MUSCARINIC ANTAGONISTS AND COMBINATIONS THEREOF FOR THE TREATMENT OF AIRWAY DISEASE IN HORSES

Abstract

The disclosure relates to the field of medicine, in particular to the field of veterinary medicine. The disclosure specifically relates to muscarinic antagonists (including long acting muscarinic antagonists (LAMAs)) for the treatment of airway disease, such as pulmonary disease, preferably recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD) in animals, preferably equines such as horses.

Claims

1. A composition in the form of a liquid formulation and comprising: a solvent comprising a mixture of water and ethanol, wherein ethanol is present in the solvent in an amount of 90-95% V/V; a glucocorticoid comprising ciclesonide or a pharmaceutically acceptable salt thereof; and a long-acting muscarinic antagonist (LAMA) or a pharmaceutically acceptable salt of the cation thereof having the following formula: ##STR00022## wherein A denotes a double-bonded group selected from among ##STR00023## X.sup. denotes an anion with a single negative charge, R.sup.1 and R.sup.2 denote C.sub.1-C.sub.4-alkyl, which may optionally be substituted by hydroxy or halogen; R.sup.3, R.sup.4, R.sup.5 and R.sup.6, which may be identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen; R.sup.7 denotes hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-halogen, halogenC.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-OH, CF3, C.sub.1-C.sub.4-alkylene-C.sub.1-C.sub.4-alkyloxy, OCOC.sub.1-C.sub.4-alkyl, OCOC.sub.1-C.sub.4-alkyl-halogen, OCOCF.sub.3 or halogen, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof, while if A denotes ##STR00024## R.sup.1 and R.sup.2 denote methyl, and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 denote hydrogen; wherein the concentration of the LAMA ranges between 0.2 to 7% m/V of the total composition, and ciclesonide or a pharmaceutically acceptable salt thereof is provided in the composition in an amount of 3.0 g/100 mL.

2. The composition of claim 1, further comprising a long-acting beta-2 adrenergic agonist (LABA) or a pharmaceutically acceptable salt thereof and selected from the group consisting of salmeterol, formoterol, bambutterol, indacaterol, vilanterol, abediterol and olodaterol hydrochloride.

3. The composition of claim 1, further comprising a pharmaceutically acceptable excipient.

4. The composition according to claim 1, wherein the LAMA is a compound of the formula: ##STR00025##

5. The composition of claim 1, wherein the concentration of LAMA ranges between 0.3 to 6.0% m/V of the total composition.

6. The composition of claim 1, wherein the concentration of LAMA ranges between 0.4 to 5% m/V of the total composition.

7. The composition of claim 1, wherein the glucocorticoid further comprises budesonide or a pharmaceutically acceptable salt thereof.

8. The composition of claim 1, wherein the liquid formation comprises a solution for inhalation.

9. The composition of claim 1, wherein the liquid formulation is a partially ethanolic formulation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1: Phase I: Temporal variations of transpulmonary pressure (PL) in two individual horses (horse ID 312 and 91) following a single administration of 800 g LAMA 1.

[0019] FIG. 2: Phase I: Temporal variations of lung resistance (RL) in two individual horses (horse ID 312 and 91) following a single administration of 800 g LAMA 1.

[0020] FIG. 3: Phase I: Temporal variations of lung elastance (EL) in two individual horses (horse ID 312 and 91) following a single administration of 800 g LAMA 1.

[0021] FIG. 4: Phase IVperiod 1: Temporal variations of transpulmonary pressure (PL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (20 puffs, 100 g/puff in aqueous formulation).

[0022] FIG. 5: Phase IVperiod 1: Temporal variations of lung resistance (RL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (20 puffs, 100 g/puff in aqueous formulation).

[0023] FIG. 6: Phase IVperiod 1: Temporal variations of lung elastance (EL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (20 puffs, 100 g/puff in aqueous formulation).

[0024] FIG. 7: Phase IVperiod 2: Temporal variations of transpulmonary pressure (PL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (4 puffs, 500 g/puff in ethanolic formulation).

[0025] FIG. 8: Phase IVperiod 2: Temporal variations of lung resistance (RL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (4 puffs, 500 g/puff in ethanolic formulation).

[0026] FIG. 9: Phase IVperiod 2: Temporal variations of lung elastance (EL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (4 puffs, 500 g/puff in ethanolic formulation).

[0027] FIG. 10: Phase IVperiod 3: Temporal variations of transpulmonary pressure (PL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (20 puffs, 100 g/puff in ethanolic formulation).

[0028] FIG. 11: Phase IVperiod 3: Temporal variations of lung resistance (RL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (20 puffs, 100 g/puff in ethanolic formulation).

[0029] FIG. 12: Phase IVPeriod 3: Temporal variations of lung elastance (EL) in two individual horses (horse ID 40 and 91) following a single administration of 2000 g LAMA 1 (20 puffs, 100 g/puff in ethanolic formulation).

[0030] FIG. 13: Phase II: Temporal variations in breathing effort score associated with the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) between days 1 and 7 (meanSEM) (n=8), where SEM is Standard Error of the Mean. * Significantly different.

[0031] FIG. 14: Phase II: Temporal variations in transpulmonary pressure (PL) associated with the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) between days 1 and 7 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

[0032] FIG. 15: Phase II: Temporal variations in lung elastance (EL) associated with the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) between days 1 and 7 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

[0033] FIG. 16: Phase II: Temporal variations in lung resistance (RL) associated with the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) between days 1 and 7 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

[0034] FIG. 17: Phase II: Temporal variations in transpulmonary pressure (PL) before and 30 minutes after the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) on Day 4 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

[0035] FIG. 18: Phase II: Temporal variations in lung resistance (RL) before and 30 minutes after the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) on Day 4 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

[0036] FIG. 19: Phase II: Temporal variations in lung elastance (EL) before and 30 minutes after the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) on Day 4 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

[0037] FIG. 20: Phase II: Temporal variations in pH of arterial blood samples associated with the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) between days 1 and 7 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

[0038] FIG. 21: Phase II: Temporal variations in paCO.sub.2 of arterial blood samples associated with the administration of clenbuterol (black bars) and three different doses of LAMA 1 (2 puffs: 200 g (white bars), four puffs: 400 g (light grey bars) and 8 puffs: 800 g (dark grey bars) between days 1 and 7 (meanSEM) (n=8), where SEM is Standard Error of the Mean.

DETAILED DESCRIPTION OF THE INVENTION

[0039] Before describing the various aspects of the present invention it shall be noted that as used herein and in the appended claims, the singular forms a, an, and the include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a preparation includes a plurality of such preparations reference to the carrier is a reference to one or more carriers and equivalents thereof known to those skilled in the art, and so forth. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values may vary by 1 to 5% unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term about was omitted from the description. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

[0040] Muscarinic Antagonists:

[0041] The term muscarinic antagonists refers to a group of substances that block the effects of acetylcholine on muscarinic receptors to reverse airway obstruction [Barnes, 2004]. Therefore muscarinic antagonists are also often denoted as anticholinergics or anticholinergic agents.

[0042] Examples for muscarinic antagonists include ipratropium bromide (which is often administered in equine medicine), atropine, aclidinium bromide, umeclidinium and glycopyrrolate.

[0043] The following subgroups of muscarinic antagonists can be defined: [0044] 1. long-acting muscarinic antagonists or LAMAs; [0045] 2. short-acting muscarinic antagonists or SAMAs.

[0046] An example of a LAMA is glycopyrrolate. An example of a SAMA is atropine.

[0047] The term long-acting muscarinic antagonists or LAMAs refers to a group of substances that block the effects of acetylcholine on muscarinic receptors for a longer period of time. Examples for LAMAs include tiotropium bromide or anticholinergics of the following general formula I:

##STR00004##

wherein
A denotes a double-bonded group selected from among

##STR00005##

X.sup. denotes an anion with a single negative charge,
R.sup.1 and R.sup.2 denote C.sub.1-C.sub.4-alkyl, which may optionally be substituted by hydroxy or halogen;
R.sup.3, R.sup.4, R.sup.5 and R.sup.6, which may be identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R.sup.7 denotes hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-halogen, halogen-C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-OH, CF3, C.sub.1-C.sub.4-alkylene-C.sub.1-C.sub.4-alkyloxy, OCOC.sub.1-C.sub.4-alkyl, OCOC.sub.1-C.sub.4-alkyl-halogen, OCOCF.sub.3 or halogen, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof, while
if A denotes

##STR00006##

R.sup.1 and R.sup.2 denote methyl and
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 denote hydrogen,
R.sup.7 cannot also be hydrogen.

[0048] Anticholinergics of the general formula I and processes for preparing them are disclosed for example in WO02/32899, which is hereby incorporated therein.

[0049] LAMA 1:

[0050] The term LAMA 1 describes a novel anticholinergic agent with the chemical name (1,2,4,5,7)-3-Oxa-9-azoniatricyclo [3.3.1.0.sup.2.4] nonane, 9,9-dimethyl-7-(1-oxo-2,2-diphenylpropoxy)-bromide or alternatively (short name) scopine 2,2-diphenylpropionate methobromide.

[0051] LAMA 1 (=scopine 2,2-diphenylpropionate methobromide) has the following chemical structure:

##STR00007##

LAMA 1 has the sum formula C.sub.24H.sub.28NO.sub.3*Br and has a molecular weight of 458.39 g/mol.

[0052] LAMA 1 is further characterized as follows:

TABLE-US-00001 scopine 2,2- diphenylpropionate Mean K.sub.D Diss. t Effects in the Kallos-Pagel Model methobromide [nM] Hm3 [h] Hm3 vs. tiotropium [00008] 0,4 0,4 3 to 10 fold lower efficacy (acute), 10 fold lower efficacy (chronic), protection over 24 hours (acute and chronic)

[0053] Beta-2 Adrenoceptor Agonists:

[0054] The term beta-2 adrenoreceptor agonists or beta-2 adrenergic agonists refers to a group of substances that stimulate 2-adrenergic receptors to relax airway smooth muscles [Tashkin and Fabbri, 2010].

[0055] The following subgroups of beta-2 adrenoreceptor agonists or beta-2 adrenergic agonists can be defined: [0056] 1. long-acting beta-2 adrenergic agonists or LABAs; [0057] 2. short-acting beta-2 adrenergic agonists or SABAs.

[0058] The term long-acting beta-2 adrenergic agonists or LABAs refers to a subgroup of substances that stimulate 2-adrenergic receptors to relax airway smooth muscles for a longer period of time.

[0059] Examples for LABAs include salmeterol, formoterol, bambutterol, indacaterol, vilanterol, abediterol and olodaterol hydrochloride.

[0060] Examples for beta-2 adrenoreceptor agonists of the SABA type include salbutamol or albuterol, clenbuterol, pirbuterol and fenoterol.

[0061] Glucocorticoids:

[0062] The term glucocorticoid refers to a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose+cortex+steroid) derives from its role in the regulation of the metabolism of glucose, its synthesis in the adrenal cortex, and its steroidal structure.

[0063] Glucocorticoids are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis.

[0064] Preferred glucocorticoids according to the present invention are ciclesonide and/or budesonide and/or fluticasone.

[0065] The term ciclesonide ((11,16)-16,17-[[(R)-Cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione, C.sub.32H.sub.44O.sub.7, M.sub.r=540.7 g/mol) is well known in the art and means/describes a glucocorticoid used to treat asthma and allergic rhinitis in humans. It is marketed for application in humans under the brand name ALVESCO (Takeda GmbH) for asthma and OMNARIS/OMNAIR (Takeda GmbH) for hay fever in the US and Canada. Ciclesonide is a prodrug. It is transformed into the active metabolite C21-C21-desisobutyrylciclesonide (=desciclesonide) via hydrolysis by intracellular esterases in the lung. Ciclesonide is a non-halogenated glucocorticoid, which predominantly exists in its form as REnantiomer.

##STR00009##

[0066] As used herein the term prodrug refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).

[0067] The terms prodrug or prodrug derivative mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). Such prodrugs either have metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound (also called the active metabolite), for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups. Most common prodrugs include esters and amide analogues of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can usually be readily prepared from the parent compounds using methods known in the art.

[0068] The term equine means of or belonging to the family Equidae, which includes the horses, asses, and zebras, preferably horses. In addition, the term equine encompasses also hybrids of members of the family Equidae (e.g., mules, hinnies, etc.)

[0069] The term patient or subject embraces mammals such as primates including humans. The term patient or subject as used herein relates specifically to horses, especially horses suffering from airway disease (particularly pulmonary disease), preferably from recurrent airway obstruction (RAO) also called heaves or equine COPD and/or summer pasture associated obstructive pulmonary disease (SPAOPD) also called Summer Pasture Associated Recurrent Airway Obstruction (SPARAO) and/or inflammatory airway disease (IAD), most preferably from RAO.

[0070] The term airway disease in horses means the following: recurrent airway obstruction (RAO) also called heaves or equine COPD, Summer Pasture Associated Obstructive Pulmonary disease (SPAOPD), inflammatory airway disease (IAD), exercise induced pulmonary hemorrhage (EIPH), infectious diseases, chronic interstitial lung disease and upper respiratory tract functional disorders.

[0071] The term pulmonary disease means: recurrent airway obstruction (RAO) also called heaves or equine COPD, Summer Pasture Associated Obstructive Pulmonary disease (SPAOPD), inflammatory airway disease (IAD), exercise induced pulmonary hemorrhage (EIPH), infectious diseases, or chronic interstitial lung disease.

[0072] The term recurrent airway obstruction (RAO) in horses means the following: a chronic syndrome of mature horses with reversible airway obstruction in the stable showing periods of laboured breathing at rest during exacerbation.

[0073] The term Summer Pasture Associated Obstructive Pulmonary disease (SPAOPD) in horses means the following: a chronic syndrome, which shares many clinical and pathological similarities with RAO at rest on the pasture, suggesting similar pathogenesis, however, it is caused by different antigens.

[0074] The term inflammatory airway disease (IAD) in horses means the following: a chronic syndrome of horses showing poor performance or coughing or excess tracheal mucus without showing periods of laboured breathing at rest.

[0075] The term effective amount as used herein means an amount sufficient to achieve a reduction of airway disease in a horse when ciclesonide is administered at a dosage as described herein. The progress of the therapy (improvement of airway disease, particularly pulmonary disease, preferably recurrent airway obstruction (RAO) and/or Summer Pasture Associated Obstructive Pulmonary disease (SPAOPD) and/or inflammatory airway disease (IAD), most preferably RAO as described herein) can be monitored by standard airway/pulmonary diagnosis, for example, by clinical examination, airway fluid cytology, endoscopy, lung function measurement, or blood-gas analysis.

[0076] The term pharmaceutically acceptable derivative thereof means but is not limited to pharmaceutically acceptable salts, derivatives, metabolites or pro-drugs of a drug. Derivatives as used herein include but are not limited to, any hydrate forms, solvates, isomers, enantiomers, racemates, racemic conglomerate and the like of the compound of choice. Suitable pharmaceutically acceptable salts are well known in the art and may be formed with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

[0077] The term pharmaceutically acceptable excipient (or carrier or adjuvants) for use with the pharmaceutical composition(s) according to the present invention include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. This is not a complete list possible pharmaceutically acceptable carriers, excipients and/or adjuvants, and one of ordinary skilled in the art would know other possibilities, which are replete in the art.

[0078] A pharmaceutical composition/preparation/medicament according to the invention may contain solvents such as water and/or ethanol, acidifiers such as hydrochloric acid, citric acid and/or phosphoric acid, and other excipients like preservatives such as benzalkonium chloride or ethanol, or stabilizers such as EDTA, butylhydroxyanisole or butylhydroxytoluene, viscosity modifiers such as hydroxypropyl methyl cellulose, or solubilizers such as hydroxypropylbeta-cyclodextrin, or substances to make the application of the composition more pleasant to the animals such as aromas or flavors.

[0079] The concentrations of each solvent can range between 1% m/V and 100% m/V, the concentration of the other excipients can range from 0.01% m/V to 10% m/V.

[0080] Administration:

[0081] Suitable forms for administration of LAMA 1 or combinations of glucocorticoids such as ciclesonide with LAMA 1 or other LAMAs and/or beta-2 adrenoreceptor agonist such as long-acting beta-2 adrenergic agonist (LABAs) are for example inhalation, parenteral or oral administration, preferably inhalation.

[0082] In the specific administration via the RESPIMAT inhaler (Boehringer Ingelheim International GmbH) the content of the pharmaceutically effective LAMA 1 should be in the range from 0.2 to 7% m/V, preferably 0.3 to 6.0% m/V or 0.4 to 5% m/V of the total composition, i.e. in amounts which are sufficient to achieve the dose range specified hereinafter.

[0083] When administered by inhalation ciclesonide may be given as an ethanolic solution or a solution containing a mixture of water and ethanol. Preferably, therefore, pharmaceutical formulations are characterised in that they comprise ciclesonide according to the preferred aspects above.

[0084] It is particularly preferred that the combination is administered via inhalation/ex inhaler, preferably it is administered once or twice a day. The administration of the combination can be performed by one inhaler containing both components of the combination. In addition, the administration of the combination can be performed subsequently by two inhalers, each of them containing one of the components of the combination. The subsequent administrations can be performed with or without a break between the administrations of the individual components. Suitable formulations may be obtained, for example, by mixing LAMA 1 with known excipients, for example water, pharmaceutically acceptable organic solvents such as mono- or polyfunctional alcohols (e.g. ethanol or glycerol), or refrigerants/propellants such as hydrofluoroalkanes (HFA), specifically HFA 227 and HFA 134a. For a liquid formulation, additional excipients for example hydrochloric acid or citric acid to adjust the [H.sup.+] concentration may be added.

[0085] It is especially preferred that LAMA 1 is administered by/via an aqueous/ethanolic droplet inhaler, for example the RESPIMAT inhaler or another inhalation device using the RESPIMAT aerosol-generating technology. Preferably LAMA 1 is administered once or twice a day. For this purpose, LAMA 1 has to be made available in a liquid solution which is suitable for the inhaler.

[0086] Most preferably the solvent in the liquid formulation (inhalation solution) comprises either water alone, or a mixture of 95% V/V ethanol and 5% V/V water, such as 90% V/V ethanol and 10% V/V water.

[0087] A further aspect of the present invention is the application of the liquid formulation (inhalation solution) using the RESPIMAT inhaler or another inhalation device using the RESPIMAT aerosol-generating technology. The RESPIMAT inhaler is disclosed for example in WO 97/12687, which is hereby incorporated therein. This inhaler can advantageously be used to produce the inhalable aerosols according to the invention. The dose of active substance delivered ex RESPIMAT inhaler can be calculated from: [0088] the concentration of active substance in the liquid formulation [g/L], [0089] the delivered volume, defined as the volume of liquid expelled from the RESPIMAT inhaler per actuation [L]. The delivered volume ex RESPIMAT inhaler has been found to be approximately 11 L per actuation, according to the following formula:

Dose [g]=Concentration [g/L].Math.Delivered Volume [L]

[0090] In the context of the present invention the term dose means the delivered dose ex inhaler.

[0091] In a further aspect of the present invention the composition is administered via an (equine) inhaler device. Suitable (equine) inhaler devices comprise for example a pressurized metered dose inhaler (pMDI) or an aqueous/ethanolic droplet inhaler. A specific form of an aqueous/ethanolic droplet inhaler is for example the RESPIMAT inhaler or another inhalation device using the RESPIMAT technology. Preferably, the (equine) inhaler device comprises/consists of an aerosol generating core based on the RESPIMAT aerosol-generating technology, and other parts to adapt the inhaler to equine use. An (equine) inhaler device is disclosed for example in WO2010149280, which is hereby incorporated therein.

[0092] In a preferred aspect the composition is an aqueous formulation and is administered via an (equine) inhaler device.

[0093] In a further aspect of the present invention the liquid formulation comprises one or more of the solvents/propellants: water, ethanol, hydrofluoroalkane(s) such as HFA 227 and HFA 134a, hydrofluoroolefin(s) such as HFO-1234ze, and optionally additional excipients. HFA is an abbreviation for hydrofluoroalkane and HFO is an abbreviation for hydrofluoroolefin.

[0094] In addition to formulations containing LAMA 1 alone, additional compositions containing in addition a glucocorticoid and/or LABA are possible. To achieve such a combination formulation a solvent consisting of ethanol in addition to water to increase the solubility of the individual drug substances can be used. Such a solvent can contain up to 95% V/V ethanol and as little as 5% V/V water. Solvents containing ethanol have the additional advantage of requiring a lower concentration or no preservative as combinations of ethanol and water can inhibit the growth or kill microorganisms.

[0095] The invention relates to muscarinic antagonists (including long acting muscarinic antagonists (LAMAs)), preferably of the general formula I, more preferably of the formula II (=LAMA 1), for the treatment of airway disease, such as pulmonary disease, preferably recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD) in animals such as equines, preferably horses.

[0096] The invention further relates to a combination of a muscarinic antagonists (including long acting muscarinic antagonists (LAMAs), preferably of the general formula I, more preferably of the formula II (=LAMA 1), with a glucocorticoid such as ciclesonide or budesonide, preferably ciclesonide, for the treatment of airway disease, such as pulmonary disease, preferably recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD) in animals such as equines, preferably horses.

[0097] The invention further relates to a combination of a muscarinic antagonists (including long acting muscarinic antagonists (LAMAs), preferably of the general formula I, more preferably of the formula II (=LAMA 1), with a glucocorticoid such as ciclesonide or budesonide, and optionally with beta-2 adrenoceptor agonists (including long acting beta-2 adrenoceptor agonists (LABAs)) for the treatment of airway disease, such as pulmonary disease, preferably recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD) in animals such as equines, preferably horses.

[0098] The invention further relates to a combination of a muscarinic antagonists (including long acting muscarinic antagonists (LAMAs), preferably of the general formula I, more preferably of the formula II (=LAMA 1), with a glucocorticoid such as ciclesonide or budesonide, or with beta-2 adrenoceptor agonists (including long acting beta-2 adrenoceptor agonists (LABAs)) for the treatment of airway disease, such as pulmonary disease, preferably recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD) in animals such as equines, preferably horses.

[0099] Preferably said beta-2 adrenoceptor agonist is salbutamol (albuterol), pirbuterol, clenbuterol, fenoterol, salmeterol, formoterol, indacaterol, vilanterol, abediterol and olodaterol (hydrochloride).

[0100] In a further aspect of the present invention the LAMA of the present invention is glycopyrrolate, ipratropium bromide, aclidinium bromide, umeclidinium or tiotropium bromide.

[0101] The invention specifically concerns a long-acting muscarinic antagonist (LAMA) or another pharmaceutically acceptable salt of the cation thereof for use as a medicament in an Equine, such as a horse.

[0102] The invention concerns a long-acting muscarinic antagonist (LAMA) or another pharmaceutically acceptable salt of the cation thereof for the use in a method of treating an airway disease in an equine, preferably a horse.

[0103] Preferably the LAMA is a compound of the general formula:

##STR00010##

wherein
A denotes a double-bonded group selected from among

##STR00011##

X.sup. denotes an anion with a single negative charge,
R.sup.1 and R.sup.2 denote C.sub.1-C.sub.4-alkyl, which may optionally be substituted by hydroxy or halogen;
R.sup.3, R.sup.4, R.sup.5 and R.sup.6, which may be identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R.sup.7 denotes hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-halogen, halogen-C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-OH, CF3, C.sub.1-C.sub.4-alkylene-C.sub.1-C.sub.4-alkyloxy, OCOC.sub.1-C.sub.4-alkyl, OCOC.sub.1-C.sub.4-alkyl-halogen, OCOCF.sub.3 or halogen, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof, while
if A denotes

##STR00012##

R.sup.1 and R.sup.2 denote methyl and
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 denote hydrogen,
R.sup.7 cannot also be hydrogen.

[0104] More preferably the LAMA is a compound of the formula (LAMA 1):

##STR00013##

[0105] In a specific aspect of the present invention the concentration of LAMA 1 ranges between 0.2 to 7% m/V, preferably 0.3 to 6.0% m/V or 0.4 to 5% m/V of the total composition.

[0106] The invention concerns a long-acting muscarinic antagonist (LAMA) or another pharmaceutically acceptable salt of the cation thereof or a pharmaceutical composition comprising a LAMA or another pharmaceutically acceptable salt of the cation thereof, in combination with a glucocorticoid such as ciclesonide or budesonide or fluticasone (preferably ciclesonide) or a pharmaceutical composition comprising ciclesonide or budesonide or fluticasone or a pharmaceutically acceptable salt thereof for use as a medicament in an Equine such as a horse.

[0107] The invention further concerns a long-acting muscarinic antagonist (LAMA) or another pharmaceutically acceptable salt of the cation thereof or a pharmaceutical composition comprising a LAMA or another pharmaceutically acceptable salt of the cation thereof, in combination with a glucocorticoid such as ciclesonide or a pharmaceutical composition comprising ciclesonide or a pharmaceutically acceptable salt thereof for use in a method of treating an airway disease in an equine, preferably a horse.

[0108] In a specific aspect of the present invention the pharmaceutical composition comprising the LAMA is a fixed dose combination/a pharmaceutical composition comprising a LAMA or pharmaceutically acceptable salts thereof and a glucocorticoid such as ciclesonide or budesonide or pharmaceutically acceptable salts thereof. A preferred combination is a LAMA of general formula I, most preferred LAMA1, in combination with ciclesonide or budesonide, preferably ciclesonide. Optionally, said pharmaceutical composition comprising the LAMA and the glucocorticoid additionally contains beta-2 adrenoreceptor agonists, such as a LABA.

[0109] In another aspect of the present invention the LAMA and the glucocorticoid are further combined with beta-2 adrenoreceptor agonists, such as a LABA or pharmaceutically acceptable salts thereof. These compounds or part of them may be formulated either as separate pharmaceutical compositions or as fixed dose combinations.

[0110] In a preferred aspect of the present invention the LAMA is a compound of the general formula:

##STR00014##

wherein
A denotes a double-bonded group selected from among

##STR00015##

X.sup. denotes an anion with a single negative charge,
R.sup.1 and R.sup.2 denote C.sub.1-C.sub.4-alkyl, which may optionally be substituted by hydroxy or halogen;
R.sup.3, R.sup.4, R.sup.5 and R.sup.6, which may be identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R.sup.7 denotes hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-halogen, halogen-C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-OH, CF3, C.sub.1-C.sub.4-alkylene-C.sub.1-C.sub.4-alkyloxy, OCOC.sub.1-C.sub.4-alkyl, OCOC.sub.1-C.sub.4-alkyl-halogen, OCOCF.sub.3 or halogen, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof, while
if A denotes

##STR00016##

R.sup.1 and R.sup.2 denote methyl and
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 denote hydrogen,
R.sup.7 cannot also be hydrogen.

[0111] Preferably the LAMA is a compound of the formula (LAMA 1):

##STR00017##

[0112] In a specific aspect of the present invention the concentration of LAMA 1 ranges between 0.2 to 7% m/V, preferably 0.3 to 6.0% m/V or 0.4 to 5% m/V of the total composition.

[0113] A specific aspect of the present invention is the combination of LAMA 1 or a pharmaceutically acceptable salt thereof with ciclesonide or a pharmaceutically acceptable salt thereof.

[0114] Another specific aspect of the present invention is the combination of LAMA 1 or a pharmaceutically acceptable salt thereof with budesonide or a pharmaceutically acceptable salt thereof.

[0115] A further aspect of the present invention is the combination of LAMA 1 or a pharmaceutically acceptable salt thereof with clenbuterol or a pharmaceutically acceptable salt thereof.

[0116] Another specific aspect of the present invention is the combination of LAMA 1 or a pharmaceutically acceptable salt thereof with ciclesonide or a pharmaceutically acceptable salt thereof and albuterol/albuterol sulfate or another pharmaceutically acceptable salt thereof.

[0117] A further specific aspect of the present invention is the combination of LAMA 1 or a pharmaceutically acceptable salt thereof with ciclesonide or a pharmaceutically acceptable salt thereof and olodaterol hydrochloride or another pharmaceutically acceptable salt thereof.

[0118] In another specific aspect of the present invention the LAMA is tiotropium bromide or a pharmaceutically acceptable salt thereof. A specific aspect of the present invention is the combination of tiotropium bromide with ciclesonide and optionally olodaterol hydrochloride.

[0119] In a specific aspect of the present invention the airway disease is a pulmonary disease. Preferably the airway disease is selected from the group consisting of: recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD).

[0120] In a further specific aspect of the present invention said LAMA or the pharmaceutical composition comprising the LAMA is (in) a liquid formulation, preferably a partially ethanolic formulation, most preferably said liquid formulation is for inhalation.

[0121] In another specific aspect of the present invention said LAMA or the pharmaceutical composition comprising the LAMA is administered via an (equine) inhaler device, preferably said inhaler device comprises:

a. a pressurized metered dose inhaler or an aqueous/ethanolic droplet inhaler such as the RESPIMAT inhaler or another inhalation device using the RESPIMAT aerosol-generating technology and
b. an adapter for equine use.

[0122] In a preferred aspect of the present invention LAMA 1 or a pharmaceutically acceptable salt of the cation thereof is administered at a dose of 100 g to 3000 g ex inhaler, 200 g to 2000 g ex inhaler, 200 g to 800 g ex inhaler, preferably at a dose of 200 g to 800 g ex inhaler.

[0123] In another preferred aspect of the present invention ciclesonide or a pharmaceutical composition comprising ciclesonide or a pharmaceutically acceptable salt thereof is administered at a dose of 100 g to 5000 g ex inhaler, 450 g to 3712.5 g ex inhaler, 900 g to 3712.5 g ex inhaler, preferably at a dose of 900 g to 3712.5 g ex inhaler.

[0124] In a further preferred aspect of the present invention the LAMA or the pharmaceutical composition comprising the LAMA is administered once or twice a day (once or twice daily), preferably once a day.

[0125] The invention further concerns a pharmaceutical composition comprising a long-acting muscarinic antagonist (LAMA) or pharmaceutically acceptable salts thereof and a LABA or pharmaceutically acceptable salts thereof and optionally a glucocorticoid such as ciclesonide or budesonide (preferably ciclesonide) or pharmaceutically acceptable salts thereof and optionally a pharmaceutically acceptable excipient.

[0126] The invention furthermore concerns a pharmaceutical composition comprising a long-acting muscarinic antagonist (LAMA) or pharmaceutically acceptable salts thereof and a glucocorticoid such as ciclesonide or budesonide (preferably ciclesonide) or pharmaceutically acceptable salts thereof and optionally a LABA or pharmaceutically acceptable salts thereof and optionally a pharmaceutically acceptable excipient.

[0127] Preferably said composition is a liquid formulation, most preferably a solution for inhalation.

[0128] In a preferred aspect of this invention the LAMA is a compound of the general formula

##STR00018##

wherein
A denotes a double-bonded group selected from among

##STR00019##

X.sup. denotes an anion with a single negative charge,
R.sup.1 and R.sup.2 denote C.sub.1-C.sub.4-alkyl, which may optionally be substituted by hydroxy or halogen;
R.sup.3, R.sup.4, R.sup.5 and R.sup.6, which may be identical or different, denote hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R.sup.7 denotes hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-halogen, halogen-C.sub.1-C.sub.4-alkyloxy, C.sub.1-C.sub.4-alkylene-OH, CF3, C.sub.1-C.sub.4-alkylene-C.sub.1-C.sub.4-alkyloxy, OCOC.sub.1-C.sub.4-alkyl, OCOC.sub.1-C.sub.4-alkyl-halogen, OCOCF.sub.3 or halogen,
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof, while
if A denotes

##STR00020##

R.sup.1 and R.sup.2 denote methyl and
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 denote hydrogen,
R.sup.7 cannot also be hydrogen.

[0129] Most preferably the LAMA is a compound of the formula (LAMA 1):

##STR00021##

[0130] In a specific aspect of the present invention the concentration of LAMA 1 ranges between 0.2 to 7% m/V, preferably 0.3 to 6.0% m/V or 0.4 to 5% m/V of the total composition.

[0131] The invention further concerns a method of treating an airway disease in an equine, preferably a horse, comprising [0132] a. administrating a therapeutically effective amount of a LAMA or a pharmaceutical composition comprising the LAMA or [0133] b. administrating a therapeutically effective amount of a pharmaceutical composition comprising a LAMA or a pharmaceutically acceptable salt thereof in combination with a glucocorticoid such as ciclesonide or a pharmaceutically acceptable salt thereof or [0134] c. administrating a therapeutically effective amount of a pharmaceutical composition comprising a LAMA or a pharmaceutically acceptable salt thereof in combination with a beta-2 adrenoreceptor agonists such as a LABA or a pharmaceutically acceptable salt thereof or [0135] d. administrating a therapeutically effective amount of a pharmaceutical composition comprising a LAMA or a pharmaceutically acceptable salt thereof in combination with a glucocorticoid such as ciclesonide or a pharmaceutically acceptable salt thereof and a beta-2 adrenoreceptor agonists such as a LABA or a pharmaceutically acceptable salt thereof or [0136] e. administrating a therapeutically effective amount of the pharmaceutical composition according to the invention (fixed dose combination) to an equine patient in need thereof, whereby said airway disease is preferably a pulmonary disease, most preferably said airway disease is selected from the group consisting of: recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD). Preferably the LAMA is LAMA 1 or a pharmaceutical composition comprising LAMA 1 or another pharmaceutically acceptable salt of the cation thereof.

EXAMPLES

[0137] The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.

[0138] The following examples 1 to 6 give examples of compositions which are possible to be administered using an inhaler based on the RESPIMAT spray generating technology.

Example 1

[0139] LAMA 1 can be formulated either as an aqueous solution or as an ethanolic solution. This first table shows examples for an aqueous solution:

TABLE-US-00002 TABLE 1 Concentration [g/100 mL] Component 0.446% 0.844% LAMA 1 0.446 0.844 0.541 1.022 Benzalkonium 0.010 0.010 chloride Edetate disodium 0.010 0.010 HCl (0.1 M) ad pH 4.0 ad pH 4.0 Water ad 100.0 mL ad 100.0 mL
where the concentration of hydrogen ions [H.sup.+] can be measured, for example, by potentiometric titration.

Example 2

[0140] LAMA 1 can be formulated either as an aqueous solution or as an ethanolic solution. This second table shows an example of formulations for an ethanolic solution with 50% V/V ethanol

TABLE-US-00003 TABLE 2 Concentration [g/100 mL] Component 0.844% 4.22% LAMA 1 0.844 4.22 1.022 5.11 HCl (0.1 M) 0.1 0.1 corresponds to 4.0 4.0 -log.sub.10 c.sub.H.sup.+ 50% V/V ad 100.0 mL ad 100.0 mL ethanol/water

Example 3

[0141] The next table shows an example of LAMA 1 formulations for an ethanolic solution with 90% V/V ethanol:

TABLE-US-00004 TABLE 3 Concentration [g/100 mL] Component 0.844% 4.22% LAMA 1 0.844 4.22 1.022 5.11 HCl (0.1 M) 0.1 0.1 equivalent to 4.0 4.0 -log.sub.10 c.sub.H.sup.+ 90% V/V ad 100.0 mL ad 100.0 mL ethanol/water

Example 4

[0142] LAMA 1 can be formulated as an ethanolic combination formulation with budesonide as shown in the following table 4:

TABLE-US-00005 TABLE 4 Concentration [g/100 mL] Component 0.844%/1.810% 4.22%/1.810% LAMA 1 0.844 4.22 1.022 5.11 Budesonide 1.810 1.810 Edetate disodium 0.001 0.001 HCl (0.1 M) 0.1 0.1 equivalent to 4.0 4.0 -log.sub.10 c.sub.H.sup.+ 90% V/V ad 100.0 mL ad 100.0 mL ethanol/water

Example 5

[0143] LAMA 1 can be formulated as an ethanolic combination formulation with ciclesonide as shown in the following table 5:

TABLE-US-00006 TABLE 5 Concentration [g/100 mL] Component 0.844%/3.00% 4.22%/1.810% LAMA 1 0.844 4.22 1.022 5.11 Ciclesonide 3.00 3.00 Butylhydroxytoluene 0.05 0.05 HCl (0.1 M) 0.1 0.1 equivalent to 4.0 4.0 -log.sub.10 c.sub.H.sup.+ 90% V/V ethanol/ 100.0 mL ad 100.0 mL water

Example 6

[0144] LAMA 1 can be formulated as an ethanolic combination formulation with ciclesonide and albuterol sulfate as shown in the following table 6:

TABLE-US-00007 Concentration [g/100 mL] Component 0.84%/3.00%/0.88% 4.22%/3.00%/0.88% LAMA 1 0.84 4.22 1.02 5.11 Ciclesonide 3.00 3.00 Albuterol 0.88 0.86 corresponds to 1.06 1.06 albuterol sulfate Butylhydroxytoluene 0.1 0.1 HCl (0.1 M) 0.4 0.4 equivalent to 3.4 3.4 -log.sub.10 c.sub.H.sup.+ 90% V/V ethanol/ ad 100.0 mL ad 100.0 mL water

Example 7: Monotherapy with LAMA 1

[0145] LAMA 1 is investigated in a study with 4 phases.

[0146] LAMA 1 is used in the formulations as described in examples 1 and 2.

[0147] Phase I and IV:

[0148] LAMA 1 is investigated in two RAO horses at different phases or periods as part of a mouldy hay challenge study. The horses are challenged every day by exposure to mouldy hay. LAMA 1 is administered via the Equine Inhaler device at different doses or formulations. Lung function parameters (change in transpulmonary pressure (PL), lung resistance (RL) and lung elastance (EL)) are measured for 24 h. A single administration of 800 g LAMA 1 (8 actuations in aqueous formulation) is performed per inhalation to two RAO horses (ID numbers: 312 and 91) in phase I. Two RAO horses are treated with LAMA 1 in phase IV (ID numbers: 40 and 91), which can be divided into three periods. 2000 g LAMA 1 (20 actuations in aqueous formulation) is administered per inhalation in period 1. 2000 g LAMA 1 (4 actuations in ethanolic formulation) is administered per inhalation in period 2. 2000 g LAMA 1 (20 actuations in ethanolic formulation) is administered per inhalation in period 3.

[0149] A decrease is observed in the lung function variables starting 5 minutes after the administration of LAMA 1. The values continue to drop until 2-8 h depending on the lung function parameter, and the dose or formulation of LAMA 1. The lung function variables are below or reach the pre-treatment values at 24 h after the single administration of LAMA 1 (Phase I: FIGS. 1-3; Phase IV, period 1: FIGS. 4-6; Phase IV, period 2: FIGS. 7-9; Phase IV, period 3: FIGS. 10-12).

[0150] Phase II:

[0151] LAMA 1 is investigated in a cross-over, blinded mouldy hay challenge study. 8 RAO horses are examined in the study, which is divided into an acclimation and a treatment phase. Placebo for LAMA 1 is administered once daily per inhalation via the Equine Inhaler device to all horses for 1 week in the acclimation period. LAMA 1 and clenbuterol are administered to the horses in a cross-over design in the treatment phase. The horses are challenged by exposure to mouldy hay throughout the acclimation and treatment phases. LAMA 1 is administered with the doses of 200 g (2 actuations)/400 g (4 actuations)/800 g (8 actuations)/horse (ex-RESPIMAT) once daily for 7 days per inhalation via the Equine Inhaler device. Nozzle A and a commercially available RESPIMAT is used in the study. Clenbuterol is administered with a dose of 0.8 g/kg per os, twice daily for 7 days. Lung function variables (change in transpulmonary pressure (PL), lung resistance (RL) and lung elastance (EL)), breathing effort score, Borborygmi score, blood gas analysis are examined during the study.

[0152] Placebo treatment does not induce significant changes on breathing effort score, lung function variables (change in transpulmonary pressure (PL), lung resistance (RL) and lung elastance (EL)), pH, paCO.sub.2 and paO.sub.2. Clenbuterol treated horses have significantly smaller breathing effort scores on study day 6 than horses treated with 2 or 4 actuations of LAMA 1 (FIG. 13). None of the treatments (LAMA 1 or clenbuterol) alters significantly PL and EL values over time (Days 4 and 8 compared to Day 1) (FIGS. 14 and 15). RL values are significantly reduced over time in the clenbuterol and 800 g LAMA 1 groups (FIG. 16). Lung function variables are measured before and 30 min after the administration of LAMA 1 on day 4. When compared with pre-treatment values, a decrease in PL, RL and EL is seen in all LAMA 1 groups at 30 min after the administration (FIG. 17-19). The change in PL and EL is statistically significant after the administration of 200 and 400 g LAMA 1. pH increases and paCO.sub.2 reduces significantly in arterial blood in the 800 g LAMA 1 group on Day 7 compared to Day 0 (FIGS. 20 and 21).

[0153] Phase III:

[0154] A single administration of 800 g LAMA 1 (8 actuations in aqueous formulation) is performed per inhalation to two healthy horses in phase III. Subsequently, ECG measurements are done for 48 h. Physiological arrhythmias are noted in both horses before and following the administration of LAMA 1. Only one observation is classified as either a first-degree heart block with aberrant intraventricular repolarization, or an artifact due to the movement of the electrodes.

Example 8

[0155] The combination of LAMA 1 and ciclesonide is investigated in a mouldy hay challenge model. 8 RAO horses are treated via inhalation using the Equine Inhaler device. Treatment with LAMA 1 monotherapy (maximum 2000 g per administration), with ciclesonide monotheraphy (maximum 3212.5 g per administration) and with the combinations of LAMA 1 and ciclesonide (maximum dose of LAMA 1 is 2000 g per administration and the maximum dose of ciclesonide is 3712.5 g per administration) is examined in the study. Lung function variables (change in transpulmonary pressure (PL), lung resistance (RL) and lung elastance (EL)) and weighted clinical score is measured in the study.

[0156] An improvement in lung function variables and weighted clinical score is observed in all treatment groups with varying extent. Similarly, the onset of the action shows difference among the treatment groups starting already a few minutes after drug administration.

REFERENCES

[0157] 1. Kutasi O., Balogh N., Lajos Z., Nagy K., Szenci O.: Diagnostic approaches for the assessment of equine chronic pulmonary disorders. J. Eq. Vet. Sci. (2011) 31: 400-410 [0158] 2. Coutil L. L, Hoffman A. M., Hodgson J., Buechner-Maxwell V., Viel L., Wood J. L. N. and Lavoie J.-P.: Inflammatory airway disease of horses. J. Vet. Intern. Med. (2007) 21: 356-361 [0159] 3. Dauvillier J., Felippe M. J. B., Lunn D. P., Lavoie-Lamoureux A., Leclere M., Beauchamp G., Lavoie J.-P.: Effect of long-term fluticasone treatment on immune function in horses with heaves. J. Vet. Intern. Med. (2011) 25: 549-557 [0160] 4. Tashkin D. P. and Fabbri L. M.: Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Resp. Research (2010) 11: 149 [0161] 5. Barnes P. J.: The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med (2004) 117 (Suppl 12A):24S-32S.