WO2012093252A1

WO2012093252A1 - Pharmaceutical composition

Info

Publication number: WO2012093252A1
Application number: PCT/GB2012/000011
Authority: WO
Inventors: Shrinivas Madhukar Purandare; Geena Malhotra
Original assignee: Cipla Limited; Turner, Craig Robert
Priority date: 2011-01-06
Filing date: 2012-01-06
Publication date: 2012-07-12

Abstract

The present invention relates to a pharmaceutical composition comprising an inhaled corticosteroid and an anticholinergic. In particular, to a pharmaceutical composition comprising tiotropium bromide and fluticasone furoate. The invention also relates to a process for preparing the pharmaceutical composition, therapeutic uses thereof in the treatment and / or prevention of respiratory, inflammatory or obstructive airway disease.

Description

PHARMACEUTICAL COMPOSITION

FIELD OF INVENTION: The present invention relates to a pharmaceutical composition comprising an inhaled corticosteroid and an anticholinergic, a process for preparing the pharmaceutical composition, therapeutic uses thereof in the treatment and / or prevention of respiratory, inflammatory or obstructive airway disease and methods of treatment employing the same. BACKGROUND OF THE INVENTION:

Asthma is a chronic, inflammatory disorder of the airways associated with airway hyper- responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing. These asthmatic episodes are associated with variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment.

Inhaled corticosteroids (ICS) are the mainstay of current asthma management and are used in patients with persistent asthma. Many patients with persistent asthma are treated with regular ICS. However, a considerable proportion of patients treated with ICS remain symptomatic, despite the use of low to moderate doses of ICS.

However, currently the therapy for the treatment of asthma includes increasing the dose of inhaled corticosteroids (ICS), addition of long-acting p2-agonist (LAB A) to the existing therapy, addition of a leukotriene receptor antagonist (LTRA) to the existing therapy or addition of sustained release theophylline.

Although LABAs have been widely prescribed for the management of asthma, their use has been controversial over the past few years. Thus, while several studies have supported the efficacy and safety of LABAs for treating asthma (other studies have reported rates of serious asthma morbidity and death with the use of these drugs. Some of these latter studies prompted the U.S. Food and Drug Administration to issue a warning about the increased risk for adverse outcomes associated with LABAs and suggesting strategies to minimize the use of these drugs. In severe asthma, the main treatment is based on inhaled steroids, but the benefit: harm ratio of inhaled steroids appears to be reduced once the total daily dose exceeds 1000 mg, with adverse effects leading to increased risk of osteoporosis, skin thinning and adrenal problems. As an alternative to high doses of inhaled steroid, moderate levels of inhaled steroid have been used in conjunction with oral steroids, leukotriene-receptor antagonists, steroid sparing alternatives, theophylline, anticholinergics or long-acting ß2 -agonists. Oral steroids and some of the alternatives, including long-acting beta-agonists, have shown adverse effects, which suggest relatively safe use of anticholinergics. Anticholinergic agents act as bronchodilators and are a potential alternative to beta agonists. Anticholinergics work by competing with acetylcholine for receptor sites at the vagus nerve- nerve or nerve-muscle junctions. This prevents transmission of reflexes induced by asthma stimuli. Use of anticholinergics provides an advantage in elderly patients as the responsiveness of β2- agonists declines with old age. Further it would be advantageous to use in patients who are intolerant to the use of beta2 -agonists.

Further, anticholinergics can also be used in patients suffering from nocturnal asthma, chronic asthma with concurrent fixed way obstruction, intrinsic asthma and also in patients with asthma of longer duration.

Thus combination therapy of an anticholinergic with an inhaled corticosteroid improves pulmonary efficiency, reduces inflammatory response and provides symptomatic relief as compared to higher doses of inhaled corticosteroid alone in patients affected by respiratory disorders such as asthma.The selection of a specific anticholinergic and inhaled corticosteroid plays a very important role in formulation of fixed dose combinations.

Further, combination therapy reduces the cost and also provides control of respiratory disorders. Reducing the dose frequency to the minimum is a main step in simplifying asthma management for improving patient adherence to the therapy. WO20041 10404 discloses combined doses of tiotropium and fluticasone propionate for administration by an oral inhalation.

W02001078739 discloses compositions containing a combination of tiotropium and fluticasone propionate for the prophylaxis and treatment of respiratory diseases. US20050148562 discloses compositions containing a combination of an anticholinergic and a steroid.

The selection of a combination of an inhaled corticosteroid (ICS) and an anticholinergic is critical since both drugs should be capable of being administered once daily. A treatment method where an anticholinergic is required to be administered once daily and an inhaled corticosteroid (ICS) is required to be administered twice daily or vice versa will not be useful since the purpose of once a day treatment is defeated.

There remains a need for a combination of anticholinergic agent and inhaled corticosteroid, which can be administered once daily for the prevention or treatment of respiratory, inflammatory or obstructive airway disease.

Also, there remains a need to formulate a pharmaceutical composition which simplifies the dosage regimen, preferably by administering a once a day, composition for the treatment of these respiratory disorders.

OBJECT OF THE INVENTION:

The object of the present invention is to provide pharmaceutical composition comprising an anticholinergic agent and an inhaled corticosteroid (ICS) for administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease. Another object of the present invention is to provide such a pharmaceutical composition comprising an anticholinergic agent and an inhaled corticosteroid (ICS) for once daily administration for the prevention or treatment of respiratory, inflammatory or obstructive airway disease. Yet another object of the present invention is to provide a process for preparing a pharmaceutical composition comprising an anticholinergic agent and an inhaled corticosteroid (ICS) for administration in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.

A further object of the present invention is to provide a method for prophylaxis or treatment of respiratory, inflammatory or obstructive airway disease which comprises administering a pharmaceutical composition comprising an anticholinergic agent and an inhaled corticosteroid (ICS).

SUMMARY OF THE INVENTION:

According to one aspect of the present invention, there is provided a pharmaceutical composition comprising tiotropium and fluticasone furoate.

Fluticasone furoate may be present in an amount of about 25 meg to about 800 meg. The tiotropium may be present in an amount of about 4.5 meg to about 18 meg. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients.

The active ingredients of the composition may be formulated for simultaneous, separate, or sequential administration. The pharmaceutical composition is preferably in a form suitable as a single medicament. For example, the composition may be a combined preparation where both actives are present in a single dosage form, for example a single MDI formulation or single DPI formulation.

In another aspect the present invention provides a method of preparing a pharmaceutical composition tiotropium and fluticasone furoate, comprising combining tiotropium with fluticasone furoate and, optionally, one or more pharmaceutically acceptable excipients.

In another aspect the present invention provides a method for prophylaxis or treatment of respiratory, inflammatory or obstructive airway disease, in a mammal, such as a human, which method comprises administrating a therapeutically effective amount of a pharmaceutical composition tiotropium and fluticasone furoate. The fluticasone furoate and tiotropium may be administered once a day. In another aspect the present invention provides use of a pharmaceutical composition comprising tiotropium and fluticasone furoate for the treatment of disorders relating to respiratory, inflammatory or obstructive airway disease. The disease may comprise asthma. The use of the composition is preferably for once daily administration. In another aspect the present invention provides a method of manufacturing a medicament for the treatment of asthma using a fluticasone furoate and tiotropium, as a combined therapy.

In another aspect of the present invention there is provided a pharmaceutical composition comprising tiotropium and fluticasone furoate for once daily administration.

Preferably, the tiotropium according to the present invention may comprise tiotropium bromide. The tiotropium bromide may be in the form of tiotropium bromide monohydrate or anhydrous crystalline tiotropium bromide. According to another aspect of the present invention, there is provided a process for manufacturing the pharmaceutical composition comprising an anticholinergic agent and an inhaled corticosteroid (ICS).

According to another aspect of the present invention there is provided a pharmaceutical composition comprising an anticholinergic agent and an inhaled corticosteroid for use in treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration of an anticholinergic agent and an inhaled corticosteroid (ICS).

DETAILED DESCRIPTION OF THE INVENTION:

As mentioned above, the selection of a specific anticholinergic agent and inhaled corticosteroid (ICS) plays a very important role in formulation of fixed dose combinations. Our inventors have found that a combination therapy of tiotropium and fluticasone furoate is effective for treating inflammatory and/or obstructive diseases of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD). Furthermore, the combination of tiotropium and fluticasone furoate provides a rapid onset of action and improved control of obstructive or inflammatory airway diseases, or reduction in the exacerbations of the diseases.

Another advantage of the combination of tiotropium and fluticasone furoate is that it facilitates the treatment of an obstructive and inflammatory airway disease with a single medicament.

Further the combination therapy, according to the present invention, provides for administration by use of a single inhaler for patients who currently have to make use of multiple inhalers. This is because fluticasone furoate can be administered once daily along with tiotropium as compared to fluticasone propionate which is to be administered twice daily. This is particularly important in case of elderly patients who may get confused between the inhalers and who also suffer from several other medical conditions such as heart disease, arthritis etc. and are receiving multiple other medications. Fluticasone is currently commercially available as a furoate salt and a propionate salt. Fluticasone furoate is a novel corticosteroid which substantially overcomes the potential side effects that are generally produced by the use of conventional corticosteroids. Moreover fluticasone furoate exhibits a 1.7 times higher binding affinity for the human glucocorticoid receptor as compared to that of fluticasone propionate and also provides prolonged protection up to 26 hours against airway hyper-responsiveness as compared to fluticasone propionate.

Fluticasone furuoate has a longer duration of action with an elimination half life of 15.1 hrs.

Further, fluticasone furoate has greater potency than other clinically used corticosteroids such as mometasone furoate, budesonide, fluticasone propionate, ciclesonide for the glucocorticoid receptor and against the proinflammatory transcription factors nuclear factor κΒ (NF-κΒ), activation protein- 1, and tumor necrosis factor- induced interieukin-8 cytokine production. Fluticasone furoate also controls chronic inflammation which is commonly associated with asthma.

Preferably, the anticholinergic agentused in the combination therapy according to the present invention is tiotropium.

The tiotropium may comprise tiotropium bromide which is an anticholinergic bronchodilator that antagonises muscarinic Ml, M2 and M3 receptors. Tiotropium, is chemically described as (la, 2β, 4β, 5a, 7B)-7-[(Hydroxydi-2-thienylaceryl) oxy]-9, 9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0^2,4] nonane bromide monohydrate. Tiotropium has a longer duration of action of up to 32 hours. Also, tiotropium exhibits an improvement in dyspnea and ceases the need for rescue therapy. The tiotropium bromide may be in the form of tiotropium bromide monohydrate or anhydrous crystalline tiotropium bromide. Tiotropium in combination with pulmonary rehabilitation (PR) associated with an increased exercise endurance time produces clinically meaningful improvements in dyspnea and health status as compared to pulmonary rehabilitation alone in COPD patients.

Further, tiotropium is more potent than ipratropium in the treatment of patients with COPD in terms of the effect of lung function, dyspnea, exacerbation rates and health status.

Thus, the present invention provides a pharmaceutical composition comprising fluticasone furoate and tiotropium along with other pharmaceutically acceptable excipients. The terms "fluticasone" and "tiotropium" are used in broad sense to include not only "fluticasone" and "tiotropium" per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.

According to the present invention, fluticasone furoate may be present in an amount of about 25 meg to about 800 meg. According to the present invention, tiotropium may be present in an amount of about 4.5 meg to about 18 meg. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients.

Preferably, the one or more pharmaceutically acceptable excipients is selected from HFC/HFA propellants, co-solvents, bulking agents, non-volatile component, buffers/pH adjusting agents, surface active agents, preservatives, complexing agents, isotonicity adjusting agents, antimicrobial agents or combinations thereof.

The pharmaceutical composition of the present invention may be administered by any suitable methods used for delivery of the drugs to the respiratory tract. Preferably, in a form suitable for inhalation. The composition of the present invention may thus be administered as metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, insufflation powders.

The various dosage forms according to the present invention may comprise carriers/excipients suitable for formulating the same.

The pharmaceutical composition may be in a form suitable for use in a metered dose inhaler. The pharmaceutical composition may comprise a propellant, preferably HFC/HFA propellants. The metered dose inhalers, according to the present invention may comprise one or more pharmaceutically acceptable excipients co-solvents, bulking agents, non-volatile component, buffers/pH adjusting agents, surface active agents, preservatives, complexing agents, or combinations thereof. Propellants are preferably those which, when mixed with the cosolvent(s), form a homogeneous propellant system in which a therapeutically effective amount of the medicament can be dissolved. The HFC/HFA propellant must be toxicologically safe and must have a vapor pressure which is suitable to enable the medicament to be administered via a pressurized MDI. According to the present invention the HFC/HFA propellants may comprise, one or more of 1,1,1, 2-tetrafluoroethane (HFA- 134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFA-227), HFC- 32 (difluoromethane), HFC-143(a) (1,1,1-trifluoroethane), HFC-134 (1,1,2,2-tetrafluoroethane), and HFC- 152a (1,1-difluoroethane) and such other propellants or combinations thereof, which may be known to the person skilled in the art.

Co-solvent is any solvent which is miscible in the formulation in the amount desired and which, when added provides a formulation in which the medicament can be dissolved. The function of the co-solvent is to increase the solubility of the medicament and the excipients in the formulation.

According to the present invention the co-solvent may comprise one or more of, C₂. C6 aliphatic alcohols, such as but not limited to ethyl alcohol and isopropyl alcohol; glycols such as but not limited to propylene glycol, polyethylene glycols, polypropylene glycols, glycol ethers, and block copolymers of oxyethylene and oxypropylene; and other substances, such as but not limited to glycerol, polyoxyethylene alcohols, and poly oxyethylene fatty acid esters; hydrocarbons such as but not limited to n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane; and ethers such as but not limited to diethyl ether or combinations thereof. Suitable surfactants may be employed in the aerosol solution formulation of the present invention which may serve to stabilize the solution formulation and improve the performance of valve systems of the metered dose inhaler.

According to the present invention the surfactant may comprise one or more ionic and/or non- ionic surfactant, but not limited to oleic acid, sorbitan trioleate, lecithin, isopropylmyristate, tyloxapol, polyvinylpyrrolidone, polysorbates such as polysorbate 80, vitamin E-TPGS, and macrogol hydroxystearates such as macrogol-15-hydroxystearate or combinations thereof.

Non-volatile component is all the suspended or dissolved constituents that would be left after evaporation of the solvent. According to the present invention, the non-volatile component may comprise one or more of monosaccharides such as but not limited to glucose, arabinose; disaccharides such as lactose, maltose; oligosaccharides and polysaccharides such as but not limited to dextrans; polyalcohol such as but not limited to glycerol, sorbitol, mannitol, xylitol; salts such as but not limited to potassium chloride, magnesium chloride, magnesium sulphate, sodium chloride, sodium citrate, sodium phosphate, sodium hydrogen phosphate, sodium hydrogen carbonate, potassium citrate, potassium phosphate, potassium hydrogen phosphate, potassium hydrogen carbonate, calcium carbonate and calcium chloride, or combinations thereof. Suitable bulking agents may be employed in metered dose inhalation formulation of the present invention.

According to the present invention, the bulking agent may comprise one or more of saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextran or mannitol or combinations thereof.

Suitable buffers or pH adjusting agents may be employed in the metered dose inhalation formulation of the present invention.

According to the present invention, the buffer or the pH adjusting agent may comprise one or more of organic or inorganic acids such as but not limited to citric acid, ascorbic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid or combinations thereof. Suitable preservatives may be employed in the pharmaceutical composition. The aerosol solution formulation of the present invention may comprise preservatives to protect the formulation from contamination with pathogenic bacteria.

According to the present invention, the preservative may comprise one or more of benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate or combinations thereof and such other preservatives which may be known to the person skilled in the art. Suitable complexing agents may be employed in the aerosol solution formulation of the present invention which is capable of forming complex bonds.

According to the present invention, the complexing agent may comprise one or more of but not limited to sodium EDTA or disodium EDTA or combinations thereof.

The pharmaceutical composition of the present invention may be administered by a dry powder inhaler (DPI). The pharmaceutically acceptable excipients suitable for dry powder inhalation according to the present invention may be selected from suitable carriers which include but are not limited to sugars such as glucose, saccharose, lactose and fructose, starches or starch derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as mannitol or sorbitol, calcium carbonate, calcium phosphate, etc. lactose, lactitol, dextrates, dextrose, maltodextrin, saccharides including monosaccharides, disaccharides, polysaccharides; sugar alcohols such as arabinose, ribose, mannose, sucrose, trehalose, maltose, dextran or combinations thereof. The pharmaceutical composition of the present invention may be administered by nebulization. Such nebulizers include, but are not limited to, a jet nebulizer, ultrasonic nebulizer and breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate air flow. The nebulizer being equipped with a mouthpiece or suitable face mask. Specifically, a nebulizer (with face mask or mouthpiece) connected to a compressor may be used to deliver the inhalation liquid of the present invention to a patient.

Nebulisation therapy has an advantage over other inhalation therapy, since it is easy to use and does not require co-ordination or much effort. It also works much more rapidly than medicines taken by mouth.

For nebulisers, the composition according to the present invention may comprise suitable excipients such as tonicity agents, pH regulators, chelating agents in a suitable vehicle. Isotonicity adjusting agents, which may be used, comprise of sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other isotonicity adjusting agents may also include, but are not limited to, mannitol, glycerol, and dextrose and mixtures thereof.

The pH may be adjusted by the addition of pharmacologically acceptable acids. Pharmacologically acceptable inorganic acids or organic acids may be used for this purpose. Examples of preferred inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid. Examples of particularly suitable organic acids are selected from the group consisting of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid or combinations thereof.

Complexing agents according to the present invention may comprise editic acid (EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate) or combinations thereof.

Preferably, the pharmaceutical composition comprises anti-microbial preservative agent. The anti-microbial agent may be added to the multi-dose packages. The formulation according to the present invention may be included in suitable containers provided with means enabling the application of the contained formulation to the respiratory tract.

The MDI composition according to the present invention may be packed in plain aluminum cans or SS (stainless steel) cans. Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the MDI. The inner surface of the container may be coated with a suitable polymer to reduce this adhesion problem. Suitable coatings may include fluorocarbon copolymers such as FEP-PES (fluorinated ethylene propylene and polyethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene. Alternatively, the inner surfaces of the cans may be anodized, plasma treated or plasma coated.

The powder for inhalation intended to be used for DPI may either be encapsulated in capsules of gelatin or HPMC or in blisters or alternatively, the dry powder may be contained as a reservoir either in a single dose or multi-dose dry powder inhalation device. Alternatively, the powder for inhalation intended to be used for DPI may be suspended in a suitable liquid vehicle and packed in an aerosol container along with suitable propellants or mixtures thereof.

Further, the powder for inhalation intended to be used for DPI may also be dispersed in a suitable gas stream to form an aerosol composition.

The pharmaceutical composition may be in the form of inhalation solution/suspension which may be administrated into the nasal passages of a subject by means of a dropper (or pipette) that includes a glass, plastic or metal dispensing tube. Fine droplets and sprays can be provided by an intranasal pump dispenser or squeeze bottle as well known in the art. According to a preferred embodiment, the pharmaceutical composition may be delivered through an elongated discharge member formed for insertion into a nasal cavity. A reservoir is coupled to the discharge member with spray actuation being achieved by squeezing the discharge member towards the reservoir.

The inhalation solution/suspension may comprise an excipient selected from a wetting agent, osmotic agent, a pH regulator, a buffering agent and a complexing agent or combinations thereof, provided in a pharmaceutically acceptable vehicle.

The pharmaceutical composition may further comprise one or more active(s) selected from anticholinergics, antihistamines, antiallergics or leukotriene antagonist or their pharmaceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.

The present invention also provides a process for manufacturing a pharmaceutical composition according to the present invention.

The present invention also provides a process of preparing a metered dose inhalation formulation, which process comprises admixing of a pharmaceutically acceptable carrier or excipient with the actives and the propellant, and providing the formulation in precrimped cans. The present invention also provides a process of preparing a dry powder inhalation formulation which process comprises admixing a pharmaceutically acceptable carrier or excipient with the actives and providing the formulation as a dry powder inhaler. The present invention also provides a method for the treatment in a mammal, such as a human, for treating asthma, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

The present invention also provides a method for the treatment in a mammal, such as a human, for treating asthma, which method comprises administration of a therapeutically effective amount of fluticasone furoate and tiotropium. Preferably the dose regime is once daily.

The present invention also provides a pharmaceutical composition comprising an anticholinergic agent and an inhaled corticosteroid for use in treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration of an anticholinergic agent and an inhaled corticosteroid (ICS).

The present invention preferably relates to methods of treating asthma characterized in that fluticasone furoate and tiotropium are administered once a day in therapeutically effective amounts.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. Example 1

Process: 1) Fluticasone furcate and Tiotropium bromide were sifted with a part quantity of lactose.

2) The cosift of step 1 was then sifted with the remaining quantity of lactose and blended.

3) The blend of step 2 was then filled in capsules. Example 2

Process:

1) Fluticasone furoate and Tiotropium bromide were sifted with a part quantity of lactose.

3) The blend of step 2 was then filled in capsules.

Example 3

Process:

3) The blend of step 2 was then filled in capsules.

Example 4

Process:

1) Fluticasone furoate and Tiotropium were homogenized with part quantity of HFA.

2) The suspension obtained in step 1 was transferred to the mixing vessel where remaining quantity of HFA was added.

3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.

Example S

Process:

1) Fluticasone furoate and Tiotropium were homogenized with lactose and part quantity of HFA.

3) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans. Example 6

Process:

1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.

2) The solution obtained in Step 1 was transferred to a mixing vessel.

3) Fluticasone furoate and Tiotropium were homogenized with a part quantity of HFA.

4) The suspension obtained in step 3 was transferred to the mixing vessel where remaining quantity of HFA was added.

5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.

Example 7

Process:

1) Glycerol was dissolved in ethanol and required quantity of HCl was added.

2) Fluticasone furoate and Tiotropium were dissolved in the solution obtained in step 1.

3) The resulting solution was transferred to the mixing vessel where HFA was added.

4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.

Example 8

Process:

1) Required quantity of HCl was added to ethanol.

4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans. Example 9

Process:

1) Citric acid anhydrous and glycerol were dissolved in ethanol.

2) Fluticasone furoate and Tiotropium were dissolved in the solution obtained in step (1).

3) The solution obtained in step (2) was transferred to the main mixing vessel where it was mixed with entire quantity of HFA 134a.

4) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans. Example 10

Process:

1) Citric acid anhydrous was dissolved in ethanol.

3) The solution obtained in step (2) was transferred to the main mixing vessel where it was mixed with entire quantity of HFA134a.

Example 11

Process:

1) Lecithin was dissolved in ethanol.

2) Tiotropium was homogenized with part quantity of HFA and transferred to the mixing vessel.

3) Fluticasoen furoate was homogenized with lecithin and ethanol. 4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added.

5) The resulting suspension was mixed, recirculated and filled in into pre-crimped aluminum cans.

Example 12

Process:

1) Oleic acid was dissolved in ethanol.

3) Fluticasoen furoate was homogenized with oleic acid and ethanol.

4) The suspension obtained instep (3) was transferred to the main mixing vessel where the remaining quantity of HFA was added.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

Claims

CLAIMS:

I . A pharmaceutical composition comprising tiotropium and fluticasone furoate.

2. A pharmaceutical composition according to claim 1, wherein the tiotropium comprises tiotropium bromide.

3. A pharmaceutical composition according to claim 2, wherein the tiotropium bromide comprises tiotropium bromide monohydrate.

4. A pharmaceutical composition according to claim 2, wherein the tiotropium bromide comprises anhydrous crystalline tiotropium bromide.

5. A pharmaceutical composition according to any of the preceding claims, wherein the tiotropium is present in an amount of about 4.5 meg to about 18 meg.

6. A pharmaceutical composition according to any of the preceding claims, wherein the fluticasone furoate is present in an amount of about 25 meg to about 800 meg.

7. A pharmaceutical composition according to any of the preceding claims, further comprising one or more pharmaceutically acceptable excipients.

8. A pharmaceutical composition according to any of the preceding claims, wherein the composition is in a form suitable as a single medicament.

9. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is in a form suitable for inhalation.

10. A pharmaceutical composition according to any one of the preceding claims wherein the composition is in a form suitable for use in a metered dose inhaler.

I I. A pharmaceutical composition according to claim 9 or 10, further comprising a propellant.

12. A pharmaceutical composition according to claim 9, 10 or 11, further comprising an excipient selected from a co-solvent, an antioxidant, a surfactant, a bulking agent, a pH adjusting agent and a lubricant or combinations thereof.

13. A pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is in a form suitable for use as a dry powder inhalation formulation.

14. A pharmaceutical composition according to claim 13, further comprising at least one pharmaceutically acceptable carrier suitable for use in dry powder inhalation formulations.

15. A pharmaceutical composition according to claim 14, wherein said carrier includes a saccharide and/or a sugar alcohol or combinations thereof.

16. A pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is in a form suitable for use as an inhalation solution/suspension.

17. A combination composition according to claim 16, further comprising an excipient selected from a wetting agent, osmotic agent, a pH regulator, a buffering agent and a complexing agent or combinations thereof, provided in a pharmaceutically acceptable vehicle.

18. A pharmaceutical composition according to any one of the preceding claims wherein the composition is in a form suitable for once daily administration.

19. A process for manufacturing a pharmaceutical composition according to any one of the preceding claims, comprising combining tiotropium with fluticasone furoate and, optionally, one or more pharmaceutically acceptable excipients.

20. A method for prophylaxis or treatment of respiratory, inflammatory or obstructive airway disease, in a mammal, such as a human, which method comprises administrating a therapeutically effective amount of a pharmaceutical composition according to any one of the preceding claims 1 to 18.

21. Use of a pharmaceutical composition according to any one of claims 1 to 18 for the treatment of disorders relating to respiratory, inflammatory or obstructive airway disease.

22. Use according to claim 21 , wherein said composition is for once daily administration.

23. Use according to claim 21 or 22, wherein the disease is asthma.

24. A method for prophylaxis or treatment of respiratory, inflammatory or obstructive airway disease, in a mammal, such as a human, which method comprises administrating to a subject in need of, a therapeutically effective amount of fluticasone furoate and tiotropium.

25. A method according to claim 22, wherein the fluticasone furoate and tiotropium is administered once a day.

26. A method of manufacturing a medicament for the treatment of asthma using a fluticasone furoate and tiotropium, as a combined therapy.

27. A method according to claim 24, 25 or 26, wherein the disease is asthma.

28. A pharmaceutical composition substantially as herein described with reference to the examples.

29. A process for making a pharmaceutical composition substantially as herein described with reference to the examples.