KR20070031392A - Combination of statins and bronchodilators - Google Patents

Abstract

The present invention provides a medicament comprising a combination of bronchodilators, glucocorticosteroids and HMG-CoA reductase inhibitors in the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD).

Respiratory disorders, chronic obstructive pulmonary disease (COPD), bronchodilators, glucocorticosteroids, HMG-CoA reductase inhibitors, pharmaceutical combinations

Description

A combination of statins and bronchodilators {COMBINATIONS OF STATINS WITH BRONCHODILATORS}

The present invention provides a medicament comprising a combination of bronchodilators, glucocorticosteroids and HMG-CoA reductase inhibitors in the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD).

Both diagnosis and management of multiple diseases focus on typical criteria and findings that characterize a particular disease for obvious reasons, thereby distinguishing it from other entities. Examples are joint-related signs and symptoms in the case of rheumatoid arthritis (RA), and lung function tests in the case of COPD.

However, because many diseases are not unique or characteristic of primary diseases, they often have significant co-morbidity rates that are often considered "other" diseases. For example, cardiovascular co-morbidity can often be considered nonspecific and may not be directly associated with primary diseases such as RA or COPD. However, co-morbidity can be as important as the traditional findings of primary disease in terms of both quality of life and social cost of the patient.

Chronic obstructive pulmonary disease (COPD) is a term used to describe a patient with irreversible airway obstruction, which is usually associated with chronic bronchitis and emphysema and is clearly associated with smoking. COPD is characterized by both an accelerated decrease in lung function and a period of acute decline in motor performance and a condition called exacerbation. As such, the disease is severe and progressive, often causing dyspnea and hypoxemia and eventually leading to death. COPD is the fourth leading cause of death in the industrialized world, placing a heavy burden on patients, their careers, healthcare resources and society. In the western world, COPD is markedly observed in smokers, but in other parts of the world, infection and indoor cooking appear to be predisposed. COPD is a disease in which inflammation-induced inflammation and impaired mucosal immune defenses can contribute to co-morbidity. Systemic inflammation persists even after quitting and can remain active for a long time.

Many patients have COPD, and the disease is difficult to treat. Treatments that affect bronchospasm, symptoms, quality of life and exacerbation exist, but there are no treatments that can delay the progression and loss of acceleration of lung function. One of the most important purposes of treatment is to slow the progression of the disease, and smoking cessation is the most important step to achieve this goal. However, rather than all COPD patients quit or hope to quit, airway obstruction will not most often disappear even if diarrhea patients quit. In this case, drug therapy can be somewhat alleviated. Recently there are several groups of tested drug therapies with different outcomes in COPD, namely bronchodilators and glucocortico-steroids. The bronchodilator class consists mainly of short- and long-acting anticholinergic and β ₂ -agonists. Although glucocorticosteroid treatment approaches are being studied more, the introduction of combination therapies using long-acting β ₂ -agonists such as formoterol and salmeterol with glucocorticosteroids such as budesonide and fluticasone propionate New drug tools are commercially available. In recent years, combination products containing long-acting β ₂ -agonists and glucocorticosteroids, for example formoterol / budesonide (AstraZeneca) and salmeterol / fluticasone propionate (GSK ) Is commercially available.

In addition, current anti-inflammatory drugs developed for signs and symptoms of certain diseases may not be suitable for long-term treatment of concomitant systemic inflammation, which is assumed to be responsible for large co-morbidities. Such therapies can reduce progressive systemic inflammation and should have good tolerance and stability.

Many experts require new therapies for all phases of COPD, but it is particularly important to find ways to eliminate or at least reduce the degradation of the disease over time.

When many inflammatory cells are activated, several inflammatory mediators will be involved in COPD. For example, in the practice of treating asthma, the effect on a single mediator has not been successful in the development of new therapies. There are different mediators involved in COPD compared to asthma, so different drugs need to be developed. Among the targets for COPD are leukotriene B ₄ inhibitors, chemokine antagonists, neutrophil elastase, phosphodiesterase-4 inhibitors, cathepsin, matrix metallo-proteinases (MMPs), protease inhibitors and many others It became. Strong evidence suggests that COPD-related lung damage results from a protease imbalance.

Matrix metalloproteinases can degrade all components of the extracellular matrix of the lung parenchyma, including elastin, collagen, proteoglycans, laminin and fibronectin (FASEB J, 12 1075 (1998)). . Although certain non-selective MMP inhibitors have been developed, there may be a problem of side effects with prolonged use. More selective inhibitors of individual MMPs such as MMP-9 and MMP-12 are currently in development.

Statins are increasingly recognized as anti-inflammatory agents. Schöbeck and Libby (Circulation, 109 (suppl. II), II-18-26 (2004)) have been described as statins (3-hydroxy-3-methyl glutaryl coenzyme A ( This was reviewed by reviewing in vitro and in vivo evidence for HMG-CoA) reductase inhibitors). No connection to statin use in any type of respiratory disorder has been reviewed at all by the authors.

Statins are the most commonly used lipid-lowering compounds. Examples are lovastatin, rosuvastatin (Crestor ™, AstraZeneca), pravastatin (Pravachol ™, Bristol-Myers Squibb), simvastatin (Zocord ™) Merck), itavastatin, cerivastatin, fluvastatin, atorvastatin (Lipitor ™, Pfizer) and mevastatin. WO 00/48626 (University of Washington) discloses a composition comprising a HMG-CoA reductase inhibitor (statin) at a concentration of less than 0.1 mg, and a method of treating lung disease, including COPD, with an aerosol formulation of statins.

EP 1 275 388 (Takeda) discloses TNF-α inhibitors (statins) for the prophylaxis and treatment of TNF-α-related diseases such as asthma and inflammatory diseases including COPD.

Statin serivastatin has been shown to reduce inflammatory activity in alveolar macrophages derived from patients with chronic bronchitis (Circulation 101 (2000), 1760). Studies on patients taking statins have shown that initiation of statin therapy is associated with a significant improvement (using specific patient selection criteria) in the FEV ₁ lowering rate not associated with tobacco use factors. Reserve Statin Basal FEV ₁ The slope was -109.2 ml / yr and the statin therapy slope was -46.7 ml / yr (Chest, 120 (4), suppl, p291S (2001)).

In the present invention, the inventors have found that a combination of HMG-CoA reductase inhibitors (preferably statins), bronchodilators and glucocorticosteroids, provided individually, sequentially or simultaneously, enhances the effect of each component and also It has been found that it can exert a better effect than the treatment of phosphorus COPD. Therapeutic effect can be observed for the rapid decline in lung function that is characteristic of COPD, and the effect can also be observed for systemic inflammation that is characteristic of COPD. The long-term effect of the combination according to the invention will be the protection of the lung function and potentially less co-morbidity (based on its effect on systemic inflammation).

In a first aspect, the present invention

(a) at least one first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt;

(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or at least one second active ingredient which is a solvate of said salt; And optionally

(c) at least one third active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt

Pharmaceutical combinations comprising a mixture or individually.

The combination of the present invention can be used for the treatment of respiratory diseases such as asthma, COPD, and fibrolytic diseases such as systemic sclerosis, alveolitis, sarcoidosis and idiopathic pulmonary fibrosis.

The pharmacologically active agents according to the present invention include lovastatin, rosuvastatin (Crestor ™, AstraZeneca), pravastatin (pravacol ™, Bristol-Myers Squibb), simvastatin (zocorde ™, Merck), itavastatin Statins such as cerivastatin, fluvastatin, atorvastatin (Lipitor ™, Pfizer) and mevastatin.

Suitable glucocorticosteroids include budesonide, fluticasone (eg as propionate ester), mometasone (eg as furoate ester), beclomethasone (eg 17-propio) Nate or as 17,21-dipropionate ester), ciclesonide, loteprednol (eg as etabonate), etiprenol (eg as dichloroacetate), triamcinolone (eg For example, as acetonide), flunisolid, joticasone, flumosonide, loplefonide, butyxocort (eg as propionate ester), prednisolone, prednisone, tifredane, WO 2002 / Steroid esters according to 12265, WO 2002/12266 and WO 2002/88167 (I), for example 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α -Methyl-3-oxo-androsto-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5- Carbonyl) oxy] -3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, steroid esters according to DE 4129535 (II), and the like.

Preferably, the bronchodilator is a long-acting β ₂ -agonist. Suitable long-acting β ₂ -agonists include salmeterol, formoterol, bambuterol, TA 2005 (2 (1H) -quinolone, 8-hydroxy-5- [1-hydroxy-2-[[2- (4-methoxy-phenyl) -1-methylethyl] -amino] ethyl] -monohydrochloride, chemically identified as [R- (R ^* , R ^* )] and also referred to as a Chemical Abstract Service Registry Number Service Registry Number) 137888-11-0, as disclosed in US Pat. No. 4.579.854 (= CHF-4226, Carmoterol), QAB149 (CAS No. 312753-) as described in WO 2002/76933. 06-3; indacaterol), formanilide derivative (III), for example 3- (4-{[6-({(2R) -2- [3- (formylamino) -4-hydroxy Phenyl] -2-hydroxyethyl} amino) hexyl] oxy} -butyl) -benzenesulfonamide, benzenesulfonamide derivative (IV) as disclosed in WO 2002/88167, for example 3- (4-{[6 -({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy-methyl) phenyl] ethyl} amino) -hexyl] oxy} butyl) bene The aryl aniline receptor agonists as disclosed in sulfonamide, WO 2003/042164 and WO 2005/025555 (V), include indole derivatives such as disclosed in WO 2004/032921. Among the anticholinergic compounds, epratropium (eg as bromide), tiotropium (eg as bromide), oxytropium (eg as bromide), tolterodine, solifenacin (eg For example, as succinate), imidafenacin, darfenacin, pesoterodine, glycopyrronium (eg as bromide), mefensolate (eg as bromide), US 2003/0055080 Quinuclidin derivatives as disclosed, such as 3 (R)-(2-hydroxy-2,2-dithien-2-ylacetoxy) -1- (3-phenoxypropyl) -1-azonia-r Cyclo [2.2.2] octane bromide and the like. Several of these compounds may optionally be administered in the form of pharmacologically acceptable esters, salts, solvates such as hydrates, or solvates of such esters or salts. Both racemic mixtures of the compounds and one or more optical isomers are within the scope of the present invention.

Suitable physiologically acceptable salts include acid addition salts derived from inorganic and organic acids, for example chlorides, bromide, sulfates, phosphates, maleates, fumarates, citrate, tartrates, benzoates, 4-methoxybenzoates , 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, acetate, succinate, lactate, glutarate, tricarvallate, hydrate Hydroxynaphthalene-carboxylate (xinapoate) or oleate salts or solvates thereof. The second active ingredient is preferably formoterol fumarate dihydrate or salmeterol xinapoate.

Preferred pharmacologically active statins for use in accordance with the present invention include rosuvastatin and atorvastatin. Preferred glucocorticosteroid agents include mometasone furoate, ciclesonide, joticasone, flumosonide, steroid (I), steroid (II), fluticasone propionate and budesonide, Even more preferred. Preferred pharmacologically active long-acting β ₂ -agonists include salmeterol xinapoate, formanide derivative (III), benzenesulfonamide derivative (IV) and formoterol (eg as fumarate dihydrate) With this, formoterol fumarate dihydrate is even more preferred. Among the more preferred anticholinergic agents are tiotropium, tolterodine, and quinuclidin derivatives as shown in US 2003/005580.

Preferably from one class there is one active ingredient, namely one statin, one bronchodilator and one glucocorticosteroid.

Preferred combinations

Atorvastatin / formoterol fumarate dihydrate,

Rosuvastatin / formoterol fumarate dihydrate,

Pravastatin / formoterol fumarate dihydrate,

Simvastatin / formoterol fumarate dihydrate,

Atorvastatin / budesonide / formoterol fumarate dihydrate,

Rosuvastatin / budesonide / formoterol fumarate dihydrate,

Rosuvastatin / ciclesonide / formoterol fumarate dihydrate,

Atorvastatin / fluticasone propionate / salmeterol xinapoate,

Atorvastatin / ciclesonide / formoterol fumarate dihydrate,

Rosuvastatin / mometasone furoate / formoterol fumarate dihydrate, and

Rosuvastatin / Fluticasone Propionate / Formoterol Fumarate Dihydrate

It includes.

The most preferred combination is

Rosuvastatin / formoterol fumarate dihydrate,

Atorvastatin / budesonide / formoterol fumarate dihydrate, and

Rosuvastatin / Budesonide / Formoterol Fumarate Dihydrate

It includes.

Another preferred combination is

Rosuvastatin / formoterol fumarate dihydrate / thiotropium bromide,

Atorvastatin / formoterol fumarate dihydrate / thiotropium bromide,

Atorvastatin / formoterol fumarate dihydrate / tolerodine,

Rosuvastatin / thiotropium bromide, and

Atorvastatin / Tiotropium Bromide

It includes.

In the manufacture of a medicament for use in the treatment of respiratory diseases according to the invention

(a) at least one first active ingredient (s) which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt;

(b) one or more second active ingredient (s) which is a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt; And optionally

(c) one or more third active ingredient (s) which are glucocorticosteroids, pharmaceutically acceptable salts or solvates thereof, or solvates of said salts

Combinations are provided comprising the mixtures individually or separately.

The invention also

(a) at least one first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt;

(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or at least one second active ingredient which is a solvate of said salt; And optionally

(c) at least one third active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt

A method of treating respiratory disease is provided comprising administering to a patient a respiratory disease a therapeutically effective amount of a combination comprising a mixture or individually.

Effective dosages of the components will vary strongly depending on the particular compound and mode of administration used, as well as the weight and disease state of the individual being treated. Oral dosages of statins will generally range from about 0.01 mg to about 200 mg, preferably from 10 to 80 mg, more preferably from 5 to 40 mg; When inhaled, a dosage range of 0.001 mg to about 25 mg is preferred, even more preferably a dose of 0.1 to 25 mg.

Suitable daily doses of long-acting β ₂ -agonists are in the range of 1 μg to 100 mg depending on the potency of each compound, for example in the case of formoterol the daily dose may be 1 to 100 μg. The preferred dosage is in the range of 3 to 48 μg (as fumarate dihydrate). Suitable daily doses for glucocorticosteroids are in the range of 50 μg to 2000 μg, for example for budesonide the daily dose is in the range of 50 μg to 1600 μg. When inhaling anticholinergic agents, the dosage is 1 μg to 300 μg, and in the case of ifpratropium bromide (Atrovent ™ Boehringer Ingelheim), the dosage is preferably 10 to 200 μg and in the case of tiotropium (Spiriva ™ Boehringer Ingelheim) the dose is 1-50 μg.

Suitably the molar ratio of the second active ingredient to the third active ingredient is from 1: 2500 to 12: 1.

The molar ratio of the second active ingredient to the third active ingredient is preferably 1: 555 to 2: 1, more preferably 1: 150 to 1: 1. The molar ratio of the second active ingredient to the third active ingredient is more preferably 1: 133 to 1: 6. The molar ratio of the second active ingredient to the third active ingredient is most preferably 1:70 to 1: 4.

The components of the invention may be administered in a mixture, ie together or separately. When administered together, the components may be administered in a single pharmaceutical composition, eg, a fixed combination provided by inhalation. Alternatively, the components may be administered individually, ie after the other two, for example, orally, statins and inhalations. The time interval for separate administration may be administration several hours after direct sequential (one after the other) administration.

Examples of respiratory diseases that can be treated in accordance with the present invention include asthma, chronic obstructive pulmonary disease (COPD), systemic sclerosis, alveolitis, sarcoidosis, cystic fibrosis, fibrotic and gastric rhinitis, and idiopathic pulmonary fibrosis.

The present invention further

(a) at least one first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt;

(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or at least one second active ingredient which is a solvate of said salt; And optionally

(c) at least one third active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt

It provides a process for the preparation of the pharmaceutical composition of the present invention, comprising mixing with a pharmaceutically acceptable adjuvant, diluent or carrier.

The therapeutically active ingredient can be administered prophylactically or as a therapeutic treatment for a period of medical condition.

Pharmaceutical compositions may be topically in the form of solutions, suspensions, fluoroalkane aerosols and dry powder formulations (eg, in the lungs and / or airways or skin); Or systemically, for example orally in the form of tablets, capsules, syrups, powders or granules, or parenterally in the form of solutions or suspensions, or subcutaneously or in the form of suppositories or foams or rectally. It can be administered by administration or transdermally.

Compositions for use in the present invention optionally further comprise one or more pharmaceutically acceptable additives, diluents and / or carriers. The composition is preferably in the form of a dry powder for inhalation wherein the particles of the pharmaceutically active ingredient have a mass median diameter of less than 10 μm.

When administered separately, administration can be via other routes. For example, statins can be administered orally and steroids and β ₂ -agonists can be administered in combination by inhalation as a powder, or as an aerosol formulation or formulation suitable for nebulization. The compound may be delivered from a single chamber / cartridge, but may also be delivered from two or three chambers / cartridges having separate channels.

Biological Data

As indicated above, COPD is a chronic disease caused by smoking in susceptible individuals. It is characterized by various respiratory symptoms, such as shortness of breath, wet cough and wheezing. These symptoms can increase rapidly with acute exacerbation at various intervals. Respiratory infections are a major cause of exacerbations that are life threatening and can have a significant impact on quality of life. Many drugs, for example, with inhaled corticosteroids (ICS), in particular long-acting beta agonists (LABA), exhibit some prophylactic effect on the occurrence of exacerbations. Symbicort®, a fixed combination of budesonide and formoterol, has been approved for the treatment of COPD based on the prevention of symptoms, quality of life and severe exacerbations. These effects include the strictest definition of severe exacerbation: hospitalization needs based on respiratory symptoms or the need for duration of oral corticosteroids.

In post-hoc analysis of long-term clinical trials of COPD, a positive effect on FEV ₁ degradation was observed in patients treated with statins. This effect has not been observed in any other treatment, including ICS. In connection with the exacerbation defined above, there was a synergistic effect of budesonide and formoterol, presented by Symbicort®. The effects on statin exacerbations are not described or unexpected. Surprisingly, the inventors have found that the effect of the combination of formoterol and budesonide (symbicort) on exacerbation can be further enhanced by statins.

Way

Meta-analysis was performed twice for moderate to severe COPD. One year from clinical trials. Concomitant medications for patients treated with budesonide (Pulmicort®), formoterol (Oxis®), formoterol + budesonide (Symbicort®) or placebo The presence or absence of statins was defined as requiring a treatment period for oral corticosteroids. The incidence of severe exacerbations was measured.

result

The results of the analysis are shown in Table 1. If the patient is treated with statins, the positive effect of the combination of formoterol and budesonide (Symbicort®) versus the single component (budesonide and formoterol, respectively) is demonstrated and further expanded. The lowest incidence of exacerbations was 0.3 per year, corresponding to a 75% reduction in the placebo group in patients taking Symbicort® plus statins.

Effect on exacerbation of severe COPD by different treatments (number of patients treated) cure Annual deterioration rate Statins Not included With statins Placebo 1.1 (n = 380) 0.6 (n = 8) Budesonide 0.9 (n = 379) 0.7 (n = 8) Formoterol 1.0 (n = 388) 0.4 (n = 9) Budesonide / Formoterol 0.7 (n = 399) 0.2 (n = 6)

The positive effect of the combination of formoterol and budesonide (Symbicort®) on exacerbation of COPD is enhanced by statins, the combination of formoterol and budesonide (Symbicort®) and Statins showed the lowest incidence of COPD exacerbations corresponding to a 82% reduction compared to the placebo group.

The invention is illustrated by the following examples.

Example  1-inhalation-dry powder

ingredient Per dose Formoterol (as fumarate dihydrate) 4.5 μg Budesonide 160 ㎍ Rosuvastatin 1 mg

Example  2-inhalation-metered dose inhaler

ingredient Per dose Formoterol (as fumarate dihydrate) 4.5 μg Budesonide 160 ㎍ Rosuvastatin 1 mg HFA 227 50 μl

Example  3-Suction-Dry Powder

ingredient Per dose Formoterol (as fumarate dihydrate) 4.5 μg Budesonide 160 ㎍ Rosuvastatin 1 mg Lactose 1, 2, 5, 10 or 20 mg or less

Example  4-inhalation / oral administration

Aerosol formulations

ingredient Per dose Formoterol (as fumarate dihydrate) 4.5 μg Budesonide 160 ㎍

Tablet formulation

ingredient Per tablet Rosuvastatin 10 mg

Example  5-inhalation / oral administration

Aerosol formulations

ingredient Per dose Formoterol (as fumarate dihydrate) 4.5 μg Budesonide 160 ㎍

Tablet formulation

ingredient Per tablet Rosuvastatin 20 mg

Claims (17)

(a) at least one first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt, (b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or at least one second active ingredient which is a solvate of said salt; And optionally (c) at least one third active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt Pharmaceutical combinations comprising a mixture or individually. The combination according to claim 1, wherein the statin is selected from lovastatin, rosuvastatin, pravastatin, simvastatin, itavastatin, cerivastatin, fluvastatin, atorvastatin and mevastatin. The combination of claim 1, wherein the statin is rosuvastatin. The combination of claim 1, wherein the statin is atorvastatin. The combination according to any one of claims 1 to 4, wherein the bronchodilator is an organ-acting β ₂ -agonist. The method according to any one of claims 1 to 5, wherein the long-acting β ₂ -agonist is salmeterol, formoterol, bambuterol, 2 (1H) -quinolone, 8-hydroxy-5- [1- Hydroxy-2-[[2- (4-methoxy-phenyl) -1-methylethyl] -amino] ethyl] -monohydrochloride, [R- (R ^* , R ^* )], 3- (4- {[6-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) hexyl] oxy} -butyl) -benzenesulfonamide or 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy-methyl) phenyl] ethyl} amino) -hexyl] oxy} butyl) benzenesulfonamide And a pharmaceutically acceptable salt or solvate thereof, or a combination thereof. The combination according to any one of claims 1 to 6, wherein the long-acting β ₂ -agonist is formoterol or a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt. 8. The combination according to any one of claims 1 to 7, wherein the long acting β ₂ -agonist is formoterol fumarate dihydrate. The combination according to any one of claims 1 to 4, wherein the bronchodilator is an anticholinergic or a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt. The anticholinergic agent according to any one of claims 1 to 4, wherein the anticholinergic agent is ypratropium (eg as bromide), tiotropium (eg as bromide), oxytropium (eg bromide). Tolterodine, solifenacin (e.g., as succinate), imidafenacin, darfenacin, pesoterodine, glycopyrronium (e.g. as bromide), mefensolate (e.g., For example, as bromide), 3 (R)-(2-hydroxy-2,2-dithien-2-ylacetoxy) -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2 .2] quinuclidin derivatives such as octane bromide and pharmaceutically acceptable salts thereof, or combinations thereof. The combination of claim 10, wherein the anticholinergic is tiotropium bromide. The glucocorticosteroid according to any one of claims 1 to 4, wherein the glucocorticosteroid is budesonide, fluticasone, mometasone, beclomethasone, ciclesonide, loteprednol, etipredol, triamcinolone, fluni. Solid, joticasone, flumosonide, loplefonide, butyxocort, prednisolone, prednisone, tipredan, 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β- Hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3 -Oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester and 6α, 9α-difluoro-11β -Hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1,4-diene-17β-carbothioic acid S Fluoromethyl esters, and agents thereof The combination is selected from acceptable salts. The combination according to any one of claims 1 to 4, wherein the glucocorticosteroid is budesonide. The combination according to any one of claims 1 to 13 for use in the treatment of respiratory diseases. The combination according to any one of claims 1 to 14 for use in the treatment of chronic obstructive pulmonary disease (COPD). (a) at least one first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt; (b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or at least one second active ingredient which is a solvate of said salt; (c) at least one third active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt A method of treating respiratory disease comprising administering to a patient with a respiratory disease a therapeutically effective amount of a combination comprising, individually or in admixture. The method of claim 16, wherein the disease is COPD.