CLIAMS:1. A pharmaceutical composition comprising combination of roflumilast and acebrophylline or salts thereof.

2. The pharmaceutical composition of claim 1, wherein roflumilast or salts thereof is present in the amount ranging from about 0.1 mg to 10 mg.

3. The pharmaceutical composition of claim 1, wherein acebrophylline or salts thereof is present in the amount ranging from about 50 mg to 1000 mg.

4. The pharmaceutical composition of claim 1, wherein the ratio of the amount of roflumilast or salts thereof to acebrophylline or salts thereof ranges from about 0.0002:1 to about 0.2:1.

5. The pharmaceutical composition of claim 1, wherein the composition is in the form of a solid oral unit dosage form.

6. The pharmaceutical composition of claim 1, wherein the composition is in the form of a bilayer tablet, which comprises of a layer of roflumilast or salts thereof and another layer of acebrophylline or salts thereof.

7. The pharmaceutical composition of claim 1, characterized in that said composition comprises roflumilast or salts thereof having average particle size in the range of 1 to 50 μm.

8. A method of treating COPD and related disorders in a patient in need thereof, which method comprises of administering a pharmaceutical composition of claim 1.

9. Use of pharmaceutical composition comprising combination of roflumilast and acebrophylline or salts thereof for manufacture of medicament for treatment of COPD and related disorders.
,TagSPECI:DESCRIPTION

The present invention relates to pharmaceutical compositions comprising novel combination of roflumilast and acebrophylline. In particular, the present invention relates to pharmaceutical compositions comprising roflumilast or salts thereof and acebrophylline or salts thereof and its use in treating chronic obstructive pulmonary disorder (COPD) and related disorders.

COPD is characterized by a progressive limitation of the airflow in the lungs. In North America, between three- and seven-million people are diagnosed with COPD each year, and this disease is presently the fourth leading cause of death in developed countries.

Roflumilast is an oral PDE4 inhibitor approved for reduction of exacerbations and improvement of lung function in COPD patients. It is a selective anti-inflammatory agent and PDE-4 enzyme inhibitor. Phosphodiesterase 4 (PDE-4) inhibitors produce airway smooth muscle relaxation by preventing the breakdown of adenosine cyclic 3',5'-monophosphate (cAMP). Phosphodiesterases enable cyclic adenosine monophosphate (cAMP), which are intracellular secondary molecules, to be inactivated through decomposition. Selective inhibition of PDE-4 induces anti-inflammatory effect by causing inhibition of proinflammatory mediators as well as bronchodilation with an increase in cAMP level; and also increasing release of anti-inflammatory mediators.

Roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy)benzamide. It is a white to off-white, non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and hexane, sparingly soluble in ethanol and freely soluble in acetone. Its empirical formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22 and represented by the following formula:

Roflumilast is commercially available under the trade name of Daxas®. It is approved in the Europe for severe COPD associated with chronic bronchitis and in US for reducing COPD exacerbations. The recommended dose is one tablet of 500 micrograms roflumilast daily.

According to the clinical data, addition of roflumilast to a Long-Acting Beta-adrenoceptor Agonist (LABA) inhibits primary fibroblast/myofibroblast function and therapeutically this may impact lung fibroblast proinflammatory and profibrotic mediator release that contributes to small airway remodeling and airway obstruction in COPD, so it may be advantageous to administer roflumilast together with another active ingredient. Such another active ingredient might be of the same or different therapeutic class and may act in synergistic way with roflumilast. Moreover, the administration of two drugs in single dosage form is most preferred dosage form due to ease of administration.

Use of combination therapies for treating COPD are known. For example, the combination of leukotriene type D4 (LTD4) antagonists with PDE-4 inhibitors is disclosed in PCT application No. WO 02/038155 and WO 03/024488. Also, combination therapies involving the use of corticosteroids with PDE4 inhibitors for COPD are disclosed in PCT application No. WO 01/32127, WO 04/067006, WO 01/19373 and WO 98/41232.

Acebrophylline belongs to category of drugs primarily affecting the respiratory system. It is a type of alkaloid and has 3 actions namely bronchodilation, mucoregulation & anti-inflammatory action. Acebrophylline inhibits phospholipase A and phosphatidylcholine, leading to lesser production of the powerful pro-inflammatory substances like leukotrienes and tumor necrosis factor. By inhibiting the synthesis and release of these inflammatory mediators, acebrophylline reduces inflammation, a key factor in airway obstruction, especially in chronic forms. It is manufactured by Molcan Corporation in Canada and is available as Ambroxol®.

Acebrophylline having the chemical name 1,2,3,6-Tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid with trans-4-[[(2-Amino-3,5-dibromophenyl)methyl] amino]cyclohexanol and is represented by the following formula

PCT application No. WO 2013/081565 discloses pharmaceutical composition comprising roflumilast and terbutaline. The composition as mentioned in the application is indicated in the prevention and/or treatment of allergic and inflammatory diseases of upper and lower respiratory tract or skin.

PCT application number WO 2013/077830 discloses pharmaceutical combination compositions of roflumilast and carmoterol. It further provides a pharmaceutical composition used in prevention and/or treatment of allergic and inflammatory diseases of skin and upper and lower respiratory tracts.

PCT application number WO 2003/024488 discloses pharmaceutical combinations comprising the PDE-4 inhibitor roflumilast and a leukotriene receptor antagonist selected from atreleuton, acitazanolast, zileuton, zafirlukast, pranlukast, and montelukast. The combinations are used for the manufacture of medicaments for treating respiratory tract disorders, such as asthma.

US Patent No. 6,288,118 discloses treatment of pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase-4 inhibitor with a beta-adrenergic bronchodilator.

US Patent Application No. 2007/0167496 discloses the pharmaceutical formulations containing combinations of roflumilast and a pharmaceutically acceptable salt of glycopyrronium and use of such pharmaceutical compositions in the prophylaxis and treatment of respiratory disease.

However, there still exists a need to find better options for treating COPD and that may eliminate or reduce side effects that are associated with current combination compositions.

The combined use of roflumilast and acebrophylline in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.

In one general aspect, there is provided a composition comprising combination of roflumilast and acebrophylline or salts thereof.

In another general aspect, there is provided a composition comprising combination of roflumilast and acebrophylline or salts thereof and one or more pharmaceutical excipients.

In another general aspect, there is provided an oral pharmaceutical composition comprising roflumilast and acebrophylline or salts thereof.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising roflumilast and acebrophylline or salts thereof.

In another general aspect, there is provided a pharmaceutical composition comprising distinct components of roflumilast and acebrophylline or salts thereof.

In another general aspect, there is provided a pharmaceutical composition comprising two different components wherein roflumilast or salts thereof and acebrophylline or salts thereof are present separately in each component.

However, due to the low dose of roflumilast there is a potential for content uniformity issues of the composition. Therefore to overcome the problem of content uniformity of roflumilast in the solid oral composition, according to present invention particles having average size ranging from about 1 μm to 50 μm can be used.

In another general aspect, there is provided a pharmaceutical composition comprising combination of roflumilast or salts thereof in amount ranging from about 0.1 mg to 10 mg and acebrophylline or salts thereof in amount ranging from about 50 mg to 1000 mg.

In another general aspect, the amount of roflumilast present in the one component may ranges from about 0.01 to 10% of the total weight of the composition and the amount of acebrophylline present in another component may ranges from about 5 to 50 % of the total weight of the composition.

In another general aspect, there is provided a pharmaceutical composition; wherein the ratio of the amount of roflumilast to acebrophylline or salts thereof ranges from about 0.0002:1 to about 0.2:1.

The pharmaceutical compositions of the present invention may be prepared in any solid oral form such as tablet; layered tablet (for instance double layer tablet); capsule; enterically coated or modified release tablets; controlled release tablet; prolonged release tablet; delayed release tablet; slow or fast release tablet; fast soluble tablet; fast soluble powder mixture; water soluble powder, tablet, or granule; granule; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule or dry powder mixture to prepare syrup; film coated tablet or a combination thereof.

The pharmaceutical compositions of the present invention may also be prepared in dosage form suitable for topical administration, such dosage forms includes nasal spray and dry powder or pressurized liquid (aerosol) composition for inhalation.

In another general aspect, there is provided a bilayer tablet composition comprising a layer of roflumilast or salts thereof and another layer acebrophylline or salts thereof.

In another general aspect, there is provided a bilayer tablet comprising a layer which comprises of roflumilast or salts thereof, and optionally pharmaceutically acceptable excipients and another layer which comprises of acebrophylline or salts thereof, and optionally pharmaceutically acceptable excipients.

The low dose of roflumilast or salts thereof used in the composition may pose problems of content uniformity of the solid oral dosage forms. Therefore it is important to select particles having average size ranging from about 1 μm to 50 μm.

In another general aspect, the pharmaceutical composition comprising combination of roflumilast and acebrophylline or salts thereof which composition retains at least 90% by weight of the total content of roflumilast or salts thereof and acebrophylline or salts thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In another general aspect, there is provided use of a pharmaceutical composition comprising combination of roflumilast and acebrophylline or salts thereof for manufacture of medicament for treatment of COPD and related disorders.

In another general aspect, there is provided a method of treating COPD and related disorders which method comprises of administering the pharmaceutical composition comprising combination of roflumilast and acebrophylline or salts thereof.

The active agents comprised in the pharmaceutical compositions of the present invention can be administered simultaneously, sequentially or separately as prepared in different dosage forms; though, they can also be administered as combined in a single dosage form.

Another characteristic feature of the pharmaceutical compositions according to the present invention is that they are prepared by formulating the active agents together with at least one pharmaceutically acceptable excipient and combining them in a single dosage form.

In an embodiment, the pharmaceutical composition in accordance with the present invention comprises combination of roflumilast and acebrophylline or salts thereof, optionally with one or more pharmaceutically acceptable excipients.

The inventors of the present invention have surprisingly found that roflumilast and acebrophylline combination may act synergistically and thus benefit in treatment of COPD related disorders.

The term “roflumilast” and “acebrophylline” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

Suitable pharmacologically acceptable salts of roflumilast are in particular water-soluble and water -insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired -in an equimolar quantitative ratio or one differing therefrom.

The term “component” as used throughout the specification refers to one or more tablets, mini-tablets, powder blend, granules, pellets, beads, solid particles, layers coated on a surface including layers or coating in the tablet (e.g. bilayer tablet) or combination thereof.

The term ‘combination’ as used throughout the specification refers to a single dosage form comprising roflumilast and acebrophylline together. The term also encompasses kit comprising separate dosage forms of roflumilast and acebrophylline which are intended to be administered together, simultaneously or sequentially for the purpose of prophylaxis or treatment.

Alternatively, the pharmaceutical compositions of the present invention may also be prepared in dosage form suitable for topical administration, such dosage forms includes nasal spray and dry powder or pressurized liquid (aerosol) composition for inhalation.

The combination of roflumilast and acebrophylline in the pharmaceutical composition may be provided in the form of two or more separate components.

In an embodiment, the composition comprises a component comprising roflumilast or salts thereof and another component comprising acebrophylline or salts thereof.

The dose of each of roflumilast and acebrophylline in the combination composition in accordance with the present invention may be selected based on particular patient need, however, particularly preferred dose of roflumilast and acebrophylline or salts in the composition ranges from about 0.1 mg to 10 mg and about 50 mg to 1000 mg respectively.

In another embodiment, the composition comprises about 0.5 mg of roflumilast or salt thereof and about 200 mg of acebrophylline or salt thereof.

In a further embodiment, the amount of roflumilast present in the composition ranges from about 0.01 to 10% of the total weight of the composition, and the amount of acebrophylline present in the composition may ranges from about 5 to 50 % of the total weight of the composition.

In a further embodiment, the ratio of the amount of roflumilast or salts thereof to acebrophylline or salts thereof in the composition ranges from about 0.0002:1 to 0.2:1.

The pharmaceutical composition of the present invention can be produced by one of the methods of wet granulation, dry granulation, dry blending. In the pharmaceutical compositions of the present invention, the active agents can be formulated separately according to any production methods in the prior art; though, they can also be formulated together by using the same production method.

The compositions according to the present invention can optionally be formulated so as to provide release types such as fast, slow, delayed, prolonged, controlled release.

In another embodiment, the pharmaceutical compositions of the present invention may be prepared in the form of a tablet; layered tablet (for instance double layer tablet); capsule; enterically coated or modified release tablets; controlled release tablet; prolonged release tablet; delayed release tablet; slow or fast release tablet; fast soluble tablet; fast soluble powder mixture; water soluble powder, tablet, or granule; granule; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule or dry powder mixture to prepare syrup; film coated tablet or a combination thereof.

The pharmaceutical compositions comprising roflumilast and acebrophylline can be comprised together in any abovementioned oral dosage forms.

A characteristic feature of the synergistically effective composition of the present invention is that said composition is prepared in oral dosage form. A characteristic feature of the synergistically effective composition of the present invention is that said composition is prepared in solid oral dosage form.

In another embodiment, the pharmaceutical composition in accordance with the present invention is provided in the form of a bilayer tablet which comprises of a layer comprising roflumilast, optionally in combination with pharmaceutical excipients and another layer comprising acebrophylline or salts thereof, optionally in combination with pharmaceutical excipients.

The composition of the present invention may exhibit excellent storage stability, in that, the pharmaceutical composition retains at least 90% by weight of the total content of roflumilast or salts thereof and acebrophylline or salts thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In another embodiment, there is provided a method of treating COPD related disorders in a patient in need thereof, which method comprises of administering the solid oral composition of roflumilast or salt thereof and acebrophylline or salts thereof in accordance with the present invention.

The active agents comprised in the pharmaceutical compositions of the present invention can be administered simultaneously, sequentially or separately as prepared in different dosage forms; though, they can also be administered as combined in a single dosage form.

Pharmaceutical excipients that can be used in the pharmaceutical composition of the present invention can be selected from a group comprising binders, disintegrants, alkalizer, viscosity enhancing agents, filling agents, drying agents, surfactants, cosolvents, stabilizing agents, lubricants, diluents, glidants, wetting agents, coating agents, anti-adhesive agents, pH regulators, flavouring agent, sweeteners, emulgators, antifoaming agents, antioxidants, protective agents, solvents or solvent combinations, colouring agents and complexing agents or the combinations thereof.

The disintegrants that can be used in the pharmaceutical compositions according to the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or the combinations thereof.

The diluents that can be used in the pharmaceutical compositions according to the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives ( for instance corn starch), sodium chloride, sucrose, talc, xylitol or the combinations thereof.

The lubricants that can be used in the pharmaceutical compositions according to the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.

The glidants that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc and the like or combinations thereof.

When a diluent is present in the composition, preferred diluents include micro crystalline cellulose, starch and lactose monohydrate. Such diluents may suitably be present in an amount from 4 to 80% within one layer of total composition or second layer of total composition or may present within both layer of composition.

When binder is present in the composition, preferred binder may be selected from Hydroxy propyl cellulose, hydroxyl propyl methyl cellulose, hydroxyl ethyl cellulose, sodium lauryl sulphate and pre- gelatinized starch. When a disintegrant is present in the composition, preferred disintegrants may be maize starch, cross carmellose sodium. Such disintegrants may suitably be present in an amount from 0.2 to 4% of the total mass of the composition.

When a lubricant is present in the composition, a preferred lubricant is magnesium stearate. Such lubricants may suitably be present in an amount of from 0.1 to 0.6% of the total mass of the composition.

When a glidant is present in the composition, a preferred glidant is magnesium stearate. Such glidant may suitably be present in an amount of from 0.1 to 0.4% of the total mass of the composition.

The present invention relates to the pharmaceutical composition of a bi-layer tablet suitable for oral administration. Each tablet is preferably made up of immediate release layer and extended release layer. The immediate release layer may comprise a compressed blend of an active agent, such as roflumilast and one or more polymers with some diluent and alkalizer. The extended release layer may comprise hydrophilic or hydrophobic polymers such as hydroxypropylmethyl cellulose within which an active ingredient, such as acebrophylline is suitably blended and this allows prolonged release of active substance within the second layer.

The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Bilayer tablet of Roflumilast and Acebrophylline
Table 1
Sr. No Ingredient Qty/Tab (mg)
ROFLUMILAST IMMEDIATE RELEASE LAYER
Mixing & Blending
1. Lactose monohydrate 89.05
2. Maize starch 30.00
3. Cross carmellose sodium 3.00
4. Tris buffer 15.00
Binder
5. Roflumilast 0.50
6. Hydroxy propyl cellulose 3.00
7. Sodium lauryl sulphate 5.00
8. Purified water q.s
9. Acetone q.s
Lubrication
10. Iron oxide yellow 0.20
11. Colloidal silicone dioxide 0.75
12. Cross carmellose sodium 3.00
13. Magnesium stearate 0.50
Weight of Roflumilast Layer 150.00
ACEBROPHYLLINE EXTENDED RELEASE LAYER
Intragranular
14. Acebrophylline 200.00
15. Lactose monohydrate 136.00
16. Hydroxy propyl methyl cellulose (Hypromellose K100M) 30.00
17. Hydroxy propyl methyl cellulose (Hypromellose K4M) 10.00
Binder
18. Sodium Lauryl sulphate 4.00
19. Hydroxy propyl cellulose 8.00
20. Purified water q.s
Extragranular
21. Microcrystalline cellulose 30.00
22. Magnesium stearate 2.00
Weight of Acebrophylline Layer 400.00
Total 550.00 mg

Procedure:
Preparation of roflumilast layer: Lactose monohydrate, maize starch and cross carmellose sodium were mixed uniformly and sieved to form a homogenous powder blend. Sodium lauryl sulphate, hydroxy propyl cellulose and roflumilast were dissolved in acetone: water mixture. The homogenous powder blend was granulated with binder solution thus prepared and formed granules were dried in fluidized bed dryer. Iron oxide yellow and magnesium stearate were mixed with dried granules.
Preparation of acebrophylline layer: Acebrophylline, lactose monohydrate, hydroxy propyl methyl cellulose (hypromellose K100M) and hydroxy propyl methyl cellulose (hypromellose K4M) mixed uniformly and sieved to form a homogenous powder blend. Hydroxy propyl cellulose was dispersed in purified water and this dispersion was used to granulate the homogenous powder blend of acebrophylline. Further the granules were dried in fluidized bed dryer and mixed with microcrystalline cellulose as extragranular part. Magnesium Stearate was used to lubricate the granules.
Finally, roflumilast blend & acebrophylline blends were mixed and compressed on compression machine.