Pharmaceutical solution formulations for pressurised metered dose inhalers

Abstract

A method for delivering two or more active drug substances to the lungs by inhalation from a single pressurized metered dose inhaler product, said inhaler containing a HFA/cosolvent based solution formulation wherein all the active drug substances are fully dissolved in the formulation.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to pharmaceutical solution to be used with pressurised metered dose inhalers (pMDIs) suitable for aerosol administration. In particular, the invention relates to aerosol solution formulations to be used with pressurised metered dose inhalers (pMDIs), suitable for the administration of a medicament to the lungs, said medicament comprising two or more active drug substances. More particularly, the invention relates to a method for delivering two or more active drug substances to the lungs by inhalation from a single inhaler. In a preferred embodiment one of the drug substances is a long-acting β₂-agonist.

2. Discussion of the Background

Treatment of pulmonary disease with inhaled aerosol drugs offers advantages over systemic therapy, including a more rapid onset and reduced adverse effects, because of direct targeting of the lungs.

Pressurised metered dose inhalers (pMDIs) are well known devices for administering pharmaceutical products to the respiratory tract by inhalation. MDI uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol. Formulations for aerosol administration via MDIs can be solutions or suspensions. Solution formulations offer the advantage of being homogeneous with the active ingredient and excipients completely dissolved in the propellant vehicle or its mixture with suitable co-solvents such as ethanol. Solution formulations also obviate physical stability problems associated with suspension formulations so assuring more consistent uniform dosage administration.

For many years the preferred propellants used in aerosols for pharmaceutical use have been a group of chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl₃F (Freon 11 or CFC-11), CCl₂F₂ (Freon 12 or CFC-12), and CClF₂-CClF₂ (Freon 114 or CFC-114).

Recently, the chlorofluorocarbon (CFC) propellants such as Freon 11 and Freon 12 have been implicated in the destruction of the ozone layer and their production is being phased out.

Hydrofluoroalkanes [(HFAs) known also as hydro-fluoro-carbons (HFCs)] contain no chlorine and are considered less destructive to ozone and these are proposed as substitutes for CFCs.

HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems have been disclosed.

Drugs commonly delivered by inhalation include short-acting and long-acting β₂-agonists, anticholinergics/antimuscarinic agents, and corticosteroids.

Long-acting β₂-Adrenoceptor agonists and antimuscarinic agents, in particular selective muscarinic receptors M3 antagonists, are the most effective bronchodilators, whereas corticosteroids are the most effective controllers of the underlying inflammatory process in the airways.

Recently, new broad spectrum anti-inflammatory drugs have been proposed, including phosphodiesterase-4 inhibitors or PDE4.

Examples of long-acting bronchodilator β₂-agonists belonging to the class of the phenylalkylamino derivatives are formoterol, salmeterol and 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone (also referred to as carmoterol). Asthma and chronic obstructive pulmonary disease (COPD) are the most common broncho-pulmonary diseases and represent a major public health problem.

Asthma is a disease characterized by airway inflammation and smooth muscle dysfunction. Therefore to achieve optimum asthma control, therapy should be targeted against these underlying components.

The combination of a long-acting inhaled β₂-agonist (LABA) and an inhaled corticosteroid (ICS) has been shown to improve lung function and to control asthma exacerbations in a more effective way than doubling the dose of ICS in patients with different degrees of asthma severity.

Bronchodilator therapy is the first step treatment in patients with COPD, but current guidelines recommend the addition of inhaled corticosteroids to bronchodilators.

As far as anticholinergics and beta-agonists are concerned, they reduce bronchoconstriction through different mechanism, and there is a long history of combination therapy in the past with short-acting agents in these classes for chronic obstructive pulmonary disease. More effective drug combinations may allow lower doses and thereby improve safety.

Therefore, it would be highly advantageous to provide a method and formulations in the form of HFA solution to be administered by MDI's aimed at providing pharmaceutical doses of two or more bronchodilating and/or anti-inflammatory compounds to the lung and especially a β₂-agonist in combination with at least a further active compound for a more efficacious treatment of broncho-pulmonary diseases, in particular asthma and COPD.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novel formulations in the form of HFA solution to be administered by MDI's for providing pharmaceutical doses of active substances, preferably comprising a β₂-agonist, into the low respiratory tract of patients suffering from pulmonary diseases such as asthma and COPD.

It is another object of the present invention to provide novel methods for preparing a pMDI which contains such a formulation.

It is another object of the present invention to provide novel methods for providing pharmaceutical doses of active substances, preferably comprising a β₂-agonist, into the low respiratory tract of patients suffering from pulmonary diseases such as asthma and COPD.

In particular, it is another object of the invention to provide novel formulations in the form of HFA solution to be administered by MDI's for providing pharmaceutical doses of a long acting β₂-agonist in combination with at least a further active ingredient, wherein both the long acting β₂-agonist and the additional active ingredient are fully dissolved in the formulation.

It is another object of the present invention to provide novel methods for preparing a PMDI which contains such a formulation.

It is another object of the present invention to provide novel methods for providing pharmaceutical doses of a long acting β₂-agonist in combination with at least a further active ingredient, wherein both the long acting β₂-agonist and the additional active ingredient are fully dissolved in the formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same become better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:

FIG. 1 shows the titration curve normalised to the usual fill volume of a pMDI can (12 ml) resulting from Example 1(a);

FIG. 2 shows the pH profile for the titration experiment reported in Example 1(b);

FIG. 3 shows the cumulative % undersize BDP and FF mass distributions for the sample as determined in Example 6; and

FIG. 4 shows the percentage (of metered dose) ACI stage by stage deposition of LABA and ICS (bars represents Mean±SD; (n=6)) as measured in Example 7.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention there is provided a pharmaceutical composition comprising two or more active substances and in particular a long acting β₂-agonist belonging to the class of phenylalkylamino derivatives in solution in a liquefied HFA propellant and a co-solvent selected from pharmaceutically acceptable alcohols.

Active ingredients which may be used in the aerosol compositions of the invention are short- and long-acting β₂-adrenergic agonists, preferably long-acting β₂-adrenergic agonists such as formoterol, salmeterol, carmoterol and salts thereof and their combinations with other active ingredients, preferably selected from the group of corticosteroids or anticholinergic atropine-like derivatives, antimuscarinic M3 inhibitors or phosphodiesterase 4 (PDE4) inhibitors.

Preferred corticosteroids are beclomethasone dipropionate, budesonide and its 22R-epimer, rofleponide, ciclesonide, fluticasone propionate, mometasone furoate or triamcinolone and its ester such as triamcinolone acetonide.

Preferred anticholinergic atropine-like derivatives are ipratropium bromide, oxitropium bromide, tiotropium bromide or glycopyrronium bromide.

Preferred long acting β2-agonists are formoterol, carmoterol and salmeterol and salts thereof.

More preferably the first active ingredient is a long acting β2-agonists belonging to the formula sketched below
wherein R is 1-formylamino-2-hydroxy-phen-5-yl (formoterol) or 8-hydroxy-2(1H)-quinolinon-5-yl (TA 2005) or one of their salts, solvates, solvates of the salts or stereoisomers.

It is preferred that the formulation be suitable for delivering a therapeutic amount of the active ingredient in one or two actuations. In a first embodiment the formulation will be suitable for delivering 6 to 12 μg/dose of formoterol fumarate. In another embodiment, the formulation will be advantageously suitable for delivering 0.5 to 8 μg/dose, preferably 1 to 4 μg/dose, more preferably from 1 to 2 μg/dose of carmoterol hydrochloride (TA 2005). As “dose” it is meant the amount of active ingredient delivered by a single actuation of the inhaler.

The formulation of the invention may further contain small amounts of a mineral acid to adjust the apparent pH to between 2.5 and 5.0.

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 formoterol fumarate 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 exhibits a shallow negative to about pH′=5.5; thereafter the acidity function drops abruptly. Surprisingly the corresponding HFA formulations turned out to much more stable below pH′ 5.5. As far as TA 2005 is concerned, the pH′ profile exhibits a shallow negative to about pH′=5.0; thereafter the acidity function drops quite abruptly.

The formulations of the invention may be contained in a pressurized MDI having part of all of the internal metallic surfaces made of anodised aluminium, 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 a mixture of fluorinated-ethylene-propylene and 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 may be used.

In fact, the chemical stability of certain active ingredients in HFA solution formulations can be dramatically improved by a proper selection of the can. On the other hand, the use of inert containers reduces 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 Al³⁺ or alkali respectively deriving from the conventional aluminium or glass cans could in turn catalyse radical oxidative or other chemical reactions of the active ingredient which give rise to the formation of degradation products.

The pharmaceutical composition may further contain a low volatility component, further improving 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 to reduce 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. In the case of active ingredients such as formoterol, it is well known that the latter (e.g., humidity) could be detrimental to the stability of the active ingredient during storage. According to a particular embodiment of the invention, there is provided a pressurised MDI for administering pharmaceutical doses consisting of a container filled with a pharmaceutical composition comprising a long-acting β₂ agonist selected from formoterol fumarate in solution in HFA 134a as a propellant in turn containing from 5% to 20%, preferably from 6% to 15% w/w ethanol as a co-solvent, the apparent pH of said solution having been adjusted to between 3.0 and 3.5 by addition of small amounts of hydrochloric acid. The expression ‘% w/w’ means the weight percentage of the component in respect to the total weight of the composition.

In another particular embodiment of the invention, there is provided a pressurised MDI filled with a pharmaceutical composition consisting of a solution comprising formoterol fumarate in combination with a corticosteroid in HFA 134a as a propellant in turn containing from 6% to 15% w/w, preferably 12% w/w ethanol as a co-solvent, the apparent pH of said solution having been adjusted to between 3.0 and 3.5 by addition of small amounts of hydrochloric acid.

In a preferred embodiment the corticosteroid is beclometasone dipropionate.

According to a further particular 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 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride (TA 2005) in combination with a corticosteroid in HFA 134a as a propellant in turn containing from 6% to 15% w/w, preferably 12% w/w ethanol as a co-solvent, 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.

In a preferred embodiment the corticosteroid is budesonide or an epimer thereof.

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 β₂-agonists such formoterol and salbutamol are either exemplified and/or claimed.

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

WO 98/34596 describes 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 concern the drug delivery to lungs.

International Application No. PCT/EP99/09002 filed on 23 Nov. 1999 published on Jun. 2, 2000 as WO 00/30608 discloses pressurised MDI's for dispensing a solution of an active ingredient in a hydrofluorocarbon propellant, a co-solvent and optionally a low-volatility component characterised in that part or all of the internal surfaces of said inhalers consist of stainless steel, anodised aluminium or are lined with an inert organic coating. The examples are referred only to steroids and anticholinergic agents.

EP 673240 proposes the use of acids as stabilisers 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 an example is presented for a β₂-agonist, i.e. fenoterol. Although salbutamol is claimed, no exemplary formulations are provided. Moreover, the stability data are reported only for ipratropium and the patentee does not distinguish between the use of organic and inorganic acids. 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 stabilise 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, so a very broad and generic range.

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

WO 00/06121 refers to 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 at storage of oxidation-sensitive active ingredients. As far as β₂-agonist such as levosalbutamol sulphate, formoterol fumarate and salmeterol xinafoate, only examples referred to suspensions are reported.

WO 99/65460 claims pressurised MDI's containing stable formulations of a β-agonist drug in suspension or solution. Examples refer to solutions of formoterol fumarate containing an HFA propellant and ethanol as co-solvent, filled in conventional aluminium or plastic coated glass cans. Samples stored under accelerated conditions (40° 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, following the teaching of WO 99/65460 stable formoterol solution formulations cannot be provided.

WO 03/074025 refers to a pharmaceutical aerosol formulation to be administered by pressurized metered dose inhalers which comprises as active ingredient a long acting β2-agonist selected from a 2(1H)-quinolinone derivative, a stereoisomer, physiologically acceptable salt and solvate thereof, in a solution consisting of a liquefied HFA propellant, a co-solvent and optionally an amount of water up to 5% on the total weight of the formulation.

The formulation is able to deliver, on actuation of the inhaler, a fraction of superfine particles equal to or less than 1.1 micron up to 50% or more so allowing the drug to reach the small peripheral airways region where it exercises its pharmacological effects.

WO 2004/075896 refers to a combined preparation comprising:

• • 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl-2(1H)-quinolinone or a physiologically acceptable salt or solvate thereof;
  • at least a further active ingredient useful for the treatment of the inflammatory or obstructive airways disease, for the simultaneous, sequential or separate use in the treatment of an inflammatory or obstructive airways disease.

One of the preferred combination products comprises the hydrochloride salt CHF 4226 and a corticosteroid: it has indeed been found that, in such a combination, both the bronchodilator and the anti-inflammatory effects increase.

According to a further aspect of the invention there is provided a method of preparing a filled device, such as an aerosol inhaler, with a composition of the invention, the method comprising:

• • (a) Preparing of 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 of 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.

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

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 aluminium 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 vapour pressure at 25° 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 5.0, preferably between 3.0 and 5.0. Strong mineral acids such as hydrochloric, nitric, sulphuric or phosphoric are preferably used to adjust the apparent pH.

The amount of acid to be added to reach the desired apparent pH will be pre-determined in the model vehicle reported before. In the case of the formulation of formoterol fumarate and its combination with beclometasone dipropionate, an amount comprised between 3 and 3.5 μl of 1.0 M hydrochloric acid should be added to obtain an apparent pH between 3.0 and 3.5.

As said before, co-deposition within the lung of a combination of two or more drugs may result in a clinical response that is greater than the sum of the response of the individual drugs administered. A recommended combination is the combination of an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABA) bronchodilator in the treatment of persistent asthma, to provide both anti-inflammatory and bronchodilating effects.

Nelson et al, in J. Allergy Clin. Immunol., 2003, 112, 29-36, hypothesized that fluticasone propionate and salmeterol in the form of a solid powder delivered simultaneously through a single dry powder inhaler can avoid deposition variation caused by natural variation in inspiratory manoeuvres on successive inhalation and might co-deposit in the airways.

The potential effect has been ascribed to the tendency of the two drugs to form particle agglomerations within the inhaler device.

On the other hand, when two active drug substances are present in the formulation as a dry powder, the size of the solid particles can be easily pre-determined by the micronization process.

A higher degree of co-deposition following the combined administration of two drugs has been found also by using a single metered dose inhaler containing salmeterol xinafoate and fluticasone propionate both in the form of solid particles suspended in the HFA propellant. Also in this case the effect has been ascribed to the formation of particle agglomerations (Intern. J. Pharmaceutics, 2006, 313, 14-22).

Clinical advantages are therefore inherent within inhalation products that can deliver a combination of two or more drugs as a single administration.

Co-deposition in the same lung region could maximize the synergistic effects, but the two active ingredients have to show exactly the same distribution profile.

It has now been found that in the pressurized metered dose inhaler product of the invention, comprising an ethanol/HFA propellant based solution formulation for aerosol administration containing a combination of two or more active drug substances, wherein said active drug substances are fully dissolved in the formulation, each liquid particle generated during the MDIs atomisation process contains drug concentrations consistent with the liquid properties of the product's solution formulation and that this consistency is maintained for the residual particles following excipient evaporation. In other words, substantially all of the liquid particles emitted on actuation of the inhaler contain the two or more drug substances in a ratio which is substantially the same as the ratio of the two or more drug substances in the solution formulation contained in the inhaler. Thus, preferably at least 85%, preferably at least 90%, more preferably at least 95%, even more preferably at least 98%, even more preferably at least 99%, of the liquid droplets emitted on actuation of the inhaler contain the two or more drug substances in a ratio (when expressed as a ratio obtained by dividing the mass of the major component by the mass of the minor component) which preferably differs by less than 15%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, even more preferably less than 1%, from the ratio of the two or more drug substances in the solution formulation contained in the inhaler. In this regard, the ratio of the two or more drug substances in the solution formulation will in part depend on the identity of the drug substances and the condition and subject being treated. However, in view of the teachings of the present specification, determination of such ratios is within the abilities of those skilled in the art. In particular, for formoterol fumarate and beclometasone dipropionate, the mass ratio of beclometasone to formoterol fumarate may preferably be 100:0.1 to 100:50, more preferably 100:1 to 100:20, even more preferably 100:2 to 100:10. For carmoterol hydrochloride and budesonide, the mass ratio of budesonide to carmoterol hydrochloride may preferably be 100:0.01 to 100:15, more preferably 100:0.05 to 100:10, even more preferably 100:0.1 to 100:7, even more preferably 100:0.5 to 100:5, even more preferably 100:0.5 to 100:4, even more preferably 100:0.5 to 100:3.

It has unexpectedly been found that each droplet of the aerosol cloud emitted on actuation of the inhaler containing a solution of different active drug substances dries to give particles of the active materials with identical size distributions in the correct ratio. In other words, the liquid droplets dry to give particles of the two or more drug substances, and the particles of the two or more drug substances have substantially the same particle size distribution. Thus, the fine particle fractions (at ≦5 μm) of the two or more drug substances preferably differ by less than 15%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, even more preferably less than 1%. In addition, the fine particle fractions (at ≦1 μm) of the two or more drug substances preferably differ by less than 15%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, even more preferably less than 1%.

This characteristic is maintained through the entire container life.

This is even more surprising in consideration of the fact that the active substances have different chemico-physical and solubility characteristics, and are present in the formulation in very different concentrations and dosage strengths. Moreover, the spray cloud of finely divided liquid particles dispersed in a gas stream emitted from the MDI, is a dynamic system quickly evaporating and moving through the air way from the actuator.

Therefore the invention is particularly directed to a method for delivering two or more active drug substances to the lung by inhalation from a single pressurized metered dose inhaler product, said inhaler containing a HFA/cosolvent based solution formulation wherein all the active drug substances are fully dissolved in the formulation.

The particle size distribution (PSD) data for two different combinations of LABA and ICS within an ethanol based solution HFA pMDI, has been measured using an Andersen Cascade Impactor (ACI) in accordance with the European guidelines.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Example 1

Effect of Hydrochloric Acid on Solution pH′ (Acidity Function)

(a) 1.0 M hydrochloric acid was added incrementally to 50 ml of HFA 43-10MEE (Vertrel XF) containing 20% w/w ethanol and the pH′ was measured after each aliquot of acid. FIG. 1 shows the resultant titration curve normalised to the usual fill volume of a pMDI can (12 ml). The pH′ profile exhibits a shallow negative slope to about pH′=5.5; thereafter the acidity function drops abruptly.

(b) Experiment (a) was repeated with formoterol formulations containing a lower concentration of ethanol (12% w/w) and with the addition of 1.0% isopropyl myristate. The resultant pH profile, for replicate bulk solutions, shown in FIG. 2 is similar in shape with the abrupt fall in pH′ per unit increment of acid again commencing at about pH′=5.5. However, only about half the acid is required to achieve the same reduction in pH′. This is largely due to the reduction in ethanol content; FIG. 2 also shows similarity in the profiles obtained with and without isopropyl myristate.

Example 2

Effect of pH′ on Stability of Formoterol Solutions in HFA 43-10MEE containing 20% w/w Ethanol

Aliquots of 1.0 M hydrochloric acid were added to 12 ml of formoterol solution in glass vials. After measurement of pH, valves were crimped on and the vials stored upright at 50° C. Vial samples containing different concentrations of acid were assayed for residual formoterol after 10 and 20 days storage. The pH′ of a third vial was determined after 40 days storage. The results are shown in Table 1. Table 1 shows changes in pH on storage; this is probably largely associated with leaching of alkali from the soft glass of the vials. However, overall consideration of the pH′ and formoterol content data implies that the stability of a solution formulation of the drug in HFA can be improved by the addition of mineral acid to provide a formulation with pH′ between 2.5 to 5.0.

TABLE 1
pH′ and Formoterol Content of Formoterol-Vertrel XF/HFA Solutions
(12 μg/100 μl)
Vehicle: Vertrel XF/HFA with 20% Ethanol and Hydrochloric Acid
St Gobain glass vials stored upright
	Acidity	Percent Residual
	Function (pH′)	Conc. Formoterol
Initial	40 days	Initial	10 days	20 days
1.8	2.8	100	4.8	Nil
2.1	4.4	100	75.1	70.7
2.6	4.2	100	97.2	86.7
3.3	4.2	100	97.1	89.9
5.6	6.6	100	95.8	92.1
7.4	6.7	100	85.4	67.2

Example 3

Stability of Acidified Formoterol-HFA 134a Solutions in Anodised Cans

Formoterol formulations (12 μg/100 μl) were prepared by dissolving 1.44 mg of formoterol fumarate in HFA 134a containing 12% w/w ethanol with and without 1.0% w/w isopropyl myristate. The latter was included as a non-volatile excipient with the potential for increasing MMAD if so desired. It also improves the solubility of formoterol in the vehicle and reduces polarity of the vehicle compared to the addition of glycerol.

pMDI cans containing 3.1 to 3.4 μl 1.0 M hydrochloric acid were set down on storage, upright and inverted, at 4° C. to 50° C. and samples taken for analysis of formoterol content at appropriate intervals.

Stability data obtained after 70 days of storage are given in Table 2.

A matrix of formulations containing 1.44 mg (12 μg/100 μl) formoterol fumarate were prepared in HFA 134a containing 12.0% w/w ethanol with or without 1.0% w/w isopropyl myristate as non-volatile excipient. Aliquots of drug concentrate were transferred to anodised cans and 3.15 to 3.35 μl of 1.0M hydrochloric acid added prior to crimping with 50 μl valves and gassing; between 22 and 28 replicates at each acid strength were prepared.

To determine residual formoterol, 30×50 μl shots were discharges into DUSA tubes. The acid range selected was anticipated to give pH′ values of 3.0 to 3.5 and to determine the formulation sensitivity to small changes in acid concentration. Cans were placed on stored upright and inverted (valve up and down respectively) at 25 to 50° C. Table 2 shows the results obtained at 40° C. and 50° C. after 11 to 40 day's storage. Each value (expressed as per cent nominal drug concentration) is obtained from a different can. Initial values were obtained for two cans of each acid strength. Inspection of the data shows that all assay values are within the reproducibility of the HPLC assay and independent of acid strength. A similar conclusion was drawn for the storage time point replicates, i.e., independent of acid strength (3.2 to 3.3 μl) or whether cans were stored upright or inverted. Consequently for kinetics calculation the mean value for initial (n=10) and subsequent time points (n=6) was used.

In Table 3 are reported the Arrhenius parameters together with estimated shelf lives at 4, 10, and 25° C. The t_5% is predicted to be greater than 3 months at ambient temperature and approximately 2 years at 4° C.

TABLE 2
Stability Data for Formoterol Fumarate Solutions (12 μg/100 μl) in HFA
134a containing 12.0% Ethanol ± 1.0% Isopropyl Myristate (values are
expressed as percent nominal)
Anodised cans fitted with 50 μl valves/30 doses collected per can
Different cans assessed at each condition
Cans stored upright (* inverted)
	STORAGE CONDITION/No isopropyl myristate
1.0M HCl	Initial	40° C.; 40 days	50° C.; 11 days	50° C.; 33 days
μl per Can	1st Can	2nd Can	1st Can	2nd Can	1st Can	2nd Can	1st Can	2nd Can
3.15	99.8	99.6	—	—	—	—	—	—
3.20	100.8	99.7	96.0	93.2*	96.7	96.5	88.5	89.9*
3.25	97.9	98.8	93.9	94.3*	96.4	96.5	92.2	91.5*
3.30	97.3	98.9	93.7	93.7*	97.0	89.1	90.9	92.8*
3.35	100.0	98.3	—	—	—	—	—	—
Mean	99.1	94.1	95.4	91.0
C.V.	1.1%	1.0%	3.2%	1.8%
	STORAGE CONDITION/1.0% isopropyl myristate
1.0M Hcl	Initial	40° C.; 33 days	50° C.; 11 days	50° C.; 31 days
μl per Can	1st Can	2nd Can	1st Can	2nd Can	1st Can	2nd Can	1st Can	2nd Can
3.15	101.1	99.3	—	—	—	—	—	—
3.20	97.0	100.2	94.4	93.2*	93.8	93.6	90.6	92.7*
3.25	101.4	100.2	98.6	95.0*	96.1	95.9	91.6	89.7*
3.30	99.9	100.8	92.8	95.3*	95.6	95.7	90.0	89.6*
3.35	99.2	97.2	—	—	—	—	—	—
Mean	99.6	94.9	95.1	90.7
C.V.	1.5%	2.2%	1.2%	1.4%

TABLE 3
Shelf Life Prediction for Acidified Formoterol Fumarate Solution
(12 μg/100 μl) in HFA 134a containing 12% w/w Ethanol ± 1.0% w/w
isopropyl Myristate (IPM)
Anodised aluminium cans
	FORMOTEROL FUMARATE (percent nominal)
Time			40° C.
(days)	Nil IPM	1% IPM	Nil IPM	1% IPM
0	99.1	99.6	99.1	99.6
11	95.4	95.1	—	—
31	—	90.7	—	—
33	91.0	—	—	94.9
40	—	—	94.1	—
Rate Const.	2.52	2.94	1.29	1.46
(day−1 × 103)
		Frequency	Activation
	Arrhenius Parameters	Factor (day−1)	Energy (kJ mol−1)
	Nil IPM	3.19 × 106	56.3
	1% w/w IPM	9.63 × 106	58.9
	Nil IPM	1.0% w/w IPM
Temper-	Rate Const.	t10%		Rate Const.	t10%
ature	(day−1)	(days)	t5%	(day−1)	(days)	t5%
4° C.	7.8 × 10−5	1344	657	7.8 × 10−5	1360	664
10° C.	1.3 × 10−4	802	392	1.3 × 10−4	789	386
25° C.	4.4 × 10−4	240	117	4.4 × 10−4	225	110

Example 4

Stability of Acidified Formoterol/BDP-HFA 134a Solutions in Cans Coated with a Fluorocarbon Polymer (DuPont 3200-200)

Formoterol and BDP combination formulations equivalent to doses of 6 μg/50 μl and 100 μg/50 l respectively, were prepared by dissolving 1.44 mg of formoterol fumarate and 24 mg of BDP in HFA 134a containing 12% w/w ethanol and 0.4% w/w of isopropyl myristate. pMDI coated cans containing 3.25 μl 1.0 M hydrochloric acid were set down on storage inverted, at 4° C. and samples taken for analysis of formoterol and BDP contents at appropriate intervals.

Stability data obtained are given in Table 4.

Each value is expressed as per cent nominal drug concentration.

The results indicate that the formulation is stable for at least 4 months at 4° C.

Example 5

Stability of Acidified TA 2005-HFA 134a Solutions in Cans Coated with a Fluorocarbon Polymer (DuPont 3200-200)

TA 2005 (3.5 μg/50 μl) were prepared by dissolving 0.84 mg of the active ingredient in HFA 134a containing 12% w/w ethanol and 1.0% w/w of ispropyl myristate. pMDI coated cans containing 1.0, 1.4, and 1.8 μl 0.08 M hydrochloric acid (corresponding respectively to an apparent pH of about 4.8, 3.2, and 2.9) were set down on storage, upright at 50° C., and samples taken for analysis of TA 2005 contents at appropriate intervals.

Stability data obtained are given in Table 5.

Each value is expressed as per cent nominal drug concentration.

The results indicate that the formulations in which the apparent pH is comprised between 3.0 and 5.0 are stable (i.e. give rise to much less than 10% loss of drug) for almost three months at 50° C., while that corresponding to an apparent pH of less than 3, is not.

TABLE 4
Formoterol/BDP combination formulations of Example 4 - Stability
data at 4° C.
	Storage Condition
		4° C.; 64 days	4° C.; 123 days
	Initial	inverted	inverted
	Formoterol	104.7	95.10	99.9
	BDP	99.4	100.10	102.6

TABLE 5
TA 2005 formulations of Example 5 - Stability data at 50° C.
	Storage Condition
	0.08M HCl		50° C.; 22 days	50° C.; 83 days
	μl per can	Initial	upright	upright
	1.0	100.0	98.3	99.4
	1.4	100.0	98.2	98.8
	1.8	100.0	90.2	88.1

Example 6

Particle Size Distribution for Formoterol Fumarate and Beclometasone Dipropionate within an Ethanol Based Solution HFA pMDI by Andersen Cascade Impactor (ACI)

The solution formulation contained BDP (100 μg) and FF (6 μg) per 50 μl dose in HFA 134a propellant vehicle with 12% w/w ethanol as cosolvent and 0.024% w/w hydrochloric acid (1M) as stabiliser. The formulation was packed in cans fitted with 50 μl valves and fired using a 0.30 mm actuator. Aerodynamic particle size assessments were conducted using an Andersen Cascade Impactor fitted with a USP induction port at the beginning and end of can-use life from each of two batches. Each determination was obtained by sampling 15 consecutive doses at a sampling flow rate of 28.31/min. For each can tested the delivered dose was determined using DUSA methodology (Dose Unit Spray Apparatus) at the beginning, middle and end of can-use life. Quantification of BDP and FF within test samples was performed using a HPLC method. Metered dose, delivered dose, fine particle dose, fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD) for each impactor measurement were calculated.

Delivery performance derived from impactor measurements are summarised in Table 6. For BDP and FF respectively, the mean delivered dose values obtained from the impactor measurements were within 95 to 100% and 91 to 101% of the mean values obtained using DUSA methodology. The consistency in the fine particle fraction (both≦5 μm and ≦1 μm), MMAD and GSD for BDP and FF is a consequence of the similar particle size distributions of the two drugs as shown in FIG. 3.

TABLE 6
Summary of Delivery Performance Characteristics (n = 4)
	Drug	BDP	FF
	Metered Dose, MD (μg)	94.5 ± 2.3	5.4 ± 0.3
	Delivered Dose (μg)	87.0 ± 2.2	4.9 ± 0.3
	Dose ≦5 μm (μg)	34.5 ± 1.1	1.9 ± <0.1
	Fraction ≦5 μm (%)	39.7 ± 2.2	38.6 ± 2.2
	Dose ≦1 μm (μg)	11.1 ± 0.2	0.6 ± <0.1
	Fraction ≦1 μm (%)	12.8 ± 0.4	11.8 ± 0.5
	MMAD (μm)	1.4 ± <0.1	1.5 ± <0.1
	GSD	2.0 ± 0.1	2.0 ± 0.1
	Shot Weight (mg)	54.0 ± 1.3

TABLE 7
Drug Mass within Samples Containing >5% of the MD (n = 4)
				Ratio:
	BDP (μg)	FF (μg)		BDP/FF
Actuator	7.5 ± 0.3	0.43 ± 0.03		17.6 ± 1.0
Induction Port	49.5 ± 3.2	2.89 ± 0.23		17.1 ± 0.3
Stage 4
(2.1-3.3 μm)	5.9 ± 0.3	0.33 ± 0.01		17.8 ± 0.5
Stage 5
(1.1-2.1 μm)	14.2 ± 0.8	0.80 ± 0.03		17.7 ± 0.5
Stage 6
(0.65-1.1 μm)	6.4 ± 0.3	0.36 ± 0.01		17.8 ± 0.7
Total:	83.6 ± 4.9	4.82 ± 0.32	Mean:	17.6 ± 0.6

Table 7 presents the mean drug deposition for samples containing >5% of the metered dose, the total being representative of 94.5±5.4% of the total metered drug mass. The mean ratio of BDP to FF presented in Table 7 is 17.6±0.6, which is consistent with the ratio of metered BDP and FF (17.6±0.6). The consistent ratio of the drug masses over the size fractions implies that each particle generated during the atomisation process contains drug concentrations consistent with the liquid properties of the product's solution formulation, and that this consistency is maintained for the residual particles following excipient evaporation, such that the measured particle size distributions for both resident drugs are identical.

Example 7

Solution Combination Containing Carmoterol Hydrochloride as LABA and Budesonide as ICS

The LABA is present in the combination at a strength 1 μg/actuation while the ICS is present at 100 μg/actuation within an acidified ethanol solution pressurized with HFA 134a. Aerodynamic assessment of fine particles was performed by sampling 10 consecutive doses from each pMDI into an ACI. The impactor was fitted with a USP induction port and operated at a sampling flow rate of 28.3 l/min. Three pMDIs were tested (from the beginning, middle, and end of batch) and were tested at the beginning and end of life. Drug deposition within the impactor was quantified using an HPLC assay. The fine particle dose (FPD) was determined by summation of the drug collected on the ACI stages between S3 and filter.

Table 8 summarizes the deposition of the LABA and the ICS on the individual stages of the ACI. The nominal dose of the combination pMDI was 1 μg LABA: 100 μg ICS. FIG. 4 summarizes these results expressed as the % metered dose.

TABLE 8
ACI Stage by Stage deposition of LABA and ICS. Data represents
Mean ± SD; (n = 6)
	Deposition Site	LABA (μg)	ICS (μg)
	Actuator	0.08 ± 0.02	6.68 ± 1.14
	Induction port	0.40 + 0.03	38.16 + 2.29
	Stage 0	0.02 + 0.01	2.88 + 0.44
	Stage 1	0.01 + 0.01	1.22 + 0.34
	Stage 2	0.00 + 0.00	0.33 + 0.13
	Stage3	0.01 + 0.00	0.91 + 0.16
	Stage 4	0.05 + 0.01	5.45 + 0.83
	Stage 5	0.18 + 0.02	18.5 + 1.83
	Stage 6	0.11 + 0.01	10.8 + 0.75
	Stage 7	0.05 + 0.00	5.29 + 0.36
	Filter	0.05 + 0.00	6.10 + 0.60

TABLE 9
Aerosol Performance of a Combination LABA: ICS HFA SOLUTION
pMDI (n = 6)
		Delivered Dose	Fine Particle	Fine particle
Active	Mass balance	(μg from ACI)	Dose (μg)	fraction (%)
LABA	96.8% ± 3.6%	0.89 ± 0.03	0.45 ± 0.03	51.0% ± 3.0%
ICS	96.3% ± 3.3%	89.7 ± 3.2	47.1 ± 2.7	52.5% ± 2.3%

The results demonstrate that the solution combination of the example provides fine particle fractions for the two components which are not statistically significantly different (p<0.05), despite the significantly different concentration of the two active drugs in the aerosol cloud. The ratio between the two active drugs is maintained in all the ACI stages allowing their co-deposition in the lungs, which could offer an increased opportunity for any synergistic interaction to occur.

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 references mentioned above are incorporated in full herein by this reference, the same as if set forth at length.

Claims

1. A method of delivering a combination of two or more active drug substances to at least one lung region tract of a subject in need thereof, comprising:

administering said two or more active drug substances to said subject by actuation of a pressurized single metered dose inhaler,

wherein said pressurized single metered dose inhaler contains a medicament which exists as a solution,

wherein said medicament comprises two or more active drug substances in a predetermined ratio dissolved in an HFA propellant and one or more co-solvents,

wherein at least one of said active drug substances is a long acting β2-adrenergic agonist,

wherein on actuation said inhaler emits liquid particles,

wherein substantially all of said liquid particles emitted on actuation of said inhaler contain said two or more active drug substances in a ratio which is substantially the same as said predetermined ratio of said two or more active drug substances in said medicament, and

wherein each of said two or more active drug substances is delivered with substantially the same particle size distribution at the same lung region tract.

2. A method according to claim 1, wherein said β2-adrenergic agonist is at least one member selected from the group consisting of formoterol, carmoterol, salmeterol, stereoisomers, a salt thereof, a solvate thereof, a solvate of a salt thereof, and mixtures thereof.

3. A method according to claim 2, wherein said medicament comprises a corticosteroid.

4. A method according to claim 3, wherein said corticosteroid is at least one member selected from the group consisting of beclomethasone dipropionate, fluticasone propionate, budesonide, the 22R-epimer of budesonide, rofleponide, ciclesonide, mometasone furoate, triamcinolone, an ester of triamcinolone, and mixtures thereof.

5. A method according to claim 4, wherein said ester of triamcinolone is triamcinolone acetonide.

6. A method according to claim 2, wherein said medicament comprises an anticholinergic atropine-like derivative or an antimuscarinic M3 inhibitor.

7. A method according to claim 6, wherein said anticholinergic atropine-like derivative is at least one member selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrronium bromide, and mixtures thereof.

8. A method according to claim 1, wherein said medicament comprises a phosphodiesterase 4 (PDE4) inhibitor.

9. A method according to claim 3, wherein said β2-adrenergic agonist is formoterol fumarate and said corticosteroid is beclometasone dipropionate.

10. A method according to claim 3, wherein said β2-adrenergic agonist is carmoterol hydrochloride and said corticosteroid is budesonide.

11. A method according to claim 1, wherein the HFA propellant comprises at least one member selected from the group consisting of HFA 134a, HFA 227, and mixtures thereof.

12. A method according to claim 1, wherein said co-solvent comprises an alcohol.

13. A method according to claim 1, wherein said co-solvent comprises ethanol.

14. A pressurized single metered dose inhaler,

wherein said pressurized single metered dose inhaler contains a medicament which exists as a solution,

wherein said medicament comprises two or more active drug substances in a predetermined ratio dissolved in an HFA propellant and one or more co-solvents,

wherein at least one of said active drug substances is a long acting β2-adrenergic agonist,

wherein on actuation said inhaler emits liquid particles,

wherein on actuation of said inhaler substantially all of said liquid particles emitted on actuation of said inhaler contain said two or more active drug substances in a ratio which is substantially the same as said predetermined ratio of said two or more active drug substances in said medicament, and

each of said two or more active drug substances is delivered with substantially the same particle size distribution at the same lung region tract.

15. An inhaler according to claim 14, wherein said β2-adrenergic agonist is at least one member selected from the group consisting of formoterol, carmoterol, salmeterol, stereoisomers, a salt thereof, a solvate thereof, a solvate of a salt thereof, and mixtures thereof.

16. An inhaler according to claim 15, wherein said medicament comprises a corticosteroid.

17. An inhaler according to claim 16, wherein said corticosteroid is at least one member selected from the group consisting of beclomethasone dipropionate, fluticasone propionate, budesonide, the 22R-epimer of budesonide, rofleponide, ciclesonide, mometasone furoate, triamcinolone, an ester of triamcinolone, and mixtures thereof.

18. An inhaler according to claim 17, wherein said ester of triamcinolone is triamcinolone acetonide.

19. An inhaler according to claim 15, wherein said medicament comprises an anticholinergic atropine-like derivative or an antimuscarinic M3 inhibitor.

20. An inhaler according to claim 19, wherein said anticholinergic atropine-like derivative is at least one member selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrronium bromide, and mixtures thereof.

21. An inhaler according to claim 14, wherein said medicament comprises a phosphodiesterase 4 (PDE4) inhibitor.

22. An inhaler according to claim 16, wherein said β2-adrenergic agonist is formoterol fumarate and said corticosteroid is beclometasone dipropionate.

23. An inhaler according to claim 16, wherein said β2-adrenergic agonist is carmoterol hydrochloride and said corticosteroid is budesonide.

24. An inhaler according to claim 14, wherein the HFA propellant comprises at least one member selected from the group consisting of HFA 134a, HFA 227, and mixtures thereof.

25. An inhaler according to claim 14, wherein said co-solvent comprises an alcohol.

26. An inhaler according to claim 14, wherein said co-solvent comprises ethanol.