MXPA06009584A - Stable pharmaceutical solution formulations for pressurized metered dose inhalers - Google Patents

Abstract

Aerosol solution formulations for use in an aerosol inhaler which comprise 8-hydroxy-5- [(1R)-1 -hydroxy-2 -[[(1R)-2- (4-methoxyphenyl)-1 -methylethyl]amino]ethyl]-2(1H)- quinolinone or a salt thereof, in particular the hydrochloride salt (TA 2005), as an active ingredient, a propellant containing a hydrofluoroalkane, and a cosolvent, stabilized by addition of a specific small amount of a high concentrated phosphoric acid and optionally by the use of a suitable can having part or all of its internal metallic surfaces lined with an inert organic coating.

Description

STABLE PHARMACEUTICAL SOLUTIONS FOR INHALERS OF PRESSURIZED MEASUREMENTS FIELD OF THE INVENTION The present invention relates to stable pharmaceutical solution formulations which will be used with pressurized metered dose inhalers (MDI) suitable for aerosol administration. In particular, the present invention relates to solutions that will be used with pressurized metered dose inhalers (MDI), which are suitable for the administration of aerosol containing the β2-agonist 8-hydroxy-5- [(IR) -l -hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone or a salt thereof (the hydrochloride salt is mentioned hereinafter in the present invention as TA 2005) and which are stable at room temperature for a pharmaceutically acceptable shelf life.

BACKGROUND OF THE INVENTION Pressurized metered dose inhalers are well-known devices for administering pharmaceutical products to the respiratory tract by inhalation. The drugs commonly supplied through Inhalation include bronchodilators such as β2-agonists and anti-cholinergic, corticosteroids, anti-leukotrienes, anti-allergic and other materials that can be administered efficiently by inhalation, thereby increasing therapeutic efficacy and reducing side effects. MDIs use a propellant to expel tiny droplets containing the pharmaceutical product into the respiratory tract as an aerosol. Formulations for aerosol administration through the MDI may be solutions or suspensions. Solution formulations offer the advantage of being homogeneous and the active ingredient and excipients are completely dissolved in the propellant vehicle or its mixture with appropriate co-solvents such as ethanol. Solution formulations also avoid the physical stability problems associated with suspension formulations to ensure a more consistent uniform dose administration. For many years, the preferred propellants used in aerosols for pharmaceutical use have been a group of chlorofluorocarbons that are commonly known as Freons or CFCs, such as CC13F (Freon 11 or CFC-11), CC12F2, (Freon 12 or CFC-12). ), and CC1F2-CC1F2 (Freon 114 or CFC-114).

Recently, chlorofluorocarbon (CFC) type propellants such as Freon 11 and Freon 12 have been implicated in the destruction of the ozone layer and their production has stopped. Hydrofluoroalkanes ((HFA) also known as hydro-fluorocarbons (HFC)) do not contain chlorine and are considered less destructive to ozone and these are proposed as substituted for CFCs. HFAs and in particular 1, 1, 1, 2-tetrafluoroethane (HFA 134a) and 1,1,1,3,3,3-hetafluoropropane (HFA 227) have been recognized as the best candidates for propellants of non-CFC type and a number of medical aerosol formulations using such HFA-based propellant systems have been described. Due to the higher polarity of the HFA propellants, in particular of HFA 134a (dielectric constant D) > to 9.5), with respect to CFC type vehicles (D < 2. 3), the solution formulations with HFA can present a greater degree of chemical stability problems with respect to the corresponding CFC formulations. The preparation of solution formulations of Stable HFA is even more critical when it comes to β2-bronchodilator agonists belonging to the class of phenylalkylamino derivatives, in particular, 8- hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (lH) -quinolinone presents chemical stability problems in This type of vehicle is highly susceptible to chemical degradation. Also, the compound 8-hydroxy-5- [(IR) -1-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone It is highly potent and its strength level of dosage is considerably lower than many other drugs that can be administered using the MDI. Thus, its concentration in the aerosol formulation is very low and this factor, together with its physicochemical properties, increase the difficulties to prepare a formulation that is stable and provides good dosage reproducibility when administered by MDI. In consideration of the problem indicated, it would be highly convenient to provide formulations in the form of HFA solutions that will be administered using MDI aimed at providing pharmaceutical doses of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR)] -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone and its therapeutic salts, in particular the hydrochloride salt (ie TA 2005), which do not require the use of refrigeration, which remain chemically and physically stable during storage under ambient temperature conditions and are characterized by adequate shelf life.

SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide formulations in the form of HFA solutions that will be administered using the DIs to provide pharmaceutical doses of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR ) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (IH) -quinolinone or its salts in the lower respiratory tract of patients suffering from pulmonary diseases such as asthma and chronic obstructive pulmonary disease (COPD) for its acronym in English), characterized by adequate shelf life at room temperature.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention there is provided a pharmaceutical composition comprising as an active ingredient 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl ] amino] ethyl] -2 (1H) -quinolinone or a salt thereof, in particular the hydrochloride salt, in a solution of a liquefied HFA propellant, a co-solvent which is selected from pharmaceutically acceptable alcohols and an amount specific phosphoric acid of high concentration (ie more than about 10 M, preferably more than about 12 M) and in particular 15 M approximately). The apparent pH of said solution is between 2.5 and 5.5. The preferred formulation is a solution in which the active ingredient is completely dissolved. The composition of the invention may be contained in a pressurized MDI which has part or all of its internal metallic surfaces made from stainless steel, anodized aluminum or coated with an inert organic coating. In fact, it has been found that, the chemical stability of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl can be dramatically improved ] amino] ethyl] -2 (HH) -quinolinone or its salts in HFA solution formulations by the use of high concentration phosphoric acid in specific amounts as well as an appropriate selection of the type of cans. Likewise, it has been observed that the stabilizing effect of phosphoric acid is not strictly correlated with its amount of percent w / w in the formulation and when approximately 15 M phosphoric acid is used, it is present in a concentration range of 0.0004 to 0.040 % percent by weight of the total weight of the formulation, the preferred concentration range being 0.0008% w / w up to 0.0075% w / w.

The corresponding apparent pH range is 2.5-5.5, preferably 3.0-5.5, more preferred 3.5-5.0. The "apparent" attribution is used because the pH is indeed characteristic of aqueous liquids in which water is the dominant component (mole fraction> 0.95). In relatively aprotic solvents, such as HFA-ethanol vehicles used in these studies, the protons are not hydrated; their activity coefficients differ significantly from those in aqueous solution. Although the Nernst equation is applied with respect to EMF and the glass electrode system of the pH meter can generate an output in variable millivolts in accordance with the proton concentration and the polarity of the vehicle, the meter reading "pH" does not It is a true pH value. The meter reading represents an apparent pH or acid function (pH '). It has previously been observed that when it is titled 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methyl-ethyl] amino] ethyl] -2 ( 1H) -quinolinone • HCl [TA 2005] in a concentration of 4 μg / 50 μl with a mineral acid and in particular with 0.08 M hydrochloric acid in a commercially available vehicle system model (HFA 43-10 MEE, Vertrel XF, Dupont), in accordance with a method developed by the applicant, the pH profile 'has a negative slope of low inclination up to pH' = 5.0 approximately; after this the acidity function drops abruptly. It is then discovered that in the presence of lower concentrations of TA 2005 and for example with a concentration of 1 μg / 50 μl (0.002% w / v) in the presence of 0.08 M HCl, the pH range is 2.5-5.5 and the The degree of stabilization is determined by the amount in percent of the acid. Subsequent experiments have shown, and is described in more detail in the following section than TA 2005 can be stabilized in a surprisingly more suitable manner with phosphoric acid of high concentration, and in particular with 15 M phosphoric acid or 85% approximately. In fact it has been discovered that the chemical degradation of TA 2005 in a solution of an HFA propellant and a co-solvent not only depends on the acidity function of the solution, but is also catalyzed by trace levels of metal ions and that the stability of TA 2005 can be increased by adding specific amounts of highly concentrated phosphoric acid to the solution both to adjust the apparent pH in a well defined range as well as to sequester the metal ions. In addition, it has been observed that the use of inert containers, in particular that have a part or the total of their internal metallic surfaces coated with an inert organic coating can increase the chemical stability of the active ingredient in the HFA propellant solution. According to a particular embodiment of the invention, a pressurized MDI is provided for administering pharmaceutical doses, consisting of a container coated with an inert coating, filled with a pharmaceutical composition comprising a solution of 8-hydroxy-5- [(IR ) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone in HFA 134a as a propellant which in turn contains from about 8 to about 15% w / w of ethanol as a cosolvent, which also contains from 0.0004% w / w to 0.0075% w / w 85% phosphoric acid (15.2 M). The apparent pH of said solution is between 3.0 and 5.5. The expression "% w / w" means the weight percentage of the component with respect to the total weight of the composition. The active ingredient in said composition that is used to fill said container has adequate chemical stability and shelf life at room temperature and meets the requirements of the ICH Q1A guideline which refers to "Stability Testing of new Active Substances (and Medicinal Products)". Stability tests of Novel Active Substances (and Medicinal Products)], in which a significant change for a drug product is defined as a 5% change in the test from its initial value. The pharmaceutical formulations of the invention may also contain additional excipients and in particular a component of low volatility in order to increase the aerodynamic diameter of the mass median (MMAD) of the aerosol particles when the inhaler is operated. However, in a preferred embodiment, the addition of other components to the formulation is avoided. In WO 98/34596, the applicant describes solution compositions for use in an aerosol inhaler, comprising an active material, a propellant containing a hydrofluoroalkane (HFA), a cosolvent and also comprising a component of low volatility to increase the aerodynamic diameter of the mass median (MMAD) of the aerosol particles when the inhaler is operated. Said application does not solve the technical problem of the chemical stability of the active ingredient but rather it is concerned with the supply of the drug to the lungs. In the international application No. PCT / EP99 / 09002 filed on 11/23/99 published on June 2, 2000, as WO 00/30608 ('608), the applicant discloses pressurized MDI to dispense a solution of an active ingredient in a hydrofluorocarbon propellant, a cosolvent and optionally a low volatility component characterized in that part or all of the internal surfaces of said Inhalers consist of stainless steel, anodized aluminum or are lined with an inert organic coating. The application? 608 makes no mention of a critical role of a mineral acid and in particular of phosphoric acid to improve the chemical stability of the active ingredient in the composition. Conversely, it states that ipatropium bromide (one of the possible active ingredients) is stable in particular types of cans, with or without acids. EP 673240 proposes the use of acids as stabilizers to prevent chemical degradation of the active ingredient in aerosol solution formulations comprising HFA. Most of the examples refer to ipatropium bromide, an anti-cholinergic drug and only one example is given for a β2-agonist, ie, fenoterol. Although salbutamol is claimed, no exemplary formulations are provided. Only stability data for ipatropium bromide are reported and no difference is made between the use of organic and inorganic acids. Phosphoric acid is only cited between the possible inorganic acids. Also, in addition to ipatropium bromide, EP 673240 does not provide guidelines regarding the amount of acid that has to be added in order to stabilize the drugs without compromising the stability of the entire composition in the can. The only mention can be found on page 5, lines 15 to 16, which indicates that an amount of inorganic acid must be added to obtain a pH value between 1 to 7, a fairly broad and generic range. WO 98/34596 relates to solution formulations containing a propellant and a physiologically acceptable polymer that can aid solubilization as well as stability of the active ingredients. WO 00/06121 relates to mixtures of propellant for di-nitrogen monoxide in aerosol and a hydrofluoroalkane in the preparation of aerosols in suspension and solution. The use of di-nitrogen monoxide can improve the storage stability of active ingredients sensitive to oxidation. As for the ß2-agonists such as levosalbutamol sulfate, formoterol fumarate and salmeterol xinafoate, only examples referring to suspensions are reported. In document EP 1 157 689 (? 689) of the Applicant, is reported (example 7) stability data of an HFA 134a solution formulation containing a dose of 3.5 μg / 50 μl of 8-hydroxy-5- [(IR) -l-hydroxy-2- [-] hydrochloride [(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone (TA 2005), 12% w / w ethanol, 1% w / w isopropyl myristate stabilized by different amounts of 0.08 M HCl (1.0 and 1.4 μl) - The formulations appear to be provided with fairly adequate stability if TA 2005 is present in a comparatively high concentration (eg, 3.5 μg / 50 μl) and if stored in position vertical. However, when the inventors of the present invention repeat the test with a rather low concentration of TA 2005 (for example 1 μg / 63 μl), they observe a progressive degradation of the active ingredient in the formulation; see comparative examples 1 and 3. Also, the formulation exemplified in the document? 689 contains isopropyl myristate as a low volatility compound in order to increase the MMAD (aerodynamic diameter of the mass median) of the delivered particles. It was subsequently discovered that it could be quite convenient to provide highly efficient TA 2005 formulations characterized by a deeper penetration to the lung by virtue of a significant fraction, of at least 30%, of fine particles, with a diameter equal to or less than 1.1 μm. Therefore, the low volatility compound should be avoided. It was also discovered later that in this type of highly efficient formulations, characterized by the presence of a fraction of particles equal to or smaller than 1.1 μm greater than 30% and even greater than 50% or more, the TA 2005 may be present in a concentration very low, starting from 0.0005% p / v based on the total volume of the composition. Said compositions have been described in another prior application of the applicant, WO 03/074025 ('025), in which stability data of an HFA solution formulation comprising 8-hydroxy-5- [(IR) hydrochloride are reported. -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone (TA 2005) stabilized by HCl. The stability is determined in a formulation that supplies 4 μg of active compound per actuation, stored in a vertical position at 5 ° C: in these cooling conditions, after 9 months, the content analysis of TA 2005 is greater than 95%; see comparative example 2. However, the inventors of the present invention subsequently discovered that when present in lower concentrations and in other storage conditions, the active ingredient in the formulation degrades rapidly. On the other hand, refrigeration is undesirable because many patients are required to carry aerosol cans with them. In accordance with the first aspect of the present invention, the inventors of the present invention have discovered that, although in accordance with the previous description of document 025 the preferred mineral acid is hydrochloric acid, the chemical stability of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone and its salts are increased by small amounts of acid phosphoric highly concentrated (ie more than about 10 M), preferably about 15 M phosphoric acid, preferably between 0.0008% and 0.01% w / w in the formulation. The mineral acid that best stabilizes the active ingredient 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (ÍH) -quinolinone and its salts in the formulation is phosphoric acid, in particular highly concentrated phosphoric acid. Aerosol formulations containing phosphoric acid are surprisingly stable at temperature environment during a long lifespan. In accordance with a further aspect of the present invention, there is provided a method for filling an aerosol inhaler with a composition of the invention, the method comprising: (a) preparing a solution of 8-hydroxy-5- [(IR) - 1- hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (IH) -quinolinone or its salts in one or more co-solvents optionally containing an ingredient additional active or excipient or an appropriate amount of a low volatility component; (b) filling the device with said solution; (c) adding a predetermined amount of a phosphoric acid; (d) adding a propellant containing a hydrofluoroalkane (HFA); and (e) is crimped with valves and gasified. The active ingredient used in the aerosol compositions of the present invention is a long-acting β2-adrenergic agonist and its combinations with other active ingredients and in particular a corticosteroid or an antimuscarinic drug. Examples of a corticosteroid are: beclomethasone dipropionate, fluticasone propionate, butixocort, mometasone furoate, triamcinolone acetonide, budesonide and its 22R epimer, ciclesonide and rofleponide. Examples of anti-muscarinics are ipatropium bromide, oxitropium bromide and tiotropium bromide. The active ingredient is 8-hydroxy-5- [(IR) -1-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (ÍH) -quinolinone or a salt of it. The preferred salt is the hydrochloride salt, sometimes referred to as TA 2005. Although the preferred formulations of the invention are in the form of solutions, in the case of the combinations, one of the two active ingredients may be present in suspension. TA 2005 can be prepared as described in the patent E.U.A. No. RE 33,024. It is preferred that the formulation be suitable for delivering a therapeutic amount of the active ingredient in one or two drives. Preferably, the formulation is appropriate to deliver 0.5-6 μg / dose, more preferred 1-4 μg / dose and in particular 1 to 2 μg / dose or 2 to 3 μg / dose, either alone or in combination. By the term "dose" is meant the amount of active ingredient delivered by a single actuation of the inhaler. The formulations of the present invention are preferably contained in cans having part or all of their internal surfaces coated with a organic inert coating. Examples of preferred coatings are epoxy-phenol, perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylene resins such as polytetrafluoroethylene, fluorinated ethylene-propylene, polyethersulfone and fluorinated ethylene-propylene polyethersulfone copolymers. Other suitable coatings may be polyamide, poly-imide, polyamide-imide, polyphenylene sulfide or combinations thereof. The most preferred coatings are perfluoroalkoxyalkane, perfluoroalkoxy-alkylene, perfluoroalkylenes such as polytetrafluoroethylene and fluorinated ethylene-propylene and copolymers of polyethersulfones and fluorinated ethylene-propylene. To further improve the stability, cans can have a rolled in flange and preferably a partial or fully boring flange can be used. The formulation is activated by a metering valve that can deliver a volume between 50 μl and 100 μl. Dosing valves equipped with gaskets made of butyl rubber, in particular bromobutyl rubber, of the type described in WO 03/078538 are preferred to further improve the stability of the product. active ingredient in the formulation. The hydrofluorocarbon propellant is preferably selected from the group of HFA 134a, HFA 227 and mixtures thereof. The co-solvent is usually an alcohol, preferably ethanol. The apparent pH range conveniently is between 2.5 and 5.5, preferably between 3.0 and 5.5, even more preferred between 3.5 and 5.0. Sufficiently concentrated phosphoric acid is used, ie more than about 10 M, preferably more than about 12 M, and even more preferred about 15 M to adjust the apparent pH. In the following examples, 85% phosphoric acid is used, ie 15.2 M. The amount of acid to be added to achieve the desired apparent pH is predetermined in the vehicle model reported above. The active ingredient 8-hydroxy-5- [(IR) -1-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (ÍH) -quinolinone or its salt is stabilized with highly concentrated phosphoric acid, preferably about 15 M. In particular, it is preferred to add phosphoric acid in an amount equivalent to 0.0004 to 0.040% w / w of 15 M phosphoric acid, based on the total weight of the phosphoric acid. composition, preferably 0.0008 up 0. 020% w / w of 15 M phosphoric acid, based on the total weight of the composition, more preferred 0.001 to 0.010% w / w of 15 M phosphoric acid based on the total weight of the composition, even more preferred 0.002 up to 0.0075% w / w of 15 M phosphoric acid, based on the total weight of the composition. For the purposes of the invention, an even more concentrated phosphoric acid other than 15 M can be used. In this case, the person skilled in the art can determine the correct percent amount in view of the description of the present application. In this embodiment, it may be preferable to avoid the addition of other excipients or the low volatility component to increase the fraction of particles with a diameter less than or equal to 1.1 μm up to at least 30% and to provide a deeper penetration to the lungs . The concentration of 8-hydroxy-5- [(IR) -1-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone can vary between 0.0005% and 0.024% p / v, taking as a base the total volume of the composition, in order to supply 0.5-6 μg per drive, preferably between 0.001% and 0.016% p / v, based on the volume total of the composition, in order to supply 1 to 4 μg per actuation, more preferred between 0.001% and 0.008% p / v, based on the volume total of the composition, to supply 1 to 2 μg per drive. For example, for 1 and 2 μg / dose, in which a metering volume of 63 μl is used, the final concentrations of the TA 2005 hydrochloride salt supplied per drive are 0.0016% and 0.0032% w / v, respectively, taking as base the total volume of the composition. Suitably, amount of co-solvent in the composition is from 6 to 30% w / w, preferably 5 to 25% w / w, more preferred 5 to 20% w / w, even more preferred still 8 to 15% p / p, based on the total weight of the composition. Under these conditions, the stability of TA 2005 is also increased at very low dose concentrations of 0.5 or 1 μg per drive. The apparent pH values are preferably between 3.0 and 5.0. The stabilizing effects of phosphoric acid are also evaluated in a TA 2005 HFA formulation which comprises as an additional active ingredient budesonide, an anti-inflammatory 20-ketosteroid that satisfies the problems of chemical stability when formulated in an aerosol solution formulation of HFA Other features of the invention will be apparent in the course of the following descriptions of example modalities which are provided to illustrate the invention and are not intended to be limiting thereof.

EXAMPLES In the following examples and comparative examples, and throughout this description, all parts and percentages are by weight, and all temperatures are in degrees Celsius, unless expressly indicated otherwise.

COMPARATIVE EXAMPLE 1 (CORRESPONDING TO EXAMPLE 7 of EP 1 157 689) Stability of acidulated solutions of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H hydrochloride ) -quinolinone (TA 2005) -HFA 134a in cans coated with a fluorocarbon polymer A formulation of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) hydrochloride is prepared -1-methylethyl] amino] ethyl] -2 (ÍH) -quinolinone (TA 2005) (3.5 μg / 50 μl) dissolving 0.84 mg of the active ingredient in HFA 134a containing 12% w / w ethanol and 1.0% w / w p of isopropyl myristate. Coated pMDI cans containing 1.0 and 1.4 μl of hydrochloric acid are placed 0. 08 M (corresponding respectively to an apparent pH of approximately 4.8 and 3.2) in storage, upright at 50 ° C, and samples are taken for content analysis of TA 2005 at the appropriate intervals. The stability data obtained are given in table 1. Each value is expressed as a nominal drug concentration in percent. The results indicate that formulations containing from 1.0 to 1.4 μl of 0.08 M HCl, whose apparent pH is between 3.0 and 5.0, are stable for almost 3 months at 50 ° C.

TABLE 1 Formulations of 8-hydroxy-5- [(IR) -1-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl hydrochloride] 2 (1H) -quinolinone (TA 2005) from Comparative Example 1 - stability data at 50 ° C COMPARATIVE EXAMPLE 2 (CORRESPONDING TO EXAMPLE 1 OF DOCUMENT WO 03/074025) A formulation is prepared to deliver a nominal dose of 1 μg of active ingredient per actuation, with the following formulation shown in Table 2.

TABLE 2 ^ equivalent to 2.0 μl The formulation (120 drives / container, excess of 30 drives) is used to fill aluminum cans that have the inner surface coated with Teflon and equipped with a metering valve that has a metering chamber of 63 μl. An actuator with an orifice diameter of 0.22 mm is used. Analogous formulations are prepared that can provide a nominal dose of 2, 3 or 4 μg of active ingredient per actuation. The formulation of 1 μg per dose is used only to determine the aerodynamic particle size distribution. A stability study is started in a formulation that can supply 4 μg per drive, storing the cans in a vertical position at 5 ° C. The results are obtained as an average of 2 cans. After 9 months the analysis of hydrochloride content of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (ÍH) -quinolinone is greater than 95% and therefore meets the requirements of the ICH Q1A guideline which refers to "Stability Testing of new Active Substances (and Medicinal Products)".

COMPARATIVE EXAMPLE 3 Two aluminum cans having the inner surface coated with Teflon are filled and equipped with commercial valves having a 63 μl metering chamber with the following formulations shown in Table 3.

TABLE 3 A stability study is carried out by storing the formulations in cans placed in vertical position at 40 ° C and 75% relative humidity. After 3 months of storage under these conditions the amount of TA 2005 in percent is 73% and 77%, respectively. In accordance with the results of comparative examples 1 to 3, TA 2005 can be stabilized (8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl ) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone) by the use of hydrochloric acid if TA 2005 is present in the solution formulation in a comparatively high concentration (3.5 μg / 50 μl; 4 μg / 63 μl, respectively) and under cooling conditions. However, if it is present in a fairly low concentration as desired for this type of active ingredient (for example 1 μg or 2 μg / 63 μl), this can no longer be stabilized by the use of hydrochloric acid. The active ingredient 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (ÍH) - hydrochloride quinolinone is a very powerful long-acting ß-agonist at a very low dose-concentration, which should be applied in a low concentration. Also, storage in a refrigerator should be avoided. However, as demonstrated by the results of the following example, the compound hydrochloride of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1- methylethyl] amino] ethyl] -2 (ÍH) -quinolinone, can also be stabilized at very low concentrations (eg 1 μg / 63 μl) by the use of phosphoric acid in an equivalent amount of 0.0004 to 0.040% w / w, preferably 0.0008 to 0.020% w / w, more preferred 0.001 to 0.010% w / w, even more preferred 0.002 to 0.0075% w / w of 15.2 M phosphoric acid, based on the total weight of the composition.

EXAMPLE 1 An analogous formulation is prepared (see Table 4) to deliver a nominal dose of 1 μg of 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (lH) -quinolinone hydrochloride (TA 2005) by drive with the following composition, using phosphoric acid as a stabilizer instead of hydrochloric acid.

TABLE 4 Analogously, formulations can also be prepared that can deliver a nominal dose of 0.5, 1.5, 2, 2.5, 3, 3.5 or 4 μg of active ingredient per actuation. The formulation of table 4 (120 drives / container, excess of 30 drives) is used to fill aluminum cans that have the internal surface coated with Teflon and are equipped with commercial valves that have a 63 μl metering chamber. A study is carried out of stability by storing the formulation in inverted cans and upright at 40 ° C and 75% relative humidity. After six months of storage under these conditions the percent recovery of the active ingredient is quite good with a residual percent amount of TA 2005 of up to 98% in the phosphoric acid range from 0.001 to 0.0027% w / w EXAMPLE 2 Two compositions containing TA 2005 and budesonide are evaluated as active ingredients and two different concentrations of phosphoric acid.

Volume of the valve: 63 μl; concentration: TA 2005 1 μg + budesonide 200 μg / drive; No. of drives: 120 (34 doses of over-filling).

The two active ingredients in the compositions are stable after 3 months of storage at 40 ° C and 75% relative humidity, providing residual percentage amounts of at least 95% TA 2005 and approximately 100% budesonide. Therefore, phosphoric acid is effective to stabilize TA 2005 also in the combination in the presence of budesonide and in the presence of small amounts of water. Obviously, numerous modifications and variations of the present invention are possible in view of the above teachings. Therefore, it should be understood that, within the scope of the appended claims, the invention may be practiced in ways other than those specifically described therein. All the patents and other references mentioned above are incorporated in their entirety in the present invention for reference, as if this were indicated in its entirety.

Claims (27)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS

1. - An aerosol formulation, comprising 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 ( 1H) -quinolinone or a salt thereof, in particular the hydrochloride salt (TA 2005), a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, and highly concentrated phosphoric acid, characterized in that said formulation is in the form of a solution, and said phosphoric acid is present in an amount equivalent to 0.0004 to 0.040% w / w of 15 M phosphoric acid, based on the total weight of the formulation.

2. The formulation according to claim 1, characterized in that said liquefied HFA propellant is at least one member that is selected from the group consisting of HFA 134a, HFA 227, and mixtures thereof.

3. - The formulation in accordance with the claim 1 or 2, characterized in that said cosolvent is ethanol.

4. - The formulation according to any of claims 1-3, characterized in that said phosphoric acid is present in an amount equivalent to

0. 0008 to 0.020% w / w of 15 M phosphoric acid, based on the total weight of the formulation.

5. The formulation according to any of claims 1-3, characterized in that said phosphoric acid is present in an amount equivalent to

0. 001 up to 0.010% w / w of 15 M phosphoric acid, based on the total weight of the formulation.

6. The formulation according to any of claims 1-3, characterized in that it has an apparent pH between 2.5 and 5.5.

7. - The formulation according to any of claims 1-6, characterized in that it has an apparent pH of 3.0 to 5.5.

8. - The formulation according to any of claims 1-6, characterized in that it has an apparent pH of 3.5 to 5.0.

9. The formulation according to any of claims 1-8, characterized in that said compound 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone or salt thereof is present in an amount of 0.0005% up to 0.024% w / v.

10. The formulation according to any of claims 1-8, characterized in that said compound 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone or salt thereof is present in an amount of 0.001% up to 0.016% w / v.

11. The formulation according to any of claims 1-10, characterized in that said co-solvent is present in an amount of 6% up to 30% w / v.

12. The formulation according to any of claims 1-10, characterized in that said co-solvent is present in an amount of 6% up to 25% w / v.

13. A pressurized metered dose inhaler, containing a formulation, characterized in that said formulation comprises 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl)] -1-methylethyl] amino] ethyl] -2 (IH) -quinolinone or a salt thereof, in particular the hydrochloride salt (TA 2005), a liquefied HFA propellant, a co-solvent that is selected from pharmaceutically alcohols acceptable, and highly concentrated phosphoric acid, in which said formulation is in the form of a solution, and said phosphoric acid is present in an amount equivalent to 0.0004 to 0.040% w / w of 15 M phosphoric acid, based on the total weight of the formulation.

14. The pressurized metered dose inhaler according to claim 13, characterized in that said liquefied HFA propellant is at least one member that is selected from the group consisting of HFA 134a, HFA 227, and mixtures thereof.

15. The pressurized metered dose inhaler according to claim 13 or 14, characterized in that said co-solvent is ethanol.

16. The pressurized metered dose inhaler according to any of claims 13-15, characterized in that said phosphoric acid is present in said formulation in an amount equivalent to 0.0008 to 0.020% w / w of 15 M phosphoric acid, taking as base the total weight of the formulation.

17. The pressurized metered dose inhaler according to any of claims 13-15, characterized in that said phosphoric acid is present in said formulation in an amount equivalent to 0.001 to 0.010% w / w of 15 M phosphoric acid, taking as base the total weight of the formulation.

18. The pressurized metered dose inhaler according to any of claims 13-15, characterized in that said solution has an apparent pH between 2.5 and 5.5.

19. The pressurized metered dose inhaler according to any of claims 13-18, characterized in that said formulation has an apparent pH of 3.0 to 5.5.

20. The pressurized metered dose inhaler according to any of claims 13-18, characterized in that said formulation has an apparent pH of 3.0 to 5.0.

21. The pressurized metered dose inhaler according to any of claims 13-18, characterized in that said compound 8-hydroxy-5- [(IR) -1-hydroxy-2- [[(IR) -2- ( -methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (lH) -quinolinone or salt thereof is present in an amount of 0.0005% up to 0.024% w / v.

22. The pressurized metered dose inhaler according to any of claims 13-18, characterized in that said compound 8-hydroxy-5- [(IR) -1-hydroxy-2- [[(IR) -2- ( 4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone or salt thereof is present in an amount of 0.001% up to 0.016% w / v.

23. The pressurized metered dose inhaler according to any of claims 13-22, characterized in that said co-solvent is present in said formulation in an amount of 6% up to 30% w / w.

24. The pressurized metered dose inhaler according to any of claims 13-22, characterized in that said co-solvent is present in said formulation in an amount of 6% up to 25% w / w.

25. The pressurized metered dose inhaler according to any of claims 13-24, characterized in that part or all of its internal metallic surfaces are coated with an inert organic coating.

26. The pressurized metered dose inhaler according to claim 25, characterized in that it is coated with an inert organic coating that is selected from the group consisting of epoxy-phenol resins, perfluoroalkoxyalkanes, perfluoroalkoxy-alkylenes, perfluoroalkylenes, polyethersulfones. , fluorinated ethylene-propylene-polyethersulfone copolymers, and mixtures thereof.

27. A method for filling an aerosol inhaler, said method comprising: (a) preparing a solution of one or more active ingredients in one or more co-solvents; (b) filling said inhaler with said solution; (c) adding a predetermined amount of phosphoric acid to said solution; (d) adding a propellant comprising a hydrofluoroalkane (HFA) to said solution; and (e) sealing with valves and gasifying characterized in that at least one of said active ingredients is 8-hydroxy-5- [(IR) -l-hydroxy-2- [[(IR) -2- (4-methoxyphenyl)] -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone or a salt thereof, in particular the hydrochloride salt (TA 2005), present in an amount of 0.0005% up to 0.024% w / v, preferably 0.001% up to 0.016% w / v, and said phosphoric acid is present in an amount equivalent to 0.0004 up to 0.040% w / w, preferably 0.0008 up to 0.020% w / w, more preferred 0.001 up to 0.010% w / w phosphoric acid 15 M , taking as a base the total weight of the final solution (formulation).