DESC:FIELD OF INVENTION:
The present invention relates to pharmaceutical compositions comprising a long acting muscarinic antagonist (LAMA) and at least one long-acting beta adrenergic agonist (LABA) for inhalation via nebulization, and processes for preparing the compositions. The invention also relates to methods of treatment and/or prevention of respiratory, inflammatory or obstructive airway disease and the use of the said composition.

BACKGROUND OF INVENTION:
Chronic obstructive pulmonary disease (COPD) causes significant morbidity and mortality throughout the world. Airflow limitation in COPD is persistent and incompletely reversible, which leads to potentially distressing symptoms, decreased exercise tolerance, and poor quality of life. It has been estimated that in 2030, COPD will be the fourth leading cause of death worldwide resulting in an economic and social burden that is both substantial and increasing. The clinical manifestations of COPD include severity of respiratory symptoms, frequency of exacerbations, severity of spirometric abnormalities and type of co-morbidity cause a gradual decline in functional ability and greater dependence upon health and social care support with both aging and disease progression. COPD is associated with mucus hyper secretion, emphysema, bronchiolitis.

Asthma is also common respiratory disease in the world and is a significant cause of morbidity worldwide. It 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. An increased inflammatory response is a major part of the pathophysiology of acute asthma and regular preventive treatment of the same is very important.

Current medical treatment to treat COPD and asthma aims to manage symptoms, maintain physical activity and pulmonary function, and prevent exacerbations. Bronchodilators are the mainstay of pharmacologic therapy for chronic obstructive pulmonary disease (COPD), and asthma. The principal bronchodilator treatments include administration of beta-agonists, muscarinic antagonists and methylxanthines. Short-acting agents are usually used for immediate relief of symptoms, whereas long-acting inhaled agents are generally preferred and are more convenient for maintenance treatment of COPD. Long-acting inhaled bronchodilators used for treatment of stable chronic obstructive pulmonary disease (COPD) include two classes of pharmacological agents: long acting beta-agonists (LABA) and long acting muscarinic antagonists (LAMA). Long-acting beta-agonist bronchodilators (LABAs) act at beta adrenergic receptors in bronchial smooth muscle to cause bronchodilation, improve lung function, reduce symptoms, protect against exercise-induced dyspnea in patients with asthma and COPD, and induce bronchodilation by causing prolonged relaxation of airway smooth muscle. The use of ?2-agonists may decline with old age.

Long acting muscarinic antagonists are anticholinergics that act by competing with acetylcholine for the receptor sites at vagus nerve or nerve-muscle junctions. This prevents the transmission of reflexes that are induced by asthma stimuli. Use of anticholinergics provides an advantage in elderly patients as the responsiveness of anticholinergics does not decline with old age.

These agents can be used as monotherapy or in combination therapy. Monotherapy with some of these pharmacotherapeutic agents may give rise to side effects such as general malaise, cough, agitation, insomnia, anxiety, trembling fingers, sweating and headaches. When respiratory symptoms are not controlled with monotherapy, combination therapy is recommended. The advantages of combination therapy include better lung function and improved symptoms. Further, combination therapy reduces the cost and provides control of respiratory disorders. Reducing the dose frequency to the minimum is a main step in simplifying COPD management for improving patient adherence to the therapy. Specifically, as airflow obstruction becomes more severe, both a long-acting muscarinic antagonist (LAMA) plus a long-acting beta-agonist (LABA) can be used.
Further, the treatment of asthma and COPD need quick onset of action of drugs, longer duration of action of drugs, improved control of obstructive or inflammatory airway diseases, reduction in the exacerbations of the diseases and minimum dosage administration especially in pediatric & elderly patients. Even from the patient compliance point of view, the treatment requires for the patient to comply with different dosage regimens, different frequencies of administration etc. Efforts to improve compliance have been aimed at by simplifying the medication packaging, providing effective medication reminders, improving patient education and limiting the number of medications prescribed simultaneously. The use of combination of long acting bronchodilators provides these benefits along with reduction in frequency of drug administration and providing patient compliance.

Currently, some marketed formulations of combinations of long-acting ß agonist (LABA) and long acting muscarinic antagonist (LAMA) are available. Some of these formulations for the treatment of asthma and/ or chronic obstructive pulmonary disease (COPD) are Tiotropium (LAMA) and Olodaterol (LABA) inhalation solution (Spiolto Respimat®/ Stiolto Respimat®) which is administered as two puffs by using a unique soft mist inhaler known as Respimat device to deliver the recommended dose; and Glycopyrronium bromide (LAMA) and Indacaterol (LABA) (Ultibro Breezhaler®) powder inhalation packed in hard capsules which is to be administered only using the dry powder inhaler i.e. Breezhaler.

Most of the available combinations of a long-acting ß agonist (LABA) with long acting muscarinic antagonist (LAMA) have to be administered twice daily. Some of these formulations come in multiple dosage units that need to be adjusted or diluted to suitable concentrations according to the dose prescribed. This may cause dose manipulation resulting in non-adherence to the administration of recommended dose. Alternately, these formulations may need to be administered using costly and complicated devices. These pose several problems with final dose to be administered and could possibly impact the delivery device in long term use.

WO2015173153 discloses combination product comprising an inhalable long-acting muscarinic antagonist (LAMA) composition combined with an inhalable fixed-dose composition comprising budesonide and formoterol.

US20150258021 discloses solution formulation for inhalation which contain one or more active substances in a solvent selected from among water, ethanol and water-ethanol mixtures; and at least one inert, non-volatile excipient.

WO2015181360 discloses an inhalable medicament of solid amorphous particles comprising an intimate admixture of two or three active ingredients selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta- agonist (LABA) and an inhaled corticosteroid (ICS), together with a pharmaceutically acceptable co-solid.

EP2999460 discloses a suspension composition for respiratory delivery of a long-acting muscarinic antagonist (LAMA), a long-acting beta adrenergic agonist (LABA), and an inhaled corticosteroid (ICS) from a metered dose inhaler (MDI).

US20040132759 describes inhalable powders of Tiotropium and Indacaterol for the treatment of inflammatory or obstructive diseases of the respiratory tract, particularly asthma and/or COPD.

US9757365 discloses pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt thereof, water, a complexing agent, the complexing agent being disodium EDTA and 0.9% by weight of sodium chloride, the pH of the composition ranges from 2.5 to 3.0 and the said composition is free of preservative, and the composition is contained in a prefilled container.

However, none of the above mentioned prior arts specifically disclose a composition comprising combination of Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof with at least one long acting beta adrenergic agonists (LABA) or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof such as Indacaterol or its pharmaceutically acceptable salts or Vilanterol or its pharmaceutically acceptable salts for inhalation via nebulization. Moreover, none of these prior arts mention or disclose stable inhalable composition of combination of Tiotropium bromide with Indacaterol maleate or Tiotropium bromide with Vilanterol trifenatate that can be administered once or twice daily for the prevention or treatment of respiratory, inflammatory or obstructive airway disease prepared using simple method of manufacturing. Hence, there still remains a need to formulate inhalable pharmaceutical compositions comprising Tiotropium bromide with at least one long-acting beta adrenergic agonist (LABA) such as Indacaterol or its salts, or Vilanterol or its salts which are stable, easy to manufacture, convenient to handle and simplify the dosage regimen by administering an effective amount of Indacaterol maleate with Tiotropium bromide or Vilanterol trifenatate with Tiotropium bromide once or twice daily and can be administered with the help of a nebulizer (e.g. high efficiency nebulizer) for relieving symptoms associated with COPD, asthma and related respiratory disorders.

OBJECT OF THE INVENTION:
An object of the present invention is to provide a pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonists or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or its pharmaceutically acceptable salt or vilanterol or its pharmaceutically acceptable salt for inhalation via nebulization.

Another object of the present invention is to provide an inhalable pharmaceutical composition comprising Tiotropium or its pharmaceutically acceptable salt and at least one long acting beta adrenergic agonists or its pharmaceutically acceptable salt for once or twice daily administration.
Yet another object of present invention is to provide an inhalable pharmaceutical composition comprising Tiotropium or its or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and minimum pharmaceutically acceptable excipients in pharmaceutically acceptable amount, thus reducing the unwanted interaction among the actives and excipient.

Further another object of the present invention is to provide a mode of administration of an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof using simple, user friendly and inexpensive nebulizer device.

The object of the present invention is to provide an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or its or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof or vilanterol or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof for administration via nebulization in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.

Yet another object of the present invention is to provide a simple process for preparing the pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and one or more pharmaceutically acceptable excipients.
A further object of the present invention is to provide a method for the treatment or prevention of asthma, COPD or a related respiratory disorder, which method comprises administering a pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate, physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof

SUMMARY OF THE INVENTION:
According to a first aspect of the present invention, there is provided a pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one LABA or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof or vilanterol or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof for inhalation via nebulization.

According to second aspect of the present invention, there is provided an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist (LABA) or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof for once or twice daily administration.

According to third aspect of the present invention, there is provided an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and minimum pharmaceutically acceptable excipients in pharmaceutically acceptable amount, thus reducing the unwanted interaction among the actives and excipient.
According to fourth aspect of the present invention, there is provided a mode of administration of a stable inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof using simple, user friendly and inexpensive nebulizer device.

According to a fifth aspect of the present invention, there is provided an inhalable pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one long acting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof selected from indacaterol or its pharmaceutically acceptable salt or vilanterol or its pharmaceutically acceptable salt for administration via nebulization in the prevention or treatment of respiratory, inflammatory or obstructive airway disease.

According to sixth aspect of the present invention there is provided a simple process for preparing the pharmaceutical composition comprising Tiotropium or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and at least one longacting beta adrenergic agonist or a pharmaceutically acceptable salt, solvate , physiologically functional derivative thereof and one or more pharmaceutically acceptable excipients.

According to seventh aspect of the present invention, there is provided a use of the inhalable pharmaceutical composition as described above in the treatment or prevention of asthma, COPD or a related disorder.

DETAILED DESCRIPTION OF THE INVENTION:
Although, drug therapy with a long-acting beta adrenergic agonist ( LABA) and long acting muscarinic antagonist (LAMA) has been recommended for the prevention or treatment of respiratory, inflammatory or obstructive airway disease such as asthma and chronic obstructive pulmonary disease (COPD), various aspects such as different dosage regimens, method of administration as well as the different frequencies of drug administration are needed to be simplified.

Further, selecting a combination of a LABA and LAMA is critical since both drugs should be capable of being administered once or twice daily. It is as well critical to select a limited set of excipients and evaluate its compatibility with the specific LABA and LAMA for the purposes of ensuring stability, and whether such stable inhalation formulation is capable of being administered without much effort using a simple, and user friendly nebulizer device. It is also necessary that such stable inhalation formulation has suitable characteristics so that the nebulizer device used to deliver the formulation should not block the device orifice or cause any damage to the componentry of the device resulting in nonuniformity of dose of actives during administration.

Thus, due to the need to formulate a stable and efficient inhalation composition which can be administered once or twice daily for the prevention of conditions that respond to or are prevented, ameliorated or eliminated by the administration of a LABA and a LAMA , the inventors of the present invention have surprisingly found that compositions comprising Tiotropium or its pharmaceutically acceptable salt and selected LABA with selective set of excipients are stable and can be administered once or twice a day achieving required therapeutic effect relatively easily with the help of simple, user friendly device via nebulization.

As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. “Exemplary” means “an example of” and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes.

According to the present invention, the long acting muscarinic antagonist (LAMA) is Tiotropium. The term “Tiotropium” is used in broad sense to include not only “Tiotropium” per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable esters, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complex, pharmaceutically acceptable co-crystals etc. Tiotropium salts include acid addition salts such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid and p-toluenesulfonic. In a preferred embodiment, the Tiotropium salt in the pharmaceutical composition described herein is Tiotropium bromide, such as Tiotropium bromide monohydrate ((1a,2ß,4ß,7ß)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02,4]nonane bromide, monohydrate).
The pharmaceutical composition of the present invention may include from about 0.0001% to about 1% w/w of Tiotropium or its salt (such as Tiotropium bromide). In an embodiment, the pharmaceutical composition of the present invention preferably may include from about 0.001% to about 0.05% w/w of Tiotropium or its salt (such as Tiotropium bromide).

According to the embodiments of present invention, the LABA include ,but are not limited to arformoterol, bambuterol, clenbuterol, formoterol, salmeterol, abediterol, carmoterol, Indacaterol , olodaterol , Vilanterol and any combinations thereof.

In a preferred embodiment, the LABA in the present invention is Indacaterol or its pharmaceutically acceptable salt. More preferably, LABA in the present invention is Indacaterol maleate.

In an embodiment, the amount of LABA in the formulation of present invention is from about 0.001% to 1.0% w/w. In one embodiment, the amount of Indacaterol maleate that can be included in the formulation of present invention is from about 0.01% to about 0.9% w/w. Preferably, the amount of Indacaterol maleate that can be included in the present invention is from about 0.03% to about 0.75% w/w. In yet another preferred embodiment, the LABA in the present invention is Vilanterol or its pharmaceutically acceptable salt. More preferably, the LABA in the present invention is Vilanterol trifenatate.In one embodiment, the amount of Vilanterol trifenatate that can be included in the formulation of present invention is from about 0.001% to about 1.0 % w/w. Preferably, the amount of vilanterol trifenatate in the present invention is from about 0.005% to about 0.5% w/w .

It has been surprisingly found that Tiotropium bromide in inhalable combination formulation with Indacaterol maleate or Vilanterol trifenatate provides relief from respiratory disorders while simultaneously reducing the frequency of dosage administration when administered via nebulizer.
The present invention thus provides a novel combination for inhalation comprising Tiotropium or its pharmaceutically acceptable salt in combination with Indacaterol or its pharmaceutically acceptable salt, or Vilanterol or its pharmaceutically acceptable salt for the prevention or treatment of respiratory, inflammatory or obstructive airway disease while simultaneously reducing the frequency of dosage administration.

In embodiments in which the composition of the present invention is administered once a day, a single dose may provide the daily dose. Alternatively, the daily dose may comprise multiple doses of the composition, e.g. two doses, which can be taken at the same time if administered once a day In embodiments in which the composition of the present invention is administered twice a day then both the doses may provide the daily dose. The daily dose may comprise multiple doses of composition e.g two or more than two doses and can be taken at different times if administered twice a day.

The dose of tiotropium bromide delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day. The dose of indacaterol or its pharmaceutically acceptable salt delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day in one or multiple doses. The dose of indacaterol or its pharmaceutically acceptable salt delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day in one or multiple doses. The dose of vilanterol or its pharmaceutically acceptable salt delivered in per inhalation of formulation is 0.001 to 0.01% w/w of total formulation when the formulation is administered once or twice a day in one or multiple doses.

The ratio of Indacaterol maleate to Tiotropium bromide in the composition of the invention is preferably from about 50:1 to about 0.5:1, preferably from about 25:1 to about 5:1.

The ratio of Vilanterol trifenatate to Tiotropium bromide in the composition of the invention is preferably from about 50:1 to about 0.5:1, preferably from about 25:1 to about 5:1.

In one embodiment, the inhalable pharmaceutical composition is a unit dose nebulizable pharmaceutical composition for inhalation comprising Tiotropium or its salt with at least one LABA. The pharmaceutical composition of present invention may be administered in nebulized form to relieve bronchospasm in a subject, such as a subject suffering from COPD. Nebulization is a safe therapy to deliver or deposit medications directly into the respiratory tract and hence achieve higher drug concentrations. It is easy to use, does not require co-ordination or much effort and works much more rapidly than medicines taken by mouth.

According to embodiment of present invention, the inhalable pharmaceutical composition comprising Tiotropium or its pharmaceutically acceptable salt and at least one LABA administered via nebulizer is in the form of suspension, solution and the like.

The nebulizable composition of present invention comprising Tiotropium or its pharmaceutically acceptable salt and at least one LABA further comprises one or more pharmaceutically acceptable excipients selected from stabilizer (or complexing agent), isotonic agent or tonicity adjusting agent, pH modifier, buffer, vehicle, preservatives and the combinations thereof. The pharmaceutical composition of the present invention thus may be administered through nebulizers.
The stabilizers or complexing agents, according to the present invention, may comprise, but are not limited to, edetic acid (EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate), trisodium edetate, edetate calcium disodium edetic acid, citric acid or its hydrate salt, sodium metabisulfite, potassium metabisulfite, ascorbic acid, ascorbyl palmitate, alpha tocopherol, nitrilotriacetic acid, fumaric acid, malic acid, maltol, pentetic acid and the salts or combinations thereof. The stabilizers or complexing agent are used in the formulation of present invention in an amount from about 0.01% to 0.5 % about w/w. Preferably, the formulations according to the invention contain a complexing agent in an amount from about 0.025% to about 0.3 % w/w.

Tonicity agents, that may be used, comprise sodium chloride, potassium chloride, zinc chloride, calcium chloride, boric acid and the like or combinations thereof. Other tonicity agents may also include, but are not limited to, mannitol, glycerol, and dextrose and the like or combinations thereof. The tonicity agents are used in the formulation of present invention in an amount from about 0.05% to 1.0 % w/w.
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 and the like or combinations thereof.

In another embodiment of the present invention, the inhalation composition has a pH from about 2.0 to about 6.0. In another embodiment, the composition has a pH from about 2.0 to about 4.0. The preferred pH range of Tiotropium bromide and Indacaterol maleate composition or Tiotropium bromide and Vilanterol trifenatate composition is from about 2.0 to about 4.5, preferably from about 2.5 to 3.5.

The inhalation composition of the present invention may contain sodium citrate at a concentration of about 0.1 to about 1.0% w/w and citric acid at a concentration of about 0.1 to 1.0% w/w to control pH.

The inhalation composition may optionally include a buffer. General and biological buffers in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES, BIS-TRIS, ADA, ACES, PIPES, MOPSO, BIS-TRIS PROPANE, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, TRIZMA, HEPPSO, POPSO, TEA, EPPS, TRICINE, GLY-GLY, BICINE, HEPBS, TAPS, and AMPD buffers.

According to the present invention, the preservative may comprise one or more of benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate and the like or combinations thereof and such other preservatives which may be known to the person having a skill in the art.

The nebulizable compositions of the present invention are formulated with a pharmacologically acceptable fluid acting as a vehicle for the dissolution of the actives to facilitate nebulization and delivery of the actives into the lungs of a patient. Pharmacologically suitable fluids include, but are not limited to, polar solvents, including, but not limited to, water or alcohols, such as ethanol, isopropanol, and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene alcohols or combination thereof. According to embodiment of present invention, the preferred vehicle is water in an amount sufficient to maintain Tiotropium or its pharmaceutically acceptable salt and at least one LABA or its pharmaceutically acceptable salt in liquid form such as suspension or solution for a considerable amount of time.
The inhalable compositions of the present invention may or may not comprises of stabilizer or complexing agent. In an embodiment of present invention, the composition comprises.

Tiotropium or its pharmaceutically acceptable salt, at least one LABA or its pharmaceutically acceptable salt selected from indacaterol or vilanterol , pharmaceutically acceptable excipients selected from isotonic agent or tonicity adjusting agent, pH modifier, buffer, vehicle, preservatives or the combinations thereof and water. In another embodiment of the present invention, the inhalable composition comprises Tiotropium or its pharmaceutically acceptable salt, at least one LABA or its pharmaceutically acceptable salt selected from indacaterol or vilanterol , pharmaceutically acceptable excipients selected from stabilizer (or complexing agent), isotonic agent or tonicity adjusting agent, pH modifier, buffer, vehicle, preservatives or the combinations thereof and water.

The compositions according to the present invention may be packed in suitable containers provided with means of enabling the delivery /deposition of the contained formulation to the respiratory tract.

Another embodiment of the present invention is a prepackaged, sterile, premixed, premeasured composition comprising Tiotropium bromide and at least one LABA or its pharmaceutically acceptable salt for inhalation administered via nebulizer. Preferably, the composition of the present invention is a ready-to-use composition which does not require any mixing or dilution by the subject prior to administration via nebulizer. The composition may be administered via nebulizer for the relief of bronchospasm in a subject suffering from COPD.

Yet another embodiment is a method of administering pharmaceutical composition of present invention comprising Tiotropium or its pharmaceutically acceptable salt and at least one LABA by inhalation via a nebulizer to a subject a pharmaceutical composition of the present invention.
Yet another embodiment is a method of relieving bronchospasm (such as that associated with COPD) comprising administering by inhalation via nebulizer to a subject in need thereof a pharmaceutical composition of the present invention.

Another embodiment of the present invention is a kit having one or more prefilled containers containing a pharmaceutical composition of the present invention. In one embodiment, each container comprises a single unit dose of pharmaceutical inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LABA or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients. In one embodiment, the kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LABA or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or single unit dose. In another embodiment, the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured single unit dose vials comprising a pharmaceutical composition of the present invention comprising a therapeutically effective amount of Tiotropium or its pharmaceutically acceptable salt and at least one LABA or its pharmaceutically acceptable salt), and instructions for using the same. In specific embodiment of present invention, kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Indacaterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or single unit dose form. In yet another specific embodiment, kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Vilanterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or single unit dose form .

Still, another embodiment of the present invention is a kit having container containing a pharmaceutical composition of the present invention. In one embodiment, the container comprises multiple doses of pharmaceutical composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LABA or its pharmaceutically acceptable salt. In one embodiment, the kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and at least one LABA or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed for multiple dose form.. In another embodiment, the prepackaged inhalation kit and/or system comprises one or more premixed, premeasured for multiple dose vials comprising a pharmaceutical composition of the present invention comprising a therapeutically effective amount of Tiotropium or its pharmaceutically acceptable salt and at least one LABA or its pharmaceutically acceptable salt and instructions for using the same.

In specific embodiment of present invention, kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Indacaterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed and/or for multiple dose form.

In yet another specific embodiment, kit and/or system comprises an inhalation composition of the present invention comprising a therapeutically effective amount of Tiotropium or its salt and Vilanterol or its pharmaceutically acceptable salt in a prepackaged, premeasured, premixed for multiple dose form.

Yet another embodiment is a kit comprising a nebulizer, instructions for using the nebulizer and the unit dose vials containing the pharmaceutical compositions of the present invention.

Yet another embodiment is a kit , suitable for once daily administration via inhalation, which comprises:
(i) a nebulizer;
(ii) a nebulizable composition comprising
(a) Tiotropium or its pharmaceutically acceptable salt;
(b) LABA;
(c) water; and
(d) pharmaceutically acceptable excipients

Yet another embodiment of the present invention is a kit, suitable for once or twice daily administration via inhalation, which comprises:
(i) a nebulizer;
(ii) a nebulizable composition comprising
(a) Tiotropium or its pharmaceutically acceptable salt;
(b) Indacaterol or its pharmaceutically acceptable salt;
(c) water; and
(d) pharmaceutically acceptable excipients.

Yet another embodiment of the present invention is a kit, suitable for once or twice daily administration via inhalation, which comprises:
(i) a nebulizer;
(ii) a nebulizable composition comprising
(a) Tiotropium or its pharmaceutically acceptable salt;
(b) Vilanterol or its pharmaceutically acceptable salt;
(c) water; and
(d) pharmaceutically acceptable excipients

Yet another particular embodiment of the present invention is a kit, suitable for once or twice daily administration via inhalation, comprising:
(i) a nebulizer;
(ii) a nebulizable composition comprising
(a) Tiotropium or its pharmaceutically acceptable salt;
(b) Indacaterol or its pharmaceutically acceptable salt;
(c) stabilizer comprising one or more of EDTA, ascorbic acid, or citric acid; and
(d) water
Yet another embodiment of the present invention is a kit, suitable for once or twice daily administration via inhalation, comprising:
(i) a nebulizer;
(ii) a nebulizable composition comprising
(a) Tiotropium or its pharmaceutically acceptable salt;
(b) Vilanterol or its pharmaceutically acceptable salt;
(c) stabilizer comprising one or more of EDTA, ascorbic acid, sodium metabisulfite or citric acid; and
(d) water
According to another embodiment of present invention, the compositions provided herein are intended for administration to a subject in need of such treatment via nebulization. Nebulizers that nebulize liquid formulations containing no propellant are suitable for use with the compositions provided herein.

Suitable nebulizers include, but not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and breadth actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow. The nebulizer being equipped with a mouthpiece or suitable face mask. The inhalation solution may be administered by nebulizers manufactured, designed or sold by Philips Respironics, such as Philips InnoSpire Go or I-neb Advance or InnoSpire Essence nebulizer system or InnoSpire Elegance nebulizer system. Other nebulizers may also include those manufactured, designed, or sold by Aerogen such as Aerogen Solo or Aerogen Ultra or Aerogen Pro. Additionally, the formulations described herein can also be nebulized using inhalers other than those described above, for example jet-stream inhalers.

A further embodiment of the present invention is to provide a process for making an inhalation composition comprising Tiotropium or its pharmaceutically acceptable salt, at least one LABA or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients. In one embodiment, the process comprises dissolving Tiotropium or its salt in stabilizing agent (pH 3.0 maintained by suitable pH adjusting agent). Adding LABA in above solution of Tiotropium salt and stirring well to obtain clear solution. Optionally adding suitable pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution of Tiotropium salt and LABA prepared above, and optionally adjusting the pH of the mixture with a pharmaceutically acceptable acid followed by filtering the formulation (for example, with a 0.2 micron filter); and filling a suitable container with the formulation.

In another embodiment, the process comprises the steps of (a) dissolving stabilizing agent in water with suitable pH; (b) adding Tiotropium or its salt to the above solution; (c) adding Indacaterol or its salt to the above solution and maintaining the pH; (d) optionally addition of pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution of step (d); (e) optionally adjusting the pH of the solution with a pharmaceutically acceptable acid; (f) optionally filtering the solution (for example, with a 0.2 micron filter); and (g ) filling a suitable container with the formulation .

In another embodiment, the process comprises the steps of (a) dissolving stabilizing agent in water with suitable pH; (b) adding Tiotropium or its salt to the above solution (c) adding Vilanterol or its salt to the above solution and maintaining the pH (d) optionally addition of pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution of step (d); (e) optionally adjusting the pH of the solution with a pharmaceutically acceptable acid; (f) optionally filtering the solution (for example, with a 0.2 micron filter); and (e) filling a suitable container with the formulation .

In an alternative embodiment of present invention, the process comprises the steps of dissolving tiotropium or its salt in water at suitable pH , adding LABA selected from Indacaterol or Vilanterol or its pharmaceutically acceptable salt to the above solution and maintaining the pH, optionally addition of pharmaceutically acceptable excipients such as a buffer, tonicity adjusting agent, or any combination thereof, to the solution and adjusting the pH of the solution with a pharmaceutically acceptable acid; optionally filtering the solution (for example, with a 0.2 micron filter) and filling a suitable container with the formulation .

According to the present invention, there is provided a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001% to about 0.05 % w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.03% to about 0.75% w/w Indacaterol or its pharmaceutically acceptable salt thereof; c) about 0.01% to about 0.5 % w/w stabilizing agent comprising disodium EDTA, ascorbic acid, sodium metabisulfite or citric acid; d) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection; and f) other pharmaceutically acceptable excipients wherein the pH of the pharmaceutical composition is about 2 to about 4.

According to the present invention, there is provided a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001 % to about 0.05% w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.005 % to about 0.5% w/w Vilanterol or its pharmaceutically acceptable salt thereof; c) about 0.01% to about 0.5% w/w stabilizing agent comprising disodium EDTA, ascorbic acid, sodium metabisulfite or citric acid; d) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection, and f) other pharmaceutically acceptable excipients, wherein the pH of the pharmaceutical composition is about 2 to about 4.

According to the present invention, there is provided a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001% to about 0.05 % w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.03% to about 0.75% w/w Indacaterol or its pharmaceutically acceptable salt thereof; c) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection; and f) other pharmaceutically acceptable excipients wherein the pH of the pharmaceutical composition is about 2 to about 4.

According to the present invention, there is provided a pharmaceutical composition suitable for administration with a nebulizer comprising: a) about 0.001 % to about 0.05% w/w Tiotropium or its pharmaceutically acceptable salt thereof; b) about 0.005 % to about 0.5% w/w vilanterol or its pharmaceutically acceptable salt thereof; c) about 0.05% to about 1.0% w/w sodium chloride; e) water for injection, and f) other pharmaceutically acceptable excipients, wherein the pH of the pharmaceutical composition is about 2 to about 4.

According to some embodiments, the pharmaceutical compositions of the present invention may be also administered by any suitable methods used for delivery of the drugs to the respiratory tract. The composition of the present invention may thus also be administered as metered dose inhalers (MDI), aerosol, drops, nasal drops, a nasal spray or an inhalation solution.and the like. Accordingly, the various dosage forms as per the present invention may comprise one or more pharmaceutically acceptable carriers/excipients suitable for formulating the same selected from co-solvents, surfactants, non-volatile component, bulking agent, buffering agent, pH adjusting agent, preservative, complexing agent,
In one embodiment, the composition of the present invention is stored and administered in a suitable container which, when in contact, do not hamper the stability of the pharmaceutical composition. Suitable containers as envisaged under the present invention are made of materials such as low density polyethylene (LDPE) or high density polyethylene (HDPE) or Polypropylene (PP), or PET or mixtures thereof.

The present invention also provides a method for the treatment in a mammal, such as a human, for treating chronic obstructive pulmonary disease and asthma, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention. The present invention further provides a mode of administration to a mammal such as human for treating chronic obstructive pulmonary disease and asthma, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention using nebulizer device.

The present invention also provides use of the pharmaceutical composition according to the present invention for the prevention or treatment of asthma, COPD or a related disorder.

It may be well acknowledged to a person skilled in the art that the said pharmaceutical composition, according to the present invention, may further comprise additional active(s) selected from inhaled corticosteroids, antihistamines, antiallergics or leukotriene antagonist and the like or combinations thereof or their pharmaceutically acceptable salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
The following examples are for illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1: Tiotropium and Indacaterol inhalation composition
Table 1: Formulation of Tiotropium and Indacaterol inhalation composition
S.no Ingredients Quantity
(% w/w)
1 Indacaterol maleate 0.0388
2 Tiotropium bromide monohydrate 0.00224
3 Disodium edetate 0.05
4 Sodium chloride 0.9
5 Hydrochloric acid 1M (to pH 3.0) Q.S.
6 Water for Injection (WFI) Q.S.

Process:
1) Disodium edetate was dissolved in Water for Injection and the pH was maintained upto 3 by adding Hydrochloric acid.
2) Tiotropium bromide monohydrate was added to above solution and stirred till it solubilized completely.
3) Indacaterol maleate was added and stirred well to obtain clear solution.
4) Sodium chloride was added to the above step and allowed to solubilize completely.
5) pH and osmolality were measured of the solution.
6) The final volume was made up to 100% with remaining WFI and the solution was filtered through 0.22 micron PVDF filter.
7) The solution was packed in suitable container.

Example 2: Tiotropium and Indacaterol inhalation composition
Table 2: Formulation of Tiotropium and Indacaterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Indacaterol maleate 0.0388
2 Tiotropium bromide monohydrate 0.00224
3 Disodium edetate 0.05
4 Sodium chloride 0.9
5 Citric acid monohydrate 0.35
6 Trisodium citrate dihydrate 0.1
7 WFI Q.S.
Process:
1) Disodium edetate was dissolved in Water for Injection.
2) Citric acid monohydrate was added to above solution and stirred to dissolve completely.
3) Tiotropium bromide monohydrate was added to the above solution and stirred.
4) Indacaterol maleate was added to above solution and stirred well to obtain clear solution.
5) Sodium chloride, Trisodium citrate dihydrate was added to the above solution.
6) Observed visually and measured pH and osmolality of the solution. The final volume was made up to 100% with remaining WFI and filtered the solution through PVDF filter.
7) The solution was packed in suitable container.

Example 3: Tiotropium and Indacaterol inhalation composition
Table 3 : Formulation of tiotropium and Indacaterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Indacaterol maleate 0.0388
2 Tiotropium bromide monohydrate 0.00224
3 Ascorbic acid 1.02
4 Sodium chloride 0.9
5 Hydrochloric acid 1M (to pH 3.0) Q.S.
6 WFI Q.S.
Process:
1) Ascorbic acid was dissolved in Water for Injection and maintained the pH upto 3 by adding Hydrochloric acid.
2) Tiotropium bromide monohydrate was added to above solution and stirred till solubilize completely.
3) Indacaterol maleate was added and stirred well to obtain clear solution.
4) Sodium chloride was added to the above step and allowed to solubilize completely.
5) Observed visually and measured pH and osmolality of the solution
6) The final volume to 100% with remaining WFI. Filtered the solution through 0.22 micron PVDF filter
7) The solution was packed in suitable container.

Example 4 : Tiotropium and Indacaterol inhalation composition
Table 4 : Formulation of tiotropium and Indacaterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Indacaterol maleate 0.0388
2 Tiotropium bromide monohydrate 0.00224
3 Sodium chloride 0.9
4 Citric acid monohydrate 0.35
5 Trisodium citrate dihydrate 0.1
6 WFI Q.S.
Process:
1) Citric acid monohydrate and trisodium citrate dehydrate were added in Water for Injection and maintained the pH.
2) Tiotropium bromide monohydrate was added to above solution and stirred till solubilize completely.
3) Indacaterol maleate was added to above solution and stirred well to obtain clear solution.
4) Sodium chloride was added to the above step and allowed to solubilize completely
5) Observed visually and measured pH and osmolality of the solution
6) The final volume to 100% with remaining WFI. Filtered the solution through 0.22 micron PVDF filter
7) The solution was packed in suitable container.

Example 5 : Tiotropium and Vilanterol inhalation composition
Table 5: Formulation of Tiotropium and Vilanterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Vilanterol Trifenatate 0.016
2 Tiotropium bromide monohydrate 0.00224
3 Disodium edetate 0.05
4 Sodium chloride 0.9
5 Citric acid monohydrate 0.35
6 Trisodium citrate dihydrate 0.1
7 WFI Q.S.
Process:
1) Disodium edetate was dissolved in Water for Injection.
2) Citric acid monohydrate was added to above solution and stirred to dissolve completely.
3) Tiotropium bromide monohydrate was added to the above solution and stirred till solubilize completely.
4) Vilanterol Trifenatate was added to above solution and stirred well to obtain clear solution.
5) Sodium chloride, Trisodium citrate dehydrate was added to the above solution.
6) Observed visually and measured pH and osmolality of the solution. The final volume was made up to 100% with remaining WFI and filter the solution through PVDF filter.
7) The solution was packed in suitable container.

Example 6: Tiotropium and Vilanterol inhalation composition
Table 6 : Formulation of tiotropium and Vilanterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Vilanterol Trifenatate 0.16
2 Tiotropium bromide monohydrate 0.00224
3 Disodium edetate 0.05
4 Sodium chloride 0.9
5 Hydrochloric acid Q.S.
6 WFI Q.S.
Process:
1) Disodium edetate was dissolved in Water for Injection and maintained the pH upto 3 by adding Hydrochloric acid.
2) Tiotropium bromide monohydrate was added to above solution and stirred till solubilize completely.
3) Vilanterol Trifenatate was added to above solution and stirred well to obtain clear solution.
4) Sodium chloride was added to the above step and allowed to solubilize completely
5) Observed visually and measured pH and osmolality of the solution
6) The final volume to 100% with remaining WFI. Filtered the solution through 0.22 micron PVDF filter
7) The solution was packed in suitable container.

Example 7: Tiotropium and Vilanterol inhalation composition
Table 7: Formulation of tiotropium and Vilanterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Vilanterol Trifenatate 0.016
2 Tiotropium bromide monohydrate 0.00224
3 Ascorbic acid 1.02
4 Sodium chloride 0.9
5 Hydrochloric acid 1M (to pH 3.0) Q.S.
6 WFI Q.S.
Process:
1) Ascorbic acid was dissolved in Water for Injection and maintained the pH upto 3 by adding Hydrochloric acid.
2) Tiotropium bromide monohydrate was added to above solution and stirred till solubilize completely.
3) Vilanterol Trifenatate was added to above solution and stirred well to obtain clear solution.
4) Sodium chloride was added to the above solution and allowed to solubilize completely
5) Observed visually and measured pH and osmolality of the solution
6) The final volume to 100% with remaining WFI. Filtered the solution through 0.22 micron PVDF filter
7) The solution was packed in suitable container.

Example 8: Tiotropium and Vilanterol inhalation composition
Table 8: Formulation of tiotropium and Vilanterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Vilanterol Trifenatate 0.016
2 Tiotropium bromide monohydrate 0.00224
3 Sodium chloride 0.9
4 Citric acid monohydrate 0.35
5 Trisodium citrate dihydrate 0.1
6 WFI Q.S.

Process:
1) Citric acid monohydrate and trisodium citrate dehydrate were dissolved in Water for Injection and maintained the pH.
2) Tiotropium bromide monohydrate was added to above solution and stirred till solubilize completely.
3) Vilanterol Trifenatate was added to above solution and stirred well to obtain clear solution.
4) Sodium chloride was added to the above step and allowed to solubilize completely
5) Observed visually and measured pH and osmolality of the solution
6) The final volume to 100% with remaining WFI. Filtered the solution through 0.22 micron PVDF filter
7) The solution was packed in suitable container.

Example 9: Tiotropium and Vilanterol inhalation composition
Table 9: Formulation of tiotropium and Vilanterol inhalation composition
S.no Ingredients Quantity
mg/1 ml
1 Vilanterol Trifenatate 0.016
2 Tiotropium bromide monohydrate 0.00224
3 Sodium metabisulfite 1.00
4 Sodium chloride 0.9
5 Hydrochloric acid 1M (to pH 3.0) Q.S.
6 WFI Q.S.
Process:
1) Sodium metabisulfite was dissolved in Water for Injection.
2) Tiotropium bromide monohydrate was added to above solution and stirred till solubilize completely.
3) Vilanterol Trifenatate was added to above solution and stirred well to obtain clear solution.
4) Sodium chloride was added to the above step and allowed to solubilize completely
5) Observed visually and measured pH and osmolality of the solution. Maintained the pH by adding Hydrochloric acid.
6) The final volume to 100% with remaining WFI. Filtered the solution through 0.22 micron PVDF filter
7) The solution was packed in suitable container.

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.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
,CLAIMS:1. A pharmaceutical formulation comprising tiotropium, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and a one long acting beta adrenergic agonists, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and pharmaceutically acceptable excipients.

2. The pharmaceutical formulation according to claim 1 wherein the amount of tiotropium and its pharmaceutically acceptable salt is from about 0.0001% to about 1% w/w of the formulation.

3. The pharmaceutical formulation according to claim 1 and 2, wherein said tiotropium is present as tiotropium bromide.

4. The formulation according to claim 1 , wherein the long acting beta adrenergic agonists is selected from arformoterol, bambuterol, clenbuterol, formoterol, salmeterol, abediterol, carmoterol, indacaterol , olodaterol , vilanterol or their pharmaceutically acceptable salts , solvates, functional derivative.

5. The formulation according to claim 4, wherein the long acting beta adrenergic agonists is selected from indacaterol maleate, vilanterol trifenatate or combination thereof.

6. The formulation according to any of claims 1 to 5, wherein the long acting beta adrenergic agonists is present in an amount from about 0.001% to 1.0% w/w of the formulation.

7. The formulation according to any of claims 1 to 6 wherein the ratio of long acting beta adrenergic agonist or its pharmaceutically acceptable salt and tiotropium or its pharmaceutically acceptable salt is from about 50:1 to about 0.5:1.

8. The formulation according to any of claims 1 to 7, further comprises a stabilizer, tonicity agents, pH modifier, buffer, vehicle, preservatives and the combinations thereof.

9. The formulation according to claims 1 to 8, wherein the stabilizer comprises of edetic acid (EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate), trisodium edetate, edetate calcium disodium edetic acid, citric acid or its hydrate salt, sodium metabisulfite, potassium metabisulfite, ascorbic acid, ascorbyl palmitate, alpha tocopherol, nitrilotriacetic acid, fumaric acid, malic acid, maltol, pentetic acid and the salts or combinations thereof.

10. The formulation according to claim 9, wherein the stabilizer is present in an amount from about 0.01% to 0.5 % about w/w of the formulation.

11. The formulation according to any of claims 1 to 9 wherein the tonicity agent comprises of sodium chloride, potassium chloride, zinc chloride, calcium chloride, boric acid mannitol, glycerol, and dextrose and the like or combinations thereof.

12. The formulation according to claim 11, wherein the tonicity agent is present in an amount from about 0.05% to 1.0 % w/w of the formulation.

13. The formulation according to claims 1 to 9 wherein the pH modifier comprises of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid and the like or combinations thereof.
14. The formulation of any of claims 1 to 9 wherein the preservative comprises of benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate and the like or combinations thereof.

15. The formulation according to any of claims 1 to 14 wherein the pH of the formulation is pH from about 2.0 to about 6.0.

16. The formulation of claims 1 to 15 further comprises a pharmacologically acceptable fluid selected from water or alcohols, such as ethanol, isopropanol, and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene alcohols or combination thereof.

17. The formulation according to any of claims 1 to 16 wherein the formulation is suspension or solution suitable for inhalation.

18. The formulation according to claim 17, wherein the formulation is in the form of an aerosol, drops, nasal drops, a nasal spray or an inhalation solution.

19. The formulation of the present invention according to proceeding claims is administered by metered dose inhalers (MDI), dry powder inhalers (DPI), nebulizer.

20. A pharmaceutical formulation comprising
(i) Tiotropium or its pharmaceutically acceptable salt;
(ii) Indacaterol or its pharmaceutically acceptable salt;
(iii) stabilizer comprising one or more of EDTA, ascorbic acid, or citric acid; and
(iv) water
21. A pharmaceutical formulation comprising
(i) Tiotropium or its pharmaceutically acceptable salt;
(ii) Vilanterol or its pharmaceutically acceptable salt;
(iii) stabilizer comprising one or more of EDTA, ascorbic acid, or citric acid; and
(iv) water

22. The formulation according to claim 21 and 22, wherein the formulation is administered in nebulized form.

23. The formulation according to any of the preceding claims, wherein the formulation does not require any mixing or dilution prior to administration.

24. The formulation according to any of the preceding claims, wherein the formulation is available as a prepackaged, premeasured single unit dose vial.

25. The formulation according to claim 24, wherein composition is available as a prepackaged, premeasured two or more unit dose vials.

26. A kit comprising a nebulizer, instructions for using the nebulizer and the unit dose vials containing formulation according to any of the preceding claims.

27. The kit according to claim 26, wherein the nebulizer is selected from a jet nebulizer, ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer.

28. A kit according to claim 27, wherein the kit contains one or more unit dose vials containing the formulation according to the preceding claims.

29. A composition according to any of claims 1-21, wherein the composition is contained in a prefilled container.

30. A composition according to claim 29, wherein the container is a low density polyethylene container.

31. A method of relieving bronchospasm associated with chronic obstructive pulmonary disease by administering the formulation according to any of claims 1-21.

32. A process of preparing a pharmaceutical formulation according to any of the claims 1-22, wherein the process comprises the steps of:
(a) dissolving tiotropium or its pharmaceutically acceptable salt thereof
in water;
(b) addition of pharmaceutically acceptable excipients such as a buffer, complexing agent, tonicity adjusting agent, or any combination thereof, to the solution of step (a);
(c) adding solution of long acting beta adrenergic agonists or its pharmaceutically acceptable salt thereof
(d) optionally adjusting the pH of the solution (for example, the solution of step (a) or step (b) with a pharmaceutically acceptable acid;
(e) filtering the solution; and
(f) filling a suitable container with the solution.

33. A pharmaceutical formulation comprising from about 0.0001% to about 1% w/w tiotropium or a pharmaceutically acceptable salt thereof, about 0.01% to about 0.5% w/w EDTA or a pharmaceutically acceptable salt thereof, about 0.05% to about 1.0% w/w sodium chloride sodium chloride, wherein the composition has a pH in the range of about 2.0 to about 4.0.

34. A pharmaceutical solution suitable for administration with a nebulizer consisting essentially of
(a) about 0.0001% to about 1% w/w tiotropium or a pharmaceutically acceptable salt thereof,
(b) about 0.01% to about 0.5% disodium EDTA;
(c) about 0.05% to about 1.0% sodium chloride; and
(d) water,
wherein the pH of the pharmaceutical composition is about 2.7.

35. The pharmaceutical composition according to any proceeding claims wherein the effective amount of formulation is administered once or twice a day.

36. A method of treatment or prevention of asthma, COPD or a related disorder comprising administering by nebulization an effective amount of formulation as claimed in the preceding claims.