WO2013081565A1

WO2013081565A1 - Pharmaceutical compositions comprising roflumilast and terbutaline

Info

Publication number: WO2013081565A1
Application number: PCT/TR2012/000198
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-11-21
Filing date: 2012-11-19
Publication date: 2013-06-06

Abstract

The present invention relates to combined use of roflumilast, which is a selective phosphodiesterase-4 (PDE-4) enzyme inhibitor, and terbutaline, which is a β2adrenergic receptor agonist; and to drug compositions comprising this pharmaceutical combination that can be used in the allergic and inflammatory diseases of skin or upper and lower respiratory tracts.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ROFLUMILAST AND TERBUTALINE

The present invention relates to combined use of roflumilast, which is a selective phosphodiesterase-4 (PDE-4) enzyme inhibitor, and terbutaline, which is a p₂-adrenergic receptor agonist; and to pharmaceutical compositions comprising this combination and to the fields of use thereof.

Besides, the present invention provides an effective pharmaceutical composition indicated in the prevention and/or treatment of allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise-induced asthma, acute bronchospasm, bronchial asthma, chronic bronchitis, allergic bronchitis, chronic obstructive pulmonary disease (COPD), asthma and bronchospasm prophylaxis; and in removal of symptoms associated with these diseases.

Roflumilast (Daxas®) is a selective anti-inflammatory, chemical name of which is 3- (cyclopropylmethoxy)-N-(3,5-dichloropyridine-4-yl)-4-(diflouromethoxy)benzamide (Formula I).

Formula (I)

Roflumilast is a selective phosphodiesterase-4 (PDE-4) enzyme inhibitor. 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 broncodilation with an increase in cAMP level; and also increasing release of anti-inflammatory mediators. Roflumilast is a PDE-4 enzyme inhibitor used by the oral route. Roflumilast was firstly described in the patent numbered WO 95/01338. Said patent comprises processes for preparation of roflumilast; pharmaceutical compositions comprising roflumilast; and use of roflumilast in the prevention and/or treatment of allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise-induced asthma.

Terbutaline (Bricanyl®) is a

receptor agonist, chemical name of which is (i?S-5-[2-(tert)-butylamino)-l-hydroxyethyl] benzene- 1, 3 -diol (Formula II).

Formula (II)

Terbutaline is a synthetic sympathomimetic agent which basically acts as a ₂-agonist. Terbutaline is an adrenergic agonist which provides relaxation of bronchial smooth muscles basically by stimulating p₂-receptors; inhibition of endogenous spasmogenic secretion; inhibition of edema caused by endogenous mediators; increase in mucociliary clearance; and relaxation of uterus muscle.

Terbutaline was firstly described in the patent numbered BE 704932. Said patent comprises processes for preparation of terbutaline; pharmaceutical compositions comprising terbutaline; and use of terbutaline in the treatment of lung diseases such as bronchial asthma, chronic bronchitis, acute bronchospasm, asthma, bronchospasm prophylaxis and chronic obstructive pulmonary disease.

Generally, allergens may cause allergic reactions when they contact with skin or eyes, when they are inhaled, eaten, drunk or injected. Allergic reaction may also occur as a part of seasonal allergy as a result of periodic exposure to such kind of substances.

Many allergic reactions are characterized by symptoms such as streaming, itching and reddening of the eyes (allergic conjunctivitis); nasal flow, itching and blockage (allergic rhinitis); allergic sinusitis in sinuses; itching, reddening and eruption of the skin (urticaria); nuisance, distension, vomiting and diarrhea in gastrointestinal system; feeling of blockage, ache, hearing disorders associated with dysfunction of Eustachian tube in ears; snooze, cough, bronchoconstriction, shortness of breath, sniffling, asthma attacks and constriction of respiratory tract associated with edema (angioedema) in respiratory tract. Allergies can also trigger asthma attacks. Asthma is a reversible airway constriction characterized in short breath and sniffle occurring as attacks. Asthma is one of the few chronic diseases most frequently seen in children and adults.

The studies conducted show that at least 38% of patients with allergic rhinitis also have asthma and at least 78% of patients with allergic asthma also have allergic rhinitis. When a respiratory function test was administered on patients without any findings of asthma, it was observed that bronchial hyperactivity was high.

Many studies have shown that an appropriate treatment of allergic rhinitis in patients with asthma results in relief in the symptoms of asthma, decrease in bronchial sensitivity, protection against bronchospasm and decrease in use of rescue drugs. When the prior art is considered, it was seen that there is a need for new pharmaceutical compositions which can be effective in the prevention and/or treatment of and in removal of symptoms associated with allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise- induced asthma, acute bronchospasm, bronchial asthma, chronic bronchitis, allergic bronchitis, chronic obstructive pulmonary disease (COPD), asthma and bronchospasm prophylaxis; and which can both prevent recurrence of these diseases and be used for removal of symptoms resulting from these diseases; which are more effective than separate use of each active agent and have fewer side effects. In an aspect, the present invention provides a treatment method comprising use of the combination of a ₂-adrenergic agonist inducing synergistic effect and a PDE-4 enzyme inhibitor in the prevention and/or treatment of allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise-induced asthma, acute bronchospasm, bronchial asthma, chronic s, allergic bronchitis, chronic obstructive pulmonary disease (COPD), asthma and ;pasm prophylaxis; and in removal of symptoms associated with these diseases. itions of the present invention can also be effective in the treatment of premature addition to given respiratory diseases. sent invention relates to combined use of a p₂-adrenergic agonist and a PDE-4 inhibitor. lgly, the inventors have discovered that an unexpected synergistic therapeutic is obtained with the combination therapy comprising roflumilast, which is a phosphodiesterase-4 (PDE-4) enzyme inhibitor, and terbutaline, which is a β₂- ic receptor agonist. ler aspect, the pharmaceutical combination comprising use of roflumilast and tie together or simultaneously shows a higher therapeutic benefit as compared to tions where these two agents are used separately. sr aspect, the required dose of active agent to obtain the desired therapeutic effect tarmaceutical compositions where roflumilast and terbutaline are used together or eously is less than the required dose amount in the separate use of terbutaline or ist only and reducing the unwanted side effects became possible this way. to prove this, the inventors have studied on the interaction between roflumilast and t e. The synergic interaction between roflumilast and terbutaline was investigated letized guinea pigs weighing approximately 500 g. The pigs were respired via an espiratory pump at a constant tidal volume and at a rate of 50 breaths/min. The stance was measured by a rodent lung function recording system. Roflumilast and ne compounds were given intravenously by using a catheter. After that, the pigs owed to be stabilized. The pigs were disconnected from the respirator and then amounts of drugs blended with lactose were administered intratracheally using a The trachea was reconnected to the respirator and changes in pulmonary cs were recorded. 10 minutes after this procedure 15 g/kg acetylcholine was ered. Acetylcholine (15 μg kg) was injected in every 10 minutes for 80 min. loline administered caused three to four-fold increase in the pulmonary resistance, een observed that both roflumilast and terbutaline inhibited the acetylcholine- induced bronchoconstriction dose-dependently. When roflumilast was administered at the dose of 1 μΒ kg, it did not inhibit the bronchospasm; thus it was not effective at this dose. However, when roflumilast was administered at the dose of 5 μg/kg and 10 μg/kg, it was observed that it inhibited the bronchospasm 50% and 85%, respectively. Similarly, terbutaline also did not inhibit the bronchospasm at the dose of 1 μg/kg. In the case that it was administered at the dose of 5 μg kg and 10 g kg, it was observed that it inhibited the bronchospasm 30% and 90%, respectively. Therefore, it was seen that both roflumilast and terbutaline did not show any bronchodilatory effects at the lowest dose of 1 μg/kg.

However, when roflumilast and terbutaline were applied together at the lowest dose of 1 μg kg, they almost completely attenuated bronchoconstriction induced by acetylcholine. Accordingly, it has been concluded that when roflumilast and terbutaline were administered simultaneously in doses, which alone were not effective at all, they showed very strong bronchodilatory effects in the pigs. This proved that the combination of roflumilast and terbutaline showed a synergic effect on the attenuation of acetylcholine- induced bronchoconstriction. This also indicated the overadditive nature of the interaction between the two compounds.

The pharmaceutical composition of the invention comprises

1. Roflumilast as a PDE-4 enzyme inhibitor,

2. Terbutaline as p₂-adrenergic agonist, and

3. At least one pharmaceutically acceptable excipient.

The treatments where the pharmaceutical composition of the invention is used comprise administration of effective amounts of a PDE-4 enzyme inhibitor and a p₂-adrenergic agonist; and the activity of said pharmaceutical composition in the prevention and/or treatment of and in removal of symptoms associated with allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise-induced asthma, acute bronchospasm, bronchial asthma, chronic bronchitis, allergic bronchitis, chronic obstructive pulmonary disease (COPD), asthma and bronchospasm prophylaxis is synergistic. On the other hand, the pharmaceutical compositions of the present invention can be prepared as a drug composition to be administered on mammals including humans for the prevention and/or treatment of and for removal of symptoms associated with allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise-induced asthma, acute bronchospasm, bronchial asthma, chronic bronchitis, allergic bronchitis, chronic obstructive pulmonary disease (COPD), asthma and bronchospasm prophylaxis.

The terms "rofiumilast" and "terbutaline" used in the present invention refers to free bases or pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, various polymorphic forms, amorphous and crystalline forms of said active agents or combinations thereof.

A characteristic of the pharmaceutical composition of the invention is that said composition comprises rofiumilast and terbutaline as active agents.

The dose of the drug which is delivered to the lungs is an important parameter in order to provide an effective inhalation treatment in the case that the composition is in the dry powder form. The average particle size of the active agents have a considerable influence on the delivery of the drug to the lungs as high as possible. In order to determine the dose of drug that is delivered to the lungs the Fine Particle Fraction (FPF) value of the drug particles are measured. Surprisingly, the inventors have observed that when rofiumilast and terbutaline used as active agents have an average particle size in the range of 1 to 5 μηι, FPF (Fine Particle Fraction) values of rofiumilast and terbutaline are in the range of 10- 50% and % 15-60 indicating high deposition of the drug particles in the lung.

Accordingly, another characteristic of the pharmaceutical composition is that said composition comprises rofiumilast and terbutaline which have average particle size in the range of 1 to 5 μπι. Another characteristic of the pharmaceutical composition of the invention is that said composition comprises at least one pharmaceutically acceptable excipient in addition to rofiumilast and terbutaline comprised as active agents.

Another characteristic of the pharmaceutical composition of the invention is that said composition is used in the prevention and/or treatment of allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise-induced asthma, acute bronchospasm, bronchial asthma, chronic bronchitis, allergic bronchitis, chronic obstructive pulmonary disease (COPD), asthma and bronchospasm prophylaxis; in removing the symptoms associated with these diseases; in alleviating the symptoms resulting from said diseases and in slowing down the progression of these diseases.

The active agents comprised in the pharmaceutical compositions of the invention can be delivered simultaneously, consecutively or separately as prepared in separate dosage forms, whereas they can also be delivered as combined in a single dosage form. A characteristic of the pharmaceutical compositions of the invention is that said compositions are prepared by formulating the dosage forms separately and combining the obtained dosage forms in a single kit. In the case that the two active agents are prepared in separate dosage forms, said dosage forms can be same as or different from each other.

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

Another characteristic of the pharmaceutical compositions of the invention is that the total amount of active agents in the formulation is in the range of 0.1 to 95%, preferably in the range of 1 to 90% by weight. Another characteristic of the pharmaceutical compositions of the invention is that said pharmaceutical compositions comprise terbutaline in the range of 0.1 to 30 mg, preferably in the range of 0.1 mg to 20 mg, more preferably in the range of 0.1 mg to 15 mg per unit dosage form.

Another characteristic of the pharmaceutical compositions of the invention is that said pharmaceutical compositions comprise roflumilast in the range of 0.1 to 15 mg, preferably in the range of 0.1 to 10 mg, more preferably in the range of 0.1 to 5 mg per unit dosage form.

The dose of active agents in the pharmaceutical composition may change depending on the administration route, age of the user individuals and conditions of them. Another characteristic of the pharmaceutical compositions of the invention is that said pharmaceutical compositions comprise terbutaline in the range of 0.1 to 80%, preferably in the range of 0.1 to 70%, more preferably in the range of 0.05 to 60% by weight.

Another characteristic of the pharmaceutical compositions of the invention is that said pharmaceutical compositions comprise roflumilast in the range of 0.001 to 10%, preferably in the range of 0.001 to 5%, more preferably in the range of 0.001 to 4% by weight.

The compositions of the invention can be prepared together with at least one pharmaceutically acceptable excipient or as oral, parental, inhalation dosage forms comprising only the active agents. The pharmaceutical compositions of the invention can be prepared in solid forms comprising tablet; double-layer tablet; capsule; enterically coated or modified-release tablets; controlled-release tablet, extended-release tablet; delayed-release tablet; slow or fast-release tablet; fast soluble tablet; effervescent tablet; effervescent granule; 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; dragee; orodispersible tablet; film tablet or combinations thereof; or in any one of such liquid forms as syrup or suspension.

The pharmaceutical compositions comprising terbutaline and roflumilast can be together in any one of the above-mentioned dosage forms. On the other hand, the compositions comprising terbutaline and roflumilast can also be prepared formulating the active agents separately or in any one of the above-mentioned dosage forms. In this case, the dosage forms comprising the two active agents can be same as or different from each other.

In other words, the pharmaceutical compositions comprising the combination of the invention can be in any one of the above-mentioned dosage forms or in combinations of these dosage forms or in the form of a treatment pack comprising this combination.

A characteristic of the composition of the invention with synergistic effect is that said composition is prepared in a solid oral dosage form. The preferred solid oral dosage forms of the invention can be one of tablet, film-coated tablet, controlled-release tablet, effervescent tablet, enteric-coated tablet forms or combinations thereof.

The pharmaceutical compositions of the invention comprise at least one pharmaceutically acceptable excipient in addition to the active agents.

The excipients that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, surfactants, stabilizing agents, lubricants, diluents, glidants, wetting agents, coating agents designed to provide various release properties, anti-adhesive agents, pH regulators, effervescent acids, effervescent bases, gel forming agents, flavoring agents, sweeteners, emulsifying agents, anti-foaming agents, protecting agents, solvent or solvent mixtures, coloring agents and complexing agents, or combinations thereof.

The disintegrants that can be used in the pharmaceutical compositions of the 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 combinations thereof.

The diluents that can be used in the pharmaceutical compositions of the 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 (e.g. corn starch), sodium chloride, sucrose, talc, xylitol or combinations thereof.

The lubricants that can be used in the pharmaceutical compositions of the 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 of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc or combinations thereof. The binders that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch or combinations thereof.

The effervescent acids that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid, maleic acid or combinations thereof.

The effervescent bases that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or combinations thereof.

The pH regulators that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartarate, fumarate, acetate, maleate and amino acid salts or combinations thereof. The surfactants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol or combinations thereof.

The stabilizing agents that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotineamide, cyclodextrin or combinations thereof.

The sweeteners and/or taste regulating agents that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride or combinations thereof.

The flavoring agents that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising menthol, lemon, orange, vanilla, strawberry, rasp berry, caramel or combinations thereof. The pharmaceutical compositions of the invention can optionally be formulated such that they provide release types such as fast-, slow-, delayed-, extended-, controlled- release.

With this purpose, the release rate-determining polymers that can be used within the scope of the invention can be selected from a group comprising pH-dependent polymers, non pH- dependent polymers, swellable polymers, non-swellable polymers, hydrophilic polymers, hydrophobic polymers and/or one or more hydrophobic substances, sodium alginate, polyactides, polyglycolides, polyactide-co-glycolides, polyactic acids, polyglycolic acids, polyactic acid-co-glycolic acids, polyaprolactone, polycarbonates, polyesteramides, polyanhydrides, polyamino acids, polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, polydioxanones, polyalkylene alkylates, polyethylene glycol and polyorthoester copolymers, biodegradable polyurethanes, hydrogels, mixtures and copolymers thereof, high molecular weight water-soluble polymers such as polyethylene oxide, carbomer, ionic polymers such as calcium carboxy methyl cellulose or carboxy methyl cellulose; non-ionic polymers such as hydroxy propyl methyl cellulose; natural or synthetic polysaccharides such as alkyl celluloses, hydroxy alkyl celluloses, cellulose ethers, nitro cellulose, dextrin, agar, carrageenan, pectin, starch and starch derivatives or mixtures thereof; hydrophilic polysaccharide polymers such as xanthan gum, chitosan; polyvinyls such as cellulosic polymers, methacrylate polymers, methacrylate copolymers, polyvinyl pyrrolidone, polyvinylpyrrolidone- polyvinyl acetate copolymers, polyvinyl alcohol; natural resins such as polyacrylic acids, alginates, gelatin, guar gum; ethyl cellulose, cellulose acetate, cellulose propionate (high, medium or low molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polyvinyl acetate, polyvinyl chloride, sodium bicarbonate or combinations thereof. The coating compositions to be used for determining release rate can also comprise at least another pharmaceutically acceptable excipient in addition to release rate-determining polymers given above. Release rate determining polymers can be comprised in the formulation composition prepared according to the invention, whereas they can also be comprised in the coating composition of the oral dosage forms produced with said formulations.

The solid dosage forms of the invention can be coated with coatings such as protective coating, enteric-coating, film-coating and/or those designed to provide various release properties (such as fast-release, slow-release, controlled-release) afterwards. In the case that active agents are prepared in separate dosage forms, coatings with the same or different properties can be used in said dosage forms.

The film-coating agents that can be used within the scope of the invention can be selected from a group comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; polyvinyl alcohols such as iron oxides, titanium oxide, polyethylene glycol; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone; and polysaccharides such as pullulan; or combinations thereof.

Sugar-based coating agents that can be used within the scope of the invention can be saccharose only or optionally any one of agents selected from a group comprising talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof. The enteric-coating agents that can be used within the scope of the invention can be selected from a group comprising cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac; or combinations thereof.

The coating-agents that can be used to provide delayed release within the scope of the invention can be selected from a group comprising cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof. On the other hand, the pharmaceutical composition of the invention can be produced adding terbutaline and roflumilast and optionally a pharmaceutically acceptable excipient by any production method in the prior art; for example, by one of wet granulation, dry granulation, dry blending methods. In the pharmaceutical composition of the invention, the active agents can be formulated separately by any one of these production methods in the prior art; whereas they can also be formulated together by using the same production method.

In the case that the active agents are formulated separately, the two separate active agent formulations prepared can be combined on a single kit in a single dosage form or in separate dosage forms.

The following examples are given to explain the pharmaceutical compositions of the invention and the preparation methods thereof; the scope of the invention cannot be limited to these examples.

EXAMPLES

EXAMPLE 1: Double-layer tablet dosage form comprising Roflumilast & Terbutaline

Terbutaline, disintegrant, diluent and the other excipients are mixed; and the first mixture is obtained after adding lubricant into this mixture.

Roflumilast and the diluent are mixed. The obtained mixture is granulated with a granulation solution comprising binder. The obtained granules are dried; and the second mixture is obtained after mixing these granules with the glidant and the other excipients.

The two mixtures obtained are fed into tablet compression machine and compressed into double-layer tablets.

EXAMPLE 2: Film-Coated Tablet Dosage Form Comprising Roflumilast & Terbutaline

Terbutaline, roflumilast and the diluent are mixed. The mixture is granulated with a granulation solution comprising binder. The obtained granules are dried, and mixed with the disintegrant and the other excipients. The final mixture obtained is compressed into tablets in tablet compression machine and coated with the film-coating agent. EXAMPLE 3: Combined Dosage Form Comprising Roflumilast Film-Coated Tablet & Terbutaline Tablet

Production method for roflumilast film-coated tablet: Roflumilast is mixed with lactose and starch. The mixture is wetted adding a granulation solution prepared with hydroxypropyl methyl cellulose into the mixture. The wetted mixture is dried and granulated. Magnesium stearate is added into the obtained granules and this mixture is compressed into tablets. The compressed tablets are coated with the film-coating agent.

Production method for terbutaline tablet: Two separate mixtures are obtained mixing terbutaline with lactose and mixing starch with water. These two mixtures are mixed together and the obtained wet mixture is stirred until obtaining granules. The obtained granules are pulverized and dried. The dry mixture is treated with magnesium stearate and compressed into tablets.

The dosage forms produced separately as instructed are presented combining them together in a blister.

EXAMPLE 4: Combined Dosage Form Comprising Roflumilast Film-Coated Tablet & Terbutaline Controlled-Release Tablet

Production method for roflumilast film-coated tablet: Roflumilast is mixed with lactose and starch. The mixture is wetted adding a granulation solution prepared with hydrophilic polymer into the mixture. The wetted mixture is dried and granulated. Magnesium stearate is added into the obtained granules and this mixture is compressed into tablets. The compressed tablets are coated with the film-coating agent. Production method for terbutaline controlled-release tablet: Chitosan, xanthan gum, terbutaline and sodium bicarbonate are mixed. Magnesium stearate is added into this mixture and the tablets are formed into a desired shape.

The separately produced dosage forms are presented by combining them in a blister.

Claims

1. A pharmaceutical composition, characterized in that said composition comprises roflumilast and terbutaline or pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, different polymorphic forms, amorphous and crystalline forms or combinations thereof as active agents.

2. The pharmaceutical composition according to claim 1, characterized in that said composition comprises terbutaline in the range of 0.1 to 30 mg per unit dosage form.

3. The pharmaceutical composition according to claims 1 and 2, characterized in that said composition comprises terbutaline in the range of 0.1 to 20 mg per unit dosage form.

4. The pharmaceutical composition according to claims 1 to 3, characterized in that said composition comprises terbutaline in the range of 0.1 to 15 mg per unit dosage form.

5. The pharmaceutical composition according to claims 1 to 4, characterized in that said composition comprises roflumilast in the range of 0.1 to 15 mg per unit dosage form.

6. The pharmaceutical composition according to claims 1 to 5, characterized in that said composition comprises roflumilast in the range of 0.1 to 10 mg per unit dosage form.

7. The pharmaceutical composition according to claims 1 to 6, characterized in that said composition comprises roflumilast in the range of 0.1 to 5 mg per unit dosage form.

8. The pharmaceutical composition according to claims 1 to 7, characterized in that said composition comprises roflumilast and terbutaline which have average particle size in the range of 1 to 5 μιη.

9. The pharmaceutical composition according to any one of the preceding claims, characterized in that the active agents comprised in said pharmaceutical composition are formulated simultaneously, consecutively or separately.

10. The pharmaceutical composition according to claim 9, characterized in that the active agents comprised in said pharmaceutical composition are formulated separately to be used in the form of a kit where they are present together.

1 1. The pharmaceutical composition according to claim 10, characterized in that said pharmaceutical composition is formulated so as to be in the same dosage form.

12. The pharmaceutical composition according to any one of the preceding claims, characterized in that said pharmaceutical composition is formulated in oral, parental, inhalation dosage forms.

13. The pharmaceutical composition according to claim 12, characterized in that the active agents are formulated in oral dosage forms.

14. The pharmaceutical composition according to claim 13, characterized in that said oral dosage forms are selected from solid forms comprising tablet; double-layer tablet; capsule; enterically coated or modified-release tablets; controlled-release tablet, extended-release tablet; delayed-release tablet; slow or fast-release tablet; fast soluble tablet; effervescent tablet; effervescent granule; 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; dragee; orodispersible tablet; film tablet or combinations thereof; or in any one of such liquid forms as syrup or suspension.

15. The pharmaceutical composition according to any one of the preceding claims, characterized in that said compositions comprise at least one pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15, characterized in that the pharmaceutically acceptable excipients are selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, surfactants, stabilizing agents, lubricants, diluents, glidants, wetting agents, coating agents designed to provide various release properties, anti-adhesive agents, pH regulators, effervescent acids, effervescent bases, gel forming agents, flavoring agents, sweeteners, emulsifying agents, anti-foaming agents, protecting agents, solvent or solvent mixtures, coloring agents and complexing agents, or combinations thereof.

17. The pharmaceutical composition according to any one of the preceding claims, characterized in that said compositions are used in the prevention and/or treatment of allergic and inflammatory diseases of upper and lower respiratory tract or skin such as seasonal allergic rhinitis, perennial allergic rhinitis, allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin-induced asthma, exercise-induced asthma, acute bronchospasm, bronchial asthma, chronic bronchitis, allergic bronchitis, chronic obstructive pulmonary disease (COPD), asthma and bronchospasm prophylaxis; and for removal of symptoms associated with these diseases.