WO2020217116A2

WO2020217116A2 - Long acting inhalation compositions of indacaterol

Info

Publication number: WO2020217116A2
Application number: PCT/IB2020/052975
Authority: WO
Inventors: Hiren Patel; Bikash Kumar Sahoo; Sanjay Saha
Original assignee: Orbicular Pharmaceutical Technologies Pvt Ltd
Priority date: 2019-03-28
Filing date: 2020-03-28
Publication date: 2020-10-29
Also published as: WO2020217116A3

Abstract

The present invention relates to stable long acting inhalation composition comprising indacaterol or its acceptable salts at a concentration from about 15 mcg/mL up to about 150 mcg/mL, and optionally comprising one or more anticholinergic agent. It also relates to use of such compositions for the prevention and/or treatment of respiratory, inflammatory or chronic obstructive airway disease (CORD).

Description

LONG ACTING INHLATION COMPOSITIONS OF INDACATEROL

FIELD OF THE INVENTION

The present invention relates to stable long acting inhalation

composition comprising indacaterol or its acceptable salts at a concentration from about 15 mcg/mL up to about 150 mcg/mL, and optionally an

anticholinergic agent and/or corticosteroid. It also relates to use of such compositions for the prevention and/or treatment of respiratory, inflammatory or obstructive airway disease.

BACKGROUND OF THE INVENTION

Chronic obstructive pulmonary disease (COPD) is a severe respiratory condition that makes breathing difficult; increasing its prevalence worldwide and currently the fourth leading cause of death in the UK & US, and predicted to rank third in the global impact of disease by the year 2020.

COPD is a preventable and treatable disease state characterized by air flow limitation that is not fully reversible. The airflow obstruction is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs it also produces significant systemic consequences. COPD is associated with mucus hyper secretion,

emphysema, bronchiolitis.

Currently, therapy for the treatment or prevention of COPD and asthma includes the use of one or more long acting bronchodilators and an inhaled corticosteroid (ICS). The choice of bronchodilators includes beta2-agonists and anticholinergics. Further, beta2-agonists can be short acting for immediate relief, or long acting for long term prevention of asthma symptoms. b2 Adrenergic receptor agonists have become the first-line drugs for the treatment of asthma for many years because of their strong promotion of bronchodilation.

Long acting beta2-agonists (LABAs) improve lung function, reduce symptoms and protect against exercise-induced dyspnea in patients with asthma and COPD. LABAs induce bronchodilation by causing prolonged relaxation of airway smooth muscle. In addition to prolonged bronchodilation, LABAs exert other effects such as inhibition of airway smooth-muscle cell proliferation and inflammatory mediator release, as well as non-smooth- muscle effects, such as stimulation of mucociliary transport, cytoprotection of the respiratory mucosa and attenuation of neutrophil recruitment and activation. The use of a LABA reduces the frequency of drug administration.

Anticholinergic agents also act as bronchodilators and are potential alternatives to beta agonists, particularly LABAs. However, anticholinergics can also be administered along with LABAs for the management of asthma. Anticholinergics 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. Further it would be advantageous to use anticholinergics in patients who are intolerant to the use of beta2- agonists.

It is known that beta2-agonists provide a symptomatic relief in bronchoconstriction, another component of COPD, which is inflammation, requires a separate treatment such as with steroids.

Corticosteroids exhibit inhibitory effects on inflammatory cells and inflammatory mediators involved in the pathogenesis of respiratory disorders such as COPD. Treatment with a corticosteroid/glucocorticoid is considered one of the most potent and effective therapies currently available for COPD.

Indacaterol is chemically known as (R)-5-[2-[(5,6-Diethyl-2,3-dihydro- 1 H-inden-2-yl)amino]-1 -hydroxyethyl]-8-hydroxyquinolin-2(1 H)-one is a ultra- long acting beta2-agonist.

Indacaterol has a fast onset of action which is similar to that of formoterol and faster than that of salmeterol. Furthermore, indacaterol exhibits a longer duration of action than salmeterol as well as has greater

cardiovascular safety margin as compared to salmeterol and formoterol.

Chinese application CN103860463 discloses a propellant-free solution of indacaterol maleate. The composition comprising low concentration of indacaterol maleate i.e. 2pg/mL to 15 pg/mL, isotonicity agent, antioxidant, complexing agent and buffering agent.

U.S. Pat. No. 10,179,139 discloses pharmaceutical composition that includes a beta2-agonist selected from indacaterol and formoterol in combination with a corticosteroid selected from fluticasone and ciclesonide, and, optionally, one or more pharmaceutically acceptable excipients. It also discloses that compositions can be administered as metered dose inhalers (MDI), dry powder inhalers (DPI), nebulizer, nasal spray, nasal drops, insufflation powders. It also discloses inhalation solution of indacaterol in combination with anticholinergic agent and/or corticosteroid, along with other excipients.

It is the objective of the present invention that provides an inhalation solution comprising indacaterol maleate suitable for administration by nebulization has an advantage over other inhalation therapy, since it is easy to use and does not require co-ordination or much effort.

The invention also provides advantages that the compositions doesn’t comprises propellant(s), and the indacaterol maleate solution can be stably stored for a long period of time, and is directly inhaled and administered after atomization, and is convenient to use.

SUMMARY OF THE INVENTION

The present invention relates to stable long acting inhalation composition comprising indacaterol or its acceptable salts.

In one aspect, the present invention, relates to a stable long acting inhalation composition comprising indacaterol or its acceptable salts at a concentration from about 15 mcg/mL up to about 150 mcg/mL.

In another aspect, the present invention also relates to a stable long acting inhalation composition comprising indacaterol or its acceptable salts at a concentration from about 15 mcg/mL up to about 150 mcg/mL, may further comprise one or more anticholinergic agent and/or corticosteroid.

In another aspect, the present invention relates to an inhalation solution comprising indacaterol maleate suitable for administration by nebulization has an advantage over other inhalation therapy.

In another aspect, the present invention relates to stable long acting inhalation compositions of indacaterol maleate are free from propellants, stable for a long period of time.

In one aspect the stable long acting inhalation composition comprising Indacaterol maleate, mannitol or L-arginine or sodium chloride, tartaric acid, sodium tartrate, water for injection, and optionally benzalkonium chloride and EDTA.

In one aspect the stable long acting inhalation composition comprising Indacaterol maleate, mannitol or L-arginine or sodium chloride, citric acid, sodium citrate, water for injection, and optionally benzalkonium chloride and EDTA.

In one aspect the stable long acting inhalation composition comprising Indacaterol maleate, glycopyrrolate, mannitol or L-arginine or sodium chloride, tartaric acid, sodium tartrate, water for injection, and optionally benzalkonium chloride and EDTA.

In one aspect the stable long acting inhalation composition comprising Indacaterol maleate, glycopyrrolate, mannitol or L-arginine or sodium chloride, citric acid, sodium citrate, water for injection, and optionally benzalkonium chloride and EDTA.

In another aspect, the stable long acting inhalation composition comprising Indacaterol maleate, glycopyrrolate, mannitol or L-arginine, tartaric acid, sodium tartrate, water for injection and optionally benzalkonium chloride and EDTA.

In one aspect, the present invention relates to stable long acting inhalation compositions of indacaterol maleate used to treat chronic

obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema and related disorders.

DETAILED DESCRIPTION OF FIGURES

Figure 1 : Graphical depiction of formulations with change in pH.

Figure 2: Graphical depiction of formulations with change in Osmolality.

Figure 3: Graphical depiction of formulations with change in Indacaterol content.

Figure 4: Graphical depiction of Formulations with change in Glycopyrrolate content. DETAILED DESCRIPTION OF THE INVENTION

The term“indacaterol”, is used in broad sense to include not only “indacaterol” but also any pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives,

pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.

The term“glycopyrrolate”, is used in broad sense to include not only “glycopyrrolate” but also any pharmaceutically acceptable salts,

pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.

The present invention relates to stable long acting inhalation

composition comprising indacaterol or its acceptable salts.

In another aspect, the present invention also relates to a stable long acting inhalation composition comprising indacaterol or its acceptable salts at a concentration from about 15 mcg/mL up to about 150 mcg/mL, may further comprising one or more anticholinergic agent and/or corticosteroid.

The present invention relates to an inhalation solution comprising indacaterol maleate suitable for administration by nebulization has an advantage over other inhalation therapy like the compositions of the invention doesn’t comprises propellant(s), can be stored for a long period of time, and is directly inhaled and administered after atomization, and is convenient to use.

The present invention relates to an inhalation solution comprising indacaterol maleate suitable for administration by nebulization has an advantage over other inhalation therapy like the compositions of the invention doesn’t comprises propellant(s), can be stored for a long period of time, and is directly inhaled and administered as a mist, and is convenient to use.

The present invention relates to an inhalation solution comprising indacaterol maleate suitable for administration by nebulization has an advantage over other inhalation therapy like the compositions of the invention doesn’t comprises propellant(s), can be stored for a long period of time, and is directly inhaled and administered as a mist using suitable device, and is convenient to use.

In one embodiment, the composition comprising indacaterol at a concentration of about 10 mcg/mL to about 150 mcg/mL.

In further embodiments, the compositions contain indacaterol at a concentration of about 10 mcg/mL to about 150 mcg/mL.

The indacaterol is formulated, in certain compositions provided herein, at a concentration of about 10 mcg/mL to about 150 mcg/mL.

In further embodiments, the compositions contain indacaterol at a concentration of about 10 mcg/mL to about 140 mcg/mL.

In further embodiments, the compositions contain indacaterol at a concentration of about 10 mcg/mL to about 130 mcg/mL.

In further embodiments, the compositions contain indacaterol at a concentration of about 20 mcg/mL to about 140 mcg/mL.

The stable long acting inhalation compositions comprising indacaterol or its acceptable salts, are formulated with a pharmacologically suitable fluid.

Pharmacologically suitable fluids include, but are not limited to, polar solvents, including, but not limited to, compounds that contain hydroxyl groups or other polar groups. Such solvents include, but are 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.

Polar solvents also include portico solvents, including, but not limited to, water, aqueous saline solutions with one or more pharmaceutically acceptable salt(s), alcohols, glycols or a mixture thereof.

In the embodiments herein, the compositions have a pH of about 2.0 to about 8.0.

In other embodiments, the compositions have a pH of about 4.0 to about 6.0. In another embodiments, the pH is about 4.5 to about 5.5.

In another embodiments, the compositions are formulated at a pH of about 4, 4.4 or 4.6 up to about 5.5, 5.7 or 6. 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 inorganic acids which may be used include one or more of, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid or combinations thereof.

Examples of particularly suitable organic acids which may be used include one or more of, but not limited to, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid or combinations thereof. Examples of bases which may be used include one or more of, but not limited to, aqueous ammonia solution, ammonium carbonate, sodium borate, sodium carbonate, and sodium hydroxide or combinations thereof.

In one embodiment, the buffer, selected from, but not limited to, citric acid/phosphate, acetate, ascorbic acid barbital, borate, tartaric acid, Britton- Robinson, acidulate, citrate, formate, maleate, phosphate, Rideau-Ward, succinct, citrate-phosphate-borate (Teorell- Stanhagen), vernal acetate, MES (2-(N-morpholino) ethane sulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)imino- tris-( hydroxymethyl)methane), ADA (N-(2-actinide)-2-iminodiacetic acid), ACES (N-(carbamoyl methyl)-2- aminoethane sulfonic acid), PIPES

(piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2- hydroxypropanesulfonic acid), BISTRIS PROPANE (1 ,3-bis

(tris(hydroxymethyl)methylamine)propane), BES (N,N-bis (2-hydroxyethyl)-2- aminoethanesulfonic acid), MOPS (3-Nmorpholino) propane sulfonic acid), TES (N-tris (hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N- (2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2- hydroxyethyl)amino)-2-hydroxypropan-esulfomc acid), MOBS (4-(N- morpholino)-butane sulfonic acid), TAPSO (3-(N- tris(hydroxymethyl)methylamine)-2-hydroxypropanesulfonic acid), TRIZMA(® (tris(hydroxymethylaminomethane), HEPPSO (N-(2-hydroxyethylpiperazine- N-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N'-bis(2- hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N- (2- hydroxyethyl)piperazine-N'-(3-propanesulfonic acid), TRICINE (N- tris(hydroxyl-methyl)methyl glycine), GLYGLY (glycylglycine), BICINE (N,N- bis(2-hydroxyethyl) lysine), HEPBS (N-(2-hydroxyethyl)piperazine-N'-(4- butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3- aminopropanesulfonic acid), AMPD (2-amino-2-methyl-1 ,3-propanediol), and/or any other buffers known to those of skill in the art.

In another embodiment the buffer agents may comprise one or more of organic or inorganic acids such as but not limited to citric acid/sodium hydrogensulphate borate buffer, phosphates (sodium hydrogen

orthophosphate, disodium hydrogen phosphate), trometamol, tartrate buffer, acetate buffer, citrate buffer, sodium citrate dehydrate, citric acid

monohydrate, sodium dihydrogen phosphate dehydrate, anhydrous disodium hydrogen phosphate or equivalent conventional buffers.

In one embodiment, the buffer is selected from the group but not limited to citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer, maleate buffer, tartrate buffer and the like or mixtures thereof.

In one embodiment, tonicity adjusting agents may be added to provide the desired ionic strength.

Both inorganic and organic tonicity adjusting agents may be used in the compositions provided herein.

Tonicity adjusting agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tart rate, boric acid, arginine, mannitol, calcium chloride, calcium disodium edentate, calcium glaciate, calcium lactate, citric acid, dextrose,

diethanolamine, dimethyl sulfoxide, edentate disodium, edentate disodium monohydrate, fluoresce in sodium, fructose, galaxies, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, manifold, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium

biphosphate, sodium bisulfate, sodium borate, sodium bromide, sodium acidulate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinct, sodium sulfate, sodium sulfite, sodium tart rate, sodium hyposulfite, orbital, sucrose, tartaric acid, triethanolamine, urea, urethane, Uri dine and zinc sulfate.

The compositions may further comprise other additives like surfactants, stabilizers, complexing agents, antioxidants, or preservatives which prolong the duration of use of the finished pharmaceutical formulation.

Complexing agents include, but are not limited to,

ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as the disodium salt, citric acid, nitrilotriacetic acid and the salts thereof. In one embodiment, the complexing agent is EDTA.

Preservatives include, but are not limited to, those that protect the solution from contamination with pathogenic particles and/or microorganisms including benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate and the like or mixtures thereof.

Antioxidants include, but are not limited to, vitamins, provitamins, ascorbic acid, vitamin E or salts or esters thereof.

Surfactants include, but not limited to Polysorbates such as

polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 65, polysorbate 85, sorbitan fatty acid esters such as Span 20, Span 40, Span 60 Span 80, Span 120; sodium lauryl sulfate; polyethoxylated castor oil;

polyethoxylated hydrogenated castor oil, sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB) Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N,N-dimethyldodecylamine-N-oxide,

Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride.

Carboxylates, Sulphonates, Petroleum sulphonates,

alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters,

Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it’s ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2-alkyl 1 -hydroxyethyl 2-imidazolines, N-coco 3- aminopropionic acid/sodium salt, N-tallow 3-iminodipropionate disodium salt, N-carboxymethyl n-dimethyl n-9 octadecenyl ammonium hydroxide, n- cocoamidethyl n-hydroxyethylglycine sodium salt etc.

The compositions provided herein also may include a cosolvent, which increases the solubility of additives or the active ingredient(s). Co -solvents for use herein include, but are not limited to, hydroxylated solvents or other polar solvents, such as alcohols such as isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, and polyoxyethylene alcohols.

In one embodiment, the stable long acting inhalation composition comprising:

a. Indacaterol maleate

b. L-arginine

c. Tartaric acid

d. Sodium tartrate

e. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising

a. Indacaterol maleate

b. Mannitol

c. Tartaric acid

d. Sodium tartrate

e. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising:

a. Indacaterol maleate

b. Sodium chloride

c. Tartaric acid

d. Sodium tartrate

e. water for injection and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising,

a. Indacaterol maleate

b. L-arginine

c. Citric acid

d. Sodium citrate

e. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising,

a. Indacaterol maleate

b. Mannitol

c. Citric acid

d. Sodium citrate

e. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising,

a. Indacaterol maleate

b. Sodium chloride

c. Citric acid

d. Sodium citrate

e. water for injection

and optionally benzalkonium chloride and EDTA.

In another embodiment of the invention, the compositions may further comprise one or more anticholinergic agent and/or corticosteroid.

In another embodiment of the invention, the compositions may further comprise other beta₂-agonist selected from the group of formoterol, arformoterol, salmeterol, olodaterol, vilanterol, carmoterol; corticosteroids selected from the group of fluticasone, mometasone, beclomethasone, ciclesonide, budesonide, flunisolide; anticholinergic agents selected from the group of aclidinium, glycopyrronium or glycopyrrolate, ipratropium, tiotropium and umeclidinium. In one embodiment, the stable long acting inhalation composition comprising,

a. Indacaterol maleate

b. Glycopyrrolate

c. L-arginine

d. Tartaric acid

e. Sodium tartrate

f. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising,

a. Indacaterol maleate

b. Glycopyrrolate

c. Mannitol

d. Tartaric acid

e. Sodium tartrate

f. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising,

a. Indacaterol maleate

b. Glycopyrrolate

c. Sodium chloride

d. Tartaric acid

e. Sodium tartrate

f. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising

a. Indacaterol maleate

b. Glycopyrrolate

c. L-arginine

d. Citric acid

e. Sodium citrate f. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising

a. Indacaterol maleate

b. Glycopyrrolate

c. Mannitol

d. Citric acid

e. Sodium citrate

f. water for injection

and optionally benzalkonium chloride and EDTA.

In one embodiment, the stable long acting inhalation composition comprising

a. Indacaterol maleate

b. Glycopyrrolate

c. Sodium chloride

d. Citric acid

e. Sodium citrate

f. water for injection

and optionally benzalkonium chloride and EDTA.

The volume of inhalation solution depends on the nebulizer used. In certain embodiments, the volume is from about 0.1 ml_ up to about 5 ml_.

In other embodiments, the volume is about 4 ml_. In other

embodiments, the volume is about 3 ml_. In other embodiments, the volume is about 2 ml_. In other embodiments, the volume is about 1 ml_.

In one embodiment of the invention, a method of treating chronic obstructive pulmonary disease or undesired and/or uncontrolled

bronchoconstriction comprising the steps of:

a. adding a stable long acting inhalation composition comprising

indacaterol or its acceptable salts at concentration from about 15 mcg/mL up to about 150 mcg/mL to a nebulizer;

b. directly administering said composition to a subject in need thereof. In another embodiment of the invention, a method of treating a patient having chronic obstructive pulmonary disease (COPD) or undesired and/or uncontrolled bronchoconstriction, or maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema and similar conditions, comprising administering to the patient, with a high efficiency nebulizers or any advanced or equivalent versions of nebulizers or similar devices, at a dose of indacaterol that produces a significantly improved therapeutic effect in the patient compared to administration of the same dose of the indacaterol with a conventional nebulizer, soft mist inhaler, metered dose inhaler or dry powder inhaler.

To further illustrate the invention, the following examples are provided. It is to be understood that these examples are provided for illustrative purposes and are not to be construed as limiting the scope of the present invention in any manner whatsoever.

Examples:

Example 1 :

Manufacturing Process:

1. Collect 1 10 % of water for injection and further collect 80 % of water for

injection. 2. Add dispensed quantity of Indacaterol and stir for 40 to 80 mins get the clear solution and record pH.

3. Add dispensed quantities of mannitol or arginine for formulations F1 to F4 to the above step and stir for 15- 25 mins till the solution becomes clear.

4. Add sodium tartrate to the above solution and stir for 15-25 mins to get clear homogeneous solution and check the pH.

5. Further add tartaric acid to the above stirred solution and stir for 15 min to get clear solution and check the pH.

6. Finally make up the volume to 100% using water for injection and check the pH.

7. Filter the solution through 0.22m membrane filter and filled to suitable

containers.

Stability Details:

Example 2: Physico-Chemical Stability evaluation of Indacaterol in Inhalation Solution

^*- Clear colourless free from visible particle

Example 3: Physico-Chemical Stability evaluation of Indacaterol and

Glycopyrrolate in Inhalation Solution

^*- Clear colourless free from visible particle

From the above examples of formulations F1 to F5, the stability of aqueous inhalation solution was carried out at two conditions 40°C,75% relative humidity (RH) and 25°C,60% RH for one month. The result indicates that the solution of the present invention remains chemically stable, there is no degradation from initial content of indacaterol in alone and when it is formulated with glycopyrrolate and other physical parameters like pH, osmolality, viscosity remain same. Further per formulation F5, addition of sodium EDTA as chelating agent and

benzalkonium chloride as preservative aids in the physicochemical stability of the drug product.

Claims

We Claim,

1. A stable long acting inhalation composition comprising indacaterol or its acceptable salts at concentration from about 15 mcg/mL up to about 150 mcg/mL.

2. The composition according to claim 1 , indacaterol is in the range from about 20 mcg/mL to about 140 mcg/mL.

3. The composition according to claim 1 , further comprises tonicity adjusting agents, buffers, solvents, preservatives, antioxidants, complexing agents and the like.

4. The composition according to claim 3, tonicity adjusting agent selected from but not limited to L-arginine, mannitol, sorbitol, D-arabitol, erythritol, sodium chloride, sugars such as sucrose, dextrose, and the like or mixtures thereof;

buffers selected from but not limited to tartrate buffer, acetate buffer, citrate buffer and phosphate buffer;

solvents include water for injection.

5. A stable long acting inhalation composition comprising,

a. indacaterol maleate

b. mannitol or L-arginine

c. tartaric acid

d. sodium tartrate

e. water for injection

and optionally benzalkonium chloride and EDTA.

6. The composition according to claim 1 , may further comprising one or more anticholinergic agent and/or corticosteroid.

7. A stable inhalation composition comprising,

a. indacaterol maleate

b. glycopyrrolate

c. mannitol or L-arginine

d. tartaric acid

e. sodium tartrate

f. water for injection

and optionally benzalkonium chloride and EDTA.

8. The composition according to preceding claims, is used to treat chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema and related disorders.

9. The composition according to claim 1 , having a pH between about 4.5 to about 5.5.

10. The composition according to preceding claims, can be administered as nebulizer, nasal spray, nasal drops, soft mist inhaler or nebulized aerosol.