Field of the Invention

The present invention provides for pharmaceutical compositions comprising novel combination of roflumilast and acebrophylline. By using such combination composition, treatment of chronic obstructive pulmonary disorder (COPD) and related disorders may be possible. The present invention also provides methods of preparing such combination compositions of roflumilast and acebrophylline or pharmaceutically acceptable salts thereof. The present invention further provides the methods of treating inflammatory diseases or disorders using such combination compositions.

Background of the Invention

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 and acebrophylline or pharmaceutically acceptable salts thereof. The present invention also provides methods of preparing such combination compositions and methods of treating inflammatory diseases or disorders using such combination compositions.

Chronic obstructive pulmonary disorder (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-(diflu oro 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 C17H14C12F2N2O ₃ 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 D ₄ (LTD ₄ ) 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 Publication 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 & antiinflammatory 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 l,2,3,6-Tetrahydro-l,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

The solubility of active ingredients of the PDE 4 inhibitor class in water and aqueous systems may, depending on the chemical structure. Thus, the solubility in water found for the PDE 4 inhibitor roflumilast, which is described in PCT publication number W0 1995/01338, is just 0.53 mg/I at 21°C. It is a known fact that the bioavailability of a medicinal substance depends basically on the release of the medicinal substance from the pharmaceutical dosage form. Also, faster release and dissolution of the medicinal substance from the formulation means faster absorption thereof. Hence with medicinal substances, which are slightly soluble in water, the bioavailability is frequently limited by the solubility or rate of dissolution. This makes it very difficult to produce suitable dosage forms that can exhibit desired release and therapeutic response.

Roflumilast is currently available as immediate release formulation whereas acebrophylline is available as both immediate and extended release formulations. Roflumilast is designated as BCS class II drug having poor solubility and high permeability which is also a weak acid having pKa of 8.74 with pH dependent solubility. On the other hand, acebrophylline is categorized as BCS class I drug having high solubility and high permeability and this high solubility of acebrophylline may lead to difficulty in providing a slow release rate from a formulation, particularly in combination therapy with active ingredient having different solubility profile.

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

PCT Publication 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 Publication 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.

US Patent No. 6,372,255 discloses multi-layer tablet for the instant and prolonged release of active substances comprising at least two layers where the first outer layer comprises a mixture of excipients and an active substance, allowing for the immediate release of the active substance of the first layer, and a second layer, comprising same active substance as that of first layer, is arranged in contact with the first layer.

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 of roflumilast with other drugs and acebrophylline with other drugs.

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.

Summary of the Invention

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

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

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

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

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

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.

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 μπι to 50 μπι can be used.

In another general aspect, there is provided a pharmaceutical composition comprising combination of roflumilast or pharmaceutically acceptable salts thereofin 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 pharmaceutically acceptable salts thereof ranges from about 0.0002: 1 to about 0.2: 1.

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 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.

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 dual 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.

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.

With a view to counteract the contrasting solubility of the roflumilast and acebrophylline, it remain challenging to provide a combination formulation which exhibits release of both the actives in a manner that can provide desired therapeutic response of the two drug combination.

The inventors of the present invention have surprisingly found that, this object can be achieved by providing a dual release composition comprising roflumilast and acebrophylline or pharmaceutically acceptable salts thereof. In particular, the composition exhibits immediate release of roflumilast or pharmaceutically acceptable salts thereof and extended release of acebrophylline or pharmaceutically acceptable salts thereof.

Roflumilast has low solubility and by employing an alkalizer to impart alkaline environment to the dosage form may enhance the solubility of roflumilast.

The composition of the present invention provides synergistic effect in the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease and also resolves the inherent disadvantages for a combination of the said drugs with other drugs in a conventional formulation.

In another general aspect, there is provided a pharmaceutical composition comprising roflumilast and acebrophylline or pharmaceutically acceptable salts thereof, wherein the composition exhibits immediate release of roflumilast or salt thereof and extended release of acebrophylline or salt thereof.

In another general aspect, the pharmaceutical composition comprises separate components of roflumilast and acebrophylline or pharmaceutically acceptable salts thereof, each exhibiting different release profile, preferably the composition exhibits dual release profile.

In another general aspect, there is provided a pharmaceutical composition comprising one or more components exhibiting immediate release of roflumilast or pharmaceutically acceptable salts thereof and one or more components exhibiting extended release of acebrophylline or pharmaceutically acceptable salts thereof.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising roflumilast and acebrophylline or salts thereof, wherein the composition exhibits immediate release of roflumilast or pharmaceutically acceptable salts thereof and extended release of acebrophylline or pharmaceutically acceptable salts thereof.

In another general aspect, there is provided a pharmaceutical composition comprising roflumilast, acebrophylline or pharmaceutically acceptable salts thereofand an alkalizer, wherein the composition exhibits immediate release of roflumilast or pharmaceutically acceptable salts thereof and extended release of acebrophylline or pharmaceutically acceptable salts thereof.

In another general aspect, the component comprising roflumilast or pharmaceutically acceptable salts thereofexhibits pH 10 or above.

In another general aspect, there is provided a pharmaceutical composition comprising one or more components comprising roflumilast or pharmaceutically acceptable salts thereofand one or more alkalizers, and one or more components of acebrophylline or salts thereof. In another general aspect, the pharmaceutical composition comprises alkalizer in an amount from about 0.5 to 20 % by weight of the composition. The amount of alkalizer may be about 5 to 30 % by weight of the component comprising roflumilast.

In another general aspect, the release of roflumilast or pharmaceutically acceptable salts thereof and acebrophylline or salts thereof from the composition takes place simultaneously or sequentially.

In another general aspect, the release of roflumilast from the composition starts before the release of acebrophylline begins.

In another general aspect, the component of the composition comprising roflumilast may be formed by dissolving roflumilast or pharmaceutically acceptable salts thereof in suitable solvents, preferably acetone, and adsorbing the solution onto lactose. Such specific component of roflumilast may improve its release from the composition.

In another general aspect, the component of the composition comprising roflumilast formed by dissolving roflumilast or pharmaceutically acceptable salts thereof in suitable solvents, preferably acetone, and adsorbing the solution onto lactose enhance its content uniformity in the composition.

In another general aspect, there is provided a bilayer tablet comprising roflumilast and acebrophylline or salts thereof, wherein the first layer of the composition exhibits immediate release of roflumilast or pharmaceutically acceptable salts thereof and the second layer of as the composition exhibits extended release of acebrophylline or pharmaceutically acceptable salts thereof.

Upon administration of the pharmaceutical composition of the present invention, it is preferred that the release of roflumilast begins within a short time, for example in less than about 30 minutes, preferably less than about 15 minutes and most preferably in less than about 5 minutes after administration. Release of the acebrophylline is delayed relative to the roflumilast, and may also be extended to take place over a longer time scale relative to that of roflumilast.

In another general aspect, there is provided a pharmaceutical composition comprising roflumilast and acebrophylline or pharmaceutically acceptable salts thereof, wherein the composition exhibits immediate release of roflumilast or pharmaceutically acceptable salts thereof and extended release of acebrophylline or pharmaceutically acceptable salts thereof, characterized in that the amount of roflumilast or pharmaceutically acceptable salts thereof ranges from about 0.1 mg to 10 mg and amount of acebrophylline or pharmaceutically acceptable salts thereof ranges from about 50 mg to 1000 mg.

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 may be formulated so as to provide release types such as immediate, delayed, prolonged or controlled release.

Accordingly, the invention provides a pharmaceutical preparation tablet form comprising two or more active ingredients with pre-determined release profiles, at least one active ingredient having a release profile that differs substantially from the release profile of the other active ingredient.

Preferred pharmaceutical composition of the invention provide immediate release of roflumilast by using a alkalizer in an effective manner in a one layer; use a combination of two specific hydroxypropyl methyl cellulose polymers in a second layer to aid effective release of the drug over a specific period of time independent of pH affects; provide a two drug combination therapy having a synergistic effect over the control of inflammatory conditions of the lungs such as asthma and chronic obstructive pulmonary disease; allow reduced frequency of drug dosing and hence improve patient compliance; maintain a steady drug concentration in the blood circulation with the help of a extended release layer; and minimize incidence and severity of adverse side effects.

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 pharmaceutically acceptable salts thereofand acebrophylline or pharmaceutically acceptable salts thereofwhen 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 pharmaceutically acceptable salts thereoffor 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 pharmaceutically acceptable salts thereof.

Detailed Description of the Invention

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 pharmaceutically 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 l-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 "dual release" as used herein means release of the active ingredient from the composition, which is the combination of immediate release and release selected from controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release.

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.

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

In an embodiment, the combination composition of roflumilast and acebrophyUine or salts thereof comprises two components in a single dosage form providing dual release of roflumilast and acebrophyUine or salts thereof.

In another embodiment, the combination composition of roflumilast and acebrophyUine or salts thereof comprises two components; wherein first component comprises roflumilast or salts thereof and one or more pharmaceutically acceptable excipients and component comprises acebrophyUine or salts thereof and one or more pharmaceutically acceptable excipients.

The solubility of roflumilast in the composition can be improved by adjusting the formulation pH above 10 by using suitable alkalizer. Further, its solubility can also be improved by dissolving roflumilast in suitable solvents.

The composition comprising roflumilast or pharmaceutically acceptable salts thereof and acebrophyUine or salts thereof is present in the form of soUd oral dosage form. Preferably, in the form of a tablet, in particular the tablet is a bUayered tablet.

Upon administration of the pharmaceutical composition of the present invention, it is preferred that the release of roflum ast begins within a short time, for example in less than about 30 minutes, preferably less than about 15 minutes and most preferably in less than about 5 minutes after administration. Release of the acebrophylUne is delayed relative to the roflumilast, and may also be extended to take place over a longer time scale relative to that of roflumUast.

In an embodiment, the composition comprises one or more alkalizers. Preferably, the component comprising roflumilast comprises alkalizer. Alkalizer may be suitably present in an amount from 2 to 20 % of the total weight of the said composition and 5 to 30 % of the weight of roflumilast component.

The first component of the composition of present invention comprises roflumilast or pharmaceutically acceptable salts thereof and may suitably present in an amount ranging from 0.01 to 10% of the total weight of said composition. The second component of the composition may contain the amount of acebrophyUine or pharmaceutically acceptable salts thereof in the range from 5 to 50 % of the total weight of the composition.

The dose of each of roflumilast and acebrophyUine 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 acebrophyUine or pharmaceuticaUy acceptable salts thereof in the composition ranges from about 0.1 mg to 10 mg and about 50 mg to 1000 mg respectively.

In another embodiment, the ratio of the amount of roflumilast or pharmaceutically acceptable salts thereof to acebrophyUine or salts thereof in the composition ranges from about 0.0002: 1 to 0.2: 1.

In another embodiment, the composition comprises about 0.5 mg of roflumilast or pharmaceuticaUy acceptable salts thereof and about 200 mg of acebrophyUine or salt thereof.

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 optionaUy be formulated so as to provide release types such as fast, slow, delayed, prolonged, controlled release. 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 pharmaceutically acceptable 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 pharmaceutically acceptable salts thereof and acebrophylline or pharmaceutically acceptable 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 pharmaceutically acceptable salts thereofand acebrophylline or pharmaceutically acceptable 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.

The pharmaceutical composition according to the present invention was designed to provide an alkaline environment for active compound such as roflumilast for increasing its solubility. The alkalizer is used to create an alkaline microenvironment in the composition to optimize drug release.

The alkalizers of the compositions described herein are capable of raising the pH of the environment for roflumilast compounds in the one layer. In one embodiment, the alkalizers of the compositions described herein are capable of raising the pH of the environment in the composition to typically above pH 10, irrespective of the starting pH of active ingredient.

Suitable alkalizers include, but are not limited to, organic and inorganic basic compounds of a wide range of aqueous solubilities and molecular weights and the like and mixtures thereof. Representative examples of inorganic basic salts include ammonium hydroxide, alkali metal salts, alkaline earth metal salts such as magnesium oxide, magnesium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, aluminum hydroxide, potassium carbonate, sodium bicarbonate and the like and mixtures thereof.

The excipients that can be used in 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.

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

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.