Aerosol solution formulations for use in an aerosol inhaler which comprise 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]-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 exhibit improved shelf life. The formulation may be optionally contained in a can having part or all of its internal metallic surfaces lined with an inert organic coating.

Description of the Invention

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novel formulations in the form of HFA solutions to be administered by MDIs for providing pharmaceutical doses of a .beta..sub.2-agonists into the lower respiratory tract of patients suffering from pulmonary diseases such as asthma and chronic obstructive pulmonary disease (COPD), characterized by having an adequate shelf-life.

It is another object of the present invention to provide novel formulations which comprise 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinolinone or a salt thereof, in particular the hydrochloride salt (TA 2005).

It is an object of the present invention to provide formulations in the form of HFA solutions to be administered by MDIs for providing pharmaceutical doses of 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinoline or a salt thereof, in particular the hydrochloride salt (TA 2005) with an acceptable shelf-life.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that aerosol formulations, which comprise 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl-2(1H)-quinolinone or a salt thereof, a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, and phosphoric acid, in which the formulation is in the form of a solution, and the phosphoric acid is present in an amount equivalent to 0.0004 to 0.040% by weight of 15 M phosphoric acid, based on the total weight of the formulation exhibit an improved shelf life.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention there is provided a pharmaceutical composition comprising a .beta..sub.2-agonist belonging to the class of phenylalkylamino derivatives in a solution of a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, in which the apparent pH of the solution has been adjusted to between 2.5 and 5.0 by addition of small amounts of a mineral acid.

In particular it is provided a formulation comprising as active compound 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinolinone or a salt thereof, in particular the hydrochloride salt, in a solution of a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, in which the apparent pH of the solution has been adjusted to between 2.5 and 5.0 by addition of a specific amount of high concentrated (i.e., more than about 10 M, preferably more than about 12 M and in particular about 15 M) phosphoric acid. The composition of the invention may be contained in a pressurized MDI having part or all of its internal metallic surfaces made of stainless steel, anodised aluminum or lined with an inert organic coating.

In fact, it has been found that, in the case of certain active ingredients such as .beta..sub.2-agonists, their chemical stability in HFA solution formulations could be dramatically improved by a proper and combined selection of the kind of cans as well as the apparent pH range. The attribution `apparent` is used as pH is indeed characteristic of aqueous liquids where water is the dominant component (Mole Fraction >0.95). In relatively aprotic solvents, such as the HFA-ethanol vehicles used in these studies, protons are non-hydrated; their activity coefficients differ significantly from those in aqueous solution. Although the Nernst equation with respect to EMF applies and the pH-meter glass electrode system will generate a variable milli-volt output according to proton concentration and vehicle polarity, the "pH" meter reading is not a true pH value. The meter reading represents an apparent pH or acidity function (pH').

When TA 2005 was titrated with a strong acid in a model vehicle system commercially available (HFA 43-10MEE, VERTREL XF, Dupont), according to a method developed by the applicant, the pH' profile exhibited a shallow negative slope to about pH'=5.0; thereafter the acidity function dropped abruptly.

On the other hand, the use of inert containers avoids the leaching of metal ions or alkali as a consequence of the action of the acid contained in the formulation on the inner walls of the cans. Metal ions such Al.sup.3+ or alkali respectively deriving from the conventional aluminum or glass cans could in turn catalyze radical oxidative or other chemical reactions of the active ingredient which give rise to the formation of degradation products.

According to another embodiment of the present invention there is also provided a pharmaceutical composition further containing a low volatility component in such a way as to, besides increasing the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler as explained in the following, further improve the stability of the formulation. In fact, the addition of a low volatility component with a reduced polarity with respect to the co-solvent such as an ester may allow either a reduction in the amount of acid to be added for adjusting the pH and diminish the polarity of the medium so limiting the possible uptake of environmental water.

According to another embodiment of the invention, there is provided a pressurised MDI consisting of a coated container filled with a pharmaceutical composition consisting of a solution of TA 2005 in HFA 134a as a propellant in turn containing ethanol as a co-solvent with or without isopropyl myristate as a low volatility component, the apparent pH of said solution having been adjusted to between 3.0 and 5.0 by addition of small amounts of a mineral acid.

It has in particular been found that in presence of lower concentrations of TA 2005 and for example with a concentration of 1 .mu.g/50 .mu.l (0.002% w/v) in the presence of 0.08 M HCl, the pH interval is of 2.5-5.5 and the degree of stabilization is determined by the percent amount of the acid.

Further experiments have shown, and it will be described in detail in the following, that TA 2005 can be better stabilized with high concentrated phosphoric acid, and in particular with 85% (about 15 M) phosphoric acid.

In fact, it has now been found that TA 2005 chemical degradation in a solution of a HFA propellant and a co-solvent not only depends on the acidity function of the solution, but it is also catalyzed by trace levels of metal ions and that TA 2005 stability can be enhanced by adding to the solution specific amounts of high concentration phosphoric acid both to adjust the apparent pH in a well defined range and to sequester metal ions.

Moreover, it has been found that the stabilizing effect of phosphoric acid is not strictly correlated with its w/w percent amount in the formulation and it is present in a concentration interval from 0.0004 to 0.040% by weight, based on the total weight of the formulation.

The corresponding apparent pH interval is of 2.5 to 5.5, preferably 3.0 to 5.5, more preferably 3.5 to 5.0.

However, a person sufficiently skilled in the art can easily apply the teachings of the present invention to the preparation of HFA solution formulations containing other active ingredients bearing functional groups sensitive to hydrolytic and/or oxidative reactions, such as formamide and cathecol respectively.

WO 97/47286, EP 513127, EP 504112, WO 93/11747, WO 94/21228, WO 94/21229, WO 96/18384, WO 96/19198, WO 96/19968, WO 98/05302, WO 98/34595, and WO 00/07567 disclose HFA formulations in the form of suspensions in which .beta..sub.2-agonists such formoterol and salbutamol are either exemplified and/or claimed.

WO 99/65464 discloses HFA formulations containing two or more active ingredients in which at least one is in suspension. The preferred formulations comprise salbutamol sulfate in suspension.

WO 98/34596 discloses solution compositions 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 the chemical stability of the active ingredient but it rather concerns the drug delivery to lungs.

WO 00/30608 discloses pressurized MDIs for dispensing a solution of an active ingredient in a hydrofluorocarbon propellant, a co-solvent and optionally a low-volatility component characterized in that part or all of the internal surfaces of said inhalers consist of stainless steel, anodised aluminum or are lined with an inert organic coating. The examples are of only steroids and anticholinergic agents. However, the use of coated containers, even in the presence of an organic acid, is not sufficient for providing stable solution formulations of a phenylalkylamino derivative such as salbutamol.

EP 673240 discloses the use of acids as stabilizers for preventing the chemical degradation of the active ingredient in aerosol solution formulations comprising HFAs. Most examples relate to ipratropium bromide, an anticholinergic drug and only one example is presented for a .beta..sub.2-agonist, i.e., fenoterol. Although salbutamol is claimed, no exemplary formulations are provided. Moreover, the stability data are reported only for ipratropium and no distinction is made between the use of organic and inorganic acids. However, salbutamol cannot be stabilized at all by addition of organic acids even when stored in coated cans. Furthermore, apart from ipratropium bromide, in EP 673240 no guidance is given with respect to the amount of acid which has to be added in order to stabilize the medicaments without compromising the stability of the whole composition in the can. The only hint can be found on page 5, lines 15 to 16, which says that an amount of inorganic acid should be added to obtain a pH value from 1 to 7, a very broad and generic range.

WO 98/34596 discloses solution formulations containing a propellant and a physiologically acceptable polymer which could help the solubilization and the stability as well of the active ingredients.

WO 00/06121 discloses propellant mixtures for aerosol dinitrogen monoxide and a hydrofluoroalkane in the preparation of suspension and solution aerosols. The use of dinitrogen monoxide may improve the stability on storage of oxidation-sensitive active ingredients. As for .beta..sub.2-agonists such as levosalbutamol sulfate, formoterol fumarate, and salmeterol xinafoate, only examples of suspensions are reported.

WO 99/65460 discloses pressurized MDIs containing stable formulations of a .beta..sub.2-agonist drug in suspension or solution. The examples refer to solutions of formoterol fumarate containing an HFA propellant and ethanol as co-solvent, filled in conventional aluminum or plastic coated glass cans. Samples stored under accelerated conditions (40.degree. C., 75% relative humidity) for a very short period, one month, exhibited about 10% loss of drug. According to pharmaceutical guidelines on stability, loss of 10% of active ingredient does not meet the criteria of acceptance. Moreover, as it is evident from the data reported in Example 2 of the present application, by following the teaching of WO 99/65460, stable formoterol solution formulations cannot be provided. The applicant has indeed demonstrated that the presence of low-volatility components does not substantially affect the chemical stability of the compositions. In some cases, they could even improve it.

In EP 1 157 689 ('689) (WO 01/89480), stability data of a HFA 134a solution formulation containing 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinolinone hydrochloride (TA 2005) 3.5 .mu.g/50 .mu.l dose, 12% w/w ethanol, 1% w/w isopropyl myristate stabilised by different amounts of HCl 0.08M (1.0 and 1.4 .mu.l) were reported (Example 7). The formulations were reported to be provided with quite good stability if stored in upright position and if present in relatively high concentrations (3.5 .mu.g/50 .mu.l) (Comparative Example 1). Nevertheless, when the present inventors repeated the test with a rather low concentration (Example 2), they noticed a progressive degradation of the active ingredient in the formulation. Moreover, the formulation exemplified contained isopropyl myristate as a low volatility compound in order to increase the MMAD (mass median aerodynamic diameter) of the delivered particles. It has been subsequently found that it would be highly advantageous to provide highly efficient TA 2005 formulations characterised by a deeper lung penetration by virtue of a significant fraction, of at least 30%, of fine particles, with a diameter equal or less than 1.1 .mu.m. Therefore the low volatility compound is preferably avoided.

It has been subsequently also found that in this kind of highly efficient formulations, characterized by the presence of a fraction of particles equal to or less than 1.1 .mu.m higher than 30% and even than 50% or more, TA 2005 can be present in a very low concentration, starting from 0.0005% w/v based on the total volume of the composition.

Such compositions have been described in another previous application of the applicant, WO 03/074025, wherein stability data of a HFA solution formulation comprising 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinolinone hydrochloride (TA 2005) stabilized by HCl were reported. The stability was determined on a formulation delivering 4 .mu.g of active compound per actuation, stored upright at 5.degree. C.: in said refrigerated conditions, after nine months, the TA 2005 assay was higher than 95%. However, it has then been found by the present inventors that when present in lower concentrations and in other storage conditions, the active ingredient in the formulation rapidly degrades. Moreover, the other hand, refrigeration is undesirable because many patients are required to carry the aerosol canisters on their persons.

According to the first aspect of the present invention, it has been found by the present inventors that, while according to the previous disclosure of WO 03/074025 the preferred mineral acid was hydrochloric acid, the chemical stability of 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinoline and its salts is enhanced by small amounts of high concentrated phosphoric acid, more than 10M, preferably about 15M phosphoric acid, preferably comprised between 0.0008% and 0.01% w/w in the formulation, wherein the expression "% w/w" means the weight percentage of the component with respect to the total weight of the composition. The mineral acid that better stabilizes the active ingredient 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinoline and its salts in the formulation is phosphoric acid, in particular highly concentrated phosphoric acid.

The aerosol formulations containing phosphoric acid are surprisingly stable at room temperature for a long life time.

According to a further aspect of the present invention there is provided a method of filling an aerosol inhaler with a composition of the invention, the method comprising:

(a) preparing a solution of one or more active ingredients in one or more co-solvents optionally containing an appropriate amount of a low volatility component;

(b) filling the device with said solution;

(c) adding a pre-determined amount of a strong mineral acid;

(d) adding a propellant containing a hydrofluoroalkane (HFA); and

(e) crimping with valves and gassing.

Active ingredients which may be used in the aerosol compositions of the present invention are short- and long-acting .beta..sub.2-adrenergic agonists such as salbutamol, formoterol, salmeterol, TA 2005 and salts thereof and their combinations with steroids such as beclomethasone dipropionate, fluticasone propionate, budesonide and its 22R-epimer or with anticholinergic atropine-like derivatives such as ipratropium bromide, oxitropium bromide, tiotropium bromide.

Preferably the active ingredient is a long acting .beta..sub.2-agonist belonging to the formula sketched below -- see Original Patent.

TA 2005 may be prepared as described in U.S. Pat. No. RE 33,024, which is incorporated herein by reference.

It is preferred that the formulation be suitable for delivering a therapeutic amount of the active ingredient in one or two actuations. Preferably the formulation will be suitable for delivering 0.5-6 .mu.g/dose, more preferably 1-4 .mu.g/dose, and in particular 1 to 2 .mu.g/dose or 2 to 3 .mu.g/dose. By "dose" it 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 the internal surfaces made of anodised aluminum, stainless steel or lined with an inert organic coating. Examples of preferred coatings are epoxy-phenol resins, perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes such as polytetrafluoroethylene, fluorinated-ethylene-propylene, polyether sulfone and copolymers of fluorinated-ethylene-propylene polyether sulfone. Other suitable coatings could be polyamide, polyimide, polyamideimide, polyphenylene sulfide or their combinations.

To further improve the stability, cans having a rolled-in rim and preferably a part or full rollover rim are used.

The formulation is actuated by a metering valve capable of delivering a volume of between 50 .mu.l and 100 .mu.l.

Metering valves fitted with gaskets made of chloroprene-based rubbers can preferably be used to reduce the ingress of moisture which, as previously mentioned, can adversely affect the stability of the drug during storage. Optionally, further protection can be achieved by packaging the product in a sealed aluminum pouch.

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 low volatility component, when present, has a vapor pressure, at 25.degree. C., lower than 0.1 kPa, preferably lower than 0.05 kPa. Advantageously, it could be selected from the group of glycols, particularly propylene glycol, polyethylene glycol and glycerol or esters, for example ascorbyl palmitate, isopropyl myristate and tocopherol esters.

The compositions of the present invention may contain from 0.1 to 10% w/w of said low volatility component, preferably between 0.3 to 5% w/w, more preferably between 0.4 and 2.0% w/w.

Propylene glycol, polyethylene glycol, glycerol with residual water less than 0.1% w/w and esters of long-chain fatty acids are the preferred low-volatility components. More preferred are those with a dipole moment less than 2.0 or with a dielectric static constant less than 20, preferably less than 10. Particularly preferred is isopropyl myristate.

The function of the low volatility component is to modulate the MMAD of the aerosol particles and optionally to further improve the stability of the formulation. With respect to the latter aspect, particularly preferred is the use of isopropyl myristate.

The apparent pH range is advantageously comprised between 2.5 and 5.5, preferably between 3.0 and 5.5, even more preferably between 3.5 and 5.0.

Rather concentrated, i.e., more than about 10 M, preferably more than about 12 M, and most preferably about 15 M phosphoric acid is used to adjust the apparent pH. In the examples that follow 85%, i.e., 15.2M phosphoric acid has been used. The amount of acid to be added to reach the desired apparent pH will be pre-determined in the model vehicle reported before

In a particularly preferred embodiment, the active ingredient is 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinolinone or its salt is stabilized with rather concentrated, preferably about 15 M phosphoric acid. In particular, it is preferred to add phosphoric acid in an amount equivalent to 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, still more preferably 0.002 to 0.0075% w/w of 15 M phosphoric acid, based on the total weight of the composition. For the purposes of the present invention a still higher concentrated phosphoric acid other than 15 M can be utilized. In this case, the person skilled in the art will be able to determine the right percent amount in view of the disclosure in the present application. In this embodiment, it may also be preferred to avoid addition of the low-volatility component to increase the fraction of particles with a diameter less than or equal to 1.1 .mu.m to at least 30% and to provide deeper lung penetration.

In the case of the hydrochloride salts or TA 2005, the concentration will vary between 0.0005% and 0.024% w/v, based on the total volume of the composition, in order to deliver 0.5-6 .mu.g per actuation, preferably between 0.001% and 0.016% w/v, based on the total volume of the composition, in order to deliver 1 to 4 .mu.g per actuation, more preferably between 0.001% and 0.008% w/v, based on the total volume of the composition, in order to deliver 1 to 2 .mu.g per actuation. For instance, for 1 and 2 .mu.g/dose, wherein a 63 .mu.l metering volume is used, the final concentrations of TA 2005 hydrochloride delivered per actuation would be 0.0016% and 0.0032% w/v, respectively, based on the total volume of the composition. The amount of co-solvent in the composition is suitably 5 to 30% w/w, preferably 5 to 25% w/w, more preferably 5 to 20% w/w, based on the total weight of the composition.

In these conditions, the stability of TA 2005 is enhanced also at the very low dose strength of 1 .mu.g per actuation.

The apparent pH value is preferably comprised between 3.5 and 5.0.

In the examples that follow, the stabilizing effects of phosphoric acid were also tested in a TA 2005 HFA formulation comprising as a further active ingredient budesonide, an anti-inflammatory 20-ketosteroid which meets with chemical stability problems when formulated in a HFA aerosol solution formulation.
 

Claim 1 of 31 Claims

1. An aerosol formulation, which comprises 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl-2(1H)-quinolinone or a salt thereof, a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, and phosphoric acid, wherein 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% by weight of 15 M phosphoric acid, based on the total weight of the formulation, and wherein said 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am- ino]ethyl]-2(1H)-quinolinone or salt thereof is present in an amount of 0.0005% to 0.0032% w/v, based on the total volume of the formulation.

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