HK1087009B - Medicament comprising a highly potent long-lasting beta2-agonist in combination with other active ingredients - Google Patents

Description

Comprising a high effective long-acting beta2Pharmaceutical compositions of agonists and other active ingredients

Background

Asthma is a disease that is becoming more common and is one of the most common childhood diseases. It can be identified by recurrent wheezing and intermittent airflow limitation. Despite many advances in its knowledge, its pathology remains a disease that is not well understood and is often poorly treated.

Previously, contraction of airway smooth muscle was considered to be the most important feature of asthma. There has been a significant change in the management of asthma by recognizing that asthma is a chronic inflammation. Uncontrolled airway inflammation can lead to mucosal damage and structural changes that result in irreversible narrowing of the airway and fibrosis of the lung tissue. The aim of the treatment should therefore be to control the symptoms to enable normal life, while providing a basis for the treatment of the underlying inflammation.

Symptoms can be controlled by: first generation beta₂-adrenoceptor agonists such as salbutamol, fenoterol and terbutaline, or the second generation of beta₂Adrenoceptor agonists such as formoterol and salmeterol (long-acting beta)₂Agonists) to overcome the disadvantage of short duration of action, particularly for patients with nocturnal asthma. Indeed, prophylactic treatment is provided by corticosteroids such as beclomethasone dipropionate, fluticasone propionate, mometasone furoate and budesonide.

Another respiratory disease with steadily increasing incidence worldwide is Chronic Obstructive Pulmonary Disease (COPD). Most COPD patients get lung disease by smoking. According to the trend of smoking, it is predicted to rise to the fifth most prevalent cause of disability worldwide by 2020 (Leckie M et al, Exp Opin Invest Drugs 2000, 9, 3-23).

Chronic Obstructive Pulmonary Disease (COPD) is defined as a condition characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema. Chronic bronchitis is characterized by excessive secretion of bronchial mucus, whereas emphysema refers to abnormal, permanent enlargement of the air cavities in the terminal bronchioles, with no significant fibrosis of their walls (American thoracic society). Various symptoms are treated as specific diseases.

Chronic obstructive bronchitis is caused by obstruction of the peripheral airways by bronchiolitis.

Drugs intended for the treatment of pulmonary diseases such as asthma and COPD are currently administered by pulmonary delivery, which relies on the inhalation of an aerosol through the mouth and throat to enable the drug to reach the lungs. They may be administered as aqueous or hydroalcoholic formulations by nebulizer, as dry powders by dry powder inhalers or in halogenated hydrocarbon propellants. Propellant-based systems require suitable pressurized metered dose inhalers (pMDIs) that release a metered dose of drug upon each actuation.

Complex treatments with different medications and devices can lead to poor patient compliance, resulting in poor treatment and, in turn, adverse effects on their quality of life. This is particularly evident in the case of chronic asthma which is treated for a long period of time, especially when prophylactic treatment is carried out, for example by inhalation of steroids, which treatment does not directly alleviate the symptoms. The aim of the current therapeutic strategy is to combine long-acting beta by immobilization₂Agonists and corticosteroids to control symptoms and reduce inflammation simultaneously.

Compositions comprising salmeterol and fluticasone propionate, in the form of a dry powder and an HFA formulation, are currently marketed under the trade name seletide ®. The respective doses of the combined preparation were administered twice daily. A nominal dose of 50 micrograms racemic salmeterol xinafoate and 1/3 doses of fluticasone propionate 100, 250, and 500 micrograms per inhalation powder formulation can be delivered. With HFA formulations, a nominal dose of 25 micrograms salmeterol and 50, 125 or 250 micrograms fluticasone per puff of the inhaler can be delivered.

Compositions containing formoterol and budesonide in dry powder form are currently marketed under the trade name Symbicort ® and are administered twice daily for each single dose. A nominal dose of 6 micrograms of formoterol rac-fumarate and 100 or 200 micrograms of budesonide can be delivered per inhalation.

Many prior art articles relate to the use of β in combination₂Agonists and other classes of drugs, in particular corticosteroids and anticholinergics.

Moreover, various compositions have been proposed in the patent literature. However, there has never been shown in the prior art that an increase in both bronchodilatory and anti-inflammatory efficacy can be achieved by using long acting agonists (LABA) in combination therapy, thereby enabling a reduction in dose without affecting therapeutic efficacy.

In this respect, it would be highly advantageous, for example, to provide a combination of an agonist and a steroid which: i) maintain a rapid onset of action with a longer duration of action, allowing the formulation to be administered once a day, thus delaying the onset of tolerance to agonists and greatly improving patient compliance, particularly in chronic and nocturnal asthma patients; allowing for a reduction in corticosteroid dosage.

2(1H) -quinolone derivatives have been disclosed in the past, for example, in EP147719 and WO 00/75114, and are characterized as potent and long-acting bronchodilators for the treatment or prevention of various chronic obstructive pulmonary diseases.

Medicaments comprising specific 2(1H) -quinolinone derivatives LABA and corticosteroids for the treatment of inflammatory or obstructive airways diseases are currently disclosed in WO 02/45703. It is generally indicated in the specification that the composition can be used to reduce the dose of corticosteroid required to obtain a defined therapeutic effect compared to the dose required for treatment with corticosteroid alone, but no evidence of support is reported.

8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl]Amino group]Ethyl-2 (1H) -quinolinone hydrochloride, known as the experimental code TA2005, is a highly potent and long-acting beta₂Agonists, which are also characterized by a fast-acting action, were first disclosed in EP 147719. In this specification it is indicated that the compounds may be administered orally or parenterally. With respect to the daily dose, only a very broad general range is reported, namely 0.01-30. mu.g, in particular 0.01-3. mu.g, per kg of body weight (corresponding to approximately 0.7-2100. mu.g, in particular 0.7-210. mu.g). JP 09-309830 specifies its use as an inhaled anti-inflammatory, but even in this case only a wide general dose range, i.e. 1-20. mu.g, e.g. 3-10. mu.g, is reported.

The results of two clinical studies are shown in Eur Resp J8 (Supp l19), 1995, 258 s. In the latter (P1300), mild asthmatics inhaled single doses of 6 and 9 μ g TA2005 and placebo from metered nebulizer systems at weekly intervals. At this dose level, TA2005 produced rapid and persistent bronchodilation. The former (P1301) involved a randomized, double-blind, placebo-controlled, dose-escalation, safety study. Healthy male volunteers inhaled single doses of 0.8, 1.6, 3.2, 6.4, 9.6, 12.8 μ g from a metered nebulizer system. TA2005 results in dose-dependent increases in heart rate, tremor and lung function and decreases in plasma potassium. According to the authors, the maximum side-effect free dose of TA2005 was 9.6 μ g. Thus a very large therapeutic window of 0.8-9.6 μ g is suggested, but no effective and safe dose is determined.

In EP1157689, the applicant describes a solution comprising a β belonging to the class of phenylalkylamino derivatives in a HFA propellant and a cosolvent₂Aerosol pharmaceutical compositions of agonists, the apparent pH of which is adjusted to 2.5-5.0 to ensure a sufficient shelf life of the drug. In this specification it has been pointed out that the TA2005 formulation will advantageously be suitable for delivering 2-10 μ g/dose, preferably 3-5 μ g/dose. A3.5 μ g/dose HFA134a formulation comprising 12% w/w ethanol and 1.0% IPM is reported in example 7.

Numerous other patents and patent applications, namely US 6221398, US 5874063, US6030604, WO 98/41193, WO 98/31352, WO 01/78693, WO 01/89480 and WO 03/080939, are possible beta in compositions containing other drugs such as corticosteroids, anticholinergics or phosphodiesterase-4-inhibitors₂TA2005 is mentioned in the agonist list.

In the literature of the prior art, there is no disclosure that the particular combination of the TA2005 product with other active ingredients provides the beneficial pharmacological characteristics as the combination product of the invention.

Disclosure of Invention

The present invention provides a medicament comprising the following components, separately or together: 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl-2 (1H) -quinolinone and/or a physiologically acceptable salt and/or solvate thereof (Compound A) and one or more further active ingredients, wherein the further active ingredients are preferably selected from corticosteroids, anticholinergic/antimuscarinic agents or phosphodiesterase-4-inhibitors.

The corticosteroid for the treatment of an inflammatory or obstructive airways disease may preferably be selected from budesonide and its epimer, beclomethasone dipropionate, flunisolide, fluticasone propionate, ciclesonide, triamcinolone acetonide, rofleponide palmitate and mometasone furoate, for simultaneous, sequential or separate administration in the prophylaxis or treatment of an inflammatory or obstructive airways disease such as asthma or COPD.

The anticholinergic/antimuscarinic agent may be selected from commercially available compounds such as ipratropium bromide, oxitropium bromide or tiotropium bromide or other selective antimuscarinic M3 agents.

Suitable antimuscarinic agents are also glycopyrrolate or the 3R-2' R epimer thereof.

Preferred phosphodiesterase-4-inhibitors are ciclomailast and roflumilast.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of (a) as defined above and one or more other active substances as defined above together, optionally together with at least one pharmaceutically acceptable carrier.

The present invention also provides the use of (a) as defined above in combination with one or more other active substances as defined above for the preparation of a pharmaceutical composition or kit for the prevention or treatment of any inflammatory or obstructive airways disease by simultaneous, sequential or separate administration of (a) and the other active substance.

A preferred combination product comprises the hydrochloride salt of compound a (TA 2005, also known under the experimental code CHF 4226) and a corticosteroid. It has been found in practice that₂Both bronchodilatory and anti-inflammatory effects are increased when agonists and corticosteroids are combined.

The current pharmacological treatment for COPD aims at alleviating symptoms and reducing exacerbations. Bronchodilators only cause a small improvement in the spirometric measure, but can improve symptoms and exercise tolerance and reduce exacerbations of infections.

In COPD patients, the contribution of anticholinergic/antimuscarinic drugs is important because they alleviate airway narrowing due to vagal cholinergic tone.

Comprising a long-acting beta₂A combination of an adrenergic receptor agonist, such as TA2005, and an antimuscarinic agent is an effective and very interesting treatment for COPD. In the combination product of the invention, a synergistic effect between TA2005 and tiotropium bromide in bronchospasm control has been demonstrated in vitro and in vivo animal models.

The efficacy of the combination can be enhanced by the addition of corticosteroids that act synergistically with TA2005 on inflammatory mediators. Indeed, as demonstrated in the examples below, TA2005 produced a synergistic interaction in controlling plasma exudation of the airways.

In this regard, another useful combination includes phosphodiesterase-4-inhibitors, which are capable of relaxing airway smooth muscle, inhibiting the activation of specific inflammatory cells, and modulating the activity of the pulmonary nerves.

Thus, the dosage of any active ingredient suggested for use in the combination product of the invention can be reduced without affecting the therapeutic effect, thereby reducing the risk of side effects associated with its use.

In a particular aspect, the invention provides a medicament wherein compound (a) in the composition is present as the hydrochloride salt (TA 2005) in a suitable amount to provide a daily dose of 0.5 to 8 μ g, advantageously 1 to 6 μ g, preferably 1 to 4 μ g, for simultaneous, sequential or separate administration once or twice daily, preferably once daily, for the treatment of an inflammatory or obstructive airways disease such as asthma or COPD.

Useful combination products include TA2005 and corticosteroids and/or anticholinergic/antimuscarinic drugs and/or phosphodiesterase-4-inhibitors.

Examples of preferred combination products include:

-TA 2005 and an acetal corticosteroid selected from budesonide and ciclesonide;

TA2005 and tiotropium bromide as selective M1 and M3 muscarinic receptor antagonists;

-TA 2005+ corticosteroid + antimuscarinic;

-TA 2005+ antimuscarinic agent + phosphodiesterase-4-inhibitor.

The effective dose of TA2005 in the combination product may be 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4 μ g.

In fact, it has been found that at these dose strengths, TA2005 is therapeutically effective upon inhalation.

Bronchodilator efficacy of TA2005, defined as the increase in forced expiratory volume (FEV1) in one second from baseline as determined by spirometry, has been evaluated in a clinical pilot trial on a panel of asthmatic patients.

The results show that an average and sustained increase of approximately 30% greater than baseline in FEV1 has been achieved after administration of a single dose of 1 μ g.

As mentioned above, compound (a) is preferably used in the form of its hydrochloride salt (TA 2005). Other suitable physiological salts of compound (a) include bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, methanesulphonate, ascorbate (acorbate), salicylate, acetate, succinate, lactate, glutarate or gluconate. Solvates of the salts, such as hydrates, hemihydrate or others, pharmaceutically acceptable organic solvents are also encompassed by the invention.

Among the corticosteroids, acetal corticosteroids such as budesonide and its 22R-epimer, rofleponide and ciclesonide are particularly preferred. The medicament of the invention may comprise an anticholinergic atropine-like derivative such as ipratropium bromide, oxitropium bromide, tiotropium bromide or glycopyrrolate or its 3R, 2' R-enantiomer to provide a particularly effective medicament for the treatment of COPD.

A preferred anticholinergic, antimuscarinic agent is tiotropium bromide.

The ratio of compound (a) to corticosteroid that can be used in the compositions of the present invention is varied. Depending on the steroid chosen, the weight ratios that may be used in the scope of the present invention will vary depending on the different molecular weights of the various steroids and their different potency.

The pharmaceutical composition according to the present invention may comprise compound (a) and corticosteroid in a weight ratio ranging from 1: 3200 to 1: 10. In particular for budesonide and ciclesonide, the weight ratio is in the range of 1: 1600 to 1: 50, preferably 1: 1000 to 1: 50.

Another corticosteroid which may be advantageously used in combination is mometasone furoate, and in this case in a weight ratio in the range of 1: 800 to 1: 50, preferably 1: 400 to 1: 100, more preferably 1: 200 to 1: 100.

As tiotropium bromide, the weight ratio is in the range of 1: 100, preferably 1: 50, more preferably 1: 20.

The desired dosage regimen is once or twice a day, preferably once a day, wherein a suitable daily dosage range of compound (a) is suitably from 0.5 to 8 μ g, preferably from 1 to 4 μ g, more preferably from 1 to 2 μ g or from 2 to 4 μ g, depending on the patient (age, weight, etc.) and the kind and severity of the disease.

The combination of the invention is preferably administered by inhalation. Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations.

For dry powder administration, single or multi-dose inhalers known from the prior art may be used, wherein the powder may be filled in gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

Diluents or carriers which are generally non-toxic and chemically inert to the medicament, such as lactose and other ingredients suitable for improving the respirable fraction, may be added to the powder medicament.

Inhalation aerosols containing a propellant gas, such as a hydrofluoroalkane, may contain the active ingredient of the compositions of the invention in solution or in dispersed form.

The propellant-driven formulation may also contain other ingredients such as co-solvents, stabilizers or optionally other excipients.

Propellant-free inhalable formulations comprising the compositions of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by jet or ultrasonic nebulizers or soft mist nebulizers such as Respimat ® as known in the art.

The treatment of inflammatory or obstructive airways diseases in accordance with the present invention may be symptomatic or prophylactic.

Inflammatory or obstructive airways diseases to which the claimed compositions may be applied include asthma of any type or origin including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma-induced bacterial infections of the following. Treatment of asthma may also be understood to include treatment of subjects, e.g. subjects less than 4 or 5 years of age, exhibiting wheezing symptoms and subjects diagnosed or diagnosable as "wheezy infants", a defined category of patients of major medical interest. The prophylactic efficacy in treating asthma manifests itself in a reduction in the frequency or severity of symptomatic attack, e.g., acute asthma or bronchoconstrictor attack, improvement in lung function or excessive improvement in airway responsiveness. It may also manifest as a reduced need for treatment of other symptoms. The disease-preventing effect of asthma is particularly evident in subjects who are prone to "Morning palpation (Morning)" or "palpation". "morning emergency palpation" is a recognized symptom of asthma that is common to a substantial percentage of asthma and is characterized by asthma attacks, e.g., within about 4-6a.m hours, i.e., usually at a time substantially distant from any previously administered symptomatic asthma treatment.

Other inflammatory or obstructive airways diseases and conditions to which the present invention may be applied include Acute Lung Injury (ALI), Adult Respiratory Distress Syndrome (ARDS), chronic obstructive lung, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis and emphysema, bronchiolitis, bronchiectasis and excessive worsening of airways response following other drug therapy, particularly other inhaled drug therapy.

Other inflammatory or obstructive airways diseases to which the present invention may be applied include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and associated with repeated inhalation of dusts) of any type or origin, including, for example, aluminosis, pneumoconiosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacco poisoning and byssinosis.

The present invention also provides a pharmaceutical kit comprising compound (a) and at least one further compound (combination compound) in separate unit dosage forms suitable for administration of an effective amount of (a) and the combination compound, as described below. Such kits are also suitable for containing one or more inhalation devices for administering (a) and combining the compounds. For example, the kit may comprise one or more dry powder inhalation devices suitable for delivering dry powder from a capsule, and one capsule containing dry powder comprising dosage units of (a) and one capsule containing dry powder comprising dosage units of a combination compound. In another example, the kit may comprise a multi-dose dry powder inhalation device comprising the dry powder comprising (a) in its reservoir, and a multi-dose dry powder inhalation device comprising the dry powder comprising the combination compound in its reservoir. In another example, the kit may comprise a metered dose inhaler containing an aerosol of (a) contained in a propellant and a metered dose inhaler containing an aerosol of the combination compound contained in a propellant.

Detailed Description

The invention is illustrated with reference to the following examples.

The unexpected characteristics of the TA2005 in combination with corticosteroids according to the invention were demonstrated in the following tests: according to Kublin R et al, Int Arch Allergy Immunol 1992; 98: 266-272 in the Sephadex induced in vivo model of pneumonia; in a system such as nauyn-Schmiedeberg's arch, pharmacol, 362: 184-189, 2000 in vitro assays with the human U-937-derived macrophage cell line; and in the acetaldehyde-induced bronchoconstriction model (Berti et al, Arzneim-Forsch/Drug Res 1994; 44: 323-326).

Moreover, the pharmacological interaction between TA2005 and a muscarinic M3-receptor antagonist, tiotropium bromide, has been demonstrated in vitro and in vivo methods.

Example 1In vitro testing of the anti-inflammatory efficacy of the combinations of the invention on a human U-937 derived macrophage cell line

U-937 cells were cultured and macrophage-identified by 10ng/ml phorbol myristate acetate for 48 hours.

The cells were then incubated with 1. mu.g/ml Lipopolysaccharide (LPS) or LPS and a range of concentrations of beta₂-agonist, corticosteroid or combination are incubated together. TNF α and IL-10 were assayed after various times in culture. The medium was collected and the cells were lysed for cyclic adenosine 3 ', 5' -monophosphate (cAMP) assay.

TNF alpha and IL-10 were assayed in culture by commercially available ELISA assays, simultaneously with commercially available³The H-cAMP assay system measures cAMP.

In the absence and presence of 10^-10And 10^-8The concentration of M provides a dose-response curve for corticosteroids in the context of TA 2005. TNFa and IL-10 release were inhibited by budesonide alone, but cAMP levels were not affected. The addition of TA2005 potentiates the effect of TNF α and counteracts the side effects of budesonide on IL-10 release.

Interestingly, the addition of TA2005 resulted in a strong stimulation of cAMP by budesonide.

Example 2In vivo testing of the anti-inflammatory efficacy of the composition of the invention in a Sephadex induced pulmonary edema model

Pulmonary edema in rats induced by Sephadex is a model leading to inflammatory cell infiltration and persistent interstitial edema. Evaluation of beta with another Long-acting₂The adrenergic receptor agonist, formoterol, had anti-inflammatory activity of TA2005 alone and in combination with budesonide.

The Sephadex beads (5mg/ml) were administered intratracheally to anesthetized rats (200-. The control group received 1ml/kg saline.

The test substances are suspended in saline and suitably diluted in a Sephadex suspension for intratracheal administration.

24 hours after administration, animals were sacrificed and lungs were removed and weighed. The percent inhibition of Sephadex induced edema was then determined.

Intratracheal instillation of Sephadex beads resulted in a statistically significant increase in lung weight (33 ± 3%) compared to control animals.

Administration of TA2005 (0.001, 0.01, 0.05 and 0.1nmol/kg), formoterol (0.01, 0.1, 1 and 2nmol/kg) and budesonide (15, 30, 60, 120, 240 and 480nmol/kg) produced a dose-dependent relief of Sephadex-induced pulmonary edema. The ineffective doses of TA2005(0.01nmol/kg) and formoterol (0.1nmol/kg) were selected in combination with low ineffective doses of budesonide (15, 30, 60 and 120nmol/kg) according to the dose-response curve. Budesonide at doses as low as 15nmol/kg already significantly inhibited Sephadex induced pulmonary edema in the presence of TA2005, whereas 240nmol/kg was required in the absence of TA 2005. The enhancement was very insignificant in the presence of formoterol, and only a significant decrease in lung weight gain induced by Sephadex was observed with the 120nmol/kg dose of corticosteroid.

Example 3Effect of the combination of TA2005 and budesonide on acetaldehyde-induced bronchoconstriction in Guinea pigs

Has been described according to Berti et al, Arzneim-Forsch/Drug Res 1994; 44: 323-326, the ability of TA2005 to control bronchoconstriction and neurogenic inflammation caused by acetaldehyde (AcCHO) was studied in anesthetized, artificially ventilated guinea pigs.

Intravenous injection of achho resulted in dose-dependent bronchoconstriction with an increase in blood histamine and evans blue extravasation in tracheal tissue, suggesting altered vascular permeability.

The protective activity of TA2005 (0.1-10pmol), formoterol (0.3-30pmol) or budesonide (31.25-500nmol) was determined after intratracheal superfusion alone or in combination.

All effects of AcCHO were effectively antagonized by TA2005 and formoterol. However, TA2005 was almost twice as potent as formoterol in preventing bronchoconstriction, histamine release and plasmapheresis. TA2005 also exhibited a significantly longer duration of action at all selected doses. For example, when two β's are compared at nearly the same effective dose, e.g., peak dose (10 and 30pmol)₂With an adrenoceptor agonist, the anti-bronchoconstrictor effect of TA-2005 was still fully manifested after 24 minutes, whereas the effect of formoterol was reduced by about 50%.

The corticosteroid budesonide also reduced the effects of AcCHO in the guinea pig airways. But as expected its efficacy was in the nanomolar range and was significantly less than that observed with TA2005 and formoterol.

Tracheal superfusion in combination with TA2005 and budesonide produced a synergistic interaction in the guinea pig airways that dominated the three major effects of AcCHO, such as bronchoconstriction, histamine release and plasmapheresis. Budesonide ED alone, taking into account the parameter bronchoconstriction₅₀The value (396nmol) decreased by 5.3 and 14.3 fold when combined with 0.1 and 0.3pmol TA2005, respectively. Synergistic interaction is also achieved by the addition of formoterol to the corticosteroid. However, the potency of this combination is less than that obtained with TA 2005. In fact, budesonide, when combined with 0.3 and 1pmol formoterol, had an ED₅₀The values were reduced by a factor of 3.0 and 5.9, respectively.

Example 4Effect of budesonide on TA 2005-induced desensitization of isolated tracheal strips from ovalbumin-sensitized guinea pigs

Long term use of beta₂Agonists cause lung beta₂-adrenoreceptor downregulation. This phenomenon may be counteracted by simultaneous treatment with corticosteroids.

In this study, the treatment was carried out by mixing salbutamol (5 x 10) in very large concentrations^-6M) two 20 minute periods of contact tracheal strips from guinea pigs sensitized with ovalbumin (100mg/kg ip and 100mg/kg sc, 20 days prior to sacrifice) were treated with beta-tracheal strips₂-desensitization. In some experiments, the guinea pig was receiving 50mg/kg budesonide in the peritoneal membrane 24 and 1.5 hours prior to sacrifice.

At beta₂Following desensitization, TA2005 reduced the efficacy of relaxing the carba-inducible contraction by a factor of about 3. Budesonide pretreatment reversed the TA2005 dose-response curve to the right, even enhancing its relaxation by about 6-fold.

Example 5Effect of the TA 2005/Tiotropium Bromide combination on carba-inducible bronchoconstriction of Guinea pig isolates

Study of beta on Guinea pig tracheal bands isolated with kappa contractility₂Adrenergic receptor agonists TA2005 and M₃-pharmacological interaction between the receptor antagonist tiotropium bromide.

TA 2005(10^-12M) and tiotropium bromide (3 x 10)^-1M) inhibited kappa-induced contraction by 29.3. + -. 6.1% and 17.1. + -. 2.2%, respectively. When the two treatments were combined, the relaxation was much greater (59.1. + -. 7.7%).

The results are shown in FIG. 1 (note: CHF 4226 is a synonym for TA 2005).

Example 6Effect of TA2005 in combination with Tiotropium Bromide on acetylcholine-induced bronchoconstriction in Guinea pigs

Such as those originally described by Konzet t and R ö sser, Nauyn-Schmiedeberg's ArchPharmacol, 1940; 195: 556-557 the guinea pig was prepared.

Bronchoconstriction was induced by intravenous administration of acetylcholine (20 μ g/kg). Different concentrations of tiotropium bromide (0.1-30pmol) or TA2005 (0.3-100pmol), alone or in combination, were investigated for anti-bronchospasm activity.

Both TA2005 and tiotropium bromide dose-dependently antagonized acetylcholine-induced bronchoconstriction. Tiotropium bromide produced 5.2 times more potency (P < 0.001) than TA2005 (ED respectively)₅₀3.2 and 16.7 pmol).

If combined, a synergistic interaction was observed (FIG. 2).

The interaction was particularly apparent when 0.1pmol tiotropium bromide was combined with 3pmol TA 2005. In this case, the effect of acetylcholine was reduced by 63% (P < 0.001), whereas in the absence of tiotropium bromide, the inhibitory effect was only 18%.

According to the present results, M was shown to be applied to the tracheal mucosa of anesthetized Guinea pigs₃Tiotropium and beta as muscarinic receptor antagonists₂Agonist TA2005 in combination with superfusion, provides a synergistic interaction in limiting acetylcholine-induced bronchoconstriction.

Example 7Formulations for metered dose inhalers comprising TA2005 and budesonide HFA formulations for metered dose inhalers were prepared with the following combinations:

components	Number of
					Per unit cell		Rated dose
	mg	％	μg
				TA2005	0.15	0.0016w/v	1
Budesonide	30.00	0.317w/v	200
				Ethanol	1650.0	15w/w	-
Adjusting the pH to about 3.5-4.0			-
				Water (optional)	220.05	2.0w/w
Appropriate amount of HFA134a to 9.45ml	9114.5	-	-

The pH of the formulation has been adjusted with a suitable amount of mineral acid.

The formulation (120-jet/can, 30-jet excess) was filled in an aluminum can (two-step pressure fill) with Teflon coated inner surface and equipped with a metering valve with a 63 μ l metering chamber.

Example 8Powder formulations for dry powder inhalers comprising TA2005 and budesonide

A powder formulation for a dry powder inhaler was prepared with the following composition:

components	Number of
				Per unit dose
	mg	％
			TA2005	0.001
Budesonide	0.400
			Alpha-lactose monohydrate 212-355 μm	8.6151	86.2
Premixing	0.9839	10
Total weight of	10

Preparation of the formulations

A premix was obtained as follows: alpha-lactose monohydrate SpheroLac 100(Meggle EP D30) having a primary particle size of 50-400 μm is co-milled with magnesium stearate having a primary particle size of 3-35 μm in a ratio of 98: 2w/w in a jet mill.

Approximately 86% w/w alpha-lactose monohydrate CapsuLac (212 and 355 μm) was placed in a 2.51 stainless steel vessel and then 10% w/w premix was added. The powder was mixed in a Turbula mixer at 32r.p.m. for 4 hours. TA-2005 and budesonide were added to the powder and mixed in a Turbula mixer to give a ratio of 1 μm and 400 μ g of active ingredient to 10mg of carrier, respectively.

Claims (11)

1. A pharmaceutical composition for inhalation comprising an effective amount of compound (a) and/or a physiologically acceptable salt and/or solvate thereof and a corticosteroid, wherein the effective amount of compound (a) is 8-hydroxy-5- [ (1R) -1-hydroxy-2- [ [ (1R) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl-2 (1H) -quinolinone in the range of 0.5-2 μ g per unit dose and the weight ratio between compound (a) and corticosteroid is 1: 1000-1: 50.

2. A composition according to claim 1, wherein compound (a) is in the form of a hydrochloride salt.

3. Use of a composition according to claim 1 for the preparation of a medicament for the treatment of inflammatory or obstructive airways diseases including asthma and COPD in which the daily dose of compound (a) is in the range 0.5 to 8 μ g.

4. The use according to claim 3, wherein the daily dose of compound (A) is in the range of 1-6 μ g.

5. The use according to claim 3, wherein the daily dose of compound (A) is in the range of 2-4 μ g.

6. The composition according to claim 1, wherein the corticosteroid is selected from the group consisting of budesonide and its epimer, beclomethasone dipropionate, fluticasone propionate, flunisolide, ciclesonide, triamcinolone acetonide, rofleponide palmitate and mometasone furoate.

7. The composition according to claim 6, wherein the corticosteroid is budesonide or its epimer 22R.

8. The composition according to claim 1, further comprising at least one pharmaceutically acceptable carrier.

9. A pharmaceutical composition according to claim 1, which is administered by means of a pressurized metered dose inhaler, wherein the compound (a) and corticosteroid are in propellant gas solution or suspension.

10. The pharmaceutical composition according to claim 1, which is administered by a nebulizer comprising a solution or suspension of compound (a) and corticosteroid in an aqueous, alcoholic or hydroalcoholic medium.

11. The pharmaceutical composition according to claim 1, which is administered by a dry powder inhaler, wherein compound (a) and the corticosteroid are in dry powder form.