WO2012098495A1

WO2012098495A1 - Pharmaceutical composition that includes revamilast and a beta-2 agonist

Info

Publication number: WO2012098495A1
Application number: PCT/IB2012/050215
Authority: WO
Inventors: Neelima Khairatkar-Joshi; Raghuram ANUPINDI; Thamil Selvan VAIYAPURI; Amol S. WAGHCHOURE
Original assignee: Glenmark Pharmaceuticals Sa
Priority date: 2011-01-19
Filing date: 2012-01-17
Publication date: 2012-07-26

Abstract

The present patent application relates to a pharmaceutical composition that includes a PDE4 enzyme inhibitor, namely revamilast, and a beta- 2 adrenergic receptor agonist; a process for preparing such a composition; and its use in treating a respiratory disorder in a subject.

Description

PHARMACEUTICAL COMPOSITION THAT INCLUDES REVAMILAST AND A BETA- 2 AGONIST

PRIORITY DOCUMENTS

This patent application claims priority to Indian Provisional Patent Application numbers 158/MUM/2011 (filed on January 19, 2011) and 1571/MUM/2011 (filed on

May 25, 201 1), the contents of each of which are incorporated by reference herein.

TECHNICAL FIELD

The present patent application relates to a pharmaceutical composition that includes a phosphodiesterase-4 ("PDE4") enzyme inhibitor and a beta-2 adrenergic receptor agonist ("beta-2 agonist"). Particularly, the application relates to a

pharmaceutical composition that includes a benzofuropyridine compound as a PDE4 enzyme inhibitor and a beta-2-agonist; a process for preparing such composition; and its use in treating a respiratory disorder in a subject.

BACKGROUND

Many individuals suffer from respiratory disorders related to airway

inflammation, including a number of severe lung diseases such as asthma and chronic obstructive pulmonary disease ("COPD"). Beta-2 agonists (such as salbutamol,

terbutaline, levalbuterol, salmeterol, formoterol, indacaterol, and bambuterol) have been approved to treat certain respiratory disorders.

Salbutamol sulphate (USAN: albuterol sulfate) is chemically, al-[(tert- butylamino)methyl]-4-hydroxy-m-xylene-a, a'-diol sulphate (2: l)(salt). Salbutamol sulphate is commercially available as an inhalation aerosol as 108 μg (equivalent to 90 μg salbutamol base), VENTOLIN HFA® (marketed by Glaxo SmithKline), as 2mg and 4mg tablets (marketed by Mylan, Watson, Mutual Pharma), and as an inhalation solution as 1.5mg/3mL and 0.75mg/3mL (equivalent to 1.25mg/3mL and 0.63mg/3mL salbutamol base), ACCUNEB® (marketed by Dey) in the United States. It is indicated for the treatment and prevention of bronchospasm in patients with reversible obstructive airway disease and prevention of exercise-induced bronchospasm.

Terbutaline sulphate is chemically, (±)-a-[(tertbutylamino)methyl]-3,5- dihydroxybenzyl alcohol sulphate (2: 1) (salt). Terbutaline sulphate is commercially available as an injectable solution of lmg/mL (equivalent to 0.82mg/mL terbutaline base) marketed by Teva, Bedford and as a tablet of 2.5 mg and 5 mg (equivalent to 2.05 mg and 4.1 mg of the free base) (marketed by Impax and Lannett) in the United States. It is indicated for the prevention and reversal of bronchospasm in patients 12 years of age and older with asthma and reversible bronchospasm associated with bronchitis and emphysema.

Levalbuterol (also called levosalbutamol) hydrochloride is chemically (R)-al- [[(1,1 -dimethylethyl)amino]methyl]-4-hydroxy- 1 ,3-benzenedimethanol hydrochloride. It is commercially available in the USA as Xopenex® inhalation solution as 0.36 mg, 0.73 mg and 1.44 mg (equivalent to 0.3 lmg, 0.63mg, or 1.25mg of levalbuterol base), for administration by nebulization. It also available as LEVOLIN tablets (lmg and 2mg), or as LEVOLIN syrup (lmg/5mL), for oral administration. It is indicated for the treatment or prevention of bronchospasm in adults, adolescents and children 6 years of age and older with reversible obstructive airway disease.

Salmeterol xinafoate is chemically 4-hydroxy-al-[[[6-(4-phenylbutoxy) hexyl] amino]methyl]- 1 ,3-benzenedimethanol, 1 -hydro xy-2 -naphthalene carboxylate.

Salmeterol xinafoate is commercially available as 50μg inhalation powder as

SEREVENT ® (marketed by Glaxo) in the United States. It is indicated for the maintenance treatment of asthma (as an add-on therapy, in the prevention of bronchospasm (only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid (ICS)), and prevention of exercise- induced bronchospasm.

Formoterol fumarate is chemically (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2- [ [( 1 RS)-2-(4-methoxyphenyl)- 1 -methylethyl] -amino] ethyl] formanilide fumarate dehydrate. Formoterol fumarate is commercially available as and 12μg dry powder inhalation as FORADIL ® (marketed by Novartis) in the United States. It is indicated for the treatment of asthma (as an add-on therapy) and in the prevention of bronchospasm, acute prevention of exercise-induced bronchospasm and for the long- term maintenance treatment of bronchoconstriction in patients with COPD including chronic bronchitis and emphysema.

Indacaterol maleate is chemically (i?)-5-[2-[(5,6-Diethyl-2,3-dihydro-lH- inden-2-yl)amino]-l-hydroxyethyl]-8-hydroxyquinolin-2(lH)-one. It is presently approved in Europe as 15(^g capsule for inhalation (marketed by Novartis). It is indicated for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD.

Bambuterol, a long acting beta-adrenoreceptor agonist is chemically known as

(RS)-5- [2-(ieri-butylamino)- 1 -hydroxyethyl]benzene- 1 ,3-diyl bis(dimethylcarbamate) .

Bambuterol

Bambuterol hydrochloride is commercially available as BAMBEC Tablets (lOmg) and marketed as by AstraZeneca in UK. It is approved for the management of asthma, bronchospasm and/or reversible airways obstruction.

There still exists a need for improved therapeutic treatments for respiratory disorders like asthma and COPD.

SUMMARY

The present invention relates to a pharmaceutical composition that includes a PDE4 enzyme inhibitor (e.g., benzofuropyridine compound) and a beta-2 agonist. A preferred PDE4 enzyme inhibitor is N9-(3,5-dichloro-4-pyridyl)-6- difiuoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide-N-oxide [INN: Revamilast] or its pharmaceutically acceptable salt. The inventors have surprisingly found that a pharmaceutical composition that includes a PDE4 enzyme inhibitor of the present invention (particularly, revamilast or its pharmaceutically acceptable salt) and a beta-2 agonist is more effective in the treatment of respiratory disorders, and provides better therapeutic value then both the actives alone (when administered individually) for the treatment of respiratory disorders.

One embodiment of the present invention is a pharmaceutical composition that includes:

a) a PDE4 enzyme inhibitor of the formula:

formula (I)

wherein:

R¹ is alkyl or alkyl substituted by one or more halogen groups;

R² is hydrogen;

R is hydrogen;

Ar is a heteroaryl ring or a heteroaryl ring substituted by one or more halogen groups;

n is 2;

p is 3;

T, V and W are C;

U is N;

each dotted line [— ] in the ring represents a bond;

X is O;

Y is -C(0)NR⁴;

R⁴ is hydrogen; or a tautomer, stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and b) a beta-2 agonist.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes:

a) revamilast or its pharmaceutically acceptable salt; and

b) a beta-2 agonist

Suitable beta-2 agonists include, but are not limited to, short acting beta-2 agonists (SABA) and long acting beta-2 agonists (LABA). SAB As include, but are not limited to, salbutamol, terbutaline, levosalbutamol, pirbuterol, procaterol,

metaproterenol, fenoterol, bitolterol, and their pharmaceutically acceptable salts. LAB As include, but are not limited to, salmeterol, formoterol, bambuterol, indacaterol, vilanterol, arformoterol, olodaterol, abediterol, milveterol, bedoradrine, clenbuterol, reproterol, PF-610355, GSK-597901, GSK-159802, GSK-678007, and their salts.

The pharmaceutical composition of the present invention may include a therapeutically effective amount of the PDE4 enzyme inhibitor and beta-2 agonist.

The pharmaceutical composition of the present invention may optionally comprise one or more pharmaceutically acceptable excipients.

In another embodiment, the invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a beta-2 agonist. The therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 50 mg and preferably from about 0.1 mg to about 30 mg.

Preferably, the beta-2 agonist includes salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol, bambuterol or a pharmaceutically acceptable salt thereof.

In one specific embodiment, the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt (e.g. salbutamol sulphate). The therapeutically effective amount of salbutamol or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 30 mg, and preferably from about 0.05 mg to about 20 mg.

In another specific embodiment, the present invention relates to a

pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and terbutaline or its

pharmaceutically acceptable salt (e.g., terbutaline sulphate). The therapeutically effective amount of terbutaline or its pharmaceutically acceptable salt to be administered per day may range from about 0.1 mg to about 20 mg, and preferably from about 0.2 mg to about 10 mg.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt (e.g., levosalbutamol hydrochloride). The therapeutically effective amount of levosalbutamol or its pharmaceutically acceptable salt to be administered per day may range from about 0.1 mg to about 6 mg, and preferably from about 0.2 mg to about 6 mg.

In a further specific embodiment, the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and salmeterol or its

pharmaceutically acceptable salt (e.g., salmeterol xinafoate). The therapeutically effective amount of salmeterol or its pharmaceutically acceptable salt to be administered per day may range from about 10μg to about 500μg, preferably from about 20μg to about 500μg and more preferably from about 50μg to about 100μg.

In another specific embodiment, the present invention relates to a

pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and formoterol or its

pharmaceutically acceptable salt (e.g., formoterol fumarate). The therapeutically effective amount of formoterol or its pharmaceutically acceptable salt to be administered per day may range from about ^g to about 5(^g, and preferably from about l(^g to about 25μg.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and indacaterol or its

pharmaceutically acceptable salt (e.g., indacaterol maleate). The therapeutically effective amount of indacaterol or its pharmaceutically acceptable salt to be administered per day may range from about 10(^g to about 50(^g, and more preferably from about 15(^g to about 30(^g.

In a further specific embodiment, the present invention relates to a

pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and bambuterol or its

pharmaceutically acceptable salt (e.g., bambuterol hydrochloride). The therapeutically effective amount of bambuterol or its pharmaceutically acceptable salt to be administered per day may range from about lmg to about 30mg, preferably, from about 5mg to about 30mg and more preferably from about lOmg to about 20mg.

The therapeutically effective amount of the active ingredients can be administered as a single dose or in divided doses, either once daily or two/three/four times a day. The PDE4 enzyme inhibitor and beta-2 agonist may be administered in a single dosage form or in separate dosage forms. The PDE4 enzyme inhibitor and beta- 2 agonist may be administered by the same or different routes and either separately, simultaneously, or sequentially.

In an embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 0.05 mg to about 20 mg of salbutamol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 0.2 mg to about 10 mg of terbutaline or its pharmaceutically acceptable salt.

In yet another embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 0.2 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In a further embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 20μg to about 500μg of salmeterol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 10μg to about 25 μg of formoterol or its pharmaceutically acceptable salt.

In a further embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 150 μg to about 300 μg of indacaterol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 5mg to about 30mg of bambuterol or its pharmaceutically acceptable salt.

In a further embodiment, the pharmaceutical composition of the present invention is in the form of a fixed dose combination formulation of revamilast or its pharmaceutically acceptable salt and the beta-2 agonist.

Alternately, the pharmaceutical composition of the present invention is in the form of a kit comprising two or more separate formulations of revamilast or its pharmaceutically acceptable salt and the beta-2 agonist. In another embodiment, there is provided a pharmaceutical composition containing revamilast or its pharmaceutically acceptable salt and a beta-2 agonist at a weight ratio ranging from about 0.01 : 100 to about 100:0.01, preferably from about 0.1 :50 to about 50: 1, and more preferably from about 0.1 : 10 to about 10: 1, respectively. Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol bambuterol or a pharmaceutically acceptable salt thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.01 :30 to about 50:0.01 and preferably from about 0.1 :20 to about 6:0.01.

In another specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and terbutaline or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.01 :20 to about 50:0.1 and preferably from about 0.1 : 10 to about 15:0.1.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.01 :6 to about 5:0.01 and preferably from about 0.1 :6 to about 15:0.1.

In a further specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and salmeterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.1 :5 to about 50:0.01 and preferably from about 1 :5 to about 15:0.01.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 1 :5 to about 50:0.001 and preferably from about 1 :0.25 to about 30:0.01. In another specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and indacaterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.1 :5 to about 50:0.1 and preferably from about 1 :3 to about 20:0.1.

In a further specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and bambuterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.01 : 30 to about 50: 1 and preferably from about 0.1 :20 to about 3: 1.

In one embodiment, the present invention relates to a pharmaceutical composition includes revamilast or its pharmaceutically acceptable salt and a beta-2 agonist, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In another embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and a beta-2 agonist for the treatment of a respiratory disorder in a subject in need thereof.

The respiratory disorder may be airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, bronchospasm, exercise-induced bronchospasm, bronchospasm associated with COPD, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, or aid in smoking cessation therapy. Preferably, the respiratory disorder is asthma, COPD or exercise-induced bronchospasm.

In a further embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition of the present invention.

In another embodiment, the present invention relates to a method of treating a respiratory disorder, the method including administering a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and a beta-2 agonist to a subject in need thereof. Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol bambuterol or a pharmaceutically acceptable salt thereof.

In a specific embodiment, the present invention relates to a method of treating a respiratory disorder in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about 0.01 mg to about 30 mg salbutamol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, COPD or exercise-induced bronchospasm in a subject comprising

administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, from about 0.05 mg to about 20 mg salbutamol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating asthma in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, from about 0.1 mg to about 16 mg salbutamol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of treating COPD in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, from about 0.1 mg to about 16 mg salbutamol or its pharmaceutically acceptable salt.

In a further specific embodiment, the present invention relates to a method of treating exercise-induced bronchospasm in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, from about 0.1 mg to about 16 mg salbutamol or its pharmaceutically acceptable salt. In another embodiment, the present invention relates to a method of treating a respiratory disorder in a subject comprising administering to the subject a

pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about O. lmg to about 20mg of terbutaline or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, reversible bronchospasm associated with bronchitis or emphysema in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.2mg to about lOmg terbutaline or its

pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating asthma in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of treating reversible bronchospasm associated with bronchitis in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a method of treating emphysema in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a method of treating a respiratory disorder in a subject comprising administering to the subject a

pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about O.Olmg to about 6mg of levosalbutamol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating COPD, bronchospasm or asthma in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.2 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating bronchospasm in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of treating asthma in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a method of treating COPD in a subject comprising administering to the subject a

pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject comprising administering to the subject a

pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about 0.01 mg to about 0.5 mg salmeterol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, exercise-induced bronchospasm or bronchospasm associated with COPD in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.02mg to about 0.5 mg salmeterol or its

pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating asthma in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.05 mg to about 0.1 mg salmeterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of preventing exercise-induced bronchospasm in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.05 mg to about 0.1 mg salmeterol or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a method of treating bronchospasm associated with COPD in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.05 mg to about 0.1 mg salmeterol or its pharmaceutically acceptable salt.

pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about 0.00 lmg to about 0.05 mg formoterol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, exercised induced bronchospasm or COPD in a subject comprising administering to the subject a pharmaceutical composition that includes from about O.lmg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about O.Olmg to about 0.025 mg formoterol or its pharmaceutically acceptable salt. In a specific embodiment, the present invention relates to a method of treating asthma in a subject comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about O.Olmg to about 0.025 mg formoterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of treating exercised induced bronchospasm in a subject comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about O.Olmg to about 0.025 mg formoterol or its pharmaceutically acceptable salt.

pharmaceutical composition that includes from about lmg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about O.Olmg to about 0.025 mg formoterol or its pharmaceutically acceptable salt.

pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.1 mg to about 0.5 mg indacaterol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating COPD in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.15 mg to about 0.3 mg indacaterol or its pharmaceutically acceptable salt.

In yet another embodiment, the present invention relates to a method of treating a respiratory disorder in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about 1 mg to about 30 mg of bambuterol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, bronchospasm or COPD in a subject comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 5 mg to about 30 mg of bambuterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating asthma in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating bronchospasm in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating COPD in a subject comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt.

In a further embodiment, the present invention relates to use of therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a beta-2 agonist in the preparation of a pharmaceutical composition for the treatment of a respiratory disorder in a subject. Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol bambuterol or its pharmaceutically acceptable salt. In another embodiment, the present invention provides a process for preparing a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt, a beta-2 agonist and a pharmaceutically acceptable excipient, wherein the composition is in the form of a fixed dose combination formulation. The process comprises admixing revamilast or its pharmaceutically acceptable salt with the beta-2 agonist.

Alternately, the process comprises formulating revamilast or its

pharmaceutically acceptable salt and the beta-2 agonist in such a way that they are not in intimate contact with each other.

In another embodiment, the invention relates to a process for preparing a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt, a beta-2 agonist and a pharmaceutically acceptable excipient, wherein the composition is in the form of a kit comprising two or more separate formulations of revamilast or its pharmaceutically acceptable salt and the beta-2 agonist.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a graph showing the effect of revamilast, salbutamol, and the combination of revamilast and salbutamol on methacholine induced

bronchoconstriction in ovalbumin sensitized female Balb/C mice.

Figure 2 is a graph showing the effect of revamilast, salmeterol and the combination of revamilast and salmeterol on ovalbumin induced bronchoconstriction in guinea pigs.

Figure 3 is a bar graph showing the effect of revamilast, bambuterol, and the combination of revamilast and bambuterol on ovalbumin induced eosinophilia in ovalbumin sensitized guinea pigs. DETAILED DESCRIPTION

Definitions:

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth earlier in a provisional application from which priority is claimed are in conflict, the definition in the present application shall control the meaning of the terms.

The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating a respiratory disorder, produces an intended therapeutic benefit in the subject. The therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 50 mg and preferably from about 0.1 mg to about 30 mg. The therapeutically effective amount of salbutamol or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 30 mg, and preferably from about 0.05 mg to about 20 mg. The therapeutically effective amount of terbutaline or its pharmaceutically acceptable salt to be administered per day may range from about 0.1 mg to about 20 mg, and preferably from about 0.2 mg to about 10 mg. The therapeutically effective amount of levosalbutamol or its pharmaceutically acceptable salt to be administered per day may range from about 0. Img to about 6 mg, and preferably from about 0.2 mg to about 6 mg. The therapeutically effective amount of salmeterol or its

pharmaceutically acceptable salt to be administered per day may range from about 10μg to about 500μg, preferably from about 20μg to about 500μg and more preferably from about 50μg to about 100μg. The therapeutically effective amount of formoterol or its pharmaceutically acceptable salt to be administered per day may range from about ^g to about 50μg, and preferably from about 10μg to about 25μg. The therapeutically effective amount of indacaterol or its pharmaceutically acceptable salt to be administered per day may range from about 100μg to about 500μg, and more preferably from about 150μg to about 300μg. The therapeutically effective amount of bambuterol or its pharmaceutically acceptable salt to be administered per day may range from about lmg to about 30mg, preferably, from about 5mg to about 30mg and more preferably, from about lOmg to about 20mg.

The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes a PDE4 enzyme inhibitor and a beta-2 agonist.

By "salt" or "pharmaceutically acceptable salt", it is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid addition salts include hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts.

The term "treating" or "treatment" as used herein includes the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder or its symptoms.

The term "synergistic" or "synergy", as used herein, refers to a combination exhibiting an effect greater than would be expected from the sum of the effects of the individual components of the combination alone. The term "synergistic" or "synergy" with regard to the combination of the PDE4 enzyme inhibitor (preferably revamilast or its pharmaceutically acceptable salt) with a beta-2 agonist which is used in the treatment of a respiratory disorder either in the form of the pharmaceutical composition, combination product or a kit according to the invention refers to an efficacy for the treatment of the respiratory disorder that is greater than would be expected from the sum of their individuals effects. The advantages for the synergistic combinations of the present invention include, but are not limited to, lowering the required dose of one or more of the active compounds of the combination, reducing the side effects of one or more of the active compounds of the combination and/or rendering one or more of the active compounds more tolerable to the subject in need of treatment of the respiratory disorder.

By the term "respiratory disorder", it is meant to any condition or disease related to respiration or the respiratory system such as airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, bronchospasm, exercise- induced bronchospasm, bronchospasm associated with COPD, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, or aid in smoking cessation therapy. In one preferred embodiment, the respiratory disorder is asthma, COPD or exercise-induced bronchospasm.

The term "subject" includes mammals, such as humans and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.

By "pharmaceutically acceptable excipients", it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

Asthma and COPD are major chronic diseases related to airway obstruction. The Global Initiative for Chronic Obstructive Lung Disease provides guidelines for the distinction between asthma and COPD. Asthma is believed to be a chronic inflammatory disease wherein the airflow limitation is more or less reversible while it is more or less irreversible in case of COPD. Asthma among other things is believed to be triggered by inhalation of sensitizing agents (like allergens) unlike noxious agents (like particles and certain gases) in case of COPD. Though both are believed to have an inflammatory component, the inflammation in asthma is believed to be mostly eosinophilic and CD-4 driven, while it is believed to be mostly neutrophilic and CD- 8 driven in COPD. Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in 1 second (FEVi), peak expiratory flow rate and severity (e.g., acute, intermittent, mild persistent, moderate persistent, and severe persistent). Asthma may also be classified as allergic (extrinsic) or non-allergic (intrinsic), based on whether symptoms are precipitated by allergens or not. Asthma can also be categorized according to following types viz., nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, and cough variant asthma.

COPD, also known as chronic obstructive lung disease (COLD), chronic obstructive airway disease (CO AD), or chronic obstructive respiratory disease (CORD), is believed to be the co-occurrence of chronic bronchitis (characterized by a long-term cough with mucus) and emphysema (characterized by destruction of the lungs over time), a pair of commonly co-existing diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs, causing shortness of breath. An acute exacerbation of COPD is a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days and is believed to be triggered by an infection with bacteria or viruses or by environmental pollutants. Based on the FEVi values, COPD can be classified as mild, moderate, severe and very severe.

PDE4 Enzyme Inhibitors:

Suitable PDE4 enzyme inhibitors include benzofuropyridine PDE4 enzyme inhibitors, such as those described in WO 2006/064355, which is incorporated herein by reference in its entirety.

In one embodiment, the PDE4 enzyme inhibitor has the formula:

formula (I)

wherein:

R¹ is alkyl or alkyl substituted by one or more halogen groups;

R² is hydrogen;

R³ is hydrogen;

n is 2;

p is 3;

T, V and W are C;

U is N;

each dotted line [— ] in the ring represents a bond;

X is O;

Y is -C(0)NR⁴;

R⁴ is hydrogen;

or a tautomer, stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

All stereoisomers of the compounds of the formula (I), including enantiomers and diastereomers are separately contemplated.

A preferred compound of formula (I) is N9-(3,5-dichloro-4-pyridyl)-6- difiuoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide -N-oxide [INN:

Revamilast] or its pharmaceutically acceptable salt. Beta-2 Agonists

metaproterenol, fenoterol, bitolterol, and their pharmaceutically acceptable salts. LAB As include, but are not limited to, salmeterol, formoterol, bambuterol, indacaterol, vilanterol, arformoterol, olodaterol, abediterol, milveterol, bedoradrine, clenbuterol, reproterol, PF-610355, GSK-597901, GSK-159802, GSK-678007, and their pharmaceutically acceptable salts.

Preferably, the beta-2 agonist includes salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol, bambuterol or its pharmaceutically acceptable salt.

PDE4 enzyme inhibitor / Beta-2 Agonist Combination

The present invention relates to a pharmaceutical composition that includes a PDE4 enzyme inhibitor (such as a benzofuropyridine compound of formula (I) above), and a beta-2 agonist.

In another embodiment, the present invention provides a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt; a beta-2 agonist; and optionally a pharmaceutically acceptable excipient.

In another embodiment, the invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a beta-2 agonist. The therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 50 mg and preferably from about 0.1 mg to about 30 mg. Preferably, the discrete dosage strengths of revamilast or its pharmaceutically acceptable salt to be administered per day may be 0.1 mg, 0.2mg, 0.5mg, lmg, 1.5mg, 2mg, 2.5 mg, 3mg, 3.5 mg, 4 mg, 4.5 mg, 5mg, 5.5 mg, 6 mg, 6.5 mg, 7mg, 7.5 mg, 8mg, 8.5 mg, 9 mg, 9.5 mg, lOmg, 12 mg, 15 mg and 20 mg.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt. The therapeutically effective amount of salbutamol or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 30 mg, and preferably from about 0.05 mg to about 20 mg. Preferably, the discrete dosage strengths of salbutamol or its pharmaceutically acceptable salt to be administered per day may be 0.18mg, 0.22mg, 0.36mg, 0.43mg, 0.54mg, 0.65mg, 0.72mg, 0.86mg, 0^g, 1.080mg, 1.25mg, 1.89mg, 2.5mg, 3.75mg, 4mg, 6mg, 8mg, lOmg, lOmg, 12mg, 14mg or 16mg.

In an embodiment, the present invention relates to a pharmaceutical composition that includes from about O.Olmg to about 50 mg revamilast or its pharmaceutically acceptable salt and about O.Olmg to about 30mg of salbutamol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 0.05 mg to about 20 mg of salbutamol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.1 mg to about 16 mg of salbutamol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises from about 1 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt and from about O.lmg to about 16mg of salbutamol or its pharmaceutically acceptable salt. In another specific embodiment, the present invention relates to a

pharmaceutically acceptable salt. The therapeutically effective amount of terbutaline or its pharmaceutically acceptable salt to be administered per day may range from about 0.1 mg to about 20 mg, and preferably from about 0.2 mg to about 10 mg. Preferably, the discrete dosage strengths of terbutaline or its pharmaceutically acceptable salt to be administered per day may be 1 mg, 2 mg, 2.5mg, 4.1mg, 5.0mg, 7.5mg, lOmg, 12.5mg, 15mg, or 20mg.

Thus in a preferred embodiment, the present invention relates to a

pharmaceutical composition that includes from about 0.0 lmg to about 50mg of revamilast or its pharmaceutically acceptable salt and from about 0.1 mg to about 20 mg terbutaline or its pharmaceutically acceptable salt.

In another preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 0.2 mg to about 10 mg of terbutaline or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 1 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 0.2 mg to about 10 mg of terbutaline or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration, wherein unit dose of the composition comprises about 1 mg to about 10 mg of revamilast or its

pharmaceutically acceptable salt and about lmg to about 20mg of terbutaline or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt. The therapeutically effective amount of

levosalbutamol or its pharmaceutically acceptable salt to be administered per day may range from about O.lmg to about 6 mg, and preferably from about 0.2 mg to about 6 mg. Preferably, the discrete dosage strengths of levosalbutamol or its pharmaceutically acceptable salt to be administered per day may be 0.3 lmg, 0.36mg, 0.62mg, 0.73mg, 0.93mg, 1.25mg, 1.44mg, 1.89mg, 2.5mg, 3.75mg, lmg, 2mg, 3mg, 4mg or 6mg.

Thus in a preferred embodiment, the present invention relates to a

pharmaceutical composition that includes from about 0.0 lmg to about 50mg of revamilast or its pharmaceutically acceptable salt and from about O.lmg to about 6 mg levosalbutamol or its pharmaceutically acceptable salt.

In yet another preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 0.2 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 1 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 0.2 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises about 1 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt and about 0.3mg to about 2mg of levosalbutamol or its pharmaceutically acceptable salt.

In a further specific embodiment, the present invention relates to a

pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and salmeterol or its

pharmaceutically acceptable salt. The therapeutically effective amount of salmeterol or its pharmaceutically acceptable salt to be administered per day may range from about 10μg to about 500μg, preferably, from about 20μg to about 500μg, and more preferably from about 50μg to about 100μg. Preferably, the discrete dosage strengths of salmeterol or its pharmaceutically acceptable salt to be administered per day may be 0.05mg or O.lmg.

Thus in a preferred embodiment, the present invention relates to a

pharmaceutical composition that includes from about 0.0 lmg to about 50mg of revamilast or its pharmaceutically acceptable salt and from about 10μg to about 500μg of salmeterol or its pharmaceutically acceptable salt.

In a further preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 20μg to about 500μg of salmeterol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 1 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 50μg to about 100μg of salmeterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutically acceptable salt and about 50μg to about 100μg of salmeterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutically acceptable salt. The therapeutically effective amount of formoterol or its pharmaceutically acceptable salt to be administered per day may range from about ^g to about 50μg, and preferably from about 10μg to about 25μg. Preferably, the discrete dosage strengths of formoterol or its pharmaceutically acceptable salt to be administered per day may be 12μg or 24μg.

Thus in a preferred embodiment, the present invention relates to a

pharmaceutical composition that includes from about 0.0 lmg to about 50mg of revamilast or its pharmaceutically acceptable salt and from about to about 5(^g of formoterol or its pharmaceutically acceptable salt.

In another preferred embodiment, the present invention relates to a

pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 10μg to about 25 μg of formoterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises about 1 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt and about 12μg to abut 24μg of formoterol or its pharmaceutically acceptable salt.

pharmaceutically acceptable salt. The therapeutically effective amount of indacaterol or its pharmaceutically acceptable salt to be administered per day may range from about 100μg to about 500μg, and more preferably from about 150μg to about 300μg. Preferably, the discrete dosage strengths of indacaterol or its pharmaceutically acceptable salt to be administered per day may be 150μg or 300μg.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about O.Olmg to about 50mg of revamilast or its pharmaceutically acceptable salt and from about 100μg to about 500μg of indacaterol or its pharmaceutically acceptable salt.

In a further preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 150 μg to about 300 μg of indacaterol or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a pharmaceutical composition that includes from about 1 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 150 μg to about 300 μg of indacaterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutically acceptable salt and about 150μg to about 300μg of indacaterol or its pharmaceutically acceptable salt.

In a further specific embodiment, the present invention relates to a pharmaceutical composition that includes a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and bambuterol or its

pharmaceutically acceptable salt. The therapeutically effective amount of bambuterol or its pharmaceutically acceptable salt to be administered per day may range from about lmg to about 30mg, preferably from about 5mg to about 30mg, and preferably from about lOmg to about 20mg. Preferably, the discrete dosage strengths of bambuterol or its pharmaceutically acceptable salt to be administered per day may be lOmg or 20mg.

Thus in a preferred embodiment, the present invention relates to a

pharmaceutical composition that includes from about 0.0 lmg to about 50mg of revamilast or its pharmaceutically acceptable salt and from about lmg to about 30mg of bambuterol or its pharmaceutically acceptable salt.

In another preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 5mg to about 30mg of bambuterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes from about 1 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt. In another specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration, wherein unit dose of the composition comprises from about 1 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt.

The optimal dose of the active ingredients can vary as a function of the severity of disease, route of administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredients.

The therapeutically effective amount of the active ingredients can be administered as a single dose or in divided doses, either once daily or two/three/four times a day.

In the pharmaceutical composition as described herein, the active ingredient may be in the form of a single dosage form (i.e., fixed-dose formulation in which both the active ingredients are present together) or they may be divided doses, formulated separately, each in its individual dosage forms but as part of the same therapeutic treatment, program or regimen, either once daily or two/three/four times a day.

In an embodiment, the pharmaceutical composition of the present invention is in the form of a fixed dose combination formulation of revamilast or its

pharmaceutically acceptable salt and the beta-2 agonist.

Alternately, the pharmaceutical composition of the present invention is in the form of a kit comprising two or more separate formulations of revamilast or its pharmaceutically acceptable salt and the beta-2 agonist.

The two or more separate formulations can be administered by same or different routes, either separately, simultaneously, or sequentially, where the sequential administration is close in time or remote in time. For sequential

administration, the period of time may be in the range from 10 min to 12 hours.

Thus in a specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration wherein the composition is in the form of a kit having a unit dose formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another unit dose formulation comprising about 0.63mg or 0.75mg or 1.25mg or 1.5mg or 2mg or 4mg salbutamol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about 0.63mg or 0.75mg or 1.25mg or 1.5mg or 2mg or 4mg or 6mg or 8mg or lOmg or 12mg or 14mg or 16mg salbutamol or its pharmaceutically acceptable salt.

In a further specific embodiment, the present invention relates to a pharmaceutical composition for oral administration wherein the composition is in the form of a kit having a unit dose formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another unit dose formulation comprising about lmg or 2.5mg or 5mg of terbutaline or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about lmg or 2.5mg or 5mg or 7.5mg or lOmg or 12.5mg or 15mg or 20mg of terbutaline or its pharmaceutically acceptable salt. In another specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration wherein the composition is in the form of a kit having a unit dose formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another unit dose formulation comprising about 0.3 lmg or 0.63mg or 1.25 mg or 2mg of levosalbutamol or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about 0.3 lmg or 0.63mg or 1.25 mg or 2mg or 4mg or 6mg of levosalbutamol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutical composition in the form of a kit having a unit dose oral formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another inhalation formulation comprising about 50μg or about 100μg of salmeterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about 50μg or about 10(^g of salmeterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutical composition in the form of a kit having a unit dose oral formulation comprising about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another inhalation formulation comprising about 12μg or about 24μg of formoterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or l Omg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about 12μg or about 24μg of formoterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration wherein the composition is in the form of a kit having a unit dose formulation comprising about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another unit dose formulation comprising about 15(^g or 300μg of indacaterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or l Omg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about 15(^g or about 30(^g of indacaterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration wherein the composition is in the form of a kit having a unit dose formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another unit dose formulation comprising about lOmg or about 20mg of bambuterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about lOmg or about 20mg of bambuterol or its pharmaceutically acceptable salt.

In another embodiment, there is provided a pharmaceutical composition containing revamilast or its pharmaceutically acceptable salt and a beta-2 agonist at a weight ratio ranging from about 0.01 : 100 to about 100:0.1, preferably from about 0.1 :50 to about 50: 1, and more preferably from about 0.1 : 10 to about 10: 1, respectively. Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol bambuterol or its pharmaceutically acceptable salt.

Specifically, the weight ratio of revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt may range from about 0.1 : 16 to about 30:0.1 and preferably from about 1 : 16 to about 20:0.1. More preferably, the weight ratio of revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt may be 1:16 or 1:15 or 1:14 or 1:13 or 1:12 or 1:11 or 1:10 or 1:9 or 1:8 or 1:7 or 1:6 or 1:5 or 1:4 or 1:3 or 1:2, or 1:1, or 1:0.1 or 2:0.1 or 2:0.5 or 2:1 or 2:3 or 2:5 or 2:7 or 3:0.1 or 3:1 or 3:2 or 3:4 or 3:5 or 3:7 or 3:8 or 4:0.1 or 4:0.5 or 4:1 or 4:5 or 4:7 or 5:0.1 or 5:1 or 5:2 or 5:3 or 5:4 or 5:6 or 5:7 or 5:8 or 6:0.1 or 6:0.5 or 6:1 or 7:0.1 or 8:0.1 or 8:0.5 or 8:1 or 9:0.1 or 10:0.1 or 11:0.1 or 12:0.1 or 13:0.1 or 14:0.1 or 15:0.1 or 16:0.1 or 17:0.1 or 18:0.1 or 19:0.1 or 20:0.1.

In another specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and terbutaline or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.01:20 to about 50:0.1 and preferably from about 0.1:10 to about 15:0.1. Specifically, the weight ratio of revamilast or its pharmaceutically acceptable salt and terbutaline or its pharmaceutically acceptable salt may be 0.1:10 or 0.1:9 or 0.1:8 or 0.1:7 or 0.1:6 or 0.1:5 or 0.1:4 or 0.1:3 or 0.1:2 or 0.1:1 or 1:1 or 1:0.1 or 1:0.125 or 1:0.5 or 1:2 or 1:3 or 1:4 or 1:5 or 2:0.1 or 2:3 or 2:5 or 3:0.1 or 3:1 or 3:2 or 3:4 or 3:5 or 4:0.1 or 4:0.25 or 4:0.5 or 4:1 or 4:3 or 4:5 or 5:0.15:1 or 5:2 or 5:3 or 5:4 or 6:0.16:0.25 or 6:0.5 or 6:1 or 7:0.1 or 8:0.1 or 8:0.25 or 8:0.5 or 8:1 or 9:0.1 or 10:0.1 or 10:0.25 or 11:0.1 or 1:0.1 or 13:0.1 or 14:0.1 or 15:0.1.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.01:6 to about 5:0.01 and preferably from about 0.1:6 to about 15:0.1. Specifically, the weight ratio of revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt ranges from about 0.1 :6 to about 15:0.1, and preferably from about 1:6 to about 10:0.1. More preferably, the weight ratio of revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt may be 1:6 or 1:5 or 1:4 or 1:3 or 1:2, or 1:1, or 2:1 or 2:1 or 3:1 or4:l or5:l or6:l or 7:1 or 8:1 or 1:0.1 or 1:0.15 or 1:0.18 or 1:0.2 or 1:0.24 or 1:0.3 or 1:0.375 or 1:0.4 or 1:0.475 or 1:0.6 or 1:0.72 or 1:0.825 or 1:0.95 or 1 : 1.25 or 1 : 1.88 or 2:0.1 or 2:0.3 or 2:0.5 or 2:3 or 3:0.1 or 3:0.4 or 3:2 or 4:0.1 or 4:0.3 or 4:3 or 5:0.1 5:0.3 or 5:0.4 or 5:0.6 or 5:0.72 or 5:0.95 or 5:2 or 5:3 or 6:0.1 or 7:0.1 or 8:0.1 or 8:0.3 or 8:3 or 9:0.1 or 10:0.1 or 10:0.3.

In a further specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and salmeterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.1 :5 to about 50:0.01 and preferably from about 1 :5 to about 15:0.01. Specifically, the weight ratio of revamilast or its pharmaceutically acceptable salt and salmeterol or its pharmaceutically acceptable salt may range from about 1 : 1 to about 6:0.01, and preferably from about 1 :0.1 to about 4:0.01. More preferably, the weight ratio of revamilast or its pharmaceutically acceptable salt and salmeterol or its pharmaceutically acceptable salt may be 1 :5 or 1 :4 or 1 :3 or 1 :2 or 1 : 1 or 1 :0.1 or 6:0.1 or 6:0.05 or 2:0.1 or 4:0.1 or 8:0.1 or 8:0.05 or 1 :0.01 or 2:0.01 or 3:0.01 or 4:0.01 or 5:0.01 or 6:0.01 or 7:0.01 or 8:0.01 or 9:0.01 or 10:0.01 or 11 :0.01 or 1 :0.01 or 13:0.01 or 14:0.01 or 15:0.01.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 1 :5 to about 50:0.001 and preferably from about 1 :0.25 to about 30:0.01. Specifically, the weight ratio of revamilast or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt may be 1 :0.25 or 1 :0.15 or 1 :0.1 or 1 :0.06 or 1 :0.03 or 1 : 1 or 1 :0.01 or 2:0.01 or 3:0.01 or 4:0.01 or 5:0.01 or 6:0.01 or 7:0.01 or 8:0.01 or 9:0.01 or 10:0.01 or 10:0.02 or 10:0.24 or 10:0.03 or 10:0.06 or 10:0.12 or 1 1 :0.01 or 12:0.01 or 13:0.01 or 14:0.01 or 15:0.01 or 20:0.01 or 25:0.01 or 30:0.01.

In another specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and indacaterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.1 :5 to about 50:0.1 and preferably from about 1 :3 to about 20:0.1. Specifically, the weight ratio of revamilast or its pharmaceutically acceptable salt and indacaterol may be 1:3 or 1:2 or 1:1 or 1:0.1 or 1:0.15 or 2:0.1 or 2:0.15 or 3:0.1 or 3:0.15 or 4:0.1 or 4:0.15 or 5:0.1 or 6:0.1 or 6:0.15 or 7:0.1 or 8:0.1 or 8:0.15 or 9:0.1 or 10:0.1 or 10:0.15 or 10:0.3 or 11:0.1 or 1:0.1 or 13:0.1 or 14:0.1 or 15:0.1 or 16:0.1 or 17:0.1 or 18:0.1 or 19:0.1 or 20:0.1.

In a further specific embodiment, the present invention relates to a

pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and bambuterol or its pharmaceutically acceptable salt in a weight ratio ranging from about 0.01:30 to about 50:1 and preferably from about 0.1:20 to about 3:1. Specifically, the weight ratio of revamilast or its pharmaceutically acceptable salt and bambuterol or its pharmaceutically acceptable salt may range from about 0.1:20 to about 3:1, and preferably from about 1 : 20 to about 2:1. More preferably the weight ratio of revamilast or its pharmaceutically acceptable salt and bambuterol or its pharmaceutically acceptable salt is 1:20 or 1:19 or 1:18 or 1:17 or 1:16 or 1:15 or 1:14 or 1:13 or 1:12 or 1:11 or 1:10 or 1:9 or 1:8 or 1:7 or 1:6 or 1:5 or 1:4 or 1:3 or 1:2, or 1:1, or 2:1 or 2:5 or 3:1 or 3:5 or3:10or4:5.

In one embodiment, the present invention relates to a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt; a beta-2 agonist; and an additional active agent.

The additional active agent may be selected from anticholinergic agent (e.g., tiotropium, ipratropium, aclidinium or a salt thereof), leukotriene receptor antagonists (e.g., montelukast or zafirlukast or a salt thereof), glucocorticoids (e.g., fluticasone, budesonide, beclomethasone, flunisolide, dexamethasone, ciclesonide, triamcinolone, mometasone, prednisone, prednisolone, methylprednisolone or a salt thereof), or histamine receptor antagonist (e.g., cetirizine, levocetirizine, azelastine, astemizole, loratadine, rupatadine, fexofenadine, desloratadine, terfenadine or a salt thereof).

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt; a beta-2 agonist; and a leukotriene receptor antagonist selected from montelukast, zafirlukast or a salt thereof.

In another preferred embodiment, the present invention relates to a

pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt; a beta-2 agonist; and a histamine receptor antagonist selected from cetirizine, levocetirizine, azelastine, astemizole, loratadine, rupatadine, fexofenadine, desloratadine, terfenadine or a salt thereof.

As contemplated herein, the active ingredients may be administered together in a single dosage form or they may be administered in different dosage forms. They may be administered at the same time or they may be administered either close in time or remotely, such as, where one drug is administered in the morning and the second drug is administered in the evening. The combination may be used prophylactically or after the onset of symptoms has occurred.

The pharmaceutical composition of the present invention may be administered orally, nasally, intra-tracheally, parenterally, transdermally, transmucosal, inhalation or by any other route that a physician or a health-care provider may determine to be appropriate. Preferably, the pharmaceutical composition is administered by the oral route.

The pharmaceutical compositions of the invention include those for oral, parenteral, intra-tracheal, transdermal, transmucosal and nasal administration, or by inhalation route among others. Preferably, pharmaceutical composition of present invention is for oral administration. In a preferred embodiment, both the active ingredients, e.g., revamilast or its pharmaceutically acceptable salt and the beta-2 agonist, are formulated as a pharmaceutical composition suitable for oral

administration.

The pharmaceutical compositions for oral administration may be in

conventional forms, for example, tablets, capsules, granules (synonymously, "beads" or "particles" or "pellets"), suspensions, emulsions, powders, dry syrups, and the like. The capsules may contain granule/pellet/particle/mini-tablets/mini-capsules containing the active ingredients. The amount of active that may be incorporated in the pharmaceutical composition may range from about 1% w/w to about 98% w/w; or from about 5% w/w to about 90% w/w.

The pharmaceutical compositions for parenteral administration include but are not limited to solutions for intravenous, subcutaneous or intramuscular

injection/infusion, suspensions for intramuscular or subcutaneous injection, emulsions for intramuscular or subcutaneous injection and implants.

The pharmaceutical compositions for transdermal or transmucosal

administration include but are not limited to patches, gels, creams, ointments and the like.

As set forth above, the pharmaceutical composition may include at least one pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents/viscosifying agents, surfactants, propellants, and solvents.

In one embodiment, the present invention relates to a pharmaceutical composition that includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt; a beta-2 agonist, and a pharmaceutically acceptable excipient. Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol bambuterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, salbutamol or its pharmaceutically acceptable salt and a

pharmaceutically acceptable excipient.

In another specific embodiment, the present invention relates to a

pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, terbutaline or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient. In yet another specific embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, levosalbutamol or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

In a further embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, salmeterol or its pharmaceutically acceptable salt and a

pharmaceutically acceptable excipient.

In another embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and a

pharmaceutically acceptable excipient.

In yet another embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, indacaterol or its pharmaceutically acceptable salt and a

pharmaceutically acceptable excipient.

In a further embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, bambuterol or its pharmaceutically acceptable salt and a

pharmaceutically acceptable excipient.

In an embodiment, the present invention relates to a pharmaceutical composition includes revamilast or its pharmaceutically acceptable salt and a beta-2 agonist, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

Thus in a specific embodiment, the present invention relates to a

pharmaceutical composition includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof. In a preferred embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about O.lmg to about 16mg of salbutamol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of respiratory disorder in a subject in need thereof.

In another specific embodiment, the present invention relates to a

pharmaceutical composition includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and terbutaline or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about 0.25 mg to about 10 mg of terbutaline or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of respiratory disorder in a subject in need thereof.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of respiratory disorder in a subject in need thereof.

In another specific embodiment, the present invention relates to a

pharmaceutical composition includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and salmeterol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about 0.05 mg to about 0.1 mg salmeterol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In a further specific embodiment, the present invention relates to a

pharmaceutical composition includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about 12μg to about 24μg formoterol or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a pharmaceutical composition includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and indacaterol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about 150μg to about 300μg indacaterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a

pharmaceutical composition includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and bambuterol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition for oral administration that includes from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of a respiratory disorder in a subject in need thereof.

Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol, bambuterol or salt thereof.

Thus in an embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt for the treatment of a respiratory disorder in a subject in need thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes from about O. lmg to about 30mg of revamilast or its pharmaceutically acceptable salt and from about 0.05 mg to about 20 mg salbutamol or its pharmaceutically acceptable salt for the treatment of asthma, or COPD or exercise-induced bronchospasm in a subject in need thereof. In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.18mg, 0.22mg, 0.36mg, 0.43mg or 0.54mg or 0.65mg or 0.72mg or 0.86mg or O^g or 1.08mg or 1.25mg or 1.89mg or 2.5mg or 3.75mg or 4mg or 6mg or 8mg or 12mg or 14mg or 16mg salbutamol or its pharmaceutically acceptable salt for the treatment of asthma, or COPD or exercise- induced bronchospasm in a subject in need thereof.

In another embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and terbutaline or its pharmaceutically acceptable salt for the treatment of a respiratory disorder in a subject in need thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes from about O. lmg to about 30mg of revamilast or its pharmaceutically acceptable salt and from about 0.2mg to about 20mg of terbutaline or its pharmaceutically acceptable salt for the treatment of asthma, reversible bronchospasm associated with bronchitis or emphysema in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and about 1 mg or 2 mg or 2.5mg or 4. lmg or 5.0mg or 7.5mg or lOmg or 12.5mg or 15mg or 20mg of terbutaline or its

pharmaceutically acceptable salt for the treatment of asthma, reversible bronchospasm associated with bronchitis or emphysema in a subject in need thereof.

In yet another embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt for the treatment of a respiratory disorder in a subject in need thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 0.2 mg to about 6 mg of

levosalbutamol or its pharmaceutically acceptable salt for the treatment of

bronchospasm or asthma in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and about 0.3 Img or 0.36mg or 0.62mg or 0.73mg or 0.93mg or 1.25mg or 1.44mg or 1.89mg or 2.5mg or 3.75mg or Img or 2mg or 3mg or 4mg or 6mg of levosalbutamol or its pharmaceutically acceptable salt for the treatment of bronchospasm or asthma in a subject in need thereof.

In a further embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and salmeterol or its pharmaceutically acceptable salt for the treatment of a respiratory disorder in a subject in need thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 0.05mg to about 0.1 mg of salmeterol or its pharmaceutically acceptable salt for the treatment of asthma, exercise-induced bronchospasm or bronchospasm associated with COPD in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and about 0.05mg or about O. lmg of salmeterol or its pharmaceutically acceptable salt for the treatment of asthma, exercise-induced bronchospasm or bronchospasm associated with COPD in a subject in need thereof.

In another embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt for the treatment of a respiratory disorder in a subject in need thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about O.Olmg to about 0.025 mg of formoterol or its pharmaceutically acceptable salt for the treatment of asthma, exercise-induced bronchospasm or COPD in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and about 12μg or about 24μg of formoterol or its pharmaceutically acceptable salt for the treatment of asthma, exercise-induced bronchospasm or COPD in a subject in need thereof.

In a further embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and indacaterol or its pharmaceutically acceptable salt for the treatment of a respiratory disorder in a subject in need thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 0.1 mg to about 0.5 mg of indacaterol or its pharmaceutically acceptable salt for the treatment of COPD in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes about 0.5mg or Img or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and about 15(^g or about 30(^g of indacaterol or its pharmaceutically acceptable salt for the treatment of COPD in a subject in need thereof.

In yet another embodiment, the present invention relates to a pharmaceutical composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and bambuterol or its pharmaceutically acceptable salt for the treatment of a respiratory disorder in a subject in need thereof.

In a specific embodiment, the present invention relates to a pharmaceutical composition that includes from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt for the treatment of asthma, bronchospasm or COPD in a subject in need thereof.

In a preferred embodiment, the present invention relates to a pharmaceutical composition that includes about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and about 10 mg or about 20 mg of bambuterol or its pharmaceutically acceptable salt for the treatment of asthma, bronchospasm or COPD in a subject in need thereof.

In a further embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering the subject a pharmaceutical composition of the present invention.

In another embodiment, the present invention relates to a method of treating a respiratory disorder, the method including administering a pharmaceutical

composition that includes an effective amount of revamilast or its pharmaceutically acceptable salt and beta-2 agonist to a subject in need thereof. Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol bambuterol or its pharmaceutically acceptable salt.

Thus in a specific embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about 0.01 mg to about 30 mg salbutamol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, COPD or exercise-induced bronchospasm in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, from about 0.05 mg to about 20 mg salbutamol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating asthma in a subject, the method comprising administering to the subject a

pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, from about 0.1 mg to about 16 mg salbutamol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of treating COPD in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, from about 0.1 mg to about 16 mg salbutamol or its pharmaceutically acceptable salt.

In a further specific embodiment, the present invention relates to a method of treating exercise-induced bronchospasm in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, from about 0.1 mg to about 16 mg salbutamol or its pharmaceutically acceptable salt.

In one embodiment, the present invention relates to a method of treating bronchoconstriction related to a respiratory disorder (e.g., asthma, COPD or exercise- induced bronchospasm) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about O.lmg to about 16mg of salbutamol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In another embodiment, the present invention relates to a method of providing bronchodilation in the treatment of a respiratory disorder (e.g., asthma, COPD or exercise-induced bronchospasm) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about O.lmg to about 16mg of salbutamol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In a further embodiment, the present invention relates to a method of treating airway inflammation in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about O.lmg to about 16mg of salbutamol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In a further embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about O.lmg to about 16mg of salbutamol or its pharmaceutically acceptable salt, wherein the composition exhibits rapid onset of action.

In one embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about O. lmg to about 20mg of terbutaline or its pharmaceutically acceptable salt. In a preferred embodiment, the present invention relates to a method of treating asthma, reversible bronchospasm associated with bronchitis or emphysema in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.2mg to about lOmg terbutaline or its pharmaceutically acceptable salt.

pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of treating reversible bronchospasm associated with bronchitis in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a method of treating emphysema in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt.

In one embodiment, the present invention relates to a method of treating bronchoconstriction related to a respiratory disorder (e.g., asthma, reversible bronchospasm associated with bronchitis, reversible bronchospasm associated with emphysema) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt, wherein the composition exhibits synergy. In another embodiment, the present invention relates to a method of providing bronchodilation in treating a respiratory disorder (e.g., asthma, reversible

bronchospasm associated with bronchitis, reversible bronchospasm associated with emphysema) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In one embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, comprising administering to the subject a

pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.25 mg to about 10 mg terbutaline or its pharmaceutically acceptable salt, wherein the composition exhibits rapid onset of action.

In one embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about O.Olmg to about 6mg of levosalbutamol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating bronchospasm or asthma in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.2 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating bronchospasm in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt. In another specific embodiment, the present invention relates to a method of treating asthma in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

In one embodiment, the present invention relates to a method of treating bronchoconstriction related to a respiratory disorder (e.g., asthma or bronchospasm) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In another embodiment, the present invention relates to a method of providing bronchodilation in treating a respiratory disorder (e.g., asthma or bronchospasm) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In one embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.25 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt, wherein the composition exhibits rapid onset of action.

In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about 0.01 mg to about 0.5 mg salmeterol or its pharmaceutically acceptable salt. In a preferred embodiment, the present invention relates to a method of treating asthma, exercise-induced bronchospasm or bronchospasm associated with COPD in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.02mg to about 0.5 mg salmeterol or its pharmaceutically acceptable salt.

pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.05 mg to about 0.1 mg salmeterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of preventing exercise-induced bronchospasm in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.05 mg to about 0.1 mg salmeterol or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a method of treating bronchospasm associated with COPD in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.05 mg to about 0.1 mg salmeterol or its pharmaceutically acceptable salt.

In one embodiment, the present invention relates to a method of treating bronchoconstriction related to a respiratory disorder (e.g., asthma, exercise-induced bronchospasm or bronchospasm associated with COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.05mg to about O.lmg of salmeterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy. In another embodiment, the present invention relates to a method of providing bronchodilation in treating a respiratory disorder (e.g., asthma, exercise-induced bronchospasm or bronchospasm associated with COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.05mg to about O.lmg of salmeterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In a further embodiment, the present invention relates to a method of reducing airway resistance in treatment of a respiratory disorder (e.g., asthma, exercise-induced bronchospasm or bronchospasm associated with COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.05mg to about O.lmg of salmeterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.05mg to about O.lmg of salmeterol or its pharmaceutically acceptable salt, wherein the composition exhibits rapid onset of action.

In one embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about O.OOlmg to about 0.05 mg formoterol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, exercised induced bronchospasm or COPD in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about O.lmg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about O.Olmg to about 0.025 mg formoterol or its pharmaceutically acceptable salt.

pharmaceutical composition that includes from about lmg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 12μg to about 24μg formoterol or its pharmaceutically acceptable salt.

In another specific embodiment, the present invention relates to a method of treating exercised induced bronchospasm in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 12μg to about 24μg formoterol or its pharmaceutically acceptable salt.

In yet another specific embodiment, the present invention relates to a method of treating COPD in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 12μg to about 24μg formoterol or its pharmaceutically acceptable salt.

In one embodiment, the present invention relates to a method of treating bronchoconstriction relates to a respiratory disorder (e.g., asthma, exercised induced bronchospasm or COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 12μg to about 24μg of formoterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In another embodiment, the present invention relates to a method of providing bronchodilation in treatment of a respiratory disorder (e.g., asthma, exercised induced bronchospasm or COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 12μg to about 24μg of formoterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 12μg to about 24μg of formoterol or its pharmaceutically acceptable salt, wherein the composition exhibits rapid onset of action.

In an embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 0.1 mg to about 0.5 mg indacaterol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating COPD in a subject, the method comprising administering to the subject a

pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 0.15 mg to about 0.3 mg indacaterol or its pharmaceutically acceptable salt.

In one embodiment, the present invention relates to a method of treating bronchoconstriction related to a respiratory disorder (e.g. COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.15mg to about 0.3mg of indacaterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In another embodiment, the present invention relates to a method of providing bronchodilation in treatment of a respiratory disorder (e.g. COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.15 mg to about 0.3 mg of indacaterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 0.15 mg to about 0.3mg of indacaterol or its pharmaceutically acceptable salt, wherein the composition exhibits rapid onset of action.

In one embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt, and from about 1 mg to about 30 mg of bambuterol or its pharmaceutically acceptable salt.

In a preferred embodiment, the present invention relates to a method of treating asthma, bronchospasm or COPD in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 0.1 mg to about 30 mg revamilast or its pharmaceutically acceptable salt, and from about 5 mg to about 30 mg of bambuterol or its pharmaceutically acceptable salt.

pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt.

In a specific embodiment, the present invention relates to a method of treating bronchospasm in a subject, the method comprising administering to the subject a pharmaceutical composition that includes from about 1 mg to about 20 mg revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt. In a specific embodiment, the present invention relates to a method of treating COPD in a subject, the method comprising administering to the subject a

In one embodiment, the present invention relates to a method of treating bronchoconstriction related to a respiratory disorder (e.g., asthma, bronchospasm or COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In another embodiment, the present invention relates to a method of providing bronchodilation in the treatment of a respiratory disorder (e.g., asthma, bronchospasm or COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In a further embodiment, the present invention relates to a method of reducing the eosinophil count in the treatment of a respiratory disorder (e.g., asthma, bronchospasm or COPD) in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt, wherein the composition exhibits synergy.

In one embodiment, the present invention relates to a method of treating a respiratory disorder in a subject, comprising administering to the subject a pharmaceutical composition that includes from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt, wherein the composition exhibits rapid onset of action.

In an embodiment, the present invention relates to use of therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a beta-2 agonist in the preparation of a pharmaceutical composition for the treatment of a respiratory disorder in a subject. Preferably, the beta-2 agonist is salbutamol, terbutaline, levosalbutamol, salmeterol, formoterol, indacaterol bambuterol or its pharmaceutically acceptable salt.

Various animal models have been used for the evaluation of the therapeutic efficacy of drug candidates for respiratory disorders such as asthma and COPD. For example, one commonly used strategy for evaluation of drug candidates in asthma is the allergen sensitization and challenge method. One commonly used such model is the ovalbumin (OVA) sensitization and challenge in mice. The model is believed to generate increased OVA-specific IgE and Igll , eosinophilia (intraluminal, peribronchial, and perivascular). The model is also believed to increase recruitment of lymphocytes in the airways. The model may also generate Th2-type cytokines, and airway hyper-responsiveness is also observed many times.

A commonly used model for evaluation of drug candidates in COPD involves the chronic exposure of the animal (e.g., rats) to S0₂. Another model that can be used for evaluation of drug candidates in COPD involves the exposure of animals (e.g., rats) to lipopolysaccharide (LPS). Tobacco smoke is also used in animal models to induce conditions similar to COPD.

In another embodiment, the present invention provides a process for the preparing a pharmaceutical composition that includes revamilast or its

pharmaceutically acceptable salt, a beta-2 agonist and a pharmaceutically acceptable excipient, wherein the composition is in the form of a fixed dose combination formulation. The process comprises admixing revamilast or its pharmaceutically acceptable salt with the beta-2 agonist. Alternately, the process comprises formulating revamilast or its

For example, the process for making the pharmaceutical composition may include (1) granulating either or both the active ingredients, combined or separately, along with pharmaceutically acceptable carriers so as to obtain granulates, and (2) converting the granulates into suitable dosage forms for oral administration. The typical processes involved in the preparation of the pharmaceutical compositions include various unit operations such as mixing, sifting, solubilizing, dispersing, granulating, lubricating, compressing, coating, and the like. These processes, as contemplated by a person skilled in the formulation art, have been incorporated herein for preparing the pharmaceutical compositions of the present invention.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention. EXAMPLES

EXAMPLE 1 : Effect of combination of revamilast and salbutamol on methacholine (MCh) challenge test in ova sensitized mice.

Revamilast, salbutamol, and a combination of the two were evaluated by the methacholine challenge test in ova sensitized female Balb/C mice. Balb/C mice weighing 25-30 gm were used for induction of acute airway inflammation by intraperitoneal injections of 10 μg ovalbumin (Ova, Calbiochem) emulsified in Al(OH)₃ (Merck) on day 0 and day 7. Mice were challenged with 1% ovalbumin nebulization (in PBS) for 30 minutes in a 45x30x30 cm perspex glass chamber on day 14, 15 and 16, except ova-saline control group. Animals were grouped as per Table 1 and the methacholine challenge test was performed 24 hours after the last ovalbumin challenge.

Vehicle, revamilast (0.3mg/kg) or salbutamol (lmg/kg) were administered by the oral route, one hour prior to MCh aerosol challenge (1.56, 3.125, 6.25, 12.5, 25 & 50 mg/ml in cumulative fashion for 150 sec) using noninvasive whole body plethysmo graph (Buxco apparatus, USA). MCh-induced bronchoconstriction at each of the doses was recorded for a period of 150 seconds in the form of enhanced pause (penh).

Table 1

Dose

Groups Treatment (n) Salbutamol Revamilast

Exposure to (mg kg, p.o.) (mg kg, p.o.)

1 Ova-Sal control (6) - -

2 Ova-Ova control (8) - -

3 Revamilast (10) - 0.3 MCh

4 Salbutamol (9) 1 -

5 Combination (7) 1 0.3 The effect of the respective treatments on MCh induced bronchoconstriction was calculated as a percent inhibition in penh with respect to the vehicle (MCh) control group taking into consideration the Ova sensitized control group.

The combination of revamilast and salbutamol produced significantly superior inhibition of MCh induced bronchoconstriction (penh) compared to the individual and the sum of the activity of the two individual treatments. The results are shown in Table 2 and Fig 1.

Table 2

""/XO.OOl, Ova-Ova control vs Ova-Sal control; ^&p< 0.01 , ^mp< 0.001 , Combination group vs Ova- Ova control; ^sp< 0.001, Combination group vs revamilast;^*p< 0.05, ^*""/?< 0.001, Combination group vs Salbutamol.

EXAMPLE 2: Effect of combination of revamilast and salmeterol xenafoate on bronchoconstriction in ovalbumin sensitized model in male guinea pigs.

The animals were actively sensitized intraperitoneally on Day 0 and Day 2 with 5 mg and 10 mg ovalbumin/animal suspended in 0.1 ml saline + 0.1 ml 10% aluminium hydroxide. The vehicle control animals received 0.2 ml of normal saline/animal. On day 21 the animals were weighed and given respective treatment (Table 3) 1 hr prior to the Ovalbumin challenge. Table 3

The recording of airway resistance (RxV) was carried out with a non-invasive respiratory analyzer. Initially, the baseline RxV was recorded for 5 min, followed by exposure to saline (1 min at 1.5 bar pressure) with data recording for 5 min. The animals were then exposed to 0.3 % Ovalbumin (1 min at 1.5 bar pressure) and RxV was recorded for further 25 min. The data was averaged at 5 min intervals to obtain mean values.

The percentage inhibition of RxV (cm H₂0/sec) at different time intervals was calculated with respect to the baseline value in comparison to that of the vehicle control. Statistical analysis was done by two-way anova followed by Bonferroni multiple comparison tests using GraphPad Prism software. It was found that the combination of revamilast and salmeterol xenafoate produced significantly superior inhibition in airway resistance as compared to the individual and sum of the activities of both treatments in this model (Fig 2 and Table 4).

Table 4

% inhibition of bronchoconstriction in

Treatment Dose (mg/kg, p.o.) respect with Ovalbumin control at Groups different time intervals (min)

Salmeterol Revamilast 5 15 25

1 - -

2 0.01-lh

prior - 4.5±24.3 24.81±31.2 6.07±32.2

3 - 0.3-lh prior 7.74±22.7 33.55±6.8 40.87±10.3

4 0.01-lh 0.3-lh prior

prior 67.72±5.3 56.37±1 51.87±9.3 EXAMPLE 3: Effect of revamilast with bambuterol on ovalbumin induced eosinophilia in ova sensitized guinea pig.

The additive and synergistic effect of revamilast with bambuterol on ovalbumin induced eosinophilia in sensitized female guinea pigs was evaluated.

Healthy female guinea pigs were actively sensitized on Day 0 and Day 2 with intraperitoneal injection of 5 mg and 10 mg respectively of ovalbumin per animal suspended in 0.1 ml saline + 0.1 ml 10% aluminium hydroxide. On day 21 the animals were weighed, and randomized into 5 groups (Table 5).

Revamilast and bambuterol were dosed orally lhr and 3hr prior to the ovalbumin challenge respectively. Ovalbumin (1% in NS) was nebulized for 3 min at the flow rate of 0.05 ml min-¹ using Buxco nebulizer control. Saline control animals were given saline exposure under similar conditions. 48 hours post-ova challenge, the animals were euthanized by injecting high dose of urethane (1.5 g/kg i.p.) and the trachea was exposed for cannulation. Branchoalveolar lavage (BAL) fluid was collected from each animal using phosphate buffer saline. Total leukocyte count was recorded from the BAL fluid and the remainder was centrifuged for 20min at 2000 rpm for pellet formation. Using the pellet, a smear was prepared for the estimation of eosinophils.

The results are expressed as percentage inhibition of eosinophils compared with that of vehicle (ovalbumin) control taking into consideration the saline control group.

Table 5

Dose (mg/kg, p.o) Time of BAL

Groups Treatment («)

Bambuterol Revamilast collection

Saline-saline control 48h after saline

1 - - (8) exposure

2 Ova-Ova control (5) - -

3 Revamilast (6) - 0.3 48h after ova

4 Bambuterol (8) 1 exposure

5 Combination (7) 1 0.3 The combination of revamilast and bambuterol produced significantly superior inhibition in ovalbumin induced eosinophilia compared to the individual and sum of the activities of both treatments in ova sensitized animals. The results are shown in Table 6 and Fig 3.

Table 6

pO.001, saline vs Ova control; ^mp< 0.001, p< 0.001, ^®p< 0.05, Ova control, revamilast and bambuterol vs Combination respectively.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS We claim:

1. A pharmaceutical composition comprising from about 0.01 mg to about 50 mg of 3,5-dichloro-4-{[6-(difluoromethoxy)[l]benzofuro[3,2-c]pyridine-9- yl]carboxamido} pyridine 1 -oxide [INN: Revamilast] or its pharmaceutically acceptable salt and a beta-2 agonist.

2. The pharmaceutical composition according to claim 1 , wherein the

composition comprises from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt.

3. The pharmaceutical composition according to claim 1 , wherein the

composition comprises from about 1 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the composition comprises revamilast or its pharmaceutically acceptable salt and the beta-2 agonist at a weight ratio ranging from about 0.01 : 100 to about 100:0.01.

5. The pharmaceutical composition according to any one of claims 1-3, wherein the composition comprises revamilast or its pharmaceutically acceptable salt and the beta-2 agonist at a weight ratio ranging from about 0.1 :50 to about 50: 1.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the beta-2 agonist is salbutamol, levosalbutamol, terbutaline, salmeterol, formoterol, indacaterol, bambuterol or a salt thereof.

7. The pharmaceutical composition according to any one of claims 1-5, wherein the beta-2 agonist is salbutamol, levosalbutamol, terbutaline, bambuterol or a salt thereof, and said composition is suitable for oral administration.

8. The pharmaceutical composition according to any one of claims 1-7 for

treatment of a respiratory disorder in a subject, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

9. A method of treating a respiratory disorder in a subject, said method comprising administering to the subject the pharmaceutical composition according to any one of claims 1-7, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

10. Use of revamilast or its pharmaceutically acceptable salt and the beta-2 agonist in the preparation of the pharmaceutical composition according to any one of claims 1-7 for treatment of a respiratory disorder in a subject, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

1 1. A pharmaceutical composition for oral administration comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about O. lmg to about 16mg of salbutamol or its pharmaceutically acceptable salt.

12. The pharmaceutical composition according to claim 1 1, wherein the

13. The pharmaceutical composition according to any one of claims 1 1-12,

wherein the composition comprises revamilast or its pharmaceutically acceptable salt and salbutamol or its pharmaceutically acceptable salt at a weight ratio ranging from about 0.1 : 16 to about 30:0.1.

14. The pharmaceutical composition according to any one of claims 1 1-12,

wherein the composition contains revamilast or its pharmaceutically acceptable salt and salbutamol at a weight ratio ranging from about 1 : 16 to about 20:0.1.

15. The pharmaceutical composition according to any one of claims 1 1-14,

wherein the composition is a fixed dose combination formulation.

16. The pharmaceutical composition according to any one of claims 11-15, for treatment of a respiratory disorder in a subject, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

17. A method of treating a respiratory disorder in a subject, said method

comprising administering to the subject the pharmaceutical composition according to any one of claims 1 1-15, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

18. The method according to claim 17, wherein the respiratory disorder is asthma, COPD, or exercise-induced bronchospasm.

19. A pharmaceutical composition for oral administration comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 0.2 mg to about 6 mg of levosalbutamol or its pharmaceutically acceptable salt.

20. The pharmaceutical composition according to claim 19, wherein the

21. The pharmaceutical composition according to any one of claims 19-20,

wherein the composition contains revamilast or its pharmaceutically acceptable salt and levosalbutamol or its pharmaceutically acceptable salt at a weight ratio ranging from 0.1 :6 to about 15:0.1.

22. The pharmaceutical composition according to any one of claims 19-20,

wherein the composition comprises revamilast or its pharmaceutically acceptable salt and levosalbutamol at a weight ratio ranging from about 1 :6 to about 10:0.1.

23. The pharmaceutical composition according to any one of claims 19-22,

wherein the composition is a fixed dose combination formulation.

24. The pharmaceutical composition according to any one of claims 19-23, for treatment of a respiratory disorder in a subject, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

25. A method of treating a respiratory disorder in a subject, said method

comprising administering to the subject the pharmaceutical composition according to any one of claims 19-23, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

26. The method according to claim 25, wherein the respiratory disorder is asthma, or bronchospasm.

27. A pharmaceutical composition for oral administration comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 10 mg to about 20 mg of bambuterol or its pharmaceutically acceptable salt.

28. The pharmaceutical composition according to claim 27, wherein the

29. The pharmaceutical composition according to any one of claims 27-28,

wherein the composition contains revamilast or its pharmaceutically acceptable salt and bambuterol or its pharmaceutically acceptable salt at a weight ratio ranging from 0.1 :20 to about 3: 1.

30. The pharmaceutical composition according to any one of claims 27-28,

wherein composition contains revamilast or its pharmaceutically acceptable salt and bambuterol at a weight ratio ranging from about 1 : 20 to about 2: 1.

31. The pharmaceutical composition according to any one of claims 27-30,

wherein composition is a fixed dose combination formulation.

32. The pharmaceutical composition according to any one of claims 27-31, for treatment of a respiratory disorder in a subject, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

33. A method of treating a respiratory disorder in a subject, said method

comprising administering to the subject the pharmaceutical composition according to any one of claims 27-31, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

34. The method according to claim 33, wherein the respiratory disorder is asthma, COPD, or bronchospasm.

35. A pharmaceutical composition comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 20μg to about 500μg of salmeterol or its pharmaceutically acceptable salt.

36. The pharmaceutical composition according to claim 35, wherein the

37. The pharmaceutical composition according to any one of claims 35-36,

wherein the composition comprises revamilast or its pharmaceutically acceptable salt and salmeterol or its pharmaceutically acceptable salt at a weight ratio ranging from 1 : 1 to about 6:0.01.

38. The pharmaceutical composition according to any one of claims 35-36,

wherein the composition comprises revamilast or its pharmaceutically acceptable salt and salmeterol at a weight ratio ranging from about 1 :0.1 to about 4:0.01.

39. The pharmaceutical composition according to any one of claims 35-38,

wherein the composition is in the form of a kit containing a unit dose oral formulation comprising revamilast or its pharmaceutically acceptable salt and another inhalation formulation comprising salmeterol or its pharmaceutically acceptable salt.

40. The pharmaceutical composition according to any one of claims 35-39, for treatment of a respiratory disorder in a subject, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

41. A method of treating a respiratory disorder in a subject, said method

comprising administering to the subject the pharmaceutical composition according to any one of claims 35-39, wherein the composition exhibits synergy for the treatment of the respiratory disorder.

42. The method according to claim 41, wherein the respiratory disorder is asthma, bronchospasm associated with COPD, or exercise-induced bronchospasm.