HK1103280B - Stable pharmaceutical solution formulations for pressurized metered dose inhalers - Google Patents

Description

Stable pharmaceutical solution formulations for pressurized metered dose inhalers

Technical Field

The present invention relates to stable pharmaceutical solution formulations for use with pressurized Metered Dose Inhalers (MDIs) suitable for aerosol administration. In particular, the present invention relates to solutions containing beta for use with pressurized Metered Dose Inhalers (MDIs) suitable for aerosol administration₂Agonist 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl]Amino group]Ethyl radical]-2- (1H) -quinolinone or a salt thereof (hereinafter the hydrochloride salt is referred to as TA2005) and is stable over a pharmaceutically acceptable shelf life at room temperature.

Background

Pressurized metered dose inhalers are known devices for applying pharmaceutical products to the respiratory tract by inhalation.

Drugs that are typically delivered by inhalation include, for example, beta₂Bronchodilators of agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergies and other substances that can be effectively administered by inhalation, thus increasing the therapeutic index and reducing the side effects thereof.

MDIs use a propellant to spray droplets containing the pharmaceutical product as an aerosol into the respiratory tract. Formulations for aerosol administration via MDIs may be solutions or suspensions. The advantage of a solution formulation is that it is homogeneous, with the active ingredient and adjuvants completely dissolved in the propellant vehicle or its mixture with a suitable cosolvent (e.g. ethanol). Solution formulations also avoid the physical stability problems associated with suspension formulations, thereby ensuring consistent and uniform dosing.

Preferred propellants for use in medicinal aerosols for many years have been a group of chlorofluorocarbon compounds, commonly known as freons or CFCs, e.g. CCl₃F (Freon 11 or CFC-11), CCl₂F₂(Freon 12 or CFC-12) and CClF₂-CClF₂(Freon 114 or CFC-114).

Recently, chlorofluorocarbon (CFC) propellants such as freon 11 and freon 12 and the like have been considered to be involved in the destruction of the ozone layer, and therefore the production thereof is gradually being stopped.

Hydrofluoroalkanes ((HFAs), also known as hydrogen-fluorine-carbon (HFCs)) do not contain chlorine and are considered to be less damaging to the ozone layer, suggesting them as replacements for CFCs.

HFAs, in particular 1, 1, 1, 2-tetrafluoroethane (HFA 134a) and 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA 227) have been recognised as being the best candidates for non-CFC propellants, and a number of pharmaceutical aerosol formulations utilising such HFA propellant systems have been disclosed.

Due to the higher polarity of the HFA propellants, in particular the polarity of HFA134a (dielectric constant D.gtoreq.9.5) is higher than that of CFC carriers (D.gtoreq.2.3), HFA solution formulations may suffer from a number of chemical stability problems compared to corresponding CFC formulations.

When relating to bronchodilators beta which are phenylalkylamino derivatives₂For agonists, it is more critical to prepare stable HFA solution formulations; in particular, 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl]Amino group]Ethyl radical]-2- (1H) -quinolinone suffers from chemical stability problems in this type of support and it is very sensitive to chemical degradation.

In addition, 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone has a high potency at a dose strength level far below that of many other drugs that can be administered by MDIs. Thus, its concentration in aerosol formulations is very low, a factor which, together with its physicochemical properties, increases the difficulty in preparing formulations which are stable and which provide good dose reproducibility when administered by MDIs.

In view of these problems described above, it would be a significant advantage to provide a formulation in the form of an HFA solution for administration by MDIs, in order to provide a pharmaceutically acceptable dosage of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, and therapeutically acceptable salts thereof, particularly the hydrochloride salt (i.e., TA2005), which does not require refrigeration, is chemically and physically stable over a shelf life at room temperature, and is characterized by a sufficiently long shelf life.

Summary of The Invention

It is therefore an object of the present invention to provide a formulation in the form of a HFA solution for administration by MDIs for providing a pharmaceutically acceptable dose of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof, into the lower respiratory tract of a patient with a pulmonary disorder, such as asthma and Chronic Obstructive Pulmonary Disease (COPD), the pharmaceutical being characterized by a sufficiently long shelf life at room temperature.

Detailed description of the preferred embodiments

The present invention provides a pharmaceutical composition comprising as active ingredient 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof (particularly the hydrochloride salt), a co-solvent selected from pharmaceutically acceptable alcohols, and a specific amount of a high concentration (i.e., greater than about 10M, preferably greater than about 12M, more preferably greater than about 15M) of phosphoric acid in a liquefied HFA propellant solution. The apparent pH of the solution is between 2.5 and 5.5.

The formulation is preferably a solution in which the active ingredient is completely dissolved.

The compositions of the present invention may be incorporated into pressurized MDI having a metallic inner surface made partially or entirely of stainless steel, anodized aluminum, or lined with an inert organic coating.

It has in fact been found that the chemical stability of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof, in a HFA solution formulation can be significantly improved by using a specific amount of a high concentration of phosphoric acid and selecting an appropriate container.

Furthermore, it has been noted that the stabilizing effect of phosphoric acid is not strictly related to its w/w percentage in the formulation, when about 15M phosphoric acid is used, its concentration ranges from 0.0004 to 0.040% by weight of the total formulation, the preferred concentration range being from 0.0008 to 0.0075% by weight.

The corresponding apparent pH value ranges from 2.5 to 5.5, preferably from 3.0 to 5.5, more preferably from 3.5 to 5.0.

The attribute "apparent" is used because the pH value is indeed a property of aqueous solutions with water as the major component (mole fraction > 0.95). In relatively aprotic solvents such as the HFA-ethanol carriers used in these studies, the protons are non-hydrated; their activity coefficients are significantly different from those in aqueous solutions. Although the Nernst equation associated with EMF is applied and the pH meter glass electrode system will produce a variable millivolt output depending on proton concentration and carrier polarity, the pH meter reading is not a true value. This meter reading represents an apparent pH or acidity function (pH').

It has been found that in a commercially available model support system (HFA 43-10MEE, Vertrel XF, Dupont), when 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone is titrated with a mineral acid, in particular with 0.08M hydrochloric acid, at a concentration of 4 μ g/50 μ l, the pH 'curve shows a shallow negative slope, according to the method proposed by the applicant, to about pH' ═ 5.0; after which the acidity function suddenly drops.

Furthermore, it was found that the concentration of TA2005 was low, e.g., 1. mu.g/50. mu.l (0.002% w/v) in 0.08M HCl, the pH ranged from 2.5 to 5.5, and the degree of stability was determined by the percentage of acid.

Surprisingly, more experiments have shown (as will be described in detail below) that TA2005 is better stabilized with high concentrations of phosphoric acid, particularly with about 15M or 85% phosphoric acid.

It has in fact been found that the chemical degradation of TA2005 in a solution of HFA propellant and co-solvent is not only dependent on the acidity function of the solution, it can also be catalyzed by trace levels of metal ions, and that the apparent pH can be adjusted within a well-defined range by adding a specific amount of high concentration of phosphoric acid to the solution, and can also act as a metal ion-blocking agent, thereby enhancing the stability of TA 2005.

Furthermore, it has been found that the use of an inert container, particularly one in which part or all of its metallic internal surface is lined with an inert organic coating, can enhance the chemical stability of the active ingredient in the HFA propellant solution.

According to a particular embodiment of the present invention there is provided a pressurized MDI for use in the dosing of drugs consisting of a container lined with an inert coating containing a pharmaceutical composition comprising a solution of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone in HFA134a as propellant comprising about 8-15% w/w ethanol as co-solvent further comprising 0.0004% w/w to 0.0075% w/w 85% (15.2M) phosphoric acid.

The apparent pH of the solution is between 3.0 and 5.5. "% w/w" refers to the weight percent of the ingredient relative to the total weight of the composition.

The active ingredient of such a pharmaceutical composition placed in said container has good chemical stability and shelf life at room temperature, which complies with the ICH guidelines Q1A for "stability tests for new active substances (and pharmaceutical products)", in which a significant change of the pharmaceutical product is defined as a 5% change in the result of the determination compared to the initial value.

The pharmaceutical composition of the invention may further comprise other excipients, in particular low volatility components, to increase the Mass Median Aerodynamic Diameter (MMAD) of the aerosol particles on actuation of the inhaler.

In a preferred embodiment, however, the addition of other ingredients to the formulation is avoided.

In WO 98/34596, the applicant describes a solution composition for use in an aerosol inhaler comprising an active material, a propellant containing a Hydrofluoroalkane (HFA), a cosolvent and further comprising a low volatility component to increase the Mass Median Aerodynamic Diameter (MMAD) of the aerosol particles on actuation of the inhaler. Said application does not address the technical problem of chemical stability of the active ingredient, but only concerns the delivery of the drug to the lung.

In international application PCT/EP99/09002, filed on 23/11/99, 2/2000, published on 2/6 (publication No. WO00/30608 (' 608)), the applicant disclosed pressurised MDIs for the administration of a solution of an active ingredient in a hydrofluorocarbon propellant, a co-solvent and optionally a low volatility ingredient, characterised in that part or all of the internal surface of the inhaler is made of stainless steel, anodised aluminium or is lined with an inert organic coating. The' 608 application does not describe the critical role of inorganic acids, particularly phosphoric acid, in improving the chemical stability of the active ingredients in the composition. Instead it only describes that ipratropium bromide (a possible active ingredient) is stable in a particular container with or without acid.

EP 673240 proposes the use of an acid as a stabilizer to prevent chemical degradation of the active ingredient in HFA-containing aerosol solution formulations. Most of the examples relate to ipratropium bromide, which is an anticholinergic drug, while only one example relates to β₂An agonist, i.e. fenoterol. Although salbutamol is claimed, no exemplary formulation is provided. Only the stability data for ipratropium bromide is reported and no distinction is made between the use of organic and inorganic acids. Phosphoric acid is only one of the possible mineral acids cited. Furthermore, there is no guidance in EP 673240 for the amount of acid that must be added to stabilize the drug without compromising the stability of the overall composition in the container, other than ipratropium bromide. The only implications that can be found on page 5, lines 15-16, are that of saying: the mineral acid should be added in an amount to give a pH of 1-7, which is a very broad and general range.

WO 98/34596 relates to solution formulations comprising a propellant and a physiologically acceptable polymer which aids in the dissolution and stability of the active ingredient.

WO 00/06121 relates to propellant mixtures of aerosol nitrous oxide and a hydrofluoroalkane in the preparation of suspension and solution aerosols.The use of dinitrogen monoxide improves the stability of oxidation-sensitive active ingredients during storage. For beta is₂Agonists such as levosalbutamol sulphate, formoterol fumarate and salmeterol xinafoate, only examples relating to suspensions have been reported.

In the EP 1157689 (' 689) application, stability data are reported for a HFA134a solution formulation (example 7) containing a dose of 3.5. mu.g/50. mu.l of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride (TA 2005), 12% w/w ethanol and 1% w/w isopropyl myristate, and stabilized by the addition of varying amounts of 0.08M HCL (1.0 and 1.4. mu.l).

If the concentration of TA2005 is relatively high (e.g., 3.5. mu.g/50. mu.l) and stored upright, the formulation appears to have very good stability. However, when the inventors repeated this experiment at a lower concentration of TA2005 (e.g. 1 μ g/63 μ l), they found that there was an incremental degradation of the active ingredient in the formulation; see comparative examples 1 and 3.

In addition, the formulation example in' 689 included isopropyl myristate as a low volatility compound to increase MMAD (mass median aerodynamic diameter) of the delivery particles. It has subsequently been found that it is highly advantageous to provide a highly effective TA2005 formulation which is characterised by a relatively deep lung penetration due to a significant proportion (at least 30%) of particles having a diameter of 1.1 μm or less. The use of low volatility compounds should therefore be avoided.

It was also found thereafter that in such very effective formulations, characterized by the presence of a fraction of particles with a diameter equal to or less than 1.1 μm in a proportion exceeding 30%, even 50% or more, the concentration of TA2005 could be very low, which could start from 0.0005% w/v based on the total capacity of the composition.

Said composition has been described in another previous application of the applicant (WO 03/074025 (' 025)) in which stability data are reported for a HFA solution formulation comprising 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride (TA 2005) and stabilized by HCL.

The stability of a formulation delivering 4 μ g of active ingredient at a single actuation was measured and stored upright at 5 ℃: TA2005 measurements exceeded 95% after 9 months under the stated refrigeration conditions; see comparative example 2.

However, the present inventors have found that the active ingredient in the formulation degrades rapidly when the concentration is low and under other storage conditions.

On the other hand, the use of refrigeration is undesirable as many patients are required to carry aerosol canisters with them.

According to a first aspect of the present invention, the present inventors have found that the stability of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, and salts thereof, is increased by a small amount of a high concentration of phosphoric acid (i.e., more than 10M), preferably about 15M, preferably containing 0.0008% to 0.01% w/w phosphoric acid in the formulation, according to the prior disclosure of' 025, the preferred mineral acid is hydrochloric acid. The inorganic acid which is capable of more effectively stabilizing the active ingredient 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone and its salts in the preparation is phosphoric acid, particularly phosphoric acid at a relatively high concentration.

Surprisingly, aerosol formulations containing phosphoric acid are stable over a long shelf life at room temperature.

Another aspect of the invention provides a method of charging an aerosol inhaler with a composition of the invention, the method comprising:

(a) preparing a solution of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof, in one or more co-solvents, optionally containing other active ingredients or adjuvants or suitable amounts of low volatility ingredients;

(b) charging the device with the solution;

(c) adding a predetermined amount of phosphoric acid;

(d) adding a propellant containing Hydrofluoroalkane (HFA);

(e) the valve was crimped and inflated.

The active ingredient useful in the aerosol compositions of the present invention is long-acting beta₂-adrenergic agonists, and compositions thereof with other active ingredients, in particular corticosteroids or antimuscarinic drugs. Corticosteroids are for example beclomethasone dipropionate, fluticasone propionate, butencort, mometasone, furoates, triamcinolone acetonide, budesonide and its 22R-epimer, ciclesonide and rofleponide. Antimuscarinic drugs are, for example, ipratropium bromide, oxitropium bromide and tiotropium bromide.

The active ingredient is 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone or a salt thereof. A preferred salt is the hydrochloride salt, often referred to as TA 2005.

Although the preferred formulation of the invention is in the form of a solution, in the composition one of the two active ingredients may be present in suspension.

TA2005 can be prepared as described in us patent RE 33,024.

We recommend formulations that require only one or two actuations to deliver a therapeutically effective amount of the active ingredient. Preferred formulations will be suitable for delivery of 0.5-6. mu.g/dose, more preferably 1-4. mu.g/dose, especially 1-2. mu.g/dose or 2-3. mu.g/dose, either alone or in combination. By "dose" we mean the amount of active ingredient delivered by a single actuation of the inhaler.

The formulations of the present invention are preferably packaged in containers having some or all of their interior surfaces lined with an inert organic coating. Examples of preferred coatings are epoxy phenol resins, perfluoroalkoxyalkanes, perfluoroalkoxyalkenes, perfluoroolefins (e.g., polytetrafluoroethylene), fluorinated-ethylene-propylene, polyethersulfone, and copolymers of fluorinated-ethylene-propylene polyethersulfone. Other suitable coatings may be polyamides, polyimides, polyamideimides, polyphenylene sulfides, or combinations thereof.

The most preferred coatings are copolymers of perfluoroalkoxyalkanes, perfluoroalkoxy-olefins, perfluoroolefins (e.g., polytetrafluoroethylene), fluorinated-ethylene-propylene, and fluorinated-ethylene-propylene polyethersulfones.

To further increase stability, containers with inner roll-in edges and preferably partially or fully turned edges may be used.

The formulation is actuated through a metering valve capable of delivering volumes of 50 μ l to 100 μ l at a time.

Metering valves fitted with gaskets made of butyl rubber, in particular bromobutyl rubber as disclosed in WO 03/078538, may be preferred to further improve the stability of the active ingredient in the formulation.

The hydrofluorocarbon propellant is preferably selected from HFA134a, HFA 227 and mixtures thereof.

The co-solvent is generally an alcohol, preferably ethanol.

The apparent pH range is advantageously between 2.5 and 5.5, preferably between 3.0 and 5.5, more preferably between 3.5 and 5.0. High concentrations of phosphoric acid, i.e., greater than about 10M, preferably greater than about 12M, and most preferably about 15M, are used to adjust the apparent pH. 85%, i.e. 15.2M phosphoric acid was used in the following examples.

The amount of acid to be added to achieve the desired apparent pH will be predicted in the model support reported previously.

The active ingredient 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof, is stabilized using a high concentration of phosphoric acid, preferably about 15M phosphoric acid. In particular, it is preferred that the amount of phosphoric acid added is 0.0004 to 0.040% w/w of 15M phosphoric acid based on the total weight of the composition, preferably 0.0008 to 0.020% w/w of 15M phosphoric acid based on the total weight of the composition, more preferably 0.001 to 0.010% w/w of 15M phosphoric acid based on the total weight of the composition, and still more preferably 0.002 to 0.0075% w/w of 15M phosphoric acid based on the total weight of the composition. Higher concentrations of phosphoric acid in excess of 15M may also be used for the purposes of the present invention. In such a case, one skilled in the art would be able to determine the appropriate percentage based on the scope of the present disclosure. In this embodiment, it may also be preferable to avoid the addition of other adjuvants or low-volatility components in order to increase the proportion of particles having a diameter of less than or equal to 1.1 μm to at least 30% in order to achieve a deeper lung penetration.

The concentration of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone can be varied from 0.0005% to 0.024% w/v based on the total volume of the composition so that 0.5-6 μ g can be delivered per actuation; preferably 0.001% to 0.016% w/v based on the total volume of the composition, so as to deliver 1-4 μ g per actuation; more preferably 0.001% to 0.008% w/v based on the total volume of the composition so as to deliver 1-2 μ g per actuation energy. For example, for 1 and 2 μ g/dose, where a metered volume of 63 μ l is used, the final concentrations of the hydrochloride salt TA2005 delivered at each actuation are 0.0016% and 0.0032% w/v, respectively, based on the total volume of the composition. Suitable amounts of co-solvent in the composition are from 6 to 30% w/w, preferably from 5 to 25% w/w, more preferably from 5 to 20% w/w, more preferably from 8 to 15% w/w, all based on the total weight of the composition.

Under these conditions, the stability of TA2005 was also improved at very low dosing concentrations of 0.5 or 1 μ g per actuation.

The apparent pH is preferably between 3.0 and 5.0.

In addition, the stabilizing effect of phosphoric acid was tested in TA2005 HFA formulations, which also contained an active ingredient, budesonide, and an anti-inflammatory 20-ketosteroid, which were added to the HFA aerosol solution formulations during their preparation and which experienced chemical stability problems.

Other features of the present invention will become more apparent during the course of the following description of specific embodiments, which are intended to illustrate the invention without limiting its scope.

Detailed description of the preferred embodiments

Examples

In the following examples and comparative examples, and within the scope of the specification, all parts and percentages are by weight and all temperatures are in degrees celsius unless otherwise indicated.

Comparative example 1 (corresponding to example 7 in EP 1157689)

Stability of acidified 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride (TA 2005) -HFA 134a solution in a container having a fluorocarbon polymer coating.

A preparation of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride (TA 2005) was prepared by dissolving 0.84mg of the active ingredient in HFA134a containing 12% w/w ethanol and 1.0% w/w isopropyl myristate (3.5. mu.g/50. mu.l). Containers coated with pMDI were stored upright at 50 ℃ and containing 1.0 and 1.4. mu.l of 0.08M hydrochloric acid (corresponding to apparent pH values of about 4.8 and 3.2, respectively), and sampled at appropriate intervals for analysis of TA2005 content.

The stability data obtained are shown in table 1.

Each value is expressed as a percentage of the nominal drug concentration.

The results show that at 50 ℃, the formulation containing 1.0-1.4 μ l of 0.08M hydrochloric acid is stable for about three months, with the apparent pH of the formulation between 3.0 and 5.0.

Table 1: stability data comparing the 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride (TA 2005) formulation of example 1 at 50 deg.C

Comparative example 2 (corresponding to example 1 in WO 03/074025)

Formulations were prepared according to the formulations shown in table 2 below, and were capable of delivering a nominal dose of 1 μ g of active ingredient per actuation.

Table 2:

equivalent to 2.0. mu.l

The formulations (120 actuations/canister, over 30 actuations) were loaded into aluminum canisters whose inner surfaces were coated with Teflon (Teflon) and equipped with a metering valve having a 63 μ l metering chamber. An actuator with an aperture of 0.22mm was used.

Similar formulations were prepared that were capable of delivering a nominal dose of 2, 3 or 4 μ g of active ingredient per actuation. The formulation used 1 μ g per dose was used only for the measurement of the aerodynamic particle size distribution.

These jars were stored upright at 5 ℃ and stability studies were performed on formulations capable of delivering 4 μ g of active ingredient per actuation.

Results were averaged over 2 tanks.

After 9 months, the analytical result for 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride was higher than 95%, thus meeting the requirements of ICH guide Q1A for "stability test for new active substances (and pharmaceutical products)".

Comparative example 3:

the formulations shown in table 3 below were loaded into two aluminum cans coated on their inner surfaces with teflon and fitted with a commercially available valve having a 63 mul metering chamber.

Table 3:

these formulations were stored upright at 40 ℃ and 75% relative humidity and then subjected to stability studies. After three months of storage under these conditions, the percentage of TA2005 was 73% and 77%, respectively.

According to the results of comparative examples 1 to 3, if TA2005 in the solution preparation was present at a higher concentration (3.5. mu.g/50. mu.l and 4. mu.g/63. mu.l, respectively), and TA2005 (8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl) could be stabilized by using hydrochloric acid under refrigeration conditions]Amino group]Ethyl radical]-2- (1H) -quinolinone hydrochloride). However, if this active ingredient is present at the desired low concentration (e.g. 1. mu.g or 2. mu.g/63. mu.l), it will no longer be able to be stabilized using hydrochloric acid. Active ingredient 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl]Amino group]Ethyl radical]-2- (1H) -quinolinone hydrochloride is a very effective long-acting beta₂Agonists, which are effective at very low dosage concentrations, should therefore be applied at low concentrations. In addition, refrigerated preservation should be avoided.

However, as shown by the results in the following examples, 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride can also be stabilized at very low concentrations (e.g., 1. mu.g/63. mu.l) by using phosphoric acid in an amount equivalent to 0.0004-0.040% w/w, preferably 0.0008-0.020% w/w, more preferably 0.001-0.010% w/w, still more preferably 0.002-0.0075% w/w of 15.2M phosphoric acid, based on the total weight of the composition.

Example 1:

similar formulations were prepared (see Table 4) according to the following composition, which delivered a nominal dose of 1 μ g of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone hydrochloride per actuation (TA 2005), and phosphoric acid was used as a stabilizer instead of hydrochloric acid.

Table 4:

similarly, formulations capable of delivering a nominal dose of 0.5, 1.5, 2, 2.5, 3, 3.5 or 4 μ g of active ingredient may also be prepared.

The formulations in table 4 (120 actuations/canister, over 30 actuations) were loaded into aluminum canisters, which were coated on the inside surface with teflon, and fitted with a commercially available valve having a 63 μ l metering chamber.

These formulations were stored upright and inverted at 40 ℃ and 75% relative humidity and then subjected to stability studies. After six months of storage under these conditions, the percent recovery of active ingredient was very high, with up to 98% of TA2005 remaining when phosphoric acid was 0.001-0.0027% w/w.

Example 2:

two compositions were tested, which contained TA2005 and budesonide as active ingredients, and two different concentrations of phosphoric acid.

Composition (I)	Mg	％w/w
			Budesonide	30.8	0.2800
TA2005(CHF4226)	0.154	0.0014
			Anhydrous ethanol	1650	15.0000
Water (W)	16.5	0.1500
			85% phosphoric acid (15.2M)	0.35 or 0.7	0.0032 or 0.0064
HFA 134a	9302.196 or 9301.846	84.5654 or 84.5622
			Total amount of	11000	100.0000

Valve volume: 63 μ l; concentration: TA 20051. mu.g + budesonide 200. mu.g/actuation, actuation number: 120 times (34 overfill doses).

Both active ingredients in the composition were stable after three months of storage at 40 ℃ and 75% relative humidity, with at least 95% TA2005 remaining and about 100% budesonide.

Thus phosphoric acid is also effective in stabilizing TA2005 in the presence of a small amount of water in conjunction with the association of TA2005 with budesonide.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

All patents and other documents mentioned above are incorporated by reference in their entirety for all purposes.

Claims (15)

1. An aerosol formulation comprising 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof; liquefying the HFA propellant; a co-solvent selected from pharmaceutically acceptable alcohols; and concentrated phosphoric acid, wherein the formulation is in the form of a solution in an amount equivalent to 0.0004 to 0.040% w/w of 15M phosphoric acid based on the total weight of the formulation, wherein the amount of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof, is 0.0005% to 0.024% w/v.

2. The formulation of claim 1 wherein the liquefied HFA propellant is at least one member selected from the group consisting of HFA134a, HFA 227, and mixtures thereof.

3. The formulation of claim 1, wherein the co-solvent is ethanol.

4. The formulation of claim 1, wherein the amount of phosphoric acid corresponds to 0.0008-0.020% w/w 15M phosphoric acid based on the total weight of the formulation.

5. The formulation of claim 4, wherein the amount of phosphoric acid is equivalent to 0.001-0.010% w/w 15M phosphoric acid based on the total weight of the formulation.

6. The formulation of claim 4 having an apparent pH of between 2.5 and 5.5.

7. The formulation of claim 6 having an apparent pH of between 3.0 and 5.5.

8. The formulation of claim 7 having an apparent pH of between 3.5 and 5.0.

9. The formulation of claim 1 wherein the amount of 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] -2- (1H) -quinolinone, or a salt thereof, is 0.001% -0.016% w/v.

10. The formulation of claim 1, wherein the co-solvent is present in an amount of 6% to 30% w/v.

11. The formulation of claim 10, wherein the co-solvent is present in an amount of 6% to 25% w/v.

12. A pressurized metered dose inhaler containing the formulation of claim 1.

13. The pressurized metered dose inhaler according to claim 12, wherein part or all of the metal inner surface is lined with an inert organic coating.

14. The pressurized metered dose inhaler of claim 13 lined with an inert organic coating selected from the group consisting of: epoxy phenol resins, perfluoroalkoxyalkanes, perfluoroalkoxyalkenes, perfluoroalkenes, polyethersulfones, fluorinated-ethylene-propylene polyethersulfone copolymers, and mixtures thereof.

15. A method of filling an aerosol inhaler with the formulation of claim 1, the method comprising:

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

(b) charging said solution into said inhaler;

(c) adding a predetermined amount of phosphoric acid to the solution;

(d) adding a propellant containing Hydrofluoroalkane (HFA) to said solution;

(e) the valve was crimped and inflated.