1 μm) particles.

The quality of the particles determines which of the three main mechanisms dominates.

In the case of aerosol-therapeutic drugs acting locally on the smooth muscle of the airways, in particular beta₂Agonists, which have been reported in the pastThe particles should preferentially deposit in the upper to middle lung region (bronchiole region) so that they should have an MMAD of about 1.5(2.0) to about 5.0 μm, preferably about 3 μm (Zanen P et al Int J Pharm 1994, 107, 211-.

In fact, particles having an aerodynamic diameter greater than about 5 μm will not typically reach the lungs, since they tend to impact the pharyngeal laryngeal wall and swallow, possibly orally, while particles smaller than 1.5(2.0) μm, i.e., from about 0.5 to about 2 μm, are able to reach the alveolar region, which has been considered undesirable, since they can absorb into the bloodstream and may enhance the undesirable systemic effects of the drug. Particles less than about 0.5 μm in diameter are generally considered therapeutically ineffective because they can be exhaled.

Thus, β₂pMDI formulations of agonists are typically very limited formulations capable of delivering particles with a majority of particles 2-5 μm and less than 1 μm, since the former are small enough that they reach the upper to middle lung region, but too large to reach the alveoli. This is also the inherent particle size of a formulation in suspension form where conventional pure drug micronization (air jet milling) can reduce the drug particle size to about 2-3 μm.

On the other hand, the density of β -adrenoceptors is known to be higher at the end of the bronchioles (Barnes P et al Am Rev Respir Dis 1983, 127, 758-. Furthermore, the inflammation of asthma is not confined to large central airways, but also extends to small peripheral airways. Eosinophilic inflammatory processes associated with asthma have been seen to involve both the bronchi and the alveolar region (Wang S J Immunol 2001, 166, 2741-. Recently, Martin R reported in J Allergy Clin Immunol 2002, 109(Suppl 2), 447-460 that peripheral lung disease appears to increase the risk of recurrent asthma exacerbation, while disease-related anatomical changes in the small airways of the peripheral lung are primarily fatal asthma. In this regard, in its opinion, drug administration with particles having a diameter of about 1 μm (referred to as "ultrafine" aerosols) may be beneficial. The clinical importance of peripheral lung disease makes this area an important therapeutic target so that particles that can reach and deposit in this area can better control the disease. It has also been reported that, among particles smaller than 0.5 μm, particles having a diameter of less than or equal to 0.3 μm, preferably 5-300nm, can be deposited by sedimentation into the alveolar region of the lung. Particles in this range are referred to in the literature as "ultrafine" particles.

"ultra-fine" particles produced from di-2-ethylhexyl sebacate (DEHS) have also been reported as models with good airway permeability (Anderson P et al, Chest 1990, 97, 1115-1120). Pharmaceutical aerosol particles < 0.1 μm in diameter may therefore be particularly effective in the case of obstruction of the airways of asthmatic patients, where the pathology is associated with mucus hypersecretion which prevents dispersion of the drug or is affected in the patient by obstructive pulmonary disease such as COPD. Intuitively, one would expect that mucus-reduced airway cavities and permanent contractions would require a finer cloud for perfusion.

Based on the inherent anti-inflammatory properties of LABAs, a related formulation capable of delivering a large fraction of fine particles would be expected to be very beneficial in patients with broncho-pulmonary obstructive diseases. Amirav I et al in JNucl Med 2002, 43, 487-491 emphasize the need to target narrow peripheral airways with ultrafine aerosols to improve aerosol delivery in the treatment of inflammatory airway diseases, particularly acute bronchiolitis.

Formoterol, { (R, R) - (+ -) -N- [ 2-hydroxy-5- [ 1-hydroxy-2- [ [2- (4-methoxy-phenyl) -1-methylethyl]Amino group]Ethyl radical]-phenyl radical]Formamide } is a selectivity for beta₂Receptor agonists, administered by inhalation, exert a prolonged bronchodilatory action for up to 12 hours. The current CFC formulationsAnd (5) selling.

Based on the above considerations, it would be particularly beneficial to provide a highly effective formoterol formulation which is administered via a pMDI characterized by deeper lung penetration, wherein surprisingly, the systemic exposure is significantly less high than the formulations currently marketed.

Summary of The Invention

It is an object of the present invention to provide a pharmaceutical aerosol solution formulation for administration by pMDI having a pharmaceutically suitable shelf life comprising formoterol as the active ingredient, an HFA propellant and an amount of co-solvent, wherein the active ingredient is completely dissolved in the propellant-co-solvent system and the amount of residual water is less than 1500ppm based on the total weight of the formulation. Said solution, when the formulation is actuated, is capable of providing at least 30% of a particle fraction equal to or less than 1.1 μm, said particle fraction being defined by the content of the Angstrom stepwise impactor stage S6-AF relative to the total amount of fine particle dose collected by this stage S3-AF of the Angstrom stepwise impactor.

The formulations of the invention are capable of delivering large fractions of particles equal to or less than 1.1 μm in diameter, which include both very fine particles, as defined by Martin R in J Allergy Clin Immunol 2002, 109(Suppl 2), 447-460, and particles equal to or less than 0.3 μm in diameter (ultra-fine particles, as defined by other authors). In view of these features, the formulations of the present invention are hereinafter referred to as ultrafine formulations.

Sub-micron aerosol formulations (including HFA formulations) have only been reported in the prior art as microemulsions containing surfactants such as lecithin (WO 01/78689, WO 00/27363; Dickinson P et al J Drug Target 2001, 9, 295-302).

As a preferred aspect of the present invention there is provided a pharmaceutical aerosol formulation comprising a solution of 0.003 to 0.192% w/v formoterol or a pharmaceutically acceptable salt thereof, such as the fumarate salt, as active ingredient in a liquefied HFA propellant and a co-solvent, preferably selected from pharmaceutically acceptable alcohols, characterised by a particle fraction of 1.1 μm or less of greater than or at least 30% and a moisture content as measured by the karl-fischer method of less than 1500 ppm. The pH of the formulation is advantageously between 2.5 and 5.0, as determined in the model carrier system reported in EP 1157689.

It has surprisingly been found that after administration of a formoterol solution formulation with a majority of particles equal to or smaller than 1.1 μm, the plasma levels of the active ingredient absorbed early are compared with the plasma levels of the CFC reference formulation on the market (fordil) with a minority of particles smaller than 1.1 μm.

Furthermore, it has been found that the total systemic exposure corresponding to the fraction of drug absorbed through the lungs plus the amount swallowed and absorbed through the intestines is slightly lower than the reference formulation, making the formulation of the invention better tolerated.

Low systemic exposure to formoterol is particularly beneficial because the extent of drug absorption into the bloodstream is associated with side effects on the cardiovascular system.

As reported in EP1157689 by the applicant, the chemical stability of formoterol in solutions of HFA propellant and co-solvent can be greatly improved by adjusting the apparent pH. The chemical stability of the compound can also be improved by adding a small amount of isopropyl myristate.

It has now been found that formoterol in such a formulation is extremely sensitive to residual moisture and that the amount of water above 1500ppm based on the total weight of the formulation is reduced to a level no longer acceptable for pharmaceutical use (below 90% w/w), as demonstrated in example 3. The effect of residual moisture content on the chemical stability of the active ingredient is particularly evident in high potency ultrafine formulations without isopropyl myristate.

The prior art discloses beta delivered by pressurized metered dose inhaler aerosol₂-a solution formulation of an agonist in HFA.

WO94/13262 entitled Boehringer Ingelheim provides aerosol solution formulations comprising a drug, an HFC propellant, a co-solvent and an inorganic or organic acid as stabilizers against chemical degradation of the active ingredient. Most examples relate to ipratropium bromide, an anticholinergic. Although formoterol is cited among the other active ingredients, there is no example to reportAnd (4) carrying out the following steps. As to mention of beta₂Agonists, only the fenoterol-containing formulation, which is a short acting derivative chemically unrelated to formoterol, are listed. Furthermore, there is no teaching in WO94/13262 of the amount of acid that must be added in order to stabilize these drugs, other than ipratropium bromide, without compromising the stability of the overall composition in the canister. The only implications can be found on page 5, lines 15-16, where it is mentioned that a certain amount of mineral acid should be added to obtain a pH value of 1-7, a range that is too broad and non-exclusive. With respect to the moisture content, it is described in this application that small amounts of water (up to about 5% by weight) may also be present in the propellant/co-solvent system. In the case of ipratropium bromide, it is reported that the addition of 1% water reduces the decomposition due to dehydration. This document does not describe water vs. beta₂The effect of the agonist, in particular the amount of residual water above 1500ppm, may have an effect on the chemical stability of formoterol in solution in the propellant/cosolvent system.

WO 98/34596, entitled 3M, relates to solution formulations containing a propellant and a physiologically acceptable polymer which can aid in the dissolution and stability of the active ingredient.

WO 98/34595 entitled Jago Research mentions aerosol formulations in the form of solutions or suspensions, wherein the propellant is a mixture of HFA and carbon dioxide. The presence of carbon dioxide may improve the physical and chemical stability of the active compound. Formoterol is cited among the active compounds which can be used, but the examples are not reported.

WO 00/06121 entitled Jago Research relates to propellant mixtures for aerosols containing nitrous oxide and a hydrofluoroalkane in the preparation of suspension and solution aerosols. The use of nitrous oxide may improve the stability of oxidation-sensitive active ingredients during storage. For LABAs such as formoterol fumarate and salmeterol xinafoate, only examples relating to suspensions are reported.

WO 99/65460 entitled Baker Norton for beta-cyclodextrin in suspension or solution₂-agonistsPressurized MDI for stable formulation of medicaments is claimed. The example relates to a formoterol fumarate solution comprising an HFA propellant and ethanol as a co-solvent, contained in a conventional aluminium or plastic coated glass can. Samples stored for a short period of time (1 month) under accelerated conditions (40 ℃, 75% relative humidity) lost 10% of the drug. According to the pharmaceutical guidelines ICH Q1A "Stability Testing of new Active substructures (and medicinal Products)" at 10 months 1993, the change in the Active ingredient from its initial value of 5% does not meet acceptable standards. Moreover, even said document does not have a great effect of extracting residual moisture on the chemical stability of formoterol and salts thereof.

In WO 98/56349, the applicant describes a solution composition for an aerosol inhaler comprising an active substance, a propellant containing a Hydrofluoroalkane (HFA), a co-solvent, and further comprising a low volatility component to increase the Mass Median Aerodynamic Diameter (MMAD) of the aerosol particles on actuation of the inhaler. In some cases a small amount of water may be added to the composition to enhance the dissolution of the active material and/or low volatility component in the co-solvent.

In EP1157689 the applicant discloses aerosol pharmaceutical compositions comprising beta₂A solution of an agonist (belonging to the class of phenylalkylamino derivatives) in an HFA propellant, a cosolvent with an apparent pH adjusted to 2.5-5.0, to ensure a suitable shelf life. In a particular embodiment of the invention, isopropyl myristate (IPM) is added as a low volatility component to increase MMAD of the aerosol particles and further improve the stability of the formulation. As regards the effect of water, it is only stated in general terms that humidity (in the case of certain active ingredients such as formoterol) can impair the (chemical) stability during storage. The HFA134a solution formulation containing 12% w/w ethanol based on formoterol with or without 1.0% w/w IPM is reported in example 5. EP1157689 does not teach a further improvement of the stability of the relevant formulation, especially in the case of IPM (improvement of the chemical stability of formoterol), by strictly controlling the residual amount of water. In EP1157689 no composition with or without IPM is preferred.

As mentioned above, the formulations of the present invention may also include additional active ingredients. In particular, corticosteroids are added to long-acting beta₂Agonists are able to optimally control asthma in most patients and relatively fixed combinations are increasingly used as convenient control agents for patients with persistent asthma. Each class of drug has also been reported to enhance the beneficial effects of the other class. Indeed, corticosteroids increase β₂Expression of the receptor and prevention thereof by long-acting beta₂Down-regulation by agonist contact, whereas₂Agonists may enhance the anti-inflammatory effects of corticosteroids (Barnes P et al Eur Respir J2002, 19, 182-191).

It is therefore another object of the present invention to provide a highly potent formoterol formulation which contains a steroid. The high ultrafine particle fraction in the formulation of the invention enables both drugs to reach small peripheral airway regions, which can lead to their synergistic effects in peripheral lung disease (see above). Furthermore, in view of the above characteristics, by maintaining the same therapeutic effect, it is possible to develop formulations comprising a fixed combination of formoterol and a steroid, wherein the latter can be present in lower doses.

Another aspect of the invention is to provide a highly potent formoterol formulation in combination with anticholinergic atropine-like derivatives such as ipratropium bromide, oxitropium bromide and tiotropium bromide in order to provide a particularly effective medicament for the treatment of COPD.

There is also provided a method of charging an aerosol inhaler with a composition of the invention, the method comprising:

(a) preparing a solution of one or more active ingredients dissolved in one or more co-solvents,

(b) the pH of the solution is optionally adjusted,

(c) the solution is charged into the apparatus and,

(d) the valve is curled, and the gas is filled,

(e) adding a propellant containing Hydrofluoroalkane (HFA),

another aspect of the invention includes the use of formoterol fully dissolved in a propellant/co-solvent system and capable of providing, upon actuation, at least a 30% fraction of emittance particles having an aerodynamic diameter equal to or less than 1.1 μm for the treatment of respiratory disorders such as asthma and COPD.

In view of the technical feature of providing a particle fraction of at least 30% of aerodynamic diameter less than 1.1 μm when actuated, the formulation of the invention can be used particularly effectively for the treatment of asthma, COPD and general airway obstruction symptoms, where the pathology is associated with mucus hypersecretion that hinders the diffusion of drugs.

Furthermore, it is clinically useful as a treatment for urging the regression of alveolar edema and surfactant deficiency-related diseases such as Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).

Detailed Description

The aerosol formulations of the invention comprise an HFA propellant and a cosolvent, wherein the active ingredient is completely dissolved, such that these formulations, upon actuation, are capable of giving an emitted fraction of particles equal to or less than 1.1 μm greater than or equal to 30%, the fraction being defined by the content of the impactor stage S6-AF relative to the total amount of fine particle dose collected by the stage S3-AF of the andreander cascade impactor, advantageously higher than 40%, preferably higher than 50%, more preferably higher than 60%, even more preferably higher than 70%. Advantageously, the formulation of the present invention is free of other excipients such as surfactants, other than solubilizing agents and propellants.

Examples of HFA propellants include 1, 1, 1, 2-tetrafluoroethane (HFA134a) and 1, 1, 1, 2, 3, 3, 3-heptafluoro-n-propane (HFA227) and mixtures thereof. The preferred propellant is 1, 1, 1, 2-tetrafluoroethane (HFA134 a). Another propellant of interest is 1, 1, 1, 2, 3, 3, 3-heptafluoro-n-propane (HFA 227).

The cosolvent is selected from lower alkyl (C)₁-C₄) Alcohols, polyols, polyAlkylene glycols, and combinations thereof. Other suitable cosolvents are (poly) alkoxy derivatives, including polyalkoxy alcohols, [ for example, available under the trade mark ]The 2- (2-ethoxyethoxy) ethanol obtained]。

Preferably the co-solvent is an alcohol. Ethanol is preferred. Since the presence of water must be avoided as much as possible, the co-solvent is even more preferably anhydrous ethanol, optionally in 3Drying on a sieve. The concentration of co-solvent (e.g. ethanol) will vary depending on the final concentration of active ingredient in the formulation and the propellant. The amount of ethanol should not exceed about 40% w/w of the total weight of the formulation. Advantageously it represents between 5 and 30% w/w, preferably between 10 and 20% w/w, even more preferably between 12 and 15% w/w.

The active ingredient useful in the aerosol compositions of the present invention is formoterol and stereoisomers, physiologically acceptable salts and solvates thereof.

Suitable physiological salts include chloride, bromide, sulfate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, mesylate, ascorbate, salicylate, acetate, succinate, lactate, glutarate or gluconate.

In one embodiment of the invention, it is preferred to use (R, R) - (±) formoterol, more preferably in the form of the fumarate.

The active ingredient may be used alone or in admixture with steroids such as Beclomethasone Dipropionate (BDP), flunisolide, mometasone furoate, fluticasone propionate, ciclesonide, budesonide and their 22R-epimers, and with anticholinergic atropine-like derivatives such as ipratropium bromide, oxitropium bromide, tiotropium bromide or with drugs useful in the control of respiratory diseases such as methylxanthines, anticleucinones and phosphodiesterase inhibitors.

Preferred combinations include formoterol and BDP, budesonide or 22R-epimers thereof.

The concentration of formoterol in the HFA formulation will depend on the amount of drug that is preferably delivered in one or two actuations.

In the foregoing, the drug concentrations are given in (w/v) as well as fumarate. The corresponding percentage (w/w) can be calculated by determining the density of the support.

The formulation of the invention will be filled into a canister equipped with a suitable metering valve. Preferably the formulation is actuated through a metering valve capable of delivering a volume of 25-100. mu.l, for example 50. mu.l or 63. mu.l. 100. mu.l are also suitable.

The concentration of formoterol will vary between 0.003-0.192% w/v, preferably 0.006-0.048% w/v, so as to deliver 3-48 mug, preferably 6-12 mug, per actuation.

For example, for a 12 μ g dose, the final concentration of formoterol fumarate delivered per actuation would be 0.012% w/v when using a 100 μ l metered volume; the final concentration of formoterol fumarate will double, for example 0.024% w/v when a 50 mul metered volume is used and 0.019% w/v when a 63 mul metered volume (which is preferred) is used.

The desired dosage regimen is 2 or 1 times daily, with a suitable daily dosage in the range of 6-48 μ g.

The apparent pH range is advantageously between 2.5 and 5.0, preferably between 3.0 and 4.5. Preferably, a strong mineral acid such as hydrochloric acid, nitric acid, phosphoric acid, more preferably hydrochloric acid, is used to adjust the apparent pH.

The amount of acid to be added to achieve the desired apparent pH will be predicted in the model vehicle reported in EP1157689 and will depend on the type and concentration of active ingredient and the amount of co-solvent. For a solution of formoterol fumarate in 12% w/w ethanol and a suitable amount to 10ml of HFA134a of 0.019% w/v, an amount comprising 3.85-4.85. mu.l of 1M HCl, preferably 4.15-4.55. mu.l of 1M HCl, most preferably 4.35. mu.l, is advantageously added. In general, the concentration of 1M HCl is between 0.030% w/w and 0.045% w/w, preferably between 0.035% and 0.040% w/w, based on the total weight of the formulation.

The amount of water is less than 1500ppm, preferably less than 1000ppm, even more preferably less than 500ppm, based on the total weight of the formulation.

The formulations of the present invention will be filled into cans suitable for the delivery of pharmaceutical aerosol formulations, such as plastic or plastic-coated glass bottles, or preferably metal cans, such as aluminum cans. The formulation may also be contained in a tank having part or all of its inner surface made of anodized aluminum, stainless steel, or lined with an inert organic coating. Examples of preferred coatings are epoxy-phenol resins, perfluorinated polymers such as perfluoroalkoxyalkanes, perfluoroalkoxyalkenes, perfluoroalkenes such as poly-tetrafluoroethylene (Teflon), fluorinated-ethylene-propylene, polyethersulfone and fluorinated-ethylene-propylene polyethersulfone copolymers. Other suitable coatings may be polyamide, polyimide, polyamideimide, polyphenylene sulfide, or combinations thereof.

To further improve stability, cans with rounded edge edges, preferably gold-clad necks or gold-clad inner edges, partially or fully turned edges, may be used according to the teachings of co-pending application No. WO 02/72448.

The tank was sealed with a metering valve. The metering valve is designed to deliver a metered amount of formulation per actuation and the addition of a gasket prevents leakage of propellant through the valve.

The gasket may comprise any suitable elastomeric material such as low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubber, butyl rubber, neoprene, EPDM (a polymer of ethylene propylene diene monomer) and TPE (thermoplastic elastomer). EPDM and TPE rubbers are preferred. EPDM rubbers are particularly preferred. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example from Valois, France (e.g., DF10, DF30, DF60), Bespak plc, UK (e.g., BK300, BK356, BK357) and 3M-Neotechnic Ltd, UK (e.g., Spraymeser). The DF31 valve of Valois, france is also suitable. The valve seal, in particular the gasket seal, and the seal around the metering chamber are preferably made of a material which is inert to the contents of the formulation, in particular when the contents comprise ethanol, and resistant to extraction into the contents of the formulation.

The valve material, in particular the material from which the metering chamber is made, is preferably made of a material which is inert to the contents of the formulation, in particular when the contents comprise ethanol, and resistant to deformation. Particularly suitable materials for preparing the metering chamber include polyesters such as polybutylene terephthalate (PBT) and acetals, particularly PBT.

The material from which the metering chamber and/or valve stem is made may be fluorinated, partially fluorinated or impregnated with a fluorine-containing substance to prevent drug deposition.

Conventional bulk preparation methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture can be used for industrial large scale manufacture of filled canisters. Thus, for example, in a high volume manufacturing process, the metering valve is crimped onto an aluminum can to form an empty can. The drug is added to the feed vessel and the mixture of ethanol, optionally water and liquefied propellant is pressurized through the feed vessel into a process vessel. An aliquot of the formulation was then filled into a canister via a metering valve.

In another method, an aliquot of the liquefied formulation is added to an open can under conditions of sufficient cold so that the formulation does not evaporate, and then a metering valve is crimped onto the can.

In another method, an aliquot of the drug dissolved in the solubilizer is dispensed into an empty can, the metering valve is crimped onto it, and the propellant is then loaded into the can through the valve. Preferably, the process is carried out in an inert environment, for example by blowing in nitrogen, in order to avoid the absorption of moisture in the air.

Each filled canister is conveniently loaded into a suitable channel device prior to use to form a metered dose inhaler for administering a medicament to the lungs of a patient. Suitable access means include, for example, valve actuators and cylindrical or conical access whereby medicament can be delivered from a filled canister through a metering valve into the mouth of a patient, such as a mouthpiece actuator.

In a typical arrangement, the valve stem is located in a nozzle block having an orifice leading to the expansion chamber. The expansion chamber has an outlet extending to the mouthpiece. Actuator (outlet) port diameters in the range of 0.15-0.45mm, in particular in the range of 0.2-0.45mm are generally suitable, for example 0.25, 0.30, 0.33 or 0.42 mm. 0.22mm is also suitable. For certain formulations, it would be useful to utilize laser-drilled actuator orifices having diameters in the range of 0.10-0.22mm, particularly 0.12-0.18mm, such as those described in co-pending application number EP 1130521.6.

The use of these fine pores also increases the cloud generation time and reduces its speed. These changes facilitate coordination of cloud generation and slow inhalation by the patient.

Because of the need to avoid water ingress into the formulation inlet, it may be preferable to overwrap the MDI product in a package that is preferably resilient, capable of preventing water ingress. It may also be preferred to add to the package a material (e.g., molecular sieve) that is capable of adsorbing any propellant and co-solvent that may leak from the canister.

The aerodynamic particle size distribution of each test formulation of the invention can be characterized using a multistage cascade impactor following the procedure described in European Pharmacopeia, second edition, 1995, part V.5.9.1, pages 15-17. In this particular case, an Angstrom Cascade Impactor (ACI) was used operating at a flow rate of 28.31/min. Drug deposition on each ACI plate was determined by High Pressure Liquid Chromatography (HPLC). The average delivered dose was calculated from the cumulative deposition in ACI. The average inhalable dose (fine particle dose) was obtained from the deposition of stage 3(S3) onto the filter (AF) (equivalent to a particle size ≦ 4.7 μm) divided by the number of actuations per trial, while the average "ultra-fine" dose was obtained from the deposition of stage 6 onto the filter (equivalent to a particle ≦ 1.1 μm).

Administration of the formulations of the invention may be indicated for the treatment of mild, moderate or severe, acute or chronic symptoms or for the prophylactic treatment of respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). Other respiratory conditions characterized by obstruction of the peripheral airways due to inflammation and the presence of mucus, such as chronic obstructive bronchiolitis and chronic bronchitis, may also benefit from such formulations.

The present invention is described below with reference to examples.

Example 1 ultra-Fine formoterol HFA formulation

A formulation was prepared with the following composition:

equivalent to 4.35. mu.l

The formulation was loaded under pressure (120 actuations/canister, over 40 actuations) into a standard aluminum canister (two-stage pressure fill) equipped with a metering valve with a 63 μ l metering chamber. Two actuators with an aperture of 0.30 and 0.42mm were used. Results were obtained as an average of 2 cans.

The aerodynamic particle size distribution was determined by ACI as described on page 17, lines 4-12.

The delivery characteristics of this formulation compared to the reference CFC formulation (fordil) currently available on the market are reported in table 1. The following parameters are specifically reported: i) nominal dose: theoretical dose for a single actuation; ii) delivered dose: the amount of active particles deposited to all ACI stages; iii) inhalable dose (fine particle dose): an amount of active particles having a particle size of 4.7 μm or less (S3-AF); iv) respirable fraction (fine fraction): ratio of inhalable dose to delivered dose; v) "ultra fine" dose: an amount of active particles equal to or less than 1.1 μm (S6-AF); iv) "ultrafine" fraction: the ratio of the "ultra fine" dose to the inhalable dose.

Table 1-delivery characteristics of the formoterol HFA solution formulation of example 1.

	Nominal dose (ug)	Delivery dose (μ g)	Inhalable dose (mug)	Respirable fraction (%)	Ultra-fine dosage (mug)	Ultra-fine fraction (%)
							Formulation example item 10.30mm	12	10.02	3.31	32.5	2.53	76.4
Formulation example item 10.42mm	12	10.84	2.14	19.7	1.57	73.3
							Foradil	12	11.1	5.70	51.4	1.18	20.7

The results show that the reference formulation shows a higher respirable fraction after actuation, whereas the formulation of the invention produces a much higher percentage of particles with a diameter equal to or less than 1.1 μm, which are believed to reach the distal ends of the bronchioles better.

Example 2 pharmacokinetic Studies

The aim of this study was to evaluate the pharmacokinetics of formoterol after single administration of the formoterol formulation of example 1 in a dose of 120 μ g (10 puffs x 12 μ g/puff) in 6 healthy volunteers compared to the marketed CFC formulation (fordil). The protocol is reported below:

treatment of

Foradil CFC 120. mu.g (10 puffs x 12. mu.g/puff): reference formulation

formoterol/HFA orifice 0.42mm 120 μ g (10 puff x 12 μ g/puff): assay formulations

formoterol/HFA orifice 0.30mm 120 μ g (10 puff x 12 μ g/puff): assay formulations

The study was a single dose crossover study; subjects received the drug at 8 am. The clearing time (wash-out) in the different treatments is at least 1 week. The patient is instructed to take 10 doses. The time 0 for each dose is defined as the time at which the MDI is actuated for the first time.

Biological analysis

Formoterol was determined using HPLC/MS validation with 2pg/mL LOQ.

Pharmacokinetic parameters are reported in table 2, while plasma concentrations for the first 2 hours are shown in figure 1.

TABLE 2 pharmacokinetic parameters

	ForadilCFC	Formoterol from example 1 HFA 0.42mm	Formoterol from example 1 HFA 0.30mm
				Cmax(pg ml)	159±34-	150±36	158±32
AUC(0-20min)(pgml*h)	35.4±9.0	34.3±7.3	36.5±7.3
				AUC(pgml*h)	655±153	611±103	578±98

C_maxIs the maximum plasma concentration

AUC_0-20minIs the area under the curve of plasma levels from 0h to 20 min;

AUC_tis the area under the curve from 0h to the plasma level at the last measurable data point.

The results confirm that the formoterol formulation of example 1, although characterized by a high fraction of particles equal to or less than 1.1 μm, shows a different particle size distribution, shows plasma levels at time intervals of 0 to 20min, which reflects the amount of drug absorbed from the lungs, comparable to the reference formulation.

Surprisingly, the total systemic exposure (see fig. 1), corresponding to the sum of the fraction of drug absorbed through the lungs and the amount swallowed and absorbed through the intestines, is slightly lower for the formulations of the invention than for the reference formulations. This may be considered as having the following benefits: since for drugs that produce their activity at lung level, reduced systemic exposure may correspondingly reduce the risk of unwanted systemic effects.

In preliminary clinical trials, it was also demonstrated that the formulations of examples 1 and 2 have bronchodilator action comparable to the reference formulation in CFC propellants and good tolerability.

Example 3 Effect of residual moisture on formoterol assay

The formulation of example 1 filled in standard aluminium cans was stored under different conditions (25 ℃, 40 ℃) for different times (0, 3, 6 months).

Formoterol was determined by HPLC, while the moisture content was determined by the karl-fischer method.

The results reported in fig. 2 show an inverse linear relationship between the measured residual amounts of formoterol and water. The data in parentheses refer to time and temperature conditions, respectively. Formoterol with a residual moisture below 1500ppm meets the ICH guidelidine Q1A requirement, whereas when the residual moisture is above 1500ppm, the determination drops to below 90%.

Example 4 stability study

A stability study of the formulation prepared in example 1 stored in upright and inverted cans at 5 c was performed.

Formoterol and its main related substances (degradation products) were determined by HPLC.

At 12 months formoterol measured above 95%, thus meeting the ICH guidelidine Q1A requirements. Under these storage conditions, the moisture content remained below 1000 ppm.

Storage conditions and reference productsThe same, but better shelf life, the latter being maintained at refrigerator temperature for up to 9 months.

Claims (16)

1. A pharmaceutical aerosol formulation for administration by pressurized metered dose inhalers comprising: at least one active ingredient in a solution of liquefied HFA propellant and ethanol as co-solvent, and a strong acid selected from hydrochloric acid, nitric acid or phosphoric acid; the active ingredient is selected from formoterol or a stereoisomer, physiologically acceptable salt and solvate thereof; the HFA propellant is selected from HFA134a or HFA 227; the amount of ethanol is 5-30% w/w; characterized in that the ethanol is in anhydrous form and the amount of residual water is lower than 1500ppm, based on the total weight of the formulation.

2. The formulation of claim 1, wherein the amount of residual water is less than 1000 ppm.

3. The formulation of claim 1, wherein the amount of residual water is less than 500 ppm.

4. A formulation as in any of claims 1-3, wherein the fraction of particles delivered at actuation of the inhaler that are equal to or less than 1.1 μm is greater than or equal to 30%.

5. A formulation as in any of claims 1-3, wherein the delivered ultrafine fraction with a diameter equal to or less than 1.1 μm is greater than 50%.

6. A formulation as claimed in any one of claims 1 to 3, wherein the active ingredient is (R, R) - (±) -formoterol fumarate at a concentration of between 0.003-0.192% w/v.

7. A formulation according to claim 6 wherein the concentration of active ingredient is between 0.006 and 0.048% w/v.

8. A formulation as claimed in any one of claims 1 to 3 wherein the pH is between 2.5 and 5.0.

9. The formulation of claim 8, wherein the pH is between 3.5 and 4.0.

10. A formulation as claimed in claim 8 or 9 wherein the pH is adjusted by the addition of hydrochloric acid.

11. The formulation of claim 1, wherein the concentration of absolute ethanol is 10-20% w/w.

12. The formulation of claim 11, comprising 0.012-0.048% w/v formoterol fumarate, 12% w/w absolute ethanol, 0.037% w/w HCl 1M, and HFA134 a.

13. The formulation according to claim 11 comprising 0.006-0.024% w/v formoterol fumarate, 12% w/w absolute ethanol, 0.023% w/w HCl 1M and HFA134 a.

14. A formulation according to any one of claims 1 to 3, further comprising another active ingredient selected from the group consisting of: steroids or anticholinergic atropine-like substances.

15. The formulation according to claim 14, wherein the steroid is beclomethasone dipropionate, fluticasone propionate, ciclesonide or budesonide and 22R-epimers thereof.

16. The formulation according to claim 14, wherein the anticholinergic atropine-like substance is ipratropium bromide, oxitropium bromide or tiotropium bromide.