WO2024157282A1

WO2024157282A1 - Pharmaceutical compositions of green propellant

Info

Publication number: WO2024157282A1
Application number: PCT/IN2024/050067
Authority: WO
Inventors: Kiran ROTE; Pradeep Bhadauria
Original assignee: Cipla Limited
Priority date: 2023-01-24
Filing date: 2024-01-24
Publication date: 2024-08-02

Abstract

Described herein are compositions of pMDIs for administration of medications, wherein the composition comprises a green propellant, an active ingredient, and a pharmaceutical acceptable excipient. The invention further describes a process for preparation of said green-propellant based composition.

Description

PHARMACEUTICAL COMPOSITIONS OF GREEN PROPELLANT

PRIORITY DETAILS

This application claims the benefit of Indian Provisional Application No. 202321004627 filed on January 24, 2023, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF AN INVENTION

The invention relates to a pharmaceutical composition for inhalation comprising an active pharmaceutical ingredient and a pharmaceutically acceptable green propellant. Particularly, disclosed is a pharmaceutical composition for inhalation comprising an active pharmaceutical ingredient selected from the group consisting of an inhaled corticosteroid, a short acting beta agonist, a long-acting beta agonist, a long-acting muscarinic antagonist, or combinations thereof and a pharmaceutically acceptable green propellant HFA-152a and/or HFO-1234ze(E). Also disclosed are processes for preparing such compositions and method for preventing or treating respiratory disorders using such compositions.

BACKGROUND OF INVENTION

Hydrofluoroalkane (HFAs), have been used as propellants in pressurized metered dose inhalers (pMDIs) for many years. They replaced chlorofluorocarbons (CFCs), which were ozone depletion agents. HFAs were introduced in 1987 as an alternative propellant in inhalers. Two HFAs in particular - 1,1,1,2-tetrafluoroethane (HFA- 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) are commonly used as propellants to deliver and aerosolize medicines from pMDIs. These offer many of the same benefits as CFCs for many inhalation device applications - high propellant performance and non-toxicity in humans - but also have the advantage of not interacting with the ozone layer. As a result, HFA-containing drug devices have become widespread across the globe. However, they do have a significant drawback. They have a relatively high global warming potential (GWP), meaning that they trap relatively high levels of solar heat in the atmosphere - in doing so, they contribute significantly to climate change (UK Progress on reducing F-gas Emissions Fifth report of session 2017-19, published on 25 April 2018 by authority of the House of Commons). GWP is the heat absorbed by any greenhouse gas in the atmosphere, as a multiple of the heat that would be absorbed by the same mass of carbon dioxide (CO2). The GWP of CO2 is 1. For other gases, it depends on the gas and the time frame. The higher the figure, the higher the GWP. 1, 1,1,2- Tetrafluoroethane (HFC-134a), which is commonly used in pMDIs, has a GWP of 1430, meaning it absorbs 1430 times more heat than the same mass of CO2.

The pressurized inhaler (pMDI) market is expected to grow at 7. 1% CAGRto reach more than 2Bn USD mark and hence the number of inhalers to be dispensed accordingly. Therefore, failure to find more sustainable alternative propellants now could mean that patients will lose access to vital and effective inhalation drug products in the future. There is growing concern among consumers and among businesses about reducing their own environmental impact. Increasingly, consumers and businesses are taking measures to reduce their environmental footprint. More and more, businesses want to engage and partner with suppliers that are equally “green”. The pharmaceutical industry has been exploring alternatives to standard propellants for use in inhalation drug delivery devices and other medical devices. The two potential “greener” candidates currently being considered are : 1,1 -Difluoroethane (HFA-152a) and 1,3,3,3-Tetrafluoropropene (HFO-1234ze(E)). These nextgeneration propellants have several key benefits for inhalation drug developers. They are more environmentally friendly than traditional HFAs, exhibiting a lower GWP. HFA-152a, for example has a GWP of 124 compared with the 1430 for traditional inhaler propellant 1,1,1,2-Tetrafluoroethane (HFC-134a). HFO- 1234ze(E), meanwhile has a GWP of less than 1, lower even than CO2. These GWP figures mean that, when in the atmosphere, both HFA-152a and HFO-1234ze(E) do not trap as much heat from the sun, resulting in a less significant global heating effect. In addition, they have a far shorter atmospheric life (AL) compared with existing propellants. HFA-152a, for example, has an AL of 1.4 years, compared with 14 years for currently used inhaler propellants. This means that these new- generation propellants remain in the atmosphere for less time than traditional alternatives, further minimizing their warming effect and environmental impact (https://www.recipharm.com/system/files?file=MDIs%20Tackling%20a%20chan ging%20climate.pdf).

While they offer important and exciting environmental benefits, the new generation of propellants does have certain disadvantages that need to be considered before they are adopted by the pharmaceutical industry. These include: (1) the use of these new propellants is still in its infancy not just in the pharma space, but elsewhere in the economy, and it is too early to say whether they are straightforward and effective replacements for traditional propellants, (2) as with other gases, both HF A- 152a and HFO-1234ze(E) have their own unique properties that means further work have to be done adjusting pMDIs device designs in order to create an effective finished product with an adequate shelf life. Further, while considering new propellant in drug formulation, there are several other factors to be determined such toxicology of propellant, interaction of new propellant with drug and device, interaction of new propellant with manufacturing equipment etc. Even after doing all these, the pharmaceutical companies must pass the regulatory barriers and make the product commercially available to patients at an affordable price.

US patent 9,114,164; US patent 9,517,216; US patent 10,959,965; US patent application 2021/0244688A1 and US patent application 2021/0244688A1 disclosed the aerosol compositions of salbutamol sulphate with HFA-152a. US patent 10,792,256 disclosed the aerosol compositions of salmeterol with HFA- 152a. US patent 10,258,568 disclosed the aerosol compositions of beclomethasone and/or fluticasone propionate along with HFA-152a. US patent 10,888,546 disclosed the aerosol compositions of glycopyrronium bromide and fluticasone propionate and/or Indacaterol along with HFA-152a. US patent 11,103,480 disclosed aerosol compositions of budesonide and glycopyrronium and formoterol along with HFA-152a. US patent 11,103,480 disclosed aerosol compositions of beclomethasone and glycopyrronium and formoterol along with HFA-152a. US patent application 2021/0322377A1 disclosed the aerosol compositions of glycopyrronium and formoterol along with HFA-152a. US patent 11,260,052 disclosed aerosol compositions of indacaterol along with HFA-152a. US patent application 2019/0374519 Al disclosed aerosol compositions oftiotropium along with HFA-152a. US patent application 2019/0247339 Al disclosed aerosol compositions of budesonide and formoterol along with HFA-152a. US patent application 2018/0264007A1 disclosed aerosol compositions of mometasone and/or formoterol along with HFA-152a. US patent application 2020/0009089A1 disclosed aerosol compositions of beclomethasone and/or formoterol along with HFA-152a. PCT publication W02022/029403A1; US patent application US 2021/0275439A1; US patent application US 2021/0393598A1 disclosed aerosol compositions of fluticasone and/or vilanterol and/or umeclidinium along with HFA- 152a. US patent application US 2022/0040086A1 disclosed aerosol compositions of ipratropium along with HFA-152a.

US patent US 9,308,199 broadly disclosed compositions of HFO-1234ze(E). The PCT publications WO 2023/283438A1, WO 2023/283439A1, and WO 2023/283441 Al disclosed aerosol compositions of aerosphere™ based budesonide, glycopyrronium and formoterol along with HFO-1234ze(E) or FIFA- 152a.

There is a need for a pMDI aerosol formulation that has a reduced GWP in comparison with HFA-134a and HFA-227ea, that has acceptable flammability and toxicity performance, which forms stable suspensions or solutions with an active pharmaceutical ingredient selected from the group consisting of an inhaled corticosteroid, a short acting beta agonist, a long-acting beta agonist, a long-acting muscarinic antagonist, or combinations thereof.

SUMMARY OF INVENTION Disclosed is a pharmaceutical composition for inhalation comprising an active pharmaceutical agent and a green propellant. In one embodiment, the composition further comprises a pharmaceutically acceptable excipient. In another embodiment, the active pharmaceutical agent is selected from the group consisting of an inhaled corticosteroid, a short acting beta agonist, a long-acting beta agonist, a long-acting muscarinic antagonist, or combinations thereof. In yet another embodiment, the inhaled corticosteroid is selected from, but not limited to, beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate or furoate, methyl-prednisolone, mometasone furoate, prednisone, and triamcinolone or salt or ester or combination thereof; the short acting beta agonist is selected from, but not limited to, albuterol (salbutamol), levalbuterol (levosalbutamol), metaproterenol, and terbutaline or salt or ester or combination thereof; the long- acting beta agonist is selected from, but not limited to, bambuterol, clenbuterol, formoterol, arformoterol, salmeterol, carmoterol, milveterol, indacaterol acetate or maleate, vilanterol trifenatate and saligenin- or indole-containing and adamantyl- derived P2 agonists or salt or ester or combination thereof; the long-acting muscarinic antagonist is selected from, but not limited to, glycopyrronium bromide or chloride, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium, atropine, benzatropin, umeclidinium and oxitropium or salt or ester or combination thereof. In yet another embodiment, the green propellant is selected from HFA- 152a and HFO-1234ze(E) or combination thereof. In yet another embodiment, the pharmaceutically acceptable excipient is selected from a co-solvent, a surfactant, a pH adjusting agent such as weak acid or mineral acid, or combination thereof. In still another embodiment, the co-solvent is selected from, but not limited to, ethanol, glycerol, polyethylene glycol or combination thereof; the surfactant is selected from, but not limited to, oleic acid, sorbitan trioleate, sorbitan mono-oleate, polyvinylpyrrolidone, magnesium stearate, stearic acid, calcium stearate, sodium stearate, glycerol monostearate and sodium stearyl fumarate or combinations thereof.

In another embodiment, provided is a method of preventing or treating a respiratory disorder such as asthma, chronic obstructive pulmonary disorder, chronic cough and respiratory disorders or diseases caused by allergy using the pharmaceutical composition for inhalation comprising an active pharmaceutical agent and a green propellant disclosed here. The compositions of this inventions are suitable for oral or nasal inhalation route. The administration or delivery of compositions can be done using pressurized metered dose inhaler (pMDI) or breath actuated inhaler (BAI) or nebulizer (Neb).

Also provided herein are process of preparing a pharmaceutical composition for inhalation comprising an active pharmaceutical agent and a green propellant.

DETAILED DESCRIPTION

Unless specifically defined otherwise, the technical terms, as used herein, have their normal meaning as understood in the art. The following terms are specifically defined for the sake of clarity. The term “active pharmaceutical ingredient or active agent” is used interchangeably herein to include an agent such as drug, compound, composition, or other substance that may be used on, or administered to, a human or animal for any purpose, including therapeutic, pharmaceutical, pharmacological, diagnostic, cosmetic, and prophylactic agents and immunomodulators. Active agents may be used interchangeably with the terms drug, pharmaceutical API, medicament, drug substance, or therapeutic agent.

“Mass median aerodynamic diameter” or “MMAD” as used herein refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol contains particles with an aerodynamic diameter smaller than the MMAD, with the MMAD being calculated according to monograph 601 of the United States Pharmacopoeia (“USP).

“Extra fine particle” as used herein refers to the particle having MMAD less than 2pm or preferably less than 1 m.

“Extra fine aerosol formulation or composition or extra fine suspension” as used herein refers to the composition having more than 50% or 60% or 70% or 80% or 90% or 95% of particle having MMAD less than 2pm or preferably less than 1pm.

A “therapeutically effective amount” is the amount of compound which achieves a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of a disease or disorder, specifically respiratory disorder. A therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease or disorder in a patient; returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder; and/or reduces the likelihood of the onset of the disease or disorder.

The terms “stable” or “chemical stable” refer to composition wherein the individual degradation products of active agent remain below the limits specified by regulatory requirements during the shelf life of the product for human use (e.g., 1% of total chromatographic peak area per ICH guidance Q3B(R2)) and there is acceptable mass balance (e.g., as defined in ICH guidance Q1E) between active agent assay and total degradation products.

The term “substantial” refers to more than 90% or 95% or 99% or 99.99%. For e.g., the propellant substantially free of any impurities means that the impurities in or associated with propellant are less than 10% or less than 5% or less than 1% or absent in the propellant.

The term “%w/w” refers to the weight of an active or excipient by weight of the composition.

The active agent in the invention is an inhaled corticosteroid, a short acting beta agonist, a long-acting beta agonist, a long-acting muscarinic antagonist, or combinations thereof and used in the treatment and control of several respiratory- related disorders, but particularly asthma and chronic obstructive pulmonary disease (COPD). The active agent is conveniently delivered using pMDI or breath actuated MDI (BAI). HF A- 152a (Zephex® 152a) is a new, sustainable medical propellant that has been under development by Koura for several years for use in pMDI’s for treatment of respiratory disorders such as asthma and COPD. Below are some specific physicochemical characteristics of HFA-152a. Apart from HFA-152a, hydrofluoroolefms (HFOs), a family of unique products that offer comparable performance to today’s most widely used stationary and mobile refrigerants, blowing agents and aerosol propellants. HFO-1234ze(E) (Solstice) is trans-1, 3,3,3- tetrafluoroprop-l-ene. The suffix (E) indicates that it is an isomer. The other isomer (suffix (Z)) is cis-l,3,3,3-tetrafhioroprop-l-ene. The physical properties of the (E) and (Z) isomers are different: both are ultralow GWP molecules with GWP<1. In an embodiment, the green propellant is substantially pure that is more than 99% or 99.95% or 99.99% pure and substantially devoid of any toxic impurity.

A pressurised metered dose inhaler is an inhaler which delivers an aerosolised dose of a pharmaceutical composition using a pressurised liquefied propellant. A pressurised metered dose inhaler typically comprises a canister (or vial) comprising a liquid pharmaceutical composition, a metering valve, an actuator, and a mouthpiece. For stability improvement of composition, various canister specifications such as 19ml coated canister, 14ml plain, 14ml coated can also be used. Similarly, various capacity valves such as 25mcl, 50mcl can also be used to minimise the retention of the active agent within the canister. Further, the actuator can be fitted with currently available or known dose counters. To improve the performance of the product through shelf life, use of various valve having gasket such as EPDM, nitrile, COCE, Buna etc can be used. Similar types of canister or valves may be used in case of breath actuated inhaler. The pressurised metered dose inhalers are well known to those of ordinary skill in the art, and many such devices are commercially available, with representative devices including AeroBid Inhaler System (Forest Pharmaceuticals), Atrovent Inhalation Aerosol (Boehringer Ingelheim), FloventR™ (GlaxoSmithKline), Maxair Inhaler (3M), ProventilR™ Inhaler (Schering) and SereventR™ Inhalation Aerosol (GlaxoSmithKline). Further, various breath actuated inhalers present in market are Synchrobreathe™, Redihaler™, Easibreathe™, K-haler® and other available breath actuated inhalers. Also, the invention composition (solution or suspension) can also be delivered using currently available nebulizers such as Respimat®, Philips I-Neb™ (Philips), the Pari LC Sprint (Pari GmbH), the AERx® Pulmonary Delivery System (Aradigm Corp.) and the Pari LC Plus Reusable Nebulizer (Pari GmbH).

In a first embodiment of this invention, disclosed is a pharmaceutical composition for inhalation comprising an active pharmaceutical agent and a green propellant. In another embodiment, the composition further comprises a pharmaceutically acceptable excipient. In another embodiment, the active pharmaceutical agent is selected from the group consisting of an inhaled corticosteroid, a short acting beta agonist, a long-acting beta agonist, a long-acting muscarinic antagonist, or combinations thereof. In yet another embodiment, the inhaled corticosteroid is selected from, but not limited to, beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone or salt or ester or combination thereof; the short acting beta agonist is selected from, but not limited to, albuterol, levalbuterol, metaproterenol, and terbutaline or salt or ester or combination thereof; the long- acting beta agonist is selected from, but not limited to, bambuterol, clenbuterol, formoterol, arformoterol, salmeterol, carmoterol, milveterol, indacaterol, vilanterol trifenatate and saligenin- or indole-containing and adamantyl-derived P2 agonists or salt or ester or combination thereof; the long-acting muscarinic antagonist is selected from, but not limited to, glycopyrronium, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium, atropine, benzatropin, umeclidinium and oxitropium or salt or ester or combination thereof. In yet another embodiment, the green propellant is selected from HFA-152a and HFO-1234ze(E) or combination thereof. The green propellant is present in at least about 50% or 60% or 70% or 80% or 90% or 99% w/w of the composition. In some embodiments, both HFA-152a and HFO1234ze(E) are present in a composition and their individual concentration ranges from 50% to 99%. For e.g, if HFA-152a is present in 50% w/w then HFO- 1234ze(E) is present in from 30% to about 49% w/w of the composition. So, if the concentration of HFA-152a is decreased below 50% w/w then concentration of HFO-1234ze(E) can be increased to more than 30% to match the q.s. in the composition depending on the weights of other active and excipients in the composition. In yet another embodiment, the pharmaceutically acceptable excipient is selected from a co-solvent, a surfactant, or pH adjusting agent such as mineral acid or weal acid or combination thereof. In still another embodiment, the cosolvent is selected from, but not limited to, ethanol, glycerol, polyethylene glycol or combination thereof; the surfactant is selected from, but not limited to, oleic acid, sorbitan trioleate, sorbitan mono-oleate, polyvinylpyrrolidone, magnesium stearate, stearic acid, calcium stearate, sodium stearate, glycerol monostearate and sodium stearyl fumarate or combinations thereof. The mineral acid or weak acid is selected from but not limited to, hydrochloric acid, sulphuric acid, tartaric acid, citric acid, boric acid, malic acid, oxalic acid, lactic acid, succinic acid, phosphoric acid, acetic acid and likes. Compositions obtained is in the form of solution or suspension depending upon the solubility of respective active agent in propellant or co-solvent. In general, in suspension for inhalation, the particle size (MMAD) of active agent is between 1 micron to 5 micron, preferably between 2 to 4 microns. In another embodiment, the active agent has extrafme particle size that is less than 1 micron.

In another embodiment, provided is a method of preventing or treating a respiratory disorder such as asthma, chronic obstructive pulmonary disorder (COPD), chronic cough and respiratory disorders or diseases caused by allergy using the pharmaceutical composition for inhalation comprising an active pharmaceutical agent and a green propellant disclosed here. The composition may be used for rescue or maintenance treatment of asthma or maintenance treatment of COPD. The compositions of this inventions are suitable for oral or nasal inhalation route. The administration or delivery of compositions can be done using pressurized metered dose inhaler (pMDI) or breath actuated inhaler (BAI) or nebulizer (Neb). Also provided herein are process of preparing a pharmaceutical composition for inhalation comprising an active pharmaceutical agent and a green propellant.

The compositions of various active agents with green propellants are disclosed herein: A. Compositions of Beclomethasone Dipropionate:

In one embodiment, disclosed is a pharmaceutical composition for inhalation comprising beclomethasone or salt or ester thereof, a green propellant selected from HFA-152a and HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition comprising beclomethasone or salt or ester thereof, a green propellant selected from HFA-152a and HFO-1234ze(E), and co-solvent. In another embodiment, the beclomethasone or ester thereof is present as beclomethasone dipropionate. The beclomethasone dipropionate is present in a concentration from about 0.001% w/w to about 1% w/w, or from about 0.01% w/w to about 0.1 %w/w, or preferably from about 0.05%w/w to about 0.7%w/w of the composition, or most preferably in about 0.42%w/w of the composition. In another embodiment, the green propellant is HFO-1234ze(E) or HFA-152a and is present in the concentration of at least 80% or 90% or 95% or 99% w/w of the composition. In alternate embodiment, the green propellant is a combination of HFO-1234ze(E) and HFA-152a; wherein the HFO-1234ze(E) is present in the concentration from 1% to about 99% w/w of the composition; and wherein the HFA-152a is present in the concentration from 99% to about 1% w/w of the composition. Alternatively, the composition comprises a combination of the green propellant (HFA-152a and/or HFO-1234ze(E)) and non-green propellant (HFA-134 and/or HFA-227a). In yet another embodiment, the composition further comprises the co- solvent which is ethanol and is present in the concentration from about 1% to about 15% w/w of the composition. In some embodiments, ethanol is present in about 15% w/w in beclomethasone containing compositions. Alternatively, in some embodiments, the co- solvent is glycerol, polyethylene glycol (various grades can be used such as PEG 1000) or combination thereof; wherein the glycerol or polyethylene glycol is present in the concentration from about 0.3% to about 2% w/w of the composition.

In another embodiment, provided is a pharmaceutical composition for inhalation comprising beclomethasone dipropionate in a concentration of about 0.08%, 0.17%, 0.34% or 0.42%w/w, ethanol in a concentration of about 15% w/w and a green propellant HFO-1234ze(E) in a concentration of about 84% w/w of the composition.

In another embodiment, provided is a pharmaceutical composition for inhalation comprising beclomethasone dipropionate in a concentration of about 0.08%, 0.17%, 0.34% or 0.42%w/w, glycerol in a concentration of about 1.3% w/w and a green propellant HFO-1234ze(E) in a concentration of about 84% w/w of the composition.

In another embodiment, provided is a pharmaceutical composition for inhalation comprising beclomethasone dipropionate in a concentration of about 0.08%, 0.17%, 0.34% or 0.42% w/w, polyethylene glycol in a concentration of about 0.3% w/w and a green propellant HFO-1234ze(E) in a concentration of about 84% w/w of the composition.

In some embodiment, the above beclomethasone compositions can be made by replacing green propellant HFO-1234ze(E) with HFA-152a. The beclomethasone compositions obtained herein are in the form of solution or suspension. The beclomethasone compositions are suitable for administration by inhalation route using pMDI, BAI or nebulizers available in the market.

B. Budesonide and Salbutamol Compositions

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a combination of budesonide or salt or ester thereof, and salbutamol or salt or ester thereof, a green propellant selected from HFA-152a and HFO- 1234ze(E). In another embodiment, the budesonide or salt thereof is present as budesonide; and wherein the salbutamol or salt thereof is present as salbutamol sulphate. In another embodiment, the composition further comprises a co-solvent, a surfactant or combination thereof.

The composition comprises budesonide in a concentration from about 0.001% w/w to about 1 % w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.3% w/w of, or most preferably about 0.17% w/w, or 0.22% w/w the composition. The pharmaceutical composition comprises salbutamol sulphate and is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.3% w/w of, or most preferably about 0.17% w/w, or 0.22% w/w the composition.

The green propellant is HFO-1234ze(E) or HFA-152a and is present in a concentration of at least 80% or 90% or 95% or 99% w/w of the composition. Alternatively, the green propellant is a combination of HFO-1234ze(E) and HFA- 152a; wherein the HFO-1234ze(E) is present in the concentration from 1% to about 99% w/w of composition; and wherein the HFA- 152a is present in the concentration from 99% to about 1% w/w of composition.

In another embodiment, the co- solvent is ethanol, polyethylene glycol or combination thereof. In one embodiment, the co- solvent is ethanol and is present in the concentration from about 0.5 to 2% w/w, or in about 2% w/w of the composition. In alternate embodiment, the co-solvent is polyethylene glycol and is present in the concentration from about 0.01%to about 0.5% w/w, or in about 0.1% w/w of the composition. In yet another embodiment, the surfactant is polyvinylpyrrolidone and is present in the concentration from about 0.0001% to about 0.05% w/w or in about 0.001% w/w of the composition. In yet another embodiment, the surfactant is oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof and is present in the concentration from about 0.001% to about 0.5% w/w, or in about 0.03% w/w of the composition. In yet another embodiment, the surfactant is magnesium stearate and is present in the concentration from about 0. 1% to about 0.2% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate and a combination of green propellant HFA-152a and HFO-1234ze(E); wherein the HFA-152a and HFO- 1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate and a combination of green propellant HFA-152a or HFO-1234ze(E) and non-green propellant HFA- 134a; wherein the HFA-152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from UFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide and about 0.17% or about 0.22% w/w of salbutamol sulphate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w of ethanol, and agreen propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, the budesonide is suspended or completely dissolved in a propellant system. Similarly, salbutamol is suspended or completely dissolved in a propellant system. Alternatively, budesonide is suspended in a propellant system and salbutamol is completely dissolved in a propellant system.

C. Ciclesonide Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a ciclesonide or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). In another embodiment, the composition further comprises a co-solvent, a surfactant or combination thereof. The compositions comprise ciclesonide and is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.15% or about 0.2% or about 0.3% w/w, or 0.4% w/w the composition. The green propellant is HFO-1234ze(E) or HFA-152a and is present in a concentration of at least 80% or 90% or 95% or 99% w/w of the composition. Alternatively, the green propellant is a combination of HFO-1234ze(E) and HFA- 152a; wherein the HFO-1234ze(E) is present in the concentration from 1% to about 99% w/w of composition; and wherein the HFA- 152a is present in the concentration from 99% to about 1% w/w of composition. In another embodiment, the co- solvent is ethanol, polyethylene glycol or combination thereof. In one embodiment, the cosolvent is ethanol and is present in the concentration from about 0.5 to 15% w/w, or in about 2% or 15% w/w of the composition. In alternate embodiment, the cosolvent is polyethylene glycol and is present in the concentration from about 0.01% to about 0.5% w/w, or in about 0.1% w/w of the composition. In yet another embodiment, the surfactant is polyvinylpyrrolidone and is present in the concentration from about 0.0001%to about 0.05% w/w or in about 0.001% w/w of the composition. In yet another embodiment, the surfactant is oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof and is present in the concentration from about 0.001% to about 0.5% w/w, or in about 0.03% w/w of the composition. In yet another embodiment, the surfactant is magnesium stearate and is present in the concentration from about 0.1% to about 0.2% w/w of the composition. In yet another embodiment, composition further comprises mineral acid or weak acid in the concentration from 0.001 % w/w to 0.5% w/w of the composition. More specifically, mineral acid or weak acid is in the concentration of about 0.024% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide and a combination of green propellant HFA-152a and HFO-1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide and a combination of green propellant HFA-152a or HFO-1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from about 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from UFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the ciclesonide is suspended or completely dissolved in a propellant system.

D. Fluticasone Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a fluticasone or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid or combination thereof. The composition has fluticasone as either fluticasone propionate or fluticasone furoate and is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.086%, or about 0.11%, or about 0.21%, or about 0.27%, or about 0.28%, or about 0.42%, or about 0.43%, or about 0.55% of the composition. The green propellant is HFO-1234ze(E) or HFA-152a and is present in a concentration of at least 80% or 90% or 95% or 99% w/w of the composition. Alternatively, the green propellant is a combination of HFO-1234ze(E) and HFA-152a; wherein the HFO-1234ze(E) is present in the concentration from 1% to about 99% w/w of composition; and wherein the HFA-152a is present in the concentration from about 99% to about 1% w/w of composition. In another embodiment, the co- solvent is ethanol, polyethylene glycol or combination thereof. In one embodiment, the cosolvent is ethanol and is present in the concentration from about 0.5 to 15% w/w, or in about 2% or 15% w/w of the composition. In alternate embodiment, the cosolvent is polyethylene glycol and is present in the concentration from about 0.01% to about 0.5% w/w, or in about 0.1% w/w of the composition. In yet another embodiment, the surfactant is polyvinylpyrrolidone and is present in the concentration from about 0.0001%to about 0.05% w/w or in about 0.001% w/w of the composition. In yet another embodiment, the surfactant is oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof and is present in the concentration from about 0.001% to about 0.5% w/w, or in about 0.03% w/w of the composition. In yet another embodiment, the surfactant is magnesium stearate and is present in the concentration from about 0.1% to about 0.2% w/w of the composition. In yet another embodiment, composition further comprises mineral acid or weak acid in the concentration from 0.001 % w/w to 0.5% w/w of the composition. More specifically, mineral acid or weak acid is in the concentration of about 0.024% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate and a combination of green propellant HFA-152a and HFO-1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate and a combination of green propellant HFA-152a or HFO-1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from about 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0. 1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 2% w/w of polyethylene glycol, about 0.001% w/w or about 0.0085% w/w of polyvinylpyrrolidone, about 0.1% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 2% w/w of polyethylene glycol, about 0.001% w/w or about 0.0085% w/w of polyvinylpyrrolidone, and a green propellant selected from HFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 2% w/w of polyethylene glycol, about 0.001% w/w or about 0.0085% w/w of polyvinylpyrrolidone, about 0.03% w/w of magnesium stearate and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.001% w/w or about 0.0085% w/w of polyvinylpyrrolidone, about 0.03% w/w of magnesium stearate and a green propellant selected from HFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 15% w/w of polyethylene glycol, about 0.001% w/w or about 0.0085% w/w of polyvinylpyrrolidone, about 0.024% w/w of HFA-134a and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 15% w/w of polyethylene glycol, about 0.001% w/w or about 0.0085% w/w of polyvinylpyrrolidone, about 0.03% w/w of magnesium stearate and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 2% w/w of polyethylene glycol, about 0.001% w/w of ethanol, about 0.001% w/w or about 0.0085% w/w of polyvinylpyrrolidone, about 0.1% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0. 1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, the fluticasone propionate or furoate is suspended or completely dissolved in a propellant system.

E. Budesonide and Formoterol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a budesonide or salt or ester thereof, formoterol or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). The budesonide or salt or ester thereof is present as budesonide, and formoterol or salt or ester thereof is present as formoterol fumarate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof.

The budesonide is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.086%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The formoterol fumarate is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005% or 0.01% or 0.1% or 0.5% or 1% w/w of the composition.

The green propellant is HFO-1234ze(E) or HFA-152a and is present in a concentration of at least 80% or 90% or 95% or 99% w/w of the composition. Alternatively, the green propellant is a combination of HFO-1234ze(E) and HFA- 152a; wherein the HFO-1234ze(E) is present in the concentration from about 1% to about 99% w/w of composition; and wherein the FIFA- 152a is present in the concentration from about 1% to about 99% w/w of composition. In another embodiment, the co- solvent is ethanol, polyethylene glycol or combination thereof. In one embodiment, the co- solvent is ethanol and is present in the concentration from about 0.5 to 15% w/w, or in about 2% or 15% w/w of the composition. In alternate embodiment, the co- solvent is polyethylene glycol and is present in the concentration from about 0.01% to about 0.5% w/w, or in about 0.1% w/w of the composition. In yet another embodiment, the surfactant is polyvinylpyrrolidone and is present in the concentration from about 0.0001% to about 0.05% w/w or in about 0.001% w/w of the composition. In yet another embodiment, the surfactant is oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof and is present in the concentration from about 0.001% to about 0.5% w/w, or in about 0.03% w/w of the composition. In yet another embodiment, the surfactant is magnesium stearate and is present in the concentration from about 0. 1% to about 0.2% w/w of the composition. In yet another embodiment, composition further comprises mineral acid or weak acid in the concentration from 0.001 % w/w to 0.5% w/w of the composition. More specifically, mineral acid or weak acid is in the concentration of about 0.024% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a combination of green propellant HFA-152a and HFO-1234ze(E); wherein the HFA-152a and HFO- 1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a combination of green propellant HFA-152a or HFO-1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.4% w/w of budesonide, about 0.011% w/w of formoterol fumarate, about 0.1% or 0.3% w/w of poly ethylene glycol 1000, about 0.001% w/w of polyvinylpyrrolidone (PVP-K25), about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the budesonide is suspended or completely dissolved in a propellant system. Similarly, formoterol is suspended or completely dissolved in a propellant system. Alternatively, budesonide is suspended in a propellant system and formoterol is completely dissolved in a propellant system.

F. Fluticasone and Formoterol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a fluticasone or salt or ester thereof, formoterol or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). The fluticasone or salt or ester thereof is present as fluticasone furoate or fluticasone propionate, and formoterol or salt or ester thereof is present as formoterol fumarate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof.

The fluticasone propionate/furoate is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.086%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The formoterol fumarate is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005% or 0.01% or 0. 1% or 0.5% or 1% w/w of the composition.

The green propellant is HFO-1234ze(E) or HFA-152a and is present in a concentration of at least 80% or 90% or 95% or 99% w/w of the composition. Alternatively, the green propellant is a combination of HFO-1234ze(E) and HFA- 152a; wherein the HFO-1234ze(E) is present in the concentration from about 1% to about 99% w/w of composition; and wherein the HFA-152a is present in the concentration from about 1% to about 99% w/w of composition. In another embodiment, the co- solvent is ethanol, polyethylene glycol or combination thereof. In one embodiment, the co- solvent is ethanol and is present in the concentration from about 0.5 to 15% w/w, or in about 2% or 15% w/w of the composition. In alternate embodiment, the co- solvent is polyethylene glycol and is present in the concentration from about 0.01% to about 0.5% w/w, or in about 0.1% w/w of the composition. In yet another embodiment, the surfactant is polyvinylpyrrolidone and is present in the concentration from about 0.0001% to about 0.05% w/w or in about 0.001% w/w of the composition. In yet another embodiment, the surfactant is oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof and is present in the concentration from about 0.001% to about 0.5% w/w, or in about 0.03% w/w of the composition. In yet another embodiment, the surfactant is magnesium stearate and is present in the concentration from about 0. 1% to about 0.2% w/w of the composition. In yet another embodiment, composition further comprises mineral acid or weak acid in the concentration from 0.001 % w/w to 0.5% w/w of the composition. More specifically, mineral acid or weak acid is in the concentration of about 0.024% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a combination of green propellant HFA-152a and HFO- 1234ze(E); wherein the HFA- 152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a combination of green propellant HFA-152a or HFO-1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the fluticasone is suspended or completely dissolved in a propellant system. Similarly, formoterol is suspended or completely dissolved in a propellant system. Alternatively, fluticasone is suspended in a propellant system and formoterol is completely dissolved in a propellant system.

G. Glycopyrronium and Formoterol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a glycopyrronium or salt or ester thereof, formoterol or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). The glycopyrronium or salt or ester thereof is present as glycopyrronium bromide or glycopyrronium chloride, and formoterol or salt or ester thereof is present as formoterol fumarate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof.

The glycopyrronium bromide or glycopyrronium chloride is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.02%, or about 0.03%, or about 0. 11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The formoterol fumarate is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005% or 0.01% or 0.1% or 0.5% or 1% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA- 152a and HFO-1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA- 152a or HFO-1234ze(E) and non-green propellant HFA-134a; wherein the HFA- 152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO- 1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the glycopyrronium is suspended or completely dissolved in a propellant system. Similarly, formoterol is suspended or completely dissolved in a propellant system. Alternatively, glycopyrronium and formoterol are completely dissolved in a propellant system. In one embodiment, glycopyrronium active agent is incorporated in composition as premix of glycopyrronium and magnesium stearate.

H. Budesonide, Glycopyrronium and Formoterol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a budesonide or salt or ester thereof, glycopyrronium or salt or ester thereof, formoterol or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). The glycopyrronium or salt or ester thereof is present as glycopyrronium bromide or glycopyrronium chloride, budesonide or salt or ester thereof is present as budesonide, and formoterol or salt or ester thereof is present as formoterol fumarate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof. The budesonide is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.086%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The glycopyrronium bromide or glycopyrronium chloride is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.02%, or about 0.03%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The formoterol fumarate is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005% or 0.01% or 0.1% or 0.5% or 1% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA-152a and HFO- 1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA-152a or HFO- 1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO- 1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA- 152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the glycopyrronium is suspended or completely dissolved in a propellant system. Similarly, formoterol is suspended or completely dissolved in a propellant system. Similarly, budesonide is suspended or completely dissolved in a propellant system. Alternatively, glycopyrronium and formoterol are completely dissolved in a propellant system and budesonide is suspended in a propellant system. Alternatively, budesonide, glycopyrronium and formoterol are suspended in propellant system. In one embodiment, glycopyrronium active agent is incorporated in composition as premix of glycopyrronium and magnesium stearate. Alternatively, the budesonide of above embodiments can be replaced with other inhaled corticosteroids such as mometasone furoate (0.3% w/w or 0.4% w/w), Fluticasone propionate or furoate, Ciclesonide etc and these embodiments are specifically illustrated in example 16.

I. Indacaterol and Formoterol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising indacaterol or salt or ester thereof, formoterol or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). The indacaterol or salt or ester thereof is present as indacaterol acetate or maleate or malate, and formoterol or salt or ester thereof is present as formoterol fumarate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof.

The indacaterol or salt thereof is present in a concentration from about 0.001% w/w to about 1 % w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.086%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about

0.55% of the composition. The formoterol fumarate is present in a concentration from about 0.0001% w/w to l% w/w ofthe composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005% or 0.01% or 0.1% or 0.5% or 1% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA- 152a and HFO-1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA- 152a or HFO-1234ze(E) and non-green propellant UFA- 134a; wherein the HFA- 152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about

0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the indacaterol acetate or maleate is suspended or completely dissolved in a propellant system. Similarly, formoterol is suspended or completely dissolved in a propellant system. Alternatively, formoterol is completely dissolved in a propellant system and indacaterol is suspended in a propellant system. Alternatively, indacaterol and formoterol are suspended in propellant system.

J. Budesonide, Indacaterol and Formoterol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a budesonide or salt or ester thereof, indacaterol or salt or ester thereof, formoterol or salt or ester thereof, and a green propellant selected from HFA-152a andHFO-1234ze(E). The indacaterol or salt or esterthereofis present as indacaterol acetate or maleate or malate, and budesonide or salt or ester thereof is present as budesonide, and formoterol or salt or esterthereofis present as formoterol fumarate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof.

The budesonide is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.086%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The indacaterol or salt thereof is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.02%, or about 0.03%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The formoterol fumarate is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005% or 0.01% or 0.1% or 0.5% or 1% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA-152a and HFO- 1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a combination of green propellant HFA-152a or HFO- 1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO- 1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from UFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.1% w/w of magnesium stearate, and a green propellant selected from UFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the indacaterol is suspended or completely dissolved in a propellant system. Similarly, formoterol is suspended or completely dissolved in a propellant system. Similarly, budesonide is suspended or completely dissolved in a propellant system. Alternatively, indacaterol and formoterol are completely dissolved in a propellant system and budesonide is suspended in a propellant system. Alternatively, budesonide, indacaterol and formoterol are suspended in propellant system. In an alternate embodiment, the budesonide in above embodiment can be replaced with another inhaled corticosteroids mentioned in instant specification.

K. Fluticasone and Salmeterol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a fluticasone or salt or ester thereof, salmeterol or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). The fluticasone or salt or ester thereof is present as fluticasone furoate or fluticasone propionate, and salmeterol or salt or ester thereof is present as salmeterol xinafoate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof.

The fluticasone propionate/furoate is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.086%, or about 0.11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, or about 0.35%, about 0.42%, or about 0.44%, or about 0.55% of the composition. The salmeterol xinafoate is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001%, or 0.005%, or 0.01%, or 0.02%, or 0.03%, or 0.04%, or 0.05%, or 0.1% or 0.5% or 1% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, and agreen propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, and a combination of green propellant HFA-152a and HFO- 1234ze(E); wherein the HFA- 152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition. In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, and a combination of green propellant HFA-152a or HFO-1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising a about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from UFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.1% w/vf of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.1% w/vf of magnesium stearate, and a green propellant selected from HFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the fluticasone is suspended or completely dissolved in a propellant system. Similarly, salmeterol is suspended or completely dissolved in a propellant system. Alternatively, fluticasone is suspended in a propellant system and salmeterol is completely dissolved in a propellant system.

K. Tiotropium and Ipratropium composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a tiotropium or salt or ester thereof, ipratropium or salt or ester thereof, and a green propellant selected from HFA-152a and HFO-1234ze(E). The tiotropium or salt or ester thereof is present as tiotropium bromide or tiotropium chloride, and the ipratropium or salt or ester thereof is present as ipratropium bromide or ipratropium chloride. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof.

The tiotropium bromide or tiotropium chloride is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.02%, or about 0.03%, or about 0.04%, or about 0. 11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The ipratropium or salt thereof is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005%, or 0.01%, or 0.03% or 0.1% or 0.5% or 1% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, and a green propellant selected from HFA-152a and HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, and a combination of green propellant HFA-152a and HFO-1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition. In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, and a combination of green propellant HFA-152a or HFO-1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO-1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E). In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the tiotropium bromide is suspended or completely dissolved in a propellant system. Similarly, ipratropium bromide is suspended or completely dissolved in a propellant system. Alternatively, tiotropium bromide and ipratropium bromide are completely dissolved in a propellant system.

L. Tiotropium, Ipratropium and Salbutamol Composition

In one embodiment, provided is a pharmaceutical composition for inhalation comprising a tiotropium or salt or ester thereof, ipratropium or salt or ester thereof, salbutamol or salt or ester thereof and a green propellant selected from HFA-152a and HFO-1234ze(E). The tiotropium or salt or ester thereof is present as tiotropium bromide or tiotropium chloride, and the ipratropium or salt or ester thereof is present as ipratropium bromide or ipratropium chloride and salbutamol or salt or ester is present as salbutamol sulphate. In another embodiment, the composition further comprises a co-solvent, a surfactant, mineral acid/ weak acid, or combination thereof. The tiotropium bromide or tiotropium chloride is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.4% w/w of, or most preferably about 0.083%, or about 0.02%, or about 0.03%, or about 0.04%, or about 0. 11%, or about 0.15% or about 0.21%, or about 0.27%, or about 0.28%, or about 0.3%, about 0.42%, or about 0.43%, or about 0.55% of the composition. The ipratropium or salt thereof is present in a concentration from about 0.0001% w/w to 1% w/w of the composition. Preferably, it is present in a concentration of about 0.008%, or 0.001% or 0.005%, or 0.01%, or 0.03% or 0.1% or 0.5% or 1% w/w of the composition. The salbutamol sulphate is present in a concentration from about 0.001% w/w to about 1% w/w, or preferably from about 0.01% w/w to about 0.5 % w/w, or most preferably from about 0.05%w/w to about 0.3% w/w of, or most preferably about 0. 14% w/w, or about 0.17% w/w or 0.22% w/w the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, and a green propellant selected from HFA-152a and HFO- 1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, and a combination of green propellant HFA-152a and HFO- 1234ze(E); wherein the HFA-152a and HFO-1234ze(E) is present in a concentration from about 1 to 99% w/w of composition. In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, and a combination of green propellant HFA-152a or HFO- 1234ze(E) and non-green propellant HFA-134a; wherein the HFA-152a or HFO- 1234ze(E) is present in a concentration from about 89% w/w and HFA-134a is present in a concentration from about 10% w/w of composition. Alternatively, the concentrations of green and non-green propellants may range from 1 to about 99% w/w of the composition.

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.001% w/w of polyvinylpyrrolidone and a green propellant selected from UFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.1% w/w of polyethylene glycol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.1% w/w of polyethylene glycol, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.1% w/w of polyethylene glycol, about 0.001% w/w of polyvinylpyrrolidone, about 2% w/w of ethanol and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, and a green propellant selected from HFA- 152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.1% w/w of magnesium stearate, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, about 0.03% w/w of oleic acid, sorbitan trioleate, sorbitan mono-oleate or combination thereof, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, disclosed is a pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate e, about 0.024% w/w of mineral acid or weak acid, about 2% w/w or about 15% w/w of ethanol, and a green propellant selected from HFA-152a and/or HFO-1234ze(E).

In another embodiment, the tiotropium bromide is suspended or completely dissolved in a propellant system. Similarly, ipratropium bromide is suspended or completely dissolved in a propellant system. Similarly, salbutamol sulphate is suspended or completely dissolved in a propellant system. Alternatively, tiotropium bromide, salbutamol sulphate and ipratropium bromide are completely dissolved in a propellant system.

The invention is described, but not limited to, by the examples as below: EXAMPLES

Example 1 : Beclomethasone Dipropionate Inhaler formulations with Green Propellant

Table 1

*The other strength Beclomethasone dipropionate includes 0.08%, 0.17%, 0.34%

Manufacturing Process for Composition 1A:

Beclomethasone Dipropionate was dissolved in ethanol and weighted the required quantity of this solution in canister, and canister was crimped with valve.

The canister was charged with the required quantity of propellant.

The Canister was sonicated for l-90min and quarantined the canister for stabilization.

Manufacturing process for composition IB and 1C

Glycerol/ PEG was dissolved in ethanol.

Beclomethasone was dissolved in the above mixture.

The required quantity of the above mixture was weighed in canister and crimped the canister with valve.

The canister was charged with the required quantity of propellant.

Valve: Valve with metering chamber capacity from 50 - 63mcl was used.

Canister: Plain or FCP coated canister with a capacity of 14 - 19ml was used.

Example 2: Budesonide and Salbutamol Inhaler formulations with Green Propellant

Table 2

Manufacturing Process:

Manufacturing process for formulation containing active agent and propellant.

Weighed the required quantity of active agent (Budesonide and Salbutamol sulphate) in a canister and crimped with the valve.

The canister was charged with the required quantity of the propellant.

The canister was sonicated for 1 -90min and quarantined the canister for stabilization.

Manufacturing process for formulation containing active agent, surfactant, and propellant.

The surfactant was dissolved in the propellant.

The required quantity of active agent (Budesonide and Salbutamol sulphate) was weighed in canister and crimped the canister with valve.

The canister was charged with the required quantity of mixture of surfactant and remaining propellant.

Manufacturing process for formulation containing active agent, ethanol, Surfactant and Propellant

The surfactant was dissolved in ethanol and propellant.

The required quantity of active agent was weighed in the canister and crimped the canister with valve.

The canister was charged with the required quantity of mixture of surfactant, ethanol, and propellant.

Manufacturing process for formulation containing active agent, ethanol, acid, and propellant.

The acid was dissolved in ethanol.

The active agent was dissolved in the above mixture.

The canister was charged with the required quantity of propellant.

Valve: Valve with metering chamber capacity from 50 - 63mcl was used.

Canister: Plain or FCP coated canister with a capacity of 14 - 19ml was used.

Example 3 : Ciclesonide Inhaler formulations with Green Propellant

Table 3

Table 4

*The other strength includes 0.2%, 0.15%

Manufacturing Process: The compositions of Example 3 were manufactured as per the process described in Example 2.

Example 4: Fluticasone Propionate Inhaler formulation with Green Propellant

Table 5

*The other strength includes 0.083, 0.086, 0.11, 0.21,0.27, 0.28, 0.42, 0.43, 0.55

Table 6

Manufacturing process: The compositions of this example were manufactured as per the process described in Example 2.

Example 5: Budesonide and Formoterol Inhaler formulations with Green Propellant

Table 7

*The other strength includes 0.2, 0.15.

Table 8

*The other strength includes 0.2, 0.15.

Example 6: Fluticasone Propionate and Formoterol Fumarate Dihydrate Inhaler formulation with Green Propellant

Table 9

Table 10

Example 8: Glycopyrronium and Formoterol Fumarate Inhaler formulation with Green Propellant

Table 11

Example 9: Budesonide, Glycopyrronium and Formoterol Fumarate Inhaler formulation with Green Propellant

Table 12

Example 10: Indacaterol, and Formoterol Fumarate Inhaler formulations with Green Propellant

Table 13

Example 11 : Indacaterol, Formoterol Fumarate and Inhaled corticosteroid Inhaler formulations with Green Propellant

Tabel 14

Example 12: Fluticasone Propionate and Salmeterol Xinafoate Inhaler formulations with Green Propellant

Table 15:

The other strength includes 0.083, 0.086, 0.11, 0.21,0.27, 0.28, 0.42, 0.43, 0.55 able 16

Example 13: Fluticasone Inhaler formulations with Green Propellant

Table 17

*The other strength includes 0.2, 0.15.

Example 14: Tiotropium Bromide Monohydrate and Ipratropium Bromide monohydrate Inhaler formulations with Green Propellant

Table 18

Example 15: Tiotropium Bromide, Ipratropium Bromide and Salbutamol Inhaler formulation with Green Propellant

Table 19

Example 16: Glycopyrronium, Formoterol Fumarate and Inhaled corticosteroids Inhaler formulation with Green Propellant

Table 20

Example 17: Budesonide and Formoterol Fumarate Inhaler formulation with Green Propellant

Table 21

Example 18: Delivered Dose Uniformity and aerodynamic particle size distribution measurements of formulations of Example 17

One of the four Critical Quality Attributes (CQAs) that determine the safety, quality and efficacy of orally inhaled and nasal drug products (OINDPs), delivered dose is the total amount of drug emitted from the drug device that is available to the user, when the device is actuated correctly. The Delivered Dose Uniformity, or DDU, must be ensured within and between devices. DDU is measured by firing the test device into a sampling apparatus which contains a filter. The active drug caught on the filter is then dissolved in solvent and analysed using High Pressure Liquid Chromatography (HPLC). Together with delivered dose, aerodynamic particle size distribution (APSD) is typically identified as a Critical Quality Attribute (CQA) for orally inhaled and nasal drug products (OINDPs) making it a primary focus for in vitro characterisation. The APSD of an OINDP defines how particles behave in a moving air stream. It is intuitively relevant to the understanding of likely lung deposition and hence potential drug efficacy. Typically, particles should be in the range of 1 to 5 microns to be effective, any larger than 5 microns and they are likely to impact the oropharynx and be swallowed, any smaller than 1 micron and it is possible that the particles will remain entrained in the air system.

Table 22

*BUDE: Budesonide; FORMO: Formoterol; RSD: Relative standard deviation; BOU: Beginning of unit; EOU: End of unit

Table 23

*IP - Induction port, SI, S2, S3, S4, S5, S6, S7 - Stage 1 to stage 7, MOC - micro-orifice contactor, MB - Mass balance, FPM - Fine particle mass, MMAD - Mass median aerodynamic diameter

Testing procedure for delivered dose uniformity:

The test was performed at the initial and end of container life on the ten containers. (Noted down the initial weight of containers)

Equipment

1. The apparatus consists of a filter-support base, a collection tube and an actuator adaptor which ensures that the front face of the inhaler actuator was flushed with the front face of the sample collection tube.

2. The filter paper and other materials used in the construction of the apparatus must be compatible with the active ingredient and solvents that are used to extract the active ingredient from the filter paper (Manufactured by PALL Life Sciences - Type A/E-I glass Libre, 25 mm 61630 assembled in mexico or equivalent is suitable.)

3. Suitable vacuum pump with a flow regulator (Make Copley) was used.

4. Adapter for adjusting flow rate (flow adapter) was used.

5. Suitable apparatus for measuring air through the Dose collection apparatus i.e. flow meter (Make: Copley) was used.

6. Reax 2 shaker (Make: Heildoph) was used.

7. Syringe filter 0.45microns, TYPE: SY25TG, 25 mm (Manufactured by mdi) was used.

8. Dispenser was used.

Priming procedure:

1. The priming actuation were discharged into a suitable suction system.

2. The container was fit in with the actuator (Inhaler).

3. The inhaler was shaken for 5 seconds. 1 spray was discharged immediately by holding the container in pressed down for 1 second.

4. The container was then released and paused for 2 seconds.

5. Step no.3 and 4 was repeated for one more actuation.

Testing Scheme

The separate actuator dedicated actuator was used to discharge the waste actuations and for determination of DELIVERED DOSE UNIFORMITY for each container.

Cleaning procedure:

For apparatus:

The apparatus was thoroughly cleaned first with water and then with methanol. The apparatus was dried using tissue paper followed by drier and then using an airline fitted with an appropriate jet.

For actuator:

The actuator was wiped with the tissue paper, the orifice was cleaned using an air line fitted with an appropriate jet.

For Valve:

The outer and inner part of the valve stem were rinsed with 5ml of diluent by using disposable syringe for 2 to 3 times by holding the container in inverted position, after rinsing the valve with diluent, valve stem was dried by tissue and air jet.

Blank preparation:

1. The filter paper was placed on the filter- support base. The sample collection tube was screw fit to the filter support base. One end of the collection tube is designed to hold the filter paper tightly against the filter-support base.

2. When assembled, the joints between the components of the apparatus are airtight so that when a vacuum is applied to the base of the filter, all the air drawn through the collection tube passes through the inhaler. The airflow should not change when the connection and tubing are twisted slightly.

3. The apparatus was held with the help of a clamp.

4. The vacuum connector of the assembled sample collection tube was connected to the vacuum pump using a rubber connection tube.

5. The adapter on the inhaler side of the sample collection tube was screw fitted and connected with the flow meter using a suitable tube.

6. The pump was switched on and the rate of air flow was set to 28.3 ± 5% (26.9 - 29.7 L/min) litres per minute, using flow adapter.

7. After the flow rate, has been set, the flow adapter was removed and replaced it by actuator adapter in a way that the inhaler when inserted, lines up along the horizontal axis of the sample collection tube.

8. The air flow was maintained for at least 15 seconds and then switched off.

9. The actuator adaptor was removed and the sample collection tube at the inhaler end with the end cap was sealed and unscrewed the filter support base from the sample collection tube. The filter paper inside the tube was pushed with the help of funnel.

10. A funnel was placed in the collection tube, kept the actuator adaptor in the funnel and dispensed 25 ml diluent to give washings to the actuator adaptor, collecting it in the collection tube. The funnel was removed and sealed with another end cap.

11. The collection tube by shaken to check the leak. The sealed collection tube mounted vertically in the Reax 2 shaker, set control knob of speed control on position 9 and shake for 10 minutes.

12. The solution was filtered using syringe filter 0.45microns (mdi syringe filter, 0.45 pm pore size, 25mm Dia. Cat. No.

S YTG0602MNXX104), the first 2ml of the filtrate were discarded and then injected this solution directly.

Sample collection

The filter was placed on the filter- support base. The sample collection tube was screw filled to the filter support base. One end of the collection tube was designed to hold the filter paper tightly against the filter-support base.

1. When assembled, the joints between the components of the apparatus are airtight so that when a vacuum is applied to the base of the filter, all the air drawn through the collection tube passes through the inhaler. The airflow should not change when the connection and tubing are twisted slightly

2. The apparatus was held with the help of a clamp.

3. The container was placed with actuator (inhaler) on the balance and tare the weight.

4. The vacuum connector of the assembled sample collection tube connected to the vacuum pump using a rubber connection tube.

5. The adapter on the inhaler side of the sample collection tube screwed and connected with the flow meter using a suitable tube.

6. The pump switched on and set the rate of air flow to 28.3 L/min ± 5% (26.9 - 29.7 L/min) using flow adapter.

7. After the flow rate, has been set, removed the flow adapter and replaced it by actuator adapter in a way that the inhaler when inserted, lines up along the horizontal axis of the sample collection tube.

8. The primed inhaler was shaken well for 5 seconds and inserted the inhaler into the sample collection tube using a suitable actuator adapter. Discharged 1 spray immediately by holding the container pressed down for 1 second. Released the container and then paused for 2 seconds. Removed the inhaler from the actuator adaptor and repeated this step for one more actuation.

9. After the 2nd actuation has been delivered into the sample collection tube, paused for 5 seconds switched off the pump, again paused for 5 seconds and then removed the inhaler from actuator adaptor.

10. Weighed the inhaler and recorded the weight (W).

11. W / 2 x 1000 = X mg. This should be within the limit of individual value as per valve delivery test.

Note: Any deviation in the shot weight should be confirmed with respective DDU. If no impact on DDU, determination not to be repeated.

Sample Preparation:

1. Removed the actuator adaptor and sealed the sample collection tube at the inhaler end with the end cap and unscrewed the filter support base from the sample collection tube. Pushed the filter paper inside the tube with the help of funnel.

2. Placed a funnel in the collection tube, kept the actuator adaptor in the funnel and dispensed 25 ml diluent giving washings to the collar and collected it in the collection tube. Removed the funnel and sealed with another end cap.

3. The collection tube was shaken by hand to check the leak. Mounted the sealed collection tube vertically in the Reax 2 shaker, control knob of speed control was set on position 9 and the tube was shaken for 10 minutes so that drug will get extracted in diluent.

4. Filtered this solution using syringe filter 0.45microns (mdi syringe filter, 0.45 pm pore size, 25mm Dia. Cat. No. SYTG0602MNXX104), discarded the first 2ml of the filtrate and then injected this solution directly.

5. Repeated testing procedures for remaining containers.

6. Recorded the DDU determination of individual container and all determinations should fall within the acceptance criteria.

7. Carried out the sampling procedure for doses at the end stage.

8. Wasted the actuations for the end stage as per the procedure given below.

9. Recorded doses at Initial and end of individual container.

/

Waste Actuations and Measurement in the End of Container Life

1. After the measurement of the dose at the beginning of container life has been completed, the actuator was cleaned as per cleaning procedure of actuator.

2. A dedicated actuator was used for all waste actuations. For end stage, discharged the doses to waste until spray no. 116.

3. The container was placed in the actuator dedicated for waste actuations and the inhaler was shaken for 5 seconds between each waste actuations.

4. The waste actuations were discharged into a suitable suction system.

5. The container was allowed to rest for 1 minute to equilibrate ambient temperature after every 40 actuations.

6. After the waste actuations to the end have been completed, the valve was cleaned as per cleaning procedure of valve.

7. Then container was inserted into its cleaned actuator used for sampling and continued with test.

8. Before the measurement at the end of the container life, 2 actuations were discharged to waste.

9. Calculation:

Content of Formoterol fumarate dihydrate delivered per actuation in mcg

Weight in Purity of WS

Sample mg of on anhydrous

Area standard 6A 10ml 10ml 10ml 10ml 25ml basis (%)

—X —X X X -X -X X xlOOO

Mean peak 50ml 100ml 100ml 100ml 20ml 2 sprays 100

Area of

Formoterol in Standard

Solution

6A

Content of Formoterol fumarate dihydrate delivered per actuation in %

Amount in mcg (A)

% Label claim = x 100

Content of Budesonide delivered per actuation in mcg

Weight in mg Purity of WS on

Sample Area (Sum of Epimer of Standard

B & Epimer A) 6A 5ml 10ml 25ml as such basis (%)

1000

— - X - X X X X - X

Mean peak Area of 100ml 100ml 20ml 2 100

Budesonide in Standard spray

Solution 6A s

(Sum of Epimer B & Epimer A)

Content of Budesonide delivered per actuation in %

Amount in mcg (A)

% Label claim = x 100

160

Testing Procedure for Aerodynamic Particle Size Distribution by Next Generation Impactor

Number of units to be tested -5.

The test was performed at the beginning and end of container life.

Equipment’s

• NGI (next generation impactor)

• End caps for Induction port (IP)

• Suitable actuator adapter which ensures that the front face of the inhaler actuator is flush with the front face of the induction port.

• Adapter for flow setting (flow adapter)

• Suitable vacuum pump (Make Copley)

• Suitable apparatus for measuring air through the NGI apparatus (e.g. flow meter) (Make Copley)

• Dispenser

Chromatographic conditions:

Buffer (a) Weighed and dissolved 1 ,38g of Sodium Dihydrogen orthophosphate monohydrate (equivalent to 0.01M) and 2.4433g of another buffer

(Mobile phase) decane-1 -sulphonate (equivalent to 0.01M) in 500ml of purified water and mixed well. Filtered through 0.45pm mdi membrane filter, (Make: Merk, Filter no.: HVE0047 or Make: mdi, Filter No.: HNN0901XXXX104) and added 500ml of purified water.

(b) The pH meter to be used was calibrated as per the applicable procedure.

(c) The appropriate quantity of Orthophosphoric acid was taken in a measuring cylinder.

(d) Adjusted the pH of the dissolved mixture of Step (a) to 2.9 ±0.05 using Orthophosphoric acid of Step (c) in a drop-wise manner.

(e) The pH meter displayed the stable reading and recorded the same.

Mobile phase 1) A clean beaker or equivalent vessel was taken.

2) The appropriate sizes of graduated measuring cylinder was taken. Prepared a degassed mixture of Buffer and Acetonitrile in the ratio (670:330)

3) 670 ml of buffer (Refer the buffer preparation details below) was added to the 330 ml of Acetonitrile into a clean beaker or equivalent vessel of Step 1).

4) Degassed the solvent mixture of Step 3).

5) Allowed the degassed mixture to attain room temperature that would had approximately taken 5 to 10 min. of time.

Note: Mobile phase can be used within 7 days.

Buffer (Diluent) Preparation of 0,0 IM of disodium hydrogen orthophosphate dihydrate i. Weighed and dissolved 1.7799 g disodium hydrogen orthophosphate dihydrate into 1000 ml of purified water and mixed well. ii. Referred the step (b) and (c).

iii. Adjusted the pH of the dissolved mixture of Step (i) to pH 3.00 ±0.05 with orthophosphoric acid of Step (c) in a drop-wise manner. iv. Refer the step (e), (f).

Diluent I. A clean beaker or equivalent vessel was taken.

II. The appropriate sizes of graduated measuring cylinder were taken, prepared a degassed mixture of Buffer and Acetonitrile in the ratio (70:30)

III. 70 ml of buffer (Refer the buffer preparation details below) was added to the 30 ml of Acetonitrile into a clean beaker or equivalent vessel of Step I).

IV. Degassed the solvent mixture of Step III).

V. Allowed the degassed mixture to attain room temperature that would approximately take 5 to 10 min. of time.

Column type HYPERSIL BDS C18, 100 X 4.6 mm, 3microns

Column temperature 28°C

Injection volume 50mcl

Flow rate 1.5ml/minute

Wavelength 224 & 240 nm

Run time about 10 minutes

Blank solution Diluent

Retention time Formoterol about 4 minutes

Budesonide epimer B about 7 minutes.

Budesonide epimer A about 8 minutes.

Measurement conditions:

Measurement in the NGI should be performed at a relative humidity within 40%RH to 60%RH.

Standard Solution Preparation:

Prepare the standard solution 1, 2, 3, 4 and 5 in duplicate and label them as standard solution 1A, IB, 2A, 2B ,3A, 3B ,4A, 4B, 5A and 5B respectively.

Standard solution 1 Weighed about 25mg of Formoterol fumarate dihydrate WS and transferred accurately in to a 50ml volumetric flask. Added about 25ml of diluent, sonicated to dissolve the mixture and made up the volume with diluent.

Standard solution 2 Pipetted 10ml of Solution 1 into the 100ml volumetric flask. Made the volume with diluent.

Standard solution 3 Pipeted 10ml of Solution 2 into the 100ml volumetric flask. Made the volume with diluent.

Standard solution 4 Weighed about 40 mg of Budesonide WS and transferred accurately in to a 100ml volumetric flask. Added about 50ml of diluent, sonicated to dissolve and made the volume with diluent.

Standard solution 5 Pipeted 10ml of Solution 3 and 5ml of Solution 4 in a 100ml volumetric flask.

Made the volume with diluent.

Sampling Procedure:

All the containers to be tested were primed before starting the sample collection.

Priming procedure:

1. The priming actuation were discharged into a suitable suction system.

2. The container was placed in the actuator (Inhaler).

3. The inhaler were shaken for 5 seconds. Discharged 1 spray immediately by holding the container pressed down for 1 second.

4. The container then released and paused for 2 seconds.

5. Repeated step no.3 and 4 for one more actuation.

6. The container was now ready for sampling.

Testing Scheme

Cleaning Procedure:

For apparatus:

The stage set, cups and IP were washed with water and then rinsed it with methanol. The IP was dried using tissue paper followed by drier and the stage set and cups were wiped with tissue paper. The apparatus was dried completely with the help of an airline fitted with an appropriate jet to ensure that all solvent was removed from the apparatus.

For actuator:

For Valve:

Note: Clean the apparatus after each sampling as per cleaning procedure.

Blank preparation:

A clean cup from the NGI was placed, 10 ml diluent was added and covered with parafilm. The cups were sonicated 10 seconds and then filled with the vial. Injected this solution to liquid chromatography.

Preparation of sample collection equipment

The NGI including the stage set, cups and induction port (IP) were prepared for each measurement as follows:

1. Before using the apparatus ensured that the apparatus was clean and dry as per cleaning procedure.

2. The parafilm was place on IP and sealed to make it airtight. When assembled, the joints between the components of the apparatus were airtight so that when a vacuum was applied to the base of NGI, all the air drawn through the NGI passes through the inhaler.

3. For adjustment of the air-flow through the apparatus, connected the flow adaptor to the IP and sealed it with parafilm.

Sample collection:

1. Recorded the values for relative humidity.

2. Connected the vacuum connector to the vacuum pump using a rubber connection tube.

3. The rate of air flow was set to 30 L/min ± 5% (28.5 - 31.5 L/min) using flow adapter.

4. After the flow rate, was set, removed the flow adapter and replaced it by actuator adapter in position at the end of the IP so that the inhaler when inserted, lines up along the horizontal axis of the IP.

5. The primed inhaler was placed on the balance and weight was tared.

6. The primed inhaler was shaken for 5 seconds and inserted the inhaler into the IP using a suitable actuator adapter.

7. Discharged 1 spray immediately by holding the container pressed down for 1 second. Released the container and then paused for 2 seconds. Removed the inhaler from the actuator adapter and repeated this step for three more actuations. Paused for 2 seconds after every actuation.

8. After the 4^th actuation was delivered into the IP, paused for 5 seconds then switched off the pump again for 5 seconds and then removed the inhaler from actuator adaptor.

9. Weight of inhaler was recorded (in g.)

10. W /4 X 1000 = X mg. This should be within the limit of average value for valve delivery test.

Note: Any deviation in the shot weight should be confirmed with respective Mass balance. If no impact on Mass balance, determination not to be repeated.

11. Dismantled the apparatus.

Sample Preparation:

INDUCTION PORT (IP):

The IP and Actuator adaptor were removed. Sealed the side of IP facing the container with the end cap. Placed the funnel at the other end and kept the Actuator adaptor in the funnel. Dispensed 25 ml of diluent giving thorough washings to inner side of the Actuator adaptor. Removed the Actuator adaptor and funnel carefully from the IP. Sealed this end with second end cap. Then induction port was shaken so that drug gets extracted in diluent i.e. about 3-4 minutes. Injected the solution to chromatograph.

STAGES (1 -7 & MOO:

Dispensed 10 ml of diluent in each cup of respective stage and covered it with parafilm sealing it tightly. Swirled all cups thoroughly for about 5 seconds and placed in plastic tray. Kept the plastic tray along with all cups in a sonicator, sonicated for 10 minutes to dissolve drug completely.

Note: While dispensing, placedd the cup near the tip of the dispenser. Slowly dispense the diluent to avoid splashing.

• Injected the solution to chromatograph.

• Repeated the same procedure for NGI at end stage.

• Wasted the actuations for the end stage as per the procedure given below.

• Recorded doses at initial and end of individual container and all values were within the acceptance criteria.

Waste Actuations of Measurement at the End of Container Life

1. After the measurement of the dose at the beginning of container life was completed, the actuator was cleaned as per cleaning procedure of actuator.

2. A dedicated actuator was used for all waste actuations. Discharged the doses to waste until spray no.114.

3. The container was placed in the actuator dedicated for waste actuations and the inhaler was shaken for 5 seconds between each actuation.

4. The waste actuations were discharged into a suitable suction system manually.

5. Allowed the container to equilibrate to room temperature (i.e. about 1 minute) after every 40 actuations.

6. After the waste actuations to the end was complete, cleaned the valve as per cleaning procedure of valve.

Then inserted the container into the cleaned actuator which was used for determination at initial stage of container and wasted two actuations for container fitting and continued with test.

Calculations:

Content of Formoterol fumarate dihydrate delivered per actuation in mcg.

For IP,

Weight in mg of Purity of WS

Sample Area Standard 5 A 10ml 10ml 10ml 25ml on anhydrous basis (%)

= - _x - _x - _x - _x - _x - _x - _x 1000

Mean peak Area of Formoterol 50ml 100ml 100ml 100ml 4 100 in Standard Solution 5A sprays

For stages (1 -7 & MOC),

Weight in mg of Purity of WS

Sample Area Standard 5 A 10ml 10ml 10ml 10ml on anhydrous basis (%)

= - _x - _x - _x - _x - _x - _x - _x 1000

Content of Budesonide delivered per actuation in mcg

For IP,

Sample Area Weight in mg of Purity of WS

(Sum of Epimer B & Epimer A) Standard 5A 5ml 25ml on as such basis (%)

= - _x - _x - X - x - x 1000

Mean peak Area of Standard 100ml 100ml 4 100

Solution 5A sprays

(Sum of Epimer B & Epimer A)

For stages (1 -7 & MOC),

Sample Area Weight in mg of Purity of WS

(Sum of Epimer B & Epimer A) Standard 5 A 5ml 10ml on as such basis (%)

= - _x - x - x - x - x 1000

Mean peak Area of standard 100ml 100ml 4 100

Solution 5A sprays

(Sum of Epimer B & Epimer A)

(Note: All Individual mass balance should be between 85-115% of label claim.)

Fine particle mass (<5pm), MMAD and GSD is calculated using CITDAS software COPLEY UK.

The overall APSD performance of the formulation with propellant HFA-152a was similar to Symbicort. However, inclusion of PEG and PVP helped in minimizing the variability. The delivered dose uniformity of all the formulation with HFA 152a, resulted in DDU close to the target.

The examples described herein above fully illustrate the practice of the preferred embodiments of the present invention and are intended to be for illustrative purpose only and should not be considered in any way to limit the scope of the present invention.

Claims

We Claim,

1. A pharmaceutical composition for inhalation comprising an active pharmaceutical agent and a green propellant.

2. The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable excipient.

3. The pharmaceutical composition of claim 1, wherein the active pharmaceutical agent is selected from the group consisting of an inhaled corticosteroid, a short acting beta agonist, a long-acting beta agonist, a long-acting muscarinic antagonist, or combinations thereof.

4. The pharmaceutical composition of claim 3, wherein the inhaled corticosteroid is selected from, but not limited to, beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone or salt or ester or combination thereof; and wherein the short acting beta agonist is selected from, but not limited to, albuterol, levalbuterol, metaproterenol, and terbutaline or salt or ester or combination thereof; wherein the long-acting beta agonist is selected from, but not limited to, bambuterol, clenbuterol, formoterol, arformoterol, salmeterol, carmoterol, milveterol, indacaterol, vilanterol trifenatate and saligenin- or indole-containing and adamantyl-derived 02 agonists or salt or ester or combination thereof; and wherein the long-acting muscarinic antagonist is selected from, but not limited to, glycopyrronium, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium, atropine, benzatropin, umeclidinium and oxitropium or salt or ester or combination thereof.

5. The pharmaceutical composition of claim 1, wherein the green propellant is selected from HFA-152a and HFO-1234ze(E) or combination thereof.

6. The pharmaceutical composition of claim 2, wherein pharmaceutically acceptable excipient is selected from a co-solvent, a surfactant, pH adjusting agent or combination thereof.

7. The pharmaceutical composition of claim 6, wherein the co-solvent is selected from, but not limited to, ethanol, glycerol, polyethylene glycol or combination thereof.

8. The pharmaceutical composition of claim 6, wherein the surfactant is selected from, but not limited to, oleic acid, sorbitan trioleate, sorbitan mono-oleate, polyvinylpyrrolidone, magnesium stearate, stearic acid, calcium stearate, sodium stearate, glycerol monostearate and sodium stearyl fumarate or combinations thereof.

9. The pharmaceutical composition of claim 6, wherein the pH adjusting agent is mineral acid or weak acid and is selected from group consisting of hydrochloric acid, sulphuric acid, tartaric acid, citric acid, boric acid, malic acid, oxalic acid, lactic acid, succinic acid, phosphoric acid, acetic acid, or combination thereof.

10. A pharmaceutical composition for inhalation comprising beclomethasone dipropionate in a concentration of about 0.08%, 0.17%, 0.34% or 0.42%w/w, ethanol in a concentration of about 15% w/w, and about 84% w/w of a green propellant HFA-152a and/or HFO- 1234ze(E).

11. A pharmaceutical composition for inhalation comprising a combination of about 0.17% or about 0.22% w/w of budesonide, and about 0.17% or about 0.22% w/w of salbutamol sulphate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

12. A pharmaceutical composition for inhalation comprising about 0.15% or about 0.2% or about 0.3% w/w or 0.4% w/w of ciclesonide, and a green propellant selected from HFA- 152a and HFO-1234ze(E).

13. A pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

14. A pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

15. A pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.0085% or about 0.011% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

16. A pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

17. A pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.02% w/w or 0.03% w/w of glycopyrronium bromide, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

18. A pharmaceutical composition for inhalation comprising about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

19. A pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of budesonide, about 0.1% w/w or 0.2% w/w of indacaterol acetate or maleate, about 0.01% w/w of formoterol fumarate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

20. A pharmaceutical composition for inhalation comprising about 0.3% w/w or 0.4% w/w or about 0.5% w/w of fluticasone propionate, about 0.044% or about 0.035% w/w of salmeterol xinafoate, and a green propellant selected from HFA-152a and HFO-1234ze(E).

21. A pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, and a green propellant selected from HFA-152a and HFO-1234ze(E).

22. A pharmaceutical composition for inhalation comprising about 0.02% w/w or 0.04% w/w of tiotropium bromide, about 0.01% or about 0.03% w/w of ipratropium bromide, about 0.14% w/w or 0.22% w/w of salbutamol sulphate, and a green propellant selected from HFA-152a and HFO-1234ze(E).