Field of the invention

The invention provides medicaments comprising combinations of glucocorticosteroids and HMG-CoA reductase inhibitors in the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD).

Background of the invention

Both diagnosis and management of many diseases focus, for obvious reasons, on typical criteria and manifestations, which are characteristic for that particular disease (thereby discriminating it from other entities). Examples are joint-related signs and symptoms in rheumatic arthritis (RA) and lung functions test in COPD. However, many diseases have significant co-morbidity, which often have been regarded as "other" diseases, since they are not unique or characteristic to the primary disease. For example, cardiovascular co-morbidity may often be viewed as unspecific and not directly linked to primary diseases such as RA or COPD. Yet, co-morbidity may be just as important as the traditional manifestations of the primary disease, both in terms of quality of life for the patients and for the cost for society.

Chronic obstructive pulmonary disease (COPD) is a term used to describe patients with irreversible airway obstruction, usually in association with chronic bronchitis and emphysema, and epidemiologically clearly linked to smoking. COPD is characterised by both an accelerated decline in lung function and periods of acute deterioration in symptoms and exercise capacity termed exacerbations. The disease thus is serious and progressive and often leads to severe breathing disabilities, hypoxemia and eventually to death. COPD is the fourth leading cause of death in the industrialised world and exerts a heavy burden on patients, their careers, healthcare resources and society. In the western world COPD is predominantly observed in smokers, but in other parts of the world infections and in-door cooking seem to predispose. COPD is a disease where inflammation and impaired mucosal immune defence, induced by smoking, may contribute to co-morbidity. A systemic inflammation continues to be active also long after smoking cessation.

Patients with COPD are numerous and the disease is difficult to treat. Treatments exist that have effect on bronchospasm, symptoms, quality of life and exacerbations, however there is none that is able to slow down the progressive and accelerated loss of lung function. One of the primary objectives of treatment is to reduce the progression of the disease and to obtain this smoking cessation is the most important step. However, far from all COPD patients can or even wish to give up smoking and even if the patients stop smoking the airway obstruction will most often not disappear. In these cases pharmacological therapy may provide some relief. Up to date there are only a few groups of pharmacological treatments that have been tested with different results in COPD, namely bronchodilating agents and glucocortico- steroids. The bronchodilating class consists mainly of short and long-acting anticholinergics and β ₂ -agonists. The glucocorticosteroid treatment approach is more questioned, but with the introduction of combination therapies using the long-acting β ₂ -agonists such as formoterol and salmeterol together with glucocorticosteroids such as budesonide and fluticasone propionate, a new pharmacological tool has become available. In recent years combination products containing a long-acting β ₂ -agonist and a glucocorticosteroid e.g. formoterol/budesonide (AstraZeneca) and salmeterol /fluticasone propionate (GSK) have become available.

In addition current anti-inflammatory drugs, developed for signs and symptoms of a particular disease, may not be optimized for long-term treatment of the concomittant systemic inflammation which is hypothesized being responsible for much of the co-morbidity. Such therapy must be able to reduce an ongoing, systemic inflammation - and yet have good tolerability and safety.

Description of the invention

Many specialists express the need for new therapies for all aspects of COPD, but it is particularly important to find ways to eliminate or at least reduce the declining of the disease with time.

Several inflammatory mediators are likely to be involved in COPD as many inflammatory cells are activated. In medical practice for the treatment of e.g. asthma the influence on a single mediator has been unsuccessful in the development of new therapies. There are different mediators involved in COPD compared to asthma and therefore it is

necessary to develop different drugs. Among targets for COPD have been mentioned leukotriene B ₄ inhibitors, chemokine antagonists, neutrophil elastase, phosphodiesterase-4 inhibitors, cathepsins, matrix metallo-proteinases (MMPs), protease inhibitors and many others. Compelling evidence suggests that the lung damage associated with COPD results from an imbalance between proteases.

Matrix metalloproteinases are capable of degrading all of the components of the extracellular matrix of lung parenchyma including elastin, collagen, proteoglycans, laminin and fibronectin (FASEB J, 12 1075 (1998)). It has been developed some nonselective MMP inhibitors, but the side effects may be a problem in long-term use. More selective inhibitors of individual MMPs, such as MMP-9 and MMP-12 are now in development.

Statins are increasingly being recognized as anti-inflammatory agents. Schonbeck and Libby (Circulation, 109 (suppl. II), 11-18-26 (2004)) are addressing this by reviewing in vitro and in vivo evidence regarding statins (3 -hydroxy-3 -methyl glutaryl coenzyme A (HMG- CoA) reductase inhibitors) as antiinflammatory agents. Any connections of use of statins in respiratory disorders of any land are not addressed at all by these authors.

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

EP 1 275 388 (Takeda) provides a TNF-α inhibitor (statins) for the prevention and treatment of TNF-α- associated diseases such as inflammatory diseases including asthma and COPD. The statin cerivastatin has been shown to reduce inflammatory activity in alveolar macrophages derived from chronic bronchitis patients (Circulation 101 (2000), 1760). In a study with patients receiving statins it was shown that initiation of statin therapy was associated with a significant improvement (certain patient inclusion criteria were used) in the rate of FEV ₁ decline that was unrelated to cigarette use factors. The prestatin baseline FEV ₁ slope was -109.2 ml/yr and following statin therapy the slope was -46.7 ml/yr (Chest, 120 (4), suppl, p291S (2001)).

We have now found that a combination of a HMG-CoA reductase inhibitor (preferably a statin) and a glucocorticosteroid given separately, sequentially or simultaneously may potentiate the effect of either component and also produce a better effect than conventional COPD treatments. The therapeutic effect may be observed with regard to the fast decline in 5 lung function that is a hallmark of COPD, and effects may be observed regarding the systemic inflammation that is also characteristic of COPD. The long-term effect of a combination according to the invention will be conservation of lung function and putatively less comorbidity (based on effects on the systemic inflammation).

In a first aspect the invention provides a pharmaceutical combination comprising, in o admixture or separately:

(a) a first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and

(b) a second active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt s The combinations of the invention can be used for the treatment of respiratory diseases such as asthma and COPD and fibrolytic diseases like systemic sclerosis, alveolitis, sarcoidosis and idiopathic pulmonary fibrosis, particularly COPD.

The pharmacologically active agents in accordance with the present invention include statins like lovastatin, rosuvastatin (Crestor™, AstraZeneca), pravastatin, simvastatin, 0 itavastatin, cerivastatin, fluvastatin, atorvastatin (Lipitor™, Pfizer) and mevastatin.

Suitable glucocorticosteroids include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17-propionate or 17,21- dipropionate esters), loteprednol (e.g. as etabonate), etiprednol (e.g. as dicloacetate), ciclesonide, triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, 5 rofleponide, butixocort (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters according to WO 2002/12265, WO 2002/12266 and WO 2002/88167 (I) e.g. 6α,9α- difluoro- 17α- [(2-furanylcarbonyl)oxy] - 11 β-hydroxy- 16α-methyl-3-oxo-androsta- 1 ,4-diene- 17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-llβ-hydroxy-16α-methyl-3-oxo- 17α-propionyloxy-androsta-l ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) o ester and 6α,9α-difluoro-l lβ-hydroxy-16α-methyl-17α-[(4-methyl-l,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester, steroid

esters according to DE 4129535 (II), steroids according to WO 2002/00679 (III), steroids according to WO 2005/041980 (IV), steroids GSK 870086, GSK 685698, GSK 799943 and the like.

Several of these compounds could be administered in the form of pharmacologically acceptable esters, salts, solvates, such as hydrates, or solvates of such esters or salts, if any.

Both racemic mixtures as well as one or more optical isomers of the above compounds are within the scope of the invention.

Suitable physiologically acceptable salts include acid addition salts derived from inorganic and organic acids, for example the chloride, bromide, sulphate, phosphate, maleate, fumarate, citrate, tartrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4- chlorobenzoate, p-toluenesulphonate, methane-sulphonate, ascorbate, acetate, succinate, lactate, glutarate, tricarballylate, hydroxynaphthalene-carboxylate (xinafoate) or oleate salts or solvates thereof.

The preferred pharmacologically active statins for use in accordance with the present invention include rosuvastatin and atorvastatin. The preferred glucocorticosteroid agents include mometasone furoate, ciclesonide, zoticasone, flumoxonide, steroid (I), steroid (II) , steroid (III), steroid (IV), fluticasone propionate and budesonide, and even more preferred is budesonide.

The preferred combinations include: atorvastatin/budesonide rosuvastatin/budesonide simvastatin/budesonide rosuvastatin/ciclesonide atorvastatin/fluticasone propionate atorvastatin/ciclesonide rosuvastatin/mometasone furoate and rosuvastatin/fluticasone propionate

The most preferred combinations are atorvastatin/budesonide and rosuvastatin/budesonide.

According to the invention there is provided a combination comprising, in admixture or separately:

(a) a first active ingredient which is a statin, a pharmacetucally acceptable salt or solvate thereof, or a solvate of such a salt, and

(b) a second active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt

5 in the manufacture of a medicament for use in the treatment of respiratory diseases.

The invention also provides a method of treating a respiratory disease which comprises administering to the patient a therapeutically effective amount of a combination comprising, in admixture or separately:

(a) a first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate o thereof or a solvate of such a salt, and

(b) a second active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt

The effective dose of the components will strongly depend on the particular compound used and the mode of administration, as well as the weight and disease state of the individual s being treated. An orally administered dose of the 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; for inhalation a dose range of 0.001 mg to about 25 mg is preferred, even more preferably is a dose from 0.1 to 25 mg.

The suitable daily dose for the glucocorticosteroids is in the range of 50 μg to 2000 μg, 0 where e.g. for budesonide the daily dose is in the range of 50 μg to 1600 μg.

The components of the invention can be administered in admixture, i.e. together, or separately. When administered together the components can be administered as a single pharmaceutical composition such as a fixed combination given by e.g. inhalation. Alternatively the components can be administered separately, i.e. one after the other e.g. the s statin orally and the remaining component by inhalation. The time interval for separate administration can be anything from direct sequential (one after the other) administration to administration several hours apart.

Examples of respiratory diseases that can be treated according to the invention include asthma, chronic obstructive pulmonary disease (COPD), systemic sclerosis, alveolitis, 0 sarcoidosis, cystic fibrosis, fibrinous and pseudomembraneous rhinitis and idiopathic pulmonary fibrosis.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing

(a) a first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and (b) a second active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt with a pharmaceutically acceptable adjuvant, diluent or carrier.

The therapeutically active ingredients may be administered prophylactically as a preventive treatment or during the course of a medical condition as a treatment of cure, The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, fluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or foams or transdermally.

The composition used in the invention optionally additionally comprises 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 ingredients have a mass median diameter of less than 10 μm.

Tobacco smoke model of COPD

Compounds and combinations of compounds can be tested in an acute smoke model. In this model, mice are exporesed to tobacco smoke once or twice daily for 1-9 days. Read-outs in the model include cell infiltration and inflammatory mediators in broncho-alveolar lavage and tissue histopathology. The model can also be applied to guinea pigs. In an extended version of the model, effects of compounds on chronic pathologic changes to lungs over 3-6 months can be determined.

Biological tests

At present, no disease modifying medical treatment exists for COPD. Current symptomatic treatment includes different bronchodilating agents and, in exacerbation prone

5 patients, inhaled corticosteroids (ICS). However even if ICS, particularly in combination with long acting beta agonists, are useful for prevention of exacerbations, they have no effect on FEV ₁ decline. In post-hoc analyses of clinical long-term trials of COPD, we have observed a positive effect on FEVi decline in patients treated with statins. This effect was not seen with any other treatment including ICS. The aim with the present analysis was to investigate o whether the effect of a statin could be potentiated by ICS comparing the effect of statins alone with the combination of ICS on FEV ₁ decline.

Methods

s A meta-analysis was performed from 4 clinical trials in moderate to severe COPD, one study had 6 months duration, the other 3 lasted 12 months. For the present purpose, patients from the placebo arms (n= 910) were selected. In this pooled placebo group, patients with allowed medication including statins and/or ICS were examined for change of FEV ₁ during treatment. Outliers with FEV ₁ change > ±1 liter were excluded. 0

Results

The result of the analysis is shown in the table. The positive effect of statin treatment vs other placebo treated patient was further amplified if the patients received the combination of s statins and ICS.

Table 1. Effect of Statin treatment alone or combined with Inhaled Corticosteroids (ICS) on FEVi decline in COPD

0

Thus, the positive effect of statin treatment on FEV ₁ decline in COPD is potentiated by inhaled corticosteroids.

The invention is illustrated by the following examples

Example 1 - Inhalation - Dry powder

Ingredients Per dose

Budesonide 160 μg

Rosuvastatin l mg

Example 2 - Inhalation - Metered dose inhaler

Ingredients Per dose

Budesonide 160 μg

Rosuvastatin l mg

HFA 227 50 μl

Example 3 - Inhalation - Dry powder

Ingredients Per dose

Budesonide 160 μg

Rosuvastatin l mg Lactose up to 1, 2, 5, 10 or 20 mg

Example 4 - Inhalation/Oral administration

Aerosol formulation

Ingredients Per dose/tablet Budesonide 160 μg

A tablet formulation Rosuvastatin 10 mg